CN106478651B - Substituted heteroaryl compound and combinations thereof and purposes - Google Patents

Abstract

The present invention provides substituted heteroaryl compound and combinations thereof and purposes.The compound is stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug of compound shown in formula (I) compound represented or formula (I).The present invention also provides the pharmaceutical compositions comprising the compound, the adjustable protein kinase of described pharmaceutical composition, the especially activity of Aurora A and jak kinase, for preventing, handling, treat and mitigating the disease or disorder of protein kinase, especially Aurora A and the mediation of jak kinase activity.

Description

Substituted heteroaryl compound and combinations thereof and purposes

Priority information

The application request on 08 31st, 2015 to China State Intellectual Property Office submit, number of patent application be The priority and right of 201510551362.4 patent application, and by referring to being incorporated by herein.

Invention field

The invention belongs to drug fields, and in particular to a kind of substituted heteraryl as protein kinase activity inhibitor Close object, comprising the pharmaceutical composition of the compound and the compound and its pharmaceutical composition in treating a variety of various diseases Using.More specifically, compound of the present invention can be used 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

Protein kinase family includes the relevant enzyme of a big class formation, they control intracellular various signal transduction processes, Similar 250-300 amino acid catalytic domain is usually contained, the phosphorylation of target proteins matter substrate is catalyzed.It was reported that many diseases It is related with the abnormal cell response that protein kinase mediated event causes.These diseases include benign and pernicious proliferative disease Disease, allograft rejection, graft versus host disease, autoimmune caused by disease, the inappropriate activation of immune system Disease, inflammatory disease, bone disease, metabolic disease, neurological disease and neurodegenerative disease, cancer, cardiovascular disease, allergy and Asthma, Alzheimer disease and hormone related condition.Correspondingly, medicinal chemistry arts are made a large amount of effort and can be used as with finding Imitate the kinases inhibitor of 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 process such as cell Proliferation, migration, differentiation and lifes It deposits and plays a crucial role.The receptors of multiple families and nonreceptor tyrosine kinase family listed business these events: catalysis phosphorus Acid is transferred to the tyrosine residue of specific cells protein target from ATP.Currently, having confirmed that the above-mentioned general phase of each kinase families Motif (Hanks et al., the FASEB J., 1995,9,576-596 answered；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 are not limited to Aurora, Axl, abl, Akt, bcr-abl, Blk, Brk, Btk, c-Met, c-src, c- Fms, CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Flt-3, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, Fps, Frk,Fyn,Hck,JAK,IGF-1R,INS-R,KDR,Lck,Lyn,MEK,p38,PDGFR,PIK,PKC,PYK2,ros,Tie, Tie-2, TRK, Yes and Zap70, etc..

Aurora A family is the related serine/threonine kinase of a kind of height, is mitotic crucial tune Agent is saved, the accurate and equal separation (section) for the genomic material from mother cell to daughter cell is required.Aurora The member of kinase families include the related 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 advanced stage phase to the M phase, including centerbody Maturation, mitosis entrance, centerbody separation, the two poles of the earth mitotic spindle assembly object, the Chromosomal arrangement on 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 is by crimping spiral shell with various substrates, including centrosome protein (centrosome), conversion acidity It revolves albumen, cdc25b, Eg5 and centromere protein matter A interaction and mediates multiple functions.Aurora-A overexpression is Aurora- A- induces tumorigenic essential feature.

Aurora-B be it is a kind of to accurate chromosome isolation, cytokinesis, protein localization to kinetochore and silk Grain, correct micro-pipe-centromere attachment and adjusting Mitotic checkpoint play the chromosomin of key effect.Aurora-B is first First during early period 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 is 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 the incorrect micro-pipe of repairing-centromere attachment (Hauf S, et al., J.Cell Biol.,2003,161:281-294；Ditchfield C,et al.,J.Cell Biol.,2003,161:267-280；Lan W,et al.,Curr.Biol.,2004,14:273-286.).In the case where Aurora-B inactivation, mitosis is damaged It is bad, cause aneuploid cell quantity to increase, (Weaver BA, et al., Cancer occur for genic instability and tumour Cell,2005,8:7-12).Aurora-B inhibits the biology for causing abnormal centromere-micro-pipe to adhere to, cannot achieve chromosome to take Fail (Goto H, et al., J Biol.Chem., 2003,278:8526-8530 to, cytokinesis；Severson AF,et al.,Curr.Biol.,2000,10:1162-1171).It does not include that the abnormal mitotic repetitive cycling of cytokinesis is drawn Rise huge polyploidy and eventually lead to Apoptosis (Hauf S, et al., J.Cell Biol., 2003,161:281- 94；Ditchfield C,et al.,J.Cell Biol.,2003,161:267-80；Giet R,et al.,J.Cell Biol.,2001；152:669-82；Murata-Hori M,Curr.Biol.,2002,12:894-899；Kallio M J,et al.,Curr.Biol.,2002,12:900-905)。

Verified Aurora is overexpressed and a variety of malignant proliferative disorders, such as the carcinoma of the rectum, breast cancer, lung cancer, cancer of pancreas, preceding Column gland cancer, bladder cancer, head and neck cancer, cervix cancer, oophoroma, liver cancer and gastric cancer etc. are closely related, excite exploitation for cancer The interest of the Aurora inhibitor for the treatment of.In normal cell, Aurora-A inhibition cause to delay but and non-blacked mitosis, Monopole mitotic spindle centerbody separation defect and cytokinesis failure (Marumoto T, et al., J.Biol.Chem.,2003,278:51786-51795).It is (Panc- Ι, Μ Ι Α PaCa- in three kinds of human pancreatic cancer cells In 2dnSU.86.86), Aurora-A inhibitor shows encouraging antitumous effect, and Aurora-A inhibits as the result is shown Agent be able to suppress tumour cell growth and, tumorigenicity in murine xenogralt it is intimate all eliminate (Hata T, et al.,Cancer Res.,2005,65:2899-2905)。

FLT3 (the relevant tyrosine kinase 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 composition, extracellular ligand-binding domain comprising five immunoglobulin class structure compositions, the domain cross-film (TM), nearly film (JM) domain With the domain cytoplasm C- terminal tyrosine kinases (TK).(Agnes F,et al.Gene,l994,145:283-288；Scheijen B,et al.,Oncogene,2002,21:3314-3333)。

The ligand of FLT3 was cloned in 1993, studies show that, it includes marrow that it, which is Hematopoietic marrow microenvironment cell, Expressed in fibroblast and other cells type I transmembrane protein (Lyman SD, et al., Cell, 1993,75, 1157-1167).Film combines the tyrosine kinase activity with the equal energy activated receptor of soluble form and stimulates the ancestral in marrow and blood Cell growth.The zygotic induction receptor dimer of ligand-receptor, and activated protein kinase domain；Then it its autophosphorylation and is catalyzed each The substrate protein phosphorylation of kind signal transduction pathway, such as signal transduction and Activator protein 5 (STAT5), RAS/ mitogen Protein kinase (RAS/MAPK), phosphoinositide 3-kinase (PI3K), the Src of activation be of the same race and glue protogene (SHC), contains Inositol -5- the phosphatase (SHIP) of SH2 and the cytoplasmic tyrosine phosphoric acid with 2 Src- homology 2 (SH2) domains (SHP2) Enzyme, play a significant role in cell Proliferation, differentiation and existence (Dosil M., et al., Mol.Cell Biol., 1993, 13:6572-6585.Zhang S,Biochem.Biophys.Res.Commun.,l999,254:440-445).In addition to hematopoiesis is thin Except born of the same parents, FLT3 gene also expression (Maroc N, the et al., Oncogene, 1993,8:909- in placenta, sexual gland and brain 918) and in immune response play a significant role (deLapeyriere O.et al., Leukemia, 1995,9:1212- 1218)。

FLT3 is also related with the hemopoietic system dysfunction before malignant proliferative lesion, such as piastrenemia, true property blood Before platelet increase disease, myelofibrosis (MF), chronic idiopathic myelofibrosis (IMF), polycythemia (PV), canceration Include, but are not limited to leukaemia, (non-Hodgkin lymphoma), Huo Qijin to myelodysplastic syndrome, hematologic malignancies Family name's disease (also known as Hodgkin lymphoma) and myeloma, such as, acute lymphatic leukemia (ALL), the white blood of acute myeloid Disease (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophil leukemia (CNL), it is closely related.Acute myeloid leukaemia (AML) of the FLT3 in 70-100% In, in the acute lymphoblastic leukemia (ALL) of He Gao percentage with it is each it is horizontal be overexpressed (Griffin JD, et al., Haematol J.,2004,5:188-190).In primitive cell crisis, also in the smaller of chronic myelogenous leukemia (CML) It is overexpressed in hypotype.Research has been displayed B pedigree leukaemia cell ALL and AML and continually co-expresses FLT3, causes FLT3 composing type The autocrine or paracrine signal transduction of activation recycle (Zheng R, et.al.Blood., 2004,103:267-274).In addition, FLT3 ligand is in the cell serum of langerhans cell histiocytosis and Patients with SLE with high level Expression, the dendritic cells Signal Regulation for further displaying FLT3 and autoimmune disease are extremely closely related.

More and more evidences show that a plurality of types of leukaemia and myeloproliferative syndrome have the prominent of tyrosine kinase Become.FLT3 mutation is one of mutation most frequent in AML, is occurred in about 1/3 patient.Two are described in leukaemic The FLT3 of seed type is mutated.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: It 4326-4335) is mutated with activation cycle comprising Asp835Tyr (D835Y), Asp835Val (D835V), Asp835His (D835H), Asp835Glu (D835E), Asp835Ala (D835A), Asp835Asn (D835N), Asp835 missing and Ile836 Lack (Yamamoto Y, et al., Blood, 2001,97:2434-2439；Abu-Duhier FM,et al., Br.J.Haematol.,2001,113:983-988).Internal series-connection duplication (ITD) mutation in the domain JM facilitates in AML about The FLT3 Activating mutations of 17-34%.FLT3-ITD low frequency mutation is also detected 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 related 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).

Currently, in the FLT3 inhibitor ground as some or all recurrence or stubbornness AML patient with FLT3 mutation Monotherapy has entered clinical test.Generally, these are statistics indicate that FLT3 can be used to develop for treating AML and other related The therapeutic targets of the kinase inhibitor of disease.

Janus kinases (JAK) is intracellular non-receptor tyrosine kinase, and by turning JAK-STAT access, transduction is thin The signal that intracellular cytokine mediates.JAK family is sent out in the cell function that the proliferation that cell factor relies on is adjusted and is related to immune response Wave important role.Cell factor causes receptor dimerization, can promote the mutual phosphoric acid of JAKs in this way in conjunction with their receptor Change, can also promote cytokine receptor internal specific tyrosine motif phosphorylation.Identify that the STATs of these phosphorylation motifs is gathered Collect on receptor, is then activated during the tyrosine phosphorylation that JAK is relied on.Due to activation, STATs and receptor are dissociated, Dimerization, and it is displaced to nucleus, in conjunction with the specific site DNA, and change transcription.

Mammal JAK family member known to being currently, there are four kinds: (Janus swashs by JAK1 (Janus kinases -1), JAK2 Enzyme -2), JAK3 (Janus kinases, leucocyte；JAKL；L-JAK and Janus kinases -3) and TYK2 (protein tyrosine kinase 2). JAK1, JAK2 and TYK2 are wide expressions, and JAK3 is reported in priority expression in natural kill (NK) cell, without at it (" 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 the signal transduction of certain I types and II cytokines.The γ of it and I cytokines receptor The signal transduction of public chain (IFN-γ) interferon, and the signal of the IL-10 family member by II cytokines receptor It transduces all critically important.Genetic biology studies have shown that JAK1 functionally and physiologically with I type interferon (for example, IFNalpha), II type interferon (for example, IFNgamma), IL-2 to IL-6 cytokine receptor complex are related.Further It is logical in IFN, IL-IO, IL-2/IL-4 and IL-6 to demonstrate the kinases to the characterization of the tissue from JAK1 knock-out mice for ground Key effect in road.

JAK1 expression in cancer cell can promote individual cells atrophy, potentially them is made to flee from tumour, be transferred to body Other positions of body.By the cell factor of JAK1 transduction signal, horizontal raising involves a large amount of immune and inflammation disease Disease.JAK1 or JAK family kinase inhibitors can be used for adjusting or treating these diseases (Kisseleva et al., 2002, Gene 285:1-24；Levy et al.,2005,Nat.Rev.Mol.Cell Biol.,3:651-662).Target the people of IL-6 access Resource monoclonal antibody (Torr pearl monoclonal antibody Tocilizumab) is ratified to close for treating moderate to severe rheumatoid by EU Committee Save scorching (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 receptor man The signal transduction of family member is relevant.JAK2 signal is activated in the downstream of hprl receptor.Research shows that in myeloproliferative In the disease such as diseases 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 the case where no cell factor stimulates Lower activation downstream signal leads to spontaneous growth and/or the hypersensitivity to cell factor, is considered the process to these diseases Play a part of promotion.The more multimutation or transposition for leading to JAK2 functional disturbance are 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, which 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 passes through the tyrosine phosphorus of interleukin-2-receptor Acidification activation, transduction signal.Since JAK3 is limited to express in candidate stem cell more, relative to other JAKs, it is in cell factor Effect in signal transduction is stringenter.The mutation of JAK3 will lead to 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 access that JAK3 is mediated has been used for treating immunosupress indication (for example, graft rejection and rheumatoid arthritis) (Baslund et al.,2005,Arthritis&Rheumatism 52:2686-2692；Changelian et al., 2003,Science 302:875-878)。

TYK2 and IFN-α, IL-6, IL-10 to IL-12 signal transduction are related.Biochemical research and knock out mice TYK2 is disclosed in the important function of immunology.TYK2 deficient mice energy growth and breeding, but panimmunity defect is shown, it is main If to infection, there are hypersensitivities and the existing defects in terms of oncological surveillance.It is opposite, inhibit TYK2 can be improved resist allergy, The ability of autoimmunity and inflammatory disease.Particularly, targeting TYK2 seems to become treatment IL-12-, IL-23- or I type IFN- is situated between The innovative strategy for the disease led.The disease includes but is not limited to rheumatoid arthritis, multiple sclerosis, lupus, silver bits Disease, psoriasis arthropathica, inflammatory bowel disease, uveitis, sarcoidosis and cancer (Shaw, M.et al., Proc.Natl.Acad.Sci.,USA,2003,100,11594-11599；Ortmann,R.A.,and Shevach, E.M.Clin.Immunol,2001,98,109-118；Watford et al,Immunol.Rev.,2004,202:139).

European commission has been recently approved the complete source of people of the shared 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 Outside, target IL-12 and IL-23 access antibody carried out for treating Crohn disease clinical test (Mannon et al., N.Engl.J.Med.,2004,351:2069-79)。

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

Therefore, all four members of JAK/STAT access, especially JAK family, are considered in asthma reaction, chronic resistance It works in the pathogenesis of plug property tuberculosis, bronchitis and other relevant lower respiratory tract inflammatory diseases.JAK/STAT is logical Road equally (includes, but are not limited to iritis, uvea in ocular inflammatory disease (diseases)/disease (conditions) Inflammation, sclerotitis, conjunctivitis) and chronic anaphylaxis reaction in work.Since cell factor swashs using various various forms of JAK Enzyme (O'Sullivan et al., Mol.Immunol, 2007,44:2497；Murray J.,Immunol,2007,178: 2623), different selective jak kinases in antagonism family are logical to treat the relevant disease of the specific cells factor or JAK/STAT Variability or the relevant disease of polymorphism may be useful in road.

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

The sustained activation of STAT3 or STAT5 has been proved to be present in many entity tumors, including lacteal tumor, Vipoma, Prostate tumor, ovarioncus and liver cancer, while existing in a large amount of blood tumor, including lymthoma and leukaemia.In this respect, The inactivation of JAK/STAT signal in neoplastic hematologic disorder is capable of inhibiting cell to be proliferated and/or induces cell apoptosis.Although in tumour cell STAT3 can still be counted as most important upstream activat person by many kinase activations, JAK2, it can be activated derived 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, inhibit jak kinase to these diseases It treats and plays beneficial effect.

It knows clearly, kinases inhibitor is poly- as new immunosupress, anti-inflammatory double action medicine and anticancer medicine Numerous concerns are collected.Therefore, inhibit the protein kinase such as novel agent of Aurora A, FLT3 kinases and jak kinase or improve examination Agent is needed for a long time, it can be used as the immunosuppressor of organ transplant, antitumor agent, it can also be used to prevent and treat autoimmunity Disease is (for example, multiple sclerosis, psoriasis, rheumatoid arthritis, asthma, type-1 diabetes mellitus, inflammatory bowel disease, Crow grace Disease, polycythemia vera, primary thrombocytosis, myelofibrosis, autoimmune thyroid disease, the sea A Erzi Silent disease), it is related to the disease (for example, eczema) of overactivity inflammatory reaction, allergy, chronic obstructive pulmonary disease, bronchitis, cancer (for example, prostate cancer, acute myelocytic leukemia, chronic granulocytic leukemia, acute lymphoblastic leukemia, white blood Disease, Huppert's disease) and the caused immune response (for example, fash, contact dermatitis or diarrhea) of other treatment, etc..This Compound, composition and the method for invention description directly correspond to these needs and other purposes.

Abstract of invention

The present invention provides one kind to inhibit, adjusts and/or regulate and control one or more protein kinases, as jak kinase, FLT3 swash Enzyme and the active compound of Aurora A, for treating proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease Disease, graft rejection and their complication.Present invention provides the methods for preparing these compounds, use these chemical combination The method that object treats the above-mentioned disease of mammal, the especially mankind, and the pharmaceutical composition comprising these compounds.This hair Bright compound and combinations thereof has preferable potential applicability in clinical practice.Compared with existing similar compound, change of the invention Closing object has better pharmacological activity, medicine for property, physicochemical property and/or toxicological characteristics.Specifically, the compounds of this invention pair Kinase targets show the Kinase Selectivity of preferable inhibitory activity and optimization, show in pharmacokinetic trial in animal body Good absorption and higher bioavilability are shown.In addition, the compounds of this invention also has more excellent membrane permeability, it is suitable for Local administration, 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 alloisomerisms of one kind compound as shown in formula (I) compound represented or formula (I) Body, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

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

In some embodiments, Z¹For H, C₁-C₁₂Alkyl, C₃-C₁₂Naphthenic base or 3-12 former molecular heterocycle, Wherein, each C₁-C₁₂Alkyl, C₃-C₁₂The former molecular heterocycle of naphthenic base and 3-12 individually optionally by 1,2,3,4 or 5 R³Replaced group；

A is pyrazolyl, optionally by 1,2 or 3 R⁴Replaced group；

R¹For H, F, Cl, Br, I, N₃、CN、NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxy, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, 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-C₁₂Alkoxy, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂The former molecular heteroaryl of aryl and 5-12 individually optionally by 1,2,3,4 or 5 R⁸Replaced group；

Each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Alkylamino, C₃-C₁₂Naphthenic base, 4-7 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 original are molecular miscellaneous Aryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocycle) ,-(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-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkylamino, C₃-C₁₂Naphthenic base, 4-7 former molecular heterocycle, C₆-C₁₂ Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 A molecular heterocycle of original) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 atom composition Heteroaryl) individually optionally by 1,2,3,4 or 5 R⁸Replaced group；

Each R³And R⁴It is separately F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂ Naphthenic base) or-(C₁-C₄Alkylidene)-(3-12 former molecular heterocycle), wherein each C₁-C₁₂Alkyl, C₂-C₁₂Alkene Base, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 original are molecular miscellaneous Aryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) and-(C₁-C₄Alkylidene)-(3-12 former molecular heterocycle) independence Optionally by 1,2,3,4 or 5 R⁸Replaced group；

Each R^5a、R^5b、R^5c、R^5e、R^6a、R^6b、R^6cAnd R^6eIt is separately H, C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂ Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,- (C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocycle) ,-(C₁-C₄Alkylene Base)-(C₆-C₁₂Aryl) or-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) or R^5aAnd R^5b, R^6aAnd R^6b, Together with the nitrogen-atoms being connected with them, 3-12 former molecular heterocyclyl groups are formed, wherein each C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 atom group At heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(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-C₆Halogenated alkyl, C₁- C₆Alkoxy, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆Replaced the substituent group of alkylamino；

Each R^5d、R^5f、R^6d、R^6fAnd R⁶ⁱIt is separately C₁-C₁₂Alkyl, C₁-C₁₂Miscellaneous alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂ Alkynyl, C₁-C₁₂Alkoxy, C₁-C₁₂Alkylamino, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl, 5- The molecular heteroaryl of 12 originals ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 atom group At heterocycle) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl Base) ,-(C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₆Sub- miscellaneous alkyl)-(3-12 former molecular heterocycle) ,- (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-C₆Alkoxy, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆Replaced the substituent group of alkylamino；

Each R^6gIt independently is C₂-C₁₂Alkyl, C₁-C₁₂Miscellaneous alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxy alkyl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Halogenated alkyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 The molecular heteroaryl of a original ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 atom composition Heterocycle) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,- (C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₆Sub- miscellaneous alkyl)-(3-12 former molecular heterocycle) ,-(C₁-C₆ Sub- miscellaneous alkyl)-(C₆-C₁₂Aryl) or-(C₁-C₆Sub- miscellaneous alkyl)-(5-12 former molecular heteroaryl), 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-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆Replaced the substituent group of alkylamino；

Each R⁸It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Halogenated alkyl, C₃-C₁₂Naphthenic base, C₆-C₁₂Aryl, 3-12 former molecular heterocycle, 5-12 atom composition Heteroaryl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Alkylamino, C₁-C₁₂Alkoxy, C₁-C₁₂Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)- (C₃-C₁₂Naphthenic base) ,-NH (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-NH (C₀-C₄Alkylidene)-(3-12 is former molecular Heterocycle) ,-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 heterocycle) 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 one kind compounds as shown in formula (II) compound represented or formula (II) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or it before Medicine,

In other embodiments, Z¹For H, C₁-C₆Alkyl, C₃-C₆Naphthenic base or 4-7 former molecular heterocycle, Wherein, each C₁-C₆Alkyl, C₃-C₆Naphthenic base and 4-7 former molecular heterocycle are optionally by 1,2 or 3 R³Group institute Replace.

In some embodiments, A are as follows:

Wherein, each minor structure shown in formula (A-1)~(A-3) is only It stands optionally by 1 or 2 R⁴Replaced group.

In other embodiments, R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₄Alkyl, C₁-C₄Alkoxy, C₂- C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, the molecular heteroaryl of 5-6 original ,- 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-C₄Alkoxy, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Ring Alkyl, 4-7 former molecular heterocycle, phenyl and the 5-6 molecular heteroaryl of original it is individually optional by 1,2 or 3 R⁸ Replaced group.

In some embodiments, each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 atom The heteroaryl of composition ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(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-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 The molecular heteroaryl of a original ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4-7 is former molecular Heterocycle) ,-(C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) individually optionally By 1,2 or 3 R⁸Replaced group.

In other embodiments, each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₄Alkane Base, C₂-C₄Alkenyl, C₁-C₄Alkylamino, C₃-C₆Naphthenic base, 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-C₆Naphthenic base) ,-(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-C₄Alkenyl, C₁-C₄Alkane ammonia Base, C₃-C₆Naphthenic base, 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-C₂It is sub- Alkyl)-(C₃-C₆Naphthenic base) ,-(C₁-C₂Alkylidene)-(4-7 former molecular heterocycle) ,-(C₁-C₂Alkylidene)-phenyl With-(C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl) individually optionally by 1,2 or 3 R⁸Replaced group.

In some embodiments, each R³And R⁴It is separately F, Cl, CN, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₃-C₆Ring Alkyl, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Ring Alkyl) or-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle), wherein each C₁-C₄Alkyl, C₂-C₄Alkenyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)- (C₃-C₆Naphthenic base) and-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle) individually optionally by 1,2 or 3 R⁸Group It 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, pyridyl group, pyrimidine radicals, pyridazinyl, thiazole Base, pyrrole radicals or oxazolyl, wherein each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, piperidyl, pyrrolidinyl, Morpholinyl, piperazinyl, pyridyl group, pyrimidine radicals, pyridazinyl, thiazolyl, pyrrole radicals and oxazolyl it is individually optional by 1,2 or 3 R⁸Replaced group.

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-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl Base ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle) ,-(C₁-C₃It is sub- 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 the 4-7 molecular heterocyclyl groups of original, wherein each C₁-C₄Alkyl, C₂-C₄Alkene Base, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C₁- C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle) ,-(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-C₃Halogenated alkyl, C₁-C₃Alkoxy, C₁-C₃Hydroxy alkyl, C₁-C₃Amino alkane Base or C₁-C₃Replaced the substituent group of alkylamino.

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, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidines Base, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, 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, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, Tetrahydrofuran base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, pyrrole radicals, pyrrole Oxazolyl, imidazole radicals and oxazolyl it is individually optional 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 group replaced.

In some embodiments, each R^5d、R^5f、R^6d、R^6fAnd R⁶ⁱIt is separately C₁-C₄Alkyl, C₁-C₆Miscellaneous alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Alkoxy, C₁-C₄Alkylamino, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, benzene Base, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4-7 atom The heterocycle of composition) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) ,-(C₁- C₄Sub- miscellaneous alkyl)-(C₃-C₆Naphthenic base) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 former molecular heterocycle) ,-(C₁-C₄It is sub- 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-C₃Halogenated alkyl, C₁-C₃Alkoxy, C₁-C₃ Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃Replaced the substituent group of alkylamino.

In other embodiments, each R^5d、R^5f、R^6d、R^6fAnd R⁶ⁱIt is separately methyl, ethyl, n-propyl, different Propyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, piperidyl, pyrroles Alkyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazole Base, pyrrole radicals, pyrazolyl, imidazole radicals, oxazolyl, C₁-C₄Miscellaneous alkyl ,-(C₁-C₂Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₂ Alkylidene)-(4-7 former molecular heterocycle) ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylidene)-(5-6 atom The heteroaryl of composition) ,-(C₁-C₄Sub- miscellaneous alkyl)-(C₃-C₆Naphthenic base) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 is former molecular Heterocycle) ,-(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 group replaced.

In other embodiments, each R^6gIt independently is C₂-C₆Alkyl, C₁-C₆Miscellaneous alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynes Base, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl, C₁-C₆Halogenated alkyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, Phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4-7 is former Molecular heterocycle) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) ,- (C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₆Naphthenic base) ,-(C₁-C₆Sub- miscellaneous alkyl)-(4-7 former molecular heterocycle) ,-(C₁-C₆It is sub- Miscellaneous alkyl)-phenyl or-(C₁-C₆Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), wherein above-mentioned each group optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Halogenated alkyl, C₁-C₃Alcoxyl Base, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃Replaced the substituent group of alkylamino.

In some embodiments, each R^6gIndependently be ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, Tert-butyl, 3- methyl-1-butyl, 2-methyl-1-butene base, 1,2- dimethyl-1- propyl, neopentyl, acrylic, 2- metering system Base, trifluoromethyl, methylol, ethoxy, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, piperidyl, pyrroles Alkyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, 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)-tetrahydro -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-C₆Naphthenic base) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 former molecular heterocycle) ,-(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 On the spot it is selected from F, Cl, Br, CN, N₃、-OH、-NH₂、-CF₃、-CH₃、-CH₂CH₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N (CH₃)₂Or-CH₂NH₂Substituent group replaced.

In other embodiments, each R⁸It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₃-C₆Naphthenic base, phenyl, 4-7 former molecular heterocycle, 5-6 original Molecular heteroaryl, C₁-C₄Aminoalkyl, C₁-C₄Alkylamino, C₁-C₄Alkoxy, C₁-C₄Hydroxy alkyl ,-NH (C₀-C₃Alkylene Base)-(C₃-C₆Naphthenic base) ,-NH (C₀-C₃Alkylidene)-(4-7 former molecular heterocycle) ,-N [(C₀-C₃Alkylidene)- (C₃-C₆Naphthenic base)]₂、-N[(C₀-C₃Alkylidene)-(4-7 former molecular heterocycle)]₂、-O(C₀-C₃Alkylidene)-(C₃- C₆Naphthenic base) ,-O (C₀-C₃Alkylidene)-(4-7 former molecular heterocycle) ,-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 compositions, and it includes the compounds in the embodiment above of the present invention.

In some embodiments, pharmaceutical composition of the present invention further include pharmaceutically acceptable auxiliary material, Excipient, carrier, solvent or their combination.

In other embodiments, pharmaceutical composition of the present invention, wherein further include other therapeutic agents, The other therapeutic agents are selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 (PDE4) inhibitor, beta-2-adrenoreceptor excitement Agent, nonsteroidal GR agonist, anticholinergic drug, antihistamine, anti-inflammatory reagent, immunosuppressor, is immunized corticosteroid At least one of regulator, the drug for treating atherosclerosis and drug for treating pulmonary fibrosis.

On the other hand, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine preparation, The drug is for preventing, handling, treating or mitigating protein kinase mediated disease.

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

In other embodiments, protein kinase mediated disease of the present invention is proliferative diseases, exempts from self 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 Odd gold lymthoma, non-Hodgkin lymphoma, gastric cancer, cancer of the esophagus, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid gland Cancer, bladder cancer, kidney, brain tumor, head and neck cancer, the cancer of CNS (central nervous system), glioblastoma, non-small cell lung cancer, palace Neck cancer, orchioncus, lymph cancer, Huppert's disease, malignant lymphoma, Small Cell Lung Cancer, neuroblastoma, nerve in point It is white to secrete cell tumour, medullary carcinoma of thyroid gland, melanoma, retinoblastoma, uterine cancer, oophoroma, acute myelocytic Blood disease, acute lymphoblastic leukemia, 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, Chronic Obstructive Pulmonary Disease Disease, asthma, systemic loupus erythematosus, skin lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, psoriasis, I type Diabetes, respiratory anaphylactic disease, nasosinusitis, eczema, morbilli, 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 purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine preparation, The drug 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 their combination.

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

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

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

Any embodiment in either present invention face can be combined with other embodiments, as long as they It is not in contradiction.In addition, any technical characteristic can be adapted for it in any embodiment of either side of the present invention Technical characteristic in its embodiment, as long as they are not in contradiction.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.

Detailed description of the invention book

Definition and general terms

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined Or more it is different from the application or in the case where contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.

It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.

Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.

Unless otherwise stated, following definition should be obtained using used herein.For purposes of the present invention, chemical element with The periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.

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

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

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

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

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

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

" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.

" diastereoisomer " refer to there are two or multiple chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereoisomer is mixed Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to separate by closing object.

Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.

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

Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.

According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.

The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.

The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can 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 " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.

As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included.

In general, term it is " substituted " indicate one or more of given structure can substituted hydrogen atom it is specific Replaced substituent group.Unless otherwise indicated, the group of a substitution can have a substituent group to may replace group is each Position replaced.When more than one position can be by one or more substitutions selected from specific group in given structural formula Replaced base, then substituent group can replace at various locations identical or differently.

Term " optional " either " optionally " mean event or environment described later can with but need not occur, should Illustrate to include the thing or the occasion that environment occurs or do not occur.For example, " optionally by alkyl-substituted heterocyclic group " anticipates Taste alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted scene and heterocyclic group not by alkyl Substituted scene.

Term " unsubstituted " indicates specified group without substituent group.

Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention It includes, but is 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, halogenated alkyl, alkenyl, alkynyl, alkoxy, hydroxy alkyl, alkylthio group, alkyl Amino, aminoalkyl, naphthenic base, heterocycle, aryl and heteroaryl etc., wherein each R^6a、R^6b、R^6c、R^6d、R^6e、R^6f、R^6gAnd R⁶ⁱ With definition as described in the present invention.

In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, It is not influenced mutually between the same symbol between expressed specific option either refer among the different groups, can also be with table Show in the same group, is not influenced mutually between expressed specific option between the same symbol.

It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C₁-C₆Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.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 respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention 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 It applies in scheme, alkyl group contains 1-4 carbon atom；Also in some embodiments, alkyl group contains 1-3 carbon atom. Replaced the substituent group that the alkyl group can be described optionally by one or more present invention.

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), tert-butyl (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), 2- amyl (- CH (CH₃)CH₂CH₂CH₃), 3- amyl (- 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-1-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 (- C (CH₃)₂CH₂CH₂CH₃), 3- methyl -2- amyl (- CH (CH₃)CH(CH₃)CH₂CH₃), 4- methyl -2- penta Base (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- amyl (- C (CH₃)(CH₂CH₃)₂), 2- methyl -3- amyl (- 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..

It is obtained that term " alkylidene " expression removes two or more hydrogen atoms from the linear chain or branched chain alkyl of saturation The divalent or polyvalent hydrocarbon radical of saturation.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In some realities It applies in scheme, alkylidene group contains 1-6 carbon atom；In other embodiments, it is former to contain 1-4 carbon for alkylidene group Son；In other embodiments, alkylidene group contains 0-4 carbon atom；Also in some embodiments, alkylidene group Contain 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, it is former to contain 1-2 carbon for alkylidene group Son.Alkylidene contains 0 carbon atom and refers to that alkylidene is not present, and 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 can be inserted in term " miscellaneous alkyl " expression alkyl, wherein alkyl and hetero atom have such as Meaning of the present invention.Miscellaneous alkyl is connected by carbon atom with other groups.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 Outer some embodiments are that miscellaneous alkyl group contains 1-3 carbon atom.The example of " miscellaneous alkyl " includes, but is not limited to ,- CH₂OCH₃、-CH₂CH₂OCH₂CH₃、-CH₂CH₂OCH₃、-CH₂SCH₃、-CH₂N(CH₃)₂、-CH₂OCH₂(CH₃)₂、-CH₂CH₂OCH₃、- CH₂CH₂OCH₂CH₃Deng.

Term " sub- miscellaneous alkyl " indicate remove from miscellaneous alkyl the obtained saturation of two or more hydrogen atoms divalent or Polyvalent hydrocarbon radical.Sub- miscellaneous alkyl is connected by carbon atom with other groups.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, it is former to contain 1-3 carbon for sub- miscellaneous alkyl group Son.The example of sub- miscellaneous alkyl includes, but are not limited to-CH₂OCH₂-、-CH₂CH₂OCH₂CH₂-、-CH₂CH₂OCH₂-、-CH₂SCH₂-、- CH₂N(CH₃)CH₂-、-CH₂OCH₂(CH₃)CH₂-、-CH₂CH₂NHCH₂-、-CH₂CH₂NHCH₂CH₂Etc..

Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp²Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention Replaced the substituent group stated comprising 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 includes, but is not limited to, vinyl (- CH =CH₂), allyl (- CH₂CH=CH₂) etc..What the alkenyl group can be described optionally by one or more present invention Replaced substituent group.

Term " alkynyl " indicates the linear chain or branched chain 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 can be retouched optionally by one or more present invention Replaced the substituent group stated.In some embodiments, alkynyl group includes 2-8 carbon atom；In other embodiments, Alkynyl group includes 2-6 carbon atom；In other embodiment, alkynyl group includes 2-4 carbon atom.Alkynyl group Example includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH₂C ≡ CH), 1- propinyl (- C ≡ C-CH₃) etc..

Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In some implementations In scheme, alkoxy base contains 1-6 carbon atom；In other embodiments, it is former to contain 1-4 carbon for alkoxy base Son；In other embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally by one Replaced the substituent group that a or multiple present invention describe.

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

Term " halogenated alkyl ", " halogenated alkenyl " or " halogenated alkoxy " indicates alkyl, and alkenyl or alkoxy base are by one Replaced a or multiple halogen atoms, such example includes, but is not limited to, bis-fluoro ethyls (- CH₂CHF₂,-CF₂CH₃,- CHFCH₂F), trifluoroethyl (- CH₂CF₃,-CF₂CH₂F,-CFHCHF₂), trifluoromethyl (- CF₃), trifluoromethoxy (- OCF₃) etc..

Term " hydroxy alkyl " and " hydroxy alkoxy base " indicate alkyl or alkoxy, depend on the circumstances, one or more Replaced hydroxyl group, wherein " hydroxy alkyl " can be used interchangeably with " hydroxyalkyl ", and such example includes, but and unlimited In methylol (- CH₂OH), ethoxy (- CH₂CH₂OH,-CHOHCH₃), hydroxypropyl (- CH₂CH₂CH₂OH,-CH₂CHOHCH₃,- CHOHCH₂CH_3,), hydroxymethoxy (- OCH₂OH) etc..

Term " carbocylic radical " or " carbocyclic ring " indicate containing 3-12 carbon atom, monovalent or multivalence nonaromatic saturation Or part unsaturated monocycle, bicyclic or three-ring system.Carbon bicyclic group includes that spiral shell carbon bicyclic group, condensed carbon bicyclic group and bridge carbon are double Ring group, suitable carbocylic radical group include, but is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.The example of carbocylic radical group into One step includes cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkene Base, cyclohexyl, 1- cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, suberyl, Cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..

Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.In some embodiments, naphthenic base includes 3-12 carbon atom；In other embodiments, naphthenic base includes 3-8 Carbon atom；In other embodiments, naphthenic base includes 3-6 carbon atom.In some embodiments, naphthenic base be comprising The C of 7-12 carbon atom₇-C₁₂Naphthenic base further includes C₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂Condensed-bicyclic alkyl and C₇- C₁₂Bridge bicyclic alkyl；In other embodiments, naphthenic base is the C comprising 8-11 carbon atom₈-C₁₁Naphthenic base, into one Step includes C₈-C₁₁Spiral shell bicyclic alkyl, C₈-C₁₁Condensed-bicyclic alkyl and C₈-C₁₁Bridged ring bicyclic alkyl.The example of naphthenic base includes, But it is not limited to: C₃-C₆Naphthenic base specifically refers to cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.The group of naphthene base can be only It is on the spot unsubstituted or replaced one or more substituent groups described in the invention.

Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to comprising 3-12 annular atom, unit price or Multivalence, saturation or part is unsaturated, nonaromatic monocyclic, bicyclic or tricyclic system, the choosing of wherein at least one annular atom From nitrogen, sulphur and oxygen atom.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base, and-CH₂Group can be optionally by-C (=O)-substitution.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can be optionally oxidized to N- oxygen compound.Heterocycle includes the unsaturated heterocycle of heterocycle (that is: Heterocyclylalkyl) and part of saturation.The reality of heterocycle Example includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolin Base, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro Thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane Base, high piperazine 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 (such as 1,4- sulphur azepineBase, 1,2- sulphur azepineBase), indoles Quinoline base, 1,2,3,4- tetrahydro isoquinolyl, 1,3- benzo two dislike cyclopentadienyl, 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..It is miscellaneous - CH in ring group₂Group includes, but are not limited to 1,1- dioxo isothiazole alkanone -2- base, pyrrole by-C (=the O)-example substituted 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.The example that sulphur atom is oxidized in heterocycle includes, but are not limited to ring Fourth sulfuryl, 1,1- dioxothiomorpholinyl, 1,1- dioxotetrahydro thienyl and 1,1- dioxotetrahydro -2H- thiapyran base, Deng.The heterocyclyl groups can be optionally replaced one or more substituent groups described in the invention.

In some embodiments, heterocycle is the 3-8 molecular heterocycle of original, refer to it is comprising 3-8 annular atom, Unit price or multivalence, saturation or part is unsaturated, nonaromatic monocycle, wherein at least one annular atom be selected from nitrogen, sulphur and Oxygen atom.Unless otherwise stated, 3-8 former molecular heterocycle can be carbon-based or nitrogen base, and-CH₂Group can be optional Ground is substituted by-C (=O)-.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 heterocycle includes, but are not limited to: azelidinyl, oxa- ring fourth Base, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazoles Alkyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, four Hydrogen pyranose, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Piperazinyl, dioxanes base, dithianyl, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptane Base, oxygen azepineBase, diazaBase, sulphur azepineBase, etc..- CH in heterocycle₂The example packet that group is substituted by-C (=O)- It includes, but is not limited to, 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base and 3,5- dioxy piperazine piperidinyl, etc.. The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base and 1,1- dioxothiomorpholinyl.Described 3-8 former molecular heterocyclyl groups can be optionally replaced one or more substituent groups described in the invention.

In other embodiments, heterocycle is 4-7 former molecular heterocycle, is referred to comprising 4-7 annular atom , unit price or multivalence, saturation or part is unsaturated, nonaromatic monocycle, wherein at least one annular atom is selected from nitrogen, sulphur And oxygen atom.Unless otherwise stated, 4-7 former molecular heterocycle can be carbon-based or nitrogen base, and-CH₂Group can appoint Selection of land is substituted by-C (=O)-.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 heterocycle includes, but are not limited to: azelidinyl, oxa- ring Butyl, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, miaow Oxazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 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, dioxanes base, dithianyl, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl Alkyl, oxygen azepineBase, diazaBase and sulphur azepineBase.The former molecular heterocyclyl groups of described 4-7 can be optional Ground is replaced one or more substituent groups described in the invention.

Term " bridge is bicyclic ", " bridged ring ", " bridge bicyclic group " and " bridged ring base " are used interchangeably here, all refer to unit price or Multivalence, saturation or part is unsaturated but nonaromatic bicyclic system, two rings in the ring system share two atoms With more than two singly-bounds.Such system may include independent or conjugation unsaturated system, but its nuclear structure does not wrap Containing aromatic rings or heteroaromatic (but aromatic group can be used as substituent group thereon).

Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " are used interchangeably here, all refer to list Valence or multivalence, saturation or part is unsaturated but nonaromatic ring system, two rings in the ring system share a key. Such system may include independent or conjugation unsaturated system, but its nuclear structure does not include aromatic rings or heteroaromatic (but aromatic group can be used as substituent group thereon).

Term " loop coil base ", " loop coil ", " spiral shell bicyclic group " or " spiral shell is bicyclic " are used interchangeably here, refer to unit price or more Valence, saturation or the unsaturated ring system in part, one of ring originate from specific ring carbon atom on another ring, and two A ring only shares this atom.For example, as described in following formula a-1 and formula a-2, the ring system of a saturation (ring B and B ') it is referred to as " condensed-bicyclic ", and ring A ' and ring B shares a carbon atom, referred to as " loop coil " 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 is optionally replaced one or more substituent groups described in the invention.

Term " Heterocyclylalkyl " refers to saturation monocycle, the bicyclic or tricyclic of the unit price containing 3-12 annular atom or multivalence System, wherein at least one annular atom are selected from nitrogen, sulphur or oxygen atom.Unless otherwise stated, Heterocyclylalkyl can be carbon-based or nitrogen Base, and-CH₂Group can be substituted optionally by-C (=O)-.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, dioxanes base, dithianyl, isoxazolidinyl, isothiazole alkyl, 1,2- oxazines base, 1,2- thiophene Piperazine base, hexahydro-pyridazine base, high piperazine 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 It is miscellaneousBase (e.g., Isosorbide-5-Nitrae-dioxaBase, 1,2- dioxaBase), sulphur azepineBase (e.g., Isosorbide-5-Nitrae-sulphur azepineBase, 1,2- sulphur nitrogen It is 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 Simultaneously simultaneously [3,2-b] furyl, hexahydro furyl be simultaneously for [c] pyrrole radicals, octahydro -1H- isoindolyl, hexahydro furyl for base, octahydro cyclopenta [2,3-b] furyl and ten dihydro-isoquinoline bases.The heterocycloalkyl can be optionally by one or more present invention Replaced described substituent group.

In some embodiments, Heterocyclylalkyl is 7-12 former molecular Heterocyclylalkyl, is referred to containing 7-12 ring Atom, monovalent or multivalence, the miscellaneous bicyclic alkyl of the spiral shell of saturation condenses 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 stated, Heterocyclylalkyl can be carbon-based or nitrogen base, and-CH₂Group It can optionally be substituted by-C (=O)-.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can be with Optionally it is oxidized to N- oxygen compound.Described 7-12 former molecular heterocycloalkyl can optionally by one or Replaced multiple substituent groups described in the invention.

In some embodiments, Heterocyclylalkyl is 4-7 former molecular Heterocyclylalkyl, is referred to former containing 4-7 ring Son, monovalent or multivalence, the heterocycle of saturation, wherein at least one annular atom is selected from nitrogen, sulphur or oxygen atom.Unless in addition saying Bright, Heterocyclylalkyl can be carbon-based or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.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, dioxanes base, dithianyl, isoxazolidinyl, isothiazole alkyl, six Hydrogen pyridazinyl, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase and sulphur AzepineBase.The former molecular heterocycloalkyl of described 4-7 can be optionally by one or more described in the invention Substituent group replaced.

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

Contain one or more degrees of unsaturation in " unsaturated " the expression group of term as used in the present invention.

Term " hetero atom " refers to O, S, N, P and Si, the form including any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole base N), NH (as the NH in pyrrolidinyl) or NR (NR in pyrrolidinyl replaced as N-).

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

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

Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 original Molecular ring, and there are one or more tie points to be connected with the rest part of molecule.Term " aryl " can be with term " fragrance Ring " is used interchangeably.The example of aryl group may include phenyl, naphthalene and anthryl.The aryl group can individually optionally Replaced one or more substituent groups described in the invention.

Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom, Bicyclic and three-ring system, wherein at least one ring system are aromatic, and at least one aromatic ring system includes one or more A hetero atom, wherein each ring system includes 5-7 former molecular ring, and have one or more tie points and molecule remaining Part is connected.Term " heteroaryl " can be used interchangeably with term " hetero-aromatic ring " or " heteroaromatics ".In some embodiment party In case, heteroaryl is the heteroatomic 5-12 former molecular heteroaryl that O, S and N are independently selected from comprising 1,2,3 or 4.? In other embodiments, heteroaryl is the heteroatomic 5-10 atom composition that O, S and N are independently selected from comprising 1,2,3 or 4 Heteroaryl.Also in some embodiments, heteroaryl is the heteroatomic 5-6 that O, S and N are independently selected from comprising 1,2,3 or 4 A molecular heteroaryl of original.The heteroaryl groups are optionally taken by one or more substituent groups 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 (such as 3- indazolyl, 4- indazolyl, 5- indazolyl, 6- indazole Base, 7- indazolyl), imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [4,3-c] pyridyl group, pyrazoles And [3,4-b] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] Pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridyl group, etc..5-12 atom The example of the heteroaryl groups of composition further includes 5-6 former molecular single ring heteroaryl group, and the example includes, but and unlimited In monocycle below, furyl (such as 2- furyl, 3- furyl), imidazole radicals (such as 1- imidazole radicals, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals), isoxazolyl (such as 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl), oxazolyl (such as 2- oxazolyl, 4- dislike Oxazolyl, 5- oxazolyl), pyrrole radicals (such as 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals), pyridyl group (such as 2- pyridyl group, 3- pyridine Base, 4- pyridyl group), pyriconyl, pyrimidine radicals (such as 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals), pyrimidine ketone group, hybar X Base, pyridazinyl (such as 3- pyridazinyl, 4- pyridazinyl), pyrazinyl (such as 2- pyrazinyl, 3- pyrazinyl), thiazolyl (such as 2- thiazolyl, 4- thiazolyl, 5- thiazolyl), tetrazole radical (such as 5- tetrazole radical), triazolyl (such as 2- triazolyl and 5- triazolyl), thienyl (such as 2- thienyl, 3- thienyl), pyrazolyl (such as 1- pyrazolyl, 3- pyrazolyl, 4- pyrazolyl, 5- pyrazolyl), pyrazoline ketone group, Isothiazolyl, 1,2,3- oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 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 " refers to that containing at least two hetero atom 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, Oxadiazoles base, thiazolyl, isothiazolyl, thiadiazolyl group, di azoly, triazolyl, indazolyl, pyrazolo [4,3-c] pyridyl group, pyrrole Azoles simultaneously [3,4-b] pyridyl group, imidazo [4,5-b] pyridyl group and 1H- benzo [d] imidazole radicals.

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

Term " alkyl amino " and " alkylamino " can be exchanged with each other use comprising " N- alkylamino " and " N, N- dioxane Amino ", wherein amino group is separately replaced 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 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 formed on nitrogen-atoms Group.In other embodiments, alkylamino is one or two C₁-C₄Alkyl is connected to the lower level formed on nitrogen-atoms Alkylamino group.Also in other embodiments, alkylamino is one or two C₁-C₃Alkyl is connected on nitrogen-atoms The alkylamino group of the lower level of formation.Suitable alkylamino radicals can be alkyl monosubstituted amino or dialkyl amido, alkane ammonia The example of base includes, 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 " indicates amino group replaced one or two aryl group, and such example includes, but It is not limited to N- phenylamino.Some of embodiments are that the aromatic ring in fragrant amino can be further substituted.

Term " aminoalkyl " includes the C replaced one or more amino₁-C₁₂Linear or branched alkyl group group.? In some embodiments, aminoalkyl is the C replaced one or more amino groups₁-C₁₂Alkyl；In other embodiment party In case, aminoalkyl is the C replaced one or more amino groups₁-C₆" aminoalkyl of lower level ", in other realities It applies in scheme, aminoalkyl is the C replaced one or more amino groups₁-C₄Alkyl；Also in other embodiments, Aminoalkyl is the C replaced one or more amino groups₁-C₃Alkyl.The example of aminoalkyl includes, but is not limited to, Aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.

As described in the invention, substituent group draws one and is keyed to the ring system formed on the ring at center (such as formula b institute Show) it represents substituent group all substitutive positions in the ring system and selects a substitution.For example, formula b, which represents substituent R, can select one Replace D ring on it is all can be with substituted position, as shown in formula c~formula e.

As described in the invention, one connection be keyed to formed on the center of ring ring system (as shown in formula f, Middle X and X ' independently is CH₂, NH or O) represent connecting key can in ring system any attachable position and molecule its remaining part Split-phase connects.The position that formula f represents any possible connection on F ring and E ring can be connected (such as formula f-1~formula with molecule rest part Shown in f-8).

As described in the invention, two connections are keyed to the ring system (as formula i shows) formed on the center of ring and represent Two connecting keys can be connected any attachable position in ring system with molecule rest part, and the both ends connected (endpoint Q and endpoint Q ') can be exchanged with each other.Formula i represents the position that any two may connect on G ring can be with molecule Rest part is connected.

When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, t-butyl formate (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used to block or protect the functionality of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group can refer 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 formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C₁-C₂₄) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.It is completely begged for about pro-drug By following documents can be referred to: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.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 product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic 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 alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C₁-C₄Alkyl)₄Salt.The present invention, which is also intended to contemplate, to be appointed The compound of the group of what included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be by quaternized Effect obtains.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises The amine cation that appropriate, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulphur Acidulants, phosphoric acid compound, nitric acid compound, C_1-8Sulphonic acid compound and aromatic sulphonic acid compound.

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

Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.

" inflammatory disease " used in the present invention refers to excessive inflammation caused by excessive or out of control inflammatory responses Property symptom, host tissue damage or function of organization any disease for losing, disorder or symptom." inflammatory disease " also refers to by leucocyte The pathologic state that inflow and/or Neutrophil chemotaxis mediate.

" inflammation " used in the present invention refers to by tissue damaged or topical protective response caused by destroying, it is for breaking Tissue that is bad, diluting or separate (isolation) harmful substance and be damaged.Inflammation is flowed into leucocyte and/or neutrophil cell becomes The property changed has significant connection.Inflammation can produce in the infection and non-infectious mode of pathogenic organism and virus, such as heart Wound or Reperfu- sion after muscle infarction or apoplexy, to the immune response and autoimmune response of exotic antigen.Therefore, this can be used The inflammatory disease of disclosure of the invention compound treatment includes: to react with specific system of defense and non-specific defense system reaction Relevant disease.

" specific system of defense " refers to that the component of immune system reacts to the presence of specific antigen.Result from specificity The example of the inflammation of system of defense reaction includes classical response, autoimmune disease and the delayed type hypersensitivity, DTH to exotic antigen Response (cell-mediated by T-).The repulsion of chronic inflammatory disease, transplanting solid tissue and organ is (such as kidney and bone-marrow transplantation Repel) and graft versus host disease (GVHD) be other examples of specific system of defense inflammatory reaction.

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

" allergy " used in the present invention refers to that any symptom for generating allergy, histologic lesion or function of organization lose.Such as " arthritis disease " used in the present invention refers to any characterized by being attributable to various etiologic etiological arthritis damages Disease." dermatitis " refers to the skin disease characterized by being attributable to various etiologic etiological scytitis as used in the present invention Large family in any one." graft rejection " refers to the funeral of the function of transplanting or surrounding tissue as used in the present invention Tissue is transplanted in the confrontation that mistake, pain, swelling, leukocytosis and decrease of platelet are characterized, such as organ or cell (such as marrow) Any immune response.Treatment method of the invention includes the method for treating disease relevant to inflammatory cell activation.

Term " cancer " and " cancer " refer to or describe the physiology in patient usually characterized by cell growth out of control Illness." tumour " includes one or more cancer cells.The example of cancer includes but is not limited to cancer (carcinoma), lymthoma, embryo Cytoma, sarcoma and leukaemia or malignant lymph proliferative disease (lymphoid malignancies).Such cancer is more Specific example includes squamous cell carcinoma (such as epithelium squamous cell carcinoma), lung cancer (including Small Cell Lung Cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of lung and lung carcinoma squamosum), peritoneal cancer, hepatocellular carcinoma (hepatocellular cancer), gastric cancer (gastric Or stomach cancer) (including human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical carcinoma, oophoroma, orchioncus, bladder Cancer, hepatoma (hepatoma), breast cancer, colon and rectum carcinoma, colorectal cancer, carcinoma of endometrium or uterine cancer, 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, acute lymphoblastic leukemia, chronic granulocytic leukemia (CML), chronic lymphocytic leukemia and neck Cancer.

The description of the compound of the present invention

The invention discloses a kind of novel compounds, can be used as protein kinase activity, especially jak kinase, FLT3 swashs Enzyme and the active inhibitor of Aurora A.Compound as kinases inhibitor can be used for treating and unsuitable albumen Kinase activity, is especially unsuitable jak kinase, FLT3 kinases and the relevant disease of Aurora A activity, for example, treatment and Prevention is related to the disease that the jak kinase, FLT3 kinases and Aurora A of signal path mediate.Such disease includes proliferative Disease, autoimmune disease, anaphylactia, inflammatory disease, graft rejection and their complication.Particularly, of the invention Compound can be used to treat following disease, such as cancer (colorectal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, stomach Cancer, cancer of the esophagus, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, bladder cancer, kidney, brain tumor, head and neck cancer, It is the cancer of CNS (central nervous system), glioblastoma, non-small cell lung cancer, cervical carcinoma, orchioncus, lymph cancer, multiple It is myeloma, malignant lymphoma, Small Cell Lung Cancer, neuroblastoma, neuroendocrine cell tumour, medullary carcinoma of thyroid gland, black It is melanoma, retinoblastoma, uterine cancer, oophoroma, acute myelocytic leukemia, acute lymphoblastic leukemia, slow Property myelocytic leukemia (CML), chronic lymphocytic leukemia), primary macroglobulinaemia, monocytic leukemia, Sezary syndrome, infectious mononucleosis, colitis, pancreatitis, atherosclerosis, pulmonary fibrosis, true property are red Cytosis, primary thrombocytosis, myelofibrosis, Chronic Obstructive Pulmonary Disease (COPD), asthma, systemic red Yabbi sore, skin lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, psoriasis, type-1 diabetes mellitus, respiratory tract mistake Quick property disease, nasosinusitis, eczema, morbilli, food hypersenstivity, insect venom allergies, inflammatory bowel disease, Crohn disease, rheumatoid close Save 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 inhibition to one or more protein kinases Activity.

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

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

In some embodiments, Z¹For H, C₁-C₁₂Alkyl, C₃-C₁₂Naphthenic base or 3-12 former molecular heterocycle, Wherein, each C₁-C₁₂Alkyl, C₃-C₁₂The former molecular heterocycle of naphthenic base and 3-12 individually optionally by 1,2,3,4 or 5 R³Replaced group；

A is pyrazolyl, optionally by 1,2 or 3 R⁴Replaced group；

R¹For H, F, Cl, Br, I, N₃、CN、NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxy, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, 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 Alkoxy, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl and 5-12 A molecular heteroaryl of original is individually optionally by 1,2,3,4 or 5 R⁸Replaced group；

Each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Alkylamino, C₃-C₁₂Naphthenic base, 4-7 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 original are molecular miscellaneous Aryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocycle) ,-(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-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkylamino, C₃-C₁₂Naphthenic base, 4-7 former molecular heterocycle, C₆-C₁₂ Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 A molecular heterocycle of original) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 atom composition Heteroaryl) individually optionally by 1,2,3,4 or 5 R⁸Replaced group；

Each R³And R⁴It is separately F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂ Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocycle) ,-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-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3- The molecular heterocycle of 12 originals, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Ring Alkyl) and-(C₁-C₄Alkylidene)-(3-12 former molecular heterocycle) 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- C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 atom composition Heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(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-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂ Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 A molecular heterocycle of original) ,-(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-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent group of alkylamino is taken Generation；Or

R^5aAnd R^5bCan also and together with nitrogen-atoms that they are connected, form the 3-12 molecular heterocyclyl groups of original, Wherein, described 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-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl Or C₁-C₆Replaced the substituent group of alkylamino；

R^6aAnd R^6bCan also and together with nitrogen-atoms that they are connected, form the 3-12 molecular heterocyclyl groups of original, Wherein, described 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-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl Or C₁-C₆Replaced the substituent group of alkylamino；

R^7aAnd R^7bCan also and together with nitrogen-atoms that they are connected, form the 3-12 molecular heterocyclyl groups of original, Wherein, described 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-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl Or C₁-C₆Replaced the substituent group of alkylamino；

Each R^5d、R^5f、R^6d、R^6f、R⁶ⁱ、R^7dAnd R^7fIt is separately C₁-C₁₂Alkyl, C₁-C₁₂Miscellaneous alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxy, C₁-C₁₂Alkylamino, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Virtue Base, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 Former molecular heterocycle) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 is former molecular Heteroaryl) ,-(C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₁₂Naphthenic base) ,-(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), 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- C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆Replaced the substituent group of alkylamino；

Each R^6gIt independently is C₂-C₁₂Alkyl, C₁-C₁₂Miscellaneous alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxy alkyl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Halogenated alkyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 The molecular heteroaryl of a original ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 atom composition Heterocycle) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,- (C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₆Sub- miscellaneous alkyl)-(3-12 former molecular heterocycle) ,-(C₁-C₆ Sub- miscellaneous alkyl)-(C₆-C₁₂Aryl) or-(C₁-C₆Sub- miscellaneous alkyl)-(5-12 former molecular heteroaryl), 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-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆Replaced the substituent group of alkylamino；

Each R⁸It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Halogenated alkyl, C₃-C₁₂Naphthenic base, C₆-C₁₂Aryl, 3-12 former molecular heterocycle, 5-12 atom composition Heteroaryl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Alkylamino, C₁-C₁₂Alkoxy, C₁-C₁₂Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)- (C₃-C₁₂Naphthenic base) ,-NH (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-NH (C₀-C₄Alkylidene)-(3-12 is former molecular Heterocycle) ,-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 heterocycle) 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 one kind compounds as shown in formula (II) compound represented or formula (II) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or it before Medicine,

In other embodiments, Z¹For H, C₁-C₆Alkyl, C₃-C₆Naphthenic base or 4-7 former molecular heterocycle, Wherein, each C₁-C₆Alkyl, C₃-C₆Naphthenic base and 4-7 former molecular heterocycle are optionally by 1,2 or 3 R³Group institute Replace.

In some embodiments, Z¹For H, C₁-C₆Alkyl, C₃-C₆Naphthenic base or 4-7 former molecular heterocycle, In, each C₁-C₆Alkyl, C₃-C₆Naphthenic base and 4-7 former molecular heterocycle are optionally by 1,2 or 3 R³Group is taken Generation.

In some embodiments, A are as follows:

Wherein, each son shown in formula (A-1), (A-2) and (A-3) Structure is individually optionally by 1 or 2 R⁴Replaced group.

In other embodiments, R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₄Alkyl, C₁-C₄Alkoxy, C₂- C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, the molecular heteroaryl of 5-6 original ,- 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-C₄Alkoxy, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl and 5-6 Former molecular heteroaryl is individually optionally by 1,2 or 3 R⁸Replaced group.

In some embodiments, each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 atom The heteroaryl of composition ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(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-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 The molecular heteroaryl of a original ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4-7 is former molecular Heterocycle) ,-(C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) individually optionally By 1,2 or 3 R⁸Replaced group.

In other embodiments, each R²And R^2aIt is separately H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₄Alkane Base, C₂-C₄Alkenyl, C₁-C₄Alkylamino, C₃-C₆Naphthenic base, 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-C₆Naphthenic base) ,-(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-C₄Alkenyl, C₁-C₄Alkane ammonia Base, C₃-C₆Naphthenic base, 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-C₂It is sub- Alkyl)-(C₃-C₆Naphthenic base) ,-(C₁-C₂Alkylidene)-(4-7 former molecular heterocycle) ,-(C₁-C₂Alkylidene)-phenyl With-(C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl) individually optionally by 1,2 or 3 R⁸Replaced group.

In some embodiments, each R³And R⁴It is separately F, Cl, CN, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₃-C₆Ring Alkyl, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Ring Alkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle) ,-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-C₄Alkenyl, C₃-C₆Naphthenic base, 4-7 original are molecular miscellaneous Ring group, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) and-(C₁-C₃Alkylidene)- (4-7 former molecular heterocycle) is individually optionally by 1,2 or 3 R⁸Replaced group.

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, pyridyl group, pyrimidine radicals, pyridazinyl, thiazole Base, pyrrole radicals or oxazolyl, wherein each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, piperidyl, pyrrolidinyl, Morpholinyl, piperazinyl, pyridyl group, pyrimidine radicals, pyridazinyl, thiazolyl, pyrrole radicals and oxazolyl it is individually optional by 1,2 or 3 R⁸Replaced group.

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-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 original Molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), wherein each C₁- C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 atom composition Heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle) ,- (C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) optionally by 1,2 or 3 independence Ground is selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Halogenated alkyl, C₁-C₃Alkoxy, C₁-C₃Hydroxyl alkane Base, C₁-C₃Aminoalkyl or C₁-C₃Replaced the substituent group of alkylamino；Or

R^5aAnd R^5bCan also and together with nitrogen-atoms that they are connected, form the 4-7 molecular heterocyclyl groups of original, Wherein, described 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-C₃Halogenated alkyl, C₁-C₃Alkoxy, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁- C₃Replaced the substituent group of alkylamino；

R^6aAnd R^6bCan also and together with nitrogen-atoms that they are connected, form the 4-7 molecular heterocyclyl groups of original, Wherein, described 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-C₃Halogenated alkyl, C₁-C₃Alkoxy, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁- C₃Replaced the substituent group of alkylamino；

R^7aAnd R^7bCan also and together with nitrogen-atoms that they are connected, form the 4-7 molecular heterocyclyl groups of original, Wherein, described 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-C₃Halogenated alkyl, C₁-C₃Alkoxy, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁- C₃Replaced the substituent group of alkylamino.

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, tert-butyl, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, pyrimidine Base, pyridazinyl, pyrazinyl, thiazolyl, pyrrole radicals, pyrazolyl, imidazole radicals or oxazolyl, wherein each methyl, ethyl, just Propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrole Cough up alkyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, 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 Dai Ji.

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-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Alkoxy, C₁-C₄Alkylamino, C₃-C₆Naphthenic base, 4-7 original are molecular miscellaneous Ring group, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4- 7 molecular heterocycles of original) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl Base) ,-(C₁-C₄Sub- miscellaneous alkyl)-(C₃-C₆Naphthenic base) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 former molecular heterocycle) ,- (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-C₃Halogenated alkyl, C₁-C₃Alkane Oxygroup, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃Replaced the substituent group of alkylamino.

In other embodiments, each R^5d、R^5f、R^6d、R^6f、R⁶ⁱ、R^7dAnd R^7fIt is separately methyl, ethyl, just Propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, piperidines Base, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, 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 heterocycle) ,-(C₁-C₂Alkylidene)-phenyl ,-(C₁-C₂Alkylidene)- (5-6 former molecular heteroaryl) ,-(C₁-C₄Sub- miscellaneous alkyl)-(C₃-C₆Naphthenic base) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 Former molecular heterocycle) ,-(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 group replaced.

In other embodiments, each R^6gIt independently is C₂-C₆Alkyl, C₁-C₆Miscellaneous alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynes Base, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl, C₁-C₆Halogenated alkyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, Phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4-7 is former Molecular heterocycle) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) ,- (C₁-C₆Sub- miscellaneous alkyl)-(C₃-C₆Naphthenic base) ,-(C₁-C₆Sub- miscellaneous alkyl)-(4-7 former molecular heterocycle) ,-(C₁-C₆It is sub- Miscellaneous alkyl)-phenyl or-(C₁-C₆Sub- miscellaneous alkyl)-(5-6 former molecular heteroaryl), wherein above-mentioned each group optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Halogenated alkyl, C₁-C₃Alcoxyl Base, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃Replaced the substituent group of alkylamino.

In some embodiments, each R^6gIndependently be ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, Tert-butyl, 3- methyl-1-butyl, 2-methyl-1-butene base, 1,2- dimethyl-1- propyl, neopentyl, acrylic, 2- metering system Base, trifluoromethyl, methylol, ethoxy, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, piperidyl, pyrroles Alkyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, 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)-tetrahydro -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-C₆Naphthenic base) ,-(C₁-C₄Sub- miscellaneous alkyl)-(4-7 former molecular heterocycle) ,-(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 On the spot it is selected from F, Cl, Br, CN, N₃、-OH、-NH₂、-CF₃、-CH₃、-CH₂CH₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N (CH₃)₂Or-CH₂NH₂Substituent group replaced.

In other embodiments, each R⁸It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₃-C₆Naphthenic base, phenyl, 4-7 former molecular heterocycle, 5-6 original Molecular heteroaryl, C₁-C₄Aminoalkyl, C₁-C₄Alkylamino, C₁-C₄Alkoxy, C₁-C₄Hydroxy alkyl ,-NH (C₀-C₃Alkylene Base)-(C₃-C₆Naphthenic base) ,-NH (C₀-C₃Alkylidene)-(4-7 former molecular heterocycle) ,-N [(C₀-C₃Alkylidene)- (C₃-C₆Naphthenic base)]₂、-N[(C₀-C₃Alkylidene)-(4-7 former molecular heterocycle)]₂、-O(C₀-C₃Alkylidene)-(C₃- C₆Naphthenic base) ,-O (C₀-C₃Alkylidene)-(4-7 former molecular heterocycle) ,-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), tautomer, solvate, metabolism produce Object, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.

Disclosed compound of present invention can containing asymmetric or chiral centre, therefore can different stereoisomer forms deposit ?.The present invention is directed to all stereoisomer forms of compound shown in formula (I), including but not limited to diastereoisomer, Enantiomter, atropisomer and geometry (or conformation) isomers and their mixture such as racemic mixture, become Component part of the invention.

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

Compound shown in formula (I) can exist with different tautomeric forms, and all these tautomers, Tautomer as described in the present invention, is included within the scope of the present invention.

Compound shown in formula (I) can exist in a salt form.In some embodiments, the salt, which refers to, pharmaceutically may be used The salt of receiving.Term " pharmaceutically acceptable " refers to that substance or composition must be with other ingredients and/or use comprising preparation Its mammal treated is compatible chemically and/or in toxicology.In other embodiments, the salt is not necessarily pharmacy Upper acceptable salt, can be and be used to prepare and/or purify compound shown in formula (I) and/or for separating this formula (I) shownization Close the intermediate of the enantiomer of object.

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

The inorganic acid that salt can be obtained by its derivative includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.

The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

Can obtain the inorganic base of salt by its derivative includes, for example, ammonium salt and periodic table I race to XII race metal.? In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.

Can obtain the organic base of salt by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.

Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.

In addition, compound disclosed by the invention, the salt including them, in the form of their hydrate or can also include it The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, for their crystallization.Disclosed compound of present invention can be with pharmacy Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations And unsolvated form.

Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as³H、¹⁴C and¹⁸Those of F compound, or wherein there is non radioactive isotope, such as²H and¹³C.The compound of such isotope enrichment can be used for being metabolized research and (use¹⁴C), Reaction kinetics research are (using for example²H or³H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound of F 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 It is substituted described by the embodiment and preparation process in routine techniques or the present invention known using suitable isotope labeling reagent former Carry out used unmarked reagent to prepare.

In addition, higher isotope especially deuterium (that is,²H or D) substitution can provide certain treatment advantages, these advantages are By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substituent group of compound shown in formula (I).Isotope enrichment factor can be used To define the concentration of such higher isotope especially deuterium.Term " isotope enrichment factor " used in the present invention refers to meaning Determine the ratio between the isotope abundance of isotope and natural abundance.If the substituent group of the compounds of this invention is designated as deuterium, The compound at least 3500 (52.5% deuterium incorporation at each specified D-atom), at least for each specified D-atom 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutical solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution₂O, acetone-d₆、 DMSO-d₆Those of solvate.

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

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

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In a little embodiments, pharmaceutical composition of the present invention, further include pharmaceutically acceptable auxiliary material, carrier, excipient, Solvent or their combination.In other embodiments, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Mist dosage form.

On the other hand, the present invention relates to treatments by one or more protein kinases, as jak kinase, FLT3 kinases and The method of disease or disorder that Aurora A is adjusted, the treatment method include giving the present invention public affairs of mammalian effective amount Open compound or pharmaceutical composition.In some embodiments, the disease or disorder are selected from proliferative diseases, autoimmunity disease Disease, anaphylactia, inflammatory disease, graft rejection or cancer.

On the other hand, the present invention relates to use the compounds of this invention or medicine composite for curing disease disclosed by the invention or Disorder, the disease or disorder be selected from proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease, graft rejection or Cancer.

On the other hand, the present invention relates to compounds disclosed by the invention or pharmaceutical composition in preparation treatment disease or disorder Drug 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 use the compounds of this invention disclosed by the invention or pharmaceutical composition to prepare drug Purposes, the drug are used for the activity of regulatory protein kinases, and the activity of Aurora A, such as Aurora-A is especially inhibited to swash Enzyme, Aurora-B kinases or Aurora-C kinases.

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

The present invention provides a kind of pharmaceutical composition, and it includes listed compounds in disclosed compound of present invention or embodiment； With pharmaceutically acceptable auxiliary material, excipient, carrier, solvent or their combination.Change in pharmaceutical composition disclosed by the invention The amount for closing object, which refers to, can effectively detect the amount for inhibiting biological sample or patient's body protein kinase.

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

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

" pharmaceutically acceptable auxiliary material " used in the present invention means relevant to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Every kind of auxiliary material must be other at split-phase with pharmaceutical composition in mixing Hold, interaction the effect of to avoid will be greatly reduced disclosed compound of present invention when administering to a patient and to will lead to be not medicine The interaction of acceptable pharmaceutical composition on.In addition, every kind of auxiliary material must be it is pharmaceutically acceptable, for example, having Sufficiently high purity.

Suitable pharmaceutically acceptable auxiliary material can be different according to selected specific dosage form.In addition, can combined according to them Specific function in object selects pharmaceutically acceptable auxiliary material.For example, may be selected to can help to produce the certain of equal one dosage type low temperature Pharmaceutically acceptable auxiliary material.The certain pharmaceutically acceptable auxiliary materials that can help to produce stabilizer type may be selected.It may be selected Facilitate to carry or transport disclosed compound of present invention when administering to a patient from an organ of body or partially to the another of body One organ or partial certain pharmaceutically acceptable auxiliary materials.The certain pharmaceutically acceptable of enhancing patient compliance may be selected Auxiliary material.

Suitable pharmaceutically acceptable auxiliary material includes following kind of auxiliary material: diluent, filler, adhesive, disintegration Agent, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, flavoring Agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilizer, Surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable auxiliary materials can provide more than one function, And alternative function is provided, this is depended in preparation in the presence of there are which other auxiliary materials in how much auxiliary materials and preparation.

Technical staff grasps the knowledge and skills of this field, so that they can select for the suitable of appropriate amount of the invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。

In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Well-known technique, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object effect, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of open compound, pays close attention to its application and belong to the scope of the present invention.

Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。

Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes those dosage forms for being suitable for following administration route: (1) being administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, granule and cachet；(2) parenteral, example Such as sterile solution agent, suspension and freeze-dried powder agent；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.

In 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 Object can be configured to nose administration dosage form.In other embodiment, compound disclosed by the invention can be configured to transdermal Form of administration.Also in some embodiments, compound disclosed by the invention can be configured to Topical dosage forms.

Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to gastric acid effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to fatty acid, rouge Fat, phenyl salicylate, wax, shellac, ammonification shellac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of substance.Film coating includes, but are not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.It is multiple Tabletting is the compressed tablets by preparing more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.

Tabules can be by one kind that powder, crystallization or granular active constituent are individual or describe with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrating agent, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.

Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, and one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is by being added glycerol, sorbierite or the plasticizing of similar polyalcohol.It is raw that soft gelatin shell may include the pre- preventing microorganism of preservative It is long.Suitable preservative be as described in the present invention those, including methylparaben and propylben and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and suspension in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；It is prepared described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.

Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used The acetal of receiving, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal；And have one or more The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.

Other useful liquid and semisolid dosage form include, but are not limited to comprising active constituent provided by the invention and second level Change those of mono- or poly- alkylene glycol dosage form, described mono- or poly- alkylene glycol includes: 1,2- dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ether, polyethylene glycol -550- dimethyl ether, poly- second The approximate average molecular weight of glycol -750- dimethyl ether, wherein 350,550,750 finger polyethylene glycol.These preparations can be further Including one or more antioxidant, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, ethanol amine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, coke Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.

Where appropriate, can be by the dosage unit preparations microencapsulation of oral administration.It can also be prepared into extending or tie up Hold the composition of release, such as by being coated by microparticle material or be embedded in polymer, wax or the like.

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

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

Colorant and flavoring agent can be used in all above-mentioned dosage forms.

Compound disclosed in this invention can also be in conjunction with the soluble polymer as target medicine carrier.It is such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl The oxide polylysine that amine phenol or palmitoyl residues replace.In addition, compound disclosed in this invention can in reality One kind Biodegradable polymeric used in the control release of existing drug combines, for example, polylactic acid, poly-epsilon-caprolactone, gathering Hydroxybutyric acid, polyorthoester, polyacetals, poly- dihydropyran, the crosslinking of polybutylcyanoacrylate and hydrogel or amphiphilic block are total Polymers.

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

Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect It prepares, or the substance co-formulation with the expected effect of supplement.

Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body administration.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.

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

Be intended for parenteral administration pharmaceutical composition may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.

Suitably include, but are not limited to containing transporter: water, salt water, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers injection, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injection.Non- transporter includes, but are not limited to fixed oil, castor oil, corn oil, the cottonseed of plant origin Oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil middle chain Triglycerides and palm seed oil.Water miscibility carrier includes, but are not limited to the poly- second two of ethyl alcohol, 1,3-BDO, liquid Alcohol (such as Liquid Macrogol and polyethylene glycol 400), propylene glycol, glycerol, n-methyl-2-pyrrolidone, N, N- dimethylacetamide Amine and dimethyl sulfoxide.

Suitable antimicrobial or preservative include, but are not limited to phenol, cresols, mercurial, benzyl alcohol, chlorobutanol, Methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride (such as benzethonium chloride), methylparaben and Propylben and sorbic acid.Suitable isotonic agent includes, but are not limited to sodium chloride, glycerol and glucose.Suitable buffer Include, but are not limited to phosphate and citrate.Suitable antioxidant is such as those of present invention description, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is such as those of present invention description, including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitable emulsifier includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene is de- Water sorbitol monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agent include, but are not limited to EDTA. Suitable pH adjusting agent includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but unlimited In cyclodextrin, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-β-cyclodextrin, Sulfobutylether-beta-cyclodextrin and sulfobutyl group Ether 7- beta-cyclodextrin (CyDex,Lenexa,KS)。

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

In some embodiments, pharmaceutical composition is provided with instant sterile solution.In other embodiments, Pharmaceutical composition is provided with sterile dried soluble product, including freeze-dried powder agent and hypodermic tablet, is using preceding use Carrier reconstruct.In other embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In other implementation In scheme, pharmaceutical composition is formulated into the sterile dry insolubility product reconstructed before use with carrier.Also some In embodiment, pharmaceutical composition is formulated into instant without bacterial emulsion.

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

Pharmaceutical composition can be configured to suspension, solid, semisolid or thixotropic liquid, the reservoir administration as implantation. In some embodiments, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, is insoluble to body fluid But the external polymeric membrane for allowing the active constituent in pharmaceutical composition to diffuse through is surrounded.

Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silicon oxygen 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 external polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Object, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second Alkene, the copolymer of ethlyene dichloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer are poly- to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.

On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable for any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspension or liquid composite.In some embodiments, medicine group disclosed in this invention Closing object can be configured to be suitable for the dosage form with dry powder doses to patient's inhalation.In other embodiment, present invention institute is public The pharmaceutical composition opened can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Pass through inhalation delivery to lung Dry powder composite generally comprises fine powdered compound disclosed in this invention and one or more fine powdered medicines Acceptable excipient on.Pharmaceutically acceptable excipient be especially suitable for dry powder doses is those skilled in the art institute Know comprising lactose, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding system It is standby to obtain.In general, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D₅₀Value (for example, with Laser diffractometry measurement) Lai Dingyi.

Aerosol can be prepared by the way that compound disclosed in this invention to be suspended or dissolved in liquefied propellant.It is suitble to Propellant include chlorohydrocarbon, hydro carbons and other liquefied gas.Representative propellant includes: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (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 usually passes through Metered dose inhaler (MDI) administers to a patient.Such device dawn known to those skilled in the art

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

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

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

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

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

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

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

The purposes of the compounds of this invention and composition

The present invention, which provides, uses compound disclosed in this invention and medicine composite for curing, prevention, or improves by one kind Or multiple protein kinases, such as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also referred to as FLK-2) or The disease or disorderly that Aurora A (including Aurora-A, Aurora-B and Aurora-C) behavior is mediated or otherwise influenced Disorderly or by one or more protein kinases, such as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also referred to as FLK-2) or Aurora A (including Aurora-A, Aurora-B and Aurora-C) behavior mediate or otherwise The method of one or more symptoms of the disease or disorder of influence.

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

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

In some embodiments, the present invention provides a kind of compound disclosed in this invention or comprising presently disclosed The pharmaceutical composition of compound, for treating, preventing or improve by unsuitable JAK1 kinases behavior mediation or otherwise The disease of influence or disorder are mediated or the otherwise disease that influences or disorder by unsuitable JAK1 kinases behavior One or more symptoms.In other embodiments, the disease, disorder or disease or one or more symptoms of disorder It is related to unsuitable JAK2 kinases behavior.Also in some embodiments, the one of the disease, disorder or disease or disorder Kind or a variety of symptoms are related to unsuitable JAK3 kinases behavior.

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

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

" unsuitable jak kinase behavior " refers to that the JAK for occurring to deviate normal jak kinase behavior with particular patient swashs Enzyme behavior.Unsuitable jak kinase behavior can show as example active abnormal growth or jak kinase time of the act point With the form of the deviation in control.This unsuitable kinases behavior is derived from, for example, the overexpression or mutation of protein kinase and Caused inappropriate or uncontrolled behavior.Therefore, the present invention provides the method for the treatment of these diseases and disorder.

Consistent with above description, such disease or disorder include but is not limited to: primary macroglobulinaemia, list Monocytic leukaemia, Sezary syndrome, infectious mononucleosis, colitis, pancreatitis, atherosclerosis, lung Fibrosis, bone marrow proliferative diseases, such as polycythemia vera (PCV), essential thrombocythemia, agnogenic myeloid Fibrosis (IMF)；Leukaemia, for example, marrow series leukemia include chronic myelogenous leukemia (CML), resistance to Imatinib CML form, The hypotype of acute myeloid leukemia (AML) and AML, acute megakaryoblastic leukemia (AMKL)；Lymphoproliferative disease, such as Acute lymphoblastic leukemia (ALL), myeloma；Cancer include colorectal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, Gastric cancer, cancer of the esophagus, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, bladder cancer, kidney, brain tumor, neck It is cancer, the cancer of CNS (central nervous system), glioblastoma, non-small cell lung cancer, cervical carcinoma, orchioncus, lymph cancer, more Hair property myeloma, malignant lymphoma, Small Cell Lung Cancer, neuroblastoma, neuroendocrine cell tumour, medullary thyroid sample Cancer, melanoma, retinoblastoma, uterine cancer and oophoroma, etc.；With with immunologic function disorder, immune deficiency, immune adjust Save related diseases associated with inflammation or disorder, autoimmune disease, tissue transplantation rejection, graft versus host disease(GVH disease), wound healing, Nephrosis, multiple sclerosis, thyroiditis, type-1 diabetes mellitus, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel disease include 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 a kind of compound disclosed in this invention or the medicine comprising presently disclosed compound Compositions, for preventing and/or treating the proliferative diseases, autoimmune disease, anaphylaxis of mammal (including the mankind) 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, the method includes give effectively treatment illness amount or effectively prevention illness amount one or more medicines disclosed herein Compositions or compound.On the other hand, it suffers from provided herein is a kind for the treatment of or risky suffer from proliferative diseases, exempts from self 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, the method includes giving one or more medicines disclosed herein of effective therapeutic dose or effective preventive dose Compositions or compound.In particular instances, proliferative diseases are selected from cancer (for example, solid tumor such as uterine leio muscle Tumor or prostate cancer), polycythemia vera, primary thrombocytosis, myelofibrosis, leukaemia (for example, AML, CML, ALL or CLL) and Huppert's disease.

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

On the other hand, provided herein is a kind of compounds disclosed herein, or the pharmaceutical composition comprising compound is disclosed herein Object is used to prepare the drug for treating or preventing proliferative diseases.In particular instances, proliferative diseases are selected from cancer (for example, real Body tumor, leiomyosarcoma of uterus or prostate cancer), polycythemia vera, primary thrombocytosis, myleo Change, leukaemia (for example, AML, CML, ALL or CLL) and Huppert's disease.

On the other hand, the side of the mammal of autoimmune disease is susceptible or suffering from provided herein is treatment and/or prevention Method, the method includes giving one or more pharmaceutical compositions disclosed herein of effective therapeutic dose or effective preventive dose or change Close object.In particular instances, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, wolf Sore ephritis, dermatomyositis, Sjogren syndrome, psoriasis, type-1 diabetes mellitus and inflammatory bowel disease.

On the other hand, provided herein is a kind of compounds 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-1 diabetes mellitus and inflammatory bowel disease.

On the other hand, provided herein is a kind of compounds disclosed herein, or the pharmaceutical composition comprising compound is disclosed herein Object is used to prepare the drug for treating or preventing autoimmune disease.In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, psoriasis, I Patients with type Ⅰ DM and inflammatory bowel disease.

On the other hand, the method that the mammal of anaphylactia is susceptible or suffering from provided herein is treatment and/or prevention, The method includes giving the one or more pharmaceutical compositions disclosed herein or chemical combination of effective therapeutic dose or effective preventive dose Object.In certain embodiments, anaphylactia is selected from respiratory anaphylactic disease, nasosinusitis, eczema and morbilli, food mistake Quick and insect venom allergies.

On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing anaphylactia.? In specific embodiment, anaphylactia be selected from respiratory anaphylactic disease, nasosinusitis, eczema and morbilli, food hypersenstivity and Insect venom allergies.

On the other hand, provided herein is a kind of compounds disclosed herein, or the pharmaceutical composition comprising compound is disclosed herein Object is used to prepare the drug for treating or preventing anaphylactia.In certain embodiments, anaphylactia is selected from respiratory tract Anaphylactia, nasosinusitis, eczema and morbilli, food hypersenstivity and insect venom allergies.

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

On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing inflammatory disease.In spy In fixed embodiment, inflammatory disease is selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis and silver Consider disease arthritis to be worth doing.

On the other hand, provided herein is a kind of compounds disclosed herein, or the pharmaceutical composition comprising compound is disclosed herein Object is used to prepare the drug for treating or preventing inflammatory disease.In certain embodiments, inflammatory disease be selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.

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

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

On the other hand, provided herein is a kind of compounds disclosed herein, or the pharmaceutical composition comprising compound is disclosed herein Object is used to prepare the drug for treating or preventing graft rejection.In particular instances, graft rejection is organ-graft refection, tissue Graft rejection and cell transplant rejection.

On the other hand, it is used as drug provided herein is one kind to be especially used as treating and/or preventing disease medicament noted earlier Compound disclosed herein.It is also provided with compound manufacture treatment disclosed herein and/or prevents the medicine of disease noted earlier Object.

One special projects of this method include giving a effective amount of present invention of study subject with inflammation to disclose chemical combination For a period of time, the time is enough to reduce the level of inflammation of study subject object, and preferably terminates the process of the inflammation.The party The special embodiment of method includes giving a effective amount of present invention public affairs of tested patients for suffering from or being susceptible to suffer from bone rheumatoid arthritis Open compound for a period of time, the time is enough to reduce or prevent the arthritis of the patient respectively, and preferably terminates institute State the process of inflammation.

Another special projects of this method include giving a effective amount of present invention of study subject with proliferative diseases For a period of time, the hyperplasia that the time is enough to reduce study subject is horizontal, and preferably terminates the increasing for open compound The process of growing property disease.The special embodiment of this method include give the tested patients with cancer it is a effective amount of be disclosed herein For a period of time, the time is enough to reduce or prevent the cancer symptom of the patient respectively compound, and preferably described in termination The process of cancer.

Combination therapy

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

On the one hand, the present invention provides treatment, prevention or the method for improving disease or illness, including giving safe and effective amount Combination medicine comprising disclosed compound of present invention Yu one or more therapeutically active agents.In some embodiments, combine medicine Object includes one or two kinds of other therapeutic agents.

The example of other therapeutic agents includes including but is not limited to: anticancer agent, including chemotherapeutics and antiproliferative；Anti-inflammatory agent； With immunity regulatin remedy agent or immunosuppressor.

On the other hand, the present invention provides the product including the compounds of this invention and at least one other therapeutic agent, can prepare At the combination simultaneously, separately or sequentially applied in the treatment.In some embodiments, treatment is for by one or more eggs White kinases, such as the treatment of disease or symptom that jak kinase, FLT3 kinases or Aurora A activity mediate.Joint preparation provides Product include be present in same pharmaceutical composition comprising be disclosed herein compound and other therapeutic agents composition, or with Compound and other therapeutic agents are disclosed herein existing for different form, for example, medicine box.

On the other hand, the present invention provides a kind of comprising compound and the drug of another or a variety of therapeutic agents is disclosed herein Composition.In some embodiments, pharmaceutical composition may include pharmaceutically acceptable auxiliary material, figuration as described above Agent, carrier, solvent or their combination.

On the other hand, the present invention provides the medicine box of the single pharmaceutical composition comprising two kinds or more, wherein at least one Pharmaceutical composition includes disclosed compound of present invention.In some embodiments, medicine box includes individually keeping the composition Tool, such as container, separated bottle or separated foil box.The example of this kind of medicine box is blister package, is commonly used for package panel Agent, capsule etc..

The present invention also provides purposes of the compounds of this invention in the disease or symptom that treatment albumen kinase activity mediates, Wherein patient previously (such as in 24 hours) has been treated with other therapeutic agents.The present invention also provides other treatments Agent is in treatment albumen kinases, the purposes in disease and symptom mediated such as jak kinase, FLT3 kinases and Aurora A activity, Wherein patient previously (such as in 24 hours) has been treated with the compounds of this invention.

Compound disclosed herein can be used as single active ingredient application or as such as adjuvant, common with other therapeutic agents Application.

In some embodiments, other therapeutic agents include chemotherapeutics and/or antiproliferative.Known chemotherapeutic Object includes, but is not limited to, other therapies or anticancer drug, operation, radiotherapy that can be used in combination with the compounds of this invention (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)), biological response modifiers (interferon, between leucocyte Element), tumor necrosis factor (TNF, TRAIL receptor target object), overheat and cold therapy, the reagent for mitigating any adverse reaction (such as antiemetic) and other approved chemotherapeutics include but is not limited to, alkylating drug (mustargen (mechlorethamine), Chlorambucil (chlorambucil), cyclophosphamide (cyclophosphamide), melphalan (melphalan), ifosfamide (ifosfamide)), antimetabolite (methotrexate (MTX) (methotrexate), pemetrexed (pemetrexed) etc.), (6-MP (6-mercaptopurine), 5- fluorine urine are phonetic for purine antagonist and Pyrimidine antagonists Pyridine (5-fluorouracil), cytarabine (cytarabile), gemcitabine (gemcitabine)), spindle poison (vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine)), podophyllotoxin (according to Support pool glycosides (etoposide), Irinotecan (irinotecan), Hycamtin (topotecan)), antibiotic (Doxorubicin (doxorubicin), bleomycin (bleomycin), mitomycin (mitomycin)), nitroso ureas (Carmustine (carmustine), lomustine (lomustine)), (KSP passes through mitotic kinesins to cell division cycle inhibitor Inhibitor, CENP-E and CDK inhibitor), enzyme (asparaginase (asparaginase)), hormone (tamoxifen (tamoxifen), Leuprorelin (leuprolide), Flutamide (flutamide), megestrol acetate (megestrol), fill in rice Loose (dexamethasone) etc.).Anti-angiogenesis reagent (Avastin (avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (belimumab), brentuximab, Cetuximab (cetuximab), WAY-CMA 676 (gemtuzumab), her monoclonal antibody (ipilimumab), ofatumumab, Victibix (panitumumab), Lucentis (ranibizumab), rituximab list Anti- (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab)).Kinase inhibitor (she Imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), nilotinib (nilotinib), Lapatinib (lapatinib), gram Zhuo for Buddhist nun (crizotinib), ruxolitinib, vemurafenib, vandetanib, Pazopanib, etc.).Drug inhibition or activate cancer approach such as mTOR, HIF (hypoxia inducible factor) approach and other.Cancer Disease is treated wide forum and is seenhttp://www.nci.nih.gov/, FAD approve oncologic inventory seehttp:// www.fda.gov/cder/cancer/druglist-rame.htmAnd Merck Manual, the 18th edition .2006, all contents All it is combined with bibliography.In other embodiments, the compound of the present invention can be with combination cell toxin anticancer agent. Such anticancer agent can be found the 13rd edition Merck index (2001) is inner.These anticancer agents include, but are not limited to, Tianmen Winter amidase, bleomycin, carboplatin, Carmustine, Chlorambucil, cis-platinum, L-ASP, cyclophosphamide, 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, prednisone, procarbazine, Raloxifene, chain azoles are mould Element, tamoxifen, thioguanine, Hycamtin, vincaleukoblastinum, vincristine and eldisine.Combine with the compound of the present invention Other suitable cytotoxic drugs of medication include, but is not limited to, these are admittedly applied to tumor disease treatment Compound, as described in following documents: Goodman and Gilman's The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.)；These anticancer agents include, but are not limited to, ammonia Shandong Meter Te (aminoglutethimide), l- L-Asparaginasum, imuran, 5-azacitidine, Cladribine (cladribine), busulfan (busulfan), diethylstilbestrol, 2', it is 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 include suitably newfound cell with the cytotoxin class anticancer agent of the compound of the present invention use in conjunction Toxic substance, including, but be not limited to, oxaliplatin (oxaliplatin), gemcitabine (gemcitabine), card training His shore (capecitabine), macrolides antineoplastic and its natural or synthetic derivative, Temozolomide (temozolomide) (Quinn et al., J.Clin.Oncology, 2003,21 (4), 646-651), tositumomab (bexxar), trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004,23, abstract 3181), and driving 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 their own match Body.Such reagent includes, but is not limited to, antibody therapy such as Herceptin (trastuzumab), Cetuximab (cetuximab), her monoclonal antibody (ipilimumab) and handkerchief trastuzumab (pertuzumab).Such therapy also includes, but It is not limited to, small molecule kinase inhibitors such as Imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), Ni Luo For Buddhist nun (nilotinib), Lapatinib (lapatinib), gram Zhuo replaces Buddhist nun (crizotinib), ruxolitinib, Vemurafenib, vandetanib, pazopanib, Afatinib (afatinib), amuvatinib, Axitinib (axitinib), posupini (bosutinib), brivanib, canertinib, cabozantinib, Si Dinibu (cediranib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, Ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, for husky Buddhist nun (motesanib), linatinib (neratinib), niraparib, Oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, saracatinib (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, Tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, Volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941 (Folkes, et al., J.Med.Chem.2008,51,5522), BZE235, etc..

In some embodiments, compound disclosed herein can also be co-administered with other medicines.The other medicines Including, immunosuppressor, immunomodulator, other anti-inflammatory agents, such as treating or preventing allogeneic or xenograft Acute or chronic repulsion, inflammatory, autoimmune disease drug；Or chemotherapeutics, such as malignant cell antiproliferative.For example, Disclosed compound of present invention can combine with following active component: the plain inhibitor of calcium nerve, such as cyclosporin A or FK506； MTOR inhibitors, for example, rapamycin, 40-O- (2- hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9；Ascosin with immunosuppressive properties, such as ABT-281, ASM981 Deng；Corticosteroid；Cyclophosphamide；Imuran；Methotrexate (MTX)；Leflunomide；Mizoribine；Mycophenolic Acid or salt；Wheat Examine phenolic acid mofetil ester；15- deoxyspergualin or its immunosupress homologue, analog or derivative；Pkc inhibitor, such as Described in WO 02/38561 or WO 03/82859, such as the compound of embodiment 56 or 70；Immunosupress monoclonal antibody, Such as the monoclonal antibody of leukocyte receptors, for example, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or its ligand；Other immunomodulatory compounds, such as at least partly extracellular domain with CTLA4 Recombination binding molecule or its mutant, such as at least extracellular portion of CTLA4 being connected with non-CTLA4 protein sequence or its Mutant, such as CTLA4Ig (such as being named as ATCC 68629) or its mutant, such as LEA29Y；Adhesion molecule inhibitor, Such as LFA-1 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 disclosed compound of present invention and other immunotherapeutic agent/immunomodulators, anti-inflammatory agent, chemotherapy or anti-infective In the case that treatment is administered in combination, immunosuppressor, immunomodulator, anti-inflammatory agent, chemotherapeutant or the anti-sense of administering drug combinations The dosage for contaminating compound certainly can be according to the type of combination medicine used, such as whether it is that steroidal or calcineurin inhibit Agent, specific drug used, illness to be treated etc. and change.

On the one hand, the present invention provides a kind of comprising disclosed compound of present invention and β₂The connection of adrenoceptor agonists It closes.β₂The example of adrenoceptor agonists includes salmeterol, salbutamol, Formoterol, salmefamol, Fei Nuote Sieve, Yi Tanteluo, naminterol, Clenbuterol, pirbuterol, Flerobuterol, reproterol, promulgates special sieve, indenes at carmoterol Da Teluo, Terbutaline and their salt, such as xinafoate (1- hydroxy-2-naphthoic acid salt), the husky butylamine of salmeterol The sulfate or free alkali of alcohol or the fumarate of Formoterol.In some embodiments, long-acting beta₂Adrenocepter Agonist, such as effective bronchiectasis is provided up to 12 hours or the compound of longer time, it is preferred.

β₂Adrenoceptor agonists can be with the form of pharmaceutically acceptable sour forming salt.It is described pharmaceutically The acid of receiving is selected from sulfuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (such as 1- or 3- hydroxy-2-naphthoic acid), cinnamic acid, substituted meat Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3- (1- naphthalene) 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 comprising disclosed compound of present invention and corticosteroid.Suitably Corticosteroid refers to those oral and sucking corticosteroids, and its has the prodrug of anti-inflammatory activity.Example includes that methyl sprinkles Ni Songlong, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-[(4- methyl-1,3-thiazole - 5- carbonyl) oxygroup] -17 β of -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters, 6 α, fluoro- 17 α-[(the 2- furan of 9 α-two Mutter carbonyl) oxygroup]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- fluorine methyl esters (furancarboxylic acid Fluticasone) ,-16-17 α of Alpha-Methyl-3- oxo of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-- 17 β of propionyloxy-androsta-1,4- diene- Thiocarboxylic acid S- (2- oXo-tetrahydro furans -3S- 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) oxygroup--17 β of androstane -1,4- diene-thiocarboxylic acid S- cyano methyl ester and 6 α, 9 α-two Fluoro- -17 β of -17 α of -16 Alpha-Methyl of 11 beta-hydroxy-(1- ethyl cyclopropyl carbonyl) oxygroup -3- oxo-androst -1,4- diene-is thio Carboxylic acid S- methyl fluoride ester, beclomethasone ester (such as 17- propionic ester or 17,21- dipropionic acid rouge), budesonide (budesonide), Flunisolide (flunisolide), Mometasone ester (such as momestasone furoate), Triamcinolone acetonide (triamcinolone Acetonide), ([[(R)-cyclohexyl is sub- by 16 α, 17- for sieve fluoronaphthalene moral (rofleponide), ciclesonide (ciclesonide) Methyl] bis- (oxygroups)] -11 β, 21- dihydroxy-pregnant steroid -1,4- diene -3,20- diketone), butixocort propionate (butixocort Propionate), RPR-106541 and ST-126.Preferred corticosteroid includes fluticasone propionate (fluticasone Propionate), -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-[(4- methyl-1,3-thiazole -5- carbonyl) oxygroup] - - 17 β of 3- oxo-androst -1,4- diene-thiocarboxylic acid S- methyl fluoride ester, 6 α, fluoro- 17 α-of 9 α-two [(2- furanylcarbonyl) oxygen Base]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- 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) oxygroup-androstane -1,4- diene -17 - 17 α of β-thiocarboxylic acid S- cyano methyl ester and -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-(1- methylcyclopropyl groups carbonyl) oxygen - 17 β of base -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters.In some embodiments, corticosteroid is 6 α, - 16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of fluoro- 17 α-of 9 α-two [(2- furanylcarbonyl) oxygroup]-11 beta-hydroxy-sulphur For carboxylic acid S- methyl fluoride ester.

On the other hand, the present invention provides a kind of joint comprising disclosed compound of present invention and nonsteroidal GR agonist. To Transcription inhibition with selectivity (compared with transcriptional activation), can be used for combination therapy with glucocorticoid agonist activity Nonsteroidal compound includes the compound that those covered in following patent: WO 03/082827, WO 98/54159, WO 04/005229、WO 04/009017、WO 04/018429、WO 03/104195、WO 03/082787、WO 03/082280、WO 03/059899、WO 03/101932、WO 02/02565、WO 01/16128、WO 00/66590、WO 03/086294、WO 04/026248, WO 03/061651 and WO 03/08277.More nonsteroidal compounds are in WO 2006/000401, WO It is included in 2006/000398 and WO 2006/015870.

On the other hand, the present invention provides a kind of comprising disclosed compound of present invention and nonsteroidal anti-inflammatory drug (NSAID's) Joint.The example of NSAID's includes nasmil, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (such as theophylline, PDE4 inhibitor or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene close At inhibitor (such as montelukast), iNOS inhibitor, trypsase and elastatinal, Beta 2 integrin antagonist With adenosine receptor agonist or antagonist (e.g., adenosine 2a receptor stimulating agent), (such as chemokine receptors is short of money for cytokine antagonist 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/ 30537, compound disclosed in WO 02/50021, WO 95/34534 and WO 99/62875.CCR3 inhibitor include those Compound disclosed in WO 02/26722.

In some embodiments, the present invention relates to disclosed compound of present invention inhibits with phosphodiesterase 4 (PDE4) Application in the joint of agent, the application especially in inhalant dosage form.PDE4 specific inhibitor for this aspect of the present invention It can be known inhibition PDE4 enzyme or be found any compound as PDE4 inhibitor, they are only that PDE4 inhibits Agent is not to inhibit other members in PDE family, such as the compound of PDE3 and PDE5.Compound includes cis- -4- cyano -4- (3- Cyclopentyloxy -4- methoxyphenyl) hexamethylene -1- carboxylic acid, 2- carbomethoxy -4- cyano -4- (3- cyclo propyl methoxy -4- two Fluorine methoxyl group phenyl) hexamethylene -1- ketone and cis--[4- cyano -4- (3- cyclo propyl methoxy -4- difluoro-methoxy phenyl) ring Hexane -1- alcohol]；It also include that cis- -4- cyano -4- [3- (cyclopropyl oxygroup) -4- methoxyphenyl] hexamethylene -1- carboxylic acid is (also referred to as Xi Luosi) and its salt, ester, prodrug or physical form, in 09 month 1996 No. 03 United States Patent (USP) US 5,552,438 authorized Middle disclosure, this patent and its disclosed compound are incorporated herein by reference in their entirety.

On the other hand, the present invention provides a kind of joint comprising disclosed compound of present invention and anticholinergic agent.Cholinolytic Can agent example be those be used as muscarinic receptor antagonist compounds, especially those as M1 or M3 receptor antagonist, M₁/M₃Or M₂/M₃Receptor dual antagonist or M₁/M₂/M₃The compound of the general antagonist of receptor.The example compound packet of inhalation Include ipratropium (for example, as bromide, CAS 22254-24-6, withSold for trade name), Oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium (for example, as bromide, CAS 136310-93- 5, withIt is sold for trade name)；Be also interested in there are also 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, withSold for trade name), oxybutynin (CAS 5633-20-5, withIt is sold for trade name Sell), terodiline (CAS 15793-40-5), Tolterodine (CAS 124937-51-5 or its tartrate CAS124937- 52-6, withSold for trade name), Austria for ammonium (for example, as bromide, CAS 26095-59-0, withSold for trade name), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, Or its succinate CAS 242478-38-2, i.e. compound YM-905, withIt is sold for trade name).

On the other hand, the present invention provides a kind of joint comprising disclosed compound of present invention and H1 antagonist.H1 antagonist Example include, but are not limited to Amlexanox (amelexanox), western this imidazoles (astemizole), azatadine (azatadine), azelastine (azelastine), Acrivastine (acrivastine), Brompheniramine (brompheniramine), cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine), chloropheniramine (chlorpheniramine), clemastine (clemastine), marezine (cyclizine), Carebastine (carebastine), cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), diformazan indenes (dimethindene), Ebastine (ebastine), epinastine (epinastine), second Fluorine benefit 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 It applies in scheme, the present invention provides a kind of joint comprising disclosed compound of present invention and H3 antagonist (and/or inverse agonist).H3 The example of antagonist includes those compounds disclosed in WO 2004/035556 and WO 2006/045416.It can be used for and this Other united histamine receptor antagonists of disclosure of the invention compound include H4 receptor antagonist (and/or inverse agonist), such as Compound disclosed in Jablonowski et al., J.Med.Chem., 2003,46:3957-3960.

Another aspect, it includes disclosed compound of present invention that the present invention, which provides a kind of, with PDE4 inhibitor and β₂Adrenaline The joint of receptor stimulating agent.

In another aspect, it includes disclosed compound of present invention that the present invention, which provides a kind of, with anticholinergic drug and PDE-4 inhibitor Joint.

It is above-described combine therefore, including defined above group be prepared into pharmaceutical composition with can be convenient come using It closes and represents another aspect of the present invention with the pharmaceutical composition of pharmaceutically acceptable excipient or carrier.

These united each compounds with alone or in combination pharmaceutical preparation form order of administration or can be administered simultaneously. In one embodiment, each compound component is administered simultaneously with combined pharmaceutical preparation form.Known treatment agent is suitble to Dosage is easy to be understood by the person skilled in the art.

Therefore, on the other hand, the present invention provides a kind of pharmaceutical composition, controls comprising compound disclosed by the invention with other Treat the joint of activating agent.

In some embodiments, pharmaceutical composition provided by the invention includes disclosed compound of present invention and chemotherapeutics Joint.

In some embodiments, pharmaceutical composition provided by the invention includes disclosed compound of present invention and antiproliferative Joint.

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

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

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

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

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

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

In other embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and anti-inflammatory examination The joint of agent.

In other embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and immune tune Save the joint of agent.

In other embodiment, pharmaceutical composition provided by the invention include disclosed compound of present invention be used for move The joint of the drug of pulse atherosclerosis.

In other embodiment, pharmaceutical composition provided by the invention include disclosed compound of present invention be used for control Treat the joint of the drug of pulmonary fibrosis.

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

Disclosed compound of present invention can also be advantageously utilised in the combination with other compounds, or and other therapeutic agents, especially It is in the combination of antiproliferative.Such antiproliferative includes, but are not limited to aromatase inhibitor；Antiestrogenic；Topology is different Structure enzyme I inhibitor；Topoisomerase II inhibitors；Microtubule active agent；Alkylating agent；Histon deacetylase (HDAC) inhibitor；Induction The compound of cell differentiation procedure；Cyclooxygenase-2 inhibitors；MMP inhibitor；MTOR inhibitors；Antitumor antimetabolite；Platinum Close object；The compound of the compound of targeting/reduction albumen or lipid kinase activity and other anti-angiogenesis；Targeting, reduce or Inhibit the compound of albumen or lipid phosphate esterase active；Gonadorelin excitomotor；Antiandrogen；Methionine aminopeptidase inhibits Agent；Diphosphonate；Biological response modifiers；Antiproliferation antibodies；Heparanase inhibitors；The carcinogenic hypotype inhibitor of Ras；Telomere Enzyme inhibitor；Proteasome inhibitor；The medicament for treating neoplastic hematologic disorder；Targeting reduces or inhibits the active compound of Flt-3； Hsp90 inhibitor；TemozolomideAnd Calciumlevofolinate.

Term used herein " aromatase inhibitor " refers to that the compound inhibited estrogen production, i.e. inhibition substrate are male Alkene diketone and testosterone are converted to the compound of oestrone and estradiol respectively.The term includes, but are not limited to: steroid, especially It is atamestane (atamestane), Exemestane (exemestane) and formestane (formestane)；And especially Non-steroids, especially aminoglutethimide (aminoglutethimide), Rogletimide (roglethimide), pyrrole Rumi Spy (pyridoglutethimide), Trilostane (trilostane), Testolactone (testolactone), ketoconazole (ketoconazole), fluorine chlorazol (vorozole), Fadrozole (fadrozole), Anastrozole (anastrozole) and come it is bent Azoles (letrozole).Exemestane can be with commercially available, as trade mark isForm administration.Fu Mei Smooth (formestane) can be with commercially available, as trade mark isForm administration.Fadrozole It (fadrozole) can be with commercially available, as trade mark isForm administration.Anastrozole (anastrozole) can be with It is commercially available, as trade mark isForm administration.Letrozole (letrozole) can be with commercially available, such as Trade mark is OrForm administration.Aminoglutethimide (aminoglutethimide) can be with city It sells, 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 are not limited to tamoxifen (tamoxifen), fulvestrant (fulvestrant), Raloxifene (raloxifene) and raloxifene hydrochloride (raloxifene hydrochloride).Tamoxifen (tamoxifen) can With with commercially available, as trade mark isForm administration.Raloxifene hydrochloride (raloxifene It hydrochloride) can be with commercially available, as trade mark isForm administration.Fulvestrant It (fulvestrant) can be with dosage form disclosed in United States Patent (USP) US 4,659,516 or commercially available, as trade mark isForm administration.The present invention includes that the combination of antiestrogenic chemotherapeutic is particularly useful for the treatment of estrogen receptor in sun The tumour of property, such as tumor of breast.

Term used herein " antiandrogen " refers to any substance that can inhibit male sex hormone biological action, it is wrapped It includes, but is not limited to, Bicalutamide (bicalutamide, trade name), dosage form can be according to United States Patent (USP) US 4,636,505 prepare.

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

Term used herein " topoisomerase I inhibitor " includes, but are not limited to topotecan (topotecan), Ji Horse 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 administration.Doxorubicin can be with commercially available, as trade mark isOr Form administration.Epirubicin can be with commercially available, as trade mark isForm administration.Idarubicin can be with commercially available, as trade mark isForm administration.Mitoxantrone can be with commercially available, as trade mark isForm administration.

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

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

Term " histon deacetylase (HDAC) inhibitor " or " hdac inhibitor " refer to inhibition of histone deacetylase, and Compound with antiproliferative activity.It is included in 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] it -2E-2- acrylamide and its can pharmaceutically connect The salt received.Especially include Vorinostat (SAHA).

Term " antitumor antimetabolite " includes, but are not limited to 5-fluor-uracil (5-fluorouracil) or 5-FU； Capecitabine (capecitabine)；Gemcitabine (gemcitabine)；DNA demethylation 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 administration.This term further includes monoclonal antibody Herceptin (trastuzumab), can be with commercially available, as trade mark isForm administration.

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

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

A) it targets, reduces or inhibit platelet derived growth factor receptor (PDGFR) active compound；Targeting reduces Or inhibit the active compound of PDGFR, the compound of especially inhibition pdgf receptor includes N- phenyl-2-pyrimidine-amine derivatives, Such as Imatinib (imatinib), SU101, SU6668, GFB-111 etc.；

B) target, reduce or inhibit fibroblast growth factor acceptor (FGFR) active compound；

C) target, reduce or inhibit insulin-like growth factor receptor -1 (IGF-1R) active compound；Targeting reduces Or inhibiting the active compound of IGF-1R, the compound of especially inhibition IGF-1 receptor active includes those in patent WO 02/ Compound disclosed in 092599；

D) targeting, reduction or the compound for inhibiting Trk receptor tyrosine kinase family active；

E) targeting, reduction or the compound for inhibiting Axl Receptor Tyrosine Kinase family active；

F) targeting, reduction or the compound for inhibiting c-Met receptor active；

G) targeting, reduction or the compound for inhibiting Kit/SCFR receptor tyrosine kinase activity；

H) target, reduce or inhibit C-kit receptor tyrosine kinase (a part in PDGFR family) active chemical combination Object；Targeting, the compound for reducing or inhibiting C-kit receptor tyrosine kinase family active, especially inhibit the change of c-Kit receptor Close object, including Imatinib (imatinib) etc.；

I) it targets, reduce or inhibit c-Abl family and their gene fusion products, such as the change of BCR-Abl kinase activity Close object；Targeting, the compound for reducing or inhibiting c-Abl family member and their gene fusions include N- phenyl -2- pyrimidine - Amine derivative, such as Imatinib, PD180970, AG957, NSC 680410, from the PD173955 of ParkeDavis

J) it targets, Raf family member in reduction or inhibition 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 at The compound of member and/or cell cycle protein dependent kinase family (CDK) member activity；Especially those are in United States Patent (USP) Staurosporine derivatives disclosed in US 5,093,330, such as midostaurin (midostaurin)；More examples of compounds It further include UCN-01；Safingol (safingol)；BAY 43-9006；Bryostatin 1；Piperazine Li Fuxin (Perifosine)；She Mo Fuxin (llmofosine)；RO 318220 and RO 320432；GO 6976；Isis 3521；LY333531/LY379196； Isoquinoline compound, such as in WO 00/09495 those disclosed；FTIs；PD184352；Or a kind of QAN697 (P13K suppression Preparation)；

K) target, reduce or inhibit the active compound of protein tyrosine kinase inhibitor；Targeting reduces or inhibits The active compound of protein tyrosine kinase inhibitor includes GleevecOr tyrosine phosphorylation Inhibitor；The preferred low molecular weight of tyrphostin (Mr < 1500) compound or its pharmaceutically acceptable salt, especially Its compound for being selected from the third two eyeball class of two eyeball class of benzyl allyl or S- aryl sheet or Double bottom object quinolines, is further selected from tyrosine Phosphorylation inhibitor A23/RG-50810, AG 99, tyrphostin 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) target, reduce or inhibit receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, The equal or heterodimer of ErbB3, ErbB4) active compound；Targeting reduces or inhibits Epidermal Growth Factor Receptor Family Compound refer in particular to inhibit EGF receptor family member (such as EGF receptor, ErbB2, ErbB3, ErbB4, or can with EGF or The substance that EGF associated ligands combine) compound, albumen or antibody, is especially summarized in the following documents or it is specific openly Compound, albumen or monoclonal antibody: WO 97/02266 (such as embodiment 39), EP 0 564 409, WO 99/03854, EP 0520722、EP 0 566 226、EP 0 787 722、EP 0 837 063、US 5,747,498、WO 98/10767、WO 97/30034, WO 97/49688 and WO 97/38983, WO 96/30347 (such as CP 358774), 96/33980 (such as chemical combination of WO Object ZD 1839), WO 95/03283 (such as compound ZM105180), Herceptin (Trastuzumab), Cetuximab, Yi Rui Sand, Erlotinib, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, E7.6.3, and 7H- pyrrolo--[2, the 3-d] pyrimidine derivatives being disclosed in WO 03/013541.

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

The compound of targeting, reduction or inhibition albumen or lipid kinase activity is -1 inhibitor of phosphatase, phosphatase 2A suppression Preparation, PTEN inhibitor or CDC25 inhibitor, such as okadaic acid or derivatives thereof.

The compound of Cell differentiation inducing activity process is vitamin A acid, α-, γ-or Delta-Tocopherol, α-, γ-or δ-fertility triolefin Phenol.

Term used herein " cyclooxygenase-2 inhibitors " includes, but are not limited to Cox-2 inhibitor, and 5- is alkyl-substituted 2- fragrant amino phenylacetic acid and its derivative, such as celecoxib, rofecoxib, etoricoxib, cut down Former times or 5- alkyl -2- fragrant amino phenylacetic acid are examined in ground, 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 are not limited to Etidronic Acid, Clodronate, Tiludronic Acid, pa rice phosphine Acid, alendronic acid, ibandronic acid, Risedronic Acid and zoledronic acid.Etidronic Acid can be with commercially available, such as trade nameForm administration.Clodronate can be with commercially available, such as trade name's Form administration.Tiludronic Acid can be with commercially available, such as trade nameForm administration；Pamidronic acid (Pamidronic It acid) can be with commercially available, such as trade name Aredia^TM(AREDIA^TM) form administration；Alendronic acid can 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 administration.

Term " mTOR inhibitors ", which refers to, inhibits 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 inhibit acetylsulfuric acid depolymerized heparin Compound.This term includes, but unlimited PI-88.

Term used herein " biological response modifiers " refers to lymphokine or interferon, such as interferon gamma.

Term used herein " the carcinogenic hypotype of Ras (such as H-Ras, K-Ras or N-Ras) inhibitor " refers to targeting, reduces Or inhibit the compound of Ras carcinogenic activity, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra)。

Term used herein " telomerase inhibitor " refers to the compound targeted, lowered or inhibited telomerase activity.Target To, reduce or inhibit the compound of telomerase activation to refer in particular to inhibit the compound of telornerase receptor, such as telomere mycin.

Term used herein " methionine aminopeptidase inhibitor " refers to targeting, reduction or inhibits methionine aminopeptidase activity Compound.Targeting, reduction or the inhibition active compound of methionine aminopeptidase include bengamide or derivatives thereof.

Term used herein " proteasome inhibitor " refers to targeting, reduction or the active chemical combination of protease inhibition body Object.Targeting, reduction or the active compound of protease inhibition body include PS-341 and MLN 341.

Term used herein " Matrix Metalloproteinase Inhibitors " or " MMP inhibitor " include, but are not limited to glue Former albumen peptides and non-peptide inhibitor, tetracycline derivant, such as hydroxamic acid peptide inhibitor Batimastat (batimastat) With its equivalent homologue Marimastat (marimastat, BB-2516) of oral bio, prinomastat (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996。

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

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

The endogenous that term used herein " HSP90 inhibitor " includes, but are not limited to targeting, reduces or inhibit HSP90 The compound of atpase activity；Pass through the degradation of ubiquitin protein body enzymatic pathway, targeting, the chemical combination for reducing or inhibiting HSP90 client protein Object.Targeting, the Endogenous ATP for reducing or the compound of the Endogenous ATP enzymatic activity of HSP90 being inhibited to refer in particular to inhibit HSP90 The compound of enzymatic activity, albumen or antibody, for example, 17- allyl amino, 17-AAG (17AAG), The relevant compound of his geldanamycin, red shell rhzomorph and hdac inhibitor.

Term used herein " antiproliferation antibodies " includes, but are not limited to Herceptin (HERCEPTIN^TM), toltrazuril Monoclonal antibody-DM1, Tarceva (TARCEVA^TM), bevacizumab (AVASTIN^TM), Rituximab, PR064553 (anti-CD40) and 2C4 antibody.Antibody means complete monoclonal antibody, polyclonal antibody, complete by least two The multi-specificity antibody and antibody fragment (as long as they have desired bioactivity) that whole antibody is formed.It is thin for acute marrow For the treatment of born of the same parents' sample leukaemia (AML), the leukemia therapy of disclosed compound of present invention and standard can be used in combination, especially It is used in combination with the therapy treated for AML.Specifically, disclosed compound of present invention and such as farnesyl- can be turned It moves enzyme inhibitor and/or other is used for drug such as daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, the rice of AML treatment Anthraquinone, idarubicin, carboplatin and PKC412 is ask to be administered in combination.

Compound disclosed by the invention can also be advantageously utilised in combination with other compounds or with other therapeutic agents In combination, especially other anti-malarial agents.Such anti-malarial agents include, but are not limited to chloroguanide (proguanil), Chlorproguanil (chlorproguanil), trimethoprim (trimethoprim), chloroquine (chloroquine), Mefloquine (mefloquine), Lumefantrine (lumefantrine), Atovaquone (atovaquone), pyrimethamine-sulfanilamide (SN) (pyrimethamine- Sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinindium (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfanilamide (SN) Class drug, qinghaosu, Arteflene (arteflene), Artemether, Artesunate, primaquine, sucking NO, L-arginine, dipropyl Alkene triamine NONO ester (NO donor), Rosiglitazone (PPARy agonist), active carbon, hematopoietin, levamisol, And Malaridine.

Compound disclosed by the invention also may be advantageously used with the combination with other compounds or the group of other therapeutic agents In conjunction, such as treatment leishmaniasis, trypanosomiasis, the other therapeutic agents of 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, Fluoroquinolones medicine, macrolides medicine, aminoglycoside medicine, sulphadiazine and pyrimethamine.

The structure of the active constituent determined by code name, common name or trade name 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 Such as IMS World Publications)) in know.

Compound above-described, being applied in combination with disclosed compound of present invention, can be by those skilled in the art Member prepares and is administered according to above-mentioned method recorded in the literature.

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

" joint " indicates the medicine box of the fixing joint in single dose unit form or the part for administering drug combinations, In compound disclosed by the invention and joint companion can be in same time individual application or can be in certain time interval It inside applies respectively, joint companion is especially made to show cooperation, for example act synergistically.Term " co-administered " as used herein Or " administering drug combinations " etc. are intended to include single individual (such as the patient) for being applied to selected joint companion and needing it, and anticipate Be intended to include wherein substance without going through identical administration route or the therapeutic scheme being administered simultaneously.Term " drug as used herein Joint " indicates to mix more than one active constituents or combine obtained product, and both fixed connection including active constituent Close also includes that on-fixed is combined.Term " fixing joint " indicates active constituent compound for example disclosed by the invention, and joint companion It is administered simultaneously in the form of single entities or dosage in patient.Term " on-fixed joint " indicates that the active constituent such as present invention discloses Compound, and joint companion be used as corpus separatum simultaneously, jointly or without specific time limitation ground successively administer to a patient, In the administration mode in patient's body provide the treatment effective level of two kinds of compounds.The latter applies also for cocktail therapy, Such as apply three or more active constituents.

Treatment method

In some embodiments, treatment method disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention include by pair Patient in need gives the disclosed compound of present invention of safe and effective amount or the pharmaceutical composition comprising disclosed compound of present invention Object, the method to treat disease mentioned above.

In some embodiments, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can To be administered by any suitable administration route, including Formulations for systemic administration and local administration.Formulations for systemic administration includes oral administration, stomach Parenteral administration, cutaneous penetration and rectally.Typical parenteral refers to through injection or administered by infusion, including vein Interior, intramuscular and subcutaneous injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and nose Interior administration.In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can To be oral administration.In other embodiments, disclosed compound of present invention or the drug comprising disclosed compound of present invention Composition can be inhalation.In a further embodiment, disclosed compound of present invention or can comprising disclosed compound of present invention To be intranasal administration.

In some embodiments, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can With once daily, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, It is administered once a day, twice, three times or four times.In some embodiments, it is administered once a day.In other embodiment In, it is taken twice daily.It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.This Disclosure of the invention compound or the appropriate dosage regimen of the pharmaceutical composition comprising disclosed compound of present invention depend on the compound Pharmacokinetic property, such as dilution, distribution and half-life period, these can be by determination of technical staff.In addition, the present invention discloses The appropriate dosage regimen of compound or the pharmaceutical composition comprising disclosed compound of present invention, including implement the program it is lasting when Between, depending on treated disease, the severity of disease being treated, the age of patient under consideration and physical condition are treated The medical history of patient, the simultaneously factor within the scope of technical staff's knowledge and experience such as property, desired therapeutic effect of therapy. Such technical staff should also be understood that the reaction for individual patient to dosage regimen, or individual patient as time goes by When needing to change it may require that adjust suitable dosage regimen.

Disclosed compound of present invention can be administered simultaneously, or before it or later with one or more other therapeutic agents. The compounds of this invention can be administered with other therapeutic agents by identical or different administration route respectively, or therewith with medicine group Solvate form administration.

For the individual of about 50-70kg, the present invention discloses pharmaceutical composition 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 constituent Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination medicine be depending on the species of medication individual, weight, Age and individual instances, treated disorder (disorder) or disease (disease) or its severity.Has common technical ability Doctor, clinician or animal doctor can be easy determine prevent, treat or inhibit disorder (disorder) or disease (disease) The effective quantity of required each active constituent in development process.

Dose Characteristics cited above using advantageous mammal (such as mouse, rat, dog, monkey) or its from It is confirmed in the external and in vivo studies of body organ, tissue and sample.Disclosed compound of present invention is with solution, such as aqueous solution form Use in vitro, can also such as enteral of suspension or aqueous solution form in vivo, it is parenterally, especially intravenous to use.

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

In addition, compound disclosed by the invention can be administered with prodrug forms.In the present invention, disclosed compound of present invention " prodrug " be that can finally release the functional derivatives of disclosed compound of present invention in vivo when administering to a patient.In the past When medicine form gives compound disclosed by the invention, one of implementable following manner of those skilled in the art or more: (a) Change the internal onset time of compound；(b) the internal acting duration of compound is changed；(c) the internal of compound is changed Conveying or distribution；(d) the internal solubility of compound is changed；And the side effect or other difficult points for (e) overcoming compound to be faced. The typical functional derivatives of prodrug are used to prepare, comprising in vivo chemically or the mode of the enzyme compound that cracks Variant.Comprising preparing these variants of phosphate, amide, ester, monothioester, carbonate and carbaminate to those skilled in the art It is well-known for member.

General synthesis step

For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.

Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.

The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.

Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is using 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 (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as referring to mark It is quasi-.When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used (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 indicated with hertz (Hz).

The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-M of Agilent (column model: Zorbax SB-C18,2.1 × 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%-95% (contains 0.1% The CH of formic acid₃CN) in (H containing 0.1% formic acid₂O the ratio in)), using electrospray ionisation (ESI), at 210nm/254nm, It is detected with UV.

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

The use of logogram word below is 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 methylene chloride

CDCl₃Deuterated chloroform

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 4-dimethylaminopyridine

DMSO dimethyl sulfoxide

DHP 3,4- dihydropyran

DIAD diisopropyl azodiformate

PPTs 4- toluenesulfonic acid pyridine

Et₃N, TEA triethylamine

EtOAc, EA ethyl acetate

EtOH ethyl alcohol

Et₂O ether

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

G grams

H hours

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

HCl hydrochloric acid

HOAT 1- hydroxyl -7- azepine benzotriazole

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 sodium hydroxide

NaOMe sodium methoxide

Na₂SO₄Sodium sulphate

Na₂S₂O₃Sodium thiosulfate

NaHCO₃Sodium bicarbonate

NaOAc ammonium acetate

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

NBS bromosuccinimide

MeOH methanol

ML, ml milliliters

Pd(OAc)₂Palladium acetate

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 trifluoroacetic anhydride

TFA trifluoroacetic acid

TBAF tetrabutyl ammonium fluoride

Ti(Oi-Pr)₄Four isopropyl titanates

TsCl 4- toluene sulfochloride

The typical synthesis step of disclosed compound of present invention is prepared as shown in following 1~synthetic schemes of synthetic schemes 4.It removes Non- other explanation, each Z¹、A、R¹、R²、R^2a、R⁴There is definition as described in the present invention with m.Each n independently is 0,1,2 or 3；Respectively PG, LG independently are blocking group, and Y is hetero atom.

Synthetic schemes 1:

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

Synthetic schemes 2:

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

Synthetic schemes 3:

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

Synthetic schemes 4:

With such as formula (8) shown in structure the general synthesis that can be described by synthetic schemes 4 of disclosed compound of present invention Method is prepared, and specific steps can 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 can also With obtain with formula (8) shown in structure kinases inhibitor.

Embodiment

Intermediate 1N⁴((3R, 6S)-(6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) 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- oluene sulfonic acides 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, reaction mixture is cooled to 0 DEG C, then is added thereto 4- toluene sulfonyl chloride (15.66g, 82.1mmol).Reaction mixture stirs 30 minutes at 0 DEG C, then moves to and is stirred at room temperature Overnight.Mixture is diluted with methylene chloride (250mL), successively with hydrochloric acid (300mL, 1M), water (300mL) and saline solution (300mL) washing.The organic phase separated is dried over anhydrous sodium sulfate, filtering, and is concentrated under reduced pressure.Gained residue is through silica gel column layer (EtOAc/PE (v/v)=2/1) purifying is analysed, obtaining title compound is 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- oluene sulfonic acides ester (10.24g, 34.1mmol) be dissolved in DMSO (60mL), and thereto be added (1,3- dioxoisoindolin -2- base) potassium (8.21g, 44.3mmol).Reaction mixture is stayed overnight in 130 DEG C and stirred under nitrogen atmosphere, is then down to room temperature, and be poured into water.Gained Mixture is extracted with methylene chloride (300mL × 3), and combined organic phase is washed with water (100mL × 3), anhydrous Na₂SO₄It is dry, Then it is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=1/1), and it is white for obtaining 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 methylene chloride (40mL), under nitrogen protection, thereto be added triethylamine (1.30g, 12.8mmol) and DMAP (209.2mg, 1.7mmol).Mixture is cooled to 0 DEG C, and methane sulfonyl chloride is added under nitrogen protection (0.8mL,10.0mmol).Gained mixture stirs 30 minutes at 0 DEG C, then moves to and is stirred overnight at room temperature.Mixture is with two Chloromethanes (100mL) dilution, successively with hydrochloric acid (100mL, 1M), water (100mL) and saturated salt solution (100mL) washing.It separates Organic phase be dried over anhydrous sodium sulfate, filter, and be concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v) =1/200) it purifies, obtaining title compound is 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 sodium azide (2.16g, 33.2mmol) is added thereto.Reaction Mixture stirs 23 hours at 140 DEG C, then is diluted with methylene chloride (100mL), is then washed with water (100mL × 3).It separates Organic layer anhydrous Na₂SO₄It is dry, it is then concentrated under reduced pressure, obtains crude product.Crude product is not purified to be directly used in next step instead It answers.

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 methanol (70mL), and Pd (OH) is added thereto₂/ C (240mg, 0.17mmol, mass fraction 10%).Reaction mixture is stayed overnight in room temperature and stirred under nitrogen atmosphere, is then filtered.Filtrate decompression concentration, obtains crude product.Slightly Not purified be directly used in of product is reacted in next step.

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

2,4,5- trichloropyrimidines (1.45g, 7.9mmol) are dissolved in MeOH (40mL), and triethylamine is added thereto (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).Reaction mixture is stirred at room temperature overnight, and is then concentrated under reduced pressure, residue obtained through silica gel column chromatography (EtOAc/PE (v/v)=1/3) purifying, obtaining title compound is that (450mg, three step of step 4) to step 6) are total for white solid 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone

2- ((3S, 6R) -6- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) is different Indoline -1,3- diketone (370.0mg, 0.88mmol) and 1- methyl-1 H- pyrazoles -4- amine hydrochlorate (354.2mg, It 2.65mmol) is dissolved in n-BuOH (10mL), and DIPEA (683.1mg, 5.29mmol) is added thereto.Reaction mixture exists It is stirred overnight at 150 DEG C, is then concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/30), Obtaining title compound is red 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) N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) 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-1 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 ethyl alcohol (5mL) In, and hydrazine hydrate (198.6mg, 2.94mmol) is added thereto.Reaction mixture is stirred at room temperature 4 hours, then depressurizes Concentration.Gained residue is through the silica gel column chromatography (NH of 7M₃Methanol solution/DCM (v/v)=1/20) purifying, obtain title compound Object 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 intermediate⁴((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) 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.Reaction mixture stirs at 50 DEG C It 2 hours, after reaction, is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/ (NH₃MeOH solution (7M)) (v/v) =30/1) it purifies, obtaining title compound is 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

To the ethyl alcohol of (3S, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furan-3-ol (2.36g, 16.3mmol) Et is added in (40mL) solution₃N (3.4mL, 24mmol) and 2,4,5- trichloropyrimidine (2.98g, 16.2mmol).Reaction mixture It is stirred at room temperature overnight, after reaction, is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/ 60) it purifies, obtaining title compound is 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-1 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 DIPEA (6.7mL, 38mmol) and 1- methyl-1 H- pyrazoles-are added in n-BuOH (40mL) solution of (4.58g, 15.7mmol) 4- amine hydrochlorate (2.51g, 18.8mmol).Reaction mixture is warming up to 150 DEG C, and tube sealing reaction is stirred overnight, after reaction, It is concentrated under reduced pressure.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-1 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan It mutters and Et is added in simultaneously methylene chloride (80mL) solution of [3,2-b] furan-3-ol (5.53g, 15.7mmol)₃N(3.5mL, 25mmol) and DMAP (383.2mg, 3.14mmol).Mixture is cooled to 0 DEG C, and thereto be added mesyl chloride (1.6mL, 21mmol).Gained mixture stirs 30 minutes at 0 DEG C, then moves to and is stirred overnight at room temperature.After reaction, water is used (80mL) quenching reaction, is then allowed to stand layering.Isolate organic phase, water phase is extracted with DCM (40mL × 2), and merging all has Machine phase.Combined organic phase is washed with water (40mL × 3), anhydrous Na₂SO₄It dries, filters, is concentrated under reduced pressure, obtaining title compound is Gray solid (2.70g, yield 40%).

MS(ESI,pos.ion)m/z:431.1[M+H]⁺。

Step 5) N⁴((3S, 6R) -6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base) 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan It mutters and sodium azide is added in simultaneously DMF (15mL) solution of [3,2-b] furans -3- base mesylate (2.45g, 5.69mmol) (1.48g,22.8mmol).Reaction mixture is stirred overnight at 140 DEG C, and after reaction, reaction mixture is with water (100mL) Dilution, stratification isolate organic phase, and water phase is extracted with DCM (100mL × 3), merge all organic phases.What is merged has Machine is mutually washed with water (100mL × 2), anhydrous Na₂SO₄It dries, filters, is concentrated under reduced pressure, obtaining title compound is dark oil object (2.15g, yield 100%).

MS(ESI,pos.ion)m/z:378.1[M+H]⁺。

Step 6) N⁴((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) 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) chloro- N of -5-²(1- methyl-1 H- Pyrazoles -4- base) pyrimidine -2,4- diamines (2.15g, 5.69mmol) methanol (25mL) solution in be added Pd/C (mass fraction 10%, 430mg).Gained suspension is at room temperature and H₂It is stirred overnight in atmosphere.After reaction, reaction mixture is logical Diatomite filtering is crossed, filter cake is washed with MeOH (30mL).Filtrate decompression is concentrated, gained residue is through silica gel column chromatography (DCM/ MeOH (v/v)=40/1 arrives DCM/ (NH₃MeOH solution (7M)) (v/v)=40/1) purifying, it is solid for yellow to obtain title compound Body (232.0mg, yield 12%).

MS(ESI,pos.ion)m/z:352.2[M+H]⁺。

Intermediate 3 (3S, 6S)-N³(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)

To the DCM (300mL) of (3R, 6R)-hexahydro furyl simultaneously [3,2-b] furans -3,6- glycol (29.0g, 198.4mmol) Pyridine (40mL, 490mmol) is added in solution.Reaction mixture stirs 0.5 hour at 0 DEG C, and trifluoromethanesulfonic acid is then added Acid anhydride (169.0g, 599.2mmol).Gained mixture is stirred at room temperature 3 hours, then uses the aqueous solution (200mL, 1M) of hydrochloric acid Quenching reaction, stratification separate organic phase, and water phase is extracted with DCM (500mL × 2).Combined organic phase anhydrous Na₂SO₄ It dries, filters, is concentrated under reduced pressure.At room temperature, residue is beaten 1 hour with MeOH (200mL).Filtering, the filter cake of collection is through depressurizing Dry, obtaining title compound is faint yellow solid (75.0g, yield 92.0%).

Step 2) (3S, 6S)-N³,N⁶Dibenzyl 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, reaction mixture is concentrated under reduced pressure, and obtains 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,N⁶Dibenzyl 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, filtering.Gained filtrate decompression is concentrated, concentrated residues object is through silica gel column chromatography (DCM/MeOH (v/v) 5/1)=50/1 to 20/1 to purifying, obtaining title compound is greenish liquid (0.8g, yield 60%).

MS(ESI,pos.ion)m/z:145.2[M+H]⁺。

Step 4) (3S, 6S)-N³(2,5- dichloro pyrimidine -4- base) hexahydro furyl simultaneously [3,2-b] furans -3,6- diamines

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

MS(ESI,pos.ion)m/z:291.0[M+H]⁺。

4 N of intermediate⁴((3R, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) 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 the DCM of (3R, 6S)-hexahydro furyl simultaneously [3,2-b] furans -3,6- glycol (29.0g, 198.4mmol) In (300mL) solution be added pyridine (40mL, 490mmol), stirring 30 minutes after be added thereto chlorobenzoyl chloride (28.0g, 199.2mmol).Gained mixture is stirred at room temperature 3 hours, then uses aqueous solution (500mL, 1M) quenching reaction of hydrochloric acid, Stratification, isolates organic phase, and water phase is extracted with DCM (500mL × 2).Combined organic phase anhydrous Na₂SO₄It is dry, mistake Filter is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=7/1 to 3/1 to 2/1), is obtained titled Conjunction object is white solid (14g, yield 28.2%).

MS(ESI,pos.ion)m/z:251.0[M+H]⁺。

Step 2) (3R, 6S) -6- (((trifluoromethyl) sulfonyl) oxygroup) 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) be added pyridine (18mL), then thereto be added trifluoromethanesulfanhydride anhydride (10mL, 59.2mmol).Gained mixture is stirred at room temperature 3 hours, after reaction, is quenched with the aqueous solution (300mL, 1M) of HCl Reaction stands its layering, separates organic phase, and water phase is extracted with DCM (300mL × 2), merges all organic phases.What is merged has Machine mutually uses anhydrous Na₂SO₄It dries, filters, is concentrated under reduced pressure, obtaining title compound is 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) oxygroup) 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).Reaction mixture is in room It temperature lower stirring 12 hours, is then concentrated under reduced pressure.Gained residue through silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 5/1 to 3/1) it purifies, obtaining title compound is 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).Reaction mixture is stirred at room temperature 1 Hour, then use CH₃COOH adjusts its pH=7.It is greenish liquid that gained mixture, which is concentrated under reduced pressure to give title compound, (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

To the MeOH of (3R, 6R) -6- (benzyl amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol (3.0g, 12.8mmoL) Pd/C (mass fraction 10%, 2.0g) is added in (60mL) solution.Gained suspension is stirred overnight in room temperature and atmosphere of hydrogen. After reaction, reaction mixture is filtered, gained filtrate is concentrated under reduced pressure, and obtaining title compound is light green liquid (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.Reaction mixture is stirred at room temperature 5 hours, after reaction, is concentrated under reduced pressure.Gained Residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 3/1 to 1/1), and obtaining title compound is 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) are added in DCM (50mL) solution 11mmoL).Gained mixture It is stirred at room temperature 3 hours.After reaction, reaction mixture is concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=5/1 to 2/1) purifying, obtaining title compound is 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 It stirs 5 hours at room temperature, and NaOMe (400mg, 7.4mmoL) is added thereto, mixture is further continued for stirring 1 hour.Reaction knot Shu Hou, reaction mixture are concentrated under reduced pressure, and gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=5/1 to 2/1), Obtaining title compound is white solid (3.0g, yield 67.0%).

MS(ESI,pos.ion)m/z:292.0[M+H]⁺。

Step 9) (3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl-1 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 are added in n-BuOH (20mL) solution of (700mg, 2.4mmoL) Hydrochlorate (660mg, 4.9mmoL).Reaction mixture stirs 1 hour at 130 DEG C, after reaction, is concentrated under reduced pressure.Gained filtrate It is diluted in H₂It in O (50mL), and is stirred at room temperature 1 hour, then filters, collect that filter cake is vacuum dried obtains title compound Object 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-1 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan It mutters and pyridine (0.2mL) and methylsulfonyl is added in simultaneously DCM (12mL) solution of [3,2-b] furan-3-ol (100mg, 0.28mmoL) Chlorine (100mg, 0.87mmoL).Reaction mixture is stirred at room temperature 14 hours, then with saturation Na₂CO₃Aqueous solution (50mL) is quenched It goes out reaction, stratification isolates organic phase, and water phase is extracted with DCM (50mL × 2).Combined organic phase anhydrous Na₂SO₄It is dry It is dry, filtering, filtrate decompression concentration.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) N⁴((3R, 6R) -6- azido hexahydro furyl simultaneously [3,2-b] furans -3- base) 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan It mutters and sodium azide is added in simultaneously DMF (10mL) solution of [3,2-b] furans -3- base methanesulfonates (90mg, 0.21mmoL) (65mg,1mmol).Reaction mixture stirs 12 hours at 130 DEG C, and after reaction, reaction is quenched with water (20mL), stands Layering, separates organic phase, and water phase is extracted with DCM (20mL × 2).Combined organic phase anhydrous Na₂SO₄It dries, filters, depressurizes Being concentrated to give title compound is yellow oil (79.0mg, yield 100%).

MS(ESI,pos.ion)m/z:378.1[M+H]⁺。

Step 12) N⁴((3R, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (70mg, 0.19mmoL) MeOH (10mL) solution in be added Pd/C (mass fraction 10%, 70mg).Gained suspension is at room temperature and H₂It is stirred 6 hours in atmosphere.After reaction, reaction mixture is filtered, Filtrate decompression is concentrated again, 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) -3- methylurea

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

By hexahydro furyl, simultaneously [3,2-b] furans -3,6- glycol (10.00g, 68.4mmol) is dissolved in methylene chloride (60mL) In, and pyridine (1.08g, 13.7mmol) is added thereto, reaction mixture is cooled to 0 DEG C, then 4- methylbenzene is added thereto Sulfonic acid chloride (15.66g, 82.1mmol).Reaction mixture stirs 30 minutes at 0 DEG C, then moves to and is stirred overnight at room temperature.Mixing Object is diluted with methylene chloride (250mL), successively with hydrochloric acid (300mL, 1M), water (300mL) and saline solution (300mL) washing.Point Organic phase out is dried over anhydrous sodium sulfate, filtering, and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/ V) it=2/1) purifies, obtaining title compound is 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 6- hydroxyl hexahydro furyl, simultaneously [3,2-b] furans -3- base 4- oluene sulfonic acides ester (10.24g, 34.1mmol) dissolves In DMSO (60mL), and (1,3- dioxoisoindolin -2- base) potassium (8.21g, 44.3mmol) is added thereto.Reaction is mixed It closes object to stay overnight in 130 DEG C and stirred under nitrogen atmosphere, is then down to room temperature, and be poured into water.Gained mixture methylene chloride (300mL × 3) extraction, combined organic phase are washed with water (100mL × 3), anhydrous Na₂SO₄It is dry, then it is concentrated under reduced pressure.Gained Residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=1/1), and obtaining title compound is 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 methylene chloride (40mL), and triethylamine (1.30g, 12.8mmol) and N, N- are added thereto Lutidines -4- amine (209.2mg, 1.7mmol).Mixture is cooled to 0 DEG C, and methane sulfonyl chloride is added under nitrogen protection (0.8mL,10.0mmol).Gained mixture stirs 30 minutes at 0 DEG C, then moves to and is stirred overnight at room temperature.Mixture is with two Chloromethanes (100mL) dilution, successively with hydrochloric acid (100mL, 1M), water (100mL) and saturated salt solution (100mL) washing.It separates Organic phase be dried over anhydrous sodium sulfate, filter, and be concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v) =1/200) it purifies, obtaining title compound is 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 sodium azide (2.16g, 33.2mmol) is added thereto.Reaction is mixed It closes object to stir 23 hours at 140 DEG C, then is diluted with methylene chloride (100mL), then washed with water (100mL × 3).It separates Organic layer anhydrous Na₂SO₄It is dry, it is then concentrated under reduced pressure, obtains crude product.Not purified be directly used in of crude product is reacted in next step.

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), (previous step slightly produces isoindoline -1,3- diketone Object) it is dissolved in methanol (70mL), and Pd (OH) is added thereto₂/ C (240mg, 0.17mmol, mass fraction 10%).Reaction Mixture is stayed overnight in room temperature and stirred under nitrogen atmosphere, is then filtered.Filtrate decompression concentration, obtains crude product.Crude product is without pure Change is directly used in reacts in next step.

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

2,4,5- trichloropyrimidines (1.45g, 7.9mmol) are dissolved in MeOH (40mL), and triethylamine is added thereto (970mg, 9.6mmol) and 2- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) isoindoline -1,3- diketone (previous step Crude product).Reaction mixture is stirred at room temperature overnight, and is then concentrated under reduced pressure, residue obtained through silica gel column chromatography (EtOAc/PE (v/v)=1/3) purify, obtain title compound be white solid (450mg, three step gross production rate of step 4) to step 6): 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-1 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-1 H- pyrazoles -4- amine hydrochlorate (354.2mg, 2.65mmol) are dissolved in N-BuOH (10mL), and DIPEA (683.1mg, 5.29mmol) is added thereto.Reaction mixture is stirred overnight at 150 DEG C, Then it is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/30), and it is red for obtaining 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) N⁴(6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrazoles -4- Base) pyrimidine -2,4- diamines

By 2-, (hexahydro furyl is simultaneously by 6- ((the chloro- 2- of 5- ((1- methyl-1 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 ethyl alcohol (5mL), and to its Middle addition hydrazine hydrate (198.6mg, 2.94mmol).Reaction mixture is stirred at room temperature 4 hours, is then concentrated under reduced pressure.Gained Residue is through the silica gel column chromatography (NH of 7M₃Methanol solution/DCM (v/v)=1/20) purifying, it is solid for white to obtain title compound 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro furan Mutter simultaneously [3,2-b] furans -3- base) -3- methylurea

To N⁴(6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrazoles -4- base) 4-dimethylaminopyridine is added in methylene chloride (10mL) solution of pyrimidine -2,4- diamines (178.4mg, 0.51mmol) (12.4mg, 0.10mmol) and triethylamine (79.6mg, 0.79mmol).Reaction mixture is cooled to 0 DEG C, is then added thereto Methyl amido formyl chloride (59.1mg, 0.63mmol).Mixture stirs 30 minutes at 0 DEG C, then heats to room temperature and stirs Overnight.Add water (5mL) quenching reaction, and is extracted with methylene chloride (10mL).The organic phase separated is dried over anhydrous sodium sulfate, mistake Filter, and be concentrated under reduced pressure.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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -3- methylurea

To N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (178.4mg, 0.51mmol) methylene chloride (10mL) solution in be added DMAP (12.4mg, 0.10mmol) and triethylamine (79.6mg, 0.79mmol).Reaction mixture is cooled to 0 DEG C, and methylamino is then added thereto Formyl chloride (59.1mg, 0.63mmol).Mixture stirs 30 minutes at 0 DEG C, then heats to room temperature and is stirred overnight.Add water (5mL) quenching reaction, mixture with methylene chloride (10mL) extract.The organic phase separated is dried over anhydrous sodium sulfate, mistake Filter, and be concentrated under reduced pressure.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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrazoles -4- base) In methylene chloride (8mL) solution of pyrimidine -2,4- diamines (100.3mg, 0.29mmol) be added 4-dimethylaminopyridine (7.0mg, 0.06mmol) and triethylamine (45.3mg, 0.45mmol).Reaction system is cooled to 0 DEG C, and 2- methyl-prop is then added thereto Alkane -1- sulfonic acid chloride (56.2mg, 0.36mmol).Mixture is stirred 30 minutes at 0 DEG C and is moved back to room temperature, and is continued stirred Night.Add water (10mL) quenching reaction, gained mixture is extracted with methylene chloride (10mL).The organic phase separated is through anhydrous sodium sulfate It dries, filters, and is concentrated under reduced pressure.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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (100.3mg, 0.29mmol) methylene chloride (8mL) solution in be added DMAP (7.0mg, 0.06mmol) and triethylamine (45.3mg, 0.45mmol).Reaction system is cooled to 0 DEG C, and 2- methyl-prop is then added thereto Alkane -1- sulfonic acid chloride (56.2mg, 0.36mmol).Mixture is stirred 30 minutes at 0 DEG C and is moved back to room temperature, and is continued stirred Night.Add water (10mL) quenching reaction, gained mixture is extracted with methylene chloride (10mL).The organic phase separated is through anhydrous sodium sulfate It dries, filters, and is concentrated under reduced pressure.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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrazoles -4- base) In n-butanol (20mL) solution of pyrimidine -2,4- diamines (32mg, 0.091mmol) be added 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, is then concentrated under reduced pressure. Gained residue through silica gel column chromatography (MeOH/DCM (v/v)=1/30) purify, obtain title compound be 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (32mg, 0.091mmol) n-butanol (20mL) solution in be added 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 depressurizes Concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/30), and obtaining title compound is 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrazoles -4- base) In DCM (3mL) solution of pyrimidine -2,4- diamines (100.3mg, 0.2851mmol), addition triethylamine (179.8mg, 1.777mmol) and cyclopropanesulfonyl chloride (207.6mg, 1.477mmol).Reaction system is stirred at room temperature 2 hours, then plus Water (20mL) quenching reaction, and extracted with the mixed solvent of DCM and MeOH (v/v=10/1,40mL × 3).Combined organic phase Through anhydrous Na₂SO₄It dries, filters and is concentrated under reduced pressure.Gained residue is pure through silica gel column chromatography (DCM/MeOH (v/v)=15/1) Change, obtaining title compound is 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (100.3mg, 0.2851mmol) DCM (3mL) solution in, be added triethylamine (179.8mg, 1.777mmol) and cyclopropanesulfonyl chloride (207.6mg, 1.477mmol).Reaction system is stirred at room temperature 2 hours, then plus Water (20mL) quenching reaction, and extracted with the mixed solvent of DCM and MeOH (v/v=10/1,40mL × 3).Combined organic phase Through anhydrous Na₂SO₄It dries, filters and is concentrated under reduced pressure.Gained residue is pure through silica gel column chromatography (DCM/MeOH (v/v)=15/1) Change, obtaining title compound is 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Furans simultaneously [3,2-b] furans -3- base) -2,2,2- trifluoroethane sulfonamide

To N4- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) the chloro- N2- of -5- (1- methyl-1 H- pyrazoles -4- base) In methylene chloride (10mL) solution of pyrimidine -2,4- diamines (86.3mg, 0.244mmol) be added 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 it Middle addition 2,2,2- trifluoroethane sulfonyl chloride (71.3mg, 0.388mmol).After adding, reaction mixture maintains 0 DEG C to stir 30 points Then clock is moved to and is stirred overnight at room temperature.After reaction, it is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50 it) purifies, obtaining title compound is 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 are as follows: 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2,2- trifluoroethane sulfonamide

To N⁴((3S, 6R) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (86.3mg, 0.244mmol) methylene chloride (10mL) solution in triethylamine is added (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.After adding, reaction mixture maintains 0 DEG C Stirring 30 minutes, then moves to and is stirred overnight at room temperature.After reaction, it is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) purifying, obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrazoles -4- base) In methylene chloride (10mL) solution of pyrimidine -2,4- diamines (101mg, 0.287mmol) be added 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 it Middle addition pyrrolidines -1- sulfonic acid chloride (81.6mg, 0.481mmol).After adding, reaction mixture maintains 0 DEG C of stirring 30 minutes, so It moves back to being stirred overnight at room temperature.After reaction, it is concentrated under reduced pressure.Gained residue through silica gel column chromatography (MeOH/DCM (v/v)= 1/50) it purifies, obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (101mg, 0.287mmol) methylene chloride (10mL) solution in triethylamine is added (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.After adding, reaction mixture maintains 0 DEG C of stirring It 30 minutes, then moves to and is stirred overnight at room temperature.After reaction, it is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/ DCM (v/v)=1/50) purifying, obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrazoles -4- base) In methylene chloride (4mL) solution of pyrimidine -2,4- diamines (50.0mg, 0.14mmol) be added 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, reaction mixture maintains 0 DEG C to stir 30 points Then clock is moved to and is stirred overnight at room temperature.After reaction, it is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/60 it) purifies, obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (50.0mg, 0.14mmol) methylene chloride (4mL) solution in be added 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, reaction mixture maintains 0 DEG C to stir 30 points Then clock is moved to and is stirred overnight at room temperature.After reaction, it is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/60 it) purifies, obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrazoles -4- base) In methylene chloride (10mL) solution of pyrimidine -2,4- diamines (200mg, 0.569mmol) be added triethylamine (115mg, 1.137mmol) and 4- fluorophenylsulfonyl chloride (166mg, 0.853mmol).After adding, reaction mixture is stirred overnight at room temperature.Reaction After, it is concentrated under reduced pressure.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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (200mg, 0.569mmol) methylene chloride (10mL) solution in be added triethylamine (115mg, 1.137mmol) and 4- fluorophenylsulfonyl chloride (166mg, 0.853mmol).After adding, reaction mixture is stirred overnight at room temperature.Reaction After, it is concentrated under reduced pressure.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 are as follows: 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-1 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-1 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) chloro- N of -5-²(1- methyl-1 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 methylene chloride (6mL).Reaction mixture is stirred overnight at room temperature, is then depressurized dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50), and obtaining title compound is 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-1 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-1 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 be added N,N-dimethylformamide (2mL).Reaction system is warming up to 100 DEG C, stirs 8 hours.After reaction, It is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/60), and it is solid for white to obtain title compound 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-1 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-1 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) chloro- N of -5-²(1- methyl-1 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 methylene chloride (6mL).Reaction mixture is stirred overnight at room temperature, so After be concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50), obtains title compound as 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-1 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-1 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, it is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/60), is obtained titled Conjunction object 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrazoles -4- base) In methylene chloride (5mL) solution of pyrimidine -2,4- diamines (200.0mg, 0.57mmol) be added triethylamine (115.1mg, 1.14mmol).Reaction system is cooled to 0 DEG C, and reaction system then is added in piperidines -1- sulfonic acid chloride (125.3mg, 0.68mmol) In.Gained reaction mixture maintains 0 DEG C to stir 30 minutes, then moves to and is stirred overnight at room temperature.After reaction, it depressurizes dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), and obtaining title compound is 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (200.0mg, 0.57mmol) methylene chloride (5mL) solution in triethylamine is added (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 reaction mixture maintains 0 DEG C to stir 30 minutes, then moves to and is stirred overnight at room temperature.Reaction terminates Afterwards, it is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), obtains title compound as 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrazoles -4- base) In methylene chloride (5mL) solution of pyrimidine -2,4- diamines (200.0mg, 0.57mmol) be added triethylamine (115.1mg, 1.14mmol).Reaction system is cooled to 0 DEG C, and reaction system then is added in morpholine -4- sulfonic acid chloride (126.6mg, 0.68mmol) In.Gained reaction mixture maintains 0 DEG C to stir 30 minutes, then moves to and is stirred overnight at room temperature.After reaction, it depressurizes dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), and obtaining title compound is 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (200.0mg, 0.57mmol) methylene chloride (5mL) solution in triethylamine is added (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 reaction mixture maintains 0 DEG C to stir 30 minutes, then moves to and is stirred overnight at room temperature.Reaction terminates Afterwards, it is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), obtains title compound as 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) 1,1- dioxo isothiazolidine

The chloro- N- of step 1) 3- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl-1 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) 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.Reaction mixture stirs 30 at 0 DEG C Minute, it then moves to and is stirred overnight at room temperature.After reaction, water (1mL) is added to be quenched, decompression is spin-dried for solvent.Gained residue Being purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) and obtaining title compound is white solid (134.0mg, yield 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-1 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-1 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, it is added DBU (66.3mg, 0.44mmol), reaction solution is warming up to 100 DEG C, is stirred overnight.After reaction, gained mixture Add water (15mL) to dilute, (10mL × 3) are then extracted with dichloromethane.Combined organic phase is washed with water (10mL), anhydrous slufuric acid Sodium dries, filters, filtrate decompression concentration.Gained residue is pure through silica gel column chromatography (MeOH/DCM (v/v)=1/50 to 1/20) Change, obtaining target compound is 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 are as follows: 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-1 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) 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.Reaction mixture stirs at 0 DEG C It 30 minutes, then heats to room temperature and continues stirring 4 hours.After reaction, add water (0.5mL) to be quenched, and be concentrated under reduced pressure.Institute It obtains residue to purify through silica gel column chromatography (MeOH/DCM (v/v)=1/50 to 1/30), obtaining title compound is 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 are as follows: 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-1 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) 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.Reaction mixture is stirred overnight at -10 DEG C, After reaction, water (0.5mL) is added to be quenched.Mixture is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (MeOH/DCM (v/ V) it=1/30) purifies, obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²-(1- Methyl-1 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.Reaction mixture is stirred at -10 DEG C Night adds water (0.5mL) to be quenched after reaction.Mixture is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/30 it) purifies, obtaining title compound is 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 are as follows: 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- (tetrahydrofuran -3- base) Methanesulfonamide

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

3- (bromomethyl) tetrahydrofuran (1.00g, 6.06mmol) is added into the sodium sulfite aqueous solution (10mL) of saturation. Reaction mixture is warming up to return stirring 24 hours, is then concentrated under reduced pressure.Ethyl alcohol (20mL) is added into gained residue, gained Mixture is warming up to 50 DEG C, stirs 30 minutes, filters while hot immediately.It is white solid that filtrate decompression, which is concentrated to give title compound, (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- It answers system to be warming up to return stirring to stay overnight.After reaction, reaction mixture is concentrated under reduced pressure, and obtaining title compound is yellow solid (294.3mg, yield 100%).

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

At 0 DEG C, to N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) 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 The tetrahydrofuran (3mL) that (tetrahydrofuran -3- base) methane sulfonyl chloride (162.4mg, 0.88mmol) is added in (3mL) solution is molten Liquid.Reaction mixture stirs 30 minutes at 0 DEG C, then moves to room temperature and continues stirring 7 hours.After reaction, add water (1mL) It is quenched, gained mixture is concentrated under reduced pressure.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 are as follows: 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-1 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 In (10mL).Reaction mixture is warming up to return stirring and reacts 6 hours, after reaction, is concentrated under reduced pressure to give white solid.To Methanol (100mL) is added in obtained solid, is warming up to 50 DEG C, stirs 20 minutes, filters while hot immediately.Filtrate decompression is concentrated to give mark 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

To the DMF (21.7mg, 0.297mmol) of 2- (benzyloxy) ethane sulfonic acid sodium (614.1mg, 2.578mmol) and four Thionyl chloride (0.6mL, 8mmol) is added in hydrogen furans (20mL) solution.It is small that reaction mixture is warming up to return stirring reaction 5 When.After reaction, it is cooled to room temperature, filters, filter cake is washed with methylene chloride (50mL).Filtrate decompression is concentrated to get titled Conjunction object is yellow liquid (712.4mg).Crude product is directly used in react in next step, without being further purified.

(((the chloro- 2- of 5- ((1- methyl-1 H- pyrazoles -4- base) amino) is phonetic by (3S, 6R) -6- by step 3) 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (301.1mg, 0.8559mmol) and triethylamine (357.4mg, 3.532mmol) be dissolved in DCM In (8mL).Reaction 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, it moves to room temperature to continue to be stirred overnight, after reaction, be concentrated under reduced pressure.Institute Residue through silica gel column chromatography (DCM/MeOH (v/v)=60/1) purify, obtain title compound be 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-1 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-1 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) it is molten Liquid is cooled to -40 DEG C, and then the DCM solution (5.5mL, 5.5mmol, 1M) of Boron tribromide is added dropwise in above-mentioned reaction system. Reaction system is stirred to react 4 hours at -40 DEG C, after reaction, water (10mL) is added to be quenched.Gained mixture sodium hydroxide Powder is adjusted to pH=8, is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/NH₃MeOH solution (7M) (v/v) =10/1) it purifies, obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (150mg, 0.426mmol) DCM (10mL) solution in be added TEA (103mg, 1.02mmol).Reaction mixture is cooled to 0 DEG C, and reactant then is added in phenyl methane sulfonyl chlorine (161mg, 0.844mmol) In system.Reaction mixture is stirred overnight at 0 DEG C, is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50 it) purifies, obtaining title compound is 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 are as follows: 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-1 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 aqueous solution (20.0mL).Reaction mixing Object is warming up to reflux, is stirred to react 24 hours, is then concentrated under reduced pressure.Ethyl alcohol (30mL) is added into gained residue, is warming up to It 50 DEG C, stirs 30 minutes, heat filtering immediately.Filtrate decompression concentration, 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 DMF (340mg, 4.59mmol) and thionyl chloride (1.09g, 9.19mmol).Reaction mixture is warming up to reflux and stirring 4 is small When, it then cools to room temperature, filters.It is brown liquid (0.782g, yield 100%) that filtrate decompression, which is concentrated to get crude product,.

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

Step 3) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (201mg, 0.568mmol) THF (10mL) solution in be added TEA (345mg, 3.41mmol).Reaction mixture is cooled to 0 DEG C, then, tetrahydrofuran -3- sulfonic acid chloride (389mg, 2.27mmol) is added anti- It answers in system.Reaction system is warming up to 50 DEG C and is stirred to react overnight, is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) purifying, obtaining title compound is 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 are as follows: 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- cyclopenta Methanesulfonamide

To N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (200mg, 0.568mmol) DCM (5mL) solution in be added TEA (175mg, 1.71mmol).Reaction mixture is cooled to 0 DEG C, then, cyclopenta methane sulfonyl chloride (81.6mg, 0.481mmol) is added anti- It answers in system.It is stirred to react at 0 DEG C of reaction system overnight, is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/ DCM (v/v)=1/40) purifying, obtaining title compound is 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 are as follows: 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) pyrrolidin-2-one

The chloro- N- of step 1) 4- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (216.0mg, 0.61mmol) DCM (5mL) solution in be added TEA (93.1mg, 0.92mmol).Reaction mixture is cooled to -10 DEG C, then, reactant is added in 4- chlorobutanoylchloride (103.1mg, 0.73mmol) In system.Reaction mixture stirs 20 minutes at -10 DEG C, then moves to room temperature and continues 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), and obtaining title compound is 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-1 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-1 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 DBU is added (85.3mg,0.56mmol).Reaction system is warming up to 100 DEG C and is stirred to react overnight, is then concentrated under reduced pressure.Gained residue is through silicon Plastic column chromatography (MeOH/DCM (v/v)=1/45) purifying, obtaining title compound is 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 are as follows: 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) amino) niacin nitrile

To N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (112.7mg, 0.85mmol) and 6- chlorine apellagrin nitrile n-butanol (4mL) solution in be added DIPEA(112.7mg,0.87mmol).Reaction mixture is warming up to 150 DEG C of tube sealing reactions and stays overnight, and after reaction, depressurizes dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/55), and obtaining title compound is 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 are as follows: 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-1 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (246.3mg, 0.70mmol) DCM (4mL) solution in be added TEA (106.3mg, 1.05mmol).Reaction mixture is cooled to -10 DEG C, then by 2- methylpropane -2- sulphinyl chlorine (118.1mg, 0.84mmol) It is added in reaction system.Reaction mixture stirs 15 minutes at -10 DEG C, then moves to room temperature and continues stirring 30 minutes.Reaction After, gained mixture is concentrated under reduced pressure, and residue purifies titled through silica gel column chromatography (MeOH/DCM (v/v)=1/60) Conjunction object 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-1 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-1 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) it is molten Metachloroperbenzoic acid (160.3mg, 0.93mmol) is added in liquid.Reaction system is stirred at room temperature overnight, and is then depressurized dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/60), and obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (202.3mg, 0.57mmol) DCM (4mL) solution in be added TEA (86.3mg, 0.85mmol).Reaction mixture is cooled to 0 DEG C, then, cyclopropylmethyl sulfonic acid chloride (106.3mg, 0.68mmol) is added anti- It answers in system.Reaction mixture stirs 30 minutes at 0 DEG C, then moves to room temperature reaction overnight, after reaction, depressurizes dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/60), and obtaining title compound is 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 are as follows: 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2- cyano -2- methylpropane -1- sulfonamide

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

2- cyan-acetic ester (20g, 176.82mmol) is suspended in the in the mixed solvent of DMF (200mL) and water (10mL), At 0 DEG C, K is added portionwise thereto₂CO₃(101.83g,442.07mmol).Reaction system stirs 30 minutes at this temperature, so Afterwards, iodomethane (62.75g, 442.1mmol) is added dropwise thereto, is dripped off in 1 hour, gained mixture is stirred overnight at room temperature.Instead After answering, add water (500mL) quenching reaction, and extract (500mL × 3) with EtOAc.Combined organic phase is through saturated salt solution (600mL) is washed, and anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure.Gained residue chromatographs (PE/EtOAc through Flash silica column (v/v)=10/1 it) purifies, obtaining title compound is light 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 into 2- cyano -2 Methylpropionic acid ethyl ester (10.34g, 73.25mmol) methanol solution (200mL) Secondary addition NaBH₄(5.54g,146mmol).Reaction system is stirred overnight at room temperature.After reaction, reaction solution saturation chlorination Aqueous ammonium is adjusted to pH=7~8, then extracts (100mL × 3) with EtOAc.Combined organic phase is through saturated salt solution (150mL) is washed, and anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v) =20/1 to 10/1) it purifies, obtaining title compound is colorless oil (4.0g, yield 55.09%).

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

The bromo- 2,2- dimethyl propionitrile of step 3) 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).Reaction mixture is stirred at room temperature overnight, and after reaction, mixture is concentrated under reduced pressure, and gained residue is through silica gel Column chromatographs (PE/EtOAc (v/v)=20/1) purifying, and obtaining title compound is 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 -2- methylpropane -1- sodium sulfonate

The bromo- 2,2- dimethyl propionitrile (3.27g, 20.2mmol) of 3- is added in saturated sodium bisulfite solution (25mL).Instead It answers mixture to be warming up to reflux, is stirred to react 24 hours, is then concentrated under reduced pressure.Ethyl alcohol (50mL) is added into gained residue, It is warming up to 50 DEG C, after stirring 30 minutes, heat filtering immediately.Filtrate decompression concentration, gained residue add toluene (50mL) to dilute, so Decompression is spin-dried for afterwards.It is white solid (2.68g, yield 71.7%) that title compound is obtained after gained residue is vacuum dried.

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 -2- methylpropane -1- sulfonic acid chloride

2- cyano -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, 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 without further purification, is directly used in next step.

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

At 0 DEG C, to N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) 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 tetrahydro of 2- cyano -2- methylpropane -1- sulfonic acid chloride (207mg, 1.1396mmol) is added in hydrogen furans (10mL) solution Furans (10mL) solution.Reaction mixture is stirred at room temperature 2 hours, after reaction, is concentrated under reduced pressure, 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 are as follows: 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2,2- trifluoroethane sulfonamide

To N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (120mg, 0.341mmol) THF (10mL) solution in be added TEA (70.2mg, 0.691mmol).Reaction mixture is cooled to 0 DEG C, then adds 2,2,2- trifluoroethane sulfonyl chloride (96.3mg, 0.525mmol) Enter in reaction system.It is stirred to react at 0 DEG C of reaction system overnight, is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) purifying, obtaining title compound is 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 is 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-1 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).Reaction mixture is cooled to 0 DEG C, then 2- methylpropane -1- sulphinyl chlorine (194.2mg, 1.24mmol) is added in reaction system.Reaction mixture is 0 It is stirred 30 minutes at DEG C, then moves to room temperature reaction overnight, after reaction, be concentrated under reduced pressure.Gained residue is through silica gel column layer (MeOH/DCM (v/v)=1/45) purifying is analysed, obtaining title compound is 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-1 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) be added DIPEA (59.8mg, 0.46mmol) and 1- methyl-1-H- pyrazoles-4- amine hydrochlorate (30.7mg, 0.23mmol).Reaction mixture is warming up to 150 DEG C, Tube sealing reaction is stayed overnight, and after reaction, is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/55) Purifying, obtaining title compound is 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 are as follows: 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-1 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

It is added at 0 DEG C into tetrahydrofuran -3- amine (1.79g, 20.58mmol) and the mixture of anhydrous DCM (21.0mL) Anhydrous DCM (3.50mL) solution of chlorosulfonic acid (0.80g, 6.9mmol).Reaction mixture stirs 30 minutes at 0 DEG C, then subtracts Pressure concentration, the vacuum dried target compound that obtains of gained residue is 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 Phosphorus pentachloride (1.46g, 7.00mmol) is added in the suspending system of (21.0mL).Reaction mixture is warming up to 80 DEG C, and stirring is anti- It answers 3 hours.After reaction, it is cooled to room temperature and filters.Filter cake is washed with toluene (10.0mL), and filtrate decompression is concentrated to get mark Topic compound is brown liquid (0.23g, yield 18%).

The chloro- N- of step 3) 5- (1- methyl-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (0.10g, 0.29mmol) and triethylamine (0.20mL, 1.40mmol) DCM (10.0mL) it is molten (tetrahydrofuran -3- base) sulfamic acid chloride (0.11g, 0.61mmol) is slowly added in liquid.Reaction system was stirred at room temperature Then night is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/ (NH₃MeOH solution (3M)) (v/v)=50/1 arrive 30/1) it purifies.Gained crude product is prepared thin-layer chromatography (EtOAc/MeOH (v/v)=30/1) purifying, and obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (190mg, 0.540mmol) THF (10mL) solution in be added TEA (659mg, 6.48mmol).Reaction 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 is stirred to react overnight at 0 DEG C, is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) purifying, obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (231mg, 0.656mmol) DCM (10mL) solution in be added TEA (330mg, 3.26mmol).Reaction mixture is cooled to 0 DEG C, then, cyclobutylmethyl alkanesulphonyl chlorides (440mg, 2.61mmol) is added and is reacted In system.Reaction mixture is stirred overnight at 0 DEG C, after reaction, is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/50) purifying, obtaining title compound is 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 are as follows: 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (30mg, 0.09mmoL) DCM (20mL) solution in TEA (0.2mL) and 2- methyl-prop is added Alkane -1- sulfonic acid chloride (40mg, 0.26mmoL).Reaction system stirs 5 hours at room temperature, is then concentrated under reduced pressure.Gained residue warp Silica gel column chromatography (DCM/MeOH (v/v)=10/1) purifying, obtaining title compound is 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-1 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

The bromo- 2- methybutane (2.01g, 13.3mmol) of 1- is added in saturated aqueous sodium sulfite (40.0mL).Instead It answers mixture to be warming up to reflux, is stirred to react 24 hours, is then concentrated under reduced pressure.Ethyl alcohol (50mL) is added into gained residue, It is warming up to 50 DEG C, after stirring 30 minutes, heat filtering immediately.Filtrate decompression concentration, gained residue are titledly vacuum dried Conjunction object 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, be stirred overnight, after reaction, be concentrated under reduced pressure title compound crude product be yellow liquid (1.7g, yield 100%).Crude product is directly used in next step without further purification.

Step 3) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (201mg, 0.571mmol) THF (20mL) solution in be added TEA (983mg, 5.76mmol).Reaction mixture is cooled to 0 DEG C, and then, 2- methybutane -1- sulfonic acid chloride (389mg, 2.29mmol) is added In reaction system.Reaction system is stirred at room temperature overnight, and after reaction, is concentrated under reduced pressure.Gained residue is through silica gel column layer (MeOH/DCM (v/v)=1/50) purifying is analysed, obtaining title compound is 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 are as follows: 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- (tetrahydrofuran -2- base) Methanesulfonamide

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

Saturation Na is added in 2- (bromomethane) tetrahydrofuran (2.01g, 12.2mmol)₂SO₃In aqueous solution (40.0mL).Instead It answers mixture to be warming up to reflux, is stirred to react 24 hours, is then concentrated under reduced pressure.Ethyl alcohol (50mL) is added into gained residue, It is warming up to 50 DEG C, after stirring 30 minutes, heat filtering immediately.Filtrate decompression concentration.Gained residue is titledly vacuum dried Conjunction object 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 heating of the mixture of (tetrahydrofuran -2- base) Loprazolam sodium (2.21g, 11.7mmol) and thionyl chloride (30mL) To 80 DEG C, be stirred overnight, after reaction, be concentrated under reduced pressure title compound crude product be yellow liquid (2.2g, yield 100%).Crude product is directly used in next step without further purification.

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

To N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (203mg, 0.577mmol) THF (20mL) solution in be added TEA (710mg, 12.2mmol).Reaction mixture is cooled to 0 DEG C, then, by (tetrahydrofuran -2- base) methane sulfonyl chloride (1.1g, 5.98mmol) It is added in reaction system.Reaction system is stirred overnight at room temperature, after reaction, is concentrated under reduced pressure.Gained residue is through silicagel column (MeOH/DCM (v/v)=1/50) purifying is chromatographed, obtaining title compound is 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 are as follows: 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 by (3S, 6R) -6- by 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

To tetrahydrofuran (20mL) solution of piperidines -4- alcohol (2g, 19.773mmol) and triethylamine (4g, 39.530mmol) Middle dropwise addition dimethyl dicarbonate butyl ester (5.2g, 24mmol).Reaction system is stirred overnight at room temperature, after reaction, is concentrated under reduced pressure.Institute It obtains residue to purify through silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 5/1), obtaining title compound is 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, 5.969mmol) and azoformic acid is added in anhydrous tetrahydro furan (50mL) solution of triphenylphosphine (1.96g, 7.47mmol) Diisopropyl ester (1.5mL, 7.6mmol), drips off in 30 minutes.Reaction system is stirred at room temperature 1 hour, then moves to room temperature and stirs It mixes overnight.Reaction mixture is concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=20/1 to 4/1) Purifying, obtaining title compound is 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

To the ethyl alcohol of 4- (4- nitro -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (1.35g, 4.56mmol) Pd/C (135mg, 10% content) is added in (30mL) solution.Reaction system reacts 2 hours in room temperature, atmosphere of hydrogen, then, Reaction mixture filtering, filtrate decompression concentration.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=50/1 to 25/1) Purifying, obtaining title compound is 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 be added and cesium carbonate (2.91g, 8.93mmol), BINAP (284mg, 0.456mmol) and Pd(OAc)₂(102mg,0.454mmol).Reaction mixture is warming up to 105 DEG C in nitrogen atmosphere, is stirred overnight, and reaction terminates Afterwards, it is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), and it is red for obtaining 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) oxygroup) 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 protection atmosphere, Methane sulfonyl chloride (662mg, 5.78mmol) is added thereto.Gained reaction mixture stirs 30 minutes at 0 DEG C, then moves to It is stirred overnight at room temperature.After reaction, mixture adds DCM (100mL) to dilute, with water (50mL) and saturated salt solution (50mL) according to Secondary washing, the organic phase separated filter after being dried over anhydrous sodium sulfate, filtrate decompression concentration.Gained residue is through silica gel column chromatography (EtOAc/DCM (v/v)=1/2) purifying, obtaining title compound is 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) oxygroup) 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 Sodium azide (241mg, 3.71mmol) is added in (10mL) solution.Reaction system is warming up to 140 DEG C, is stirred overnight.Reaction knot Shu Hou, mixture add ethyl acetate (100mL) to dilute, are then washed with water (50mL × 2), the organic phase separated is through anhydrous slufuric acid It is filtered after sodium is dry, it is red oil (600mg, yield 89.0%) that filtrate decompression, which is concentrated to give title compound,.

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 by 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 after reaction at room temperature in atmosphere of hydrogen, Mixture filtering, filtrate decompression concentration.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).Reaction mixture is cooled to 0 DEG C, then, by cyclopropyl Methane sulfonyl chloride (1.51g, 9.77mmol) is added in reaction system.Reaction system is stirred overnight at room temperature, after reaction, is subtracted Pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50), and obtaining title compound is 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 be added hydrogen chloride acetic acid solution (8mL, 24mmol, 3M).Gained reaction system stirs at normal temperature After overnight, it is concentrated under reduced pressure.Gained residue is dissolved in DCM (20mL), is adjusted to pH=10 with saturated sodium bicarbonate aqueous solution, so After be concentrated under reduced pressure.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 are as follows: 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-1 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

LiAlH₄It is suspended in THF that ((97%, 3.96g, 101.2mmol, 200mL) at -10 DEG C, is added dropwise 2,2- thereto Ethyl difluoro (24.76g, 199.5mmol).After adding, reaction 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.The vacuum distillation of gained mixture collects 90~96 DEG C of fraction and obtains title compound Object 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。

The bromo- 1,1- Difluoroethane of step 2) 2-

At 0 DEG C, to PPh₃Br is added dropwise in DCM (50mL) solution of (15.77g, 60.12mmol)₂(3.2mL, 62.45mmol).After adding, reaction 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, reaction mixture maintains -10 DEG C Under continue stirring 1 hour.The vacuum distillation of gained mixture collects 43~50 DEG C of fraction and obtains title compound as colorless oil Object (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

The bromo- 1,1- Difluoroethane (1.90g, 13.11mmol) of 2- is dissolved in the mixed solvent of EtOH (15mL) and water (15mL) In, sodium sulfite (5.20g, 41.26mmol) is added thereto.Reaction system is warming up to 100 DEG C, is stirred overnight, and reaction terminates Afterwards, it is concentrated under reduced pressure.Ethyl alcohol (50mL) is added into gained residue, is warming up to 50 DEG C, after stirring 30 minutes, heat filtering immediately. Filter cake is washed with ethyl alcohol (30mL × 3), and it is white solid (2.21g, yield that filtrate decompression, which is concentrated to get title compound, 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 into 2,2- difluoromethane sodium sulfonate (2.70g, 16.06mmol) and the mixture of toluene (30mL)₅ (7.48g,35.93mmol).Reaction mixture is warming up to 120 DEG C and is stirred overnight, and after reaction, is concentrated under reduced pressure to give crude product For yellow oil (1.94g, yield 73.4%).Crude product is directly used in without further purification to react in next step.

Step 5) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl-1 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) chloro- N of -5-²(1- methyl-1 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 be added triethylamine (1.44g, 14.23mmol).Reaction system stirs 15 minutes at -10 DEG C, then Add water (30mL) quenching reaction, and is extracted with DCM (100mL × 3).Combined organic phase is washed through saturated salt solution (100mL), nothing Aqueous sodium persulfate is dried, filtered and is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/10), Obtaining title compound is buff white solid (18.0mg, yield 3.1%).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 are as follows: 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-1 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), and 2- is added thereto Methylpropane -1,3- glycol (30.11g, 334.1mmol), reaction mixture are warming up to 50 DEG C of stirrings 2 hours, then, thereto It is added cylite (57.08g, 333.7mmol).Reaction mixture is warming up to 65 DEG C and is stirred overnight.After reaction, add water (500mL) dilution, and (500mL × 3) are extracted with EtOAc.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is depressurized dense Contracting.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=20/1 to 10/1), and it is faint yellow for obtaining 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, to the DCM of 3- (benzyloxy) -2- methylpropane -1- alcohol (20.64g, 114.5mmol) in nitrogen atmosphere DAST (74mL, 560mmol) is added dropwise in (250mL) solution, after adding, is reacted 1 day under reaction system room temperature.After reaction, 0 At DEG C, add water (150mL) quenching reaction, separate organic phase, washs (1M, 100mL × 2), anhydrous Na with diluted hydrochloric acid aqueous solution₂SO₄ It dries, filters and is concentrated under reduced pressure.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.

The fluoro- 2- methylpropane -1- alcohol of step 3) 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 in 3MPa atmosphere of hydrogen with the mixture of THF (150mL) and is warming up to 70 DEG C of stirrings, reaction is overnight. Reaction mixture filtering, filter cake are washed with THF (60mL), and filtrate is evaporated under reduced pressure, and the fraction at 100 DEG C of collection obtains titled Conjunction object 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。

The fluoro- 2- methylpropane of the bromo- 3- of step 4) 1-

At 0 DEG C, simple substance bromine is added dropwise into DCM (200mL) solution of triphenylphosphine (16.85g, 64.24mmol) (3.3mL,64mmol).Reaction mixture stirs 30 minutes at 0 DEG C, be then added fluoro- -1 alcohol of 2- methylpropane of 3- (4.93g, 53.5mmol).Reaction system is stirred overnight at 0 DEG C.After reaction, mixture is evaporated under reduced pressure, and collects evaporating at 100 DEG C Getting title compound is 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。

The fluoro- 2- methylpropane -1- sodium sulfonate of step 5) 3-

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

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。

The fluoro- 2- methylpropane -1- sulfonic acid chloride of step 6) 3-

DMF is added into 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).Reaction mixture, which is warming up to, to be flowed back and stirs in nitrogen atmosphere Overnight.After reaction, mixture be concentrated under reduced pressure title compound be yellow semisolid (1.85g, yield 100%).It is thick to produce Object is directly used in react in next step, without being further purified.

Step 7) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (223.8mg, 0.6362mmol) DCM (5mL) solution in be added TEA (1.2mL, 8.6mmol), reaction mixture is cooled to 0 DEG C, then by the fluoro- 2- methylpropane -1- sulfonic acid chloride (1.85g, 10.6mmol) of 3- DCM (5mL) solution is added in above-mentioned system.Reaction mixture maintains 0 DEG C to stir 40 minutes.After reaction, add water (50mL) Quenching reaction simultaneously extracts (50mL × 3) with DCM.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained Residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=40/1), and obtaining title compound is that (109.1mg is produced yellow solid 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 is 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -2,2- difluoropropane -1- sulfonamide

Bis- fluoropropyl trifluoromethayl sulfonic acid ester of step 1) 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 Trifluoromethanesulfonic anhydride (10.5mL, 62.4mmol) is added dropwise, add to move back to 0 DEG C and be stirred overnight.Instead After answering, after mixture is diluted with DCM (75mL), it is poured into ice water (100mL).Organic phase is separated, 20%Na is used₂CO₃It is water-soluble Liquid (50mL) and saturated salt solution (50mL) successively wash, anhydrous Na₂SO₄After drying, it is filtered, and concentrated under reduced pressure to give target chemical combination Object is dark oil object (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

It is added into ethyl alcohol (120mL) solution of bis- fluoropropyl trifluoromethayl sulfonic acid ester (11.41g, 50.01mmol) of 2,2- Thiocarbamide (3.81g, 50.1mmol), reaction mixture are warming up to return stirring 2 hours.After reaction, mixture is concentrated under reduced pressure, Obtaining title compound is yellow solid (15.22g, yield 100%).

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, into acetonitrile (100mL) solution of sodium chlorite (13.57g, 150.0mmol) be added 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, is added Enter ice water (100mL) quenching reaction.Organic solvent is removed under reduced pressure at 15 DEG C, gained residue adds water (100mL) to dilute, then uses EtOAc (100mL × 2) extraction.Combined organic phase is dried, filtered through saturated common salt water washing, anhydrous sodium sulfate, filtrate decompression Being concentrated to give title compound is 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-1 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) 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). Reaction mixture stirs 30 minutes at 0 DEG C, then moves to and is stirred overnight at room temperature.After gained mixture adds DCM (10mL) to dilute, It is washed with water (10mL × 2).The organic phase separated is dried over anhydrous sodium sulfate, filtering, filtrate decompression concentration.Gained residue is through silicon Plastic column chromatography (MeOH/DCM (v/v)=1/50 to 1/20) purifying, obtaining crude product is white solid.Crude product is prepared efficient liquid Phase chromatography is further purified, and obtaining target compound is 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 is 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) -1- (3- fluorine cyclobutyl) Methanesulfonamide

Step 1) 3- oxo cyclobutane formate methyl esters

H is added into methanol (500mL) solution of 3- oxo cyclobutane formate (20.1g, 176mmol)₂SO₄Aqueous solution (9.5mL,17.48mmol,1.84M).Reaction system is warming up to 75 DEG C, is stirred overnight, and after reaction, is concentrated under reduced pressure.Gained Residue is adjusted to pH=10 with saturated sodium bicarbonate aqueous solution, and mixture extracts (200mL × 3) with DCM.Combined organic phase warp Saturated common salt water washing (100mL), is then dried over anhydrous sodium sulfate, filtering, be concentrated under reduced pressure title compound be yellow oil Shape object (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

It is molten to the MeOH (50mL) of 3- oxo cyclobutane formate methyl esters (11.5g, 89.8mmol) at 0 DEG C in nitrogen atmosphere Sodium borohydride (3.72g, 98.6mmol) is added in liquid.Reaction mixture stirs 30 minutes at 0 DEG C, then moves to room temperature continuation Stirring 30 minutes.Saturated aqueous ammonium chloride (50mL) quenching reaction is added into gained mixture, is then extracted with ethyl acetate Take (200mL × 3).Combined organic phase is washed through saturated salt solution (100mL), is then dried, filtered with anhydrous sodium sulfate, filtrate It is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=3/1), and it is solid for brown to obtain title compound 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 is stirred to react 1 at -78 DEG C Hour, it then moves to and is stirred overnight at room temperature.At 0 DEG C, add water (50mL) quenching reaction, is then extracted with DCM (200mL × 3).It closes And organic phase be dried over anhydrous sodium sulfate after be concentrated under reduced pressure, obtain title compound be 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) methanol

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.Reaction mixture stirs 1 hour under -10 °, moves to room temperature, It is stirred overnight.Reaction mixture is cooled to 0 DEG C, then successively slowly plus water (10mL), 15%KOH aqueous solution (10mL) and in addition 40mL water, quenching reaction.Gained mixture is filtered through diatomite.Filtrate is extracted with ether (200mL × 3), combined organic phase It is dried over anhydrous sodium sulfate, filters, filtrate decompression concentration.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=6/1) Purifying, obtaining title compound is 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, and then (3- fluorine cyclobutyl) methanol (1.36g, 13.1mmol) is added in above-mentioned system.Mixture is 0 It is stirred overnight at DEG C, then uses saturated aqueous sodium sulfite (50mL) quenching reaction.Gained mixture is with DCM (100mL × 3) Extraction.Combined organic phase is washed through saturated salt solution (50mL), after anhydrous sodium sulfate is dry, be concentrated under reduced pressure title compound 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

Saturated aqueous sodium sulfite (30.0mL) is added in 1- (bromomethyl) -3- fluorine cyclobutane (2.10g, 13.0mmol) In.Reaction system is warming up to 100 DEG C and stirs 24 hours, is then concentrated under reduced pressure.Ethyl alcohol (20mL) is added into gained residue, rises Temperature is to 50 DEG C, stirring 30 minutes, immediately heat filtering.Filtrate decompression concentration, gained residue is in DCM (50mL) and H₂O(20mL) It is layered in system.The water phase separated be concentrated under reduced pressure title compound be 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).Reaction mixture is warming up to 70 DEG C of stirrings Overnight, after reaction, be concentrated under reduced pressure crude product be yellow oil (680mg, yield 38%).Crude product is straight without further purification It connects in next step.

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

To N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (150mg, 0.426mmol) THF (20mL) solution in be added TEA (513mg, 5.07mmol) and DMAP (5mg, 0.040mmol).Reaction mixture is cooled to 0 DEG C, then by (3- fluorine cyclobutyl) sulfonyl methane Chlorine (690mg, 3.70mmol) is added in reaction system.Reaction mixture stirs 1 hour at 0 DEG C, after reaction, depressurizes dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), and obtaining title compound is 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 are as follows: 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) tri- fluoro- 2- methylpropane -1- sulfonamide of 3,3,3-

The fluoro- 2- methyl-propyl trifluoromethayl sulfonic acid ester of step 1) 3,3,3- tri-

Three second are added into DCM (20mL) solution of the fluoro- 2- methylpropane -1- alcohol (800mg, 6.25mmol) of 3,3,3- tri- Amine (950mg, 9.39mmol).Reaction 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.Reaction mixture is diluted with DCM (50mL), then uses the hydrochloric acid of 1M Aqueous solution (50mL × 2) washing, the organic phase separated be concentrated under reduced pressure after being dried over anhydrous sodium sulfate title compound be 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

To EtOH (10mL) solution of the fluoro- 2- methyl-propyl trifluoromethayl sulfonic acid ester (950mg, 9.39mmol) of 3,3,3- tri- Middle addition thiocarbamide (950mg, 9.39mmol).Reaction mixture is warming up to 80 DEG C, stirs 1 hour.After reaction, mixture subtracts It is yellow oil (1g, yield 70%) that pressure, which is concentrated to get title compound,.

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。

The fluoro- 2- methylpropane -1- sulfonic acid chloride of step 3) 3,3,3- tri-

At 5 DEG C, concentrated hydrochloric acid (4mL, 12M) is added into 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 stirs 30 minutes, after reaction, water is added (10mL) quenching reaction.Organic solvent is removed under reduced pressure at 15 DEG C, residue adds water (10mL) to dilute, with ethyl acetate (50mL × 3) it extracts.Combined organic phase is concentrated under reduced pressure to give title compound after being dried over anhydrous sodium sulfate be yellow oil (500mg, yield 99.5%).

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

To N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (150mg, 0.426mmol) THF (10mL) solution in be added TEA (305mg, 3.01mmol) and DMAP (5mg, 0.040mmol).Reaction mixture is cooled to 0 DEG C, then by the fluoro- 2- methyl-prop of 3,3,3- tri- Alkane -1- sulfonic acid chloride (500mg, 2.37mmol) is added in reaction system.It stirs 1 hour at 0 DEG C of reaction system, subtracts after reaction Pressure concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), and obtaining title compound is 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 are as follows: 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-1 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro furyl simultaneously [3,2-b] furans -3- base) Methanesulfonamide

At 0 DEG C, to N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) 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 dropwise addition methane sulfonyl chloride (200mg, 1.746mmol), drips off in 30 minutes.Reaction mixture is at 0 DEG C Under be stirred overnight, add water (50mL) quenching reaction, then with DCM (100mL × 3) extract.Combined organic phase is through being concentrated under reduced pressure Obtaining title compound is white solid (580mg, yield 94.9%).

MS(ESI,pos.ion)m/z:430.1[M+H]⁺。

Step 2) N- ((3S, 6R) -6- ((the chloro- 2- of 5- ((1- methyl-1 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) Methanesulfonamide (375mg, 0.872mmol) THF (75mL) solution in It is added n-BuLi (hexane solution of 1.6mL, 3.5mmol, 2.2M).Reaction mixture stirs 0.5 hour at -78 DEG C, Then DCM (1mL) solution of acetone (60.0mg, 1.03mmol) is slowly added thereto.After adding, reaction mixture is -78 Then plus water H continue stirring 3 hours at DEG C,₂O (40mL) is quenched and is extracted with DCM (30mL × 3), combined organic phase decompression Concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), and obtaining crude product is white solid.It is thick to produce Object is prepared thin-layer chromatography (MeOH/DCM (v/v)=1/30) purifying, and obtaining title compound is white solid (125mg, yield 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 are as follows: 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) two fluoro- 2- methylpropane -1- sulfonamide of -3,3-

Step 1) 3- (benzyloxy) -2 methyl propanal

At 0 DEG C, divide into 3- benzyloxy -2- methyl -propyl- 1- alcohol (24.03g, 133.3mmol) DCM (150mL) solution Secondary addition DMP (68.12g, 160.6mmol) mixture stirs 30 minutes at 0 DEG C, and then heating to room temperature, to continue stirring 5 small When.After reaction, it filters, filter cake is washed with DCM (300mL).Filtrate decompression concentration.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=40/1 to 30/1) purifying, obtaining title compound is 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, dripped into 3- (benzyloxy) -2 methyl propanal (19.32g, 108.4mmol) DCM (300mL) solution Add DAST (86mL, 651mmol), is dripped off in 30 minutes.Reaction mixture stirs 1 hour at -78 DEG C, then moves to room temperature and stirs It mixes overnight.At 0 DEG C, it is slowly added to water (200mL) quenching reaction into reaction mixture, is then extracted with DCM (300mL).Point Organic phase out is through anhydrous Na₂SO₄After drying, it is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/ 0 to 80/1) it purifies, obtaining title compound is 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。

The fluoro- 2- methyl propyl- 1- alcohol of step 3) 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 in 2MPa atmosphere of hydrogen with the mixture of THF (150mL) and is warming up to 70 DEG C and is stirred overnight.Reaction After, filtering, and filter cake, filtrate decompression distillation are washed with THF (30mL), the fraction 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。

The fluoro- 2- methylpropane of the bromo- 1,1- bis- of step 4) 3-

At 0 DEG C, into DCM (150mL) solution of triphenylphosphine (10.23g, 39.00mmol) be added dropwise bromine simple substance (2mL, 39.0mmol), reaction mixture stirs 30 minutes at 0 DEG C.Then, by the fluoro- 2- methyl propyl- 1- alcohol of 3,3- (3.5g, (20mL solution is added in above-mentioned system DCM 32mmol).Reaction mixture stirs 3 hours at 0 DEG C.Then, it is evaporated under reduced pressure, The fraction for collecting 40~45 DEG C, obtaining title compound is 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。

The fluoro- 2- methylpropane -1- sodium sulfonate of step 5) 3,3- bis-

The fluoro- 2- methylpropane (850mg, 4.9133mmol) of the bromo- 1,1- bis- of 3-, sodium sulfite (2.44g, 19.4mmol) and The mixture of water (30mL) tube sealing reaction at 100 DEG C is stayed overnight.Reaction mixture is concentrated under reduced pressure.Gained residue ethyl alcohol After (60mL) dilution, 30 minutes are stirred at 50 DEG C, immediately heat filtering.Filter cake is washed with ethyl alcohol (30mL).Filtrate decompression concentration Obtaining title compound is white solid (1.6g, yield 170%).

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。

The fluoro- 2- methylpropane -1- sulfonic acid chloride of step 6) 3,3- bis-

To the fluoro- 2- methylpropane -1- sodium sulfonate (960m of 3,3- bis-_g, 4.8942mmol) THF (40mL) solution in be added DMF (0.2mL, 3mmol) and thionyl chloride (1.8mL, 25mmol).In nitrogen atmosphere, reaction mixture, which is warming up to, to be flowed back and stirs It mixes overnight.After reaction, be concentrated under reduced pressure crude product be yellow solid-liquid mixture.Crude product is without further purification It is directly used in and reacts in next step.

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

To N⁴((3R, 6S) -6- amino hexahydro furyl simultaneously [3,2-b] furans -3- base) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (254.7mg, 0.7240mmol) DCM (8mL) solution in be added TEA (1mL, 7.2mmol).Reaction mixture is cooled to 0 DEG C, by the fluoro- 2- methylpropane -1- sulfonic acid chloride (943mg, 4.896mmol) of 3,3- bis- DCM (12mL) solution be added in above-mentioned reaction system.Reaction system stirs 30 minutes at 0 DEG C, and then plus water (30mL) is quenched It goes out reaction, and is extracted with DCM (50mL × 3).Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained Residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=40/1), and obtaining title compound is that (43.9mg is produced yellow solid 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 are as follows: 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-1 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

It is added into ethyl alcohol (20mL) solution of (fluoro- 2 methyl-propyl of 2-) triflate (1.0g, 4.461mmol) Thiocarbamide (340mg, 4.467mmol).Reaction mixture is warming up to 80 DEG C and stirs 2 hours.After reaction, title is concentrated under reduced pressure to obtain 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)。

The fluoro- 2- methylpropane -1- sulfonic acid chloride of step 2) 2-

At 5 DEG C, into acetonitrile (10mL) solution of sodium sulfite (2.02g, 17.9mmol) be added concentrated hydrochloric acid (6mL, 12M).Then, at 10 DEG C, thereto be added 2- (the fluoro- 2- methyl-propyl of 2-) isothiourea trifluoromethayl sulfonic acid (1.34g, (5mL) solution 4.46mmol).Reaction mixture stirs 30 minutes at 10 DEG C, after reaction, water (30mL) is added and is quenched Reaction.Organic solvent is removed under reduced pressure at 15 DEG C, residue adds water (20mL) to dilute, and is extracted with ethyl acetate (30 × 3mL).It closes And organic phase washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, filter and be concentrated under reduced pressure title compound 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-1 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) chloro- N of -5-²(1- methyl-1 H- pyrrole Azoles -4- base) pyrimidine -2,4- diamines (220mg, 0.6254mmol) anhydrous DCM (10mL) solution in be added TEA (222mg, 2.194mmol) and DMAP (15.3mg, 0.125mmol).At -20 DEG C, by the fluoro- 2- methylpropane -1- sulfonic acid chloride of 2- (546mg, 3.1268mmol) it is added in above-mentioned reaction system.Reaction system is stirred overnight at room temperature, after reaction, is concentrated under reduced pressure.Gained Residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=50/1 to 20/1), and obtaining title compound is 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 are as follows: 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-1 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-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro furyl simultaneously [3,2-b] furans -3- base) Methanesulfonamide (150mg, 0.426mmol) THF (20mL) solution in It is added n-BuLi (hexane solution of 1.45mL, 2.5M).Reaction 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) quenching reaction.Reaction mixture is concentrated under reduced pressure, gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/ 30) it purifies, obtaining title compound is 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 are as follows: 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:

The LC/MS/MS system employed in biological test embodiment A and embodiment B of the invention includes Agilent 1200 serial vacuum degassing furnaces, binary syringe pump, orifice plate automatic sampler, column insulating box, charged spray ionize the source (ESI) Agilent G6430 three-level level four bars mass spectrograph.Wherein, quantitative analysis is carried out under MRM mode, the parameter of MRM conversion It summarizes in the following table.

Table A

Analysis uses μM column of Agilent XDB-C18,2.1 × 30mm, 3.5, injects 5 μ L samples.Analysis condition: mobile phase For 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient is summarized In the following table

Table B

In addition, the also 6330 series LC/MS/MS spectrometer of Agilent for analysis, is infused equipped with G1312A binary Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrometer uses ESI radioactive source.Use titer Suitable cationic model treatment is carried out to each analyte and MRM conversion carries out optimal analysis.It uses during analysis Capcell MP-C18 column, specification are as follows: 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 samples.

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 method:

Method 1:

People or rat liver microsomes are placed in progress duplicate hole incubation in polypropylen tubes.Typically being incubated for mixed liquor includes People or rat liver microsomes (0.5mg protein/mL), target compound (5 μM) and total volume are the NADPH (1.0mM) of 200 μ L Kaliumphosphate buffer (PBS, 100mM, pH value 7.4), compound is dissolved in DMSO, and is diluted using PBS, it is made The concentration of final DMSO solution is 0.05%.And it is incubated in the water-bath communicated at 37 DEG C with air, preincubate 3 minutes Albumen is added in backward mixed liquor and starts to react.Same volume is added in point (0,5,10,15,30 and 60min) in different times Ice-cold acetonitrile terminates reaction.With 4000rpm centrifugation 10 minutes, deproteinized is removed, collects supernatant, 100 μ L supernatants add 100 μ L water Dilution is used for sample analysis.LC/MS/MS analysis obtains sample peak area and internal standard peak area ratio, and the drug of 0min point is contained It takes temperature work 100%, calculates the relative amount of each time point drug.With " drug is opposite to be contained in GraphPad Prism 5.01 Amount " calculates the half-life period of drug to " incubation time " mapping, and then calculates inherent clearance rate.

Then the linear concentration range of each target compound, is surveyed by measurement by the method for LC/MS/MS Set the goal concentration of the compound in people or rat liver microsomes mixtures incubated.

The microsome of denaturation is used to be incubated in parallel as negative control using dextromethorphan (70 μ Μ) as positive control Educate test.Negative control is incubated at 37 DEG C, and reaction terminates for point (0,15 and 60 minute) in different times；Positive control, It is incubated at 37 DEG C, reaction terminates for point (0,5,10,15,30 and 60 minute) in different times.It is all adopted in each measuring method With positive and negative control sample, to guarantee the integrality of microsome incubation system.

Method 2:

In addition, stability data of the compound of the present invention in people or rat liver microsomes can also be obtained by following tests It arrives:

People or rat liver microsomes are placed in duplicate hole in polypropylen tubes to be incubated for.Typical mixtures incubated include people or Rat liver microsomes (ultimate density: 0.5mg albumen/mL), target compound (ultimate density: 1.5 μM) and total volume are 30 μ L K- buffer solution (contain 1.0mMEDTA, 100mM, pH 7.4).Compound is dissolved in DMSO, and dilute with K- buffer solution It releases, makes the ultimate density 0.2% of DMSO.Preincubate after ten minutes, is added 15 μ L NADPH (ultimate density: 2mM) and carries out enzyme Promote reaction, entire test carries out in 37 DEG C of incubation tube.135 μ L are added in point (0,15,30 and 60 minute) in different times Acetonitrile (containing IS) terminates reaction.With 4000rpm centrifugation 10 minutes, deproteinized is removed, 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, and reaction is in different times It terminates within point (0,15,30 and 60 minute).It all include positive control sample in each measuring method, to guarantee that microsome is incubated for body The integrality of system.

Data analysis

For each reaction, concentration (as a percentage) of the compound in people or rat liver microsomes are incubated for is pressed The plotted as percentage of opposite zero time point infers internal liver clearance rate CL with this_int(ref.:Naritomi Y, Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.).As a result referring to table 1, table 1 is compound provided in an embodiment of the present invention in people With the experimental result of stability in rat liver microsomes.

The experimental result of 1 compound provided in an embodiment of the present invention stability in people and rat liver microsomes of table

NT: it does not test

As shown in Table 1, when the compounds of this invention being incubated in people and rat liver microsomes, compound table of the present invention Reveal stability appropriate.

The medicine of embodiment B mouse, rat, dog and monkey after being injected intravenously and taking orally quantitative the compounds of this invention is for power Learn evaluation

The present invention comments the compounds of this invention in mouse, rat, dog or the intracorporal pharmacokinetic of monkey Estimate.The compounds of this invention is with aqueous solution or the aqueous solution of 2%HPMC+1% Tween-80, the saline solution of 5%DMSO+5%, and 4% MC or capsule form are administered.Intravenous injection is administered, experimental animal gives the dosage of 0.5,1 or 2mg/kg.For mouth It takes dosage (p.o.), rat and mouse are 0.5,1,5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25 at time point, It takes within 0.5,1.0,2.0,3.0,4.0,6.0,8.0,12 and 24 hour blood (0.3mL), and is centrifuged 10 at 3,000 or 4,000rpm Minute.Plasma solutions are collected, and are saved at -20 DEG C or -70 DEG C until carrying out above-mentioned LC/MS/MS analysis.The results show that When compound intravenous injection provided by the invention is administered or is administered orally, in the medicine generation that compound of the present invention has been shown, is dynamic Mechanical property, including preferably absorbing and good oral administration biaavailability.

As a result referring to table 2, table 2 is for compound provided in an embodiment of the present invention in the intracorporal medicine of rat for the experiment knot of feature Fruit.

The compound provided in an embodiment of the present invention of table 2 is in the intracorporal medicine of rat for the experimental result of feature

As shown in Table 2, when compound intravenous injection provided by the invention being administered or is administered orally, chemical combination of the present invention Object shows good pharmacokinetic property in rat body, including preferably absorbs (AUC_last) and good oral bio benefit Expenditure (F).

Embodiment C Kinase activity assays

Disclosed compound of present invention can be evaluated as the effectiveness of kinases inhibitor by following experiment.

The general description of kinase assay

Kinase assay passes through detection incorporation γ-³³The myelin basic protein (MBP) of P-ATP is come what is completed.Prepare 20 μ g/ MBP (Sigma#M-1891) trishydroxymethylaminomethane buffer salt solution (TBS of ml；50mM Tris pH 8.0,138mM NaCl, 2.7mM KCl), it is coated with white 384 orifice plate (Greiner) of high associativity, every 60 μ L of hole.It 4 DEG C, is incubated for for 24 hours.It uses later 100 μ L TBS board-washing 3 times.Kinase reaction is in kinase buffer liquid [the 5mM Hepes pH 7.6,15mM that total volume is 34 μ L NaCl, 0.01% bovine serum albumin(BSA) (Sigma#I-5506), 10mM MgCl₂, 1mM DTT, 0.02%TritonX-100] in It carries out.Compound is dissolved in DMSO, is added in each hole, the ultimate density of DMSO is 1%.Twice of each data determination, often The measurement of a compound is at least tested twice.For example, the ultimate density of enzyme is 10nM or 20nM.Addition does not have markd ATP (10 μM) and γ-³³(the every hole 2 × 10 ATP of P label⁶Cpm, 3000Ci/mmol) start to react.Reaction is shaken at room temperature Carry out 1 hour.384 orifice plates are cleaned with the PBS of 7x, and the scintillation solution of every 50 μ L of hole is then added.It is counted with Wallac Trilux Device testing result.To those of ordinary skill in the art, this is only one of numerous detection methods, and other methods are also It can.

The IC of the above-mentioned available inhibition of test method₅₀And/or inhibition constant K_i。IC₅₀It is defined as under test conditions, suppression Make compound concentration when 50% enzymatic activity.The curve comprising 10 concentration points is made using the extension rate of 1/2log, is estimated IC₅₀Value (for example, making a typical curve by following compound concentration: 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01μM、0.003μM、0.001μM、0.0003μM、0μM)。

JAK1(h)

JAK1 (h) is in 20mM Tris/HCl pH 7.5, and 0.2mM EDTA, 500 μM have amino shown in SEQ ID NO: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 to react after MgATP mixture is added.After being incubated for 40 minutes at room temperature, it is added thereto 3% phosphoric acid solution reacts to terminate.The reaction solution of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid 5 Cleaning 3 times in minute, and be put into methanol solution and save at once before dry and scinticounting.

GEEPLYWSFPAKKK (SEQ ID NO:1).

JAK2(h)

JAK2 (h) is in 8mM MOPS pH 7.0, and 0.2mM EDTA, 100 μM have amino acid sequence shown in SEQ ID NO:2 The polypeptide of column, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) existing Under the conditions of be incubated for.Start to react after MgATP mixture is added.After being incubated for 40 minutes at room temperature, 3% phosphorus is added thereto Acid solution reacts to terminate.The reaction solution of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid at 5 minutes Interior cleaning 3 times, and be put into methanol solution and save at once before dry and scinticounting.

KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (SEQ ID NO:2).

JAK3(h)

JAK3 (h) is in 8mM MOPS pH 7.0, and 0.2mM EDTA, 500 μM have amino acid sequence shown in SEQ ID NO:3 The polypeptide of column, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) existing Under the conditions of be incubated for.Start to react after MgATP mixture is added.After being incubated for 40 minutes at room temperature, 3% phosphorus is added thereto Acid solution reacts to terminate.The reaction solution of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid at 5 minutes Interior cleaning 3 times, and be put into methanol solution and save at once before dry and scinticounting.

GGEEEEYFELVKKKK (SEQ ID NO:3).

TYK2(h)

TYK2 (h) is in 8mM MOPS pH 7.0, and 0.2mM EDTA, 250 μM have amino acid sequence shown in SEQ ID NO:4 The polypeptide of column, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) existing Under the conditions of be incubated for.Start to react after MgATP mixture is added.After being incubated for 40 minutes at room temperature, 3% phosphorus is added thereto Acid solution reacts to terminate.The reaction solution of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid at 5 minutes Interior cleaning 3 times, and be put into methanol solution and save at once before dry and scinticounting.

GGMEDIYFEFMGGKKK (SEQ ID NO:4).

FLT3(h)

FLT3 (h) is in 8mM MOPS pH 7.0, and 0.2mM EDTA, 50 μM have amino acid sequence shown in SEQ ID NO:5 Polypeptide, 10mM magnesium acetate and [γ-³³P-ATP] item existing for (specific activity about 500cpm/pmol, concentration determine according to demand) It is incubated under part.Start to react after MgATP mixture is added.After being incubated for 40 minutes at room temperature, 3% phosphoric acid is added thereto Solution reacts to terminate.The reaction solution of 10 μ L is distributed on P30 filter in mottled, and in 5 minutes with 75mM phosphoric acid Cleaning 3 times, and be put into methanol solution and save at once before dry and scinticounting.

EAIYAAPFAKKK (SEQ ID NO:5).

Aurora-A(h)

For Aurora-A (h) in 8mM MOPS pH 7.0,0.2mM EDTA, 200 μM have ammonia shown in SEQ ID NO:6 The polypeptide (Kemptide) of base acid sequence, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration according to Demand determines) it is existing under the conditions of be incubated for.Start to react after MgATP mixture is added.After being incubated for 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate reaction.The reaction solution of 10 μ L is distributed on P30 filter in mottled, is used in combination 75mM phosphoric acid cleans 3 times in 5 minutes, and is put into methanol solution and saves at once before dry and scinticounting.

LRRASLG (SEQ ID NO:6).

Aurora-B(h)

For Aurora-B (h) in 8mM MOPS pH 7.0,0.2mM EDTA, 30 μM have amino shown in SEQ ID NO: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 to react after MgATP mixture is added.After being incubated for 40 minutes at room temperature, it is added thereto 3% phosphoric acid solution reacts to terminate.The reaction solution of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid 5 Cleaning 3 times in minute, and be put into methanol solution and save at once before dry and scinticounting.

AKRRRLSSLRA (SEQ ID NO:7).

Kinase assay in the present invention be completed by Millipore company, 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 based on using activity Site guidance type Competition binding assay method quantitative detection compound.The test in conjunction with three kinds of compounds by carrying out, 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 from the T7 bacteriophage bacterium for cultivating kinases label derived from BL21 bacterial strain in escherichia coli host Strain, after being in the Escherichia coli of logarithmic growth phase with T7 phage-infect, lysate is centrifuged by 32 DEG C of oscillation incubations to bacteriolyze Filtering removal cell fragment, remaining kinases go in HEK-293 cell and carry out qPCR detection with DNA marker.Streptavidin After coated particle handles 30min with biotinylated smaller ligand room temperature, affine resin can produce for kinase assay.Match Body particle is after extra biotin closing, through confining liquid (SEABLOCK^TM(Pierce), 1% bovine serum albumin(BSA), 0.05% Tween-20,1mM DTT) the unbonded ligand of cleaning, reduces non-specific binding.By 1 × combination buffer (20% SEABLOCK^TM, 0.17 × phosphate buffer solution, 0.05% polysorbas20,6mMDTT) in combine kinases, ligand is affine particle and Test compound is combined reaction, and all reactions are carried out in 96 orifice plates, and reaction final volume is 0.135mL, room temperature vibration It swings and is incubated for 1h, washing buffer (1 × phosphate buffer solution, 0.05% polysorbas20) is added and cleans affine particle, elution is added After (1 × phosphate buffer solution, 0.05% polysorbas20,0.5 μM of non-biotinylated affinity ligand) is resuspended in buffer, room temperature vibration It swings and is incubated for 30min, the concentration of kinases in eluent is detected by qPCR.Kinase activity measurement described in the text is in the U.S. The KINOMEscan of DiscoveRx company (Albrae St.Fremont, CA 94538, USA)^TMDepartment is measured.

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

NT: it does not test

JAK1, JAK2 and FLT3 kinase assay result of 4 compound of the embodiment of the present invention of table

NT: it does not test

By table 3 and table 4 it is found that 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 swash to JAK1, Aurora-A and Aurora-B The inhibitory activity of enzyme is more significant.

Finally it should be noted that being used to implement the present invention there are also other modes.Correspondingly, the embodiment of the present invention is It will illustratively be illustrated, but be not limited to content described in the invention, it is also possible to made by within the scope of the present invention Modification or in the claims added equivalent.All publications or patent cited in the present invention will all be used as this hair Bright bibliography.

Claims (26)

1. a kind of compound is stereoisomer, the tautomerism of compound shown in formula (I) compound represented or formula (I) Body or pharmaceutically acceptable salt,

Wherein,

Z¹For H, C₁-C₆Alkyl；

A is pyrazolyl, optionally by 1,2 or 3 R⁴Replaced group；

R¹For H, F, Cl, Br, CN, NO₂、C₁-C₄Alkyl or C₁-C₄Alkoxy；

R²For H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Cycloalkanes Base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(4-7 atom The heterocycle of composition) ,-NR^6aR⁶ⁱ,-OC (=O) R^6d、-N(R^6e) C (=O) R^6d、-N(R^6e) C (=O) NR^6aR^6bOr-N (R^6e)S (=O)₂R^6g, wherein each C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkylamino, C₃-C₆Naphthenic base, 4-7 Former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl and-(C₁-C₃Alkylidene)-(4-7 is former molecular miscellaneous Ring group) individually optionally by 1,2 or 3 R⁸Replaced group；

Each R^2aIt is separately H, F, Cl, Br or C₁-C₄Alkyl；

R⁴For F, Cl, CN, C₁-C₄Alkyl, 4-7 former molecular heterocycle, wherein each C₁-C₄Alkyl and 4-7 atom The heterocycle of composition is individually optionally by 1,2 or 3 R⁸Replaced group；

Each R^6a、R^6bAnd R^6eIt is separately H, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, 4-7 original Molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle Base) or R^6aAnd R^6b, and together with the nitrogen-atoms that they are connected, form 4-7 former molecular heterocyclyl groups, wherein Each C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 Former molecular heteroaryl and-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle) optionally by 1,2 or 3 independence Ground is selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Halogenated alkyl, C₁-C₃Alkoxy, C₁-C₃Hydroxyl alkane Base, C₁-C₃Aminoalkyl or C₁-C₃Replaced the substituent group of alkylamino；

Each R^6dAnd R⁶ⁱIt is separately C₁-C₄Alkyl C₁-C₄Alkoxy, C₁-C₄Alkylamino, 4-7 former molecular heterocycle, The former molecular heteroaryl of phenyl or 5-6, wherein above-mentioned each group optionally by 1,2 or 3 independently selected from F, Cl, Br, CN、N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Halogenated alkyl, C₁-C₃Alkoxy, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃Replaced the substituent group of alkylamino；

Each R^6gIt independently is C₂-C₁₂Alkyl, C₂-C₁₂Alkenyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxy alkyl, C₁-C₁₂Aminoalkyl, C₁- C₁₂Halogenated alkyl, C₃-C₁₂Naphthenic base, 3-12 former molecular heterocycle, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl Base ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Naphthenic base) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocycle) ,-(C₁-C₄ Alkylidene)-(C₆-C₁₂Aryl) or-(C₁-C₄Alkylidene)-(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-C₆Halogenated alkyl, C₁-C₆ Alkoxy, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆Replaced the substituent group of alkylamino；

Each R⁸It independently is F, Cl, Br ,-OH ,-NH₂、C₁-C₄Alkyl or C₁-C₄Halogenated alkyl；With

M is 0,1 or 2.

2. a kind of compound is stereoisomer, the tautomerism of compound shown in formula (I) compound represented or formula (I) Body or pharmaceutically acceptable salt,

Wherein,

Z¹For H, C₁-C₆Alkyl；

A is pyrazolyl, optionally by 1,2 or 3 R⁴Replaced group；

R¹For H, F, Cl, Br, CN or C₁-C₄Alkyl；

R²For-N (R^6e) S (=O)₂NR^6aR^6b；

R^2aFor H, F, Cl, Br or C₁-C₄Alkyl；

R⁴For F, Cl, methyl or ethyl；

R^6aFor H, R^6bFor piperidyl, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose or piperazinyl, wherein Each piperidyl, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose and piperazinyl it is individually optional by 1,2 Or 3 independently selected from F, Cl, Br, CN ,-OH ,-NH₂、-CF₃、-CH₃Or-CH₂CH₃Substituent group replaced；

Or R^6aAnd R^6b, and together with the nitrogen-atoms that they are connected, form pyrrolidinyl or morpholinyl, wherein each pyrroles Alkyl and morpholinyl it is individually optional by 1,2 or 3 independently selected from F, Cl, Br, CN ,-OH ,-NH₂、-CF₃、-CH₃Or- CH₂CH₃Substituent group replaced；

R^6eFor H, methyl or ethyl；

M is 0,1 or 2.

3. compound according to claim 2 is the vertical of compound shown in formula (II) compound represented or formula (II) Body isomers, tautomer or pharmaceutically acceptable salt,

4. compound according to claim 1 or 2, wherein A are as follows:

Wherein, each self-structure shown in formula (A-1), (A-2) and (A-3) Individually optionally by 1 or 2 R⁴Replaced group.

5. compound according to claim 1, wherein R²For H, F, Cl, Br, I ,-NO₂、N₃、CN、C₁-C₄Alkyl, C₂-C₄ Alkenyl, C₁-C₄Alkylamino, C₃-C₆Naphthenic base, 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, phenyl, 5-6 original are molecular Heteroaryl ,-(C₁-C₂Alkylidene)-(4-7 former molecular heterocycle) ,-NR^6aR⁶ⁱ,-OC (=O) R^6d、-N(R^6e) C (=O) R^6d、-N(R^6e) C (=O) NR^6aR^6bOr-N (R^6e) S (=O)₂R^6g, wherein each C₁-C₄Alkyl, C₂-C₄Alkenyl, C₁-C₄Alkane Amino, C₃-C₆Naphthenic base, 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 and - (C₁-C₂Alkylidene)-(4-7 former molecular heterocycle) individually optionally by 1,2 or 3 R⁸Replaced group.

6. compound according to claim 1, wherein R⁴For F, Cl, methyl, ethyl, n-propyl, isopropyl, piperidyl, Pyrrolidinyl, morpholinyl or piperazinyl, wherein each methyl, ethyl, n-propyl, isopropyl, piperidyl, pyrrolidinyl, Quinoline base and piperazinyl it is individually optional by 1,2 or 3 R⁸Replaced group.

7. compound according to claim 1, wherein each R^6a、R^6bAnd R^6eIt is separately H, methyl, ethyl, positive third Base, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrroles Alkyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazole Base, pyrrole radicals, pyrazolyl, imidazole radicals or oxazolyl, wherein each methyl, ethyl, n-propyl, isopropyl, normal-butyl, different Butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, tetrahydro furan Mutter base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, 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 group replaced.

8. compound according to claim 1, wherein each R^6dAnd R⁶ⁱIt is separately methyl, ethyl, n-propyl, different Propyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl-phenyl, piperidyl, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydro- 2H- pyranose, piperazinyl, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, pyrrole radicals, pyrazolyl, imidazole radicals or evil Oxazolyl, 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 group replaced.

9. compound according to claim 1, wherein each R^6gIt independently is C₂-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl, C₁-C₆Halogenated alkyl, C₃-C₆Naphthenic base, 4-7 former molecular heterocycle, benzene Base, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Naphthenic base) ,-(C₁-C₃Alkylidene)-(4-7 atom The heterocycle of composition) ,-(C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), 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-C₃Alkyl, C₁- C₃Halogenated alkyl, C₁-C₃Alkoxy, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃Replaced the substituent group of alkylamino.

10. compound according to claim 1, wherein each R^6gIndependently be ethyl, n-propyl, isopropyl, normal-butyl, Isobutyl group, sec-butyl, tert-butyl, 3- methyl-1-butyl, 2-methyl-1-butene base, 1,2- dimethyl-1- propyl, neopentyl, third Alkenyl, 2- methylpropenyl, trifluoromethyl, methylol, ethoxy, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Phenyl, pyrrolidinyl, morpholinyl, tetrahydrofuran base, tetrahydro -2H- pyranose, piperazinyl, pyridyl group, pyrimidine radicals, is rattled away at piperidyl 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)-tetrahydro -2H- pyranose,-(C₁-C₂Alkylidene)-morpholine Base ,-(C₁-C₂Alkylidene)-piperazinyl ,-(C₁-C₂Alkylidene)-phenyl or-(C₁-C₂Alkylidene)-(5-6 is former molecular miscellaneous Aryl), 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 group replaced.

It is the compound or its stereoisomer, tautomer or pharmaceutically of one of 11. a kind of compound Acceptable salt:

It is the compound or its stereoisomer, tautomer or pharmaceutically of one of 12. a kind of compound Acceptable salt:

13. a kind of pharmaceutical composition, it includes compound described in claim 1-12 any one,

Optionally, described pharmaceutical composition further includes in pharmaceutically acceptable auxiliary material, excipient, carrier and solvent extremely Few one kind.

14. pharmaceutical composition according to claim 13, described pharmaceutical composition further includes other therapeutic agents, described Other therapeutic agents are selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 inhibitors, beta-2-adrenoreceptor agonists, cortex class Sterol, nonsteroidal GR agonist, anticholinergic drug, antihistamine, anti-inflammatory reagent, immunosuppressor, immunomodulator, use Drug in treatment atherosclerosis and at least one of drug for treating pulmonary fibrosis.

15. compound described in claim 1-12 any one or claim 13-14 any one described pharmaceutical composition exist The purposes in drug is prepared, the drug is for preventing, handling, treating or mitigating protein kinase mediated disease.

16. purposes according to claim 15, wherein the protein kinase mediated disease be JAK- mediate disease, The disease of FLT3- mediation, the disease of Aurora- mediation, proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease Disease, graft rejection.

17. purposes according to claim 16, the proliferative diseases are cancer, polycythemia vera, primary Piastrenemia or myelofibrosis.

18. purposes according to claim 17, the cancer is acute myelocytic leukemia, the white blood of chronic myeloid Disease or acute lymphoblastic leukemia.

19. purposes according to claim 16, the autoimmune disease is Chronic Obstructive Pulmonary Disease, asthma, system Property lupus erythematosus, skin lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, psoriasis or type-1 diabetes mellitus.

20. purposes according to claim 16, the anaphylactia be respiratory anaphylactic disease, nasosinusitis, eczema, Morbilli, food hypersenstivity or insect venom allergies.

21. purposes according to claim 16, the inflammatory disease is inflammatory bowel disease, rheumatoid arthritis, juvenile form Arthritis or psoriasis arthropathica.

22. purposes according to claim 21, the inflammatory bowel disease is Crohn disease.

23. purposes according to claim 16, the graft rejection is organ-graft refection, tissue transplantation rejection or cell Graft rejection.

24. compound described in claim 1-12 any one or claim 13-14 any one described pharmaceutical composition exist The purposes in drug is prepared, the drug is used for the activity of regulatory protein kinases.

25. purposes according to claim 24, wherein the protein kinase is that jak kinase, FLT3 kinases and Aurora swash At least one of enzyme.

26. purposes according to claim 24, wherein the protein kinase be JAK1 kinases, Aurora-A kinases and At least one of Aurora-B kinases.