CN106478607A - Heteroaryl compound replacing and combinations thereof and purposes - Google Patents

Abstract

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

Description

Heteroaryl compound replacing and combinations thereof and purposes

Invention field

The invention belongs to drug world and in particular to a class as kinase activity inhibitor noval chemical compound, prepare them Method, the pharmaceutical composition comprising described compound and described compound and its pharmaceutical composition treating multiple difference diseases Application in disease.More specifically, compound of the present invention can as jak kinase family (include JAK1, JAK2, JAK3 and TYK2), FLT3 kinases (also referred to as FLK-2) and Aurora A (including Aurora-A, Aurora-B and Aurora-C) Activity or function inhibitor.

Background of invention

Protein kinase family comprises the related enzyme of a big class formation, and they control intracellular various signal transduction processes, Usually contain 250-300 similar amino acid catalytic domain, the phosphorylation of catalysis target proteins matter substrate.According to records, many diseases Sick with protein kinase mediated abnormal cell response is relevant.These diseases include optimum He pernicious proliferative disease, immunity Disease that the inappropriate activation of system leads to, allograft rejection, transplanting versus-host disease, autoimmune disease, inflammatory Disease, osteopathia, metabolic disease, sacred disease and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, A Er Ci Haimo disease and hormone related condition.Correspondingly, medicinal chemistry arts make a large amount of effort, can be used as effective albumen using searching The compound of kinase inhibitor.

Kinases can be divided into multiple families according to the difference of the substrate of phosphorylation.Tyrosine phosphorylation is to the various biologies of regulation Process such as cell proliferation, migration, differentiation and existence play vital action receptor and nonreceptor tyrosine kinase man Race controls above-mentioned biological process：Catalytic phosphatase is transferred to the tyrosine residue of particular target protein from ATP.At present, really Recognize each kinase families above-mentioned corresponding motif (Hanks et al., FASEB J., 1995,9,576-596；Knighton et.al.,Science,1991,253,407-414；Garcia-Bustos en al.EMBO J.,1994,13:2352- 2361).Example in protein kinase family includes but is 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..

Wherein, Aurora A family is a class serine/threonine kinase, its be mitotic crucial adjust because Son, is necessary for the accurate and equal separation (segtion) from blast cell to the genomic material of daughter cell.Aurora swashs The member of enzyme family includes the relevant kinases of three classes, referred to as Aurora-A, Aurora-B and Aurora-C (also referred to as Aurora- 1st, Aurora-2 and Aurora-3).

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

Aurora-B be a kind of to accurate chromosome isolation, cytokinesiss, protein localization to centromere and silk Grain, correct micro-pipe-centromere adheres to and adjusts the chromosomin that Mitotic checkpoint plays pivotal role.Aurora-B is first First during early stage localization in chromosome, then during prometaphase and mid-term localization between the sister chromatids in Centromere area (Zeitlin SG, et al., J.Cell Biol., 2001；155:1147-1157).Aurora-B participates in establishing The orientation of chromosome, wherein sisters' centromere connect to the opposite pole of the two poles of the earth spindle via double orientation attachment.In mitosiss In the stage, the Main Function of Aurora-B is to repair incorrect micro-pipe-centromere attachment (Hauf S, et al., J.Cell Biol.,2003,161:281-294；Ditchfield C,et al.,J.Cell Biol.,2003,161:267-280；Lan W,et al.,Curr.Biol.,2004,14:273-286.).In the case of Aurora-B inactivation, mitosiss are damaged Bad, cause aneuploid cell quantity to increase, genic instability and tumor occur (Weaver BA, et al., Cancer Cell,2005,8:7-12).Aurora-B suppression causes the biology that chromosome is adhered to, cannot be realized to abnormal centromere-micro-pipe to take To, cytokinesiss failure (Goto H, et al., J Biol.Chem., 2003,278:8526-8530；Severson AF,et al.,Curr.Biol.,2000,10:1162-1171).The mitotic repetitive cycling not including the exception of cytokinesiss is drawn Rise huge polyploidy and ultimately result in apoptosis (Hauf S, et al., J.Cell Biol., 2003,161:281- 94；Ditchfield C,et al.,J.Cell Biol.,2003,161:267-80；Giet R,et al.,J.Cell Biol.,2001；152:669-82；Murata-Hori M,Curr.Biol.,2002,12:894-899；Kallio M J,et al.,Curr.Biol.,2002,12:900-905).

Verified Aurora overexpression and multiple malignant proliferative disorders, such as rectal cancer, breast carcinoma, pulmonary carcinoma, cancer of pancreas, front Row adenocarcinoma, bladder cancer, head and neck cancer, cervical cancer, ovarian cancer, hepatocarcinoma and gastric cancer etc. are closely related, excite and are developed for cancer The interest of the Aurora inhibitor for the treatment of.In normal cell, Aurora-A suppression cause delay but and non-blacked mitosiss, The centrosome separation defect of one pole mitosis spindle and cytokinesiss failure (Marumoto T, et al., J.Biol.Chem.,2003,278:51786-51795).In three-type-person's class pancreatic carcinoma (Panc- Ι, Μ Ι Α PaCa- In 2dnSU.86.86), Aurora-A inhibitor shows challenging antitumous effect, result display Aurora-A suppression Agent can suppress tumor cell growth and, the tumorigenicity in murine xenogralt almost all eliminate (Hata T, et al.,Cancer Res.,2005,65:2899-2905).

FLT3 (the related 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 forms, and comprises the extracellular ligand-binding domain of five immunoglobulinses structure compositions, cross-film (TM) domain, nearly film (JM) domain With Cytoplasm C- terminal tyrosine kinases (TK) domain.(Agnes F,et al.Gene,l994,145:283-288；Scheijen B,et al.,Oncogene,2002,21:3314-3333).

The part of FLT3 was cloned in 1993, showed according to the study, and it is that Hematopoietic marrow microenvironment cell includes bone marrow Expression in fibroblast and other cells type I transmembrane protein (Lyman SD, et al., Cell, 1993,75, 1157-1167).The tyrosine kinase activity of film combination and soluble form equal energy activated receptor simultaneously stimulates the ancestral in bone marrow and blood Cell growth.The zygotic induction receptor dimer of ligand-receptor, and activated protein kinase domain；Then its autophosphorylation be catalyzed each Plant the substrate protein phosphorylation of signal transduction pathway, such as signal transduction and Activator protein 5 (STAT5), RAS/ mitogen The protein kinase (RAS/MAPK) of activation, phosphoinositide 3-kinase (PI3K), Src be of the same race and glue protogene (SHC), contains The inositol -5- phosphatase (SHIP) of SH2 and the cytoplasmic tyrosine phosphoric acid with 2 Src- homologys 2 (SH2) domain (SHP2) Enzyme, its 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).Except hemopoietic is thin Outside born of the same parents, FLT3 gene also in Placenta Hominiss, gonad and brain expression (Maroc N, et al., Oncogene, 1993,8:909- 918) and play a significant role in immunne response (deLapeyriere O.et al., Leukemia, 1995,9:1212- 1218).

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

Increasing evidence shows that polytype leukemia and myeloproliferative syndrome have the prominent of tyrosine kinase Become.FLT3 mutation is one of most frequent mutation in AML, occurs in about 1/3 patient.Two are described in leukaemic The FLT3 mutation of type.These include a series of internal series-connections in the generation from inhibition nearly film domain and replicate (ITD) (Nakao M,et al.,Leukemia,1996,10:1911-1918；Thiede C et al.,Blood,2002,99: 4326-4335), it is mutated with activation cycle, it includes Asp835Tyr (D835Y), Asp835Val (D835V), Asp835His (D835H), Asp835Glu (D835E), Asp835Ala (D835A), Asp835Asn (D835N), Asp835 disappearance and Ile836 Disappearance (Yamamoto Y, et al., Blood, 2001,97:2434-2439；Abu-Duhier FM,et al., Br.J.Haematol.,2001,113:983-988).Internal series-connection in JM domain replicates (ITD) mutation and contributes in AML about The FLT3 Activating mutations of 17-34%.Also detect that FLT3-ITD low frequency is mutated in myelodysplastic syndrome (MDS) (Yokota S.,et al.,Leukemia,l997,11:1605-1609；Horiike S,et al.,Leukemia,1997, 11:1442-1446).FLT3-ITD and FLT3-Asp835 mutation is all relevant with the phosphorylation of FLT3 autophosphorylation and downstream targets (Mizuki M,et al.,Blood,2000,96:3907-3914；Mizuki M,et al.,Blood,2003,101:3164- 3173；HayakawaF,et al.,Oncogene,2000,19:624-631).

At present, the recurrence that there is FLT3 mutation in the FLT3 inhibitor grinding as some or all or obstinate AML patient's Monotherapy has been enter into clinical trial.Generally, these as shown by datas FLT3 can be used to be developed for treat AML relevant with other The therapeutic targets of the kinase inhibitor of disease.

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

It is currently, there are mammal JAK family member known to four kinds：(Janus swashs for JAK1 (Janus kinases -1), JAK2 Enzyme -2), JAK3 (Janus kinases, leukocyte；JAKL；L-JAK and Janus kinases -3) and TYK2 (protein tyrosine kinase 2). JAK1, JAK2 and TYK2 are wide expression, and JAK3 is reported in NKT (NK) cell and preferentially expresses, and not at 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 to the signal transduction of some I types and II cytokines.Its γ with I cytokines receptor The signal transduction of public chain (IFN-γ) interferon, and the signal by the IL-10 family member of II cytokines receptor Transduction is all critically important.Functionally and physiologically with I type interferon (for example, genetic biology research display, JAK1 IFNalpha), II type interferon (for example, IFNgamma), IL-2 with IL-6 cytokine receptor complex are related.Further Ground, demonstrates this kinases in IFN to the sign of the tissue from JAK1 knock-out mice, IL-IO, IL-2/IL-4 and IL-6 lead to Pivotal role in road.

JAK1 expression in cancer cell can promote individual cells atrophy, potentially make them flee from tumor, be transferred to body Other positions of body.By the cytokine of JAK1 transduction signal, the raising of its level involves substantial amounts of immunity and inflammation disease Disease.JAK1 or JAK family kinase inhibitors can be used for adjusting or treat these diseases (Kisseleva et al., 2002, Gene 285:1-24；Levy et al.,2005,Nat.Rev.Mol.Cell Biol.,3:651-662).The people of targeting IL-6 path Resource monoclonal antibody (Torr pearl monoclonal antibody Tocilizumab) is ratified to close to severe rheumatoid for treating moderate by EU Committee Section 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 race member is relevant.JAK2 signal is activated in the downstream of hprl receptor.Research shows in myeloproliferative In the disease such as disease such as polycythemia vera, primary thrombocytosiss and idiopathic myelofibrosis, generally deposit It is mutated (JAK2V617F) in the JAK2 of acquired activation.The JAK2 albumen of mutation can be in the situation not having cytokine to stimulate Lower activation downstream signal, leads to spontaneous growth and/or the allergy to cytokine, and it is considered the process to these diseases Play a part promotion.The more multimutation of JAK2 functional disorder or transposition is led to be found in (Ihle in other malignant tumor J.N.and Gilliland D.G.,Curr.Opin.Genet.Dev.,2007,17:8；Sayyah J.and Sayeski P.P.,Curr.Oncol.Rep.,2009,11:117).JAK2 inhibitor has described as has effect to proliferative disease (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 mainly expresses in immunocyte, and by the tyrosine phosphorus of interleukin-2-receptor Acidifying activation, transduction signal.Due to being limited to express JAK3 in hematopoietic stem cell, with respect to other JAKs, it is in cytokine more Effect in signal transduction is stricter.The mutation of JAK3 can 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 path of JAK3 mediation has been used for treating immunosuppressant indication (for example, transplant rejection and rheumatoid arthritiss) (Baslund et al.,2005,Arthritis&Rheumatism 52:2686-2692；Changelian et al., 2003,Science 302:875-878).

TYK2 and IFN-α, IL-6, IL-10 and IL-12 signal transduction is related.Biochemical research and knock out mice Disclose the important function in immunology for the TYK2.TYK2 deficient mice energy growth and breeding, but show panimmunity defect, main If infection is existed hypersensitivity and in terms of oncological surveillance existing defects.Contrary, suppression TYK2 can improve opposing allergy, Autoimmune and the ability of inflammatory diseasess.Especially, targeting TYK2 seems to become treatment IL-12-, IL-23- or I type IFN- is situated between The innovative strategy of the disease led.Described disease includes but is not limited to rheumatoid arthritiss, multiple sclerosis, lupus, silver bits Disease, psoriasis arthropathica, inflammatory bowel, uveitis, sarcoidosises, and cancer (Shaw, M.et al., Proc.Natl.Acad.Sci.,USA,2003,100,11594-11599；Ortmann,R.A.,and Shevach, E.M.Clin.Immunol,2001,98,109-118；Watford et al,Immunol.Rev.,2004,202:139).

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

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

Therefore, whole four members of JAK/STAT path, particularly JAK family, are considered in asthma reaction, chronic resistance Plug property pneumonopathy, works in bronchitis, and other related pathogenesis of lower respiratory tract inflammatory disease.JAK/STAT leads to Road equally (includes, but not limited to iritis, tunica uvea in ocular inflammatory disease (diseases)/disease (conditions) Inflammation, scleritis, conjunctivitis) and chronic anaphylaxis reaction in work.Because the JAK that cytokine applies various multi-forms swashs Enzyme (O'Sullivan et al., Mol.Immunol, 2007,44:2497；Murray J.,Immunol,2007,178: 2623), in antagonism family different choice jak kinase, to treat the related disease of the specific cells factor or JAK/STAT lead to In road, the disease of variability or polymorphism correlation is probably useful.

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

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

Know clearly, kinases inhibitor gathers as new immunosuppressant, antiinflammatory dual function medicine and anticancer medicine Numerous concerns are collected.Therefore, the suppression protein kinase such as novel agent of Aurora A, FLT3 kinases and jak kinase or improvement examination Agent is needed for a long time, and it can be as the immunosuppressant of organ transplantation, antitumor agent it can also be used to prevent and treat autoimmune Disease (for example, multiple sclerosis, psoriasises, rheumatoid arthritiss, asthma, type i diabetes, inflammatory bowel, Crow grace Disease, polycythemia vera, primary thrombocytosiss, myelofibrosises, autoimmune thyroid disease, A Erzi sea Silent disease), it is related to the disease (for example, eczema) of overactivity inflammatory reaction, allergy, chronic obstructive pulmonary disease, bronchitis, cancer (for example, carcinoma of prostate, acute myeloid leukemia, chronic granulocytic leukemia, acute lymphoblastic leukemia, white blood Disease, multiple myeloma) and the immunoreation (for example, erythra, contact dermatitis or diarrhoea) that causes of other treatment, etc..This The compound of invention description, compositionss and method directly correspond to these to be needed and other purposes.

Abstract of invention

The invention provides a class suppression, regulation and/or one or more protein kinase of regulation and control, such as jak kinase, FLT3 swash Enzyme and the compound of Aurora A activity, for treating proliferative disease, autoimmune disease, anaphylactic disease, inflammatory disease Disease, transplant rejection and their complication.Present invention provides the method preparing these compounds, using these chemical combination Thing treats mammal, the especially method of the above-mentioned disease of the mankind, and the pharmaceutical composition comprising these compounds.This Bright compound and combinations thereof possesses preferable potential applicability in clinical practice.Compared with existing similar compound, the change of the present invention Compound has more preferable pharmacologically active, medicine for property, physicochemical property and/or toxicological characteristics.Specifically, the compounds of this invention pair Kinase targets show preferable inhibitory activity and the Kinase Selectivity optimizing.Additionally, the compounds of this invention also have more excellent Membrane permeability, be suitable to local and be administered, and dissolubility is preferably, therefore has more excellent druggability.

Specifically：

In a first aspect of the present invention, the present invention relates to compound as shown in formula (I) for the one kind or compound shown in formula (I) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or it before Medicine,

Wherein,

Z is C₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂The miscellaneous bicyclic group of the former molecular spiral shell of condensed-bicyclic alkyl, 7-12 or 7-12 Individual former molecular condense miscellaneous bicyclic alkyl, wherein, Z is by 1,2,3,4 or 5 R²Group is replaced；

Z¹For H, C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, described each C₁-C₁₂ Alkyl, C₃-C₁₂Cycloalkyl and 3-12 former molecular heterocyclic radical are individually optionally by 1,2,3,4 or 5 R^2aGroup is replaced；

A is

R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^9aR^9b、- OR^9c,-C (=O) OR^9c,-C (=O) NR^9aR^9bOr-S (=O)₂NR^9aR^9b, wherein, described each C₁-C₁₂Alkyl, C₁-C₁₂Alcoxyl Base, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl and 5-12 are individual former Molecular heteroaryl is individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R²It independently is F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂,-C (=O) CH₂CN ,-NHC (=O) CH₂CN、- N(CH₃) C (=O) CH₂CN、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl, 3-12 Former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^10aR^10b、-O-(C₀-C₄Alkylidene)- R^10c、-O-(C₁-C₄Alkylidene)-OR^10c,-C (=O) R^10d,-OC (=O) R^10d、-N(R^10e) C (=O) R^10d,-C (=O) NR^10aR^10b、-N(R^10e) C (=O) NR^10aR^10b,-C (=O) N (R^10e) C (=O) R^10d,-S (=O)₂R^10f、-N(R^10e) S (=O)₂R^10fOr-S (=O)₂NR^10aR^10b, or, two adjacent R²And together with the atom being connected with them, form C₃-C₁₂Cycloalkyl Or 3-12 former molecular heterocycloalkyl, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂ Alkoxyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl and 3-12 former molecular heterocycloalkyl is individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R^2aIt independently is H, F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂ Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl or 5-12 atom composition Heteroaryl, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl, 3- 12 former molecular heterocyclic radicals, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl and 3-12 former molecular heterocycle alkane Base group is individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

R³For H, C₃-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl Base, wherein, described each C₃-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical and 5-12 former molecular heteroaryl Base is individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

R⁴For C₁-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂- C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, Wherein, R⁴Optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R⁵、R⁶、R⁷And R⁸It is separately H, C₁-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁- C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl or 5-12 former molecular heteroaryl, wherein, described each C₁-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂ Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl and 5- 12 former molecular heteroaryls are individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R^3a、R^4a、R^5a、R^6a、R^7aAnd R^8aIt is separately H, F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂ Alkynyl, C₁-C₁₂Alkoxyl, C₁-C₁₂Alkylamino ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 Individual former molecular heterocyclic radical), C₆-C₁₂Aryl or 5-12 former molecular heteroaryl, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₁-C₁₂Alkylamino ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀- C₄Alkylidene)-(3-12 former molecular heterocyclic radical), C₆-C₁₂Aryl and 5-12 former molecular heteroaryl are individually optional Ground is by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R^9a、R^9b、R^9c、R^10a、R^10b、R^10cAnd R^10eIt is separately H, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 Former molecular heterocyclic radical) ,-(C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) or-(C₀-C₄Alkylidene)-(5-12 is former molecular Heteroaryl), or R^9aAnd R^9b, R^10aAnd R^10bAnd together with the nitrogen-atoms being connected with them, form 3-12 former molecular heterocycle Base group, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl ,-(C₀- C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₀-C₄Alkylidene)- (C₆-C₁₂Aryl) ,-(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl) and 3-12 former molecular heterocyclic radical base Roll into a ball optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Alkyl halide Base, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent group of alkylamino is replaced；

Each R^10dAnd R^10fIt is separately C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂ Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)- (C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Virtue Base) or-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl), wherein, above-mentioned each group is optionally by 1,2,3 or 4 Independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxyl alkane Base, C₁-C₆Aminoalkyl or C₁-C₆The substituent group of alkylamino is replaced；

Each R¹¹It independently is F, Cl, Br, I, CN ,-NO₂、N₃、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Haloalkyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical, 5-12 atom composition Heteroaryl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Alkylamino, C₁-C₁₂Alkoxyl, C₁-C₁₂Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)- (C₃-C₁₂Cycloalkyl) ,-NH (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-NH (C₀-C₄Alkylidene)-(3-12 is former molecular Heterocyclic radical) ,-NH (C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-N [(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkanes Base)]₂、-N[(C₀-C₄Alkylidene)-(C₆-C₁₂Aryl)]₂、-N[(C₀-C₄Alkylidene)-(3-12 former molecular heterocycle Base)]₂、-N[(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl)]₂、-O-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkanes Base) ,-O- (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-O- (C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) or- O-(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl)；With

Each m independently is 0,1 or 2.

In some embodiments, Z be the miscellaneous bicyclic group of the former molecular spiral shell of 8-11 or 8-10 former molecular condense Miscellaneous bicyclic alkyl, wherein, Z is by 1,2,3 or 4 R²Group is replaced.

In other embodiments, Z is following subformula:

Or their stereoisomer, wherein, each X, X ', X²And X³It is separately-CH₂- ,-NH- or-O-, condition It is, X²And X³It is not simultaneously-O-；Each minor structure shown in formula (Z-1)～(Z-54) or its stereoisomer are independently by 1,2 Or 3 R²Group is replaced.

In other embodiments, Z is following subformula：

Or their stereoisomer, wherein, each minor structure shown in formula (Z-55)～(Z-73) or its stereoisomer Independently by 1,2 or 3 R²Group is replaced.

In some embodiments, Z¹For H, C₁-C₆Alkyl, C₃-C₆Cycloalkyl or 4-7 former molecular heterocyclic radical, its In, described each C₁-C₆Alkyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are optionally by 1,2 or 3 R^2aGroup institute Replace.

In some embodiments, R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₆Alkyl, C₁-C₆Alkoxyl, C₂-C₆ Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical ,-NR^9aR^9b、-OR^9c,-C (=O) OR^9c,-C (= O)NR^9aR^9bOr-S (=O)₂NR^9aR^9b, wherein, described each C₁-C₆Alkyl, C₁-C₆Alkoxyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃- C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are individually optionally by 1,2 or 3 R¹¹Group is replaced.

In other embodiments, each R²It independently is H, F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂,-C (=O) CH₂CN ,-NHC (=O) CH₂CN、-N(CH₃) C (=O) CH₂CN、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alkoxyl, C₃-C₆Cycloalkanes Base, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-NR^10aR^10b、-O-(C₀-C₃Alkylidene)- R^10c、-O-(C₁-C₃Alkylidene)-OR^10c,-C (=O) R^10d,-OC (=O) R^10d、-N(R^10e) C (=O) R^10d,-C (=O) NR^10aR^10b、-N(R^10e) C (=O) NR^10aR^10b,-C (=O) N (R^10e) C (=O) R^10d,-S (=O)₂R^10f、-N(R^10e) S (=O)₂R^10fOr-S (=O)₂NR^10aR^10b, or, two adjacent R²And together with the atom being connected with them, form C₃-C₆Cycloalkyl or 4-7 former molecular heterocycloalkyl, wherein, described each C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alkoxyl, C₃-C₆Cycloalkanes The individual former molecular heterocyclic radical of base, 4-7, phenyl, 5-6 former molecular heteroaryl and 4-7 former molecular Heterocyclylalkyl Group is individually optionally by 1,2 or 3 R¹¹Group is replaced；

Each R^2aIt independently is H, F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alkane Epoxide, C₃-C₆The individual former molecular heterocyclic radical of cycloalkyl, 4-7, phenyl or 5-6 former molecular heteroaryl.

In some embodiments, R³For H, C₃-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Amino alkane Base, C₂-C₆Thiazolinyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, its In, described each C₃-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Aminoalkyl, C₂-C₆Thiazolinyl, C₃-C₆Cycloalkanes Base, phenyl, 4-7 former molecular heterocyclic radical and 5-6 former molecular heteroaryl are individually optionally by 1,2 or 3 R¹¹Base Group is replaced.

In other embodiments, R³For H ,-CH₂C(CH₃)₂OH、-(CH₂)₂CH₂OH、-CH₂CH(OH)CH₃, piperidines Base, pyrrolidinyl, morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, pyrrole radicals or oxazolyl, Wherein, described each piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, thiazolyl, pyrrole radicals and Oxazolyl is individually optionally by 1,2 or 3 R¹¹Group is replaced.

In some embodiments, R⁴For C₁-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Amino alkane Base, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical or 5-6 are individual former molecular Heteroaryl, wherein, R⁴Optionally by 1,2 or 3 R¹¹Group is replaced.

In other embodiments, each R⁵、R⁶、R⁷And R⁸It is separately H, C₁-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Aminoalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocycle Base, phenyl or 5-6 former molecular heteroaryl, wherein, described each C₁-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Alkyl halide Base, C₁-C₆Aminoalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆The individual former molecular heterocyclic radical of cycloalkyl, 4-7, phenyl and 5-6 Individual former molecular heteroaryl is individually optionally by 1,2 or 3 R¹¹Group is replaced.

In some embodiments, each R^3a、R^4a、R^5a、R^6a、R^7aAnd R^8aIt is separately H, F, Cl, CN, C₁-C₆Alkane Base, C₂-C₆Thiazolinyl, C₁-C₆Alkoxyl, C₁-C₆Alkylamino ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀-C₃Alkylidene)- (4-7 former molecular heterocyclic radical), phenyl or 5-6 former molecular heteroaryl, wherein, described each C₁-C₆Alkyl, C₂-C₆ Thiazolinyl, C₁-C₆Alkoxyl, C₁-C₆Alkylamino ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀-C₃Alkylidene)-(4-7 Former molecular heterocyclic radical), a phenyl and 5-6 former molecular heteroaryl is individually optionally by 1,2 or 3 R¹¹Group is taken Generation.

In other embodiments, each R^9a、R^9b、R^9c、R^10a、R^10b、R^10cAnd R^10eIt is separately H, C₁-C₆Alkane Base, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkoxyl, C₃-C₆Cycloalkyl ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀- C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₀-C₃Alkylidene)-phenyl or-(C₀-C₃Alkylidene)-(5-6 is former Molecular heteroaryl), or R^9aAnd R^9b, R^10aAnd R^10bAnd together with the nitrogen-atoms being connected with them, form 4-7 atom group The heterocyclyl groups becoming, wherein, described each C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkoxyl, C₃-C₆Cycloalkanes Base ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical), 4-7 former Molecular heterocyclyl groups ,-(C₀-C₃Alkylidene)-phenyl and-(C₀-C₃Alkylidene)-(5-6 former molecular heteroaryl) Optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent group of alkylamino is replaced.

In other embodiments, each R^9a、R^9b、R^9c、R^10a、R^10b、R^10cAnd R^10eIt is separately H, methyl, second Base, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, pi-allyl, vinyl, acrylic, C₁-C₄Alkoxyl, Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl ,-methylene-cyclopropyl ,-Asia Ethyl-cyclopropyl base ,-methylene-cyclobutyl ,-ethylidene-cyclobutyl ,-methylene-cyclopenta ,-ethylidene-cyclopenta ,-methylene Base-cyclohexyl ,-ethylidene-cyclohexyl ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical), phenyl, pyridine radicals, rattle away Piperazine base, pyrimidine radicals ,-(C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), wherein, Described methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, pi-allyl, vinyl, acrylic, C₁-C₄Alkoxyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl ,-methylene- Cyclopropyl ,-ethylidene-cyclopropyl ,-methylene-cyclobutyl ,-ethylidene-cyclobutyl ,-methylene-cyclopenta ,-ethylidene-ring Amyl group ,-methylene-cyclohexyl ,-ethylidene-cyclohexyl ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical), benzene Base, pyridine radicals, pyridazinyl, pyrimidine radicals ,-(C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 is former molecular miscellaneous Aryl) optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、-CF₃,-OCH₃,-CH₂OH,- CH₂CH₂OH,-NHCH₃,-N(CH₃)₂Or-CH₂NH₂Substituent group replaced.

In some embodiments, each R^10dAnd R^10fIt is separately C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₁-C₄Alkoxyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁- C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)- Phenyl or-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), wherein, above-mentioned each group is optionally by 1,2 or 3 solely On the spot it is selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxyl alkane Base, C₁-C₃Aminoalkyl or C₁-C₃The substituent group of alkylamino is replaced.

In other embodiments, each R^10dAnd R^10fIt is separately methyl, ethyl, n-pro-pyl, isopropyl, positive fourth Base, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, pi-allyl, vinyl, acrylic, benzene Base, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, C₁-C₄Alkoxyl ,-methylene-cyclopropyl ,-ethylidene-cyclopropyl ,-Asia Methyl-cyclobutyl ,-ethylidene-cyclobutyl ,-methylene-cyclopenta ,-ethylidene-cyclopenta or-methylene-cyclohexyl or-Asia Ethyl-cyclohexyl, wherein, above-mentioned each group optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、- CF₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N(CH₃)₂Or-CH₂NH₂Substituent group replaced.

In other embodiments, each R¹¹It independently is F, Cl, Br, I, CN ,-NO₂、N₃、-OH、-NH₂, methyl, second Base, n-pro-pyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, methylol, ethoxy, methylamino, Dimethylamino or aminomethyl.

In a second aspect of the present invention, the present invention relates to compound as shown in formula (II) for the one kind or chemical combination shown in formula (II) The stereoisomer of thing, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or it before Medicine,

Wherein,

W is C₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂The miscellaneous bicyclic group of the former molecular spiral shell of condensed-bicyclic alkyl, 7-12 or 7-12 Individual former molecular condense miscellaneous bicyclic alkyl, wherein, W is by 1,2,3,4 or 5 R¹⁴Group is replaced；

W₁For H, C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Aminoalkyl, C₁-C₆Hydroxy alkyl, C₃- C₆Cycloalkyl or 4-7 former molecular heterocyclic radical；

R¹²For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂The individual former molecular heteroaryl of aryl, 5-12 ,- NR^15aR^15b、-OR^15c,-C (=O) OR^15c,-C (=O) NR^15aR^15bOr-S (=O)₂NR^15aR^15b, wherein, described each C₁-C₁₂Alkane Base, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Virtue Base and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R¹⁷Group is replaced；

Each R¹³It independently is H, F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₁-C₁₂Alkoxyl ,-(C₀-C₄Alkylidene)- (C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical), C₆-C₁₂Aryl or 5-12 atom group The heteroaryl becoming, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₁-C₁₂Alkoxyl ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Ring Alkyl) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical), C₆-C₁₂Aryl and 5-12 former molecular heteroaryl Base is individually optionally by 1,2,3,4 or 5 R¹⁷Group is replaced；

Each R¹⁴It independently is F, Cl, Br, I, NO₂、N₃、CN、C₃-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxyl Base alkyl, C₃-C₁₂Alkoxyl, C₁-C₁₂Alkylamino, C₁-C₁₂Aminoalkyl, C₃-C₁₂Cycloalkyl, 4-7 former molecular heterocycle Base, C₆-C₁₂Aryl, 6- cyano group pyridazine -3- base,-CH₂CN、-CH₂CH₂CN ,-C (=O) R^16d,-S (=O)₂R^16e,-C (=O) NR^16aR^16b,-S (=O)₂NR^16aR^16b,-C (=O) O-R^16c、-N(R^16a) C (=O) R^16f、-N(R^16a) S (=O)₂R^16gOr-OC (=O) R^16f, wherein, described each-CH₂CN、-CH₂CH₂CN、C₃-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxyl alkane Base, C₃-C₁₂Alkoxyl, C₁-C₁₂Alkylamino, C₁-C₁₂Aminoalkyl, C₃-C₁₂The individual former molecular heterocyclic radical of cycloalkyl, 4-7, C₆-C₁₂Aryl and 6- cyano group pyridazine -3- base are individually optionally by 1,2,3,4 or 5 R¹⁷Group is replaced；

Each R^15a、R^15b、R^15c、R^16aAnd R^16bIt is separately H, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃- C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₀Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylene Base)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆- C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl), or, R^15aAnd R^15b, and be connected with them Nitrogen-atoms together, form 3-12 former molecular heterocyclyl groups, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂- C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₀The individual former molecular heteroaryl of aryl, 5-12 ,- (C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylene Base)-(C₆-C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) optionally by 1,2 or 3 independently Selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁-C₄Hydroxyl alkane Base, C₁-C₄Aminoalkyl and C₁-C₄The substituent group of alkylamino is replaced；

Each R^16d、R^16eAnd R^16gIt is separately C₂-C₁₂Alkyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocycle Base, C₆-C₁₀Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylene Base)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₀Aryl) or-(C₁-C₄Alkylidene)-(5-12 Individual former molecular heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl, C₁-C₄Aminoalkyl or C₁-C₄ The substituent group of alkylamino is replaced；

Each R^16cAnd R^16fIt is separately C₁-C₃Alkyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆- C₁₀Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3- 12 former molecular heterocyclic radicals) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 atom group Become heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、 C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl, C₁-C₄Aminoalkyl or C₁-C₄The taking of alkylamino Replaced for base；

Each R¹⁷It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₃-C₆Cycloalkyl, C₆-C₁₂Aryl, 4-7 former molecular heterocyclic radical, 5-12 former molecular heteroaryl Base, C₁-C₆Aminoalkyl, C₁-C₆Alkylamino, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)-(C₃-C₆Ring Alkyl) ,-NH (C₀-C₄Alkylidene)-(4-7 former molecular heterocyclic radical) ,-N [(C₀-C₄Alkylidene)-(C₃-C₆Cycloalkyl) ]₂、-N[(C₀-C₄Alkylidene)-(4-7 former molecular heterocyclic radical)]₂、-O(C₀-C₄Alkylidene)-(C₃-C₆Cycloalkyl) or-O (C₀-C₄Alkylidene)-(4-7 former molecular heterocyclic radical)；With

N is 0,1 or 2.

In some embodiments, W be the miscellaneous bicyclic group of the former molecular spiral shell of 8-11 or 8-10 former molecular condense Miscellaneous bicyclic alkyl, wherein, W is by 1,2,3 or 4 R¹⁴Group is replaced.

In some embodiments, W is following subformula：

Or their stereoisomer, wherein, each Y, Y ', Y²And Y³It is separately-CH₂- ,-NH- or-O-, condition It is Y²And Y³It is asynchronously-O-；Each minor structure shown in formula (W-1)～(W-51) or its stereoisomer are independently by 1,2 or 3 Individual R¹⁴Group is replaced.

In other embodiments, W is following subformula：

Or their stereoisomer, wherein, each minor structure shown in formula (W-52)～(W-70) or its stereoisomer Independently by 1,2 or 3 R¹⁴Group is replaced.

In some embodiments, W₁For H, methyl, ethyl, n-pro-pyl, isopropyl or cyclopropyl.

In other embodiments, R¹²For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₄Alkyl, C₁-C₄Alkoxyl, C₂- C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical ,-NR^15aR^15b、-OR^15c,-C (=O) OR^15c、- C (=O) NR^15aR^15bOr-S (=O)₂NR^15aR^15b, wherein, described each C₁-C₄Alkyl, C₁-C₄Alkoxyl, C₂-C₄Thiazolinyl, C₂-C₄ Alkynyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are individually optionally by 1,2 or 3 R¹⁷Group is replaced.

In some embodiments, each R¹³It independently is H, F, Cl, CN, C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₁-C₄Alcoxyl Base ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) or-(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical), and wherein, institute State each C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₁-C₄Alkoxyl ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) and-(C₀-C₃Alkylidene)- (4-7 former molecular heterocyclic radical) is individually optionally by 1,2 or 3 R¹⁷Group is replaced.

In other embodiment party's schemes, each R¹⁴It independently is F, Cl, Br, I ,-NO₂、N₃、CN、C₃-C₆Alkyl, C₂-C₆Alkene Base, C₂-C₆Alkynyl, C₁-C₆Hydroxy alkyl, C₃-C₆Alkoxyl, C₁-C₆Alkylamino, C₁-C₆Aminoalkyl, C₃-C₆Cycloalkyl, 4-7 Individual former molecular heterocyclic radical, phenyl, 6- cyano group pyridazine -3- base,-CH₂CN、-CH₂CH₂CN ,-C (=O) R^16d,-S (=O)₂R^16e,-C (=O) NR^16aR^16b,-S (=O)₂NR^16aR^16b,-C (=O) O-R^16c、-N(R^16a) C (=O) R^16f、-N(R^16a) S (= O)₂R^16gOr-OC (=O) R^16f, wherein, described each-CH₂CN、-CH₂CH₂CN、C₃-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁- C₆Hydroxy alkyl, C₃-C₆Alkoxyl, C₁-C₆Alkylamino, C₁-C₆Aminoalkyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocycle Base, phenyl and 6- cyano group pyridazine -3- base are individually optionally by 1,2 or 3 R¹⁷Group is replaced.

In some embodiments, each R¹⁴It independently is F, Cl, Br, I ,-NO₂、N₃、CN、

In other embodiments, each R^15a、R^15b、R^15c、R^16aAnd R^16bIt is separately H, C₁-C₄Alkyl, C₂-C₄ Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆A cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,- (C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylene Base)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), or, R^15aAnd R^15b, and the nitrogen being connected with them Atom together, forms 4-7 former molecular heterocyclyl groups, wherein, described each C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynes Base, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylene Base)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl and- (C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、- NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl and C₁- C₃The substituent group of alkylamino is replaced.

In other embodiments, each R^16d、R^16eAnd R^16gIt is separately C₂-C₆Alkyl, C₃-C₆Cycloalkyl, 4-7 Individual former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,- (C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylidene)-(5-6 Individual former molecular heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃ The substituent group of alkylamino is replaced.

In some embodiments, each R^16cAnd R^16fIt is separately C₁-C₃Alkyl, C₃-C₆Cycloalkyl, 4-7 atom The heterocyclic radical of composition, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Sub- Alkyl)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 atom group Become heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、 C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The taking of alkylamino Replaced for base.

In a third aspect of the present invention, the present invention proposes a kind of pharmaceutical composition.According to a particular embodiment of the invention, Described pharmaceutical composition comprises pharmaceutically acceptable adjuvant, excipient, carrier, solvent or combinations thereof further.

In other embodiments, described pharmaceutical composition further comprises other therapeutic agents, and described other are controlled Treat agent and be selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 (PDE4) inhibitor, beta-2-adrenoreceptor agonists, cortex class Sterin, nonsteroidal GR agonist, anticholinergic, antihistaminic, anti-inflammatory reagent, immunosuppressant, immunomodulator, use In the atherosclerotic medicine for the treatment of, for treating at least one of medicine of pulmonary fibrosiss.

In a fourth aspect of the present invention, the present invention relates to compound disclosed by the invention or pharmaceutical composition are preparing medicine In purposes, described medicine be used for prevent, process, treat or mitigate protein kinase mediated disease.

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

In other embodiments, protein kinase mediated disease of the present invention is proliferative disease, autologous exempts from Epidemic disease, anaphylactic disease, inflammatory diseasess or transplant rejection.

In other embodiments, protein kinase mediated disease of the present invention is cancer, polycythemia vera Disease, primary thrombocytosiss, acute myeloid leukemia, acute lymphoblastic leukemia, myelofibrosises, acute Myelocytic leukemia, chronic granulocytic leukemia, acute lymphoblastic leukemia, chronic obstructive pulmonary disease, asthma, it is System property lupus erythematosus, skin lupus erythematosuss, lupus nephritis, dermatomyositiss, sjogren syndrome, psoriasises, type i diabetes, exhale Inhale road anaphylactic disease, sinusitis, eczema, measles, food anaphylaxiss, insect venom allergies, inflammatory bowel, Crohn disease, class wind Wet arthritis, juvenile arthritises, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplantation row Scold.

In a fifth aspect of the present invention, the present invention relates to compound disclosed by the invention or pharmaceutical composition are preparing medicine In purposes, described medicine be used for regulatory protein kinases activity.

In some embodiments, protein kinase of the present invention is selected from jak kinase, FLT3 kinases, Aurora A At least one of.

In some embodiments, protein kinase of the present invention is specifically for JAK1, AuroraA or Aurora B kinases At least one of.

In a sixth aspect of the present invention, the present invention relates to formula (I) and the preparation of compound shown in formula (II), separation and purification Method.

According to embodiments of the invention, inventor is found by biologic test, and the compound that the present invention provides has albumen Kinase inhibiting activity, can be used as preferable kinases inhibitor.

It should be noted that arbitrary embodiment of the either side of the present invention, can carry out with other embodiments Combination, as long as they are not in contradiction.Additionally, in arbitrary embodiment of either side of the present invention, Ren Yiji Art feature goes for this technical characteristic in other embodiments, as long as they are not in contradiction.

In addition, it is necessary to explanation, content noted earlier only outlines certain aspects of the invention, but is not limited to these Aspect.The content of these aspects and other aspect is made more specific complete description below.

Detailed description of the invention book

Definition and general terms

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

It will further be appreciated that some features of the present invention, it is clearly visible, carry out in multiple independent embodiments Description is but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity, Single embodiment is described but it is also possible to individually or with the sub-portfolio being arbitrarily suitable for provide.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents according to the present invention and public publication are integrally incorporated this by reference Bright.

Unless otherwise indicated it should application is used herein obtains following definition.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by.

In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or the spy describing with reference to this embodiment or example Point is contained at least one embodiment or the example of the present invention.In this manual, to the schematic representation of above-mentioned term not Identical embodiment or example must be directed to.And, the specific features of description, structure, material or feature can be in office Combine in an appropriate manner in one or more embodiments or example.Additionally, in the case of not conflicting, the skill of this area The feature of the different embodiments described in this specification or example and different embodiment or example can be tied by art personnel Close and combine.

There are unless otherwise stated or in context obvious conflict, article " " used herein, " one (kind) " " described " is intended to including " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (being 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 described embodiment using or use.

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

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

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

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

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

" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror image relationship.

" diastereomer " refers to the stereoisomerism of two or more chiral centres and its molecule not mirror image each other Body.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereomer mixes Compound can be by high resolution analysises operation as electrophoresis and chromatograph, and such as HPLC is separating.

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

Many organic compound are existed with optical active forms, and that is, they have makes the plane of linearly polarized light rotate Ability.When describing optically active compound, represent molecule with regard to one or more handss using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for linearly polarized light rotation caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix be (+) or the compound of d be dextrorotation.A kind of specific stereoisomerism Body is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50 of enantiomer:50 mixture Referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or stereospecificity when, May occur in which this situation.

Any asymmetric atom (for example, carbon etc.) of the open compound of the present invention can be enriched with raceme or enantiomer Presented in, for example (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excessive.

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

The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomer, diastereomer, for example, by chromatography and/or fractional crystallization Method.

With known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art Familiar method splits into optical antipode, e.g., by carrying out to its diastereoisomeric salt obtaining separating.Racemic product Thing can also be separated by chiral chromatogram, e.g., using the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomer can be prepared by asymmetric synthesis, for example, refers 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 Tong Guo the mental retardation with different-energy builds (low Energy barrier) mutual inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical equilibrium of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include migrating, by proton, the mutual inversion of phases to carry out, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electronss Lai The mutual inversion of phases carrying out.The instantiation of ketoenol tautomerization is pentane -2,4- diketone and 4- hydroxyl amyl- 3- alkene -2- ketone is mutual The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One of phenol-keto tautomerism is specifically real Example is pyridine -4- alcohol and the change of pyridine -4 (1H) -one tautomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.

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

In general, " substituted " hydrogen atom representing that one or more of given structure can be substituted of term is concrete Substituent group is replaced.Unless other aspects show, a group replacing can have a substituent group, and in group, each may replace Position replaced.When in given structural formula, more than one position can be selected from one or more replacements of concrete group Base is replaced, then substituent group can replace in each position identical or differently.

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

Term " optional " or " optionally " mean event described later or environment can but need not occur, should The occasion occurring or not occurring including this thing or environment is described.For example, " heterocyclic group optionally being replaced by alkyl " meaning Taste alkyl can but necessarily exist, this explanation includes scene that heterocyclic group replaced by alkyl and heterocyclic group not by alkyl The scene replacing.

Term " optionally by ... replace ", can be exchanged with term " unsubstituted or quilt ... replaces " and use, that is, Described structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group bag of the present invention Include, but be not limited to D, F, Cl, Br, I, CN, N₃、-NO₂、-OH、-SH、-NH₂,-C (=O) CH₂CN ,-NHC (=O) CH₂CN、-N (CH₃) C (=O) CH₂CN、-NR^10aR^10b,-C (=O) R^10d,-OC (=O) R^10d,-C (=O) OR^10c、-N(R^10e) C (=O) R^10d,-C (=O) NR^10aR^10b、-N(R^10e) C (=O) NR^10aR^10b,-C (=O) N (R^10e) C (=O) R^10d,-S (=O)₂R^10f、-N (R^10e) S (=O)₂R^10f,-S (=O)₂NR^10aR^10b, alkyl, haloalkyl, thiazolinyl, alkynyl, alkoxyl, hydroxy alkyl, alkane sulfur Base, alkylamino, aminoalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl etc., wherein, R^10a、R^10b、R^10c、R^10d、R^10eAnd R^10f There is definition as described in the present invention.

In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode that adopted in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can be exchanged, and all should be interpreted broadly, It both may refer in different groups, does not affect mutually it is also possible to table between same-sign between expressed concrete option Show in identical group, do not affect mutually between expressed concrete option between same-sign.

In each several part of this specification, the substituent group of the open compound of the present invention is open according to radical species or scope.Special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “C₁-C₆Alkyl " refers in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each several part of the present invention, describe connect substituent.When this structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if this structure needs linking group and for this The Markush group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connecting or arylene group.

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

The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-pro-pyl (n- Pr、-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,- CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), the tert-butyl group (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), 2- amyl group (- CH (CH₃)CH₂CH₂CH₃), 3- amyl group (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 3- methyl isophthalic acid-butyl (- CH₂CH₂CH(CH₃)₂), 2- first Base -1- butyl (- CH₂CH(CH₃)CH₂CH₃), n-hexyl (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- hexyl (- CH (CH₃) CH₂CH₂CH₂CH₃), 3- hexyl (- CH (CH₂CH₃)(CH₂CH₂CH₃)), 2- methyl -2- amyl group (- C (CH₃)₂CH₂CH₂CH₃), 3- first Base -2- amyl group (- CH (CH₃)CH(CH₃)CH₂CH₃), 4- methyl -2- amyl group (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- penta Base (- C (CH₃)(CH₂CH₃)₂), 2- methyl -3- amyl group (- CH (CH₂CH₃)CH(CH₃)₂), 2,3- dimethyl -2- butyl (- C (CH₃)₂CH(CH₃)₂), 3,3- dimethyl -2- butyl (- CH (CH₃)C(CH₃)₃), n-heptyl, n-octyl, etc..

Obtained by term " alkylidene " expression removes two or more hydrogen atoms from the straight or branched alkyl of saturation The bivalence of saturation or polyvalent hydrocarbon radical.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.Real at some Apply in scheme, alkylidene group contains 1-6 carbon atom；In other embodiments, to contain 1-4 carbon former for alkylidene group Son；In other embodiments, alkylidene group contains 0-4 carbon atom；Also in some embodiments, alkylidene group Containing 0-3 carbon atom；Also in other embodiments, alkylidene group contains 1-3 carbon atom.Alkylidene contains 0 Carbon atom refers to that alkylidene does not exist, and it is directly a singly-bound.The example of alkylidene includes methylene (- CH₂-), ethylidene (-CH₂CH₂-), isopropylidene (- CH (CH₃)CH₂-) etc..

Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp²Double bond, wherein, described alkenyl group can optionally be retouched by one or more present invention The substituent group stated is replaced, and it includes " cis " and the positioning of " tans ", or the positioning of " E " and " Z ".In some embodiments In, alkenyl group comprises 2-8 carbon atom；In other embodiments, alkenyl group comprises 2-6 carbon atom；Another In a little embodiments, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH =CH₂), pi-allyl (- CH₂CH=CH₂) etc..Described alkenyl group can optionally be described by one or more present invention Substituent group is replaced.

Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is carbon-to-carbon sp tri- key, wherein, described alkynyl group can optionally be retouched by one or more present invention The substituent group stated is replaced.In some embodiments, alkynyl group comprises 2-8 carbon atom；In other embodiments, Alkynyl group comprises 2-6 carbon atom；In other embodiment, alkynyl group comprises 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 " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In some enforcements In scheme, alkoxy base contains 1-6 carbon atom；In other embodiments, to contain 1-4 carbon former for alkoxy base Son；In other embodiment, alkoxy base contains 1-3 carbon atom.Described alkoxy base can be optionally by one The substituent group that individual or multiple present invention describe is replaced.

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

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

Term " hydroxy alkyl " and " hydroxy alkoxy base " represent alkyl or alkoxyl, depend on the circumstances, one or more Oh group is replaced, and wherein, " hydroxy alkyl " and " hydroxyalkyl " can exchange use, and such example comprises, but does not limit In methylol (- CH₂OH), ethoxy (- CH₂CH₂OH,-CH(OH)CH₃), hydroxymethoxy (- OCH₂OH), etc..

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

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

Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprise 3-12 annular atom, unit price or Multivalence, saturation or partly undersaturated, nonaromatic monocyclic, bicyclic or tricyclic system, wherein at least one annular atom selects From nitrogen, sulfur and oxygen atom.Unless otherwise indicated, heterocyclic radical can be carbon-based or nitrilo, and-CH₂- group can be optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.Heterocyclic radical includes the heterocyclic radical of saturation (i.e.：Heterocyclylalkyl) and partly undersaturated heterocyclic radical.The reality of heterocyclic radical Example includes, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 1- pyrrolin Base, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydro Furyl, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, two thiophenes Alkyl, thiophene alkyl, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase (e.g., Isosorbide-5-Nitrae- Oxygen azepineBase, 1,2- oxygen azepineBase), diazaBase (e.g., Isosorbide-5-Nitrae-diazaBase, 1,2- diazaBase), dioxaBase (e.g., Isosorbide-5-Nitrae-dioxaBase, 1,2- dioxaBase), sulfur azepineBase is (as 1,4- sulfur azepineBase, 1,2- sulfur azepineBase), indoline base, 1,2,3,4- tetrahydro isoquinolyl, 1,3- benzodioxole base, 2- oxa- -5- azabicyclo [2.2.1] Hept- 5- base, 2- azaspiro [4.4] nonyl, 1,6- dioxo spiro [4.4] nonyl, 2- azaspiro [4.5] decyl, 8- nitrogen Miscellaneous spiral shell [4.5] decyl, 7- azaspiro [4.5] decyl, 3- azaspiro [5.5] undecyl, 2- azaspiro [5.5] hendecane Base, octahydro -1H- isoindolyl, octahydro Pentamethylene. simultaneously [c] pyrrole radicals, hexahydro furyl simultaneously [3,2-b] furyl and ten dihydro isoquinolines Quinoline base, etc..- CH in heterocyclic radical₂- group is included, but not limited to 2- oxo-pyrrolidine base, oxygen by the example of-C (=O)-replacement Generation -1,3- thiazolidinyl, 2- piperidone base and 3,5- dioxy piperazine piperidinyl.In heterocyclic radical, the oxidized example of sulphur atom includes, But be not limited to, sulfolane base, 1,1- dioxothiomorpholinyl, 1,1- dioxotetrahydro thienyl and 1,1- dioxotetrahydro- 2H- thiapyran base, etc..Described heterocyclyl groups can optionally be taken by one or more substituent groups described in the invention Generation.

In some embodiments, heterocyclic radical is 3-8 former molecular heterocyclic radical, refer to comprise 3-8 annular atom, Unit price or multivalence, saturation or partly undersaturated, nonaromatic monocyclic, wherein at least one annular atom be selected from nitrogen, sulfur and Oxygen atom.Unless otherwise indicated, 3-8 former molecular heterocyclic radical can be carbon-based or nitrilo, and-CH₂- group can be optional Ground is by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally by It is oxidized to N- oxygen compound.The example of 3-8 former molecular heterocyclic radical includes, but are not limited to：Azelidinyl, oxa- ring fourth Base, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazoles Alkyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulfur cyclopenta, four Hydrogen pyranose, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Piperazinyl, dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptane Base, oxygen azepineBase, diazaBase, sulfur azepineBase, etc..- CH in heterocyclic radical₂- group is by the example bag of-C (=O)-replacement Include, but be not limited to, 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base and 3,5- dioxy piperazine piperidinyl, etc.. In heterocyclic radical, the oxidized example of sulphur atom includes, but not limited to sulfolane base and 1,1- dioxothiomorpholinyl.Described 3-8 former molecular heterocyclyl groups can optionally be replaced by one or more substituent groups described in the invention.

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

In other embodiments, heterocyclic radical is 7-12 former molecular heterocyclic radical, refers to comprise 7-12 ring former Son, unit price or multivalence, saturation or partly the miscellaneous bicyclic group of undersaturated spiral shell, condense miscellaneous bicyclic group or the miscellaneous bicyclic group of bridge, wherein At least one annular atom is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, 7-12 former molecular heterocyclic radical can be carbon-based Or nitrilo, and-CH₂- group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxidation Thing.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.The example of 7-12 former molecular heterocyclic radical includes, but It is not limited to：Indoline base, 1,2,3,4- tetrahydro isoquinolyl, 1,3- benzodioxole base, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, 2- azaspiro [4.4] nonyl are (as 2- azaspiro [4.4] nonane -4- base, 2- azaspiro [4.4] nonyl Alkane -2- base), 1,6- dioxo spiro [4.4] nonyl is (as 1,6- dioxo spiro [4.4] nonane -9- base, 1,6- dioxo spiro [4.4] nonane -4- base), 2- azaspiro [4.5] decyl (e.g., 2- azaspiro [4.5] decane -8- base, 2- azaspiro [4.5] last of the ten Heavenly stems Alkane -2- base), 7- azaspiro [4.5] decyl is (as 7- azaspiro [4.5] decane -2- base, 7- azaspiro [4.5] decane -8- Base), 3- azaspiro [5.5] undecyl (e.g., 3- azaspiro [5.5] hendecane -3- base, 3- azaspiro [5.5] hendecane -9- Base), 2- azaspiro [5.5] undecyl, 8- azaspiro [4.5] decyl, Decahydroisoquinolinpreparation base, octahydro -1H- isoindolyl (e.g., octahydro -1H- iso-indoles -5- base, octahydro -1H- iso-indoles -7- base), octahydro Pentamethylene. simultaneously [c] pyrrole radicals (e.g., octahydro ring Pentane simultaneously [c] pyrroles -5- base, octahydro Pentamethylene. simultaneously [c] pyrroles -2- base), hexahydro furyl simultaneously [3,2-b] furyl (e.g., hexahydro Furo [3,2-b] furan -2- base, hexahydro furyl simultaneously [3,2-b] furan -3- base) and ten dihydro-isoquinoline bases.Described 7-12 Individual former molecular heterocyclyl groups can optionally be replaced by one or more substituent groups described in the invention.

In other embodiment, heterocyclic radical is the miscellaneous bicyclic group of the former molecular spiral shell of 7-12, refers to comprise 7-12 Annular atom, unit price or multivalence, saturation or the partly miscellaneous bicyclic group of undersaturated, nonaromatic spiral shell, wherein at least one ring Atom is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, the miscellaneous bicyclic group of the former molecular spiral shell of 7-12 can be carbon-based or nitrogen Base, and-CH₂- group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxide. The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.The miscellaneous bicyclic group of described 7-12 former molecular spiral shell comprises 7- The miscellaneous bicyclic group of spiral shell of 12 former molecular saturations is (i.e.：The miscellaneous bicyclic alkyl of the former molecular spiral shell of 7-12) and partly undersaturated The miscellaneous bicyclic group of spiral shell.The example of the miscellaneous bicyclic group of the former molecular spiral shell of 7-12 includes, but are not limited to：2- azaspiro [4.4] nonyl (as 2- azaspiro [4.4] nonane -4- base, 2- azaspiro [4.4] nonane -2- base), 1,6- dioxo spiro [4.4] nonyl are (such as 1,6- dioxo spiro [4.4] nonane -9- base, 1,6- dioxo spiro [4.4] nonane -4- base), 2- azaspiro [4.5] decyl (e.g., 2- azaspiro [4.5] decane -8- base, 2- azaspiro [4.5] decane -2- base), 7- azaspiro [4.5] decyl are (as 7- nitrogen Miscellaneous spiral shell [4.5] decane -2- base, 7- azaspiro [4.5] decane -8- base), 3- azaspiro [5.5] undecyl (e.g., 3- azaspiro [5.5] hendecane -3- base, 3- azaspiro [5.5] hendecane -9- base), 2- azaspiro [5.5] undecyl, 8- azaspiro [4.5] decyl, etc..The miscellaneous bicyclic group group of described 7-12 former molecular spiral shell can optionally be sent out by one or more Bright described substituent group is replaced.

Also in other embodiments, heterocyclic radical is the miscellaneous bicyclic group of the former molecular spiral shell of 8-11, refers to comprise 8-11 Individual annular atom, unit price or multivalence, saturation or the partly miscellaneous bicyclic group of undersaturated, nonaromatic spiral shell, wherein at least one Annular atom is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, the miscellaneous bicyclic group of the former molecular spiral shell of 8-11 can be carbon-based or nitrogen Base, and-CH₂- group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxide. The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.The miscellaneous bicyclic group of described 8-11 former molecular spiral shell comprises 8- The miscellaneous bicyclic group of spiral shell (the miscellaneous bicyclic alkyl of the former molecular spiral shell of 8-11) of 11 former molecular saturations and partly undersaturated spiral shell Miscellaneous bicyclic group.The example of the miscellaneous bicyclic group of the former molecular spiral shell of 8-11 includes, but are not limited to：2- azaspiro [4.4] nonyl is (such as 2- azaspiro [4.4] nonane -4- base, 2- azaspiro [4.4] nonane -2- base), 1,6- dioxo spiro [4.4] nonyl is (as 1,6- Dioxo spiro [4.4] nonane -9- base, 1,6- dioxo spiro [4.4] nonane -4- base), 2- azaspiro [4.5] decyl (e.g., 2- Azaspiro [4.5] decane -8- base, 2- azaspiro [4.5] decane -2- base), 7- azaspiro [4.5] decyl is (as 7- azaspiro [4.5] decane -2- base, 7- azaspiro [4.5] decane -8- base), 3- azaspiro [5.5] undecyl (e.g., 3- azaspiro [5.5] Hendecane -3- base, 3- azaspiro [5.5] hendecane -9- base), 2- azaspiro [5.5] undecyl, 8- azaspiro [4.5] decane Base, etc..The miscellaneous bicyclic group group of described 8-11 former molecular spiral shell can be optionally by one or more described in the invention Substituent group replaced.

Also in other embodiment, heterocyclic radical be 7-12 former molecular condense miscellaneous bicyclic group, refer to comprise 7- 12 annular atoms, unit price or multivalence, saturation or partly undersaturated, nonaromatic condense miscellaneous bicyclic group, wherein at least One annular atom is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, former molecular to condense miscellaneous bicyclic group can be carbon to 7-12 Base or nitrilo, and-CH₂- group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxygen Compound.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.Described 7-12 former molecular condense miscellaneous bicyclic What base comprised 7-12 former molecular saturation condenses miscellaneous bicyclic group (i.e.：7-12 is former molecular to condense miscellaneous bicyclic alkyl) and Partly undersaturated condense miscellaneous bicyclic group.The 7-12 former molecular example condensing miscellaneous bicyclic group includes, but are not limited to：Octahydro Cyclopenta simultaneously [c] pyrrole radicals, octahydro -1H- isoindolyl, indoline base, 1,2,3,4- tetrahydro isoquinolyl, 1,3- benzo two Cyclopentadienyl, hexahydro furyl simultaneously [3,2-b] furyl, hexahydro furyl simultaneously [2,3-b] furyl and ten dihydro-isoquinoline bases.Described 7- 12 former molecular to condense miscellaneous bicyclic group group and can optionally be taken by one or more substituent groups described in the invention Generation.

Term " bridge is bicyclic ", " bridged ring ", " bridge bicyclic group " and " bridged ring base " are used interchangeably herein, all referring to unit price or Multivalence, saturation or partly undersaturated nonaromatic bicyclic system, two in described member ring systems ring shares two atoms With plural singly-bound.Such system can comprise independent or conjugation unsaturated system, but its core texture 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 " is used interchangeably herein, all referring to list Valency or multivalence, saturation or partly unsaturated but nonaromatic member ring systems, two in described member ring systems ring shares a key. Such system can comprise independent or conjugation unsaturated system, but its core texture does not comprise aromatic rings or heteroaromatic (but aromatic group can be used as substituent group thereon).

Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell is bicyclic " is used interchangeably herein, refers to unit price or many Valency, saturation or partly undersaturated member ring systems, one of ring originates from specific ring carbon atom on another ring, and two Individual ring only shares an atom.For example, as under described by facial a-1 and formula a-2, the member ring systems (ring B and B ') of a saturation It is referred to as " condensed-bicyclic ", and ring A ' and ring B shares a carbon atom, is referred to as " volution " or " spiral shell is bicyclic "；Ring C ' and ring C is then It is 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 heterocycle Base, and each ring optionally replaces by one or more substituent groups described in the invention.

Term " Heterocyclylalkyl " refers to that the saturation of the unit price containing 3-12 annular atom or multivalence is monocyclic, bicyclic or three rings System, wherein at least one annular atom is selected from nitrogen, sulfur or oxygen atom.Unless otherwise indicated, Heterocyclylalkyl can be carbon-based or nitrogen Base, and-CH₂- group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxide. The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.The example of miscellaneous bicyclic alkyl includes, but are not limited to：Azetidin Base, oxetanylmethoxy, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydro-thienyl, tetrahydrofuran base, piperazine Piperidinyl, piperazinyl, morpholinyl, dialkyl group, dithiane base, isoxazolidinyl, isothiazole alkyl, 1,2- piperazine base, 1,2- thiophene Piperazine base, hexahydro-pyridazine base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase (e.g., 1, 4- oxygen azepineBase, 1,2- oxygen azepineBase), diazaBase (e.g., Isosorbide-5-Nitrae-diazaBase, 1,2- diazaBase), dioxy MiscellaneousBase (e.g., Isosorbide-5-Nitrae-dioxaBase, 1,2- dioxaBase), sulfur azepineBase (e.g., Isosorbide-5-Nitrae-sulfur azepineBase, 1,2- sulfur nitrogen MiscellaneousBase), 2- azaspiro [4.4] nonyl, 1,6- dioxo spiro [4.4] nonyl, 2- azaspiro [4.5] decyl, 8- nitrogen Miscellaneous spiral shell [4.5] decyl, 7- azaspiro [4.5] decyl, 3- azaspiro [5.5] undecyl, 2- azaspiro [5.5] hendecane Base, octahydro cyclopenta simultaneously [c] pyrrole radicals, octahydro -1H- isoindolyl, hexahydro furyl simultaneously [3,2-b] furyl, hexahydro furyl be simultaneously [2,3-b] furyl and ten dihydro-isoquinoline bases.Described heterocycloalkyl can be optionally by one or more present invention Described substituent group is replaced.

In some embodiments, Heterocyclylalkyl is 7-12 former molecular Heterocyclylalkyl, refers to containing 7-12 ring Atom, unit price or multivalence, the miscellaneous bicyclic alkyl of spiral shell of saturation, condense miscellaneous bicyclic alkyl or the miscellaneous bicyclic alkyl of bridge, wherein at least One annular atom is selected from nitrogen, sulfur or oxygen atom.Unless otherwise indicated, Heterocyclylalkyl can be carbon-based or nitrilo, and-CH₂- group Can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring are permissible Optionally it is oxidized to N- oxygen compound.Described 7-12 former molecular heterocycloalkyl can optionally by one or Multiple substituent groups described in the invention are replaced.

In some embodiments, Heterocyclylalkyl is 4-7 former molecular Heterocyclylalkyl, refers to former containing 4-7 ring Son, univalent or multivalence, the heterocyclic radical of saturation, wherein at least one annular atom is selected from nitrogen, sulfur or oxygen atom.Unless in addition said Bright, Heterocyclylalkyl can be carbon-based or nitrilo, and-CH₂- group can be optionally by-C (=O)-replacement.The sulphur atom of ring can To be optionally oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.4-7 atom composition The example of Heterocyclylalkyl include, but are not limited to：Azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, pyrazoles Alkyl, imidazolidinyl, piperidyl, piperazinyl, morpholinyl, dialkyl group, dithiane base, isoxazolidinyl, isothiazole alkyl, six Hydrogen pyridazinyl, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase and Sulfur azepineBase.4-7 described former molecular heterocycloalkyl can optionally be retouched by one or more present invention The substituent group stated is replaced.

In other embodiments, Heterocyclylalkyl is the miscellaneous bicyclic alkyl of the former molecular spiral shell of 7-12, refers to containing 7- 12 annular atoms, unit price or the miscellaneous bicyclic alkyl of spiral shell of multivalence, saturation, wherein at least one annular atom is selected from nitrogen, sulfur or oxygen Atom.Unless otherwise indicated, Heterocyclylalkyl can be carbon-based or nitrilo, and-CH₂- group can be optionally by-C (=O)-replace Generation.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxidation and close Thing.The example of the miscellaneous bicyclic alkyl of the former molecular spiral shell of 7-12 includes, but are not limited to：2- azaspiro [4.4] nonyl, 1,6- bis- Oxaspiro [4.4] nonyl, 2- azaspiro [4.5] decyl, 8- azaspiro [4.5] decyl, 7- azaspiro [4.5] decane Base, 3- azaspiro [5.5] undecyl and 2- azaspiro [5.5] undecyl, etc..7-12 described former molecular spiral shell is miscellaneous Bicycloalkyl radicals can optionally be replaced by one or more substituent groups described in the invention.

In other embodiments, Heterocyclylalkyl be 7-12 former molecular condense miscellaneous bicyclic alkyl, refer to containing 7-12 annular atom, unit price or multivalence, saturation condense miscellaneous bicyclic alkyl, wherein at least one annular atom be selected from nitrogen, sulfur Or oxygen atom.Unless otherwise indicated, Heterocyclylalkyl can be carbon-based or nitrilo, and-CH₂- group can optionally by-C (= O)-substitute.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 7-12 former molecular example condensing miscellaneous bicyclic alkyl includes, but are not limited to：Octahydro -1H- isoindolyl is (e.g., Octahydro -1H- iso-indoles -5- base, octahydro -1H- iso-indoles -7- base), octahydro Pentamethylene. simultaneously [c] pyrrole radicals (e.g., octahydro Pentamethylene. And [c] pyrroles -5- base, octahydro Pentamethylene. simultaneously [c] pyrroles -2- base), hexahydro furyl simultaneously [3,2-b] furyl (e.g., hexahydro furyl And [3,2-b] furan -2- base, hexahydro furyl simultaneously [3,2-b] furan -3- base), hexahydro furyl simultaneously [2,3-b] furyl and 12 Hydrogen isoquinoline base.Described 7-12 former molecular to condense miscellaneous bicycloalkyl radicals and can optionally be sent out by one or more Bright described substituent group is replaced.

In other embodiments, Heterocyclylalkyl be 8-10 former molecular condense miscellaneous bicyclic alkyl, refer to containing 8-10 annular atom, unit price or multivalence, saturation condense miscellaneous bicyclic alkyl, wherein at least one annular atom is selected from nitrogen, sulfur Or oxygen atom.Unless otherwise indicated, 8-10 former molecular to condense miscellaneous bicyclic alkyl can be carbon-based or nitrilo, and-CH₂- Group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring N- oxygen compound can be optionally oxidized to.The 8-10 former molecular example condensing miscellaneous bicyclic alkyl includes, but does not limit In：Octahydro -1H- isoindolyl (e.g., octahydro -1H- iso-indoles -5- base, octahydro -1H- iso-indoles -7- base), octahydro Pentamethylene. are simultaneously [c] pyrrole radicals (e.g., octahydro Pentamethylene. simultaneously [c] pyrroles -5- base, octahydro Pentamethylene. simultaneously [c] pyrroles -2- base), hexahydro furyl simultaneously [3, 2-b] furyl (e.g., hexahydro furyl simultaneously [3,2-b] furan -2- base, hexahydro furyl simultaneously [3,2-b] furan -3- base), hexahydro furyl And [2,3-b] furyl and ten dihydro-isoquinoline bases.Described 8-10 former, and molecular to condense miscellaneous bicycloalkyl radicals permissible Optionally replaced by one or more substituent groups described in the invention.

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

One or more degrees of unsaturation are contained in term " undersaturated " the expression group being used in the present invention.

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

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

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

Term " aryl " represents and contains 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double Ring and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and it is individual former that each of which member ring systems comprise 3-7 Molecular ring, and have one or more junction points to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance Ring " exchanges and uses.The example of aromatic yl group can include phenyl, naphthyl and anthryl.Described aromatic yl group can individually optionally Replaced by one or more substituent groups described in the invention.

Term " heteroaryl " represent contain 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom monocyclic, Bicyclic and three-ring system, wherein at least one member ring systems are aromatic, and at least one aromatic ring system comprises one or many Individual hetero atom, each of which member ring systems comprise 5-7 former molecular ring, and have one or more junction points and molecule remaining Partly it is connected.Term " heteroaryl " can be exchanged with term " hetero-aromatic ring " or " heteroaromaticss " and use.In some embodiment party In case, heteroaryl is to comprise 1,2,3 or 4 heteroatomic 5-12 former molecular heteroaryls being independently selected from O, S and N.? In other embodiments, heteroaryl is to comprise 1,2,3 or 4 heteroatomic 5-10 atom compositions being independently selected from O, S and N Heteroaryl.Also in some embodiments, heteroaryl is to comprise 1,2,3 or 4 heteroatomic 5-6 being independently selected from O, S and N Individual former molecular heteroaryl.Described 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- indole Base, 6- indyl, 7- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), indazolyl is (as 3- indazolyl, 4- indazolyl, 5- indazolyl, 6- indazole Base, 7- indazolyl), imidazo [1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, pyrazolo [4,3-c] pyridine radicals, pyrazoles And [3,4-b] pyridine radicals, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] Pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine radicals, etc..5-12 atom The heteroaryl groups of composition also include 5-6 former molecular single ring heteroaryl group, and the example includes, but is not limited to following Monocyclic, furyl (as 2- furyl, 3- furyl), imidazole radicals are (as 1- imidazole radicals, 2- imidazole radicals, 4- imidazole radicals, 5- imidazoles Base), isoxazolyl (as 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl), oxazolyl (as 2- oxazolyl, 4- oxazolyl, 5- oxazolyl), pyrrole radicals (as 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals), pyridine radicals are (as 2- pyridine radicals, 3- pyridine radicals, 4- Pyridine radicals), pyriconyl, pyrimidine radicals (as 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals), pyrimidine ketone group, hybar X base, rattle away Piperazine base (such as 3- pyridazinyl, 4- pyridazinyl), pyrazinyl (as 2- pyrazinyl, 3- pyrazinyl), thiazolyl are (as 2- thiazolyl, 4- thiophene Oxazolyl, 5- thiazolyl), tetrazole radical (as 5- tetrazole radical), triazolyl (as 2- triazolyl and 5- triazolyl), thienyl is (as 2- thiophene Fen base, 3- thienyl), pyrazolyl (as 1- pyrazolyl, 3- pyrazolyl, 4- pyrazolyl, 5- pyrazolyl), pyrazoline ketone group, different thiophene Oxazolyl, 1,2,3- di azoly, 1,2,5- di azoly, 1,2,4- di azoly, 1,2,3- triazolyl, 1,2,3- thio biphosphole Base, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, pyrazinyl and cyanuro 1,3,5 etc..

Term " oxazolyl " refers to comprise at least two hetero atoms and wherein at least one is nitrogen-atoms, by 5 or 9 Former molecular heteroaromatic ring systems.The example of oxazolyl include, but is not limited to pyrazolyl, imidazole radicals, oxazolyl, isoxazolyl, Di azoly, thiazolyl, isothiazolyl, thiadiazolyl group, di azoly, triazolyl, indazolyl, pyrazolo [4,3-c] pyridine radicals, pyrrole Azoles simultaneously [3,4-b] pyridine radicals, imidazo [4,5-b] pyridine radicals and 1H- benzo [d] imidazole radicals.

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

Term " alkylamino " or " alkyl amino " are used interchangeably, including " N- alkyl amino " and " N, N- dialkyl amino Base ", wherein, amino group is separately replaced by one or two alkyl group.Wherein, some embodiments are, alkane Amino is one or two C₁-C₁₂Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms.Real at other Apply in scheme, alkylamino is one or two C₁-C₆Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms. In other embodiments, alkylamino is one or two C₁-C₄Alkyl is connected to the alkyl of the lower level formed on nitrogen-atoms Amino group.Also in other embodiments, alkylamino is one or two C₁-C₃Alkyl is connected to and is formed on nitrogen-atoms Lower level alkylamino group.Suitable alkylamino radicals can be alkyl monosubstituted amino or dialkyl amido, alkylamino Example includes, but is not limited to, N- methylamino (- NHCH₃), N- ethylamino, N, N- dimethylamino (- NH (CH₃)₂), N, N- diethyl Amino, N- ethyl propyl -2- amino etc..

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

Term " aminoalkyl " includes the C being replaced by one or more amino₁-C₁₂Straight or branched alkyl group.? In some embodiments, aminoalkyl is the C being replaced by one or more amino groups₁-C₁₂Alkyl；In other embodiment party In case, aminoalkyl is the C being replaced by one or more amino groups₁-C₆" aminoalkyl of lower level ", real at other Apply in scheme, aminoalkyl is the C being replaced by one or more amino groups₁-C₄Alkyl；Also in other embodiments, Aminoalkyl is the C being replaced by one or more amino groups₁-C₃Alkyl.The example of aminoalkyl includes, but is not limited to, Aminomethyl (- CH₂NH₂), aminoethyl (- CH₂CH₂NH₂,-CH(NH₂)CH₃), aminopropyl, ammonia butyl and ammonia hexyl.

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

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

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

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

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

" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterized.Such product can be by being administered compound through peroxidating, reducing, water Solution, amidated, desamido- acts on, esterification, degreasing, and enzymatic lysises etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt of compound and the inorganic salt of the present invention.Medicine On, acceptable salt is known to us in art, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion exchange obtaining these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora 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, bitterness Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that suitable alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C₁-C₄Alkyl)₄Salt.The present invention is also intended to contemplate and appoints The quaternary ammonium salt that the compound of the group of what comprised N is formed.Water solublity or oil-soluble or dispersion product can pass through quaternized Effect obtains.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further includes The amine cation that suitable, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, sulfur Acidulants, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

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

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

" inflammatory diseasess " used in the present invention refer to the excessive inflammation being led to by inflammatory responses excessive or out of control Property symptom, host tissue infringement or function of organization any disease of losing, disorderly or symptom." inflammatory diseasess " also refer to by leukocyte Inflow and/or the pathologic state of Neutrophil chemotaxis mediation.

" inflammation " used in the present invention refers to by tissue damaged or destroys the topical protective response causing, it is used for brokenly Bad, dilute or separate (isolation) be harmful to material and impaired tissue.Inflammation flows into leukocyte and/or neutrophil cell becomes The property changed has significant contact.Inflammation can result from pathogenic organism and viral infection and non-infectious mode, the such as heart Wound after muscle infarction or apoplexy or Reperfu- sion, the immunne response to exotic antigen and autoimmune response.Therefore, it can with this The inflammatory diseasess of disclosure of the invention compounds for treating include：React with specificity system of defense and non-specific defense system reacts Related disease.

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

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

" allergy " used in the present invention refers to that any symptom, histologic lesion or the function of organization that produce allergy lose.As " arthritis disease " used in the present invention refers to damage, to be attributable to various etiologic etiological arthritis, be characterized any Disease." dermatitis " refers to be attributable to the dermatosis that various etiologic etiological scytitiss are characterized as used in the present invention Extended familys in any one." transplant rejection " refers to the function funeral with transplanting or surrounding tissue as used in the present invention The antagonism transplanting tissue that mistake, pain, swelling, leukocytosiss and thrombocytopenia are characterized, such as organ or cell (as bone marrow) Any immunoreation.The Therapeutic Method of the present invention includes the method for treating the disease related to inflammatory cell activation.

Term " cancer " and " cancer " are referred to or describe the physiology being generally characterized with cell growth out of control in patient Disease." tumor " comprises one or more cancerous cell.The example of cancer includes but is not limited to cancer (carcinoma), lymphoma, embryo Glucagonoma, sarcoma and leukemia, or malignant lymph proliferative disease (lymphoidmalignancies).Such cancer more The example of body includes squamous cell carcinoma (as epithelium squamous cell carcinoma), pulmonary carcinoma (includes small cell lung cancer, nonsmall-cell lung cancer (NSCLC), adenocarcinoma of lung and lung squamous cell carcinoma), peritoneal cancer, hepatocarcinoma (hepatocellular cancer), gastric cancer (gastric Or stomach cancer) (inclusion human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical cancer, ovarian cancer, hepatocarcinoma (liver Cancer), bladder cancer, hepatoma (hepatoma), breast carcinoma, colon and rectum carcinoma, colorectal cancer, carcinoma of endometrium or Uterus carcinoma, salivary-gland carcinoma, renal carcinoma or renal cancer (kidney or renal cancer), carcinoma of prostate, carcinoma vulvae, thyroid Cancer, liver cancer (hepatic carcinoma), anus cancer, carcinoma of penis and head and neck cancer.

The description of the compound of the present invention

The invention discloses the novel compound of a class, can as protein kinase, particularly jak kinase, FLT3 kinases and The inhibitor of Aurora A activity.Compound as kinases inhibitor can be used for treatment and unsuitable protein kinase Activity, particularly unsuitable jak kinase, the FLT3 kinases disease related with Aurora A activity, for example treat and prevent It is related to the disease of the jak kinase, FLT3 kinases and Aurora A mediation of signal path.Such disease includes proliferative disease Disease, autoimmune disease, anaphylactic disease, inflammatory diseasess, transplant rejection and their complication.Especially, of the present inventionization Compound can be used to treat following disease, and such as cancer, polycythemia vera, primary thrombocytosiss, bone marrow are fine Dimensionization, acute myeloid leukemia, acute lymphoblastic leukemia, chronic granulocytic leukemia (CML), chronic obstructive Lung disease (COPD), asthma, systemic lupus erythematosus (sle), skin lupus erythematosuss, lupus nephritis, dermatomyositiss, sjogren syndrome, Psoriasises, type i diabetes, respiratory anaphylactic disease, sinusitis, eczema, measles, food anaphylaxiss, insect venom allergies, inflammatory Enteropathy, Crohn disease, rheumatoid arthritiss, juvenile arthritises, psoriasis arthropathica, organ-graft refection, tissue move Plant repulsion, cell transplant rejection, etc..

In some embodiments, to one or more protein kinase, the open compound of the present invention shows that stronger suppression is lived Property.

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

Wherein, each Z, Z¹, A and R¹There is definition as described in the present invention.

In some embodiments, Z is C₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂Condensed-bicyclic alkyl, 7-12 atom composition The miscellaneous bicyclic group of spiral shell or 7-12 former molecular condense miscellaneous bicyclic alkyl, wherein, Z is optionally by 1,2,3,4 or 5 R²Group Replaced；

Z¹For H, C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, described each C₁-C₁₂ Alkyl, C₃-C₁₂Cycloalkyl and 3-12 former molecular heterocyclic radical are individually optionally by 1,2,3,4 or 5 R^2aGroup is replaced；

A is

R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^9aR^9b、- OR^9c,-C (=O) R^9d,-OC (=O) R^9d,-C (=O) OR^9c、-N(R^9e) C (=O) R^9d,-C (=O) NR^9aR^9b、-N(R^9e) C (= O)NR^9aR^9b,-S (=O)₂R^9f、-N(R^9e) S (=O)₂R^9fOr-S (=O)₂NR^9aR^9b, wherein, described each C₁-C₁₂Alkyl, C₁-C₁₂ Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl and 5-12 Individual former molecular heteroaryl is individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R²It independently is F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂,-C (=O) CH₂CN ,-NHC (=O) CH₂CN、- N(CH₃) C (=O) CH₂CN、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl, 3-12 Former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^10aR^10b、-O-(C₀-C₄Alkylidene)- R^10c、-O-(C₁-C₄Alkylidene)-OR^10c,-C (=O) R^10d,-OC (=O) R^10d、-N(R^10e) C (=O) R^10d,-C (=O) NR^10aR^10b、-N(R^10e) C (=O) NR^10aR^10b,-C (=O) N (R^10e) C (=O) R^10d,-S (=O)₂R^10f、-N(R^10e) S (=O)₂R^10fOr-S (=O)₂NR^10aR^10b, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃- C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl and 5-12 former molecular heteroaryl individually optional ground quilt 1st, 2,3,4 or 5 R¹¹Group is replaced；

Or, two adjacent R²And together with the atom being connected with them, form C₃-C₁₂Cycloalkyl or 3-12 atom group The heterocycloalkyl becoming, wherein, described C₃-C₁₂Cycloalkyl and 3-12 former molecular heterocycloalkyl are individually optional Ground is by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R^2aIt independently is H, F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂ Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 atom composition Heteroaryl ,-NR^10aR^10b、-O-(C₀-C₄Alkylidene)-R^10c、-O-(C₁-C₄Alkylidene)-OR^10c,-C (=O) R^10d,-OC (= O)R^10d、-N(R^10e) C (=O) R^10d,-C (=O) NR^10aR^10b、-N(R^10e) C (=O) NR^10aR^10b,-C (=O) N (R^10e) C (= O)R^10d,-S (=O)₂R^10f、-N(R^10e) S (=O)₂R^10fOr-S (=O)₂NR^10aR^10b, wherein, described each C₁-C₁₂Alkyl, C₂- C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5- 12 former molecular heteroaryls and 3-12 former molecular heterocycloalkyl are individually optionally by 1,2,3,4 or 5 R¹¹ Group is replaced；

R³For H, C₃-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl Base, wherein, described each C₃-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical and 5-12 former molecular heteroaryl Base is individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

R⁴For C₁-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂- C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, Wherein, R⁴Optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R⁵、R⁶、R⁷And R⁸It is separately H, C₁-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁- C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl or 5-12 former molecular heteroaryl, wherein, described each C₁-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂ Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl and 5- 12 former molecular heteroaryls are individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R^3a、R^4a、R^5a、R^6a、R^7aAnd R^8aIt is separately H, F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂ Alkynyl, C₁-C₁₂Alkoxyl, C₁-C₁₂Alkylamino ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 Individual former molecular heterocyclic radical), C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^9aR^9b、-OR^9c,-C (=O) R^9d、- C (=O) OR^9c、-N(R^9e) C (=O) R^9d,-C (=O) NR^9aR^9b、-N(R^9e) C (=O) NR^9aR^9b,-S (=O)₂R^9f、-N(R^9e)S (=O)₂R^9fOr-S (=O)₂NR^9aR^9b, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₁-C₁₂Alkylamino ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocycle Base), C₆-C₁₂Aryl and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R^9a、R^9b、R^9c、R^9e、R^10a、R^10b、R^10cAnd R^10eIt is separately H, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂- C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3- 12 former molecular heterocyclic radicals) ,-(C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) or-(C₀-C₄Alkylidene)-(5-12 atom group The heteroaryl becoming), wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkanes Base ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₀-C₄ Alkylidene)-(C₆-C₁₂Aryl) and-(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl) optionally by 1,2,3 or 4 Independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxyl Base alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent group of alkylamino is replaced；Or

R^9a、R^9bTogether with the nitrogen-atoms that can also and be connected with them, form 3-12 former molecular heterocyclyl groups, Wherein, described 3-12 former molecular heterocyclyl groups optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl Or C₁-C₆The substituent group of alkylamino is replaced；

R^10a、R^10bTogether with the nitrogen-atoms that can also and be connected with them, form 3-12 former molecular heterocyclyl groups, Wherein, described 3-12 former molecular heterocyclyl groups optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl Or C₁-C₆The substituent group of alkylamino is replaced；

Each R^9d、R^9f、R^10dAnd R^10fIt is separately C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alcoxyl Base, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄ Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)- (C₆-C₁₂Aryl) or-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl), wherein, above-mentioned each group optionally by 1, 2nd, 3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁- C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent group of alkylamino is replaced；

Each R¹¹It independently is F, Cl, Br, I, CN ,-NO₂、N₃、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Haloalkyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical, 5-12 atom composition Heteroaryl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Alkylamino, C₁-C₁₂Alkoxyl, C₁-C₁₂Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)- (C₃-C₁₂Cycloalkyl) ,-NH (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-NH (C₀-C₄Alkylidene)-(3-12 is former molecular Heterocyclic radical) ,-NH (C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-N [(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkanes Base)]₂、-N[(C₀-C₄Alkylidene)-(C₆-C₁₂Aryl)]₂、-N[(C₀-C₄Alkylidene)-(3-12 former molecular heterocycle Base)]₂、-N[(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl)]₂、-O-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkanes Base) ,-O- (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-O- (C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) or- O-(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl)；With

Each m independently is 0,1 or 2.

In other embodiments, Z be the miscellaneous bicyclic group of the former molecular spiral shell of 8-11 or 8-10 former molecular thick Close miscellaneous bicyclic alkyl, wherein, Z is optionally by 1,2,3 or 4 R²Group is replaced.

In some embodiments, Z is following subformula:

Or their stereoisomer, wherein, each X, X ', X²And X³It is separately-CH₂- ,-NH- or-O-, condition It is, X²And X³It is not simultaneously-O-；Each minor structure shown in formula (Z-1)～(Z-54) or its stereoisomer individually optional ground quilt 1st, 2 or 3 R²Group is replaced.

In other embodiments, Z is following subformula：

Or their stereoisomer, wherein, each minor structure shown in formula (Z-55)～(Z-73) or its stereoisomer Individually optionally by 1,2 or 3 R²Group is replaced.

In some embodiments, Z¹For H, C₁-C₆Alkyl, C₃-C₆Cycloalkyl or 4-7 former molecular heterocyclic radical, its In, described each C₁-C₆Alkyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are optionally by 1,2 or 3 R^2aGroup institute Replace.

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

In some embodiments, R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₆Alkyl, C₁-C₆Alkoxyl, C₂-C₆ Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical ,-NR^9aR^9b、-OR^9c,-C (=O) R^9d,-C (= O)OR^9c,-C (=O) NR^9aR^9b,-S (=O)₂R^9fOr-S (=O)₂NR^9aR^9b, wherein, described each C₁-C₆Alkyl, C₁-C₆Alcoxyl Base, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are individually optionally by 1,2 or 3 R¹¹ Group is replaced.

In other embodiments, each R²It independently is F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂,-C (=O) CH₂CN ,-NHC (=O) CH₂CN、-N(CH₃) C (=O) CH₂CN、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alkoxyl, C₃-C₆Cycloalkanes Base, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-NR^10aR^10b、-O-(C₀-C₃Alkylidene)- R^10c、-O-(C₁-C₃Alkylidene)-OR^10c,-C (=O) R^10d,-OC (=O) R^10d、-N(R^10e) C (=O) R^10d,-C (=O) NR^10aR^10b、-N(R^10e) C (=O) NR^10aR^10b,-C (=O) N (R^10e) C (=O) R^10d,-S (=O)₂R^10f、-N(R^10e) S (=O)₂R^10fOr-S (=O)₂NR^10aR^10b, wherein, described each C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alkoxyl, C₃-C₆Cycloalkyl, 4-7 Individual former molecular heterocyclic radical, phenyl and 5-6 former molecular heteroaryl groups are individually optionally by 1,2 or 3 R¹¹Group Replaced；

Or, two adjacent R²And together with the atom being connected with them, form C₃-C₆Cycloalkyl or 4-7 atom composition Heterocycloalkyl, wherein, described C₃-C₆Cycloalkyl and 4-7 former molecular heterocycloalkyl individually optionally by 1, 2 or 3 R¹¹Group is replaced；

Each R^2aIt independently is H, F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alkane Epoxide, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-NR^10aR^10b、-O- (C₀-C₃Alkylidene)-R^10c、-O-(C₁-C₃Alkylidene)-OR^10c,-C (=O) R^10d,-OC (=O) R^10d、-N(R^10e) C (=O) R^10d,-C (=O) NR^10aR^10b、-N(R^10e) C (=O) NR^10aR^10b,-C (=O) N (R^10e) C (=O) R^10d,-S (=O)₂R^10f、-N (R^10e) S (=O)₂R^10fOr-S (=O)₂NR^10aR^10b.

In some embodiments, R³For H, C₃-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Amino alkane Base, C₂-C₆Thiazolinyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, its In, described each C₃-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Aminoalkyl, C₂-C₆Thiazolinyl, C₃-C₆Cycloalkanes Base, phenyl, 4-7 former molecular heterocyclic radical and 5-6 former molecular heteroaryl are individually optionally by 1,2 or 3 R¹¹Base Group is replaced.

In other embodiments, R³For H ,-CH₂C(CH₃)₂OH、-(CH₂)₂CH₂OH、-CH₂CH(OH)CH₃, piperidines Base, pyrrolidinyl, morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, pyrrole radicals or oxazolyl, Wherein, described each piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, thiazolyl, pyrrole radicals and Oxazolyl is individually optionally by 1,2 or 3 R¹¹Group is replaced.

In some embodiments, R⁴For C₁-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Amino alkane Base, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical or 5-6 are individual former molecular Heteroaryl, wherein, R⁴Optionally by 1,2 or 3 R¹¹Group is replaced.

In other embodiments, each R⁵、R⁶、R⁷And R⁸It is separately H, C₁-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Aminoalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocycle Base, phenyl or 5-6 former molecular heteroaryl, wherein, described each C₁-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Alkyl halide Base, C₁-C₆Aminoalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆The individual former molecular heterocyclic radical of cycloalkyl, 4-7, phenyl and 5-6 Individual former molecular heteroaryl is individually optionally by 1,2 or 3 R¹¹Group is replaced.

In some embodiments, each R^3a、R^4a、R^5a、R^6a、R^7aAnd R^8aIt is separately H, F, Cl, CN, C₁-C₆Alkane Base, C₂-C₆Thiazolinyl, C₁-C₆Alkoxyl, C₁-C₆Alkylamino ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀-C₃Alkylidene)- (4-7 former molecular heterocyclic radical), phenyl, 5-6 former molecular heteroaryl ,-NR^9aR^9b、-OR^9c,-C (=O) R^9d、-C (=O) OR^9c,-C (=O) NR^9aR^9b,-S (=O)₂R^9fOr-S (=O)₂NR^9aR^9b, wherein, described each C₁-C₆Alkyl, C₂-C₆Alkene Base, C₁-C₆Alkoxyl, C₁-C₆Alkylamino ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀-C₃Alkylidene)-(4-7 is former Molecular heterocyclic radical), a phenyl and 5-6 former molecular heteroaryl is individually optionally by 1,2 or 3 R¹¹Group is replaced.

In other embodiments, each R^9a、R^9b、R^9c、R^9e、R^10a、R^10b、R^10cAnd R^10eIt is separately H, C₁-C₆ Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkoxyl, C₃-C₆Cycloalkyl ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,- (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₀-C₃Alkylidene)-phenyl or-(C₀-C₃Alkylidene)-(5-6 Individual former molecular heteroaryl), wherein, described each C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkoxyl, C₃-C₆Ring Alkyl ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₀-C₃ Alkylidene)-phenyl and-(C₀-C₃Alkylidene)-(5-6 former molecular heteroaryl) optionally by 1,2 or 3 independently selected from F、Cl、Br、CN、N₃、-NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁- C₃Aminoalkyl or C₁-C₃The substituent group of alkylamino is replaced；Or

R^9a、R^9bTogether with the nitrogen-atoms that can also and be connected with them, form 4-7 former molecular heterocyclyl groups, its In, described 4-7 former molecular heterocyclyl groups optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-NO₂、- OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃Alkane The substituent group of amino is replaced；

R^10a、R^10bTogether with the nitrogen-atoms that can also and be connected with them, form 4-7 former molecular heterocyclyl groups, Wherein, described 4-7 former molecular heterocyclyl groups optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、- NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁- C₃The substituent group of alkylamino is replaced.

In other embodiments, each R^9a、R^9b、R^9c、R^9e、R^10a、R^10b、R^10cAnd R^10eSeparately be H, methyl, Ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, pi-allyl, vinyl, acrylic, C₁-C₄Alcoxyl Base, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl ,-methylene-cyclopropyl ,- Ethylidene-cyclopropyl ,-methylene-cyclobutyl ,-ethylidene-cyclobutyl ,-methylene-cyclopenta ,-ethylidene-cyclopenta ,-Asia Methyl-cyclohexyl base ,-ethylidene-cyclohexyl ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical), phenyl, pyridine radicals, Pyridazinyl, pyrimidine radicals ,-(C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), its In, described methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, pi-allyl, vinyl, propylene Base, C₁-C₄Alkoxyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl ,-methylene Base-cyclopropyl ,-ethylidene-cyclopropyl ,-methylene-cyclobutyl ,-ethylidene-cyclobutyl ,-methylene-cyclopenta ,-sub- second Base-cyclopenta ,-methylene-cyclohexyl ,-ethylidene-cyclohexyl ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocycle Base), phenyl, pyridine radicals, pyridazinyl, pyrimidine radicals ,-(C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 atom group Become heteroaryl) optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、-CF₃,-OCH₃,- CH₂OH,-CH₂CH₂OH,-NHCH₃,-N(CH₃)₂Or-CH₂NH₂Substituent group replaced.

In some embodiments, each R^9d、R^9f、R^10dAnd R^10fIt is separately C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄ Alkynyl, C₁-C₄Alkoxyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl Base ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Sub- Alkyl)-phenyl or-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), wherein, above-mentioned each group is optionally by 1,2 Or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃ Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent group of alkylamino is replaced.

In other embodiments, each R^9d、R^9f、R^10dAnd R^10fIt is separately methyl, ethyl, n-pro-pyl, isopropyl Base, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, pi-allyl, vinyl, propylene Base, phenyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, C₁-C₄Alkoxyl ,-methylene-cyclopropyl ,-ethylidene-ring third Base ,-methylene-cyclobutyl ,-ethylidene-cyclobutyl ,-methylene-cyclopenta ,-ethylidene-cyclopenta or-methylene-hexamethylene Base or-ethylidene-cyclohexyl, wherein, above-mentioned each group optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、- OH、-NH₂、-CF₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N(CH₃)₂Or-CH₂NH₂Substituent group replaced.

In some embodiments, each R¹¹It independently is F, Cl, Br, I, CN ,-NO₂、N₃、-OH、-NH₂、C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical, 5-6 are individual former Molecular heteroaryl, C₁-C₄Aminoalkyl, C₁-C₄Alkylamino, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl ,-NH (C₀-C₃Alkylene Base)-(C₃-C₆Cycloalkyl) ,-NH (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-N [(C₀-C₃Alkylidene)- (C₃-C₆Cycloalkyl)]₂、-N[(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical)]₂、-O(C₀-C₃Alkylidene)-(C₃- C₆Cycloalkyl) or-O (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical).

In other embodiments, each R¹¹It independently is F, Cl, Br, I, CN ,-NO₂、N₃、-OH、-NH₂, methyl, second Base, n-pro-pyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, methylol, ethoxy, methylamino, Dimethylamino or aminomethyl.

Also in some embodiments, the present invention relates to the compound of one of or its stereoisomer, mutually Tautomeric, nitrogen oxides, solvate, pharmaceutically acceptable salt, but it is not limited to these compounds：

On the other hand, the present invention relates to the solid of compound as shown in formula (II) for the one kind or compound shown in formula (II) Isomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

Wherein, each W, W₁、R¹²、R¹³With n, there is definition as described in the present invention.

In some embodiments, W is C₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂Condensed-bicyclic alkyl, 7-12 atom composition The miscellaneous bicyclic group of spiral shell or 7-12 former molecular condense miscellaneous bicyclic alkyl, wherein, W is by 1,2,3,4 or 5 R¹⁴Group is taken Generation；

W₁For H, C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Aminoalkyl, C₁-C₆Hydroxy alkyl, C₃- C₆Cycloalkyl or 4-7 former molecular heterocyclic radical；

R¹²For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂The individual former molecular heteroaryl of aryl, 5-12 ,- NR^15aR^15b、-OR^15c,-C (=O) R^15d,-OC (=O) R^15d,-C (=O) OR^15c、-N(R^15e) C (=O) R^15d,-C (=O) NR^15aR^15b、-N(R^15e) C (=O) NR^15aR^15b,-S (=O)₂R^15f、-N(R^15e) S (=O)₂R^15fOr-S (=O)₂NR^15aR^15b, its In, described each C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 atom composition Heterocyclic radical, C₆-C₁₂Aryl and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R¹⁷Group is taken Generation；

Each R¹³It independently is H, F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₁-C₁₂Alkoxyl ,-(C₀-C₄Alkylidene)- (C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical), C₆-C₁₂Aryl, 5-12 atom composition Heteroaryl ,-NR^15aR^15b、-OR^15c,-C (=O) R^15d,-C (=O) OR^15c,-C (=O) NR^15aR^15b,-S (=O)₂R^15f、-N (R^15e) S (=O)₂R^15fOr-S (=O)₂NR^15aR^15b, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₁-C₁₂Alkoxyl ,- (C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical), C₆-C₁₂Aryl Individually optionally with the individual former molecular heteroaryl of 5-12 by 1,2,3,4 or 5 R¹⁷Group is replaced；

Each R¹⁴It independently is F, Cl, Br, I, NO₂、N₃、CN、C₃-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxyl Base alkyl, C₃-C₁₂Alkoxyl, C₁-C₁₂Alkylamino, C₁-C₁₂Aminoalkyl, C₃-C₁₂Cycloalkyl, 4-7 former molecular heterocycle Base, C₆-C₁₂Aryl, 6- cyano group pyridazine -3- base,-CH₂CN、-CH₂CH₂CN ,-C (=O) R^16d,-S (=O)₂R^16e,-C (=O) NR^16aR^16b,-S (=O)₂NR^16aR^16b,-C (=O) O-R^16c、-N(R^16a) C (=O) R^16f、-N(R^16a) S (=O)₂R^16gOr-OC (=O) R^16f, wherein, described each-CH₂CN、-CH₂CH₂CN、C₃-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxyl alkane Base, C₃-C₁₂Alkoxyl, C₁-C₁₂Alkylamino, C₁-C₁₂Aminoalkyl, C₃-C₁₂The individual former molecular heterocyclic radical of cycloalkyl, 4-7, C₆-C₁₂Aryl and 6- cyano group pyridazine -3- base are individually optionally by 1,2,3,4 or 5 R¹⁷Group is replaced；

Each R^15a、R^15b、R^15c、R^15e、R^16aAnd R^16bIt is separately H, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynes Base, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₀Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄ Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)- (C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl), and wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂ Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₀Aryl, 5-12 former molecular Heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,- (C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) optionally by 1,2 Or 3 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl, C₁-C₄Aminoalkyl and C₁-C₄The substituent group of alkylamino is replaced；Or

R^15a、R^15bTogether with the nitrogen-atoms that can also and be connected with them, form 3-12 former molecular heterocyclyl groups, Wherein, described 3-12 former molecular heterocyclyl groups optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl, C₁-C₄Aminoalkyl And C₁-C₄The substituent group of alkylamino is replaced；

Each R^15dAnd R^15fIt is separately C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl ,-(C₀- C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₀-C₄Alkylidene)- (C₆-C₁₂Aryl) or-(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl), wherein, above-mentioned each group optionally by 1, 2nd, 3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁- C₄Hydroxy alkyl, C₁-C₄Aminoalkyl or C₁-C₄The substituent group of alkylamino is replaced；

Each R^16d、R^16eAnd R^16gIt is separately C₂-C₁₂Alkyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocycle Base, C₆-C₁₀Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylene Base)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₀Aryl) or-(C₁-C₄Alkylidene)-(5-12 Individual former molecular heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl, C₁-C₄Aminoalkyl or C₁-C₄ The substituent group of alkylamino is replaced；

Each R^16cAnd R^16fIt is separately C₁-C₃Alkyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆- C₁₀Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3- 12 former molecular heterocyclic radicals) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 atom group Become heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、 C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl, C₁-C₄Aminoalkyl or C₁-C₄The taking of alkylamino Replaced for base；

Each R¹⁷It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₃-C₆Cycloalkyl, C₆-C₁₂Aryl, 4-7 former molecular heterocyclic radical, 5-12 former molecular heteroaryl Base, C₁-C₆Aminoalkyl, C₁-C₆Alkylamino, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)-(C₃-C₆Ring Alkyl) ,-NH (C₀-C₄Alkylidene)-(4-7 former molecular heterocyclic radical) ,-N [(C₀-C₄Alkylidene)-(C₃-C₆Cycloalkyl) ]₂、-N[(C₀-C₄Alkylidene)-(4-7 former molecular heterocyclic radical)]₂、-O(C₀-C₄Alkylidene)-(C₃-C₆Cycloalkyl) or-O (C₀-C₄Alkylidene)-(4-7 former molecular heterocyclic radical)；With

N is 0,1 or 2.

In other embodiments, W be the miscellaneous bicyclic group of the former molecular spiral shell of 8-11 or 8-10 former molecular thick Close miscellaneous bicyclic alkyl, wherein, W is by 1,2,3 or 4 R¹⁴Group is replaced.

In some embodiments, W is following subformula：

Or their stereoisomer, wherein, each Y, Y ', Y²And Y³It is separately-CH₂- ,-NH- or-O-, condition It is Y²And Y³It is asynchronously-O-；Each minor structure shown in formula (W-1)～(W-51) or its stereoisomer are independently by 1,2 or 3 Individual R¹⁴Group is replaced.

In other embodiments, W is following subformula：

Or their stereoisomer, wherein, each minor structure shown in formula (W-52)～(W-70) or its stereoisomer Independently by 1,2 or 3 R¹⁴Group is replaced.

In some embodiments, W₁For H, methyl, ethyl, n-pro-pyl, isopropyl or cyclopropyl.

In other embodiments, R¹²For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₄Alkyl, C₁-C₄Alkoxyl, C₂- C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical ,-NR^15aR^15b、-OR^15c,-C (=O) R^15d、-C (=O) OR^15c,-C (=O) NR^15aR^15b,-S (=O)₂R^15f, or-S (=O)₂NR^15aR^15b, wherein, described each C₁-C₄Alkyl, C₁- C₄Alkoxyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are individually optionally by 1,2 Or 3 R¹⁷Group is replaced.

In some embodiments, each R¹³It independently is H, F, Cl, CN, C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₁-C₄Alcoxyl Base ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,- NR^15aR^15b、-OR^15c,-C (=O) R^15d,-C (=O) OR^15c,-C (=O) NR^15aR^15b,-S (=O)₂R^15fOr-S (=O)₂NR^15aR^15b, wherein, described each C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₁-C₄Alkoxyl ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) With-(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) individually optionally by 1,2 or 3 R¹⁷Group is replaced.

In other embodiment party's schemes, each R¹⁴It independently is F, Cl, Br, I ,-NO₂、N₃、CN、C₃-C₆Alkyl, C₂-C₆Alkene Base, C₂-C₆Alkynyl, C₁-C₆Hydroxy alkyl, C₃-C₆Alkoxyl, C₁-C₆Alkylamino, C₁-C₆Aminoalkyl, C₃-C₆Cycloalkyl, 4-7 Individual former molecular heterocyclic radical, phenyl, 6- cyano group pyridazine -3- base,-CH₂CN、-CH₂CH₂CN ,-C (=O) R^16d,-S (=O)₂R^16e,-C (=O) NR^16aR^16b,-S (=O)₂NR^16aR^16b,-C (=O) O-R^16c、-N(R^16a) C (=O) R^16f、-N(R^16a) S (= O)₂R^16gOr-OC (=O) R^16f, wherein, described each-CH₂CN、-CH₂CH₂CN、C₃-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁- C₆Hydroxy alkyl, C₃-C₆Alkoxyl, C₁-C₆Alkylamino, C₁-C₆Aminoalkyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocycle Base, phenyl and 6- cyano group pyridazine -3- base are individually optionally by 1,2 or 3 R¹⁷Group is replaced.

In some embodiments, each R¹⁴It independently is F, Cl, Br, I ,-NO₂、N₃、CN、

In other embodiments, each R^15a、R^15b、R^15c、R^15e、R^16aAnd R^16bIt is separately H, C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl Base ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Sub- Alkyl)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), and wherein, described each C₁-C₄Alkyl, C₂-C₄Alkene Base, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁- C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)- Phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) optionally by 1,2 or 3 independently selected from F, Cl, Br, CN、N₃、-NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Amino alkane Base and C₁-C₃The substituent group of alkylamino is replaced；Or

R^15a、R^15bTogether with the nitrogen-atoms that can also and be connected with them, form 4-7 former molecular heterocyclyl groups, Wherein, described 4-7 former molecular heterocyclyl groups optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、- NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl and C₁- C₃The substituent group of alkylamino is replaced.

In some embodiments, each R^15dAnd R^15fIt is separately C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₁-C₄Alkoxyl ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀-C₃Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C₀-C₃Alkylidene)-phenyl or-(C₀-C₃Alkylidene)-(5-6 former molecular heteroaryl), and wherein, above-mentioned each base Roll into a ball optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃ Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent group of alkylamino is replaced.

In other embodiments, each R^16d、R^16eAnd R^16gIt is separately C₂-C₆Alkyl, C₃-C₆Cycloalkyl, 4-7 Individual former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,- (C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylidene)-(5-6 Individual former molecular heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃ The substituent group of alkylamino is replaced.

In some embodiments, each R^16cAnd R^16fIt is separately C₁-C₃Alkyl, C₃-C₆Cycloalkyl, 4-7 atom The heterocyclic radical of composition, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Sub- Alkyl)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 atom group Become heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、 C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The taking of alkylamino Replaced for base.

In other embodiments, each R¹⁷It independently is F, Cl, Br, I, CN ,-NO₂、N₃、-OH、-NH₂、C₁-C₄Alkane Base, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical, 5-6 Individual former molecular heteroaryl, C₁-C₄Aminoalkyl, C₁-C₄Alkylamino, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl ,-NH (C₀-C₃ Alkylidene)-(C₃-C₆Cycloalkyl) ,-NH (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-N [(C₀-C₃Alkylene Base)-(C₃-C₆Cycloalkyl)]₂、-N[(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical)]₂、-O(C₀-C₃Alkylidene)- (C₃-C₆Cycloalkyl) or-O (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical).

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 (II), tautomer, solvate, metabolism are produced Thing, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.

The open compound of the present invention can contain asymmetric or chiral centre, therefore can deposit different stereoisomer forms ?.It is contemplated that all stereoisomer forms of formula (I) and compound shown in formula (II), including but not limited to diastereomeric Isomer, enantiomer, atropisomer and geometry (or conformation) isomer, and the such as raceme mixing of their mixture Thing, becomes the ingredient of the present invention.

In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then this structure All stereoisomers all consider within the present invention, and be included in the invention as the open compound of the present invention.When Spatial chemistry is expressed the real wedge shape line (solidwedge) of particular configuration or when dotted line indicates, then the stereoisomer of this structure This clearly and is defined.

Formula (I) and compound shown in formula (II) can be existed with different tautomeric forms, and all these mutual Tautomeric, tautomer as described in the present invention, it is included within the scope of the present invention.

Formula (I) and compound shown in formula (II) can exist in a salt form.In some embodiments, described salt refers to Pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to that material or compositionss must be with the other compositions comprising preparation And/or the mammal treated with it is chemically and/or compatible in toxicology.In other embodiments, described salt differs Surely it is pharmaceutically acceptable salt, could be for preparation and/or purification formula (I) and compound shown in formula (II) and/or be used for Separate the intermediate of this formula (I) and the enantiomer of compound shown in formula (II).

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

Such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. can be included by its derivative mineral acid obtaining salt.

Can by its derivative organic acid obtaining salt include for example acetic acid, propanoic 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, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

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

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

Primary amine, secondary amine and tertiary amine can be included by its derivative organic base obtaining salt, substituted amine includes naturally occurring The amine of replacement, cyclic amine, deacidite etc..Some organic amines include, for example, 2-aminopropane., benzathine benzylpenicillin (benzathine), choline salt (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine And trometamol.

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

In addition, compound disclosed by the invention, including their salt it is also possible to their hydrate forms or comprise it The form of solvent (such as ethanol, DMSO, etc.) obtains, for their crystallization.The open compound of the present invention can be with pharmacy Upper acceptable solvent (inclusion water) inherently or passes through design forming solvate；Therefore, it is contemplated that including solvation And unsolvated form.

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

On the other hand, compound of the present invention includes the compound defined in the present invention of isotope enrichment, for example, its In there is radiosiotope, such as³H、¹⁴C and¹⁸Those compounds of F, or wherein there is non radioactive isotope, such as²H and¹³C.The compound of such isotope enrichment can be used for metabolism research and (uses¹⁴C), Reaction kinetics research are (using for example²H or³H), detection or imaging technique, as positron emission tomography (PET) or inclusion medicine or substrate tissue measure of spread SPECT (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.The formula (I) of isotope enrichment and compound shown in formula (II) can pass through this area skill Using suitable isotope marks examination described by routine techniquess familiar to art personnel or the embodiment in the present invention and preparation process Agent substitutes originally used unmarked reagent to prepare.

Additionally, higher isotope particularly deuterium is (i.e.,²H or D) replacement some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements reduce or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in the present invention is counted as formula (I) and the substituent group of compound shown in formula (II).Isotope can be used Enrichment factor is defining the concentration of such higher isotope particularly deuterium.Term " isotope enrichment factor " used in the present invention Refer to specified ratio between isotopic isotope abundance and natural abundance.If the substituent group of the compounds of this invention is referred to It is set to deuterium, this compound has at least 3500 for each D-atom specified, and (at each specified D-atom, 52.5% deuterium is mixed Enter), at least 4000 (60% deuterium mix), at least 4500 (67.5% deuterium mixes), at least 5000 (75% deuterium mixes), extremely Few 5500 (82.5% deuterium mixes), at least 6000 (90% deuterium mixes), at least 6333.3 (95% deuterium mixes), at least The same position of 6466.7 (97% deuterium mixes), at least 6600 (99% deuterium mixes) or at least 6633.3 (99.5% deuterium mixes) Plain enrichment factor.The pharmaceutically useful solvate of the present invention includes the such as D that wherein recrystallisation solvent can be that isotope replaces₂O, third Ketone-d₆、DMSO-d₆Those solvates.

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

On the other hand, the present invention relates to formula (I) and the preparation of compound shown in formula (II), separate and purification method.

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the compounds of this invention.One In a little embodiments, pharmaceutical composition of the present invention, further include pharmaceutically acceptable adjuvant, carrier, excipient, Solvent or combinations thereof.In other embodiments, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Mist dosage form.In further embodiments, comprise therapeutic agent further, described therapeutic agent is included selected from chemotherapeutics, antiproliferative, phosphorus Acid diesters enzyme 4 inhibitor, beta-2-adrenoreceptor agonists, corticosteroid, nonsteroidal GR agonist, anticholinergic, Antihistaminic, anti-inflammatory reagent, immunosuppressant, immunomodulator, it is used for treating atherosclerotic medicine, is used for treating At least one of medicine of pulmonary fibrosiss.

On the other hand, the present invention relates to treatment is subject to one or more protein kinase, such as jak kinase, FLT3 kinases and Disease or the method for disorder that Aurora A is adjusted, the present invention that described Therapeutic Method includes giving patient effective amounts comes into the open Compound or pharmaceutical composition.In some embodiments, described disease or disorderly selected from proliferative disease, autoimmune disease, Anaphylactic disease, inflammatory diseasess, transplant rejection, cancer, polycythemia vera, primary thrombocytosiss, bone marrow are fine Dimensionization, acute myeloid leukemia, chronic granulocytic leukemia, acute lymphoblastic leukemia, Chronic obstructive pulmonary disease Disease, asthma, systemic lupus erythematosus (sle), skin lupus erythematosuss, lupus nephritis, dermatomyositiss, sjogren syndrome, psoriasises, I type Diabetes, respiratory anaphylactic disease, sinusitis, eczema, measles, food anaphylaxiss, insect venom allergies, inflammatory bowel, Crow Grace disease, rheumatoid arthritiss, juvenile arthritises, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or thin Born of the same parents' transplant rejection.

On the other hand, the present invention relates to using the compounds of this invention disclosed by the invention or medicine composite for curing disease or Disorder, described disease or disorderly selected from proliferative disease, autoimmune disease, anaphylactic disease, inflammatory diseasess, transplant rejection, Cancer, polycythemia vera, primary thrombocytosiss, myelofibrosises, acute myeloid leukemia, chronic marrow Cell leukemia, acute lymphoblastic leukemia, chronic obstructive pulmonary disease, asthma, systemic lupus erythematosus (sle), skin-type are red Yabbi skin ulcer, lupus nephritis, dermatomyositiss, sjogren syndrome, psoriasises, type i diabetes, respiratory anaphylactic disease, sinusitis, Eczema, measles, food anaphylaxiss, insect venom allergies, inflammatory bowel, Crohn disease, rheumatoid arthritiss, juvenile form joint Inflammation, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplant rejection.

On the other hand, the present invention relates to compound disclosed by the invention or pharmaceutical composition are preparing the purposes of medicine, institute State medicine for preventing, processing, treat or mitigating protein kinase mediated disease.According to embodiments of the invention, described disease Selected from proliferative disease, autoimmune disease, anaphylactic disease, inflammatory diseasess, transplant rejection, cancer, polycythemia vera Disease, primary thrombocytosiss, myelofibrosises, acute myeloid leukemia, chronic granulocytic leukemia, acute pouring Bar chronic myeloid leukemia, chronic obstructive pulmonary disease, asthma, systemic lupus erythematosus (sle), skin lupus erythematosuss, lupus nephritis, Dermatomyositiss, sjogren syndrome, psoriasises, type i diabetes, respiratory anaphylactic disease, sinusitis, eczema, measles, food mistake Quick, insect venom allergies, inflammatory bowel, Crohn disease, rheumatoid arthritiss, juvenile arthritises, psoriasis arthropathica, Organ-graft refection, tissue transplantation rejection or cell transplant rejection.

On the other hand, the present invention relates to preparing medicine using the compounds of this invention disclosed by the invention or pharmaceutical composition Purposes, described medicine is used for the activity of regulatory protein kinases.According to embodiments of the invention, described protein kinase includes being selected from At least one of jak kinase, FLT3 kinases, Aurora A.

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

The present invention provides a kind of pharmaceutical composition, and it comprises the open compound of the present invention, or listed compound in embodiment； With pharmaceutically acceptable adjuvant, excipient, carrier, solvent or combinations thereof.Change in pharmaceutical composition disclosed by the invention The amount of compound refers to effectively to suppress the amount of biological specimen or protein kinase in the patient.

It will also be appreciated that some compounds of the present invention can exist for treating in a free form, or if suitably Can be presented in its pharmaceutically acceptable derivates.Some nonrestrictive enforcements of pharmaceutically acceptable derivant 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 of offer compound of the present invention or its metabolite or residue or derivant indirectly.

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

The present invention " pharmaceutically acceptable adjuvant " used means related to form of administration or pharmaceutical composition concordance Pharmaceutically acceptable material, mixture or solvent.Every kind of adjuvant must become split-phase with other of pharmaceutical composition in mixing Hold, so that the present invention openly interaction of effect of compound and can lead to not be medicine can be substantially reduced when avoiding patient be administered The interaction of acceptable pharmaceutical composition on.Additionally, every kind of adjuvant must be pharmaceutically acceptable, for example, have Sufficiently high purity.

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

Suitably pharmaceutically acceptable adjuvant includes following kind of adjuvant：Diluent, filler, binding agent, disintegrate Agent, lubricant, fluidizer, granulating agent, coating materials, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, taste masking Agent, odor mask, coloring agent, anticaking agent, wetting agent, chelating agen, plasticiser, viscosifier, antioxidant, preservative, stabilizer, Surfactant and buffer agent.Technical staff can be appreciated that, some pharmaceutically acceptable adjuvants can provide more than one function, And alternative function is provided, this depends on thering is in how many this adjuvants and preparation there are which other adjuvant in preparation.

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

In Remington:The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable compositionss are disclosed in Dekker, New York, and for its preparation Known technology, the respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any undesirable life Thing acts on, or so that any other composition in harmful way and pharmaceutically acceptable compositionss occurs to interact and the present invention Outside the incompatible any commonly employed carrier of open compound, pay close attention to its application and belong to the scope of the present invention.

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

Therefore, on the other hand, the present invention relates to preparing the technique of pharmaceutical composition, described pharmaceutical composition comprises the present invention Open compound and pharmaceutically acceptable adjuvant, excipient, carrier, solvent or combinations thereof, it is each that this technique includes mixing Plant composition.Comprise the pharmaceutical composition of the open compound of the present invention, can mix to make under such as ambient temperature and atmospheric pressure Standby.

Compound disclosed by the invention is usually formulated as being adapted to pass through the dosage form that required approach is administered to patient.Example As dosage form includes the dosage form that those are suitable for following route of administration：(1) oral administration, such as tablet, capsule, caplet agent, ball Agent, containing tablet, powder, syrup, elixir, suspensoid, solution, Emulsion, granule and cachet；(2) parenteral, example As sterile solution agent, suspensoid and freeze-dried powder agent；(3) transdermal administration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) local is administered, for example ointment, ointment, lotion, molten Liquor, paste, spray, foam and gel.

In some embodiments, compound disclosed by the invention can be configured to peroral dosage form.In other embodiment party In case, compound disclosed by the invention can be configured to inhalant dosage form.In other embodiments, chemical combination disclosed by the invention Thing can be configured to nose administration 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.

The present invention provide pharmaceutical composition can with compressed tablet, develop piece, can chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets are providing.Enteric coatel tablets be be resistant to gastric acid effect but in intestinal dissolving or disintegrate material bag The compressed tablet of clothing, thus prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to fatty acid, fat Fat, phenyl salicylate, wax, Lac, ammonification Lac and cellulose acetate phthalate ester.The compacting that coated tablet surrounds for sugar-coat Piece, it beneficial to covering taste beastly or abnormal smells from the patient and can prevent tablet from aoxidizing.Thin membrane coated tablet is to use water solublity The thin layer of material or the compressed tablet of thin film covering.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses and sweet tablet identical general characteristic.Multiple Tabletting is through the compressed tablet more than a press cycles preparation, including multilayer tablet and pressed coated or dry coated tablet.

Tabuleses can by powder, crystallization or granular active component one kind individually or with present invention description Or variety carrier or excipient composition are preparing, described carrier and excipient include binding agent, disintegrating agent, controlled release polymer, profit Lubrication prescription, diluent and/or coloring agent.Fumet and sweeting agent are particularly useful when forming chewable tablet and lozenge.

The pharmaceutical composition that the present invention provides can be provided with soft capsule or hard capsule, and it can be fine by gelatin, methyl Tie up element, starch or calcium alginate to prepare.Described hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section Fill in another section, therefore enclose active component completely.SEC (SEC) is soft, spherical shell, such as gelatin shell, It passes through to add glycerol, Sorbitol or the plasticizing of similar polyhydric alcohol.Soft gelatin shell can comprise preservative and carry out prophylaxis of microbial life Long.Suitable preservative be as described in the present invention those, including methyl hydroxybenzoate and propylparaben, and sorbic acid.This Liquid, semisolid and solid dosage formss that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form include Solution in Allyl carbonate, vegetable oil or triglyceride and suspensoid.The capsule comprising such solution can be as in the U.S. Patent U.S.Pat.Nos.4,328,245；Described in 4,409,239 and 4,410,545 preparing.Described capsule can also be adopted Use coating as is known to persons skilled in the art, thus improving or maintain the dissolution of active component.

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

Other useful liquid and semisolid dosage form include, but are not limited to comprise the active component of present invention offer and two grades Change those dosage forms of list-or poly- alkylene glycol, described list-or poly- alkylene glycol include：1,2- dimethoxymethane, diethylene glycol Dimethyl ether, triethylene glycol dimethyl ether., tetraethylene glycol dimethyl ether, Polyethylene Glycol -350- dimethyl ether, Polyethylene Glycol -550- dimethyl ether, poly- second Glycol -750- dimethyl ether, the approximate mean molecule quantity of wherein 350,550,750 finger Polyethylene Glycol.These preparations can be further Including one or more antioxidant, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propylgallate, Vitamin E, hydrogen Quinone, Hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, Sorbitol, phosphoric acid, bisulfites, Jiao Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.

When suitably, can be by the dosage unit preparations microencapsulation of oral administration.Can also be prepared into extending or tie up Hold the compositionss of release, for example, pass through microparticle material coating or be embedded in polymer, wax or the like.

The combination of oral medication that the present invention provides can also be carried in the form of liposome, micelle, microsphere or nanometer system For.Micelle dosage form can be prepared with the method for U.S.Pat.No.6,350,458 description.

The pharmaceutical composition that the present invention provides can be provided with the granule of non-effervescent or effervescent and powder, to reconstruct Liquid dosage form.Pharmaceutically acceptable carrier used in non-effervescent granule or powder and excipient can include diluting Agent, sweeting agent and wetting agent.Pharmaceutically acceptable carrier used in effervescent granule or powder and excipient can wrap Include organic acid and carbon dioxide source.

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

Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.Such Polymer includes Polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl Radix Asparagi acyl Amine phenol or the oxide polylysine of palmitoyl residues replacement.Additionally, compound disclosed in this invention can with reality Used in the control release of existing medicine, a class Biodegradable polymeric combines, for example, polylactic acid, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, poe, polyacetals, the crosslinking of poly- dihydropyran, polybutylcyanoacrylate and hydrogel or amphiphilic block are altogether Polymers.

The pharmaceutical composition that the present invention provides can be configured to immediately or Modified release dosage forms, include delay-, slow release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.

The pharmaceutical composition that the present invention provides can be common with the other active component without compromising on expected therapeutical effect Prepare, or the material co-formulation with supplementary expected effect.

The pharmaceutical composition that the present invention provides can be by injection, infusion or implantation parenteral, for local or complete Body is administered.As parenteral that the present invention uses include intravenouss, intra-arterial, intraperitoneal, intrathecal, in ventricle, in urethra, breast In bone, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical composition that the present invention provides can be configured to be suitable to any dosage form of parenteral, including solution, mixes Suspension, Emulsion, micelle, liposome, microsphere, nanometer system and being suitable to makes consolidating of solution or suspension before the injection in a liquid Body form.Such dosage form can be prepared according to the conventional method known to the skilled person in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, ibid).

Be intended for parenteral pharmaceutical composition can include one or more pharmaceutically acceptable carrier and Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life The preservative of thing growth, stabilizer, dissolution enhancers, isotonic agent, buffer agent, antioxidant, local anesthetic, suspending agent and dispersion Agent, wetting agent or emulsifying agent, chelating agent, sequestering agent or chelating agen, antifreezing agent, cryoprotective agent, thickening agent, pH adjusting agent And noble gases.

Suitably include, but are not limited to containing transporter：Water, saline, normal 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 not limited to the fixed oil of plant origin, Oleum Ricini, Semen Maydis oil, Semen Gossypii The middle chain of oil, olive oil, Oleum Arachidis hypogaeae semen, Oleum menthae, safflower oil, Oleum sesami, Oleum Glycines, hydrogenated vegetable oil, hydrogenated soybean oil and Oleum Cocois Triglyceride and palm seed oil.Water miscibility carrier includes, but not limited to ethanol, 1,3 butylene glycol, the poly- second of liquid two Alcohol (such as Liquid Macrogol and PEG400), propylene glycol, glycerol, METHYLPYRROLIDONE, N, N- dimethylacetamide Amine and dimethyl sulfoxide.

Suitable antimicrobial or preservative include, but not limited to phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, Methyl parahydroxybenzoate and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylparaben and sorbic acid.Suitable isotonic agent includes, but not limited to sodium chloride, glycerol and glucose.Suitable buffer agent Include, but not limited to phosphate and citrate.Suitable antioxidant is as 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 as present invention description, including sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and Polyvinylpyrrolidone. Suitable emulsifying agent includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene takes off Water sorbitol monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agen 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 chelating agent includes, but does not limit In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin-, HP-β-CD, Sulfobutylether-beta-schardinger dextrin-and sulfobutyl group Ether 7- beta-schardinger dextrin-(CyDex,Lenexa,KS).

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

In some embodiments, pharmaceutical composition to be provided with instant sterile solution.In other embodiments, Pharmaceutical composition is provided with aseptic dried soluble product, and including freeze-dried powder agent and hypodermic tablet, it is used before use Carrier reconstructs.In other embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In other enforcement In scheme, pharmaceutical composition is formulated into use and insolubility product is dried with the aseptic of carrier reconstruct before.Also at some In embodiment, pharmaceutical composition is formulated into instant no bacterial emulsion.

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

Pharmaceutical composition can be configured to suspensoid, solid, semisolid or thixotropic liquid, the reservoir administration as implantation. In some embodiments, pharmaceutical composition disclosed in this invention is dispersed in solid interior substrate, and it is insoluble to body fluid But the outside polymeric membrane that the active component in permission pharmaceutical composition diffuses through is surrounded.

Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or unplasticizied Polrvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silica Alkane, silicone carbonate copolymer, the hydrogel of ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysiss of polyvinyl alcohol and coach.

Suitable outside polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Thing, ethylene/vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polychlorostyrene second The copolymer of alkene, ethlyene dichloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer gather to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.

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

Aerosol can be by being suspended or dissolved in liquefied propellant preparing compound disclosed in this invention.It is suitable for Propellant include chlorohydrocarbon, hydro carbons and other liquid gas.Representational propellant includes：Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), 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.The aerosol comprising compound disclosed in this invention generally passes through Metered dose inhaler (MDI) is administered to patient.Such device dawn known to those skilled in the art

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

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

Be suitable for the pharmaceutical composition that is administered of local can be formulated into ointment, ointment, suspensoid, lotion, powder, Solution, paste, gel, spray, aerosol or oil preparation.For example, ointment, ointment and gel can use water or oil Substrate, and the thickening agent that is suitable for and/or gel and/or solvent are configuring.Such substrate can include, water, and/or oily example As liquid-liquid paraffin and vegetable oil (such as Oleum Arachidis hypogaeae semen or Oleum Ricini), or solvent such as Polyethylene Glycol.Made according to medium property Thickening agent and gel include soft paraffin, aluminium stearate, cetearyl alcohol, Polyethylene Glycol, lanoline, Cera Flava, poly- carboxylic second Alkene and cellulose derivative, and/or glyceryl monostearate and/or nonionic emulsifier.

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

Externally-applied powder can molding in the presence of powder the substrate such as Pulvis Talci, Lactose or starch being arbitrarily suitable for.Drop Can be formulated with comprising one or more dispersant, the water of solubilizing agent, suspending agent or preservative or non-aqueous matrix.

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

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

The compounds of this invention and the purposes of compositionss

The present invention provides and 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 Aurora A (including Aurora-A, Aurora-B and Aurora-C) behavior mediation or the disease or disorderly otherwise affecting Disorderly or by one or more protein kinase, as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also referred to as FLK-2) or Aurora A (include Aurora-A, Aurora-B and Aurora-C) behavior mediation or otherwise The method of one or more symptom of the disease of impact or disorder.

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

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

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

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

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

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

Consistent with above description, such disease or disorder include but is not limited to：Myeloproliferative diseases, for example very Property erythrocytosiss (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF)；Leukemia, such as medullary system Leukemia includes chronic myelogenous leukemia (CML), the CML form of resistance to imatinib, acute myeloid leukemia (AML) and AML's Hypotype, acute megakaryoblastic leukemia (AMKL)；Lymphoproliferative disease, such as acute lymphoblastic leukemia (ALL), bone Myeloma；Cancer includes incidence cancer, carcinoma of prostate breast carcinoma, ovarian cancer, melanoma, pulmonary carcinoma, the cerebral tumor, cancer of pancreas and renal carcinoma；With The diseases associated with inflammation relevant with immunologic function disorder, immunodeficiency, immunomodulating or disorder, autoimmune disease, tissue shifting Plant repulsion, graft versus host disease, wound healing, nephropathy, multiple sclerosiss, thyroiditiss, type i diabetes, sarcoidosises, silver bits Disease, allergic rhinitis, inflammatory bowel include Crohn disease and ulcerative colitiss (UC), systemic lupus erythematosus (sle) (SLE), close Section inflammation, osteoarthritis, rheumatoid arthritiss, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and xerophthalmia are comprehensive Levy (or keratoconjunctivitis sicca (KCS)).

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

On the other hand, the present invention provides a kind for the treatment of to suffer from or the risky mammal suffering from disease disclosed herein Method, methods described includes giving effectively treatment disease amount or effective one or more medicine disclosed herein preventing disease amount Compositions or compound.On the other hand, provided herein is a kind for the treatment of is suffered from or risky suffered from proliferative disease, autologous exempts from Epidemic disease, the method for the mammal of anaphylactic disease, inflammatory diseasess or transplant rejection.

In a kind of method in terms for the treatment of, the present invention provides treatment and/or prevention to be susceptible or suffering from proliferative disease The method of mammal, methods described includes giving one or more medicine disclosed herein of effectively treatment amount or effective preventive dose Compositions or compound.In particular instances, proliferative disease is selected from cancer (for example, solid tumor such as uterine leio muscle Tumor or carcinoma of prostate), polycythemia vera, primary thrombocytosiss, myelofibrosises, leukemia (for example, AML, CML, ALL or CLL) and multiple myeloma.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing proliferative disease.? In specific embodiment, proliferative disease be selected from cancer (for example, solid tumor such as leiomyosarcoma of uterus or carcinoma of prostate), Polycythemia vera, primary thrombocytosiss, myelofibrosises, leukemia (for example, AML, CML, ALL or CLL) And multiple myeloma.

On the other hand, provided herein is class compound disclosed herein, or comprise the drug regimen of compound is disclosed herein Thing, for the medicine of preparation treatment or prevention proliferative disease.In particular instances, (for example, in fact proliferative disease is selected from cancer Body tumor, leiomyosarcoma of uterus or carcinoma of prostate), polycythemia vera, primary thrombocytosiss, myleo Change, leukemia (for example, AML, CML, ALL or CLL) and multiple myeloma.

On the other hand, provided herein is treatment and/or prevention are susceptible or suffering from the side of the mammal of autoimmune disease Method, methods described includes giving one or more pharmaceutical composition disclosed herein or the change of effectively treatment amount or effective preventive dose Compound.In particular instances, autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus (sle), skin lupus erythematosuss, wolf Skin ulcer nephritis, dermatomyositiss, sjogren syndrome, psoriasises, type i diabetes and inflammatory bowel.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing autoimmune disease. In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus (sle), skin lupus erythematosuss, wolf Skin ulcer nephritis, dermatomyositiss, sjogren syndrome, psoriasises, type i diabetes and inflammatory bowel.

On the other hand, provided herein is class compound disclosed herein, or comprise the drug regimen of compound is disclosed herein Thing, for the medicine of preparation treatment or prevention autoimmune disease.In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus (sle), skin lupus erythematosuss, lupus nephritis, dermatomyositiss, sjogren syndrome, psoriasises, I Patients with type Ⅰ DM and inflammatory bowel.

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

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

On the other hand, provided herein is class compound disclosed herein, or comprise the drug regimen of compound is disclosed herein Thing, for the medicine of preparation treatment or prevention anaphylactic disease.In certain embodiments, anaphylactic disease is selected from respiratory tract Anaphylactic disease, sinusitis, eczema and measles, food anaphylaxiss and insect venom allergies.

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

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

On the other hand, provided herein is class compound disclosed herein, or comprise the drug regimen of compound is disclosed herein Thing, for the medicine of preparation treatment or prevention inflammatory diseasess.In certain embodiments, inflammatory diseasess be selected from inflammatory bowel, Crohn disease, rheumatoid arthritiss, juvenile arthritises and psoriasis arthropathica.

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

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

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

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

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

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

Therapeutic alliance

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

On the one hand, the present invention provides treatment, the method for preventing or improve disease or disease, including giving safe and effective amount Comprise the combination medicine of the open compound of the present invention and one or more therapeutically active agent.In some embodiments, joint medicine Thing comprises one or two other therapeutic agents.

The example of other therapeutic agents includes including but is not limited to：Anticarcinogen, including chemotherapeutics and antiproliferative；Antiinflammatory； With immunity regulatin remedy agent or immunosuppressant.

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 Become the combination simultaneously, separately or sequentially applied in the treatment.In some embodiments, treatment is for by one or more egg The disease of white kinases, such as jak kinase, FLT3 kinases or Aurora A activity mediation or the treatment of symptom.Combining preparation provides Product include being present in the compositionss comprising that compound and other therapeutic agents are disclosed herein in same pharmaceutical composition, or with Compound disclosed herein and other therapeutic agents that multi-form exists, for example, medicine box.

On the other hand, the present invention provides and a kind of comprises the medicine of compound and another or multiple therapeutic agent is disclosed herein Compositionss.In some embodiments, pharmaceutical composition can comprise pharmaceutically acceptable adjuvant, figuration as above Agent, carrier or solvent.

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

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

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

In some embodiments, described other therapeutic agent includes, chemotherapeutics and/or antiproliferative.Known chemotherapeutic Thing includes, but is not limited to, other therapies being used in combination with the compounds of this invention or cancer therapy drug, operation, X-ray therapy (a little example such as gamma-radiation, neutron beam X-ray therapy, electron beam evaporation therapy, proton therapy, brachytherapy and system Isotope therapy), incretotherapy, taxaneses (paclitaxel (taxol), Docetaxel (taxotere) etc.), Platinum derivatives (cisplatin (cisplatin), carboplatin (carboplatin)), (interferon, between leukocyte for biological response modifier Element), tumor necrosis factor (TNF, TRAIL receptor target thing), overheated and cryotherapy, mitigate the reagent of any untoward reaction (as Bendectin) and other approved chemotherapeutics, including but not limited to, alkylating drug (chlormethine (mechlorethamine), chlorambucil (chlorambucil), cyclophosphamide (cyclophosphamide), L-Sarcolysinum (melphalan), ifosfamide (ifosfamide)), antimetabolite (methotrexate (methotrexate), pemetrexed (pemetrexed) etc.), (6-MP (6-mercaptopurine), 5- fluorine urine are phonetic for purine antagonist and Pyrimidine antagonists Pyridine (5-fluorouracil), cytosine arabinoside (cytarabile), gemcitabine (gemcitabine)), spindle poison (vinblastine (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)), cell division cycle inhibitor (KSP pass through mitotic kinesins Inhibitor, CENP-E and CDK inhibitor), enzyme (asparaginase (asparaginase)), hormone (tamoxifen (tamoxifen), leuprorelin (leuprolide), flutamide (flutamide), megestrol (megestrol), fill in rice Loose (dexamethasone) etc.).Angiogenesis inhibitor reagent (Avastin (avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (belimumab), brentuximab, Cetuximab (cetuximab), gemtuzumab Ozogamicin Mylotarg CDP 771 (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), Erlotinib (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), AMN107 (nilotinib), Lapatinib (lapatinib), gram Zhuo replace Buddhist nun (crizotinib), ruxolitinib, vemurafenib, vandetanib, Pazopanib, etc.).Drug inhibition or activation cancer approach such as mTOR, HIF (hypoxia inducible factor) approach and other.Cancer The wide forum of disease treatment seeshttp://www.nci.nih.gov/, FAD accreditation oncologic inventory seehttp:// www.fda.gov/cder/cancer/druglist-rame.htm, and Merck Manual, the 18th edition .2006, all of content All it is combined with list of references.In other embodiments, the compound of the present invention can be in conjunction with cytotoxic anticancer agent. Such anticarcinogen can find the 13rd edition Merck index (2001) is inner.These anticarcinogen include, but are not limited to, Tianmen Winter amidase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, L-ASP, cyclophosphamide, arabinose born of the same parents Glycosides, dacarbazine, actinomycin D, daunorubicin, amycin (doxorubicin), epirubicin, etoposide, 5-fluorouracil, Hexamethyl tripolycyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, chlormethine, Ismipur, Mesna, methotrexate, ametycin, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, chain azoles are mould Element, tamoxifen, thioguanine, hycamtin, vinblastine, vincristine and vindesine.Combine with the compound of the present invention Other suitable cytotoxic drugs of medication include, but is not limited to, and these are admittedly applied to neoplastic disease treatment Compound, as described in documents below：Goodman and Gilman's The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.)；These anticarcinogen include, but are not limited to, ammonia Shandong Meter Te (aminoglutethimide), l- asparaginase, azathioprine, 5-azacytidine, cladribine (cladribine), busulfan (busulfan), diethylstilbestrol, 2', 2'- difluoro dCDP choline, Docetaxel, red Hydroxyl nonyl adenine (erythrohydroxynonyladenine), ethinylestradiol, 5-fluorouracil deoxynucleoside, 5- Fluorodeoxyuridine monophosphate, Fludarabine Phosphate (fludarabinephosphate), fluoxymesterone (fluoxymesterone), flutamide (flutamide), hydroxyprogesterone caproate, idarubicin (idarubicin), interferon, vinegar Sour medroxyprogesterone, megestrol acetate, melphalan (melphalan), mitotane (mitotane), paclitaxel, 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 nucleoside and vinorelbine.

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

Also in other embodiments, the compound of the present invention can be with binding signal transduction inhibitor.Signal transduction Inhibitor using EGFR family as target, such as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l),15-23；Harari et al., Oncogene, 2000,19 (53), 6102-6114) and the joining of each of which Body.Such reagent includes, but is not limited to, antibody therapy such as Herceptin (trastuzumab), Cetuximab (cetuximab), her monoclonal antibody (ipilimumab) and handkerchief trastuzumab (pertuzumab).Such therapy also includes, but It is not limited to, small molecule kinase inhibitors such as imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Erlotinib (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), SKI-606 (bosutinib), brivanib, canertinib, cabozantinib, AZD2171 (cediranib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, Ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), Momelotinib, does not replace husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib, oprozomib, Olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, plug Block and replace Buddhist nun (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, tivantinib, Tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941 (Folkes, etal., J.Med.Chem.2008,51,5522), BZE235, etc..

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

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

On the one hand, the present invention provides one kind to comprise the open compound of the present invention and β₂The connection of-adrenoceptor agonists Close.β₂The example of-adrenoceptor agonists includes salmaterol, albuterol, formoterol, Salmefamol, Fei Nuote Sieve, carmoterol, Yi Tanteluo, naminterol, Clenbuterol, pirbuterol, flerobuterol, reproterol, special sieve of promulgation, indenes Da Teluo, terbutaline, and their salt, the xinafoate (1- hydroxy-2-naphthoic acid salt) of such as salmaterol, husky butylamine The sulfate of alcohol or the fumarate of free alkali or formoterol.In some embodiments, long-acting beta₂- adrenoceptor Agonist, for example, provide effective bronchiectasis to reach the compound of 12 hours or longer time, be preferred.

β₂- adrenoceptor agonists can be with the form of pharmaceutically acceptable acid forming salt.Described pharmaceutically may be used The acid accepting is selected from sulphuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (as 1- or 3- hydroxy-2-naphthoic acid), cinnamic acid, the meat replacing Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3- (1- naphthyl) acrylic acid, benzoic acid, 4- methoxybenzoic 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 the open compound of the present invention and corticosteroid.Suitably Corticosteroid refers to those corticosteroid that are oral and sucking, and its has the prodrug of anti-inflammatory activity.Example includes methyl and sprinkles Ni Songlong, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), 6 alpha, 9 alpha-difluoro-11 beta-hydroxy -16 Alpha-Methyl -17 α-[(4- methyl-1,3-thiazole - 5- carbonyl) epoxide] -3- oxo-androst -1,4- diene -17 β-thiocarboxylic acid S- fluorine methyl ester, 6 α, fluoro- 17 α of 9 α-two-[(2- furan Mutter carbonyl) epoxide] -11 beta-hydroxy -16 Alpha-Methyl -3- oxo-androst -1,4- diene -17 β-thiocarboxylic acid S- fluorine methyl ester (furancarboxylic acid Fluticasone), 6 alpha, 9 alpha-difluoro-11 beta-hydroxy -16 Alpha-Methyl -3- oxo -17 α-propionyloxy-androsta -1,4- diene -17 β - Thiocarboxylic acid S- (2- oXo-tetrahydro furan -3S- base) ester, 6 alpha, 9 alpha-difluoro-11 beta-hydroxy -16 Alpha-Methyl -3- oxo -17 α - (2,2,3,3- tetramethyl cyclopropyl carbonyl) epoxide-androstane -1,4- diene -17 β-thiocarboxylic acid S- cyano methyl ester and 6 α, 9 α-two Fluoro- 11 beta-hydroxy -16 Alpha-Methyl -17 α-(1- ethyl cyclopropyl carbonyl) epoxide -3- oxo-androst -1,4- diene -17 β-thio Carboxylic acid S- methyl fluoride ester, beclomethasone ester (as 17- propionic ester or 17,21- dipropionic acid fat), budesonide (budesonide), Flunisolide (flunisolide), mometasone ester (as momestasone furoate), Triamcinolone Acetonide (triamcinolone Acetonide), ([[(R)-cyclohexyl is sub- for 16 α, 17- for sieve fluoronaphthalene moral (rofleponide), ciclesonide (ciclesonide) Methyl] double (epoxides)] -11 β, 21- dihydroxy-pregnant steroid -1,4- diene -3,20- diketone), butixocort propionate (butixocort Propionate), RPR-106541 and ST-126.Preferably corticosteroid includes fluticasone propionate (fluticasone Propionate), 6 alpha, 9 alpha-difluoro-11 beta-hydroxy -16 Alpha-Methyl -17 α-[(4- methyl-1,3-thiazole -5- carbonyl) epoxide] - 3- oxo-androst -1,4- diene -17 β-thiocarboxylic acid S- methyl fluoride ester, 6 α, fluoro- 17 α of 9 α-two-[(2- furanylcarbonyl) oxygen Base] -11 beta-hydroxy -16 Alpha-Methyl -3- oxo-androst -1,4- diene -17 β-thiocarboxylic acid S- methyl fluoride ester, 6 α, 9 α-two are fluoro- 11 beta-hydroxy -16 Alpha-Methyl -3- oxo -17 α-(2,2,3,3- tetramethyl cyclopropyl carbonyl) epoxide-androstane -1,4- diene -17 β-thiocarboxylic acid S- cyano methyl ester and 6 alpha, 9 alpha-difluoro-11 beta-hydroxy -16 Alpha-Methyl -17 α-(1- methylcyclopropyl groups carbonyl) oxygen Base -3- oxo-androst -1,4- diene -17 β-thiocarboxylic acid S- fluorine methyl ester.In some embodiments, corticosteroid is 6 α, Fluoro- 17 α of 9 α-two-[(2- furanylcarbonyl) epoxide] -11 beta-hydroxy -16 Alpha-Methyl -3- oxo-androst -1,4- diene -17 β-sulfur For carboxylic acid S- methyl fluoride ester.

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

On the other hand, the present invention provides one kind to comprise the open compound of the present invention and nonsteroidal anti-inflammatory drug (NSAID's) Joint.The example of NSAID's includes sodium cromoglicate, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (as theophylline, PDE4 inhibitor or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene close Become inhibitor (as montelukast), iNOS inhibitor, trypsin and elastase inhibitor, Beta 2 integrin antagonist With adenosine receptor agonist or antagonist (e.g., adenosine 2a receptor stimulating agent), cytokine antagonist (as chemokine receptors is short of money Anti-agent, including CCR3 antagonist), cytokine synthesis inhibitor or 5-LO inhibitor.Wherein, iNOS (inductivity one Nitric oxide synthase) administration of inhibitor preferred oral.The example of iNOS inhibitor includes those in WO 93/13055, WO 98/ 30537th, the compound disclosed in WO 02/50021, WO 95/34534 and WO 99/62875.CCR3 inhibitor include those Compound disclosed in WO 02/26722.

In some embodiments, the present invention relates to the open compound of the present invention is being suppressed 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 Can be known suppression PDE4 enzyme or any compound being found as PDE4 inhibitor, they are only PDE4 suppression Agent, is not other members in suppression PDE family, the such as compound of PDE3 and PDE5.Compound includes cis -4- cyano group -4- (3- Cyclopentyloxy -4- methoxyphenyl) hexamethylene -1- carboxylic acid, 2- carbomethoxy -4- cyano group -4- (3- cyclo propyl methoxy -4- two Fluorine methoxyphenyl) hexamethylene -1- ketone and cis-[4- cyano group -4- (3- cyclo propyl methoxy -4- difluoro-methoxy phenyl) ring Hexane -1- alcohol]；Also hexamethylene -1- carboxylic acid is (also referred to as to include cis -4- cyano group -4- [3- (ring propoxyl group) -4- methoxyphenyl] Xi Luosi) and its salt, ester, prodrug or physical form, it was in 1996 09 month No. 03 United States Patent (USP) US authorized 5,552,438 Disclosed in, this patent and compound disclosed in it are incorporated herein by reference in their entirety.

On the other hand, the present invention provides a kind of joint comprising the open compound of the present invention and anticholinergic.Cholinolytic Can the example of agent be the compound that those are used as muscarinic receptor antagonist, particularly 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 bag of inhalation Include ipratropium (for example, as bromide, CAS 22254-24-6, withSell for trade name), Oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium (for example, as bromide, CAS 136310-93- 5, withSell for trade name)；Be also interested in also have Revatropate (for example, as hydrobromate, CAS 262586-79-8) and the LAS-34273 disclosed in WO01/04118.The example compound of oral administration includes piperazine logical sequence Xiping (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or its hydrobromate CAS 133099-07-7, withSell for trade name), oxibutynin (CAS 5633-20-5, withSell for trade name Sell), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or its tartrate CAS 124937- 52-6, withSell for trade name), difficult to understand for ammonium (for example, as bromide, CAS 26095-59-0, withSell for trade name), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, Or its succinate CAS 242478-38-2, i.e. compound YM-905, withSell for trade name).

On the other hand, the present invention provides a kind of joint comprising the open compound of the present invention and H1 antagonist.H1 antagonist Example include, but not limited to ammonia and come promise (amelexanox), this imidazoles western (astemizole), azatadine (azatadine), azelastine (azelastine), acrivastine (acrivastine), brompheniramine (brompheniramine), cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine), chlorpheniramine (chlorpheniramine), clemastine (clemastine), marezine (cyclizine), carebastine (carebastine), Cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), diformazan indenes (dimethindene), ebastine (ebastine), epinastine (epinastine), second Fluorine profit piperazine (efletirizine), fexofenadine (fexofenadine), hydroxyzine (hydroxyzine), ketotifen (ketotifen), Loratadine (loratadine), levocabastine (levocabastine), Mizolastine (mizolastine), mequitazine (mequitazine), mianserin (mianserin), the primary STING of promise (noberastine), meclizine (meclizine), Tecastemizole (norastemizole), olopatadine (olopatadine), piperacetazine (picumast), ratio Lamine (pyrilamine), phenergan (promethazine), special Fei Nading (terfenadine), tripelennamine (tripelennamine), temelastine (temelastine), alimemazine (trimeprazine) and triprolidine (triprolidine), preferably cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine) and fexofenadine (fexofenadine).Real at other Apply in scheme, the present invention provides one kind to comprise the joint of the open compound of the 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.Can be used for and this Disclosure of the invention compound other histamine receptor antagonists united include H4 receptor antagonist (and/or inverse agonist), for example, exist Jablonowski et al.,J.Med.Chem.,2003,46:Compound disclosed in 3957-3960.

Another aspect, the present invention provides one kind to comprise the open compound of the present invention, with PDE4 inhibitor and β₂- epinephrine The joint of receptor stimulating agent.

Also on the one hand, the present invention provides one kind to comprise the open compound of the present invention, with anticholinergic and PDE-4 suppression The joint of agent.

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

These in combination each compound with alone or in combination pharmaceutical dosage forms order of administration or can be administered simultaneously. In one embodiment, each compound component is to be administered simultaneously with the pharmaceutical dosage forms of combination.Known treatment agent be suitable for Dosage is easy to be understood by the person skilled in the art.

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

In some embodiments, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention and chemotherapeutics Joint.

In some embodiments, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention and antiproliferative Joint.

In some embodiments, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention and di-phosphate ester The joint of enzyme 4 (PDE4) inhibitor.

In other embodiments, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention and β 2- kidney The joint of upper parathyrine receptor stimulating agent.

In other embodiments, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention and cortex class The joint of sterin.

In other embodiments, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention and non-steroidal The joint of class GR agonist.

In other embodiments, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention and cholinolytic The joint of energy medicine.

In other embodiment, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention and antihistamine The joint of medicine.

In other embodiment, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention to be tried with antiinflammatory The joint of agent.

In other embodiment, the pharmaceutical composition that the present invention provides is comprised the open compound of the present invention and is adjusted with immunity The joint of section agent.

In other embodiment, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention and is used for moving The joint of the medicine of pulse atherosclerosis.

In other embodiment, the pharmaceutical composition that the present invention provides comprises the open compound of the present invention and is used for controlling Treat the joint of the medicine of pulmonary fibrosiss.

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

The open compound of the present invention can also be advantageously utilised in and the combining of other compounds, or and other therapeutic agents, especially It is in the combination of antiproliferative.Such antiproliferative includes, but not limited to aromatase inhibitor；Estrogen antagonist；Topology is different Structure enzyme I inhibitor；Topoisomerase II inhibitors；Microtubule active agent；Alkylating agent；Antibiotic FR 901228；Induction The compound of cell differentiation procedure；Cyclooxygenase-2 inhibitors；MMP inhibitor；MTOR inhibitors；Antitumor antimetabolite；Platinum Compound；The compound of targeting/reduction albumen or lipid kinase activity and the compound of other angiogenesis inhibitor；Targeting, reduction or Suppression albumen or the compound of lipid phosphate esterase active；Gonadorelin excitomotor；Androgen antagonist；Methionine aminopeptidase suppresses Agent；Diphosphonate；Biological response modifier；Antiproliferation antibodies；Heparanase inhibitors；Ras carcinogenic hypotype inhibitor；Telomere Enzyme inhibitor；Proteasome inhibitor；The medicament for the treatment of neoplastic hematologic disorder；The compound of targeting, reduction or suppression Flt-3 activity； Hsp90 inhibitor；TemozolomideAnd calcium folinate.

Term used herein " aromatase inhibitor ", refers to the compound suppressing estrogen to produce, and that is, suppression substrate is male Alkene diketone and testosterone change into the compound of estrone and estradiol respectively.This term includes, but are not limited to：Steroid, especially It is atamestane (atamestane), exemestane (exemestane) and formestane (formestane)；And, particularly Non-steroids, especially aminoglutethimide (aminoglutethimide), Rogletimide (roglethimide), pyrrole Rumi Special (pyridoglutethimide), trilostane (trilostane), testolactone (testolactone), Ketoconazole (ketoconazole), fluorine chlorazol (vorozole), fadrozole (fadrozole), Anastrozole (anastrozole) and come bent Azoles (letrozole).Exemestane can be with commercially available, as trade mark isForm administration.Fu Mei Smooth (formestane) can be with commercially available, as trade mark isForm administration.Fadrozole (fadrozole) can be with commercially available, as trade mark isForm administration.Anastrozole (anastrozole) can be with Commercially available, such as trade mark isForm administration.Letrozole (letrozole) can be with commercially available, such as Trade mark is OrForm administration.Aminoglutethimide (aminoglutethimide) can be with city Sell, such as trade mark is Form administration.The present invention includes the combination of aromatase inhibitor chemotherapeutic It is particularly useful for the treatment of the tumor that hormone receptor is positive, such as breast tumor.

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

Term used herein " androgen antagonist " refers to any material that can suppress androgen biological action, and it wraps Include, but be not limited to, bicalutamide (bicalutamide, trade name), its dosage form can be according to United States Patent (USP) US 4,636,505 preparing.

Term used herein " gonadorelin excitomotor " includes, but not limited to 1: PN: WO02056903 PAGE: 25 claimed protein (abarelix), Ge She Rayleigh (goserelin) and goserelin acetate.Goserelin, in United States Patent (USP) US 4, is disclosed in 100,274, can be with city Sell, such as trade mark is Form administration.1: PN: WO02056903 PAGE: 25 claimed protein (abarelix) can be according to United States Patent (USP) Method preparation dosage form disclosed in US 5,843,901.

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 With with commercially available, such as trade mark is ConcorForm administration.

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

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

Term used herein " alkylating agent " includes, but not limited to 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 " Antibiotic FR 901228 " or " hdac inhibitor " refer to inhibition of histone deacetylase, and There is the compound of antiproliferative activity.It includes the compound disclosed in WO 02/22577, especially N- hydroxyl -3- [4- [[(2- ethoxy) [2- (1H- indol-3-yl) ethyl]-amino] methyl] phenyl] -2E-2- acrylamide, N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- base)-ethyl]-amino] methyl] phenyl] -2E-2- acrylamide and its pharmaceutically can connect The salt being subject to.Especially include Vorinostat (SAHA).

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

Term used herein " platinum compounds " includes, but are not limited to carboplatin (carboplatin), cDDP (cis- Platin), cisplatin (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 " the change of targeting/reduction albumen or lipid kinase activity or albumen or lipid phosphatase activity Compound, or the compound of other angiogenesis inhibitor " include, but not limited to protein tyrosine kinase and/or serine and/or Threonine inhibitor, or lipid kinase inhibitors, for example

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

B) compound of targeting, reduction or suppression fibroblast growth factor acceptor (FGFR) activity；

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

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

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

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

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

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

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

J) Raf family member in targeting, reduction or suppression Protein kinase C (PKC) and serine/threonine kinases, MEK, SRC, JAK, FAK, PDK and Ras/MAPK family member, Pl (3) kinase families member, or Pl (3) kinases associated kinase family become Member, and/or the compound of cell cycle protein dependent kinase family (CDK) member activity；Particularly those are in United States Patent (USP) US 5,093, the staurosporine derivatives disclosed in 330, such as midostaurin (midostaurin)；More examples of compounds Also include, UCN-01；Safingol (safingol)；BAY43-9006；Bryostatin 1；Piperazine Li Fuxin (Perifosine)；Emol Good fortune is new (llmofosine)；RO 318220 and RO 320432；GO 6976；Isis 3521；LY333531/LY379196；Different Quinoline compound, such as in WO 00/09495 those disclosed；FTIs；PD184352；Or a kind of QAN697 (P13K suppression Agent)；

K) compound of targeting, reduction or suppression protein tyrosine kinase inhibitor activity；Targeting, reduction or suppression The compound of protein tyrosine kinase inhibitor activity includes GleevecOr tyrosine phosphorylation Inhibitor；Tyrphostin preferred low-molecular-weight (Mr<1500) compound, or its pharmaceutically acceptable salt, especially It is selected from the compound of this third two eyeball class of benzyl allyl two eyeball class or S- aryl or Double bottom thing quinolines, is further selected from tyrosine Phosphorylation inhibitor A23/RG-50810, AG 99, tyrphostin AG 213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44 (+) Enantiomer, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG957 and Adaphostin (4- { [(2,5- dihydroxy phenyl) methyl] amino }-benzoic acid Buddha's warrior attendant alkyl ester, NSC 680410, adaphostin)；With

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

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

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

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

Term used herein " cyclooxygenase-2 inhibitors " includes, but not limited to Cox-2 inhibitor, and 5- alkyl replaces 2- virtue aminophenyl acetic acid and its derivant, such as celecoxibRofecoxibEtoricoxib, Valdecoxib, or 5- alkyl -2- virtue aminophenyl acetic acid, such as 5- methyl -2- (2'- chloro- 6'- fluoroanilino) phenylacetic acid or reed Former times examined by rice

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

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

Term used herein " heparanase inhibitors " refers to, targeting, reduction or suppression acetylsulfuric acid depolymerized heparin Compound.This term includes, but does not limit PI-88.

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

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

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

Term used herein " methionine aminopeptidase inhibitor " refers to targeting, reduction or suppression methionine aminopeptidase activity Compound.The compound of targeting, reduction or suppression methionine aminopeptidase activity includes bengamide or derivatives thereof.

Term used herein " proteasome inhibitor " refers to the chemical combination of targeting, reduction or protease inhibition body activity Thing.The compound of targeting, reduction or protease inhibition body activity includes PS-341 and MLN 341.

Term used herein " matrix metallo-proteinase inhibitor " or " MMP inhibitor " include, but not limited to glue Former albumen peptides and non-peptide inhibitor, tetracycline derivant, such as hydroxamic acid peptide inhibitor batimastat (batimastat) Equivalent homologue Marimastat (marimastat, BB-2516) with its oral bio, Pu Masita (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

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

The compound of targeting, reduction or suppression FMS- sample tyrosine kinase receptor (Flt-3R) especially suppresses Flt-3 to be subject to Compound, albumen or the antibody of body kinase families member, such as PKC412, midostaurin (midostaurin), D-82041 DEISENHOFEN Derivant, SU11248 and MLN518.

Term used herein " HSP90 inhibitor " includes, but are not limited to the endogenouss of targeting, reduction or suppression HSP90 The compound of atpase activity；Chemical combination by ubiquitin protein body enzymatic pathway degraded, targeting, reduction or suppression HSP90 client protein Thing.The compound of the Endogenous ATP enzymatic activity of targeting, reduction or suppression HSP90 refers in particular to suppress the Endogenous ATP of HSP90 The compound of enzymatic activity, albumen or antibody, for example, 17- allyl amino, 17-AAG (17AAG), its Compound, red shell rhzomorph and the hdac inhibitor of his geldanamycin correlation.

Term used herein " antiproliferation antibodies " includes, but not limited to Herceptin (HERCEPTIN^TM), toltrazuril Monoclonal antibody-DM1, Erlotinib (TARCEVA^TM), bevacizumab (AVASTIN^TM), Rituximab PR064553 (anti-CD40) and 2C4 antibody.Antibody means complete monoclonal antibody, polyclonal antibody, complete by least 2 Multi-specificity antibody and antibody fragment (as long as they have desired biological activity) that whole antibody is formed.Thin for acute marrow For the treatment of born of the same parents' sample leukemia (AML), open for present invention compound can be used in combination with the leukemia therapy of standard, especially It is to be used in combination with the therapy treated for AML.Specifically, open for present invention compound can be turned with such as farnesyl- Move enzyme inhibitor and/or other are used for medicine such as daunorubicin, amycin, Ara-C, VP-16, teniposide, the rice that AML treats Support anthraquinone, idarubicin, carboplatin and PKC412 administering drug combinations.

Compound disclosed by the invention can also be advantageously utilised in other compounds combine or with other therapeutic agents In combination, especially other anti-malarial agents.Such anti-malarial agents include, but are not limited to proguanil (proguanil), chlorproguanil (chlorproguanil), trimethoprim (trimethoprim), chloroquine (chloroquine), mefloquine (mefloquine), Benflumetol (lumefantrine), atovaquone (atovaquone), pyrimethamine-sulfanilamide (pyrimethamine- Sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinidine (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfanilamide Class medicine, arteannuin, arteflene (arteflene), Artemether, artesunate, primaquine, suction NO, L-Arginine, dipropyl Alkene triamine NONO ester (NO donor), rosiglitazone (PPARy agonist), activated carbon, erythropoietin, levamisole, And malaridine.

Compound disclosed by the invention can also be advantageously used in other compounds combine or other therapeutic agents group In conjunction, such as treatment leishmaniasis, the other therapeutic agents of african trypanosomiasis, toxoplasmosis and cerebral cysticercosiss.Such medicament includes, but It is not limited to Nivaquine (M B), atovaquone-proguanil, Artemether-lumenfantrine, quinine sulfate, artesunate, quinine, doxycycline (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, sulfadiazine, pyrimethamine, compound sulfamethoxazole methylisoxazole, sulfamethoxazole, Ah Miramycin (azitromycin), atovaquone, dexamethasone, praziquantel, Albendazole (albendazole), beta-lactam, Fluoroquinolones medicine, macrolides medicine, aminoglycoside medicine, sulfadiazine and pyrimethamine.

Can be from classic " The by code name, common name or the structure of active component determined by trade name and its preparation 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 data base's (such as Patents International (example As IMS World Publications)) in know.

Compound that is above-described, being applied in combination with present invention disclosure compound, can be by people in the art Member, according to the method preparation described in above-mentioned document and administration.

Compound disclosed by the invention can also be combined with therapeutic process, improves 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 Sensitivity weak ground oncotherapy.

" joint " represents the medicine box of the fixing joint in single dose unit form or the part for administering drug combinations, its In compound disclosed by the invention and joint companion can be in same time individual application or can be in certain time interval Inside apply respectively, particularly make joint companion show cooperation, such as synergism.As the term is employed herein " co-administered " Or " administering drug combinations " etc. are intended to include be applied to selected joint companion and need its single individuality (such as patient), and anticipate It is intended to including wherein material without going through identical route of administration or the therapeutic scheme that is administered simultaneously." medicine as the term is employed herein Joint " represents the product obtained by the mixing of more than one active component or joint, and has both included the fixing connection of active component Close and also include on-fixed joint.Term " fixing joint " represents active component compound for example disclosed by the invention, and joint companion It is applied to patient in the form of single entities or dosage simultaneously.Term " on-fixed joint " represents that the active component such as present invention is open Compound, and joint companion all as corpus separatum simultaneously, common or no special time limit ground and successively patient be administered, its In this administering mode providing the treatment effect level of two kinds of compounds in the patient.The latter applies also for HAART, For example apply three or more active component.

Therapeutic Method

In some embodiments, Therapeutic Method disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or the pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention is included by right Patient in need gives the open compound of the present invention of safe and effective amount or the drug regimen comprising the open compound of the present invention Thing, the method to treat disease mentioned above.

In some embodiments, the open compound of the present invention or comprise the pharmaceutical composition of the open compound of the present invention can To be administered by any suitable route of administration, it is administered including Formulations for systemic administration and local.Formulations for systemic administration includes oral administration, stomach Parenteral administration, transdermal administration and rectally.Typical parenteral refers to by injection or administered by infusion, including vein Interior, intramuscular and subcutaneous injection or administered by infusion.Local administration inclusion is applied to skin and ophthalmic, ear, intravaginal, suction and nose Interior administration.In one embodiment, the open compound of the present invention or comprise the pharmaceutical composition of the open compound of the present invention can To be oral administration.In other embodiments, the open compound of the present invention or the medicine comprising the open compound of the present invention Compositionss can be inhalation.In a further embodiment, the open compound of the present invention or comprise the open compound of the present invention can To be intranasal administration.

In some embodiments, the open compound of the present invention or comprise the pharmaceutical composition of the open compound of the present invention can With once daily, or according to dosage regimen, at the appointed time in section, it is administered several times in different time intervals.For example, Be administered once a day, twice, three times or four times.In some embodiments, it is administered once a day.In other embodiment In, it is taken twice daily.Can be administered until reaching the therapeutic effect wanted or indefinitely maintaining the therapeutic effect wanted.This The appropriate dosage regimen of disclosure of the invention compound or the pharmaceutical composition comprising the open compound of the present invention depends on this compound Pharmacokinetic property, for example dilution, distribution and the half-life, these can be by determination of technical staff.Additionally, the present invention is open Compound or comprise the open compound of the present invention pharmaceutical composition appropriate dosage regimen, include the enforcement program lasting when Between, depending on treated disease, the order of severity of disease being treated, the age of patient under consideration and health, treated The factor in the range of technical staff's knowledge and experience such as the property of the medical history of patient, simultaneously therapy, the therapeutic effect wanted. Such technical staff should also be understood that the reaction for individual patient to dosage regimen, or elapses individual patient over time In order to be sufficiently accurate it may be desired to adjust suitable dosage regimen when needing to change.

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

For the individuality of about 50-70kg, the open pharmaceutical composition of the present invention and combination can be containing about 1-1000mg, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active component Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination medicine be depending on the individual species of medication, body weight, Age and individual instances, treated disorder (disorder) or disease (disease) or its order of severity.Possesses conventional technical ability Doctor, clinicist or veterinary can easily determine prevention, treatment or suppression disorderly (disorder) or disease (disease) The effective dose of required each active component in evolution.

Dose Characteristics cited above using favourable mammal (such as mice, rat, Canis familiaris L., monkey) or its from Confirm in the external and in vivo test of body organ, tissue and specimen.The open compound of the present invention is with solution, such as aqueous solution form In vitro using it is also possible to such as suspension or aqueous solution form enteral in vivo, parenteral, especially intravenouss use.

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

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

General synthesis step

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

Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I) and formula (II).Following reaction scheme and embodiment are used for lifting further Example explanation present disclosure.

The professional of art will be recognized that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds of many present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, according to the present invention, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art Completed by method of modifying, such as suitable protection disturbs group, by using reagent known to other except described in the invention , or modification reaction condition being made some routines.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the present invention.

The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, not through being further purified, unless other aspects show during use.General reagent is from western Gansu Province, Shantou chemical industry Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao's purchase Can buy.

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

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

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

¹H H NMR spectroscopy uses Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer record.¹H H NMR spectroscopy is with CDC1₃、 DMSO-d₆、CD₃OD or acetone-d₆For solvent (in units of ppm), marked as reference with TMS (0ppm) or chloroform (7.26ppm) Accurate.When multiplet occurs, by using following abbreviation：S (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant J, is represented with hertz (Hz).

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

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

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

AcOH、HOAc、CH₃COOH acetic acid

Ac₂O acetic anhydride

BOC, Boc tert-butoxycarbonyl

(Boc)₂O Bis(tert-butoxycarbonyl)oxide

BH₃DMS borane dimethylsulf iotade

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

N-BuOH n-butyl alcohol

Cs₂CO₃Cesium carbonate

CH₂Cl₂, DCM dichloromethane

CDC1₃Deuterochloroform

CH₃I iodomethane

DIEA、DIPEA、i-Pr₂NEt diisopropyl ethyl amine

DMF N,N-dimethylformamide

DMP dimethyl phthalate

DMAP DMAP, N, N- lutidines -4- amine

DMSO dimethyl sulfoxide

DHP 3,4- dihydropyran

DIAD diisopropyl azodiformate

PPTs 4- toluene sulfonic acide pyridine

Et₃N, TEA triethylamine

EtOAc, EA ethyl acetate

EtOH ethanol

Et₂O ether

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

G gram

H hour

HATU 2- (7- azepine -1H- 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) Lithamide.

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

Na₂SO₄Sodium sulfate

Na₂S₂O₃Sodium thiosulfate

NaHCO₃Sodium bicarbonate

NaOAc ammonium acetate

Ti(Oi-Pr)₄Metatitanic acid four isopropyl ester

NBS bromo-succinimide

MeOH methanol

ML, ml milliliter

Pd(OAc)₂Palladium

Pd/C palladium/carbon

PCl₅Phosphorus pentachloride

PE petroleum ether (60-90 DEG C)

PTSA p-methyl benzenesulfonic acid

PDC Pyridinium dichromate

RT, rt, r.t. room temperature

Rt retention time

RaneyNi Raney's nickel

THF oxolane

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 the open compound of the preparation present invention is as shown in following synthetic schemes 1～synthetic schemes 5.Remove Non- other explanation, each Z, Z¹、W、W₁、A、R¹、R²、R³、R^3a、R⁴、R^4a、R⁵、R^5a、R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R¹²、R¹³、R¹⁴、n With m, there is definition as described in the present invention.P is 0,1,2 or 3 for 0,1,2,3 or 4, q；PG is blocking group；Each R^ssIt independently is R³、R^3a、R⁴、R^4a、R⁵、R^5a、R⁶、R^6a、R⁷、R^7a、R⁸Or R^8a.

Synthetic schemes 1：

Have as formula (6) or (7) shown in structure the open compound of the present invention can by synthetic schemes 1 describe general Synthetic method prepares, and concrete steps refer to embodiment.In synthetic schemes 1, substituted dichloro pyrimidine (1) and with protection Base optionally substituted heterocyclic compound (2) in alkali, such as triethylamine, diisopropyl ethyl amine or Cs₂CO₃In the presence of, generate and appoint Choose generation heteroaryl compound (3).Compound (3) and optionally substituted aminopyrazole compound (4) or its hydrochlorate, Alkali, such as diisopropyl ethyl amine, triethylamine or in acid, such as trifluoroacetic acid, the ethyl acetate solution of hydrogen chloride, or suitable Under Pd catalyst, the such as catalytic action of palladium, reacting generating compound (5).Compound (5) in blocking group can be in acidity Under the conditions of, such as trifluoroacetic acid, the ethyl acetate solution of hydrogen chloride, or in the presence of hydrazine hydrate, or in other felicity conditions, As under the conditions of tetrabutyl ammonium fluoride remove, obtain kinases inhibitor (6).Under suitable conditions to compound (6) in draw Enter different substituent groups, can obtain with formula (7) shown in structure kinases inhibitor.

Synthetic schemes 2：

Have as formula (10) or (11) shown in structure the open compound of the present invention can be described by synthetic schemes 2 one As synthetic method prepare, concrete steps refer to embodiment.In synthetic schemes 2, compound (3) and optionally substituted amino Pyrazole compound (8) or its hydrochlorate, in alkali, such as diisopropyl ethyl amine, triethylamine or Cs₂CO₃Or in acid, such as trifluoro second Acid, the ethyl acetate solution of hydrogen chloride, or in suitable Pd catalyst, such as under the catalytic action of palladium, reaction generates chemical combination Thing (9).Compound (9) in blocking group can be in acid condition, the ethyl acetate solution of such as trifluoroacetic acid or hydrogen chloride, or In the presence of hydrazine hydrate, or in other felicity conditions, such as remove under the conditions of tetrabutyl ammonium fluoride, obtain kinases inhibitor (10).Under suitable conditions to compound (10) in introduce different substituent groups, can obtain with formula (11) shown in structure Kinases inhibitor.

Synthetic schemes 3：

Have as formula (14) or (15) shown in structure the open compound of the present invention can be described by synthetic schemes 3 one As synthetic method prepare, concrete steps refer to embodiment.In synthetic schemes 3, compound (3) and optionally substituted amino Imidazolium compoundss (12) or its hydrochlorate, in suitable Pd catalyst, such as under the catalytic action of palladium, reacting generating compound (13).Compound (13) in blocking group can in acid condition, such as in the ethyl acetate solution of trifluoroacetic acid or hydrogen chloride, or Person is in the presence of hydrazine hydrate, or in other felicity conditions, such as removes under the conditions of tetrabutyl ammonium fluoride, obtains protein kinase suppression Agent (14).Under suitable conditions to compound (14) in introduce different substituent groups, can obtain with formula (15) shown knot The kinases inhibitor of structure.

Synthetic schemes 4：

Have as formula (19) shown in structure the general synthesis that can be described by synthetic schemes 4 of the open compound of the present invention Method prepares, and concrete steps refer to embodiment.In synthetic schemes 4, compound (3) in blocking group can be in acid bar Under part, such as trifluoroacetic acid, the ethyl acetate solution of hydrogen chloride, or in the presence of hydrazine hydrate, or under otherwise suitable conditions, As under the conditions of tetrabutyl ammonium fluoride remove, obtain compound (16).Then, under suitable conditions to compound (16) middle introducing Different substituent groups, can obtain compound (17).Compound (17) and optionally substituted amino azole compound (18) or its Hydrochlorate, in alkali, such as diisopropyl ethyl amine, triethylamine or Cs₂CO₃Or in acid, such as trifluoroacetic acid, the acetic acid second of hydrogen chloride Ester solution, or in suitable Pd catalyst, such as under the catalytic action of palladium, reaction obtain with formula (19) shown in structure egg White kinase inhibitor.

Synthetic schemes 5:

Have as formula (25) or (26) shown in structure the open compound of the present invention can be described by synthetic schemes 5 one As synthetic method prepare, concrete steps refer to embodiment.In synthetic schemes 5, substituted dichloro pyrimidine (20) with carry Protection group optionally substituted heterocyclic compound (21) in alkali, in the presence of triethylamine or diisopropyl ethyl amine, generate and appoint Choose generation heteroaryl compound (22).Compound (22) and optionally substituted 1- methyl isophthalic acid H- pyrazoles -4- ammonia (23) or its salt Hydrochlorate, in alkali, such as diisopropyl ethyl amine, triethylamine or Cs₂CO₃Or in acid, such as trifluoroacetic acid, the ethyl acetate of hydrogen chloride Solution, or in suitable Pd catalyst, such as under the catalytic action of palladium, reacting generating compound (24).Compound (24) in Blocking group can in acid condition, such as trifluoroacetic acid, the ethyl acetate solution of hydrogen chloride, or the effect in hydrazine hydrate Under, or under otherwise suitable conditions, such as remove under the conditions of tetrabutyl ammonium fluoride, obtain kinases inhibitor (25).Suitable Under conditions of to compound (25) in introduce different substituent groups, can obtain with formula (26) shown in structure protein kinase suppression Preparation.

Preparation embodiment

Embodiment 1 1- (5- ((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) pyrimidine - 4- yl) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone

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

LAH (22.80g, 600mmol) is suspended in THF (600mL), at 0 DEG C, is added dropwise to tetrahydrochysene phthaloyl thereto by several times Imines (39.45g, 260.9mmol).Add rear reaction system to stir 18 hours at 60 DEG C, be subsequently cooled to 0 DEG C, delay successively Slow addition water (25mL), 15%KOH aqueous solution (25mL) and water (75mL), continue stirring 1 hour, silicon under gained mixture room temperature Diatomaceous earth filters, and washs filter cake, filtrate reduced in volume with DCM (500mL), and obtaining product iso-indoles is yellow oil, and this slightly produces Thing is directly used in next step reaction.

This crude product is dissolved in DCM (300mL), at 0 DEG C, is added thereto to Et successively₃N(39.61g,391.4mmol) (Boc)₂O (68.32g, 313.1mmol), added in 0.5 hour, moved to room temperature after adding, and continued stirring 21 hours.Will be anti- Answer mixture concentrating under reduced pressure, gained residue is dissolved in EtOAc (600mL), then successively use aqueous citric acid solution (1M, 2 × 130mL), saturation NaHCO₃Aqueous solution (2 × 130mL), saturated aqueous common salt (250mL) washing, the organic layer isolated is with anhydrous Sodium sulfate is dried, and filters and concentrating under reduced pressure, and gained residue, through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purification, obtains mark Topic compound is Chinese red grease (45.00g, yield 77.3%).

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

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

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

3a, 4,7,7a- tetrahydrochysene -1H- iso-indoles -2 (3H)-t-butyl formate (4.91g, 22mmol) and (NH₄)₂SO₄ (1.55g, 12mmol) is dissolved in H₂In O (40mL), at 5 DEG C, it is dividedly in some parts KMnO thereto₄(8.20g, 52mmol), 0.5 Add in hour, after adding, reactant liquor continues stirring 6 hours at 5 DEG C, then filters, filter cake is washed with water (40mL × 3), Filtrate uses CH₂Cl₂(40mL × 3) extract, and water layer is adjusted to pH=2～3 with the aqueous hydrochloric acid solution of 3M, then use EtOAc (50mL × 3) extract, the organic faciess of merging are washed with saline solution (50mL × 3), anhydrous Na₂SO₄It is dried, be filtered, and concentrated under reduced pressure to give pale yellow Color solid (4.52g, yield 71.5%).

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

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

Step 3) 5- oxo hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate

Will be molten for 2,2'- (1- (tertbutyloxycarbonyl) tetrahydro pyrrolidine -3,4- diyl) acetoacetic acid (3.40g, 11.8mmol) Solution is in Ac₂In O (21mL), and it is added thereto to NaOAc (0.78g, 9.5mmol).Reactant liquor reacts 3 hours at 120 DEG C, so After be down to room temperature and filter, filter cake is washed with EtOAc (20mL × 2), and by filtrate reduced in volume, gained residue is through silica gel column layer Analysis (PE/EtOAc (v/v)=1/4) purification, obtaining title compound is crocus grease (1.38g, yield 55.0%).

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

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

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

By 5- oxo hexahydro Pentamethylene., simultaneously [c] pyrroles -2 (1H)-t-butyl formate (9.57g, 42.5mmol) is dissolved in DCM (170mL), in, at 0 DEG C, it is added thereto to BnNH₂(4.56g, 42.5mmol) and AcOH (2.55g, 42.5mmol), after adding, Reactant liquor stirs 0.5 hour at 0 DEG C.Then, it is added thereto to NaBH (OAc) in batches₃(18.00g, 85.0mmol), gained Mixture continues to stir 20 hours at room temperature.Add saturation NaHCO₃Aqueous solution (142mL) is quenched reaction, then uses DCM (250mL × 3) extract.The organic faciess merging are washed with saturated aqueous common salt (250mL × 3), anhydrous Na₂SO₄It is dried, filter and subtract Pressure concentrates.Through silica gel column chromatography (EtOAc, 100%) purification, obtain title compound is yellow solid to gained residue (7.44g, yield 55.3%).

LC-MS(ESI,pos.ion)m/z:317.3[M+H]⁺；

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

Step 5) 5- amino hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate

By 5- (benzyl amino)) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate (6.50g, 20.5mmol) and AcOH (1.23g, 20.5mmol) is dissolved in MeOH (150mL), is added thereto to Pd (OH)₂/ C (mass fraction 10%, 1.00g), gained reaction system is warming up to 40 DEG C, is stirred overnight in atmosphere of hydrogen.Gained reactant mixture is through kieselguhr mistake Filter, filtrate reduced in volume, gained residue is dissolved in saturation NaHCO₃In aqueous solution (70mL), then use DCM (100mL × 3) Extraction, the organic faciess of merging are washed with saline solution (100mL × 3), anhydrous Na₂SO₄It is dried, be filtered, and concentrated under reduced pressure to give title Compound is light yellow solid (4.00g, yield 86.2%).

LC-MS(ESI,pos.ion)m/z:227.2[M+H]⁺；

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

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

By 5- amino hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate (3.11g, 13.74mmol) and 2,4,5- Trichloropyrimidine (1.46g, 7.96mmol) is dissolved in EtOH (60mL), is added thereto to Et₃N(2.21g,21.84mmol).Plus After complete, reactant mixture is stirred overnight at normal temperatures, after reaction terminates, concentrating under reduced pressure.Gained residue is dissolved in EtOAc (50mL) and in the mixed solvent of water (50mL), with EtOAc (150mL × 3) extraction, the organic faciess saturated aqueous common salt of merging (150mL) wash, anhydrous Na₂SO₄It is dried, filter and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v) =5/1) purification, obtaining title compound is yellow solid (2.97g, yield 100%).

LC-MS(ESI,pos.ion)m/z:373.0[M+H]⁺.

Step 7) N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine

To 5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate In dichloromethane (40mL) solution of (3.36g, 9.00mmol) add hydrogen chloride ethyl acetate solution (20mL, 80mmol, 4M).After gained reaction system stirs 2 hours at normal temperatures, concentrating under reduced pressure.Gained residue is dissolved in water (20mL), to institute Obtain and in solution, add saturated sodium bicarbonate aqueous solution to be adjusted to pH=8～9, then use DCM/MeOH (v/v=10/1,50mL × 6) extract.The organic faciess merging are washed with saturated aqueous common salt (100mL), anhydrous Na₂SO₄It is dried, filter and concentrating under reduced pressure, institute Obtain residue through silica gel column chromatography (MeOH/DCM (v/v)=1/10 to 1/5) purification, obtaining title compound is yellow solid (2.45g, yield 99.6%).

MS(ESI,pos.ion)m/z:273.2[M+H]⁺.

Step 8) 1- (5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone

To N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (1.3g, 4.8mmol) and acetic anhydride In dichloromethane (30mL) solution of (0.58g, 5.7mmol), add triethylamine (0.96g, 9.5mmol).Reactant mixture exists Stir 10 minutes under room temperature.Then, concentrating under reduced pressure.Gained residue is pure through silica gel column chromatography (DCM/MeOH (v/v)=100/1) Change, obtaining title compound is white solid (1.14g, yield 76%).

LC-MS(ESI,pos.ion)m/z:315.2.[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.01 (s, 1H), 5.57 (d, J=6.9Hz, 1H), 4.56-4.40 (m, 1H), 3.65-3.55 (m, 3H), 3.39 (dd, J=10.9,3.4Hz, 1H), 2.84-2.65 (m, 2H), 2.52 (dq, J= 15.5,7.6Hz,2H),2.06(s,3H),1.44-1.31(m,2H).

Step 9) 2- methyl isophthalic acid-(4- nitro -1H- pyrazol-1-yl) propan-2-ol

To 4- nitro -1H- pyrazoles (1.01g, 8.93mmol) and 2,2- dimethyl propylene oxide (1.94g, 26.9mmol) DMF (20mL) solution in add cesium carbonate (5.76g, 17.7mmol), gained reaction system stirs 3.5 hours at 100 DEG C. Add water and (100mL) reaction is quenched, and extracted with ethyl acetate (250mL × 3).The organic faciess saturated aqueous common salt merging (100mL) wash, anhydrous Na₂SO₄It is dried, filter and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v) =4/1) purification, obtaining title compound is yellow oil (1.52g, yield 91.9%).

LC-MS(ESI,pos.ion)m/z:186.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.26(s,1H),8.07(s,1H),4.11(s,2H),1.22(s, 6H).

Step 10) 1- (4- amino -1H- pyrazol-1-yl) -2- methyl propan-2-ol

Molten to the methanol (50mL) of 2- methyl isophthalic acid-(4- nitro -1H- pyrazol-1-yl) propan-2-ol (1.52g, 8.21mmol) In liquid, add Pd/C (150mg, mass fraction 10%).Reaction system is placed in autoclave, in the atmosphere of hydrogen of 2MPa under room temperature In be stirred overnight, then filter.It is purple grease (1.2g, yield 94%) that filtrate reduced in volume obtains title compound.

LC-MS(ESI,pos.ion)m/z:156.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.19(s,1H),7.03(s,1H),3.91(s,2H),1.82(s, 2H),1.13(s,6H).

Step 11) 1- (5- ((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) pyrimidine - 4- yl) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone

To 1- (4- amino -1H- pyrazol-1-yl) -2- methyl propan-2-ol (63mg, 0.405mmol) and 1- (5- ((2,5- Dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) and ethyl ketone (100mg, 0.317mmol) 1,4- bis- Cesium carbonate (207mg, 0.635mmol), palladium (14mg, 0.063mmol) and BINAP is added in oxygen six ring (6mL) solution (39mg,0.063mmol).After gained reaction system is stirred overnight at 100 DEG C, concentrating under reduced pressure.Gained residue is through silicagel column Chromatography (PE/EtOAc (v/v)=25/1) purification, obtaining title compound is yellow solid (82mg, yield 59.6%).

LC-MS(ESI,pos.ion)m/z:434.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.86(s,1H),7.74(s,1H),7.60(s,1H),6.77(s, 1H), 5.24 (d, J=7.2Hz, 1H), 4.40 (m, 1H), 4.01 (s, 2H), 3.63 (m, 3H), 3.39 (dd, J=10.8, 3.4Hz,1H),2.81-2.69(m,2H),2.52-2.45(m,2H),2.07(s,3H),1.49-1.41(m,2H),1.18(s, 6H).

Embodiment 2 3- (5- ((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) pyrimidine - 4- yl) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- oxypropionitrile

Step 1) 3- (5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- Oxypropionitrile

To N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (1.3g, 4.8mmol), 2- cyano group The dichloromethane (30mL) of acetic acid (0.81g, 9.5mmol), EDCI (1.8g, 9.4mmol) and HOAT (1.3g, 9.6mmol) is molten Triethylamine (1.4g, 14mmol) is added in liquid.Gained reaction system stirs 3.5 hours at normal temperatures.Then, concentrating under reduced pressure.Institute Obtain residue through silica gel column chromatography (DCM/MeOH (v/v)=100/1) purification, obtaining title compound is white solid (1.16g, yield 72%).

LC-MS(ESI,pos.ion)m/z:340.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.00 (s, 1H), 5.75 (d, J=7.4Hz, 1H), 4.51 (ddd, J= 17.4,7.5,2.6Hz,1H),3.71-3.58(m,3H),3.50-3.42(m,3H),2.90-2.67(m,2H),2.51(dq,J =14.4,7.2Hz, 2H), 1.50-1.37 (m, 2H).

Step 2 3- (5- ((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) pyrimidine -4- Base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- oxypropionitrile

To 1- (4- amino -1H- pyrazol-1-yl) -2- methyl propan-2-ol (63mg, 0.405mmol) and 3- (5- ((2,5- Dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- oxypropionitrile (100mg, 0.293mmol) 1,4- dioxane (6mL) solution in add cesium carbonate (192mg, 0.589mmol), palladium (13mg, 0.057mmol) and BINAP(39mg,0.057mmol).Gained reaction system is stirred overnight at 100 DEG C, then concentrating under reduced pressure.Gained residue warp Silica gel column chromatography (PE/EtOAc (v/v)=30/1) purification, obtaining title compound is yellow solid (64mg, yield 47.5%).

LC-MS(ESI,pos.ion)m/z:459.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.87(s,1H),7.73(s,1H),7.61(s,1H),6.78(s, 1H), 5.25 (d, J=6.0Hz, 1H), 4.41 (d, J=7.4Hz, 1H), 4.02 (s, 2H), 3.66 (d, J=24.5Hz, 4H), 3.43(s,2H),2.89-2.73(m,2H),2.56-2.47(m,2H),1.47-1.42(m,2H),1.19(s,6H).

Embodiment 3 3- (5- ((the chloro- 2- of 5- ((1- (piperidines -3- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- oxypropionitrile

Step 1) 3- hydroxy piperidine -1- t-butyl formate

To in DCM (20mL) solution of piperidin-3-ol (1.13g, 11.2mmol) and triethylamine (3.05g, 30.2mmol) Add Bis(tert-butoxycarbonyl)oxide (2.60g, 11.9mmol).Gained reaction system stirs concentrating under reduced pressure after 1 hour at normal temperatures.Institute Residue through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purification, obtain title compound be weak yellow liquid (1.88g, Yield 83.6%).

LC-MS(ESI,pos.ion)m/z:146.3[(M+H)–56]⁺.

Step 2) 3- (4- nitro -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

At 0 DEG C, in atmosphere of inert gases, to 4- nitro -1H- pyrazoles (801.2mg, 7.085mmol), triphenylphosphine Drip in THF (30mL) solution of (2.79g, 10.6mmol) and 3- hydroxy piperidine -1- t-butyl formate (1.64g, 8.15mmol) Plus THF (20mL) solution of diisopropyl azodiformate (2.17g, 10.7mmol), drip off in 30 minutes.Reaction system is 0 Stir 1 hour at DEG C, then move to and under room temperature, continue stirring 18 hours, concentrating under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/10) purification, obtaining title compound is white solid (1.92g, yield 91%)

LC-MS(ESI,pos.ion)m/z:241.3[M+H–56]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.26(s,1H),8.09(s,1H),4.28-4.20(m,1H),4.13 (d, J=10.9Hz, 1H), 3.79 (dt, J=13.2,4.3Hz, 1H), 3.51-3.41 (m, 1H), 3.13 (ddd, J=13.3, 9.7,3.4Hz,1H),2.21-2.13(m,2H),1.80-1.70(m,1H),1.65-1.62(m,1H),1.47(s,9H).

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

Ethanol to 3- (4- nitro -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (1.08g, 3.64mmol) (30mL) add Pd/C (300mg, mass fraction 10%) in solution.At normal temperatures, in atmosphere of hydrogen, reaction 2.5 is little for reaction system When.Filter, filter cake is washed with methanol (150mL), it is yellow oil (860mg, yield that filtrate reduced in volume obtains title compound 88%).

LC-MS(ESI,pos.ion)m/z:267.4[M+H]⁺.

Step 4) 3- (4- ((the chloro- 4- of 5- ((2- (2- Cyanoacetyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) Pyrimidine -2-base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

3- (4- amino -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (253.6mg, 0.9523mmol), 3- (5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-base -3- oxypropionitrile (208.7mg, 0.6135mmol), palladium (14.7mg, 0.0655mmol), BINAP (35.4mg, 0.0568mmol) and cesium carbonate (578.3mg, 1.775mmol) is dissolved in 1,4- dioxane (10mL).Reaction system is warming up to backflow, in atmosphere of inert gases Middle stirring 3 hours, concentrating under reduced pressure.Gained residue, through silica gel column chromatography (DCM/MeOH (v/v)=45/1) purification, obtains titled Compound is white solid (86mg, yield 24.6%)

LC-MS(ESI,pos.ion)m/z:570.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.87(s,1H),7.73(s,1H),7.57(s,1H),6.75(s, 1H), 5.24 (d, J=7.1Hz, 1H), 4.49-4.36 (m, 1H), 4.33-4.25 (m, 1H), 4.15-4.06 (m, 1H), 4.05- 3.94(m,1H),3.74-3.58(m,3H),3.47-3.41(m,3H),3.20-3.06(m,1H),2.90-2.74(m,3H), 2.57-2.47(m,2H),2.26-2.17(m,1H),2.10-1.95(m,1H),1.86-1.75(m,2H),1.47-1.42(m, 11H).

Step 5) 3- (5- ((the chloro- 2- of 5- ((1- (piperidines -3- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) Hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- oxypropionitrile

By 3- (4- ((the chloro- 4- of 5- ((2- (2- Cyanoacetyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) pyrimidine - 2- yl) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (86mg, 0.1509mmol) is dissolved in the acetic acid second of hydrogen chloride In ester solution (3mL, 1.5mmol, 0.5M), stir 0.5 hour under gained reaction system room temperature.Saturation is added in reaction system Aqueous sodium carbonate (20mL), the mixture mixed extractant solvent of DCM/MeOH (v/v=10/1,40mL × 6), the having of merging Machine layer, through anhydrous sodium sulfate drying, filters and concentrating under reduced pressure.Gained residue is through preparing the thin layer chromatography (NH of DCM/7M₃ MeOH solution (v/v)=10/1) obtain title compound be faint yellow solid (20.3mg, yield 28.6%).

LC-MS(ESI,pos.ion)m/z:470.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃+CD₃OD)δ(ppm):7.74 (d, J=5.6Hz, 2H), 7.55 (d, J=3.9Hz, 1H),4.65-4.57(m,1H),4.42-4.32(m,1H),3.70-3.56(m,3H),3.34-3.23(m,6H),3.02-2.93 (m,1H),2.89-2.82(m,1H),2.78-2.70(m,1H),2.48-2.39(m,2H),2.16-2.09(m,1H),2.06- 2.00(m,1H),1.98-1.90(m,2H),1.44-1.34(m,2H).

Embodiment 4 1- (5- ((the chloro- 2- of 5- ((1- (piperidines -3- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone

Step 1) 3- (4- ((4- ((2- acetyl group octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) -5- chloropyrimide -2- Base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

By 3- (4- amino -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (251.8mg, 0.9456mmol), 1- (5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone (204.3mg, 0.6482mmol), palladium (14.9mg, 0.0664mmol), BINAP (37.6mg, 0.0604mmol) and cesium carbonate (618.6mg, 1.899mmol) is dissolved in 1,4- dioxane (10mL).Reaction system, in atmosphere of inert gases, is warming up to back Stream stirring 3 hours, then concentrating under reduced pressure.Gained residue, through silica gel column chromatography (DCM/MeOH (v/v)=40/1) purification, obtains mark Topic compound is faint yellow solid (185mg, yield 52.4%).

LC-MS(ESI,pos.ion)m/z:545.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.85(s,1H),7.74(s,1H),7.57(s,1H),6.78(s, 1H), 5.39 (d, J=7.0Hz, 1H), 5.11-5.04 (m, 1H), 5.00-4.94 (m, 1H), 4.47-4.36 (m, 1H), 4.35- 4.24 (m, 1H), 4.14-4.05 (m, 1H), 4.05-3.94 (m, 1H), 3.65-3.49 (m, 3H), 3.37 (ddd, J=11.0, 7.6,3.5Hz,1H),3.18-3.07(m,1H),2.86-2.63(m,3H),2.56-2.43(m,2H),2.25-2.17(m, 1H), 2.05 (d, J=3.2Hz, 3H), 2.03-1.95 (m, 1H), 1.45 (s, 9H), 1.38-1.34 (m, 2H).

Step 2) 1- (5- ((the chloro- 2- of 5- ((1- (piperidines -3- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) Hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone

By 3- (4- ((4- ((2- acetyl group octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) -5- chloropyrimide -2- base) ammonia Base) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (185mg, 0.3394mmol) is dissolved in the ethyl acetate solution of hydrogen chloride In (6mL, 3mmol, 0.5M), reaction system is stirred at room temperature 30 minutes.Reaction washes with water (20mL × 2) after terminating, and merges Aqueous phase saturated aqueous sodium carbonate be adjusted to pH=10, then use DCM/MeOH mixed solvent (v/v=10/1,50mL × 6) extract.The organic layer anhydrous sodium sulfate drying merging, filters and concentrating under reduced pressure, gained residue is through preparing ripple layer chromatography (the NH of DCM/7M₃MeOH solution (v/v)=10/1) purification, obtain title compound be faint yellow solid (68.3mg, yield 45.2%).

LC-MS(ESI,pos.ion)m/z:445.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.86(s,1H),7.79(s,1H),7.57(s,1H),6.81(s, 1H), 5.25 (d, J=7.1Hz, 1H), 4.52-4.35 (m, 2H), 3.68-3.58 (m, 3H), 3.55 (dd, J=12.5, 3.2Hz, 1H), 3.39 (dd, J=10.9,3.3Hz, 1H), 3.32-3.22 (m, 2H), 2.98-2.90 (m, 1H), 2.83-2.70 (m,2H),2.54-2.43(m,2H),2.26-2.18(m,1H),2.11-2.03(m,4H),1.96-1.82(m,2H),1.49- 1.38(m,2H).

Embodiment 5 3- (5- ((the chloro- 2- of 5- ((1- (piperidin-4-yl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- oxypropionitrile

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

Drip in the oxolane (20mL) of piperidines -4- alcohol (2g, 19.773mmol) and triethylamine (4g, 39.530mmol) Plus dimethyl dicarbonate butyl ester (5.2g, 24mmol).After gained reaction system is stirred at room temperature overnight, concentrating under reduced pressure.Gained remains Through silica gel column chromatography (PE/EtOAc (v/v)=1/10 to 1/5) purification, obtain title compound is that (3.91g produces white solid to thing Rate 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, 4.9687mmol), 4- nitro -1H- pyrazoles (675mg, 5.9692mmol) add azoformic acid with anhydrous tetrahydro furan (50mL) solution of triphenylphosphine (1.96g, 7.47mmol) Diisopropyl ester (1.5mL, 7.6mmol), dripped off in 30 minutes.Reaction system is stirred at room temperature 1 hour, then moves to room temperature and stirs Mix overnight.By reactant mixture concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=20/1 to 4/1) Purification, 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

Ethanol to 4- (4- nitro -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (1.35g, 4.56mmol) (30mL) add Pd/C (135mg, mass fraction 10%) in solution.Reaction system is reacted 2 hours in room temperature, atmosphere of hydrogen, Then, reactant mixture filters, filtrate reduced in volume.Through silica gel column chromatography, (DCM/MeOH (v/v)=50/1 arrives gained residue 25/1) purification, obtaining title compound is brown oil (955mg, yield 78.7%).

LC-MS(ESI,pos.ion)m/z:211.1[M–55]⁺.

Step 4) 4- (4- ((the chloro- 4- of 5- ((2- (2- Cyanoacetyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) Pyrimidine -2-base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

To 3- (5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-base -3- oxo third Nitrile (350mg, 1.029mmol), 4- (4- amino -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (411mg, 1.543mmol) In Isosorbide-5-Nitrae-dioxane (25mL) solution of cesium carbonate (1.1g, 3.4mmol), add palladium (23.1mg, 0.103mmol) With BINAP (64.1mg, 0.103mmol).Reaction system re-fills nitrogen after deaerating 2 minutes, then heats to 105 DEG C, stirs Mix 2 hours.Reactant mixture concentrating under reduced pressure, residue through silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 25/1) purification, Obtaining title compound is faint yellow solid (254mg, yield 43.31%).

LC-MS(ESI,pos.ion)m/z:570.3[M+H]⁺

Step 5) 3- (5- ((the chloro- 2- of 5- ((1- (piperidin-4-yl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) Hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- oxypropionitrile

To 4- (4- ((the chloro- 4- of 5- ((2- (2- Cyanoacetyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) pyrimidine - 2- yl) amino) -1H- pyrazol-1-yl) and piperidines -1- t-butyl formate (254mg, 0.4455mmol) dichloromethane (12mL) molten The ethyl acetate solution (6mL, 24mmol, 4M) of hydrogen chloride is added in liquid.After gained reaction system stirs 30 minutes at normal temperatures, Concentrating under reduced pressure.Gained residue is dissolved in water (20mL), is added thereto to saturated sodium bicarbonate aqueous solution and solution is adjusted to pH =8～9, then use mixed solvent (v/v=10/1,50mL × 6) extraction of DCM/MeOH.The organic faciess saturated common salt merging Water (100mL) washs, anhydrous Na 2SO₄It is dried, filter and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/10) purification, obtaining title compound is faint yellow solid (77mg, yield 36.77%).

LC-MS(ESI,pos.ion)m/z:470.5[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.04(s,1H),7.86(s,1H),7.83(s,1H),7.45(s, 1H), 6.91 (d, J=7.6Hz, 1H), 4.49 (dd, J=15.6,7.8Hz, 1H), 4.21 (t, J=11.3Hz, 1H), 3.93 (s, 2H), 3.39 (d, J=6.2Hz, 2H), 3.14 (d, J=17.7Hz, 4H), 2.71 (dd, J=34.0,23.2Hz, 4H), 2.24 (dd, J=12.0,6.3Hz, 2H), 2.01 (d, J=11.4Hz, 2H), 1.84 (dd, J=20.6,11.5Hz, 2H), 1.53 (dd, J=13.9,7.9Hz, 2H).

Embodiment 6 1- (5- ((the chloro- 2- of 5- ((1- (piperidin-4-yl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone

Step 1) 4- (4- ((4- ((2- acetyl group octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) -5- chloropyrimide -2- Base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

To 1- (5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone (350mg, 1.110mmol), 4- (4- amino -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (443.6mg, 1.666mmol) In Isosorbide-5-Nitrae-dioxane (25mL) solution of cesium carbonate (1.1g, 3.4mmol), add palladium (25mg, 0.1114mmol) With BINAP (69.2mg, 0.111mmol).Reaction system re-fills nitrogen after deaerating 2 minutes.Gained reaction system is at 105 DEG C After lower stirring 2 hours, concentrating under reduced pressure.Gained residue through silica gel column chromatography (MeOH/DCM (v/v)=50/1 to 25/1) purification, Obtaining title compound is faint yellow solid (585mg, yield 96.65%).

LC-MS(ESI,pos.ion)m/z:545.5[M+H]⁺.

Step 2) 1- (5- ((the chloro- 2- of 5- ((1- (piperidin-4-yl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) Hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone

To 4- (4- ((4- ((2- acetyl group octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) -5- chloropyrimide -2- base) ammonia Base) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (585mg, 1.073mmol) dichloromethane (12mL) solution in add The ethyl acetate solution (6mL, 24mmol, 4M) of hydrogen chloride.Reaction system is stirred at room temperature 30 minutes, then concentrating under reduced pressure. Gained residue is dissolved in water (20mL), be added thereto to saturated sodium bicarbonate aqueous solution by resulting solution be adjusted to pH=8～ 9, then use mixed solvent (v/v=10/1,50mL × 6) extraction of DCM/MeOH.The organic faciess saturated aqueous common salt merging (100mL) wash, anhydrous Na₂SO₄It is dried, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v) =1/10) purification, obtaining title compound is white solid (375mg, yield 78.52%).

LC-MS(ESI,pos.ion)m/z:445.4[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.04(s,1H),7.86(s,1H),7.84(s,1H),7.45(s, 1H), 6.94 (d, J=7.7Hz, 1H), 4.49 (td, J=9.8,2.1Hz, 1H), 4.18 (td, J=11.3,5.7Hz, 1H), 3.41 (dd, J=8.8,5.2Hz, 4H), 3.12 (d, J=12.6Hz, 2H), 2.71 (t, J=11.3Hz, 3H), 2.64-2.53 (m, 1H), 2.24 (dd, J=12.0,5.8Hz, 2H), 2.00 (d, J=10.8Hz, 2H), 1.95 (s, 3H), 1.82 (tt, J= 11.8,6.1Hz,2H),1.59-1.45(m,2H).

Embodiment 7 3- (5- ((the chloro- 2- of 5- ((1- (pyridine -2- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- oxypropionitrile

Step 1) 2- (4- nitro -1H- pyrazol-1-yl) pyridine

DMF to 4- nitro -1H- pyrazoles (2.01g, 17.7mmol) and 2- iodo-pyridin (4.37g, 21.3mmol) (20mL) Copper diiodide (674mg, 3.54mmol), cesium carbonate (11.6g, 35.5mmol) and hexamethylene -1,2- two are added in solution Amine (407mg, 3.56mmol), then, reaction system stirs 4 hours at 100 DEG C.Add water (100mL) reaction is quenched, gained mix Compound is extracted with EtOAc (250mL × 3).The organic faciess merging are washed with saturated aqueous common salt (100mL), anhydrous Na₂SO₄It is dried, Filter and concentrating under reduced pressure, through silica gel column chromatography (PE/EtOAc (v/v)=15/1) purification, obtain title compound is gained residue White solid (1.8g, yield 53.6%).

LC-MS(ESI,pos.ion)m/z:191.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.28(s,1H),8.51-8.47(m,1H),8.26(s,1H),8.06- 8.02(m,1H),7.94-7.88(m,1H),7.37-7.33(m,1H).

Step 2) 1- (pyridine -2- base) -1H- pyrazoles -4- amine

To in methanol (80mL) solution of 2- (4- nitro -1H- pyrazol-1-yl) pyridine (1.52g, 8.21mmol), add Pd/C (210mg, mass fraction 10%).Reaction system is placed in autoclave, stirred in the atmosphere of hydrogen of 2MPa under room temperature At night, then, filter, it is purple grease (1.62g, yield 98.6%) that filtrate reduced in volume obtains title compound.

LC-MS(ESI,pos.ion)m/z:161.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.35 (d, J=3.9Hz, 1H), 8.09 (d, J=0.4Hz, 1H), 7.89 (d, J=8.3Hz, 1H), 7.78-7.72 (m, 1H), 7.41 (s, 1H), 7.13-7.08 (m, 1H), 3.10 (s, 2H).

Step 3) 5- ((the chloro- 2- of 5- ((1- (pyridine -2- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) six Hydrogen Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate

To 5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate The 1,4- dioxane of (501mg, 1.34mmol) and 1- (pyridine -2- base) -1H- pyrazoles -4- amine (259mg, 1.62mmol) (20mL) add in solution palladium (60mg, 0.267mmol), BINAP (167mg, 0.268mmol) and cesium carbonate (872mg, 2.67mmol).After gained reaction system is stirred overnight at 108 DEG C, concentrating under reduced pressure.Gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=3/1) purification, obtaining title compound is yellow solid (589mg, yield 88.3%).

LC-MS(ESI,pos.ion)m/z:497.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.91 (s, 1H), 8.35 (d, J=4.5Hz, 1H), 7.95 (d, J= 8.3Hz,1H),7.90(s,1H),7.81-7.75(m,2H),7.17-7.12(m,1H),6.85(s,1H),5.35-5.31(m, 1H),4.54-4,50(m,1H),3.51-3.38(m,4H),2.80-2.78(m,2H),2.60-2.51(m,2H),1.47(s, 9H),1.44-1.39(m,2H).

Step 4) the chloro- N of 5- ⁴ - (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base)-N ² - (1- (pyridine -2- base) -1H- pyrazoles -4- Base) pyrimidine -2,4- diamidogen

To 5- ((the chloro- 2- of 5- ((1- (pyridine -2- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro ring Pentane simultaneously adds chlorination in dichloromethane (20mL) solution of [c] pyrroles -2 (1H)-t-butyl formate (589mg, 1.19mmol) The ethyl acetate solution (10mL, 30mmol, 3M) of hydrogen.After gained reaction system is stirred at room temperature overnight, concentrating under reduced pressure.Gained Residue is dissolved in ethyl acetate (20mL), is added thereto to saturated sodium bicarbonate aqueous solution and is adjusted to pH=10, Ran Houyong EtOAc (50mL × 3) extracts.The organic faciess merging are washed with saturated aqueous common salt (50mL × 3), anhydrous Na 2SO₄It is dried, filter And it is concentrated under reduced pressure to give title compound for yellow solid (400mg, yield 85.1%).

LC-MS(ESI,pos.ion)m/z:397.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.85 (s, 1H), 8.37 (d, J=3.8Hz, 1H), 7.94 (d, J= 8.3Hz, 1H), 7.84 (d, J=9.0Hz, 2H), 7.80-7.75 (m, 1H), 7.59 (d, J=9.0Hz, 1H), 7.16-7.12 (m,1H),6.68(s,1H),4.61-4.56(m,1H),2.89-2.87(m,4H),2.74-2.72(m,2H),2.38-2.32 (m,2H),1.49-1.44(m,2H).

Step 5) 3- (5- ((the chloro- 2- of 5- ((1- (pyridine -2- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) Hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- oxypropionitrile

To the chloro- N of 5-⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base)-N²- (1- (pyridine -2- base) -1H- pyrazoles -4- base) is phonetic In dichloromethane (5mL) solution of pyridine -2,4- diamidogen (100mg, 0.252mmol) and 2- cyanoacetic acid (25mg, 0.294mmol) Add EDCI (97mg, 0.506mmol), HOAT (68mg, 0.501mmol) and Et₃N(54mg,0.533mmol).Gained reacts System stirs concentrating under reduced pressure after 6 hours at normal temperatures.Gained residue is pure through silica gel column chromatography (MeOH/DCM (v/v)=10/1) Change, obtaining title compound is white solid (50.1mg, yield 72.8%).

LC-MS(ESI,pos.ion)m/z:464.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.41 (s, 1H), 8.91 (s, 1H), 8.42 (d, J=4.1Hz, 1H), 7.96 (d, J=6.4Hz, 1H), 7.88 (d, J=8.2Hz, 1H), 7.78 (s, 1H), 7.31-7.26 (m, 1H), 7.09 (s,1H),4.60-4.57(m,1H),3.94(s,2H),3.65-3.48(m,3H),3.46-3.41(m,2H),2.76-2.72 (m,2H),2.35-2.31(m,2H),1.58-1.51(m,2H).

Embodiment 8 1- (5- ((the chloro- 2- of 5- ((1- (pyridine -2- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone

To the chloro- N of 5-⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base)-N²- (1- (pyridine -2- base) -1H- pyrazoles -4- base) is phonetic Add in dichloromethane (5mL) solution of pyridine -2,4- diamidogen (100mg, 0.252mmol) and cyanoacetic acid (31mg, 0.304mmol) Enter triethylamine (57mg, 0.563mmol).Gained reaction system is stirred at room temperature overnight rear concentrating under reduced pressure.Gained residue warp Prepare thin layer chromatography (PE/EtOAc (v/v)=20/1) purification, obtaining title compound is yellow solid (80mg, yield 72.3%).

LC-MS(ESI,pos.ion)m/z:439.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.91 (s, 1H), 8.34 (d, J=4.0Hz, 1H), 7.96 (d, J= 8.3Hz,1H),7.90(s,1H),7.82-7.76(m,2H),7.17-7.13(m,1H),6.96(s,1H),5.32-5.28(m, 1H),4.57-4.53(m,1H),3.69-3.61(m,3H),3.44-3.39(m,1H),2.94-2.80(m,2H),2.65-2.59 (m,2H),2.08(s,3H),1.48-1.41(m,2H).

The chloro- N of embodiment 9 5- ² - (1- (6- methoxypyridine -3- base) -1H- pyrazoles -4- base)-N ⁴ - (octahydro Pentamethylene. is simultaneously [c] pyrroles -5- base) pyrimidine -2,4- diamidogen

Step 1) the chloro- 5- of 2- (4- nitro -1H- pyrazol-1-yl) pyridine

2- chloro- 5- iodine is added in dry DMF (80.0mL) solution of 3- nitro -1H- pyrazoles (2.50g, 22.11mmol) Pyridine (6.36g, 26.55mmol), Hydro-Giene (Water Science). (0.85g, 4.47mmol), hexamethylene -1,2- diamidogen (0.52g, 4.54mmol) with cesium carbonate (14.54g, 44.62mmol).Reaction system re-fills nitrogen after deaerating 2 minutes, then heats up To 100 DEG C, it is stirred overnight.Reaction system adds ethyl acetate (100mL) dilution, filters, and filter cake is washed with methanol (550mL), filter Liquid concentrating under reduced pressure.Through silica gel column chromatography (EA/PE (v/v)=1/4 to 1/2) purification, it is light for obtaining title compound to gained residue Yellow solid (0.36g, yield 7%).

LC-MS(ESI,pos.ion)m/z:225.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.80 (d, J=2.8Hz, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.07 (dd, J=8.6,2.9Hz, 1H), 7.53 (d, J=8.6Hz, 1H).

Step 2) 2- methoxyl group -5- (4- nitro -1H- pyrazol-1-yl) pyridine

It is suspended to the MeOH (15.0mL) of the chloro- 5- of 2- (4- nitro -1H- pyrazol-1-yl) pyridine (0.36g, 1.60mmol) In liquid, add the methanol solution (5.0mL, 25.0mmol, 5mol/L) of Feldalat NM.It is little that reaction system is warming up to 50 DEG C of stirrings 12 When, after reaction terminates, concentrating under reduced pressure.Gained residue add water (15.0mL) dilution, then filter.Filter cake water (5.0mL) is washed, Filtrate add methylene chloride (20mL × 3) extraction.The organic layer anhydrous sodium sulfate drying merging, filters and concentrating under reduced pressure, gained After residue is merged with filter cake, it is yellow solid (0.32g, yield 91%) that drying under reduced pressure obtains title compound.

LC-MS(ESI,pos.ion)m/z:221.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.53 (s, 1H), 8.49 (d, J=2.7Hz, 1H), 8.27 (s, 1H), 7.92 (dd, J=8.9,2.8Hz, 1H), 6.90 (d, J=8.9Hz, 1H), 4.00 (s, 3H).

Step 3) 1- (6- methoxypyridine -3- base) -1H- pyrazoles -4- amine

MeOH (10.0mL) to 2- methoxyl group -5- (4- nitro -1H- pyrazol-1-yl) pyridine (0.32g, 1.50mmol) Pd/C (0.067g, mass fraction 10%) is added in suspension.Reaction system at room temperature, in atmosphere of hydrogen, stirs 1 hour, Then filter.Filter cake is washed with methanol (10.0mL), filtrate reduced in volume.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/1 NH arriving DCM/3M₃MeOH solution (v/v)=20/1) purification, obtain title compound be black solid (0.15g, yield 54%).

LC-MS(ESI,pos.ion)m/z:191.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.48 (d, J=2.7Hz, 1H), 8.02 (dd, J=8.9,2.8Hz, 1H), 7.66 (s, 1H), 7.26 (s, 1H), 6.90 (d, J=8.9Hz, 1H), 4.17 (s, 2H), 3.87 (s, 3H).

Step 4) 5- ((the chloro- 2- of 5- ((1- (6- methoxypyridine -3- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate

To 5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate In anhydrous Isosorbide-5-Nitrae-dioxane (10.0mL) solution of (0.30g, 0.81mmol), addition 1- (6- methoxypyridine -3- base) - 1H- pyrazoles -4- amine (0.15g, 0.79mmol), palladium (0.037g, 0.17mmol), BINAP (0.10g, 0.16mmol) and Cesium carbonate (0.53g, 1.64mmol).Reaction system re-fills nitrogen after deaerating 2 minutes, and is warming up to 100 DEG C and is stirred overnight. Reactant mixture concentrating under reduced pressure, gained residue, through silica gel column chromatography (EtOAc/PE (v/v)=1/2 to 2/1) purification, obtains title Compound is yellow solid (0.24g, yield 57%).

LC-MS(ESI,pos.ion)m/z:527.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.43 (d, J=2.6Hz, 1H), 8.23 (s, 1H), 7.93 (dd, J= 8.9,2.8Hz, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 6.83 (d, J=8.9Hz, 1H), 6.80 (s, 1H), 5.34 (d, J= 7.1Hz,1H),4.48-4.35(m,1H),3.97(s,3H),3.53-3.45(m,2H),3.43-3.33(m,2H),2.74- 2.65(m,2H),2.52-2.41(m,2H),1.48-1.45(m,11H).

Step 5) the chloro- N of 5- ² - (1- (6- methoxypyridine -3- base) -1H- pyrazoles -4- base)-N ⁴ - (octahydro Pentamethylene. is simultaneously [c] Pyrroles's -5- base) pyrimidine -2,4- diamidogen

To 5- ((the chloro- 2- of 5- ((1- (6- methoxypyridine -3- base) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate (0.24g, 0.46mmol) dichloromethane (10.0mL) solution The middle ethyl acetate solution (10mL, 30mmol, 3M) adding hydrogen chloride.Reaction system is stirred at room temperature 30 minutes, then subtracts Pressure concentrates.Gained residue adds methylene chloride (10mL) and saturation Na2CO₃Continue 15 points of stirring after aqueous solution (10mL) dilution Clock.Gained mixture uses DCM (20mL × 3) and DCM/MeOH (v/v)=10/1,20mL × 3 successively) extraction.Merge is organic Layer anhydrous sodium sulfate drying, filters and concentrating under reduced pressure, gained residue is through the silica gel column chromatography (NH of DCM/3M₃MeOH molten Liquid (v/v)=50/1 to 25/1) purification, obtaining title compound is yellow solid (0.17g, yield 87%).

LC-MS(ESI,pos.ion)m/z:427.4[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.25 (s, 1H), 8.53 (d, J=2.6Hz, 1H), 8.38 (s, 1H), 8.06 (dd, J=8.9,2.8Hz, 1H), 7.90 (s, 1H), 7.78 (s, 2H), 6.95 (d, J=8.9Hz, 1H), 4.53- 4.41(m,1H),3.89(s,3H),2.89-2.82(m,2H),2.82-2.74(m,2H),2.64-2.55(m,2H),2.27- 2.15(m,2H),1.53-1.40(m,2H).

(((the chloro- 2- of 5- ((1- (6- methoxypyridine -3- base) -1H- pyrazoles -4- base) amino) is phonetic for 5- for embodiment 10 3- Pyridine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -3- oxypropionitrile

To the chloro- N of 5-²- (1- (6- methoxypyridine -3- base) -1H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrrole Cough up -5- base) add 2- cyanoacetic acid in anhydrous DCM (2.0mL) suspension of pyrimidine -2,4- diamidogen (75mg, 0.18mmol) (0.004g, 0.045mmol), EDCI (0.007g, 0.037mmol), HOAT (0.006g, 0.043mmol) and triethylamine (0.005g,0.051mmol).Reaction system is stirred at room temperature 30 minutes, then plus DCM (30mL) dilution, and with water (10mL × 2) wash, the organic faciess anhydrous sodium sulfate drying separating, filter, filtrate reduced in volume.Gained residue is through silica gel column layer Analysis (the NH of DCM/3M₃MeOH solution (v/v)=100/1 to 50/1) purification, obtain title compound be faint yellow solid (75mg, yield 86%).

LC-MS(ESI,pos.ion)m/z:494.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.42 (d, J=2.7Hz, 1H), 8.20 (s, 1H), 7.96-7.90 (m, 2H), 7.77 (s, 1H), 6.86-6.81 (m, 2H), 5.29 (d, J=7.1Hz, 1H), 4.51-4.38 (m, 1H), 3.97 (s, 3H),3.75-3.64(m,3H),3.49-3.43(m,3H),2.92-2.71(m,2H),2.61-2.48(m,2H),1.55-1.41 (m,2H).

(((the chloro- 2- of 5- ((1- (6- methoxypyridine -3- base) -1H- pyrazoles -4- base) amino) is phonetic for 5- for embodiment 11 1- Pyridine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone

To the chloro- N of 5-²- (1- (6- methoxypyridine -3- base) -1H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrrole Cough up -5- base) add triethylamine in DCM (3.0mL) suspending system of pyrimidine -2,4- diamidogen (0.050g, 0.12mmol) (0.020g, 0.19mmol) and acetic anhydride (0.015g, 0.15mmol), reaction system is stirred at room temperature 30 minutes, then subtracts Pressure concentrates.Gained residue is through the silica gel column chromatography (NH of DCM/3M₃MeOH solution (v/v)=100/1 to 50/1) purification, obtain Title compound is white solid (37mg, yield 67%).

LC-MS(ESI,pos.ion)m/z:469.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.42 (d, J=2.6Hz, 1H), 8.21 (s, 1H), 7.93 (dd, J= 9.0,2.8Hz, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 6.86-6.81 (m, 2H), 5.28 (d, J=7.1Hz, 1H), 4.50- 4.37(m,1H),3.97(s,3H),3.67-3.59(m,3H),3.44-3.37(m,1H),2.83-2.69(m,2H),2.57- 2.46(m,2H),2.07(s,3H),1.50-1.43(m,2H).

Embodiment 12 1- (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -2- cyclopropyl ethyl ketone

Step 1) 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Pentamethylene. And [c] pyrroles -2 (1H)-t-butyl formate

To 5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate The n-butyl alcohol (5mL) of (579.6mg, 1.55mmol) and 1- methyl isophthalic acid H- pyrazoles -4- amine hydrochlorate (213.0mg, 1.34mmol) N, N- diisopropyl ethyl amine (668.2mg, 5.17mmol) is added in suspension., at 150 DEG C, tube sealing is anti-for gained reaction system After answering overnight, concentrating under reduced pressure.Gained residue, through silica gel column chromatography (MeOH/DCM (v/v)=1/80) purification, obtains title compound Thing is buff white solid (672.6mg, yield 100%).

LC-MS(ESI,pos.ion)m/z:434.3[M+H]⁺.

Step 2) the chloro- N of 5- ² - (1- methyl isophthalic acid H- pyrazoles -4- base)-N ⁴ - (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine - 2,4- diamidogen

To 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino), hexahydro Pentamethylene. is simultaneously The acetic acid second of hydrogen chloride is added in DCM (10mL) solution of [c] pyrroles -2 (1H)-t-butyl formate (672.6mg, 1.55mmol) Ester solution (10mL, 40mmol).Gained reaction system is stirred at room temperature overnight rear concentrating under reduced pressure.Gained residue is dissolved in water (30mL), in, add saturated aqueous sodium carbonate to be adjusted to pH=10 in resulting solution, then use DCM (250mL × 2) to extract. The organic faciess merging are washed with saturated aqueous common salt (250mL), anhydrous Na 2SO₄It is dried, filter and concentrating under reduced pressure, gained residue Through silica gel column chromatography (MeOH/DCM (v/v)=1/5) purification, obtaining title compound is buff white solid (410mg, yield 79.2%).

LC-MS(ESI,pos.ion)m/z:334.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):10.01(s,1H),7.88(s,1H),7.66(s,1H),7.55(s, 1H), 6.70 (s, 1H), 5.54 (s, 1H), 4.40 (m, 1H), 3.89 (s, 3H), 3.39 (d, J=11.6Hz, 2H), 3.29 (m, 2H),2.94(m,2H),2.51(m,2H),1.83(m,2H).

Step 3) 1- (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro ring Pentane simultaneously [c] pyrroles -2 (1H)-yl) -2- cyclopropyl ethyl ketone

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine -2,4- Add in DCM (15mL) solution of diamidogen (101.0mg, 0.30mmol) and 2- cyclopropaneacetic acid (64.6mg, 0.64mmol) HOAT (89.2mg, 0.66mmol), EDCI (122.4mg, 0.63mmol) and Et₃N(104.0mg,1.03mmol).Reaction mixing Thing is stirred at room temperature 0.5 hour, then add water (30mL) reaction is quenched, and with dichloromethane (100mL × 3) extraction.Merge Organic faciess washed with saturated aqueous common salt (100mL), anhydrous Na 2SO₄It is dried, filter and concentrating under reduced pressure, gained residue is through silicon Plastic column chromatography (MeOH/DCM (v/v)=1/30) purification, obtaining title compound is buff white solid (83.2mg, yield 66.1%).

LC-MS(ESI,pos.ion)m/z:416.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.68(s,1H),7.56(s,1H),6.71(s, 1H), 5.25 (d, J=7.2Hz, 1H), 4.42 (m, 1H), 3.90 (s, 3H), 3.65 (d, J=6.2Hz, 2H), 3.61 (m, 1H), 3.41 (dd, J=10.8,3.2Hz, 1H), 2.78 (m, 2H), 2.50 (td, J=15.8,7.9Hz, 2H), 2.25 (m, 2H), 1.45 (m, 2H), 1.11 (m, 1H), 0.59 (q, J=5.4Hz, 2H), 0.19 (q, J=5.0Hz, 2H).

The chloro- N of embodiment 13 5- ⁴ - (2- (Cyclopropylsulfonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base)-N ² - (1- first Base -1H- pyrazoles -4- base) pyrimidine -2,4- diamidogen

Under nitrogen protection, by chloro- for 5- N²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- Base) pyrimidine -2,4- diamidogen (60mg, 0.18mmol) and triethylamine (28mg, 0.28mmol) be suspended in anhydrous DCM (10.0mL) and Cyclopropyl sulfonyl chloride (31mg, 0.22mmol) is added in the suspending system of gained in the mixed solvent of DMF (0.50mL).Reactant System is stirred at room temperature overnight, then concentrating under reduced pressure.Through silica gel column chromatography, (DCM/MeOH (v/v)=50/1 arrives gained residue 30/1 to 20/1) purification, obtaining title compound is white solid (31mg, yield 39%).

LC-MS(ESI,pos,ion)m/z:438.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(s,1H),7.67(s,1H),7.54(s,1H),6.58(s, 1H), 5.38 (d, J=7.5Hz, 1H), 4.42-4.29 (m, 1H), 3.90 (s, 3H), 3.42-3.29 (m, 4H), 2.83-2.74 (m,2H),2.54-2.45(m,2H),2.42-2.33(m,1H),1.55-1.45(m,2H),1.26-1.20(m,2H),1.07- 0.99(m,2H).

Embodiment 14 (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro ring Pentane simultaneously [c] pyrroles -2 (1H)-yl) (cyclopropyl) ketone

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine -2,4- Cyclopropyl first is added in dichloromethane (5mL) solution of diamidogen (70mg, 0.210mmol) and triethylamine (35mg, 0.346mmol) Acyl chlorides (27mg, 0.258mmol).Gained reaction system stirs concentrating under reduced pressure after 20 minutes at normal temperatures.Gained residue is through system Standby thin layer chromatography (PE/EtOAc (v/v)=20/1) purification, obtaining title compound is yellow solid (26mg, yield 30.9%).

LC-MS(ESI,pos.ion)m/z:402.1[M+H]⁺；

1H NMR(400MHz,CDCl₃)δ(ppm):7.87(s,1H),7.66(s,1H),7.53(s,1H),6.69(s, 1H), 5.25 (d, J=7.1Hz, 1H), 4.46-4.38 (m, 1H), 3.88 (s, 3H), 3.84-3.77 (m, 1H), 3.63 (d, J= 6.6Hz, 2H), 2.83-2.69 (m, 2H), 2.53-2.44 (m, 2H), 1.69-1.58 (m, 4H), 1.01 (t, J=3.6Hz, 2H),0.79-0.74(m,2H).

Embodiment 15 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro ring Pentane simultaneously [c] pyrroles -2 (1H)-Ethyl formate

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine -2,4- Chloro-carbonic acid second is added in dichloromethane (5mL) solution of diamidogen (71mg, 0.213mmol) and triethylamine (35mg, 0.346mmol) Ester (27mg, 0.258mmol).Gained reaction system stirs concentrating under reduced pressure after 20 minutes at normal temperatures.Gained residue is through preparation Thin layer chromatography (MeOH/DCM (v/v)=1/20) purification, obtaining title compound is yellow solid (22mg, yield 25.5%).

LC-MS(ESI,pos.ion)m/z:406.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.86(s,1H),7.66(s,1H),7.51(s,1H),6.60(s, 1H),5.26(d,1H),4.39(m,9.2Hz,1H),4.14(q,2H),3.87(s,3H),3.47(d,4H),2.74-2.67(m, 2H),2.50-2.41(m,2H),1.46-1.40(m,2H),1.26(s,3H).

Embodiment 16 1- (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -2- methyl propan-2-ol

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine -2,4- In MeOH (10mL) solution of diamidogen (118.9mg, 0.36mmol) add 2,2- dimethyl propylene oxide (44.1mg, 0.61mmol).Reaction system tube sealing reaction at 80 DEG C overnight, is subsequently cooled to room temperature concentrating under reduced pressure.Gained residue warp Silica gel column chromatography (MeOH/DCM (v/v)=1/10) purification, obtaining title compound is buff white solid (107.9mg, yield 74.6%).

LC-MS(ESI,pos.ion)m/z:406.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃And MeOH-d₄)δ(ppm):7.75(s,1H),7.64(s,1H),7.53(s,1H), (4.33 m, 1H), 3.83 (s, 3H), 3.33 (m, 2H), 2.94 (d, J=9.3Hz, 2H), 2.74 (m, 1H), 2.67 (m, 1H), 2.63 (s, 2H), 2.38 (dt, J=12.9,6.6Hz, 2H), 1.49 (m, 2H), 1.24 (s, 6H).

The chloro- N of embodiment 17 5- ⁴ - (2- ((ring third methyl) sulfonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base)-N ² -(1- Methyl isophthalic acid H- pyrazoles -4- base) pyrimidine -2,4- diamidogen

Step 1) cyclopropylmethyl sodium sulfonate

Saturated sodium sulfite aqueous solution (20.0mL) is added in (bromomethyl) cyclopropane (2.0g, 14.83mmol).Reaction System is warming up to return stirring 24 hours, after reaction terminates, concentrating under reduced pressure.Add ethanol (30mL) in residue, gained mixes Compound stirs 30 minutes at 50 DEG C, filters immediately after.Filtrate reduced in volume, after gained residue adds toluene (20mL) dilution Concentrating under reduced pressure again.Obtaining final product title compound after gained residue drying under reduced pressure is white solid (1.25g, yield 53%).

LC-MS(ESI,neg.ion)m/z:135.1[M–Na]^–；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):2.34 (d, J=6.5Hz, 2H), 0.99-0.89 (m, 1H), 0.45- 0.33(m,2H),0.19-0.09(m,2H).

Step 2) cyclopropylmethyl sulfonic acid chloride

DMF is added in anhydrous tetrahydro furan (10.0mL) solution of cyclopropylmethyl sodium sulfonate (0.48g, 3.04mmol) (0.26mL, 3.40mmol) and thionyl chloride (0.73g, 6.15mmol).Reaction system is warming up to backflow, stirs 3 hours, then It is cooled to room temperature and filter.It is brown liquid (0.47g, 100%) that filtrate reduced in volume obtains title compound.Crude product without Purification is directly used in next step.

Step 3) the chloro- N of 5- ⁴ - (2- ((ring group methyl) sulfonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base)-N ² - (1- first Base -1H- pyrazoles -4- base) pyrimidine -2,4- diamidogen

Under nitrogen protection, to the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- Base) pyrimidine -2,4- diamidogen (0.20g, 0.60mmol) and triethylamine (0.20mL, 1.40mmol) be suspended in anhydrous DCM (20.0mL) and DMF (0.50mL) mixed solvent in gained suspending system in add cyclopropylmethyl sulfonic acid chloride (0.14g, 0.91mmol).After gained reaction system stirs 2 hours at normal temperatures, concentrating under reduced pressure.Gained residue is through silica gel column chromatography (the NH of DCM/3M₃MeOH solution (v/v)=50/1 to 30/1) purification, obtain title compound be faint yellow solid (50mg, produce Rate 18%).

LC-MS(ESI,pos.ion)m/z:452.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.87(s,1H),7.65(s,1H),7.52(s,1H),6.58(s, 1H), 5.29 (d, J=5.8Hz, 1H), 4.35-4.27 (m, 1H), 3.88 (s, 3H), 3.44-3.37 (m, 2H), 3.36-3.30 (m, 2H), 2.94 (d, J=7.1Hz, 2H), 2.77-2.70 (m, 2H), 2.51-2.44 (m, 2H), 1.50-1.44 (m, 2H), 1.19-1.13(m,1H),0.76-0.70(m,2H),0.41-0.35(m,2H).

Embodiment 18 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino)-N- ethyl Hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide

At 0 DEG C, be added dropwise to in benzyl chloroformate (506.5mg, 3.235mmol) ethamine tetrahydrofuran solution (6mL, 12mmol,2M).Reaction system is stirred at room temperature 10 minutes, then add water (20mL) reaction, mixture ethyl acetate are quenched EtOAc (30mL × 3) extracts.The organic faciess merging, through anhydrous sodium sulfate drying, filter and concentrating under reduced pressure, obtain N- methylcarbamoyl ethyl Phenyl ester is colourless liquid.To in N- methylcarbamoyl ethyl phenyl ester DCM (20mL) solution add triethylamine (162.8mg, 1.609mmol) and The chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine -2,4- diamidogen (107.6mg,0.3223mmol).After gained reaction system is stirred at room temperature overnight, concentrating under reduced pressure.Gained residue is through silica gel Column chromatography (DCM/MeOH (v/v) (v/v)=15/1) purification, obtaining title compound is white solid (95mg, yield 59%).

LC-MS(ESI,pos.ion)m/z:405.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.85(s,1H),7.66(s,1H),7.52(s,1H),6.72(s, 1H), 5.36 (d, J=7.2Hz, 1H), 4.42 (dd, J=15.3,7.7Hz, 1H), 4.18-4.26 (m, 1H), 3.87 (s, 3H), 3.48 (dd, J=10.1,7.5Hz, 2H), 3.37-3.23 (m, 4H), 2.79-2.69 (m, 2H), 2.49-2.38 (m, 2H), 1.53-1.41 (m, 2H), 1.15 (t, J=7.2Hz, 3H).

Embodiment 19 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino)-N- ring third Base hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide

Step 1) N- ethylene-acetic acid phenyl ester

At 0 DEG C, anhydrous to phenyl chloroformate (2.00g, 12.78mmol) and triethylamine (3.60mL, 25.08mmol) In DCM (20.0mL) solution, it is slowly added to cyclopropylamine (1.10g, 19.24mmol), reaction system is stirred at room temperature overnight.Institute Obtain reactant mixture and add DCM (50mL) dilution, then washed with water (40mL × 2) and saturated aqueous common salt (40mL) successively, separate Organic layer through anhydrous sodium sulfate drying, filter, filtrate reduced in volume.Gained residue is through silica gel column chromatography (EA/PE (v/v) =1/20 to 1/10) purification, obtaining title compound is white solid (0.85g, yield 38%).

LC-MS(ESI,pos.ion)m/z:178.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.40-7.31(m,2H),7.23-7.16(m,1H),7.16-7.08 (m,2H),5.22(s,1H),2.81-2.63(m,1H),0.83-0.75(m,2H),0.67-0.59(m,2H).

Step 2 (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino)-N- cyclopropyl Hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl)-Methanamide

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine -2,4- In THF (5.0mL) solution of diamidogen (0.10g, 0.30mmol), add N- ethylene-acetic acid phenyl ester (0.12g, 0.68mmol) and Triethylamine (0.15mL, 1.10mmol).Reaction system is warming up to return stirring 24 hours, after reaction terminates, concentrating under reduced pressure.Gained Residue is through the silica gel column chromatography (NH of DCM/3M₃MeOH solution (v/v)=100/1 to 50/1 to 30/1) purification, obtain title Compound is faint yellow solid (50mg, yield 40%).

LC-MS(ESI,pos.ion)m/z:417.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.86(s,1H),7.65(s,1H),7.52(s,1H),6.64(s, 1H), 5.33 (d, J=7.2Hz, 1H), 4.49 (s, 1H), 4.47-4.35 (m, 1H), 3.87 (s, 3H), 3.50-3.43 (m, 2H),3.35-3.29(m,2H),2.78-2.70(m,2H),2.68-2.62(m,1H),2.48-2.39(m,2H),1.52-1.43 (m,2H),0.75-0.70(m,2H),0.50-0.45(m,2H).

Embodiment 20 1- (9- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) -3- Azaspiro [5,5] hendecane -3- base) -2- cyclopropyl ethyl ketone

Step 1) 9- oxo -3- azaspiro [5.5] hendecane -7- alkene -3- t-butyl formate

EtOH to 4- formyl piperidine -1- t-butyl formate (10.0g, 46.9mmol) and KOH (1.3g, 23.5mmol) (200mL) in solution, add butyl- 3- alkene -2- ketone (3.9g, 56.3mmol), gained reactant mixture is warming up to 70 DEG C of stirrings 16 Hour.After reaction terminates, concentrating under reduced pressure.Gained residue, through silica gel column chromatography (EtOAc/PE (v/v)=1/4) purification, obtains mark Topic compound is light brown oil thing (5.2g, yield 41.8%).

LC-MS(ESI,pos.ion)m/z:210.2[M-55]⁺.

Step 2) 9- oxo -3- azaspiro [5.5] hendecane -3- t-butyl formate

DCM to 9- oxo -3- azaspiro [5.5] hendecane -7- alkene -3- t-butyl formate (5.2g, 19.6mmol) (80mL) add Pd/C (0.5g, mass fraction 10%) in solution, at normal temperatures, in atmosphere of hydrogen, stirring is anti-for gained suspension Should overnight.Reactant mixture is filtered, filtrate reduced in volume, gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/ 4) purification, obtaining title compound is light brown oil thing (3.1g, 59.0%).

LC-MS(ESI,pos.ion)m/z:212.1[M-55]⁺.

Step 3) 9- amino -3- azaspiro [5.5] hendecane -3- t-butyl formate

EtOH (40mL) to 9- oxo -3- azaspiro [5.5] hendecane -3- t-butyl formate (5.35g, 20.0mmol) Methanol solution (7M, 40mL, 280.0mmol) and the Ti (Oi-Pr) of ammonia is added in solution₄(11.30g, 40.0mmol), reactant System is stirred at room temperature overnight.Then, by NaBH₄(1.51g, 40.0mmol) is dividedly in some parts in reaction system, after adding, gained Reactant mixture is stirred at room temperature 5 hours, adds water and (40mL) reaction is quenched, and stirring was filtered after 1 hour.Filtrate reduced in volume, Through silica gel column chromatography (MeOH/DCM (v/v)=1/25) purification, obtain title compound is faint yellow solid to gained residue (1.20g, 22.4%).

LC-MS(ESI,pos.ion)m/z:269.3[M+H]⁺.

Step 4) 9- ((2,5- dichloro pyrimidine -4- base) amino) -3- azaspiro [5.5] hendecane -3- t-butyl formate

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

LC-MS(ESI,pos.ion)m/z:415.0[M+H]⁺.

Step 5) 9- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) -3- azaspiro [5.5] hendecane -3- t-butyl formate

To 9- ((2,5- dichloro pyrimidine -4- base) amino) -3- azaspiro [5.5] hendecane -3- t-butyl formate The n-butyl alcohol (3mL) of (230.0mg, 0.55mmol) and 1- methyl isophthalic acid H- pyrazoles -4- amine hydrochlorate (185.4mg, 1.39mmol) In solution, add DIPEA (215.7mg, 1.67mmol), gained reaction system is warming up to 150 DEG C, is stirred overnight.Reaction terminates Afterwards, it is cooled to room temperature, concentrating under reduced pressure.Gained residue is pure through silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 70/1) Change, obtaining title compound is faint yellow solid (87.0mg, 33.0%).

LC-MS(ESI,pos.ion)m/z:476.1[M+H]⁺.

Step 6) the chloro- N of 5- ² - (1- methyl isophthalic acid H- pyrazoles -4- base)-N ⁴ - (3- azaspiro [5.5] hendecane -9- base) pyrimidine - 2,4- diamidogen

To 9- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) -3- azaspiro [5.5] The ethyl acetate solution of hydrogen chloride is added in DCM (5mL) solution of hendecane -3- t-butyl formate (87.0mg, 0.18mmol) (2mL, 8mmol), gained reaction system stirs 5 hours at normal temperatures.Reaction finishes, concentrating under reduced pressure, and gained residue is dissolved in In methanol (2mL), it is adjusted to pH=10 with saturated aqueous sodium carbonate, then use the mixed extractant solvent of DCM (20mL × 3).Close And organic faciess through saturated aqueous common salt (20mL) wash, anhydrous sodium sulfate drying, filter and concentrating under reduced pressure, gained residue through system Standby thin layer chromatography (DCM/MeOH (v/v)=5/1) purification, obtaining title compound is faint yellow solid (54.0mg, 78.6%).

LC-MS(ESI,pos.ion)m/z:376.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)8.73(s,1H),7.85(s,1H),7.72(s,1H),7.44(s, 1H),6.62(s,1H),3.77(s,3H),3.03(m,5H),1.84-1.23(m,12H).

Step 7) 1- (9- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) -3- azepine Spiral shell [5,5] hendecane -3- base) -2- cyclopropyl ethyl ketone

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (3- azaspiro [5.5] hendecane -9- base) pyrimidine -2,4- Diamidogen (60.2mg, 0.16mmol), 2- cyclopropaneacetic acid (24.7mg, 0.25mmol) and triethylamine (34.5mg, 0.34mmol) Dichloromethane (5mL) solution in add EDCI (61.4mg, 0.32mmol) and HOAT (44.2mg, 0.33mmol), reactant System is stirred at room temperature 3 hours.Reactant mixture add water (15mL) be quenched, and with DCM (10mL × 3) extraction.Merge is organic Layer anhydrous sodium sulfate drying, filters and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=30/1) Purification, obtaining title compound is white solid (47.5mg, yield 64.8%)

LC-MS(ESI,pos.ion)m/z:458.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.86(s,1H),7.69-7.62(m,1H),7.54-7.47(m,1H), 6.63(s,1H),5.12(s,1H),4.00-3.91(m,1H),3.87(s,3H),3.64-3.54(m,2H),3.46-3.33(m, 2H), 2.28 (d, J=6.6Hz, 2H), 2.02-1.94 (m, 2H), 1.82-1.70 (m, 2H), 1.60-1.55 (m, 2H), 1.43- 1.27(m,6H),1.09-1.01(m,1H),0.61-0.52(m,2H),0.21-0.12(m,2H).

Embodiment 21 1- (9- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) -3- Azaspiro [5,5] hendecane -3- base) -2- methyl propan-2-ol

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (3- azaspiro [5.5] hendecane -9- base) pyrimidine -2,4- In DMF (2mL) solution of diamidogen (100.3mg, 0.27mmol) add 2,2- dimethyl propylene oxide (58.5mg, 0.81mmol), reaction system is warming up to 80 DEG C of tube sealing reactions overnight.Then, add water (20mL) reaction is quenched, and with DCM (10mL × 3) extract.The organic layer anhydrous sodium sulfate drying merging, filters and concentrating under reduced pressure, gained residue is through silica gel column chromatography (EA/PE (v/v)=1/80 to 1/50) purification, obtaining title compound is faint yellow solid (69.4mg, yield 58.1%).

LC-MS(ESI,pos.ion)m/z:448.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.85(s,1H),7.68(s,1H),7.48(s,1H),6.60(s, 1H), 5.11 (d, J=7.1Hz, 1H), 3.95-3.90 (m, 1H), 3.87 (s, 3H), 3.57-3.46 (m, 1H), 3.37-3.29 (m,1H),2.67-2.52(m,2H),2.31(s,2H),1.99-1.90(m,2H),1.78-1.71(m,2H),1.50-1.35 (m,6H),1.29-1.26(m,2H),1.15(s,6H).

Embodiment 22 (9- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) -3- azepine Spiral shell [5,5] hendecane -3- base) (cyclopropyl) ketone

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (3- azaspiro [5.5] hendecane -9- base) pyrimidine -2,4- Three are added in diamidogen (150mg, 0.3990mmol), DCM (10mL) solution of Cyclopropyl carbonyl chloride (51mg, 0.48785mmol) Ethamine (61mg, 0.60283mmol).After gained reaction system is stirred at room temperature overnight, concentrating under reduced pressure.Gained residue is through silicon Plastic column chromatography (PE/EtOAc (v/v)=1/50 to 1/25) purification, obtaining title compound is white solid (105mg, yield 59.26%).

LC-MS(ESI,pos.ion)m/z:444.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.01(s,1H),7.85(s,1H),7.73(s,1H),7.44(s, 1H), 6.66 (d, J=7.8Hz, 1H), 3.94 (s, 1H), 3.77 (s, 3H), 3.63 (s, 2H), 3.45 (s, 2H), 1.97 (s, 2H), 1.78 (d, J=13.2Hz, 2H), 1.68 (d, J=15.1Hz, 2H), 1.61 (d, J=13.4Hz, 3H), 1.47 (s, 1H), 1.36 (s, 1H), 1.22-1.13 (m, 2H), 0.69 (dd, J=9.8,5.8Hz, 4H).

The chloro- N of embodiment 23 5- ⁴ - (3- (Cyclopropylsulfonyl) -3- azaspiro [5,5] hendecane -9- base)-N ² - (1- first Base -1H- pyrazoles -4- base) pyrimidine -2,4- diamidogen

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (3- azaspiro [5.5] hendecane -9- base) pyrimidine -2,4- Three are added in diamidogen (150mg, 0.3990mmol), DCM (10mL) solution of cyclopropyl sulfonyl chloride (67.5mg, 0.480mmol) Ethamine (61mg, 0.60283mmol).Reactant mixture is stirred at room temperature overnight, then concentrating under reduced pressure, and residue is through silicagel column Chromatography (DCM/MeOH (v/v)=50/1 to 25/1) purification, obtaining title compound is faint yellow solid (150mg, yield 78.31%).

LC-MS(ESI,pos.ion)m/z:480.3[M+H]⁺；

¹H NMR(400MHz,CDCl3)δ(ppm):7.86(s,1H),7.65(s,1H),7.51(s,1H),6.68(s, 1H), 5.11 (d, J=7.4Hz, 1H), 3.94 (dd, J=7.3,3.6Hz, 1H), 3.87 (s, 3H), 3.29 (dd, J=11.0, 5.2Hz, 4H), 2.27 (ddd, J=12.9,8.1,4.9Hz, 1H), 2.02-1.93 (m, 2H), 1.77 (d, J=13.2Hz, 2H), 1.72-1.67 (m, 2H), 1.56-1.50 (m, 2H), 1.43 (t, J=12.1Hz, 2H), 1.37-1.32 (m, 2H), 1.18 (dd, J=4.8,2.0Hz, 2H), 0.98 (dd, J=7.7,2.1Hz, 2H).

Embodiment 24 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino)-N- ethyl Hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulfonamide

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine -2,4- Et is added in anhydrous DCM (5.0mL) solution of diamidogen (0.20g, 0.60mmol)₃N (0.25mL, 1.80mmol) and N- ethyl sulphur Acyl chlorides (0.18g, 1.24mmol), reaction system is stirred at room temperature overnight.Reaction terminate after, add water (10mL) reaction is quenched, Gained mixture is extracted with DCM (50mL × 3).The organic layer anhydrous sodium sulfate drying merging, filters and concentrating under reduced pressure, gained Residue is through the silica gel column chromatography (NH of DCM/3M₃MeOH solution (v/v)=100/1 to 50/1) purification, obtain title compound For white solid (0.12g, yield 45%).

LC-MS(ESI,pos.ion)m/z:441.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.86(s,1H),7.64(s,1H),7.51(s,1H),6.62(s, 1H), 5.38 (d, J=7.5Hz, 1H), 4.39-4.26 (m, 1H), 4.16 (t, J=5.9Hz, 1H), 3.87 (s, 3H), 3.25- 3.17 (m, 6H), 2.81-2.69 (m, 2H), 2.52-2.41 (m, 2H), 1.49-1.38 (m, 2H), 1.22 (t, J=7.2Hz, 3H).

Embodiment 25 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro ring Pentane simultaneously [c] pyrroles -2 (1H)-phenyl formate

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrazoles -5- base) pyrimidine -2,4- Triethylamine (0.047g, 0.47mmol) and phenyl chloroformate is added in DCM (8mL) suspension of diamidogen (0.10g, 0.30mmol) (0.059g,0.38mmol).Reaction system be stirred at room temperature reaction 2 hours, then add water (20mL) reaction is quenched, be used in combination DCM extracts (50mL × 3).The organic layer merging, through anhydrous sodium sulfate drying, filters, filtrate reduced in volume.Gained residue warp Silica gel column chromatography (the NH of DCM/3M₃MeOH solution (v/v)=100/1 to 50/1 to 30/1) purification, obtaining title compound is Yellow solid (85mg, yield 62%).

LC-MS(ESI,pos.ion)m/z:454.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.87 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.35 (t, J= 7.9Hz, 2H), 7.19 (t, J=7.4Hz, 1H), 7.13 (d, J=7.6Hz, 2H), 6.69 (s, 1H), 5.31 (d, J=7.3Hz, 1H),4.50-4.36(m,1H),3.87(s,3H),3.78-3.64(m,2H),3.64-3.49(m,2H),2.86-2.73(m, 2H),2.59-2.46(m,2H),1.54-1.45(m,2H).

Embodiment 26 1- (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) -2- 1-Phenylethanone.

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrazoles -5- base) pyrimidine -2,4- Triethylamine (0.026g, 0.26mmol) and 2- phenyllacetyl chloride is added in DCM (5mL) suspension of diamidogen (51mg, 0.15mmol) (0.033g,0.21mmol).Reaction system is stirred at room temperature reaction overnight, then add water (10mL) reaction is quenched, and use DCM Extraction (30mL × 3).The organic layer merging, through anhydrous sodium sulfate drying, filters, filtrate reduced in volume.Gained residue is through silica gel Column chromatography (the NH of DCM/3M₃MeOH solution (v/v)=100/1 to 50/1 to 30/1) purification, obtaining crude product is yellow solid. Solid crude product is through preparing the thin layer chromatography (NH of DCM/3M₃MeOH solution (v/v)=40/1) purification, obtaining title compound is Yellow solid (28mg, yield 41%).

LC-MS(ESI,pos.ion)m/z:452.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.86(s,1H),7.63(s,1H),7.51(s,1H),7.37-7.27 (m, 4H), 6.62 (s, 1H), 5.12 (d, J=6.7Hz, 1H), 4.39-4.27 (m, 1H), 3.86 (s, 3H), 3.73-3.64 (m, 3H),3.61-3.50(m,2H),3.46-3.38(m,1H),2.75-2.61(m,2H),2.53-2.31(m,2H),1.36-1.29 (m,2H).

Embodiment 27 (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro ring Pentane simultaneously [c] pyrroles -2 (1H)-yl) (phenyl) ketone

The chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrazoles -5- base) pyrimidine -2,4- two Triethylamine (0.023g, 0.23mmol) is added in DCM (3mL) suspension of amine (0.058g, 0.17mmol).Reactant mixture is cold But to 0 DEG C, it is subsequently adding Benzenecarbonyl chloride. (0.027g, 0.19mmol).After reactant mixture stirs 30 minutes at 0 DEG C, add water (20mL) reaction is quenched, gained mixture is extracted with DCM (30mL × 3).The organic layer merging is through anhydrous sodium sulfate drying, mistake Filter, filtrate reduced in volume.Gained residue is through the silica gel column chromatography (NH of DCM/3M₃MeOH solution (v/v)=100/1 to 50/ To 30/1) purification, obtaining crude product is yellow solid.Solid crude product is through preparing the thin layer chromatography (NH of DCM/3M₃MeOH solution (v/v)=40/1) purification, obtaining title compound is yellow solid (32mg, yield 42%).

LC-MS(ESI,pos.ion)m/z:438.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.87(s,1H),7.66(s,1H),7.54(s,1H),7.52-7.48 (m, 2H), 7.43-7.38 (m, 3H), 6.80 (s, 1H), 5.26 (d, J=6.8Hz, 1H), 4.39-4.27 (m, 1H), 3.99- 3.89(m,1H),3.86(s,3H),3.78-3.69(m,1H),3.67-3.58(m,1H),3.46-3.35(m,1H),2.80- 2.65(m,2H),2.58-2.47(m,1H),2.41-2.29(m,1H),1.58-1.47(m,2H).

Embodiment 28 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino)-N- phenyl Hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide

Step 1) N-carboxyaniline. phenyl ester

At 0 DEG C, molten to the DCM (20mL) of aniline (941.3mg, 10.11mmol) and triethylamine (2.07g, 20.46mmol) Benzenecarbonyl chloride. (3.80g, 24.27mmol) is added in liquid.Add rear reactant mixture to stir 0.5 hour at 0 DEG C, then move to Stir 2 hours under room temperature.Reaction terminate after, add water (30mL) be quenched react and use DCM (100mL × 3) extract.Merge is organic Layer, through saturated aqueous common salt (100mL) washing, anhydrous sodium sulfate drying, filters, filtrate reduced in volume.Gained residue is through silicagel column Chromatography (EtOAc/PE (v/v)=1/20) purification, obtaining title compound is white solid (2.16g, yield 100%).

LC-MS(ESI,pos.ion)m/z:214.2[M+H]⁺.

Step 2) 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino)-N- phenyl six Hydrogen Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine -2,4- Diamidogen (164.9mg, 0.49mmol) and Et₃Phenylamino first is added in EtOH (20mL) solution of N (224.6mg, 2.22mmol) Acid phenenyl ester (202.1mg, 0.95mmol).Reaction system is stirred at room temperature overnight, then add water (30mL) reaction is quenched, be used in combination DCM (100mL × 3) extracts.The organic layer merging washs through saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, filters, filter Liquid concentrating under reduced pressure.Through silica gel column chromatography (MeOH/DCM (v/v)=1/20) purification, obtain title compound is off-white to gained residue Color solid (165.2mg, yield 73.8%).

LC-MS(ESI,pos.ion)m/z:453.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.88 (s, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.42 (d, J= 7.7Hz, 2H), 7.32 (d, J=7.5Hz, 2H), 7.06 (t, J=7.4Hz, 1H), 6.74 (s, 1H), 6.22 (s, 1H), 5.38 (d, J=7.3Hz, 1H), 448 (m, 1H), 3.90 (s, 3H), 3.80 (m, 2H), 3.52 (dd, J=10.6,2.2Hz, 2H), 2.85 (m, 2H), 2.52 (dt, J=14.6,7.5Hz, 2H), 1.56 (m, 2H).

Embodiment 29 (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro ring Pentane simultaneously [c] pyrroles -2 (1H)-yl) (morpholine) ketone

Step 1) morpholine -4- carboxylic acid 4- nitro phenyl ester

To chloro-carbonic acid 4- nitro phenyl ester (389.3mg, 1.93mmol) and Et₃The DCM of N (304.3mg, 3.01mmol) (10mL) add morpholine (185.0mg, 2.12mmol) in solution.Reaction system is stirred at room temperature 3.5 hours, then adds water (30mL) reaction is quenched, gained mixture is extracted with DCM (100mL × 3).The organic layer merging is through saturated aqueous common salt (100mL) Washing, anhydrous sodium sulfate drying, filters, filtrate reduced in volume.Gained residue through silica gel column chromatography (EtOAc/PE (v/v)= 1/2) purification, obtaining title compound is greenish yellow solid (487.2mg, yield 100%).

LC-MS(ESI,pos.ion)m/z:253.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.28 (d, J=9.1Hz, 2H), 7.33 (d, J=9.1Hz, 2H), 3.79(m,4H),3.71(s,2H),3.61(s,2H).

Step 2) (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro ring penta Alkane simultaneously [c] pyrroles -2 (1H)-yl) (morpholine) ketone

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine -2,4- Diamidogen (85.7mg, 0.26mmol) and Et₃Morpholine -4- carboxylic is added in EtOH (10mL) solution of N (276.2mg, 2.73mmol) Sour 4- nitro phenyl ester (82.4mg, 0.33mmol).Reaction system is warming up to 100 DEG C, and tube sealing reaction overnight, is subsequently cooled to room Temperature, add water (30mL) reaction is quenched, then use DCM (100mL × 3) extract.The organic layer merging is through saturated aqueous common salt (100mL) Washing, anhydrous sodium sulfate drying, filters, filtrate reduced in volume.Gained residue through silica gel column chromatography (MeOH/DCM (v/v)= 1/40) purification, obtaining title compound is beige solid (72.7mg, yield 63.4%).

LC-MS(ESI,pos.ion)m/z:447.4[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.86(s,1H),7.68(s,1H),7.56(s,1H),7.29(s, 1H), 5.38 (d, J=4.6Hz, 1H), 4.30 (s, 1H), 3.88 (s, 3H), 3.71 (m, 6H), 3.47 (m, 4H), 2.66 (s, 2H),2.41(s,2H),2.32(s,2H),1.51(s,2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):163.0,157.9,157.6,152.8,131.0,123.4,120.9, 104.1,72.4,66.7,61.7,54.0,53.5,46.9,40.8,39.4,38.7.

Embodiment 30 6- (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-yl) pyridazine -3- formonitrile HCN

To the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) pyrimidine -2,4- Diamidogen (85.8mg, 0.26mmol) and Et₃6- chlorine pyridazine -3- is added in EtOH (10mL) solution of N (80.4mg, 0.80mmol) Formonitrile HCN (72.8mg, 0.52mmol).Reaction system is stirred at room temperature overnight, then add water (30mL) reaction is quenched, and use DCM (100mL × 3) extract.The organic layer merging washs through saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, filters, and filtrate subtracts Pressure concentrates.Gained residue, through silica gel column chromatography (MeOH/DCM (v/v)=1/50) purification, obtains title compound solid for rice white Body (109.6mg, yield 97.6%).

LC-MS(ESI,pos.ion)m/z:437.4[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)9.03(s,1H),7.85(m,2H),7.75(s,1H),7.45(s, 1H), 7.02 (d, J=9.6Hz, 1H), 6.93 (d, J=7.8Hz, 1H), 4.59 (m, 1H), 3.79 (s, 3H), 3.72 (m, 4H), 2.84(s,2H),2.33(m,2H),1.62(m,2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.2,157.5,131.1,130.1,128.2,124.2,118.2, 111.8,72.7,60.7,52.9,40.8,39.1,37.6.

Embodiment 31 N ⁴ - (2- (tert. butylsulfonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) the chloro- N of -5- ² - (1- first Base -1H- pyrazoles -4- base) pyrimidine -2,4- diamidogen

Step 1) N ⁴ - (2- (terf-butylsulfinyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) the chloro- N of -5- ² - (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamidogen

At 0 DEG C, to the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) Pyrimidine -2,4- diamidogen (98.5mg, 0.30mmol) and Et₃In DCM (8mL) solution of N (132.8mg, 1.31mmol), add uncle DCM (2mL) solution of butyl sulphinyl chlorine (92.8mg, 0.66mmol).Reactant mixture stirs 1 hour at 0 DEG C, adds water (50mL) reaction is quenched, gained mixture is extracted with DCM (100mL × 3).The organic layer merging is through saturated aqueous common salt (100mL) Washing, anhydrous sodium sulfate drying, filters, filtrate reduced in volume.Gained residue through silica gel column chromatography (MeOH/DCM (v/v)= 1/50) purification, obtaining title compound is buff white solid (129.5mg, yield 100%).

LC-MS(ESI,pos.ion)m/z:438.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.86(s,1H),7.69(s,1H),7.52(s,1H),6.98(s, 1H), 5.50 (d, J=5.0Hz, 1H), 4.29 (m, 1H), 3.89 (s, 3H), 3.49 (dd, J=11.5,6.9Hz, 1H), 3.41 (dd, J=11.0,2.9Hz, 1H), 3.17 (m, 2H), 2.66 (m, 2H), 2.38 (m, 2H), 1.59 (m, 2H), 1.22 (s, 9H).

Step 2) N ⁴ - (2- (tert. butylsulfonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) the chloro- N of -5- ² - (1- methyl- 1H- pyrazoles -4- base) pyrimidine -2,4- diamidogen

To N⁴- (2- (terf-butylsulfinyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) the chloro- N of -5-²- (1- methyl isophthalic acid H- Pyrazoles -4- base) pyrimidine -2,4- diamidogen (133.6mg, 0.30mmol) DCM (10mL) solution in add m-chloro peroxide benzene by several times Formic acid (138.6mg, 0.68mmol).Reaction system is warming up to backflow, and stirring reaction overnight, then adds again in system Metachloroperbenzoic acid (131.5mg, 0.65mmol).Reaction system is warming up to backflow, continues stirring reaction overnight.Reaction terminates Afterwards, it is cooled to room temperature, is adjusted to pH=10 with saturated aqueous sodium carbonate, then use DCM (100mL × 3) to extract.Merge has Machine layer washs through saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, filters, filtrate reduced in volume.Gained residue is through silica gel Column chromatography (MeOH/DCM (v/v)=1/80) purification, obtaining title compound is buff white solid (42.7mg, yield 30.8%).

LC-MS(ESI,pos.ion)m/z:454.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:454.1795[M+H]⁺,C₁₉H₂₉ClN₇O₂S[M+H]⁺Theoretical value： 454.1792.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.87(s,1H),7.66(s,1H),7.53(s,1H),7.02(s, 1H), 5.29 (d, J=7.0Hz, 1H), 4.26 (m, 1H), 3.88 (s, 3H), 3.55 (d, J=10.8Hz, 2H), 3.39 (dd, J =10.5,6.0Hz, 2H), 2.69 (d, J=4.5Hz, 2H), 2.44 (m, 2H), 1.50 (m, 2H), 1.41 (s, 9H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):169.0,158.0,157.7,152.9,131.0,123.3,120.9, 64.8,60.8,55.2,52.9,41.3,39.2,38.1,30.6,24.5,19.1；

Embodiment 32 2- (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) acetonitrile

Step 1) 5- (cyano group methene base) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate

At 0 DEG C, to the oxolane of sodium hydride (60% [w/w] is suspended in mineral oil, 5.65g, 141.25mmol) (200mL) it is added dropwise to diethyl (cyano ethyl) phosphate ester (25.98g, 146.66mmol) in solution.Reaction system maintains 0 DEG C Stirring 1 hour, then, moves to and is stirred at room temperature 2 hours.Then by 5- oxo hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-formic acid uncle Oxolane (100mL) solution of butyl ester (15.34g, 68.09mmol) is added dropwise in said mixture.Gained reaction system exists Be stirred overnight under room temperature, add water (150mL) reaction is quenched, then use ethyl acetate (250mL × 3) extract.The organic layer merging Washed with saturated aqueous common salt (250mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume.Gained residue is through silica gel column layer Analysis (EtOAc/PE (v/v)=1/10) purification, obtaining title compound is crocus grease (12.94g, yield 76.5%).

LC-MS(ESI,pos.ion)m/z:193.2[M–C₄H₈+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):5.29(s,1H),3.58(s,2H),3.39(s,1H),3.13(m, 3H), 2.82 (m, 2H), 2.59 (d, J=18.3Hz, 1H), 2.44 (d, J=14.3Hz, 1H), 1.48 (s, 9H).

Step 2) 5- amino -5- (cyano methyl) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate

To 5- (cyano group methene base) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate (14.69g, Strong aqua ammonia (28% [w/w] aqueous solution, 163.03g, 1.30mol) is added in MeOH (30mL) solution 59.16mmol).Reaction System is placed in autoclave and is warming up to 110 DEG C of reactions 64 hours, is subsequently cooled to room temperature concentrating under reduced pressure.Gained residue is through silicon Plastic column chromatography (MeOH/DCM (v/v)=1/60) purification, obtaining title compound is yellow oil (6.28g, yield 40%).

LC-MS(ESI,pos.ion)m/z:266.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):3.50 (s, 2H), 3.46 (m, 2H), 3.28 (d, J=8.7Hz, 2H), 2.96 (m, 2H), 2.58 (s, 2H), 1.97 (dd, J=13.2,8.0Hz, 2H), 1.55 (m, 2H), 1.47 (s, 9H).

Step 3) 5- (cyano methyl) -5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate

To 2,4,5- trichloropyrimidine (3.65g, 19.90mmol) and 5- amino -5- (cyano methyl) hexahydro Pentamethylene. simultaneously [c] Et is added in n-butyl alcohol (80mL) solution of pyrroles -2 (1H)-t-butyl formate (5.23g, 19.71mmol)₃N(4.13g, 40.81mmol).After adding, reaction system is warming up in 150 DEG C of tube sealings reacts overnight.It is subsequently cooled to room temperature concentrating under reduced pressure. Through silica gel column chromatography (EtOAc/PE (v/v)=1/4) purification, obtain title compound is yellow oil to gained residue (1.11g, yield 13.5%).

LC-MS(ESI,pos.ion)m/z:412.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.13 and 8.12 (s, 1H), 5.82 and 5.40 (s, 1H), 3.50 (m, 2H), 3.38 (s, 2H), 3.30 and 3.19 (s, 2H), 2.85 (m, 2H), 2.72 (m, 2H), 1.92 and 1.73 (dd, J=13.6, 6.1Hz, 2H), 1.49 and 1.47 (s, 9H).

Step 4) 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) -5- (cyano group first Base) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate

To 5- (cyano methyl) -5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H) - T-butyl formate (631.5mg, 1.53mmol) and 1- methyl isophthalic acid H- pyrazoles -4- amine hydrochlorate (213.2mg, 1.60mmol) are just Et is added in butanol (10mL) solution₃N(322.1mg,3.18mmol).Reaction system is warming up to reacts overnight in 150 DEG C of tube sealings, Then concentrating under reduced pressure.Through silica gel column chromatography (MeOH/DCM (v/v)=1/50) purification, obtain title compound is Huang to gained residue Color solid (283.0mg, yield 39.1%).

LC-MS(ESI,pos.ion)m/z:473.3[M+H]⁺.

Step 5) 2- (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) octahydro ring Pentane simultaneously [c] pyrroles -5- base) acetonitrile

To 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) -5- (cyano methyl) Hexahydro Pentamethylene. simultaneously adds chlorine in DCM (10mL) solution of [c] pyrroles -2 (1H)-t-butyl formate (272.0mg, 0.58mmol) Change the ethyl acetate solution (10mL, 40mmol) of hydrogen.Reactant mixture is stirred at room temperature reaction 0.5 hour, then reduces pressure dense Contracting.Gained residue is dissolved in water (10mL), and resulting solution saturated aqueous sodium carbonate is adjusted to pH=10, then uses DCM (100mL × 3) extract.The organic layer merging washs through saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, filters, and filtrate subtracts Pressure concentrates.Gained residue, through silica gel column chromatography (MeOH/DCM (v/v)=1/10) purification, obtains title compound solid for ecru Body (109.9mg, yield 51.2%).

LC-MS(ESI,pos.ion)m/z:373.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:373.1658[M+H]⁺,C₁₇H₂₂ClN₈[M+H]⁺Theoretical value：373.1656；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.91(s,1H),7.64(s,1H),7.44(s,1H),6.57(s, 1H), 6.43 (s, 1H), 3.90 (s, 3H), 3.24 (s, 2H), 2.86 (m, 2H), 2.78 (d, J=10.2Hz, 2H), 2.69 (d, J =2.6Hz, 2H), 2.49 (dd, J=13.3,7.7Hz, 2H), 1.79 (dd, J=13.4,5.2Hz, 2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.0,157.6,153.6,122.7,122.4,118.1,105.4, 63.1,53.5,44.4,41.6,39.3,29.7,25.0.

Embodiment 33 1- (9- ((the chloro- 2- of 5- ((1- (piperidin-4-yl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) -3- azaspiro [5.5] hendecane -3- base) ethyl ketone

Step 1) 9- oxo -3- azaspiro [5.5] hendecane -7- alkene -3- t-butyl formate

EtOH to 4- formyl piperidine -1- t-butyl formate (10.0g, 46.9mmol) and KOH (1.3g, 23.5mmol) (200mL) in solution, add butyl- 3- alkene -2- ketone (3.9g, 56.3mmol), gained reactant mixture is warming up to 70 DEG C of stirrings 16 Hour.After reaction terminates, concentrating under reduced pressure.Gained residue, through silica gel column chromatography (EtOAc/PE (v/v)=1/4) purification, obtains mark Topic compound is light brown oil thing (5.2g, yield 41.8%).

MS(ESI,pos.ion)m/z:210.2[M-55]⁺.

Step 2) 9- oxo -3- azaspiro [5.5] hendecane -3- t-butyl formate

DCM to 9- oxo -3- azaspiro [5.5] hendecane -7- alkene -3- t-butyl formate (5.2g, 19.6mmol) (80mL) add Pd/C (0.5g, mass fraction 10%) in solution, at normal temperatures, in atmosphere of hydrogen, stirring is anti-for gained suspension Should overnight.Reactant mixture is filtered, filtrate reduced in volume, gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/ 4) purification, obtaining title compound is light brown oil thing (3.1g, yield 59.0%).

MS(ESI,pos.ion)m/z:212.1[M-55]⁺.

Step 3) 9- amino -3- azaspiro [5.5] hendecane -3- t-butyl formate

EtOH (40mL) to 9- oxo -3- azaspiro [5.5] hendecane -3- t-butyl formate (5.35g, 20.0mmol) Methanol solution (40mL, 280.0mmol, 7M) and the Ti (Oi-Pr) of ammonia is added in solution₄(11.30g, 40.0mmol), reactant System is stirred at room temperature overnight.By NaBH₄(1.51g, 40.0mmol) is dividedly in some parts in reaction system, and after adding, gained reacts Mixture is stirred at room temperature 5 hours, adds water and (40mL) reaction is quenched, and stirring was filtered after 1 hour.Filtrate reduced in volume, gained Through silica gel column chromatography (MeOH/DCM (v/v)=1/25) purification, obtain title compound is that (1.20g produces faint yellow solid to residue Rate 22.4%).

MS(ESI,pos.ion)m/z:269.3[M+H]⁺.

Step 4) 9- ((2,5- dichloro pyrimidine -4- base) amino) -3- azaspiro [5.5] hendecane -3- t-butyl formate

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

MS(ESI,pos.ion)m/z:415.0[M+H]⁺.

Step 5) N- (2,5- dichloro pyrimidine -4- base) -3- azaspiro [5.5] hendecane -9- amine

To 9- ((2,5- dichloro pyrimidine -4- base) amino) -3- azaspiro [5.5] hendecane -3- t-butyl formate (1.05g, The ethyl acetate solution (25mL, 3mmol, 2M) of hydrogen chloride is added in DCM (10mL) solution 2.53mmol).Reactant mixture It is stirred at room temperature 1 hour.After reaction terminates, reactant liquor is washed with water (50mL × 2).The aqueous phase merging is water-soluble with saturation NaOH Liquid (4M) is adjusted to pH=12, then uses mixed solvent DCM/MeOH (10/1 (v/v), 100mL × 5) to extract, the organic faciess of merging Use anhydrous Na₂SO₄It is dried, filters and concentrating under reduced pressure, obtaining title compound is white solid (708mg, yield 89%).

MS(ESI,pos.ion)m/z:315.2[M+H]⁺.

Step 6) 1- (9- ((2,5- dichloro pyrimidine -4- base) amino) -3- azaspiro [5.5] hendecane -3- base) ethyl ketone

To N- (2,5- dichloro pyrimidine -4- base) -3- azaspiro [5.5] hendecane -9- amine (301.8mg, 0.9575mmol) With addition acetic anhydride (120.4mg, 1.179mmol) in dichloromethane (20mL) solution of TEA (202.6mg, 2.002mmol). Reactant mixture is stirred at room temperature 30 minutes, after reaction terminates, concentrating under reduced pressure.Gained residue is through silica gel column chromatography (DCM/ MeOH (v/v)=70/1) purification, obtaining title compound is white solid (190mg, yield 55.54%).

MS(ESI,pos.ion)m/z:357.3[M+H]⁺.

Step 7) 4- (4- ((4- ((3- acetyl group -3- azaspiro [5.5] hendecane -9- base) amino) -5- chloropyrimide -2- Base) amino) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate

To 1- (9- ((2,5- dichloro pyrimidine -4- base) amino) -3- azaspiro [5.5] hendecane -3- base) ethyl ketone (312.4mg, 0.8743mmol), 4- (4- amino -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (337.8mg, 1.268mmol) add BINAP with 1,4- dioxane (14mL) solution of cesium carbonate (817.4mg, 2.509mmol) (54.1mg, 0.0869mmol) and Pd (OAc)₂(20.3mg,0.0904mmol).Reactant mixture is warming up to 100 DEG C and stirs 6 Hour, after reaction terminates, concentrating under reduced pressure.Gained residue, through silica gel column chromatography (DCM/MeOH (v/v)=40/1) purification, obtains mark Topic compound is yellow solid (280mg, yield 54.5%).

MS(ESI,pos.ion)m/z:587.6[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.85(s,1H),7.70(s,1H),7.53(s,1H),6.92(s, 1H), 5.13 (d, J=7.1Hz, 1H), 4.31-4.13 (m, 3H), 3.99-3.88 (m, 1H), 3.72-3.66 (m, 2H), 3.56 (dd, J=11.4,6.1Hz, 2H), 3.40 (dd, J=11.4,6.3Hz, 2H), 2.87 (t, J=11.6Hz, 2H), 2.15- 2.09(m,2H),2.08(s,3H),2.01-1.91(m,4H),1.89-1.86(m,2H),1.80-1.70(m,3H),1.62- 1.53(m,3H),1.46(s,9H).

Step 8) 1- (9- ((the chloro- 2- of 5- ((1- (piperidin-4-yl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) -3- azaspiro [5.5] hendecane -3- base) ethyl ketone

By 4- (4- ((4- ((3- acetyl group -3- azaspiro [5.5] hendecane -9- base) amino) -5- chloropyrimide -2- base) ammonia Base) -1H- pyrazol-1-yl) piperidines -1- t-butyl formate (280mg, 0.4768mmol) is added to the ethyl acetate of hydrogen chloride In (8mL, 16mmol, 2M) solution.Reactant mixture is stirred at room temperature 2 hours, after reaction terminates, concentrating under reduced pressure.Gained is residual Stay thing through silica gel column chromatography (DCM/ (NH₃MeOH solution (7M) (v/v)=20/1) purification, obtain title compound solid for yellow Body (57.2mg, yield 24.6%).

MS(ESI,pos.ion)m/z:487.4[M+H]⁺；

HRMS(ESI,pos.ion)m/z:487.2672[M+H]⁺,C₂₄H₃₆ClN₈O[M+H]⁺Theoretical value： 487.2701；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.84 (s, 1H), 7.74 (s, 1H), 7.57 (d, J=6.6Hz, 1H), 7.18-6.96 (m, 1H), 5.13 (d, J=4.9Hz, 1H), 4.31-4.21 (m, 1H), 3.98-3.87 (m, 1H), 3.58-3.51 (m, 2H), 3.45-3.36 (m, 4H), 2.96 (t, J=11.8Hz, 2H), 2.28-2.21 (m, 2H), 2.19-2.11 (m, 2H), 2.07 (d, J=1.4Hz, 3H), 2.00-1.89 (m, 2H), 1.77-1.67 (m, 2H), 1.58-1.50 (m, 2H), 1.47-1.29 (m,6H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):169.0,158.0,157.4,153.0,130.7,123.4,117.6, 104.2,57.6,50.7,49.9,44.1,42.5,39.4,37.4,34.2,31.3,30.9,29.7,27.5,21.4.

Embodiment 34 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino)-N- ring third Base hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulfonamide

Step 1) ring the third ammonium cyclopropylamino sulfonate

At 0 DEG C, in anhydrous DCM (50.0mL) solution of cyclopropylamine (2.94g, 51.5mmol), it is slowly added dropwise chlorosulfonic acid Anhydrous DCM (9.0mL) solution of (2.00g, 17.18mmol)) solution, its time for adding more than 30 minutes, after dripping, reaction Mixture stirs 30 minutes at 0 DEG C, then moves to room temperature and continues to stir 1 hour, after reaction terminates, filters.Gained filter cake Washed with anhydrous DCM (10.0mL), then drying under reduced pressure obtains title compound is white solid (3.33g, yield 100%).

MS(ESI,pos.ion)m/z:58.2[M₁]⁺；

MS(ESI,neg.ion)m/z:136.0[M₂]^-.

Step 2) cyclopropylamino sulfonic acid chloride

To in the suspension of ring the third ammonium cyclopropylamino sulfonate (3.33g, 17.1mmol) and dry toluene (50.0mL) Add phosphorus pentachloride (3.57g, 17.1mmol).Reactant mixture is warming up to 75 DEG C and stirs 2 hours, after reaction terminates, cooling To room temperature, filter, filter cake is rinsed with dry toluene (10.0mL).Through concentrating under reduced pressure, obtain title compound is brown to gained filtrate Liquid (0.65g, yield 24%).

Step 3) 5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino)-N- cyclopropyl Hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulfonamide

At 0 DEG C, to the chloro- N of 5-²- (1- methyl isophthalic acid H- pyrazoles -4- base)-N⁴- (octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) Pyrimidine -2,4- diamidogen (0.10g, 0.30mmol) and Et₃Add in anhydrous DCM (10.0mL) solution of N (0.21mL, 1.50mmol) Enter cyclopropylamino sulfonic acid chloride (0.10g, 0.63mmol).Reactant mixture stirs 15 minutes at 0 DEG C, then moves to room temperature and stirs Mix overnight.After reaction terminates, reactant mixture concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/NH₃MeOH solution (3M) (v/v)=100/1 to 50/1) purification, obtaining title compound is white solid (30mg, yield 22%).

MS(ESI,pos.ion)m/z:453.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:453.1585[M+H]⁺,C₁₈H₂₆ClN₈O₂S[M+H]⁺Theoretical value： 453.1582；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.86(s,1H),7.64(s,1H),7.49(s,1H),6.62(s, 1H), 5.33 (d, J=7.3Hz, 1H), 4.72 (d, J=4.5Hz, 1H), 4.38-4.27 (m, 1H), 3.88 (s, 3H), 3.32- 3.25(m,4H),2.78-2.72(m,2H),2.62-2.57(m,1H),2.51-2.45(m,2H),1.48-1.41(m,2H), 0.73-0.65(m,4H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.03,157.65,153.02,131.05,123.19,121.01, 104.35,54.24,52.70,40.51,39.27,24.82,18.45,6.90.

(((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) is phonetic for 9- for embodiment 35 1- Pyridine -4- base) amino) -3- azaspiro [5.5] hendecane -3- base) ethyl ketone

To 1- (9- ((2,5- dichloro pyrimidine -4- base) amino) -3- azaspiro [5.5] hendecane -3- base) ethyl ketone (83mg, 0.534mmol) the 1,4- dioxy with 1- (4- amino -1H- pyrazol-1-yl) -2- methyl propan-2-ol (129mg, 0.361mmol) Cesium carbonate (225mg, 0.690mmol), Pd (OAc) is added in six rings (20mL) solution₂(15mg, 0.067mmol) and BINAP (45mg,0.072mmol).Reactant mixture is stirred overnight at 100 DEG C, after reaction terminates, concentrating under reduced pressure, and gained residue warp Silica gel column chromatography (MeOH/DCM=1/30) purification, obtaining title compound is yellow solid (30mg, yield 17.5%).

MS(ESI,pos.ion)m/z:476.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:476.2540[M+H]⁺,C₂₃H₃₅ClN₇O₂[M+H]⁺Theoretical value： 476.2463；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.85 (s, 1H), 7.75 (d, J=11.3Hz, 1H), 7.57 (d, J= 12.3Hz, 1H), 7.00 (s, 1H), 5.16 (s, 1H), 4.02-3.90 (m, 2H), 3.93 (d, J=16.2Hz, 1H), 3.60- 3.52(m,2H),3.42-3.99(m,2H),2.09(s,3H),1.99-1.94(m,2H),1.76-1.72(s,2H),1.59- 1.53(m2H),1.48-1.33(m,6H),1.18(s,6H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):169.11,157.86,157.50,152.72,131.52,130.04, 123.10,121.78,70.92,62.25,42.59,37.48,34.38,30.97,29.82,27.67,27.03,26.92, 21.62.

Embodiment 36 5- ((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) pyrimidine -4- Base) amino)-N- cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide

Step 1) 5- ((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate

To 5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-t-butyl formate (143.5mg, 0.38mmol) and 1- (4- amino -1H- pyrazol-1-yl) -2-'s methyl propan-2-ol (68.8mg, 0.44mmol) Pd (OAc) is added in 1,4- dioxane (20mL) solution₂(19.3mg, 0.09mmol), BINAP (98%, 54.4mg, 0.08mmol) with cesium carbonate (98%, 272.3mg, 0.82mmol).Reactant mixture is stirred overnight at 100 DEG C, and reaction terminates Afterwards, concentrating under reduced pressure, through silica gel column chromatography (EtOAc/PE (v/v)=2/1) purification, obtain title compound is yellow to gained residue Solid (56.2mg, yield 29.7%).

MS(ESI,pos.ion)m/z:492.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.85 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 5.36 (d, J= 5.8Hz, 1H), 4.41 (m, 1H), 4.03 (s, 2H), 3.50 (m, 2H), 3.38 (d, J=9.5Hz, 2H), 2.71 (m, 2H), 2.46(m,2H),1.46(m,11H),1.20(s,6H).

Step 2) 1- (4- ((the chloro- 4- of 5- ((octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) pyrimidine -2-base) amino) - 1H- pyrazol-1-yl) -2- methyl propan-2-ol

To 5- ((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) hexahydro Pentamethylene. simultaneously in DCM (10mL) solution of [c] pyrroles -2 (1H)-t-butyl formate (176.4mg, 0.45mmol) plus Enter the ethyl acetate solution (10mL, 40mmol, 4M) of hydrogen chloride.Reactant mixture is stirred at room temperature 0.5 hour, and reaction terminates Afterwards, concentrating under reduced pressure.Gained residue is dissolved in water (10mL), and uses saturation Na2CO₃Aqueous solution adjusts its pH=10, so DCM (100mL × 3) is used to extract afterwards.The organic faciess merging are washed with saturated aqueous common salt (100mL), anhydrous Na₂SO₄It is dried, then Concentrating under reduced pressure.Through silica gel column chromatography (MeOH/DCM (v/v)=1/8) purification, it is faint yellow for obtaining title compound to gained residue Solid (64.5mg, yield 45.9%).

MS(ESI,pos.ion)m/z:392.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ(ppm)7.82(s,2H),7.79(s,1H),7.58(s,1H),6.64(s, 1H),4.52(m,1H),4.03(s,2H),3.51(s,1H),2.90(m,4H),2.71(s,2H),2.26(m,2H),1.51(d, J=13.4Hz, 2H), 1.20 (s, 6H).

Step 3) 5- ((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino)-N- cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide

To 1- (4- ((the chloro- 4- of 5- ((octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) pyrimidine -2-base) amino) -1H- pyrrole Azoles -1- base) -2- methyl propan-2-ol (55.9mg, 0.14mmol) and Et₃The EtOH (10mL) of N (110.1mg, 1.09mmol) is molten Clopentylamino phenyl formate (45.2mg, 0.26mmol) is added in liquid.Reactant mixture is stirred overnight at 50 DEG C, reaction knot Shu Hou, reactant liquor is down to room temperature, then reaction is quenched with water (30mL), and gained mixture is extracted with DCM (100mL × 3).Merge Organic faciess are washed with saturated aqueous common salt (100mL), anhydrous Na₂SO₄It is dried, filter and concentrating under reduced pressure.Gained residue is through silicagel column Chromatography (MeOH/DCM (v/v)=1/20) purification, obtaining title compound is buff white solid (52.6mg, yield 77.6%).

MS(ESI,pos.ion)m/z:475.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:475.2339[M+H]⁺,C₂₂H₃₂ClN₈O₂[M+H]⁺Theoretical value： 475.2337；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.86(s,1H),7.76(s,1H),7.62(s,1H),7.20(s, 1H),5.42(s,1H),4.56(s,1H),4.42(s,1H),4.03(s,2H),3.47(2,2H),3.34(s,2H),2.75(s, 2H),2.66(s,1H),2.43(s,2H),1.49(s,2H),1.20(s,6H),0.73(s,2H),0.49(s,2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.2,157.8,157.6,152.6,131.6,122.9,121.9, 70.8,62.1,53.2,52.2,41.1,39.1,29.7,26.9,23.3,6.9.

Embodiment 37 1- (4- ((the chloro- 4- of 5- ((3- (mesyl) -3- azaspiro [5.5] hendecane -9- base) amino) Pyrimidine -2-base) amino) -1H- pyrazol-1-yl) -2- methyl propan-2-ol

Step 1) N- (2,5- dichloro pyrimidine -4- base) -3- (methyl sulphonyl) -3- azaspiro [5.5] hendecane -9- amine

To N- (2,5- dichloro pyrimidine -4- base) -3- azaspiro [5.5] hendecane -9- amine (220mg, 0.698mmol) Et is added in DCM (10mL) solution₃N (109mg, 1.07mmol) and DMAP (19.1mg, 0.223mmol).Reactant mixture is cold But to 0 DEG C, it is subsequently adding methane sulfonyl chloride (102mg, 0.890mmol).Gained mixture is stirred overnight at 0 DEG C, then subtracts Pressure concentrates.Through silica gel column chromatography (MeOH/DCM (v/v)=1/80) purification, obtain title compound is yellow solid to gained residue (176mg, yield 64.1%).

MS(ESI,pos.ion)m/z:393.0[M+H]⁺.

Step 2) (((the chloro- 4- of 5- ((3- (methyl sulphonyl) -3- azaspiro [5.5] hendecane -9- base) amino) is phonetic for 4- for 1- Pyridine -2- base) amino) -1H- pyrazol-1-yl) -2- methyl propan-2-ol

To N- (2,5- dichloro pyrimidine -4- base) -3- (methyl sulphonyl) -3- azaspiro [5.5] hendecane -9- amine The 1 of (142mg, 0.361mmol) and 1- (4- amino -1H- pyrazol-1-yl) -2- methyl propan-2-ol (70mg, 0.451mmol), Cesium carbonate (234mg, 0.718mmol), Pd (OAc) is added in 4- dioxane (20mL) solution₂(16mg, 0.071mmol) and BINAP(45mg,0.072mmol).Reactant mixture is stirred overnight at 105 DEG C, after reaction terminates, concentrating under reduced pressure.Gained is residual Stay thing through silica gel column chromatography (DCM/MeOH=40/1) purification, obtaining title compound is yellow solid (80mg, yield 43.3%).

MS(ESI,pos.ion)m/z:512.0[M+H]⁺；

HRMS(ESI,pos.ion)m/z:512.2209[M+H]⁺,C₂₂H₃₅N₇O₃S[M+H]⁺Theoretical value： 512.2131；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.96(s,2H),8.02(s,1H),7.86(s,1H),7.73(s, 1H),7.50(s,1H),3.96(s,2H),3.12-3.10(m,4H),2.86(s,3H),2.00-1.98(m,1H),1.77- 1.64(m,10H),1.44-1.42(m,2H),1.06(s,6H).

Embodiment 38 1- (4- ((the chloro- 4- of 5- ((2- (methyl sulphonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) Pyrimidine -2-base) amino) -1H- pyrazol-1-yl) propan-2-ol

Step 1) 1- (4- nitro -1H- pyrazol-1-yl) propan-2-ol

DMF to 4- nitro -1H- pyrazoles (1.02g, 9.02mmol) and 1- bromine propan-2-ol (3.65g, 26.3mmol) (10mL) add cesium carbonate (8.65g, 26.5mmol) in solution.Reactant mixture stirs 3.5 hours at 100 DEG C.Reaction knot Shu Hou, is quenched reaction with water (50mL), then uses EtOAc (100mL × 3) to extract.The organic faciess anhydrous Na merging₂SO₄Dry Dry, filter, it is yellow oil (1.51g, yield 97.8%) that concentrating under reduced pressure obtains title compound.

MS(ESI,pos.ion)m/z:172.2[M+H]⁺.

Step 2) 1- (4- amino -1H- pyrazol-1-yl) propan-2-ol

Add in EtOH (20mL) solution of 1- (4- nitro -1H- pyrazol-1-yl) propan-2-ol (1.51g, 8.82mmol) Enter Pd/C (300mg, mass fraction 10%).Reactant mixture as in autoclave, at room temperature, 2MPa H₂React in atmosphere Overnight, filter after reaction terminates, gained is filtered concentrating under reduced pressure.Gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=1/ 30) purification, obtaining title compound is brown solid (1.0g, yield 80.3%).

MS(ESI,pos.ion)m/z:142.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.17(s,1H),7.03(s,1H),4.16-4.10(m,1H),4.02 (dd, J=13.8,2.7Hz, 1H), 3.85 (dd, J=13.8,7.9Hz, 1H), 2.95 (s, 2H), 1.19 (d, J=6.3Hz, 3H).

Step 3) N- (2,5- dichloro pyrimidine -4- base) -2- (methyl sulphonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine

DCM to N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (500mg, 1.83mmol) (10mL) add Et in solution₃N (340mg, 3.36mmol) and DMAP (45mg, 0.368mmol).Will be cold for gained mixture system But to 0 DEG C, and it is added thereto to methane sulfonyl chloride (310mg, 2.71mmol).Reactant mixture is stirred overnight at 0 DEG C, reaction After end, concentrating under reduced pressure, gained residue, through silica gel column chromatography (MeOH/DCM (v/v)=1/100) purification, obtains title compound For yellow solid (300mg, yield 46.7%).

MS(ESI,pos.ion)m/z:351.2[M+H]⁺.

Step 4) (((the chloro- 4- of 5- ((2- (methyl sulphonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) is phonetic for 4- for 1- Pyridine -2- base) amino) -1H- pyrazol-1-yl) propan-2-ol

To N- (2,5- dichloro pyrimidine -4- base) -2- (methyl sulphonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (132mg, 0.375mmol) the 1,4- dioxane with 1- (4- amino -1H- pyrazol-1-yl) propan-2-ol (82mg, 0.580mmol) (20mL) cesium carbonate (241mg, 0.739mmol), Pd (OAc) are added in solution₂(16mg, 0.071mmol) and BINAP (46mg, 0.073mmol).Reactant mixture is stirred overnight at 105 DEG C, after reaction terminates, concentrating under reduced pressure, and gained residue is through silicagel column Chromatography (MeOH/DCM (v/v)=1/30) purification, obtaining title compound is yellow solid (100mg, yield 58.4%).

MS(ESI,pos.ion)m/z:456.4[M+H]⁺；

HRMS(ESI,pos.ion)m/z:456.1580[M+H]⁺,C₁₈H₂₇ClN₇O₃S[M+H]⁺Theoretical value： 456.1506；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.04 (s, 1H), 7.85 (d, J=8.1Hz, 1H), 7.82 (s, 1H), 7.42 (s, 1H), 6.97 (d, J=7.4Hz, 1H), 4.91 (s, 1H), 4.43-4.37 (m, 1H), 3.96-3.89 (m, 3H), 3.23 (dd, J=9.3,7.1Hz, 2H), 3.13-3.10 (m, 2H), 2.91 (s, 3H), 2.69 (s, 2H), 2.25 (s, 2H), 1.52 (dd, J=18.4,10.1Hz, 2H), 1.01 (d, J=5.8Hz, 3H)；

¹³C NMR(150MHz,DMSO-d₆)δ(ppm):157.65,157.37,153.29,129.43,123.35, 119.87,65.70,58.91,53.59,40.06,39.99,37.56,32.85,20.90.

Embodiment 39 1- (4- ((the chloro- 4- of 5- ((2- (methyl sulphonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) Pyrimidine -2-base) amino) -1H- pyrazol-1-yl) -2- methyl propan-2-ol

To N- (2,5- dichloro pyrimidine -4- base) -2- (methyl sulphonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (160mg, 0.455mmol) the 1,4- dioxy with 1- (4- amino -1H- pyrazol-1-yl) -2- methyl propan-2-ol (110mg, 0.708mmol) Cesium carbonate (310mg, 0.951mmol), Pd (OAc) is added in six rings (20mL) solution₂(21mg, 0.093mmol) and BINAP (57mg,0.091mmol).Reactant mixture is stirred overnight at 105 DEG C, after reaction terminates, concentrating under reduced pressure, and gained residue warp Silica gel column chromatography (MeOH/DCM (v/v)=1/30) purification, obtaining title compound is yellow solid (100mg, yield 46.7%).

MS(ESI,pos.ion)m/z:470.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:470.1773[M+H]⁺,C₁₉H₂₉ClN₇O₃S[M+H]⁺Theoretical value： 470.1663；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.04 (s, 1H), 7.85 (d, J=5.8Hz, 2H), 7.42 (s, 1H), 6.96 (d, J=7.7Hz, 1H), 4.44-4.37 (m, 1H), 3.93 (s, 2H), 3.23 (dd, J=9.3,7.0Hz, 2H), 3.17 (d, J=5.2Hz, 1H), 3.13-3.10 (m, 2H), 2.91 (s, 3H), 2.69 (s, 2H), 2.25 (s, 2H), 1.51 (dd, J=18.9,11.7Hz, 2H), 1.04 (s, 6H)；

¹³C NMR(150MHz,DMSO-d₆)δ(ppm):157.69,157.39,153.34,129.25,123.35, 120.32,69.42,62.42,53.62,48.63,40.02,37.61,32.86,27.22.

Embodiment 40 5- ((the chloro- 2- of 5- ((1- (pyrrolidin-3-yl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base)-N- cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide

Step 1) 3- hydroxyl pyrrolidine -1- t-butyl formate

To pyrrolidine -3- alcohol hydrochloride (2.00g, 16.2mmol) and Et₃The anhydrous DCM of N (6.80mL, 48.8mmol) (40.0mL) add (Boc) in suspension₂O(4.24g,19.4mmol).Reactant mixture is stirred at room temperature 3 hours, reaction After end, concentrating under reduced pressure.Gained residue, through silica gel column chromatography (EtOAc/PE (v/v)=1/4 to 1/2 to 1/1) purification, obtains mark Topic compound is colourless viscous shape liquid (2.20g, yield 76%).

MS(ESI,pos.ion)m/z:132.2[(M-56)+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):4.48-4.33(m,1H),3.51-3.24(m,4H),1.97-1.82 (m,2H),1.44(s,9H).

Step 2) 3- (4- nitro -1H- pyrazol-1-yl) pyrrolidine -1- t-butyl formate

3- hydroxypyrrole is added in THF (35.0mL) suspension of 4- nitro -1H- pyrazoles (0.50g, 4.43mmol) Alkane -1- t-butyl formate (1.00g, 5.33mmol) and triphenyl see (1.75g, 6.68mmol).Mixture is cooled to 0 DEG C, and It is added thereto to anhydrous THF (15.0mL) solution of DIAD (1.36g, 6.73mmol), time for adding was more than 20 minutes.Gained mixes It is combined in and stirs 30 minutes at 0 DEG C, then move to and be stirred overnight at room temperature, after reaction terminates, concentrating under reduced pressure, gained residue is through silica gel Column chromatography (EtOAc/PE (v/v)=10/1 to 5/1) purification, the crude product obtaining title compound glues shape liquid for brown (2.10g, containing impurity, wherein target product is 1.25g, yield 100%).

MS(ESI,pos.ion)m/z:227.0[(M-56)+H]⁺.

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

EtOH to 3- (4- nitro -1H- pyrazol-1-yl) pyrrolidine -1- t-butyl formate (1.25g, 4.43mmol) (30.0mL) add Pd/C (mass fraction 10%, 0.30g) in solution.Reactant mixture is stirred in room temperature and atmosphere of hydrogen At night, after reaction terminates, filter, filter cake is washed with MeOH (10.0mL).Gained is considered liquid concentrating under reduced pressure, residue is through silica gel column layer Analysis (DCM 100% to DCM/NH₃MeOH (3M) solution (v/v)=100/1 to 50/1) purification, obtain title compound be brown Viscous shape liquid (0.65g, yield 58%).

MS(ESI,pos.ion)m/z:253.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.16(s,1H),7.01(s,1H),4.79-4.67(m,1H),3.82- 3.73(m,1H),3.70-3.44(m,3H),2.90(s,2H),2.36-2.24(m,2H),1.45(s,9H).

Step 4) N- cyclopropyl -5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H) - Methanamide

Second to N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (110.5mg, 0.41mmol) N- cyclopropylamino phenyl formate (144.2mg, 0.81mmol) is added in alcohol (2mL) solution.Reactant mixture stirs at 50 DEG C Mix 10 hours, reaction terminate after, concentrating under reduced pressure, gained residue through silica gel column chromatography (DCM/MeOH (v/v)=30/1) purification, Obtaining title compound is brown oil (138.2mg, yield 96%).

MS(ESI,pos.ion)m/z:356.0[M+H]⁺.

Step 5) 3- (4- ((the chloro- 4- of 5- ((2- (cyclopropylcarbamoyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) ammonia Base) pyrimidine -2-base) amino) -1H- pyrazol-1-yl) pyrrolidine -1- t-butyl formate

To N- cyclopropyl -5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-formyl Amine (152.2mg, 0.43mmol) and 3- (4- amino-pyrazol -1- base) pyrrolidine -1- t-butyl formate (130.4mg, Pd (OAc) is added in 1,4- dioxane (4mL) solution 0.52mmol)₂(10.2mg,0.05mmol)、BINAP(27.3mg, 0.04mmol) with cesium carbonate (275.6mg, 0.85mmol).Reactant mixture is at 100 DEG C and N₂The lower stirring of protection 6 hours, reaction After end, concentrating under reduced pressure, gained residue, through silica gel column chromatography (DCM/MeOH (v/v)=60/1 to 30/1) purification, obtains title Compound is brown solid (124.3mg, yield 51%).

MS(ESI,pos.ion)m/z:572.3[M+H]⁺.

Step 6) 5- ((the chloro- 2- of 5- ((1- (pyrrolidin-3-yl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) - N- cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide

The EtOAc solution (3M, 8mL, 24mmol) of HCl is added to 3- (4- ((the chloro- 4- of 5- ((2- (cyclopropylamino first Acyl group) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) pyrimidine -2-base) amino) -1H- pyrazol-1-yl) pyrrolidine -1- formic acid In DCM (2mL) solution of the tert-butyl ester (124.2mg, 0.22mmol).Reactant mixture is stirred at room temperature 1 hour, and reaction terminates Afterwards, concentrating under reduced pressure.Residue is diluted with water (4mL), and gained mixture is adjusted to pH=9 with the NaOH aqueous solution of 1M, then subtracts Pressure concentrates, and gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=20/1 to DCM/NH₃MeOH solution (7M) (v/v) =10/1) purification, obtaining title compound is red solid (45.4mg, yield 44%).

MS(ESI,pos.ion)m/z:236.6[(M+2H)/2]⁺；

HRMS(ESI,pos.ion)m/z:472.2303[M+H]⁺,C₂₂H₃₁ClN₉O[M+H]⁺Theoretical value：472.2335；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.86(s,1H),7.78(s,1H),7.54(s,1H),6.78(s, 1H), 5.35 (d, J=7.5Hz, 1H), 4.79 (ddd, J=10.9,7.2,3.5Hz, 1H), 4.52 (s, 1H), 4.41 (dd, J= 15.3,7.7Hz, 1H), 3.47 (dd, J=10.1,7.6Hz, 2H), 3.35-3.31 (m, 3H), 3.27 (dd, J=12.1, 6.4Hz, 1H), 3.12-3.06 (m, 1H), 2.73 (t, J=10.7Hz, 2H), 2.65 (dd, J=5.3,3.4Hz, 1H), 2.47- 2.40(m,2H),2.38-2.31(m,1H),2.28-2.18(m,3H),1.53-1.45(m,2H),0.76-0.68(m,2H), 0.50-0.44(m,2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.2,157.9,157.5,153.0,131.1,129.9,123.3, 119.0,61.9,53.6,53.2,52.2,46.3,41.2,39.1,33.0,23.4,6.9.

Embodiment 41 5- ((the chloro- 2- of 5- ((1- (2- hydroxypropyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base)-N- cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide；With

Embodiment 42 N- cyclopropyl -5- ((2- ((1- (2- hydroxypropyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide

To N- cyclopropyl -5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-formyl Amine (535.5mg, 1.50mmol) and the 1,4- of 1- (4- amino -1H- pyrazol-1-yl) propan-2-ol (271.2mg, 1.92mmol) Pd (OAc) is added in dioxane (30mL) solution₂(73.0mg, 0.32mmol), BINAP (98%, 194.8mg, 0.31mmol) with cesium carbonate (98%, 1.04g, 3.13mmol).Reactant mixture is stirred overnight at 100 DEG C, and reaction terminates Afterwards, concentrating under reduced pressure, gained residue, through silica gel column chromatography (DCM/MeOH (v/v)=20/1) purification, obtains 5- ((the chloro- 2- of 5- ((1- (2- hydroxypropyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino)-N- cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrrole Coughing up -2 (1H)-Methanamides is light pink solid (279.8mg, yield 40.4%).Use (DCM/MeOH (v/v)=10/1) again instead Eluent, obtains N- cyclopropyl -5- ((2- ((1- (2- hydroxypropyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) simultaneously [c] pyrroles -2 (1H)-Methanamide is light pink solid (134.2mg, yield 20.9%) to hexahydro Pentamethylene..

Wherein, 5- ((the chloro- 2- of 5- ((1- (2- hydroxypropyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino)-N- The characterize data of cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide：

MS(ESI,pos.ion)m/z:461.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:461.2150[M+H]⁺,C₂₁H₃₀ClN₈O₂[M+H]⁺Theoretical value： 461.2180；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.86(s,1H),7.76(s,1H),7.59(s,1H),6.82(s, 1H), 5.37 (d, J=7.4Hz, 1H), 4.54 (s, 1H), 4.42 (m, 1H), 4.22 (m, 1H), 4.13 (dd, J=13.8, 2.7Hz, 1H), 3.96 (dd, J=13.8,8.0Hz, 1H), 3.57 (s, 1H), 3.48 (dd, J=9.9,7.3Hz, 2H), 3.34 (d, J=10.0Hz, 2H), 2.76 (m, 2H), 2.67 (m, 1H), 2.45 (m, 2H), 1.51 (m, 2H), 1.25 (d, J=6.3Hz, 3H),0.74(m,2H),0.50(m,2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):158.2,158.0,157.5,153.0,131.6,123.0,121.4, 67.2,58.9,53.2,52.2,41.1,39.1,23.3,20.1,6.9.

N- cyclopropyl -5- ((2- ((1- (2- hydroxypropyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) hexahydro The characterize data of Pentamethylene. simultaneously [c] pyrroles -2 (1H)-Methanamide：

MS(ESI,pos.ion)m/z:427.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:427.2542[M+H]⁺,C₂₁H₃₁N₈O₂[M+H]⁺Theoretical value：427.2570；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.90 (d, J=4.7Hz, 1H), 7.83 (s, 1H), 7.53 (s, 1H), (6.70 s, 1H), 5.78 (d, J=5.8Hz, 1H), 4.97 (s, 1H), 4.52 (s, 1H), 4.22 (m, 2H), 4.14 (dd, J= 13.8,2.4Hz, 1H), 3.96 (dd, J=13.8,8.1Hz, 1H), 3.77 (s, 1H), 3.48 (dd, J=10.1,7.6Hz, 2H), 3.31 (d, J=10.4Hz, 2H), 2.75 (m, 2H), 2.65 (m, 1H), 2.42 (m, 2H), 1.44 (m, 2H), 1.25 (d, J =6.3Hz, 3H), 0.74 (m, 2H), 0.49 (m, 2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):162.6,159.8,158.1,132.0,124.8,122.8,122.1, 67.2,59.0,52.0,50.8,41.2,39.2,23.3,20.1,6.9.

Embodiment 43 5- ((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) pyrimidine -4- Base) amino)-N- cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulfonamide

Step 1) N- cyclopropyl -5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H) - Sulfonamide

At 0 DEG C, to N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (0.27g, 0.987mmol7) and Et₃It is slowly added dropwise cyclopropylamino sulphur in anhydrous DCM (10.0mL) suspension of N (0.70mL, 5.00mmol) Anhydrous DCM (5.0mL) solution of acyl chlorides (0.31g, 1.98mmol).After dripping, reactant mixture moves to and is stirred at room temperature 30 points Clock, is then quenched reaction, stratification with water (20mL).Isolate organic layer, water layer is extracted with DCM (30mL × 3).Merge Organic faciess are washed with saturated aqueous common salt (30mL), anhydrous Na₂SO₄It is dried, filter, filtrate reduced in volume, gained residue is through silica gel Column chromatography (EtOAc/PE (v/v)=1/3) purification, obtaining title compound is yellow solid (0.17g, yield 44%).

MS(ESI,pos.ion)m/z:392.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.02 (s, 1H), 5.70 (d, J=7.7Hz, 1H), 4.51-4.38 (m, 1H),3.85(s,1H),3.35-3.22(m,4H),2.84-2.71(m,2H),2.63-2.57(m,1H),2.53-2.44(m, 2H),1.50-1.37(m,2H),0.75-0.70(m,4H).

Step 2) 5- ((the chloro- 2- of 5- ((1- (2- hydroxy-2-methyl propyl group) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino)-N- cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulfonamide

To N- cyclopropyl -5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulphonyl 1- (4- amino -1H- pyrazoles -1- is added in anhydrous 1,4- dioxane (10.0mL) suspension of amine (0.11g, 0.28mmol) Base) -2- methyl propan-2-ol (54mg, 0.35mmol), Pd (OAc)₂(14mg,0.06mmol)、BINAP(37mg,0.06mmol) With cesium carbonate (0.20g, 0.61mmol).Reactant mixture deaerates 2 minutes, is re-filled with nitrogen, is then heated to 105 DEG C of stirrings 3 Hour, after reaction terminates, concentrating under reduced pressure, gained residue is pure through silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 30/1) Change, obtain crude product, crude product through preparing thin layer chromatography (DCM/MeOH (v/v)=20/1) purification, obtains title compound again For brown solid (55mg, yield 38%).

MS(ESI,pos.ion)m/z:511.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:511.1974[M+H]⁺,C₂₁H₃₂ClN₈O₃S[M+H]⁺Theoretical value： 511.2001；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.06(s,1H),7.87(s,1H),7.84(s,1H),7.54(d,J =1.9Hz, 1H), 7.43 (s, 1H), 6.97 (s, 1H), 4.67 (s, 1H), 4.44-4.32 (m, 1H), 3.94 (s, 2H), 3.25- 3.21(m,2H),3.11-3.03(m,2H),2.75-2.65(m,2H),2.46-2.44(m,1H),2.30-2.20(m,2H), 1.56-1.46(m,2H),1.05(s,6H),0.63-0.56(m,2H),0.56-0.49(m,2H).

Embodiment 44 1- (4- ((the chloro- 4- of 5- ((2- (Cyclopropylsulfonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) ammonia Base) pyrimidine -2-base) amino) -1H- pyrazol-1-yl) propan-2-ol

Step 1) 2- (Cyclopropylsulfonyl)-N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine

At 0 DEG C, to Et₃Octahydro Pentamethylene. is simultaneously [c] for N (120mg, 1.17402mmol) and N- (2,5- dichloro pyrimidine -4- base) Deca cyclopropanesulfonyl chloride in DCM (20mL, the 311mmol) solution of pyrroles's -5- amine (100mg, 0.3661mmol) (77mg, 0.5477mmol).After dripping, reactant mixture is stirred at room temperature 6 hours, then concentrating under reduced pressure.Gained residue is through silicon Plastic column chromatography (DCM/MeOH (v/v)=40/1) purification, obtaining title compound is faint yellow solid (102mg, yield 73.9%).

MS(ESI,pos.ion)m/z:377.3[M+H]⁺.

Step 2) 1- (4- ((the chloro- 4- of 5- ((2- (Cyclopropylsulfonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) amino) Pyrimidine -2-base) amino) -1H- pyrazol-1-yl) propan-2-ol

To 2- (Cyclopropylsulfonyl)-N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (101.2mg, 0.2682mmol), 1- (4- amino-pyrazol -1- base) propan-2-ol (58.8mg, 0.417mmol), BINAP (15.2mg, 0.0237mmol) and Pd (OAc)₂Add in 1,4- dioxane (15mL) solution of (6.3mg, 0.028mmol) Cesium carbonate (261.0mg, 0.800mmol).Reactant mixture is in N₂It is warming up to 100 DEG C under protection, is stirred overnight, reaction terminates Afterwards, concentrating under reduced pressure, through silica gel column chromatography (DCM/MeOH (v/v)=40/1) purification, it is yellowish for obtaining crude product to gained residue Color solid, again through preparing thin layer chromatography (DCM/MeOH (v/v)=30/1) purification, obtain title compound is white solid to crude product (30mg, yield 23.2%).

MS(ESI,pos.ion)m/z:482.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.86(s,1H),7.73(s,1H),7.57(s,1H),6.63(s, 1H), 5.38 (d, J=7.4Hz, 1H), 4.33 (m, 1H), 4.21 (m, 1H), 4.11 (dd, J=13.8,2.5Hz, 1H), 3.94 (dd, J=13.8,8.0Hz, 1H), 3.36 (m, 2H), 3.31 (m, 2H), 2.77 (m, 2H), 2.47 (m, 2H), 2.35 (m, 1H), 1.49 (m, 2H), 1.23 (d, J=6.3Hz, 3H), 1.21 (m, 2H), 1.01 (m, 2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):157.9,157.6,152.9,131.5,129.9,123.0,121.2, 67.3,58.8,54.2,52.5,40.5,39.3,29.7,25.1,20.1,4.5.

Embodiment 45 5- ((the chloro- 2- of 5- ((1- (2- hydroxypropyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base)-N- ethyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulfonamide

Step 1) 5- ((2,5- dichloro pyrimidine -4- base) amino)-N- ethyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulphur Amide

To N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (303.4mg, 1.111mmol) TEA (354.7mg, 3.505mmol) is added in DCM (5mL) solution.Mixture is cooled to 0 DEG C, and is added thereto to N- ethyl ammonia DCM (4mL) solution of base sulfonic acid chloride (100mg, 0.6964mmol).Reactant mixture is stirred at room temperature overnight, and reaction terminates Afterwards, concentrating under reduced pressure.Through silica gel column chromatography (DCM/MeOH (v/v)=70/1) purification, it is white for obtaining title compound to gained residue Color solid (95mg, yield 22.49%).

MS(ESI,pos.ion)m/z:380.4[M+H]⁺.

Step 2) 5- ((the chloro- 2- of 5- ((1- (2- hydroxypropyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) - N- ethyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulfonamide

To 5- ((2,5- dichloro pyrimidine -4- base) amino)-N- ethyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulfonamide Add in the mixture of (95mg, 0.2498mmol) and 1- (4- amino-pyrazol -1- base) propan-2-ol (44.6mg, 0.316mmol) Cs₂CO₃(168.4mg,0.5168mmol)、BINAP(17.2mg,0.0276mmol)、Pd(OAc)₂(6.8mg,0.030mmol) With 1,4- dioxane (10mL).Reactant mixture is in N₂The lower back flow reaction of protection 4 hours.After reaction terminates, concentrating under reduced pressure, institute Obtain residue through silica gel column chromatography (DCM/MeOH (v/v)=20/1) purification, obtaining title compound is faint yellow solid (35.4mg, yield 29.2%).

MS(ESI,pos.ion)m/z:485.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:485.1853[M+H]⁺,C₁₉H₃₀ClN₈O₃S[M+H]⁺Theoretical value： 485.1850；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.84(s,1H),7.72(s,1H),7.57(s,1H),6.96-6.78 (m, 1H), 5.44 (d, J=6.9Hz, 1H), 4.35-4.29 (m, 1H), 4.27 (t, J=5.7Hz, 1H), 4.23-4.16 (m, 1H), 4.11 (dd, J=13.8,2.4Hz, 1H), 3.94 (dd, J=13.8,8.0Hz, 1H), 3.27-3.15 (m, 6H), 2.79- 2.72 (m, 2H), 2.51-2.40 (m, 2H), 1.49-1.40 (m, 2H), 1.22 (t, J=7.1Hz, 6H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):157.9,157.7,152.7,131.6,122.9,121.4,67.2, 58.9,54.4,52.7,40.4,39.5,39.1,20.1,15.7.

Embodiment 46 1- (4- ((the chloro- 4- of 5- ((2- ((Cvclopropvlmethvl) sulfonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- Base) amino) pyrimidine -2-base) amino) -1H- pyrazol-1-yl) propan-2-ol

Step 1) cyclopropyl methanesulfonic sodium

To in the sodium sulfite aqueous solution (10mL) of saturation Deca 1- bromo- 1- methyl cyclopropane (1.00g, 7.4074mmol).After dripping, reactant mixture is stirred overnight at 100 DEG C, after reaction terminates, concentrating under reduced pressure.Residual to gained Stay in thing and add EtOH (20mL), be warming up to 50 DEG C and stir 5 hours, filter, collect filter cake to obtain title compound is that white is solid Body (1.12g, yield 95.6%).

Step 2) cyclopropyl mesyl chloride

The Deca thionyl chloride in THF (10mL, the 123mmol) solution of cyclopropyl methanesulfonic sodium (1.12g, 7.08mmol) (2.1mL,29mmol).After dripping, reactant liquor stirs 5 hours at 100 DEG C, then concentrating under reduced pressure, and obtaining product is brown Grease (1.00g, yield 91.3%).

Step 3) 2- ((Cvclopropvlmethvl) sulfonyl)-N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrrole Cough up -5- amine

At 0 DEG C, to N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (200.2mg, 0.7329mmol) and Et₃Deca cyclopropyl methylsulfonyl in DCM (30mL, the 467mmol) solution of N (120mg, 1.1740mmol) DCM (5mL) solution of chlorine (200mg, 1.2935mmol).After dripping, reactant mixture is stirred at room temperature 5 hours, reaction After end, concentrating under reduced pressure.Gained residue, through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purification, obtains title compound For faint yellow solid (180.1mg, yield 62.8%).

MS(ESI,pos.ion)m/z:391.2[M+H].

Step 4) 1- (4- ((the chloro- 4- of 5- ((2- ((Cvclopropvlmethvl) sulfonyl) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) Amino) pyrimidine -2-base) amino) -1H- pyrazol-1-yl) propan-2-ol

To 2- ((Cvclopropvlmethvl) sulfonyl)-N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- Amine (180.5mg, 0.46mmol), 1- (4- amino-pyrazol -1- base) propan-2-ol (97.3mg, 0.69mmol), BINAP (29.3mg, 0.046mmol) and Pd (OAc)₂Add in 1,4- dioxane (15mL) solution of (10.2mg, 0.044mmol) Cesium carbonate (451.2mg, 1.38mmol).Reactant mixture is at 100 DEG C and N₂It is stirred overnight under protection.After reaction terminates, decompression Concentrate, through silica gel column chromatography (DCM/MeOH (v/v)=40/1) purification, obtain crude product is faint yellow solid to gained residue, Again through preparing thin layer chromatography (DCM/MeOH (v/v)=30/1) purification, obtain title compound is faint yellow solid to crude product (125.6mg, yield 55%).

MS(ESI,pos.ion)m/z:496.1[M+H]；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.05 (s, 1H), 7.84 (d, J=13.4Hz, 2H), 7.43 (s, 1H), 6.98 (d, J=5.3Hz, 1H), 4.98 (s, 1H), 4.39 (d, J=4.9Hz, 1H), 3.93 (s, 3H), 3.34 (s, 2H), (3.16 d, J=8.7Hz, 2H), 3.05 (d, J=6.3Hz, 2H), 2.68 (s, 2H), 2.24 (s, 2H), 1.51 (s, 2H), 1.23 (s, 1H), 1.01 (s, 3H), 0.60 (d, J=6.0Hz, 2H), 0.35 (s, 2H)；

¹³C NMR(100MHz,DMSO-d₆)δ(ppm):158.1,157.8,153.8,130.0,123.8,120.4, 110.0,66.1,59.3,53.6,52.8,37.8,21.3,5.3,4.8.

Embodiment 47 5- ((the chloro- 2- of 5- ((1- (2- hydroxypropyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base)-N- cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulfonamide

Step 1) N- cyclopropyl -5- ((2,5- dichloro pyrimidine -4- base) amino) hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H) - Sulfonamide

At 0 DEG C, to N- (2,5- dichloro pyrimidine -4- base) octahydro Pentamethylene. simultaneously [c] pyrroles -5- amine (200mg, 0.7322mmol) and Et₃Deca N- cyclopropylamino sulphur in N (225mg, 2.2013mmol) DCM (40mL, 622mmol) solution DCM (4mL, the 62mmol) solution of acyl chlorides (228mg, 1.4653mmol), after dripping, reactant mixture is stirred at room temperature 6 Hour, after reaction terminates, concentrating under reduced pressure.Gained residue, through silica gel column chromatography (DCM/MeOH (v/v)=40/1) purification, obtains mark Topic compound is faint yellow solid (120mg, yield 41.8%).

MS(ESI,pos.ion)m/z:392.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ (ppm) 7.98 (s, 1H), 5.81 (d, J=7.6Hz, 1H), 5.08 (s, 1H), (4.41 m, 1H), 3.24 (d, J=2.6Hz, 4H), 2.75 (s, 2H), 2.55 (s, 1H), 2.45 (m, 2H), 1.43 (m, 2H), 0.68(m,2H),0.64(m,2H).

Step 2) 5- ((the chloro- 2- of 5- ((1- (2- hydroxypropyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) - N- cyclopropyl hexahydro Pentamethylene. simultaneously [c] pyrroles -2 (1H)-sulfonamide

To Pd (OAc)₂(10mg, 0.0436512mmol), BINAP (26mg, 0.04mmol), 1- (4- amino-pyrazol -1- Base) hexahydro Pentamethylene. is simultaneously for propan-2-ol (113mg, 0.80mmol) and N- cyclopropyl -5- ((2,5- dichloro pyrimidine -4- base) amino) Cesium carbonate is added in 1,4- dioxane (25mL) solution of [c] pyrroles -2 (1H)-sulfonamide (158mg, 0.4028mmol) (400mg,1.23mmol).Reactant mixture is at 100 DEG C and N₂It is stirred overnight under protection, after reaction terminates, concentrating under reduced pressure, gained Through silica gel column chromatography (MeOH/DCM (v/v)=1/40) purification, obtain crude product is faint yellow solid to residue, crude product warp again Prepare thin layer chromatography (MeOH/DCM (v/v)=1/30) purification, obtaining title compound is white solid (48mg, yield 24.0%).

MS(ESI,pos.ion)m/z:497.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.02(s,1H),7.84(s,1H),7.79(s,1H),7.51(s, 1H), 7.41 (s, 1H), 6.94 (d, J=6.3Hz, 1H), 4.36 (m, 1H), 3.91 (s, 3H), 3.20 (m, 2H), 3.15 (d, J =5.1Hz, 1H), 3.05 (d, J=9.0Hz, 2H), 2.67 (s, 2H), 2.43 (m, 1H), 2.24 (s, 2H), 1.49 (m, 2H), 0.99 (d, J=5.2Hz, 3H), 0.57 (m, 2H), 0.51 (m, 2H)；

¹³C NMR(151MHz,DMSO-d₆)δ(ppm):158.1,157.8,153.8,130.1,129.9,123.8, 120.3,66.8,66.2,59.4,54.0,49.1,38.1,24.9,21.3,6.6.

Embodiment 48 2- (2- acetyl group -5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) Amino) octahydro Pentamethylene. simultaneously [c] pyrroles -5- base) acetonitrile

To 2- (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) octahydro Pentamethylene. And [c] pyrroles -5- base) acetonitrile (92.8mg, 0.25mmol) and Et₃In DCM (10mL) solution of N (60.4mg, 0.60mmol) Add DCM (2mL) solution of acetic anhydride (40.8mg, 0.40mmol).Reactant mixture is stirred at room temperature 15 minutes, reaction knot Shu Hou, add water H₂O (30mL) is quenched reaction, and is extracted with DCM (100mL × 3).The organic faciess merging are through saturated aqueous common salt (100mL) washing, anhydrous sodium sulfate drying concentrating under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/ 20) purification, obtaining title compound is faint yellow solid (85.9mg, yield 83.2%).

MS(ESI,pos.ion)m/z:415.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:415.1763[M+H]⁺,C₁₉H₂₄ClN₈O[M+H]⁺Theoretical value： 415.1762；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.94 (s, 1H), 7.64 (s, 1H), 7.47 (d, J=9.1Hz, 1H), (6.86 s, 1H), 5.45 and 5.14 (s, 1H), 3.90 and 3.89 (s, 3H), 3.66 and 3.38 (m, 2H), 3.63 and 3.61 (s, 2H), 3.57 and 3.12 (d, J=5.6Hz, 2H), 2.92 (m, 2H), 2.74 (m, 1H), 2.48 (m, 1H), 2.08 and 2.05 (s, 3H), 2.00 and 1.71 (m, 2H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):169.6,157.0(s),156.89,153.8,122.4,117.6, 117.5,64.6,63.3,53.0,52.6,51.4,50.4,44.2,43.2,43.1,42.1,42.0,40.5,40.2,39.4, 39.3,29.7,25.8,22.5.

Embodiment 49 2- (5- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) octahydro Pentamethylene. simultaneously [c] pyrroles -3a- base) acetonitrile

With reference to the synthetic method of above-described embodiment 32 and synthetic schemes 5, prepare title compound.Required raw material is Can commercially, described in document or organic synthesis field technical staff do not carry out excessive test and be easy for Synthesis.

MS(ESI,pos.ion)m/z:373.1.

Biological Test Example

LC/MS/MS system employed in biological test embodiment A and embodiment B of the present invention includes Agilent 1200 serial vacuum degassing furnaces, binary syringe pump, orifice plate automatic sampler, post calorstat, charged spray ionizes (ESI) source Agilent G6430 three-level level Four bar mass spectrograph.Quantitative analyses are carried out under MRM pattern, and the parameter of MRM conversion is as in Table A：

Table A

Many reaction detection scannings	490.2→383.1
		Fragmentation voltage	230V
Capillary voltage	55V
		Temperature degree is dried	350℃
Nebulizer	0.28MPa
		Dry gas stream speed	10L/min

Analysis uses Agilent XDB-C18,2.1 x 30mm, 3.5 μM of posts, injects 5 μ L sample.Analysis condition：Flowing Mutually be 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient is such as Shown in table B：

Table B

Additionally, for the serial LC/MS/MS spectrogrph of also Agilent 6330 of analysis, equipped with G1312A binary note Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrogrph adopts ESI radioactive source.Using titer Each analyte is carried out with suitable cation models treated and MRM conversion carries out optimal analysis.Use during analyzing Capcell MP-C18 post, specification is：100 x 4.6mm I.D., 5 μM (Phenomenex, Torrance, California, USA).Mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A)：5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70: 30, v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L sample.

Stability in embodiment A people and rat liver microsomes

In the present embodiment, inventor have detected compound the stablizing in people and rat liver microsomes of the present invention respectively Property, detection mode can be carried out by following two methods：

Method 1：

People or rat liver microsomes are placed in polypropylen tubes and carry out duplicate hole incubation.Typical incubation mixed liquor includes People or rat liver microsomes (0.5mg protein/mL), target compound (5 μM) and the NADPH (1.0mM) that cumulative volume is 200 μ L Kaliumphosphate buffer (PBS, 100mM, pH value be 7.4), by compound dissolution in DMSO, and diluted using PBS so as to The concentration of final DMSO solution is 0.05%.And be incubated in the water-bath communicating with air at 37 DEG C, preincubate 3 minutes Add albumen in backward mixed liquor and start to react.In different time points (0,5,10,15,30 and 60min), add same volume Ice-cold acetonitrile terminating reaction.It is centrifuged 10 minutes with 4000rpm, except Deproteinization, collect supernatant, 100 μ L of supernatant liquid add 100 μ L water Dilution, for sample analysis.LC/MS/MS analysis draws sample peak area and internal standard peak area ratio, and the medicine of 0min point is contained Take temperature work 100%, calculate the relative amount of each time point medicine.So that " medicine contains relatively in GraphPad Prism 5.01 Amount " calculates the half-life of medicine to " incubation time " mapping, and then calculates inherent clearance rate.

The linear concentration scope of each target compound, through measuring, then, is surveyed by the method for LC/MS/MS Set the goal concentration in people or rat liver microsomes mixtures incubated for the compound.

The microsome that degeneration is used, as negative control, carries out parallel incubating using dextromethorphan (70 μ Μ) as positive control Educate test.Negative control, is incubated at 37 DEG C, and reaction terminates in different time points for (0,15 and 60 minute)；Positive control, It is incubated at 37 DEG C, reaction terminates in different time points for (0,5,10,15,30 and 60 minute).All adopt in each assay method With positive and negative control sample, to ensure the integrity of microsome incubation system.

Method 2：

People or rat liver microsomes are placed in duplicate hole incubation in polypropylen tubes.Typical mixtures incubated include people or Rat liver microsomes (ultimate density：0.5mg albumen/mL), target compound (ultimate density：1.5 μM) and cumulative volume be 30 μ L K- buffer solution (EDTA containing 1.0mM, 100mM, pH 7.4).By compound dissolution in DMSO and dilute with K- buffer solution Release, the ultimate density making DMSO is 0.2%.After preincubate 10 minutes, add 15 μ LNADPH (ultimate densities：2mM) carry out enzymatic Reaction, whole test is carried out in 37 DEG C of incubation tube.In different time points (0,15,30 and 60 minute), add 135 μ L second Nitrile (containing IS) terminating reaction.It is centrifuged 10 minutes with 4000rpm, except Deproteinization, collect supernatant, 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 the different time Point terminates for (0,15,30 and 60 minute).Positive control sample is all included, to ensure microsome incubation body in each assay method The integrity of system.

Data analysiss

For each reaction, concentration (as a percentage) in people or rat liver microsomes incubation for the compound is pressed The plotted as percentage of relative zero time point, to infer internal CLint 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 livermicrosomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.).Referring to table 1, table 1 is compound provided in an embodiment of the present invention in people to result Experimental result with stability in rat liver microsomes.

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

NT: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 suitable stability.

Embodiment B mice, rat, the dog and monkey pharmacokineticss after intravenous injection and oral quantitation the compounds of this invention Evaluate

The present embodiment to the compounds of this invention, commented by the pharmacokinetic parameter in mice, rat, dog or monkey body Estimate.The compounds of this invention with the aqueous solution of aqueous solution or 2%HPMC+1% tween 80, the saline solution of 5%DMSO+5%, 4% MC or capsule form are administered.For intravenous administration, laboratory animal gives the dosage of 0.5,1 or 2mg/kg.For mouth Take dosage (p.o.), rat and mice are 0.5,1,5 or 10mg/kg, and dog or monkey are 10mg/kg.It is 0.25,0.5 in time point, Take within 1.0,2.0,3.0,4.0,6.0,8.0,12 and 24 hours blood (0.3mL), and be centrifuged 10 points under 3,000 or 4,000rpm Clock.Collect plasma solutions, and preserve at -20 DEG C or -70 DEG C until carrying out above-mentioned LC/MS/MS analysis.Result shows, will When the compound intravenous injection administration of present invention offer or oral administration, the medicine that compound of the present invention shows is for power Learn property, absorb (AUC including preferable_last) oral administration biaavailability (F) become reconciled.Wherein, provided in an embodiment of the present invention Medicine in rat body for the compound is as shown in table 2 for the experimental result of feature.

Medicine in rat body for table 2 compound provided in an embodiment of the present invention is for the experimental result of feature

As shown in Table 2, when the compound intravenous injection present invention being provided or oral administration, compound of the present invention exists The pharmacokinetic property showing in rat body, absorbs (AUC including preferable_last) oral administration biaavailability become reconciled (F).

Embodiment C Kinase activity assays

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

The general description of kinase assay

Kinase assay pass through detection mix γ-³³The myelin basic protein (MBP) of P-ATP is come to complete.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 white 384 orifice plates (Greiner) of high associativity, every hole 60 μ L.4 DEG C, it is incubated 24h.Use afterwards 100 μ L TBS wash plate 3 times.Kinase buffer liquid [the 5mM Hepes pH 7.6,15mM that kinase reaction is 34 μ L in cumulative volume NaCl, 0.01% bovine serum albumin (Sigma#I-5506), 10mM MgCl₂, 1mM DTT, 0.02%TritonX-100] 5mM Hepes pH 7.6,15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), 10mM MgCl₂,1mM DTT, 0.02%TritonX-100) in carry out.By compound dissolution in DMSO, add in each hole, the ultimate density of DMSO For 1%, and add in each hole.Often twice according to surveying and determination of hole count, the mensure of each compound is at least tested twice.Such as, enzyme Ultimate density be 10nM or 20nM.Add do not have markd ATP (10 μM) and γ-³³ATP (every hole 2 × 10 of P labelling⁶Cpm, 3000Ci/mmol) start to react.Concussion carries out 1 hour at room temperature for reaction.The 384 orifice plates PBS of 7x, Ran Houjia Enter the scintillation solution of every hole 50 μ L.With Wallac Trilux enumerator testing result.To those of ordinary skill in the art, This is only one of numerous detection methods, and other methods also may be used.

The IC that above-mentioned test method can be inhibited₅₀And/or inhibition constant K_i.IC₅₀It is defined as under test conditions, suppression Make compound concentration during 50% enzymatic activity.Make the curve comprising 10 concentration point using the extension rate of 1/2log, estimation IC₅₀Value (for example, makes a typical curve by following compound concentration：3μM、1μM、0.3μM、0.1μM、0.03μM、 0.01μM、0.003μM、0.001μM、0.0003μM、0μM).

JAK1(h)

In 20mM Tris/HCl pH 7.5,0.2mM EDTA, 500 μM have SEQ ID NO to JAK1 (h)：Amino shown in 1 The polypeptide of acid sequence, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) deposit It is incubated under the conditions.Start after adding MgATP mixture to react.Under room temperature, incubation is added thereto to for 40 minutes afterwards 3% phosphoric acid solution carrys out terminating reaction.By the reactant liquor of 10 μ L be in mottled be distributed on P30 filter, and with 75mM phosphoric acid 5 Minute in cleaning 3 times, and be dried and scinticounting before put at once in methanol solution preserve.

GEEPLYWSFPAKKK(SEQ ID NO：1).

JAK2(h)

In 8mM MOPS pH 7.0,0.2mM EDTA, 100 μM have SEQ ID NO to JAK2 (h)：Aminoacid sequence shown in 2 Row polypeptide, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) exist Under the conditions of be incubated.Start after adding MgATP mixture to react.Under room temperature, incubation is added thereto to 3% phosphorus in 40 minutes afterwards Acid solution carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid at 5 minutes Interior cleaning 3 times, and be dried and scinticounting before put at once in methanol solution preserve.

KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC(SEQ ID NO：2).

JAK3(h)

In 8mM MOPS pH 7.0,0.2mM EDTA, 500 μM have SEQ ID NO to JAK3 (h)：Aminoacid sequence shown in 3 Row polypeptide, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) exist Under the conditions of be incubated.Start after adding MgATP mixture to react.Under room temperature, incubation is added thereto to 3% phosphorus in 40 minutes afterwards Acid solution carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid at 5 minutes Interior cleaning 3 times, and be dried and scinticounting before put at once in methanol solution preserve.

GGEEEEYFELVKKKK(SEQ ID NO：3).

TYK2(h)

In 8mM MOPS pH 7.0,0.2mM EDTA, 250 μM have SEQ ID NO to TYK2 (h)：Aminoacid sequence shown in 4 Row polypeptide, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) exist Under the conditions of be incubated.Start after adding MgATP mixture to react.Under room temperature, incubation is added thereto to 3% phosphorus in 40 minutes afterwards Acid solution carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid at 5 minutes Interior cleaning 3 times, and be dried and scinticounting before put at once in methanol solution preserve.

GGMEDIYFEFMGGKKK(SEQ ID NO：4).

FLT3(h)

In 8mM MOPS pH 7.0,0.2mM EDTA, 50 μM have SEQ ID NO to FLT3 (h)：Aminoacid sequence shown in 5 Polypeptide, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) bar of existing It is incubated under part.Start after adding MgATP mixture to react.Under room temperature, incubation is added thereto to 3% phosphoric acid in 40 minutes afterwards Solution carrys out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid in 5 minutes Cleaning 3 times, and put into preservation in methanol solution before drying and scinticounting at once.

EAIYAAPFAKKK(SEQ ID NO：5).

Aurora-A(h)

In 8mM MOPS pH 7.0,0.2mM EDTA, 200 μM have SEQ ID NO to Aurora-A (h)：Ammonia shown in 6 The polypeptide (Kemptide) of base acid sequence, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration according to Demand determine) exist under conditions of be incubated.Start after adding MgATP mixture to react.It is incubated 40 minutes afterwards under room temperature, It is added thereto to 3% phosphoric acid solution and carry out terminating reaction.The reactant liquor of 10 μ L is distributed on P30 filter in mottled, is used in combination 75mM phosphoric acid cleaned 3 times in 5 minutes, and put into preservation in methanol solution before drying and scinticounting at once.

LRRASLG(SEQ ID NO：6).

Aurora-B(h)

In 8mM MOPS pH 7.0,0.2mM EDTA, 30 μM have SEQ ID NO to Aurora-B (h)：Amino shown in 7 The polypeptide of acid sequence, 10mM magnesium acetate and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) deposit It is incubated under the conditions.Start after adding MgATP mixture to react.Under room temperature, incubation is added thereto to for 40 minutes afterwards 3% phosphoric acid solution carrys out terminating reaction.By the reactant liquor of 10 μ L be in mottled be distributed on P30 filter, and with 75mM phosphoric acid 5 Minute in cleaning 3 times, and be dried and scinticounting before put at once in methanol solution preserve.

AKRRRLSSLRA(SEQ ID NO：7).

Kinase assay in the present invention be by Millipore company of Britain to complete (Millipore UK Ltd, Dundee Technology Park,Dundee DD2 1SW,UK).

In addition, the kinase activity of compound can pass through KINOMEscan^TMDetection, this detection is based on using active sites Point guidance type Competition binding assay method detection by quantitative compound.This test is carried out by being combined with three kinds of compounds, i.e. DNA mark Note enzyme, fixed ligand and detection compound, carry out the competition energy of qPCR detection compound and fixed ligands by DNA marker Power.

Most of experiment is all the T7 phage bacterium cultivating kinases labelling from escherichia coli host derived from BL21 bacterial strain Strain, is in after the escherichia coli of exponential phase with T7 phage-infect, 32 DEG C of oscillation incubations, to bacteriolyze, lysate are centrifuged Filter and remove cell debriss, remaining kinases goes in HEK-293 cell and carries out qPCR detection with DNA marker.Streptavidin Coated granule is with after biotinylated smaller ligand room temperature treatment 30min, producing affine resin for kinase assay.Join After body granule is closed through unnecessary biotin, through confining liquid (SEABLOCK^TM(Pierce), 1% bovine serum albumin, 0.05% Tween 20,1mM DTT) clean unconjugated part, reduce non-specific binding.By the combination buffer (20% in 1x SEABLOCK^TM, 0.17 × phosphate buffered solution, 0.05% polysorbas20,6mM DTT) in combine kinases, part is affine granule and Test compound is combined reaction, and all reactions are all to carry out in 96 orifice plates, and reaction final volume is 0.135mL, and room temperature is shaken Swing incubation 1h, add lavation buffer solution (1x phosphate buffered solution, 0.05% polysorbas20) to clean affine granule, add eluting to delay After rushing liquid resuspended (1x phosphate buffered solution, 0.05% tween 20,0.5 μM of non-biotinylated affinity ligand), shaken at room temperature Incubation 30min, detects the concentration of kinases in eluent by qPCR.It is in the U.S. that kinase activity described in literary composition measures The KINOMEscan of DiscoveRx company (Albrae St.Fremont, CA 94538, USA)^TMDepartment is measured.

The compounds of this invention, in kinase assay, all shows to albumen such as jak kinase, Aurora A and FLT3 kinases The inhibitory activity of kinases.

Referring to table 3 and table 4, wherein, table 3 is the JAK1 of compound provided in an embodiment of the present invention to Kinase activity assays result Kinases and Aurora-A kinase assay result；Table 4 is the JAK2 kinases of compound provided in an embodiment of the present invention, Aurora-B swashs Enzyme and FLT3 kinase assay result.

JAK1 the and Aurora-A kinase assay result of table 3 embodiment of the present invention compound

NT：Test

JAK2, Aurora-B and FLT3 kinase kinase experimental result of table 4 embodiment of the present invention compound

NT：Test

From table 3 and table 4, compound of the present invention in kinase assay to JAK1, JAK2, Aurora-A, Aurora-B and FLT3 kinases is respectively provided with inhibitory activity, especially to JAK1, Aurora-A and Aurora-B inhibitory activity more Significantly.

Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, embodiments of the invention are To illustratively illustrate, but be not limited to content described in the invention.It is understood that above-described embodiment is example Property it is impossible to be interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changes, replacing and modification.Being also possible to is the modification made within the scope of the present invention or in the claims The equivalents added.All publications cited in the present invention or patent are all using the list of references as the present invention.

Claims (38)

1. a kind of compound, it is the compound shown in formula (I) or the stereoisomer of compound, tautomerism shown in formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

Wherein,

Z is C₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂The miscellaneous bicyclic group of the former molecular spiral shell of condensed-bicyclic alkyl, 7-12 or 7-12 former Molecular condense miscellaneous bicyclic alkyl, wherein, Z is by 1,2,3,4 or 5 R²Group is replaced；

Z¹For H, C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, described each C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl and 3-12 former molecular heterocyclic radical are individually optionally by 1,2,3,4 or 5 R^2aGroup is replaced；

A is

R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂ Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^9aR^9b、-OR^9c、- C (=O) OR^9c,-C (=O) NR^9aR^9bOr-S (=O)₂NR^9aR^9b, wherein, described each C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂ Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl and 5-12 are individual former molecular Heteroaryl is individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R²It independently is F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂,-C (=O) CH₂CN ,-NHC (=O) CH₂CN、-N (CH₃) C (=O) CH₂CN、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl, 3-12 Former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^10aR^10b、-O-(C₀-C₄Alkylidene)- R^10c、-O-(C₁-C₄Alkylidene)-OR^10c,-C (=O) R^10d,-OC (=O) R^10d、-N(R^10e) C (=O) R^10d,-C (=O) NR^10aR^10b、-N(R^10e) C (=O) NR^10aR^10b,-C (=O) N (R^10e) C (=O) R^10d,-S (=O)₂R^10f、-N(R^10e) S (=O)₂R^10fOr-S (=O)₂NR^10aR^10b, or, two adjacent R²And together with the atom being connected with them, form C₃-C₁₂Cycloalkyl Or 3-12 former molecular heterocycloalkyl, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂ Alkoxyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl and 3-12 former molecular heterocycloalkyl is individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R^2aIt independently is H, F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl or 5-12 are individual former molecular miscellaneous Aryl, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl, 3-12 Former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl and 3-12 former molecular Heterocyclylalkyl base Group is individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

R³For H, C₃-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂ Alkynyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, its In, described each C₃-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂ Alkynyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical and 5-12 former molecular heteroaryl are independent Optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

R⁴For C₁-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Aminoalkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynes Base, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, wherein, R⁴Optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R⁵、R⁶、R⁷And R⁸It is separately H, C₁-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Amino Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl or 5-12 are individual Former molecular heteroaryl, wherein, described each C₁-C₁₂Hydroxy alkyl, C₃-C₁₂Alkyl, C₁-C₁₂Haloalkyl, C₁-C₁₂Amino alkane Base, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl and 5-12 are individual former Molecular heteroaryl is individually optionally by 1,2,3,4 or 5 R¹¹Group is replaced；

Each R^3a、R^4a、R^5a、R^6a、R^7aAnd R^8aIt is separately H, F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynes Base, C₁-C₁₂Alkoxyl, C₁-C₁₂Alkylamino ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 Former molecular heterocyclic radical), C₆-C₁₂Aryl or 5-12 former molecular heteroaryl, wherein, described each C₁-C₁₂Alkyl, C₂- C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₁-C₁₂Alkylamino ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄ Alkylidene)-(3-12 former molecular heterocyclic radical), C₆-C₁₂Aryl and 5-12 former molecular heteroaryl are individually optionally By 1,2,3,4 or 5 R¹¹Group is replaced；

Each R^9a、R^9b、R^9c、R^10a、R^10b、R^10cAnd R^10eIt is separately H, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 is former Molecular heterocyclic radical) ,-(C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) or-(C₀-C₄Alkylidene)-(5-12 is former molecular miscellaneous Aryl), or R^9aAnd R^9b, R^10aAnd R^10bAnd together with the nitrogen-atoms being connected with them, form 3-12 former molecular heterocyclic radical Group, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkyl ,-(C₀-C₄ Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₀-C₄Alkylidene)- (C₆-C₁₂Aryl) ,-(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl) and 3-12 former molecular heterocyclic radical base Roll into a ball optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Alkyl halide Base, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl, C₁-C₆Aminoalkyl or C₁-C₆The substituent group of alkylamino is replaced；

Each R^10dAnd R^10fIt is separately C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Alkoxyl, C₃-C₁₂Cycloalkanes Base, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃- C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) Or-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl), wherein, above-mentioned each group is optionally by 1,2,3 or 4 solely On the spot it is selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Hydroxyl alkane Base, C₁-C₆Aminoalkyl or C₁-C₆The substituent group of alkylamino is replaced；

Each R¹¹It independently is F, Cl, Br, I, CN ,-NO₂、N₃、-OH、-NH₂、C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Haloalkyl, C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocyclic radical, 5-12 are individual former molecular miscellaneous Aryl, C₁-C₁₂Aminoalkyl, C₁-C₁₂Alkylamino, C₁-C₁₂Alkoxyl, C₁-C₁₂Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)-(C₃- C₁₂Cycloalkyl) ,-NH (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-NH (C₀-C₄Alkylidene)-(3-12 former molecular heterocycle Base) ,-NH (C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl) ,-N [(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ]₂、-N[(C₀-C₄Alkylidene)-(C₆-C₁₂Aryl)]₂、-N[(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical)]₂、- N[(C₀-C₄Alkylidene)-(5-12 former molecular heteroaryl)]₂、-O-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-O- (C₀-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-O- (C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) or-O- (C₀-C₄ Alkylidene)-(5-12 former molecular heteroaryl)；With

Each m independently is 0,1 or 2.

2. compound according to claim 1, wherein, Z be the miscellaneous bicyclic group of the former molecular spiral shell of 8-11 or 8-10 former Molecular condense miscellaneous bicyclic alkyl, wherein, Z is by 1,2,3 or 4 R²Group is replaced.

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

Or their stereoisomer, wherein, each X, X ', X₂And X₃It is separately-CH₂- ,-NH- or-O-, condition is, X² And X³It is not simultaneously-O-；Each minor structure shown in formula (Z-1)～(Z-54) or its stereoisomer are independently by 1,2 or 3 R²Group is replaced.

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

Or their stereoisomer, wherein, each minor structure shown in formula (Z-55)～(Z-73) or its stereoisomer are independent Ground is by 1,2 or 3 R²Group is replaced.

5. compound according to claim 1, wherein, Z¹For H, C₁-C₆Alkyl, C₃-C₆Cycloalkyl or 4-7 atom composition Heterocyclic radical, wherein, described each C₁-C₆Alkyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are optionally by 1,2 or 3 Individual R^2aGroup is replaced.

6. compound according to claim 1, wherein, R¹For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₆Alkyl, C₁-C₆ Alkoxyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical ,-NR^9aR^9b、-OR^9c,-C (= O)OR^9c,-C (=O) NR^9aR^9bOr-S (=O)₂NR^9aR^9b, wherein, described each C₁-C₆Alkyl, C₁-C₆Alkoxyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are individually optionally by 1,2 or 3 R¹¹Group is replaced.

7. compound according to claim 1, wherein, each R²It independently is F, Cl, Br, I ,-NO₂、N₃、CN、-OH、- NH₂,-C (=O) CH₂CN ,-NHC (=O) CH₂CN、-N(CH₃) C (=O) CH₂CN、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alcoxyl Base, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-NR^10aR^10b、-O- (C₀-C₃Alkylidene)-R^10c、-O-(C₁-C₃Alkylidene)-OR^10c,-C (=O) R^10d,-OC (=O) R^10d、-N(R^10e) C (=O) R^10d,-C (=O) NR^10aR^10b、-N(R^10e) C (=O) NR^10aR^10b,-C (=O) N (R^10e) C (=O) R^10d,-S (=O)₂R^10f、-N (R^10e) S (=O)₂R^10fOr-S (=O)₂NR^10aR^10b, or, two adjacent R²And together with the atom being connected with them, formed C₃-C₆Cycloalkyl or 4-7 former molecular heterocycloalkyl, wherein, described each C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alkane Epoxide, C₃-C₆The individual former molecular heterocyclic radical of cycloalkyl, 4-7, phenyl, 5-6 former molecular heteroaryl and 4-7 atom group The heterocycloalkyl becoming is individually optionally by 1,2 or 3 R¹¹Group is replaced；

Each R^2aIt independently is H, F, Cl, Br, I ,-NO₂、N₃、CN、-OH、-NH₂、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alkoxyl, C₃-C₆The individual former molecular heterocyclic radical of cycloalkyl, 4-7, phenyl or 5-6 former molecular heteroaryl.

8. compound according to claim 1, wherein, R³For H, C₃-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Alkyl halide Base, C₁-C₆Aminoalkyl, C₂-C₆Thiazolinyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical or 5-6 atom group The heteroaryl becoming, wherein, described each C₃-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Aminoalkyl, C₂-C₆ Thiazolinyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical and 5-6 former molecular heteroaryl individually optional ground quilt 1st, 2 or 3 R¹¹Group is replaced.

9. compound according to claim 1, wherein, R³For H ,-CH₂C(CH₃)₂OH、-(CH₂)₂CH₂OH、-CH₂CH(OH) CH₃, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, pyrrole radicals or Oxazolyl, wherein, described each piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, pyridine radicals, pyrimidine radicals, pyridazinyl, thiazolyl, Pyrrole radicals and oxazolyl are individually optionally by 1,2 or 3 R¹¹Group is replaced.

10. compound according to claim 1, wherein, R⁴For C₁-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Aminoalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, 4-7 former molecular heterocyclic radical or 5-6 are individual Former molecular heteroaryl, wherein, R⁴Optionally by 1,2 or 3 R¹¹Group is replaced.

11. compounds according to claim 1, wherein, each R⁵、R⁶、R⁷And R⁸It is separately H, C₁-C₆Hydroxyl alkane Base, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Aminoalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 4-7 former Molecular heterocyclic radical, phenyl or 5-6 former molecular heteroaryl, wherein, described each C₁-C₆Hydroxy alkyl, C₃-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Aminoalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocycle Base, phenyl and 5-6 former molecular heteroaryl is individually optionally by 1,2 or 3 R¹¹Group is replaced.

12. compounds according to claim 1, wherein, each R^3a、R^4a、R^5a、R^6a、R^7aAnd R^8aSeparately be H, F, Cl、CN、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alkoxyl, C₁-C₆Alkylamino ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,- (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical), phenyl or 5-6 former molecular heteroaryl, wherein, described each C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₁-C₆Alkoxyl, C₁-C₆Alkylamino ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀-C₃Sub- Alkyl)-(4-7 former molecular heterocyclic radical), phenyl and 5-6 former molecular heteroaryl be individually optionally by 1,2 or 3 R¹¹Group is replaced.

13. compounds according to claim 1, wherein, each R^9a、R^9b、R^9c、R^10a、R^10b、R^10cAnd R^10eSeparately For H, C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkoxyl, C₃-C₆Cycloalkyl ,-(C₀-C₃Alkylidene)-(C₃-C₆Ring Alkyl) ,-(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₀-C₃Alkylidene)-phenyl or-(C₀-C₃Alkylene Base)-(5-6 former molecular heteroaryl), or R^9aAnd R^9b, R^10aAnd R^10bAnd together with the nitrogen-atoms being connected with them, formed 4-7 former molecular heterocyclyl groups, wherein, described each C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Alkoxyl, C₃-C₆Cycloalkyl ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical), 4-7 former molecular heterocyclyl groups ,-(C₀-C₃Alkylidene)-phenyl and-(C₀-C₃Alkylidene)-(5-6 is former molecular Heteroaryl) optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Halogen Substituted alkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent group of alkylamino is replaced.

14. compounds according to claim 1, wherein, each R^9a、R^9b、R^9c、R^10a、R^10b、R^10cAnd R^10eSeparately For H, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, pi-allyl, vinyl, acrylic, C₁-C₄Alkoxyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl ,-methylene- Cyclopropyl ,-ethylidene-cyclopropyl ,-methylene-cyclobutyl ,-ethylidene-cyclobutyl ,-methylene-cyclopenta ,-ethylidene-ring Amyl group ,-methylene-cyclohexyl ,-ethylidene-cyclohexyl ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical), benzene Base, pyridine radicals, pyridazinyl, pyrimidine radicals ,-(C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylidene)-(5-6 is former molecular miscellaneous Aryl), wherein, described methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, pi-allyl, second Thiazolinyl, acrylic, C₁-C₄Alkoxyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, pyrrolidinyl, morpholinyl, piperazine Piperazine base ,-methylene-cyclopropyl ,-ethylidene-cyclopropyl ,-methylene-cyclobutyl ,-ethylidene-cyclobutyl ,-methylene-ring penta Base ,-ethylidene-cyclopenta ,-methylene-cyclohexyl ,-ethylidene-cyclohexyl ,-(C₁-C₃Alkylidene)-(4-7 atom composition Heterocyclic radical), phenyl, pyridine radicals, pyridazinyl, pyrimidine radicals ,-(C₁-C₃Alkylidene)-phenyl and-(C₁-C₃Alkylidene)-(5-6 Former molecular heteroaryl) optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-NO₂、-OH、-NH₂、-CF₃,- OCH₃,-CH₂OH,-CH₂CH₂OH,-NHCH₃,-N(CH₃)₂Or-CH₂NH₂Substituent group replaced.

15. compounds according to claim 1, wherein, each R^10dAnd R^10fIt is separately C₁-C₄Alkyl, C₂-C₄Alkene Base, C₂-C₄Alkynyl, C₁-C₄Alkoxyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 are individual former molecular Heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,- (C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), wherein, above-mentioned each group is optional Ground is by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alcoxyl Base, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl or C₁-C₃The substituent group of alkylamino is replaced.

16. compounds according to claim 1, wherein, each R^10dAnd R^10fSeparately be methyl, ethyl, n-pro-pyl, Isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, pi-allyl, vinyl, Acrylic, phenyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, C₁-C₄Alkoxyl ,-methylene-cyclopropyl ,-ethylidene- Cyclopropyl ,-methylene-cyclobutyl ,-ethylidene-cyclobutyl ,-methylene-cyclopenta ,-ethylidene-cyclopenta or-methylene- Cyclohexyl or-ethylidene-cyclohexyl, wherein, above-mentioned each group optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、-CF₃、-OCH₃、-CH₂OH、-CH₂CH₂OH、-NHCH₃、-N(CH₃)₂Or-CH₂NH₂Substituent group replaced.

17. compounds according to claim 1, wherein, each R¹¹It independently is F, Cl, Br, I, CN ,-NO₂、N₃、-OH、- NH₂, methyl, ethyl, n-pro-pyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, methylol, hydroxyl Ethyl, methylamino, dimethylamino or aminomethyl.

18. compounds according to claim 1, it has the structure of one of：

Or its stereoisomer, tautomer, nitrogen oxides, solvate or pharmaceutically Acceptable salt.

A kind of 19. compounds, it is the compound shown in formula (II) or the stereoisomer of compound shown in formula (II), mutually makes a variation Structure body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

Wherein,

W is C₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂The miscellaneous bicyclic group of the former molecular spiral shell of condensed-bicyclic alkyl, 7-12 or 7-12 former Molecular condense miscellaneous bicyclic alkyl, wherein, W is by 1,2,3,4 or 5 R¹⁴Group is replaced；

W₁For H, C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxyl, C₁-C₆Aminoalkyl, C₁-C₆Hydroxy alkyl, C₃-C₆Ring Alkyl or 4-7 former molecular heterocyclic radical；

R¹²For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₁₂Alkyl, C₁-C₁₂Alkoxyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂ Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl, 5-12 former molecular heteroaryl ,-NR^15aR^15b、- OR^15c,-C (=O) OR^15c,-C (=O) NR^15aR^15bOr-S (=O)₂NR^15aR^15b, wherein, described each C₁-C₁₂Alkyl, C₁-C₁₂Alkane Epoxide, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₂Aryl and 5-12 are individual Former molecular heteroaryl is individually optionally by 1,2,3,4 or 5 R¹⁷Group is replaced；

Each R¹³It independently is H, F, Cl, CN, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₁-C₁₂Alkoxyl ,-(C₀-C₄Alkylidene)-(C₃- C₁₂Cycloalkyl) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical), C₆-C₁₂Aryl or 5-12 are individual former molecular Heteroaryl, wherein, described each C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₁-C₁₂Alkoxyl ,-(C₀-C₄Alkylidene)-(C₃-C₁₂Cycloalkanes Base) ,-(C₀-C₄Alkylidene)-(3-12 former molecular heterocyclic radical), C₆-C₁₂Aryl and 5-12 former molecular heteroaryl Individually optionally by 1,2,3,4 or 5 R¹⁷Group is replaced；

Each R¹⁴It independently is F, Cl, Br, I, NO₂、N₃、CN、C₃-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxyl alkane Base, C₃-C₁₂Alkoxyl, C₁-C₁₂Alkylamino, C₁-C₁₂Aminoalkyl, C₃-C₁₂The individual former molecular heterocyclic radical of cycloalkyl, 4-7, C₆-C₁₂Aryl, 6- cyano group pyridazine -3- base,-CH₂CN、-CH₂CH₂CN ,-C (=O) R^16d,-S (=O)₂R^16e,-C (=O) NR^16aR^16b,-S (=O)₂NR^16aR^16b,-C (=O) O-R^16c、-N(R^16a) C (=O) R^16f、-N(R^16a) S (=O)₂R^16gOr-OC (=O) R^16f, wherein, described each-CH₂CN、-CH₂CH₂CN、C₃-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₁-C₁₂Hydroxyl alkane Base, C₃-C₁₂Alkoxyl, C₁-C₁₂Alkylamino, C₁-C₁₂Aminoalkyl, C₃-C₁₂The individual former molecular heterocyclic radical of cycloalkyl, 4-7, C₆-C₁₂Aryl and 6- cyano group pyridazine -3- base are individually optionally by 1,2,3,4 or 5 R¹⁷Group is replaced；

Each R^15a、R^15b、R^15c、R^16aAnd R^16bIt is separately H, C₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Ring Alkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₀Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)- (C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Virtue Base) ,-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl), or, R^15aAnd R^15b, and the nitrogen-atoms being connected with them Together, 3-12 former molecular heterocyclyl groups, wherein, described each C are formed₁-C₁₂Alkyl, C₂-C₁₂Thiazolinyl, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₀Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Sub- Alkyl)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆- C₁₂Aryl) and-(C₁-C₄Alkylidene)-(5-12 former molecular heteroaryl) optionally by 1,2 or 3 independently selected from F, Cl、Br、CN、N₃、-NO₂、-OH、-NH₂、C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl, C₁-C₄ Aminoalkyl and C₁-C₄The substituent group of alkylamino is replaced；

Each R^16d、R^16eAnd R^16gIt is separately C₂-C₁₂Alkyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆- C₁₀Aryl, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3- 12 former molecular heterocyclic radicals) ,-(C₁-C₄Alkylidene)-(C₆-C₁₀Aryl) or-(C₁-C₄Alkylidene)-(5-12 atom group Become heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、 C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl, C₁-C₄Aminoalkyl or C₁-C₄The taking of alkylamino Replaced for base；

Each R^16cAnd R^16fIt is separately C₁-C₃Alkyl, C₃-C₁₂Cycloalkyl, 3-12 former molecular heterocyclic radical, C₆-C₁₀Virtue Base, 5-12 former molecular heteroaryl ,-(C₁-C₄Alkylidene)-(C₃-C₁₂Cycloalkyl) ,-(C₁-C₄Alkylidene)-(3-12 Former molecular heterocyclic radical) ,-(C₁-C₄Alkylidene)-(C₆-C₁₂Aryl) ,-(C₁-C₄Alkylidene)-(5-12 is former molecular Heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁- C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₁-C₄Hydroxy alkyl, C₁-C₄Aminoalkyl or C₁-C₄The substituent group of alkylamino Replaced；

Each R¹⁷It independently is F, Cl, Br, I, CN, NO₂、N₃、-OH、-NH₂、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆ Haloalkyl, C₃-C₆Cycloalkyl, C₆-C₁₂An aryl, 4-7 former molecular heterocyclic radical, 5-12 former molecular heteroaryl, C₁-C₆Aminoalkyl, C₁-C₆Alkylamino, C₁-C₆Alkoxyl, C₁-C₆Hydroxy alkyl ,-NH (C₀-C₄Alkylidene)-(C₃-C₆Cycloalkanes Base) ,-NH (C₀-C₄Alkylidene)-(4-7 former molecular heterocyclic radical) ,-N [(C₀-C₄Alkylidene)-(C₃-C₆Cycloalkyl)]₂、- N[(C₀-C₄Alkylidene)-(4-7 former molecular heterocyclic radical)]₂、-O(C₀-C₄Alkylidene)-(C₃-C₆Cycloalkyl) or-O (C₀- C₄Alkylidene)-(4-7 former molecular heterocyclic radical)；With

N is 0,1 or 2.

20. compounds according to claim 19, wherein, W is the miscellaneous bicyclic group of the former molecular spiral shell of 8-11 or 8-10 Former molecular condense miscellaneous bicyclic alkyl, wherein, W is by 1,2,3 or 4 R¹⁴Group is replaced.

21. compounds according to claim 19, wherein, W is following subformula：

Or their stereoisomer, wherein, each Y, Y ', Y²And Y³It is separately-CH₂- ,-NH- or-O-, condition is Y²With Y³It is asynchronously-O-；Each minor structure shown in formula (W-1)～(W-51) or its stereoisomer are independently by 1,2 or 3 R¹⁴Base Group is replaced.

22. compounds according to claim 19, wherein, W is following subformula：

Or their stereoisomer, wherein, each minor structure shown in formula (W-52)～(W-70) or its stereoisomer are independent Ground is by 1,2 or 3 R¹⁴Group is replaced.

23. compounds according to claim 19, wherein, W₁For H, methyl, ethyl, n-pro-pyl, isopropyl or cyclopropyl.

24. compounds according to claim 19, wherein, R¹²For H, F, Cl, Br, I, N₃、CN、-NO₂、C₁-C₄Alkyl, C₁- C₄Alkoxyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical ,-NR^15aR^15b、-OR^15c、- C (=O) OR^15c,-C (=O) NR^15aR^15bOr-S (=O)₂NR^15aR^15b, wherein, described each C₁-C₄Alkyl, C₁-C₄Alkoxyl, C₂- C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl and 4-7 former molecular heterocyclic radical are individually optionally by 1,2 or 3 R¹⁷Group Replaced.

25. compounds according to claim 19, wherein, each R¹³It independently is H, F, Cl, CN, C₁-C₄Alkyl, C₂-C₄Alkene Base, C₁-C₄Alkoxyl ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) or-(C₀-C₃Alkylidene)-(4-7 former molecular heterocycle Base), wherein, described each C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₁-C₄Alkoxyl ,-(C₀-C₃Alkylidene)-(C₃-C₆Cycloalkyl) and- (C₀-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) individually optionally by 1,2 or 3 R¹⁷Group is replaced.

26. compounds according to claim 19, wherein, each R¹⁴It independently is F, Cl, Br, I ,-NO₂、N₃、CN、C₃-C₆ Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Hydroxy alkyl, C₃-C₆Alkoxyl, C₁-C₆Alkylamino, C₁-C₆Aminoalkyl, C₃-C₆ Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 6- cyano group pyridazine -3- base,-CH₂CN、-CH₂CH₂CN ,-C (=O) R^16d,-S (=O)₂R^16e,-C (=O) NR^16aR^16b,-S (=O)₂NR^16aR^16b,-C (=O) O-R^16c、-N(R^16a) C (=O) R^16f、- N(R^16a) S (=O)₂R^16gOr-OC (=O) R^16f, wherein, described each-CH₂CN、-CH₂CH₂CN、C₃-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, C₁-C₆Hydroxy alkyl, C₃-C₆Alkoxyl, C₁-C₆Alkylamino, C₁-C₆Aminoalkyl, C₃-C₆Cycloalkyl, 4-7 former Molecular heterocyclic radical, phenyl and 6- cyano group pyridazine -3- base are individually optionally by 1,2 or 3 R¹⁷Group is replaced.

27. compounds according to claim 19, wherein, each R¹⁴It independently is F, Cl, Br, I ,-NO₂、N₃、CN、

28. compounds according to claim 19, wherein, each R^15a、R^15b、R^15c、R^16aAnd R^16bIt is separately H, C₁- C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 atom composition Heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,- (C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl), or, R^15aAnd R^15b, and and it The nitrogen-atoms that are connected together, form 4-7 former molecular heterocyclyl groups, wherein, described each C₁-C₄Alkyl, C₂-C₄Alkene Base, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁- C₃Alkylidene)-(C₃-C₆Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)- Phenyl and-(C₁-C₃Alkylidene)-(5-6 former molecular heteroaryl) optionally by 1,2 or 3 independently selected from F, Cl, Br, CN、N₃、-NO₂、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Amino alkane Base and C₁-C₃The substituent group of alkylamino is replaced.

29. compounds according to claim 19, wherein, each R^16d、R^16eAnd R^16gIt is separately C₂-C₆Alkyl, C₃- C₆Cycloalkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆ Cycloalkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl or-(C₁-C₃Alkylene Base)-(5-6 former molecular heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br、CN、N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl Or C₁-C₃The substituent group of alkylamino is replaced.

30. compounds according to claim 19, wherein, each R^16cAnd R^16fIt is separately C₁-C₃Alkyl, C₃-C₆Ring Alkyl, 4-7 former molecular heterocyclic radical, phenyl, 5-6 former molecular heteroaryl ,-(C₁-C₃Alkylidene)-(C₃-C₆Ring Alkyl) ,-(C₁-C₃Alkylidene)-(4-7 former molecular heterocyclic radical) ,-(C₁-C₃Alkylidene)-phenyl ,-(C₁-C₃Alkylene Base)-(5-6 former molecular heteroaryl), wherein, above-mentioned each group optionally by 1,2,3 or 4 independently selected from F, Cl, Br、CN、N₃、-OH、-NH₂、C₁-C₃Alkyl, C₁-C₃Haloalkyl, C₁-C₃Alkoxyl, C₁-C₃Hydroxy alkyl, C₁-C₃Aminoalkyl Or C₁-C₃The substituent group of alkylamino is replaced.

31. compounds according to claim 19, it has the structure of one of：

Or its stereoisomerism Body, tautomer, nitrogen oxides, solvate or pharmaceutically acceptable salt.

A kind of 32. pharmaceutical compositions, it comprises the compound described in claim 1-31 any one.

33. pharmaceutical compositions according to claim 32, its comprise further pharmaceutically acceptable adjuvant, excipient, Carrier, solvent or combinations thereof.

34. pharmaceutical compositions according to claim 32, wherein comprise other therapeutic agents, described other therapeutic agents further Selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 inhibitors, beta-2-adrenoreceptor agonists, corticosteroid, non-steroidal Class GR agonist, anticholinergic, antihistaminic, anti-inflammatory reagent, immunosuppressant, immunomodulator, it is used for treating tremulous pulse Atherosis medicine, for treating at least one of medicine of pulmonary fibrosiss.

Compound described in 35. claim 1-31 any one or claim 32-34 any one described pharmaceutical composition exist Prepare the purposes in medicine, described medicine is used for preventing, process, treat or mitigate protein kinase mediated disease.

36. purposes according to claim 35, disease that wherein said protein kinase mediated disease mediates for JAK-, The disease of FLT3- mediation, the disease of Aurora- mediation, proliferative disease, autoimmune disease, anaphylactic disease, inflammatory disease Disease, transplant rejection, cancer, polycythemia vera, primary thrombocytosiss, myelofibrosises, acute myelocytic Leukemia, chronic granulocytic leukemia, acute lymphoblastic leukemia, chronic obstructive pulmonary disease, asthma, systemic erythema Lupus, skin lupus erythematosuss, lupus nephritis, dermatomyositiss, sjogren syndrome, psoriasises, type i diabetes, respiratory tract anaphylaxis Property disease, sinusitis, eczema, measles, food anaphylaxiss, insect venom allergies, inflammatory bowel, Crohn disease, rheumatoid joint Inflammation, juvenile arthritises, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplant rejection.

Compound described in 37. claim 1-31 any one or claim 32-34 any one described pharmaceutical composition exist Prepare the purposes in medicine, described medicine is used for the activity of regulatory protein kinases.

38. purposes according to claim 37, wherein said protein kinase swashs selected from jak kinase, FLT3 kinases, Aurora At least one of enzyme.