CN105461694B - Substituted heteroaryl compound and combinations thereof and purposes - Google Patents

Substituted heteroaryl compound and combinations thereof and purposes Download PDF

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CN105461694B
CN105461694B CN201510622121.4A CN201510622121A CN105461694B CN 105461694 B CN105461694 B CN 105461694B CN 201510622121 A CN201510622121 A CN 201510622121A CN 105461694 B CN105461694 B CN 105461694B
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disease
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CN105461694A (en
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习宁
李敏雄
李晓波
戴伟龙
胡海洋
张涛
陈武宏
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

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

Description

Substituted heteroaryl compound and combinations thereof and purposes
Invention field
The invention belongs to drug fields, and in particular to a kind of noval chemical compound as kinase activity inhibitor prepares them Method, the pharmaceutical composition comprising the compound and the compound and its pharmaceutical composition treating a variety of different diseases Application in disease.More specifically, compound of the present invention can be used as jak kinase family (including JAK1, JAK2, JAK3 and TYK2), FLT3 kinases (also referred to as FLK-2) and Aurora A (including Aurora-A, Aurora-B and Aurora-C) Activity or function inhibitor.
Background of invention
Protein kinase family includes the relevant enzyme of a big class formation, they control intracellular various signal transduction processes, Similar 250-300 amino acid catalytic domain is usually contained, the phosphorylation of target proteins matter substrate is catalyzed.It was reported that many diseases It is related with the abnormal cell response that protein kinase mediated event causes.These diseases include benign and pernicious proliferative disease Disease, allograft rejection, graft versus host disease, autoimmune caused by disease, the inappropriate activation of immune system Disease, inflammatory disease, bone disease, metabolic disease, neurological disease and neurodegenerative disease, cancer, cardiovascular disease, allergy and Asthma, Alzheimer disease and hormone related condition.Correspondingly, medicinal chemistry arts largely make great efforts to find as controlling Treat the effective kinases inhibitor of agent.
Kinases can be divided into multiple families (for example, protein-tyrosine, protein-silk ammonia by the substrate of phosphorylation Acid/threonine, lipid, etc.).Tyrosine phosphorylation is to adjust various biological process such as cell Proliferation, migration, differentiation and lifes One of central event deposited.The receptors of multiple families and nonreceptor tyrosine kinase family listed business these events: catalytic phosphatase from ATP is transferred to the tyrosine residues of specific cells protein target.Currently, having confirmed that above-mentioned each kinase families general homology Motif (Hanks et al., FASEB J., 1995,9,576-596；Knighton et.al.,Science,1991,253, 407-414；Garcia-Bustos en al.EMBO J.,1994,13:2352-2361).Kinases in protein kinase family Example includes, but are not limited to Aurora, Axl, abl, Akt, bcr-abl, Blk, Brk, Btk, c-Met, c-src, c-fms, CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Flt-3, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, Fps, Frk,Fyn,Hck,JAK,IGF-1R,INS-R,KDR,Lck,Lyn,MEK,p38,PDGFR,PIK,PKC,PYK2,ros,Tie, Tie-2, TRK, Yes and Zap70, etc..
Aurora A family is the related serine/threonine kinase of a kind of height, is mitotic crucial tune Agent is saved, the accurate and equal separation (segtion) for the genomic material from mother cell to daughter cell is required.Aurora The member of kinase families include the related kinases of three classes, referred to as Aurora-A, Aurora-B and Aurora-C (also referred to as Aurora-1, Aurora-2 and Aurora-3).Although these kinases have significant program homology, localization and function Can still there are different (Richard D.Carvajal, et al., Clin.Cancer Res., 2006,12 (23): 6869- greatly each other 6875；Daruka Mahadevan,et al.,Expert Opin.Drug Discov.,2007,2(7):1011-1026).
Aurora-A generally expresses and adjusts the cell cycle events occurred from the phase in advanced stage S through the M phase, including centerbody at Ripe (Berdnik D, et al., Curr.Biol., 2002,12:640-647), mitosis enter (Hirota T, et al., Cell,2003,114:585-598；Dutertre S, et al., J.Cell Sci., 2004,117:2523-2531), center Body separation (Marumoto T, et al., J.Biol.Chem., 2003,278:51786-51795), the two poles of the earth mitotic spindle assembly object (Eyers PA, et al., Curr Biol., 2003,13:691-7), Chromosomal arrangement (Marumoto T, et on equatorial plate al.,J.Biol.Chem.,2003,278:51786-95；Kunitoku N, et al., Dev Cell, 2003,5:853-64), Cytokinesis (Marumoto T, et al., J Biol Chem., 2003,278:51786-95) and mitosis terminate.From G2 increases through M phase Aurora-A protein level and kinase activity, and peak activity is in the prometaphase.Once activation, Aurora- A converts acid curling by including that centrosome protein (centrosomin) interaction mediates its multiple functions with various substrates - crimp protein, cdc25b, Eg5 and centromere protein matter A.
Aurora-B is that accurate chromosome is isolated, cytokinesis (Hauf S, et al., J.Cell Biol., 2003,161:281-94；Ditchfield C,et al.,J.Cell Biol.,2003,161:267-280；Giet R,et al.,J.Cell Biol.,2001,152:669-682；Goto H,et al.,J.Biol.Chem.,2003,278:8526- 8530), (Murata-Hori M, et are adhered in protein localization to kinetochore and centromere, correct micro-pipe-centromere Al., Curr.Biol., 2002,12:894-899), and adjust chromosome passenger's albumen of Mitotic checkpoint key. Localization is in chromosome first during early period by Aurora-B, and then localization is single in sisters' dyeing during prometaphase and mid-term Interior kinetochore area (Zeitlin SG, et al., J.Cell Biol., 2001,155:1147-1157) between body.Aurora- B participates in establishing the biology orientation of chromosome, and wherein sisters centromere is connected to the opposite pole of the two poles of the earth spindle via double orientation attachment. The mistake of the process, shows as partially oriented connection status (centromere is connected to from bipolar micro-pipe) or orientation connects altogether State (two sisters centromeres are connected to the micro-pipe from same stages) is connect, if the not correction up before the later period starts, will be led Cause the unstability and aneuploidy of chromosome.It is that repairing is incorrect micro- in the main function of the Aurora-B of mitosis point (Hauf S, et al., J.Cell Biol., 2003,161:281-294 are adhered in pipe-centromere；Ditchfield C,et al.,J.Cell Biol.,2003,161:267-280；Lan W,et al.,Curr.Biol.,2004,14:273-286).? In the case that Aurora-B is inactivated, Mitotic checkpoint is damaged, and causes increased number of aneuploid cell, mrna instability (Weaver BA, et al., Cancer Cell, 2005,8:7-12) occurs for qualitative and tumour.
Aurora-A overexpression is the tumorigenic required feature of Aurora-A- induction.It is overexpressed in tool Aurora-A Cell in, mitotic feature be there are multiple centerbodies and multipolar spindle (Meraldi Pet al., EMBO J., 2002,21:483-492.).Although obtaining the attachment of abnormal microtubule-centromere, cell still abolishes Mitotic checkpoint and from mid-term To the later period, cause many chromosome separation defects.Cytokinesis will not occur for these cells, and develop other thin Born of the same parents' period, polyploidy and progressive chromosome instability (Anand S, et al., Cancer Cell, 2003,3:51-62).
Verified Aurora is overexpressed and a variety of malignant proliferative disorders, such as the carcinoma of the rectum, breast cancer, lung cancer, cancer of pancreas, preceding Column gland cancer, bladder cancer, head and neck cancer, cervix cancer, oophoroma, liver cancer and gastric cancer etc., it is closely related, exploitation is excited for cancer The interest of the Aurora inhibitor for the treatment of.In normal cell, Aurora-A inhibition causes to delay but and non-blacked mitosis Into the centerbody separation defect of, monopole mitotic spindle and cytokinesis failure (Marumoto T, et al., J.Biol.Chem.,2003,278:51786-51795).The encouraging antitumous effect of Aurora-A inhibitor is shown in three kinds Human pancreatic cancer cell is in (Panc- Ι, Μ Ι Α PaCa-2dnSU.86.86), wherein having growth suppression in cell culture System and tumorigenicity in murine xenogralt it is intimate all eliminate (Hata T, et al., Cancer Res., 2005,65:2899-2905)。
Aurora-B inhibits to cause abnormal centromere-micro-pipe attachment, the biology orientation that cannot achieve chromosome, cytokinesis Failure (Goto H, et al., J.Biol.Chem., 2003,278:8526-8530；Severson AF,et al., Curr.Biol.,2000,10:1162-1171).Do not include the abnormal mitosis of cytokinesis repetitive cycling cause it is huge Polyploidy and eventually lead to Apoptosis (Hauf S, et al., J.Cell Biol., 2003,161:281-94； Ditchfield C,et al.,J.Cell Biol.,2003,161:267-80；Giet R, et al., J.Cell Biol., 2001；152:669-82；Murata-Hori M,Curr.Biol.,2002,12:894-899；Kallio M J,et al., Curr.Biol.,2002,12:900-905)。
Inhibit Aurora-A or Aurora-B activity that Chromosomal arrangement is caused to damage in tumour cell, Mitotic checkpoint Abolishment, polyploidy and subsequent cell death.These in vitro effects are in the cell of conversion than in non-transformed or undifferentiated Cell in more preferable (Ditchfield C, et al., J.Cell Biol., 2003,161:267-280), thus, target The internal selectivity to cancer may be implemented in Aurora.Although it is foreseen that may be to the quick of hemopoietic system and gastrointestinal system to it Noble cells has certain toxicity, but the activity in xenograft models still shows that reasonable treatment refers to clinical tolerability Number.Under the premise of preclinical anti-tumor activity and tumor-selective potentiality, several Aurora As have been developed at present and have been inhibited Agent.
FLT3 (the relevant tyrosine kinase 3 of Flt3, FMS-), also referred to as FLK-2 (fetal livers kinases 2) and the STK-I (mankind Stem cell kinases 1), belong to receptor tyrosine kinase (RTK-III) family member (Gtirewalt DL et al., Nat.Rev.Cancer,2003,3:650-665；Rosnet O,et al.,Genomics,1991,9:380-385；Yarden Y,et al.,Nature,1986；323:226-232；Stanley E R,et al.,J.Cell Biochem.,1983,21: 151-159；Yarden Y,et al.,EMBO J.,1987,6:3341-3351).FLT3 is transmembrane protein, by four structures Domain composition, extracellular ligand-binding domain comprising five immunoglobulin class structure compositions, the domain cross-film (TM), nearly film (JM) domain With the domain cytoplasm C- terminal tyrosine kinases (TK).(Agnes F,et al.Gene,l994,145:283-288；Scheijen B,et al.,Oncogene,2002,21:3314-3333)。
The ligand of FLT3 was cloned in 1993, studies show that, it includes marrow that it, which is Hematopoietic marrow microenvironment cell, Expressed in fibroblast and other cells type I transmembrane protein (Lyman SD, et al., Cell, 1993,75, 1157-1167).Film combines the tyrosine kinase activity with the equal energy activated receptor of soluble form and stimulates the ancestral in marrow and blood Cell growth.The zygotic induction receptor dimer of ligand-receptor, and activated protein kinase domain；Then it its autophosphorylation and is catalyzed each The substrate protein phosphorylation of kind signal transduction pathway, such as the signal transducer and activator (STAT5), RAS/ mitogen of transcription 5 Protein kinase (RAS/MAPK), phosphoinositide 3-kinase (PI3K), the Src of original activation be of the same race and glue protogene (SHC), contains Inositol -5- the phosphatase (SHIP) of SH2 and the cytoplasmic tyrosine phosphoric acid with 2 Src- homology 2 (SH2) domains (SHP2) Enzyme, play a significant role in cell Proliferation, differentiation and existence (Dosil M., et al., Mol.Cell Biol., 1993, 13:6572-6585.Zhang S,Biochem.Biophys.Res.Commun.,l999,254:440-445).In addition to hematopoiesis is thin Except born of the same parents, FLT3 gene also expression (Maroc N, the et al., Oncogene, 1993,8:909- in placenta, sexual gland and brain 918) and in immune response play a significant role (deLapeyriere O.et al., Leukemia, 1995,9:1212- 1218)。
FLT3 also with the hemopoietic system dysfunction before malignant proliferative lesion, such as piastrenemia, true property blood platelet Bone is obtained before increase disease, myelofibrosis (MF), chronic idiopathic myelofibrosis (IMF), polycythemia (PV), canceration Marrow hyperplasia exception syndrome, hematologic malignancies include, but are not limited to leukaemia, (non-Hodgkin lymphoma), lymphogranulomatosis (also known as Hodgkin lymphoma) and myeloma, such as, acute lymphatic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophil leukemia (CNL), it is closely related.Acute myeloid leukaemia (AML) of the FLT3 in 70-100% In, in the acute lymphoblastic leukemia (ALL) of He Gao percentage with it is each it is horizontal be overexpressed (Griffin JD, et al., Haematol J.,2004,5:188-190).In primitive cell crisis, also in the smaller of chronic myelogenous leukemia (CML) It is overexpressed in hypotype.Research has been displayed B pedigree leukaemia cell ALL and AML and continually co-expresses FL, causes FLT3 composing type living The autocrine or paracrine signal transduction of change recycle (Zheng R, et.al.Blood., 2004,103:267-274).In addition, FLT3 ligand is in langerhans cell histiocytosis and Patients with SLE cell serum with high-level table It reaches, the dendritic cells Signal Regulation for further displaying FLT3 and autoimmune disease is extremely closely related.
More and more evidences show that a plurality of types of leukaemia and myeloproliferative syndrome have the prominent of tyrosine kinase Become.FLT3 mutation is one of body change most frequent in AML, is occurred in about 1/3 patient.It is described in leukaemic Two kinds of FLT3 Activating mutations.These include a series of in the internal series-connection occurred from the nearly film domain of inhibition duplication (ITD)(Nakao M,et al.,Leukemia,1996,10:1911-1918；Thiede C et al.,Blood,2002, 99:4326-4335) it is mutated with activation cycle comprising Asp835Tyr (D835Y), Asp835Val (D835V), Asp835His (D835H), Asp835Glu (D835E), Asp835Ala (D835A), Asp835Asn (D835N), Asp835 are lacked The Ile836 that becomes estranged lacks (Yamamoto Y, et al., Blood, 2001,97:2434-2439；Abu-Duhier FM,et al.,Br.J.Haematol.,2001,113:983-988).Internal series-connection duplication (ITD) mutation in the domain JM facilitates in AML The FLT3 Activating mutations of about 17-34%.FLT3-ITD is also able to detection (MDS) in myelodysplastic syndrome with low frequency (Yokota S.,et al.,Leukemia,l997,11:1605-1609；Horiike S,et al.,Leukemia,1997, 11:1442-1446).ITDs is confined to the domain JM always in frame.However, there are change in length and position in different patients Change.These repetitive routines can be used to destroy the domain JM from inhibitory activity, cause FLT3 composing type to activate.FLT3-ITD and FLT3-Asp835 mutation it is related with the phosphorylation of FLT3 autophosphorylation and downstream targets (Mizuki M, et al., Blood, 2000,96:3907-3914；Mizuki M,et al.,Blood,2003,101:3164-3173；Hayakawa F,et al., Oncogene,2000,19:624-631)。
Currently, the FLT3 inhibitor ground is as some or all recurrence with FLT3 mutation or obstinate AML patient Monotherapy have reached clinical test.Generally, these are statistics indicate that FLT3 is to be used for AML and other related diseases for developing The attractive therapeutic targets of the kinase inhibitor of disease.
Janus kinases (JAK) is an intracellular non-receptor tyrosine kinase family, logical by turning JAK-STAT Road, the signal that the transducer cell factor mediates.JAK family adjusts and is related to the cell of immune response in the proliferation that cell factor relies on It plays an important role in function.Cell factor causes receptor dimerization, can promote JAKs phase in this way in conjunction with their receptor Mutual phosphorylation can also promote cytokine receptor internal specific tyrosine motif phosphorylation.Identify these phosphorylation motifs STATs is focused on receptor, is then activated during the tyrosine phosphorylation that JAK is relied on.Due to activation, STATs with Receptor dissociation, dimerization, and it is displaced to nucleus, in conjunction with the specific site DNA, and change transcription.
Mammal JAK family member known to being currently, there are four kinds: (Janus swashs by JAK1 (Janus kinases -1), JAK2 Enzyme -2), JAK3 (Janus kinases, leucocyte；JAKL；L-JAK and Janus kinases -3) and TYK2 (protein tyrosine kinase 2). JAK1, JAK2 and TYK2 are general expression, and JAK3 is reported and preferentially expresses in natural kill (NK) cell, without other T cell in express (" Biology and significance of the JAK/STAT signaling pathways. " Growth Factors,April 2012；30(2):88).
JAK1 is necessary the signal transduction of certain I types and II cytokines.The γ of it and I cytokines receptor Public chain (γ c) interaction, induces IL-2 receptor family, IL-4 receptor family, and gp130 receptor family issues signal.It is to I The signal of type (IFN-α/β) and II type (IFN-γ) interferon, and the IL-10 family member by II cytokines receptor Signal transduction it is also critically important.Heredity and biological study show, JAK1 functionally and physiologically with I type interferon (for example, IFNalpha), II type interferon (for example, IFNgamma), IL-2 to IL-6 cytokine receptor complex are related.Further It is logical in IFN, IL-IO, IL-2/IL-4 and IL-6 to demonstrate the kinases to the characterization of the tissue from JAK1 knock-out mice for ground Key effect in road.
JAK1 expression in cancer cell can promote individual cells atrophy, potentially them is made to flee from tumour, be transferred to body Other positions of body.By the cell factor of JAK1 transduction signal, horizontal raising involves a large amount of immune and inflammation disease Disease.JAK1 or JAK family kinase inhibitors can be used for adjusting or treating these diseases (Kisseleva et al., 2002, Gene 285:1-24；Levy et al.,2005,Nat.Rev.Mol.Cell Biol.,3:651-662).Target the people of IL-6 access Resource monoclonal antibody (Torr pearl monoclonal antibody Tocilizumab) is ratified to close for treating moderate to severe rheumatoid by EU Committee Save scorching (Scheinecker et al., 2009, Nat.Rev.Drug Discov., 8:273-274).
JAK2 and II cytokines receptor family (such as interferon receptors), GM-CSF receptor family, gp130 receptor man The signal transduction of family member is relevant.JAK2 signal is activated in the downstream of hprl receptor.Research shows that in myeloproliferative In the disease such as diseases such as polycythemia vera, primary thrombocytosis and idiopathic myelofibrosis, generally deposit (JAK2V617F) is mutated in the JAK2 of acquired activation.The JAK2 albumen of mutation can be the case where no cell factor stimulates Lower activation downstream signal leads to spontaneous growth and/or the hypersensitivity to cell factor, is considered the process to these diseases Play a part of promotion.The more multimutation of JAK2 functional disturbance or transposition is caused to be found in the description to other malignant tumours (Ihle J.N.and Gilliland D.G.,Curr.Opin.Genet.Dev.,2007,17:8；Sayyah J.and Sayeski P.P.,Curr.Oncol.Rep.,2009,11:117).JAK2 inhibitor has described as to proliferative diseases There are effect (Santos et al, Blood, 2010,115:1131；Barosi G.and Rosti.V., Curr.Opin.Hematol,2009,16:129,Atallah E.and Versotvsek S.,Exp.Rev.Anticancer Ther.,2009,9:663)。
JAK3 only be present in IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complex Public gamma cells factor acceptor chain is related.JAK3 is mainly expressed in immunocyte, and passes through the tyrosine phosphorus of interleukin-2-receptor Acidification activation, transduction signal.Since JAK3 is limited to express in candidate stem cell more, relative to other JAKs, it is in cell factor Effect in signal transduction is stringenter.The mutation of JAK3 will lead to severe combined immunodeficiency (SCID) (O'Shea et al.,2002,Cell,109(suppl.):S121-S131).Based on its adjust lymphocyte in effect, targeting JAK3 and The access that JAK3 is mediated has been used for treating immunosupress indication (for example, graft rejection and rheumatoid arthritis) (Baslund et al.,2005,Arthritis&Rheumatism 52:2686-2692；Changelian et al., 2003,Science 302:875-878)。
TYK2 and IFN-α, IL-6, IL-10 to IL-12 signal transduction are related.Biochemical research and knock out mice TYK2 is disclosed in the important function of immunology.TYK2 deficient mice energy growth and breeding, but panimmunity defect is shown, it is main If to infection, there are hypersensitivities and the existing defects in terms of oncological surveillance.It is opposite, inhibit TYK2 can be improved resist allergy, The ability of autoimmunity and inflammatory disease.Particularly, targeting TYK2 seems to become treatment IL-12-, IL-23- or I type IFN- is situated between The innovative strategy for the disease led.The disease includes but is not limited to rheumatoid arthritis, multiple sclerosis, lupus, silver bits Disease, psoriasis arthropathica, inflammatory bowel disease, uveitis, sarcoidosis and cancer (Shaw, M.et al., Proc.Natl.Acad.Sci.,USA,2003,100,11594-11599；Ortmann,R.A.,and Shevach, E.M.Clin.Immunol,2001,98,109-118；Watford et al,Immunol.Rev.,2004,202:139). [“Janus Kinase(JAK)Inhibitors in Rheumatoid Arthritis.”Current Rheumatology Reviews,2011,7,306-312]。
European commission has been recently approved the complete source of people of the shared p40 subunit of targeting IL-12 and IL-23 cell factor Monoclonal antibody (Ustekinumab), for treat moderate to severe plaque psoriasis (Krueger et al., 2007, N.Engl.J.Med.,356:580-92；Reich et al.,2009,Nat.Rev.Drug Discov.,8:355-356).This Outside, target IL-12 and IL-23 access antibody carried out for treating Crohn disease clinical test (Mannon et al., N.Engl.J.Med.,2004,351:2069-79)。
When adjusting not normal, the response that JAK- is mediated can positively or negatively influence cell, cause overactivity to be disliked respectively Property tumour, or immune and hematopoietic defect, which imply the practicabilities of jak kinase inhibitor.JAK/STAT signal path involves To many proliferation and cancer associated processes, including cell cycle progression, apoptosis, angiogenesis, infiltration, transfer and immune system are escaped Keep away (Haura et al., Nature Clinical Practice Oncology, 2005,2 (6), 315-324；Verna et al.,Cancer and Metastasis Reviews,2003,22,423-434).In addition, JAK/STAT signal path is to making The generation and differentiation of hemocytoblast, proinflammatory and anti-inflammatory dual regulation and immune response play an important role (O'Sullivan et al.,Molecular Immunology,2007,44:2497)。
Therefore, all four members of JAK/STAT access, especially JAK family, are considered in asthma reaction, chronic resistance It works in the pathogenesis of plug property tuberculosis, bronchitis and other relevant lower respiratory tract inflammatory diseases.JAK/STAT is logical Road equally (includes, but are not limited to iritis, uvea in ocular inflammatory disease (diseases)/disease (conditions) Inflammation, sclerotitis, conjunctivitis) and chronic anaphylaxis reaction in work.Since cell factor swashs using various various forms of JAK Enzyme (O'Sullivan et al., Mol.Immunol, 2007,44:2497；Murray J.,Immunol,2007,178: 2623), different selective jak kinases in antagonism family are logical to treat the relevant disease of the specific cells factor or JAK/STAT Variability or the relevant disease of polymorphism may be useful in road.
Rheumatoid arthritis (RA) is a kind of autoimmune disease characterized by chronic joint inflammation.Take JAK suppression The patient with rheumatoid arthritis of preparation shows the inhibition of the JAK1 and JAK3 module by signal caused to cytokine profiles, it To lymphocyte function, including proleulzin (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21 are critically important [Fleischmann,R.et al.,“Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis."N.Engl.J.Med.,2012,367,495-507].It is assumed that directly making specific JAK sub- The micromolecular inhibitor of type inactivation can not only mitigate the clinical symptoms of RA, those can also be inhibited to promote being permitted for RA disease progression Excessive adjusting (" the Inhibitors of JAK for the treatment of rheumatoid of more proinflammatory cytokines arthritis:rationale and clinical data.”Clin.Invest.,2012,2(1),39-47)。
The sustained activation of STAT3 or STAT5 has been proved to be present in many entity human tumours, including lacteal tumor, pancreas Tumor, prostate tumor, ovarioncus and liver cancer, while existing in a large amount of blood tumor, including lymthoma and leukaemia.In this side Face, the inactivation of the JAK/STAT signal in neoplastic hematologic disorder proliferation capable of inhibiting cell and/or induces cell apoptosis.Although tumour cell In STAT3 can still be counted as most important upstream activat person by many kinase activations, JAK2, it can be activated derived from each STAT3 (Mohamad Bassam Sonbol, Belal Firwana, Ahmad in the human tumor cell line of kind entity tumor Zarzour,Mohammad Morad,Vishal Rana and Ramon V.Tiu “Comprehensive review of JAK inhibitors in myeloproliferative neoplasms.”Therapeutic Advances in Hematology 2013,4(1),15-35；Hedvat M,Huszar D,Herrmann A,Gozgit J M,Schroeder A,Sheehy A,et al.“The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors."Cancer Cell 2009,16(6):487-97).Therefore, inhibit JAK Kinases plays beneficial effect to the treatment of these diseases.
It knows clearly, kinases inhibitor is poly- as new immunosupress, anti-inflammatory double action medicine and anticancer medicine Numerous concerns are collected.Therefore, inhibit the protein kinase such as novel agent of Aurora A, FLT3 kinases and jak kinase or improve examination Agent is needed for a long time, it can be used as the immunosuppressor of organ transplant, antitumor agent, it can also be used to prevent and treat autoimmunity Disease is (for example, multiple sclerosis, psoriasis, rheumatoid arthritis, asthma, type-1 diabetes mellitus, inflammatory bowel disease, Crow grace Disease, polycythemia vera, primary thrombocytosis, myelofibrosis, autoimmune thyroid disease, the sea A Erzi Silent disease), it is related to the disease (for example, eczema) of overactivity inflammatory reaction, allergy, chronic obstructive pulmonary disease, bronchitis, cancer (for example, prostate cancer, acute myelocytic leukemia, chronic granulocytic leukemia, acute lymphoblastic leukemia, white blood Disease, Huppert's disease) and the caused immune response (for example, fash, contact dermatitis or diarrhea) of other treatment, etc..This Compound, composition and the method for invention description directly correspond to these needs and other purposes.
Summary of the invention
The present invention provides one kind to inhibit, adjusts and/or regulate and control one or more protein kinases, as jak kinase, FLT3 swash Enzyme and the active compound of Aurora A, for treating proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease Disease, graft rejection and their complication.Present invention provides the methods for preparing these compounds, use these compounds The method for treating the above-mentioned disease of mammal, the especially mankind, and the pharmaceutical composition comprising these compounds.The present invention Compound and combinations thereof have preferable potential applicability in clinical practice.Compared with existing similar compound, chemical combination of the invention Object has better pharmacological activity, medicine for property, physicochemical property and/or toxicological characteristics.Specifically, the compounds of this invention is to mesh Mark kinases shows the Kinase Selectivity of preferable inhibitory activity and optimization, shows in pharmacokinetic trial in animal body Good absorption and very high bioavilability out.Therefore, the compounds of this invention has more excellent druggability.
Specifically:
On the one hand, the present invention relates to the alloisomerisms of one kind compound as shown in formula (I) compound represented or formula (I) Body, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein, W, Ar, Z, B and R1With meaning as described in the present invention.
In some embodiments, W is the monocyclic heterocycles base group of the 4-7 molecular saturation of original, optionally by 1, 2,3,4 or 5 R2Replaced group；
Ar is C6-C12Aryl or 5-12 former molecular heteroaryl, wherein Ar is optionally by 1,2,3,4 or 5 R8Base Replaced group；
Z is H, C1-C12Alkyl, C3-C12Naphthenic base or 3-12 former molecular heterocycle, wherein each C1-C12Alkane Base, C3-C12The former molecular heterocycle of naphthenic base and 3-12 is individually optionally by 1,2,3,4 or 5 R3Replaced group；
B is pyrazolyl, imidazole radicals or indazolyl, wherein B is optionally by 1,2,3,4 or 5 R4Replaced group；
R1For H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Alkoxy, C1-C12Alkyl amino, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl, 5-12 original are molecular miscellaneous Aryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb、-(CR6R7)nC (=O) R5、-(CR6R7)nOC (=O) R5、-O(CR6R7)n- R5、-N(Rc) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc)C (=O) NRaRb、-(CR6R7)nS (=O)mR5、-N(Rc) S (=O)mR5Or-S (=O)mNRaRb, wherein each C1-C12Alkane Base, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Alkoxy, C1-C12Alkyl amino, C3-C12Naphthenic base, 3-12 original are molecular Heterocycle, C6-C12The former molecular heteroaryl of aryl and 5-12 is individually optionally by 1,2 or 3 R9Replaced group；
Each R2、R3、R4And R8It is separately H, F, Cl, Br, I, NO2、CN、N3、C1-C12Alkyl, C2-C12Alkenyl, C2- C12Alkynyl, C1-C12Alkoxy, C1-C12Alkyl amino, C1-C12Hydroxy alkyl, C3-C12Naphthenic base, C6-C12Aryl, 3-12 original Molecular heterocycle, 5-12 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb、-(CR6R7)nC (= O)R5、-(CR6R7)nOC (=O) R5、-O(CR6R7)n-R5、-N(Rc) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc) C (=O) NRaRb、-(CR6R7)nS (=O)mR5、-N(Rc) S (=O)mR5Or-S (=O)mNRaRb, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Alkoxy, C1-C12Alkyl ammonia Base, C1-C12Hydroxy alkyl, C3-C12Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle and 5-12 atom composition Heteroaryl individually optionally by 1,2,3,4 or 5 R9Replaced group；
Each R5It independently is H, C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Halogenated alkyl, C1-C12Alcoxyl Base, C1-C12Hydroxy alkyl, C1-C12Alkyl amino, C1-C12Aminoalkyl, C3-C12Naphthenic base, C6-C12Aryl, 3-12 atom The heterocycle of composition or 5-12 former molecular heteroaryl, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C1-C12Halogenated alkyl, C1-C12Alkoxy, C1-C12Hydroxy alkyl, C1-C12Alkyl amino, C1-C12Aminoalkyl, C3-C12 Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle and the 5-12 molecular heteroaryl of original it is individually optional by 1, 2 or 3 R9Replaced group；
Each R6And R7It is separately H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C3-C12Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle or 5-12 former molecular heteroaryl, or R6、R7, and together with the carbon atom that they are connected, form C3-C12Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle Base or 5-12 former molecular heteroaryl groups, wherein above-mentioned each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12 Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle and the 5-12 molecular heteroaryl of original it is individually optional by 1, 2 or 3 R9Replaced group；
Each R9It independently is F, Cl, Br, I, CN, NO2、N3、NH2、OH、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Halogenated alkyl, C1-C12Alkoxy, C1-C12Hydroxy alkyl, C1-C12Alkyl amino, C1-C12Aminoalkyl, C3-C12Cycloalkanes Base, C6-C12Aryl, 3-12 former molecular heterocycle, 5-12 former molecular heteroaryl ,-NH (CH2)n-(C3-C12Ring Alkyl) ,-NH (CH2)n-(C6-C12Aryl) ,-NH (CH2)n(3-12 former molecular heterocycle) ,-NH (CH2)n-(5-12 A molecular heteroaryl of original) ,-N [(CH2)n-(C3-C12Naphthenic base)]2、-N[(CH2)n-(C6-C12Aryl)]2、-N[(CH2)n- (3-12 former molecular heterocycle)]2、-N[(CH2)n(5-12 former molecular heteroaryl)]2、-O(CH2)n-(C3-C12 Naphthenic base) ,-O (CH2)n-(C6-C12Aryl) ,-O (CH2)n(3-12 former molecular heterocycle) or-O (CH2)n-(5-12 A molecular heteroaryl of original)；
Each Ra、RbAnd RcIt is separately H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base ,-(C1- C4Alkylidene)-(C3-C6Naphthenic base), 3-6 former molecular heterocycle ,-(C1-C4Alkylidene)-(3-6 is former molecular miscellaneous Ring group), C6-C12Aryl ,-(C1-C4Alkylidene)-(C6-C12Aryl), 5-12 former molecular heteroaryl or-(C1-C4Alkylene Base)-(5-12 former molecular heteroaryl) or Ra、Rb, and together with the nitrogen-atoms that is connected with them, form 3-8 atom The heterocyclyl groups of composition, wherein above-mentioned each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base ,-(C1-C4It is sub- Alkyl)-(C3-C6Naphthenic base), 3-6 former molecular heterocycle ,-(C1-C4Alkylidene)-(3-6 former molecular heterocycle Base), C6-C10Aryl ,-(C1-C4Alkylidene)-(C6-C12Aryl), 5-12 former molecular heteroaryl ,-(C1-C4Alkylene Base)-(5-12 former molecular heteroaryl) and the 3-8 molecular heterocyclyl groups of original are optionally by 1,2,3 or 4 independence Selected from F, Cl, Br, CN, N3、OH、NH2、C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy or C1-C6Alkyl amino takes Replaced Dai Ji；
Each n independently is 0,1,2,3 or 4；With
Each m independently is 1 or 2.
In other embodiments, Ar is phenyl or the 5-6 molecular heteroaryl of original, wherein Ar optionally by 1, 2,3 or 4 R8Replaced group.
In some embodiments, Ar is phenyl, furyl, imidazole radicals, isoxazolyl, oxazolyl, pyrrole radicals, pyridine Base, pyriconyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, triazol radical, thienyl, Pyrazolyl, oxygen phenodiazine oxazolyl, sulphur phenodiazine oxazolyl, pyrazinyl or triazine radical, wherein Ar is optionally by 1,2 or 3 R8Group is taken Generation.
In other embodiments, Z H, C1-C6Alkyl, C3-C6Naphthenic base or 3-6 former molecular heterocycle, Wherein, each C1-C6Alkyl, C3-C6The former molecular heterocycle of naphthenic base and 3-6 is individually optionally by 1,2 or 3 R3Base Replaced group.
In some embodiments, Z H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl.
In another embodiment, R1For H, F, Cl, Br, CN, N3、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6 Alkoxy, C1-C6Alkyl amino, C3-C6Naphthenic base, 3-6 former molecular heterocycle ,-(CR6R7)n-ORc、-(CR6R7)n- NRaRb、-(CR6R7)nC (=O) R5、-(CR6R7)nOC (=O) R5、-O(CR6R7)n-R5、-N(Rc) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRbOr-S (=O)mNRaRb, wherein each C1-C6Alkyl, C2-C6Alkenyl, C2-C6 Alkynyl, C1-C6Alkoxy, C1-C6Alkyl amino, C3-C6The former molecular heterocycle of naphthenic base and 3-6 individually optionally by 1, 2 or 3 R9Replaced group.
In some embodiments, R1For H, F, Cl, Br, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy Base, ethyoxyl, positive propoxy, isopropoxy, methylamino, dimethylamino, piperidyl, pyrrolidinyl, morpholinyl or piperazinyl, In, each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, first ammonia Base, dimethylamino, piperidyl, pyrrolidinyl, morpholinyl and piperazinyl it is individually optional by 1,2 or 3 R9Replaced group.
In other embodiments, each R2、R4And R8It is separately H, F, Cl, Br, CN, N3、NO2、C1-C6Alkane Base, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkyl amino, C1-C6Hydroxy alkyl, C3-C6Naphthenic base, 3-6 Former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb、- (CR6R7)nC (=O) R5、-(CR6R7)nOC (=O) R5、-O(CR6R7)n-R5、-N(Rc) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRbOr-S (=O)mNRaRb, wherein each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkyl amino, C1-C6Hydroxy alkyl, C3-C6Naphthenic base, 3-6 former molecular heterocycle, phenyl and 5-6 former molecular heteroaryl is individually optionally by 1,2 or 3 R9Replaced group.
In some embodiments, each R2、R4And R8It is separately H, F, Cl, CN, methyl, ethyl, n-propyl, different Propyl, cyclopropyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, lignocaine, Methylol, 1- ethoxy, 2- ethoxy, 3- hydroxypropyl, 2- hydroxypropyl, 2- hydroxy-2-methyl propyl, 2- hydroxyl propyl- 2- base, C3-C6Naphthenic base, 4-6 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(CR6R7)n-ORc、- (CR6R7)n-NRaRb、-(CR6R7)nC (=O) R5、-(CR6R7)nOC (=O) R5、-N(Rc) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRbOr-S (=O)mNRaRb, wherein each methyl, ethyl, n-propyl, isopropyl, cyclopropyl Base, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, lignocaine, methylol, 1- Ethoxy, 2- ethoxy, 3- hydroxypropyl, 2- hydroxypropyl, 2- hydroxy-2-methyl propyl, 2- hydroxyl propyl- 2- base, C3-C6Cycloalkanes Base, 4-6 former molecular heterocycle, phenyl and the 5-6 molecular heteroaryl of original it is individually optional by 1,2 or 3 R9Base Replaced group.
In other embodiments, each R5It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6It is halogenated Alkyl, C1-C6Alkoxy, C1-C6Hydroxy alkyl, C1-C6Alkyl amino, C1-C6Aminoalkyl, C3-C6Naphthenic base, phenyl, 3-6 A molecular heterocycle of original or 5-6 former molecular heteroaryl, wherein each C1-C6Alkyl, C2-C6Alkenyl, C2-C6 Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Hydroxy alkyl, C1-C6Alkyl amino, C1-C6Aminoalkyl, C3-C6Ring Alkyl, phenyl, 3-6 former molecular heterocycle and the 5-6 molecular heteroaryl of original it is individually optional by 1,2 or 3 R9 Replaced group.
In some embodiments, each R6And R7It is separately H, F, Cl, Br, CN, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, phenyl, 3-6 former molecular heterocycle or 5-6 former molecular heteroaryl or R6、 R7, and the carbon atom being connected with them is formed together C3-C6Naphthenic base, phenyl, 3-6 former molecular heterocycle or 5-6 are former Molecular heteroaryl groups, wherein above-mentioned each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, phenyl, 3-6 The molecular heterocycle of a original and 5-6 former molecular heteroaryl it is individually optional by 1,2 or 3 R9Replaced group.
In other embodiments, each R9It independently is F, Cl, Br, CN, N3、OH、NH2、C1-C6Alkyl, C2-C6Alkene Base, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Hydroxy alkyl, C1-C6Alkyl amino, C1-C6Aminoalkyl, C3-C6Naphthenic base, phenyl, 3-6 former molecular heterocycle, 5-6 former molecular heteroaryl ,-NH (CH2)n-(C3-C6Ring Alkyl) ,-NH (CH2)nPhenyl ,-NH (CH2)n(3-6 atom forms heterocycle) ,-NH (CH2)n(5-6 former molecular Heteroaryl) ,-N [(CH2)n-(C3-C6Naphthenic base)]2、-N[(CH2)nPhenyl]2、-N[(CH2)n(3-6 former molecular miscellaneous Ring group)]2、-N[(CH2)n(5-6 former molecular heteroaryl)]2、-O(CH2)n-(C3-C6Naphthenic base) ,-O (CH2)nBenzene Base ,-O (CH2)n(3-6 former molecular heterocycle) or-O (CH2)n(5-6 former molecular heteroaryl).
In some embodiments, each Ra、RbAnd RcIt is separately H, C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C6Naphthenic base ,-(C1-C2Alkylidene)-(C3-C6Naphthenic base), 3-6 former molecular heterocycle ,-(C1-C2Alkylidene)- (3-6 former molecular heterocycle), phenyl ,-(C1-C2Alkylidene)-phenyl, 5-6 former molecular heteroaryl or-(C1- C2Alkylidene)-(5-6 former molecular heteroaryl) or Ra、Rb, and together with the nitrogen-atoms that is connected with them, form 3-6 Former molecular heterocyclyl groups, wherein above-mentioned each C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C6Naphthenic base ,-(C1- C2Alkylidene)-(C3-C6Naphthenic base), 3-6 former molecular heterocycle ,-(C1-C2Alkylidene)-(3-6 is former molecular miscellaneous Ring group), phenyl ,-(C1-C2Alkylidene)-phenyl, 5-6 former molecular heteroaryl and-(C1-C2Alkylidene)-(5-6 is former Molecular heteroaryl) optionally F, Cl, CN, N are independently selected from by 1,2 or 33、OH、NH2、C1-C4Alkyl, C1-C4Alkyl halide Base, C1-C4Alkoxy or C1-C4Replaced the substituent group of alkyl amino.
In other embodiments, W is one of the heterocyclyl groups that following heterocyclic compound is formed:
Wherein, heterocycle shown in formula (W-1)~(W-20) is formed by each heterocyclyl groups individually optionally by 1,2 or 3 R2Group It is replaced.
In some embodiments, W is one of minor structure below:
Wherein, each subformula shown in above-mentioned formula (W-31)~(W-65) is independently appointed Selection of land is by 1,2 or 3 R2Replaced group.
In other embodiments, B is following subformula:
Wherein, formula (H), (I), (J), (K), (L), (M), (N), (O), minor structure shown in (P) or (Q) is individually optionally by 1,2 or 3 R4Replaced group.
On the other hand, the present invention relates to a kind of pharmaceutical compositions, and it includes compounds disclosed by the invention.
In one embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable auxiliary material, tax Shape agent, carrier, solvent or their combination.
In other embodiments, pharmaceutical composition of the present invention, wherein further include therapeutic agent, it is described Therapeutic agent is selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 (PDE4) inhibitor, beta-2-adrenoreceptor agonists, cortex Steroids, nonsteroidal GR agonist, anticholinergic drug, antihistamine, anti-inflammatory reagent, immunosuppressor, immunomodulator, For treating the drug of atherosclerosis, the drug for treating pulmonary fibrosis and their combination.
On the other hand, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine preparation, The drug is for preventing, handling, treating or mitigating the protein kinase mediated disease of patient.
In some embodiments, protein kinase mediated disease of the present invention is JAK-, FLT3- or Aurora- The disease of mediation.
In other embodiments, protein kinase mediated disease of the present invention is proliferative diseases, exempts from self Epidemic disease, anaphylactia, inflammatory disease or graft rejection.
In other embodiments, protein kinase mediated disease of the present invention is cancer, polycythemia vera Disease, primary thrombocytosis, it is acute myelocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, acute Myelocytic leukemia chronic granulocytic leukemia, acute lymphoblastic leukemia, Chronic Obstructive Pulmonary Disease, asthma, is System property lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, psoriasis, type-1 diabetes mellitus, is exhaled at skin lupus erythematosus Inhale road anaphylactia, nasosinusitis, eczema, morbilli, food hypersenstivity, insect venom allergies, inflammatory bowel disease, Crohn disease, class wind Wet arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplantation row Reprimand.
On the other hand, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine preparation, The drug is used to reconcile the activity of protein kinase.
In some embodiments, protein kinase of the present invention be jak kinase, FLT3 kinases, Aurora A or Their combination.
On the other hand, the method for preparation, separation and the purifying of the compound for being included the present invention relates to formula (I).
Biological results show that compound provided by the invention can be used as preferable kinases inhibitor.
Any embodiment in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Detailed description of the invention
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined Or more it is different from the application or in the case where contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.
It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition used herein should be applied.For purposes of the present invention, chemical element with The periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.
There is apparent conflict unless otherwise indicated or in context, the article " one " used herein, " one (kind) " " described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by Trying object is people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.
" stereoisomer " refers to identical chemical constitution, but the spatially different change of arrangement mode of atom or group Close object.Stereoisomer includes enantiomter, diastereoisomer, conformer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be overlapped with its mirror image Molecule.
" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
" diastereoisomer " refer to there are two or multiple chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereoisomer is mixed Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to separate by closing object.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.
Many organic compounds exist with optical active forms, i.e., they, which have, rotates the plane of linearly polarized light Ability.When describing optically active compound, indicate molecule about one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for the rotation of linearly polarized light caused by appointed compound, Wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50:50 mixture of enantiomter Referred to as racemic mixture or racemic modification, when chemical reaction or in the process without stereoselectivity or stereospecificity when, It may occur in which such case.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included.
It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or non-substituted ".Generally For, " substituted " the one or more hydrogen atoms indicated in given structure of term are replaced specific substituent group." optionally " Unless otherwise indicated, an optional substituent group can be replaced at various substitutable position of that group.When being given More than one position can be replaced one or more substituent groups selected from specific group, then substituent group can in structural formula out To replace at various locations identical or differently.
Term " optional " either " optionally " mean event or environment described later can with but need not occur, should Illustrate to include the thing or the occasion that environment occurs or do not occur.For example, " optionally by alkyl-substituted heterocyclic group " anticipates Taste alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted scene and heterocyclic group not by alkyl Substituted scene.
Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention It includes, but is not limited to D, F, Cl, Br, I, N3、CN、NO2、OH、SH、NH2, alkyl, halogenated alkyl, alkenyl, alkynyl, alkoxy, hydroxyl Alkyl, alkylthio group, alkyl amino, aminoalkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-(CR6R7)n-ORc、- (CR6R7)n-NRaRb、-(CR6R7)nC (=O) R5、-(CR6R7)nOC (=O) R5、-O(CR6R7)n-R5、-N(Rc) C (=O) R5、- (CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc) C (=O) NRaRb、-(CR6R7)nS (=O)mR5、-N(Rc) S (=O)mR5Or-S (=O)mNRaRb, etc..Wherein, R5、R6、R7、Ra、Rb、Rc, m and n there is such as this hair The bright meaning.
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, It is not influenced mutually between the same symbol between expressed specific option either refer among the different groups, can also be with table Show in the same group, is not influenced mutually between expressed specific option between the same symbol.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-C6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl；" 4-7 former for term Molecular heterocycle " refers to the molecular heterocycle of independent disclosed 4 originals, the molecular heterocycle of 5 originals, 6 originals Molecular heterocycle or 7 molecular heterocycles of original.
In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl ", " heterocycle " or " aryl ", then it should be understood that should " alkyl ", " heterocycle Base " or " aryl " respectively represent the alkylidene group, sub- heterocyclyl groups or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1- 12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group Contain 1-4 carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The alkyl group can be optional Replaced the substituent group that ground is described by the present invention.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1-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 (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Two obtained saturations of hydrogen atom are removed in term " alkylidene " expression from the linear chain or branched chain alkyl of saturation Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In some embodiments, sub- Alkyl group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；In other realities It applies in scheme, alkylidene group contains 0-4 carbon atom；Also in some embodiments, it is former to contain 0-3 carbon for alkylidene group Son；Also in other embodiments, alkylidene group contains 1-2 carbon atom.Alkylidene contains 0 carbon atom and refers to alkylene Base is not present, and is directly a singly-bound.The example of alkylidene includes, but are not limited to methylene (- CH2), ethylidene (- CH2CH2), isopropylidene (- CH (CH3)CH2) etc..
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention Replaced the substituent group stated comprising the positioning of " cis " and " tans ", or the positioning of " E " and " Z ".In one embodiment, Alkenyl group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another embodiment party In case, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH=CH2)、 Allyl (- CH2CH=CH2) etc..
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is tri- key of carbon-to-carbon sp.In one embodiment, alkynyl group includes 2-8 carbon atom；In another implementation In scheme, alkynyl group includes 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.Alkynyl The example of group includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), propinyl (- C ≡ C-CH3) etc. Deng.The alkynyl group can be optionally replaced one or more substituent groups described in the invention.
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more Replaced the substituent group that the present invention describes.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, positive propoxy ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, isopropoxy ,-OCH (CH3)2), 1- butoxy (n-BuO, n-butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, isobutyl oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, sec-butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, tert-butoxy ,-OC (CH3)3), 1- amoxy (n-pentyloxy ,-OCH2CH2CH2CH2CH3), 2- amoxy (- OCH (CH3) CH2CH2CH3), 3- amoxy (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourth Oxygroup (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " halogenated alkyl ", " halogenated alkenyl " or " halogenated alkoxy " indicate alkyl, and alkenyl or alkoxy base are by one Replaced a or multiple halogen atoms, such example includes, but is not limited to, trifluoromethyl (- CF3), trifluoromethoxy (- OCF3), bis-fluoro ethyls (- CH2CHF2,-CF2CH3,-CHFCH2F), trifluoroethyl (- CH2CF3,-CF2CH2F,-CFHCHF2), etc..
Term " hydroxy alkyl " and " hydroxy alkoxy base " indicate alkyl or alkoxy, depend on the circumstances, one or more Replaced hydroxyl group, wherein " hydroxy alkyl " can be used interchangeably with " hydroxyalkyl ", and such example includes, but and unlimited In methylol (- CH2OH), 2- ethoxy (- CH2CH2OH), 1- ethoxy (- CH (OH) CH3), 2- hydroxyl propyl- 2- base (- COH (CH3)2), 2- hydroxy-2-methyl propyl (- CH2COH(CH3)2), 3- hydroxypropyl (- CH2CH2CH2OH), 2- hydroxypropyl (- CH2CH(OH)CH3), hydroxymethoxy (- OCH2OH) etc..
Term " carbocylic radical " or " carbocyclic ring " indicate containing 3-12 carbon atom, monovalent or multivalence nonaromatic saturation Or part unsaturated monocycle, bicyclic or three-ring system.Carbon bicyclic group includes spiral shell carbon bicyclic group and condensed carbon bicyclic group, suitably Carbocylic radical group includes, but is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.The example of carbocylic radical group further comprises, but Be not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, Cyclohexyl, 1- cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, suberyl, ring are pungent Base, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..
Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.Bicyclic cycloalkyl includes spiral shell bicyclic alkyl, condensed-bicyclic alkyl and bridge bicyclic alkyl.In one embodiment, naphthenic base packet Containing 3-12 carbon atom；In another embodiment, naphthenic base includes 3-8 carbon atom；In yet another embodiment, naphthenic base Include 3-6 carbon atom.The example of naphthenic base includes, but are not limited to: C3-C6Naphthenic base specifically refers to cyclopropyl, cyclobutyl, ring Amyl and cyclohexyl.The group of naphthene base can be independently unsubstituted or by one or more substitution described in the invention Replaced base.
Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to comprising 3-12 annular atom, unit price or Multivalence, saturation or part it is unsaturated, nonaromatic monocyclic, bicyclic or tricyclic, wherein at least one annular atom be selected from nitrogen, Sulphur and oxygen atom.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base, and-CH2Group can optionally by-C (= O)-substitution, the sulphur atom of ring can optionally be oxidized to S- oxide, and the nitrogen-atoms of ring can optionally be oxidized to N- oxygen Compound.There are the heterocycle one or more tie points to be connected with the rest part of molecule.Heterocycle includes saturation The unsaturated heterocycle of heterocycle (Heterocyclylalkyl) and part.The example of heterocycle includes, but are not limited to: Oxyranyle, nitrogen Heterocycle butyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, Imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur rings penta It is base, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio Quinoline base, piperazinyl, dioxanes base, dithianyl, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia ring Heptane base, nitrogen list trioxepane, oxygen azepineBase (e.g., Isosorbide-5-Nitrae-oxygen azepineBase, 1,2- oxygen azepineBase), diazaBase is (e.g., 1,4- diazaBase, 1,2- diazaBase), dioxaBase (e.g., Isosorbide-5-Nitrae-dioxaBase, 1,2- dioxaBase), sulphur AzepineBase (such as 1,4- sulphur azepineBase, 1,2- sulphur azepineBase), indoline base, 1,2,3,4- tetrahydro isoquinolyl, 1,3- benzene And two dislike cyclopentadienyl, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, 2- azaspiro [4.4] nonyl, 1,6- dioxo spiro [4.4] nonyl, 2- azaspiro [4.5] decyl, 8- azaspiro [4.5] decyl, 7- azaspiro [4.5] decyl, 3- nitrogen Miscellaneous spiral shell [5.5] undecyl, 2- azaspiro [5.5] undecyl, octahydro -1H- isoindolyl, octahydro pentamethylene simultaneously [c] pyrroles Base, hexahydro furyl simultaneously [3,2-b] furyl and ten dihydro-isoquinoline bases, etc..- CH in heterocycle2Group is substituted by-C (=O)- Example include, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base and 3,5- dioxy piperazine Piperidinyl.The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base, 1,1- dioxothiomorpholinyl.Institute The heterocyclyl groups stated can be optionally replaced one or more substituent groups described in the invention.
Also in one embodiment, heterocycle is the 3-8 molecular heterocycle of original, is referred to comprising 3-8 annular atom Unit price or multivalence, saturation or part unsaturated nonaromatic monocycle or bicyclic, wherein at least one annular atom be selected from nitrogen, Sulphur and oxygen atom.Unless otherwise stated, 3-8 former molecular heterocycle can be carbon-based or nitrogen base, and-CH2Group can be with Optionally substituted by-C (=O)-.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can be optional Ground is oxidized to N- oxygen compound.Described 3-8 former molecular heterocycle has its of one or more tie points and molecule Remaining part split-phase connects.The example of 3-8 former molecular heterocycle includes, but are not limited to: azetidine, oxetanes, sulphur Azetidine, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, two Hydrogen furyl, tetrahydro-thienyl, dihydrothiophene, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro Thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane base, high piperazine base, height Piperidyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase and sulphur azepineBase.The 3-8 A molecular heterocyclyl groups of original can be optionally replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 4 molecular heterocycles of original, refers to the unit price comprising 4 annular atoms Or multivalence, saturation or part are unsaturated, nonaromatic monocycle, and it is former that wherein at least one annular atom is selected from nitrogen, sulphur and oxygen Replaced son.4 molecular heterocycles of original include the unsaturated heterocycle of heterocycle and part of 4 molecular saturations of original Base.Unless otherwise stated, 4 molecular heterocycles of original can be carbon-based or nitrogen base, and-CH2Group can be optionally by-C (=O)-substitution.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can be optionally oxidized to N- oxygen compound.There are 4 molecular heterocycles of original one or more tie points to be connected with the rest part of molecule. The example of 4 molecular heterocycles of original includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl, ring fourth Sulfuryl.4 molecular heterocyclyl groups of original can be optionally by one or more substituent groups described in the invention It is replaced.
In another embodiment, heterocycle is 5 molecular heterocycles of original, refers to the unit price comprising 5 annular atoms Or multivalence, saturation or part are unsaturated, nonaromatic monocycle, and it is former that wherein at least one annular atom is selected from nitrogen, sulphur and oxygen Son.5 molecular heterocycles of original include the unsaturated heterocycle of heterocycle and part of 5 molecular saturations of original.Unless In addition illustrate, 5 molecular heterocycles of original can be carbon-based or nitrogen base, and-CH2Group can be optionally by-C (=O)- Substitution.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxidation Close object.There are 5 molecular heterocycles of original one or more tie points to be connected with the rest part of molecule.5 originals The example of molecular heterocycle includes, but are not limited to: pyrrolidinyl, 1- pyrrolinyl, 2- pyrrolinyl, 3- pyrrolinyl, Pyrazolinyl, pyrazolidinyl, pyrazoline base, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, thiophane Base, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, isoxazolidinyl, isothiazole alkyl.- CH in heterocycle2Base Group includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl by-C (=the O)-example substituted.In heterocycle The example that sulphur atom is oxidized includes, but are not limited to 1,1- dioxotetrahydro thienyl.5 molecular heterocycles of original Base group can be optionally replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 6 molecular heterocycles of original, refers to the unit price comprising 6 annular atoms Or multivalence, saturation or part are unsaturated, nonaromatic monocycle, and it is former that wherein at least one annular atom is selected from nitrogen, sulphur and oxygen Son.6 molecular heterocycles of original include the unsaturated heterocycle of heterocycle and part of 6 molecular saturations of original.Unless In addition illustrate, 6 molecular heterocycles of original can be carbon-based or nitrogen base, and-CH2Group can be optionally by-C (=O)- Substitution.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxidation Close object.There are 6 molecular heterocycles of original one or more tie points to be connected with the rest part of molecule.6 originals The example of molecular heterocycle includes, but are not limited to: THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, Tetrahydro thiapyran base, piperidyl, dihydropyridine base, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene are disliked Alkyl, 1,2- oxazines base, 1,2- thiazinyl, hexahydro-pyridazine base.- CH in heterocycle2The example packet that group is substituted by-C (=O)- It includes, but is not limited to, 2- piperidone base and 3,5- dioxy piperazine piperidinyl.The example that sulphur atom is oxidized in heterocycle includes, but not It is limited to, 1,1- dioxothiomorpholinyl, 1,1- dioxo -2H- tetrahydro thiapyran base.6 molecular heterocycles of original Group can be optionally replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 7 molecular heterocycles of original, refers to the unit price comprising 7 annular atoms Or multivalence, saturation or part are unsaturated, nonaromatic monocycle, and it is former that wherein at least one annular atom is selected from nitrogen, sulphur and oxygen Son.7 molecular heterocycles of original include the unsaturated heterocycle of heterocycle and part of 7 molecular saturations of original.Unless In addition illustrate, 7 molecular heterocycles of original can be carbon-based or nitrogen base, and-CH2Group can be optionally by-C (=O)- Substitution.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxidation Close object.There are 7 molecular heterocycles of original one or more tie points to be connected with the rest part of molecule.7 originals The example of molecular heterocycle includes, but are not limited to: high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptane Base, oxygen azepineBase (1,4- oxygen azepineBase, 1,2- oxygen azepineBase), diazaBase (1,4- diazaBase, 1,2- phenodiazine It is miscellaneousBase), dioxaBase (1,4- dioxaBase, 1,2- dioxaBase), sulphur azepineBase (1,4- sulphur azepineBase, 1,2- Sulphur azepineBase).- CH in heterocycle2Group includes, but are not limited to 7- oxo aza ring heptan by-C (=O)-example substituted Alkyl.The example that sulphur atom is oxidized in heterocycle includes, but are not limited to 1,1- dioxo thia cycloheptyl alkyl.Described 7 Former molecular heterocyclyl groups can be optionally replaced one or more substituent groups described in the invention.
In one embodiment, heterocycle is 3-6 former molecular heterocycle, refers to the list comprising 3-6 annular atom Valence or multivalence, saturation or the unsaturated nonaromatic monocycle in part, it is former that wherein at least one annular atom is selected from nitrogen, sulphur and oxygen Son.Unless otherwise stated, 3-6 former molecular heterocycle can be carbon-based or nitrogen base, and-CH2Group can be optionally It is substituted by-C (=O)-.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can be optionally by oxygen It is melted into N- oxygen compound.The former molecular heterocycle of described 3-6 has its remaining part of one or more tie points and molecule Split-phase connects and can be optionally replaced one or more substituent group described in the invention.
In one embodiment, heterocycle is 4-6 former molecular heterocycle, refers to the list comprising 4-6 annular atom Valence or multivalence, saturation or the unsaturated nonaromatic monocycle in part, it is former that wherein at least one annular atom is selected from nitrogen, sulphur and oxygen Son.Unless otherwise stated, 4-6 former molecular heterocycle can be carbon-based or nitrogen base, and-CH2Group can be optionally It is substituted by-C (=O)-.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can be optionally by oxygen It is melted into N- oxygen compound.The former molecular heterocycle of described 4-6 has its remaining part of one or more tie points and molecule Split-phase connects and can be optionally replaced one or more substituent group described in the invention.
In one embodiment, heterocycle is the monocyclic heterocycles base of 4-7 former molecular saturation, is referred to comprising 4-7 The unit price of annular atom or multivalence, saturation, nonaromatic monocycle, it is former that wherein at least one annular atom is selected from nitrogen, sulphur and oxygen Son.Unless otherwise stated, the monocyclic heterocycles base of 4-7 former molecular saturation can be carbon-based or nitrogen base, and-CH2Group can Optionally to be substituted by-C (=O)-.The sulphur atom of ring can optionally be oxidized to S- oxide, and the nitrogen-atoms of ring can appoint Selection of land is oxidized to N- oxygen compound.The monocyclic heterocycles base of the former molecular saturation of described 4-7 has one or more connect Contact is connected with the rest part of molecule.The monocyclic heterocycles base of the former molecular saturation of described 4-7 includes 4 atom compositions The monocyclic heterocycles base of saturation, the monocyclic heterocycles bases of 5 molecular saturations of original, 6 molecular saturations of original monocyclic heterocycles The monocyclic heterocycles base of base and 7 molecular saturations of original.The monocyclic heterocycles base group of the former molecular saturation of described 4-7 can With optionally replaced one or more substituent groups described in the invention.
The example of the monocyclic heterocycles base of 4-7 former molecular saturation includes, but are not limited to: 4 molecular saturations of original Monocyclic heterocycles base, such as azelidinyl, oxetanylmethoxy, thietanyl；The monocyclic heterocycles of 5 molecular saturations of original Base, such as pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuran base, tetrahydro-thienyl, 1,3- dioxy cyclopenta, two sulphur rings penta Base, isoxazolidinyl, isothiazole alkyl；The monocyclic heterocycles base of 6 molecular saturations of original, such as 1,2-oxazines base, 1,2-thiazines Base, hexahydro-pyridazine base, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, Dithianyl, thiophene oxane base；The monocyclic heterocycles base of 7 molecular saturations of original, such as high piperazine base, homopiperidinyl, oxepane Alkyl, thia cycloheptyl alkyl, oxygen azepineBase (1,4- oxygen azepineBase, 1,2- oxygen azepineBase), diazaBase (1,4- phenodiazine It is miscellaneousBase, 1,2- diazaBase), dioxaBase (1,4- dioxaBase, 1,2- dioxaBase), sulphur azepineBase (1,4- Sulphur azepineBase, 1,2- sulphur azepineBase).- CH in the monocyclic heterocycles base heterocycle of 4-7 former molecular saturation2Group quilt- C (=O)-substitution example include, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base and 3,5- dioxy piperazine piperidinyl.The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base, 1,1- dioxo Thiophane, 1,1- dioxotetrahydro thiapyran, 1,1- dioxothiomorpholinyl.
Term " condensed-bicyclic " and " condensed-bicyclic base " are used interchangeably here, all refer to unit price or multivalence saturation or Part is unsaturated but nonaromatic ring system, and two rings in the ring system share a key.Such system can wrap Containing independent or conjugation unsaturated system, but its nuclear structure does not include aromatic rings or heteroaromatic (but aromatic group can Using as substituent group thereon).
Term " spiral shell bicyclic group " and " spiral shell is bicyclic " are used interchangeably here, and the saturation for referring to unit price or multivalence or part are not Saturated ring system, one of ring is originating from specific ring carbon atom on another ring, and two rings only share this original Son.For example, the ring system (ring U and U ') of a saturation is referred to as " condensed-bicyclic ", and ring V and ring as described in following formula a U shares a carbon atom, referred to as " spiral shell is bicyclic ".Each ring in condensed-bicyclic base and spiral shell bicyclic group can be carbocylic radical or Heterocycle, and each ring is optionally replaced one or more substituent groups described in the invention.
Term " Heterocyclylalkyl " refers to saturation monocycle, the bicyclic or tricyclic of the unit price containing 3-12 annular atom or multivalence System, wherein at least one annular atom are selected from nitrogen, sulphur or oxygen atom.
Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original, and 1,2,3,4- tetralyl It is the molecular carbocylic radical group of 10 originals.
Contain one or more degrees of unsaturation in " unsaturated " the expression group of term as used in the present invention.
Term " hetero atom " refers to O, S, N, P and Si, the form including any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole base N), NH (as the NH in pyrrolidinyl) or NR (NR in pyrrolidinyl replaced as N-).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " azido " or " N3" indicate a nitrine structure.This group can be connected with other groups, for example, Triazonmethane (MeN can be connected to form with a methyl3), or phenylazide (PhN is connected to form with a phenyl3)。
Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 original Molecular ring, and there are one or more tie points to be connected with the rest part of molecule.Term " aryl " can be with term " fragrance Ring " is used interchangeably.The example of aryl group may include phenyl, naphthalene and anthryl.The aryl group can individually optionally Replaced one or more substituent groups described in the invention.
Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom, Bicyclic and three-ring system, wherein at least one ring are aromatic, and at least one aromatic rings includes one or more hetero atoms, Wherein each ring system includes 5-7 former molecular ring, and has one or more tie points to be connected with molecule rest part. Term " heteroaryl " can be used interchangeably with term " hetero-aromatic ring " or " heteroaromatics ".In one embodiment, heteroaryl For heteroatomic 5-12 former molecular heteroaryl for being independently selected from O, S and N comprising 1,2,3 or 4.In another implementation case In, heteroaryl is the heteroatomic 5-10 former molecular heteroaryl that O, S and N are independently selected from comprising 1,2,3 or 4.Another In one embodiment, heteroaryl is former molecular miscellaneous comprising 1,2,3 or 4 heteroatomic 5-6 for being independently selected from O, S and N Aryl.The heteroaryl groups are optionally replaced one or more substituent groups described in the invention.
The example of 5-12 former molecular heteroaryl groups includes, but is not limited to these following bicyclic heteroaryls: Benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyl, 3- indyl, 4- indyl, 5- indoles Base, 6- indyl, 7- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), indazolyl (such as 3- indazolyl, 4- indazolyl, 5- indazolyl, 6- indazole Base, 7- indazolyl), imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [4,3-c] pyridyl group, pyrazoles And [3,4-b] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] Pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridyl group, etc..5-12 atom The example of the heteroaryl groups of composition further includes 5-6 former molecular single ring heteroaryl group, and the example includes, but and unlimited In monocycle below, furyl (such as 2- furyl, 3- furyl), imidazole radicals (such as 1- imidazole radicals, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals), isoxazolyl (such as 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl), oxazolyl (such as 2- oxazolyl, 4- dislike Oxazolyl, 5- oxazolyl), pyrrole radicals (such as 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals), pyridyl group (such as 2- pyridyl group, 3- pyridine Base, 4- pyridyl group), pyriconyl, pyrimidine radicals (such as 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals), pyrimidine ketone group, hybar X Base, pyridazinyl (such as 3- pyridazinyl, 4- pyridazinyl), pyrazinyl (such as 2- pyrazinyl, 3- pyrazinyl), thiazolyl (such as 2- thiazolyl, 4- thiazolyl, 5- thiazolyl), tetrazole radical (such as 5- tetrazole radical), triazolyl (such as 2- triazolyl and 5- triazolyl), thienyl (such as 2- thienyl, 3- thienyl), pyrazolyl (such as 1- pyrazolyl, 3- pyrazolyl, 4- pyrazolyl, 5- pyrazolyl), pyrazoline ketone group, Isothiazolyl, 1,2,3- oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,3- triazolyl, 1,2,3- are thio Di azoly, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, pyrazinyl and cyanuro 1,3,5 etc..
Term " oxazolyl " refers to that containing at least two hetero atom and wherein at least one is nitrogen-atoms, by 5 or 9 Former molecular heteroaromatic ring systems.The example of oxazolyl include, but is not limited to pyrazolyl, imidazole radicals, oxazolyl, isoxazolyl, Oxadiazoles base, thiazolyl, isothiazolyl, thiadiazolyl group, di azoly, triazolyl, indazolyl, Pyrazolopyridine base and benzo [d] Imidazole radicals.
No matter term " carboxyl " is single use or is used in conjunction with other terms, such as " carboxyalkyl ", expression-CO2H；Term No matter " carbonyl " is single use or is used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", indicate-(C=O)-.
Term " alkyl amino " or " alkylamino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino Group is separately replaced one or two alkyl group.Wherein, some embodiments are that alkylamino is one or two A C1-C12Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms.In other embodiments, alkylamino It is one or two C1-C6Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms.In other embodiments In, alkylamino is one or two C1-C4Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms.Also another In outer some embodiments, alkylamino is one or two C1-C3Alkyl is connected to the alkyl ammonia of the lower level formed on nitrogen-atoms Base group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and the example of alkylamino includes, but not It is limited to, N- methylamino (- NHCH3), N- ethylamino, N, N- dimethylamino (- NH (CH3)2), N, N- lignocaine, N- ethyl third Base -2- amino etc..
Term " fragrant amino " indicates amino group replaced one or two aryl group, and such example includes, but It is not limited to N- phenylamino.Some of embodiments are that the aromatic ring in fragrant amino can be further substituted.
Term " aminoalkyl " includes the C replaced one or more amino1-C12Linear or branched alkyl group group.? In some embodiments, aminoalkyl is the C replaced one or more amino groups1-C12Alkyl；In other embodiment party In case, aminoalkyl is the C replaced one or more amino groups1-C6" aminoalkyl of lower level ", in other realities It applies in scheme, aminoalkyl is the C replaced one or more amino groups1-C4Alkyl；Also in other embodiments, Aminoalkyl is the C replaced one or more amino groups1-C3Alkyl.The example of aminoalkyl includes, but is not limited to, Aminomethyl (- CH2NH2), aminoethyl (- CH2CH2NH2,-CH(NH2)CH3), aminopropyl, ammonia butyl and ammonia hexyl.
As described in the invention, it draws a key and substituent group is connected to the ring system of ring being centrally formed (such as formula b institute Show) it represents substituent group any substitutive position in the ring system and can replace.For example, formula b represent substituent group can be in C Any possible substituted position on ring and D ring, as shown in formula c~formula g.
As described in the invention, two connections are keyed to ring system (as shown in the formula h) generation formed on the center of ring Two connecting keys of table can be connected any attachable position in ring system with molecule rest part, and two connecting pins Point K and K ' can be exchanged with each other.The position that formula h represents two any possible connections on W ring can be with molecule rest part It is connected.
Such as shown in following formula j, two connect the center for being keyed to piperidine ring, and representing two connecting keys can be in piperazine The position that any two can connect in phenazine ring is connected with the rest part of molecule, and even each K of connection end point2And K22Being can With what is be exchanged with each other.Formula j indicates that piperidine ring M can be connected in the position that any two can connect with molecule rest part, such as Shown in formula j-1~j-12.
When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used to block or protect the functionality of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group can refer to document: T W.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.It is completely begged for about pro-drug By following documents can be referred to: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.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 product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.
" inflammatory disease " used in the present invention refers to excessive inflammation caused by excessive or out of control inflammatory responses Property symptom, host tissue damage or function of organization any disease for losing, disorder or symptom." inflammatory disease " also refers to by leucocyte The pathologic state that inflow and/or Neutrophil chemotaxis mediate.
" inflammation " used in the present invention refers to by tissue damaged or topical protective response caused by destroying, it is for breaking Tissue that is bad, diluting or separate (isolation) harmful substance and be damaged.Inflammation is flowed into leucocyte and/or neutrophil cell becomes The property changed has significant connection.Inflammation can produce in the infection and non-infectious mode of pathogenic organism and virus, such as heart Wound or Reperfu- sion after muscle infarction or apoplexy, to the immune response and autoimmune response of exotic antigen.Therefore, this can be used The inflammatory disease of disclosure of the invention compound treatment includes: to react with specific system of defense and non-specific defense system reaction Relevant disease.
" specific system of defense " refers to that the component of immune system reacts to the presence of specific antigen.Result from specificity The example of the inflammation of system of defense reaction includes classical response, autoimmune disease and the delayed type hypersensitivity, DTH to exotic antigen Response (cell-mediated by T-).The repulsion of chronic inflammatory disease, transplanting solid tissue and organ is (such as kidney and bone-marrow transplantation Repel) and graft versus host disease (GVHD) be other examples of specific system of defense inflammatory reaction.
" autoimmune disease " used in the present invention refers to and body fluid or cell-mediated to body itself component response The set of any disease of relevant tissue damage.
" allergy " used in the present invention refers to that any symptom for generating allergy, histologic lesion or function of organization lose.Such as " arthritis disease " used in the present invention refers to any characterized by being attributable to various etiologic etiological arthritis damages Disease." dermatitis " refers to the skin disease characterized by being attributable to various etiologic etiological scytitis as used in the present invention Large family in any one." graft rejection " refers to the funeral of the function of transplanting or surrounding tissue as used in the present invention Tissue is transplanted in the confrontation that mistake, pain, swelling, leukocytosis and decrease of platelet are characterized, such as organ or cell (such as marrow) Any immune response.Treatment method of the invention includes the method for treating disease relevant to inflammatory cell activation.
Term " cancer " and " cancer " refer to or describe the physiology in patient usually characterized by cell growth out of control Illness." tumour " includes one or more cancer cells.The example of cancer includes but is not limited to cancer (carcinoma), lymthoma, embryo Cytoma, sarcoma and leukaemia or malignant lymph proliferative disease (lymphoid malignancies).Such cancer is more Specific example includes squamous cell carcinoma (such as epithelium squamous cell carcinoma), lung cancer (including Small Cell Lung Cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of lung and lung carcinoma squamosum), peritoneal cancer, hepatocellular carcinoma (hepatocellular cancer), gastric cancer (gastric Or stomach cancer) (including human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical carcinoma, oophoroma, liver cancer (liver Cancer), bladder cancer, hepatoma (hepatoma), breast cancer, colon and rectum carcinoma, colorectal cancer, carcinoma of endometrium or Uterine cancer, salivary-gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma of vulva, thyroid gland Cancer, liver cancer (hepatic carcinoma), cancer of anus, carcinoma of penis and head and neck cancer.
The description of the compound of the present invention
The invention discloses a kind of novel compounds, can be used as protein kinase activity, especially jak kinase, FLT3 swashs Enzyme and the active inhibitor of Aurora A.Compound as kinases inhibitor can be used for treating and unsuitable albumen Kinase activity, is especially unsuitable jak kinase, FLT3 kinases and the relevant disease of Aurora A activity, for example, treatment and Prevention is related to the disease that the jak kinase, FLT3 kinases and Aurora A of signal path mediate.Such disease includes proliferative Disease, autoimmune disease, anaphylactia, inflammatory disease, graft rejection and their complication.Particularly, of the invention Compound can be used to treat following disease, such as cancer, polycythemia vera, primary thrombocytosis, marrow Fibrosis, property myelocytic leukemia, acute lymphoblastic leukemia, chronic granulocytic leukemia (CML), chronic obstructive Lung disease (COPD), asthma, systemic loupus erythematosus, skin lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, Psoriasis, type-1 diabetes mellitus, respiratory anaphylactic disease, nasosinusitis, eczema, morbilli, food hypersenstivity, insect venom allergies, inflammatory Enteropathy, Crohn disease, rheumatoid arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue move Plant repulsion, cell transplant rejection, etc..
In one embodiment, disclosed compound of present invention, which can be shown, shows stronger suppression to one or more protein kinases System activity.
On the one hand, the present invention relates to the alloisomerisms of one kind compound as shown in formula (I) compound represented or formula (I) Body, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein, W, Ar, Z, B and R1With meaning as described in the present invention.
In one embodiment, in some embodiments, W is the monocyclic heterocycles base base of 4-7 former molecular saturation Group, optionally by 1,2,3,4 or 5 R2Replaced group；
Ar is C6-C12Aryl or 5-12 former molecular heteroaryl, wherein Ar is optionally by 1,2,3,4 or 5 R8Base Replaced group；
Z is H, C1-C12Alkyl, C3-C12Naphthenic base or 3-12 former molecular heterocycle, wherein each C1-C12Alkane Base, C3-C12The former molecular heterocycle of naphthenic base and 3-12 is individually optionally by 1,2,3,4 or 5 R3Replaced group；
B is pyrazolyl, imidazole radicals or indazolyl, wherein B is optionally by 1,2,3,4 or 5 R4Replaced group；
R1For H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Alkoxy, C1-C12Alkyl amino, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl, 5-12 original are molecular miscellaneous Aryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb、-(CR6R7)nC (=O) R5、-(CR6R7)nOC (=O) R5、-O(CR6R7)n- R5、-N(Rc) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc)C (=O) NRaRb、-(CR6R7)nS (=O)mR5、-N(Rc) S (=O)mR5Or-S (=O)mNRaRb, wherein each C1-C12Alkane Base, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Alkoxy, C1-C12Alkyl amino, C3-C12Naphthenic base, 3-12 original are molecular Heterocycle, C6-C12The former molecular heteroaryl of aryl and 5-12 is individually optionally by 1,2 or 3 R9Replaced group；
Each R2、R3、R4And R8It is separately H, F, Cl, Br, I, NO2、CN、N3、C1-C12Alkyl, C2-C12Alkenyl, C2- C12Alkynyl, C1-C12Alkoxy, C1-C12Alkyl amino, C1-C12Hydroxy alkyl, C3-C12Naphthenic base, C6-C12Aryl, 3-12 original Molecular heterocycle, 5-12 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb、-(CR6R7)nC (= O)R5、-(CR6R7)nOC (=O) R5、-O(CR6R7)n-R5、-N(Rc) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc) C (=O) NRaRb、-(CR6R7)nS (=O)mR5、-N(Rc) S (=O)mR5Or-S (=O)mNRaRb, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Alkoxy, C1-C12Alkyl ammonia Base, C1-C12Hydroxy alkyl, C3-C12Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle and 5-12 atom composition Heteroaryl individually optionally by 1,2,3,4 or 5 R9Replaced group；
Each R5It independently is H, C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Halogenated alkyl, C1-C12Alcoxyl Base, C1-C12Hydroxy alkyl, C1-C12Alkyl amino, C1-C12Aminoalkyl, C3-C12Naphthenic base, C6-C12Aryl, 3-12 atom The heterocycle of composition or 5-12 former molecular heteroaryl, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C1-C12Halogenated alkyl, C1-C12Alkoxy, C1-C12Hydroxy alkyl, C1-C12Alkyl amino, C1-C12Aminoalkyl, C3-C12 Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle and the 5-12 molecular heteroaryl of original it is individually optional by 1, 2 or 3 R9Replaced group；
Each R6And R7It is separately H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C3-C12Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle or 5-12 former molecular heteroaryl, or R6、R7, and together with the carbon atom that they are connected, form C3-C12Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle Base or 5-12 former molecular heteroaryl groups, wherein above-mentioned each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12 Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle and the 5-12 molecular heteroaryl of original it is individually optional by 1, 2 or 3 R9Replaced group；
Each R9It independently is F, Cl, Br, I, CN, NO2、N3、NH2、OH、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Halogenated alkyl, C1-C12Alkoxy, C1-C12Hydroxy alkyl, C1-C12Alkyl amino, C1-C12Aminoalkyl, C3-C12Cycloalkanes Base, C6-C12Aryl, 3-12 former molecular heterocycle, 5-12 former molecular heteroaryl ,-NH (CH2)n-(C3-C12Ring Alkyl) ,-NH (CH2)n-(C6-C12Aryl) ,-NH (CH2)n(3-12 former molecular heterocycle) ,-NH (CH2)n-(5-12 A molecular heteroaryl of original) ,-N [(CH2)n-(C3-C12Naphthenic base)]2、-N[(CH2)n-(C6-C12Aryl)]2、-N[(CH2)n- (3-12 former molecular heterocycle)]2、-N[(CH2)n(5-12 former molecular heteroaryl)]2、-O(CH2)n-(C3-C12 Naphthenic base) ,-O (CH2)n-(C6-C12Aryl) ,-O (CH2)n(3-12 former molecular heterocycle) or-O (CH2)n-(5-12 A molecular heteroaryl of original)；
Each Ra、RbAnd RcIt is separately H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base ,-(C1- C4Alkylidene)-(C3-C6Naphthenic base), 3-6 former molecular heterocycle ,-(C1-C4Alkylidene)-(3-6 is former molecular miscellaneous Ring group), C6-C12Aryl ,-(C1-C4Alkylidene)-(C6-C12Aryl), 5-12 former molecular heteroaryl or-(C1-C4Alkylene Base)-(5-12 former molecular heteroaryl) or RaAnd Rb, and together with the nitrogen-atoms that is connected with them, form 3-8 atom The heterocyclyl groups of composition, wherein above-mentioned each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base ,-(C1-C4It is sub- Alkyl)-(C3-C6Naphthenic base), 3-6 former molecular heterocycle ,-(C1-C4Alkylidene)-(3-6 former molecular heterocycle Base), C6-C10Aryl ,-(C1-C4Alkylidene)-(C6-C12Aryl), 5-12 former molecular heteroaryl ,-(C1-C4Alkylene Base)-(5-12 former molecular heteroaryl) and the 3-8 molecular heterocyclyl groups of original are optionally by 1,2,3 or 4 independence Selected from F, Cl, Br, CN, N3、OH、NH2、C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy or C1-C6Alkyl amino takes Replaced Dai Ji；
Each n independently is 0,1,2,3 or 4；With
Each m independently is 1 or 2.
In other embodiments, Ar is phenyl or the 5-6 molecular heteroaryl of original, wherein Ar optionally by 1, 2,3 or 4 R8Replaced group.
In some embodiments, Ar is phenyl, furyl, imidazole radicals, isoxazolyl, oxazolyl, pyrrole radicals, pyridine Base, pyriconyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, triazol radical, thienyl, Pyrazolyl, oxygen phenodiazine oxazolyl, sulphur phenodiazine oxazolyl, pyrazinyl or triazine radical, wherein Ar is optionally by 1,2 or 3 R8Group is taken Generation.
In other embodiments, Z H, C1-C6Alkyl, C3-C6Naphthenic base or 3-6 former molecular heterocycle, Wherein, each C1-C6Alkyl, C3-C6The former molecular heterocycle of naphthenic base and 3-6 is individually optionally by 1,2 or 3 R3Base Replaced group.
In some embodiments, Z H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl.
In another embodiment, R1For H, F, Cl, Br, CN, N3、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6 Alkoxy, C1-C6Alkyl amino, C3-C6Naphthenic base, 3-6 former molecular heterocycle ,-(CR6R7)n-ORc、-(CR6R7)n- NRaRb、-(CR6R7)nC (=O) R5、-(CR6R7)nOC (=O) R5、-O(CR6R7)n-R5、-N(Rc) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRbOr-S (=O)mNRaRb, wherein each C1-C6Alkyl, C2-C6Alkenyl, C2-C6 Alkynyl, C1-C6Alkoxy, C1-C6Alkyl amino, C3-C6The former molecular heterocycle of naphthenic base and 3-6 individually optionally by 1, 2 or 3 R9Replaced group.
In some embodiments, R1For H, F, Cl, Br, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy Base, ethyoxyl, positive propoxy, isopropoxy, methylamino, dimethylamino, piperidyl, pyrrolidinyl, morpholinyl or piperazinyl, In, each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, first ammonia Base, dimethylamino, piperidyl, pyrrolidinyl, morpholinyl and piperazinyl it is individually optional by 1,2 or 3 R9Replaced group.
In other embodiments, each R2、R4And R8It is separately H, F, Cl, Br, CN, N3、NO2、C1-C6Alkane Base, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkyl amino, C1-C6Hydroxy alkyl, C3-C6Naphthenic base, 3-6 Former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb、- (CR6R7)nC (=O) R5、-(CR6R7)nOC (=O) R5、-O(CR6R7)n-R5、-N(Rc) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRbOr-S (=O)mNRaRb, wherein each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkyl amino, C1-C6Hydroxy alkyl, C3-C6Naphthenic base, 3-6 former molecular heterocycle, phenyl and 5-6 former molecular heteroaryl is individually optionally by 1,2 or 3 R9Replaced group.
In some embodiments, each R2、R4And R8It is separately H, F, Cl, CN, methyl, ethyl, n-propyl, different Propyl, cyclopropyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, lignocaine, Methylol, 1- ethoxy, 2- ethoxy, 3- hydroxypropyl, 2- hydroxypropyl, 2- hydroxy-2-methyl propyl, 2- hydroxyl propyl- 2- base, C3-C6Naphthenic base, 4-6 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(CR6R7)n-ORc、- (CR6R7)n-NRaRb、-(CR6R7)nC (=O) R5、-(CR6R7)nOC (=O) R5、-N(Rc) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRbOr-S (=O)mNRaRb, wherein each methyl, ethyl, n-propyl, isopropyl, cyclopropyl Base, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, lignocaine, methylol, 1- Ethoxy, 2- ethoxy, 3- hydroxypropyl, 2- hydroxypropyl, 2- hydroxy-2-methyl propyl, 2- hydroxyl propyl- 2- base, C3-C6Cycloalkanes Base, 4-6 former molecular heterocycle, phenyl and the 5-6 molecular heteroaryl of original it is individually optional by 1,2 or 3 R9Base Replaced group.
In other embodiments, each R5It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6It is halogenated Alkyl, C1-C6Alkoxy, C1-C6Hydroxy alkyl, C1-C6Alkyl amino, C1-C6Aminoalkyl, C3-C6Naphthenic base, phenyl, 3-6 A molecular heterocycle of original or 5-6 former molecular heteroaryl, wherein each C1-C6Alkyl, C2-C6Alkenyl, C2-C6 Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Hydroxy alkyl, C1-C6Alkyl amino, C1-C6Aminoalkyl, C3-C6Ring Alkyl, phenyl, 3-6 former molecular heterocycle and the 5-6 molecular heteroaryl of original it is individually optional by 1,2 or 3 R9 Replaced group.
In some embodiments, each R6And R7It is separately H, F, Cl, Br, CN, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, phenyl, 3-6 former molecular heterocycle or 5-6 former molecular heteroaryl or R6、 R7, and the carbon atom being connected with them is formed together C3-C6Naphthenic base, phenyl, 3-6 former molecular heterocycle or 5-6 are former Molecular heteroaryl groups, wherein above-mentioned each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, phenyl, 3-6 The molecular heterocycle of a original and 5-6 former molecular heteroaryl it is individually optional by 1,2 or 3 R9Replaced group.
In other embodiments, each R9It independently is F, Cl, Br, CN, N3、OH、NH2、C1-C6Alkyl, C2-C6Alkene Base, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Hydroxy alkyl, C1-C6Alkyl amino, C1-C6Aminoalkyl, C3-C6Naphthenic base, phenyl, 3-6 former molecular heterocycle, 5-6 former molecular heteroaryl ,-NH (CH2)n-(C3-C6Ring Alkyl) ,-NH (CH2)nPhenyl ,-NH (CH2)n(3-6 atom forms heterocycle) ,-NH (CH2)n(5-6 former molecular Heteroaryl) ,-N [(CH2)n-(C3-C6Naphthenic base)]2、-N[(CH2)nPhenyl]2、-N[(CH2)n(3-6 former molecular miscellaneous Ring group)]2、-N[(CH2)n(5-6 former molecular heteroaryl)]2、-O(CH2)n-(C3-C6Naphthenic base) ,-O (CH2)nBenzene Base ,-O (CH2)n(3-6 former molecular heterocycle) or-O (CH2)n(5-6 former molecular heteroaryl).
In some embodiments, each Ra、RbAnd RcIt is separately H, C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C6Naphthenic base ,-(C1-C2Alkylidene)-(C3-C6Naphthenic base), 3-6 former molecular heterocycle ,-(C1-C2Alkylidene)- (3-6 former molecular heterocycle), phenyl ,-(C1-C2Alkylidene)-phenyl, 5-6 former molecular heteroaryl or-(C1- C2Alkylidene)-(5-6 former molecular heteroaryl) or Ra、Rb, and together with the nitrogen-atoms that is connected with them, form 3-6 Former molecular heterocyclyl groups, wherein above-mentioned each C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C6Naphthenic base ,-(C1- C2Alkylidene)-(C3-C6Naphthenic base), 3-6 former molecular heterocycle ,-(C1-C2Alkylidene)-(3-6 is former molecular miscellaneous Ring group), phenyl ,-(C1-C2Alkylidene)-phenyl, 5-6 former molecular heteroaryl and-(C1-C2Alkylidene)-(5-6 is former Molecular heteroaryl) optionally F, Cl, CN, N are independently selected from by 1,2 or 33、OH、NH2、C1-C4Alkyl, C1-C4Alkyl halide Base, C1-C4Alkoxy or C1-C4Replaced the substituent group of alkyl amino.
In other embodiments, W is one of the heterocyclyl groups that following heterocyclic compound is formed:
Its In, heterocycle shown in formula (W-1)~(W-20) is formed by each heterocyclyl groups individually optionally by 1,2 or 3 R2Group institute Replace.
In some embodiments, W is one of minor structure below:
Wherein, each subformula shown in above-mentioned formula (W-31)~(W-65) individually optionally by 1,2 or 3 R2Replaced group.
In other embodiments, B is following subformula:
Wherein, formula (H), (I), (J), (K), (L), (M), (N), (O), minor structure shown in (P) or (Q) is individually optionally by 1,2 or 3 R4Replaced group.
Also in some embodiments, the present invention relates to the compound of one of or its stereoisomer, mutually Tautomeric, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, but it is not limited to these Compound:
Unless otherwise mentioned, the stereoisomer of compound shown in formula (I), tautomer, solvate, metabolism produce Object, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
Disclosed compound of present invention can containing asymmetric or chiral centre, therefore can different stereoisomer forms deposit ?.The present invention is directed to all stereoisomer forms of compound shown in formula (I), including but not limited to diastereoisomer, Enantiomter, atropisomer and geometry (or conformation) isomers and their mixture such as racemic mixture, become Component part of the invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.
Compound shown in formula (I) can exist with different tautomeric forms, and all these tautomers, As is described in the claims, it is included within the scope of the present invention.
Compound shown in formula (I) can exist in a salt form.In one embodiment, the salt refers to and can pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refer to substance or composition must with other ingredients comprising preparation and/or use it The mammal for the treatment of is compatible chemically and/or in toxicology.In another embodiment, the salt, which is not necessarily, pharmaceutically may be used The salt of receiving can be and be used to prepare and/or purify compound shown in formula (I) and/or for separating compound shown in this formula (I) Enantiomer intermediate.
Pharmaceutical acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Object/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.
The inorganic acid that salt can be obtained by its derivative includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.
The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
Can obtain the inorganic base of salt by its derivative includes, for example, ammonium salt and periodic table I race to XII race metal.? In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
Can obtain the organic base of salt by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.
In addition, compound disclosed by the invention, the salt including them, in the form of their hydrate or can also include it The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, for their crystallization.Disclosed compound of present invention can be with pharmacy Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations And unsolvated form.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as3H、14C and18Those of F compound, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for being metabolized research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.18The compound of F enrichment to PET or It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art It is substituted described by the embodiment and preparation process in routine techniques or the present invention known using suitable isotope labeling reagent former Carry out used unmarked reagent to prepare.
In addition, higher isotope especially deuterium (that is,2H or D) substitution can provide certain treatment advantages, these advantages are By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substituent group of compound shown in formula (I).Isotope enrichment factor can be used To define the concentration of such higher isotope especially deuterium.Term " isotope enrichment factor " used in the present invention refers to meaning Determine the ratio between the isotope abundance of isotope and natural abundance.If the substituent group of the compounds of this invention is designated as deuterium, The compound at least 3500 (52.5% deuterium incorporation at each specified D-atom), at least for each specified D-atom 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutical solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution2O, acetone-d6、 DMSO-d6Those of solvate.
On the other hand, the present invention relates to the intermediates of compound shown in preparation formula (I).
On the other hand, the present invention relates to the methods of preparation, separation and the purifying of compound shown in formula (I).
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or their combination.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
On the other hand, the present invention relates to one or more protein kinases are treated, such as jak kinase, FLT3 kinases and Aurora The method of disease or disorder that kinases is adjusted, the treatment method include giving the of the invention of mammalian effective amount to disclose chemical combination Object or pharmaceutical composition.In some embodiments, the disease or disorder are selected from proliferative diseases, autoimmune disease, mistake Quick property disease, inflammatory disease or graft rejection.
On the other hand, the present invention relates to use the compounds of this invention or medicine composite for curing disease disclosed by the invention or Disorder, the disease or disorder are selected from proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease or transplanting row Reprimand.
On the other hand, the present invention relates to compounds disclosed by the invention or pharmaceutical composition in preparation treatment disease or disorder Drug purposes, the disease be selected from proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease or transplanting row Reprimand.
On the other hand, the purposes of drug, institute are prepared the present invention relates to compound disclosed by the invention or pharmaceutical composition State activity of the drug for regulatory protein kinases.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, and it includes listed compounds in disclosed compound of present invention or embodiment； With pharmaceutically acceptable auxiliary material, excipient, carrier, solvent or their combination.Change in pharmaceutical composition disclosed by the invention The amount for closing object, which refers to, can effectively detect the amount for inhibiting biological sample or patient's body protein kinase.
It will also be appreciated that certain compounds of the invention can exist for treating in a free form, or if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
Drug pharmaceutical compositions disclosed by the invention can prepare and be packaged as (bulk) form in bulk, wherein extractable safety A effective amount of formula (I) compound represented, then gives patient with powder or syrup form.Alternatively, drug disclosed by the invention Composition can prepare and be packaged as unit dosage forms, wherein each physically discrete unit contains formula (I) institute of safe and effective amount The compound shown.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention can usually contain, for example, 0.5mg to 1g, Or the compound disclosed by the invention of 1mg to 700mg or 5mg to 100mg.
" pharmaceutically acceptable auxiliary material " used in the present invention means relevant to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Every kind of auxiliary material must be other at split-phase with pharmaceutical composition in mixing Hold, interaction the effect of to avoid will be greatly reduced disclosed compound of present invention when administering to a patient and to will lead to be not medicine The interaction of acceptable pharmaceutical composition on.In addition, every kind of auxiliary material must be it is pharmaceutically acceptable, for example, having Sufficiently high purity.
Suitable pharmaceutically acceptable auxiliary material can be different according to selected specific dosage form.In addition, can combined according to them Specific function in object selects pharmaceutically acceptable auxiliary material.For example, may be selected to can help to produce the certain of equal one dosage type low temperature Pharmaceutically acceptable auxiliary material.The certain pharmaceutically acceptable auxiliary materials that can help to produce stabilizer type may be selected.It may be selected Facilitate to carry or transport disclosed compound of present invention when administering to a patient from an organ of body or partially to the another of body One organ or partial certain pharmaceutically acceptable auxiliary materials.The certain pharmaceutically acceptable of enhancing patient compliance may be selected Auxiliary material.
Suitable pharmaceutically acceptable auxiliary material includes following kind of auxiliary material: diluent, filler, adhesive, disintegration Agent, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, flavoring Agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilizer, Surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable auxiliary materials can provide more than one function, And alternative function is provided, this is depended in preparation in the presence of there are which other auxiliary materials in how much auxiliary materials and preparation.
Technical staff grasps the knowledge and skills of this field, so that they can select for the suitable of appropriate amount of the invention Pharmaceutically acceptable auxiliary material.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Auxiliary material, and for selecting suitable pharmaceutically acceptable auxiliary material.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Well-known technique, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object effect, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of open compound, pays close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to the technique of preparation pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable auxiliary material, excipient, carrier, solvent or their combination, the technique include that mixing is each Kind ingredient.Pharmaceutical composition comprising disclosed compound of present invention can mix under such as environment temperature and atmospheric pressure to make It is standby.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes those dosage forms for being suitable for following administration route: (1) being administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to gastric acid effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to fatty acid, rouge Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of substance.Film coating includes, but are not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.It is multiple Tabletting is the compressed tablets by preparing more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active constituent are individual or describe with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrating agent, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, and one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is by being added glycerol, sorbierite or the plasticizing of similar polyalcohol.It is raw that soft gelatin shell may include the pre- preventing microorganism of preservative It is long.Suitable preservative be as described in the present invention those, including methylparaben and propylben and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and suspension in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；It is prepared described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used The acetal of receiving, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal；And have one or more The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Other useful liquid and semisolid dosage form include, but are not limited to comprising active constituent provided by the invention and second level Change those of mono- or poly- alkylene glycol dosage form, described mono- or poly- alkylene glycol includes: 1,2- dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ether, polyethylene glycol -550- dimethyl ether, poly- second The approximate average molecular weight of glycol -750- dimethyl ether, wherein 350,550,750 finger polyethylene glycol.These preparations can be further Including one or more antioxidant, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, ethanol amine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, coke Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.
Where appropriate, can be by the dosage unit preparations microencapsulation of oral administration.It can also be prepared into extending or tie up Hold the composition of release, such as by being coated by microparticle material or be embedded in polymer, wax or the like.
Combination of oral medication provided by the invention can also be mentioned in the form of liposome, micella, microballoon or nanometer system For.Micella dosage form can be prepared with the method that U.S.Pat.No.6,350,458 is described.
Pharmaceutical composition provided by the invention can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.The pharmaceutically acceptable carrier used in non-effervescent or pulvis and excipient may include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier used in effervescent or pulvis and excipient can wrap Include organic acid and carbon dioxide source.
Colorant and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be in conjunction with the soluble polymer as target medicine carrier.It is such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl The oxide polylysine that amine phenol or palmitoyl residues replace.In addition, compound disclosed in this invention can in reality One kind Biodegradable polymeric used in the control release of existing drug combines, for example, polylactic acid, poly-epsilon-caprolactone, gathering Hydroxybutyric acid, polyorthoester, polyacetals, poly- dihydropyran, the crosslinking of polybutylcyanoacrylate and hydrogel or amphiphilic block are total Polymers.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect It prepares, or the substance co-formulation with the expected effect of supplement.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body administration.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can be prepared according to conventional method known to the technical staff in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, ibid).
Be intended for parenteral administration pharmaceutical composition may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Suitably include, but are not limited to containing transporter: water, salt water, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers injection, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injection.Non- transporter includes, but are not limited to fixed oil, castor oil, corn oil, the cottonseed of plant origin Oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil middle chain Triglycerides and palm seed oil.Water miscibility carrier includes, but are not limited to the poly- second two of ethyl alcohol, 1,3-BDO, liquid Alcohol (such as Liquid Macrogol and polyethylene glycol 400), propylene glycol, glycerol, n-methyl-2-pyrrolidone, N, N- dimethylacetamide Amine and dimethyl sulfoxide.
Suitable antimicrobial or preservative include, but are not limited to phenol, cresols, mercurial, benzyl alcohol, chlorobutanol, Methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride (such as benzethonium chloride), methylparaben and Propylben and sorbic acid.Suitable isotonic agent includes, but are not limited to sodium chloride, glycerol and glucose.Suitable buffer Include, but are not limited to phosphate and citrate.Suitable antioxidant is such as those of present invention description, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is such as those of present invention description, including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitable emulsifier includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene is de- Water sorbitol monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agent include, but are not limited to EDTA. Suitable pH adjusting agent includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but unlimited In cyclodextrin, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-β-cyclodextrin, Sulfobutylether-beta-cyclodextrin and sulfobutyl group Ether 7- beta-cyclodextrin (CyDex,Lenexa,KS)。
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must comprising it is antibacterial or fungistatic concentrations resist it is micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.
In one embodiment, pharmaceutical composition is provided with instant sterile solution.In another embodiment, drug Composition is provided with sterile dried soluble product, including freeze-dried powder and hypodermic tablet, and carrier is used before use Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine Compositions are formulated into the sterile dry insolubility product reconstructed before use with carrier.Also in one embodiment, Pharmaceutical composition is formulated into instant without bacterial emulsion.
Pharmaceutical composition disclosed in this invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, Pulse-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition can be configured to suspension, solid, semisolid or thixotropic liquid, the reservoir administration as implantation. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, be insoluble to body fluid but The external polymeric membrane for allowing the active constituent in pharmaceutical composition to diffuse through is surrounded.
Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silicon oxygen Alkane, silicone carbonate copolymer, the hydrogel of the ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.
Suitable external polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Object, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second Alkene, the copolymer of ethlyene dichloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer are poly- to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable for any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention Object can be configured to be suitable for the dosage form with dry powder doses to patient's inhalation.In yet another embodiment, disclosed in this invention Pharmaceutical composition can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Pass through the dry powder of inhalation delivery to lung Composition generally comprise fine powdered compound disclosed in this invention and it is one or more it is fine powdered pharmaceutically Acceptable excipient.Pharmaceutically acceptable excipient be especially suitable for dry powder doses is known to those skilled in the art Dawn comprising lactose, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding preparation It obtains.In general, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value is (for example, with swashing The measurement of optical diffraction method) Lai Dingyi.
Aerosol can be prepared by the way that compound disclosed in this invention to be suspended or dissolved in liquefied propellant.It is suitble to Propellant include chlorohydrocarbon, hydro carbons and other liquefied gas.Representative propellant includes: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1- difluoro Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.Aerosol comprising compound disclosed in this invention usually passes through Metered dose inhaler (MDI) administers to a patient.Such device dawn known to those skilled in the art
Aerosol may include pharmaceutically acceptable excipient that is additional, being used by MDIs, such as surface-active Agent, lubricant, cosolvent and other excipient, with improve preparation physical stability, improve valve characteristic, improve dissolubility, Or improve taste.
The pharmaceutical composition for being suitable for cutaneous penetration can be prepared into discontinuous patch agent, it is intended that keep with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example Such as liquid-liquid paraffin and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.Made according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, poly- carboxylic second Alkene and cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
Lotion can be prepared with water or oil matrix, and generally also contain one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickener.
Externally-applied powder can form in the presence of any suitable powder matrix such as talcum powder, lactose or starch.Drops It can be formulated with the water comprising one or more dispersing agents, solubilizer, suspending agent or preservative or non-aqueous matrix.
Topical formulations can be by being administered using one or many daily in affected part；The impermeable plastic wound dressing for covering skin is preferential It is used.Adhesiveness store system can realize continuous or extended administration.
When treating eyes or other organs such as mouth and skin, the combination as topical ointment or cream can be applied Object.When being formulated as ointment, compound disclosed in this invention can be used together with paraffin or water-soluble ointment matrix.Or Person, compound disclosed in this invention can be configured to cream together with Oil-in-water emulsifiable paste agent matrix or oil-in-water base.
The purposes of the compounds of this invention and composition
The present invention, which provides, uses compound disclosed in this invention and medicine composite for curing, prevention, or improves by one kind Or multiple protein kinases, such as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also referred to as FLK-2) or The disease or disorderly that Aurora A (including Aurora-A, Aurora-B and Aurora C) behavior is mediated or otherwise influenced Disorderly or by one or more protein kinases, such as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (including Aurora-A, the Aurora-B and Aurora C) behavior of (also referred to as FLK-2) or Aurora A mediate or otherwise The method of one or more symptoms of the disease or disorder of influence.
FLT3 kinases can be the wild type and/or mutation of FLT3 kinases.
Jak kinase can be the wild type and/or mutation of JAK1, JAK2, JAK3 or TYK2 kinases.
In one embodiment, the present invention provides a kind of compound disclosed in this invention or includes presently disclosedization The pharmaceutical composition for closing object, for treating, preventing or improves by unsuitable JAK1 kinases behavior mediation or otherwise shadow Loud disease or disorder or mediated by unsuitable JAK1 kinases behavior or otherwise influenced the one of disease or disorder Kind or a variety of symptoms.In another embodiment, the disease, disorder or disease or one or more symptoms of disorder with not JAK2 kinases behavior appropriate is related.Also in one embodiment, the disease, disorder or disease or one kind or more of disorder Kind symptom is related to unsuitable JAK3 kinases behavior.
In some embodiments, the present invention provides a kind of compound disclosed in this invention or comprising presently disclosed The pharmaceutical composition of compound, for treating, preventing or improve by unsuitable FLT3 kinases behavior mediation or otherwise The disease of influence or disorder are mediated or the otherwise disease that influences or disorder by unsuitable FLT3 kinases behavior One or more symptoms.
In some embodiments, the present invention provides a kind of compound disclosed in this invention or comprising presently disclosed The pharmaceutical composition of compound is mediated or with other for treating, preventing or improve by unsuitable Aurora-A kinases behavior Disease or disorder that mode influences or the disease for being mediated by unsuitable Aurora-A kinases behavior or otherwise being influenced Or one or more symptoms of disorder.In other embodiments, one kind of the disease, disorder or disease or disorder or A variety of symptoms are related to unsuitable Aurora-B kinases behavior.Also in some embodiments, the disease, disorder or disease Disease or one or more symptoms of disorder are related to unsuitable Aurora C kinases behavior.
" unsuitable jak kinase behavior " refers to that the JAK for occurring to deviate normal jak kinase behavior with particular patient swashs Enzyme behavior.Unsuitable jak kinase behavior can show as example active abnormal growth or jak kinase time of the act point With the form of the deviation in control.This unsuitable kinases behavior is derived from, for example, the overexpression or mutation of protein kinase and Caused inappropriate or uncontrolled behavior.Therefore, the present invention provides the method for the treatment of these diseases and disorder.
Consistent with above description, such disease or disorder include but is not limited to: bone marrow proliferative diseases, such as very Property polycythemia (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF)；Leukaemia, such as medullary system Leukaemia includes chronic myelogenous leukemia (CML), the CML form of resistance to Imatinib, acute myeloid leukemia (AML) and AML Hypotype, acute megakaryoblastic leukemia (AMKL)；Lymphoproliferative disease, for example, acute lymphoblastic leukemia (ALL) and Myeloma etc.；Cancer includes head-neck carcinoma, prostate cancer breast cancer, oophoroma, melanoma, lung cancer, brain tumor, cancer of pancreas and kidney Cancer；With diseases associated with inflammation related with immunologic function disorder, immune deficiency, immunological regulation or disorder, autoimmune disease, group Knit graft rejection, graft versus host disease(GVH disease), wound healing, nephrosis, multiple sclerosis, thyroiditis, type-1 diabetes mellitus, sarcoidosis, Psoriasis, allergic rhinitis, inflammatory bowel disease include Crohn disease and ulcerative colitis (UC), systemic loupus erythematosus (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and Dry eye syndrome (or keratoconjunctivitis sicca (KCS)).
On the one hand, the present invention provides a kind of compound disclosed in this invention or the medicine comprising presently disclosed compound Compositions, for preventing and/or treating the proliferative diseases, autoimmune disease, anaphylaxis of mammal (including the mankind) Disease, inflammatory disease or graft rejection.
On the other hand, the present invention provides a kind for the treatment of and suffers from or the risky mammal for suffering from disease disclosed herein Method, the method includes give effectively treatment illness amount or effectively prevention illness amount one or more medicines disclosed herein Compositions or compound.On the other hand, it suffers from provided herein is a kind for the treatment of or risky suffer from proliferative diseases, exempts from self Epidemic disease, anaphylactia, inflammatory disease or graft rejection mammal method.
In a kind of method in terms for the treatment of, the present invention provides treatment and/or prevention is susceptible or suffering from proliferative diseases The method of mammal, the method includes giving one or more medicines disclosed herein of effective therapeutic dose or effective preventive dose Compositions or compound.In particular instances, proliferative diseases are selected from cancer (for example, solid tumor such as uterine leio muscle Tumor or prostate cancer), polycythemia vera, primary thrombocytosis, myelofibrosis, leukaemia (for example, AML, CML, ALL or CLL) and Huppert's disease.
On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing proliferative diseases.? In specific embodiment, proliferative diseases be selected from cancer (for example, solid tumor such as leiomyosarcoma of uterus or prostate cancer), Polycythemia vera, primary thrombocytosis, myelofibrosis, leukaemia (for example, AML, CML, ALL or CLL), And Huppert's disease.
On the other hand, provided herein is a kind of compounds disclosed herein, or the pharmaceutical composition comprising compound is disclosed herein Object is used to prepare the drug for treating or preventing proliferative diseases.In particular instances, proliferative diseases are selected from cancer (for example, real Body tumor such as leiomyosarcoma of uterus or prostate cancer), polycythemia vera, primary thrombocytosis, marrow it is fine Dimensionization, leukaemia (for example, AML, CML, ALL or CLL) and Huppert's disease.
On the other hand, the side of the mammal of autoimmune disease is susceptible or suffering from provided herein is treatment and/or prevention Method, the method includes giving one or more pharmaceutical compositions disclosed herein of effective therapeutic dose or effective preventive dose or change Close object.In particular instances, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, wolf Sore ephritis, dermatomyositis, Sjogren syndrome, psoriasis, type-1 diabetes mellitus and inflammatory bowel disease.
On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing autoimmune disease. In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, wolf Sore ephritis, dermatomyositis, Sjogren syndrome, psoriasis, type-1 diabetes mellitus and inflammatory bowel disease.
On the other hand, provided herein is a kind of compounds disclosed herein, or the pharmaceutical composition comprising compound is disclosed herein Object is used to prepare the drug for treating or preventing autoimmune disease.In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, psoriasis, I Patients with type Ⅰ DM and inflammatory bowel disease.
On the other hand, the method that the mammal of anaphylactia is susceptible or suffering from provided herein is treatment and/or prevention, The method includes giving the one or more pharmaceutical compositions disclosed herein or chemical combination of effective therapeutic dose or effective preventive dose Object.In certain embodiments, anaphylactia is selected from respiratory anaphylactic disease, nasosinusitis, eczema and morbilli, food mistake Quick and insect venom allergies.
On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing anaphylactia.? In specific embodiment, anaphylactia is selected from respiratory anaphylactic disease, nasosinusitis, eczema and morbilli, food hypersenstivity and Insect venom allergies.
On the other hand, provided herein is a kind of compounds disclosed herein, or the pharmaceutical composition comprising compound is disclosed herein Object is used to prepare the drug for treating or preventing anaphylactia.In certain embodiments, anaphylactia is selected from respiratory tract Anaphylactia, nasosinusitis, eczema and morbilli, food hypersenstivity and insect venom allergies.
On the other hand, the method that the mammal of inflammatory disease is susceptible or suffering from provided herein is treatment and/or prevention, institute The method of stating includes giving the one or more pharmaceutical compositions disclosed herein or compound of effective therapeutic dose or effective preventive dose. In certain embodiments, inflammatory disease is selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis And psoriasis arthropathica.
On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing inflammatory disease.In spy In fixed embodiment, inflammatory disease is selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis and silver Consider disease arthritis to be worth doing.
On the other hand, provided herein is a kind of compounds disclosed herein, or the pharmaceutical composition comprising compound is disclosed herein Object is used to prepare the drug for treating or preventing inflammatory disease.In certain embodiments, inflammatory disease be selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.
On the other hand, the method that the mammal of graft rejection is susceptible or suffering from provided herein is treatment and/or prevention, institute The method of stating includes giving the one or more pharmaceutical compositions disclosed herein or compound of effective therapeutic dose or effective preventive dose. In particular instances, graft rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing graft rejection.In spy In fixed embodiment, graft rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, provided herein is a kind of compounds disclosed herein, or the pharmaceutical composition comprising compound is disclosed herein Object is used to prepare the drug for treating or preventing graft rejection.In particular instances, graft rejection is organ-graft refection, tissue Graft rejection and cell transplant rejection.
On the other hand, it is used as drug provided herein is one kind to be especially used as treating and/or preventing disease medicament noted earlier Compound disclosed herein.It is also provided with compound manufacture treatment disclosed herein and/or prevents the medicine of disease noted earlier Object.
One special projects of this method include giving a effective amount of present invention of study subject with inflammation to disclose chemical combination For a period of time, the time is enough to reduce the level of inflammation of study subject object, and preferably terminates the process of the inflammation.The party The special embodiment of method includes giving a effective amount of present invention public affairs of tested patients for suffering from or being susceptible to suffer from bone rheumatoid arthritis Open compound for a period of time, the time is enough to reduce or prevent the arthritis of the patient respectively, and preferably terminates institute State the process of inflammation.
Another special projects of this method include giving a effective amount of present invention of study subject with proliferative diseases For a period of time, the hyperplasia that the time is enough to reduce study subject is horizontal, and preferably terminates the increasing for open compound The process of growing property disease.The special embodiment of this method include give the tested patients with cancer it is a effective amount of be disclosed herein For a period of time, the time is enough to reduce or prevent the cancer symptom of the patient respectively compound, and preferably described in termination The process of cancer.
Combination therapy
The compounds of this invention can be used as individual active agent administration, or can be administered with other therapeutic agents, Including being determined as safe and efficient other compounds with same or similar therapeutic activity and for such administering drug combinations.
On the one hand, the present invention provides treatment, prevention or the method for improving disease or illness, including giving safe and effective amount Combination medicine comprising disclosed compound of present invention Yu one or more therapeutically active agents.In one embodiment, combination medicine Include one or two kinds of other therapeutic agents.
The example of other therapeutic agents includes including but is not limited to: anticancer agent, including chemotherapeutics and antiproliferative；Anti-inflammatory agent； With immunity regulatin remedy agent or immunosuppressor.
On the other hand, the present invention provides the product including the compounds of this invention and at least one other therapeutic agent, can prepare At the combination simultaneously, separately or sequentially applied in the treatment.In some embodiments, treatment is for by one or more eggs White kinases, such as the treatment of disease or symptom that jak kinase, FLT3 kinases or Aurora A activity mediate.Joint preparation provides Product include be present in same pharmaceutical composition comprising be disclosed herein compound and other therapeutic agents composition, or with Compound and other therapeutic agents are disclosed herein existing for different form, for example, medicine box.
On the other hand, the present invention provides a kind of comprising compound and the drug of another or a variety of therapeutic agents is disclosed herein Composition.In one embodiment, pharmaceutical composition may include as described above pharmaceutically acceptable excipient, carrier, Adjuvant or solvent.
On the other hand, the present invention provides the medicine box of the single pharmaceutical composition comprising two kinds or more, wherein at least one Pharmaceutical composition includes disclosed compound of present invention.In one embodiment, medicine box includes the work for individually keeping the composition Tool, such as container, separated bottle or separated foil box.The example of this kind of medicine box is blister package, be commonly used for package troche, Capsule etc..
The present invention also provides purposes of the compounds of this invention in the disease or symptom that treatment albumen kinase activity mediates, Wherein patient previously (such as in 24 hours) has been treated with other therapeutic agents.The present invention also provides other treatments Agent is in treatment albumen kinases, the purposes in disease and symptom mediated such as jak kinase, FLT3 kinases and Aurora A activity, Wherein patient previously (such as in 24 hours) has been treated with the compounds of this invention.
Compound disclosed herein can be used as single active ingredient application or as such as adjuvant, common with other therapeutic agents Application.
In some embodiments, other therapeutic agents include chemotherapeutics and/or antiproliferative.Known chemotherapeutic Object includes, but is not limited to, other therapies or anticancer drug, operation, radiotherapy that can be used in combination with the compounds of this invention (a little example such as γ radiation, neutron beam radiotherapy, electron beam evaporation therapy, proton therapy, brachytherapy and system Isotope therapy), endocrinotherapy, taxanes (taxol (taxol), Docetaxel (taxotere) etc.), Platinum derivatives (cis-platinum (cisplatin), carboplatin (carboplatin)), biological response modifiers (interferon, between leucocyte Element), tumor necrosis factor (TNF, TRAIL receptor target object), overheat and cold therapy, the reagent for mitigating any adverse reaction (such as antiemetic) and other approved chemotherapeutics include but is not limited to, alkylating drug (mustargen (mechlorethamine), Chlorambucil (chlorambucil), cyclophosphamide (cyclophosphamide), melphalan (melphalan), ifosfamide (ifosfamide)), antimetabolite (methotrexate (MTX) (methotrexate), pemetrexed (pemetrexed) etc.), (6-MP (6-mercaptopurine), 5- fluorine urine are phonetic for purine antagonist and Pyrimidine antagonists Pyridine (5-fluorouracil), cytarabine (cytarabile), gemcitabine (gemcitabine)), spindle poison (vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine)), podophyllotoxin (according to Support pool glycosides (etoposide), Irinotecan (irinotecan), Hycamtin (topotecan)), antibiotic (Doxorubicin (doxorubicin), bleomycin (bleomycin), mitomycin (mitomycin)), nitroso ureas (Carmustine (carmustine), lomustine (lomustine)), (KSP passes through mitotic kinesins to cell division cycle inhibitor Inhibitor, CENP-E and CDK inhibitor), enzyme (asparaginase (asparaginase)), hormone (tamoxifen (tamoxifen), Leuprorelin (leuprolide), Flutamide (flutamide), megestrol acetate (megestrol), fill in rice Loose (dexamethasone) etc.).Anti-angiogenesis reagent (Avastin (avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (belimumab), brentuximab, Cetuximab (cetuximab), WAY-CMA 676 (gemtuzumab), her monoclonal antibody (ipilimumab), ofatumumab, Victibix (panitumumab), Lucentis (ranibizumab), rituximab list Anti- (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab)).Kinase inhibitor (she Imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), nilotinib (nilotinib), Lapatinib (lapatinib), gram Zhuo for Buddhist nun (crizotinib), ruxolitinib, vemurafenib, vandetanib, Pazopanib, etc.).Drug inhibition or activate cancer approach such as mTOR, HIF (hypoxia inducible factor) approach and other.Cancer Disease is treated wide forum and is seenhttp://www.nci.nih.gov/, FAD approve oncologic inventory seehttp:// www.fda.gov/cder/cancer/druglist-rame.htmAnd Merck Manual, the 18th edition .2006, all contents All it is combined with bibliography.In other embodiments, the compound of the present invention can be with combination cell toxin anticancer agent. Such anticancer agent can be found the 13rd edition Merck index (2001) is inner.These anticancer agents include, but are not limited to, Tianmen Winter amidase, bleomycin, carboplatin, Carmustine, Chlorambucil, cis-platinum, L-ASP, cyclophosphamide, arabinose born of the same parents Glycosides, Dacarbazine, actinomycin D, daunorubicin, adriamycin (Doxorubicin), epirubicin, Etoposide, 5-fluor-uracil, Hexamethyl melamine, hydroxycarbamide, ifosfamide, Irinotecan, folinic acid, lomustine, mustargen, Ismipur, Mesna, methotrexate (MTX), mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, Raloxifene, chain azoles are mould Element, tamoxifen, thioguanine, Hycamtin, vincaleukoblastinum, vincristine and eldisine.Combine with the compound of the present invention Other suitable cytotoxic drugs of medication include, but is not limited to, these are admittedly applied to tumor disease treatment Compound, as described in following documents: Goodman and Gilman's The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.)；These anticancer agents include, but are not limited to, ammonia Shandong Meter Te (aminoglutethimide), l- L-Asparaginasum, imuran, 5-azacitidine, Cladribine (cladribine), busulfan (busulfan), diethylstilbestrol, 2', it is 2'- difluoro dCDP choline, Docetaxel, red Hydroxyl nonyl adenine (erythrohydroxynonyladenine), ethinylestradiol, 5 FU 5 fluorouracil deoxyribonucleoside, 5- Fluorodeoxyuridine monophosphate, fludarabine phosphate (fludarabine phosphate), Fluoxymesterone (fluoxymesterone), Flutamide (flutamide), hydroxyprogesterone caproate, idarubicin (idarubicin), interferon, vinegar Sour Medroxyprogesterone, megestrol acetate, melphalan (melphalan), mitotane (mitotane), taxol, Pentostatin (pentostatin), N- phosphate base-L-Aspartic acid (PALA), plicamycin (plicamycin), methyl cyclohexane nitrous Urea (semustine), Teniposide (teniposide), testosterone propionate, phosphinothioylidynetrisaziridine (thiotepa), trimethyl melamine Amine, urine nucleosides and vinorelbine.
Other include suitably newfound cell with the cytotoxin class anticancer agent of the compound of the present invention use in conjunction Toxic substance, including, but be not limited to, oxaliplatin (oxaliplatin), gemcitabine (gemcitabine), card training His shore (capecitabine), macrolides antineoplastic and its natural or synthetic derivative, Temozolomide (temozolomide) (Quinn et al., J.Clin.Oncology, 2003,21 (4), 646-651), tositumomab (bexxar), trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004,23, abstract 3181), and driving albumen spindle protein inhibitor Eg5 (Wood et al.,Curr.Opin.Pharmacol.2001,1,370-377)。
Also in other embodiments, the compound of the present invention can be with binding signal transduction inhibitor.Signal transduction Inhibitor using EGFR family as target, such as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l),15-23；Harari et al., Oncogene, 2000,19 (53), 6102-6114) and their own match Body.Such reagent includes, but is not limited to, antibody therapy such as Herceptin (trastuzumab), Cetuximab (cetuximab), her monoclonal antibody (ipilimumab) and handkerchief trastuzumab (pertuzumab).Such therapy also includes, but It is not limited to, small molecule kinase inhibitors such as Imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), Ni Luo For Buddhist nun (nilotinib), Lapatinib (lapatinib), gram Zhuo replaces Buddhist nun (crizotinib), ruxolitinib, Vemurafenib, vandetanib, pazopanib, Afatinib (afatinib), amuvatinib, Axitinib (axitinib), posupini (bosutinib), brivanib, canertinib, cabozantinib, Si Dinibu (cediranib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, Ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, for husky Buddhist nun (motesanib), linatinib (neratinib), niraparib, Oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, saracatinib (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, Tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, Volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941 (Folkes, et al., J.Med.Chem.2008,51,5522), BZE235, etc..
In some embodiments, compound disclosed herein can also be co-administered with other medicines.The other medicines Including, immunosuppressor, immunomodulator, other anti-inflammatory agents, such as treating or preventing allogeneic-or xenograft Acute or chronic repulsion, inflammatory, autoimmune disease drug；Or chemotherapeutics, such as malignant cell antiproliferative.For example, Disclosed compound of present invention can combine with following active component: the plain inhibitor of calcium nerve, such as cyclosporin A or FK506； MTOR inhibitors, for example, rapamycin, 40-O- (2- hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9；Ascosin with immunosuppressive properties, such as ABT-281, ASM981 Deng；Corticosteroid；Cyclophosphamide；Imuran；Methotrexate (MTX)；Leflunomide；Mizoribine；Mycophenolic Acid or salt；Wheat Examine phenolic acid mofetil ester；15- deoxyspergualin or its immunosupress homologue, analog or derivative；Pkc inhibitor, such as Described in WO 02/38561 or WO 03/82859, such as the compound of embodiment 56 or 70；Immunosupress monoclonal antibody, Such as the monoclonal antibody of leukocyte receptors, for example, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or its ligand；Other immunomodulatory compounds, such as at least partly extracellular domain with CTLA4 Recombination binding molecule or its mutant, such as at least extracellular portion of CTLA4 being connected with non-CTLA4 protein sequence or its Mutant, such as CTLA4Ig (such as being named as ATCC 68629) or its mutant, such as LEA29Y；Adhesion molecule inhibitor, Such as LFA-1 antagonist, the antagonist of ICAM-1 or -3, VCAM-4 antagonist or VLA-4 antagonist；Or chemotherapeutics, such as Japanese yew Alcohol, gemcitabine, cis-platinum, Doxorubicin or 5 FU 5 fluorouracil；Or anti-infective.
In disclosed compound of present invention and other immunotherapeutic agent/immunomodulators, anti-inflammatory agent, chemotherapy or anti-infective In the case that treatment is administered in combination, immunosuppressor, immunomodulator, anti-inflammatory agent, chemotherapeutant or the anti-sense of administering drug combinations The dosage for contaminating compound certainly can be according to the type of combination medicine used, such as whether it is that steroidal or calcineurin inhibit Agent, specific drug used, illness to be treated etc. and change.
On the one hand, the present invention provides a kind of comprising disclosed compound of present invention and β2The connection of adrenoceptor agonists It closes.β2The example of adrenoceptor agonists includes salmeterol, salbutamol, Formoterol, salmefamol, Fei Nuote Sieve, Yi Tanteluo, naminterol, Clenbuterol, pirbuterol, Flerobuterol, reproterol, promulgates special sieve, indenes at carmoterol Da Teluo, Terbutaline and their salt, such as xinafoate (1- hydroxy-2-naphthoic acid salt), the husky butylamine of salmeterol The sulfate or free alkali of alcohol or the fumarate of Formoterol.In one embodiment, long-acting beta2Adrenocepter swashs Dynamic agent, such as preferably, it is to provide effective bronchiectasis up to 12 hours or the compound of longer time.
β2Adrenoceptor agonists can be with the form of pharmaceutically acceptable sour forming salt.It is described pharmaceutically The acid of receiving is selected from sulfuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (such as 1- or 3- hydroxy-2-naphthoic acid), cinnamic acid, substituted meat Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3- (1- naphthalene) acrylic acid, benzoic acid, 4- methoxy benzoic acid, 2- or 4-HBA, 4- chlorobenzoic acid and 4- Phenylbenzoic acid.
On the other hand, the present invention provides a kind of joint comprising disclosed compound of present invention and corticosteroid.Suitably Corticosteroid refers to those oral and sucking corticosteroids, and its has the prodrug of anti-inflammatory activity.Example includes that methyl sprinkles Ni Songlong, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-[(4- methyl-1,3-thiazole - 5- carbonyl) oxygroup] -17 β of -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters, 6 α, fluoro- 17 α-[(the 2- furan of 9 α-two Mutter carbonyl) oxygroup]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- fluorine methyl esters (furancarboxylic acid Fluticasone) ,-16-17 α of Alpha-Methyl-3- oxo of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-- 17 β of propionyloxy-androsta-1,4- diene- Thiocarboxylic acid S- (2- oXo-tetrahydro furans -3S- base) ester, -17 α of -16 Alpha-Methyl -3- oxo of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy - (2,2,3,3- tetramethyl cyclopropyl carbonyl) oxygroup--17 β of androstane -1,4- diene-thiocarboxylic acid S- cyano methyl ester and 6 α, 9 α-two Fluoro- -17 β of -17 α of -16 Alpha-Methyl of 11 beta-hydroxy-(1- ethyl cyclopropyl carbonyl) oxygroup -3- oxo-androst -1,4- diene-is thio Carboxylic acid S- methyl fluoride ester, beclomethasone ester (such as 17- propionic ester or 17,21- dipropionic acid rouge), budesonide (budesonide), Flunisolide (flunisolide), Mometasone ester (such as momestasone furoate), Triamcinolone acetonide (triamcinolone Acetonide), ([[(R)-cyclohexyl is sub- by 16 α, 17- for sieve fluoronaphthalene moral (rofleponide), ciclesonide (ciclesonide) Methyl] bis- (oxygroups)] -11 β, 21- dihydroxy-pregnant steroid -1,4- diene -3,20- diketone), butixocort propionate (butixocort Propionate), RPR-106541 and ST-126.Preferred corticosteroid includes fluticasone propionate (fluticasone Propionate), -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-[(4- methyl-1,3-thiazole -5- carbonyl) oxygroup] - - 17 β of 3- oxo-androst -1,4- diene-thiocarboxylic acid S- methyl fluoride ester, 6 α, fluoro- 17 α-of 9 α-two [(2- furanylcarbonyl) oxygen Base]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- methyl fluoride ester, 6 α, 9 α-two are fluoro- - 17 α of -16 Alpha-Methyl -3- oxo of 11 beta-hydroxy-(2,2,3,3- tetramethyl cyclopropyl carbonyl) oxygroup-androstane -1,4- diene -17 - 17 α of β-thiocarboxylic acid S- cyano methyl ester and -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-(1- methylcyclopropyl groups carbonyl) oxygen - 17 β of base -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters.In some embodiments, corticosteroid is 6 α, - 16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of fluoro- 17 α-of 9 α-two [(2- furanylcarbonyl) oxygroup]-11 beta-hydroxy-sulphur For carboxylic acid S- methyl fluoride ester.
On the other hand, the present invention provides a kind of joint comprising disclosed compound of present invention and nonsteroidal GR agonist. To Transcription inhibition with selectivity (compared with transcriptional activation), can be used for combination therapy with glucocorticoid agonist activity Nonsteroidal compound includes the compound that those covered in following patent: WO 03/082827, WO 98/54159, WO 04/005229、WO 04/009017、WO 04/018429、WO 03/104195、WO 03/082787、WO 03/082280、WO 03/059899、WO 03/101932、WO 02/02565、WO 01/16128、WO 00/66590、WO 03/086294、WO 04/026248, WO 03/061651 and WO 03/08277.More nonsteroidal compounds are in WO 2006/000401, WO It is included in 2006/000398 and WO 2006/015870.
On the other hand, the present invention provides a kind of comprising disclosed compound of present invention and nonsteroidal anti-inflammatory drug (NSAID's) Joint.The example of NSAID's includes nasmil, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (such as theophylline, PDE4 inhibitor or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene close At inhibitor (such as montelukast), iNOS inhibitor, trypsase and elastatinal, Beta 2 integrin antagonist With adenosine receptor agonist or antagonist (e.g., adenosine 2a receptor stimulating agent), (such as chemokine receptors is short of money for cytokine antagonist Anti-agent, including CCR3 antagonist), cytokine synthesis inhibitor or 5-LO inhibitor.Wherein, iNOS (inductivity one Nitric oxide synthase) inhibitor is preferably administered orally.The example of iNOS inhibitor includes those in WO 93/13055, WO 98/ 30537, compound disclosed in WO 02/50021, WO 95/34534 and WO 99/62875.CCR3 inhibitor include those Compound disclosed in WO 02/26722.
In one embodiment, the present invention relates to disclosed compound of present invention with phosphodiesterase 4 (PDE4) inhibitor Joint in application, the application especially in inhalant dosage form.PDE4 specific inhibitor for this aspect of the present invention can To be known inhibition PDE4 enzyme or be found any compound as PDE4 inhibitor, they are only PDE4 inhibitor, It is not to inhibit other members in PDE family, such as the compound of PDE3 and PDE5.Compound includes cis- -4- cyano -4- (3- ring Amyl oxygroup -4- methoxyphenyl) hexamethylene -1- carboxylic acid, 2- carbomethoxy -4- cyano -4- (3- cyclo propyl methoxy -4- difluoro Methoxyphenyl) hexamethylene -1- ketone and cis--[4- cyano -4- (3- cyclo propyl methoxy -4- difluoro-methoxy phenyl) hexamethylene Alkane -1- alcohol]；It also include that cis- -4- cyano -4- [3- (cyclopropyl oxygroup) -4- methoxyphenyl] hexamethylene -1- carboxylic acid is (also referred to as western Lip river department) and its salt, ester, prodrug or physical form, in 09 month 1996 No. 03 United States Patent (USP) US 5,552,438 authorized Open, this patent and its disclosed compound are incorporated herein by reference in their entirety.
On the other hand, the present invention provides a kind of joint comprising disclosed compound of present invention and anticholinergic agent.Cholinolytic Can agent example be those be used as muscarinic receptor antagonist compounds, especially those as M1 or M3 receptor antagonist, M1/M3Or M2/M3Receptor dual antagonist or M1/M2/M3The compound of the general antagonist of receptor.The example compound packet of inhalation Include ipratropium (for example, as bromide, CAS 22254-24-6, withSold for trade name), Oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium (for example, as bromide, CAS 136310-93- 5, withIt is sold for trade name)；Be also interested in there are also Revatropate (for example, as hydrobromate, CAS 262586-79-8) and the LAS-34273 disclosed in WO01/04118.The example compound of oral administration includes piperazine logical sequence Xiping (CAS 28797-61-7), darifenacin (CAS 133099-04-4 or its hydrobromate CAS 133099-07-7, withSold for trade name), oxybutynin (CAS 5633-20-5, withIt is sold for trade name Sell), terodiline (CAS 15793-40-5), Tolterodine (CAS 124937-51-5 or its tartrate CAS124937- 52-6, withSold for trade name), Austria for ammonium (for example, as bromide, CAS 26095-59-0, withSold for trade name), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, Or its succinate CAS 242478-38-2, i.e. compound YM-905, withIt is sold for trade name It sells).
On the other hand, the present invention provides a kind of joint comprising disclosed compound of present invention and H1 antagonist.H1 antagonist Example include, but are not limited to Amlexanox (amelexanox), western this imidazoles (astemizole), azatadine (azatadine), azelastine (azelastine), Acrivastine (acrivastine), Brompheniramine (brompheniramine), cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine), chloropheniramine (chlorpheniramine), clemastine (clemastine), marezine (cyclizine), Carebastine (carebastine), cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), diformazan indenes (dimethindene), Ebastine (ebastine), epinastine (epinastine), second Fluorine benefit piperazine (efletirizine), fexofenadine (fexofenadine), hydroxyzine (hydroxyzine), Ketotifen (ketotifen), Loratadine (loratadine), levocabastine (levocabastine), Mizolastine (mizolastine), mequitazine (mequitazine), Mianserin (mianserin), the primary sting of promise (noberastine), meclizine (meclizine), Tecastemizole (norastemizole), olopatadine (olopatadine), piperacetazine (picumast), than Lamine (pyrilamine), phenergan (promethazine), special Fei Nading (terfenadine), Tripelennamine (tripelennamine), temelastine (temelastine), nedeltran (trimeprazine) and triprolidine (triprolidine), preferably cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine) and fexofenadine (fexofenadine).In another implementation In scheme, the present invention provides a kind of joint comprising disclosed compound of present invention and H3 antagonist (and/or inverse agonist).H3 is short of money The example of anti-agent includes those compounds disclosed in WO 2004/035556 and WO 2006/045416.It can be used for and this hair Other histamine receptor antagonists that bright open chemical combination Internet of Things are closed include H4 receptor antagonist (and/or inverse agonist), such as Compound disclosed in Jablonowski et al., J.Med.Chem., 2003,46:3957-3960.
Another aspect, it includes disclosed compound of present invention that the present invention, which provides a kind of, with PDE4 inhibitor and β2Adrenaline The joint of receptor stimulating agent.
Also on the one hand, the present invention provides a kind of comprising disclosed compound of present invention, inhibits with anticholinergic drug and PDE-4 The joint of agent.
It is above-described combine therefore, including defined above group be prepared into pharmaceutical composition with can be convenient come using It closes and represents another aspect of the present invention with the pharmaceutical composition of pharmaceutically acceptable excipient or carrier.
These united each compounds with alone or in combination pharmaceutical preparation form order of administration or can be administered simultaneously. In one embodiment, each compound component is administered simultaneously with combined pharmaceutical preparation form.Known treatment agent is suitble to Dosage is easy to be understood by the person skilled in the art.
Therefore, on the other hand, the present invention provides a kind of pharmaceutical composition, controls comprising compound disclosed by the invention with other Treat the joint of activating agent.
In some embodiments, pharmaceutical composition provided by the invention includes disclosed compound of present invention and chemotherapeutics Joint.
In some embodiments, pharmaceutical composition provided by the invention includes disclosed compound of present invention and antiproliferative Joint.
In one embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and phosphodiesterase The joint of 4 (PDE4) inhibitor.
In another embodiment, pharmaceutical composition provided by the invention includes on disclosed compound of present invention and β 2- kidney The joint of adrenoceptor agonist.
In another embodiment, pharmaceutical composition provided by the invention includes that disclosed compound of present invention and cortex class are solid The joint of alcohol.
In another embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and nonsteroidal The joint of GR agonist.
In another embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and anticholinergic The joint of medicine.
In yet another embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and antihistamine Joint.
In other embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and anti-inflammatory examination The joint of agent.
In other embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and immune tune Save the joint of agent.
In other embodiment, pharmaceutical composition provided by the invention include disclosed compound of present invention be used for move The joint of the drug of pulse atherosclerosis.
In other embodiment, pharmaceutical composition provided by the invention include disclosed compound of present invention be used for control Treat the joint of the drug of pulmonary fibrosis.
In internal medicine oncology, combine that carry out treating cancer patient be conventional means using different form of therapy.Inside In section's oncology, the one or more other co-therapies forms for being added to the present composition be can be, for example, performing the operation, putting Treatment, chemotherapy, single transduction inhibitor or regulator (for example, kinase inhibitor or regulator) and/or monoclonal antibody.
Disclosed compound of present invention can also be advantageously utilised in the combination with other compounds, or and other therapeutic agents, especially It is in the combination of antiproliferative.Such antiproliferative includes, but are not limited to aromatase inhibitor；Antiestrogenic；Topology is different Structure enzyme I inhibitor；Topoisomerase II inhibitors；Microtubule active agent；Alkylating agent；Histon deacetylase (HDAC) inhibitor；Induction The compound of cell differentiation procedure；Cyclooxygenase-2 inhibitors；MMP inhibitor；MTOR inhibitors；Antitumor antimetabolite；Platinum Close object；The compound of the compound of targeting/reduction albumen or lipid kinase activity and other anti-angiogenesis；Targeting, reduce or Inhibit the compound of albumen or lipid phosphate esterase active；Gonadorelin excitomotor；Antiandrogen；Methionine aminopeptidase inhibits Agent；Diphosphonate；Biological response modifiers；Antiproliferation antibodies；Heparanase inhibitors；The carcinogenic hypotype inhibitor of Ras；Telomere Enzyme inhibitor；Proteasome inhibitor；The medicament for treating neoplastic hematologic disorder；Targeting reduces or inhibits the active compound of Flt-3； Hsp90 inhibitor；TemozolomideAnd Calciumlevofolinate.
Term used herein " aromatase inhibitor " refers to that the compound inhibited estrogen production, i.e. inhibition substrate are male Alkene diketone and testosterone are converted to the compound of oestrone and estradiol respectively.The term includes, but are not limited to: steroid, especially It is atamestane (atamestane), Exemestane (exemestane) and formestane (formestane)；And especially Non-steroids, especially aminoglutethimide (aminoglutethimide), Rogletimide (roglethimide), pyrrole Rumi Spy (pyridoglutethimide), Trilostane (trilostane), Testolactone (testolactone), ketoconazole (ketoconazole), fluorine chlorazol (vorozole), Fadrozole (fadrozole), Anastrozole (anastrozole) and come it is bent Azoles (letrozole).Exemestane can be with commercially available, as trade mark isForm administration.Fu Mei Smooth (formestane) can be with commercially available, as trade mark isForm administration.Fadrozole It (fadrozole) can be with commercially available, as trade mark isForm administration.Anastrozole (anastrozole) can be with With commercially available, as trade mark isForm administration.Letrozole (letrozole) can with commercially available, As trade mark is OrForm administration.Aminoglutethimide (aminoglutethimide) can be with It is commercially available, as trade mark is Form administration.The present invention includes aromatase inhibitor chemotherapeutic Combination is particularly useful for the treatment of the tumour that hormone receptor is positive, such as tumor of breast.
Term used herein " antiestrogenic ", refers to the compound in Estrogen Receptor antagonising oestrogen effectiveness. The term includes, but are not limited to tamoxifen (tamoxifen), fulvestrant (fulvestrant), Raloxifene (raloxifene) and raloxifene hydrochloride (raloxifene hydrochloride).Tamoxifen (tamoxifen) can With with commercially available, as trade mark isForm administration.Raloxifene hydrochloride (raloxifene It hydrochloride) can be with commercially available, as trade mark isForm administration.Fulvestrant It (fulvestrant) can be with dosage form disclosed in United States Patent (USP) US 4,659,516 or commercially available, as trade mark isForm administration.The present invention includes that the combination of antiestrogenic chemotherapeutic is particularly useful for the treatment of estrogen receptor and is in Positive tumour, such as tumor of breast.
Term used herein " antiandrogen " refers to any substance that can inhibit male sex hormone biological action, it is wrapped It includes, but is not limited to, Bicalutamide (bicalutamide, trade name), dosage form can be according to United States Patent (USP) US 4,636,505 prepare.
Term used herein " Gonadorelin excitomotor " includes, but are not limited to abarelix (abarelix), Ge She Rayleigh (goserelin) and goserelin acetate.Goserelin is disclosed in United States Patent (USP) US 4,100,274, can be with city It sells, as trade mark is Form administration.Abarelix (abarelix) can be according to United States Patent (USP) Method disclosed in US 5,843,901 prepares dosage form.
Term used herein " topoisomerase I inhibitor " includes, but are not limited to topotecan (topotecan), Ji Horse replaces health (gimatecan), Irinotecan (irinotecan), camptothecine (camptothecian) and the like, 9- nitro Camptothecine (9-nitrocamptothecin) and macromolecular camptothecin conjugated compound PNU-166148 are (in WO 99/17804 Compound A1).Irinotecan can be with commercially available, as trade mark isForm administration.Topology is replaced Health can be with commercially available, as trade mark isForm administration.
Term used herein " Topoisomerase II inhibitors " includes, but are not limited to anthracycline compound, such as how soft ratio Star (doxorubicin), its Lipidosome, trade nameDaunomycin (daunorubicin)；Epirubicin (epirubicin)；Idarubicin (idarubicin)；The not soft pyrrole star of naphthalene (nemorubicin)；Anthraquinones mitoxantrone (mitoxantrone) and Losoxantrone (losoxantrone)；Podophillotoxines Etoposide (etoposide) and Teniposide (teniposide).Etoposide can be with commercially available, as trade mark isForm administration.Teniposide can be with commercially available, if trade mark is VM26-'s Form administration.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 It can be with commercially available, as trade mark isForm administration.
Term " microtubule active agent " refers to microtubule stabilizer, microwave destabiliser and microtubule polymerization inhibitor.It includes, but not It is limited to taxanes, such as taxol (paclitaxel) and Docetaxel (docetaxel)；Vinca alkaloids, such as Changchun Alkali (vinblastine), especially vinblastine sulfate, vincristine, especially vincristine sulphate and vinorelbine (vinorelbine)；discodermolides；Colchicin；And Epothilones and its derivative, such as epothilone B or D Or derivatives thereof.Taxol can be with commercially available, as trade mark isForm administration.Docetaxel can be with With commercially available, as trade mark isForm administration.Vinblastine sulfate can be with commercially available, such as trade mark For VINBLASTINForm administration.Vincristine sulphate can be with commercially available, as trade mark isShape Formula administration.Discodermolide can be obtained according to method disclosed in United States Patent (USP) US 5,010,099.It further include in WO 98/10121, United States Patent (USP) 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653,98/22461 and of WO Epothilones analog derivative disclosed in WO 00/31247, particularly preferred ebomycin A and/or B.
Term used herein " alkylating agent " includes, but are not limited to cyclophosphamide (cyclophosphamide), different ring phosphorus Amide (ifosfamide), melphalan (melphalan) or Nitrosourea (nitrosourea, such as BCNU or carmustine).Ring phosphinylidyne Amine can be with commercially available, such asForm administration.Ifosfamide can with commercially available, As trade mark is Form administration.
Term " histon deacetylase (HDAC) inhibitor " or " hdac inhibitor " refer to inhibition of histone deacetylase, and Compound with antiproliferative activity.It is included in compound disclosed in WO 02/22577, especially N- hydroxyl -3- [4- [[(2- ethoxy) [2- (1H- indol-3-yl) ethyl]-amino] methyl] phenyl] -2E-2- acrylamide, N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- base)-ethyl]-amino] methyl] phenyl] it -2E-2- acrylamide and its can pharmaceutically connect The salt received.Especially include Vorinostat (SAHA).
Term " antitumor antimetabolite " includes, but are not limited to 5-fluor-uracil (5-fluorouracil) or 5-FU； Capecitabine (capecitabine)；Gemcitabine (gemcitabine)；DNA demethylation reagent, such as U-18496 (5- ) and Decitabine (decitabine) azacytidine；Methotrexate (MTX) (methotrexate) and Edatrexate (edatrexate)；And antifol, such as pemetrexed (pemetrexed).Capecitabine can be with commercially available, such as trade mark ForForm administration.Gemcitabine can be with commercially available, as trade mark is's Form administration.This term further includes monoclonal antibody Herceptin (trastuzumab), can be with commercially available, as trade mark isForm administration.
Term used herein " platinum compounds " includes, but are not limited to carboplatin (carboplatin), cDDP (cis- Platin), cis-platinum (cisplatinum) and oxaliplatin (oxaliplatin).Carboplatin can be with commercially available, as trade mark isForm administration.Oxaliplatin can be with commercially available, as trade mark isForm Administration.
Term used herein " targeting/reduction albumen or lipid kinase activity or albumen or lipid phosphatase activeization Close the compound of object or other anti-angiogenesis " include, but are not limited to protein tyrosine kinase and/or serine and/or Threonine inhibitor or lipid kinase inhibitors, such as
A) it targets, reduces or inhibit platelet derived growth factor receptor (PDGFR) active compound；Targeting reduces Or inhibit the active compound of PDGFR, the compound of especially inhibition pdgf receptor includes N- phenyl-2-pyrimidine-amine derivatives, Such as Imatinib (imatinib), SU101, SU6668, GFB-111 etc.；
B) target, reduce or inhibit fibroblast growth factor acceptor (FGFR) active compound；
C) target, reduce or inhibit insulin-like growth factor receptor -1 (IGF-1R) active compound；Targeting reduces Or inhibiting the active compound of IGF-1R, the compound of especially inhibition IGF-1 receptor active includes those in patent WO 02/ Compound disclosed in 092599；
D) targeting, reduction or the compound for inhibiting Trk receptor tyrosine kinase family active；
E) targeting, reduction or the compound for inhibiting Axl Receptor Tyrosine Kinase family active；
F) targeting, reduction or the compound for inhibiting c-Met receptor active；
G) targeting, reduction or the compound for inhibiting Kit/SCFR receptor tyrosine kinase activity；
H) target, reduce or inhibit C-kit receptor tyrosine kinase (a part in PDGFR family) active chemical combination Object；Targeting, the compound for reducing or inhibiting C-kit receptor tyrosine kinase family active, especially inhibit the change of c-Kit receptor Close object, including Imatinib (imatinib) etc.；
I) it targets, reduce or inhibit c-Abl family and their gene fusion products, such as the change of BCR-Abl kinase activity Close object；Targeting, the compound for reducing or inhibiting c-Abl family member and their gene fusions include N- phenyl -2- pyrimidine - Amine derivative, such as Imatinib, PD180970, AG957, NSC 680410, from the PD173955 of ParkeDavis
J) it targets, Raf family member in reduction or inhibition protein kinase C (PKC) and serine/threonine kinases, MEK, SRC, JAK, FAK, PDK and Ras/MAPK family member, Pl (3) kinase families member or Pl (3) kinases associated kinase family at The compound of member and/or cell cycle protein dependent kinase family (CDK) member activity；Especially those are in United States Patent (USP) Staurosporine derivatives disclosed in US 5,093,330, such as midostaurin (midostaurin)；More examples of compounds It further include UCN-01；Safingol (safingol)；BAY 43-9006；Bryostatin 1；Piperazine Li Fuxin (Perifosine)；She Mo Fuxin (llmofosine)；RO 318220 and RO 320432；GO 6976；Isis 3521；LY333531/LY379196； Isoquinoline compound, such as in WO 00/09495 those disclosed；FTIs；PD184352；Or a kind of QAN697 (P13K suppression Preparation)；
K) target, reduce or inhibit the active compound of protein tyrosine kinase inhibitor；Targeting reduces or inhibits The active compound of protein tyrosine kinase inhibitor includes GleevecOr tyrosine phosphorylation Inhibitor；The preferred low molecular weight of tyrphostin (Mr < 1500) compound or its pharmaceutically acceptable salt, especially Its compound for being selected from the third two eyeball class of two eyeball class of benzyl allyl or S- aryl sheet or Double bottom object quinolines, is further selected from tyrosine Phosphorylation inhibitor A23/RG-50810, AG 99, tyrphostin AG 213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44 (+) Enantiomer, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG957 and Adaphostin (4- { [(2,5- dihydroxy phenyl) methyl] amino }-benzoic acid Buddha's warrior attendant alkyl ester, NSC 680410, adaphostin)；With
I) target, reduce or inhibit receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, The equal or heterodimer of ErbB3, ErbB4) active compound；Targeting reduces or inhibits Epidermal Growth Factor Receptor Family Compound refer in particular to inhibit EGF receptor family member (such as EGF receptor, ErbB2, ErbB3, ErbB4, or can with EGF or The substance that EGF associated ligands combine) compound, albumen or antibody, is especially summarized in the following documents or it is specific openly Compound, albumen or monoclonal antibody: WO 97/02266 (such as embodiment 39), EP 0564409, WO 99/03854, EP 0520722、EP 0566226、EP 0787722、EP 0837063、US 5,747,498、WO 98/10767、WO 97/ 30034, WO 97/49688 and WO 97/38983, WO 96/30347 (such as CP 358774), 96/33980 (such as compound of WO ZD 1839), WO 95/03283 (such as compound ZM105180), Herceptin (Trastuzumab), Cetuximab, Iressa, Erlotinib, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, E7.6.3, and 7H- pyrrolo--[2, the 3-d] pyrimidine derivatives being disclosed in WO 03/013541.
In addition, anti-angiogenic compounds include having other active mechanisms (for example, inhibiting not with albumen or lipid kinase It is related) compound, such as ThalidomideAnd TNP-470.
The compound of targeting, reduction or inhibition albumen or lipid kinase activity is -1 inhibitor of phosphatase, phosphatase 2A suppression Preparation, PTEN inhibitor or CDC25 inhibitor, such as okadaic acid or derivatives thereof.
The compound of Cell differentiation inducing activity process is vitamin A acid, α-, γ-or Delta-Tocopherol, α-, γ-or δ-fertility triolefin Phenol.
Term used herein " cyclooxygenase-2 inhibitors " includes, but are not limited to Cox-2 inhibitor, and 5- is alkyl-substituted 2- fragrant amino phenylacetic acid and its derivative, such as celecoxibRofecoxibEtoricoxib, Valdecoxib or 5- alkyl -2- fragrant amino phenylacetic acid, such as 5- methyl -2- (the chloro- 6'- fluoroanilino of 2'-) phenylacetic acid or reed Rice examines former times
Term used herein " diphosphonate " includes, but are not limited to Etidronic Acid, Clodronate, Tiludronic Acid, pa rice phosphine Acid, alendronic acid, ibandronic acid, Risedronic Acid and zoledronic acid.Etidronic Acid can be with commercially available, such as trade nameForm administration.Clodronate can be with commercially available, such as trade name's Form administration.Tiludronic Acid can be with commercially available, such as trade nameForm administration；Pamidronic acid (Pamidronic acid) can be with commercially available, such as trade name ArediaTM(AREDIATM) form administration；Alendronic acid It can be with commercially available, such as trade nameForm administration；Ibandronic acid can be with commercially available, such as Trade nameForm administration；Risedronic Acid can be with commercially available, such as trade nameForm administration；Zoledronic acid can be with commercially available, such as trade name Form administration.
Term " mTOR inhibitors ", which refers to, inhibits mammal rapamycin (mTOR) target protein, with antiproliferative activity Compound, such as sirolimus (sirolimus,), everolimus (CERTICANTM), CCI-779 and ABT578。
Term used herein " heparanase inhibitors " refers to, targets, reduces or inhibit acetylsulfuric acid depolymerized heparin Compound.This term includes, but unlimited PI-88.
Term used herein " biological response modifiers " refers to lymphokine or interferon, such as interferon gamma.
Term used herein " the carcinogenic hypotype of Ras (such as H-Ras, K-Ras or N-Ras) inhibitor " refers to targeting, reduces Or inhibit the compound of Ras carcinogenic activity, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra)。
Term used herein " telomerase inhibitor " refers to the compound targeted, lowered or inhibited telomerase activity.Target To, reduce or inhibit the compound of telomerase activation to refer in particular to inhibit the compound of telornerase receptor, such as telomere mycin.
Term used herein " methionine aminopeptidase inhibitor " refers to targeting, reduction or inhibits methionine aminopeptidase activity Compound.Targeting, reduction or the inhibition active compound of methionine aminopeptidase include bengamide or derivatives thereof.
Term used herein " proteasome inhibitor " refers to targeting, reduction or the active chemical combination of protease inhibition body Object.Targeting, reduction or the active compound of protease inhibition body include PS-341 and MLN 341.
Term used herein " Matrix Metalloproteinase Inhibitors " or " MMP inhibitor " include, but are not limited to glue Former albumen peptides and non-peptide inhibitor, tetracycline derivant, such as hydroxamic acid peptide inhibitor Batimastat (batimastat) With its equivalent homologue Marimastat (marimastat, BB-2516) of oral bio, prinomastat (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996。
Term used herein " for treating the reagent of neoplastic hematologic disorder " includes, but are not limited to FMS- sample tyrosine kinase Inhibitor.Targeting reduces or inhibits FMS- sample tyrosine kinase receptor (Flt-3R) active compound；Interferon, 1-b-D- Arabinofuranosyl adenin cytimidine (ara-c) and bisulfan；With ALK inhibitor, such as targeting reduces or inhibits anaplastic lymphoma kinase Compound.
Targeting, reduce or inhibit FMS- sample tyrosine kinase receptor (Flt-3R) compound especially inhibit Flt-3 by The compound of body kinase families member, albumen or antibody, such as PKC412, midostaurin (midostaurin), staurosporin Derivative, SU11248 and MLN518.
The endogenous that term used herein " HSP90 inhibitor " includes, but are not limited to targeting, reduces or inhibit HSP90 The compound of atpase activity；Pass through the degradation of ubiquitin protein body enzymatic pathway, targeting, the chemical combination for reducing or inhibiting HSP90 client protein Object.Targeting, the Endogenous ATP for reducing or the compound of the Endogenous ATP enzymatic activity of HSP90 being inhibited to refer in particular to inhibit HSP90 The compound of enzymatic activity, albumen or antibody, for example, 17- allyl amino, 17-AAG (17AAG), The relevant compound of his geldanamycin, red shell rhzomorph and hdac inhibitor.
Term used herein " antiproliferation antibodies " includes, but are not limited to Herceptin (HERCEPTINTM), toltrazuril Monoclonal antibody-DM1, Tarceva (TARCEVATM), bevacizumab (AVASTINTM), Rituximab PR064553 (anti-CD40) and 2C4 antibody.Antibody means complete monoclonal antibody, polyclonal antibody, complete by least two The multi-specificity antibody and antibody fragment (as long as they have desired bioactivity) that whole antibody is formed.It is thin for acute marrow For the treatment of born of the same parents' sample leukaemia (AML), the leukemia therapy of disclosed compound of present invention and standard can be used in combination, especially It is used in combination with the therapy treated for AML.Specifically, disclosed compound of present invention and such as farnesyl- can be turned It moves enzyme inhibitor and/or other is used for drug such as daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, the rice of AML treatment Anthraquinone, idarubicin, carboplatin and PKC412 is ask to be administered in combination.
Compound disclosed by the invention can also be advantageously utilised in combination with other compounds or with other therapeutic agents In combination, especially other anti-malarial agents.Such anti-malarial agents include, but are not limited to chloroguanide (proguanil), Chlorproguanil (chlorproguanil), trimethoprim (trimethoprim), chloroquine (chloroquine), Mefloquine (mefloquine), Lumefantrine (lumefantrine), Atovaquone (atovaquone), pyrimethamine-sulfanilamide (SN) (pyrimethamine- Sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinindium (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfanilamide (SN) Class drug, qinghaosu, Arteflene (arteflene), Artemether, Artesunate, primaquine, sucking NO, L-arginine, dipropyl Alkene triamine NONO ester (NO donor), Rosiglitazone (PPARy agonist), active carbon, hematopoietin, levamisol, And Malaridine.
Compound disclosed by the invention also may be advantageously used with the combination with other compounds or the group of other therapeutic agents In conjunction, such as treatment leishmaniasis, trypanosomiasis, the other therapeutic agents of toxoplasmosis and cerebral cysticercosis.Such medicament includes, but It is not limited to nivaquin, atovaquone-proguanil, Artemether-lumenfantrine, quinine sulfate, Artesunate, quinine, fortimicin (doxycycline), clindamycin (clindamycin), meglumine antimony (meglumine antimoniate), gluconic acid Antimony sodium (sodium stibogluconate), Miltefosine (miltefosine), ketoconazole (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposome, paromomycin (paromomycine), Eflornithine (eflornithine), nifurtimox (nifurtimox), suramin (suramin), melarsoprol (melarsoprol), sprinkle Ni Songlong (prednisolone), benzimidazole, sulphadiazine, pyrimethamine, synergistic sulfonamide methylisoxazole, radonil, Ah Miramycin (azitromycin), Atovaquone, dexamethasone, praziquantel, albendazole (albendazole), beta-lactam, Fluoroquinolones medicine, macrolides medicine, aminoglycoside medicine, sulphadiazine and pyrimethamine.
The structure of the active constituent determined by code name, common name or trade name and its preparation can be from classic " The Merck Index (Merck index) " current edition (such as M.J.O ' Neil et al. compile ' The MerckIndex ', the 13rd Version, Merck Research Laboratories, 2001) or from database (such as Patents International (example Such as IMS World Publications)) in know.
Compound above-described, being applied in combination with disclosed compound of present invention, can be by those skilled in the art Member prepares and is administered according to above-mentioned method recorded in the literature.
Compound disclosed by the invention can also combine with therapeutic process, improve curative effect.For example, give hormone therapy or Special radiotherapy.Compound disclosed by the invention is used especially as radiosensitizer, it is especially useful in those radiotherapies The oncotherapy of sensibility weak ground.
" joint " indicates the medicine box of the fixing joint in single dose unit form or the part for administering drug combinations, In compound disclosed by the invention and joint companion can be in same time individual application or can be in certain time interval It inside applies respectively, joint companion is especially made to show cooperation, for example act synergistically.Term " co-administered " as used herein Or " administering drug combinations " etc. are intended to include single individual (such as the patient) for being applied to selected joint companion and needing it, and anticipate Be intended to include wherein substance without going through identical administration route or the therapeutic scheme being administered simultaneously.Term " drug as used herein Joint " indicates to mix more than one active constituents or combine obtained product, and both fixed connection including active constituent Close also includes that on-fixed is combined.Term " fixing joint " indicates active constituent compound for example disclosed by the invention, and joint companion It is administered simultaneously in the form of single entities or dosage in patient.Term " on-fixed joint " indicates that the active constituent such as present invention discloses Compound Compound, and joint companion be used as corpus separatum simultaneously, jointly or without specific time limitation ground successively to patient Administration, wherein the administration mode provides the treatment effective level of two kinds of compounds in patient's body.The latter applies also for chicken tail Wine therapy, such as apply three or more active constituents.
Treatment method
In one embodiment, treatment method disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention includes by having The patient needed gives the disclosed compound of present invention of safe and effective amount or the pharmaceutical composition comprising disclosed compound of present invention, Method to treat disease mentioned above.
In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with It is administered by any suitable administration route, including Formulations for systemic administration and local administration.Formulations for systemic administration includes oral administration, stomach and intestine External administration, cutaneous penetration and rectally.Typically parenteral refers to through injection or administered by infusion, including intravenous, Intramuscular and subcutaneous injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasally Administration.In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with It is oral administration.In another embodiment, disclosed compound of present invention or the pharmaceutical composition comprising disclosed compound of present invention Object can be inhalation.In a further embodiment, disclosed compound of present invention or it can be comprising disclosed compound of present invention Intranasal administration.
In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with Once daily, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, every It is administered once, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, daily It is administered twice.It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.It is of the invention public Open medicine generation of the appropriate dosage regimen of compound or the pharmaceutical composition comprising disclosed compound of present invention depending on the compound Kinetic property, such as dilution, distribution and half-life period, these can be by determination of technical staff.In addition, disclosed compound of present invention Or the appropriate dosage regimen of the pharmaceutical composition comprising disclosed compound of present invention, it the duration including implementing the program, takes Certainly in treated disease, the severity of disease being treated, the age of patient under consideration and physical condition, patient under consideration Medical history, the simultaneously factor within the scope of technical staff's knowledge and experience such as property, desired therapeutic effect of therapy.It is such Technical staff should also be understood that the reaction for individual patient to dosage regimen, or individual patient needs to become as time goes by When change it may require that adjust the dosage regimen of matters.
Disclosed compound of present invention can be administered simultaneously, or before it or later with one or more other therapeutic agents. The compounds of this invention can be administered with other therapeutic agents by identical or different administration route respectively, or therewith with medicine group Solvate form administration.
For the individual of about 50-70kg, the present invention discloses pharmaceutical composition and combination can be containing about 1-1000mg, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active constituent Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination be depending on individual species, weight, the age and Individual instances, treated disease (disorder) or disease (disease) or its severity.The doctor for having common technical ability Teacher, clinician or animal doctor can be easy to determine to prevent, treat or inhibit disease (disorder) or disease (disease) development The effective quantity of each active constituent needed in the process.
Dose Characteristics cited above using advantageous mammal (such as mouse, rat, dog, monkey) or its from It is confirmed in the external and in vivo studies of body organ, tissue and sample.Disclosed compound of present invention is with solution, such as aqueous solution form Use in vitro, can also such as enteral of suspension or aqueous solution form in vivo, it is parenterally, especially intravenous to use.
In one embodiment, the treatment effective dose of disclosed compound of present invention is daily about 0.1mg to about 2, 000mg.Its pharmaceutical composition should provide the compound of about 0.1mg to about 2,000mg dosage.In a specific embodiment In, the pharmaceutical dosage unit forms of preparation can provide about 1mg to about 2,000mg, and about 10mg to about 1,000mg, about 20mg is to about 500mg, or about 25mg to about 250mg main active or each main component in every dosage unit form combination.One In specific embodiment, the pharmaceutical dosage unit forms of preparation can provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.
In addition, compound disclosed by the invention can be administered with prodrug forms.In the present invention, disclosed compound of present invention " prodrug " be that can finally release the functional derivatives of disclosed compound of present invention in vivo when administering to a patient.In the past When medicine form gives compound disclosed by the invention, one of implementable following manner of those skilled in the art or more: (a) Change the internal onset time of compound；(b) the internal acting duration of compound is changed；(c) the internal of compound is changed Conveying or distribution；(d) the internal solubility of compound is changed；And the side effect or other difficult points for (e) overcoming compound to be faced. The typical functional derivatives of prodrug are used to prepare, comprising in vivo chemically or the mode of the enzyme compound that cracks Variant.Comprising preparing these variants of phosphate, amide, ester, monothioester, carbonate and carbaminate to those skilled in the art It is well-known for member.
General synthesis step
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.
The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy is recorded using Bruker 300MHz, 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopy with CDC13、DMSO-d6、CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as Reference standard.When there is multiplet, following abbreviation will be used: s (singlet, unimodal), d (doublet, bimodal), T (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).
The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-M of Agilent (column model: Zorbax SB-C18,2.1 × 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%-95% (contains 0.1% The CH of formic acid3CN) in (H containing 0.1% formic acid2O the ratio in)), using electrospray ionisation (ESI), at 210nm/254nm, It is detected with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar type Number: NOVASEP50/80mm DAC), detected in 210nm/254nm with UV.
The use of logogram word below is through the present invention:
AcOH、HOAc、CH3COOH acetic acid
ACN,MeCN,CH3CN acetonitrile
Boc2O di-tert-butyl dicarbonate
BOC, Boc tert-butoxycarbonyl
The double diphenyl phosphines of BINAP 1,1'- dinaphthalene -2,2'-
N-BuOH n-butanol
Cbz-Cl benzyl chloroformate
CH2Cl2, DCM methylene chloride
CDC13Deuterated chloroform
Cs2CO3Cesium carbonate
DIEA、DIPEA、i-Pr2NEt diisopropyl ethyl amine
DMF dimethylformamide
DMAP 4-dimethylaminopyridine
DMSO dimethyl sulfoxide
EDC, EDCI 1- (3- dimethylamino-propyl) -3- ethyl-carboddiimide hydrochloride
EDTA ethylenediamine tetra-acetic acid
Et3N, TEA triethylamine
EtOAc, EA ethyl acetate
G grams
H hours
HATU 2- (7- azepine -1H- benzotriazole -1- base) -1,1,3,3- tetramethylurea hexafluorophosphoric acid ester
HCl hydrochloric acid
HOAT 1- hydroxyl -7- azepine benzotriazole
K2CO3Potassium carbonate
LDA lithium diisopropyl amido
ML, ml milliliters
Min minutes
NaHCO3Sodium bicarbonate
NH4Cl ammonium chloride
M mol/L
Na2CO3Sodium carbonate
Na2SO4Sodium sulphate
NaOH sodium hydroxide
NaH sodium hydride
T-BuONa sodium tert-butoxide
Pd/C palladium/carbon
Pd(OH)2Palladium dydroxide
Pd(OAc)2Palladium acetate
Pd2(dba)3Three (dibenzylidene indenes acetone) two palladiums
PE petroleum ether (60~90 DEG C)
RT, rt, r.t. room temperature
Rt retention time
TFA trifluoroacetic acid
The typical synthesis step of disclosed compound of present invention is prepared as shown in following synthetic schemes 1~8.Unless in addition saying It is bright, each R1、R2、R4, Z, Ar and W have as described in the present invention definition；PG is blocking group, and X is halogen atom；P is 0,1,2, 3,4 or 5；Q is 0,1,2 or 3.
Synthetic schemes 1:
With such as formula(5)The general synthesis that the disclosed compound of present invention of shown structure can be described by synthetic schemes 1 Method is prepared, and specific steps can refer to embodiment.In synthetic schemes 1, substituted 2,4- dichloro pyrimidine (1) and amine chemical combination Object (2) in suitable alkali, such as triethylamine or diisopropyl ethyl amine, in the presence of react, obtain compound (3).Compound (3) with Optionally replace 1H- pyrazoles -4- amine (4) or its hydrochloride, in acid, under the action of trifluoroacetic acid or aqueous hydrochloric acid solution, or Alkali, under the action of triethylamine, diisopropyl ethyl amine or cesium carbonate, or in suitable Pd catalyst, such as Pd (OAc)2、Pd (dppf)Cl2Or Pd2(dba)3Under the action of, it reacts under microwave irradiation conditions, the suitable temperature range of the reaction is 50 DEG C~200 DEG C between, generate kinase inhibitor (5)。
Synthetic schemes 2:
With such as formula(7)The general synthesis that the disclosed compound of present invention of shown structure can be described by synthetic schemes 2 Method is prepared, and specific steps can refer to embodiment.In synthetic schemes 2, intermediate (3) with the 1H- pyrazoles -3- that optionally replaces Amine (6) or its hydrochloride, in acid, under the action of trifluoroacetic acid or aqueous hydrochloric acid solution, or in alkali, such as triethylamine, diisopropyl Under the action of ethylamine or cesium carbonate, or in suitable Pd catalyst, such as Pd (OAc)2、Pd(dppf)Cl2Or Pd2(dba)3 Under the action of, it reacts under microwave irradiation conditions, the suitable temperature range of the reaction generates between 50 DEG C~200 DEG C Kinase inhibitor (7)。
Synthetic schemes 3:
With such as formula(9)The general synthesis that the disclosed compound of present invention of shown structure can be described by synthetic schemes 3 Method is prepared, and specific steps can refer to embodiment.In synthetic schemes 3, intermediate (3) with the 6- amino -2H- that optionally replaces Indazole (8) or its hydrochloride, in acid, under the action of trifluoroacetic acid or aqueous hydrochloric acid solution, or in alkali, such as triethylamine, diisopropyl Under the action of base ethylamine or cesium carbonate, or in suitable Pd catalyst, such as Pd (OAc)2、Pd(dppf)Cl2Or Pd2 (dba)3Under the action of, it reacts under microwave irradiation, the suitable temperature range of the reaction is raw between 50 DEG C~200 DEG C At kinase inhibitor (9)。
Synthetic schemes 4:
With such as formula(3)The general synthesis side that the midbody compound of shown structure can also be described by synthetic schemes 4 Method is prepared, and specific steps can refer to embodiment.In synthetic schemes 4, substituted 2,4- dichloro pyrimidine (1) and aminated compounds (10) in suitable alkali, if reacted in the presence of triethylamine or diisopropyl ethyl amine, obtain compound (11).Then, compound (11) and iodide (12) in highly basic, as react under the action of sodium hydride or sodium hydroxide generate midbody compound (3)。
Synthetic schemes 5:
With such as formula(17)The general synthesis that the disclosed compound of present invention of shown structure can be described by synthetic schemes 5 Method is prepared, and specific steps can refer to embodiment.In synthetic schemes 5, substituted 2,4- dichloro pyrimidine (1) and amine chemical combination Object (13) in suitable alkali, if reacted in the presence of triethylamine or diisopropyl ethyl amine, obtain compound (14).Compound (14) With optionally replace 1H- pyrazoles -4- amine (4) or its hydrochloride, in acid, under under the action of trifluoroacetic acid or aqueous hydrochloric acid solution, Or in alkali, under the action of triethylamine, diisopropyl ethyl amine or cesium carbonate, or in suitable Pd catalyst, such as Pd (OAc)2、Pd(dppf)Cl2Or Pd2(dba)3Under the action of, it reacts under microwave irradiation conditions, the suitable temperature of the reaction Range is spent between 50 DEG C~200 DEG C, generation compound (15).Compound (15) in protecting group in acid condition, such as three Fluoroacetic acid, the ethyl acetate solution of hydrochloric acid or other it is suitable under the conditions of remove, obtain compound (16).Compound (16) With aromatic compound(20)React under alkaline condition generate kinase inhibitor (17)。
Synthetic schemes 6:
With such as formula(14)The general synthesis side that the midbody compound of shown structure can also be described by synthetic schemes 6 Method is prepared, and specific steps can refer to embodiment.In synthetic schemes 6, substituted 2,4- dichloro pyrimidine (1) and aminated compounds (18) in suitable alkali, if reacted in the presence of triethylamine or diisopropyl ethyl amine, obtain compound (19).Then, compound (19) and iodide (12) in highly basic, such as sodium hydride or sodium hydroxide, under the action of react and generate midbody compound (14)。
Synthetic schemes 7:
With such as formula(23)The general synthesis that the disclosed compound of present invention of shown structure can be described by synthetic schemes 7 Method is prepared, and specific steps can refer to embodiment.In synthetic schemes 7, compound (14) with the 1H- pyrazoles-that optionally replaces 3- amine (6) or its hydrochloride, in acid, under under the action of trifluoroacetic acid or aqueous hydrochloric acid solution, or in alkali, such as triethylamine, two different Under the action of ethylamine or cesium carbonate, or in suitable Pd catalyst, such as Pd (OAc)2、Pd(dppf)Cl2Or Pd2 (dba)3Under the action of, react under microwave irradiation conditions, the suitable temperature range of the reaction 50 DEG C~200 DEG C it Between, it generates compound (21).Protecting group in compound (21) in acid condition, such as trifluoroacetic acid, the ethyl acetate of hydrochloric acid Solution or other it is suitable under the conditions of remove, obtain compound (22).Compound (22) and aromatic compound(20)In alkalinity Under the conditions of react generate kinase inhibitor (23)。
Synthetic schemes 8:
With such as formula(26)The general synthesis that the disclosed compound of present invention of shown structure can be described by synthetic schemes 8 Method is prepared, and specific steps can refer to embodiment.In synthetic schemes 8, compound (14) with the 6- amino-that optionally replaces 2H- indazole (8) or its hydrochloride, in acid, under under the action of trifluoroacetic acid or aqueous hydrochloric acid solution, or in alkali, such as triethylamine, two Under the action of diisopropylethylamine or cesium carbonate, or in suitable Pd catalyst, such as Pd (OAc)2、Pd(dppf)Cl2Or Pd2 (dba)3Under the action of, react under microwave irradiation conditions, the suitable temperature range of the reaction 50 DEG C~200 DEG C it Between, it generates compound (24).Protecting group in compound (24) in acid condition, such as trifluoroacetic acid, the ethyl acetate of hydrochloric acid Solution or other it is suitable under the conditions of remove, obtain compound (25).Compound (25) and aromatic compound(20)In alkalinity Under the conditions of react generate kinase inhibitor (26)。
Embodiment
1 6- of embodiment (4- ((the chloro- 2- of 5- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) piperidines - 1- yl)-nicotinonitrile
Step 1) (1- (5- cyanopyridine -2- base) piperidin-4-yl) t-butyl carbamate
By piperidin-4-yl t-butyl carbamate (3.00g, 15.00mmol), the chloro- nicotinonitrile of 6- (2.08g, 15.00mmol) and Na2CO3(3.20g, 30.19mmol) is dissolved in DMF (40mL), and reaction solution stirs 4 hours at 90 DEG C. After reaction, it is cooled to room temperature, is added water (120mL), and extracted with ethyl acetate (100mL × 3), combined organic phase is used Saturated salt solution (300mL) washing, anhydrous sodium sulfate are dried, filtered and are concentrated under reduced pressure.Gained residue is through petroleum ether and acetic acid The mixed solvent (10/1 (v/v), 80mL) of ethyl ester is beaten, and it is white solid (4.50g, yield that title compound, which is obtained by filtration, 99%).
LC-MS(ESI,pos.ion)m/z:247.0[(M-C4H8)+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.40 (d, J=2.36Hz, 1H), 7.62-7.59 (dd, J= 2.36Hz, 9.08Hz, 1H), 6.63 (d, J=9.08Hz, 1H), 4.45 (m, 1H), 4.36-4.33 (m, 2H), 3.75 (m, 1H), 3.14-3.07(m,2H),2.08-2.06(m,2H),1.45(s,9H),1.43-1.37(m,2H)。
Step 2) 6- (4- amino piperidine -1- base)-nicotinonitrile
(1- (5- cyanopyridine -2- base) piperidin-4-yl) t-butyl carbamate (1.79g, 5.92mmol) is dissolved in In methylene chloride (20mL), and at 0 DEG C, the ethyl acetate solution (3.0M, 6.0mL, 18mmol) of hydrogen chloride is added thereto, After reaction system is stirred at room temperature overnight, it is concentrated under reduced pressure.Residue is diluted with water (20mL), and with methylene chloride (30mL × 2) Extraction, the organic layer separated discard, and water phase is adjusted to pH=9 with saturated aqueous sodium carbonate, then, with methylene chloride and methanol The mixed solution of (10/1 (v/v), 30mL × 3) extracts.Merge organic phase, is washed with saturated brine (50mL), through anhydrous slufuric acid Sodium is dried, filtered and is concentrated under reduced pressure, and obtaining title compound is white solid (1.08g, yield 90%).
LC-MS(ESI,pos.ion)m/z:203.0[M+H]+；
1H NMR(300M Hz,CDCl3): δ (ppm) 8.39 (d, J=2.37Hz, 1H), 7.58 (dd, J=9.06Hz, 2.37Hz, 1H), 6.61 (d, J=9.09Hz, 1H), 4.39-4.32 (m, 2H), 3.05-2.05 (m, 3H), 1.96-1.90 (m, 2H),1.45-1.26(m,2H)。
Step 3) 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl)-nicotinonitrile
To 2,4,5- trichloropyrimidine (500mg, 2.75mmol) and 6- (4- amino piperidine -1- base)-nicotinonitrile In isopropanol (35mL) solution of (670mg, 3.3mmol), it is added triethylamine (560mg, 5.5mmol).Gained reaction system exists It stirs 2 hours, is cooled to room temperature at 80 DEG C, be concentrated under reduced pressure.DCM (50mL) and water (25mL) are added into gained residue, point Layer separates organic phase, and saturated common salt washes (20mL), and anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure, and gained residue is through silicon Plastic column chromatography (DCM/EtOAc (v/v)=15/1) purifying, obtaining title compound is white solid (750mg, yield 78%).
LC-MS(ESI,pos.ion)m/z:348.8[M+H]+；
1H NMR(300MHz,CDCl3) δ (ppm): 8.42 (d, J=3Hz, 1H), 8.05 (s, 1H), 6.66 (dd, J= 3Hz, 3Hz, 1H), 6.66 (d, J=9Hz, 1H), 5.35 (d, J=9Hz, 1H), 4.38 (m, 3H), 3.20 (t, J=12Hz, 2H), 2.19 (d, J=9Hz, 2H), 1.55 (m, 2H).
Step 4) 6- (4- ((the chloro- 2- of 5- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) piperidines -1- Base)-nicotinonitrile
To 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl)-nicotinonitrile (120mg, 0.34mmol) In isopropanol (7mL) solution of 1- methyl-1 H- pyrazoles -4- amine (40mg, 0.41mmol), the aqueous hydrochloric acid solution of 3M is added (1.5mL).Gained reaction system is warming up to 80 DEG C, stirs 12 hours.After reaction, it is cooled to room temperature, is concentrated under reduced pressure.To institute It obtains and DCM (30mL) and water (15mL) is added in residue, layering separates organic phase, and saturated common salt washes (20mL), anhydrous slufuric acid Sodium is dried, filtered and is concentrated under reduced pressure, and gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=120/1), obtains title Compound is beige solid (90mg, yield 63.8%).
LC-MS(ESI,pos.ion)m/z:409.8[M+H]+；
1H NMR(300MHz,DMSO-d6) δ (ppm): 9.05 (s, 1H), 8.50 (d, J=3Hz, 1H), 7.85 (m, 2H), 7.77 (s, 1H), 7.43 (s, 1H), 6.99 (d, J=6Hz, 1H), 6.75 (d, J=6Hz, 1H), 4.53 (m, 2H), 4.28 (m, 1H), 3.78 (s, 3H), 3.08 (t, J=13.5Hz, 2H), 1.97 (m, 2H), 1.59 (m, 2H).
2 6- of embodiment (4- (the chloro- 2- of 5- (1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) piperazine Pyridine -1- base)-nicotinonitrile
To 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl)-nicotinonitrile (100mg, 1,5- dimethyl -1H- pyrazoles -3- amine (40mg, 0.41mmol) and trifluoro are added in n-butanol (5mL) solution 0.286mmol) Acetic acid (212 μ L, 2.86mmol).Gained reaction system is warming up to 120 DEG C, tube sealing reaction 24 hours, is cooled to reaction system After room temperature, it is concentrated under reduced pressure.Ethyl acetate (50mL) dilution is added into gained residue, is then successively washed with water (15mL × 3), Saturated common salt washes (20mL), and anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (DCM/ EtOAc/MeOH (v/v/v)=25/5/1) purifying, obtaining title compound is white solid (53mg, yield 44%).
LC-MS(ESI,pos.ion)m/z:423.7[M+H]+；
1H NMR(300MHz,DMSO-d6) δ (ppm): 9.17 (s, 1H), 8.49 (d, J=2.3Hz, 1H), 7.87 (s, 1H), 7.84 (dd, J=9.1,2.3Hz, 1H), 7.00 (d, J=9.2Hz, 1H), 6.78 (d, J=7.8Hz, 1H), 6.35 (s, 1H),4.57-4.51(m,2H),4.32-4.19(m,1H),3.60(s,3H),3.07-2.99(m,2H),2.22(s,3H), 2.00-1.95(m,2H),1.65-1.52(m,2H)。
3 6- of embodiment (4- (the chloro- 2- of 5- (5- methyl-1 H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) piperidines -1- Base)-nicotinonitrile
To 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl)-nicotinonitrile (100mg, 5- methyl-1 H- pyrazoles -3- amine (114mg, 0.858mmol) and trifluoro are added in aqueous isopropanol (10mL) 0.286mmol) Acetic acid (106 μ L, 1.43mmol).Gained reaction system is warming up to 80 DEG C, tube sealing reaction 48 hours, is cooled to room to reaction system Wen Hou is concentrated under reduced pressure into 0.5mL.Water (20mL) dilution is added into gained residue, then uses the NaHCO of 1M3Aqueous solution tune To pH=8, then extracted with methylene chloride (15mL × 5).Combined organic phase washes (30mL) with saturated common salt, anhydrous sulphur Sour sodium is dried, filtered and is concentrated under reduced pressure, and gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=30/1), must be marked Topic compound is white solid (48mg, yield 41%).
LC-MS(ESI,pos.ion)m/z:409.7[M+H]+；
1H NMR(300MHz,DMSO-d6) δ (ppm): 11.76 (brs, 1H), 9.11 (s, 1H), 8.49 (d, J=1.8Hz, 1H), 7.88 (s, 1H), 7.84 (dd, J=9.1,2.4Hz, 1H), 7.00 (d, J=9.1Hz, 1H), 6.80 (brs, 1H), 6.32 (brs,1H),4.57-4.51(m,2H),4.33-4.21(m,1H),3.07-2.98(m,2H),2.19(s,3H),2.00-1.95 (m,2H),1.67-1.50(m,2H)。
4 6- of embodiment (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) amino) Piperidin-1-yl)-nicotinonitrile
To 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl)-nicotinonitrile (100mg, 0.29mmol) In isopropanol (10mL) solution of 2,3- dimethyl -2H- indazole -6- amine hydrochlorate (68mg, 0.35mmol), the salt of 3M is added Aqueous acid (1mL).Gained reaction system is warming up to 80 DEG C, stirs 24 hours.After reaction system is cooled to room temperature, depressurize dense Contracting.DCM (30mL) and water (15mL) are added into gained residue, layering separates organic phase, and saturated common salt washes (20mL), Anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure, and gained residue is pure through silica gel column chromatography (DCM/MeOH (v/v)=100/1) Change, obtaining title compound is white solid (90mg, yield 63.8%).LC-MS(ESI,pos.ion)m/z:474.1[M+H]+；
1H NMR(300MHz,DMSO-d6) δ (ppm): 9.23 (s, 1H), 8.51 (d, J=2.4Hz, 1H), 8.12 (d, J= 1.5Hz,1H),7.98(s,
1H), 7.86 (dd, J=9.0Hz, J=2.4Hz, 1H), 7.48 (d, J=5.7Hz, 1H), 7.15 (dd, J= 9.0Hz, J=1.5Hz, 1H), 7.02 (d, J=9.3Hz, 1H), 6.92 (d, J=7.8Hz, 1H), 4.58-4.52 (m, 2H), 4.43-4.30(m,1H),3.94(s,3H),3.08-3.17(m,2H),2.53(s,3H),2.05-1.98(m,2H),1.69- 1.55(m,2H)。
5 6- of embodiment (4- ((the chloro- 2- of 5- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) (methyl) ammonia Base) piperidin-1-yl)-nicotinonitrile
Step 1) (1- (5- cyanopyridine -2- base) piperidin-4-yl) (methyl) t-butyl carbamate
To methyl (piperidin-4-yl)-t-butyl carbamate (620mg, 2.88mmol), the chloro- nicotinonitrile of 6- In DMF (20mL) solution of (200mg, 1.44mmol), K is added2CO3(600mg,4.32mmol).Reaction system is at 120 DEG C After stirring 2 hours, it is cooled to room temperature, and be concentrated under reduced pressure.DCM (40mL) is added into gained residue, and is washed with water (20mL), Anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure, and gained residue is purified through silica gel column chromatography (100%DCM), is obtained titled Conjunction object is white solid (394mg, yield 86%).
LC-MS(ESI,pos.ion)m/z:316.8[M+H]+；
1H NMR(300MHz,CDCl3) δ (ppm): 8.40 (d, J=2.4Hz, 1H), 7.60 (dd, J=2.4Hz, J= 9Hz, 1H), 6.61 (d, J=9Hz, 1H), 4.51-4.56 (m, 3H), 2.91-3.01 (m, 1H), 2.70 (s, 4H), 1.80- 1.74(m,2H),1.55-1.69(m,2H),1.45(s,9H)。
Step 2) 6- (4- (methyl) amino) piperidin-1-yl)-nicotinonitrile
To (1- (5- cyanopyridine -2- base) piperidin-4-yl) (methyl) t-butyl carbamate (430mg, 1.36mmol) Methylene chloride (40mL) solution in, be added trifluoroacetic acid (2.33g, 20.4mmol), it is small that reaction system stirs 6 at 50 DEG C When, it then cools to room temperature, and be concentrated under reduced pressure.DCM (40mL) dilution is added into gained residue, and successively uses the hydrogen-oxygen of 1M Change sodium water solution (30mL) washing, saturated salt solution (50mL) washing is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, obtain It is yellow oil (265mg, yield 100%) to title compound.
LC-MS(ESI,pos.ion)m/z:216.9[M+1]+；
1H NMR(300M Hz,CDCl3) δ (ppm): 8.39 (d, J=2.4Hz, 1H), 7.58 (dd, J=2.4Hz, J= 9Hz, 1H), 6.61 (d, J=9Hz, 1H), 4.33 (m, 2H), 3.07 (m, 2H), 2.69 (m, 1H), 2.47 (s, 3H), 1.99 (m, 2H),1.36(m,2H)。
Step 3) 6- (4- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) piperidin-1-yl)-nicotinonitrile
To 2,4,5- trichloropyrimidine (185mg, 1.02mmol) and 6- (4- (methyl) amino) piperidin-1-yl) -3- cyano pyrrole In isopropanol (40mL) solution of pyridine (265mg, 1.224mmol), it is added triethylamine (206mg, 2.04mmol).Gained reactant It ties up at 80 DEG C and stirs 2 hours, be cooled to room temperature, and be concentrated under reduced pressure.DCM (50mL) and water are added into gained residue (30mL), layering, separates organic phase, saturated salt solution (20mL) is washed, and anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure, gained Residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=8/1), and obtaining title compound is white solid (266mg, yield 72%).
1H NMR(300MHz,CDCl3) δ (ppm): 8.42 (d, J=2.4Hz, 1H), 8.09 (s, 1H), 7.62 (dd, J= 2.1Hz, J=9.3Hz, 1H), 6.66 (d, J=9Hz, 1H), 5.66-4.73 (m, 1H), 4.56-4.64 (m, 2H), 3.06 (s, 3H),3.10-3.00(m,2H),1.96-1.91(m,2H),1.87-1.74(m,2H)。
Step 4) 6- (4- ((the chloro- 2- of 5- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) (methyl) amino) Piperidin-1-yl)-nicotinonitrile
To 6- (4- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) piperidin-1-yl)-nicotinonitrile (250mg, 0.69mmol) and in isopropanol (25mL) solution of 1- methyl-1 H- pyrazoles -4- amine (80mg, 0.82mmol), the salt of 3M is added Aqueous acid (2.5mL).Gained reaction system is warming up to 80 DEG C, stirs 24 hours, then cools to room temperature, and be concentrated under reduced pressure. DCM (50mL) and water (30mL) are added into gained residue, layering separates organic phase, and saturated common salt washes (20mL), anhydrous Sodium sulphate is dried, filtered and is concentrated under reduced pressure, and gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=100/1), is obtained Title compound is white solid (230mg, yield 78.8%).
LC-MS(ESI,pos.ion)m/z:423.7[M+H]+；
1H NMR(300MHz,DMSO-d6) δ (ppm): 9.15 (brs, 1H), 8.49 (d, J=2.4Hz, 1H), 7.98 (s, 1H), 7.83 (dd, J=2.4Hz, J=6.3Hz, 1H), 7.74 (brs, 1H), 7.44 (s, 1H), 7.01 (d, J=9.0Hz, 1H),4.65-4.59(m,2H),4.42-4.53(m,1H),3.78(s,3H),3.06-2.97(m,2H),2.98(s,3H), 1.85-1.72(m,4H)。
6 6- of embodiment (4- (methyl (5- methyl -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) piperidin-1-yl)-nicotinonitrile
Step 1) 6- (4- ((the chloro- 5- methylpyrimidine -4- base of 2-) amino) piperidin-1-yl)-nicotinonitrile
Triethylamine is added into ethyl alcohol (25mL) solution of the chloro- 5- methylpyrimidine (401.3mg, 2.462mmol) of 2,4- bis- (747.5mg, 7.387mmol) and 6- (4- amino piperidine -1- base)-nicotinonitrile hydrochloride (704.2mg, 2.950mmol). Gained reaction system is warming up to reflux, stirs 22 hours, is cooled to room temperature to reaction system, is concentrated under reduced pressure.Gained residue warp Silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, obtaining title compound is white solid (490mg, yield 60.7%).
LC-MS(ESI,pos.ion)m/z:328.9[M+H]+。
Step 2) 6- (4- ((the chloro- 5- methylpyrimidine -4- base of 2-) (methyl) amino) piperidin-1-yl)-nicotinonitrile
At 0 DEG C, to the anhydrous tetrahydro furan of sodium hydride (91.1mg, 2.28mmol, 60% are dispersed in mineral oil) In (10mL) suspension, 6- (4- ((the chloro- 5- methylpyrimidine -4- base of 2-) amino) piperidin-1-yl)-nicotinonitrile is instilled Anhydrous tetrahydro furan (15mL) solution of (490mg, 1.490mmol).Gained reaction mixture moves to be stirred at room temperature 30 minutes after, Iodomethane (423.8mg, 2.986mmol) is added dropwise thereto.After adding, reaction system continues stirring 6 hours at room temperature, again It is added iodomethane (423.8mg, 2.986mmol).After being stirred overnight, water (50mL) quenching reaction is added into reaction system, uses second Acetoacetic ester (100mL × 3) extraction.Combined organic layer washes (100mL) through saturated common salt, and anhydrous sodium sulfate dries, filters simultaneously It is concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=3/2), and it is faint yellow for obtaining title compound Solid (120mg, yield 23.5%).
LC-MS(ESI,pos.ion)m/z:342.9[M+H]+。
Step 3) 6- (4- (methyl (5- methyl -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) Piperidin-1-yl)-nicotinonitrile
By 6- (4- ((the chloro- 5- methylpyrimidine -4- base of 2-) (methyl) amino) piperidin-1-yl)-nicotinonitrile (120mg, 0.3501mmol), DIPEA (146.2mg, 1.131mmol) and 1- methyl-1 H- pyrazoles -4- amine hydrochlorate (76.7mg, It 0.574mmol) being dissolved in n-BuOH (3mL), gained reaction system is warming up to 150 DEG C, and tube sealing reaction 20 hours, to reaction system It is cooled to room temperature, is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=40/1), is obtained faint yellow Solid.It is white solid (78.6mg, yield 55.7%) that this crude product is recrystallized to give title compound in acetone.
LC-MS(ESI,pos.ion)m/z:404.0[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 9.13 (s, 1H), 8.48 (d, J=2.3Hz, 1H), 7.83 (dd, J =9.1,2.4Hz, 1H), 7.77 (s, 2H), 7.47 (s, 1H), 6.99 (d, J=9.1Hz, 1H), 4.60 (d, J=12.9Hz, 2H), 4.38 (s, 1H), 3.78 (s, 3H), 3.03 (t, J=11.6Hz, 2H), 2.88 (s, 3H), 2.17 (s, 3H), 1.83- 1.70(m,4H)。
7 6- of embodiment (3- ((the chloro- 2- of 5- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) (methyl) ammonia Base) pyrrolidin-1-yl)-nicotinonitrile
Step 1) (1- (5- cyanopyridine -2- base) pyrrolidin-3-yl) (methyl) t-butyl carbamate
Into ethyl alcohol (25mL) solution of methyl (pyrrolidin-3-yl) t-butyl carbamate (1.01g, 5.04mmol), Triethylamine (1.52g, 15.0mmol) is added and the chloro- 3- itrile group pyridine (692.6mg, 4.999mmol) of 6-, gained reaction system exist It stirs 14 hours, is then concentrated under reduced pressure at room temperature.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=4/1), Obtaining title compound is white solid (1.02g, yield 66.6%).
LC-MS(ESI,pos.ion)m/z:303.0[M+H]+。
Step 2) 6- (3- (methylamino) pyrrolidin-1-yl)-nicotinonitrile hydrochloride
To (1- (5- cyanopyridine -2- base) pyrrolidin-3-yl) (methyl) t-butyl carbamate (1.02g, In ethyl acetate (20mL) solution 3.37mmol), the ethyl acetate solution (3M, 20mL, 60mmol) of hydrogen chloride, gained is added Reaction system is stirred at room temperature 2 hours, is then concentrated under reduced pressure, and obtaining title compound is white solid (800mg, yield 99%).
LC-MS(ESI,pos.ion)m/z:203.1[M+H]+。
Step 3) 6- (3- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) pyrrolidin-1-yl)-nicotinonitrile
Into ethyl alcohol (25mL) solution of 2,4,5- trichloropyrimidines (303mg, 1.6519mmol), triethylamine is added (665.7mg, 6.579mmol) and 6- (3- (methylamino) pyrrolidin-1-yl)-nicotinonitrile hydrochloride (587.9mg, 2.463mmol), gained reaction system is reacted 18 hours at room temperature, is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying, obtaining title compound is white solid (350mg, yield 40.7%).
LC-MS(ESI,pos.ion)m/z:349.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.45 (dd, J=2.2,0.6Hz, 1H), 8.16 (s, 1H), 7.65 (dd, J=8.9,2.3Hz, 1H), 6.43-6.39 (m, 1H), 5.24 (dd, J=8.9,7.8Hz, 1H), 3.96 (s, 1H), 3.83 (s, 1H), 3.60-3.48 (m, 2H), 3.20 (s, 3H), 2.41 (dd, J=8.5,4.1Hz, 1H), 2.31 (dd, J=12.7, 9.0Hz,1H)。
Step 4) 6- (3- ((the chloro- 2- of 5- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) (methyl) amino) Pyrrolidin-1-yl)-nicotinonitrile
By 6- (3- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) pyrrolidin-1-yl)-nicotinonitrile (330mg, 0.9450mmol), DIPEA (491.3mg, 3.801mmol) and 1- methyl-1 H- pyrazoles -4- amine hydrochlorate (254.1mg, It 1.902mmol) being dissolved in n-BuOH (5mL), gained reaction system is warming up to 150 DEG C, and tube sealing reaction 16 hours, to reactant System is concentrated under reduced pressure after being cooled to room temperature.Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=80/1), is obtained yellowish Color solid, it is white solid (220mg, yield 56.7%) that this crude product is recrystallized to give title compound in acetone.
LC-MS(ESI,pos.ion)m/z:410.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.45 (d, J=1.8Hz, 1H), 8.03 (s, 1H), 7.71-7.59 (m, 2H), 7.49 (s, 1H), 6.74 (s, 1H), 6.39 (d, J=8.9Hz, 1H), 5.15-5.04 (m, 1H), 3.91 (s, 1H), 3.85 (s, 3H), 3.82-3.73 (m, 1H), 3.52 (dd, J=18.1,9.0Hz, 2H), 3.11 (s, 3H), 2.43-2.23 (m, 2H).
8 6- of embodiment (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) (methyl) Amino) piperidin-1-yl)-nicotinonitrile
6- (4- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) piperidin-1-yl)-nicotinonitrile (250mg, 0.6883mmol), 2,3- dimethyl -2H- indazole -6- amine hydrochlorate (138.6mg, 0.7012mmol), palladium acetate (30.2mg, 0.135mmol), BINAP (83.5mg, 0.134mmol) and cesium carbonate (675.4mg, 2.073mmol) are suspended in anhydrous 1,4- bis- In six ring of oxygen (10mL).Reaction system is warming up to 150 DEG C, is stirred to react under microwave irradiation 2 hours, is then concentrated under reduced pressure.Gained Residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=60/1), and obtaining crude product is white solid.Crude product is in methyl alcohol It is white solid (145mg, yield 43%) that (10mL), which is recrystallized to give title compound,.
LC-MS(ESI,pos.ion)m/z:488.30[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.38 (d, J=2.1Hz, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.59 (dd, J=9.1,2.3Hz, 1H), 7.42 (d, J=8.9Hz, 1H), 6.94 (dd, J=8.9,1.5Hz, 1H), 6.64 (d, J=9.1Hz, 1H), 4.65 (ddd, J=12.0,8.0,4.1Hz, 1H), 4.54 (d, J=13.5Hz, 2H), 3.96 (d, J= 17.3Hz, 3H), 3.07 (t, J=10.6Hz, 2H), 3.03 (s, 3H), 2.51 (d, J=18.2Hz, 3H), 2.02-1.90 (m, 2H), 1.78 (qd, J=12.4,4.1Hz, 2H).
9 6- of embodiment (4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) (methyl) Amino) piperidin-1-yl)-nicotinonitrile
To 6- (4- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) piperidin-1-yl)-nicotinonitrile (250mg, 0.6883mmol) and the 1,4- dioxane (15mL) of 1,5- dimethyl -1H- pyrazoles -3- amine (153mg, 1.3766mmol) is molten 2,2,2- trifluoroacetic acid (392.5mg, 3.442mmol) is added in liquid.Reaction system is warming up to 100 DEG C and is stirred overnight, and then subtracts Pressure concentration.Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=100/1), and it is solid for white to obtain title compound Body (155mg, yield 51.42%).
LC-MS(ESI,pos.ion)m/z:438.3[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):9.59(s,1H),8.48(s,1H),7.94(s,1H),7.88- 7.79 (m, 1H), 7.00 (d, J=9.1Hz, 1H), 6.24 (s, 1H), 4.62 (d, J=13.1Hz, 2H), 4.56 (s, 1H), 3.64 (s, 3H), 3.01 (d, J=12.4Hz, 2H), 2.95 (s, 3H), 2.23 (s, 3H), 1.83 (d, J=10.7Hz, 2H), 1.74 (dd, J=20.9,11.9Hz, 2H).
10 6- of embodiment (4- ((the chloro- 2- of 5- ((1,3- dimethyl -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) (ammonia Base) piperidin-1-yl)-nicotinonitrile
By 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl)-nicotinonitrile (153.2mg, 0.4387mmol), 1,3- dimethyl -1H- pyrazoles -4- amine hydrochlorate (104.2mg, 0.7059mmol) and DIPEA (230.8mg, N-BuOH (5mL) solution 1.786mmol) is warming up to 150 DEG C, tube sealing reaction 10 hours.Then, reaction solution is concentrated under reduced pressure, Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=80/1), and obtaining crude product is yellow solid.Crude product is through making Standby thin-layer chromatography (DCM/MeOH) (v/v)=20/1) purifying, obtaining title compound is off-white powder (43.9mg, yield 23.6%).
LC-MS(ESI,pos.ion)m/z:424.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.41 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.61 (d, J= 9.0Hz, 1H), 6.65 (d, J=9.1Hz, 1H), 6.58-6.34 (m, 1H), 5.11 (d, J=7.3Hz, 1H), 4.42 (d, J= 13.6Hz, 2H), 4.24 (dt, J=10.2,6.8Hz, 1H), 3.81 (s, 3H), 3.17 (t, J=12.4Hz, 2H), 2.23 (s, 3H), 2.21-2.14 (m, 2H), 1.54 (td, J=15.0,3.9Hz, 2H).
11 6- of embodiment (4- ((the chloro- 2- of 5- ((1,3- dimethyl -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) (ammonia Base) piperidin-1-yl) pyridazine -3- formonitrile HCN
Step 1) (1- (6- cyano pyridazine -3- base) piperidin-4-yl) ammonia t-butyl formate
To piperidin-4-yl ammonia t-butyl formate (1.40g, 6.99mmol) and 6- chlorine pyridazine -3- formonitrile HCN (967.4mg, Triethylamine (976.2mg, 9.65mmol) is added in ethyl alcohol (20mL) solution 6.93mmol).Reaction system is stirred at room temperature Overnight, it is then concentrated under reduced pressure.The mixed solvent (10mL/1mL) of gained residue second alcohol and water is beaten 0.5 hour, and filtering obtains It is light tan solid (2.13g, yield 100%) to title compound.
LC-MS(ESI,pos.ion)m/z:304.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 7.83 (d, J=9.7Hz, 1H), 7.36 (d, J=9.7Hz, 1H), 6.89 (d, J=7.3Hz, 1H), 4.40 (d, J=13.4Hz, 2H), 3.60 (s, 1H), 3.18 (m, 2H), 1.84 (d, J= 10.1Hz,2H),1.35(m,2H),1.39(s,9H)。
Step 2) 6- (4- amino piperidine -1- base) pyridazine -3- formonitrile HCN
To the DCM of (1- (6- cyano pyridazine -3- base) piperidin-4-yl) ammonia t-butyl formate (2.03g, 6.69mmol) Ethyl acetate (4M, 15mL, 60mmol) solution of hydrogen chloride is added in (15mL) solution.It is small that reaction system stirs 0.5 at room temperature When, then it is concentrated under reduced pressure.Gained residue is dissolved in water (30mL), and is adjusted to pH=10 with saturated aqueous sodium carbonate, Then it is extracted with methylene chloride (250mL × 3).Combined organic phase is washed through saturated salt solution (250mL), and anhydrous sodium sulfate is dry It is dry, it filters and is concentrated under reduced pressure, obtaining title compound is crocus solid (1.20g, yield 88.2%).
LC-MS(ESI,pos.ion)m/z:204.2[M+H]+。
Step 3) 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl) pyridazine -3- formonitrile HCN
To 6- (4- amino -1- piperidines) pyridazine -3- formonitrile HCN (1.20g, 5.90mmol) and 2,4,5- trichloropyrimidine (1.50g, Triethylamine (1.74g, 17.20mmol) is added in EtOH (30mL) suspension 8.18mmol).Reaction mixture stirs at room temperature Then plus water (50mL) quenching reaction it 4 hours, is extracted with EtOAc (250mL × 3).Combined organic phase is through saturated salt solution (250mL) is washed, and anhydrous sodium sulfate is dried, filtered and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v) =1/2) it purifies, obtaining title compound is crocus solid (1.06g, yield 51.3%).
LC-MS(ESI,pos.ion)m/z:349.9[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.07 (s, 1H), 7.47 (d, J=9.6Hz, 1H), 6.92 (d, J= 9.6Hz, 1H), 5.42 (d, J=7.5Hz, 1H), 4.59 (d, J=13.7Hz, 2H), 4.43 (m, 1H), 3.33 (m, 2H), 2.27 (dd, J=12.6,2.8Hz, 2H), 1.62 (dd, J=12.0,3.7Hz, 2H).
Step 4) 6- (4- ((the chloro- 2- of 5- ((1,3- dimethyl -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) (amino) piperazine Pyridine -1- base)-pyridazine -3- formonitrile HCN
To 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl) pyridazine -3- formonitrile HCN (276.6mg, 0.79mmol) and the 1,4- dioxane of 1,3- dimethyl -1H- pyrazoles -4- amine hydrochlorate (210.0mg, 1.42mmol) In (15mL) solution, it is added Pd (OAc)2(51.5mg, 0.23mmol), BINAP (105.6mg, 0.16mmol) and cesium carbonate (778.9mg,2.39mmol).Reaction system is warming up to 150 DEG C and reacts 2 hours under microwave irradiation, is then concentrated under reduced pressure.Gained Residue through silica gel column chromatography (MeOH/DCM (v/v)=1/40) purify, obtain title compound be brown solid (64.4mg, Yield 19.2%).
LC-MS(ESI,pos.ion)m/z:425.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.92 (s, 1H), 7.69 (s, 1H), 7.48 (d, J=9.6Hz, 1H), 6.91 (d, J=9.6Hz, 1H), 6.32 (br.s, 1H), 5.12 (d, J=7.2Hz, 1H), 4.56 (d, J=13.7Hz, 2H), 4.31(m,1H),3.84(s,3H),3.32(m,2H),2.28(m,5H),1.67(m,2H)。
12 6- of embodiment (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) (ammonia Base) piperidin-1-yl) pyridazine -3- formonitrile HCN
To 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl) pyridazine -3- formonitrile HCN (167.3mg, 0.478mmol) and the 1,4- dioxane of 2,3- dimethyl -2H- indazole -6- amine hydrochlorate (199.5mg, 1.01mmol) In (15mL) solution, it is added Pd (OAc)2(30.2mg, 0.14mmol), BINAP (78.6mg, 0.12mmol) and cesium carbonate (481.0mg,1.48mmol).Reaction system is warming up to 150 DEG C and reacts 2 hours under microwave irradiation, is then concentrated under reduced pressure.Gained Residue through silica gel column chromatography (MeOH/DCM (v/v)=1/40) purify, obtain title compound be brown solid (94.2mg, Yield 41.5%).
LC-MS(ESI,pos.ion)m/z:475.3[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):9.22(s,1H),8.12(s,1H),7.99(s,1H),7.89(d,J =9.7Hz, 1H), 7.47 (dd, J=15.0,9.3Hz, 2H), 7.16 (dd, J=9.0,1.5Hz, 1H), 6.92 (d, J= 7.8Hz, 1H), 4.65 (d, J=13.1Hz, 2H), 4.40 (m, 1H), 3.95 (s, 3H), 3.24 (t, J=11.9Hz, 2H), 2.54 (s, 3H), 2.07 (d, J=12.2Hz, 2H), 1.68 (qd, J=12.6,3.9Hz, 2H).
13 6- of embodiment (4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) Piperidin-1-yl) pyridazine -3- formonitrile HCN
To 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl) pyridazine -3- formonitrile HCN (167.2mg, 0.478mmol) and the 1,4- dioxane of 1,5- dimethyl -1H- pyrazoles -3- amine hydrochlorate (145.1mg, 1.31mmol) In (15mL) solution, it is added Pd (OAc)2(26.9mg, 0.12mmol), BINAP (80.7mg, 0.12mmol) and cesium carbonate (346.6mg,1.06mmol).Reaction system is warming up to 150 DEG C and reacts 2 hours under microwave irradiation, is then concentrated under reduced pressure.Gained Residue through silica gel column chromatography (MeOH/DCM (v/v)=1/40) purify, obtain title compound be brown solid (143.5mg, Yield 70.7%).
LC-MS(ESI,pos.ion)m/z:425.1[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 9.14 (s, 1H), 7.88 (d, J=3.5Hz, 1H), 7.87 (d, J= 6.1Hz, 1H), 7.43 (d, J=9.7Hz, 1H), 6.80 (d, J=7.6Hz, 1H), 6.36 (s, 1H), 4.63 (d, J= 12.7Hz, 2H), 4.28 (m, 1H), 3.60 (s, 3H), 3.14 (m, 2H), 2.23 (s, 3H), 2.04 (d, J=11.4Hz, 2H), 1.63 (qd, J=12.7,3.8Hz, 2H).
14 6- of embodiment (4- ((the chloro- 2- of 5- ((1,3- dimethyl -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) (first Base) amino) piperidin-1-yl)-nicotinonitrile
6- (4- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) piperidin-1-yl)-nicotinonitrile (156.7mg, 0.4314mmol), DIPEA (242.5mg, 1.876mmol) and 1,3- dimethyl -1H- pyrazoles -4- amine hydrochlorate (122.4mg, N-BuOH (4mL) solution 0.8292mmol) is warming up to 150 DEG C of tube sealing reactions 16 hours.Reaction system is concentrated under reduced pressure.Gained is residual Object is stayed to purify and prepare thin-layer chromatography (DCM/MeOH) (v/v)=20/1 through silica gel column chromatography (DCM/MeOH (v/v)=60/1)) After purification, obtaining title compound is gray solid (87.5mg, yield 46%).
LC-MS(ESI,pos.ion)m/z:438.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.41 (d, J=2.2Hz, 1H), 7.95 (s, 1H), 7.65-7.57 (m, 2H), 6.65 (d, J=9.0Hz, 1H), 6.25-6.38 (m, 1H), 4.63-4.47 (m, 3H), 3.81 (s, 3H), 3.02-2.91 (m,5H),2.22(s,3H),1.88-1.94(m,2H),1.85-1.77(m,2H)。
15 6- of embodiment (4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) ammonia Base) -3- ethyl piperidine -1- base)-pyridazine -3- formonitrile HCN
Step 1) (S)-N- (1- benzyl piepridine -4- subunit) -1- phenylethylamine
1- benzyl piepridine -4- ketone (30.06g, 158.8mmol) and (1S) -1- phenylethylamine (28.92g, 238.7mmol) Toluene (300mL) solution be warming up to reflux, be stirred to react 46 hours, install water segregator with except dereaction generate water.Reaction System is cooled to room temperature and is concentrated under reduced pressure, and obtains crude product.Crude product is directly used in next step without further purification.
Step 2) 1- benzyl -3- ethyl-N- ((R) -1- phenylethyl) piperidines -4- amine
At -10 DEG C, to (S)-N- (1- benzyl piepridine -4- subunit) -1- phenylethylamine (46.35g, 158.5mmol) The tetrahydrofuran solution (125mL, 2M) of LDA is added dropwise in THF (250mL) solution.It is small that reaction system stirs 2 in nitrogen atmosphere When.Then, iodoethane (20.5mL, 255mmol) is added in above-mentioned reaction system, after adding, is stirred 2 hours.System is dropped Ethyl alcohol ethanol (250mL) and sodium borohydride (9.62g, 254mmol) is added to -78 DEG C in temperature thereto.Gained reaction mixing After object maintains -78 DEG C to continue stirring 15 minutes, moves to -10 DEG C and be stirred overnight.Reaction plus water (500mL) are quenched, and then use acetic acid Ethyl ester extracts (200mL × 3).Combined organic phase is washed through saturated salt solution (300mL), is then concentrated under reduced pressure.Gained residual For object through silica gel column chromatography (EtOAc/PE (v/v)=1/3 to 1/1 arrives 100%EtOAc) purifying, obtaining title compound is yellow oil Shape object (12.50g, yield 24.5%).
LC-MS(ESI,pos.ion)m/z:323.4[M+H]+。
Step 3) 3- ethyl-N- ((R) -1- phenylethyl) piperidines -4- amine
At 0 DEG C, to 1- benzyl -3- ethyl-N- [(1R) -1- phenylethyl] piperidines -4- amine (12.50g, Chloro-carbonic acid 1- chloro-ethyl ester (5.0mL, 46mmol) is added dropwise in 1,2- dichloroethanes (200mL) solution 38.76mmol).Instead After answering system to stir 30 minutes, it is warming up to and flows back and continue stirring 1 hour.Reaction system is concentrated under reduced pressure, the dissolution of gained residue In methanol (200mL).Gained mixture, which is warming up to, to be flowed back and is stirred overnight, and is then concentrated under reduced pressure.Gained residue is through silica gel Column chromatographs (the methanol solution MeOH/DCM=1/30 to 1/10 of the ammonia of 3M) purifying, and obtaining target product is brown oil (6.15g, yield 68.3%).
LC-MS(ESI,pos.ion)m/z:233.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.35-7.27 (m, 4H), 7.24-7.21 (m, 1H), 3.96 (q, J= 6.6Hz, 1H), 3.10-3.00 (m, 2H), 2.41 (td, J=12.3,2.6Hz, 1H), 2.14-2.07 (m, 2H), 2.00-1.94 (m, 1H), 1.86-1.80 (m, 1H), 1.32 (d, J=6.6Hz, 3H), 1.17-0.95 (m, 3H), 0.81 (t, J=7.5Hz, 3H)。
Step 4) 3- ethyl -4- (((R) -1- phenylethyl) amino) piperidines -1- t-butyl formate
At 0 DEG C, to the dichloromethane of 3- ethyl-N- ((1R) -1- phenylethyl) piperidines -4- amine (6.15g, 26.5mmol) Triethylamine (9.2mL, 66mmol) and Boc are added in alkane (100mL) solution2O(9.1mL,40mmol).Reaction system is at room temperature Be stirred overnight, be then concentrated under reduced pressure title compound be brown oil (8.80g, yield 100%).Gained crude product without It is further purified to be directly used in and react in next step.
LC-MS(ESI,pos.ion)m/z:333.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.36-7.20(m,5H),3.96-3.89(m,2H),2.68(s,1H), 2.06-1.97 (m, 2H), 1.79 (s, 1H), 1.44 (s, 9H), 1.33 (d, J=6.5Hz, 3H), 1.27-0.96 (m, 5H), 0.84 (t, J=7.4Hz, 3H).
Step 5) 4- amino -3- ethyl piperidine -1- t-butyl formate acetate
To 3- ethyl -4- (((R) -1- phenylethyl) amino) piperidines -1- t-butyl formate (8.80g, 26.5mmol) Palladium dydroxide/carbon (0.90g) is added in acetic acid (100mL) solution.Reaction system is warming up to 70 DEG C, in atmosphere of hydrogen, stirring Overnight.Reaction mixture is filtered through diatom soil hopper, filtrate decompression concentration, and obtaining target product is that (7.63g is produced yellow oil Rate 100%).Crude product is directly used in without further purification to react in next step.
LC-MS(ESI,pos.ion)m/z:173.2[M–55]+。
Step 6) 4- ((2,5- dichloro pyrimidine -4- base) amino) -3- ethyl piperidine -1- t-butyl formate
Ethyl alcohol (100mL) to 4- amino -3- ethyl piperidine -1- t-butyl formate acetate (6.04g, 26.5mmol) is molten In liquid, 2,4,5- trichloropyrimidine (4.85g, 26.4mmol) and triethylamine (14.7mL, 105mmol) is added.Reaction system is in room It temperature lower stirring 12 hours, is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/8) Purifying, obtaining title compound is white solid (4.80g, yield 48.3%).
LC-MS(ESI,pos.ion)m/z:375.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.00 (s, 1H), 5.27 (d, J=8.7Hz, 1H), 4.31-4.10 (m, 1H),4.10-3.98(m,2H),3.00-2.84(m,1H),2.56(s,1H),2.05-1.92(m,1H),1.55-1.50(m, 1H), 1.45 (s, 9H), 1.40-1.38 (m, 2H), 1.24-1.10 (m, 1H), 0.91 (t, J=7.5Hz, 3H).
Step 7) 4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) -3- second Phenylpiperidines -1- t-butyl formate
4- ((2- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) -3- ethyl piperidine -1- first Tert-butyl acrylate
4- ((2,5- dichloro pyrimidine -4- base) amino) -3- ethyl piperidine -1- t-butyl formate (0.27g, 0.71mmol) is outstanding Float in anhydrous Isosorbide-5-Nitrae-dioxane (6.0mL), be added thereto 1,5- dimethyl -1H- pyrazoles -3- amine (0.16g, 1.44mmol), palladium acetate (32mg, 0.14mmol), BINAP (90mg, 0.14mmol) and cesium carbonate (0.47g, 1.43mmol). Reaction mixture is placed in tube sealing, is taken out the air in system to the greatest extent, is re-filled nitrogen, repeatedly, be then warming up to reaction It 150 DEG C, is reacted 2 hours under microwave irradiation.Reaction mixture is concentrated under reduced pressure.Gained residue through silica gel column chromatography (DCM/3M's NH3MeOH solution (v/v)=100/1 to 50/1 to 30/1 to 10/1) purifying, obtain 4- ((5- chloro- 2- ((1,5- dimethyl- 1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) for yellow solid, (0.19g is produced -3- ethyl piperidine -1- t-butyl formate Rate 60%) and 4- ((2- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) -3- ethyl piperidine -1- first Tert-butyl acrylate is brown solid (0.20g, thick yield 67%, non-sterling).
4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) -3- ethyl piperidine - 1- t-butyl formate:
LC-MS(ESI,pos.ion)m/z:450.4[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.90 (s, 1H), 7.19 (s, 1H), 6.38 (s, 1H), 4.99 (d, J= 8.4Hz, 1H), 4.12-3.91 (m, 3H), 3.67 (s, 3H), 2.93 (t, J=12.0Hz, 1H), 2.61 (br, 1H), 2.25 (s, 3H),2.14-2.06(m,1H),1.77-1.66(m,1H),1.48(s,9H),1.45-1.38(m,2H),1.22(s,1H), 0.94 (t, J=7.5Hz, 3H).
4- ((2- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) -3- ethyl piperidine -1- first Tert-butyl acrylate:
LC-MS(ESI,pos.ion)m/z:416.0[M+H]+。
The chloro- N of step 8) 5-2(1,5- dimethyl -1H- pyrazole-3-yl)-N4(3- ethyl piperidine -4- base) pyrimidine -2,4- Diamines
4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) -3- ethyl piperidine - 1- t-butyl formate (0.19g, 0.42mmol) is suspended in DCM (10mL), and the ethyl acetate solution of hydrogen chloride is added thereto (10mL,30mmol,3M).Reaction system is stirred at room temperature 4 hours, is then concentrated under reduced pressure.Gained residue is with DCM (10mL) Dilution, is then added the Na of saturation2CO3Aqueous solution (10mL), mixture are stirred at room temperature 15 minutes.It stands, separates organic Layer, water layer successively use DCM (20mL × 3) and DCM/MeOH (v/v=10/1, (20mL × 3) extraction.Combined organic phase is through nothing Aqueous sodium persulfate is dried, filtered and is concentrated under reduced pressure.Gained residue is through the silica gel column chromatography (NH of DCM/3M3MeOH solution (v/v) =30/1 to 20/1) it purifies, obtaining title compound is white solid (0.13g, yield 88%).
LC-MS(ESI,pos.ion)m/z:350.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.89 (s, 1H), 7.20 (s, 1H), 6.41 (s, 1H), 5.00 (d, J= 8.6Hz, 1H), 3.99-3.87 (m, 1H), 3.67 (s, 3H), 3.27 (dd, J=12.5,3.5Hz, 1H), 3.19-3.10 (m, 1H),2.76-2.67(m,1H),2.45-2.36(m,1H),2.25(s,3H),2.18-2.11(m,1H),1.65-1.59(m, 1H), 1.44-1.37 (m, 2H), 1.22-1.13 (m, 1H), 0.89 (t, J=7.5Hz, 3H).
Step 9) 6- (4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) -3- Ethyl piperidine -1- base)-pyridazine -3- formonitrile HCN
The chloro- N of 5-2(1,5- dimethyl -1H- pyrazole-3-yl)-N4(3- ethyl piperidine -4- base) pyrimidine -2,4- diamines (0.12g, 0.34mmol) is suspended in EtOH (10.0mL), and 6- chlorine pyridazine -3- formonitrile HCN (96mg, 0.69mmol) is added thereto With triethylamine (0.15mL, 1.10mmol).Reaction system is stirred overnight at 40 DEG C, is then concentrated under reduced pressure.Gained residue warp Silica gel column chromatography (the NH of DCM/3M3MeOH solution (v/v)=100/1 to 75/1 to 50/1) purifying, obtaining title compound is Yellow solid (45mg, yield 29%).
LC-MS(ESI,pos.ion)m/z:453.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.95 (s, 1H), 7.48 (d, J=9.6Hz, 1H), 7.15 (s, 1H), 6.91 (d, J=9.6Hz, 1H), 6.41 (s, 1H), 5.09-4.97 (m, 1H), 4.78-4.65 (m, 1H), 4.56-4.42 (m, 1H),4.27-4.14(m,1H),3.70(s,3H),3.35-3.22(m,1H),3.05-2.93(m,1H),2.28(s,3H), 1.81-1.70 (m, 1H), 1.69-1.61 (m, 2H), 1.40-1.30 (m, 2H), 1.03 (t, J=7.5Hz, 3H).
16 6- of embodiment (4- ((the chloro- 2- of 5- ((1,3- dimethyl -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base) -3- ethyl piperidine -1- base)-nicotinonitrile
Step 1) 4- ((the chloro- 2- of 5- ((1,3- dimethyl -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) -3- second Phenylpiperidines -1- t-butyl formate
4- ((2,5- dichloro pyrimidine -4- base) amino) -3- ethyl piperidine -1- t-butyl formate (306.2mg, 0.8159mmol), DIPEA (423.4mg, 3.276mmol) and 1,3- dimethyl -1H- pyrazoles -4- amine hydrochlorate (234.6mg, It 1.589mmol) is mixed in n-butanol (5mL), reaction system is warming up to 150 DEG C and tube sealing reaction is stayed overnight.After reaction, it mixes It closes object to be concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=90/1), obtains title compound as palm fibre Color semisolid (204mg, yield 55%).
LC-MS(ESI,pos.ion)m/z:449.95[M+H]+。
The chloro- N of step 2) 5-2(1,3- dimethyl -1H- pyrazoles -4- base)-N4(3- ethyl piperidine -4- base) pyrimidine -2,4- Diamines
To 4- ((the chloro- 2- of 5- ((1,3- dimethyl -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino) -3- ethyl piperazine The ethyl acetate that hydrogen chloride is added in methylene chloride (10mL) solution of pyridine -1- t-butyl formate (204mg, 0.4533mmol) is molten Liquid (20mL, 30mmol, 1.5M).Reaction system is stirred at room temperature overnight, and is then concentrated under reduced pressure.Gained residue is through saturated carbon Acid sodium aqueous solution (40mL) neutralizes, mixed solvent (v/v=10/1,100mL × 4) extraction of the gained mixture through DCM and MeOH. Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained residue prepared thin-layer chromatography (DCM/3M's NH3MeOH solution (v/v)=10/1) purifying, obtain title compound be white solid (98mg, yield 62%).
LC-MS(ESI,pos.ion)m/z:349.95[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.90 (s, 1H), 7.71 (s, 1H), 6.28 (s, 1H), 5.05 (d, J= 8.7Hz, 1H), 4.32 (t, J=6.7Hz, 1H), 3.99-3.89 (m, 2H), 3.83 (s, 3H), 3.40 (dd, J=12.6, 2.9Hz, 1H), 3.30 (d, J=12.5Hz, 1H), 2.81 (t, J=11.3Hz, 1H), 2.51 (t, J=11.7Hz, 1H), 2.25 (s, 3H), 2.17 (dd, J=13.2,3.7Hz, 1H), 1.76-1.68 (m, 2H), 1.50-1.42 (m, 1H), 0.92 (t, J= 7.4Hz,4H)。
Step 3) 6- (4- ((the chloro- 2- of 5- ((1,3- dimethyl -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) (amino) - 3- ethyl piperidine -1- base)-nicotinonitrile
To the chloro- N of 5-2(1,3- dimethyl -1H- pyrazoles -4- base)-N4(3- ethyl piperidine -4- base) pyrimidine -2,4- diamines Triethylamine (89.7mg, 0.886mmol) and 6- chloropyridine -3- are added in EtOH (10mL) solution of (98mg, 0.2801mmol) Formonitrile HCN (51.2mg, 0.370mmol).Gained mixture, which is warming up to, to be flowed back and is stirred overnight, and is then concentrated under reduced pressure.Crude product is through making Standby thin-layer chromatography (DCM/MeOH) (v/v)=20/1) purifying, obtaining title compound is white solid (54mg, yield 42%).
LC-MS(ESI,pos.ion)m/z:452.30[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.42 (d, J=1.9Hz, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 7.62 (dd, J=9.0,2.2Hz, 1H), 6.64 (d, J=9.0Hz, 1H), 6.26 (s, 1H), 4.99 (d, J=8.6Hz, 1H), 4.54 (d, J=12.1Hz, 1H), 4.39 (d, J=13.6Hz, 1H), 4.11 (d, J=5.2Hz, 1H), 3.82 (s, 3H), 3.13 (t, J=11.5Hz, 1H), 2.83 (dd, J=13.6,10.7Hz, 1H), 2.23 (s, 3H), 2.18 (d, J=3.2Hz, 1H), 1.74-1.66 (m, 2H), 1.33-1.27 (m, 2H), 1.00 (t, J=7.5Hz, 3H).
17 6- of embodiment (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) ammonia Base) -3- ethyl piperidine -1- base) pyridazine -3- formonitrile HCN
Step 1) 4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) amino) -3- second Phenylpiperidines -1- t-butyl formate
To 4- ((2,5- dichloro pyrimidine -4- base) amino) -3- ethyl piperidine -1- t-butyl formate (457mg, 1.218mmol), 2,3- dimethyl -6- amino -2H- indazole hydrochloride (288.8mg, 1.461mmol) and sodium carbonate In the Isosorbide-5-Nitrae-dioxane (10mL) of (387.5mg, 3.656mmol), palladium acetate (54.7mg, 0.244mmol) and BINAP is added (152.5mg,0.245mmol).It eliminates the air in reaction system and re-fills nitrogen, replace 10 minutes repeatedly.Gained is anti- It answers mixture to be warming up to 150 DEG C, stirs 2 hours, after reaction, be concentrated under reduced pressure.Gained residue is chromatographed through Flash silica column (DCM/MeOH (v/v)=100/1) purifying, obtaining title compound is yellow solid (365mg, yield 59.95%).
LC-MS(ESI,pos.ion)m/z:500.4[M+H]+。
The chloro- N of step 2) 5-2(2,3- dimethyl -2H- indazole -6- base)-N4(3- ethyl piperidine -4- base) pyrimidine -2,4- Diamines
To 4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) amino) -3- ethyl piperazine The ethyl acetate that hydrogen chloride is added in methylene chloride (10mL) solution of pyridine -1- t-butyl formate (365mg, 0.730mmol) is molten Liquid (5mL, 15mmol, 3M).Reaction system is stirred at room temperature 3 hours, is then concentrated under reduced pressure.Gained residue is dissolved in water In (20mL), and it is adjusted to pH=10 with saturated sodium bicarbonate aqueous solution, then uses the mixed solvent of methylene chloride and methanol (DCM/MeOH (v/v)=10/1,50mL × 3) extraction.Combined organic phase is washed through saturated salt solution (50mL), anhydrous sodium sulfate It dries, filters and is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50 to 1/20), is obtained Title compound is yellow solid (138mg, yield 47.27%).
LC-MS(ESI,pos.ion)m/z:200.7[(M+H)/2]+。
Step 3) 6- (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) amino) -3- Ethyl piperidine -1- base) pyridazine -3- formonitrile HCN
To the chloro- N of 5-2(2,3- dimethyl -2H- indazole -6- base)-N4(3- ethyl piperidine -4- base) pyrimidine -2,4- diamines Three are added in ethyl alcohol (10mL) solution of (138mg, 0.345mmol) and 6- chlorine pyridazine -3- formonitrile HCN (72.5mg, 0.520mmol) Ethamine (70mg, 0.692mmol).Reaction system is stirred at room temperature overnight, and is then concentrated under reduced pressure.Gained residue is through silicagel column (DCM/MeOH (v/v)=100/1 to 20/1) purifying is chromatographed, obtaining title compound is yellow solid (62mg, yield 35.72%).
LC-MS(ESI,pos.ion)m/z:503.3[M+H]+；
1H NMR (400MHz, CDCl3) δ (ppm): 8.07 (s, 1H), 7.93 (s, 1H), 7.43 (t, J=9.4Hz, 2H), 7.34 (s, 1H), 6.99 (dd, J=8.9,1.5Hz, 1H), 6.86 (d, J=9.7Hz, 1H), 5.08 (d, J=8.3Hz, 1H), 4.73 (d, J=12.4Hz, 1H), 4.42 (d, J=13.1Hz, 1H), 4.23 (dt, J=10.1,6.4Hz, 1H), 4.04 (s, 3H), 3.35 (dd, J=18.7,7.1Hz, 1H), 3.02-2.93 (m, 1H), 2.56 (s, 3H), 2.37 (dd, J=13.1, 3.5Hz, 1H), 1.80-1.67 (m, 1H), 1.59 (dt, J=17.0,7.0Hz, 1H), 1.32 (dd, J=15.1,7.1Hz, 2H), 0.98 (t, J=7.5Hz, 3H).
18 6- of embodiment (4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) (first Base) amino) -3- ethyl piperidine -1- base)-nicotinonitrile
Step 1) 4- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) -3- ethyl piperidine -1- t-butyl formate
At 0 DEG C, to 4- ((2,5- dichloro pyrimidine -4- base) amino) -3- ethyl piperidine -1- t-butyl formate (1.31g, Sodium hydride is added in tetrahydrofuran (30mL) solution 3.49mmol) (60% is suspended in mineral oil, 98.6mg, 2.47mmol) Gained reaction system is maintained and is stirred 30 minutes at 0 DEG C.Iodomethane (0.2mL, 3mmol) is added dropwise in above-mentioned reaction system. Gained mixture moves to room temperature and is stirred to react 8 hours.Add water (50mL) quenching reaction, and is extracted with EtOAc (100mL × 3). Combined organic phase is concentrated under reduced pressure, and gained residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=1/10), obtains titled Conjunction object is white solid (662.3mg, yield 48.7%).
LC-MS(ESI,pos.ion)m/z:389.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.05(s,1H),4.36-4.29(m,2H),3.04(s,3H),2.86- 2.79(m,1H),2.42-2.36(m,1H),1.86-1.83(m,1H),1.78-1.63(m,2H),1.48(s,9H),1.45- 1.38 (m, 1H), 1.27-1.24 (m, 1H), 1.03-0.93 (m, 1H), 0.89 (t, J=7.3Hz, 3H).
Step 2) 4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) (methyl) ammonia Base) -3- ethyl piperidine -1- t-butyl formate
To 4- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) -3- ethyl piperidine -1- t-butyl formate (212.4mg, 0.55mmol) and in 1,4- dioxane (5mL) solution of 1,5- dimethyl -1H- pyrazoles -4- amine (94.2mg, 0.85mmol) Palladium acetate (12.5mg, 0.06mmol), BINAP (69.1mg, 0.11mmol) and sodium carbonate (117.8mg, 1.11mmol) is added. Reaction mixture under nitrogen protection, is warming up to 150 DEG C, reacts 2 hours under microwave irradiation.After reaction, mixture depressurizes Concentration, gained residue are purified through silica gel column chromatography (DCM/MeOH (v/v)=1/100), and obtaining title compound is yellow oily Object (203.0mg, yield 80.2%).
LC-MS(ESI,pos.ion)m/z:463.9[M+H]+。
The chloro- N of step 3) 5-2(1,5- dimethyl -1H- pyrazole-3-yl)-N4(3- ethyl piperidine -4- base)-N4Methyl is phonetic Pyridine -2,4- diamines
4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazoles-is added into the ethyl acetate solution (10mL, 3M) of hydrogen chloride 3- yl) amino) pyrimidine-4-yl) (methyl) amino) -3- ethyl piperidine -1- t-butyl formate (203.0mg, 0.44mmol, reference Prepared by the method for 15 step 7 of embodiment).Reaction mixture is stirred at room temperature overnight, and then, adds water (50mL) quenching reaction, And pH=8 is adjusted to the sodium hydrate aqueous solution of 1M.Then, mixture is extracted with methylene chloride (50mL × 3).What is merged has Machine is mutually concentrated under reduced pressure, and gained residue is through the silica gel column chromatography (NH of 3M3MeOH solution/DCM (v/v)=1/50 to 1/30) Title compound is white solid (87.3mg, yield 54.8%).
LC-MS(ESI,pos.ion)m/z:364.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.94(s,1H),6.40(s,1H),4.25-4.18(m,1H),3.67 (s,3H),3.31-3.15(m,2H),3.02(s,3H),2.75-2.69(m,1H),2.34-2.27(m,1H),2.25(s,3H), 1.98-1.86 (m, 1H), 1.76-1.65 (m, 2H), 1.48-1.42 (m, 1H), 0.99-0.91 (m, 1H), 0.83 (t, J= 7.4Hz,3H)。
Step 4) 6- (4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) (methyl) ammonia Base) -3- ethyl piperidine -1- base)-nicotinonitrile
The chloro- N of 5-2(1,5- dimethyl -1H- pyrazole-3-yl)-N4(3- ethyl piperidine -4- base)-N4Methylpyrimidine -2, 4- diamines (80.0mg, 0.22mmol) is suspended in EtOH (3mL), thereto be added 6- chloropyridine -3- formonitrile HCN (57.2mg, 0.41mmol) and triethylamine (0.15mL, 1.1mmol).Reaction system is warming up to 70 DEG C and is stirred to react 8 hours, then depressurizes dense Contracting.Gained residue is prepared thin-layer chromatography (MeOH/DCM (v/v)=1/10) purifying, and obtaining title compound is white solid (68.5mg, yield 66.9%).
LC-MS(ESI,pos.ion)m/z:466.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.42 (d, J=2.2Hz, 1H), 7.98 (s, 1H), 7.62 (dd, J= 9.0,2.3Hz, 1H), 7.17 (s, 1H), 6.64 (d, J=9.1Hz, 1H), 6.37 (s, 1H), 4.66-4.56 (m, 2H), 4.42 (t, J=9.2Hz, 1H), 3.67 (s, 3H), 3.03-2.98 (m, 1H), 2.96 (s, 3H), 2.66-2.59 (m, 1H), 2.25 (s, 3H), 2.06-2.02 (m, 1H), 1.83-1.69 (m, 2H), 1.15-1.04 (m, 1H), 0.95 (t, J=7.4Hz, 3H).
19 6- of embodiment (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) (first Base) amino) -3- ethyl piperidine -1- base) pyridazine -3- formonitrile HCN
The chloro- N of step 1) 5-2(2,3- dimethyl -2H- indazole -6- base)-N4(3- ethyl piperidine -4- base)-N4Methyl is phonetic Pyridine -2,4- diamines
To 4- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) -3- ethyl piperidine -1- t-butyl formate (662.3mg, 1.70mmol) and the 1,4- dioxane of 2,3- dimethyl -2H- indazole -6- amine hydrochlorate (505.1mg, 2.56mmol) Palladium acetate (38.7mg, 0.17mmol), BINAP (213.2mg, 0.34mmol) and sodium carbonate are added in (10mL) solution (542.8mg,5.12mmol).Reaction system is warming up to 150 DEG C in nitrogen atmosphere, reacts 2 hours under microwave irradiation, mixes Object is closed to be concentrated under reduced pressure.Gained residue is through the silica gel column chromatography (NH of 3M3MeOH solution/DCM (v/v)=1/100 to 1/10) Purifying, obtaining title compound is white solid (293.3mg, yield 41.6%).
LC-MS(ESI,pos.ion)m/z:207.6[(M+2H)/2]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.02 (s, 1H), 7.95 (s, 1H), 7.44 (d, J=8.9Hz, 1H), 6.99-6.96(m,1H),4.32-4.29(m,1H),4.06(s,3H),3.33-3.17(m,2H),3.08(s,3H),2.68- 2.81(m,1H),2.57(s,3H),2.39-2.33(m,1H),1.98-1.95(m,1H),1.81-1.70(m,2H),1.49- 1.41 (m, 1H), 0.98-0.94 (m, 1H), 0.83 (t, J=7.4Hz, 3H).
Step 2) 6- (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) (methyl) ammonia Base) -3- ethyl piperidine -1- base) pyridazine -3- formonitrile HCN
The chloro- N of 5-2(2,3- dimethyl -2H- indazole -6- base)-N4(3- ethyl piperidine -4- base)-N4Methylpyrimidine -2, 4- diamines (134.5mg, 0.33mmol) is suspended in EtOH (5mL), thereto be added 6- chloropyridine -3- formonitrile HCN (69.1mg, 0.50mmol) and triethylamine (0.15mL, 1.1mmol).Reaction system is kept for 30 DEG C and is stirred overnight, and is then concentrated under reduced pressure.Gained Residue prepared thin-layer chromatography (MeOH/DCM (v/v)=1/15) purifying, obtain title compound be yellow solid (87.4mg, Yield 52.0%).
LC-MS(ESI,pos.ion)m/z:517.3[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.05(s,1H),7.99(s,1H),7.48-7.42(m,2H),7.05 (s, 1H), 6.91 (dd, J=8.9,1.3Hz, 1H), 6.88 (d, J=9.6Hz, 1H), 4.83-4.81 (m, 1H), 4.61-4.54 (m, 2H), 4.03 (s, 3H), 3.33 (t, J=12.1Hz, 1H), 3.04 (s, 3H), 2.84-2.76 (m, 1H), 2.57 (s, 3H), 2.17-2.14 (m, 1H), 1.85-1.77 (m, 2H), 1.63-1.59 (m, 1H), 1.16-1.09 (m, 1H), 0.95 (t, J= 7.5Hz,3H)。
20 6- of embodiment (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) (first Base) amino) -3- ethyl piperidine -1- base)-nicotinonitrile
The chloro- N of 5-2(2,3- dimethyl -2H- indazole -6- base)-N4(3- ethyl piperidine -4- base)-N4Methylpyrimidine -2, 4- diamines (155.3mg, 0.38mmol) is suspended in EtOH (5mL), thereto be added 6- chloropyridine -3- formonitrile HCN (78.6mg, 0.57mmol) and triethylamine (0.16mL, 1.1mmol).Gained mixture, which is warming up to, to be flowed back and is stirred overnight, and is then depressurized dense Contracting.Gained residue is prepared the thin-layer chromatography (NH of 3M3MeOH solution/DCM (v/v)=1/30) purifying, obtain title compound Object is yellow solid (67.3mg, yield 34.8%).
LC-MS(ESI,pos.ion)m/z:516.4[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.42 (d, J=2.1Hz, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.61 (dd, J=9.0,2.3Hz, 1H), 7.44 (d, J=8.9Hz, 1H), 6.97 (s, 1H), 6.94 (dd, J=8.9,1.6Hz, 1H), 6.65 (d, J=9.1Hz, 1H), 4.67 (d, J=12.2Hz, 1H), 4.59-4.42 (m, 2H), 4.03 (s, 3H), 3.18 (t, J=11.8Hz, 1H), 3.03 (s, 3H), 2.75-2.60 (m, 1H), 2.57 (s, 3H), 2.08 (d, J=12.6Hz, 1H), 1.86-1.61 (m, 3H), 1.12-1.06 (m, 1H), 0.95 (t, J=7.4Hz, 3H).
Embodiment 21 6- (4- ((the chloro- 2- of 5- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) ammonia Base) -3- ethyl piperidine -1- base)-nicotinonitrile
To the chloro- N of 5-2(1,3- dimethyl -1H- pyrazoles -4- base)-N4(3- ethyl piperidine -4- base)-pyrimidine -2,4- diamines 6- chloropyridine -3- formonitrile HCN (162.3mg, 1.17mmol) and three is added in EtOH (10mL) solution of (202.7mg, 0.58mmol) Ethamine (0.35mL, 2.5mmol).Gained mixture, which is warming up to, to be flowed back and is stirred overnight, and is then concentrated under reduced pressure.Gained residue warp Thin-layer chromatography (the MeOH solution of the ammonia of 3M/DCM (v/v)=1/20) purifying is prepared, obtaining title compound is white solid (91.9mg, yield 35.1%).
LC-MS(ESI,pos.ion)m/z:452.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.42 (d, J=2.1Hz, 1H), 7.92 (s, 1H), 7.61 (dd, J= 9.0,2.3Hz, 1H), 7.36 (s, 1H), 6.64 (d, J=9.1Hz, 1H), 6.39 (s, 1H), 5.02 (d, J=8.4Hz, 1H), 4.55-4.52(m,1H),4.40-4.37(m,1H),4.17-4.10(m,1H),3.68(s,3H),3.20-3.09(m,1H), 2.88-2.82(m,1H),2.25(s,3H),2.22-2.20(m,1H),1.72-1.66(m,2H),1.56-1.50(m,1H), 1.34-1.28 (m, 1H), 1.00 (t, J=7.5Hz, 3H).
Embodiment 22 6- (4- ((2- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) -3- second Phenylpiperidines -1- base) pyridazine -3- formonitrile HCN
Step 1) N2(1,5- dimethyl -1H- pyrazole-3-yl)-N4(3- ethyl piperidine -4- base) pyrimidine -2,4- diamines
To 4- ((2- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine 4- yl) amino) -3- ethyl piperidine -1- first In methylene chloride (10mL) solution of tert-butyl acrylate (0.20g, 0.48mmol) be added hydrogen chloride ethyl acetate solution (10mL, 15mmol,3M).Reaction system is stirred overnight at room temperature, is then concentrated under reduced pressure.Gained residue is diluted with DCM (20mL), then The Na of saturation is added thereto2CO3Aqueous solution (20mL), mixture are stirred at room temperature 15 minutes.It stands, separates organic layer, water Layer is successively extracted with DCM (20mL × 3) and DCM/MeOH (v/v=10/1,20mL × 3).Combined organic phase is through anhydrous slufuric acid Sodium is dried, filtered and is concentrated under reduced pressure.Gained residue is through the silica gel column chromatography (NH of DCM/3M3MeOH solution (v/v)=50/1 To 30/1) purifying, obtaining title compound is brown solid (70mg, yield 46%).
LC-MS(ESI,pos.ion)m/z:316.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.93 (d, J=5.5Hz, 1H), 7.24 (s, 1H), 6.48 (s, 1H), 5.81 (d, J=5.9Hz, 1H), 4.63 (br, 1H), 3.69 (s, 3H), 3.28 (dd, J=12.5,3.3Hz, 1H), 3.19- 3.09 (m, 1H), 2.71 (td, J=12.2,2.4Hz, 1H), 2.46-2.34 (m, 1H), 2.27 (s, 3H), 2.18-2.06 (m, 1H), 1.75-1.69 (m, 1H), 1.42-1.30 (m, 3H), 1.21-1.12 (m, 1H), 0.90 (t, J=7.5Hz, 3H).
Step 2) 6- (4- ((the chloro- 2- of 2- ((1,5- dimethyl -1H- pyrazole-3-yl) amino) pyrimidine-4-yl) amino) -3- Ethyl piperidine -1- base) pyridazine -3- formonitrile HCN
N2(1,5- dimethyl -1H- pyrazole-3-yl)-N4(3- ethyl piperidine -4- base) pyrimidine -2,4- diamines (70mg, It 0.22mmol) is suspended in EtOH (3.0mL), 6- chlorine pyridazine -3- formonitrile HCN (63mg, 0.45mmol) and triethylamine is added thereto (0.10mL,0.72mmol).Then reaction system is stirred overnight at 35 DEG C to be concentrated under reduced pressure.Gained residue is through silica gel column chromatography (the NH of DCM/3M3MeOH solution (v/v)=50/1 to 30/1 to 15/1) purifying, obtain title compound be yellow solid (46mg, yield 50%).
LC-MS(ESI,pos.ion)m/z:419.4[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.90-7.81 (m, 1H), 7.44 (d, J=9.6Hz, 1H), 6.87 (d, J=9.7Hz, 1H), 6.36 (s, 1H), 5.99 (br, 1H), 4.69-4.58 (m, J=12.8Hz, 1H), 4.47-4.35 (m, J= 13.5Hz,1H),3.94(s,1H),3.67(s,3H),3.31-3.19(m,1H),3.00-2.90(m,1H),2.25(s,3H), 1.79-1.69 (m, 2H), 1.62-1.53 (m, 2H), 1.33-1.28 (m, 1H), 0.97 (t, J=7.5Hz, 3H).
23 6- of embodiment (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) ammonia Base) -3- ethyl piperidine -1- base)-nicotinonitrile
To the chloro- N of 5-2(2,3- dimethyl -2H- indazole -6- base)-N4(3- ethyl piperidine -4- base) pyrimidine -2,4- diamines 6- chloropyridine -3- formonitrile HCN (44mg, 0.32mmol) and triethylamine are added in EtOH (3mL) solution of (85mg, 0.21mmol) (64mg,0.63mmol).Reaction system is warming up to 80 DEG C and is stirred to react 8 hours, is then concentrated under reduced pressure.Gained residue is through making Standby thin-layer chromatography (MeOH/DCM (v/v)=1/20) is purified, and obtaining title compound is green solid (57.3mg, yield 53.7%).
LC-MS(ESI,pos.ion)m/z:501.9[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.42 (d, J=2.3Hz, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.61 (dd, J=9.0,2.2Hz, 1H), 7.45 (d, J=8.8Hz, 1H), 7.03 (d, J=9.0Hz, 1H), 6.92 (s, 1H), 6.65 (d, J=9.1Hz, 1H), 5.02 (d, J=8.7Hz, 1H), 4.59 (d, J=11.8Hz, 1H), 4.38 (d, J= 14.2Hz, 1H), 4.20 (d, J=12.2Hz, 2H), 4.04 (s, 3H), 3.25 (d, J=11.7Hz, 1H), 2.93-2.86 (m, 1H), 2.57 (s, 3H), 2.32 (d, J=9.6Hz, 2H), 2.26-2.18 (m, 1H), 2.01 (d, J=5.8Hz, 1H), 1.00 (q, J=7.4Hz, 3H).
24 6- of embodiment (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) (first Base) amino) piperidin-1-yl) pyridazine -3- formonitrile HCN
Step 1) (1- (6- cyano pyridazine -3- base) piperidin-4-yl) (methyl) ammonia t-butyl formate
To methyl (piperidin-4-yl) ammonia t-butyl formate (605.8mg, 2.83mmol) and 6- chlorine pyridazine -3- formonitrile HCN Triethylamine (1.14g, 11.30mmol) is added in ethyl alcohol (15mL) solution of (796.5mg, 5.71mmol).Reaction system is in room It is stirred overnight under temperature, is then concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=1/1), must be marked Topic compound is yellow solid (252.0mg, yield 28.1%).
LC-MS(ESI,pos.ion)m/z:318.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.45 (d, J=9.6Hz, 1H), 6.87 (d, J=9.6Hz, 1H), 4.68 (d, J=13.0Hz, 2H), 4.33 (t, J=6.7Hz, 1H), 3.11 (t, J=12.2Hz, 2H), 2.73 (s, 3H), 1.85 (d, J=11.8Hz, 2H), 1.71 (m, 2H), 1.50 (s, 9H).
Step 2) 6- (4- (methylamino) piperidin-1-yl) pyridazine -3- carbonitrile hydrochloride
(1- (6- cyano pyridazine -3- base) piperidin-4-yl) (methyl) ammonia t-butyl formate (235.4mg, 0.74mmol) is mixed It is suspended from DCM (10mL), ethyl acetate (4M, 10mL, 40mmol) solution of hydrogen chloride is added thereto.Reaction mixture room temperature Lower stirring 20 minutes, is then concentrated under reduced pressure, and obtaining title compound is yellow solid (188.2mg, yield 100%).
LC-MS(ESI,pos.ion)m/z:218.2[M+H]+。
Step 3) 6- (4- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) piperidin-1-yl) pyridazine -3- formonitrile HCN
6- (4- (methylamino)-piperidin-1-yl) pyridazine -3- carbonitrile hydrochloride (188.2mg, 0.74mmol) and 2,4,5- Trichloropyrimidine (208.9mg, 1.14mmol) is suspended in EtOH (10mL), thereto be added triethylamine (270.6mg, 2.67mmol).Reaction system is stirred at room temperature overnight, and is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/ PE (v/v)=1/1) purifying, obtaining title compound is faint yellow solid (85.4mg, yield 31.6%).
LC-MS(ESI,pos.ion)m/z:364.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.13 (s, 1H), 7.48 (d, J=9.6Hz, 1H), 6.92 (d, J= 9.6Hz, 1H), 4.74 (m, 3H), 3.19 (dd, J=18.8,7.2Hz, 2H), 3.09 (s, 3H), 2.03 (d, J=10.7Hz, 2H), 1.88 (ddd, J=24.6,12.3,4.1Hz, 2H).
Step 4) 6- (4- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- base) amino) pyrimidine-4-yl) (methyl) ammonia Base) piperidin-1-yl) pyridazine -3- formonitrile HCN
To 6- (4- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) piperidin-1-yl) pyridazine -3- formonitrile HCN (66.9mg, 0.18mmol) and the 1,4- dioxane (12mL) of 2,3- dimethyl -2H- indazole -6- amine hydrochlorate (60.8mg, 0.31mmol) In solution, it is added Pd (OAc)2(14.0mg, 0.06mmol), BINAP (31.0mg, 0.05mmol) and cesium carbonate (207.0mg, 0.64mmol).Reaction system is warming up to 150 DEG C and reacts 2 hours under microwave irradiation, be then concentrated under reduced pressure in nitrogen atmosphere. Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/60), and obtaining title compound is brown solid (29.5mg, yield 32.8%).
LC-MS(ESI,pos.ion)m/z:488.8[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.08 (s, 1H), 8.03 (s, 1H), 7.47 (d, J=9.7Hz, 2H), 6.98 (s, 1H), 6.92 (m, 2H), 4.76 (m, 1H), 4.73 (m, 2H), 4.05 (s, 3H), 3.29 (t, J=12.1Hz, 2H), 3.09 (s, 3H), 2.59 (s, 3H), 2.08 (d, J=13.8Hz, 2H), 1.88 (qd, J=12.5,4.2Hz, 2H).
25 6- of embodiment (4- ((the chloro- 2- of 5- ((2- methyl -2H- indazole -6- base) amino) pyrimidine-4-yl) amino) piperazine Pyridine -1- base) pyridazine -3- formonitrile HCN
Step 1) N- (diphenylmethylene) -2- methyl -2H- indazole -6- amine
To the bromo- 2- methyl -2H- indazole (1.0g, 4.738mmol) of 6-, benzophenone imine (1.29g, 7.12mmol) and In Isosorbide-5-Nitrae-dioxane (25mL) solution of sodium tert-butoxide (911mg, 9.480mmol), addition BINAP (295mg, 0.474mmol) and Pd2(dba)3(224mg,0.237mmol).Reaction system is removed air 5 minutes, and nitrogen is then re-filled.Institute It obtains reaction mixture and is warming up to 100 DEG C overnight, be then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v) =10/1 to 1/1) it purifies, obtaining title compound is yellow solid (1.45g, yield 98.3%).
LC-MS(ESI,pos.ion)m/z:312.4[M+H]+。
Step 2) 2- methyl -2H- indazole -6- amine
To the methylene chloride of N- (diphenylmethylene) -2- methyl -2H- indazole -6- amine (1.45g, 4.66mmol) In (15mL) solution, the EtOAc solution (10mL 4M) of HCl is added.Gained reaction system stirs 4 hours at room temperature, then depressurizes Concentration.Gained residue is dissolved in the water, and is then adjusted to pH=8~9 with saturated sodium bicarbonate aqueous solution.Mixture dichloromethane Alkane (40mL × 3) extraction, combined organic phase are washed with saturated salt solution (50mL), and anhydrous sodium sulfate dries, filters, and depressurizes Concentration.Residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 10/1), and obtaining title compound is yellow solid (678mg, yield 98.9%).
LC-MS(ESI,pos.ion)m/z:148.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.70 (s, 1H), 7.43 (d, J=8.8Hz, 1H), 6.79 (s, 1H), 6.58 (dd, J=8.8,1.8Hz, 1H), 4.10 (s, 3H), 3.66 (s, 2H).
Step 3) 4- ((2,5- dichloro pyrimidine -4- base) amino) piperidines -1- t-butyl formate
Into ethyl alcohol (50mL) solution of 2,4,5- trichloropyrimidines (2g, 10.904mmol), 4- amino piperidine -1- first is added Tert-butyl acrylate (2.62g, 13.1mmol) and triethylamine (2.21g, 21.8mmol).Reaction mixture is stirred at room temperature overnight, Then it is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=1/20to 1/10), is obtained titled Conjunction object is white solid (3.2g, yield 85%).LC-MS(ESI,pos.ion)m/z:347.3[M+H]+。
Step 4) 4- ((the chloro- 2- of 5- ((2- methyl -2H- indazole -6- base) amino) pyrimidine-4-yl) amino) piperidines -1- first Tert-butyl acrylate
To 4- ((2,5- dichloro pyrimidine -4- base) amino) piperidines -1- t-butyl formate (300mg, 0.864mmol), 2- first The 1,4- dioxane (25mL) of base -2H- indazole -6- amine (191mg, 1.298mmol) and cesium carbonate (845mg, 2.594mmol) In solution, palladium acetate (19.5mg, 0.0869mmol) and BINAP (54mg, 0.0867mmol) is added.Reaction system eliminates air 2 minutes, then re-fill nitrogen.Gained reaction mixture is warming up to 100 DEG C and stirs 4 hours, is then concentrated under reduced pressure.Gained is residual Object is stayed to purify through silica gel column chromatography (DCM/MeOH (v/v)=50/1), obtaining title compound is yellow solid (385mg, yield 97.29%).
LC-MS(ESI,pos.ion)m/z:458.5[M+H]+。
The chloro- N of step 5) 5-2(2- methyl -2H- indazole -6- base)-N4(piperidin-4-yl) pyrimidine -2,4- diamines
To 4- ((the chloro- 2- of 5- ((2- methyl -2H- indazole -6- base) amino) pyrimidine-4-yl) amino) piperidines -1- formic acid uncle The ethyl acetate (10mL, 4M) that hydrogen chloride is added in methylene chloride (15mL) solution of butyl ester (385mg, 0.8406mmol) is molten Liquid.Reaction mixture is stirred at room temperature overnight, and is then concentrated under reduced pressure.Gained residue is dissolved in water (15mL), is then used Saturated sodium bicarbonate aqueous solution is adjusted to pH=8~9.Mixture is extracted with methylene chloride (10mL × 3), and combined organic phase is used full It is washed with saline solution (20mL), anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure.Residue is through silica gel column chromatography (DCM/MeOH (v/v)=10/1 it) purifies, obtaining title compound is white solid (277mg, yield 92.10%).
LC-MS(ESI,pos.ion)m/z:358.3[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 9.20 (s, 1H), 8.16 (d, J=11.2Hz, 2H), 7.96 (s, 1H), 7.51 (d, J=8.9Hz, 1H), 7.20 (d, J=9.0Hz, 1H), 6.81 (d, J=7.7Hz, 1H), 4.08 (s, 4H), 3.04 (d, J=12.3Hz, 2H), 2.67 (t, J=11.7Hz, 2H), 1.88 (d, J=11.2Hz, 2H), 1.57 (tt, J= 11.7,6.0Hz,2H)。
Step 6) 6- (4- ((the chloro- 2- of 5- ((2- methyl -2H- indazole -6- base) amino) pyrimidine-4-yl) amino) piperidines -1- Base) pyridazine -3- formonitrile HCN
To the chloro- N of 5-2(2- methyl -2H- indazole -6- base)-N4(piperidin-4-yl) pyrimidine -2,4- diamines (257mg, 6- chlorine pyridazine -3- formonitrile HCN (151mg, 1.082mmol) and triethylamine are added in ethanol solution (10mL) 0.718mmol) (145.5mg,1.438mmol).Reaction mixture is stirred overnight at room temperature, is then filtered, and filter cake is washed with ethyl alcohol (50mL × 3) It washs.Collecting filter cake and obtaining title compound is faint yellow solid (252.2mg, yield 76.18%).
LC-MS(ESI,pos.ion)m/z:461.4[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):9.27(s,1H),8.22(s,1H),8.15(s,1H),7.99(s, 1H), 7.88 (d, J=9.7Hz, 1H), 7.54 (d, J=8.9Hz, 1H), 7.45 (d, J=9.7Hz, 1H), 7.22 (dd, J= 9.0,1.4Hz, 1H), 6.92 (d, J=7.7Hz, 1H), 4.64 (d, J=12.9Hz, 2H), 4.46-4.32 (m, 1H), 4.07 (s, 3H), 3.23 (t, J=12.2Hz, 2H), 2.08 (d, J=10.9Hz, 2H), 1.75-1.63 (m, 2H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):159.1,158.6,157.2,153.9,149.5,138.4, 131.6,128.8,124.5,120.3,118.0,117.7,111.6,103.8,102.9,48.6,44.4,40.2,31.0；
HRMS(ESI,pos.ion)m/z:461.1759[M+H]+,C22H22ClN10[M+H]+Theoretical value is 461.1712.
26 6- of embodiment (4- ((the chloro- 2- of 5- ((5- (2- hydroxyl propyl- 2- yl) -1- methyl-1 H- pyrazole-3-yl) amino) Pyrimidine-4-yl) amino) piperidin-1-yl)-nicotinonitrile
Step 1) 3- (2,5- dimethyl -1H- pyrroles -1- base) -1- methyl-1 H- pyrazoles
To 1- methyl-1 H- pyrazoles -3- amine (3.90g, 40.16mmol) and hexane -2,5- diketone (4.58g, Acetic acid (0.73g, 12.16mmol) is added in toluene (80mL) solution 40.13mmol).Reaction mixture is warming up to 155 DEG C, It is stirred overnight, then cools to room temperature and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/10) Purifying, obtaining title compound is yellow solid (6.90g, yield 98.1%).
LC-MS(ESI,pos.ion)m/z:176.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.41 (d, J=2.1Hz, 1H), 6.17 (d, J=2.2Hz, 1H), 5.87(s,2H),3.94(s,3H),2.13(s,6H)。
Step 2) 2- (3- (2,5- dimethyl -1H- pyrroles -1- base) -1- methyl-1 H- pyrazoles -5- base) propan-2-ol
At -78 DEG C, to 3- (2,5- dimethyl -1H- pyrroles -1- base) -1- methyl-1 H- pyrazoles (708.5mg, N-BuLi (tetrahydrofuran solution of 2.4M, 2.5mL, 6.0mmol) is added dropwise in THF (8mL) solution 4.04mmol).Reaction System maintains -78 DEG C to stir 0.5 hour, then moves to 0 DEG C and continues stirring 2 hours.Into system be added acetone (362.1mg, Then plus water (20mL) quenching reaction 6.24mmol), gained mixture is stirred at room temperature 3 hours, and uses ethyl acetate (50mL × 3) extraction.Combined organic phase is washed through saturated salt solution (50mL), and anhydrous sodium sulfate dries, filters, and depressurizes dense Contracting.Gained residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=1/5), and obtaining title compound is yellow oil (353.0mg, yield 37.4%).
LC-MS(ESI,pos.ion)m/z:234.4[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):5.99(s,1H),5.85(s,2H),4.10(s,3H),2.12(s, 6H),1.88(br.s,1H),1.70(s,6H)。
Step 3) 2- (3- amino -1- methyl-1 H- pyrazoles -5- base) propan-2-ol
Into ethyl alcohol (20mL) solution of hydroxylamine hydrochloride (1.13g, 16.26mmol), addition potassium hydroxide (85%, 544.0mg, 8.24mmol) water and ethyl alcohol (12mL/12mL) solution, 2- (3- (2,5- dimethyl -1H- pyrroles -1- base) -1- Methyl-1 H- pyrazoles -5- base) propan-2-ol (619.7mg, 2.66mmol).Reaction mixture is stirred at room temperature 48 hours, adds water (20mL) quenching reaction, and extracted with ethyl acetate (50mL × 3).Combined organic phase is washed through saturated salt solution (50mL), Anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure.Gained residue is pure through silica gel column chromatography (MeOH/DCM (v/v)=1/50) Change, obtaining title compound is yellow oil (400.2mg, yield 97.1%).
LC-MS(ESI,pos.ion)m/z:156.3[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):5.39(s,1H),3.82(s,3H),3.21(br.s,2H),1.56(s, 6H)。
(((the chloro- 2- of 5- ((5- (2- hydroxyl propyl- 2- yl) -1- methyl-1 H- pyrazole-3-yl) amino) is phonetic by 4- by step 4) 6- Pyridine -4- base) amino) piperidin-1-yl)-nicotinonitrile
To 6- (4- ((2,5- dichloro pyrimidine -4- base) amino) piperidin-1-yl) pyridazine -3- formonitrile HCN (70.1mg, 0.20mmol) and the 1,4- dioxy six of 2- (3- amino -1- methyl-1 H- pyrazoles -5- base) propan-2-ol (39.9mg, 0.26mmol) Pd (OAc) is added in ring (8mL) solution2(11.8mg, 0.05mmol), BINAP (98%, 29.2mg, 0.05mmol) and carbonic acid Caesium (98%, 145.2mg, 0.44mmol).Reaction mixture be warming up to 100 DEG C be stirred overnight after be concentrated under reduced pressure.Gained residue It is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), obtaining title compound is buff white solid (41.2mg, yield 43.9%).
LC-MS(ESI,pos.ion)m/z:468.5[M+H]+；
1H NMR(400MHz,DMSO-d6): δ (ppm) 9.19 (s, 1H), 8.50 (d, J=2.0Hz, 1H), 7.89 (s, 1H), 7.85 (dd, J=9.1,2.2Hz, 1H), 7.00 (d, J=9.1Hz, 1H), 6.77 (d, J=8.1Hz, 1H), 6.41 (s, 1H), 5.27 (s, 1H), 4.52 (d, J=13.2Hz, 2H), 4.32 (m, 1H), 3.85 (s, 3H), 3.00 (t, J=12.3Hz, 2H),1.95(m,2H),1.61(m,2H),1.51(s,6H)；
13C NMR(100MHz,DMSO-d6):δ(ppm)158.8,157.5,156.8,153.4,152.5,148.5, 146.0,139.9,118.6,106.4,102.7,94.8,94.2,66.8,47.7,43.8,37.8,30.5,30.2；
HRMS(ESI,pos.ion)m/z:468.2018[M+H]+,C22H27ClN9O[M+H]+Theoretical value is 468.2027.
Biologic test
The LC/MS/MS system of analysis includes the serial vacuum degassing furnace of Agilent 1200, and binary syringe pump, orifice plate is certainly Dynamic sampler, column insulating box, charged spray ionize the Agilent G6430 three-level level four bars mass spectrograph in the source (ESI).Quantitative analysis It is carried out under MRM mode, the parameter of MRM conversion is as in Table A:
Table A
More reaction detection scannings 490.2→383.1
Fragmentation voltage 230V
Capillary voltage 55V
Dryer temperature 350℃
Atomizer 40psi
Drier flow velocity 10L/min
Analysis uses μM column of Agilent XDB-C18,2.1 × 30mm, 3.5, injects 5 μ L samples.Analysis condition: mobile phase For 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient such as table Shown in B:
Table B
Time The gradient of Mobile phase B
0.5min 5%
1.0min 95%
2.2min 95%
2.3min 5%
5.0min It terminates
In addition, the also 6330 series LC/MS/MS spectrometer of Agilent for analysis, is infused equipped with G1312A binary Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrometer uses ESI radioactive source.Use titer Suitable cationic model treatment is carried out to each analyte and MRM conversion carries out optimal analysis.It uses during analysis Capcell MP-C18 column, specification are as follows: 100 × 4.6mm I.D., 5 μM (Phenomenex, Torrance, California, USA).Mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70: 30, v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L samples.
Stability in embodiment A people and rat liver microsomes
People or rat liver microsomes are placed in duplicate hole in polypropylen tubes to be incubated for.It is typical be incubated for mixed liquor include people or Rat liver microsomes (0.5mg protein/mL), target compound (5 μM) and total volume are NADPH (1.0mM) phosphoric acid of 200 μ L Potassium buffer (PBS, 100mM, pH value 7.4), untested compound is dissolved in DMSO, and is diluted using PBS, it is made The concentration of final DMSO solution is 0.05%.And it is incubated in the water-bath communicated at 37 DEG C with air, preincubate 3 minutes Albumen is added in backward mixed liquor and starts to react.Point (0,5,10,15,30 and 60 minute) in different times is added androgynous Product ice-cold acetonitrile terminates reaction.Sample is saved at -80 DEG C until carrying out LC/MS/MS analysis.
Concentration of the compound in people or rat liver microsomes mixtures incubated is measured by the method for LC/MS/MS 's.The range of linearity of concentration range is determined by each test-compound.
It is parallel to be incubated for test and use the microsome of denaturation as negative control, hatch at 37 DEG C, reaction is when different Between point (0,15 and 60 minute) terminate.
Verapamil (1 μ Μ) be used as positive control, hatch at 37 DEG C, reaction in different times point (0,5,10,15, 30 and 60 minutes) it terminates.It all include positive and negative control sample in each measuring method, to guarantee that microsome hatches system Integrality.
In addition, stability data of the compound of the present invention in people or rat liver microsomes can also be obtained by following tests It arrives.People or rat liver microsomes are placed in duplicate hole in polypropylen tubes to be incubated for.Typical mixtures incubated includes people or rat Hepatomicrosome (ultimate density: 0.5mg albumen/mL), untested compound (ultimate density: 1.5 μM) and total volume are the phosphorus of 30 μ L Sour potassium buffer solution (EDTA containing 1.0mM, 100mM, pH 7.4).Untested compound is dissolved in DMSO, and slow with potassium phosphate Solution dilution is rushed, the ultimate density 0.2% of DMSO is made.Preincubate after ten minutes, be added 15 μ L NADPH (ultimate density: Enzymatic reaction 2mM) is carried out, entire test carries out in 37 DEG C of incubation tube.(0,15,30 and 60 point of point in different times Clock), 135 μ L acetonitriles (containing IS) are added and terminate reaction.With 4000rpm centrifugation 10 minutes, deproteinized is removed, collects supernatant liquor, is used LC-MS/MS analysis.In above-mentioned test, ketanserin (1 μM) is selected as positive control, hatches at 37 DEG C, reacts different It terminated within time point (0,15,30 and 60 minute).It all include positive and negative control sample in each measuring method, it is micro- to guarantee The integrality of plastochondria hatching system.
Data analysis
For each reaction, concentration (as a percentage) of the compound in people or rat liver microsomes are incubated for is pressed The plotted as percentage of opposite zero time point infers internal liver clearance rate CL with thisint(ref.:Naritomi Y, Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.).As a result referring to table 1, table 1 is the compound that section Example of the present invention provides The experimental result of stability in people and rat liver microsomes.
The experimental result for compound stability in people and rat liver microsomes that the section Example of the present invention of table 1 provides
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 mouse, rat, dog and monkey oral or intravenous quantify the pharmacokinetics after the compounds of this invention Evaluation
The compounds of this invention is assessed in mouse, rat, dog or the intracorporal pharmacokinetic of monkey.This hair Bright compound is with aqueous solution or the aqueous solution of 2%HPMC+1% twen-80, the saline solution of 5%DMSO+5%, 4%MC or glue Scrotiform formula is administered.Intravenous injection is administered, animal gives the dosage of 1 or 2mg/kg.For oral dose (p.o.), greatly Mouse and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25,0.5,1.0,2.0,3.0,4.0 at time point, Blood (0.3mL) is taken within 6.0,8.0,12 and 24 hours, and is centrifuged 10 minutes at 3,000 or 4,000rpm.Plasma solutions are collected, and It is saved at -20 DEG C or -70 DEG C until carrying out above-mentioned LC/MS/MS analysis.As a result referring to table 2, table 2 is that present invention part is real Experimental result of the compound of example offer in the intracorporal medicine of rat for feature is provided.
The compound that the section Example of the present invention of table 2 provides is in the intracorporal medicine of rat for the experimental result of feature
As shown in Table 2, when compound intravenous injection provided by the invention being administered or is administered orally, chemical combination of the present invention Object shows good pharmacokinetic property, absorbs good and has ideal half-life period (T1/2) and higher oral bio Availability (F).
Embodiment C Kinase activity assays
Disclosed compound of present invention can be evaluated as the effectiveness of kinases inhibitor by following experiment.
The general description of kinase assay
Kinase assay passes through detection incorporation γ-33The myelin basic protein (MBP) of P-ATP is come what is completed.Prepare 20 μ g/ MBP (Sigma#M-1891) trishydroxymethylaminomethane buffer salt solution (TBS of ml；50mM Tris pH 8.0,138mM NaCl, 2.7mM KCl), it is coated with white 384 orifice plate (Greiner) of high associativity, every 60 μ L of hole.At 4 DEG C, it is incubated for 24 hours.It Afterwards with 100 μ L TBS board-washing 3 times.Kinase reaction (is prepared, for example, 5mM as needed in the kinase buffer liquid that total volume is 34 μ L Hepes pH 7.6,15mM NaCl, 0.01% bovine serum albumin(BSA) (Sigma#I-5506), 10mM MgCl2,1mM DTT, It is carried out in 0.02%TritonX-100).Compound is dissolved in DMSO, is added in each hole, compound is most in DMSO solution Final concentration of 1%.The measurement of each compound is at least tested twice.For example, the ultimate density of enzyme is 10nM or 20nM.Add Enter not having markd ATP (10 μM) and γ-33(the every hole 2 × 10 ATP of P label6Cpm, 3000Ci/mmol) start to react.Reaction Concussion carries out 1 hour at room temperature.384 orifice plates with 7 × PBS clean, the scintillation solution of every 50 μ L of hole is then added.With Wallac Trilux counter testing result.To those of ordinary skill in the art, this is only in numerous detection methods One kind, other methods also may be used.
The IC of the above-mentioned available inhibition of test method50And/or inhibition constant Ki。IC50It is defined as under test conditions, suppression Make compound concentration when 50% enzymatic activity.The curve comprising 10 concentration points is made using the extension rate of 1/2log, is estimated IC50Value (for example, making a typical curve by following compound concentration: 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01μM、0.003μM、0.001μM、0.0003μM、0μM)。
JAK1(h)
JAK1 (h) is in 20mM Tris/HCl pH 7.5,0.2mM EDTA, 500 μM of GEEPLYWSFPAKKK, 10mM vinegar Sour magnesium and [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing. Start to react after MgATP mixture is added.After being incubated for 40 minutes at room temperature, it is anti-to terminate that 3% phosphoric acid solution is added thereto It answers.The reaction solution of 10 μ L is distributed on P30 filter in mottled, and is cleaned in 5 minutes 3 times with 75mM phosphoric acid, and It is put into methanol solution and saves at once before dry and scinticounting.
JAK2(h)
JAK2 (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 100 μM of KTFCGTPEYLAPEVRREPRILSEEEQ EMFRDFDYIADWC, 10mM magnesium acetate and [γ-33P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) deposit It is incubated under the conditions.Start to react after MgATP mixture is added.After being incubated for 40 minutes at room temperature, it is added thereto 3% phosphoric acid solution reacts to terminate.The reaction solution of 10 μ L is distributed on P30 filter in mottled, and with 75mM phosphoric acid 5 Cleaning 3 times in minute, and be put into methanol solution and save at once before dry and scinticounting.
JAK3(h)
JAK3 (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 500 μM of GGEEEEYFELVKKKK, 10mM magnesium acetate [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.It is added Start to react after MgATP mixture.After being incubated for 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate reaction.It will The reaction solution of 10 μ L is distributed on P30 filter in mottled, and is cleaned in 5 minutes 3 times with 75mM phosphoric acid, and dry and It is put into methanol solution and saves at once before scinticounting.
TYK2(h)
TYK2 (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 250 μM of GGMEDIYFEFMGGKKK, 10mM magnesium acetate [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.It is added Start to react after MgATP mixture.After being incubated for 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate reaction.It will The reaction solution of 10 μ L is distributed on P30 filter in mottled, and is cleaned in 5 minutes 3 times with 75mM phosphoric acid, and dry and It is put into methanol solution and saves at once before scinticounting.
FLT3(h)
FLT3 (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 50 μM of EAIYAAPFAKKK, 10mM magnesium acetate and [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.It is added Start to react after MgATP mixture.After being incubated for 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate reaction.It will The reaction solution of 10 μ L is distributed on P30 filter in mottled, and is cleaned in 5 minutes 3 times with 75mM phosphoric acid, and dry and It is put into methanol solution and saves at once before scinticounting.
Aurora-A(h)
Aurora-A (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 200 μM of LRRASLG (Kemptide), 10mM Magnesium acetate and [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing It educates.Start to react after MgATP mixture is added.After being incubated for 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate Reaction.The reaction solution of 10 μ L is distributed on P30 filter in mottled, and is cleaned in 5 minutes 3 times with 75mM phosphoric acid, and It is put into methanol solution and saves at once before dry and scinticounting.
Aurora-B(h)
Aurora-B (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 30 μM of AKRRRLSSLRA, 10mM magnesium acetate and [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.It is added Start to react after MgATP mixture.After being incubated for 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate reaction.It will The reaction solution of 10 μ L is distributed on P30 filter in mottled, and is cleaned in 5 minutes 3 times with 75mM phosphoric acid, and dry and It is put into methanol solution and saves at once before scinticounting.
Kinase assay in the present invention be completed by Millipore company, Britain (Millipore UK Ltd, Dundee Technology Park,Dundee DD2 1SW,UK)。
In addition, the kinase activity of compound can pass through KINOMEscanTMDetection, this detection are to be based on using active sites Point guidance type Competition binding assay method quantitative detection compound.The test in conjunction with three kinds of compounds by carrying out, i.e. DNA mark Remember enzyme, fixed ligand and detection compound, the competition energy of qPCR detection compound and fixed ligands is carried out by DNA marker Power.
Most of experiment is all from the T7 bacteriophage bacterium for cultivating kinases label derived from BL21 bacterial strain in escherichia coli host Strain, after being in the Escherichia coli of logarithmic growth phase with T7 phage-infect, lysate is centrifuged by 32 DEG C of oscillation incubations to bacteriolyze Filtering removal cell fragment, remaining kinases go in HEK-293 cell and carry out qPCR detection with DNA marker.Streptavidin After coated particle handles 30min with biotinylated smaller ligand room temperature, affine resin can produce for kinase assay.Match Body particle is after extra biotin closing, through confining liquid (SEABLOCKTM(Pierce), 1% bovine serum albumin(BSA), 0.05% Polysorbas20,1mM DTT) the unbonded ligand of cleaning, reduces non-specific binding.By 1 × combination buffer (20% SEABLOCKTM, 0.17 × phosphate buffer solution, 0.05% polysorbas20,6mM DTT) in combine kinases, ligand is affine particle and Test compound is combined reaction, and all reactions are carried out in 96 orifice plates, and reaction final volume is 0.135mL, room temperature vibration Incubation 1 hour is swung, washing buffer (1 × phosphate buffer solution, 0.05% polysorbas20) is added and cleans affine particle, addition is washed After (1 × phosphate buffer solution, 0.05% polysorbas20,0.5 μM of non-biotinylated affinity ligand) is resuspended in de- buffer, room temperature Oscillation incubation 30min detects the concentration of kinases in eluent by qPCR.Kinase activity measurement described in the text is in the U.S. The KINOMEscan of DiscoveRx company (Albrae St.Fremont, CA 94538, USA)TMDepartment is measured.Kinases Activity test result is referring to table 3 and table 4.
Table 3 is JAK1 the and JAK2 kinase assay for the compound that section Example of the present invention provides as a result, table 4 is the present invention The TYK2 of compound, JAK3, Aurora A and the FLT3 kinase assay result that section Example provides.
JAK1 the and JAK2 kinase assay result for the compound that the section Example of the present invention of table 3 provides
NT: it does not test
The TYK2 of compound, JAK3, Aurora A and the FLT3 kinase assay result that the section Example of the present invention of table 4 provides
NT: it does not test
By table 3 and table 4 it is found that compound of the present invention shows extraordinary jak kinase, FLT3 in kinase assay Kinases and Aurora kinase inhibitory activity are especially significant to JAK1, JAK2, JAK3 and FLT3 kinase inhibiting activity.
Finally it should be noted that being used to implement the present invention there are also other modes.Correspondingly, the embodiment of the present invention is It will illustratively be illustrated, but be not limited to content described in the invention, it is also possible to made by within the scope of the present invention Modification or in the claims added equivalent.All publications or patent cited in the present invention will all be used as this hair Bright bibliography.

Claims (17)

1. a kind of compound is stereoisomer, the tautomerism of compound shown in formula (I) compound represented or formula (I) Body or pharmaceutically acceptable salt,
Wherein, W is one of the heterocyclyl groups that following heterocyclic compound is formed:
Wherein, heterocycle shown in formula (W-2) and (W-10) is formed by each heterocyclyl groups individually optionally by 1,2 or 3 R2Base Replaced group,
Ar is phenyl or 5-6 former molecular heteroaryl, wherein Ar is optionally by 1 or 2 R8Replaced group；
Z is H or C1-C6Alkyl；
B is pyrazolyl or indazolyl, wherein B is optionally by 1,2 or 3 R4Replaced group；
R1For H, F, Cl, Br, I, NO2, CN or C1-C6Alkyl；
Each R2、R4And R8It is separately H, F, Cl, Br, I, CN, C1-C6Alkyl or C1-C6Hydroxy alkyl.
2. compound according to claim 1, wherein Ar be phenyl, furyl, imidazole radicals, isoxazolyl, oxazolyl, Pyrrole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, triazol radical, thienyl, pyrazolyl, Oxygen phenodiazine oxazolyl, sulphur phenodiazine oxazolyl, pyrazinyl or triazine radical, wherein Ar is optionally by 1 or 2 R8Replaced group.
3. compound according to claim 1, wherein Z H, methyl, ethyl, n-propyl, isopropyl.
4. compound according to claim 1, wherein R1For H, F, Cl, Br, CN, methyl, ethyl, n-propyl or isopropyl Base.
5. compound according to claim 1, wherein each R2、R4And R8It is separately H, F, Cl, CN, methyl, second Base, n-propyl, isopropyl, methylol, 1- ethoxy, 2- ethoxy, 3- hydroxypropyl, 2- hydroxypropyl, 2- hydroxy-2-methyl third Base or 2- hydroxyl propyl- 2- base.
6. compound according to claim 1, wherein W is one of minor structure below:
Wherein, above-mentioned formula (W-32), each subformula shown in (W-39)~(W-41) are individually optionally by 1,2 or 3 R2Group It is replaced.
7. compound according to claim 1, wherein B is following subformula:
Wherein, minor structure shown in formula (H), (I), (J), (K), (L), (M), (N), (O), (P) or (Q) is only It stands optionally by 1,2 or 3 R4Replaced group.
8. compound according to claim 1 is compound or following one structure with following one structure Stereoisomer, tautomer or the pharmaceutically acceptable salt of compound:
9. a kind of pharmaceutical composition, it includes compounds described in claim 1-8 any one.
10. pharmaceutical composition according to claim 9, wherein further include pharmaceutically acceptable auxiliary material, solvent or Their combination.
11. pharmaceutical composition according to claim 10, wherein the auxiliary material is excipient or carrier.
12. according to the described in any item pharmaceutical compositions of claim 9-11, wherein therapeutic agent is further included, the therapeutic agent Selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 inhibitors, beta-2-adrenoreceptor agonists, corticosteroid, non-steroidal Class GR agonist, anticholinergic drug, antihistamine, anti-inflammatory reagent, immunosuppressor, immunomodulator, for treating artery The drug of atherosis, the drug for treating pulmonary fibrosis and their combination.
13. compound described in claim 1-8 any one or claim 9-12 any one described pharmaceutical composition are being made Purposes in standby drug, the disease that the drug is used to prevent, handle, treat or mitigate the disease of JAK- mediation, FLT3- is mediated Or the disease that Aurora- is mediated.
14. purposes according to claim 13, wherein disease that the disease that mediates of the JAK-, FLT3- are mediated or The disease that Aurora- is mediated is proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease, graft rejection marrow fibre Dimensionization, Chronic Obstructive Pulmonary Disease, type-1 diabetes mellitus, morbilli,.
15. purposes according to claim 14, wherein the proliferative diseases are cancer, polycythemia vera, original Hair property piastrenemia, acute myelocytic leukemia, chronic granulocytic leukemia or acute lymphoblastic leukemia；
The autoimmune disease is systemic loupus erythematosus, skin lupus erythematosus, lupus nephritis, Sjogren syndrome or class Rheumatic arthritis；
The anaphylactia is respiratory anaphylactic disease, food hypersenstivity or insect venom allergies；
The inflammatory disease is lupus nephritis, dermatomyositis, psoriasis, nasosinusitis, eczema, inflammatory bowel disease, rheumatoid joint Scorching, juvenile arthritis or psoriasis arthropathica；
The graft rejection is organ-graft refection, tissue transplantation rejection or cell transplant rejection；
The Chronic Obstructive Pulmonary Disease is asthma.
16. purposes according to claim 15, wherein the inflammatory bowel disease is Crohn disease.
17. compound described in claim 1-8 any one or claim 9-12 any one described pharmaceutical composition are being made Purposes in standby drug, the drug are used to adjust the activity of jak kinase, FLT3 kinases, Aurora A or their combination.
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