CN106478651A - Substituted heteroaryl compound and combinations thereof and purposes - Google Patents

Abstract

The invention provides heteroaryl compound for replacing and combinations thereof and purposes.The compound is the compound shown in formula (I) or the stereoisomer of compound, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug shown in formula (I).Present invention also offers the pharmaceutical composition comprising the compound, described pharmaceutical composition can be with regulatory protein kinases, the especially activity of Aurora A and jak kinase, for preventing, processing, treat and mitigate protein kinase, disease or disorder that especially Aurora A and jak kinase activity are mediated.

Description

Substituted heteroaryl compound and combinations thereof and purposes

Priority information

The application ask on 08 31st, 2015 to China national Department of Intellectual Property submit to, number of patent application be The priority and rights and interests of 201510551362.4 patent application, and by referring to being incorporated by herein.

Invention field

The invention belongs to drug world, and in particular to a class is used as the substituted heteraryl of protein kinase activity inhibitor Compound, the pharmaceutical composition comprising the compound and the compound and its pharmaceutical composition are in multiple various disease are treated Application.More specifically, compound of the present invention can as Aurora A (including Aurora-A, Aurora-B and Aurora-C), the activity of FLT3 kinases (also referred to as FLK-2) and jak kinase family (including JAK1, JAK2, JAK3 and TYK2) or The inhibitor of function.

Background of invention

Comprising the related enzyme of a big class formation, they control intracellular various signal transduction processes for protein kinase family, 250-300 similar amino acid catalytic domain is usually contained, is catalyzed the phosphorylation of target proteins matter substrate.It was reported that numerous disease Relevant with the abnormal cell response that protein kinase mediated event causes.These diseases include optimum He pernicious proliferative disease Disease, immune system inappropriate activate cause disease, allograft rejection, graft versus host disease, LADA 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 make a large amount of effort so that find can be used as having The kinases inhibitor of effect therapeutic agent.

Kinases can be divided into multiple families (for example, protein-tyrosine, protein-silk ammonia by the substrate of phosphorylation Acid/threonine, lipid, etc.).Tyrosine phosphorylation is to adjusting various biological processes such as cell propagation, migration, differentiation and life Deposit and play vital effect.The acceptor of multiple families and these events of nonreceptor tyrosine kinase family listed business：Catalysis phosphorus Acid is transferred to the tyrosine residue of specific cells protein target from ATP.At present, the general phase of each kinase families above-mentioned is had confirmed that Motif (Hanks et al., FASEB J., the 1995,9,576-596 for answering；Knighton et.al.,Science,1991, 253,407-414；Garcia-Bustos en al.EMBO J.,1994,13:2352-2361).Swashing in protein kinase family The example of enzyme includes, but not limited to Aurora, Axl, abl, Akt, bcr-abl, Blk, Brk, Btk, c-Met, c-src, c- Fms, CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Flt-3, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, Fps, Frk,Fyn,Hck,JAK,IGF-1R,INS-R,KDR,Lck,Lyn,MEK,p38,PDGFR,PIK,PKC,PYK2,ros,Tie, Tie-2, TRK, Yes and Zap70, etc..

Aurora A family is the highly relevant serine/threonine kinase of a class, and which is mitotic crucial tune Section agent, accurate and equal separation (section) 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).

Aurora-A is widely expressed, and adjusts the cell cycle events occurred from S late period phase to the M phase, including centerbody Maturation, mitosis entrance, centerbody separation, the Chromosomal arrangement on the two poles of the earth mitotic spindle assembly thing, equatorial plate, cytokinesis and Mitosis terminates.All increase from the G2 phase to M phase Aurora-A protein level and kinase activity, activity reaches peak in the prometaphase Value.Once activation, Aurora-A by with various substrates, including centrosome protein (centrosome), the acid curling spiral shell of conversion Rotation albumen, cdc25b, Eg5 and centromere protein matter A interact and mediate several functions.Aurora-A overexpression is Aurora- The essential feature that A- induced tumor occurs.

Aurora-B be a kind of to accurate chromosome isolation, cytokinesis, protein localization to kinetochore and silk Grain, correct micro-pipe-centromere attachment and regulation Mitotic checkpoint play the chromosomin of key effect.Aurora-B is first First during early stage localization in chromosome, then during prometaphase and mid-term localization between sister chromatids in Kinetochore area (Zeitlin SG, et al., J.Cell Biol., 2001；155:1147-1157).Aurora-B participates in establishing The orientation of chromosome, wherein sisters centromere are connected to the opposite pole of the two poles of the earth spindle via double orientation attachment.In mitosis Stage, the Main Function of Aurora-B are to repair incorrect micro-pipe-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, mitosis is damaged Bad, cause aneuploid cell quantity to increase, there is (Weaver BA, et al., Cancer in genic instability and tumour Cell,2005,8:7-12).Aurora-B suppression causes the biology that chromosome is adhered to, cannot be realized to abnormal centromere-micro-pipe to take To, cytokinesis failure (Goto H, et al., J Biol.Chem., 2003,278:8526-8530；Severson AF,et al.,Curr.Biol.,2000,10:1162-1171).Do not include that the mitotic repetitive cycling of the exception of cytokinesis is drawn Rise huge polyploidy 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).

Verified Aurora overexpression and multiple malignant proliferative disorders, the such as carcinoma of the rectum, breast cancer, lung cancer, cancer of pancreas, front Row gland cancer, carcinoma of urinary bladder, head and neck cancer, cervix cancer, oophoroma, liver cancer and cancer of the stomach etc. are closely related, excite and are developed for cancer The interest of the Aurora inhibitor for the treatment of.In normal cell, Aurora-A suppression cause delay but and non-blacked mitosis, The centerbody of one pole mitotic spindle separate defect and cytokinesis failure (Marumoto T, et al., J.Biol.Chem.,2003,278:51786-51795).In three-type-person's class pancreatic carcinoma (Panc- Ι, Μ Ι Α PaCa- In 2dnSU.86.86), Aurora-A inhibitor shows challenging antitumous effect, as a result shows that Aurora-A suppresses Agent can suppress the growth of tumour cell and, intimate whole eliminations of the tumorigenicity in murine xenogralt (Hata T, et al.,Cancer Res.,2005,65:2899-2905).

FLT3 (the related EGFR-TK 3 of Flt3, FMS-), also referred to as FLK-2 (fetal livers kinases 2) and the STK-I (mankind Stem cell kinases 1), belong to receptor tyrosine kinase (RTK-III) family member (Gtirewalt DL et al., Nat.Rev.Cancer,2003,3:650-665；Rosnet O,et al.,Genomics,1991,9:380-385；Yarden Y,et al.,Nature,1986；323:226-232；Stanley E R,et al.,J.Cell Biochem.,1983,21: 151-159；Yarden Y,et al.,EMBO J,1987,6:3341-3351).FLT3 is transmembrane protein, by four structures Domain constitutes, the extracellular ligand-binding domain comprising five immunoglobulin class structure compositions, cross-film (TM) domain, nearly film (JM) domain With cytoplasm C- terminal tyrosine kinases (TK) domain.(Agnes F,et al.Gene,l994,145:283-288；Scheijen B,et al.,Oncogene,2002,21:3314-3333).

The part of FLT3 was cloned in 1993, was shown according to the study, and which is that Hematopoietic marrow microenvironment cell includes marrow Express in fibroblast and other cells type I transmembrane protein (Lyman SD, et al., Cell, 1993,75, 1157-1167).Film combination and soluble form all the tyrosine kinase activity of activated receptor can stimulate ancestral in marrow and blood Cell growth.The zygotic induction receptor dimer of ligand-receptor, and activated protein kinase domain；Then its autophosphorylation it is catalyzed each Plant the substrate protein phosphorylation of signal transduction pathway, such as signal transduction and Activator protein 5 (STAT5), RAS/ mitogen The protein kinase (RAS/MAPK) of activation, phosphoinositide 3-kinase (PI3K), the of the same race and glue protogene of Src (SHC), contain The inositol -5- phosphatase (SHIP) of SH2 and the cytoplasmic tyrosine phosphoric acid with 2 Src- homologys 2 (SH2) domain (SHP2) Enzyme, its cell breed, differentiation and existence in play a significant role (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 gene also in placenta, sexual gland and brain expression (Maroc N, et al., Oncogene, 1993,8:909- 918) and play a significant role in immune response (deLapeyriere O.et al., Leukemia, 1995,9:1212- 1218).

FLT3 is also relevant with the hemopoietic system dysfunction before malignant proliferative pathology, such as piastrenemia, true property blood Platelet increase disease, myelofibrosis (MF), chronic idiopathic myelofibrosis (IMF), polycythemia (PV), before canceration Include, but not limited to leukaemia, (NHL), Huo Qijin to myelodysplastic syndrome, hematologic malignancies Family name's disease (also known as Hodgkin lymphoma) and myeloma, for example, acute lymphatic leukemia (ALL), the white blood of acute myeloid Sick (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), CNL (CNL), closely related.FLT3 is in the acute myeloid leukaemia (AML) of 70-100% In, and in the ALL (ALL) of high percentage with each horizontal overexpression (Griffin JD, et al., Haematol J.,2004,5:188-190).In BC, which is also in the less of chronic myelogenous leukemia (CML) Overexpression in hypotype.Research has shown that B pedigree leukaemia ALL and AML is continually co-expressed FLT3, causes FLT3 composing type The autocrine of activation or paracrine signal transduction circulation (Zheng R, et.al.Blood., 2004,103:267-274).Additionally, FLT3L is with high level in the cell serum of langerhans cell histiocytosis and Patients with SLE Expression, shows that FLT3 is extremely closely related with the dendritic cells Signal Regulation of autoimmune disease further.

Increasing evidence shows that polytype leukaemia and myeloproliferative syndrome have the prominent of EGFR-TK Become.FLT3 mutation is one of most frequent mutation in AML, occurs in about 1/3 patient.Two are described in leukaemic The FLT3 mutation of type.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, which includes Asp835Tyr (D835Y), Asp835Val (D835V), Asp835His (D835H), Asp835Glu (D835E), Asp835Ala (D835A), Asp835Asn (D835N), Asp835 disappearance and Ile836 Disappearance (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 domain replicates (ITD) mutation to be contributed in AML about The FLT3 Activating mutations of 17-34%.Also detect that FLT3-ITD low frequency is mutated in myelodysplastic syndrome (MDS) (Yokota S.,et al.,Leukemia,l997,11:1605-1609；Horiike S,et al.,Leukemia,1997, 11:1442-1446).FLT3-ITD and FLT3-Asp835 mutation is all relevant with the phosphorylation of FLT3 autophosphorylation 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 recurrence that there is FLT3 mutation in the FLT3 inhibitor for grinding as some or all or obstinate AML patient's Monotherapy has been enter into clinical testing.Generally, these as shown by datas FLT3 can be used to be developed for treating AML and other are relevant The therapeutic targets of the kinase inhibitor of disease.

Janus kinases (JAK) is intracellular non-receptor tyrosine kinase, and by turning JAK-STAT path, transduction is thin The signal of intracellular cytokine mediation.The propagation that JAK family is relied in cell factor adjusts and is related to send out in the cell function of immune response Wave important effect.Cell factor and their receptor binding, cause receptor dimerization, can so promote the mutual phosphoric acid of JAKs Change, can also promote cytokine receptor internal specific tyrosine motif phosphorylation.Recognize that the STATs of these phosphorylation motif is gathered Collect on acceptor, be then activated during the tyrosine phosphorylation that JAK is relied on.Due to activation, STATs is dissociated with acceptor, Dimerization, and nucleus is displaced to, combined with specific DNA site, and changed transcription.

It is currently, there are mammal JAK family member known to four kinds：(Janus swashs for JAK1 (Janus kinases -1), JAK2 Enzyme -2), JAK3 (Janus kinases, leucocyte；JAKL；L-JAK and Janus kinases -3) and TYK2 (protein tyrosine kinase 2). JAK1, JAK2 and TYK2 are wide expression, and JAK3 is reported in NKT (NK) cell and preferentially expresses, and not at which (" Biology and significance of the JAK/STAT signaling is expressed in its T cell 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 acceptor The signal transduction of public chain (IFN-γ) interferon, and the signal of the IL-10 family member by II cytokines acceptor Transduction is all critically important.Functionally and physiologically with I type interferon (for example, genetic biology research shows that JAK1 IFNalpha), II type interferon (for example, IFNgamma), IL-2 with IL-6 cytokine receptor complex are related.Further Ground, demonstrates the kinases to the sign of the tissue from JAK1 knock-out mice logical 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 make them flee from tumour, be transferred to body Other positions of body.By the cell factor of JAK1 transduction signal, the raising of its level involves substantial amounts of immunity and inflammation disease Disease.JAK1 or JAK family kinase inhibitors can be used to adjusting or treat these diseases (Kisseleva et al., 2002, Gene 285:1-24；Levy et al.,2005,Nat.Rev.Mol.Cell Biol.,3:651-662).The people of targeting IL-6 path Resource monoclonal antibody (Torr pearl monoclonal antibody Tocilizumab) is ratified to close to severe rheumatoid for treating moderate by EU Committee Section 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 family, gp130 acceptor man The signal transduction of race member is relevant.JAK2 signal is activated in the downstream of hprl receptor.Research shows in myeloproliferative In the disease such as disease such as polycythemia vera, primary thrombocytosis and idiopathic myelofibrosis, generally deposit (JAK2V617F) is mutated in the JAK2 of acquired activation.The JAK2 albumen of mutation can be in situation about stimulating without cell factor Lower activation downstream signal, causes spontaneous growth and/or the hypersensitivity to cell factor, and which is considered as the process to these diseases Play a part of promotion.The more multimutation of JAK2 functional disturbance or transposition is caused to be found in (Ihle in other malignant tumours J.N.and Gilliland D.G.,Curr.Opin.Genet.Dev.,2007,17:8；Sayyah J.and Sayeski P.P.,Curr.Oncol.Rep.,2009,11:117).JAK2 inhibitor has described as has effect to proliferative diseases (Santos et al,Blood,2010,115:1131；Barosi G.and Rosti V.,Curr.Opin.Hematol, 2009,16:129,Atallah E.and Versotvsek S.,Exp.Rev.Anticancer Ther.,2009,9:663).

JAK3 only be present in IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complex Public gamma cells factor acceptor chain is related.JAK3 is mainly expressed in immunocyte, and by the tyrosine phosphorus of interleukin-2-receptor Acidifying activation, transduction signal.Due to being limited to express JAK3 in candidate stem cell, with respect to other JAKs, it is in cell factor more Effect in signal transduction is stricter.The mutation of JAK3 can cause severe combined immunodeficiency (SCID). (O'Shea et al.,2002,Cell,109(suppl.):S121-S131).Based on its adjust lymphocyte in effect, targeting JAK3 and The path of JAK3 mediation 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 and IL-12 signal transduction are related.Biochemical research and knock out mice Disclose important function of the TYK2 in immunology.TYK2 deficient mice energy growth and breeding, but panimmunity defect is shown, main If there is hypersensitivity and existing defects in terms of oncological surveillance to infection.Contrary, suppression TYK2 can improve opposing allergy, Autoimmunity and the ability of inflammatory disease.Especially, targeting TYK2 seems to become treatment IL-12-, IL-23- or I type IFN- is situated between The innovative strategy of the disease that leads.The disease includes but is not limited to rheumatoid arthritis, multiple sclerosis, lupus, silver bits Disease, psoriasis arthropathica, 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).

European commission has been recently approved the complete people source of the total p40 subunit of targeting IL-12 and IL-23 cell factor Monoclonal antibody (Ustekinumab), for treat moderate to severe plaque psoriasis (Krueger et al., 2007, N.Engl.J.Med.,356:580-92；Reich et al.,2009,Nat.Rev.Drug Discov.,8:355-356).This Outward, targeting IL-12 and IL-23 path antibody carried out for treat Crohn disease clinical testing (Mannon et al., N.Engl.J.Med.,2004,351:2069-79).

When adjusting not normal, the response of JAK- mediation can positively or negatively affect cell, cause overactivity to be disliked respectively Property tumour, or immunity and hematopoietic defect, which imply the practicality of jak kinase inhibitor.JAK/STAT signal path involves To many propagation and cancer associated processes, including cell cycle progression, apoptosis, Angiogenesiss, infiltration, transfer and immune system are escaped Keep away (Haura et al., Nature Clinical Practice Oncology, 2005,2 (6), 315-324；Verna et al.,Cancer and Metastasis Reviews,2003,22,423-434).Additionally, JAK/STAT signal path is to making The generation of hemocytoblast and differentiation, proinflammatory and anti-inflammatory dual regulation, and immune response play an important role (O'Sullivan et al.,Molecular Immunology,2007,44:2497).

Therefore, whole four members of JAK/STAT path, particularly JAK family, 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.As the JAK of the various multi-forms of cell factor application swashs Enzyme (O'Sullivan et al., Mol.Immunol, 2007,44:2497；Murray J.,Immunol,2007,178: 2623), in antagonism family different choice jak kinase, treat the related disease of the specific cells factor or JAK/STAT be logical In road, the related disease of variability or polymorphism is probably useful.

Rheumatoid arthritis (RA) is a kind of autoimmune disease being characterized with chronic joint inflammation.Take JAK suppression The patient with rheumatoid arthritis of preparation shows the suppression to JAK1 the and JAK3 module by signal that cytokine profiles cause, it To lymphocyte function, including proleulzin (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21 are critically important (Fleischmann,R.,et al.“Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.”N.Engl.J.Med.,2012,367,495-507).It is assumed that directly making specific JAK sub- The micromolecular inhibitor of type inactivation not only can mitigate the clinical symptoms of RA, it is also possible to suppress those to promote being permitted for RA disease progression Undue regulation (" the Inhibitors of JAK for the treatment of rheumatoid of many proinflammatory cytokines arthritis:rationale and clinical data.”Clin.Invest.,2012,2(1),39-47).

The sustained activation of STAT3 or STAT5 has been proved to be present in many entity tumors, including lacteal tumor, Vipoma, Prostate tumor, ovarioncus and liver cancer, while exist in substantial amounts of blood tumor, including lymthoma and leukaemia.In this respect, The inactivation of the JAK/STAT signal in neoplastic hematologic disorder propagation capable of inhibiting cell and/or inducing cell apoptosis.Although in tumour cell STAT3 can be by many kinase activations, JAK2 is still counted as most important upstream activat person, it can activate come from various STAT3 (Mohamad Bassam Sonbol, Belal Firwana, Ahmad in the human tumor cell line of entity tumor Zarzour,Mohammad Morad,Vishal Rana and Ramon V.Tiu,Therapeutic Advances in Hematology 2013,4(1),15-35；Hedvat M,Huszar D,Herrmann A,Gozgit J M,Schroeder A,Sheehy A,et al.Cancer Cell 2009,16(6):487-97).Therefore, suppression jak kinase is to these diseases Treatment plays beneficial effect.

Know clearly, kinases inhibitor is poly- as new immunosupress, anti-inflammatory double action medicine and anticancer medicine Numerous concerns are collected.Therefore, suppression protein kinase such as Aurora A, the novel agent of FLT3 kinases and jak kinase or improvement examination Agent is needed for a long time, and it can be used as the immunodepressant of organ transplant, antitumor agent, it can also be used to prevent and treat autoimmunity Disease (for example, multiple sclerosis, psoriasis, rheumatoid arthritis, asthma, type i diabetes, IBD, Crow grace Disease, polycythemia vera, primary thrombocytosis, myelofibrosis, AITD, A Erzi sea Silent disease), it is related to the disease (for example, eczema) of overactivity inflammatory reaction, allergy, chronic obstructive pulmonary disease, bronchitis, cancer (for example, prostate cancer, acute myelocytic leukemia, chronic granulocytic leukemia, ALL, white blood Disease, Huppert's disease) and the immune response (for example, fash, contact dermatitis or diarrhoea) that causes of other treatment, etc..This The compound of invention description, composition and method directly correspond to these to be needed and other purposes.

Abstract of invention

The invention provides a class suppresses, adjusts and/or one or more protein kinase of regulation and control, such as jak kinase, FLT3 swashs Enzyme and the compound of 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, using 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 Bright compound and combinations thereof possesses preferable potential applicability in clinical practice.Compared with existing similar compound, the change of the present invention Compound has more preferable pharmacologically active, 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 for optimizing, and show in pharmacokinetic trial in animal body Good absorption and higher bioavilability are shown.Additionally, the compounds of this invention also has more excellent membrane permeability, it is suitable to Local is administered, and dissolubility is preferable.Therefore, the compounds of this invention has more excellent druggability.

Specifically：

On the one hand, the present invention relates to the alloisomerism of compound of the one kind as shown in formula (I) or compound shown in formula (I) Body, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

Wherein, each Z¹、A、R¹、R²、R^2aThere is definition of the present invention with m.

In some embodiments, Z¹For H, C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl or 3-12 former molecular heterocyclic radical, Wherein, each C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl and 3-12 former molecular heterocyclic radical individually optionally by 1,2,3,4 or 5 R³Group is replaced；

A is pyrazolyl, and which is optionally by 1,2 or 3 R⁴Group is replaced；

R¹For H, F, Cl, Br, I, N₃、CN、NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^5aR^5b、- OR^5c,-OC (=O) R^5d,-C (=O) OR^5c、-N(R^5e) C (=O) R^5d,-C (=O) NR^5aR^5b、-N(R^5e) S (=O)₂R^5fOr-S (=O)₂NR^5aR^5b, wherein, each C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl and 5-12 former molecular heteroaryl individually optionally by 1,2,3,4 or 5 R⁸Group is replaced；

Each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Alkylamino, C₃-C₁₂Cycloalkyl, 4-7 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 original are molecular miscellaneous Aryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁- C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-NR^6aR⁶ⁱ,-C (=O) R^6d,-OC (=O) R^6d,-C (=O) OR^6c、-N(R^6e) C (=O) R^6d,-C (=O) NR^6aR^6b、-N(R^6e) C (=O) NR^6aR^6b、-N (R^6e) S (=O)₂NR^6aR^6b,-S (=O)₂R^6f、-N(R^6e) S (=O)₂R^6gOr-S (=O)₂NR^6aR^6b, wherein, each C₁-C₁₂ Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkylamino, C₃-C₁₂Cycloalkyl, 4-7 former molecular heterocyclic radical, C₆-C₁₂ Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 Individual former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 atom composition Heteroaryl) individually optionally by 1,2,3,4 or 5 R⁸Group is replaced；

Each R³And R⁴It is separately F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂ Cycloalkyl) or-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical), and wherein, each C₁-C₁₂Alkyl, C₂-C₁₂Alkene Base, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 original are molecular miscellaneous Aryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) and-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) independence Optionally by 1,2,3,4 or 5 R⁸Group is replaced；

Each R^5a、R^5b、R^5c、R^5e、R^6a、R^6b、R^6cAnd R^6eIt is separately H, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂ Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂The individual former molecular heteroaryl of aryl, 5-12 ,- (C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylene Base)-(C₆-C₁₂Aryl) or-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl), or R^5aAnd R^5b, R^6aAnd R^6b, And together with nitrogen-atoms connected with them, form 3-12 former molecular heterocyclyl groups, wherein, each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 atom group The heteroaryl that becomes ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocycle Base) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) optionally By 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁- C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent of alkylamino is replaced；

Each R^5d、R^5f、R^6d、R^6fAnd R⁶ⁱIt is separately C₁-C₁₂Alkyl, C₁-C₁₂Miscellaneous alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂ Alkynyl, C₁-C₁₂Alkoxyl, C₁-C₁₂Alkylamino, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5- The molecular heteroaryl of 12 originals ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 atom group The heterocyclic radical for becoming) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl Base) ,-(C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(3-12 former molecular heterocyclic radical) ,- (C₁-C₆Sub- miscellaneous alkyl)-(C₆-C₁₂Aryl) or-(C₁-C₆Sub- miscellaneous alkyl)-(5-12 former molecular heteroaryl), wherein, on Each group is stated optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Halogen Substituted alkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent of alkylamino is replaced；

Each R^6gIt independently is C₂-C₁₂Alkyl, C₁-C₁₂Miscellaneous alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxy alkyl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Haloalkyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 Individual former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 atom composition Heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,- (C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₆ Sub- miscellaneous alkyl)-(C₆-C₁₂Aryl) or-(C₁-C₆Sub- miscellaneous alkyl)-(5-12 former molecular heteroaryl), and wherein, above-mentioned each base Group is optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent of alkylamino is replaced；

Each R⁸It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Haloalkyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical, 5-12 atom composition Heteroaryl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Alkylamino, C₁-C₁₂Alkoxyl, C₁-C₁₂Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)- (C₃-C₁₂Cycloalkyl) ,-NH (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-NH (C₀-C₄Alkylidene)-(3-12 is former molecular Heterocyclic radical) ,-NH (C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-N [(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkanes Base)]₂、-N[(C₀-C₄Alkylidene)-(C₆-C₁₂Aryl)]₂、-N[(C₀-C₄Alkylidene)-(3-12 former molecular heterocycle Base)]₂、-N[(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl)]₂、-O(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkanes Base) ,-O (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-O (C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) or-O (C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl)；With

M is 0,1,2,3,4 or 5.

In some embodiments, the present invention relates to compound of the one kind as shown in formula (II) or compound shown in formula (II) Stereoisomer, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or it before Medicine,

In other embodiments, Z¹For H, C₁-C₆Alkyl, C₃-C₆Cycloalkyl or 4-7 former molecular heterocyclic radical, Wherein, each C₁-C₆Alkyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are optionally by 1,2 or 3 R³Group institute Replace.

In some embodiments, A is：

Wherein, each minor structure shown in formula (A-1)～(A-3) is only Stand optionally by 1 or 2 R⁴Group is replaced.

In other embodiments, R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₄Alkyl, C₁-C₄Alkoxyl, C₂- C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆A cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,- NR^5aR^5b、-OR^5c,-OC (=O) R^5d,-C (=O) OR^5c、-N(R^5e) C (=O) R^5d,-C (=O) NR^5aR^5b、-N(R^5e) S (=O)₂R^5fOr-S (=O)₂NR^5aR^5b, wherein, each C₁-C₄Alkyl, C₁-C₄Alkoxyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Ring Alkyl, 4-7 former molecular heterocyclic radical, phenyl and 5-6 former molecular heteroaryl is individually optionally by 1,2 or 3 R⁸ Group is replaced.

In some embodiments, each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 atom The heteroaryl of composition ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) ,-NR^6aR⁶ⁱ,-C (=O) R^6d,-OC (=O) R^6d,-C (=O) OR^6c、-N(R^6e) C (=O) R^6d,-C (=O) NR^6aR^6b、-N(R^6e) C (=O) NR^6aR^6b、-N (R^6e) S (=O)₂NR^6aR^6b,-S (=O)₂R^6f、-N(R^6e) S (=O)₂R^6gOr-S (=O)₂NR^6aR^6b, wherein, each C₁-C₆ Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 Individual former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 is former molecular Heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) individually optionally By 1,2 or 3 R⁸Group is replaced.

In other embodiments, each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₄Alkane Base, C₂-C₄Thiazolinyl, C₁-C₄Alkylamino, C₃-C₆Cycloalkyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, 1,1- dioxo are different Thiazolidine -2-base, pyrrolidin-2-one-1- base, imidazolidin-2-one-1- base, oxazolidine-2- ketone-3- base, phenyl, 5-6 atom The heteroaryl of composition ,-(C₁-C₂Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₂Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl) ,-NR^6aR⁶ⁱ,-OC (=O) R^6d,-C (=O) OR^6c、-N(R^6e) C (=O) R^6d,-C (=O) NR^6aR^6b、-N(R^6e) C (=O) NR^6aR^6b、-N(R^6e) S (=O)₂NR^6aR^6b、-N(R^6e) S (=O)₂R^6gOr-S (=O)₂NR^6aR^6b, wherein, each C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₁-C₄Alkane ammonia Base, C₃-C₆Cycloalkyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, 1,1- dioxo isothiazolidine -2- base, pyrrolidines -2- Ketone -1- base, imidazolidin-2-one -1- base, oxazolidine -2- ketone -3- base, phenyl, 5-6 former molecular heteroaryl,-(C₁-C₂Sub- Alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₂Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₂Alkylidene)-phenyl With-(C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl) individually optionally by 1,2 or 3 R⁸Group is replaced.

In some embodiments, each R³And R⁴It is separately F, Cl, CN, C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₃-C₆Ring Alkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Ring Alkyl) or-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical), and wherein, each C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)- (C₃-C₆Cycloalkyl) and-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) individually optionally by 1,2 or 3 R⁸Group Replaced.

In other embodiments, each R³And R⁴It is separately F, Cl, Br, I, N₃、CN、-NO₂, methyl, ethyl, N-propyl, isopropyl, cyclopropyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, thiazole Base, pyrrole radicals or oxazolyl, wherein, each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, piperidyl, pyrrolidinyl, Morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, thiazolyl, pyrrole radicals and oxazolyl are individually optionally by 1,2 or 3 R⁸Group is replaced.

In some embodiments, each R^5a、R^5b、R^5c、R^5e、R^6a、R^6b、R^6cAnd R^6eIt is separately H, C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl Base ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Sub- Alkyl)-phenyl or-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), or R^5aAnd R^5b, R^6aAnd R^6b, and and it Connected nitrogen-atoms together, form 4-7 former molecular heterocyclyl groups, wherein, each C₁-C₄Alkyl, C₂-C₄Alkene Base, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁- C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)- Phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) individually optionally by 1,2 or 3 selected from F, Cl, Br, CN、N₃、-NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Amino alkane Base or C₁-C₃The substituent of alkylamino is replaced.

In other embodiments, each R^5a、R^5b、R^5c、R^5e、R^6a、R^6b、R^6cAnd R^6eIt is separately H, methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidines Base, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazine Base, thiazolyl, pyrrole radicals, pyrazolyl, imidazole radicals or oxazolyl, wherein, each methyl, ethyl, n-propyl, isopropyl, just Butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, Tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, pyrrole radicals, pyrrole Oxazolyl, imidazole radicals and oxazolyl are individually optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、- CF₃、-CH₃、-CH₂CH₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N(CH₃)₂Or-CH₂NH₂Substituent replaced.

In some embodiments, each R^5d、R^5f、R^6d、R^6fAnd R⁶ⁱIt is separately C₁-C₄Alkyl, C₁-C₆Miscellaneous alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₁-C₄Alkoxyl, C₁-C₄Alkylamino, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, benzene Base, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 atom The heterocyclic radical of composition) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) ,-(C₁- C₄Sub- miscellaneous alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₄Sub- miscellaneous Alkyl)-phenyl or-(C₁-C₄Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), wherein, above-mentioned each group optionally by 1, 2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃ Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent of alkylamino is replaced.

In other embodiments, each R^5d、R^5f、R^6d、R^6fAnd R⁶ⁱBe separately methyl, ethyl, n-propyl, different Propyl group, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, piperidyl, pyrroles Alkyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazole Base, pyrrole radicals, pyrazolyl, imidazole radicals, oxazolyl, C₁-C₄Miscellaneous alkyl ,-(C₁-C₂Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₂ Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylidene)-(5-6 atom The heteroaryl of composition) ,-(C₁-C₄Sub- miscellaneous alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 is former molecular Heterocyclic radical) ,-(C₁-C₄Sub- miscellaneous alkyl)-phenyl or-(C₁-C₄Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), wherein, Above-mentioned each group is optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、-CF₃、-CH₃、-CH₂CH₃、- OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N(CH₃)₂Or-CH₂NH₂Substituent replaced.

In other embodiments, each R^6gIt independently is C₂-C₆Alkyl, C₁-C₆Miscellaneous alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynes Base, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl, C₁-C₆Haloalkyl, C₃-C₆The individual former molecular heterocyclic radical of cycloalkyl, 4-7, Phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 is former Molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) ,- (C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₆Sub- Miscellaneous alkyl)-phenyl or-(C₁-C₆Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), wherein, above-mentioned each group optionally by 1st, 2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alcoxyl Base, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent of alkylamino is replaced.

In some embodiments, each R^6gIndependently be ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, The tert-butyl group, 3- methyl isophthalic acid-butyl, 2-methyl-1-butene base, 1,2- dimethyl -1- propyl group, neopentyl, acrylic, 2- metering system Base, trifluoromethyl, methylol, ethoxy, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, piperidyl, pyrroles Alkyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, C₁-C₄ Miscellaneous alkyl ,-(C₁-C₂Alkylidene)-cyclopropyl ,-(C₁-C₂Alkylidene)-cyclobutyl ,-(C₁-C₂Alkylidene)-cyclopenta ,-(C₁-C₂ Alkylidene)-cyclohexyl ,-(C₁-C₂Alkylidene)-piperidyl ,-(C₁-C₂Alkylidene)-pyrrolidinyl ,-(C₁-C₂Alkylidene)-four Hydrogen furyl ,-(C₁-C₂Alkylidene)-tetrahydrochysene -2H- pyranose,-(C₁-C₂Alkylidene)-morpholinyl ,-(C₁-C₂Alkylidene)-piperazine Piperazine base ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl) ,-(C₁-C₄Sub- miscellaneous alkane Base)-(C₃-C₆Cycloalkyl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₄Sub- miscellaneous alkyl)-benzene Base or-(C₁-C₄Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), wherein, above-mentioned each group is optionally only by 1,2 or 3 F, Cl, Br, CN, N are on the spot selected from₃、-OH、-NH₂、-CF₃、-CH₃、-CH₂CH₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N (CH₃)₂Or-CH₂NH₂Substituent replaced.

In other embodiments, each R⁸It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical, 5-6 original Molecular heteroaryl, C₁-C₄Aminoalkyl, C₁-C₄Alkylamino, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl ,-NH (C₀-C₃Alkylene Base)-(C₃-C₆Cycloalkyl) ,-NH (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-N [(C₀-C₃Alkylidene)- (C₃-C₆Cycloalkyl)]₂、-N[(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical)]₂、-O(C₀-C₃Alkylidene)-(C₃- C₆Cycloalkyl) ,-O (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-O (C₀-C₃Alkylidene)-phenyl or-O (C₀- C₃Alkylidene)-(5-6 former molecular heteroaryl).

On the other hand, the present invention relates to a kind of pharmaceutical composition, which includes the compound in the embodiment above of the present invention.

In some embodiments, pharmaceutical composition of the present invention further comprising pharmaceutically acceptable auxiliary material, Excipient, carrier, solvent or combinations thereof.

In other embodiments, pharmaceutical composition of the present invention, wherein further includes other therapeutic agents, The other therapeutic agents are exciting selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 (PDE4) inhibitor, beta-2-adrenoreceptor Agent, corticosteroid, nonsteroidal GR activator, anticholinergic drug, antihistamine, anti-inflammatory reagent, immunodepressant, immunity Conditioning agent, for treating atherosclerotic medicine and for treating at least one in the medicine of pulmonary fibrosis.

On the other hand, the present invention relates to the purposes of compound disclosed by the invention or pharmaceutical composition in medicine is prepared, The medicine is used for preventing, process, treat or mitigating protein kinase mediated disease.

In some embodiments, protein kinase mediated disease of the present invention is mediated for JAK- disease, FLT3- The disease of mediation or the disease of Aurora- mediation.

In other embodiments, protein kinase mediated disease of the present invention is proliferative diseases, autologous exempts from Epidemic disease, anaphylactia, inflammatory disease, graft rejection or cancer.

In other embodiments, protein kinase mediated disease of the present invention be cancer (such as：Colorectal cancer, suddenly Strange gold lymthoma, NHL, cancer of the stomach, cancer of the esophagus, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid gland Cancer, carcinoma of urinary bladder, kidney, brain tumor, head and neck cancer, the cancer of CNS (central nervous system), glioblastoma, non-small cell lung cancer, palace Divide in neck cancer, orchioncus, lymph cancer, Huppert's disease, malignant lymphoma, ED-SCLC, neuroblastoma, nerve Secrete cell tumour, medullary carcinoma of thyroid gland, melanoma, retinoblastoma, the cancer of the uterus, oophoroma, acute myelocytic white Blood disease, ALL, chronic granulocytic leukemia, chronic lymphocytic leukemia), primary macroglobulin Mass formed by blood stasis, monocytic leukemia, Sezary syndrome, infectious mononucleosis, colitis, pancreatitis, artery are athero- Hardening, pulmonary fibrosis, polycythemia vera, primary thrombocytosis, myelofibrosis, COPD Disease, asthma, systemic loupus erythematosus, skin lupus erythematosus, LN, dermatomyositis, Sjogren syndrome, psoriasis, I type Diabetes, respiratory anaphylactic disease, nasosinusitis, eczema, measles, food hypersenstivity, insect venom allergies, inflammatory bowel disease, Crow Grace disease, rheumatoid arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or thin Born of the same parents' graft rejection.

On the other hand, the present invention relates to the purposes of 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 is in jak kinase, FLT3 kinases and Aurora A At least one combinations thereof.

In other embodiments, protein kinase of the present invention is JAK1 kinases, Aurora-A kinases and Aurora- At least one in B kinases.

In yet a further aspect, the present invention relates to the preparation of the compound that included of formula (I), separate and purifying method.

Biological results show, the compound that the present invention is provided can be as preferable kinases inhibitor, especially As Aurora A inhibitor, such as Aurora-A kinases, Aurora-B kinases and Aurora-C kinase inhibitor.

Arbitrary embodiment of the either side of the present invention, can be combined with other embodiments, as long as they Be not in contradiction.Additionally, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for which The technical characteristic in its embodiment, as long as they are not in contradiction.

Content noted earlier only outlines certain aspects of the invention, but in terms of being not limited to these.In terms of these and its The content of his aspect is made more specific complete description below.

Detailed description of the invention book

Definition and general terms

Certain embodiments of the present invention are will now be described in more detail, the example is by the structural formula that encloses and chemical formula explanation.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.In the document for being combined, patent and similar material one Or many different from the application or conflicting in the case of (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, carry out in multiple independent embodiments Description, but it is also possible to provide in single embodiment in combination.Conversely, the various features of the present invention, for brevity, It is described in single embodiment, but it is also possible to the sub-portfolio offer individually or to be arbitrarily suitable for.

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 according to the present invention and public publication are integrally incorporated this by reference Bright.

Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined 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.

There are unless otherwise stated or in context significantly conflict, article " one " used herein, " one (kind) " " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment using or use.

Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.Tested right As for example also referring to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, little Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, described receive Examination is to liking people.

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

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

" stereoisomer " is referred to 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 have with its mirror image can not overlap property molecule；And " achirality " refer to can be overlap with its mirror image Molecule.

" enantiomter " refers to that two of a compound can not overlap but be mutually the isomers of mirror.

" diastereoisomer " refers to the alloisomerism of two or more chiral centres and its molecule not mirror image each other Body.Diastereoisomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer is mixed Compound can be by high resolution analysis operation such as electrophoresis and chromatogram, and such as HPLC is separating.

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 are present with optical active forms, i.e., they have rotates the plane of linearly polarized light Ability.When optically active compound is described, represent molecule with regard to one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for linearly polarized light rotation caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for the compound of (+) or d.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during without stereoselectivity or during stereospecificity, May occur in which such case.

The present invention is disclosed any asymmetric atom (for example, carbon etc.) of compound and can be enriched with racemic or enantiomer In the form of, for example (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excessive.

According to the selection of starting material and method, the compounds of this invention can with possible isomers or they Mixture, the form of such as racemic modification and non-corresponding isomer mixture (this is depending on the quantity of asymmetric carbon atom) deposits ?.Optically active (R)-or (S)-isomers can be prepared using chiral synthon or chiral reagent, or are torn open using routine techniques Point.If compound contains a double bond, substituent may be E or Z configuration；If containing 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, by chromatography and/or fractional crystallization Method.

The racemic modification of any gained end-product or intermediate can be passed through those skilled in the art with known method Familiar method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to obtaining.Racemic product Thing can also be separated by chiral chromatogram, e.g., using the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, refer to Jacques, 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).

Term " dynamic isomer " or " tautomeric form " refer to that Tong Guo the low energy with different-energy builds (low Energy barrier) mutual 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 the mutual inversion of phases that migrates to carry out by proton, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electrons come The mutual inversion of phases for carrying out.The instantiation of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One of phenol-keto tautomerism is concrete 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, the compound of the present invention optionally can be replaced by one or more substituents, such as General formula compound above, or as special example inside embodiment, subclass, and the class compound included by the present invention.

In general, term " substituted " represent concrete to the one or more hydrogen atoms being substituted in structure Substituent is replaced.Unless shown in terms of other, a group for replacing can have a substituent, and in group, each may replace Position replaced.When in given structural formula, more than one position can be selected from one or more replacements of concrete group Base is replaced, then substituent can replace in each position identical or differently.

Term " optional " or " optionally " mean event described later or environment can but need not occur, should Illustrate to include the occasion that the thing or environment occur or do not occur.For example, " heterocyclic group for optionally being replaced by alkyl " meaning Taste alkyl can but necessarily exist, the explanation includes the scene that heterocyclic group replaced by alkyl and heterocyclic group not by alkyl Substituted scene.

Term " unsubstituted ", represents and specifies group without substituent.

Term " optionally by ... replace ", can be exchanged with term " unsubstituted or quilt ... replaces " and use, i.e., The structure is unsubstituted or is replaced 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、-NO₂、-OH、-SH、-NH₂,-C (=O) CH₂CN ,-NHC (=O) CH₂CN、-N (CH₃) C (=O) CH₂CN、-NR^6aR⁶ⁱ,-C (=O) R^6d,-OC (=O) R^6d,-C (=O) OR^6c、-N(R^6e) C (=O) R^6d、-C (=O) NR^6aR^6b、-N(R^6e) C (=O) NR^6aR^6b、-N(R^6e) S (=O)₂NR^6aR^6b,-S (=O)₂R^6f、-N(R^6e) S (=O)₂R^6g,-S (=O)₂NR^6aR^6b, alkyl, miscellaneous alkyl, haloalkyl, thiazolinyl, alkynyl, alkoxyl, hydroxy alkyl, alkylthio group, alkyl Amino, aminoalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl etc., wherein, each R^6a、R^6b、R^6c、R^6d、R^6e、R^6f、R^6gAnd R⁶ⁱ Have and define as described in the present invention.

In addition, it is necessary to illustrate, unless otherwise explicitly point out, the describing mode for being adopted in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can be exchanged, and all should be interpreted broadly, Which had both been may refer in different groups, was not affected mutually, it is also possible to table between same-sign between expressed concrete option Show in identical group, do not affected between expressed concrete option mutually between same-sign.

In each several part of this specification, the present invention discloses the substituent of compound and discloses according to radical species or scope.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.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then represented it should be understood that being somebody's turn to do " alkyl " or " aryl " respectively The alkylidene group of connection or arylene group.

Terminology used in the present invention " alkyl " or " alkyl group ", represent contain 1 to 20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the substituent institute that the alkyl group optionally can be described by one or more present invention Replace.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 2-12 carbon atom；In other embodiments, Alkyl group contains 1-6 carbon atom；In other embodiments, alkyl group contains 2-6 carbon atom；In other reality Apply in scheme, alkyl group contains 1-4 carbon atom；Also in some embodiments, alkyl group contains 1-3 carbon atom. The substituent that the alkyl group optionally can be described by one or more present invention replaces.

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 group (- CH (CH₃)CH₂CH₂CH₃), 3- amyl group (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 2,2- dimethylbutyl (neopentyl ,-CH₂CH(CH₃)₂CH₃), 3- methyl isophthalic acid-butyl (- CH₂CH₂CH(CH₃)₂), 2-methyl-1-butene base (- CH₂CH(CH₃)CH₂CH₃), n-hexyl (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- hexyl (- CH (CH₃)CH₂CH₂CH₂CH₃), 3- hexyl (- CH (CH₂CH₃)(CH₂CH₂CH₃)), 2- Methyl -2- amyl group (- C (CH₃)₂CH₂CH₂CH₃), 3- methyl -2- amyl group (- CH (CH₃)CH(CH₃)CH₂CH₃), 4- methyl -2- penta Base (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- amyl group (- C (CH₃)(CH₂CH₃)₂), 2- methyl -3- amyl group (- 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..

Obtained by term " alkylidene " expression removes two or more hydrogen atoms from the straight or branched alkyl of saturation The divalence of saturation or polyvalent hydrocarbon radical.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In some realities Apply in scheme, alkylidene group contains 1-6 carbon atom；In other embodiments, alkylidene group contains 1-4 carbon original Son；In other embodiments, alkylidene group contains 0-4 carbon atom；Also in some embodiments, alkylidene group Containing 0-3 carbon atom；Also in some embodiments, alkylidene group contains 1-3 carbon atom；Also in other embodiment party In case, alkylidene group contains 0-2 carbon atom；Also in other embodiments, alkylidene group contains 1-2 carbon original Son.Alkylidene contains 0 carbon atom and refers to that alkylidene is not present, and which is directly a singly-bound.The example of alkylidene includes, but not It is limited to methylene (- CH₂-), ethylidene (- CH₂CH₂-), isopropylidene (- CH (CH₃)CH₂-) etc..

One or more hetero atoms are may be inserted in term " miscellaneous alkyl " expression alkyl, and wherein alkyl and hetero atom has such as Implication of the present invention.Miscellaneous alkyl is connected with other groups by carbon atom.Unless otherwise detailed instructions, miscellaneous alkyl group contains There is 1-12 carbon atom, other embodiment is that miscellaneous alkyl group contains 1-8 carbon atom, other embodiment It is that miscellaneous alkyl group contains 1-6 carbon atom, other embodiment is that miscellaneous alkyl group contains 1-4 carbon atom, separately Some embodiments outer are that miscellaneous alkyl group contains 1-3 carbon atom.The example of " miscellaneous alkyl " is included, but is not limited to ,- CH₂OCH₃、-CH₂CH₂OCH₂CH₃、-CH₂CH₂OCH₃、-CH₂SCH₃、-CH₂N(CH₃)₂、-CH₂OCH₂(CH₃)₂、-CH₂CH₂OCH₃、- CH₂CH₂OCH₂CH₃Deng.

Term " sub- miscellaneous alkyl " represent the divalence of removing the saturation obtained by two or more hydrogen atoms from miscellaneous alkyl or Polyvalent hydrocarbon radical.Sub- miscellaneous alkyl is connected with other groups by carbon atom.Unless otherwise detailed instructions, sub- miscellaneous alkyl group contains There is 1-12 carbon atom.In some embodiments, sub- miscellaneous alkyl group contains 1-6 carbon atom；In other embodiments In, sub- miscellaneous alkyl group contains 1-4 carbon atom；Also in some embodiments, sub- miscellaneous alkyl group contains 1-3 carbon original Son.The example of sub- miscellaneous alkyl includes, but are not limited to-CH₂OCH₂-、-CH₂CH₂OCH₂CH₂-、-CH₂CH₂OCH₂-、-CH₂SCH₂-、- CH₂N(CH₃)CH₂-、-CH₂OCH₂(CH₃)CH₂-、-CH₂CH₂NHCH₂-、-CH₂CH₂NHCH₂CH₂- etc..

Term " thiazolinyl " 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 optionally can be retouched by one or more present invention The substituent that states is replaced, and which includes the positioning of " cis " and " tans ", or the positioning of " E " and " Z ".In some embodiments In, alkenyl group includes 2-8 carbon atom；In other embodiments, alkenyl group includes 2-6 carbon atom；Another In a little embodiments, alkenyl group includes 2-4 carbon atom.The example of alkenyl group is included, but is not limited to, vinyl (- CH =CH₂), pi-allyl (- CH₂CH=CH₂) etc..The alkenyl group optionally can be described by one or more present invention Substituent is replaced.

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 tri- key of carbon-to-carbon sp, wherein, the alkynyl group optionally can be retouched by one or more present invention The substituent that states is replaced.In some embodiments, alkynyl group includes 2-8 carbon atom；In other embodiments, Alkynyl group includes 2-6 carbon atom；In other embodiment, alkynyl group includes 2-4 carbon atom.Alkynyl group Example is included, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH₂C ≡ CH), 1- propinyl (- C ≡ C-CH₃) etc..

Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, 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 enforcements In scheme, alkoxy base contains 1-6 carbon atom；In other embodiments, alkoxy base contains 1-4 carbon original Son；In other embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally by one The substituent that individual or multiple present invention are described is replaced.

The example of alkoxy base is included, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO ,- OCH₂CH₃), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH₂CH₂CH₃), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH₃)₂), 1- butoxy (n-BuO, n- butoxy ,-OCH₂CH₂CH₂CH₃), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH₂CH(CH₃)₂), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH₃)CH₂CH₃), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH₃)₃), 1- amoxy (n- amoxy ,-OCH₂CH₂CH₂CH₂CH₃), 2- amoxy (- OCH (CH₃) CH₂CH₂CH₃), 3- amoxy (- OCH (CH₂CH₃)₂), 2- methyl -2- butoxy (- OC (CH₃)₂CH₂CH₃), 3- methyl -2- fourth Epoxide (- OCH (CH₃)CH(CH₃)₂), 3- methyl-l- butoxy (- OCH₂CH₂CH(CH₃)₂), 2- methyl-l- butoxy (- OCH₂CH(CH₃)CH₂CH₃), etc..

Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, thiazolinyl or alkoxy base by one Individual or multiple halogen atoms are replaced, and such example includes, but is not limited to, two fluoro ethyl (- CH₂CHF₂,-CF₂CH₃,- CHFCH₂F), trifluoroethyl (- CH₂CF₃,-CF₂CH₂F,-CFHCHF₂), trifluoromethyl (- CF₃), trifluoromethoxy (- OCF₃) etc..

Term " hydroxy alkyl " and " hydroxy alkoxy base " represent alkyl or alkoxyl, depend on the circumstances, one or more Oh group is replaced, and wherein, " hydroxy alkyl " can exchange use with " hydroxyalkyl ", and such example includes, but does not limit In methylol (- CH₂OH), ethoxy (- CH₂CH₂OH,-CHOHCH₃), hydroxypropyl (- CH₂CH₂CH₂OH,-CH₂CHOHCH₃,- CHOHCH₂CH_3,), hydroxymethoxy (- OCH₂OH) etc..

Term " carbocylic radical " or " carbocyclic ring " represent containing 3-12 carbon atom, the nonaromatic saturation of unit price or multivalence Or unsaturated monocyclic, the bicyclic or three-ring system in part.Carbon bicyclic group includes spiral shell carbon bicyclic group, condenses carbon bicyclic group and bridge carbon pair Ring group, suitable carbocylic radical group are included, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbocylic radical group enters One step includes, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- thiazolinyl, 1- cyclopenta -2- thiazolinyl, 1- cyclopenta -3- alkene Base, cyclohexyl, 1- cyclohexyl -1- thiazolinyl, 1- cyclohexyl -2- thiazolinyl, 1- cyclohexyl -3- thiazolinyl, cyclohexadienyl, suberyl, Cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..

Term " cycloalkyl " represents that, containing 3-12 carbon atom, the saturation of unit price or multivalence is monocyclic, bicyclic or three ring bodies System.In some embodiments, cycloalkyl includes 3-12 carbon atom；In other embodiments, cycloalkyl is comprising 3-8 Carbon atom；In other embodiments, cycloalkyl includes 3-6 carbon atom.In some embodiments, cycloalkyl be comprising The C of 7-12 carbon atom₇-C₁₂Cycloalkyl, its include C further₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂Condensed-bicyclic alkyl and C₇- C₁₂Bridge bicyclic alkyl；In other embodiments, cycloalkyl is the C comprising 8-11 carbon atom₈-C₁₁Cycloalkyl, its enter one Step is comprising C₈-C₁₁Spiral shell bicyclic alkyl, C₈-C₁₁Condensed-bicyclic alkyl and C₈-C₁₁Bridged ring bicyclic alkyl.The example of cycloalkyl includes, But it is not limited to：C₃-C₆Cycloalkyl specifically refers to cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.The group of naphthene base can be only On the spot unsubstituted or replaced by one or more substituents described in the invention.

Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising 3-12 annular atom, univalent or Multivalence, undersaturated, the nonaromatic monocyclic, bicyclic or tricyclic system of saturation or part, wherein at least one annular atom are selected 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- oxide.The nitrogen-atoms of ring optionally can be oxidized to N- oxygen compound.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- pyrrolin Base, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydrochysene Thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkane Base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase (e.g., Isosorbide-5-Nitrae-oxygen azepineBase, 1,2- oxygen azepineBase), diazaBase (e.g., Isosorbide-5-Nitrae-diazaBase, 1,2- diazaBase), dioxaBase (e.g., 1, 4- dioxaBase, 1,2- dioxaBase), sulphur azepineBase is (as 1,4- sulphur azepineBase, 1,2- sulphur azepineBase), indoles Quinoline base, 1,2,3,4- tetrahydro isoquinolyl, 1,3- benzodioxole base, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, 2- Azaspiro [4.4] nonyl, 1,6- dioxo spiro [4.4] nonyl, 2- azaspiro [4.5] decyl, 8- azaspiro [4.5] last of the ten Heavenly stems Alkyl, 7- azaspiro [4.5] decyl, 3- azaspiro [5.5] undecyl, 2- azaspiro [5.5] undecyl, octahydro -1H- Isoindolyl, octahydro pentamethylene simultaneously [c] pyrrole radicals, hexahydro furyl simultaneously [3,2-b] furyl and ten dihydro-isoquinoline bases, etc..Miscellaneous - CH in ring group₂- group is included, but not limited to 1,1- dioxo isothiazole alkanone -2- base, pyrrole by the example of-C (=O)-replacement Cough up alkane -2- ketone -1- base, imidazolidin-2-one -1- base, oxazolidine -2- ketone -3- base, 2- oxo-pyrrolidine base, oxo -1,3- thiazole Alkyl, 2- piperidone base and 3,5- dioxy piperazine piperidinyl.In heterocyclic radical, the oxidized example of sulphur atom includes, but not limited to ring Fourth sulfuryl, 1,1- dioxothiomorpholinyl, 1,1- dioxotetrahydro thienyl and 1,1- dioxotetrahydro -2H- thiapyran base, Deng.Described heterocyclyl groups optionally can be replaced by one or more substituents described in the invention.

In some embodiments, heterocyclic radical is 3-8 former molecular heterocyclic radical, refer to comprising 3-8 annular atom, Unit price or multivalence, saturation or part undersaturated, nonaromatic monocyclic, wherein at least one annular atom 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- oxide.The nitrogen-atoms of ring can optionally by It is oxidized to N- oxygen compound.The example of 3-8 former molecular heterocyclic radical includes, but are not limited to：Azelidinyl, oxa- ring fourth Base, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazoles Alkyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulphur cyclopenta, four Hydrogen pyranose, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Piperazinyl, dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptane Base, oxygen azepineBase, diazaBase, sulphur azepineBase, etc..- CH in heterocyclic radical₂- group is by the example bag of-C (=O)-replacement Include, but be not limited to, 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base and 3,5- dioxy piperazine piperidinyl, etc.. In heterocyclic radical, the oxidized example of sulphur atom includes, but not limited to sulfolane base and 1,1- dioxothiomorpholinyl.Described 3-8 former molecular heterocyclyl groups optionally can be replaced by one or more substituents described in the invention.

In other embodiments, heterocyclic radical is 4-7 former molecular heterocyclic radical, refers to comprising 4-7 annular atom , unit price or multivalence, saturation or part undersaturated, nonaromatic monocyclic, wherein at least one annular atom be selected from nitrogen, sulphur And oxygen atom.Unless otherwise indicated, 4-7 former molecular heterocyclic radical can be carbon-based or nitrogen base, and-CH₂- group can be appointed Selection of land is by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can be optionally It is oxidized to N- oxygen compound.The example of 4-7 former molecular heterocyclic radical includes, but are not limited to：Azelidinyl, oxa- ring Butyl, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, miaow Oxazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, 1,1- dioxo isothiazole alkanone -2- Base, pyrrolidin-2-one -1- base, imidazolidin-2-one -1- base, oxazolidine -2- ketone -3- base, piperidyl, morpholinyl, thiomorpholine Base, piperazinyl, dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl Alkyl, oxygen azepineBase, diazaBase and sulphur azepineBase.4-7 described former molecular heterocyclyl groups can be optional Ground is replaced by one or more substituents described in the invention.

Term " bridge is bicyclic ", " bridged ring ", " bridge bicyclic group " and " bridged ring base " are used interchangeably herein, all referring to unit price or Multivalence, the unsaturated but nonaromatic bicyclic system of saturation or part, two in the member ring systems ring share two atoms With plural singly-bound.Such system can include the unsaturated system of independent or conjugation, but its core texture is not wrapped Containing aromatic rings or heteroaromatic (but aromatic group can be used as substituent thereon).

Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " are used interchangeably herein, all referring to list Valency or multivalence, the unsaturated but nonaromatic member ring systems of saturation or part, two in the member ring systems ring share a key. Such system can include the unsaturated system of independent or conjugation, but its core texture is not comprising aromatic rings or heteroaromatic (but aromatic group can be used as substituent thereon).

Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell is bicyclic " are used interchangeably herein, refer to unit price or many Valency, the undersaturated member ring systems of saturation or part, one of ring originate from specific ring carbon atom on another ring, and two Individual ring only shares this atom.For example, as described by following formula a-1 and formula a-2, the member ring systems of a saturation (ring B and B ') it is referred to as " condensed-bicyclic ", and ring A ' and ring B shares a carbon atom, is referred to as " volution " or " spiral shell is bicyclic "；Ring C ' and ring C is then referred to as " bridge bicyclic group ".Each ring in condensed-bicyclic base, spiral shell bicyclic group and bridge bicyclic group can be carbocylic radical or miscellaneous Ring group, and each ring optionally replaces by one or more substituents described in the invention.

Term " Heterocyclylalkyl " refers to monocyclic, bicyclic or three rings of saturation of the unit price containing 3-12 annular atom or multivalence System, wherein at least one annular atom are selected from nitrogen, sulphur or oxygen atom.Unless otherwise 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- oxide. The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.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, dialkyl group, dithiane base, isoxazolidinyl, isothiazole alkyl, 1,2- piperazine base, 1,2- thiophene Piperazine base, hexahydro-pyridazine base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase (e.g., 1, 4- oxygen azepineBase, 1,2- oxygen azepineBase), diazaBase (e.g., Isosorbide-5-Nitrae-diazaBase, 1,2- diazaBase), dioxy MiscellaneousBase (e.g., Isosorbide-5-Nitrae-dioxaBase, 1,2- dioxaBase), sulphur azepineBase (e.g., Isosorbide-5-Nitrae-sulphur azepineBase, 1,2- sulphur nitrogen MiscellaneousBase), 2- azaspiro [4.4] nonyl, 1,6- dioxo spiro [4.4] nonyl, 2- azaspiro [4.5] decyl, 8- nitrogen Miscellaneous spiral shell [4.5] decyl, 7- azaspiro [4.5] decyl, 3- azaspiro [5.5] undecyl, 2- azaspiro [5.5] hendecane Base, octahydro cyclopenta simultaneously [c] pyrrole radicals, octahydro -1H- isoindolyl, hexahydro furyl simultaneously [3,2-b] furyl, hexahydro furyl be simultaneously [2,3-b] furyl and ten dihydro-isoquinoline bases.Described heterocycloalkyl can be optionally by one or more present invention Described substituent is replaced.

In some embodiments, Heterocyclylalkyl is 7-12 former molecular Heterocyclylalkyl, refers to containing 7-12 ring Atom, unit price or multivalence, the miscellaneous bicyclic alkyl of the spiral shell of saturation, condense miscellaneous bicyclic alkyl or the miscellaneous bicyclic alkyl of bridge, 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- oxide.The nitrogen-atoms of ring is permissible N- oxygen compound is optionally oxidized to.Described 7-12 former molecular heterocycloalkyl can optionally by one or Multiple substituents described in the invention are replaced.

In some embodiments, Heterocyclylalkyl is 4-7 former molecular Heterocyclylalkyl, refers to former containing 4-7 ring Son, univalent or multivalence, the heterocyclic radical of saturation, wherein at least one annular atom are selected from nitrogen, sulphur or oxygen atom.Unless in addition said 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- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.4-7 atom composition The example of Heterocyclylalkyl include, but are not limited to：Azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, pyrazoles Alkyl, imidazolidinyl, piperidyl, piperazinyl, morpholinyl, dialkyl group, dithiane base, isoxazolidinyl, isothiazole alkyl, six Hydrogen pyridazinyl, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase and sulphur AzepineBase.4-7 described former molecular heterocycloalkyl can be optionally by one or more described in the invention Substituent replaced.

Term " n former molecular ", wherein n is integer, typically describes the number of ring member nitrogen atoms in molecule, described In molecule, the number of ring member nitrogen atoms is n.For example, piperidyl is the molecular Heterocyclylalkyl of 6 originals, and 1,2,3,4- tetralyl It is the molecular carbocylic radical group of 10 originals.

The term that used in the present invention is " undersaturated " to be represented containing one or more degrees of unsaturation in group.

Term " hetero atom " refers to O, S, N, P and Si, including 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 base N), NH (as the NH in pyrrolidinyl) or NR (as the NR in the pyrrolidinyl that N- replaces).

Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " azido " or " N₃" represent a nitrine structure.This group can be connected with other groups, for example, Triazonmethane (MeN can be connected to form with a methyl₃), or phenylazide (PhN is connected to form with a phenyl₃).

Term " aryl " represents containing 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double Ring and the carbocyclic ring system of three rings, wherein, at least one member ring systems are aromatic, and each of which member ring systems are former comprising 3-7 Molecular ring, and have one or more tie points to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance Ring " is exchanged and is used.The example of aromatic yl group can include phenyl, naphthyl and anthryl.The aromatic yl group can individually optionally Replaced by one or more substituents described in the invention.

Term " heteroaryl " represents containing 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom monocyclic, Bicyclic and three-ring system, wherein at least one member ring systems be aromatic, and at least one aromatic ring system include one or many Individual hetero atom, each of which member ring systems comprising 5-7 former molecular ring, and have one or more tie points and molecule remaining Part is connected.Term " heteroaryl " can be exchanged with term " hetero-aromatic ring " or " heteroaromatics " and be used.In some embodiment party In case, heteroaryl be comprising 1,2,3 or 4 heteroatomic 5-12 for being independently selected from O, S and N former molecular heteroaryls.? In other embodiments, heteroaryl is to constitute comprising 1,2,3 or 4 heteroatomic 5-10 atoms for being independently selected from O, S and N Heteroaryl.Also in some embodiments, heteroaryl be comprising 1,2,3 or 4 heteroatomic 5-6 for being independently selected from O, S and N Individual former molecular heteroaryl.The heteroaryl groups are optionally taken by one or more substituents described in the invention Generation.

The example of 5-12 former molecular heteroaryl groups includes, but is not limited to these following bicyclic heteroaryls： Benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyl, 3- indyl, 4- indyl, 5- indoles Base, 6- indyl, 7- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), indazolyl is (as 3- indazolyl, 4- indazolyl, 5- indazolyl, 6- indazole Base, 7- indazolyl), imidazo [1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, pyrazolo [4,3-c] pyridine radicals, pyrazoles And [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..5-12 atom The example of the heteroaryl groups of composition also includes 5-6 former molecular single ring heteroaryl group, and the example includes, but does not limit In following monocyclic, furyl (as 2- furyl, 3- furyl), imidazole radicals (as 1- imidazole radicals, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals), isoxazolyl (as 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl), oxazolyl is (as 2- oxazolyl, 4- Oxazolyl, 5- oxazolyl), pyrrole radicals (as 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals), pyridine radicals is (as 2- pyridine radicals, 3- pyridine Base, 4- pyridine radicals), pyriconyl, pyrimidine radicals (as 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals), pyrimidine ketone group, hybar X Base, pyridazinyl (such as 3- pyridazinyl, 4- pyridazinyl), pyrazinyl (as 2- pyrazinyl, 3- pyrazinyl), thiazolyl (as 2- thiazolyl, 4- thiazolyl, 5- thiazolyl), tetrazole radical (as 5- tetrazole radical), triazolyl (as 2- triazolyl and 5- triazolyl), thienyl (such as 2- thienyl, 3- thienyl), pyrazolyl (as 1- pyrazolyl, 3- pyrazolyl, 4- pyrazolyl, 5- pyrazolyl), pyrazoline ketone group, Isothiazolyl, 1,2,3- di azoly, 1,2,5- di azoly, 1,2,4- di azoly, 1,2,3- triazolyl, 1,2,3- are thio Di azoly, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, pyrazinyl and cyanuro 1,3,5 etc..

Term " oxazolyl " is referred to comprising at least two hetero atoms and wherein at least one is nitrogen-atoms, by 5 or 9 Former molecular heteroaromatic ring systems.The example of oxazolyl include, but is not limited to pyrazolyl, imidazole radicals, oxazolyl, isoxazolyl, Di azoly, 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- benzo [d] imidazole radicals.

No matter term " carboxyl ", be single use or be used in conjunction with other terms, such as " carboxyalkyl ", expression-CO₂H；Term No matter " carbonyl ", be single use or be used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represents-(C=O)-.

Term " alkyl amino " and " alkylamino " can be exchanged with each other use, and which includes " N- alkylamino " and " N, N- dioxane Amino ", wherein, amino group is separately replaced by one or two alkyl group.Wherein, some embodiments are, Alkylamino is one or two C₁-C₁₂Alkyl is connected to the alkylamino group of the lower level that formed on nitrogen-atoms.At other In embodiment, alkylamino is one or two C₁-C₆Alkyl is connected to the alkyl amino base of the lower level that formed on nitrogen-atoms Group.In other embodiments, alkylamino is one or two C₁-C₄Alkyl is connected to the lower level of formation on nitrogen-atoms Alkylamino group.Also in other embodiments, alkylamino is one or two C₁-C₃Alkyl is connected on nitrogen-atoms The alkylamino group of the lower level of formation.Suitably alkylamino radicals can be alkyl monosubstituted amino or dialkyl amido, alkane ammonia The example of base is included, but is not limited to, N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- lignocaine, N- ethyl third Base -2- amino etc..

Term " fragrant amino " represents that amino group is replaced by one or two aromatic yl group, and such example includes, but It is not limited to N- phenylamino.Some of them embodiment is that the aromatic ring on fragrant amino can be substituted further.

Term " aminoalkyl " includes the C replaced by one or more amino₁-C₁₂Straight or branched alkyl group.? In some embodiments, aminoalkyl is the C replaced by one or more amino groups₁-C₁₂Alkyl；In other embodiment party In case, aminoalkyl is the C replaced by one or more amino groups₁-C₆" aminoalkyl of lower level ", in other realities Apply in scheme, aminoalkyl is the C replaced by one or more amino groups₁-C₄Alkyl；Also in other embodiments, Aminoalkyl is the C replaced by one or more amino groups₁-C₃Alkyl.The example of aminoalkyl is included, but is not limited to, Aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.

As described in the invention, substituent draws the member ring systems formed on a ring for being bonded the center of being connected to (as formula b institute Show) represent substituent all commutable positions in the member ring systems and select a replacement.For example, formula b represents substituent R and can select one Replace all positions that can be substituted on D ring, as shown in formula c～formula e.

As described in the invention, connecting key be connected to formed in ring in the heart member ring systems (as shown in formula f, its Middle X and X ' independently is CH₂, NH or O) represent connecting key can in member ring systems any attachable position and its remaining part of molecule Split-phase connects.Formula f is represented the F ring position that may connect any with E ring and all can be connected with molecule remainder (as formula f-1～formula Shown in f-8).

As described in the invention, two connecting keys are connected to the member ring systems (as formula i is shown) for being formed in ring in the heart and represent Two connecting keys all can be connected with molecule remainder any attachable position in member ring systems, and the two ends for connecting (end points Q and end points Q ') can be exchanged with each other.Formula i represents the position that any two may connect on G ring all can be with molecule Remainder is connected.

When term " blocking group " or " PG " refer to a substituent with other reacted with functional groups, resistance is commonly used to Break or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or in protection compound amino feature, suitable amido protecting group includes acetyl group, trifluoroacetyl group, t-butyl formate (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyl (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 the substituent of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.

Term " prodrug " used in the present invention, represents a compound and is converted into the compound shown in formula (I) in vivo. Such conversion is hydrolyzed by pro-drug in blood or is affected for precursor structure through enzymatic conversion in blood or tissue.This Bright pro-drug compounds can be ester, and in existing invention, ester can be used as the phenyl ester class that have of pro-drug, aliphatic (C₁-C₂₄) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one Compound includes hydroxyl, you can be acylated the compound for obtaining prodrug form.Other prodrug form include Phosphate, such as these phosphate compounds are obtained through the di on parent.Beg for regard to pro-drug is complete By may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345.

" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art that its activity can pass through to retouch as the present invention Adopt as stating and experimentally characterized.Such product can be through peroxidating by administration compound, reduce, water Solution, amidated, desamido- are acted on, esterification, and degreasing, enzymatic lysis etc. method are obtained.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are fully contacted the metabolite produced by a period of time.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt of the compound of the present invention and inorganic salts.Medicine On, acceptable salt is known to us in art, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion-exchange obtaining 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 acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that appropriate alkali is obtained includes alkali metal, alkaline-earth metal, ammonium and N⁺(C₁-C₄Alkyl)₄Salt.The present invention is also intended to contemplate and appoints The quaternary ammonium salt formed by the compound of the group of what included N.Water-soluble or oil-soluble or dispersion product can pass through quaternized Effect is obtained.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt is further included The amine cation that appropriate, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulphur Acidulants, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

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

The as used in the present invention any disease of term " treatment " or illness, wherein some embodiment middle fingers improve disease Disease or illness (slowing down or prevent or mitigate the development of disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to relax or improve at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to (for example stablize perceptible symptom) from body or physiologically (for example stablizes body Parameter) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treat " and refer to prevent or postpone disease or disease The outbreak of disease, generation or deterioration.

" inflammatory disease " used in the present invention refers to the excessive inflammation caused due to inflammatory responses excessive or out of control 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 by tissue damaged or destroys the topical protective response for causing that it is used for breaking Bad, dilute or separate (isolation) harmful material and impaired tissue.Inflammation is flowed into leucocyte and/or neutrophil cell becomes The property changed has significant contact.Inflammation can result from infection and the non-infectious mode of pathogenic organism and virus, the such as heart Wound or Reperfu- sion after muscle infarction or apoplexy, the immune response to exotic antigen and autoimmune response.Therefore, it can with this The inflammatory disease of disclosure of the invention compounds for treating includes：React with specific system of defense and non-specific defense system reaction Related disease.

" specific system of defense " refers to that immune component is reacted to the presence of specific antigen.Result from specificity The example of the inflammation of system of defense reaction includes the classical response to exotic antigen, autoimmune disease and delayed type hypersensitivity, DTH Response (cell-mediated by T-).The repulsion of chronic inflammatory disease, transplanting solid tissue and organ is (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 is referred 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 damage, to be attributable to various etiologic etiological arthritis, be characterized any Disease." dermatitis " is referred to be attributable to the disease of skin that various etiologic etiological scytitises are characterized as used in the present invention Extended familys in any one." graft rejection " refers to the function funeral with transplanting or surrounding tissue as used in the present invention The antagonism transplanting tissue that mistake, pain, swelling, leukocytosis and decrease of platelet are characterized, such as organ or cell (as marrow) Any immune response.The treatment method of the present invention includes the method for treating the disease related to inflammatory cell activation.

Term " cancer " and " cancer " refer to or describe the usual physiology being characterized with cell growth out of control in patient Illness." tumour " includes one or more cancer cell.The example of cancer includes but is not limited to cancer (carcinoma), lymthoma, embryo Cytoma, sarcoma and leukaemia, or malignant lymph proliferative disease (lymphoid malignancies).Such cancer is more Specific example includes squamous cell carcinoma (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), cancer of the stomach (gastric Or stomach cancer) (including human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical carcinoma, oophoroma, orchioncus, bladder Cancer, hepatoma (hepatoma), breast cancer, colon and rectum carcinoma, colorectal cancer, carcinoma of endometrium or the cancer of the uterus, salivary gland Cancer, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma of vulva, thyroid cancer, medullary thyroid sample Cancer, melanoma, retinoblastoma, liver cancer (hepatic carcinoma), cancer of anus, carcinoma of penis, acute myelocytic Leukaemia, ALL, chronic granulocytic leukemia (CML), chronic lymphocytic leukemia and neck Cancer.

The description of the compound of the present invention

The invention discloses the novel compound of a class, can swash as protein kinase activity, particularly jak kinase, FLT3 Enzyme and the inhibitor of Aurora A activity.Compound as kinases inhibitor can be used to treat and unsuitable albumen Kinase activity, particularly unsuitable jak kinase, FLT3 kinases and the Aurora A related disease of activity, such as treatment with Prevention is related to the disease of the jak kinase, FLT3 kinases and Aurora A mediation of signal path.Such disease includes proliferative Disease, autoimmune disease, anaphylactia, inflammatory disease, graft rejection and their complication.Especially, the present invention Compound can be used to treat following disease, such as cancer (colorectal cancer, Hodgkin lymphoma, NHL, stomach Cancer, cancer of the esophagus, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, carcinoma of urinary bladder, kidney, brain tumor, head and neck cancer, The cancer, glioblastoma of CNS (central nervous system), non-small cell lung cancer, cervical carcinoma, orchioncus, lymph cancer, multiple Myeloma, malignant lymphoma, ED-SCLC, neuroblastoma, neuroendocrine cell tumour, medullary carcinoma of thyroid gland, black Melanoma, retinoblastoma, the cancer of the uterus, oophoroma, acute myelocytic leukemia, ALL, slow Property myelocytic leukemia (CML), chronic lymphocytic leukemia), primary macroglobulinaemia, monocytic leukemia, Sezary syndrome, infectious mononucleosis, colitis, pancreatitis, atherosclerotic, pulmonary fibrosis, true property are red Cytosis, primary thrombocytosis, myelofibrosis, COPD (COPD), asthma, systemic red Yabbi sore, skin lupus erythematosus, LN, dermatomyositis, Sjogren syndrome, psoriasis, type i diabetes, respiratory tract mistake Quick property disease, nasosinusitis, eczema, measles, food hypersenstivity, insect venom allergies, inflammatory bowel disease, Crohn disease, rheumatoid are closed Section inflammation, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection, cell transplant rejection, etc..

In some embodiments, compound disclosed by the invention shows stronger suppression to one or more protein kinase Activity.

On the one hand, the present invention relates to the alloisomerism of compound of the one kind as shown in formula (I) or compound shown in formula (I) Body, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

Wherein, each Z¹、A、R¹、R²、R^2aThere is definition of the present invention with m.

In some embodiments, Z¹For H, C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl or 3-12 former molecular heterocyclic radical, Wherein, each C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl and 3-12 former molecular heterocyclic radical individually optionally by 1,2,3,4 or 5 R³Group is replaced；

A is pyrazolyl, and which is optionally by 1,2 or 3 R⁴Group is replaced；

R¹For H, F, Cl, Br, I, N₃、CN、NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^5aR^5b、- OR^5c,-C (=O) R^5d,-OC (=O) R^5d,-C (=O) OR^5c、-N(R^5e) C (=O) R^5d,-C (=O) NR^5aR^5b、-N(R^5e) C (= O)NR^5aR^5b,-S (=O)₂R^5f、-N(R^5e) S (=O)₂R^5fOr-S (=O)₂NR^5aR^5b, wherein, each C₁-C₁₂Alkyl, C₁-C₁₂ Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl and 5-12 Individual former molecular heteroaryl is individually optionally by 1,2,3,4 or 5 R⁸Group is replaced；

Each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Alkylamino, C₃-C₁₂Cycloalkyl, 4-7 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 original are molecular miscellaneous Aryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁- C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-NR^6aR⁶ⁱ,-C (=O) R^6d,-OC (=O) R^6d,-C (=O) OR^6c、-N(R^6e) C (=O) R^6d,-C (=O) NR^6aR^6b、-N(R^6e) C (=O) NR^6aR^6b、-N (R^6e) S (=O)₂NR^6aR^6b,-S (=O)₂R^6f、-N(R^6e) S (=O)₂R^6gOr-S (=O)₂NR^6aR^6b, wherein, each C₁-C₁₂ Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkylamino, C₃-C₁₂Cycloalkyl, 4-7 former molecular heterocyclic radical, C₆-C₁₂ Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 Individual former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 atom composition Heteroaryl) individually optionally by 1,2,3,4 or 5 R⁸Group is replaced；

Each R³And R⁴It is separately F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂ Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-NR^7aR^7b、-OR^7c,-C (=O) R^7d,-C (= O)OR^7c、-N(R^7e) C (=O) R^7d,-C (=O) NR^7aR^7b、-N(R^7e) C (=O) NR^7aR^7b,-S (=O)₂R^7f、-N(R^7e) S (= O)₂R^7fOr-S (=O)₂NR^7aR^7b, wherein, each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3- The molecular heterocyclic radical of 12 originals, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Ring Alkyl) and-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) individually optionally by 1,2,3,4 or 5 R⁸Group institute Replace；

Each R^5a、R^5b、R^5c、R^5e、R^6a、R^6b、R^6c、R^6e、R^7a、R^7b、R^7cAnd R^7eIt is separately H, C₁-C₁₂Alkyl, C₂- C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 atom composition Heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocycle Base) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) or-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl), wherein, Each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂ Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 Individual former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 atom composition Heteroaryl) optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent of alkylamino is taken Generation；Or

R^5aAnd R^5bTogether with acceptable and connected with them nitrogen-atoms, 3-12 former molecular heterocyclyl groups are formed, Wherein, the 3-12 former molecular heterocyclyl groups optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl Or C₁-C₆The substituent of alkylamino is replaced；

R^6aAnd R^6bTogether with acceptable and connected with them nitrogen-atoms, 3-12 former molecular heterocyclyl groups are formed, Wherein, the 3-12 former molecular heterocyclyl groups optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl Or C₁-C₆The substituent of alkylamino is replaced；

R^7aAnd R^7bTogether with acceptable and connected with them nitrogen-atoms, 3-12 former molecular heterocyclyl groups are formed, Wherein, the 3-12 former molecular heterocyclyl groups optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl Or C₁-C₆The substituent of alkylamino is replaced；

Each R^5d、R^5f、R^6d、R^6f、R⁶ⁱ、R^7dAnd R^7fIt is separately C₁-C₁₂Alkyl, C₁-C₁₂Miscellaneous alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₁-C₁₂Alkylamino, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Virtue Base, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 Former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 is former molecular Heteroaryl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(3-12 former molecular heterocycle Base) ,-(C₁-C₆Sub- miscellaneous alkyl)-(C₆-C₁₂Aryl) or-(C₁-C₆Sub- miscellaneous alkyl)-(5-12 former molecular heteroaryl), its In, above-mentioned each group is optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl, C₁- C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent of alkylamino is replaced；

Each R^6gIt independently is C₂-C₁₂Alkyl, C₁-C₁₂Miscellaneous alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxy alkyl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Haloalkyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 Individual former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 atom composition Heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,- (C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₆ Sub- miscellaneous alkyl)-(C₆-C₁₂Aryl) or-(C₁-C₆Sub- miscellaneous alkyl)-(5-12 former molecular heteroaryl), and wherein, above-mentioned each base Group is optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent of alkylamino is replaced；

Each R⁸It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Haloalkyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical, 5-12 atom composition Heteroaryl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Alkylamino, C₁-C₁₂Alkoxyl, C₁-C₁₂Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)- (C₃-C₁₂Cycloalkyl) ,-NH (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-NH (C₀-C₄Alkylidene)-(3-12 is former molecular Heterocyclic radical) ,-NH (C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-N [(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkanes Base)]₂、-N[(C₀-C₄Alkylidene)-(C₆-C₁₂Aryl)]₂、-N[(C₀-C₄Alkylidene)-(3-12 former molecular heterocycle Base)]₂、-N[(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl)]₂、-O(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkanes Base) ,-O (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-O (C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) or-O (C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl)；With

M is 0,1,2,3,4 or 5.

In some embodiments, the present invention relates to compound of the one kind as shown in formula (II) or compound shown in formula (II) Stereoisomer, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or it before Medicine,

In other embodiments, Z¹For H, C₁-C₆Alkyl, C₃-C₆Cycloalkyl or 4-7 former molecular heterocyclic radical, Wherein, each C₁-C₆Alkyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are optionally by 1,2 or 3 R³Group institute Replace.

In some embodiments, Z¹For H, C₁-C₆Alkyl, C₃-C₆Cycloalkyl or 4-7 former molecular heterocyclic radical, its In, each C₁-C₆Alkyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are optionally by 1,2 or 3 R³Group is taken Generation.

In some embodiments, A is：

Wherein, each sub- knot shown in formula (A-1), (A-2) and (A-3) Structure is individually optionally by 1 or 2 R⁴Group is replaced.

In other embodiments, R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₄Alkyl, C₁-C₄Alkoxyl, C₂- C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆A cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,- NR^5aR^5b、-OR^5c,-C (=O) R^5d,-OC (=O) R^5d,-C (=O) OR^5c、-N(R^5e) C (=O) R^5d,-C (=O) NR^5aR^5b、-N (R^5e) C (=O) NR^5aR^5b,-S (=O)₂R^5f、-N(R^5e) S (=O)₂R^5fOr-S (=O)₂NR^5aR^5b, wherein, each C₁-C₄Alkane Base, C₁-C₄Alkoxyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl and 5-6 Former molecular heteroaryl is individually optionally by 1,2 or 3 R⁸Group is replaced.

In some embodiments, each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 atom The heteroaryl of composition ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) ,-NR^6aR⁶ⁱ,-C (=O) R^6d,-OC (=O) R^6d,-C (=O) OR^6c、-N(R^6e) C (=O) R^6d,-C (=O) NR^6aR^6b、-N(R^6e) C (=O) NR^6aR^6b、-N (R^6e) S (=O)₂NR^6aR^6b,-S (=O)₂R^6f、-N(R^6e) S (=O)₂R^6gOr-S (=O)₂NR^6aR^6b, wherein, each C₁-C₆ Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 Individual former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 is former molecular Heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) individually optionally By 1,2 or 3 R⁸Group is replaced.

In other embodiments, each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₄Alkane Base, C₂-C₄Thiazolinyl, C₁-C₄Alkylamino, C₃-C₆Cycloalkyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, 1,1- dioxo are different Thiazolidine -2-base, pyrrolidin-2-one-1- base, imidazolidin-2-one-1- base, oxazolidine-2- ketone-3- base, phenyl, 5-6 atom The heteroaryl of composition ,-(C₁-C₂Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₂Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl) ,-NR^6aR⁶ⁱ,-OC (=O) R^6d,-C (=O) OR^6c、-N(R^6e) C (=O) R^6d,-C (=O) NR^6aR^6b、-N(R^6e) C (=O) NR^6aR^6b、-N(R^6e) S (=O)₂NR^6aR^6b、-N(R^6e) S (=O)₂R^6gOr-S (=O)₂NR^6aR^6b, wherein, each C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₁-C₄Alkane ammonia Base, C₃-C₆Cycloalkyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, 1,1- dioxo isothiazolidine -2- base, pyrrolidines -2- Ketone -1- base, imidazolidin-2-one -1- base, oxazolidine -2- ketone -3- base, phenyl, 5-6 former molecular heteroaryl,-(C₁-C₂Sub- Alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₂Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₂Alkylidene)-phenyl With-(C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl) individually optionally by 1,2 or 3 R⁸Group is replaced.

In some embodiments, each R³And R⁴It is separately F, Cl, CN, C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₃-C₆Ring Alkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Ring Alkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-NR^7aR^7b、-OR^7c,-C (=O) R^7d,-C (=O) OR^7c、-N(R^7e) C (=O) R^7d,-C (=O) NR^7aR^7b、-N(R^7e) C (=O) NR^7aR^7b,-S (=O)₂R^7f、-N(R^7e) S (=O)₂R^7fOr-S (=O)₂NR^7aR^7b, wherein, each C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₃-C₆Cycloalkyl, 4-7 original are molecular miscellaneous Ring group, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) and-(C₁-C₃Alkylidene)- (4-7 former molecular heterocyclic radical) is individually optionally by 1,2 or 3 R⁸Group is replaced.

In other embodiments, each R³And R⁴It is separately F, Cl, Br, I, N₃、CN、-NO₂, methyl, ethyl, N-propyl, isopropyl, cyclopropyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, thiazole Base, pyrrole radicals or oxazolyl, wherein, each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, piperidyl, pyrrolidinyl, Morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, thiazolyl, pyrrole radicals and oxazolyl are individually optionally by 1,2 or 3 R⁸Group is replaced.

In some embodiments, each R^5a、R^5b、R^5c、R^5e、R^6a、R^6b、R^6c、R^6e、R^7a、R^7b、R^7cAnd R^7eSeparately For H, C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 original Molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), and wherein, each C₁- C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 atom composition Heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,- (C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) optionally by 1,2 or 3 independences Ground is selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxyl alkane Base, C₁-C₃Aminoalkyl or C₁-C₃The substituent of alkylamino is replaced；Or

R^5aAnd R^5bTogether with acceptable and connected with them nitrogen-atoms, 4-7 former molecular heterocyclyl groups are formed, Wherein, the 4-7 former molecular heterocyclyl groups are optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、- NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁- C₃The substituent of alkylamino is replaced；

R^6aAnd R^6bTogether with acceptable and connected with them nitrogen-atoms, 4-7 former molecular heterocyclyl groups are formed, Wherein, the 4-7 former molecular heterocyclyl groups are optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、- NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁- C₃The substituent of alkylamino is replaced；

R^7aAnd R^7bTogether with acceptable and connected with them nitrogen-atoms, 4-7 former molecular heterocyclyl groups are formed, Wherein, the 4-7 former molecular heterocyclyl groups are optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、- NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁- C₃The substituent of alkylamino is replaced.

In other embodiments, each R^5a、R^5b、R^5c、R^5e、R^6a、R^6b、R^6c、R^6e、R^7a、R^7b、R^7cAnd R^7eIndependently Ground is H, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine Base, pyridazinyl, pyrazinyl, thiazolyl, pyrrole radicals, pyrazolyl, imidazole radicals or oxazolyl, wherein, each methyl, ethyl, just Propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrole Cough up alkyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, thiophene Oxazolyl, pyrrole radicals, pyrazolyl, imidazole radicals and oxazolyl are optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、- NO₂、-OH、-NH₂、-CF₃、-CH₃、-CH₂CH₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N(CH₃)₂Or-CH₂NH₂Take Replaced for base.

In some embodiments, each R^5d、R^5f、R^6d、R^6f、R⁶ⁱ、R^7dAnd R^7fIt is separately C₁-C₄Alkyl, C₁-C₆ Miscellaneous alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₁-C₄Alkoxyl, C₁-C₄Alkylamino, C₃-C₆Cycloalkyl, 4-7 original are molecular miscellaneous Ring group, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4- The molecular heterocyclic radical of 7 originals) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl Base) ,-(C₁-C₄Sub- miscellaneous alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 former molecular heterocyclic radical) ,- (C₁-C₄Sub- miscellaneous alkyl)-phenyl or-(C₁-C₄Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), and wherein, above-mentioned each group Optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkane Epoxide, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent of alkylamino is replaced.

In other embodiments, each R^5d、R^5f、R^6d、R^6f、R⁶ⁱ、R^7dAnd R^7fBe separately methyl, ethyl, just Propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, piperidines Base, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazine Base, thiazolyl, pyrrole radicals, pyrazolyl, imidazole radicals, oxazolyl, C₁-C₄Miscellaneous alkyl ,-(C₁-C₂Alkylidene)-(C₃-C₆Cycloalkanes Base) ,-(C₁-C₂Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylidene)- (5-6 former molecular heteroaryl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 Former molecular heterocyclic radical) ,-(C₁-C₄Sub- miscellaneous alkyl)-phenyl or-(C₁-C₄Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl Base), wherein, above-mentioned each group is optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、-CF₃、- CH₃、-CH₂CH₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N(CH₃)₂Or-CH₂NH₂Substituent replaced.

In other embodiments, each R^6gIt independently is C₂-C₆Alkyl, C₁-C₆Miscellaneous alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynes Base, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl, C₁-C₆Haloalkyl, C₃-C₆The individual former molecular heterocyclic radical of cycloalkyl, 4-7, Phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 is former Molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) ,- (C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₆Sub- Miscellaneous alkyl)-phenyl or-(C₁-C₆Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), wherein, above-mentioned each group optionally by 1st, 2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alcoxyl Base, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent of alkylamino is replaced.

In some embodiments, each R^6gIndependently be ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, The tert-butyl group, 3- methyl isophthalic acid-butyl, 2-methyl-1-butene base, 1,2- dimethyl -1- propyl group, neopentyl, acrylic, 2- metering system Base, trifluoromethyl, methylol, ethoxy, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, piperidyl, pyrroles Alkyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, C₁-C₄ Miscellaneous alkyl ,-(C₁-C₂Alkylidene)-cyclopropyl ,-(C₁-C₂Alkylidene)-cyclobutyl ,-(C₁-C₂Alkylidene)-cyclopenta ,-(C₁-C₂ Alkylidene)-cyclohexyl ,-(C₁-C₂Alkylidene)-piperidyl ,-(C₁-C₂Alkylidene)-pyrrolidinyl ,-(C₁-C₂Alkylidene)-four Hydrogen furyl ,-(C₁-C₂Alkylidene)-tetrahydrochysene -2H- pyranose,-(C₁-C₂Alkylidene)-morpholinyl ,-(C₁-C₂Alkylidene)-piperazine Piperazine base ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl) ,-(C₁-C₄Sub- miscellaneous alkane Base)-(C₃-C₆Cycloalkyl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₄Sub- miscellaneous alkyl)-benzene Base or-(C₁-C₄Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), wherein, above-mentioned each group is optionally only by 1,2 or 3 F, Cl, Br, CN, N are on the spot selected from₃、-OH、-NH₂、-CF₃、-CH₃、-CH₂CH₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N (CH₃)₂Or-CH₂NH₂Substituent replaced.

In other embodiments, each R⁸It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical, 5-6 original Molecular heteroaryl, C₁-C₄Aminoalkyl, C₁-C₄Alkylamino, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl ,-NH (C₀-C₃Alkylene Base)-(C₃-C₆Cycloalkyl) ,-NH (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-N [(C₀-C₃Alkylidene)- (C₃-C₆Cycloalkyl)]₂、-N[(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical)]₂、-O(C₀-C₃Alkylidene)-(C₃- C₆Cycloalkyl) ,-O (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-O (C₀-C₃Alkylidene)-phenyl or-O (C₀- C₃Alkylidene)-(5-6 former molecular heteroaryl).

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 are produced 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 asymmetric 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, become The part of the present invention.

In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific is not indicated, then the structure All stereoisomers all consider within the present invention, and disclose compound as the present invention and be included in the invention.When Spatial chemistry is expressed the real wedge shape line (solid wedge) of particular configuration or when dotted line is indicated, then the alloisomerism of the structure Body clearly and is defined with regard to this.

Compound shown in formula (I) can be present with different tautomeric forms, and all these dynamic isomers, Dynamic isomer, is included within the scope of the present invention as described in the present invention.

Compound shown in formula (I) can be present in a salt form.In some embodiments, the salt refers to pharmaceutically may be used The salt of acceptance.Term " pharmaceutically acceptable " refers to that material or composition must be with other compositions comprising preparation and/or use The mammal of its treatment is compatible chemically and/or in toxicology.In other embodiments, the salt is not necessarily pharmacy Upper acceptable salt, could be for preparing and/or compound shown in purification formula (I) and/or for separating this formula (I) shownization The intermediate of the enantiomer of compound.

Pharmaceutically useful acid-addition salts can be formed with inorganic acid and organic acid, for example acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

Such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc. can be included by its derivative inorganic acid for obtaining salt.

Can by its derivative organic acid for obtaining salt include for example 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.

Can be included by its derivative inorganic base for obtaining salt, the metal of the I race to XII race of such as ammonium salt and periodic table.? In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.

Primary amine, secondary amine and tertiary amine can be included by its derivative organic base for obtaining salt, 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 by parent compound, alkalescence or acidic moiety with conventional chemical processes. In general, such salt can by make the free acid form of these compounds and stoichiometry suitable alkali (as Na, Ca, The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds The suitable acid reaction of metered amount is being prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of appropriate, need using 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, include their salt, it is also possible to their hydrate forms or include its The form of solvent (such as ethanol, DMSO, etc.) is obtained, for their crystallization.The present invention discloses compound can be with pharmacy Upper acceptable solvent (including water) is inherently or by design forming solvate；Therefore, it is contemplated that including solvation And unsolvated form.

Any structural formula that the present invention is given be also intended to expression these compounds not by the form of isotope enrichment and with The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention is provided, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced in the compounds of this invention Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I.

On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there is radio isotope, such as³H、¹⁴C and¹⁸Those compounds of F, or wherein there is non radioactive isotope, such as²H and¹³C.The compound of such isotope enrichment can be used for metabolism research and (use¹⁴C), Reaction kinetics research are (using for example²H or³H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate tissue measure of spread SPECT (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound of F enrichment to PET or It is especially desirable for SPECT research.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 that knows or the present invention is described former using suitable isotope labeling reagent replacement Carry out used unmarked reagent to prepare.

Additionally, higher isotope is particularly deuterium (i.e.,²H or D) replacement some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements 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 The concentration of deuterium is particularly to define such higher isotope.Term " isotope enrichment factor " used in the present invention refers to indication Fixed ratio between isotopic isotope abundance 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 mix), at least for each D-atom that specifies 4000 (60% deuterium is mixed), at least 4500 (67.5% deuterium is mixed), at least 5000 (75% deuterium is mixed), at least 5500 (82.5% deuterium mix), at least 6000 (90% deuterium is mixed), at least 6333.3 (95% deuterium is mixed), at least 6466.7 The isotope enrichment of (97% deuterium is mixed), at least 6600 (99% deuterium is mixed) or at least 6633.3 (99.5% deuterium is mixed) The factor.The pharmaceutically useful solvate of the present invention includes that wherein recrystallisation solvent can be the such as D that isotope replaces₂O, acetone-d₆、 DMSO-d₆Those solvates.

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

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

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 include pharmaceutically acceptable auxiliary material, carrier, excipient, 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 receive one or more protein kinase, such as jak kinase, FLT3 kinases and Disease or the method for disorder that Aurora A is adjusted, the treatment method include that the present invention for giving mammal effective dose is public Become civilized compound or pharmaceutical composition.In some embodiments, the disease or disorderly selected from proliferative diseases, autoimmunity disease Disease, anaphylactia, inflammatory disease, graft rejection or cancer.

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, graft rejection or Cancer.

On the other hand, the present invention relates to compound disclosed by the invention or pharmaceutical composition are preparing treatment disease or disorder Medicine purposes, the disease be selected from proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease, graft rejection Or cancer.

On the other hand, the present invention relates to preparing 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, especially suppress the activity of Aurora A, and such as Aurora-A swashs Enzyme, Aurora-B kinases or Aurora-C kinases.

The pharmaceutical composition of the compounds of this invention, preparation and administration

The present invention provides a kind of pharmaceutical composition, and which includes the present invention and discloses listed compound in compound, or embodiment； With pharmaceutically acceptable auxiliary material, excipient, carrier, solvent or combinations thereof.Change in pharmaceutical composition disclosed by the invention The amount of compound refer to can effective detection to suppressing biological specimen or the amount of protein kinase in the patient.

It will also be appreciated that some compounds of the present invention can be present in a free form for treating, or if appropriate Can be in the form of its pharmaceutically acceptable derivates.Some nonrestrictive enforcements of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when being administered to patient in need can directly or Any other adduct or the derivative of compound of the present invention or its metabolite or residue are provided indirectly.

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

Used by the present invention, " pharmaceutically acceptable auxiliary material " means related to form of administration or pharmaceutical composition uniformity Pharmaceutically acceptable material, mixture or solvent.Every kind of auxiliary material must become split-phase with other of pharmaceutical composition in mixing Hold, the present invention can be substantially reduced during avoiding patient is administered and is disclosed the interaction of effect of compound and can cause not being medicine The interaction of acceptable pharmaceutical composition on.Additionally, every kind of auxiliary material must be pharmaceutically acceptable, for example, have Sufficiently high purity.

Suitably pharmaceutically acceptable auxiliary material can be different according to selected concrete formulation.Additionally, can be according to them in combination Specific function in thing is selecting pharmaceutically acceptable auxiliary material.For example, may be selected to can help to produce some of equal one dosage type low temperature Pharmaceutically acceptable auxiliary material.The some pharmaceutically acceptable auxiliary material that can help to produce stabilizer type may be selected.May be selected Contribute to carrying or transport when patient is administered the present invention compound is disclosed from an organ of body or part to the another of body One organ or partial some pharmaceutically acceptable auxiliary material.May be selected to strengthen some pharmaceutically acceptable of patient compliance Auxiliary material.

Suitably pharmaceutically acceptable auxiliary material includes following kind of auxiliary material：Diluent, filler, adhesive, disintegration Agent, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, flavoring Agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilizer, Surfactant and buffer.Technical staff can be appreciated that some pharmaceutically acceptable auxiliary materials can provide more than one function, And alternative function is provided, this has in how many auxiliary materials and preparation the presence of which other auxiliary material depending in preparation.

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.The obtainable resource of a large amount of technical staff is additionally, there are, they describe pharmaceutically acceptable Excipient, and for selecting suitably 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 Disclose the various carriers for configuring pharmaceutically acceptable composition in Dekker, New York, and prepare for which 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 is acted on, or occur to interact with any other composition in harmful way and pharmaceutically acceptable composition and and 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).

Compound disclosed by the invention is usually formulated as being adapted to pass through the formulation that required approach is administered patient.Example Such as, formulation includes that those are suitable for the formulation of following method of administration：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent, contain tablet, pulvis, syrup, elixir, supensoid agent, solution, emulsion, granule and cachet；(2) parenteral, example 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 is administered, for example cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gel.

In some embodiments, compound disclosed by the invention can be configured to peroral dosage form.In other embodiment party In case, compound disclosed by the invention can be configured to inhalant dosage form.In other embodiments, chemical combination disclosed by the invention Thing can be configured to nose administration formulation.In other embodiment, compound disclosed by the invention can be configured to transdermal Form of administration.Also in some embodiments, compound disclosed by the invention can be configured to Topical dosage forms.

The present invention provide pharmaceutical composition can with compressed tablets, develop piece, can be chewed lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets are providing.Enteric coatel tablets are to use the material bag for being resistant to hydrochloric acid in gastric juice effect but dissolving in intestines or be disintegrated The compressed tablets of clothing, so as to prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, shellac, ammonification shellac and cellulose acetate phthalate ester.The compacting that sugar coated tablet is surrounded for sugar-coat Piece, its beneficial to taste beastly or smell is covered and can prevent tablet from aoxidizing.Thin membrane coated tablet is to use water solubility The compressed tablets that the thin layer of material or film are covered.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethylcellulose calcium Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses and sweet tablet identical general characteristic.Multiple Compressing tablet is the compressed tablets through preparing more than press cycles, including multilayer tablet and pressed coated or dry coating tablet.

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

The pharmaceutical composition that the present invention is provided can be provided with soft capsule or hard shell capsules, and which can be fine by gelatin, methyl Tie up element, starch or calcium alginate to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is constituted by two sections, one section Fill in another section, therefore enclose active component completely.SEC (SEC) is soft, spherical shell, such as gelatin shell, Which passes through to add the plasticizing of glycerine, sorbierite or similar polyalcohol.Soft gelatin shell can be comprising the pre- preventing microorganism life of preservative Long.Suitably preservative for as described in the present invention those, including methyl hydroxybenzoate and propylben, and sorbic acid.This The liquid that invention is provided, semi-solid and solid dosage forms can be encapsulated in capsule.Suitably liquid and semisolid dosage form include Solution and supensoid agent in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be as in the U.S. Patent U.S.Pat.Nos.4,328,245；Described in 4,409,239 and 4,410,545 preparing.The capsule can also be adopted Coating as is known to persons skilled in the art is used, so as to improve or maintain the dissolution of active component.

The pharmaceutical composition that the present invention is provided can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in another kind of liquid in pellet form, Which can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and Preservative.Supensoid agent can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used Two (low alkyl group) acetal of the acetal of acceptance, such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal；And have one or many The water-soluble solvent of individual hydroxyl, such as propane diols and ethanol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and also preservative can be included.For liquid dosage form, for example, the solution in polyethylene glycol Can be with the such as water dilution of enough pharmaceutically acceptable liquid-carriers, to be accurately, conveniently administered.

Other useful liquid and semisolid dosage form include, but are not limited to the active component provided comprising the present invention and two grades Change those formulations of list-or poly- alkylene glycol, the list-or poly- alkylene glycol include：1,2- dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ether, polyethylene glycol -550- dimethyl ether, poly- second Glycol -750- dimethyl ether, the approximate mean molecule quantity of wherein 350,550,750 finger polyethylene glycol.These preparations can be further Including one or more antioxidant, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, monoethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, Jiao Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.

Where appropriate, the dosage unit preparations microencapsulation that will can be administered orally.Can also be prepared into extending or tieing up The composition of release is held, for example, is passed through microparticle material coating or is embedded in polymer, wax or the like.

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

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

Can be using colouring agent and flavor enhancement in all above-mentioned formulations.

Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.Such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl The oxide polylysine that amine phenol or palmitoyl residues replace.Additionally, compound disclosed in this invention can with reality A class Biodegradable polymeric used in the control release of existing medicine is combined, for example, PLA, poly-epsilon-caprolactone, poly- The crosslinking of hydroxybutyric acid, poe, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel or amphiphilic block are altogether Polymers.

The pharmaceutical composition that the present invention is provided can be configured to immediately or Modified release dosage forms, including postponing-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.

The pharmaceutical composition that the present invention is provided can be common with other active components without compromising on expected therapeutic action Prepare, or the material co-formulation with supplementary expected effect.

The pharmaceutical composition that the present invention is provided by injection, infusion or can be implanted into parenteral, for local or complete Body is administered.As the present invention using parenteral include in intravenous, intra-arterial, intraperitoneal, intrathecal, ventricle, in urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical composition that the present invention is provided can be configured to be suitable to any formulation of parenteral, including solution, mix Suspension, emulsion, micella, liposome, microballoon, nanometer system and being suitable to makes consolidating for solution or suspension before the injection in a liquid Body form.Such formulation can be prepared according to the conventional method known to the skilled person in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, ibid).

Be intended for parenteral pharmaceutical composition can include one or more pharmaceutically acceptable carrier and Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life The preservative of thing growth, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and dispersion 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 solution, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers parenteral solution.Non- transporter includes, but not limited to the fixed oil of plant origin, castor oil, corn oil, cottonseed The middle chain of oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil Triglycerides and palm seed oil.Water miscibility carrier includes, but not limited to the poly- second two of ethanol, 1,3-BDO, liquid Alcohol (such as Liquid Macrogol and PEG400), propane diols, glycerine, METHYLPYRROLIDONE, N, N- dimethylacetamide Amine and dimethyl sulfoxide.

Suitably 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.Suitably isotonic agent includes, but not limited to sodium chloride, glycerine and glucose.Suitable buffer Include, but not limited to phosphate and citrate.Suitably antioxidant be as present invention description, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitably local anesthetic includes, but are not limited to procaine hydrochloride.Suitably suspending agent and point Powder be as the present invention description, including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitably emulsifying agent includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene takes off Water sorbitol monooleate 80 and triethanolamine oleate ester.Suitably sequestering agent or chelating agent include, but are not limited to EDTA. Suitably pH adjusting agent includes, but are not limited to NaOH, hydrochloric acid, citric acid and lactic acid.Suitably complexing agent includes, but does not limit In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin, HP-β-CD, Sulfobutylether-beta-schardinger dextrin and sulfobutyl group Ether 7- beta-schardinger dextrin (CyDex,Lenexa,KS).

The pharmaceutical composition that the present invention is provided can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped It is mounted in ampulla, bottle or syringe.The multiple dose parenteral administration must be comprising the anti-micro- of antibacterial or fungistatic concentrations Biological agent.All of parenteral administration must be all aseptic, as known in the art with practice.

In some embodiments, pharmaceutical composition is provided with instant sterile solution.In other embodiments, Pharmaceutical composition is provided with aseptic dried soluble product, and including freeze-dried powder agent and hypodermic tablet, which is using front use Carrier is reconstructed.In other embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In other enforcement In scheme, pharmaceutical composition dries insolubility product with the aseptic of carrier reconstruct before being formulated into use.Also at some In embodiment, pharmaceutical composition is formulated into instant nothing bacterial emulsion.

Pharmaceutical composition disclosed in this invention can be configured to immediately or Modified release dosage forms, including postponing-, sustained release-, Pulse-, control-, targeting-and sequencing releasing pattern.

Pharmaceutical composition can be configured to supensoid agent, solid, semisolid or thixotropic liquid, as the reservoir administration being implanted into. In some embodiments, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, and which 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 unplasticizied Polyvinyl chloride, the nylon of plasticising, the PET of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silica Alkane, silicone carbonate copolymer, the hydrogel of the 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 The copolymer of alkene, ethlyene dichloride and vinyl acetate, vinylidene chloride, ethene and propylene, ionomer are poly- to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.

On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable to any dose to patient's inhalation Type, such as dry powder doses, aerosol, supensoid agent or liquid composite.In some embodiments, medicine group disclosed in this invention Compound can be configured to be suitable to the formulation with dry powder doses to patient's inhalation.In other embodiment, present invention institute is public The pharmaceutical composition that opens can be configured to be suitable to the formulation by sprayer to patient's inhalation.By inhalation delivery to lung Dry powder composite generally comprises fine powdered compound disclosed in this invention and one or more fine powdered medicine Acceptable excipient on.The pharmaceutically acceptable excipient for being especially suitable for use as dry powder doses is those skilled in the art institute Know, which includes lactose, starch, mannitol and single-, two- and polysaccharide.Fine powder can be by such as micronizing and grinding system Standby obtain.In general, reduced size of (as micronized) compound can be by about 1 to 10 micron of D₅₀Value (for example, is used Laser diffractometry measurement) defining.

Aerosol can be by compound disclosed in this invention to be suspended or dissolved in preparing in liquefied propellant.It is suitable for 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- difluoro Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.Aerosol comprising compound disclosed in this invention generally passes through Metered dose inhaler (MDI) is administered to patient.Such device dawn known to those skilled in the art

Aerosol can include pharmaceutically acceptable excipient that is extra, can using, such as surface-active by MDIs Agent, lubricant, cosolvent and other excipient, with improve preparation physical stability, improve valve characteristic, improve dissolubility, Or improve taste.

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

Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, supensoid agent, lotion, pulvis, Solution, paste, gel, spray, aerosol or finish.For example, ointment, cream and gel can be with water or oil Matrix, and the thickener that is suitable for and/or gel and/or solvent are configuring.Such matrix can include, water, and/or oily example As liquid-liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.Made according to medium property Thickener and gel include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, poly- carboxylic second Alkene and cellulose derivative, and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.

Lotion can be prepared with water or oil matrix, and generally also contains one or more emulsifying agent, stabilizer, dispersion Agent, suspending agent or thickener.

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

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

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

The compounds of this invention and the purposes of composition

The present invention is provided using compound disclosed in this invention and medicine composite for curing, prevention, or is improved by one kind Or multiple protein kinases, such as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also referred to as FLK-2) or The disease or disorderly that Aurora A (including Aurora-A, Aurora-B and Aurora-C) behavior is mediated or otherwise affected Disorderly or by one or more protein kinase, such as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also referred to as FLK-2) or Aurora A (including Aurora-A, Aurora-B and Aurora-C) behavior mediation or otherwise The method of one or more symptom of the disease of impact or disorder.

FLT3 kinases can be the wild type of FLT3 kinases and/or saltant type.

Jak kinase can be the wild type of JAK1, JAK2, JAK3 or TYK2 kinases and/or saltant type.

In some embodiments, the present invention provides class compound disclosed in this invention or comprising presently disclosed The pharmaceutical composition of compound, for treat, prevent or improve by unsuitable JAK1 kinases behavior mediate or otherwise The disease of impact is disorderly or mediated by unsuitable JAK1 kinases behavior or the disease that otherwise affects or disorder One or more symptom.In other embodiments, one or more symptom of the disease, disorder or disease or disorder Related to unsuitable JAK2 kinases behavior.Also in some embodiments, the one of the disease, disorder or disease or disorder Plant or multiple symptoms are related to unsuitable JAK3 kinases behavior.

In some embodiments, the present invention provides class compound disclosed in this invention or comprising presently disclosed The pharmaceutical composition of compound, for treat, prevent or improve by unsuitable FLT3 kinases behavior mediate or otherwise The disease of impact is disorderly or mediated by unsuitable FLT3 kinases behavior or the disease that otherwise affects or disorder One or more symptom.

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

" unsuitable jak kinase behavior " refers to occur the JAK for deviateing normal jak kinase behavior with particular patient to swash Enzyme behavior.Unsuitable jak kinase behavior can show as example active abnormal growth or jak kinase time of the act point Form with the deviation in control.This unsuitable kinases behavior comes from, for example, the overexpression of protein kinase or mutation and The inappropriate or uncontrolled behavior for causing.Therefore, the present invention is provided and treats these diseases and disorderly method.

Consistent with above description, such disease or disorder are included but is not limited to：Primary macroglobulinaemia, list Monocytic leukaemia, Sezary syndrome, infectious mononucleosis, colitis, pancreatitis, atherosclerotic, lung Fibrillatable, bone marrow proliferative diseases, such as polycythemia vera (PCV), essential thrombocythemia, agnogenic myeloid Fibrillatable (IMF)；Leukaemia, such as marrow series leukemia include chronic myelogenous leukemia (CML), the CML form of resistance to Imatinib, The hypotype of acute myeloid leukemia (AML) and AML, acute megakaryoblastic leukemia (AMKL)；Lymphoproliferative disease, for example ALL (ALL), myeloma；Cancer include colorectal cancer, Hodgkin lymphoma, NHL, Cancer of the stomach, cancer of the esophagus, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, carcinoma of urinary bladder, kidney, brain tumor, neck Cancer, the cancer of CNS (central nervous system), glioblastoma, non-small cell lung cancer, cervical carcinoma, orchioncus, lymph cancer, many The property sent out myeloma, malignant lymphoma, ED-SCLC, neuroblastoma, neuroendocrine cell tumour, medullary thyroid sample Cancer, melanoma, retinoblastoma, the cancer of the uterus and oophoroma, etc.；And adjust with immunologic function disorder, immune deficiency, immunity The relevant diseases associated with inflammation of section or disorder, autoimmune disease, tissue transplantation rejection, graft versus host disease(GVH disease), wound healing, Ephrosis, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, psoriasis, allergic rhinitis, IBD include gram Sieve grace disease and ulcerative colitis (UC), systemic loupus erythematosus (SLE), arthritis, osteoarthritis, rheumatoid arthritis, Osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).

On the one hand, the present invention provides class compound disclosed in this invention or the medicine comprising presently disclosed compound Compositions, for preventing and/or treating the proliferative diseases of mammal (including the mankind), autoimmune disease, anaphylaxis Disease, inflammatory disease, graft rejection or cancer.

On the other hand, the present invention provides a kind for the treatment of and suffers from or the risky mammal for suffering from disease disclosed herein Method, methods described includes to give one or more medicine disclosed herein of effectively treatment illness amount or effective prevention illness amount Compositions or compound.On the other hand, provided herein is a kind for the treatment of is suffered from or risky suffer from proliferative diseases, autologous exempts from The method of the mammal of epidemic disease, anaphylactia, inflammatory disease, graft rejection or cancer.

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 one or more medicine disclosed herein for giving effectively treatment amount or effective preventive dose Compositions or compound.In particular instances, proliferative diseases are selected from cancer (for example, solid tumor such as uterine leio muscle Knurl or prostate cancer), polycythemia vera, primary thrombocytosis, myelofibrosis, leukaemia (for example, AML, CML, ALL or CLL) and Huppert's disease.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing proliferative diseases.? In specific embodiment, proliferative diseases selected from cancer (for example, solid tumor such as leiomyosarcoma of uterus or prostate cancer), Polycythemia vera, primary thrombocytosis, myelofibrosis, leukaemia (for example, AML, CML, ALL or CLL) And Huppert's disease.

On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, for preparing the medicine for the treatment of or prevention proliferative diseases.In particular instances, proliferative diseases are (for example, real selected from cancer 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, provided herein is treatment and/or prevention are susceptible or suffering from the side of the mammal of autoimmune disease Method, methods described include one or more pharmaceutical composition disclosed herein or the change for giving effectively treatment amount or effective preventive dose Compound.In particular instances, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, wolf Sore ephritis, dermatomyositis, Sjogren syndrome, psoriasis, type i diabetes and inflammatory bowel disease.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing autoimmune disease. In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, wolf Sore ephritis, dermatomyositis, Sjogren syndrome, psoriasis, type i diabetes and inflammatory bowel disease.

On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, for preparing the medicine for the treatment of or prevention autoimmune disease.In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, LN, dermatomyositis, Sjogren syndrome, psoriasis, I Patients with type Ⅰ DM and inflammatory bowel disease.

On the other hand, provided herein is treatment and/or prevention be susceptible or suffering from anaphylactia mammal method, Methods described includes one or more pharmaceutical composition disclosed herein or the chemical combination for giving effectively treatment amount or effective preventive dose Thing.In certain embodiments, anaphylactia is selected from respiratory anaphylactic disease, nasosinusitis, eczema and measles, food mistake Quick and insect venom allergies.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing anaphylactia.? In specific embodiment, anaphylactia selected from respiratory anaphylactic disease, nasosinusitis, eczema and measles, food hypersenstivity and Insect venom allergies.

On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, for preparing the medicine for the treatment of or prevention anaphylactia.In certain embodiments, anaphylactia is selected from respiratory tract Anaphylactia, nasosinusitis, eczema and measles, food hypersenstivity and insect venom allergies.

On the other hand, provided herein is the method for the treatment of and/or the mammal for preventing to be susceptible or suffering from inflammatory disease, institute The method of stating includes one or more pharmaceutical composition disclosed herein or the compound for giving effectively treatment amount or effective preventive dose. In certain embodiments, inflammatory disease is selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis And psoriasis arthropathica.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing inflammatory disease.In spy In fixed embodiment, inflammatory disease is selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis and silver Bits disease arthritis.

On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, for preparing the medicine for the treatment of or prevention inflammatory disease.In certain embodiments, inflammatory disease selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.

On the other hand, provided herein is the method for the treatment of and/or the mammal for preventing to be susceptible or suffering from graft rejection, institute The method of stating includes one or more pharmaceutical composition disclosed herein or the compound for giving effectively treatment amount or effective preventive dose. In particular instances, graft rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing graft rejection.In spy In fixed embodiment, graft rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.

On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, for preparing the medicine for the treatment of or prevention graft rejection.In particular instances, graft rejection is organ-graft refection, tissue Graft rejection and cell transplant rejection.

On the other hand, provided herein is a class is especially used as treating and/or preventing disease medicament noted earlier as medicine Compound disclosed herein.It is also provided with compound manufacture treatment disclosed herein and/or prevents the medicine of disease noted earlier Thing.

One special projects of this method include that the present invention for giving the study subject effective dose with inflammation discloses chemical combination For a period of time, the time be enough to reduce the level of inflammation of study subject thing, and preferably terminate the process of the inflammation.The party The special embodiment of method includes that the present invention of the tested patients' effective dose for giving with or being susceptible to suffer from bone rheumatoid arthritis is public Compound become civilized for a period of time, the time be enough to reduce or prevent the arthritis of the patient respectively, and preferably terminate institute State the process of inflammation.

Another special projects of this method include the present invention for giving the study subject effective dose with proliferative diseases For a period of time, the time be enough to reduce the hyperplasia level of study subject open compound, and preferably terminate the increasing The process of growing property disease.The special embodiment of the method includes to give being disclosed herein for the tested patients' effective dose with cancer For a period of time, the time be enough to reduce or prevent the cancer symptom of the patient respectively compound, and preferably terminate described The process of cancer.

Therapeutic alliance

The compounds of this invention can be administered as single active agent, or can be administered with other therapeutic agent, Including being defined as other compounds safe and efficient with same or similar therapeutic activity and for such administering drug combinations.

On the one hand, the method that the present invention provides treatment, prevents or improve disease or illness, including giving safe and effective amount The combination medicine of compound and one or more therapeutically active agent is disclosed comprising the present invention.In some embodiments, combine medicine Thing includes one or two other therapeutic agents.

The example of other therapeutic agents includes to include 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 other therapeutic agents at least one, can prepare Become in the treatment while, the combination separately or sequentially applied.In some embodiments, treatment is directed to by one or more egg White kinases, the such as treatment of the disease of jak kinase, FLT3 kinases or Aurora A activity mediation or symptom.Joint is prepared and is provided Product include to be present in same pharmaceutical composition the composition comprising compound disclosed herein and other therapeutic agents, or with Compound disclosed herein and other therapeutic agents that multi-form is present, for example, medicine box.

On the other hand, the present invention provides a kind of medicine comprising compound disclosed herein and another or multiple therapeutic agents Composition.In some embodiments, pharmaceutical composition can be comprising pharmaceutically acceptable auxiliary material, figuration as above Agent, carrier, solvent or combinations thereof.

On the other hand, the present invention provides the medicine box of the drug alone composition comprising two kinds or more, wherein at least one Pharmaceutical composition discloses compound comprising the present invention.In some embodiments, medicine box includes individually to keep the composition Instrument, such as container, separate bottle or separate paper tinsel box.The example of this kind of medicine box is blister package, is commonly used for package panel Agent, capsule etc..

Present invention also offers purposes of the compounds of this invention in the disease that treatment albumen kinase activity is mediated or symptom, Wherein patient previously (such as 24 hours in) is treated with other therapeutic agents.Present invention also offers other treatment Purposes of the agent in treatment albumen kinases, disease and symptom that such as jak kinase, FLT3 kinases and Aurora A activity is mediated, Wherein patient previously (such as 24 hours in) is treated with the compounds of this invention.

Compound disclosed herein can be applied as single-activity component or as such as adjuvant, common with other therapeutic agents Apply.

In some embodiments, other therapeutic agents described include, chemotherapeutics and/or antiproliferative.Known chemotherapeutic Thing is included, but is not limited to, other therapies that can be used in combination with the compounds of this invention or cancer therapy drug, operation, radiotherapy (a little example such as γ radiation, neutron beam radiotherapy, electron beam evaporation therapy, proton therapy, brachytherapy and system Isotope therapy), endocrinotherapy, taxanes (taxol (taxol), Docetaxel (taxotere) etc.), Platinum derivatives (cis-platinum (cisplatin), carboplatin (carboplatin)), (interferon, between leucocyte for BRM Element), TNF (TNF, TRAIL receptor target thing), overheated and cold therapy, mitigate the reagent of any bad reaction (as antiemetic) and other approved chemotherapeutics, including but not limited to, alkylating drug (mustargen (mechlorethamine), Chlorambucil (chlorambucil), endoxan (cyclophosphamide), melphalan (melphalan), ifosfamide (ifosfamide)), antimetabolite (methotrexate (MTX) (methotrexate), pemetrexed (pemetrexed) etc.), (6-MP (6-mercaptopurine), 5- fluorine urine are phonetic for purine antagonist and Pyrimidine antagonists Pyridine (5-fluorouracil), cytarabine (cytarabile), gemcitabine (gemcitabine)), spindle poison (vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine)), podophyllotoxin (according to Support pool glycosides (etoposide), Irinotecan (irinotecan), Hycamtin (topotecan)), antibiotic (Doxorubicin (doxorubicin), bleomycin (bleomycin), mitomycin (mitomycin)), nitroso ureas (BCNU (carmustine), lomustine (lomustine)), CDC inhibitor (KSP pass through mitotic kinesins Inhibitor, CENP-E and CDK inhibitor), enzyme (asparaginase (asparaginase)), hormone (tamoxifen (tamoxifen), Leuprorelin (leuprolide), Flutamide (flutamide), megestrol acetate (megestrol), fill in rice Loose (dexamethasone) etc.).Anti- angiogenesis reagent (Avastin (avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (belimumab), brentuximab, Cetuximab (cetuximab), WAY-CMA 676 (gemtuzumab), her monoclonal antibody (ipilimumab), ofatumumab, Victibix (panitumumab), Lucentis (ranibizumab), rituximab list Resist (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab)).Kinase inhibitor (she Imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), AMN107 (nilotinib), Lapatinib (lapatinib), gram Zhuo for Buddhist nun (crizotinib), ruxolitinib, vemurafenib, vandetanib, Pazopanib, etc.).Drug inhibition or activation approach such as mTOR, HIF (hypoxia inducible factor) approach of cancer and other.Cancer The wide forum of disease treatment seeshttp://www.nci.nih.gov/, FAD accreditation oncologic inventory seehttp:// www.fda.gov/cder/cancer/druglist-rame.htm, and Merck Manual, the 18th edition .2006, all of content Bibliography is all combined with.In other embodiments, the compound of the present invention can be in conjunction with cytotoxic anticancer agent. Such anticancer can be found the 13rd edition Merck index (2001) is inner.These anticancers include, but are not limited to, Tianmen Winter amidase, bleomycin, carboplatin, BCNU, Chlorambucil, cis-platinum, L-ASP, endoxan, arabinose born of the same parents Glycosides, Dacarbazine, actinomycin D, daunorubicin, adriamycin (Doxorubicin), epirubicin, Etoposide, 5-fluor-uracil, Hexamethyl melamine, hydroxycarbamide, ifosfamide, Irinotecan, folinic acid, lomustine, mustargen, Ismipur, Mesna, methotrexate (MTX), mitomycin C, mitoxantrone, prednisolone, metacortandracin, procarbazine, Raloxifene, chain azoles are mould Element, TAM, thioguanine, Hycamtin, vincaleukoblastinum, vincristine and eldisine.Combine with the compound of the present invention Other suitable cytotoxic drugs of medication are included, but is not limited to, and these are admittedly applied to ND treatment Compound, as described in documents below：Goodman and Gilman's The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.)；These anticancers include, but are not limited to, ammonia Shandong Meter Te (aminoglutethimide), l- L-Asparaginasum, imuran, 5-azacitidine, Cladribine (cladribine), busulfan (busulfan), diethylstilbestrol, 2', 2'- difluoro dCDP choline, Docetaxel, red Hydroxyl nonyl adenine (erythrohydroxynonyladenine), ethinylestradiol, 5 FU 5 fluorouracil deoxyribonucleoside, 5- Fluorodeoxyuridine monophosphate, fludarabine phosphate (fludarabine phosphate), Fluoxymesterone (fluoxymesterone), Flutamide (flutamide), hydroxyprogesterone caproate, idarubicin (idarubicin), interferon, vinegar Sour Medroxyprogesterone, megestrol acetate, melphalan (melphalan), mitotane (mitotane), taxol, Pentostatin (pentostatin), N- phosphate base-L-Aspartic acid (PALA), plicamycin (plicamycin), methyl cyclohexane nitrous Urea (semustine), Teniposide (teniposide), testosterone propionate, phosphinothioylidynetrisaziridine (thiotepa), trimethyl melamine Amine, urine nucleosides and vinorelbine.

Other suitably include newfound cell with the cytotoxin class anticancer of the compound use in conjunction of the present invention Toxic substance, including, but be not limited to, oxaliplatin (oxaliplatin), gemcitabine (gemcitabine), card training His shore (capecitabine), macrolides antineoplastic and its naturally occurring or synthetic derivative, Temozolomide (temozolomide) (Quinn et al., J.Clin.Oncology, 2003,21 (4), 646-651), tositumomab (bexxar), trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004,23, abstract 3181), and drive albumen spindle protein inhibitor Eg5 (Wood et al.,Curr.Opin.Pharmacol.2001,1,370-377).

Also in other embodiments, the compound of the present invention can be with binding signal transduction inhibitor.Signal transduction Inhibitor using EGFR family as target, such as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l),15-23；Harari et al., Oncogene, 2000,19 (53), 6102-6114) and the joining of each of which Body.Such reagent includes, but is not limited to, antibody therapy such as Herceptin (trastuzumab), Cetuximab (cetuximab), her monoclonal antibody (ipilimumab) and handkerchief trastuzumab (pertuzumab).Such therapy also includes, but It is not limited to, small molecule kinase inhibitors such as Imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), Ni Luo For Buddhist nun (nilotinib), Lapatinib (lapatinib), gram Zhuo replace Buddhist nun (crizotinib), ruxolitinib, Vemurafenib, vandetanib, pazopanib, Afatinib (afatinib), amuvatinib, Axitinib (axitinib), SKI-606 (bosutinib), brivanib, canertinib, cabozantinib, AZD2171 (cediranib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, Ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib, Oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, saracatinib (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, Tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, Volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941 (Folkes, et al., J.Med.Chem.2008,51,5522), BZE235, etc..

In some embodiments, compound disclosed herein can also be with other medicines common use.The other medicines Including, immunodepressant, immunomodulator, other antiinflammatories, for example it is used for treating or preventing allogeneic or xenograft Acute or chronic repulsion, inflammatory, the medicine of autoimmune disease；Or chemotherapeutics, such as malignant cell antiproliferative.For example, The present invention is disclosed compound and can be combined with following active component：Calcium nerve element inhibitor, such as cyclosporin A or FK506； MTOR inhibitors, such as rapamycin, 40-O- (2- hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9；Ascosin with immunosuppressive properties, such as ABT-281, ASM981 Deng；Corticosteroid；Endoxan；Imuran；Methotrexate (MTX)；Leflunomide；Mizoribine；Mycophenolic Acid or salt；Wheat Examine phenolic acid mofetil ester；15- deoxyspergualin or its immunosupress homologue, analog or derivative；Pkc inhibitor, for example Described in WO 02/38561 or WO 03/82859, the compound of such as embodiment 56 or 70；Immunosupress monoclonal antibody, The monoclonal antibody of such as leukocyte receptors, for example, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or its part；Other immunomodulatory compounds, at least part of extracellular domain for example with CTLA4 Restructuring binding molecule or its mutant, at least extracellular portion of for example connected with non-CTLA4 protein sequence CTLA4 or its Mutant, such as CTLA4Ig (being for example named as ATCC 68629) or its mutant, such as LEA29Y；Adhesion molecule inhibitor, Such as LFA-1 antagonist, the antagonist of ICAM-1 or -3, VCAM-4 antagonist or VLA-4 antagonist；Or chemotherapeutics, such as Japanese yew Alcohol, gemcitabine, cis-platinum, Doxorubicin or 5 FU 5 fluorouracil；Or anti-infective.

In the present invention compound is disclosed with other immunotherapeutic agent/immunomodulators, antiinflammatory, chemotherapy or anti-infective In the case for the treatment of administering drug combinations, the immunodepressant of administering drug combinations, immunomodulator, antiinflammatory, chemotherapeutant or anti-sense The dosage of dye compound certainly can be according to the type of combination medicine used, and for example whether which is steroidal or calcineurin suppression Agent, concrete medicine used, illness to be treated etc. and change.

On the one hand, the present invention provides one kind and discloses compound and β comprising the present invention₂The connection of-adrenoceptor agonists Close.β₂The example of-adrenoceptor agonists includes salmeterol, salbutamol, Formoterol, salmefamol, Fei Nuote Sieve, carmoterol, Yi Tanteluo, naminterol, Clenbuterol, pirbuterol, Flerobuterol, reproterol, special sieve of promulgation, indenes Da Teluo, Terbutaline, and their salt, the xinafoate (1- hydroxy-2-naphthoic acid salt) of such as salmeterol, husky butylamine The sulfate of alcohol or the fumarate of free alkali or Formoterol.In some embodiments, long-acting beta₂- adrenocepter Activator, for example, provide the compound that effective bronchiectasis reaches 12 hours or longer time, is preferred.

β₂- adrenoceptor agonists can be with the form of pharmaceutically acceptable acid forming salt.Described pharmaceutically may be used The acid of acceptance is selected from sulfuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (as 1- or 3- hydroxy-2-naphthoic acid), cinnamic acid, the meat for replacing Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3- (1- naphthyl) acrylic acid, benzoic acid, 4- methoxy benzoic acid, 2- or 4-HBA, 4- chlorobenzoic acid and 4- Phenylbenzoic acid.

On the other hand, the present invention provides a kind of joint for disclosing compound and corticosteroid comprising the present invention.Suitably Corticosteroid refers to those oral and suction corticosteroids, and its has the prodrug of anti-inflammatory activity.Example includes that methyl sprinkles Ni Songlong, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-[(4- methyl-1,3-thiazole - 5- carbonyl) epoxide] -3- oxo-androst -1,4- -17 β of diene-thiocarboxylic acid S- fluorine methyl esters, 6 α, fluoro- 17 α of 9 α-two-[(2- furan Mutter carbonyl) epoxide] -16 Alpha-Methyl -3- oxo-androst -1,4- -17 β of diene of -11 beta-hydroxy-thiocarboxylic acid S- fluorine methyl esters (furancarboxylic acid Fluticasone), 6 alpha, 9 alpha-difluoro-11 beta-hydroxy -16 Alpha-Methyl -3- -17 α of oxo--17 β of propionyloxy-androsta -1,4- diene - Thiocarboxylic acid S- (2- oXo-tetrahydro furans -3S- base) ester, -17 α of -16 Alpha-Methyl -3- oxo of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy - (2,2,3,3- tetramethyl cyclopropyl carbonyl) epoxide-androstane -1,4- -17 β of diene-thiocarboxylic acid S- cyano methyl ester and 6 α, 9 α-two Fluoro- -17 α of -16 Alpha-Methyl of 11 beta-hydroxy--17 β of (1- ethyl cyclopropyl carbonyl) epoxide -3- oxo-androst -1,4- diene-thio Carboxylic acid S- methyl fluoride ester, beclomethasone ester (as 17- propionic ester or 17,21- dipropionic acid fat), budesonide (budesonide), Flunisolide (flunisolide), Mometasone ester (as momestasone furoate), Triamcinolone acetonide (triamcinolone Acetonide), ([[(R)-cyclohexyl is sub- for 16 α, 17- for sieve fluoronaphthalene moral (rofleponide), ciclesonide (ciclesonide) Methyl] double (epoxides)] -11 β, 21- dihydroxy-pregnant steroid -1,4- diene -3,20- diketone), butixocort propionate (butixocort Propionate), RPR-106541 and ST-126.Preferred corticosteroid includes fluticasone propionate (fluticasone Propionate), -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-[(4- methyl-1,3-thiazole -5- carbonyl) epoxide] - 3- oxo-androst -1,4- -17 β of diene-thiocarboxylic acid S- methyl fluoride ester, 6 α, fluoro- 17 α of 9 α-two-[(2- furanylcarbonyl) oxygen Base] -16 Alpha-Methyl -3- oxo-androst -1,4- -17 β of diene of -11 beta-hydroxy-thiocarboxylic acid S- methyl fluoride ester, 6 α, 9 α-two are fluoro- - 17 α of -16 Alpha-Methyl -3- oxo of 11 beta-hydroxy-(2,2,3,3- tetramethyl cyclopropyl carbonyl) epoxide-androstane -1,4- diene -17 β-thiocarboxylic acid S- cyano methyl ester and -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-(1- methylcyclopropyl groups carbonyl) oxygen Base -3- oxo-androst -1,4- -17 β of diene-thiocarboxylic acid S- fluorine methyl esters.In some embodiments, corticosteroid is 6 α, - 16 Alpha-Methyl -3- oxo-androst -1,4- -17 β of diene of fluoro- 17 α of 9 α-two-[(2- furanylcarbonyl) epoxide] -11 beta-hydroxy-sulphur For carboxylic acid S- methyl fluoride ester.

On the other hand, the present invention provides a kind of joint for disclosing compound and nonsteroidal GR activator comprising the present invention. Transcription inhibition is had selective (compared with transcriptional activation), can be used for therapeutic alliance with glucocorticoid agonist activity Nonsteroidal compound includes that those covered in the compound 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 one kind and discloses compound and nonsteroidal anti-inflammatory drug (NSAID's) comprising the present invention Joint.The example of NSAID's includes nasmil, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (as theophylline, PDE4 inhibitor or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene are closed Become inhibitor (as montelukast), iNOS inhibitor, trypsase and elastatinal, Beta 2 integrin antagonist With adenosine receptor agonist or antagonist (e.g., adenosine 2a receptor stimulating agent), cytokine antagonist (as chemokine receptors is short of money Anti-agent, including CCR3 antagonist), cytokine synthesis inhibitor or 5-LO inhibitor.Wherein, iNOS (inductivity 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, the present invention relates to the present invention disclose compound with phosphodiesterase 4 (PDE4) suppress Application in the joint of agent, the especially application in inhalant dosage form.PDE4 specific inhibitor for this aspect of the present invention Can be known suppression PDE4 enzyme or any compound being found as PDE4 inhibitor, they are only PDE4 suppression Agent, is not other members in suppression PDE family, the compound of such as PDE3 and PDE5.Compound includes cis -4- cyano group -4- (3- Cyclopentyloxy -4- methoxyphenyl) hexamethylene -1- carboxylic acid, 2- carbomethoxy -4- cyano group -4- (3- cyclo propyl methoxy -4- two Fluorine methoxyphenyl) hexamethylene -1- ketone and cis-[4- cyano group -4- (3- cyclo propyl methoxy -4- difluoro-methoxy phenyl) ring Hexane -1- alcohol]；Also include that hexamethylene -1- carboxylic acid is (also referred to as cis -4- cyano group -4- [3- (ring propoxyl group) -4- methoxyphenyl] Xi Luosi) and its salt, ester, prodrug or physical form, which was in 09 month 1996 No. 03 United States Patent (USP) US 5,552,438 that authorizes Disclosed in, this patent and compound disclosed in which are incorporated herein by reference in their entirety.

On the other hand, the present invention provides a kind of joint for disclosing compound and anticholinergic comprising the present invention.Cholinolytic Can agent example be those as muscarinic receptor antagonist compounds, be particularly those as M1 or M3 receptor antagonist, 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, withSell for trade name), Oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium (for example, as bromide, CAS 136310-93- 5, withSell for trade name)；Be also interested in also have Revatropate (for example, as hydrobromate, CAS 262586-79-8) and the LAS-34273 disclosed in WO01/04118.The example compound of oral administration includes piperazine logical sequence Xiping (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or its hydrobromate CAS 133099-07-7, withSell for trade name), oxybutynin (CAS 5633-20-5, withSell for trade name Sell), terodiline (CAS 15793-40-5), Tolterodine (CAS 124937-51-5, or its tartrate CAS124937- 52-6, withSell for trade name), difficult to understand for ammonium (for example, as bromide, CAS 26095-59-0, withSell 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, withSell for trade name).

On the other hand, the present invention provides a kind of joint for disclosing compound and H1 antagonist comprising the present invention.H1 antagonist Example include, but not limited to ammonia and come promise (amelexanox), this imidazoles western (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 the joint that one kind discloses compound and H3 antagonist (and/or inverse agonist) comprising the present invention.H3 The example of antagonist includes those compounds disclosed in WO 2004/035556 and WO 2006/045416.Can be used for and this Disclosure of the invention compound other histamine receptor antagonists united include H4 receptor antagonist (and/or inverse agonist), for example, exist Jablonowski et al.,J.Med.Chem.,2003,46:Compound disclosed in 3957-3960.

Another aspect, the present invention provide one kind and disclose compound comprising the present invention, with PDE4 inhibitor and β₂- adrenaline The joint of receptor stimulating agent.

Another further aspect, the present invention provide one kind and disclose compound comprising the present invention, with anticholinergic drug and PDE-4 inhibitor Joint.

Above-described joint easily can be prepared into pharmaceutical composition to use, therefore, including defined above group Conjunction represents another aspect of the present invention with the pharmaceutical composition of pharmaceutically acceptable excipient or carrier.

These in combination each compound with alone or in combination pharmaceutical dosage forms order of administration or can be administered simultaneously. In one embodiment, each compound component is administered simultaneously with the pharmaceutical dosage forms for combining.Known treatment agent be suitable for 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, controls with other comprising compound disclosed by the invention Treat the joint of activating agent.

In some embodiments, the pharmaceutical composition that the present invention is provided discloses compound with chemotherapeutics comprising the present invention Joint.

In some embodiments, the pharmaceutical composition that the present invention is provided discloses compound and antiproliferative comprising the present invention Joint.

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

In other embodiments, the pharmaceutical composition that the present invention is provided discloses compound and β 2- kidney comprising the present invention The joint of upper parathyrine receptor stimulating agent.

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

In other embodiments, the pharmaceutical composition that the present invention is provided discloses compound and non-steroidal comprising the present invention The joint of class GR activator.

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

In other embodiment, the pharmaceutical composition that the present invention is provided discloses compound and antihistamine comprising the present invention The joint of medicine.

In other embodiment, the pharmaceutical composition that the present invention is provided discloses compound with anti-inflammatory examination comprising the present invention The joint of agent.

In other embodiment, the pharmaceutical composition that the present invention is provided discloses compound with immunity tune comprising the present invention The joint of section agent.

In other embodiment, the present invention provide pharmaceutical composition comprising the present invention disclose compound with for moving The joint of the medicine of pulse atherosclerosis.

In other embodiment, the present invention provide pharmaceutical composition comprising the present invention disclose compound with for controlling Treat the joint of the medicine of pulmonary fibrosis.

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

The present invention discloses compound and can also be advantageously utilised in and the combining of other compounds, or and other therapeutic agents, especially Which 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；Targeting/reduce albumen or the compound of lipid kinase activity and the compound of other Anti- angiogenesis；Targeting, reduce or Suppression albumen or the compound of 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；The medicament for the treatment of neoplastic hematologic disorder；Targeting, the compound for reducing or suppressing Flt-3 active； Hsp90 inhibitor；TemozolomideAnd Calciumlevofolinate.

Term used herein " aromatase inhibitor ", refers to the compound for suppressing estrogen to produce, i.e. suppression substrate is male Alkene diketone and testosterone change into the compound of oestrone and estradiol respectively.The term includes, but are not limited to：Steroid, especially Which 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 bent Azoles (letrozole).Exemestane can be with commercially available, as trade mark isForm administration.Fu Mei Smooth (formestane) can be with commercially available, as trade mark isForm administration.Fadrozole (fadrozole) can be with commercially available, as trade mark isForm administration.Anastrozole (anastrozole) can be with Commercially available, such as trade mark isForm administration.Letrozole (letrozole) can be with commercially available, such as Trade mark is OrForm administration.Aminoglutethimide (aminoglutethimide) can be with city Sell, such as trade mark is Form administration.The present invention includes the combination of aromatase inhibitor chemotherapeutic It is particularly useful for the treatment of the tumour that hormone receptor is positive, such as tumor of breast.

Term used herein " antiestrogenic ", refers to the compound in Estrogen Receptor antagonising oestrogen effectiveness. The term includes, but not limited to TAM (tamoxifen), fulvestrant (fulvestrant), Raloxifene And raloxifene hydrochloride (raloxifene hydrochloride) (raloxifene).TAM (tamoxifen) can With with commercially available, as trade mark isForm administration.Raloxifene hydrochloride (raloxifene Hydrochloride) can be with commercially available, as trade mark isForm administration.Fulvestrant (fulvestrant) can be with United States Patent (USP) US 4, the formulation disclosed in 659,516 or commercially available, such as trade mark isForm administration.The present invention includes that the combination of antiestrogenic chemotherapeutic is particularly useful for the treatment of ERs in sun The tumour of property, such as tumor of breast.

Term used herein " antiandrogen " refers to any material that can suppress male sex hormone biological action, and it wraps Include, but be not limited to, Bicalutamide (bicalutamide, trade name), its formulation can be according to United States Patent (USP) US 4,636,505 preparing.

Term used herein " Gonadorelin excitomotor " includes, but not limited to abarelix (abarelix), Ge She Rayleigh (goserelin) and goserelin acetate.Goserelin is disclosed in 100,274 in United States Patent (USP) US 4, can be with city Sell, such as trade mark is Form administration.Abarelix (abarelix) can be according to United States Patent (USP) Method disclosed in US 5,843,901 prepares formulation.

Term used herein " topoisomerase I inhibitor ", includes, but are not limited to TPT (topotecan), Ji Horse replaces health (gimatecan), Irinotecan (irinotecan), camptothecine (camptothecian) and the like, 9- nitro Camptothecine (9-nitrocamptothecin) and macromolecular camptothecin conjugated compound PNU-166148 are (in WO 99/17804 Compound A1).Irinotecan can be with commercially available, as trade mark isForm administration.Topology is replaced Health can be with commercially available, as trade mark isForm administration.

Term used herein " Topoisomerase II inhibitors " includes, but are not limited to anthracycline compound, such as how soft ratio Star (doxorubicin), its Lipidosome, trade nameDaunomycin (daunorubicin)；Epirubicin (epirubicin)；Idarubicin (idarubicin)；The not soft pyrrole star of naphthalene (nemorubicin)；Anthraquinones mitoxantrone (mitoxantrone) and Losoxantrone (losoxantrone)；Podophillotoxines Etoposide (etoposide) and Teniposide (teniposide).Etoposide can be with commercially available, as trade mark isForm administration.Teniposide can be with commercially available, as trade mark is's Form is administered.Doxorubicin can be with commercially available, as trade mark isOr Form administration.Epirubicin can be with commercially available, as trade mark is Form administration.Idarubicin can be with commercially available, as trade mark isForm administration.Mitoxantrone Can be with commercially available, as trade mark isForm administration.

Term " microtubule active agent " refers to microtubule stabilizer, microwave destabiliser and microtubule polymerization inhibitor.Which includes, but not It is limited to taxanes, such as taxol (paclitaxel) and Docetaxel (docetaxel)；Vinca alkaloids, such as Changchun Alkali (vinblastine), especially vinblastine sulfate, especially vincristine, vincristine sulphate and vinorelbine (vinorelbine)；discodermolides；Colchicin；And Epothilones and its derivative, such as epothilone B or D Or derivatives thereof.Taxol can be with commercially available, as trade mark isForm administration.Docetaxel is permissible With commercially available, as trade mark isForm administration.Vinblastine sulfate can be with commercially available, such as trade mark ForForm administration.Vincristine sulphate can be with commercially available, as trade mark isShape Formula is administered.Discodermolide can be obtained according to the method disclosed in United States Patent (USP) US 5,010,099.It is additionally included in WO 98/10121st, United States Patent (USP) 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653,98/22461 and of WO Epothilones analog derivative disclosed in WO 00/31247, particularly preferred ebomycin A and/or B.

Term used herein " alkylating agent " includes, but not limited to endoxan (cyclophosphamide), different ring phosphorus Acid amides (ifosfamide), melphalan (melphalan) or Nitrosourea (nitrosourea, such as BCNU or carmustine).Ring phosphinylidyne Amine can be with commercially available, as trade mark is Form administration.Ifosfamide can with commercially available, As trade mark isForm administration.

Term " histon deacetylase (HDAC) inhibitor " or " hdac inhibitor " refer to inhibition of histone deacetylase, and Compound with antiproliferative activity.Which includes the compound disclosed in WO 02/22577, especially N- hydroxyl -3- [4- [[(2- ethoxy) [2- (1H- indol-3-yl) ethyl]-amino] methyl] phenyl] -2E-2- acrylamide, N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- base)-ethyl]-amino] methyl] phenyl] -2E-2- acrylamide and its can pharmaceutically connect The salt that receives.Especially include Vorinostat (SAHA).

Term " antineoplastic antimetabolite " includes, but not limited to 5-fluor-uracil (5-fluorouracil) or 5-FU； Capecitabine (capecitabine)；Gemcitabine (gemcitabine)；DNA demethylation reagent, such as U-18496 (5- ) and Decitabine (decitabine) azacytidine；Methotrexate (MTX) (methotrexate) and Edatrexate (edatrexate)；And antifol, such as pemetrexed (pemetrexed).Capecitabine can be with commercially available, such as trade mark ForForm administration.Gemcitabine can be with commercially available, as trade mark isShape Formula is administered.This term also includes monoclonal antibody Herceptin (trastuzumab), can be with commercially available, as trade mark isForm administration.

Term used herein " platinum compounds " includes, but are not limited to carboplatin (carboplatin), cDDP (cis- Platin), cis-platinum (cisplatinum) and oxaliplatin (oxaliplatin).Carboplatin can be with commercially available, as trade mark isForm administration.Oxaliplatin can be with commercially available, as trade mark isForm Administration.

Term used herein " targeting/reduce the active change of albumen or lipid kinase activity or albumen or lipid phosphatase 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, for example

A) target, reduce or suppress the compound of platelet derived growth factor receptor (PDGFR) activity；Targeting, reduction Or the compound of suppression PDGFR activity, the especially compound of suppression pdgf receptor include N- phenyl-2-pyrimidine-amine derivatives, As Imatinib (imatinib), SU101, SU6668, GFB-111 etc.；

B) targeting, the compound for reducing or suppressing fibroblast growth factor acceptor (FGFR) active；

C) targeting, the compound for reducing or suppressing IGF-1-1 (IGF-1R) active；Targeting, reduction Or the compound of suppression IGF-1R activity, the especially compound of suppression IGF-1 receptor active include those in patent WO 02/ Compound disclosed in 092599；

D) compound of targeting, reduction or suppression Trk receptor tyrosine kinase family active；

E) compound of targeting, reduction or suppression Axl family active；

F) compound of targeting, reduction or suppression c-Met receptor active；

G) compound of targeting, reduction or suppression Kit/SCFR receptor tyrosine kinase activity；

H) targeting, the chemical combination for reducing or suppressing C-kit receptor tyrosine kinase (part in PDGFR family) active Thing；The compound of targeting, reduction or suppression C-kit receptor tyrosine kinase family active, especially suppresses the change of c-Kit acceptor Compound, including Imatinib (imatinib) etc.；

I) targeting, reduction or suppression c-Abl family and their gene fusion product, the such as change of BCR-Abl kinase activity Compound；Targeting, reduce or suppression c-Abl family member and their Gene Fusion things compound include N- phenyl -2- pyrimidine - Amine derivative, such as Imatinib, PD180970, AG957, NSC 680410, the PD173955 from ParkeDavis

J) Raf family member in targeting, reduction or suppression protein kinase C (PKC) and serine/threonine kinases, MEK, SRC, JAK, FAK, PDK and Ras/MAPK family member, PI (3) kinase families member, or PI (3) kinases associated kinase family become Member, and/or the compound of cell cycle protein dependent kinase family (CDK) member activity；Those are particularly in United States Patent (USP) US 5,093, the staurosporine derivatives disclosed in 330, such as midostaurin (midostaurin)；More examples of compounds Also include, UCN-01；Safingol (safingol)；BAY 43-9006；Bryostatin 1；Piperazine Li Fuxin (Perifosine)；She Mo Fuxin (llmofosine)；RO 318220 and RO 320432；GO 6976；Isis 3521；LY333531/LY379196； Isoquinoline compound, such as in WO 00/09495 those disclosed；FTIs；PD184352；Or a kind of QAN697 (P13K suppression Preparation)；

K) targeting, the compound for reducing or suppressing protein tyrosine kinase inhibitor active；Targeting, reduction suppress The compound of protein tyrosine kinase inhibitor activity includes GleevecOr tyrosine phosphorylation Inhibitor；Preferred low-molecular-weight (the Mr of tyrphostin<1500) compound, or its pharmaceutically acceptable salt, especially Which is selected from the compound of the third two eyeball class of two eyeball class of benzyl allyl or S- aryl sheet or Double bottom thing quinolines, is 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 phenyl) methyl] amino }-benzoic acid Buddha's warrior attendant alkyl ester, NSC 680410, adaphostin)；With

I) targeting, reduce or suppression receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, The equal or heterodimer of ErbB3, ErbB4) activity compound；Targeting, reduction or suppression Epidermal Growth Factor Receptor Family Compound refer in particular to suppress EGF receptor family member (such as EGF receptor, ErbB2, ErbB3, ErbB4, or can with EGF or The material that EGF associated ligands are combined) compound, albumen or antibody, is particularly summarized in the following documents or concrete openly Compound, albumen or monoclonal antibody：WO 97/02266 (as embodiment 39), EP 0 564 409, WO 99/03854, EP 0520722、EP 0 566 226、EP 0 787 722、EP 0 837 063、US 5,747,498、WO 98/10767、WO 97/30034th, WO 97/49688 and WO 97/38983, WO 96/30347 (as CP 358774), WO 96/33980 is (as chemical combination Thing ZD 1839), WO 95/03283 (as compound ZM105180), Herceptin (Trastuzumab), Cetuximab, Yi Rui Sand, Erlotinib, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, E7.6.3, and the 7H- pyrrolo- being disclosed in WO 03/013541-[2,3-d] pyrimidine derivatives.

Additionally, anti-angiogenic compounds include (for example, to suppress not with albumen or lipid kinase with other active mechanisms Related) compound, such as ThalidomideAnd TNP-470.

The compound of targeting, reduction or suppression albumen or lipid kinase activity is -1 inhibitor of phosphatase, 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- alkyl replaces 2- virtue aminophenyl acetic acid and its derivative, such as celecoxib, rofecoxib, etoricoxib, cut down Examine former times, or 5- alkyl -2- virtue aminophenyl acetic acid, such as 5- methyl -2- (the chloro- 6'- fluoroanilino of 2'-) phenylacetic acid or reed rice Examine former times

Term used herein " diphosphonate " includes, but not limited to Etidronic Acid, Clodronate, Tiludronic Acid, handkerchief rice phosphine Acid, alendronic acid, ibandronic acid, Risedronic Acid and zoledronic acid.Etidronic Acid can be with commercially available, such as trade nameForm administration.Clodronate can be with commercially available, such as trade name's Form is administered.Tiludronic Acid can be with commercially available, such as trade nameForm administration；Pamidronic acid (Pamidronic acid) can be with commercially available, such as trade name Aredia^TM(AREDIA^TM) form administration；A Lun phosphine Acid can be with commercially available, such as trade nameForm administration；Ibandronic acid can be with commercially available, such as Trade nameForm administration；Risedronic Acid can be with commercially available, such as trade nameForm administration；Zoledronic acid can be with commercially available, such as trade name's Form is administered.

Term " mTOR inhibitors " refers to suppress mammal rapamycin (mTOR) target protein, with antiproliferative activity Compound, such as sirolimus (sirolimus,), everolimus (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 does not limit PI-88.

Term used herein " BRM " refers to lymphokine or interferon, such as interferon gamma.

Term used herein " Ras carcinogenic hypotype (as H-Ras, K-Ras or N-Ras) inhibitor " is referred to target, is reduced Or the compound of suppression Ras carcinogenic activity, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra).

Term used herein " telomerase inhibitor " refers to target, reduce or suppress the compound of telomerase activation.Target To, reduce or suppression telomerase activation compound refer in particular to suppress telornerase receptor compound, such as telomere mycin.

Term used herein " methionine aminopeptidase inhibitor " refers to target, reduce or suppress methionine aminopeptidase activity Compound.Targeting, the compound for reducing or suppressing methionine aminopeptidase active include bengamide or derivatives thereof.

Term used herein " proteasome inhibitor " refers to target, reduce or protease inhibition body activity chemical combination 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) Equivalent homologue Marimastat (marimastat, BB-2516) with its oral bio, Pu Masita (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

Term used herein " for treating the reagent of neoplastic hematologic disorder " includes, but not limited to FMS- sample EGFR-TK Inhibitor.Targeting, the compound for reducing or suppressing FMS- sample tyrosine kinase receptor (Flt-3R) active；Interferon, 1-b-D- Arabinofuranosyl adenin cytimidine (ara-c) and bisulfan；With ALK inhibitor, such as targeting, reduction or suppression anaplastic lymphoma kinase Compound.

The compound of targeting, reduction or suppression FMS- sample tyrosine kinase receptor (Flt-3R) especially suppresses Flt-3 to receive The compound of body kinase families member, albumen or antibody, such as PKC412, midostaurin (midostaurin), staurosporin Derivative, SU11248 and MLN518.

Term used herein " HSP90 inhibitor " includes, but are not limited to target, reduce or suppress the endogenous of HSP90 The compound of atpase activity；The chemical combination for degraded by ubiquitin protein body enzymatic pathway, targetting, reduce or suppress HSP90 client protein Thing.Targeting, the compound of the Endogenous ATP enzymatic activity for reducing or suppressing HSP90 refer in particular to suppress the Endogenous ATP of HSP90 The compound of enzymatic activity, albumen or antibody, for example, 17- allyl amino, 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 2 Multi-specificity antibody and antibody fragment (as long as they have desired biologically active) that whole antibody is formed.Thin for acute marrow For the treatment of born of the same parents' sample leukaemia (AML), the present invention can be disclosed compound and be used in combination with the leukemia therapy of standard, especially Which is used in combination with the therapy that treats for AML.Specifically, the present invention can be disclosed compound to turn with such as farnesyl- Moving enzyme inhibitor and/or other is used for medicine such as daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, the rice that AML is treated Support anthraquinone, idarubicin, carboplatin and PKC412 administering drug combinations.

Compound disclosed by the invention can also be advantageously utilised in other compounds combine 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 ester (NO donor), Rosiglitazone (PPARy activator), activated carbon, hematopoietin, levamisol, And Malaridine.

Compound disclosed by the invention can also be advantageously used in other compounds combine or other therapeutic agents group In conjunction, the other therapeutic agents of such as treatment 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 liposome, paromomycin (paromomycine), Eflornithine (eflornithine), nifurtimox (nifurtimox), suramin (suramin), melarsoprol (melarsoprol), sprinkle Ni Songlong (prednisolone), benzimidazole, sulphadiazine, pyrimethamine, synergistic sulfonamide methylisoxazole, radonil, Ah Miramycin (azitromycin), Atovaquone, dexamethasone, praziquantel, albendazole (albendazole), beta-lactam, FQNS medicine, macrolides medicine, aminoglycoside medicine, sulphadiazine and pyrimethamine.

Determined by code name, common name or trade name, the structure of active component and its preparation can be from classic " The 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 (example As IMS World Publications)) in know.

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, prepares according to the method described in above-mentioned document and is administered.

Compound disclosed by the invention can also be combined with therapeutic process, improve curative effect.For example, give hormone therapy or Special radiotherapy.Compound disclosed by the invention is used especially as radiosensitizer, it is especially useful in those radiotherapies The oncotherapy of sensitiveness weak ground.

" joint " represents the medicine box of the fixing joint in single dose unit form or the part for administering drug combinations, its In compound disclosed by the invention and joint companion can be in same time individual application or can be in certain time interval Inside apply respectively, so that joint companion is shown cooperation, for example act synergistically.As the term is employed herein " co-administered " Or " administering drug combinations " etc. are intended to include be applied to selected joint companion and need its single individuality (such as patient), and anticipate It is intended to include that wherein material is without going through identical method of administration or the therapeutic scheme being administered simultaneously." medicine as the term is employed herein Joint " represents the product obtained by more than one active component mixing or joint, and has both included the fixing connection of active component Closing also includes that on-fixed is combined.Term " fixing joint " represents active component compound for example disclosed by the invention, and joint companion Patient is applied to simultaneously in the form of single entities or dosage.Term " on-fixed joint " represents that the active component such as present invention is disclosed Compound, and joint companion all as corpus separatum simultaneously, common or limit ground nothing special time and successively patient is administered, its In the administering mode in the patient provide two kinds of compounds treatment level of significance.The latter applies also for HAART, Three or more active component is for example applied.

Treatment method

In some embodiments, treatment method disclosed by the invention includes to give safe and effective amount to patient in need The compounds of this invention or the pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention is included by right Patient in need gives the present invention of safe and effective amount and discloses compound or disclose the drug regimen of compound comprising the present invention Thing, the method for treating disease mentioned above.

In some embodiments, the present invention disclose compound or comprising the present invention, the pharmaceutical composition of compound is disclosed can To be administered by any suitable method of administration, it is administered including Formulations for systemic administration and local.Formulations for systemic administration includes oral administration, stomach Parenteral administration, cutaneous penetration and rectally.Typical parenteral is referred to by injection or administered by infusion, including vein Interior, intramuscular and hypodermic injection or administered by infusion.Local administration includes to be applied to skin and intraocular, ear, intravaginal, suction and nose Interior administration.In one embodiment, the present invention disclose compound or comprising the present invention, the pharmaceutical composition of compound is disclosed can To be to be administered orally.In other embodiments, the present invention discloses compound or discloses the medicine of compound comprising the present invention Composition can be inhalation.In a further embodiment, the present invention disclose compound or comprising the present invention, compound is disclosed can To be intranasal administration.

In some embodiments, the present invention disclose compound or comprising the present invention, the pharmaceutical composition of compound is disclosed can 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, Be administered once a day, twice, three times or four times.In some embodiments, it is administered once a day.In other embodiment In, it is taken twice daily.Can be administered until reaching the therapeutic effect wanted or indefinitely maintaining the therapeutic effect that wants.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, for example dilution, distribution and the half-life, these can be by determination of technical staff.Additionally, the present invention is disclosed Compound or disclose comprising the present invention compound pharmaceutical composition appropriate dosage regimen, including implement the program lasting when Between, depending on treated disease, the order of severity of disease being treated, the age of patient under consideration and health, treated The medical history of patient is while the factor in the range of technical staff's knowledge and experience such as the property of therapy, therapeutic effect for wanting. Such technical staff should also be understood that the reaction for individual patient to dosage regimen, 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 disclose compound can with one or more other therapeutic agent while, or be administered before it or afterwards. The compounds of this invention can be administered by identical or different method of administration respectively with other therapeutic agents, or therewith with medicine group Solvate form is administered.

For the individuality of about 50-70kg, the present invention pharmaceutical composition disclosed and combination can be containing about 1-1000mg, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active component Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination medicine be depending on the individual species of medication, body weight, Age and individual instances, treated disorder (disorder) or disease (disease) or its order of severity.Possesses conventional technical ability Doctor, clinician or animal doctor easily can determine to prevent, treat or suppress disorderly (disorder) or disease (disease) The effective dose of each active component needed for evolution.

Dose Characteristics cited above adopt favourable mammal (such as mouse, rat, dog, monkey) or its from Confirm in the external and in vivo studies of body organ, tissue and sample.The present invention discloses compound with solution, such as aqueous solution form Use in vitro, it is also possible to such as suspension or aqueous solution form enteral in vivo, parenteral, especially intravenous use.

In some embodiments, the present invention discloses the treatment effective dose of compound for daily about 0.1mg to about 2, 000mg.Its pharmaceutical composition should provide about 0.1mg to about 2,000mg compound of dosage.In a particular In, the pharmaceutical dosage unit forms of preparation can provide about 1mg to about 2,000mg, about 10mg to about 1,000mg, and about 20mg is to about 500mg, or main active or the combination per each main component in dosage unit form of about 25mg to about 250mg.One In particular, the pharmaceutical dosage unit forms of preparation can provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.

Additionally, compound disclosed by the invention can be administered with prodrug forms.In the present invention, the present invention discloses compound " prodrug " when being that patient is administered, finally can discharge the functional derivatives that the present invention discloses compound in vivo.In the past When medicine form gives compound disclosed by the invention, those skilled in the art can implement the one kind in following manner and more than：(a) The internal onset time of change compound；The internal acting duration of (b) change compound；C () changes the internal of compound Conveying is distributed；The internal solubility of (d) change compound；And (e) overcomes the side effect or other difficult points faced by compound. For preparing the typical functional derivatives of prodrug, comprising in vivo chemically or enzyme the mode compound that cracks Variant.Comprising preparing these variants of phosphate, acid amides, ester, monothioester, carbonate and carbaminate to people in the art It is well-known for member.

General synthesis step

For the present invention is described, embodiment is listed below.But it is to be understood that the invention is not restricted to these embodiments, simply The method of the present invention is put into practice in offer.

Usually, the compound of the present 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 for this to be further illustrated The content of invention.

The professional of art will be recognized that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds of many present invention, and the model in the present invention is considered as preparing other methods of the compound of the present invention Within enclosing.For example, according to the present invention, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art Completed by method of modifying, group is disturbed in such as appropriate protection, by using reagent known to other except described in the invention , or reaction condition is made 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 present invention.

The embodiments described below, unless shown in terms of other that all of temperature is set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, not through being further purified during use, unless shown in terms of other.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 Company, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao's purchase Can buy.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is to dry in advance to use through anhydrous sodium sulfate.

Hereinafter reaction is usually to cover a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless in terms of other Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate are squeezed into by syringe.Glassware is all dried.

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

¹H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.¹H H NMR spectroscopy is with CDCl₃、D₂O、 DMSO-d₆、CD₃OD or acetone-d₆For solvent (in units of ppm), marked as reference with TMS (0ppm) or chloroform (7.26ppm) 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), ddd (doublet of doublet of doublets, dual double doublet), dddd (doublet of doublet of doublet of doublets, in pairs double doublet), dt (doublet of Triplets, double triplets), tt (triplet of triplets, three triplets).Coupling constant J, is represented with hertz (Hz).

The condition determination of Algorithm (MS) data is：6120 level Four bar HPLC-M (pillar model of Agilent： Zorbax SB-C18,2.1 × 30mm, 3.5 microns, 6min, flow velocity are 0.6mL/min.Mobile phase：5%-95% is (containing 0.1% The CH of formic acid₃CN) in (H containing 0.1% formic acid₂O the ratio in)), using electron spray ionisation (ESI), under 210nm/254nm, Detected with UV.

The use Agilent 1260pre-HPLC of pure compound or Calesep pump 250pre-HPLC (pillar type Number：NOVASEP 50/80mm DAC), detected with UV in 210nm/254nm.

The use of brief word below runs through the present invention：

AcOH、HOAc、CH₃COOH acetic acid

Ac₂O acetic anhydride

BOC, Boc tert-butoxycarbonyl

(Boc)₂O di-tert-butyl dicarbonate

BH₃DMS borane dimethylsulf iotade

The double diphenyl phosphines of BINAP 1,1'- dinaphthalene -2,2'-

N-BuOH n-butanol

Cs₂CO₃Cesium carbonate

CH₂Cl₂, DCM dichloromethane

CDCl₃Deuterochloroform

CH₃I iodomethane

DIEA、DIPEA、i-Pr₂NEt diisopropyl ethyl amine

11 carbon -7- alkene of DBU 1,8- diazabicyclo [5.4.0]

DMF N,N-dimethylformamide

DMP dimethyl phthalate

DMAP DMAP

DMSO dimethyl sulfoxide (DMSO)

DHP 3,4- dihydropyran

DIAD diisopropyl azodiformate

PPTs 4- toluene sulfonic acide pyridine

Et₃N, TEA triethylamine

EtOAc, EA ethyl acetate

EtOH ethanol

Et₂O ether

EDCI 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride

G gram

H hour

HATU 2- (7- azepine -1H- BTA -1- base) -1,1,3,3- tetramethylurea hexafluorophosphoric acid ester

HCl hydrochloric acid

HOAT 1- hydroxyl -7- azepine BTA

KOH potassium hydroxide

KMnO₄Potassium permanganate

K₂CO₃Potassium carbonate

LiCl lithium chloride

LiHMDS, LHMDS bis- (trimethyl silicon substrate) lithium amide

LAH lithium aluminium hydride

MeCN、CH₃CN acetonitrile

MsCl methane sulfonyl chloride

(NH₄)₂SO₄Ammonium sulfate

NH₄Cl ammonium chloride

NaH sodium hydride

NaBH₃CN sodium cyanoborohydride

Na₂CO₃Sodium carbonate

NaOH NaOH

NaOMe sodium methoxide

Na₂SO₄Sodium sulphate

Na₂S₂O₃Sodium thiosulfate

NaHCO₃Sodium acid carbonate

NaOAc ammonium acetate

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

NBS NBS

MeOH methyl alcohol

ML, ml milliliter

Pd(OAc)₂Palladium

Pd/C palladium/carbon

PE petroleum ether (60-90 DEG C)

PTSA p-methyl benzenesulfonic acid

PDC Pyridinium dichromate

RT, rt, r.t. room temperature

Rt retention time

Raney Ni Raney's nickel

T-BuONa sodium tert-butoxide

THF tetrahydrofuran

TFAA TFAA

TFA trifluoroacetic acid

TBAF tetrabutyl ammonium fluoride

Ti(Oi-Pr)₄Four isopropyl titanates

TsCl 4- toluene sulfochloride

Prepare the present invention the typical synthesis step of compound is disclosed as shown in following 1～synthetic schemes of synthetic schemes 4.Remove Non- other explanation, each Z¹、A、R¹、R²、R^2a、R⁴Have with m and define as described in the present invention.Each n independently is 0,1,2 or 3；Respectively PG, LG independently are blocking group, and Y is hetero atom.

Synthetic schemes 1：

Have as formula (8) shown in the present invention of structure the general synthesis that compound can be described by synthetic schemes 1 is disclosed Method is prepared, and concrete steps refer to embodiment.In synthetic schemes 1, substituted dichloro pyrimidine (1) and with protection group Optionally substituted heterocyclic compound (2) in alkali, such as in the presence of triethylamine, or diisopropyl ethyl amine, generate optionally substituted Compound (3).Compound (3) in blocking group can in acid condition, such as trifluoroacetic acid, hydrogen chloride ethyl acetate molten Liquid, or in the presence of hydrazine hydrate, or in other felicity conditions, remove such as under the conditions of tetrabutyl ammonium fluoride, obtain compound (4).Then, under suitable conditions to compound (4) in introduce different substituents, can obtain compound (5).Compound (5) with optionally substituted aminopyrazole compound (6) or its hydrochloride (7), in alkali, such as diisopropyl ethyl amine, triethylamine or Person in acid, such as under conditions of the ethyl acetate solution of trifluoroacetic acid, hydrogen chloride, or in suitable Pd catalyst, as palladium Under catalytic action, reaction obtain with formula (8) shown in structure kinases inhibitor.

Synthetic schemes 2：

Have as formula (8) shown in the present invention of structure the general synthesis that compound can be described by synthetic schemes 2 is disclosed Method is prepared, and concrete steps refer to embodiment.In synthetic schemes 2, compound (3) with optionally substituted amino-pyrazol Compound (6) or its hydrochloride (7) in acid, the such as ethyl acetate solution of trifluoroacetic acid, hydrogen chloride, or alkali for example triethylamine, two Under conditions of diisopropylethylamine is present, or in suitable Pd catalyst, such as under the catalytic action of palladium, reaction generates chemical combination Thing (9).Compound (9) in blocking group can in acid condition, such as trifluoroacetic acid, the ethyl acetate solution of hydrogen chloride, or Person or in other felicity conditions, is removed such as under the conditions of tetrabutyl ammonium fluoride in the presence of hydrazine hydrate, obtain compound (10). Under suitable conditions to compound (10) in introduce different substituents, it is also possible to obtain with formula (8) shown in structure egg White kinase inhibitor.

Synthetic schemes 3：

Have as formula (8) shown in the present invention of structure the general synthesis that compound can be described by synthetic schemes 3 is disclosed Method is prepared, and concrete steps refer to embodiment.In synthetic schemes 3, compound (1) with optionally substituted with protection group Heterocyclic compound (11) in alkali, such as in the presence of triethylamine, or diisopropyl ethyl amine, generate optionally substituted compound (5).Compound (5) with optionally substituted aminopyrazole compound (6) or its hydrochloride (7), in alkali, such as diisopropyl ethyl Amine, triethylamine, or in acid, such as under conditions of the ethyl acetate solution of trifluoroacetic acid, hydrogen chloride, or be catalyzed in suitable Pd Under the catalytic action of agent, such as palladium, reaction can also obtain the kinases inhibitor with structure shown in formula (8).

Synthetic schemes 4：

Have as formula (8) shown in the present invention of structure the general synthesis that compound can be described by synthetic schemes 4 is disclosed Method is prepared, and concrete steps refer to embodiment.In synthetic schemes 4, under suitable conditions to compound (10) in draw Enter electrophilic group, obtain compound (12).Under suitable conditions by compound (12) in electrophilic group converted and also may be used With obtain with formula (8) shown in structure kinases inhibitor.

Embodiment

Intermediate 1N ⁴ - ((3R, 6S)-(6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5- ² - (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines

Step 1) (3R, 6S) -6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- base 4- toluene sulfonic acide ester

By (3R, 6S)-hexahydro furyl, simultaneously [3,2-b] furans -3,6- glycol (10.00g, 68.4mmol) is dissolved in dichloromethane In alkane (60mL), and pyridine (1.08g, 13.7mmol) is added thereto to, reactant mixture is cooled to 0 DEG C, then is added thereto to 4- toluene sulfonyl chloride (15.66g, 82.1mmol).Reactant mixture is stirred 30 minutes at 0 DEG C, is then moved to and is stirred at room temperature Overnight.Mixture is diluted with dichloromethane (250mL), uses hydrochloric acid (300mL, 1M), water (300mL) and saline solution successively (300mL) wash.The organic phase for separating is filtered through anhydrous sodium sulfate drying, and reduced pressure concentration.Gained residue is through silica gel column layer Analysis (EtOAc/PE (v/v)=2/1) purifying, obtains title compound for colorless oil (10.24g, yield 49.8%).

LC-MS(ESI,pos.ion)m/z:301.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.79 (d, J=8.3Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 4.84 (dd, J=11.5,6.3Hz, 1H), 4.62 (t, J=4.7Hz, 1H), 4.34 (d, J=4.3Hz, 1H), 4.24 (s, 1H), 4.10-4.06 (m, 1H), 3.84 (d, J=2.0Hz, 2H), 3.80 (dd, J=9.6,6.3Hz, 1H), 3.65 (dd, J=9.6, 6.6Hz,1H),2.42(s,3H).

Step 2) 2- ((3S, 6S) -6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone

By (3R, 6S) -6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- base 4- toluene sulfonic acide ester (10.24g, 34.1mmol) be dissolved in DMSO (60mL), and be added thereto to (1,3- dioxoisoindolin -2- base) potassium (8.21g, 44.3mmol).Reactant mixture overnight, is then down to room temperature in 130 DEG C and stirred under nitrogen atmosphere, and is poured into water.Gained Mixture is extracted with dichloromethane (300mL × 3), organic phase washed with water (100mL × 3) washing of merging, anhydrous Na₂SO₄Dry, Then reduced pressure concentration.Gained residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=1/1), and it is white to obtain title compound Color solid (2.35g, yield 25.0%).

LC-MS(ESI,pos.ion)m/z:276.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.86 (dd, J=5.4,3.1Hz, 2H), 7.74 (dd, J=5.5, 3.0Hz, 2H), 5.17 (dd, J=4.3,2.2Hz, 1H), 4.84-4.74 (m, 2H), 4.44-4.35 (m, 1H), 4.17 (t, J= 8.5Hz, 1H), 4.06 (dd, J=10.1,3.3Hz, 1H), 3.97-3.85 (m, 2H).

Step 3) (3S, 6S) -6- (1,3- dioxoisoindolin -2- base) hexahydro furyl simultaneously [3,2-b] furans -3- Ji Jia Sulphonic acid ester

By 2- ((3S, 6S) -6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone (2.35g, 8.54mmol) is dissolved in dichloromethane (40mL), nitrogen protection under, be added thereto to triethylamine (1.30g, 12.8mmol) with DMAP (209.2mg, 1.7mmol).Mixture is cooled to 0 DEG C, and adds methane sulfonyl chloride under nitrogen protection (0.8mL,10.0mmol).Gained mixture is stirred 30 minutes at 0 DEG C, is then moved to and is stirred overnight at room temperature.Mixture uses two Chloromethanes (100mL) dilutes, successively with the washing of hydrochloric acid (100mL, 1M), water (100mL) and saturated aqueous common salt (100mL).Separate Organic phase through anhydrous sodium sulfate drying, filter, and reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v) =1/200) purify, title compound is obtained for white solid (2.35g, yield 77.9%).

LC-MS(ESI,pos.ion)m/z:353.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.87-7.85(m,2H),7.79-7.71(m,2H),5.16-5.15 (m,2H),5.08-5.07(m,1H),4.88-4.80(m,1H),4.26-4.19(m,1H),4.17-4.10(m,2H),3.96- 3.91(m,1H),3.09(s,3H).

Step 4) 2- ((3S, 6R) -6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone

By (3S, 6S) -6- (1,3- dioxoisoindolin -2- base) hexahydro furyl simultaneously [3,2-b] furans -3- base methanesulfonic acid Ester (2.80g, 7.9mmol) is dissolved in DMF (60mL), and is added thereto to sodium azide (2.16g, 33.2mmol).Reaction Mixture is stirred 23 hours at 140 DEG C, then is diluted with dichloromethane (100mL), is then washed with water (100mL × 3).Separate Organic layer anhydrous Na₂SO₄Dry, then reduced pressure concentration, obtains crude product.Crude product is not purified, and to be directly used in next step anti- Should.

Step 5) 2- ((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone

By 2- ((3S, 6R) -6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone (on One step crude product) it is dissolved in methyl alcohol (70mL), and it is added thereto to Pd (OH)₂/ C (240mg, 0.17mmol, mass fraction 10%).Reactant mixture overnight, is then filtered in room temperature and stirred under nitrogen atmosphere.Filtrate reduced in volume, obtains crude product.Slightly Product is not purified to be directly used in next step reaction.

LC-MS(ESI,pos.ion)m/z:275.0[M+H]⁺.

Step 6) 2- ((3S, 6R) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- Base) isoindoline -1,3- diketone

By 2,4,5- trichloropyrimidines (1.45g, 7.9mmol) are dissolved in MeOH (40mL), and are added thereto to triethylamine (970mg, 9.6mmol) and 2- ((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- two Ketone (previous step crude product).Reactant mixture is stirred at room temperature overnight, then reduced pressure concentration, residue obtained through silica gel column chromatography (EtOAc/PE (v/v)=1/3) is purified, and obtains title compound for white solid (450mg, step 4) to step 6) three steps are total Yield：13.5%).

LC-MS(ESI,pos.ion)m/z:421.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.07(s,1H),7.90-7.85(m,2H),7.79-7.73(m,2H), 5.14-5.13(m,1H),5.00-4.98(m,1H),4.91-4.86(m,1H),4.76-4.68(m,1H),4.36-4.29(m, 2H),4.13-4.07(m,1H),3.65-3.62(m,1H).

Step 7) 2- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone

Will be different for 2- ((3S, 6R) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) Indoline -1,3- diketone (370.0mg, 0.88mmol) and 1- methyl isophthalic acid H- pyrazoles -4- amine hydrochlorate (354.2mg, N-BuOH (10mL) 2.65mmol) is dissolved in, and is added thereto to DIPEA (683.1mg, 5.29mmol).Reactant mixture exists It is stirred overnight at 150 DEG C, then reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/30), It is red solid (140.0mg, yield 33.1%) to obtain title compound.

LC-MS(ESI,pos.ion)m/z:482.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.90(s,1H),7.88-7.86(m,2H),7.76-7.74(m,2H), 7.67 (s, 1H), 7.46 (s, 1H), 6.73 (s, 1H), 5.89 (d, J=7.5Hz, 1H), 5.16-5.14 (m, 1H), 4.99- 4.96 (m, 1H), 4.87 (td, J=7.6,2.2Hz, 1H), 4.67-4.60 (m, 1H), 4.32 (t, J=8.5Hz, 1H), 4.28- 4.22 (m, 1H), 4.08-4.04 (m, 1H), 3.87 (s, 3H), 3.63 (t, J=8.9Hz, 1H).

Step 8) N ⁴ - ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5- ² - (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines

By 2- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) six Hydrogen furans simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone (140.0mg, 0.29mmol) is dissolved in ethanol (5mL) In, and it is added thereto to hydrazine hydrate (198.6mg, 2.94mmol).Reactant mixture is stirred at room temperature 4 hours, then reduces pressure Concentrate.Gained residue is through the silica gel column chromatography (NH of 7M₃Methanol solution/DCM (v/v)=1/20) purifying, obtain title compound Thing is white solid (65.0mg, yield 63.6%).

LC-MS(ESI,pos.ion)m/z:351.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.65(s,1H),7.47(s,1H),6.50(s, 1H), 5.94 (s, 1H), 4.76-4.73 (m, 1H), 4.60-4.57 (m, 1H), 4.40 (d, J=4.1Hz, 1H), 4.24-4.20 (m, 1H), 4.00 (dd, J=9.2,4.4Hz, 1H), 3.87 (s, 3H), 3.80 (d, J=9.1Hz, 1H), 3.62 (d, J= 4.1Hz,1H),3.50-3.46(m,1H).

2 N of intermediate ⁴ - ((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5- ² - (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines

Step 1) (3S, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furan-3-ol

To 2- ((3S, 6S) -6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone MeNH is added in (7.30g, 26.5mmol)₂Water (mass fraction 40%, 50mL) solution.Reactant mixture is stirred at 50 DEG C 2 hours, after reaction terminates, reduced pressure concentration.Gained residue is through silica gel column chromatography (DCM/ (NH₃MeOH solution (7M)) (v/v) =30/1) purify, title compound is obtained for yellow solid (2.41g, yield 63%).

MS(ESI,pos.ion)m/z:146.3[M+H]⁺.

Step 2) (3S, 6S) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol

Ethanol to (3S, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furan-3-ol (2.36g, 16.3mmol) (40mL) Et is added in solution₃N (3.4mL, 24mmol) and 2,4,5- trichloropyrimidine (2.98g, 16.2mmol).Reactant mixture It is stirred at room temperature overnight, after reaction terminates, reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/ 60) purify, title compound is obtained for white solid (4.58g, yield 96%).

MS(ESI,pos.ion)m/z:292.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.22 (s, 1H), 7.92 (d, J=6.7Hz, 1H), 5.19 (d, J= 3.9Hz, 1H), 4.66 (d, J=3.2Hz, 1H), 4.43 (d, J=4.1Hz, 1H), 4.41-4.35 (m, 1H), 4.11-4.07 (m, 1H), 3.95 (dd, J=9.3,6.0Hz, 1H), 3.80 (dd, J=9.5,3.6Hz, 1H), 3.75 (dd, J=9.4, 4.1Hz, 1H), 3.65 (d, J=9.5Hz, 1H).

Step 3) (3S, 6S) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) six Hydrogen furans simultaneously [3,2-b] furan-3-ol

To (3S, 6S) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol Add in n-BuOH (40mL) solution of (4.58g, 15.7mmol) DIPEA (6.7mL, 38mmol) and 1- methyl isophthalic acid H- pyrazoles- 4- amine hydrochlorate (2.51g, 18.8mmol).Reactant mixture is warming up to 150 DEG C, and tube sealing reaction is stirred overnight, after reaction terminates, Reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40 to 1/10), and obtaining title compound is Brown solid (5.53g, yield 100%).

MS(ESI,pos.ion)m/z:353.0[M+H]⁺.

Step 4) (3S, 6S) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) six Hydrogen furans simultaneously [3,2-b] furans -3- base methanesulfonates

To (3S, 6S) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan Mutter in simultaneously dichloromethane (80mL) solution of [3,2-b] furan-3-ol (5.53g, 15.7mmol) and add Et₃N(3.5mL, 25mmol) with DMAP (383.2mg, 3.14mmol).Mixture is cooled to 0 DEG C, and be added thereto to mesyl chloride (1.6mL, 21mmol).Gained mixture is stirred 30 minutes at 0 DEG C, is then moved to and is stirred overnight at room temperature.After reaction terminates, water is used (80mL) reaction is quenched, then stratification.Organic phase is isolated, water is mutually extracted with DCM (40mL × 2), merging is all of to be had Machine phase.Organic phase washed with water (40mL × 3) washing of merging, anhydrous Na₂SO₄Dry, filter, reduced pressure concentration, obtaining title compound is Gray solid (2.70g, yield 40%).

MS(ESI,pos.ion)m/z:431.1[M+H]⁺.

Step 5) N ⁴ - ((3S, 6R) -6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5- ² - (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines

To (3S, 6S) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan Mutter in simultaneously DMF (15mL) solution of [3,2-b] furans -3- base mesylate (2.45g, 5.69mmol) and add sodium azide (1.48g,22.8mmol).Reactant mixture is stirred overnight at 140 DEG C, and after reaction terminates, reactant mixture is with water (100mL) Dilution, stratification, organic phase is isolated, water is mutually extracted with DCM (100mL × 3), merges all of organic phase.Merged has Machine is mutually washed with water (100mL × 2), anhydrous Na₂SO₄Dry, filter, reduced pressure concentration, title compound is obtained for dark oil thing (2.15g, yield 100%).

MS(ESI,pos.ion)m/z:378.1[M+H]⁺.

Step 6) N ⁴ - ((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5- ² - (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines

To N⁴- ((3S, 6R) -6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- Pyrazoles -4- base) pyrimidine -2,4- diamines (2.15g, 5.69mmol) methyl alcohol (25mL) solution in add Pd/C (mass fraction 10%, 430mg).Gained suspension is at ambient temperature and H₂It is stirred overnight in atmosphere.After reaction terminates, reactant mixture leads to Diatomite filtration is crossed, filter cake is washed with MeOH (30mL).By filtrate reduced in volume, gained residue is through silica gel column chromatography (DCM/ MeOH (v/v)=40/1 arrives DCM/ (NH₃MeOH solution (7M)) (v/v)=40/1) purifying, obtain title compound for yellow consolidate Body (232.0mg, yield 12%).

MS(ESI,pos.ion)m/z:352.2[M+H]⁺.

Intermediate 3 (3S, 6S)-N ³ - (2,5- dichloro pyrimidine -4- base) hexahydro furyl simultaneously [3,2-b] furans -3,6- diamines

Step 1) (3R, 6R)-hexahydro furyl simultaneously [3,2-b] furans -3,6- diyl two (triflate)

DCM (300mL) to (3R, 6R)-hexahydro furyl simultaneously [3,2-b] furans -3,6- glycol (29.0g, 198.4mmol) Pyridine (40mL, 490mmol) is added in solution.Reactant mixture is stirred 0.5 hour at 0 DEG C, is subsequently adding TFMS Acid anhydride (169.0g, 599.2mmol).Gained mixture is stirred at room temperature 3 hours, then uses salt aqueous acid (200mL, 1M) Reaction is quenched, stratification, separation organic phase, water are mutually extracted with DCM (500mL × 2).The organic phase anhydrous Na of merging₂SO₄ Dry, filter, reduced pressure concentration.Under room temperature, residue is beaten 1 hour with MeOH (200mL).Filter, the filter cake of collection is through decompression Dry, title compound is obtained for faint yellow solid (75.0g, yield 92.0%).

Step 2) (3S, 6S)-N ³ ,N ⁶ - dibenzyl hexahydro furyl simultaneously [3,2-b] furans -3,6- diamines

(3R, 6R)-hexahydro furyl simultaneously [3,2-b] furans -3,6- diyl two (triflate) (8.2g, 20mmol) Benzene methanamine (8mL, 75mmol) solution is stirred at room temperature overnight.After reaction terminates, reactant mixture reduced pressure concentration, obtain title Compound is pale red grease (13g, 200%).

MS(ESI,pos.ion)m/z:325.5[M+H]⁺.

Step 3) (3S, 6S)-hexahydro furyl simultaneously [3,2-b] furans -3,6- diamines

To (3S, 6S)-N³,N⁶- dibenzyl hexahydro furyl simultaneously [3,2-b] furans -3,6- diamines (3.0g, 9.2mmoL) Pd/C (mass fraction 10%, 1.0g) is added in MeOH (20mL) solution.Gained suspension is at room temperature and H₂8 are stirred in atmosphere Hour, after reaction terminates, filter.By gained filtrate reduced in volume, concentrated residues thing is through silica gel column chromatography (DCM/MeOH (v/v) =50/1 to 20/1 to 5/1) purify, title compound is obtained for greenish liquid (0.8g, yield 60%).

MS(ESI,pos.ion)m/z:145.2[M+H]⁺.

Step 4) (3S, 6S)-N ³ - (2,5- dichloro pyrimidine -4- base) hexahydro furyl simultaneously [3,2-b] furans -3,6- diamines

MeOH (10mL) solution to (3S, 6S)-hexahydro furyl simultaneously [3,2-b] furans -3,6- diamines (144mg, 1mmol) Middle addition 2,4,5- trichloropyrimidine (183mg, 1.0mmoL).Reactant mixture is stirred at room temperature 5 hours, after reaction terminates, subtracts Pressure is concentrated, and gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=1/1 to DCM/MeOH (v/v)=30/1), is obtained Title compound is white solid (0.1g, yield 30.0%).

MS(ESI,pos.ion)m/z:291.0[M+H]⁺.

4 N of intermediate ⁴ - ((3R, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5- ² - (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines

Step 1) (3R, 6S) -6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- yl benzoic acid ester

At 0 DEG C, to (3R, 6S)-hexahydro furyl simultaneously [3,2-b] furans -3, the DCM of 6- glycol (29.0g, 198.4mmol) (300mL) in solution add pyridine (40mL, 490mmol), stirring 30 minutes after be added thereto to chlorobenzoyl chloride (28.0g, 199.2mmol).Gained mixture is stirred at room temperature 3 hours, then reaction is quenched with salt aqueous acid (500mL, 1M), Stratification, isolates organic phase, and water is mutually extracted with DCM (500mL × 2).The organic phase anhydrous Na of merging₂SO₄Dry, mistake Filter, reduced pressure concentration.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=7/1 to 3/1 to 2/1), is obtained titled Compound is white solid (14g, yield 28.2%).

MS(ESI,pos.ion)m/z:251.0[M+H]⁺.

Step 2) (3R, 6S) -6- (((trifluoromethyl) sulfonyl) epoxide) hexahydro furyl simultaneously [3,2-b] furans -3- base benzene Formic acid esters

At 0 DEG C, to (3R, 6S) -6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- yl benzoic acid ester (12.5g, In DCM (300mL) solution 50mmol) add pyridine (18mL), be then added thereto to trifluoromethanesulfanhydride anhydride (10mL, 59.2mmol).Gained mixture is stirred at room temperature 3 hours, after reaction terminates, is quenched with the aqueous solution (300mL, 1M) of HCl Reaction, stands its layering, separates organic phase, and water is mutually extracted with DCM (300mL × 2), merges all of organic phase.Merged has Anhydrous Na mutually used by machine₂SO₄Dry, filter, reduced pressure concentration, title compound is obtained for light red solid (16g, yield 83.8%).

MS(ESI,pos.ion)m/z:383.0[M+H]⁺.

Step 3) (3R, 6R) -6- (benzylamino) hexahydro furyl simultaneously [3,2-b] furans -3- yl benzoic acid ester

To (3R, 6S) -6- (((trifluoromethyl) sulfonyl) epoxide) hexahydro furyl simultaneously [3,2-b] furans -3- yl benzoic acid Phenylmethanamine (10mL, 91mmoL) is added in THF (200mL) solution of ester (16.0g, 41.9mmol).Reactant mixture is in room Temperature descends stirring 12 hours, then reduced pressure concentration.Gained residue through silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 5/1 to 3/1) purify, title compound is obtained for white solid (8.0g, yield 53.3%).

MS(ESI,pos.ion)m/z:340.2[M+H]⁺.

Step 4) (3R, 6R) -6- (benzylamino) hexahydro furyl simultaneously [3,2-b] furan-3-ol

To (3R, 6R) -6- (benzylamino) hexahydro furyl simultaneously [3,2-b] furans -3- yl benzoic acid ester (5.0g, NaOMe (900mg, 16.7mmoL) is added in MeOH (60mL) solution 14.7mmoL).Reactant mixture is stirred at room temperature 1 Hour, then use CH₃COOH adjusts its pH=7.Gained mixture is through being concentrated under reduced pressure to give title compound for greenish liquid (2.6g, yield 75.0%).

MS(ESI,pos.ion)m/z:236.1[M+H]⁺.

Step 5) (3R, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furan-3-ol

MeOH to (3R, 6R) -6- (benzyl amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol (3.0g, 12.8mmoL) (60mL) Pd/C (mass fraction 10%, 2.0g) is added in solution.Gained suspension is stirred overnight in room temperature and atmosphere of hydrogen. After reaction terminates, reactant mixture is filtered, gained filtrate obtains title compound for light green liquid through reduced pressure concentration (1.85g, 100%).

MS(ESI,pos.ion)m/z:146.1[M+H]⁺.

Step 6) (3R, 6R) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol

MeOH (60mL) to (3R, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furan-3-ol (4.0g, 22mmoL) is molten TEA (4mL, 30mmoL) is added in liquid.Reactant mixture is stirred at room temperature 5 hours, after reaction terminates, reduced pressure concentration.Gained Residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 3/1 to 1/1), obtains title compound for white solid (8.0g, yield 53.3%).

MS(ESI,pos.ion)m/z:292.0[M+H]⁺.

Step 7) (3R, 6R) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base three Fluoromethane sulphonic acid ester

To (3R, 6R) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol (3.1g, Pyridine (4mL) and trifluoromethanesulfanhydride anhydride (2.5mL, 15mmol) is added in DCM (50mL) solution 11mmoL).Gained mixture It is stirred at room temperature 3 hours.After reaction terminates, by reactant mixture reduced pressure concentration, gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=5/1 to 2/1) purifying, title compound is obtained for white solid (3.0g, yield 67.0%).

MS(ESI,pos.ion)m/z:423.9[M+H]⁺.

Step 8) (3S, 6R) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol

To (3R, 6R) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base fluoroform NaOAc (3.0g, 36.6mmoL) is added in DMF (20mL) solution of alkyl sulfonic acid ester (3.0g, 7.1mmoL).Gained mixture exists Stir 5 hours under room temperature, and NaOMe (400mg, 7.4mmoL) is added thereto to, mixture is further continued for stirring 1 hour.Reaction knot Shu Hou, reactant mixture reduced pressure concentration, gained residue are purified through silica gel column chromatography (PE/EtOAc (v/v)=5/1 to 2/1), It is white solid (3.0g, yield 67.0%) to obtain title compound.

MS(ESI,pos.ion)m/z:292.0[M+H]⁺.

Step 9) (3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) six Hydrogen furans simultaneously [3,2-b] furan-3-ol

To (3S, 6R) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol DIPEA (1mL, 6.0mmoL) and 1- methylpyrazole -4- amine salt is added in n-BuOH (20mL) solution of (700mg, 2.4mmoL) Hydrochlorate (660mg, 4.9mmoL).Reactant mixture is stirred 1 hour at 130 DEG C, after reaction terminates, reduced pressure concentration.Gained filtrate It is diluted in H₂In O (50mL), and it is stirred at room temperature 1 hour, then filters, collects that filter cake is vacuum dried obtains title compound Thing is white solid (500mg, yield 59.1%).

MS(ESI,pos.ion)m/z:353.1[M+H]⁺.

Step 10) (3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) Hexahydro furyl simultaneously [3,2-b] furans -3- methylmethane sulphonic acid ester

To (3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan Mutter in simultaneously DCM (12mL) solution of [3,2-b] furan-3-ol (100mg, 0.28mmoL) and add pyridine (0.2mL) and methylsulfonyl Chlorine (100mg, 0.87mmoL).Reactant mixture is stirred at room temperature 14 hours, then uses saturation Na₂CO₃The aqueous solution (50mL) is quenched Go out reaction, stratification, organic phase is isolated, water is mutually extracted with DCM (50mL × 2).The organic phase anhydrous Na of merging₂SO₄Dry Dry, filter, filtrate reduced in volume.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=7/1 to 1/1), must be marked Topic compound is white solid (90.0mg, yield 73.6%).

MS(ESI,pos.ion)m/z:431.0[M+H]⁺.

Step 11) N ⁴ - ((3R, 6R) -6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5- ² - (1- first Base -1H- pyrazoles -4- base) pyrimidine -2,4- diamines

To (3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan Mutter in simultaneously DMF (10mL) solution of [3,2-b] furans -3- base methanesulfonates (90mg, 0.21mmoL) and add sodium azide (65mg,1mmol).Reactant mixture is stirred 12 hours at 130 DEG C, and after reaction terminates, reaction water (20mL) is quenched, standing Layering, separates organic phase, and water is mutually extracted with DCM (20mL × 2).The organic phase anhydrous Na of merging₂SO₄Dry, filter, decompression Title compound is concentrated to give for yellow oil (79.0mg, yield 100%).

MS(ESI,pos.ion)m/z:378.1[M+H]⁺.

Step 12) N ⁴ - ((3R, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5- ² - (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines

To N⁴- ((3R, 6R) -6- nitrine hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (70mg, 0.19mmoL) MeOH (10mL) solution in add Pd/C (mass fraction 10%, 70mg).Gained suspension is at ambient temperature and H₂Stir 6 hours in atmosphere.After reaction terminates, reactant mixture is filtered, Again by filtrate reduced in volume, gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=10/1), obtains title compound For white solid (90.0mg, yield 73.6%).

MS(ESI,pos.ion)m/z:352.2[M+H]⁺.

Embodiment 1a 1- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) -3- MU

Step 1) 6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- base 4- toluene sulfonic acide ester

By hexahydro furyl, simultaneously [3,2-b] furans -3,6- glycol (10.00g, 68.4mmol) is dissolved in dichloromethane (60mL) In, and pyridine (1.08g, 13.7mmol) is added thereto to, reactant mixture is cooled to 0 DEG C, then is added thereto to 4- methylbenzene Sulfonic acid chloride (15.66g, 82.1mmol).Reactant mixture is stirred 30 minutes at 0 DEG C, is then moved to and is stirred overnight at room temperature.Mixing Thing is diluted with dichloromethane (250mL), successively with the washing of hydrochloric acid (300mL, 1M), water (300mL) and saline solution (300mL).Point The organic phase for going out is filtered through anhydrous sodium sulfate drying, and reduced pressure concentration.Gained residue is through silica gel column chromatography (EtOAc/PE (v/ V)=2/1) purify, title compound is obtained for colorless oil (10.24g, yield 49.8%).

LC-MS(ESI,pos.ion)m/z:301.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.79 (d, J=8.3Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 4.84 (dd, J=11.5,6.3Hz, 1H), 4.62 (t, J=4.7Hz, 1H), 4.34 (d, J=4.3Hz, 1H), 4.24 (s, 1H), 4.10-4.06 (m, 1H), 3.84 (d, J=2.0Hz, 2H), 3.80 (dd, J=9.6,6.3Hz, 1H), 3.65 (dd, J=9.6, 6.6Hz,1H),2.42(s,3H).

Step 2) 2- (6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone

By simultaneously [3,2-b] furans -3- base 4- toluene sulfonic acide ester (10.24g, 34.1mmol) dissolving of 6- hydroxyl hexahydro furyl In DMSO (60mL), and it is added thereto to (1,3- dioxoisoindolin -2- base) potassium (8.21g, 44.3mmol).Reaction is mixed Compound overnight, is then down to room temperature in 130 DEG C and stirred under nitrogen atmosphere, and is poured into water.Gained mixture dichloromethane (300mL × 3) extract, organic phase washed with water (100mL × 3) washing of merging, anhydrous Na₂SO₄Dry, then reduced pressure concentration.Gained Residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=1/1), obtains title compound for white solid (2.35g, yield 25.0%).

LC-MS(ESI,pos.ion)m/z:276.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.86 (dd, J=5.4,3.1Hz, 2H), 7.74 (dd, J=5.5, 3.0Hz, 2H), 5.17 (dd, J=4.3,2.2Hz, 1H), 4.84-4.74 (m, 2H), 4.44-4.35 (m, 1H), 4.17 (t, J= 8.5Hz, 1H), 4.06 (dd, J=10.1,3.3Hz, 1H), 3.97-3.85 (m, 2H).

Step 3) 6- (1,3- dioxoisoindolin -2- base) hexahydro furyl simultaneously [3,2-b] furans -3- base methanesulfonates

Under nitrogen protection, by 2- (6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone (2.35g, 8.54mmol) is dissolved in dichloromethane (40mL), is added thereto to triethylamine (1.30g, 12.8mmol) and N, N- Lutidines -4- amine (209.2mg, 1.7mmol).Mixture is cooled to 0 DEG C, and adds methane sulfonyl chloride under nitrogen protection (0.8mL,10.0mmol).Gained mixture is stirred 30 minutes at 0 DEG C, is then moved to and is stirred overnight at room temperature.Mixture uses two Chloromethanes (100mL) dilutes, successively with the washing of hydrochloric acid (100mL, 1M), water (100mL) and saturated aqueous common salt (100mL).Separate Organic phase through anhydrous sodium sulfate drying, filter, and reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v) =1/200) purify, title compound is obtained for white solid (2.35g, yield 77.9%).

LC-MS(ESI,pos.ion)m/z:353.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.87-7.85(m,2H),7.79-7.71(m,2H),5.16-5.15 (m,2H),5.08-5.07(m,1H),4.88-4.80(m,1H),4.26-4.19(m,1H),4.17-4.10(m,2H),3.96- 3.91(m,1H),3.09(s,3H).

Step 4) 2- (6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone

By 6- (1,3- dioxoisoindolin -2- base) hexahydro furyl simultaneously [3,2-b] furans -3- base methanesulfonates (2.80g, 7.9mmol) is dissolved in DMF (60mL), and is added thereto to sodium azide (2.16g, 33.2mmol).Reaction is mixed Compound is stirred 23 hours at 140 DEG C, then is diluted with dichloromethane (100mL), is then washed with water (100mL × 3).Separate Organic layer anhydrous Na₂SO₄Dry, then reduced pressure concentration, obtains crude product.Crude product is not purified to be directly used in next step reaction.

Step 5) 2- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone

By 2- (6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base), isoindoline -1,3- diketone (slightly produce by previous step Thing) it is dissolved in methyl alcohol (70mL), and it is added thereto to Pd (OH)₂/ C (240mg, 0.17mmol, mass fraction 10%).Reaction Mixture overnight, is then filtered in room temperature and stirred under nitrogen atmosphere.Filtrate reduced in volume, obtains crude product.Crude product is without pure Change and be directly used in next step reaction.

LC-MS(ESI,pos.ion)m/z:275.0[M+H]⁺.

Step 6) 2- (6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) iso-indoles Quinoline -1,3- diketone

By 2,4,5- trichloropyrimidines (1.45g, 7.9mmol) are dissolved in MeOH (40mL), and are added thereto to triethylamine (970mg, 9.6mmol) and 2- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone (previous step Crude product).Reactant mixture is stirred at room temperature overnight, then reduced pressure concentration, residue obtained through silica gel column chromatography (EtOAc/PE (v/v)=1/3) purify, title compound is obtained for white solid (450mg, step 4) to step 6) three step gross production rates： 13.5%).

LC-MS(ESI,pos.ion)m/z:421.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.07(s,1H),7.90-7.85(m,2H),7.79-7.73(m,2H), 5.14-5.13(m,1H),5.00-4.98(m,1H),4.91-4.86(m,1H),4.76-4.68(m,1H),4.36-4.29(m, 2H),4.13-4.07(m,1H),3.65-3.62(m,1H).

Step 7) 2- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan Mutter simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone

By 2- (6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline - 1,3- diketone (370.0mg, 0.88mmol) and 1- methyl isophthalic acid H- pyrazoles -4- amine hydrochlorate (354.2mg, 2.65mmol) are dissolved in N-BuOH (10mL), and it is added thereto to DIPEA (683.1mg, 5.29mmol).Reactant mixture is stirred overnight at 150 DEG C, Then reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/30), and it is red to obtain title compound Color solid (140.0mg, yield 33.1%).

LC-MS(ESI,pos.ion)m/z:482.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.90(s,1H),7.88-7.86(m,2H),7.76-7.74(m,2H), 7.67 (s, 1H), 7.46 (s, 1H), 6.73 (s, 1H), 5.89 (d, J=7.5Hz, 1H), 5.16-5.14 (m, 1H), 4.99- 4.96 (m, 1H), 4.87 (td, J=7.6,2.2Hz, 1H), 4.67-4.60 (m, 1H), 4.32 (t, J=8.5Hz, 1H), 4.28- 4.22 (m, 1H), 4.08-4.04 (m, 1H), 3.87 (s, 3H), 3.63 (t, J=8.9Hz, 1H).

Step 8) N ⁴ - (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5- ² - (1- methyl isophthalic acid H- pyrazoles -4- Base) pyrimidine -2,4- diamines

By 2-, (hexahydro furyl is simultaneously for 6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) [3,2-b] furans -3- base) isoindoline -1,3- diketone (140.0mg, 0.29mmol) is dissolved in ethanol (5mL), and to which Middle addition hydrazine hydrate (198.6mg, 2.94mmol).Reactant mixture is stirred at room temperature 4 hours, then reduced pressure concentration.Gained Residue is through the silica gel column chromatography (NH of 7M₃Methanol solution/DCM (v/v)=1/20) purifying, obtain title compound solid for white Body (65.0mg, yield 63.6%).

LC-MS(ESI,pos.ion)m/z:351.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.65(s,1H),7.47(s,1H),6.50(s, 1H), 5.94 (s, 1H), 4.76-4.73 (m, 1H), 4.60-4.57 (m, 1H), 4.40 (d, J=4.1Hz, 1H), 4.24-4.20 (m, 1H), 4.00 (dd, J=9.2,4.4Hz, 1H), 3.87 (s, 3H), 3.80 (d, J=9.1Hz, 1H), 3.62 (d, J= 4.1Hz,1H),3.50-3.46(m,1H).

Step 9) 1- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan Mutter simultaneously [3,2-b] furans -3- base) -3- MU

To N⁴- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrazoles -4- base) DMAP is added in dichloromethane (10mL) solution of pyrimidine -2,4- diamines (178.4mg, 0.51mmol) (12.4mg, 0.10mmol) and triethylamine (79.6mg, 0.79mmol).Reactant mixture is cooled to 0 DEG C, is then added thereto to Methyl amido formyl chloride (59.1mg, 0.63mmol).Mixture is stirred 30 minutes at 0 DEG C, is then heated to room temperature and is stirred Overnight.Add water (5mL) be quenched reaction, and extracted with dichloromethane (10mL).The organic phase for separating is through anhydrous sodium sulfate drying, mistake Filter, and reduced pressure concentration.Gained residue is through the silica gel column chromatography (NH of 7M₃Methanol solution/DCM (v/v)=1/50) purifying, obtain Title compound is yellow solid (80.2mg, yield 38.7%).

LC-MS(ESI,pos.ion)m/z:409.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.64(s,1H),7.47(s,1H),6.62(s, 1H), 5.84 (d, J=7.2Hz, 1H), 4.68-4.63 (m, 1H), 4.62-4.55 (m, 3H), 4.51-4.50 (m, 1H), 4.29 (s, 1H), 4.26-4.19 (m, 1H), 4.06 (dd, J=9.6,4.9Hz, 1H), 3.87 (s, 3H), 3.84 (dd, J=9.6, 2.5Hz, 1H), 3.50 (t, J=8.6Hz, 1H), 2.80 (d, J=4.8Hz, 3H).

Embodiment 1 1- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -3- MU

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (178.4mg, 0.51mmol) dichloromethane (10mL) solution in add DMAP (12.4mg, 0.10mmol) with triethylamine (79.6mg, 0.79mmol).Reactant mixture is cooled to 0 DEG C, is then added thereto to methylamino Formyl chloride (59.1mg, 0.63mmol).Mixture is stirred 30 minutes at 0 DEG C, is then heated to room temperature and is stirred overnight.Add water (5mL) reaction is quenched, mixture with dichloromethane (10mL) extract.The organic phase for separating is through anhydrous sodium sulfate drying, mistake Filter, and reduced pressure concentration.Gained residue is through the silica gel column chromatography (NH of 7M₃Methanol solution/DCM (v/v)=1/50) purifying, obtain Title compound is yellow solid (80.2mg, yield 38.7%).

LC-MS(ESI,pos.ion)m/z:409.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.64(s,1H),7.47(s,1H),6.62(s, 1H), 5.84 (d, J=7.2Hz, 1H), 4.68-4.63 (m, 1H), 4.62-4.55 (m, 3H), 4.51-4.50 (m, 1H), 4.29 (s, 1H), 4.26-4.19 (m, 1H), 4.06 (dd, J=9.6,4.9Hz, 1H), 3.87 (s, 3H), 3.84 (dd, J=9.6, 2.5Hz, 1H), 3.50 (t, J=8.6Hz, 1H), 2.80 (d, J=4.8Hz, 3H).

Embodiment 2a N- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) -2- methylpropane -1- sulfonamide

To N⁴- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrazoles -4- base) In dichloromethane (8mL) solution of pyrimidine -2,4- diamines (100.3mg, 0.29mmol) add DMAP (7.0mg, 0.06mmol) with triethylamine (45.3mg, 0.45mmol).Reaction system is cooled to 0 DEG C, is then added thereto to 2- methyl-prop Alkane -1- sulfonic acid chloride (56.2mg, 0.36mmol).Mixture moves to room temperature after stirring 30 minutes at 0 DEG C, and continues stirred Night.Add water (10mL) reaction is quenched, gained mixture with dichloromethane (10mL) extract.The organic phase for separating is through anhydrous sodium sulfate Dry, filter, and reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50 to 1/30), is obtained Title compound is white solid (56.5mg, yield 42.0%).

LC-MS(ESI,pos.ion)m/z:472.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.91(s,1H),7.64(s,1H),7.47(s,1H),6.51(s, 1H), 5.81 (d, J=6.9Hz, 1H), 4.70-4.58 (m, 3H), 4.46 (d, J=8.2Hz, 1H), 4.28-4.22 (m, 1H), 4.08-4.03 (m, 2H), 3.93-3.90 (m, 1H), 3.88 (s, 3H), 3.48 (t, J=8.6Hz, 1H), 2.99 (d, J= 6.5Hz, 2H), 2.31-2.23 (m, 1H), 1.13 (d, J=6.7Hz, 6H).

Embodiment 2 N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methylpropane -1- sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (100.3mg, 0.29mmol) dichloromethane (8mL) solution in add DMAP (7.0mg, 0.06mmol) with triethylamine (45.3mg, 0.45mmol).Reaction system is cooled to 0 DEG C, is then added thereto to 2- methyl-prop Alkane -1- sulfonic acid chloride (56.2mg, 0.36mmol).Mixture moves to room temperature after stirring 30 minutes at 0 DEG C, and continues stirred Night.Add water (10mL) reaction is quenched, gained mixture with dichloromethane (10mL) extract.The organic phase for separating is through anhydrous sodium sulfate Dry, filter, and reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50 to 1/30), is obtained Title compound is white solid (56.5mg, yield 42.0%).

LC-MS(ESI,pos.ion)m/z:472.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.91(s,1H),7.64(s,1H),7.47(s,1H),6.51(s, 1H), 5.81 (d, J=6.9Hz, 1H), 4.70-4.58 (m, 3H), 4.46 (d, J=8.2Hz, 1H), 4.28-4.22 (m, 1H), 4.08-4.03 (m, 2H), 3.93-3.90 (m, 1H), 3.88 (s, 3H), 3.48 (t, J=8.6Hz, 1H), 2.99 (d, J= 6.5Hz, 2H), 2.31-2.23 (m, 1H), 1.13 (d, J=6.7Hz, 6H).

Embodiment 3a 6- ((6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) six Hydrogen furans simultaneously [3,2-b] furans -3- base) amino) pyridazine -3- formonitrile HCN

To N⁴- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrazoles -4- base) In n-butanol (20mL) solution of pyrimidine -2,4- diamines (32mg, 0.091mmol) add 6- chlorine pyridazine -3- formonitrile HCN (25mg, 0.179mmol) with triethylamine (42mg, 0.415mg).Reaction system is warming up to 120 DEG C of stirrings 20 hours, then reduced pressure concentration. Gained residue through silica gel column chromatography (MeOH/DCM (v/v)=1/30) purify, obtain title compound for yellow solid (17mg, 0.037mmol, yield 41%).

LC-MS(ESI,pos.ion)m/z:455.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.81 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.40 (d, J= 9.1Hz, 1H), 6.78 (d, J=9.3Hz, 1H), 4.71 (s, 1H), 4.64-4.57 (m, 3H), 4.24-4.14 (m, 2H), 4.00-3.96(m,1H),3.81(s,3H),3.69-3.66(m,3H).

Embodiment 3 6- (((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) pyridazine -3- formonitrile HCN

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (32mg, 0.091mmol) n-butanol (20mL) solution in add 6- chlorine pyridazine -3- formonitrile HCN (25mg, 0.179mmol) and triethylamine (42mg, 0.415mg).Reaction system is warming up to 120 DEG C and stirs 20 hours, then reduces pressure Concentrate.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/30), obtains title compound for yellow solid (17mg, 0.037mmol, yield 41%).

LC-MS(ESI,pos.ion)m/z:455.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.81 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.40 (d, J= 9.1Hz, 1H), 6.78 (d, J=9.3Hz, 1H), 4.71 (s, 1H), 4.64-4.57 (m, 3H), 4.24-4.14 (m, 2H), 4.00-3.96(m,1H),3.81(s,3H),3.69-3.66(m,3H).

Embodiment 4a N- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) cyclopropylsulfonamide

To N⁴- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrazoles -4- base) Pyrimidine -2, in DCM (3mL) solution of 4- diamines (100.3mg, 0.2851mmol), addition triethylamine (179.8mg, 1.777mmol) with cyclopropanesulfonyl chloride (207.6mg, 1.477mmol).Reaction system is stirred at room temperature 2 hours, Ran Houjia Water (20mL) is quenched reaction, and with the mixed solvent of DCM and MeOH (v/v=10/1,40mL × 3) extraction.The organic phase of merging Through anhydrous Na₂SO₄Dry, filter and reduced pressure concentration.Gained residue is pure through silica gel column chromatography (DCM/MeOH (v/v)=15/1) Change, title compound is obtained for faint yellow solid (24.7mg, yield 19%).

LC-MS(ESI,pos.ion)m/z:456.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.12(s,1H),7.94(s,1H),7.73(s,1H),7.61(d,J =7.2Hz, 1H), 7.44 (s, 1H), 6.32 (d, J=6.8Hz, 1H), 4.73 (t, J=4.6Hz, 1H), 4.64-4.60 (m, 1H), 4.07 (t, J=8.0Hz, 1H), 4.00 (dd, J=9.3,5.3Hz, 1H), 3.89-3.84 (m, 1H), 3.77 (s, 3H), 3.77-3.74 (m, 1H), 3.64 (t, J=8.6Hz, 1H), 3.50-3.44 (m, 1H), 2.66-2.57 (m, 1H), 1.02-0.89 (m,4H).

Embodiment 4 N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) cyclopropylsulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2, in DCM (3mL) solution of 4- diamines (100.3mg, 0.2851mmol), addition triethylamine (179.8mg, 1.777mmol) with cyclopropanesulfonyl chloride (207.6mg, 1.477mmol).Reaction system is stirred at room temperature 2 hours, Ran Houjia Water (20mL) is quenched reaction, and with the mixed solvent of DCM and MeOH (v/v=10/1,40mL × 3) extraction.The organic phase of merging Through anhydrous Na₂SO₄Dry, filter and reduced pressure concentration.Gained residue is pure through silica gel column chromatography (DCM/MeOH (v/v)=15/1) Change, title compound is obtained for faint yellow solid (24.7mg, yield 19%).

LC-MS(ESI,pos.ion)m/z:456.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.12(s,1H),7.94(s,1H),7.73(s,1H),7.61(d,J =7.2Hz, 1H), 7.44 (s, 1H), 6.32 (d, J=6.8Hz, 1H), 4.73 (t, J=4.6Hz, 1H), 4.64-4.60 (m, 1H), 4.07 (t, J=8.0Hz, 1H), 4.00 (dd, J=9.3,5.3Hz, 1H), 3.89-3.84 (m, 1H), 3.77 (s, 3H), 3.77-3.74 (m, 1H), 3.64 (t, J=8.6Hz, 1H), 3.50-3.44 (m, 1H), 2.66-2.57 (m, 1H), 1.02-0.89 (m,4H).

Embodiment 5a N- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) -2,2,2- HFC-143a sulfonamide

To N4- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N2- of -5- (1- methyl isophthalic acid H- pyrazoles -4- base) In dichloromethane (10mL) solution of pyrimidine -2,4- diamines (86.3mg, 0.244mmol) add triethylamine (50.1mg, 0.494mmol) and N, N- lutidines -4- amine (5.80mg, 0.046mmol).Reaction system is cooled to 0 DEG C, then to which Middle addition 2,2,2- trifluoroethane sulfonyl chloride (71.3mg, 0.388mmol).After adding, reactant mixture maintains 0 DEG C to stir 30 points Clock, then moves to and is stirred overnight at room temperature.After reaction terminates, reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) purify, title compound is obtained for yellow solid (65.0mg, yield 53.4%).

LC-MS(ESI,pos.ion)m/z:498.1[M+H]⁺；

HRMS(EI,pos.ion)m/z:498.0944[M+H]⁺,C₁₆H₂₀ClF₃N₇O₄S[M+H]⁺Theoretical value： 498.0860；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.14 (s, 1H), 8.01 (d, J=6.6Hz, 1H), 7.91 (s, 1H), 7.39 (s, 1H), 6.99 (d, J=6.2Hz, 1H), 4.67 (d, J=3.5Hz, 1H), 4.58-4.54 (m, 1H), 4.52- 4.47(m,1H),4.46-4.36(m,2H),4.09-4.00(m,4H),3.76(s,3H),3.52-3.50(m,1H)；

¹³C NMR(101MHz,DMSO-d₆)δ(ppm):157.33,153.71,129.48,123.72,123.32, 120.96,120.27,87.06,80.50,72.10,68.73,55.94,53.70,53.40,38.46.

Embodiment 5 N- ((3R, 6S) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2,2- HFC-143a sulfonamide

To N⁴- ((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (86.3mg, 0.244mmol) dichloromethane (10mL) solution in add triethylamine (50.1mg, 0.494mmol) and N, N- lutidines -4- amine (5.80mg, 0.046mmol).Reaction system is cooled to 0 DEG C, Then 2,2,2- trifluoroethane sulfonyl chloride (71.3mg, 0.388mmol) is added thereto to.After adding, reactant mixture maintains 0 DEG C Stirring 30 minutes, then moves to and is stirred overnight at room temperature.After reaction terminates, reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) is purified, and obtains title compound for yellow solid (65.0mg, yield 53.4%).

LC-MS(ESI,pos.ion)m/z:498.1[M+H]⁺；

HRMS(EI,pos.ion)m/z:498.0944[M+H]⁺,C₁₆H₂₀ClF₃N₇O₄S[M+H]⁺Theoretical value： 498.0860；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.14 (s, 1H), 8.01 (d, J=6.6Hz, 1H), 7.91 (s, 1H), 7.39 (s, 1H), 6.99 (d, J=6.2Hz, 1H), 4.67 (d, J=3.5Hz, 1H), 4.58-4.54 (m, 1H), 4.52- 4.47(m,1H),4.46-4.36(m,2H),4.09-4.00(m,4H),3.76(s,3H),3.52-3.50(m,1H)；

¹³C NMR(101MHz,DMSO-d₆)δ(ppm):157.33,153.71,129.48,123.72,123.32, 120.96,120.27,87.06,80.50,72.10,68.73,55.94,53.70,53.40,38.46.

Embodiment 6a N- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) pyrrolidines -1- sulfonamide

To N⁴- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrazoles -4- base) In dichloromethane (10mL) solution of pyrimidine -2,4- diamines (101mg, 0.287mmol) add triethylamine (58.2mg, 0.575mmol) and N, N- lutidines -4- amine (6.30mg, 0.051mmol).Reaction system is cooled to 0 DEG C, then to which Middle addition pyrrolidines -1- sulfonic acid chloride (81.6mg, 0.481mmol).After adding, reactant mixture maintains 0 DEG C of stirring 30 minutes, so After move to and be stirred overnight at room temperature.After reaction terminates, reduced pressure concentration.Gained residue through silica gel column chromatography (MeOH/DCM (v/v)= 1/50) purify, title compound is obtained for yellow solid (93.0mg, yield 66.8%).

LC-MS(ESI,pos.ion)m/z:485.2[M+H]⁺；

HRMS(EI,pos.ion)m/z:485.1492[M+H]⁺,C₁₈H₂₆ClN₈O₄S[M+H]⁺Theoretical value：485.1408；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.15(s,1H),7.91(s,2H),7.39(s,1H),7.20(d,J =7.9Hz, 1H), 6.97 (d, J=6.2Hz, 1H), 4.66 (d, J=3.8Hz, 1H), 4.52-4.45 (m, 2H), 4.06-3.95 (m, 3H), 3.89-3.85 (m, 1H), 3.76 (s, 3H), 3.50 (d, J=8.4Hz, 1H), 3.21-3.13 (m, 4H), 1.85- 1.80(m,4H)；

¹³C NMR(150MHz,DMSO-d₆)δ(ppm):157.43,153.87,129.72,129.48,123.40, 120.36,87.21,80.73,72.11,69.11,56.58,47.62,40.06,38.59,25.05.

Embodiment 6 N- ((3R, 6S) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) pyrrolidines -1- sulfonamide

To N⁴- ((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (101mg, 0.287mmol) dichloromethane (10mL) solution in add triethylamine (58.2mg, 0.575mmol) and N, N- lutidines -4- amine (6.30mg, 0.051mmol).Reaction system is cooled to 0 DEG C, Then pyrrolidines -1- sulfonic acid chloride (81.6mg, 0.481mmol) is added thereto to.After adding, reactant mixture maintains 0 DEG C of stirring 30 minutes, then move to and be stirred overnight at room temperature.After reaction terminates, reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/ DCM (v/v)=1/50) purifying, title compound is obtained for yellow solid (93.0mg, yield 66.8%).

LC-MS(ESI,pos.ion)m/z:485.2[M+H]⁺；

HRMS(EI,pos.ion)m/z:485.1492[M+H]⁺,C₁₈H₂₆ClN₈O₄S[M+H]⁺Theoretical value：485.1408；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.15(s,1H),7.91(s,2H),7.39(s,1H),7.20(d,J =7.9Hz, 1H), 6.97 (d, J=6.2Hz, 1H), 4.66 (d, J=3.8Hz, 1H), 4.52-4.45 (m, 2H), 4.06-3.95 (m, 3H), 3.89-3.85 (m, 1H), 3.76 (s, 3H), 3.50 (d, J=8.4Hz, 1H), 3.21-3.13 (m, 4H), 1.85- 1.80(m,4H)；

¹³C NMR(150MHz,DMSO-d₆)δ(ppm):157.43,153.87,129.72,129.48,123.40, 120.36,87.21,80.73,72.11,69.11,56.58,47.62,40.06,38.59,25.05.

Embodiment 7a N- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) -2,2- dimethylpropane -1- sulfonamide

To N⁴- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrazoles -4- base) In dichloromethane (4mL) solution of pyrimidine -2,4- diamines (50.0mg, 0.14mmol) add triethylamine (28.0mg, 0.28mmol) and N, N- lutidines -4- amine (3.2mg, 0.02mmol).Reaction system is cooled to 0 DEG C, then adds thereto Enter 2,2- dimethylpropane -1- sulfonic acid chloride (29.1mg, 0.17mmol).After adding, reactant mixture maintains 0 DEG C to stir 30 points Clock, then moves to and is stirred overnight at room temperature.After reaction terminates, reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/60) purify, title compound is obtained for yellow solid (14.0mg, yield 20%).

LC-MS(ESI,pos.ion)m/z:486.2[M+H]⁺；

HRMS(EI,pos.ion)m/z:486.1707[M+H]⁺,C₁₉H₂₉ClN₇O₄S[M+H]⁺Theoretical value：486.1612；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.90 (d, J=8.9Hz, 2H), 7.42 (s, 1H), 7.07 (s, 1H), 5.25 (d, J=5.6Hz, 1H), 5.00 (d, J=8.9Hz, 1H), 4.75 (s, 1H), 4.64 (dt, J=10.4,4.8Hz, 2H), 4.21 (t, J=8.2Hz, 1H), 4.10 (dd, J=10.2,4.7Hz, 1H), 4.10-4.04 (m, 2H), 3.87 (s, 3H), 3.55 (t, J=9.0Hz, 1H), 3.05-2.96 (m, 2H), 1.19 (s, 9H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):157.7,157.4,153.8,130.3,129.2,122.8,121.4, 86.6,81.1,73.5,72.1,65.7,56.5,39.2,31.7,29.7,29.4.

Embodiment 7 N- ((3R, 6S) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2- dimethylpropane -1- sulfonamide

To N⁴- ((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (50.0mg, 0.14mmol) dichloromethane (4mL) solution in add triethylamine (28.0mg, 0.28mmol) and N, N- lutidines -4- amine (3.2mg, 0.02mmol).Reaction system is cooled to 0 DEG C, then adds thereto Enter 2,2- dimethylpropane -1- sulfonic acid chloride (29.1mg, 0.17mmol).After adding, reactant mixture maintains 0 DEG C to stir 30 points Clock, then moves to and is stirred overnight at room temperature.After reaction terminates, reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/60) purify, title compound is obtained for yellow solid (14.0mg, yield 20%).

LC-MS(ESI,pos.ion)m/z:486.2[M+H]⁺；

HRMS(EI,pos.ion)m/z:486.1707[M+H]⁺,C₁₉H₂₉ClN₇O₄S[M+H]⁺Theoretical value：486.1612；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.90 (d, J=8.9Hz, 2H), 7.42 (s, 1H), 7.07 (s, 1H), 5.25 (d, J=5.6Hz, 1H), 5.00 (d, J=8.9Hz, 1H), 4.75 (s, 1H), 4.64 (dt, J=10.4,4.8Hz, 2H), 4.21 (t, J=8.2Hz, 1H), 4.10 (dd, J=10.2,4.7Hz, 1H), 4.10-4.04 (m, 2H), 3.87 (s, 3H), 3.55 (t, J=9.0Hz, 1H), 3.05-2.96 (m, 2H), 1.19 (s, 9H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):157.7,157.4,153.8,130.3,129.2,122.8,121.4, 86.6,81.1,73.5,72.1,65.7,56.5,39.2,31.7,29.7,29.4.

Embodiment 8a N- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) -4- fluorobenzenesulfonamide

To N⁴- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrazoles -4- base) In dichloromethane (10mL) solution of pyrimidine -2,4- diamines (200mg, 0.569mmol) add triethylamine (115mg, 1.137mmol) with 4- fluorophenylsulfonyl chloride (166mg, 0.853mmol).After adding, reactant mixture is stirred overnight at room temperature.Reaction After end, reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50), obtains title compound For white solid (240.0mg, yield 82.8%).

LC-MS(ESI,pos.ion)m/z:509.8[M+H]⁺；

HRMS(ESI,pos.ion)m/z:510.1147[M+H]+,C₂₀H₂₂ClFN₇O₄S[M+H]⁺Theoretical value： 510.1121；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.93-7.89(m,2H),7.88(s,1H),7.57(s,1H),7.48 (s, 1H), 7.21 (t, J=8.5Hz, 2H), 6.98 (s, 1H), 6.01 (s, 1H), 5.75 (d, J=6.8Hz, 1H), 4.64- 4.61 (m, 1H), 4.57 (dd, J=14.2,6.6Hz, 1H), 4.54 (d, J=3.8Hz, 1H), 4.18 (t, J=8.1Hz, 1H), 3.92-3.87 (m, 2H), 3.85 (s, 3H), 3.75 (d, J=7.9Hz, 1H), 3.41 (t, J=8.7Hz, 1H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):166.2,164.5,158.3,157.7,153.5,136.3,131.3, 130.0,129.9,123.0,121.3,116.9,116.7,87.2,81.3,73.6,71.8,60.4,54.1,39.4.

8 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -4- fluorobenzenesulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (200mg, 0.569mmol) dichloromethane (10mL) solution in add triethylamine (115mg, 1.137mmol) with 4- fluorophenylsulfonyl chloride (166mg, 0.853mmol).After adding, reactant mixture is stirred overnight at room temperature.Reaction After end, reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50), obtains title compound For white solid (240.0mg, yield 82.8%).

LC-MS(ESI,pos.ion)m/z:509.8[M+H]⁺；

HRMS(ESI,pos.ion)m/z:510.1147[M+H]⁺,C₂₀H₂₂ClFN₇O₄S[M+H]⁺Theoretical value： 510.1121；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.93-7.89(m,2H),7.88(s,1H),7.57(s,1H),7.48 (s, 1H), 7.21 (t, J=8.5Hz, 2H), 6.98 (s, 1H), 6.01 (s, 1H), 5.75 (d, J=6.8Hz, 1H), 4.64- 4.61 (m, 1H), 4.57 (dd, J=14.2,6.6Hz, 1H), 4.54 (d, J=3.8Hz, 1H), 4.18 (t, J=8.1Hz, 1H), 3.92-3.87 (m, 2H), 3.85 (s, 3H), 3.75 (d, J=7.9Hz, 1H), 3.41 (t, J=8.7Hz, 1H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):166.2,164.5,158.3,157.7,153.5,136.3,131.3, 130.0,129.9,123.0,121.3,116.9,116.7,87.2,81.3,73.6,71.8,60.4,54.1,39.4.

Embodiment 9a 3- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) oxazolidine -2- ketone

Step 1) 2- chloroethyl (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) Hexahydro furyl simultaneously [3,2-b] furans -3- base) carbamate

By N⁴- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrazoles -4- base) Pyrimidine -2,4- diamines (252.3mg, 0.717mmol), triethylamine (146.5mg, 1.448mmol) and 2- chloroethylchloroformate ester (104.2mg, 0.7288mmol) is dissolved in dichloromethane (6mL).It is stirred overnight under reactant mixture room temperature, then reduces pressure dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50), obtains title compound for white solid (205mg, yield 62.3%).

LC-MS(ESI,pos.ion)m/z:457.8[M+H]⁺.

Step 2) 3- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan Mutter simultaneously [3,2-b] furans -3- base) oxazolidine -2- ketone

To 2- chloroethyl (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) carbamate (205mg, 0.4473mmol) and DBU (106.8mg, 0.7015mmol) Mixture in add N,N-dimethylformamide (2mL).Reaction system is warming up to 100 DEG C, stirs 8 hours.After reaction terminates, Reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/60), obtains title compound solid for white Body (59.7mg, yield 31.6%).

LC-MS(ESI,pos.ion)m/z:422.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.89(s,1H),7.62(s,1H),7.47(s,1H),7.11-6.79 (m, 1H), 5.83 (d, J=6.7Hz, 1H), 4.73-4.67 (m, 2H), 4.64-4.58 (m, 1H), 4.41 (t, J=3.4Hz, 1H), 4.35 (t, J=8.0Hz, 2H), 4.23 (dd, J=8.7,7.5Hz, 1H), 4.08 (d, J=4.0Hz, 2H), 3.86 (s, 3H), 3.68 (q, J=8.3Hz, 1H), 3.55 (q, J=8.2Hz, 1H), 3.51-3.46 (m, 1H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.1,157.7,157.6,153.3,131.2,122.9,121.3, 86.1,81.7,71.3,71.2,62.2,61.1,54.1,43.1,39.3.

Embodiment 9 3- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) oxazolidine -2- ketone

Step 1) 2- chloroethyl ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine -4- Base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) carbamate

By N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (252.3mg, 0.717mmol), triethylamine (146.5mg, 1.448mmol) and 2- chloroethyl Chloro-formate (104.2mg, 0.7288mmol) is dissolved in dichloromethane (6mL).It is stirred overnight under reactant mixture room temperature, so Reduced pressure concentration afterwards.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50), obtains title compound for white Solid (205mg, yield 62.3%).

LC-MS(ESI,pos.ion)m/z:457.8[M+H]⁺.

Step 2) 3- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) oxazolidine -2- ketone

To 2- chloroethyl ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) carbamate (205mg, 0.4473mmol) and DBU (106.8mg, N,N-dimethylformamide (2mL) is added in mixture 0.7015mmol).Reaction system is warming up to 100 DEG C, stirs 8 hours. After reaction terminates, reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/60), is obtained titled Compound is white solid (59.7mg, yield 31.6%).

LC-MS(ESI,pos.ion)m/z:422.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.89(s,1H),7.62(s,1H),7.47(s,1H),7.11-6.79 (m, 1H), 5.83 (d, J=6.7Hz, 1H), 4.73-4.67 (m, 2H), 4.64-4.58 (m, 1H), 4.41 (t, J=3.4Hz, 1H), 4.35 (t, J=8.0Hz, 2H), 4.23 (dd, J=8.7,7.5Hz, 1H), 4.08 (d, J=4.0Hz, 2H), 3.86 (s, 3H), 3.68 (q, J=8.3Hz, 1H), 3.55 (q, J=8.2Hz, 1H), 3.51-3.46 (m, 1H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.1,157.7,157.6,153.3,131.2,122.9,121.3, 86.1,81.7,71.3,71.2,62.2,61.1,54.1,43.1,39.3.

Embodiment 10a N- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) six Hydrogen furans simultaneously [3,2-b] furans -3- base) piperidines -1- sulfonamide

To N⁴- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrazoles -4- base) In dichloromethane (5mL) solution of pyrimidine -2,4- diamines (200.0mg, 0.57mmol) add triethylamine (115.1mg, 1.14mmol).Reaction system is cooled to 0 DEG C, then piperidines -1- sulfonic acid chloride (125.3mg, 0.68mmol) is added reaction system In.Gained reactant mixture maintains 0 DEG C to stir 30 minutes, then moves to and is stirred overnight under room temperature.After reaction terminates, reduce pressure dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), obtains title compound for yellow solid (76.7mg, yield 27.1%).

LC-MS(ESI,pos.ion)m/z:499.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.90(s,1H),7.61(s,1H),7.48(s,1H),6.78(s, 1H), 5.83 (d, J=6.9Hz, 1H), 4.94 (s, 1H), 4.80-4.50 (m, 3H), 4.26-4.22 (m, 1H), 4.14-3.90 (m,3H),3.87(s,3H),3.49-3.45(m,1H),3.36-3.09(m,4H),1.63-1.55(m,6H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.1,157.6,153.4,131.2,122.9,121.2,104.5, 87.1,81.1,73.7,71.7,60.6,54.0,47.0,39.2,25.3,23.6.

10 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) piperidines -1- sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (200.0mg, 0.57mmol) dichloromethane (5mL) solution in add triethylamine (115.1mg,1.14mmol).Reaction system is cooled to 0 DEG C, then adds piperidines -1- sulfonic acid chloride (125.3mg, 0.68mmol) Enter in reaction system.Gained reactant mixture maintains 0 DEG C to stir 30 minutes, then moves to and is stirred overnight under room temperature.Reaction terminates Afterwards, reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), obtains title compound for Huang Color solid (76.7mg, yield 27.1%).

LC-MS(ESI,pos.ion)m/z:499.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.90(s,1H),7.61(s,1H),7.48(s,1H),6.78(s, 1H), 5.83 (d, J=6.9Hz, 1H), 4.94 (s, 1H), 4.80-4.50 (m, 3H), 4.26-4.22 (m, 1H), 4.14-3.90 (m,3H),3.87(s,3H),3.49-3.45(m,1H),3.36-3.09(m,4H),1.63-1.55(m,6H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.1,157.6,153.4,131.2,122.9,121.2,104.5, 87.1,81.1,73.7,71.7,60.6,54.0,47.0,39.2,25.3,23.6.

Embodiment 11a N- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) six Hydrogen furans simultaneously [3,2-b] furans -3- base) morpholine -4- sulfonamide

To N⁴- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrazoles -4- base) In dichloromethane (5mL) solution of pyrimidine -2,4- diamines (200.0mg, 0.57mmol) add triethylamine (115.1mg, 1.14mmol).Reaction system is cooled to 0 DEG C, then morpholine -4- sulfonic acid chloride (126.6mg, 0.68mmol) is added reaction system In.Gained reactant mixture maintains 0 DEG C to stir 30 minutes, then moves to and is stirred overnight under room temperature.After reaction terminates, reduce pressure dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), obtains title compound for yellow solid (71.1mg, yield 24.9%).

LC-MS(ESI,pos.ion)m/z:501.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.90(s,1H),7.59(s,1H),7.49(s,1H),6.95(s, 1H), 5.81 (d, J=6.9Hz, 1H), 5.42 (s, 1H), 4.72-4.57 (m, 3H), 4.29-4.19 (m, 1H), 4.08-3.91 (m, 3H), 3.86 (s, 3H), 3.80-3.70 (m, 4H), 3.48 (t, J=8.6Hz, 1H), 3.27-3.15 (m, 4H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.1,157.6,153.4,131.2,122.9,121.1,104.4, 87.1,81.0,73.6,71.7,66.1,60.8,53.9,46.2,39.2.

Embodiment 11 N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) morpholine -4- sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (200.0mg, 0.57mmol) dichloromethane (5mL) solution in add triethylamine (115.1mg,1.14mmol).Reaction system is cooled to 0 DEG C, then adds morpholine -4- sulfonic acid chloride (126.6mg, 0.68mmol) Enter in reaction system.Gained reactant mixture maintains 0 DEG C to stir 30 minutes, then moves to and is stirred overnight under room temperature.Reaction terminates Afterwards, reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), obtains title compound for Huang Color solid (71.1mg, yield 24.9%).

LC-MS(ESI,pos.ion)m/z:501.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.90(s,1H),7.59(s,1H),7.49(s,1H),6.95(s, 1H), 5.81 (d, J=6.9Hz, 1H), 5.42 (s, 1H), 4.72-4.57 (m, 3H), 4.29-4.19 (m, 1H), 4.08-3.91 (m, 3H), 3.86 (s, 3H), 3.80-3.70 (m, 4H), 3.48 (t, J=8.6Hz, 1H), 3.27-3.15 (m, 4H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.1,157.6,153.4,131.2,122.9,121.1,104.4, 87.1,81.0,73.6,71.7,66.1,60.8,53.9,46.2,39.2.

12 2- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) 1,1- dioxo isothiazolidine

Step 1) the chloro- N- of 3- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine -4- Base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) propane -1- sulfonamide

At 0 DEG C, to N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines (198.8mg, 0.57mmol) and triethylamine (94.6mg, 0.94mmol) dichloromethane 3- chloropropane -1- sulfonic acid chloride (132.1mg, 0.75mmol) is added in alkane (5mL) solution.Reactant mixture stirs 30 at 0 DEG C Minute, then move to and be stirred overnight under room temperature.Reaction terminate after, add water (1mL) be quenched, decompression be spin-dried for solvent.Gained residue Title compound is obtained for white solid (134.0mg, yield through silica gel column chromatography purifying (MeOH/DCM (v/v)=1/50) 48.2%).

MS(ESI,pos.ion)m/z:492.1[M+H]⁺.

Step 2) 2- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) 1,1- dioxo isothiazolidine

To the chloro- N- of 3- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine -4- agent) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) propane -1- sulfonamide (134.0mg, 0.27mmol) DMF solution (3mL) In, DBU (66.3mg, 0.44mmol) is added, reactant liquor is warming up to 100 DEG C, is stirred overnight.After reaction terminates, gained mixture Add water (15mL) dilution, then extracts (10mL × 3) with dichloromethane.The organic phase washed with water (10mL) of merging is washed, anhydrous slufuric acid Sodium dries, and filters, filtrate reduced in volume.Gained residue is pure through silica gel column chromatography (MeOH/DCM (v/v)=1/50 to 1/20) Change, target compound is obtained for yellow solid (85.2mg, yield 68.7%).

MS(ESI,pos.ion)m/z:456.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:456.1218[M+H]⁺,C₁₇H₂₃ClN₇O₄S[M+H]⁺Theoretical value： 456.1215；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.64(s,1H),7.46(s,1H),6.78(s, 1H), 5.83 (d, J=7.2Hz, 1H), 4.84 (dd, J=4.5,1.7Hz, 1H), 4.72-4.65 (m, 1H), 4.64-4.56 (m, 1H), 4.23 (dd, J=8.6,7.4Hz, 1H), 4.19-4.09 (m, 2H), 4.01-3.96 (m, 1H), 3.87 (s, 3H), 3.49- 3.40(m,2H),3.31-3.25(m,1H),3.23-3.16(m,2H),2.44-2.34(m,2H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.2,157.8,153.4,131.3,123.1,121.4,104.6, 86.4,81.5,71.2,71.1,61.7,53.9,46.9,45.2,39.4,19.1.

13 N- of embodiment ((3R, 6S) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methylpropane -1- sulfonamide

At 0 DEG C, to N⁴- ((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- first Base -1H- pyrazoles -4- base) pyrimidine -2,4- diamines (98.6mg, 0.28mmol) and triethylamine (45.7mg, 0.45mmol) dichloro 2- methylpropane -1- sulfonic acid chloride (50.3mg, 0.32mmol) is added in methane (2mL) solution.Reactant mixture is stirred at 0 DEG C 30 minutes, then heat to room temperature and continue to stir 4 hours.After reaction terminates, add water (0.5mL) be quenched, and reduced pressure concentration.Institute Obtain residue to purify through silica gel column chromatography (MeOH/DCM (v/v)=1/50 to 1/30), title compound is obtained for yellow solid (56.6mg, yield 42.8%).

MS(ESI,pos.ion)m/z:472.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:472.1530[M+H]⁺,C₁₈H₂₇ClN₇O₄S[M+H]⁺Theoretical value： 472.1528；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.91 (s, 1H), 7.90 (s, 1H), 7.42 (s, 1H), 5.25 (d, J= 5.3Hz, 1H), 5.04 (d, J=8.9Hz, 1H), 4.76 (s, 1H), 4.67-4.61 (m, 2H), 4.21 (t, J=8.2Hz, 1H), 4.15-4.08 (m, 1H), 4.05-4.00 (m, 2H), 3.87 (s, 3H), 3.56 (t, J=9.0Hz, 1H), 2.99-2.91 (m, 2H), 2.34-2.27 (m, 1H), 1.12 (d, J=6.7Hz, 6H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):157.8,157.5,153.8,130.4,122.9,121.4,103.7, 86.7,81.3,73.6,72.1,61.7,59.5,56.6,39.3,25.2,22.8,22.7.

14 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) pentamethylene sulfonamide

At -10 DEG C, to N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- first Base -1H- pyrazoles -4- base) pyrimidine -2,4- diamines (150.2mg, 0.43mmol) and triethylamine (217.8mg, 2.15mmol) Pentamethylene sulfonic acid chloride (291.6mg, 1.73mmol) is added in THF (2mL) solution.Reactant mixture is stirred overnight at -10 DEG C, Reaction terminate after, add water (0.5mL) be quenched.Mixture reduced pressure concentration, gained residue is through silica gel column chromatography (MeOH/DCM (v/ V)=1/30) purify, title compound is obtained for yellow solid (51.8mg, yield 25.1%).

MS(ESI,pos.ion)m/z:484.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:484.1527[M+H]⁺,C₁₉H₂₇ClN₇O₄S[M+H]⁺Theoretical value： 484.1528；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.90(s,1H),7.61(s,1H),7.49(s,1H),6.84(s, 1H), 5.82 (d, J=6.8Hz, 1H), 5.00 (d, J=7.8Hz, 1H), 4.69-4.63 (m, 2H), 4.63-4.57 (m, 1H), 4.27-4.21 (m, 1H), 4.11-4.07 (m, 1H), 4.05 (dd, J=9.6,4.7Hz, 1H), 3.91 (dd, J=9.6, 1.7Hz, 1H), 3.87 (s, 3H), 3.55-3.50 (m, 1H), 3.47 (t, J=8.7Hz, 1H), 2.09-1.98 (m, 4H), 1.84-1.79(m,2H),1.68-1.61(m,2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.2,157.8,153.6,131.4,123.0,121.4,104.7, 87.9,81.2,74.2,71.8,62.9,60.8,54.1,39.4,28.4,28.3,26.0,25.9.

Embodiment 15 N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) propane -2- sulfonamide

At -10 DEG C, to N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²-(1- Methyl isophthalic acid H- pyrazoles -4- base) pyrimidine -2,4- diamines (151.2mg, 0.43mmol) and triethylamine (109.3mg, 1.08mmol) Propane -2- sulfonic acid chloride (126.3mg, 0.89mmol) is added in THF (3mL) solution.Reactant mixture is stirred at -10 DEG C Night, reaction terminate after, add water (0.5mL) be quenched.Mixture reduced pressure concentration, gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/30) purify, title compound is obtained for yellow solid (63.4mg, yield 32.2%).

MS(ESI,pos.ion)m/z:458.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:458.1372[M+H]⁺,C₁₇H₂₅ClN₇O₄S[M+H]⁺Theoretical value： 458.1372；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.89(s,1H),7.59(s,1H),7.49(s,1H),7.03(s, 1H), 5.82 (d, J=6.8Hz, 1H), 5.21 (s, 1H), 4.69-4.65 (m, 2H), 4.64-4.58 (m, 1H), 4.24 (dd, J =8.7,7.5Hz, 1H), 4.08-4.03 (m, 2H), 3.93 (d, J=7.8Hz, 1H), 3.86 (s, 3H), 3.51-3.45 (m, 1H), 3.21 (dt, J=13.6,6.8Hz, 1H), 1.40 (d, J=4.2Hz, 6H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.1,157.7,153.4,131.3,123.0,121.3,104.6, 87.9,81.2,74.2,71.8,60.8,54.4,54.0,39.4,16.8,16.7.

Embodiment 16 N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- (tetrahydrofuran -3- base) NSC-249992

Step 1) (tetrahydrofuran -3- base) Loprazolam sodium

3- (bromomethyl) tetrahydrofuran (1.00g, 6.06mmol) is added in the sodium sulfite aqueous solution (10mL) of saturation. Reactant mixture is warming up to and is refluxed 24 hours, then reduced pressure concentration.Ethanol (20mL), gained is added in gained residue Mixture is warming up to 50 DEG C, stirs 30 minutes, filters while hot immediately.Filtrate reduced in volume obtains title compound for white solid (875.3mg, yield 76.8%).

MS(ESI,neg.ion)m/z:165.1[M–Na]^–；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):3.55-3.45 (m, 1H), 3.36 (td, J=8.1,5.0Hz, 1H), 3.28 (dd, J=15.3,7.7Hz, 1H), 3.08 (dd, J=8.3,6.6Hz, 1H), 2.29-2.23 (m, 1H), 2.19-2.10 (m,2H),1.75-1.65(m,1H),1.31-1.19(m,1H).

Step 2) (tetrahydrofuran -3- base) methane sulfonyl chloride

(tetrahydrofuran -3- base) Loprazolam sodium (300.4mg, 1.60mmol) is dissolved in thionyl chloride (5mL), and gained is anti- Answer system to be warming up to be refluxed overnight.After reaction terminates, reactant mixture reduced pressure concentration, title compound is obtained for yellow solid (294.3mg, yield 100%).

Step 3) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- (tetrahydrofuran -3- base) NSC-249992

At 0 DEG C, to N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines (148.7mg, 0.42mmol) and triethylamine (109.3mg, 1.08mmol) THF (3mL) add the tetrahydrofuran (3mL) of (tetrahydrofuran -3- base) methane sulfonyl chloride (162.4mg, 0.88mmol) molten in solution Liquid.Reactant mixture is stirred 30 minutes at 0 DEG C, is then moved to room temperature and is continued stirring 7 hours.After reaction terminates, add water (1mL) It is quenched, gained mixture reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/30), must be marked Topic compound is yellow solid (65.1mg, yield 30.8%).

MS(ESI,pos.ion)m/z:500.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:500.1485[M+H]⁺,C₁₉H₂₇ClN₇O₅S[M+H]⁺Theoretical value： 500.1477；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.88(s,1H),7.57(s,1H),7.50(s,1H),7.05(s, 1H), 5.79 (d, J=6.9Hz, 2H), 4.68-4.64 (m, 2H), 4.63-4.58 (m, 1H), 4.23 (dd, J=8.6,7.6Hz, 1H), 4.07-4.03 (m, 2H), 4.00-3.97 (m, 1H), 3.93-3.90 (m, 1H), 3.88 (dd, J=8.4,3.6Hz, 1H), 3.86 (s, 3H), 3.77 (dd, J=16.0,7.6Hz, 1H), 3.60-3.56 (m, 1H), 3.48 (t, J=8.7Hz, 1H), 3.21-3.13 (m, 2H), 2.76 (dt, J=14.3,7.1Hz, 1H), 2.26-2.19 (m, 1H), 1.78-1.71 (m, 1H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.2,157.8,153.5,131.4,123.1,121.4,104.6, 87.8,81.2,73.9,72.4,71.7,67.6,60.5,57.1,54.1,39.4,34.8,32.1.

Embodiment 17 2- (benzyloxy)-N- ((3S, 6R) -6- ((chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) Pyrimidine-4-yl) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) ethane sulphonamide

Step 1) 2- (benzyloxy) ethane sulfonic acid sodium

2- bromine oxethyl methylbenzene (3.02g, 14.0mmol) and sodium sulfite (2.18g, 17.3mmol) are dissolved in water (10mL) in.Reactant mixture is warming up to and is refluxed reaction 6 hours, after reaction terminates, is concentrated under reduced pressure to give white solid.To Methyl alcohol (100mL) is added in gained solid, 50 DEG C are warming up to, stir 20 minutes, filter while hot immediately.Filtrate reduced in volume must be marked Topic compound is white solid (1.42g, yield 42.5%).

MS(ESI,neg.ion)m/z:215.1[M–Na]^–；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.38-7.24(m,5H),4.44(s,2H),3.66-3.60(m, 1H),2.76-2.69(m,2H).

Step 2) 2- (benzyloxy) ethanesulfonyl chloride

DMF (21.7mg, 0.297mmol) and four to 2- (benzyloxy) ethane sulfonic acid sodium (614.1mg, 2.578mmol) Thionyl chloride (0.6mL, 8mmol) is added in hydrogen furans (20mL) solution.Reactant mixture is warming up to that to be refluxed reaction 5 little When.After reaction terminates, room temperature is cooled to, filters, filter cake is washed with dichloromethane (50mL).Filtrate reduced in volume obtains titled Compound is yellow liquid (712.4mg).Crude product is directly used in next step reaction, need not be further purified.

Step 3) (((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) is phonetic for (3S, 6R) -6- for 2- (benzyloxy)-N- Pyridine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) ethane sulphonamide

By N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (301.1mg, 0.8559mmol) and triethylamine (357.4mg, 3.532mmol) be dissolved in DCM (8mL) in.Reactant mixture is cooled to 0 DEG C, by the DCM of 2- (benzyloxy) ethanesulfonyl chloride (712.4mg, 3.035mmol) (10mL) solution is added in above-mentioned reaction system.Then, move to room temperature to continue to be stirred overnight, after reaction terminates, reduced pressure concentration.Institute Residue through silica gel column chromatography (DCM/MeOH (v/v)=60/1) purify, obtain title compound for white solid (348.7mg, Yield 74%).

MS(ESI,pos.ion)m/z:550.4[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.88(s,1H),7.60(s,1H),7.49(s,1H),7.37-7.28 (m, 5H), 7.15-6.82 (m, 1H), 5.78 (d, J=6.6Hz, 1H), 5.09 (d, J=7.2Hz, 1H), 4.57 (d, J= 3.0Hz, 1H), 4.52 (s, 2H), 4.50-4.45 (m, 1H), 4.32 (t, J=4.6,1H), 4.17 (dd, J=8.5,7.6Hz, 1H), 4.02-3.99 (m, 1H), 3.97-3.93 (m, 2H), 3.89-3.84 (m, 4H), 3.74 (dd, J=9.8,2.1Hz, 1H), 3.42-3.31(m,3H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.0,157.6,153.1,136.8,131.2,128.8,128.5, 128.3,122.9,121.2,104.4,87.1,81.0,74.0,73.6,71.6,65.0,60.4,53.9,52.3,39.3.

18 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- hydroxyl ethane sulfonamide

2- (benzyloxy)-N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine -4- Base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) and ethane sulphonamide (280mg, 0.5091mmol) DCM (10mL) molten Liquid is cooled to 40 DEG C, then the DCM solution (5.5mL, 5.5mmol, 1M) of Boron tribromide is added dropwise in above-mentioned reaction system. Reaction system stirring reaction 4 hours at 40 DEG C, reaction terminate after, add water (10mL) be quenched.Gained mixture NaOH Powder is adjusted to pH=8, then reduced pressure concentration.Gained residue is through silica gel column chromatography (DCM/NH₃MeOH solution (7M) (v/v) =10/1) purify, title compound is obtained for yellow solid (115.6mg, yield 49.4%).

MS(ESI,pos.ion)m/z:460.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:460.1141[M+H]⁺,C₁₆H₂₃ClN₇O₅S[M+H]⁺Theoretical value： 460.1170；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89 (s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 6.62 (d, J= 2.0Hz, 1H), 5.78 (d, J=7.1Hz, 1H), 5.02 (d, J=5.8Hz, 1H), 4.73 (d, J=4.0Hz, 1H), 4.68 (t, J=4.6Hz, 1H), 4.64-4.56 (m, 1H), 4.27-4.21 (m, 1H), 4.12 (t, J=5.2Hz, 2H), 4.10-4.04 (m, 2H), 3.97-3.90 (m, 1H), 3.87 (s, 3H), 3.49 (t, J=8.8Hz, 2H), 3.34 (dd, J=8.8,4.8Hz, 2H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.1,157.6,153.4,131.5,122.9,121.4,104.6, 87.5,81.0,73.7,71.5,60.4,57.3,54.8,54.0,39.2.

19 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- phenyl methane sulfonyl amine

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (150mg, 0.426mmol) DCM (10mL) solution in add TEA (103mg, 1.02mmol).Reactant mixture is cooled to 0 DEG C, then phenyl methane sulfonyl chlorine (161mg, 0.844mmol) is added reactant In system.Reactant mixture is stirred overnight at 0 DEG C, then reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) purify, title compound is obtained for yellow solid (120mg, yield 55.62%).

MS(ESI,pos.ion)m/z:506.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:506.1370[M+H]⁺,C₂₁H₂₅ClN₇O₄S[M+H]⁺Theoretical value： 506.1299；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.79(s,1H),7.55(s,1H),7.48(s,1H),7.40-7.36 (m, 5H), 7.08 (s, 1H), 5.76 (d, J=6.3Hz, 1H), 5.70 (s, 1H), 4.58-4.54 (m, 2H), 4.51 (d, J= 3.0Hz, 1H), 4.31 (m, 2H), 4.20-4.17 (m, 1H), 3.89-3.85 (m, 1H), 3.84 (s, 3H), 3.75 (d, J= 8.4Hz,2H),3.42-3.38(m,1H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.02,157.66,153.33,131.24,130.84,129.11, 129.03,123.03,121.18,104.38,87.74,81.07,73.74,71.69,60.78,59.87,53.98,39.36.

Embodiment 20 N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) tetrahydrofuran -3- sulfonamide

Step 1) tetrahydrofuran -3- sodium sulfonate

To saturation Na₂SO₃3- bromine tetrahydrofuran (2.00g, 14.83mmol) is added in the aqueous solution (20.0mL).Reaction mixing Thing is warming up to backflow, stirring reaction 24 hours, then reduced pressure concentration.Ethanol (30mL) is added in gained residue, be warming up to 50 DEG C, stir 30 minutes, heat filtering immediately.Filtrate reduced in volume, gained residue are vacuum dried that title compound is white Color solid (1.81g, yield 72.6%).MS(ESI,neg.ion)m/z:151.1[M–Na]^–；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):3.80 (t, J=8.6Hz, 1H), 3.71-3.64 (m, 2H), 3.63- 3.57(m,1H),3.20-3.11(m,1H),2.02-1.87(m,2H).

Step 2) tetrahydrofuran -3- sulfonic acid chloride

Tetrahydrofuran -3- sodium sulfonate (800mg, 4.59mmol) is suspended in anhydrous THF (15.0mL), is added thereto to DMF (340mg, 4.59mmol) and thionyl chloride (1.09g, 9.19mmol).Reactant mixture is warming up to and flows back and to stir 4 little When, room temperature is subsequently cooled to, is filtered.Filtrate reduced in volume obtains crude product for brown liquid (0.782g, yield 100%).

Crude product is directly used in next step reaction without further purification.

Step 3) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) tetrahydrofuran -3- sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (201mg, 0.568mmol) THF (10mL) solution in add TEA (345mg, 3.41mmol).Reactant mixture is cooled to 0 DEG C, then, tetrahydrofuran -3- sulfonic acid chloride (389mg, 2.27mmol) is added anti- Answer in system.Reaction system is warming up to 50 DEG C of stirring reactions overnight, then reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) is purified, and obtains title compound for yellow solid (80.0mg, yield 28.8%).

MS(ESI,pos.ion)m/z:486.4[M+H]⁺；

HRMS(ESI,pos.ion)m/z:486.1298[M+H]⁺,C₁₈H₂₅ClN₇O₅S[M+H]⁺Theoretical value： 486.1248；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.88(s,1H),7.56(s,1H),7.51(s,1H),6.15(dd,J =17.2,10.4Hz, 1H), 5.81 (d, J=6.4Hz, 1H), 4.67-4.63 (m, 2H), 4.62-4.57 (m, 1H), 4.25- 4.20(m,1H),4.17-4.12(m,1H),4.10(s,1H),4.07-3.98(m,3H),3.93-3.89(m,1H),3.85(s, 3H), 3.85-3.79 (m, 2H), 3.47 (t, J=8.7Hz, 1H), 2.34-2.28 (m, 2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.02,157.75,153.24,131.26,123.02,121.23, 104.47,87.90,81.16,74.07,71.64,68.47,68.44,62.42,60.89,54.07,39.37,28.43.

Embodiment 21 N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- cyclopenta NSC-249992

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (200mg, 0.568mmol) DCM (5mL) solution in add TEA (175mg, 1.71mmol).Reactant mixture is cooled to 0 DEG C, then, cyclopenta methane sulfonyl chloride (81.6mg, 0.481mmol) is added anti- Answer in system.At 0 DEG C of reaction system stirring reaction overnight, then reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/ DCM (v/v)=1/40) purifying, title compound is obtained for yellow solid (150mg, yield 52.98%).

MS(ESI,pos.ion)m/z:498.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:498.1689[M+H]⁺,C₂₀H₂₉ClN₇O₄S[M+H]⁺Theoretical value： 498.1612；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.88(s,1H),7.57(s,1H),7.50(s,1H),5.84-5.76 (m, 2H), 4.69-4.65 (m, 2H), 4.60-4.56 (m, 1H), 4.23 (t, J=8.1Hz, 1H), 4.06-4.03 (m, 2H), 3.92 (d, J=7.5Hz, 1H), 3.85 (s, 3H), 3.47 (t, J=8.7Hz, 1H), 3.11 (d, J=6.9Hz, 2H), 2.35- 2.29(m,1H),2.00-1.94(m,2H),1.67-1.61(m,2H),1.59-1.54(m,2H),1.32-1.27(m,2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.06,157.73,153.29,131.24,123.05,121.22, 104.39,87.80,81.17,74.01,71.69,60.37,59.31,54.06,39.36,35.37,32.72,24.86.

22 1- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) pyrrolidin-2-one

Step 1) the chloro- N- of 4- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine -4- Base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) butyramide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (216.0mg, 0.61mmol) DCM (5mL) solution in add TEA (93.1mg, 0.92mmol).Reactant mixture is cooled to 10 DEG C, then, 4- chlorobutanoylchloride (103.1mg, 0.73mmol) is added reactant In system.Reactant mixture is stirred 20 minutes at 10 DEG C, is then moved to room temperature and is continued stirring 30 minutes.The decompression of gained mixture is dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/60), obtains title compound for yellow solid (178.3mg, yield 63.6%).

MS(ESI,pos.ion)m/z:457.2[M+H]⁺.

Step 2) 1- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) pyrrolidin-2-one

To the chloro- N- of 4- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) butyramide (149.2mg, 0.37mmol) DMF (5mL) solution in add DBU (85.3mg,0.56mmol).Reaction system is warming up to 100 DEG C of stirring reactions overnight, then reduced pressure concentration.Gained residue is through silicon Plastic column chromatography (MeOH/DCM (v/v)=1/45) is purified, and obtains title compound for yellow solid (45.6mg, yield 33.2%).

MS(ESI,pos.ion)m/z:420.2[M+H]⁺；

HRMS(EI,pos.ion)m/z:420.1549[M+H]⁺,C₁₈H₂₃ClN₇O₃[M+H]⁺Theoretical value：420.1551；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.89(s,1H),7.64(s,1H),7.46(s,1H),6.69(s, 1H), 5.85 (d, J=6.8Hz, 1H), 4.87-4.52 (m, 4H), 4.34-4.17 (m, 1H), 4.02-4.06 (m, 2H), 3.87 (s,3H),3.62-3.42(m,2H),3.40-3.33(m,1H),2.60-2.22(m,2H),2.17-1.93(m,2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):175.1,158.1,157.6,153.4,131.2,122.8,121.4, 104.6,86.3,81.8,71.5,71.2,59.5,54.1,45.2,39.3,30.9,18.3.

23 6- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) nicotinic acid nitrile

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (112.7mg, 0.85mmol) and 6- chlorine apellagrin nitrile n-butanol (4mL) solution in add DIPEA(112.7mg,0.87mmol).Reactant mixture is warming up to 150 DEG C of tube sealing reactions overnight, after reaction terminates, reduces pressure dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/55), obtains title compound for yellow solid (33.2mg, yield 12.6%).

MS(ESI,pos.ion)m/z:454.2[M+H]⁺；

HRMS(EI,pos.ion)m/z:454.1505[M+H]⁺,C₂₀H₂₁ClN₉O₂[M+H]⁺Theoretical value：454.1507；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.42 (d, J=2.0Hz, 1H), 7.91 (s, 1H), 7.64-7.62 (m, 2H), 7.47 (s, 1H), 6.61 (s, 1H), 6.50 (d, J=8.7Hz, 1H), 5.87 (d, J=7.0Hz, 1H), 5.18 (d, J= 6.0Hz, 1H), 4.73 (t, J=4.7Hz, 1H), 4.66-4.59 (m, 2H), 4.49 (s, 1H), 4.35-4.26 (m, 1H), 4.18-4.17 (m, 1H), 3.99-3.97 (m, 1H), 3.87 (s, 3H), 3.56 (t, J=8.6Hz, 1H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.6,158.1,157.6,153.5,153.2,139.9,131.3, 122.8,121.3,118.1,107.4,98.5,86.9,81.5,73.5,72.0,59.3,54.0,50.9,39.3.

24 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methylpropane -2- sulfonamide

Step 1) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methylpropane -2- sulfenamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (246.3mg, 0.70mmol) DCM (4mL) solution in add TEA (106.3mg, 1.05mmol).Reactant mixture is cooled to 10 DEG C, then by 2- methylpropane -2- sulphinyl chlorine (118.1mg, 0.84mmol) Add in reaction system.Reactant mixture is stirred 15 minutes at 10 DEG C, is then moved to room temperature and is continued stirring 30 minutes.Reaction After end, gained mixture reduced pressure concentration, residue purify titled through silica gel column chromatography (MeOH/DCM (v/v)=1/60) Compound is yellow solid (284.8mg, yield 89.2%).

MS(ESI,pos.ion)m/z:456.2[M+H]⁺.

Step 2) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methylpropane -2- sulfonamide

To N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) six Hydrogen furans simultaneously [3,2-b] furans -3- base) -2- methylpropane -2- sulfenamide (282.4mg, 0.62mmol) DCM (4mL) molten Metachloroperbenzoic acid (160.3mg, 0.93mmol) is added in liquid.Reaction system is stirred at room temperature overnight, and then reduces pressure dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/60), obtains title compound for yellow solid (59.6mg, yield 20.4%).

MS(ESI,pos.ion)m/z:472.2[M+H]⁺；

HRMS(EI,pos.ion)m/z:472.1530[M+H]⁺,C₁₈H₂₇ClN₇O₄S[M+H]⁺Theoretical value：472.1534；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.89 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 5.82 (d, J= 6.8Hz,1H),4.83-4.51(m,3H),4.39-4.19(m,1H),4.10-4.08(m,1H),4.05-4.03(m,1H), 3.95 (d, J=9.6Hz, 1H), 3.86 (s, 3H), 3.47-3.45 (m, 2H), 1.41 (s, 9H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.0,157.6,153.3,131.1,122.9,121.1,104.3, 87.9,81.0,74.3,71.6,61.7,60.2,54.0,39.3,24.3.

25 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- cyclopropylmethyl sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (202.3mg, 0.57mmol) DCM (4mL) solution in add TEA (86.3mg, 0.85mmol).Reactant mixture is cooled to 0 DEG C, then, cyclopropylmethyl sulfonic acid chloride (106.3mg, 0.68mmol) is added anti- Answer in system.Reactant mixture is stirred 30 minutes at 0 DEG C, then moves to room temperature reaction overnight, after reaction terminates, is reduced pressure dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/60), obtains title compound for yellow solid (30.2mg, yield 11.2%).

MS(ESI,_pos.ion)m/z:470.2[M+H]⁺；

HRMS(EI,_pos.ion)m/z:470.1376[M+H]⁺,C₁₈H₂₅ClN₇O₄S[M+H]⁺Theoretical value：470.1372；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.90(s,1H),7.62(s,1H),7.48(s,1H),6.65(s, 1H), 5.81 (d, J=6.7Hz, 1H), 5.34 (t, J=4.6Hz, 1H), 4.82 (d, J=6.8Hz, 1H), 4.73-4.65 (m, 2H), 4.63-4.58 (m, 1H), 4.28-4.22 (m, 1H), 4.07-4.05 (m, 2H), 3.93 (d, J=7.8Hz, 1H), 3.87 (s, 3H), 3.01 (d, J=7.1Hz, 2H), 0.86-0.82 (m, 3H), 0.78-0.68 (m, 2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.1,157.6,153.4,131.3,122.8,121.3,104.5, 87.7,81.1,73.9,71.7,60.6,58.8,53.9,39.3,5.4,4.5.

Embodiment 26 N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- cyano group -2- methylpropane -1- sulfonamide

Step 1) 2- cyano group -2 Methylpropionic acid ethyl ester

2- cyan-acetic ester (20g, 176.82mmol) is suspended in the mixed solvent of DMF (200mL) and water (10mL), At 0 DEG C, K is dividedly in some parts thereto₂CO₃(101.83g,442.07mmol).Reaction system stirs 30 minutes at this temperature, so Afterwards, dropping iodomethane (62.75g, 442.1mmol) thereto, drips off in 1 hour, is stirred overnight under gained mixture room temperature.Instead After should terminating, add water (500mL) be quenched reaction, and extract (500mL × 3) with EtOAc.The organic phase of merging is through saturated aqueous common salt (600mL) wash, anhydrous sodium sulfate drying, filter and reduced pressure concentration.Gained residue is through Flash silica column chromatography (PE/EtOAc (v/v)=10/1) purify, title compound is obtained for pale yellow oil (17.15g, yield 68.71%).

¹H NMR(600MHz,CDCl₃)δ(ppm):4.24 (q, J=7.1Hz, 2H), 1.58 (s, 6H), 1.30 (t, J= 7.2Hz,3H).

Step 2) 3- hydroxyl -2,2- dimethyl propionitrile

At 0 DEG C, divide in the methanol solution (200mL) of 2- cyano group -2 Methylpropionic acid ethyl ester (10.34g, 73.25mmol) Secondary addition NaBH₄(5.54g,146mmol).It is stirred overnight under reaction system room temperature.After reaction terminates, reactant liquor saturation chlorination Aqueous ammonium is adjusted to pH=7～8, then extracts (100mL × 3) with EtOAc.The organic phase of merging is through saturated aqueous common salt (150mL) wash, anhydrous sodium sulfate drying, filter and reduced pressure concentration.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v) =20/1 to 10/1) purify, title compound is obtained for colorless oil (4.0g, yield 55.09%).

¹H NMR(400MHz,CDCl₃)δ(ppm):3.44 (d, J=6.3Hz, 2H), 1.23 (s, 6H).

Step 3) the bromo- 2,2- dimethyl propionitrile of 3-

At 0 DEG C, to 3- hydroxyl -2,2- dimethyl propionitrile (4g, 40.35mmol) and CBr₄(20.7g, 62.4mmol's) The anhydrous tetrahydrofuran solution of triphenylphosphine (12.7g, 48.4mmol) is added in anhydrous tetrahydrofuran solution (100mL) (100mL).Reactant mixture is stirred at room temperature overnight, after reaction terminates, mixture reduced pressure concentration, and gained residue is through silica gel Column chromatography (PE/EtOAc (v/v)=20/1) is purified, and obtains title compound for yellow oil (3.27g, yield 50.0%).

¹H NMR(400MHz,CDCl₃)δ(ppm):3.40(s,2H),1.47(s,6H).

Step 4) 2- cyano group -2- methylpropane -1- sodium sulfonate

Bromo- for 3- 2,2- dimethyl propionitrile (3.27g, 20.2mmol) is added in saturated sodium bisulfite solution (25mL).Instead Mixture is answered to be warming up to backflow, stirring reaction 24 hours, then reduced pressure concentration.Ethanol (50mL) is added in gained residue, 50 DEG C are warming up to, after stirring 30 minutes, heat filtering immediately.Filtrate reduced in volume, gained residue add toluene (50mL) to dilute, so Decompression is spin-dried for afterwards.Title compound is obtained after gained residue is vacuum dried for white solid (2.68g, yield 71.7%).

MS(ESI,neg.ion)m/z:162.2[M-Na]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):2.73(s,2H),1.40(s,6H).

Step 5) 2- cyano group -2- methylpropane -1- sulfonic acid chloride

2- cyano group -2- methylpropane -1- sodium sulfonate (1.0g, 5.40mmol) is suspended in thionyl chloride (10mL, 138mmol) In, reaction system is warming up to 80 DEG C and is stirred overnight, and after reaction terminates, is cooled to room temperature and is concentrated under reduced pressure to give title compound and be Brown liquid (980mg, yield 99.91%).Crude product is not purified, is directly used in next step.

Step 6) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- cyano group -2- methylpropane -1- sulfonamide

At 0 DEG C, to N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines (200mg, 0.5685mmol) and TEA (115.1mg, 1.137mmol) anhydrous four The anhydrous tetrahydrochysene of 2- cyano group -2- methylpropane -1- sulfonic acid chloride (207mg, 1.1396mmol) is added in hydrogen furans (10mL) solution Furans (10mL) solution.Reactant mixture is stirred at room temperature 2 hours, after reaction terminates, reduced pressure concentration, and gained residue is through silicon Plastic column chromatography (DCM/MeOH (v/v)=20/1 to 10/1) purify title compound be white solid (135mg, yield 47.78%).

MS(ESI,pos.ion)m/z:497.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:497.1457[M+H]⁺,C₁₉H₂₆ClN₈O₄S[M+H]⁺Theoretical value： 497.1481；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.88(s,1H),7.57(s,1H),7.50(s,1H),7.11(s, 1H), 6.30 (s, 1H), 5.81 (d, J=6.8Hz, 1H), 4.74 (d, J=3.8Hz, 1H), 4.68 (t, J=4.7Hz, 1H), 4.62-4.56 (m, 1H), 4.23 (t, J=8.1Hz, 1H), 4.11-4.04 (m, 2H), 4.00 (d, J=7.6Hz, 1H), 3.85 (s, 3H), 3.48 (dd, J=9.6,7.9Hz, 1H), 3.29 (d, J=1.6Hz, 2H), 1.59 (d, J=7.6Hz, 6H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.1,157.8,153.4,131.4,123.1,123.0,121.4, 104.6,87.6,81.2,77.4,73.6,71.7,60.7,54.0,39.4,30.6,27.2,27.1.

27 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2,2- HFC-143a sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (120mg, 0.341mmol) THF (10mL) solution in add TEA (70.2mg, 0.691mmol).Reactant mixture is cooled to 0 DEG C, then adds 2,2,2- trifluoroethane sulfonyl chloride (96.3mg, 0.525mmol) Enter in reaction system.At 0 DEG C of reaction system stirring reaction overnight, then reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) is purified, and obtains title compound for yellow solid (60mg, yield 35.3%).

MS(ESI,pos.ion)m/z:498.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:498.0936[M+H]⁺,C₁₆H₂₀ClF₃N₇O₄S[M+H]⁺Theoretical value 498.0860；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.88(s,1H),7.51(s,2H),6.72(s,1H),5.79(d,J =6.8Hz, 1H), 4.70-4.65 (m, 2H), 4.63-4.58 (m, 1H), 4.27-4.22 (m, 1H), 4.11 (s, 1H), 4.06 (dd, J=9.8,4.7Hz, 1H), 3.94 (dd, J=9.8,2.1Hz, 1H), 3.90 (q, J=8.9Hz, 2H), 3.85 (s, 3H), 3.48 (t, J=8.8Hz, 1H)；

¹³C NMR(100MHz,DMSO-d₆)δ(ppm):158.03,157.75,153.25,131.43,130.07, 122.91,122.57,120.73,87.52,81.19,73.47,71.72,60.78,54.04,39.39,29.84.

28 N- of embodiment ((3S, 6S) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methylpropane -1- sulfonamide

Step 1) N- ((3S, 6S) -6- ((2,5- dichloropyridine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- Base) -2- methylpropane -1- sulfonamide

To (3S, 6S)-N³- (2,5- dichloropyridine -4- base) hexahydro furyl simultaneously [3,2-b] furans -3,6- diamines TEA (156.1mg, 1.55mmol) is added in DCM (4mL) solution of (300.4mg, 1.03mmol).Reactant mixture is cooled to 0 DEG C, then 2- methylpropane -1- sulphinyl chlorine (194.2mg, 1.24mmol) is added in reaction system.Reactant mixture is 0 Stir 30 minutes at DEG C, then move to room temperature reaction overnight, after reaction terminates, reduced pressure concentration.Gained residue is through silica gel column layer Analysis (MeOH/DCM (v/v)=1/45) purifying, obtains title compound for yellow solid (142.3mg, yield 33.5%).

MS(ESI,pos.ion)m/z:412.8[M+H]⁺.

Step 2) N- ((3S, 6S) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methylpropane -1- sulfonamide

To N- ((3S, 6S) -6- ((2,5- dichloropyridine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) - In n-butanol (3mL) solution of 2- methylpropane -1- sulfonamide (78.7mg, 0.19mmol) add DIPEA (59.8mg, 0.46mmol) with 1- methyl isophthalic acid-H- pyrazoles -4- amine hydrochlorate (30.7mg, 0.23mmol).Reactant mixture is warming up to 150 DEG C, Tube sealing reaction overnight, is reacted after terminating, reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/55) Purifying, obtains title compound for yellow solid (19.4mg, yield 21.5%).

MS(ESI,pos.ion)m/z:472.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:472.1526[M+H]⁺,C₁₈H₂₇ClN₇O₄S[M+H]⁺Theoretical value： 472.1534；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.01(s,1H),7.93(s,1H),7.43(s,1H),5.20(s, 1H), 4.81 (s, 1H), 4.68 (d, J=3.2Hz, 1H), 4.58 (s, 1H), 4.23-4.06 (m, 3H), 4.03-3.94 (m, 2H), 3.87 (s, 3H), 2.95 (dd, J=6.4,1.7Hz, 2H), 2.37-2.16 (m, 1H), 2.03-1.99 (m, 1H), 1.11 (dd, J=6.7,1.3Hz, 6H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):157.5,157.4,153.6,130.1,129.9,122.9,121.5, 87.3,82.7,73.4,72.4,61.7,59.7,58.4,39.1,24.9,22.6.

The chloro- N- of 29 5- of embodiment (1- methyl isophthalic acid H- pyrazoles -4- base) -4- (((3R, 6S) -6- ((N- (tetrahydrofuran -3- Base) amino-sulfonyl) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) pyrimidine -2- amine

Step 1) tetrahydrofuran -3- ammonium (tetrahydrofuran -3- base) sulfamate

Add in mixture at 0 DEG C to tetrahydrofuran -3- amine (1.79g, 20.58mmol) with anhydrous DCM (21.0mL) Anhydrous DCM (3.50mL) solution of chlorosulfonic acid (0.80g, 6.9mmol).Reactant mixture is stirred 30 minutes at 0 DEG C, is then subtracted Pressure is concentrated, and the vacuum dried target compound that obtains of gained residue is for white semi-solid (1.74g, yield 100%).

MS(ESI,neg.ion)m/z:166.2[M₂]^-；

MS(ESI,pos.ion)m/z:88.3[M₁]⁺.

Step 2) (tetrahydrofuran -3- base) sulfamic acid chloride

To tetrahydrofuran -3- ammonium (tetrahydrofuran -3- base) sulfamate (1.74g, 6.84mmol) and toluene (21.0mL) phosphorus pentachloride (1.46g, 7.00mmol) is added in suspending system.Reactant mixture is warming up to 80 DEG C, and stirring is anti- Answer 3 hours.After reaction terminates, it is cooled to room temperature and filters.Filter cake is washed with toluene (10.0mL), and filtrate reduced in volume is marked Topic compound is brown liquid (0.23g, yield 18%).

Step 3) the chloro- N- of 5- (1- methyl isophthalic acid H- pyrazoles -4- base) -4- (((3R, 6S) -6- ((N- (tetrahydrofuran -3- base) Amino-sulfonyl) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) pyrimidine -2- amine

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (0.10g, 0.29mmol) and triethylamine (0.20mL, 1.40mmol) DCM (10.0mL) molten (tetrahydrofuran -3- base) sulfamic acid chloride (0.11g, 0.61mmol) is slowly added in liquid.Reaction system was stirred at room temperature Night, then reduced pressure concentration.Gained residue is through silica gel column chromatography (DCM/ (NH₃MeOH solution (3M)) (v/v)=50/1 arrives 30/1) purify.Through preparing thin-layer chromatography (EtOAc/MeOH (v/v)=30/1) purifying, obtain title compound is gained crude product Yellow solid (18mg, yield 12%).

MS(ESI,pos.ion)m/z:501.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:501.1448[M+H]⁺,C₁₈H₂₆ClN₈O₅S[M+H]⁺Theoretical value： 501.1430；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.14(s,1H),7.96(s,1H),7.74(s,1H),7.48- 7.42 (m, 2H), 7.38-7.33 (m, 1H), 6.32 (d, J=5.9Hz, 1H), 4.75-4.70 (m, 1H), 4.65-4.60 (m, 1H), 4.08 (t, J=7.9Hz, 1H), 3.97-3.91 (m, 1H), 3.84-3.80 (m, 1H), 3.79 (s, 3H), 3.78-3.68 (m,5H),3.68-3.61(m,2H),3.54-3.47(m,1H),2.15-2.05(m,1H),2.05-1.97(m,1H)；

¹³C NMR(150MHz,DMSO-d₆)δ(ppm):174.76,158.15,130.23,130.13,123.83, 120.68,87.30,80.60,73.22,72.58,72.39,66.65,60.17,54.56,53.24,39.13.

30 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2- methylpropane -1- sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (190mg, 0.540mmol) THF (10mL) solution in add TEA (659mg, 6.48mmol).Reactant mixture is cooled to 0 DEG C, then adds 2,2- dimethylpropane -1- sulfonic acid chloride (920mg, 5.40mmol) Enter in reaction system.Reaction system at 0 DEG C stirring reaction overnight, then reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) is purified, and obtains title compound for yellow solid (120mg, yield 45.7%).

MS(ESI,pos.ion)m/z:486.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:486.1684[M+H]⁺,C₁₉H₂₉ClN₇O₄S[M+H]⁺Theoretical value： 486.1612；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.88(s,1H),7.57(s,1H),7.49(s,1H),5.82(s, 2H), 4.66 (s, 2H), 4.59 (s, 1H), 4.23 (t, J=7.7Hz, 1H), 4.04 (s, 2H), 3.92 (d, J=7.1Hz, 1H), 3.85 (s, 3H), 3.48 (t, J=8.3Hz, 1H), 3.06-2.97 (m, 2H), 1.17 (s, 9H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.08,157.72,153.33,131.23,123.06,121.21, 104.43,87.81,81.16,73.97,71.68,65.68,60.32,54.05,39.36,31.77,29.71.

31 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- cyclobutylmethyl alkyl sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (231mg, 0.656mmol) DCM (10mL) solution in add TEA (330mg, 3.26mmol).Reactant mixture is cooled to 0 DEG C, then, cyclobutylmethyl alkanesulphonyl chlorides (440mg, 2.61mmol) is added reaction In system.Reactant mixture is stirred overnight at 0 DEG C, after reaction terminates, reduced pressure concentration.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) is purified, and obtains title compound for yellow solid (150mg, yield 47.2%).

MS(ESI,pos.ion)m/z:484.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:484.1527[M+H]⁺,C₁₉H₂₇ClN₇O₄S[M+H]⁺Theoretical value： 484.1456；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.88 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 5.81 (d, J= 6.7Hz, 1H), 5.66 (s, 1H), 4.67-4.64 (m, 2H), 4.59 (dd, J=12.8,7.6Hz, 1H), 4.23 (t, J= 8.1Hz, 1H), 4.06-4.00 (m, 2H), 3.91 (d, J=9.2Hz, 1H), 3.85 (s, 3H), 3.47 (t, J=8.7Hz, 1H), 3.17 (d, J=7.2Hz, 2H), 2.82 (dt, J=15.6,7.7Hz, 1H), 2.23-2.18 (m, 2H), 1.91-1.76 (m, 4H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.09,157.73,153.36,131.25,123.05,121.23, 104.45,87.79,81.17,74.01,71.72,60.39,59.52,54.06,39.37,30.54,28.45,28.43, 19.26.

Embodiment 32 N- ((3R, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methylpropane -1- sulfonamide

To N⁴- ((3R, 6R) -6- amido tetrahydrofuran simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (30mg, 0.09mmoL) DCM (20mL) solution in add TEA (0.2mL) and 2- methyl-prop Alkane -1- sulfonic acid chloride (40mg, 0.26mmoL).Stir 5 hours under reaction system room temperature, then reduced pressure concentration.Gained residue warp Silica gel column chromatography (DCM/MeOH (v/v)=10/1) is purified, and obtains title compound for white solid (25.0mg, yield 62.0%).

MS(ESI,pos.ion)m/z:472.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.15(s,1H),7.95(s,1H),7.73(s,1H),7.45(s, 1H), 7.27 (d, J=8.1Hz, 1H), 6.33 (d, J=7.0Hz, 1H), 4.76-4.68 (m, 1H), 4.56 (s, 2H), 4.14 (t, J=8.0Hz, 1H), 4.07-3.91 (m, 2H), 3.78 (s, 3H), 3.69-3.59 (m, 1H), 2.96 (t, J=10.1Hz, 2H), 2.12 (dt, J=13.2,6.6Hz, 1H), 2.05-1.92 (m, 1H), 1.02 (d, J=6.7Hz, 6H).

Embodiment 33 N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methybutane -1- sulfonamide

Step 1) 2- methybutane -1- sodium sulfonate

Bromo- for 1- 2- methybutane (2.01g, 13.3mmol) is added in the saturated sodium sulfite aqueous solution (40.0mL).Instead Mixture is answered to be warming up to backflow, stirring reaction 24 hours, then reduced pressure concentration.Ethanol (50mL) is added in gained residue, 50 DEG C are warming up to, after stirring 30 minutes, heat filtering immediately.Filtrate reduced in volume, gained residue are titledly vacuum dried Compound is white solid (1.7g, yield 73%).MS(ESI,neg.ion)m/z:151.0[M-Na]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):2.47-2.40(m,1H),2.27-2.20(m,1H),1.81-1.74 (m, 1H), 1.48-1.40 (m, 1H), 1.19-1.12 (m, 1H), 0.95 (dd, J=6.7,0.8Hz, 3H), 0.81 (dd, J= 7.9,7.0Hz,3H).

Step 2) 2- methybutane -1- sulfonic acid chloride

The mixture of 2- methybutane -1- sodium sulfonate (1.71g, 9.82mmol) and thionyl chloride (30mL) is warming up to 80 DEG C, it is stirred overnight, after reaction terminates, it is yellow liquid (1.7g, yield that reduced pressure concentration obtains the crude product of title compound 100%).Crude product is not purified to be directly used in next step.

Step 3) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methybutane -1- sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (201mg, 0.571mmol) THF (20mL) solution in add TEA (983mg, 5.76mmol).Reactant mixture is cooled to 0 DEG C, then, 2- methybutane -1- sulfonic acid chloride (389mg, 2.29mmol) is added In reaction system.Reaction system is stirred at room temperature overnight, after reaction terminates, reduced pressure concentration.Gained residue is through silica gel column layer Analysis (MeOH/DCM (v/v)=1/50) purifying, obtains title compound for yellow solid (120mg, yield 43%).

MS(ESI,pos.ion)m/z:486.1[M+H]⁺；

HRMS(EI,pos.ion)m/z:486.1684[M+H]⁺,C₁₉H₂₉ClN₇O₄S[M+H]⁺Theoretical value：486.1612；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.90 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 5.84 (d, J= 7.2Hz, 2H), 4.68 (d, J=3.9Hz, 2H), 4.65-4.58 (m, 1H), 4.25 (t, J=8.0Hz, 1H), 4.11-4.03 (m, 2H), 3.94 (d, J=7.4Hz, 1H), 3.88 (s, 3H), 3.50 (t, J=8.6Hz, 1H), 3.14-3.06 (m, 1H), 2.96-2.88 (m, 1H), 2.17 (s, 1H), 2.07 (dt, J=12.7,6.2Hz, 1H), 1.55 (td, J=13.1,7.2Hz, 1H), 1.42-1.32 (m, 1H), 1.13 (d, J=6.7Hz, 3H), 0.93 (t, J=7.4Hz, 3H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.07,157.73,153.30,131.22,123.06,121.18, 104.39,87.80,81.16,73.97,71.69,60.36,59.91,54.05,39.36,31.05,29.35,19.31, 10.98.

34 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- (tetrahydrofuran -2- base) NSC-249992

Step 1) (tetrahydrofuran -2- base) Loprazolam sodium

2- (bromomethane) tetrahydrofuran (2.01g, 12.2mmol) is added saturation Na₂SO₃In the aqueous solution (40.0mL).Instead Mixture is answered to be warming up to backflow, stirring reaction 24 hours, then reduced pressure concentration.Ethanol (50mL) is added in gained residue, 50 DEG C are warming up to, after stirring 30 minutes, heat filtering immediately.Filtrate reduced in volume.Gained residue is titledly vacuum dried Compound is white solid (2.2g, yield 96%).

MS(ESI,neg.ion)m/z:165.1[M-Na]^-.

Step 2) (tetrahydrofuran -2- base) methane sulfonyl chloride

The mixture of (tetrahydrofuran -2- base) Loprazolam sodium (2.21g, 11.7mmol) and thionyl chloride (30mL) heats up To 80 DEG C, it is stirred overnight, after reaction terminates, it is yellow liquid (2.2g, yield that reduced pressure concentration obtains the crude product of title compound 100%).Crude product is not purified to be directly used in next step.

Step 3) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- (tetrahydrofuran -2- base) NSC-249992

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (203mg, 0.577mmol) THF (20mL) solution in add TEA (710mg, 12.2mmol).Reactant mixture is cooled to 0 DEG C, then, by (tetrahydrofuran -2- base) methane sulfonyl chloride (1.1g, 5.98mmol) Add in reaction system.It is stirred overnight under reaction system room temperature, after reaction terminates, reduced pressure concentration.Gained residue is through silicagel column Chromatography (MeOH/DCM (v/v)=1/50) purifying, obtains title compound for yellow solid (140mg, yield 48.5%).

MS(ESI,pos.ion)m/z:500.1[M+H]⁺；

HRMS(EI,pos.ion)m/z:500.1511[M+H]⁺,C₁₉H₂₇ClN₇O₅S[M+H]⁺Theoretical value：500.1405；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89 (s, 1H), 7.60 (d, J=14.8Hz, 1H), 7.49 (d, J= 19.1Hz, 1H), 7.00 (s, 1H), 5.85 (s, 1H), 5.42 (dd, J=19.6,6.3Hz, 1H), 4.76-4.58 (m, 3H), 4.35-4.27 (m, 1H), 4.26-4.20 (m, 1H), 4.08 (d, J=7.1Hz, 1H), 4.03-3.98 (m, 1H), 3.95-3.87 (m, 2H), 3.86 (s, 3H), 3.83-3.76 (m, 1H), 3.49-3.43 (m, 1H), 3.29-3.25 (m, 1H), 3.22 (d, J= 8.1Hz,1H),2.18-2.12(m,1H),1.98-1.90(m,2H),1.67-1.58(m,1H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.11,157.76,153.32,131.39,123.04,121.35, 104.58,87.98,81.41,77.36,74.24,71.34,68.65,60.74,57.31,54.15,39.42,31.53, 25.34.

(((the chloro- 2- of 5- ((1- (piperidin-4-yl) -1H- pyrazoles -4- base) amino) is phonetic for (3S, 6R) -6- for 35 N- of embodiment Pyridine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- cyclopropylmethyl sulfonamide

Step 1) 4- hydroxy piperidine -1- t-butyl formate

Tetrahydrofuran (20mL) solution to piperidines -4- alcohol (2g, 19.773mmol) and triethylamine (4g, 39.530mmol) Middle dropping dimethyl dicarbonate butyl ester (5.2g, 24mmol).It is stirred overnight under reaction system room temperature, after reaction terminates, reduced pressure concentration.Institute Obtain residue to purify through silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 5/1), title compound is obtained for yellow solid (3.91g, yield 98.3%).

LC-MS(ESI,pos.ion)m/z:146.1[M–55]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):3.82 (d, J=8.4Hz, 3H), 3.01 (ddd, J=13.3,9.8, 3.2Hz, 2H), 1.92 (s, 1H), 1.83 (dd, J=11.0,5.5Hz, 3H), 1.44 (s, 9H).

Step 2) 4- (4- nitro -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

At 0 DEG C, to 4- hydroxy piperidine -1- t-butyl formate (1g, 4.969mmol), 4- nitro -1H- pyrazoles (675mg, Add 5.969mmol) and in anhydrous tetrahydro furan (50mL) solution of triphenylphosphine (1.96g, 7.47mmol) azoformic acid Diisopropyl ester (1.5mL, 7.6mmol), dripped off in 30 minutes.Reaction system is stirred at room temperature 1 hour, then moves to room temperature and stirs Mix overnight.By reactant mixture reduced pressure concentration, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=20/1 to 4/1) Purifying, obtains title compound for white solid (1.35g, yield 91.7%).

LC-MS(ESI,pos.ion)m/z:241.2[M–55]⁺.

Step 3) 4- (4- amino -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

Ethanol to 4- (4- nitro -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (1.35g, 4.56mmol) (30mL) Pd/C (135mg, 10% content) is added in solution.Reaction system reacts 2 hours in room temperature, atmosphere of hydrogen, then, Reactant mixture is filtered, filtrate reduced in volume.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=50/1 to 25/1) Purifying, obtains title compound for yellow solid (955mg, yield 78.7%).

LC-MS(ESI,pos.ion)m/z:211.1[M–55]⁺.

Step 4) 4- (4- ((the chloro- 4- of 5- (((3R, 6R) -6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) Pyrimidine -2-base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

To (3R, 6R) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol (2.01g, 6.88mmol) and 4- (4- amino -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (1.21g, 4.54mmol) In 1,4- dioxane (20mL) solution add and cesium carbonate (2.91g, 8.93mmol), BINAP (284mg, 0.456mmol) and Pd(OAc)₂(102mg,0.454mmol).Reactant mixture is warming up to 105 DEG C in nitrogen atmosphere, is stirred overnight, and reaction terminates Afterwards, reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), and it is red to obtain title compound Color solid (1.00g, yield 42.2%).

MS(ESI,pos.ion)m/z:522.2[M+H]⁺.

Step 5) 4- (4- ((the chloro- 4- of 5- (((3R, 6R) -6- ((methyl sulphonyl) epoxide) hexahydro furyl simultaneously [3,2-b] furan Mutter -3- base) amino) pyrimidine -2-base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

To 4- (4- ((the chloro- 4- of 5- (((3R, 6R) -6- hydroxyl hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) pyrimidine - 2- yl) amino) -1H- pyrazol-1-yl) and piperidines -1- t-butyl formate (1.01g, 1.93mmol) DCM (30mL) solution in plus Enter TEA (679mg, 6.71mmol) and DMAP (35mg, 0.286mmol).Reaction system is cooled to 0 DEG C, under nitrogen protective atmosphere encloses, It is added thereto to methane sulfonyl chloride (662mg, 5.78mmol).Gained reactant mixture is stirred 30 minutes at 0 DEG C, is then moved to It is stirred overnight at room temperature.After reaction terminates, mixture adds DCM (100mL) to dilute, with water (50mL) and saturated aqueous common salt (50mL) according to Secondary washing, the organic phase for separating are filtered after anhydrous sodium sulfate drying, filtrate reduced in volume.Gained residue is through silica gel column chromatography (EtOAc/DCM (v/v)=1/2) is purified, and obtains title compound for red solid (740mg, yield 63.7%).

MS(ESI,pos.ion)m/z:600.2[M+H]⁺.

Step 6) 4- (4- ((4- (((3R, 6S) -6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) -5- Chlorine pyrimidine -2-base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

To 4- (4- ((the chloro- 4- of 5- (((3R, 6R) -6- ((methyl sulphonyl) epoxide) hexahydro furyl simultaneously [3,2-b] furans - 3- yl) amino) pyrimidine -2-base) amino) -1H- pyrazol-1-yl) and piperidines -1- t-butyl formate (740mg, 1.23mmol) DMF (10mL) sodium azide (241mg, 3.71mmol) is added in solution.Reaction system is warming up to 140 DEG C, is stirred overnight.Reaction knot Shu Hou, mixture add ethyl acetate (100mL) to dilute, and are then washed with water (50mL × 2), and the organic phase for separating is through anhydrous slufuric acid Sodium is filtered after drying, and filtrate reduced in volume obtains title compound for red oil (600mg, yield 89.0%).

MS(ESI,pos.ion)m/z:547.2[M+H]⁺.

Step 7) 4- (4- ((4- (((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) -5- chlorine Pyrimidine -2-base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

To 4-, (((4- (((3R, 6S) -6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) -5- chlorine is phonetic for 4- Pyridine -2- base) amino) -1H- pyrazol-1-yl) and piperidines -1- t-butyl formate (600mg, 1.10mmol) MeOH (30mL) solution Middle addition Pd/C (mass fraction 10%, 500mg).Reaction system is stirred overnight under room temperature after reaction terminates in atmosphere of hydrogen, Mixture is filtered, filtrate reduced in volume.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/20), must be marked Topic compound is yellow solid (300mg, yield 52.5%).

MS(ESI,pos.ion)m/z:521.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.85(s,1H),7.73(s,1H),7.52(s,1H),7.07(s, 1H), 5.84 (d, J=6.1Hz, 1H), 4.90-4.86 (m, 1H), 4.74-4.70 (m, 1H), 4.59-4.55 (m, 1H), 4.21- 4.17(m,4H),4.07-4.05(m,1H),3.83-3.79(m,1H),3.48-3.41(m,1H),2.89-2.85(m,3H), 2.10 (d, J=10.6Hz, 2H), 1.87 (d, J=8.9Hz, 2H), 1.46 (s, 9H).

Step 8) 4- (4- ((the chloro- 4- of 5- (((3R, 6S) -6- ((Cvclopropvlmethvl sulfonamido) hexahydro furyl simultaneously [3,2- B] furans -3- base) amino) pyrimidine -2-base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

To 4- (4- ((4- (((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) -5- chlorine pyrimidine - 2- yl) amino) -1H- pyrazol-1-yl) and piperidines -1- t-butyl formate (340mg, 0.652mmol) THF (15mL) solution in plus Enter TEA (1.12g, 11.1mmol) and DMAP (8mg, 0.065mmol).Reactant mixture is cooled to 0 DEG C, then, by cyclopropyl Methane sulfonyl chloride (1.51g, 9.77mmol) is added in reaction system.It is stirred overnight under reaction system room temperature, after reaction terminates, subtracts Pressure is concentrated.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50), obtains title compound for yellow solid (140mg, yield 33.6%).

MS(ESI,pos.ion)m/z:639.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.71(s,1H),7.51(s,1H),6.81(s, 1H), 5.81 (d, J=7.0Hz, 1H), 5.39 (d, J=6.4Hz, 1H), 5.31-5.27 (m, 1H), 4.74-4.70 (m, 1H), 4.29-4.16 (m, 4H), 4.08-4.05 (m, 2H), 3.98-3.92 (m, 1H), 3.48-3.43 (m, 2H), 3.02 (d, J= 7.1Hz, 2H), 2.89 (s, 2H), 2.12 (d, J=12.3Hz, 2H), 1.47 (s, 9H), 0.86 (d, J=7.0Hz, 1H), 0.76-0.69 (m, 2H), 0.41 (d, J=4.6Hz, 2H).

Step 9) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- (piperidin-4-yl) -1H- pyrazoles -4- base) amino) pyrimidine -4- Base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- cyclopropylmethyl sulfonamide

To 4- (4- ((the chloro- 4- of 5- (((3R, 6S) -6- ((Cvclopropvlmethvl sulfonamido) hexahydro furyl simultaneously [3,2-b] furan Mutter -3- base) amino) pyrimidine -2-base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (120mg, 0.187mmol) DCM (10mL) solution in add hydrogen chloride acetic acid solution (8mL, 24mmol, 3M).Gained reaction system is stirred at normal temperatures After overnight, reduced pressure concentration.Gained residue is dissolved in DCM (20mL), is adjusted to pH=10 with saturated sodium bicarbonate aqueous solution, so Reduced pressure concentration afterwards.Gained residue is through silica gel column chromatography (DCM/NH₃MeOH solution (7M) (v/v)=20/1) purifying, must mark Topic compound is yellow solid (60mg, yield 59.3%).

MS(ESI,pos.ion)m/z:539.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:539.1951[M+H]⁺,C₂₂H₃₂ClN₈O₄S[M+H]⁺Theoretical value： 539.1877；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.18(s,1H),7.95(s,1H),7.82(s,1H),7.62(s, 1H), 7.49 (s, 1H), 6.35 (s, 1H), 4.74 (t, J=4.4Hz, 1H), 4.63-4.53 (m, 2H), 4.40-4.33 (m, 1H), 4.07 (t, J=8.0Hz, 1H), 3.99-3.94 (m, 1H), 3.89-3.85 (m, 1H), 3.77 (dd, J=9.2,2.8Hz, 1H), 3.66-3.62 (m, 1H), 3.27 (d, J=12.6Hz, 2H), 3.02 (d, J=7.0Hz, 2H), 2.96-2.89 (m, 2H), 2.09-2.00 (m, 4H), 1.05-0.97 (m, 1H), 0.62-0.53 (m, 2H), 0.34 (q, J=4.8Hz, 2H)；

¹³C NMR(100MHz,DMSO-d₆)δ(ppm):157.66,157.13,153.51,129.88,129.59, 123.15,117.43,87.55,80.04,72.98,69.42,59.77,56.50,55.94,54.02,48.53,42.78, 40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.75,29.02,28.95,28.76,28.51, 26.50,13.86,5.19,3.97.

36 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2- Difluoroethane sulfonamide

Step 1) 2,2- difluoroethanol

LiAlH₄Be suspended in THF ((97%, 3.96g, 101.2mmol, 200mL), at -10 DEG C, dropping 2,2- thereto Ethyl difluoro (24.76g, 199.5mmol).After adding, reactant mixture is continuously maintained at -10 DEG C and stirs 1 hour, uses The aqueous hydrochloric acid solution of 2M is adjusted to pH=2～3.Gained mixture vacuum distillation, the cut for collecting 90～96 DEG C obtain title compound Thing is colorless oil (7.30g, yield 44.6%).

¹H NMR(400MHz,CDCl₃)δ(ppm):5.85 (tt, J=55.7,3.8Hz, 1H), 3.81 (td, J=14.5, 3.8Hz,2H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):-127.90.

Step 2) the bromo- 1,1- Difluoroethane of 2-

At 0 DEG C, to PPh₃Br is dripped in DCM (50mL) solution of (15.77g, 60.12mmol)₂(3.2mL, 62.45mmol).After adding, reactant mixture continues to stir 0.5 hour at this temperature, then by 2,2- difluoroethanol DCM (50mL) solution of (4.10g, 49.97mmol) is added dropwise in above-mentioned system.After adding, reactant mixture maintains -10 DEG C Lower continuation stirring 1 hour.Gained mixture vacuum distillation, the cut for collecting 43～50 DEG C obtain title compound for colorless oil Thing (2.04g, yield 28.2%).

¹H NMR(400MHz,CDCl₃)δ(ppm):5.93 (tt, J=55.7,4.2Hz, 1H), 3.48 (td, J=14.2, 4.2Hz,2H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):-116.03.

Step 3) 2,2- difluoromethane sodium sulfonate

2- bromo- 1,1- Difluoroethane (1.90g, 13.11mmol) is dissolved in the mixed solvent of EtOH (15mL) and water (15mL) In, it is added thereto to sodium sulfite (5.20g, 41.26mmol).Reaction system is warming up to 100 DEG C, is stirred overnight, and reaction terminates Afterwards, reduced pressure concentration.Ethanol (50mL) is added in gained residue, 50 DEG C are warming up to, after stirring 30 minutes, heat filtering immediately. Filter cake is washed with ethanol (30mL × 3), and filtrate reduced in volume obtains title compound for white solid (2.21g, yield 100%).

MS(ESI,neg.ion)m/z:145.1[M-Na]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):6.06 (tt, J=56.5,4.5Hz, 1H), 3.00 (td, J= 15.9,4.5Hz,2H)；

¹⁹F NMR(376MHz,DMSO-d₆)δ(ppm):-112.18.

Step 4) 2,2- Difluoroethane sulfonic acid chloride

PCl is added in mixture of 2,2- difluoromethane sodium sulfonate (2.70g, 16.06mmol) with toluene (30mL)₅ (7.48g,35.93mmol).Reactant mixture is warming up to 120 DEG C and is stirred overnight, and after reaction terminates, is concentrated under reduced pressure to give crude product For yellow oil (1.94g, yield 73.4%).Crude product is not purified to be directly used in next step reaction.

Step 5) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2- Difluoroethane sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (431.8mg, 1.23mmol) and 2,2- Difluoroethane sulfonic acid chloride (1.94g, 11.79mmol) THF (20mL) solution in add triethylamine (1.44g, 14.23mmol).Reaction system stirs 15 minutes at -10 DEG C, then Add water (30mL) be quenched reaction, and extracted with DCM (100mL × 3).The organic phase of merging is washed through saturated aqueous common salt (100mL), no Aqueous sodium persulfate dries, and filters and reduced pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/10), It is buff white solid (18.0mg, yield 3.1%) to obtain title compound.MS(ESI,pos.ion)m/z:480.0[M+H]⁺；

HRMS(ESI,pos.ion)m/z:480.1037[M+H],C₁₆H₂₁ClF₂N₇O₄S[M+H]⁺Theoretical value： 480.1032；

¹H NMR(400MHz,CDCl₃+CD₃OD)δ(ppm):7.81(s,1H),7.55(s,1H),7.50(s,1H),6.16 (tt, J=54.7,4.3Hz, 1H), 4.64 (m, 2H), 4.56 (m, 1H), 4.18 (t, J=8.0Hz, 1H), 4.02 (m, 2H), 3.86 (dd, J=9.9,2.6Hz, 1H), 3.82 (s, 3H), 3.60 (td, J=13.7,4.2Hz, 2H), 3.46 (dd, J= 17.9,9.3Hz,1H)；

¹³C NMR(100MHz,CDCl₃+CD₃OD)δ(ppm):131.3(s),122.5(s),121.6(s),113.9(s), 112.3 (s), 110.7 (s), 87.6 (s), 81.0 (s), 73.4 (s), 71.2 (s), 60.1 (s), 55.9 (t, J=24.0Hz), 53.7(s),39.04(s)；

¹⁹F NMR(376MHz,CDCl₃+CD₃OD)δ(ppm):-115.59.

37 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) the fluoro- 2- methylpropane -1- sulfonamide of -3-

Step 1) 3- (benzyloxy) -2- methyl propyl- 1- alcohol

Sodium hydride (16.04g, 401.0mmol, mass fraction 60%) is suspended in THF (600mL), is added thereto to 2- Methylpropane -1,3- glycol (30.11g, 334.1mmol), reactant mixture are warming up to 50 DEG C of stirrings 2 hours, then, thereto Add cylite (57.08g, 333.7mmol).Reactant mixture is warming up to 65 DEG C and is stirred overnight.After reaction terminates, add water (500mL) dilute, and (500mL × 3) are extracted with EtOAc.The organic phase of merging is filtered and reduces pressure and be dense through anhydrous sodium sulfate drying Contracting.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=20/1 to 10/1), and it is faint yellow to obtain title compound Liquid (44.6g, yield 74.1%).

MS(ESI,pos.ion)m/z:181.4[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.37-7.27(m,3H),4.52(s,2H),3.65-3.57(m,2H), 3.54 (dd, J=9.1,4.7Hz, 1H), 3.45-3.40 (m, 1H), 2.42 (s, 1H), 2.11-2.03 (m, 1H), 0.89 (d, J =7.0Hz, 3H).

Step 2) ((the fluoro- 2- methyl propoxyl group of 3-) methyl) benzene

At -78 DEG C, in DCM from nitrogen atmosphere to 3- (benzyloxy) -2- methylpropane -1- alcohol (20.64g, 114.5mmol) (250mL) dropping DAST (74mL, 560mmol) in solution, after adding, reacts 1 day under reaction system normal temperature.After reaction terminates, 0 At DEG C, add water (150mL) reaction is quenched, separate organic phase, washed with diluted hydrochloric acid aqueous solution (1M, 100mL × 2), anhydrous Na₂SO₄ Dry, filter and reduced pressure concentration.Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 80/1), is obtained Title compound is yellow liquid (14.55g, yield 69.7%).

¹H NMR(400MHz,CDCl₃)δ(ppm):7.39-7.27 (m, 5H), 4.53 (s, 2H), 4.42 (dd, J=47.5, 5.4Hz, 2H), 3.49-3.37 (m, 2H), 2.23-2.06 (m, 1H), 1.01 (d, J=6.9Hz, 3H).

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):–227.34.

Step 3) the fluoro- 2- methylpropane -1- alcohol of 3-

((the fluoro- 2- methyl propoxyl group of 3-) methyl) benzene (14.55g, 79.84mmol), Pd/C (7.54g, mass fraction 10%) it is placed in autoclave and is warming up to 70 DEG C of stirrings in 3MPa atmosphere of hydrogen with the mixture of THF (150mL), reaction is overnight. Reactant mixture is filtered, and filter cake is washed with THF (60mL), and filtrate obtains titled through vacuum distillation, the cut at collecting 100 DEG C Compound is colourless liquid (4.93g, yield 67.0%).

¹H NMR(400MHz,CDCl₃)δ(ppm):4.41 (dddd, J=22.6,15.1,9.0,5.6Hz, 2H), 3.60 (d, J=6.0Hz, 2H), 2.10-1.94 (m, 1H), 0.95 (d, J=7.0Hz, 3H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):–226.52.

Step 4) the fluoro- 2- methylpropane of the bromo- 3- of 1-

At 0 DEG C, in DCM (200mL) solution of triphenylphosphine (16.85g, 64.24mmol), it is added dropwise to simple substance bromine (3.3mL,64mmol).Reactant mixture is stirred 30 minutes at 0 DEG C, be subsequently adding fluoro- -1 alcohol of 2- methylpropane of 3- (4.93g, 53.5mmol).Reaction system is stirred overnight at 0 DEG C.After reaction terminates, mixture is through vacuum distillation, evaporating at collecting 100 DEG C Get title compound for colourless liquid (2.02g, yield 24.3%).

¹H NMR(400MHz,CDCl₃)δ(ppm):4.39 (dddd, J=25.2,15.6,9.1,5.7Hz, 2H), 3.45 (d, J=5.9Hz, 2H), 2.28-2.11 (m, 1H), 1.06 (d, J=6.9Hz, 3H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):–225.65.

Step 5) the fluoro- 2- methylpropane -1- sodium sulfonate of 3-

The bromo- 3- of 1- fluoro- 2- methylpropane (1.9g, 12mmol), sodium sulfite (6.21g, 49.3mmol) and water (80mL) Mixture at 100 DEG C, tube sealing reaction is overnight.After reaction terminates, mixture reduced pressure concentration.Second is added in gained residue Alcohol (160mL), is warming up to 50 DEG C, after stirring 1 hour, heat filtering immediately.Filter cake is washed with ethanol (80mL).Filtrate reduced in volume It is white solid (1.89g, yield 87.0%) to obtain title compound.

MS(ESI,neg.ion)m/z:155.1[M–Na]^–；

¹H NMR(400MHz,D₂O)δ(ppm):4.51 (dddd, J=46.4,31.8,9.0,5.5Hz, 2H), 3.13 (dd, J=14.4,5.5Hz, 1H), 2.87 (dd, J=14.4,7.3Hz, 1H), 2.49 2.32 (m, 1H), 1.17 (d, J=6.9Hz, 3H)；

¹⁹F NMR(376MHz,D₂O)δ(ppm):–223.49.

Step 6) the fluoro- 2- methylpropane -1- sulfonic acid chloride of 3-

DMF is added in THF (80mL) solution of the fluoro- 2- methylpropane -1- sodium sulfonate (1.89g, 10.6mmol) of 3- (0.4mL, 5mmol) and thionyl chloride (3.9mL, 54mmol).Reactant mixture is warming up to backflow and stirs in nitrogen atmosphere Overnight.After reaction terminates, mixture reduced pressure concentration obtains title compound for yellow semisolid (1.85g, yield 100%).Thick product Thing is directly used in next step reaction, need not be further purified.

Step 7) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) the fluoro- 2- methylpropane -1- sulfonamide of -3-

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (223.8mg, 0.6362mmol) DCM (5mL) solution in add TEA (1.2mL, 8.6mmol), reactant mixture is cooled to 0 DEG C, then by fluoro- for 3- 2- methylpropane -1- sulfonic acid chloride (1.85g, 10.6mmol) DCM (5mL) solution is added in above-mentioned system.Reactant mixture maintains 0 DEG C to stir 40 minutes.After reaction terminates, add water (50mL) Reaction is quenched and (50mL × 3) is extracted with DCM.The organic phase of merging is filtered and reduced pressure concentration through anhydrous sodium sulfate drying.Gained Residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=40/1), and (109.1mg is produced for yellow solid to obtain title compound Rate 35.0%).

MS(ESI,pos.ion)m/z:490.0[M+H]⁺；

HRMS(ESI,pos.ion)m/z:490.1456[M+H]⁺,C₁₈H₂₆ClFN₇O₄S[M+H]⁺Theoretical value 490.1440；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.59(s,1H),7.49(s,1H),6.99-6.80 (m, 1H), 5.80 (d, J=7.1Hz, 1H), 5.47-5.39 (m, 1H), 4.69-4.64 (m, 2H), 4.63-4.54 (m, 1H), 4.48-4.34 (m, 1H), 4.29-4.20 (m, 2H), 4.10-4.01 (m, 2H), 3.92 (dd, J=11.4,4.1Hz, 1H), 3.86 (s, 3H), 3.48 (t, J=8.7Hz, 1H), 3.31 (dd, J=14.2,5.4Hz, 1H), 2.97 (ddd, J=14.3, 6.9,3.7Hz, 1H), 2.56-2.41 (m, 1H), 1.19 (d, J=6.9Hz, 3H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.0,157.6,153.3,131.2,122.9,121.2,104.5, 87.6 (d, J=11.9Hz), 86.9,85.2,81.1,73.8 (d, J=9.0Hz), 71.7 (d, J=3.1Hz), 60.4,55.7 (dd, J=24.1,4.5Hz), 39.2,31.1,30.9,15.9 (d, J=6.3Hz)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):-224.34,-224.41.

38 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2- difluoropropane -1- sulfonamide

Step 1) bis- fluoropropyl trifluoromethayl sulfonic acid ester of 2,2-

At -20 DEG C, to 2,2- difluoropropane -1- alcohol (5.00g, 52.0mmol) and triethylamine (9.40mL, 67.6mmol) DCM (75mL) solution in drip Trifluoromethanesulfonic anhydride (10.5mL, 62.4mmol), move to 0 DEG C after adding and be stirred overnight.Instead After should terminating, mixture is poured in frozen water (100mL) with after DCM (75mL) dilution.Organic phase is separated, uses 20%Na₂CO₃Water-soluble Liquid (50mL) and saturated aqueous common salt (50mL) are washed successively, anhydrous Na₂SO₄After drying, target chemical combination is filtered, and concentrated under reduced pressure to give Thing is dark oil thing (11.41g, yield 96.1%).

¹H NMR(400MHz,DMSO-d₆)δ(ppm):5.08 (t, J=13.5Hz, 2H), 1.72 (t, J=19.3Hz, 3H)；

¹⁹F NMR(376MHz,DMSO-d₆)δ(ppm):-74.6,-99.7.

Step 2) 2- (bis- fluoropropyl of 2,2-) isothiourea trifluoromethayl sulfonic acid

Add in ethanol (120mL) solution of bis- fluoropropyl trifluoromethayl sulfonic acid ester (11.41g, 50.01mmol) of 2,2- Thiocarbamide (3.81g, 50.1mmol), reactant mixture are warming up to and are refluxed 2 hours.After reaction terminates, mixture reduced pressure concentration, It is yellow solid (15.22g, yield 100%) to obtain title compound.

MS(ESI,pos.ion)m/z:155.1[M₁]⁺；

MS(ESI,neg.ion)m/z:149.0[M₂]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.08 (s, 4H), 3.84 (t, J=15.2Hz, 2H), 1.72 (t, J =18.8Hz, 3H)；

¹⁹F NMR(376MHz,DMSO-d₆)δ(ppm):-77.8,-89.7.

Step 3) 2,2- difluoropropane -1- sulfonic acid chloride

At 5 DEG C, in acetonitrile (100mL) solution of sodium chlorite (13.57g, 150.0mmol) add concentrated hydrochloric acid (30mL, 12M).Then, at 10 DEG C, by 2- (2,2- bis- fluoropropyl) isothiourea trifluoromethayl sulfonic acid (15.22g, 50.02mmol) Acetonitrile (20mL) solution was added in above-mentioned system in 10 minutes.After adding, mixture is stirred 30 minutes, after reaction terminates, plus Enter frozen water (100mL) and reaction is quenched.Organic solvent is removed under reduced pressure at 15 DEG C, gained residue add water (100mL) dilution, Ran Houyong EtOAc (100mL × 2) is extracted.The organic phase of merging is filtered, filtrate decompression through saturated common salt water washing, anhydrous sodium sulfate drying Title compound is concentrated to give for yellow oil (3.06g, yield 34.3%).

¹H NMR(400MHz,DMSO-d₆)δ(ppm):3.10 (t, J=14.2Hz, 2H), 1.71 (t, J=19.5Hz, 3H)；

¹⁹F NMR(376MHz,DMSO-d₆)δ(ppm):-81.6.

Step 4) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2- difluoropropane -1- sulfonamide

At 0 DEG C, to N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines (200.3mg, 0.57mmol), triethylamine (289.4mg, 2.86mmol) and DMAP 2,2- difluoropropane -1- sulfonic acid chloride (410.6mg, 2.30mmol) is added in DCM (5mL) solution of (14.6mg, 0.12mmol). Reactant mixture is stirred 30 minutes at 0 DEG C, is then moved to and is stirred overnight at room temperature.After gained mixture adds DCM (10mL) dilution, Washed with water (10mL × 2).The organic phase for separating is filtered, filtrate reduced in volume through anhydrous sodium sulfate drying.Gained residue is through silicon Plastic column chromatography (MeOH/DCM (v/v)=1/50 to 1/20) is purified, and obtains crude product for white solid.Crude product is through preparing efficient liquid Phase chromatogram is further purified, and obtains target compound for white solid (349.5mg, yield 61.4%).

MS(ESI,pos.ion)m/z:494.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:494.1192[M+H]⁺,C₁₇H₂₃ClF₂N₇O₄S[M+H]⁺Theoretical value 4494.1183；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.57(s,1H),7.49(s,1H),7.00(s, 1H), 6.13 (s, 1H), 5.79 (d, J=7.0Hz, 1H), 4.71-4.56 (m, 3H), 4.24 (t, J=8.0Hz, 1H), 4.12- 3.99 (m, 2H), 3.93 (d, J=8.4Hz, 1H), 3.86 (s, 3H), 3.66 (t, J=12.5Hz, 2H), 3.48 (t, J= 8.6Hz, 1H), 1.86 (t, J=19.3Hz, 3H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.0,157.6,153.4,131.2,122.9,121.2,119.9, 104.4,87.5,81.1,77.2,73.5,71.6,60.5,58.6,39.2,23.5.

Embodiment 39 N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- (3- fluorine cyclobutyl) NSC-249992

Step 1) 3- oxo cyclobutane formate methyl esters

H is added in methyl alcohol (500mL) solution of 3- oxo cyclobutane formate (20.1g, 176mmol)₂SO₄The aqueous solution (9.5mL,17.48mmol,1.84M).Reaction system is warming up to 75 DEG C, is stirred overnight, after reaction terminates, reduced pressure concentration.Gained Residue saturated sodium bicarbonate aqueous solution is adjusted to pH=10, and mixture extracts (200mL × 3) with DCM.The organic phase warp of merging Saturated common salt water washing (100mL), then through anhydrous sodium sulfate drying, filters, and reduced pressure concentration obtains title compound for yellow oil Shape thing (20.8g, yield 92.2%).

¹H NMR(400MHz,CDCl₃)δ(ppm):3.76(s,3H),3.46-3.36(m,2H),3.33-3.20(m,3H).

Step 2) 3- hydroxycyclobutane methyl formate

In nitrogen atmosphere, the MeOH (50mL) at 0 DEG C to 3- oxo cyclobutane formate methyl esters (11.5g, 89.8mmol) is molten Sodium borohydride (3.72g, 98.6mmol) is added in liquid.Reactant mixture is stirred 30 minutes at 0 DEG C, then moves to room temperature continuation Stirring 30 minutes.To in gained mixture, add saturated aqueous ammonium chloride (50mL) that reaction is quenched, then extracted with ethyl acetate Take (200mL × 3).The organic phase of merging is washed through saturated aqueous common salt (100mL), then uses anhydrous sodium sulfate drying, is filtered, filtrate Reduced pressure concentration.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=3/1), obtains title compound solid for brown Body (8.00g, yield 68.5%).

¹H NMR(400MHz,CDCl₃)δ(ppm):4.20-4.16 (m, 1H), 3.68 (s, 3H), 2.59 (t, J=5.8Hz, 3H),2.31(s,1H),2.20-2.12(m,2H).

Step 3) 3- fluorine cyclobutane formate methyl esters

In nitrogen atmosphere, DCM (200mL) solution of 3- hydroxycyclobutane methyl formate (7g, 53.8mmol) is cooled to -78 DEG C, then, DAST (35mL, 265mmol, 1.22g/mL) is added in above-mentioned system.Mixture stirring reaction 1 at -78 DEG C Hour, then move to and be stirred overnight at room temperature.At 0 DEG C, add water (50mL) reaction is quenched, then with DCM (200mL × 3) extract.Close And organic phase after anhydrous sodium sulfate drying reduced pressure concentration, obtain title compound for brown oil (7g, yield 98.5%).

¹H NMR(400MHz,CDCl₃)δ(ppm):3.70 (s, 3H), 3.58 (q, J=7.2Hz, 1H), 3.15-3.10 (m, 1H),2.85-2.76(m,1H),2.54-2.41(m,3H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):-151.8.

Step 4) (3- fluorine cyclobutyl) methyl alcohol

N₂In atmosphere, diethyl ether (150mL) solution of 3- fluorine cyclobutane formate methyl esters (7.02g, 53.1mmol) is cooled to- 10 DEG C, LAH (4g, 105.4mmol) is added in above-mentioned system.Reactant mixture is stirred 1 hour under -10 °, moves to room temperature, It is stirred overnight.Reactant mixture is cooled to 0 DEG C, then slowly adds water successively (10mL), the 15%KOH aqueous solution (10mL) and in addition 40mL water, is quenched reaction.Gained mixture is filtered through diatomite.Filtrate is extracted with ether (200mL × 3), the organic phase of merging Through anhydrous sodium sulfate drying, filter, filtrate reduced in volume.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=6/1) Purifying, obtains title compound for brown solid (1.36g, yield 24.6%).

¹H NMR(400MHz,CDCl₃)δ(ppm):5.21-4.99 (m, 1H), 3.61 (d, J=6.5Hz, 2H), 2.52- 2.19(m,5H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):-167.1.

Step 5) 1- (bromomethyl) -3- fluorine cyclobutane

N₂In atmosphere, Br₂The DCM (20mL) of (0.85mL, 17.0mmol, 2M) and triphenylphosphine (4.12g, 15.7mmol) Solution is cooled to 0 DEG C, then adds (3- fluorine cyclobutyl) methyl alcohol (1.36g, 13.1mmol) in above-mentioned system.Mixture is 0 It is stirred overnight at DEG C, then reaction is quenched with the saturated sodium sulfite aqueous solution (50mL).Gained mixture is with DCM (100mL × 3) Extraction.The organic phase of merging is washed through saturated aqueous common salt (50mL), and after anhydrous sodium sulfate drying, reduced pressure concentration obtains title compound and is Brown oil (2.1g, yield 96%).

¹H NMR(400MHz,CDCl₃)δ(ppm):5.22-5.01 (m, 1H), 3.43 (d, J=7.4Hz, 2H), 2.81 (ddd, J=9.1,4.5,2.0Hz, 1H), 2.48-2.34 (m, 2H), 2.22 (ddd, J=20.5,13.0,6.4Hz, 2H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):-171.2.

Step 6) (3- fluorine cyclobutyl) Loprazolam sodium

1- (bromomethyl) -3- fluorine cyclobutane (2.10g, 13.0mmol) is added the saturated sodium sulfite aqueous solution (30.0mL) In.Reaction system is warming up to 100 DEG C of stirrings 24 hours, then reduced pressure concentration.Ethanol (20mL) is added in gained residue, rise Temperature is stirred 30 minutes, heat filtering immediately to 50 DEG C.Filtrate reduced in volume, gained residue is in DCM (50mL) and H₂O(20mL) It is layered in system.The water for separating mutually reduces pressure and is concentrated to give title compound for white solid (900mg, yield 38%).

MS(ESI,neg.ion)m/z:167.1[M-Na]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):5.22-4.98 (m, 1H), 3.39 (s, 1H), 3.36 (d, J= 6.1Hz,1H),2.29-2.10(m,5H)；

¹⁹F NMR(376MHz,DMSO-d₆)δ(ppm):-168.5.

Step 7) (3- fluorine cyclobutyl) methane sulfonyl chloride

(3- fluorine cyclobutyl) Loprazolam sodium (700mg, 3.68mmol) is suspended in anhydrous THF (30mL), thereto plus Enter DMF (265mg, 3.63mmol) and thionyl chloride (4mL, 55.1mmol, 13.8M).Reactant mixture is warming up to 70 DEG C of stirrings Overnight, after reaction terminates, reduced pressure concentration obtains crude product for yellow oil (680mg, yield 38%).Crude product is not purified straight Connect for next step.

Step 8) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- (3- fluorine cyclobutyl) NSC-249992

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (150mg, 0.426mmol) THF (20mL) solution in add TEA (513mg, 5.07mmol) with DMAP (5mg, 0.040mmol).Reactant mixture is cooled to 0 DEG C, then by (3- fluorine cyclobutyl) sulfonyl methane Chlorine (690mg, 3.70mmol) is added in reaction system.Reactant mixture is stirred 1 hour at 0 DEG C, after reaction terminates, is reduced pressure dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), obtains title compound for yellow solid (90mg, yield 42.1%).

MS(ESI,pos.ion)m/z:502.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:502.1431[M+H]⁺,C₁₉H₂₆ClFN₇O₄S[M+H]⁺Theoretical value： 502.1361；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.58(s,1H),7.50(s,1H),6.96(s, 1H), 5.80 (d, J=7.0Hz, 1H), 5.57 (d, J=7.5Hz, 1H), 4.68-4.64 (m, 2H), 4.59 (dd, J=12.9, 7.6Hz, 1H), 4.24 (t, J=8.0Hz, 1H), 4.08-4.01 (m, 2H), 3.90 (d, J=8.2Hz, 1H), 3.86 (s, 3H), 3.48 (t, J=8.6Hz, 1H), 3.21 (dd, J=13.9,7.4Hz, 2H), 3.05-2.90 (m, 1H), 2.61-2.45 (m, 2H),2.39-2.28(m,2H),2.14-1.96(m,1H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.2,157.8,153.5,131.4,123.0,121.4,88.3, 87.8,81.2,74.0,71.8,60.5,58.8,54.1,39.4,35.7,24.2；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):-173.2.

40 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) the fluoro- 2- methylpropane -1- sulfonamide of 3,3,3- tri-

Step 1) the fluoro- 2- methyl-propyl trifluoromethayl sulfonic acid ester of 3,3,3- tri-

Three second are added in DCM (20mL) solution of the fluoro- 2- methylpropane -1- alcohol (800mg, 6.25mmol) of 3,3,3- tri- Amine (950mg, 9.39mmol).Reactant mixture is cooled to -20 DEG C, and then Trifluoromethanesulfonic anhydride (2.20g, 7.70mmol) adds Enter in above-mentioned system.Reaction system is stirred overnight at 0 DEG C.Reactant mixture is diluted with DCM (50mL), then with the hydrochloric acid of 1M The aqueous solution (50mL × 2) is washed, and the organic phase for separating reduced pressure concentration after anhydrous sodium sulfate drying obtains title compound for yellow Grease (1.1g, yield 68%).

¹H NMR(400MHz,CDCl₃)δ(ppm):4.64-4.46 (m, 2H), 2.79-2.67 (m, 1H), 1.29 (d, J= 7.1Hz,3H).

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):–71.6,–74.5.

Step 2) 2- (the fluoro- 2- methyl-propyl of 3,3,3- tri-) isothiourea trifluoromethayl sulfonic acid

EtOH (10mL) solution to the fluoro- 2- methyl-propyl trifluoromethayl sulfonic acid ester (950mg, 9.39mmol) of 3,3,3- tri- Middle addition thiocarbamide (950mg, 9.39mmol).Reactant mixture is warming up to 80 DEG C, stirs 1 hour.After reaction terminates, mixture subtracts Pressure is concentrated to give title compound for yellow oil (1g, yield 70%).

MS(ESI,pos.ion)m/z:187.1[M₁]⁺；

MS(ESI,neg.ion)m/z:149.0[M₂]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.20(s,2H),9.00(s,2H),3.52-3.48(m,2H), 2.89-2.76 (m, 1H), 1.17 (d, J=6.9Hz, 3H).

¹⁹F NMR(376MHz,DMSO-d₆)δ(ppm):–70.8,–77.8.

Step 3) the fluoro- 2- methylpropane -1- sulfonic acid chloride of 3,3,3- tri-

At 5 DEG C, concentrated hydrochloric acid (4mL, 12M) is added in acetonitrile (10mL) solution of sodium chlorite (865g, 9.56mmol). At 10 DEG C, by the acetonitrile of 2- (3,3,3- tri- fluoro- 2- methyl-propyl) isothiourea trifluoromethayl sulfonic acid (800mg, 2.39mmol) (10mL) solution was added in above-mentioned reaction system in 10 minutes.Mixture is stirred 30 minutes, after reaction terminates, adds water (10mL) reaction is quenched.Organic solvent is removed under reduced pressure at 15 DEG C, residue add water (10mL) dilution, with ethyl acetate (50mL × 3) extract.The organic phase of merging is concentrated under reduced pressure to give title compound for yellow oil after anhydrous sodium sulfate drying (500mg, yield 99.5%).

Step 4) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) the fluoro- 2- methylpropane -1- sulfonamide of -3,3,3- three

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (150mg, 0.426mmol) THF (10mL) solution in add TEA (305mg, 3.01mmol) with DMAP (5mg, 0.040mmol).Reactant mixture is cooled to 0 DEG C, then by fluoro- for 3,3,3- tri- 2- methyl-prop Alkane -1- sulfonic acid chloride (500mg, 2.37mmol) is added in reaction system.Stir 1 hour at 0 DEG C of reaction system, reaction subtracts after terminating Pressure is concentrated.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), obtains title compound for yellow solid (104mg, yield 46.4%).

MS(ESI,pos.ion)m/z:526.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:526.1269[M+H]⁺,C₁₈H₂₄ClF₃N₇O₄S[M+H]⁺Theoretical value： 526.1173；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.57(s,1H),7.50(s,1H),7.03(s, 1H), 6.05 (d, J=26.2Hz, 1H), 5.79 (d, J=6.8Hz, 1H), 4.68-4.63 (m, 2H), 4.60 (dd, J=12.6, 7.6Hz, 1H), 4.24 (t, J=8.0Hz, 1H), 4.06 (dd, J=7.0,5.0Hz, 2H), 3.92 (dd, J=13.9,6.2Hz, 1H), 3.86 (s, 3H), 3.48 (t, J=8.6Hz, 1H), 3.41 (d, J=14.2Hz, 1H), 3.06-2.97 (m, 1H), 2.90- 2.77 (m, 1H), 1.39 (d, J=6.9Hz, 3H)；

¹³C NMR(101MHz,CDCl₃)δ(ppm):158.2,157.8,153.5,131.4,128.4,123.0,121.4, 104.59,87.7,81.2,73.9,71.8,60.6,54.1,39.4,35.2,29.8,13.2；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):–73.4,–73.5.

41 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- hydroxy-2-methyl propane -1- sulfonamide

Step 1) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) NSC-249992

At 0 DEG C, to N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamines (500mg, 1.421mmol) and TEA (0.5mL, 4mmol) DCM (50mL) solution DCM (5mL) solution of middle dropping methane sulfonyl chloride (200mg, 1.746mmol), dripped off in 30 minutes.Reactant mixture is at 0 DEG C Under be stirred overnight, add water (50mL) reaction is quenched, then with DCM (100mL × 3) extract.The organic phase of merging is through reduced pressure concentration It is white solid (580mg, yield 94.9%) to obtain title compound.

MS(ESI,pos.ion)m/z:430.1[M+H]⁺.

Step 2) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- hydroxy-2-methyl propane -1- sulfonamide

At 78 DEG C, to N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) NSC-249992 (375mg, 0.872mmol) THF (75mL) solution in Add n-BuLi (hexane solution of 1.6mL, 3.5mmol, 2.2M).Reactant mixture is stirred 0.5 hour at 78 DEG C, Then DCM (1mL) solution of acetone (60.0mg, 1.03mmol) is slowly added thereto.After adding, reactant mixture is 78 Continue stirring 3 hours at DEG C, then add water H₂O (40mL) is quenched and is extracted with DCM (30mL × 3), the organic phase decompression of merging Concentrate.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), obtains crude product for white solid.Thick product Thing obtains title compound for white solid (125mg, yield through preparing thin-layer chromatography (MeOH/DCM (v/v)=1/30) purifying 29.4%).

MS(ESI,pos.ion)m/z:488.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:488.1468[M+H],C₁₈H₂₇ClN₇O₅S[M+H]⁺Theoretical value： 488.1483；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.14(s,1H),7.94(s,1H),7.74(s,1H),7.53(s, 1H),7.44(s,1H),6.31(s,1H),4.89(s,1H),4.71(s,1H),4.62(s,1H),4.53(m,1H),4.07(s, 1H), 3.95 (s, 1H), 3.87 (t, J=22.8Hz, 2H), 3.77 (s, 3H), 3.62 (s, 1H), 3.22 (s, 1H), 1.29 (s, 6H)；

¹³C NMR(150MHz,DMSO-d₆)δ(ppm):158.1,157.6,154.0,130.2,123.8,120.7, 87.8,80.6,73.4,69.9,68.6,63.6,60.4,54.4,39.1,29.7.

42 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) the fluoro- 2- methylpropane -1- sulfonamide of -3,3- two

Step 1) 3- (benzyloxy) -2 methyl propanal

At 0 DEG C, divide in DCM (150mL) solution of 3- benzyloxy -2- methyl -propyl- 1- alcohol (24.03g, 133.3mmol) Secondary addition DMP (68.12g, 160.6mmol) mixture is stirred 30 minutes at 0 DEG C, then heats to room temperature continuation stirring 5 little When.After reaction terminates, filter, filter cake is washed with DCM (300mL).Filtrate reduced in volume.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=40/1 to 30/1) is purified, and obtains title compound for colourless liquid (19.32g, yield 81.31%).

MS(ESI,pos.ion)m/z:201.1[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.73 (d, J=1.2Hz, 1H), 7.40-7.27 (m, 5H), 4.53 (s, 2H), 3.72-3.61 (m, 2H), 2.72-2.59 (m, 1H), 1.14 (d, J=7.1Hz, 3H).

Step 2) ((the fluoro- 2- methyl propoxyl group of 3,3- bis-) methyl) benzene

At 78 DEG C, drip in DCM (300mL) solution of 3- (benzyloxy) -2 methyl propanal (19.32g, 108.4mmol) Plus DAST (86mL, 651mmol), drip off in 30 minutes.Reactant mixture is stirred 1 hour at 78 DEG C, is then moved to room temperature and is stirred Mix overnight.At 0 DEG C, water (200mL) is slowly added to in reactant mixture reaction is quenched, then extracted with DCM (300mL).Point The organic phase for going out is through anhydrous Na₂SO₄After drying, reduced pressure concentration.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/ 0 to 80/1) purify, title compound is obtained for yellow solid (7.81g, yield 36.0%).

¹H NMR(400MHz,CDCl₃)δ(ppm):7.42-7.28 (m, 5H), 5.91 (td, J=57.0,3.7Hz, 1H), 4.53 (s, 2H), 3.50 (d, J=6.5Hz, 2H), 2.35-2.17 (m, 1H), 1.07 (d, J=7.0Hz, 3H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):–123.46,–124.21,–128.93,–129.68.

Step 3) the fluoro- 2- methyl propyl- 1- alcohol of 3,3-

By ((the fluoro- 2- methyl propoxyl group of 3,3- bis-) methyl) benzene (7.81g, 39.0mmol), Pd/C (7.84g, mass fraction 10%) it is placed in autoclave and is warming up to 70 DEG C in 2MPa atmosphere of hydrogen and is stirred overnight with the mixture of THF (150mL).Reaction After end, filtering, and filter cake being washed with THF (30mL), filtrate decompression is distilled, the cut of 100 DEG C of collection obtains title compound and is Colourless liquid (3.5g, yield 81.0%).

¹H NMR(400MHz,CDCl₃)δ(ppm):5.82 (td, J=56.7,3.8Hz, 1H), 3.64 (d, J=4.0Hz, 2H), 2.19-2.00 (m, 1H), 1.01 (d, J=7.1Hz, 3H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):–123.69,–124.44,–126.71,–127.46.

Step 4) the fluoro- 2- methylpropane of the bromo- 1,1- bis- of 3-

At 0 DEG C, in DCM (150mL) solution of triphenylphosphine (10.23g, 39.00mmol) dropping bromine simple substance (2mL, 39.0mmol), reactant mixture is stirred 30 minutes at 0 DEG C.Then, by fluoro- to 3,3- 2- methyl propyl- 1- alcohol (3.5g, (20mL solution is added in above-mentioned system DCM 32mmol).Reactant mixture is stirred 3 hours at 0 DEG C.Then, vacuum distillation, 40～45 DEG C of cut is collected, and title compound is obtained for colourless liquid (1.83g, yield 33.0%).

¹H NMR(400MHz,CDCl₃)δ(ppm):5.82 (td, J=56.4,4.1Hz, 1H), 3.41 (qd, J=10.5, 6.0Hz, 2H), 2.36-2.18 (m, 1H), 1.15 (d, J=6.9Hz, 3H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):–123.49,–124.24,–127.85,–128.60.

Step 5) the fluoro- 2- methylpropane -1- sodium sulfonate of 3,3- bis-

The bromo- 1,1- bis- fluoro- 2- methylpropane (850mg, 4.9133mmol) of 3-, sodium sulfite (2.44g, 19.4mmol) and Tube sealing reaction is overnight at 100 DEG C for the mixture of water (30mL).Reactant mixture reduced pressure concentration.Gained residue ethanol (60mL), after diluting, stir 30 minutes at 50 DEG C, heat filtering immediately.Filter cake is washed with ethanol (30mL).Filtrate reduced in volume It is white solid (1.6g, yield 170%) to obtain title compound.

MS(ESI,neg.ion)m/z:173.0[M–Na]–；

¹H NMR(400MHz,D₂O)δ(_ppm):6.00 (td, J=56.5,2.8Hz, 1H), 3.19 (dd, J=14.5, 4.5Hz, 1H), 2.87 (dd, J=14.4,8.1Hz, 1H), 2.58-2.40 (m, 1H), 1.20 (d, J=7.0Hz, 3H)；

¹⁹F NMR(376MHz,D₂O)δ(ppm):–124.29,–125.02,–125.31,–126.04.

Step 6) the fluoro- 2- methylpropane -1- sulfonic acid chloride of 3,3- bis-

To the fluoro- 2- methylpropane -1- sodium sulfonate (960m of 3,3- bis-_g, 4.8942mmol) THF (40mL) solution in add DMF (0.2mL, 3mmol) and thionyl chloride (1.8mL, 25mmol).In nitrogen atmosphere, reactant mixture is warming up to and flows back and stir Mix overnight.After reaction terminates, reduced pressure concentration obtains crude product for yellow solid-liquid mixture.Crude product is without further purification It is directly used in next step reaction.

Step 7) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) the fluoro- 2- methylpropane -1- sulfonamide of -3,3- two

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (254.7mg, 0.7240mmol) DCM (8mL) solution in add TEA (1mL, 7.2mmol).Reactant mixture is cooled to 0 DEG C, by fluoro- to 3,3- bis- 2- methylpropane -1- sulfonic acid chloride (943mg, 4.896mmol) DCM (12mL) solution add in above-mentioned reaction system.Reaction system is stirred 30 minutes at 0 DEG C, then add water (30mL) quench Go out reaction, and extracted with DCM (50mL × 3).The organic phase of merging is filtered and reduced pressure concentration through anhydrous sodium sulfate drying.Gained Residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=40/1), and (43.9mg is produced for yellow solid to obtain title compound Rate 11.9%).

MS(ESI,pos.ion)m/z:508.5[M+H]⁺；

HRMS(ESI,pos.ion)m/z:508.1345[M+H]⁺,C₁₈H₂₅ClF₂N₇O₄S[M+H]⁺Theoretical value： 507.1267；

¹H NMR(400MHz,CDCl₃)δ(_ppm):7.88(s,1H),7.58(s,1H),7.50(s,1H),7.20-6.88 (m, 1H), 5.91-5.85 (m, 1H), 5.81 (d, J=3.8Hz, 1H), 5.70-5.56 (m, 1H), 4.72-4.64 (m, 2H), 4.63-4.56(m,1H),4.29-4.20(m,1H),4.10-4.01(m,2H),3.96-3.89(m,1H),3.86(s,3H), 3.48 (t, J=8.2Hz, 1H), 3.41-3.30 (m, 1H), 3.06-2.92 (m, 1H), 2.65-2.49 (m, 1H), 1.26 (d, J =4.5Hz, 3H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):158.0,157.6,153.2,131.2,122.9,121.2,116.9 (t, J=243.0Hz), 104.4,87.5 (d, J=20.6Hz), 81.1 (d, J=2.6Hz), 73.7 (d, J=17.5Hz), 71.6 (d, J=2.3Hz), 60.4,53.9,53.2 (d, J=44.3Hz), 39.3,34.2 (t, J=20.9Hz), 12.9 (d, J =15.2Hz)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):–123.36,–123.57,–124.10,–124.31,–125.41,– 125.58,–126.16,–126.32.

43 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methyl propyl- 1- alkene -1- sulfonamide

Step 1) 2- (the fluoro- 2- methyl-propyl of 2-) isothiourea trifluoromethayl sulfonic acid

Add in ethanol (20mL) solution of (fluoro- 2 methyl-propyl of 2-) triflate (1.0g, 4.461mmol) Thiocarbamide (340mg, 4.467mmol).Reactant mixture is warming up to 80 DEG C and stirs 2 hours.After reaction terminates, reduced pressure concentration obtains title Compound is white solid (1.34g, yield 100%).

MS(ESI,pos.ion)m/z:151.1[M–OTf]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.08(s,2H),8.94(s,2H),3.53(s,1H),3.48(s, 1H),1.44(s,3H),1.39(s,3H).

Step 2) the fluoro- 2- methylpropane -1- sulfonic acid chloride of 2-

At 5 DEG C, in acetonitrile (10mL) solution of sodium sulfite (2.02g, 17.9mmol) add concentrated hydrochloric acid (6mL, 12M).Then, at 10 DEG C, be added thereto to 2- (the fluoro- 2- methyl-propyl of 2-) isothiourea trifluoromethayl sulfonic acid (1.34g, (5mL) solution 4.46mmol).Reactant mixture is stirred 30 minutes at 10 DEG C, after reaction terminates, adds water (30mL) to be quenched Reaction.Organic solvent is removed under reduced pressure at 15 DEG C, residue add water (20mL) dilution, with ethyl acetate (30 × 3mL) extract.Close And organic phase washed with saturated aqueous common salt (50mL), anhydrous sodium sulfate drying, filters and reduced pressure concentration obtains title compound and is Yellow oil (515mg, yield 66.1%).

¹H NMR(400MHz,DMSO-d₆)δ(ppm):2.94(s,1H),2.91(s,1H),1.48(s,3H),1.43(s, 3H).

Step 3) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- methyl propyl- 1- alkene -1- sulfonamide

To N⁴- ((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (220mg, 0.6254mmol) anhydrous DCM (10mL) solution in add TEA (222mg, 2.194mmol) with DMAP (15.3mg, 0.125mmol).At 20 DEG C, by fluoro- for 2- 2- methylpropane -1- sulfonic acid chloride (546mg, 3.1268mmol) add in above-mentioned reaction system.It is stirred overnight under reaction system room temperature, after reaction terminates, reduced pressure concentration.Gained Residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=50/1 to 20/1), obtains title compound for light red solid (106mg, yield 36.07%).

MS(ESI,pos.ion)m/z:470.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:470.1383[M+H]⁺,C₁₈H₂₅ClN₇O₄S[M+H]⁺Theoretical value： 470.1372；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.13 (s, 1H), 7.94 (s, 1H), 7.75 (d, J=6.6Hz, 1H), 7.66 (d, J=6.4Hz, 1H), 7.44 (s, 1H), 6.31 (d, J=5.0Hz, 1H), 6.17 (s, 1H), 4.72 (t, J= 4.5Hz, 1H), 4.59 (d, J=3.2Hz, 1H), 4.07 (q, J=8.4Hz, 1H), 3.98-3.92 (m, 1H), 3.78 (s, 3H), 3.76 (dd, J=9.7,2.8Hz, 2H), 3.68 (s, 1H), 3.60 (d, J=12.7Hz, 1H), 2.03 (s, 3H), 1.89 (s, 3H)；

¹³C NMR(150MHz,DMSO-d₆)δ(ppm):157.7,157.2,153.5,150.8,129.8,124.5, 123.4,120.3,87.4,87.1,80.2,72.8,69.6,59.8,40.1,38.7,26.1,18.9.

44 N- of embodiment ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- hydroxy propane -1- sulfonamide

Under 78 °, to N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) NSC-249992 (150mg, 0.426mmol) THF (20mL) solution in Add n-BuLi (hexane solution of 1.45mL, 2.5M).Reactant mixture maintains this temperature to stir 30 minutes, then by second Aldehyde (46mg, 1.04mmol) is added in above-mentioned reaction system.Mixture continues stirring 2 hours at 78 DEG C, then water on the rocks (5mL) reaction is quenched.By reactant mixture reduced pressure concentration, gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/ 30) purify, title compound is obtained for yellow solid (45mg, yield 13.6%).

MS(ESI,pos.ion)m/z:474.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:474.1323[M+H]⁺,C₁₇H₂₅ClN₇O₅S[M+H]⁺Theoretical value： 474.1248；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.85 (s, 1H), 7.52 (d, J=19.1Hz, 2H), 7.15 (s, 1H), 6.01 (d, J=17.3Hz, 1H), 5.77 (s, 1H), 4.67 (dd, J=54.1,45.8Hz, 3H), 4.40 (s, 1H), 4.21 (s, 1H), 4.03 (d, J=31.0Hz, 3H), 3.84 (s, 3H), 3.47 (s, 1H), 3.23 (dd, J=32.9,23.1Hz, 2H), 1.31(s,3H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.1,157.7,153.3,131.4,131.3,123.1,121.3, 87.9,81.2,73.7,71.3,63.6,60.5,59.8,53.6,39.3,23.3.

Biologic test

Experimental facilities and condition：

LC/MS/MS system employed in biological test embodiment A and embodiment B of the present invention includes Agilent 1200 serial vacuum degassing furnaces, binary syringe pump, orifice plate automatic sampler, post insulating box, charged spray ionization (ESI) source Agilent G6430 three-level level Four bar mass spectrograph.Wherein, quantitative analysis is carried out under MRM pattern, the parameter of MRM conversion Summarize in the following table.

Table A

Analysis injects 5 μ L sample using μM post of Agilent XDB-C18,2.1 × 30mm, 3.5.Analysis condition：Mobile phase Aqueous formic acid (A) for 0.1% and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient is summarized In the following table

Table B

Additionally, for the also 6330 series LC/MS/MS spectrometer of Agilent of analysis, noting equipped with G1312A binary Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrometer adopts ESI radioactive source.Using titer Carrying out suitable cation model treatment and MRM conversion to each analyte carries out optimal analysis.Use during analyzing Capcell MP-C18 post, specification is：100x 4.6mm I.D., 5 μM (Phenomenex, Torrance, California, USA).Mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A)：5mM ammonium acetate, 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 sample.

Stability in embodiment A people and rat liver microsomes

Stability of the compounds of this invention in people and rat liver microsomes can be detected by following two methods：

Method 1：

People or rat liver microsomes are placed in polypropylen tubes carries out duplicate hole incubation.Typical incubation mixed liquor includes People or rat liver microsomes (0.5mg protein/mL), target compound (5 μM) and the NADPH (1.0mM) that cumulative volume is 200 μ L Kaliumphosphate buffer (PBS, 100mM, pH value are 7.4), compound is dissolved in DMSO, and is diluted using PBS so as to The concentration of final DMSO solution is 0.05%.And be incubated in the water-bath communicated with air at 37 DEG C, preincubate 3 minutes Albumen is added in backward mixed liquor and starts reaction.In different time points (0,5,10,15,30 and 60min), same volume is added Ice-cold acetonitrile terminating reaction.It is centrifuged 10 minutes with 4000rpm, except deproteinized, supernatant is collected, 100 μ L of supernatant liquid adds 100 μ L water Dilution, for sample analysis.LC/MS/MS analysis draws sample peak area and internal standard peak area ratio, and the medicine of 0min point is contained Take temperature work 100%, calculate the relative amount of each time point medicine.So that " medicine is relative to be contained in GraphPad Prism 5.01 Amount " calculates the half-life of medicine to " incubation time " mapping, and then calculates inherent clearance rate.

Then the linear concentration scope of each target compound, is surveyed by the method for LC/MS/MS through determining Set the goal concentration of the compound in people or rat liver microsomes mixtures incubated.

Use the microsome of denaturation as negative control, parallel incubating, as positive control, is carried out using dextromethorphan (70 μ Μ) Educate test.Negative control, is incubated at 37 DEG C, reacts and terminates within (0,15 and 60 minute) in different time points；Positive control, It is incubated at 37 DEG C, reacts and terminate within (0,5,10,15,30 and 60 minute) in different time points.All adopt in each assay method With positive and negative control sample, to ensure the integrality of microsome incubation system.

Method 2：

Additionally, stability data of the compound of the present invention in people or rat liver microsomes also can be obtained by tests below Arrive：

People or rat liver microsomes are placed in duplicate hole incubation in polypropylen tubes.Typical mixtures incubated include people or Rat liver microsomes (ultimate density：0.5mg albumen/mL), target compound (ultimate density：1.5 μM) and cumulative volume be 30 μ L K- cushioning liquid (containing 1.0mMEDTA, 100mM, pH 7.4).Compound is dissolved in DMSO, and dilute with K- cushioning liquid Release, the ultimate density for making DMSO is 0.2%.After preincubate 10 minutes, 15 μ L NADPH (ultimate densities are added：2mM) enzyme is carried out Promote reaction, whole test is carried out in 37 DEG C of incubation tube.In different time points (0,15,30 and 60 minute), 135 μ L are added Acetonitrile (containing IS) terminating reaction.It is centrifuged 10 minutes with 4000rpm, except deproteinized, supernatant is collected, is analyzed with LC-MS/MS.

In above-mentioned test, ketanserin (1 μM) is selected as positive control, is incubated at 37 DEG C, reacts in the different time Point terminates for (0,15,30 and 60 minute).All include positive control sample in each assay method, to ensure microsome incubation body The integrality of system.

Data analysis

For each reaction, concentration (as a percentage) of the compound in people or rat liver microsomes incubation is pressed With respect to the plotted as percentage of zero time point, internal CLint 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 Experimental result with 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

NT:Test

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 quantitation the compounds of this invention is for power Learn and evaluate

Pharmacokinetic of the present invention to the compounds of this invention in mouse, rat, dog or monkey body is commented Estimate.The compounds of this invention with the aqueous solution or the aqueous solution of 2%HPMC+1% Tween-80, the saline solution of 5%DMSO+5%, 4% MC or capsule form are administered.Intravenous injection is administered, animal used as test gives the dosage of 0.5,1 or 2mg/kg.For mouth Dosage (p.o.) is taken, rat and mouse are 0.5,1,5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25 in time point, Blood (0.3mL) is taken within 0.5,1.0,2.0,3.0,4.0,6.0,8.0,12 and 24 hour, and 10 are centrifuged under 3,000 or 4,000rpm Minute.Plasma solutions are collected, and is preserved at -20 DEG C or -70 DEG C until carrying out above-mentioned LC/MS/MS analysis.As a result show, When the compound intravenous injection administration that the present invention is provided or oral administration, in the medicine generation that compound of the present invention shows, is dynamic Mechanical property, including preferably absorbing the oral administration biaavailability that becomes reconciled.

As a result referring to table 2, table 2 is experiment knot of medicine of the compound provided in an embodiment of the present invention in rat body for feature Really.

Medicine of the compound provided in an embodiment of the present invention of table 2 in rat body is for the experimental result of feature

As shown in Table 2, when the compound intravenous injection administration for the present invention being provided or oral administration, chemical combination of the present invention Thing shows good pharmacokinetic property in rat body, including preferably absorbing (AUC_last) become reconciled oral bio profit Expenditure (F).

Embodiment C Kinase activity assays

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

The general description of kinase assay

Kinase assay by detect mix γ-³³The myelin basic protein (MBP) of P-ATP is come completed.Prepare 20 μ g/ MBP (Sigma#M-1891) trishydroxymethylaminomethane buffer salt solution (TBS of ml；50mM Tris pH 8.0,138mM NaCl, 2.7mM KCl), white 384 orifice plate (Greiner) of high associativity is coated, per 60 μ L of hole.4 DEG C, it is incubated 24h.Use afterwards 100 μ L TBS wash plate 3 times.Kinase reaction is in kinase buffer liquid [the 5mM Hepes pH 7.6,15mM that cumulative volume is 34 μ L NaCl, 0.01% bovine serum albumin(BSA) (Sigma#I-5506), 10mM MgCl₂, 1mM DTT, 0.02%TritonX-100] in Carry out.Compound is dissolved in DMSO, is added in each hole, the ultimate density of DMSO is 1%.Twice of each data determination, per The measure of individual compound is at least tested twice.Such as, the ultimate density of enzyme is 10nM or 20nM.Addition does not have markd ATP (10 μM) and γ-³³The ATP of P mark is (per hole 2 × 10⁶Cpm, 3000Ci/mmol) start reaction.Reaction is shaken at room temperature Carry out 1 hour.The 384 orifice plates PBS of 7x, is subsequently adding the scintillation solution of 50 μ L of every hole.Counted with Wallac Trilux Device testing result.To those of ordinary skill in the art, this is only the one kind in numerous detection methods, and other methods are also Can.

The IC that above-mentioned test method can be inhibited₅₀And/or inhibition constant K_i.IC₅₀It is defined as under test conditions, suppression Make compound concentration during 50% enzymatic activity.The curve comprising 10 concentration point is made using the extension rate of 1/2log, estimation IC₅₀Value (for example, makes a typical curve by following compound concentration：3μM、1μM、0.3μM、0.1μM、0.03μM、 0.01μM、0.003μM、0.001μM、0.0003μM、0μM).

JAK1(h)

, in 20mM Tris/HCl pH 7.5,0.2mM EDTA, 500 μM with SEQ ID NO for JAK1 (h)：Amino shown in 1 The polypeptide of acid sequence, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) deposit It is incubated under the conditions.Start reaction after adding MgATP mixture.40 minutes are incubated under room temperature afterwards, be added thereto to 3% phosphoric acid solution carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid 5 Cleaning 3 times in minute, and preserve drying and being put into before scinticounting at once in methanol solution.

GEEPLYWSFPAKKK(SEQ ID NO：1).

JAK2(h)

, in 8mM MOPS pH 7.0,0.2mM EDTA, 100 μM with SEQ ID NO for JAK2 (h)：Amino acid sequence shown in 2 The polypeptide of row, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) be present Under the conditions of be incubated.Start reaction after adding MgATP mixture.40 minutes are incubated under room temperature afterwards, be added thereto to 3% phosphorus Acid solution carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid at 5 minutes Interior cleaning 3 times, and preserve drying and being put into before scinticounting at once in methanol solution.

KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC(SEQ ID NO：2).

JAK3(h)

, in 8mM MOPS pH 7.0,0.2mM EDTA, 500 μM with SEQ ID NO for JAK3 (h)：Amino acid sequence shown in 3 The polypeptide of row, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) be present Under the conditions of be incubated.Start reaction after adding MgATP mixture.40 minutes are incubated under room temperature afterwards, be added thereto to 3% phosphorus Acid solution carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid at 5 minutes Interior cleaning 3 times, and preserve drying and being put into before scinticounting at once in methanol solution.

GGEEEEYFELVKKKK(SEQ ID NO：3).

TYK2(h)

, in 8mM MOPS pH 7.0,0.2mM EDTA, 250 μM with SEQ ID NO for TYK2 (h)：Amino acid sequence shown in 4 The polypeptide of row, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) be present Under the conditions of be incubated.Start reaction after adding MgATP mixture.40 minutes are incubated under room temperature afterwards, be added thereto to 3% phosphorus Acid solution carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid at 5 minutes Interior cleaning 3 times, and preserve drying and being put into before scinticounting at once in methanol solution.

GGMEDIYFEFMGGKKK(SEQ ID NO：4).

FLT3(h)

, in 8mM MOPS pH 7.0,0.2mM EDTA, 50 μM with SEQ ID NO for FLT3 (h)：Amino acid sequence shown in 5 Polypeptide, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) bar for existing It is incubated under part.Start reaction after adding MgATP mixture.40 minutes are incubated under room temperature afterwards, be added thereto to 3% phosphoric acid Solution carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid in 5 minutes Cleaning 3 times, and preserve drying and being put into before scinticounting at once in methanol solution.

EAIYAAPFAKKK(SEQ ID NO：5).

Aurora-A(h)

, in 8mM MOPS pH 7.0,0.2mM EDTA, 200 μM with SEQ ID NO for Aurora-A (h)：Ammonia shown in 6 The polypeptide (Kemptide) of base acid sequence, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration according to Demand determine) exist under conditions of be incubated.Start reaction after adding MgATP mixture.40 minutes are incubated under room temperature afterwards, It is added thereto to 3% phosphoric acid solution and carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, is used in combination 75mM phosphoric acid was cleaned 3 times in 5 minutes, and was preserved drying and being put into before scinticounting at once in methanol solution.

LRRASLG(SEQ ID NO：6).

Aurora-B(h)

, in 8mM MOPS pH 7.0,0.2mM EDTA, 30 μM with SEQ ID NO for Aurora-B (h)：Amino shown in 7 The polypeptide of acid sequence, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) deposit It is incubated under the conditions.Start reaction after adding MgATP mixture.40 minutes are incubated under room temperature afterwards, be added thereto to 3% phosphoric acid solution carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid 5 Cleaning 3 times in minute, and preserve drying and being put into before scinticounting at once in methanol solution.

AKRRRLSSLRA(SEQ ID NO：7).

Kinase assay in the present invention be completed by Millipore company of Britain (Millipore UK Ltd, Dundee Technology Park,Dundee DD2 1SW,UK).

In addition, the kinase activity of compound can be detected by KINOMEscanTM, this detection is active based on using Site guidance type Competition binding assay method quantitative determination compound.The test is carried out by combining with three kinds of compounds, i.e. DNA Marker enzyme, fixed ligand and detection compound, carry out the competition energy of qPCR detection compound and fixed ligands by DNA marker Power.

Most of experiment is all the T7 bacteriophage bacterium of culture kinases mark from escherichia coli host derived from BL21 bacterial strain Strain, is in after the Escherichia coli of exponential phase with T7 phage-infect, and lysate is centrifuged by 32 DEG C of oscillation incubations to bacteriolyze Filtering and cell fragment being removed, remaining kinases goes in HEK-293 cell and qPCR detection carried out with DNA marker.Streptavidin Coated particle can produce affine resin for kinase assay with after biotinylated smaller ligand room temperature treatment 30min.Join After body particle is closed through unnecessary biotin, through confining liquid (SEABLOCK^TM(Pierce), 1% bovine serum albumin(BSA), 0.05% Tween-20,1mM DTT) unconjugated part is cleaned, reduce non-specific binding.By 1 × combination buffer (20% SEABLOCK^TM, 0.17 × PBS, 0.05% polysorbas20,6mMDTT) in combine kinases, part is affine particle and Test compound is combined reaction, and all reactions are carried out in 96 orifice plates, and reaction final volume is 0.135mL, and room temperature is shaken Incubation 1h is swung, is added lavation buffer solution (1 × PBS, 0.05% polysorbas20) that affine particle is cleaned, adds wash-out After buffer solution resuspended (1 × PBS, 0.05% polysorbas20,0.5 μM of non-biotinylated affinity ligand), room temperature is shaken Incubation 30min is swung, and the concentration of kinases in eluent is detected by qPCR.Kinase activity described in text determine be in the U.S. The KINOMEscan of DiscoveRx company (Albrae St.Fremont, CA 94538, USA)^TMDepartment, is measured.

Referring to table 3 and table 4, table 3 is the Aurora-A of compound provided in an embodiment of the present invention to Kinase activity assays result With Aurora-B kinase assay result, table 4 is JAK1, JAK2 and FLT3 kinase assay of compound provided in an embodiment of the present invention As a result.

Aurora-A the and Aurora-B kinase assay result of 3 embodiment of the present invention compound of table

NT：Test

JAK1, JAK2 and FLT3 kinase assay result of 4 embodiment of the present invention compound of table

NT：Test

From table 3 and table 4, compound of the present invention in kinase assay to JAK1, JAK2, Aurora-A, The protein kinases such as Aurora-B and FLT3 kinases generally have inhibitory activity, especially JAK1, Aurora-A and Aurora-B are swashed The inhibitory activity of enzyme is more significantly.

Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, embodiments of the invention are To illustratively illustrate, but be not limited to content described in the invention, it is also possible to be made within the scope of the present invention Modification or the equivalents that is added in the claims.All publications or patent cited in the present invention all will be used as this Bright bibliography.

Claims (23)

1. a kind of compound, which is the compound shown in formula (I) or the stereoisomer of compound, tautomerism shown in formula (I) The prodrug of body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or the compound,

Wherein,

Z¹For H, C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, each C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl and 3-12 former molecular heterocyclic radical are individually optionally by 1,2,3,4 or 5 R³Group is replaced；

A is pyrazolyl, and which is optionally by 1,2 or 3 R⁴Group is replaced；

R¹For H, F, Cl, Br, I, N₃、CN、NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂ Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^5aR^5b、-OR^5c、- OC (=O) R^5d,-C (=O) OR^5c、-N(R^5e) C (=O) R^5d,-C (=O) NR^5aR^5b、-N(R^5e) S (=O)₂R^5fOr-S (=O)₂NR^5aR^5b, wherein, each C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 Individual former molecular heterocyclic radical, C₆-C₁₂Aryl and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R⁸Group is replaced；

Each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkylamino, C₃-C₁₂Cycloalkyl, 4-7 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl Base ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄ Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-NR^6aR⁶ⁱ,-C (=O) R^6d,-OC (=O) R^6d,-C (=O) OR^6c、-N(R^6e) C (=O) R^6d,-C (=O) NR^6aR^6b、-N(R^6e) C (=O) NR^6aR^6b、-N (R^6e) S (=O)₂NR^6aR^6b,-S (=O)₂R^6f、-N(R^6e) S (=O)₂R^6gOr-S (=O)₂NR^6aR^6b, wherein, each C₁-C₁₂ Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkylamino, C₃-C₁₂Cycloalkyl, 4-7 former molecular heterocyclic radical, C₆-C₁₂ Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 Individual former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 atom composition Heteroaryl) individually optionally by 1,2,3,4 or 5 R⁸Group is replaced；

Each R³And R⁴It is separately F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 Individual former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkanes Base) or-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical), and wherein, each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl Base ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) and-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) independence times Selection of land is by 1,2,3,4 or 5 R⁸Group is replaced；

Each R^5a、R^5b、R^5c、R^5e、R^6a、R^6b、R^6cAnd R^6eIt is separately H, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Sub- Alkyl)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆- C₁₂Aryl) or-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl), or R^5aAnd R^5b, R^6aAnd R^6b, and and they Connected nitrogen-atoms together, forms 3-12 former molecular heterocyclyl groups, wherein, each C₁-C₁₂Alkyl, C₂-C₁₂Alkene Base, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 original are molecular miscellaneous Aryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁- C₄Alkylidene)-(C₆-C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) optionally by 1,2,3,4 Or 5 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent of alkylamino is replaced；

Each R^5d、R^5f、R^6d、R^6fAnd R⁶ⁱIt is separately C₁-C₁₂Alkyl, C₁-C₁₂Miscellaneous alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₁-C₁₂Alkylamino, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 original Molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 is former molecular miscellaneous Ring group) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-(C₁- C₆Sub- miscellaneous alkyl)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₆Sub- miscellaneous Alkyl)-(C₆-C₁₂Aryl) or-(C₁-C₆Sub- miscellaneous alkyl)-(5-12 former molecular heteroaryl), wherein, above-mentioned each group is appointed Selection of land is by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆ Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent of alkylamino is replaced；

Each R^6gIt independently is C₂-C₁₂Alkyl, C₁-C₁₂Miscellaneous alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxy alkyl, C₁-C₁₂ Aminoalkyl, C₁-C₁₂Haloalkyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 original Molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 is former molecular miscellaneous Ring group) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-(C₁- C₆Sub- miscellaneous alkyl)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₆Sub- miscellaneous Alkyl)-(C₆-C₁₂Aryl) or-(C₁-C₆Sub- miscellaneous alkyl)-(5-12 former molecular heteroaryl), wherein, above-mentioned each group is appointed Selection of land is by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆ Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent of alkylamino is replaced；

Each R⁸It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁- C₁₂Haloalkyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical, 5-12 former molecular heteroaryl Base, C₁-C₁₂Aminoalkyl, C₁-C₁₂Alkylamino, C₁-C₁₂Alkoxyl, C₁-C₁₂Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)-(C₃-C₁₂ Cycloalkyl) ,-NH (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-NH (C₀-C₄Alkylidene)-(3-12 former molecular heterocycle Base) ,-NH (C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-N [(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ]₂、-N[(C₀-C₄Alkylidene)-(C₆-C₁₂Aryl)]₂、-N[(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical)]₂、- N[(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl)]₂、-O(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-O (C₀- C₄Alkylidene)-(C₆-C₁₂Aryl) ,-O (C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) or-O (C₀-C₄Alkylene Base)-(5-12 former molecular heteroaryl)；With

M is 0,1,2,3,4 or 5.

2. compound according to claim 1, its are the vertical of the compound shown in formula (II) or compound shown in formula (II) Body isomers, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

3. compound according to claim 1, wherein, Z¹For H, C₁-C₆Alkyl, C₃-C₆Cycloalkyl or 4-7 atom composition Heterocyclic radical, wherein, each C₁-C₆Alkyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are optionally by 1,2 or 3 Individual R³Group is replaced.

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

Wherein, each minor structure shown in formula (A-1), (A-2) and (A-3) is only Stand optionally by 1 or 2 R⁴Group is replaced.

5. compound according to claim 1, wherein, R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₄Alkyl, C₁-C₄ Alkoxyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 atom composition Heteroaryl ,-NR^5aR^5b、-OR^5c,-OC (=O) R^5d,-C (=O) OR^5c、-N(R^5e) C (=O) R^5d,-C (=O) NR^5aR^5b、-N (R^5e) S (=O)₂R^5fOr-S (=O)₂NR^5aR^5b, wherein, each C₁-C₄Alkyl, C₁-C₄Alkoxyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynes Base, C₃-C₆A cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl and 5-6 former molecular heteroaryl individually optionally by 1, 2 or 3 R⁸Group is replaced.

6. compound according to claim 1, wherein, each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、 CN、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆The individual former molecular heterocyclic radical of cycloalkyl, 4-7, Phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 is former Molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) ,- NR^6aR⁶ⁱ,-C (=O) R^6d,-OC (=O) R^6d,-C (=O) OR^6c、-N(R^6e) C (=O) R^6d,-C (=O) NR^6aR^6b、-N(R^6e)C (=O) NR^6aR^6b、-N(R^6e) S (=O)₂NR^6aR^6b,-S (=O)₂R^6f、-N(R^6e) S (=O)₂R^6gOr-S (=O)₂NR^6aR^6b, its In, each C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Cycloalkyl, 4-7 original are molecular miscellaneous Ring group, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4- The molecular heterocyclic radical of 7 originals) ,-(C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl Base) individually optionally by 1,2 or 3 R⁸Group is replaced.

7. compound according to claim 1, wherein, each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、 CN、C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₁-C₄Alkylamino, C₃-C₆Cycloalkyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, 1, 1- dioxo isothiazolidine -2- base, pyrrolidin-2-one -1- base, imidazolidin-2-one -1- base, oxazolidine -2- ketone -3- base, benzene Base, 5-6 former molecular heteroaryl ,-(C₁-C₂Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₂Alkylidene)-(4-7 atom The heterocyclic radical of composition) ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl) ,- NR^6aR⁶ⁱ,-OC (=O) R^6d,-C (=O) OR^6c、-N(R^6e) C (=O) R^6d,-C (=O) NR^6aR^6b、-N(R^6e) C (=O) NR^6aR^6b、-N(R^6e) S (=O)₂NR^6aR^6b、-N(R^6e) S (=O)₂R^6gOr-S (=O)₂NR^6aR^6b, wherein, each C₁-C₄Alkane Base, C₂-C₄Thiazolinyl, C₁-C₄Alkylamino, C₃-C₆Cycloalkyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, 1,1- dioxo are different Thiazolidine -2-base, pyrrolidin-2-one-1- base, imidazolidin-2-one-1- base, oxazolidine-2- ketone-3- base, phenyl, 5-6 atom The heteroaryl of composition ,-(C₁-C₂Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₂Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C₁-C₂Alkylidene)-phenyl and-(C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl) individually optionally by 1,2 Or 3 R⁸Group is replaced.

8. compound according to claim 1, wherein, each R³And R⁴It is separately F, Cl, CN, C₁-C₄Alkyl, C₂- C₄Thiazolinyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylene Base)-(C₃-C₆Cycloalkyl) or-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical), and wherein, each C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃ Alkylidene)-(C₃-C₆Cycloalkyl) and-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) individually optionally by 1,2 or 3 R⁸Group is replaced.

9. compound according to claim 1, wherein, each R³And R⁴It is separately F, Cl, Br, I, N₃、CN、-NO₂、 Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, rattle away Piperazine base, thiazolyl, pyrrole radicals or oxazolyl, wherein, each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, piperidyl, Pyrrolidinyl, morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, thiazolyl, pyrrole radicals and oxazolyl individually optional ground quilt 1st, 2 or 3 R⁸Group is replaced.

10. compound according to claim 1, wherein, each R^5a、R^5b、R^5c、R^5e、R^6a、R^6b、R^6cAnd R^6eSeparately For H, C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 original Molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), or R^5aAnd R^5b, R^6a And R^6b, and together with nitrogen-atoms connected with them, form 4-7 former molecular heterocyclyl groups, wherein, each C₁-C₄ Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 original are molecular Heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,- (C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) optionally by 1,2 or 3 independences Ground is selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxyl alkane Base, C₁-C₃Aminoalkyl or C₁-C₃The substituent of alkylamino is replaced.

11. compounds according to claim 1, wherein, each R^5a、R^5b、R^5c、R^5e、R^6a、R^6b、R^6cAnd R^6eSeparately For H, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, Pyridazinyl, pyrazinyl, thiazolyl, pyrrole radicals, pyrazolyl, imidazole radicals or oxazolyl, wherein, each methyl, ethyl, positive third Base, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrroles Alkyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazole Base, pyrrole radicals, pyrazolyl, imidazole radicals and oxazolyl are optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-NO₂、- OH、-NH₂、-CF₃、-CH₃、-CH₂CH₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N(CH₃)₂Or-CH₂NH₂Substituent Replaced.

12. compounds according to claim 1, wherein, each R^5d、R^5f、R^6d、R^6fAnd R⁶ⁱIt is separately C₁-C₄Alkane Base, C₁-C₆Miscellaneous alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₁-C₄Alkoxyl, C₁-C₄Alkylamino, C₃-C₆Cycloalkyl, 4-7 atom The heterocyclic radical of composition, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Sub- Alkyl)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 atom group The heteroaryl for becoming) ,-(C₁-C₄Sub- miscellaneous alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 is former molecular miscellaneous Ring group) ,-(C₁-C₄Sub- miscellaneous alkyl)-phenyl or-(C₁-C₄Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), wherein, on Each group is stated optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Alkyl halide Base, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent of alkylamino is replaced.

13. compounds according to claim 1, wherein, each R^5d、R^5f、R^6d、R^6fAnd R⁶ⁱIt is separately methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, benzene Base, piperidyl, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazine Base, pyrazinyl, thiazolyl, pyrrole radicals, pyrazolyl, imidazole radicals, oxazolyl, C₁-C₄Miscellaneous alkyl ,-(C₁-C₂Alkylidene)-(C₃-C₆ Cycloalkyl) ,-(C₁-C₂Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylene Base)-(5-6 former molecular heteroaryl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4- The molecular heterocyclic radical of 7 originals) ,-(C₁-C₄Sub- miscellaneous alkyl)-phenyl or-(C₁-C₄Sub- miscellaneous alkyl)-(5-6 is former molecular Heteroaryl), wherein, above-mentioned each group is optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、-CF₃、- CH₃、-CH₂CH₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N(CH₃)₂Or-CH₂NH₂Substituent replaced.

14. compounds according to claim 1, wherein, each R^6gIt independently is C₂-C₆Alkyl, C₁-C₆Miscellaneous alkyl, C₂-C₆Alkene Base, C₂-C₆Alkynyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl, C₁-C₆Haloalkyl, C₃-C₆Cycloalkyl, 4-7 atom composition Heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylene Base)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 atom composition Heteroaryl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(4-7 former molecular heterocycle Base) ,-(C₁-C₆Sub- miscellaneous alkyl)-phenyl or-(C₁-C₆Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), wherein, above-mentioned Each group is optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Halo Alkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent of alkylamino is replaced.

15. compounds according to claim 1, wherein, each R^6gIndependently be ethyl, n-propyl, isopropyl, normal-butyl, Isobutyl group, sec-butyl, the tert-butyl group, 3- methyl isophthalic acid-butyl, 2-methyl-1-butene base, 1,2- dimethyl -1- propyl group, neopentyl, third Thiazolinyl, 2- methylpropenyl, trifluoromethyl, methylol, ethoxy, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Phenyl, piperidyl, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydrochysene -2H- pyranose, piperazinyl, pyridine radicals, pyrimidine radicals, rattle away Piperazine base, pyrazinyl, C₁-C₄Miscellaneous alkyl ,-(C₁-C₂Alkylidene)-cyclopropyl ,-(C₁-C₂Alkylidene)-cyclobutyl ,-(C₁-C₂Alkylene Base)-cyclopenta ,-(C₁-C₂Alkylidene)-cyclohexyl ,-(C₁-C₂Alkylidene)-piperidyl ,-(C₁-C₂Alkylidene)-pyrrolidines Base ,-(C₁-C₂Alkylidene)-tetrahydrofuran base ,-(C₁-C₂Alkylidene)-tetrahydrochysene -2H- pyranose,-(C₁-C₂Alkylidene)-morpholine Base ,-(C₁-C₂Alkylidene)-piperazinyl ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylidene)-(5-6 is former molecular miscellaneous Aryl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(C₃-C₆Cycloalkyl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 former molecular heterocyclic radical) ,- (C₁-C₄Sub- miscellaneous alkyl)-phenyl or-(C₁-C₄Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), and wherein, above-mentioned each group Optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、-CF₃、-CH₃、-CH₂CH₃、-OCH₃、- CH₂OH、-CH₂CH₂OH、-NHCH₃、-N(CH₃)₂Or-CH₂NH₂Substituent replaced.

16. compounds according to claim 1, wherein, each R⁸It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、 C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocycle Base, 5-6 former molecular heteroaryl, C₁-C₄Aminoalkyl, C₁-C₄Alkylamino, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl ,-NH (C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-NH (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-N [(C₀-C₃Sub- Alkyl)-(C₃-C₆Cycloalkyl)]₂、-N[(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical)]₂、-O(C₀-C₃Alkylene Base)-(C₃-C₆Cycloalkyl) ,-O (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-O (C₀-C₃Alkylidene)-phenyl Or-O (C₀-C₃Alkylidene)-(5-6 former molecular heteroaryl).

17. compounds according to claim 1, its are the compound of one of, or its stereoisomer, change Isomers, nitrogen oxides, solvate or pharmaceutically acceptable salt：

Or its stereoisomer, dynamic isomer, nitrogen oxides, Solvate or pharmaceutically acceptable salt.

A kind of 18. pharmaceutical compositions, which includes the compound described in claim 1-17 any one,

Optionally, described pharmaceutical composition includes in pharmaceutically acceptable auxiliary material, excipient, carrier and solvent extremely further Few one kind.

19. pharmaceutical compositions according to claim 18, described pharmaceutical composition include other therapeutic agents further, described Other therapeutic agents are selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 inhibitors, beta-2-adrenoreceptor agonists, cortex class Sterol, nonsteroidal GR activator, anticholinergic drug, antihistamine, anti-inflammatory reagent, immunodepressant, immunomodulator, use In treat atherosclerotic medicine and for treat pulmonary fibrosis medicine at least one.

Compound described in 20. claim 1-17 any one or claim 18-19 any one described pharmaceutical composition exist The purposes in medicine is prepared, the medicine is used for preventing, process, treat or mitigating protein kinase mediated disease.

21. purposes according to claim 20, disease that wherein described protein kinase mediated disease is mediated for JAK-, The disease of FLT3- mediation, the disease of Aurora- mediation, proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease Disease, graft rejection, cancer, polycythemia vera, primary thrombocytosis, myelofibrosis, acute myelocytic Leukaemia, chronic granulocytic leukemia, ALL, COPD, asthma, systemic erythema Lupus, skin lupus erythematosus, LN, dermatomyositis, Sjogren syndrome, psoriasis, type i diabetes, respiratory tract anaphylaxis Property disease, nasosinusitis, eczema, measles, food hypersenstivity, insect venom allergies, inflammatory bowel disease, Crohn disease, rheumatoid joint Inflammation, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplant rejection.

Compound described in 22. claim 1-17 any one or claim 18-19 any one described pharmaceutical composition exist The purposes in medicine is prepared, the medicine is used for the activity of regulatory protein kinases.

23. purposes according to claim 22, wherein described protein kinase are swashed for jak kinase, FLT3 kinases and Aurora At least one in enzyme, specifically at least one in JAK1 kinases, Aurora-A kinases and Aurora-B kinases.