CN104926794A - Substituted heteroaryl compound, and composition and application thereof - Google Patents

Substituted heteroaryl compound, and composition and application thereof Download PDF

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CN104926794A
CN104926794A CN201510114757.8A CN201510114757A CN104926794A CN 104926794 A CN104926794 A CN 104926794A CN 201510114757 A CN201510114757 A CN 201510114757A CN 104926794 A CN104926794 A CN 104926794A
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former molecular
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compound
alkyl
cycloalkyl
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CN104926794B (en
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习宁
李敏雄
李晓波
张涛
吴彦君
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Guangdong HEC Pharmaceutical
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Add And Open Up Scientific Co
Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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

Abstract

The invention provides a type of substituted heteroaryl compound, and a composition and an application thereof. the compound is a compound represented by a formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutically acceptable salt or its prodrug of the compound represented by the formula (I). The invention also provides a medicine composition comprising the compound. With the compound and medicine composition thereof, protein kinase activity can be regulated. Therefore, the compound and the medicine composition thereof can be used for controlling, treating and relieving diseases and disorders mediated by protein kinase.

Description

The heteroaryl compound replaced and composition and purposes
Invention field
The invention belongs to pharmaceutical field, be specifically related to a class as the new compound of kinase activity inhibitor, the method preparing them, the pharmaceutical composition comprising described compound and described compound and the application of pharmaceutical composition in the multiple various disease for the treatment of thereof.More particularly, compound of the present invention can as jak kinase family (comprising JAK1, JAK2, JAK3 and TYK2), FLT3 kinases (also claiming FLK-2) and the activity of Aurora A (comprising Aurora-A, Aurora-B and Aurora-C) or the inhibitor of function.
Background of invention
Protein kinase family comprises a large class formation involved enzyme, and they control intracellular various signal transduction process, usually containing 250-300 similar amino acid catalytic domain, and the phosphorylation of catalysis target proteins matter substrate.It was reported that numerous disease is replied relevant with the abnormal cells that protein kinase mediated event causes.These diseases comprise optimum cause with pernicious proliferative disease, the inappropriate activation of immunity system disease, allograft rejection, graft versus host disease, autoimmune disorder, inflammatory diseases, osteopathia, metabolic disease, sacred disease and neurodegenerative disease, cancer, cardiovascular disorder, transformation reactions and asthma, alzheimer's disease and hormone related condition.Correspondingly, medicinal chemistry arts has carried out a large amount of effort using searching as the effective kinases inhibitor of therapeutical agent.
Kinases can by the substrate of phosphorylation be divided into multiple family (such as, protein-tyrosine, protein-serine/Threonine, lipid, etc.).Tyrosine phosphorylation is one of the central event regulating various biological procedures such as cell proliferation, migration, differentiation and existence.The acceptor of multiple family and these events of nonreceptor tyrosine kinase family listed business: catalytic phosphatase is transferred to the tyrosine residues of specific cells protein target from ATP.At present, motif (Hanks et al., FASEB J., 1995,9, the 576-596 of each kinase families general homology above-mentioned has been confirmed; Knighton et.al., Science, 1991,253,407-414; Garcia-Bustos en al.EMBO J., 1994,13:2352-2361).Kinase whose example in protein kinase family comprises, but be 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, Deng.
Aurora A family is the relevant serine/threonine kinase of a class height, and it is mitotic key regulator, for from parent cell to the accurate of the genomic material of daughter cell and equal separation (segtion) is required.The member of Aurora A family comprises the relevant kinases of three classes, is called Aurora-A, Aurora-B and Aurora-C (also referred to as Aurora-1, Aurora-2 and Aurora-3).Although these kinases have significant program homology, its localization and function still have greatly difference (Richard D.Carvajal, et al., Clin CancerRes., 2006,12 (23): 6869-6875 each other; Daruka Mahadevan, et al., Expert Opin.Drug Discov., 2007,2 (7): 1011-1026).
Aurora-A expresses at large and regulates the cell cycle events occurred through the M phase from the S phase in late period, comprise centrosome maturation, (Berdnik D, et al., Curr Biol., 2002,12:640-647), mitotic division enters (Hirota T, et al., Cell 2003,114:585-598; Dutertre S, et al., J Cell Sci.2004,117:2523-2531), centrosome is separated (Marumoto T, et al., J Biol Chem., 2003,278:51786-51795), the two poles of the earth mitotic spindle assembly thing (Eyers PA, et al., Curr Biol.2003,13:691-7.), Chromosomal arrangement (Marumoto T, the et al. on equatorial plate, J Biol Chem.2003,278:51786-95; Kunitoku N, et al., Dev Cell, 2003,5:853-64), division of cytoplasm (Marumoto T, et al., J Biol Chem.2003,278:51786-95), and mitotic division terminates.All increase from G2 through M phase Aurora-A protein level and kinase activity, its peak activity is in the prometaphase.Once activation, Aurora-A interacts mediate its several functions by comprising centrosome protein (centrosomin) with various substrate, conversion acidity is curling-and crimp protein, cdc25b, Eg5 and centromere protein matter A.
Aurora-B isolates accurate karyomit(e), division of cytoplasm (Hauf S, et al., J Cell Biol., 2003,161:281-94; DitchfieldC, 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 BiolChem., 2003,278:8526-8530), protein localization is to kinetochore and kinetochore, correct microtubule-kinetochore attachment (Murata-Hori M, et al., Curr Biol.2002,12:894-899), and regulate the karyomit(e) passenger albumen of Mitotic checkpoint key.Aurora-B first during early stage localization in karyomit(e), then kinetochore district (Zeitlin SG, etal., J Cell Biol., 2001 in prometaphase and interim period localization are between sister strand; 155:1147-1157).Aurora-B participates in establishing chromosomal biological orientation, and wherein sisters kinetochore is connected to the phase antipole of the two poles of the earth spindle via double orientation attachment.The mistake of this process, show as partially oriented connection state (kinetochore is connected to from bipolar microtubule) or altogether orientation connection state (two sisters kinetochores are connected to the microtubule from same stages), if not correction up before the later stage starts, chromosomal unstable and dysploidy will be caused.Repair the attachment of incorrect microtubule-kinetochore (Hauf S, et al., J Cell Biol., 2003,161:281-294 at the Main Function of the Aurora-B of mitotic division point; Ditchfield C, et al., J Cell Biol., 2003,161:267-280; Lan W, et al., Curr Biol., 2004,14:273-286.).When Aurora-B inactivation, Mitotic checkpoint is damaged, and causes the aneuploid cell of accelerating, and (Weaver BA, et al., Cancer Cell, 2005,8:7-12) occurs for genic instability and tumour.
Aurora-A process LAN is the tumorigenic required feature of Aurora-A-induction.In the cell of tool Aurora-A process LAN, mitotic feature there is multiple centrosome and multipolar spindle (Meraldi Pet al., EMBO J, 2002,21:483-92.).Although obtain abnormal microtubule-kinetochore attachment, cell is still abolished Mitotic checkpoint and is advanced to the later stage from mid-term, causes many chromosome segregation defects.Can not there is division of cytoplasm in these cells, and develop the other cell cycle, polyploidy and Progressive symmetric erythrokeratodermia chromosome instability (Anand S, et al., Cancer Cell, 2003,3:51-62).
Verified Aurora process LAN and multiple malignant proliferative disorders, as the rectum cancer, mammary cancer, lung cancer, carcinoma of the pancreas, prostate cancer, bladder cancer, head and neck cancer, cervical cancer, ovarian cancer, liver cancer and cancer of the stomach etc., closely related, excite the interest of exploitation for the Aurora inhibitor of cancer therapy.In normal cell, Aurora-A suppress to cause delay but and non-blacked mitotic division enters, the centrosome detachment defects of one pole mitotic spindle and division of cytoplasm failure (Marumoto T, et al., J Biol Chem., 2003,278:51786-51795).The challenging antitumous effect of Aurora-A inhibitor is shown in three-type-person's class pancreatic carcinoma (Panc-Ι, Μ Ι Α PaCa-2dnSU.86.86) in, wherein there is being close to of the tumorigenicity in growth-inhibiting and murine xenogralt in cell culture and all eliminate (Hata T, et al., Cancer Res., 2005,65:2899-2905).
Aurora-B suppresses to cause abnormal kinetochore-microtubule attachment, cannot realize chromosomal biological orientation, division of cytoplasm unsuccessfully (Goto H, et al., J Biol Chem., 2003,278:8526-8530; Severson AF, et al., Curr Biol., 2000,10:1162-1171).The anomomitotic recirculation not comprising division of cytoplasm causes huge polyploidy and finally causes 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).
In tumour cell, Aurora-A or Aurora-B activity is suppressed to cause Chromosomal arrangement to damage, the abolishment of Mitotic checkpoint, polyploidy and necrocytosis subsequently.These in vitro effects in the cell transformed than (Ditchfield C, et al., J Cell Biol. better in the cell of non-transformed or undifferentiated, 2003,161:267-280), thus target Aurora can realize selectivity in the body to cancer.Although predict it may have certain toxicity to the quick noble cells of hemopoietic system and gastrointestinal system, the activity in xenograft models and clinical tolerability still demonstrate rational therapeutic index.Under the prerequisite of clinical front anti-tumor activity and tumor-selective potentiality, several Aurora A inhibitor are developed at present.
FLT3 (Flt3, the Tyrosylprotein kinase 3 that FMS-is relevant), also referred to as FLK-2 (fetal livers kinases 2) and STK-I (human stem cells kinases 1), belong to member (the Gtirewalt DL et al. of receptor tyrosine kinase (RTK-III) family, 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, etal., J.Cell.Biochem., 1983,21:151-159; Yarden Y, et al., EMBO J, 1987,6:3341-3351).FLT3 is transmembrane protein, be made up of four structural domains, comprise extracellular ligand-binding domain, cross-film (TM) territory, nearly film (JM) territory and tenuigenin C-terminal tyrosine kinases (TK) territory of five immunoglobulin (Ig) class formation compositions.(Agnes F,et al.Gene,l994,145:283-288；Scheijen B,et al.,Oncogene,2002,21:3314-3333)。
The part of FLT3 was cloned in 1993, showed according to the study, and it is type i transmembrane protein (the Lyman SD that Hematopoietic marrow microenvironment cell comprises marrow fibroblast and other cells, et al., Cell, 1993,75,1157-1167).Film combine and soluble form all energy activated receptor tyrosine kinase activity and stimulate the growth of progenitor cells in marrow and blood.The zygotic induction receptor dimer of ligand-receptor, and activated protein kinase territory, then its autophosphorylation the substrate protein phosphorylation of the various signal transduction pathway of catalysis, such as transcribe signal transducer and the activator (STAT5) of 5, the protein kinase (RAS/MAPK) that RAS/ is inhibition of mitogen-activated, phosphoinositide 3-kinase (PI3K), Src of the same race with glue protogene (SHC), inositol-5-Phosphoric acid esterase (SHIP) containing SH2 and there is the cytoplasmic tyrosine Phosphoric acid esterase in 2 Src-homologys 2 (SH2) territory (SHP2), it is in cell proliferation, differentiation and (the Dosil M. that plays a significant role in surviving, et al., Mol Cell Biol., 1993, 13:6572-6585.Zhang S, Biochem Biophys Res Commun., l999, 254:440-445).Except hematopoietic cell, FLT3 gene also expresses (Maroc N in placenta, sexual gland and brain, et al., Oncogene, 1993,8:909-918) and play a significant role in immunne response (deLapeyriere O.et al., Leukemia, 1995,9:1212-1218).
FLT3 also with malignant proliferative pathology before hemopoietic system dysfunction, as thrombocytosis, true property thrombocytosis, myelofibrosis (MF), chronic idiopathic myelofibrosis (IMF), polycyth(a)emia (PV), myelodysplastic syndrome is obtained before canceration, hematologic malignancies comprises, but be not limited to, leukemia, (non-Hodgkin lymphoma), lymphogranulomatosis (also known as Hodgkin lymphoma) and myelomatosis, such as, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic lymphocytic leukemia (CML), CNL (CNL), closely related.FLT3 is in the acute myeloid leukaemia (AML) of 70-100%, with in the acute lymphoblastic leukemia (ALL) of high per-cent with each horizontal process LAN (Griffin JD, et al., Haematol J., 2004,5:188-190).In blast cell crisis, it is process LAN in the less hypotype of chronic myelogenous leukemia (CML) also.Research has shown B pedigree leukemia cell ALL and AML coexpression FL continually, the autocrine causing FLT3 composing type to activate or paracrine signal transduction circulation (Zheng R, et.al.Blood., 2004,103:267-274).In addition, FLT3L is with high level expression in langerhans cell histiocytosis and Patients with SLE cell serum, and the dendritic cell Signal Regulation of display FLT3 and autoimmune disorder is abnormal closely related further.
Increasing evidence shows the sudden change that polytype leukemia and myeloproliferative syndrome have Tyrosylprotein kinase.FLT3 sudden change is that in AML, body one of changes the most frequently, occurs in the patient of about 1/3.The FLT3 Activating mutations of two types is described in leukaemic.These comprise a series of internal series-connection occurring in the nearly film territory of inhibition and copy (ITD) (Nakao M, et al., Leukemia, 1996,10:1911-1918; Thiede C et al., Blood, 2002,99:4326-4335), and activation cycle sudden change, it comprises Asp835Tyr (D835Y), Asp835Val (D835V), Asp835His (D835H), Asp835Glu (D835E), Asp835Ala (D835A), Asp835Asn (D835N), Asp835 disappearance and Ile836 lack (Yamamoto Y, et al., Blood, 2001,97:2434-2439; Abu-Duhier FM, et al., Br.J.Haematol., 2001,113:983-988).Internal series-connection in JM territory copies the FLT3 Activating mutations that (ITD) sudden change contributes to about 17-34% in AML.FLT3-ITD is also detected (MDS) (Yokota S., et al., Leukemia, l997,11:1605-1609 with low frequency at myelodysplastic syndrome; Horiike S, et al., Leukemia, 1997,11:1442-1446).ITDs always in frame, and is confined to JM territory.But in different patient, its length and location changes.These repetitive routines can be used for destroy JM territory from inhibit activities, cause FLT3 composing type to activate.FLT3-ITD with FLT3-Asp835 sudden change all with phosphorylation relevant (Mizuki M, et al., Blood, 2000, the 96:3907-3914 of FLT3 autophosphorylation and downstream targets; Mizuki M, et al., Blood, 2003,101:3164-3173; Hayakawa F, et al., Oncogene, 2000,19:624-631).
At present, the FLT3 inhibitor ground reaches clinical trial as the monotherapy of recurrence or obstinate AML patient that some or all has FLT3 sudden change.Generally, these data show that FLT3 is used to develop for the attractive therapeutic targets of AML with the kinase inhibitor of other diseases related.
Janus kinases (JAK) is an intracellular non-receptor tyrosine kinase family, by turning JAK-STAT path, and the signal of transducer cell factor mediation.JAK family regulates in the propagation that cytokine relies on and relates in the cell function of immunne response and plays an important role.Cytokine and their receptors bind, cause receptor dimerization, can impel the mutual phosphorylation of JAKs like this, also can impel cytokine receptor internal specific tyrosine motif phosphorylation.Identify that the STATs of these phosphorylation motif is aggregated on acceptor, then activated in the tyrosine phosphorylation process of JAK dependence.Due to activation, STATs and acceptor dissociate, dimerization, and are displaced to nucleus, are combined with specific DNA site, and change is transcribed.
At present, there are four kinds of known Mammals JAK family members: JAK1 (Janus kinases-1), JAK2 (Janus kinases-2), JAK3 (Janus kinases, white corpuscle; JAKL; L-JAK and Janus kinases-3) and TYK2 (protein tyrosine kinase 2).JAK1, JAK2 and TYK2 is general expression, and JAK3 is in the news preferential at natural killer (NK) cells, and in other T cell, do not express (" Biology and significance of the JAK/STAT signaling pathways. " Growth Factors, April 2012; 30 (2): 88).
The signal transduction of JAK1 to some I type and II cytokines is necessary.The public chain of γ (γ c) of it and I cytokines acceptor interacts, and induction IL-2 receptor family, IL-4 receptor family, gp130 receptor family sends signal.It is to the signal of I type (IFN-α/β) and II type (IFN-γ) Interferon, rabbit, and also very important by the signal transduction of the IL-10 family member of II cytokines acceptor.Heredity and biological study show, JAK1 functionally with physiology on relevant with I type Interferon, rabbit (such as, IFNalpha), II type Interferon, rabbit (such as, IFNgamma), IL-2 with IL-6 cytokine receptor complex.Further, the keying action of this kinases in IFN, IL-IO, IL-2/IL-4 and IL-6 path is demonstrated to the sign of the tissue deriving from JAK1 knock-out mice.
JAK1 in cancer cell expresses can impel individual cells atrophy, makes them flee from tumour potentially, is transferred to other positions of health.By the cytokine of JAK1 transduction signal, the raising of its level involves a large amount of immunity and inflammatory disease.JAK1 or JAK family kinase inhibitors can be used for regulating or treating these diseases (Kisseleva et al., 2002, Gene 285:1-24; Levy et al., 2005, Nat.Rev.Mol.Cell Biol., 3:651-662).The human monoclonal antibody (holder pearl monoclonal antibody Tocilizumab) of target IL-6 path is used for the treatment of moderate to severe rheumatoid arthritis (Scheinecker et al. by EU Committee's approval, 2009, Nat.Rev.Drug Discov.8:273-274).
The signal transduction of JAK2 and II cytokines receptor family (such as Interferon Receptors), GM-CSF receptor family, gp130 receptor family member is relevant.JAK2 signal is activated in the downstream of hprl receptor.Research shows in the diseases such as myeloproliferative disease such as polycythemia vera, primary thrombocytosis and idiopathic myelofibrosis, JAK2 sudden change (JAK2V617F) of the acquired activation of ubiquity.The JAK2 albumen of sudden change can activate downstream signal when not having cytokine to stimulate, and cause spontaneous growth and/or the allergy to cytokine, it is considered to play a part promotion to the process of these diseases.(Ihle J.N.and Gilliland D.G., Curr.Opin.Genet.Dev., 2007,17:8 in the description causing the more multimutation of JAK2 functional disorder or transposition to be found in other malignant tumours; Sayyah J.and Sayeski P.P., Curr.Oncol.Rep., 2009,11:117).JAK2 inhibitor has been described to have effect (Santos et al, Blood, 2010,115:1131 to proliferative disease; Barosi G.and Rosti V., Curr.Opin.Hematol, 2009,16:129, Atallah E.and Versotvsek S., Exp.Rev.Anticancer Ther.2009,9:663).
JAK3 is only relevant to the public gamma cells factor acceptor chain be present in IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complex.JAK3 mainly expresses in immunocyte, and is activated by the tyrosine phosphorylation of interleukin-2-receptor, transduction signal.Express at hemopoietic stem cell because JAK3 is limited to more, relative to other JAKs, its effect in cytokine signaling is stricter.The sudden change of JAK3 can cause severe combined immunodeficiency (SCID). and (O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131).The effect in lymphocyte is being regulated based on it, the path that target JAK3 and JAK3 mediates has been used to treatment immunosuppression indication (such as, transplant rejection and rheumatoid arthritis) (Baslund et al., 2005, Arthritis & Rheumatism 52:2686-2692; Changelian et al., 2003, Science 302:875-878).
TYK2 and IFN-α, IL-6, IL-10 and IL-12 signal transduction is relevant.Biochemical research and knock out mice disclose the vital role of TYK2 at immunology.TYK2 deficient mice energy growth and breeding, but show panimmunity defect, main is hypersensitivity to infecting and defective oncological surveillance.Contrary, suppress TYK2 can improve the ability of opposing allergy, autoimmunity and inflammatory diseases.Especially, target TYK2 seems to become the innovative strategy of the disease for the treatment of IL-12-, IL-23-or I type IFN-mediation.Described disease includes but not limited to rheumatoid arthritis, multiple sclerosis, lupus, psoriatic, psoriasis arthropathica, inflammatory bowel, 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 have approved the complete human monoclonal antibody (Ustekinumab) of the p40 subunit that target IL-12 and IL-23 cytokine have recently, be used for the treatment of 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).In addition, the antibody of target IL-12 and IL-23 path has carried out the clinical trial being used for the treatment of Crohn's disease (Mannon et al., 2004, N.Engl.J.Med.351:2069-79).
When regulating not normal, the response of JAK-mediation can forward or negatively affect cell, causes overactivity malignant tumour respectively, or immunity and hematopoietic defect, which imply the practicality of jak kinase inhibitor.JAK/STAT signal path involves much propagation and cancer associated processes, comprises cell cycle progression, apoptosis, vasculogenesis, infiltrate, transfer and immunity system escape (Haura et al., Nature Clinical PracticeOncology, 2005,2 (6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003,22,423-434).In addition, JAK/STAT signal path to the generation and differenciation of hemopoietic stem cell, proinflammatory and anti-inflammatory dual regulation, and immunne response plays an important role (O'Sullivan et al., Molecular Immunology 2007,44:2497).
Therefore, whole four members of JAK/STAT path, particularly JAK family, are considered at asthma reaction, chronic obstructive pulmonary disease, bronchitis, and work in the pathogenesis of other relevant lower respiratory tract inflammatory diseases.JAK/STAT path works equally in ocular inflammatory disease (diseases)/disease (conditions) (including, but not limited to iritis, uveitis, scleritis, conjunctivitis) and chronic anaphylaxis reaction.Due to the various multi-form jak kinase of cytokine application (O'Sullivan et al., Mol.Immunol, 2007,44:2497; Murray J., Immunol, 2007,178:2623), the jak kinase of different choice in antagonism family, it may be useful for treating the disease that in the disease or JAK/STAT path that the specific cells factor is correlated with, variability or polymorphism are correlated with.
Rheumatoid arthritis (RA) is a kind of autoimmune disorders being feature with chronic joint inflammation.The patient with rheumatoid arthritis taking JAK inhibitor demonstrates the suppression of JAK1 and the JAK3 module by signal to cytokine profiles initiation, it is to lymphocyte function, comprise interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21 is very important [Fleischmann, R.et al. " Placebo-controlled trialof tofacitinib monotherapy in rheumatoid arthritis. " N.Engl.J.Med.367,495 – 507 (2012)].By inference, directly make the micromolecular inhibitor of specific JAK hypotype inactivation not only can alleviate the clinical symptom of RA, also those undue adjustments impelling many pro-inflammatory cytokines of RA disease progression (" Inhibitors of JAK for the treatment of rheumatoid arthritis:rationale andclinical data. " Clin.Invest. (2012) 2 (1), 39 – 47) can be suppressed.
The sustained activation of STAT3 or STAT5 has been proved to be and has been present in many entity people tumours, comprises lacteal tumor, Vipoma, prostate tumor, oophoroma and liver cancer, is also present in a large amount of blood tumors simultaneously, comprises lymphoma and leukemia.In this respect, the inactivation propagation capable of inhibiting cell of the JAK/STAT signal in neoplastic hematologic disorder and/or cell death inducing.Although the STAT3 in tumour cell can by many kinase activations, JAK2 is still counted as most important upstream activat person, it can activate STAT3 (the MohamadBassam Sonbol in the human tumor cell line coming from various noumenal tumour, Belal Firwana, Ahmad Zarzour, Mohammad Morad, Vishal Rana and Ramon V.Tiu " Comprehensive review of JAK inhibitors in myeloproliferative neoplasms. " Therapeutic Advances inHematology 2013,4 (1), 15-35; Hedvat M, Huszar D, Herrmann A, Gozgit J M, Schroeder A, Sheehy A, et al. " The JAK2inhibitor AZD1480potently blocks Stat3signaling and oncogenesis in solid tumors. " Cancer Cell2009; 16 (6): 487 – 97.).Therefore, the treatment of jak kinase to these diseases is suppressed to play useful effect.
Know clearly, kinases inhibitor have accumulated numerous concern as new immunosuppression, anti-inflammatory dual function medicine and anticancer medicine.Therefore, need arrestin kinases as Aurora A for a long time, the novel agent of FLT3 kinases and jak kinase or improvement reagent, it can be used as the immunosuppressor of organ transplantation, antineoplastic agent, also can be used for prevention and therapy autoimmune disorders (such as, multiple sclerosis, psoriatic, rheumatoid arthritis, asthma, type i diabetes, inflammatory bowel, Crohn's disease, polycythemia vera, primary thrombocytosis, myelofibrosis, autoimmune thyroid disease, alzheimer disease), relate to the disease of overactivity inflammatory reaction (such as, eczema), irritated, chronic obstructive pulmonary disease, bronchitis, cancer (such as, prostate cancer, acute myelocytic leukemia, chronic granulocytic leukemia, acute lymphoblastic leukemia, leukemia, multiple myeloma) and the immune response that causes of other treatment is (such as, fash, contact dermatitis or diarrhoea), etc..The compound that the present invention describes, composition and method directly corresponding these need and other objects.
Abstract of invention
The invention provides a class to suppress, regulate and/or regulate and control one or more protein kinases, as the compound of jak kinase, FLT3 kinases and Aurora A activity, be used for the treatment of proliferative disease, autoimmune disorders, anaphylactic disease, inflammatory diseases, transplant rejection and their complication.Present invention provides the method for these compounds of preparation, use these compounds for treating Mammalss, especially the method for the above-mentioned disease of the mankind, and comprise the pharmaceutical composition of these compounds.Compound of the present invention and composition thereof possess good potential applicability in clinical practice.Compared with existing similar compound, compound of the present invention has better pharmacologically active, medicine for character, physico-chemical property and/or toxicological characteristics.Specifically, the compounds of this invention demonstrates good inhibit activities to kinase targets, and the Kinase Selectivity optimized, and demonstrates good absorption and higher bioavailability in pharmacokinetic trial in animal body.In addition, the compounds of this invention also has more excellent membrane permeability, is suitable for topical, and solvability is better, therefore has more excellent druggability.
Specifically:
On the one hand, the present invention relates to a kind of steric isomer such as formula compound shown in the compound shown in (I) or formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug,
Wherein, Z, Z 1, A, W and R 1there is implication as described in the present invention.
In some embodiments, Z is C 7-C 12spiral shell bicyclic alkyl, C 7-C 12mix bicyclic group or 7-12 of condensed-bicyclic alkyl, 7-12 former molecular spiral shell formerly molecularly condenses assorted bicyclic alkyl, and wherein, Z is optionally by 1,2,3,4 or 5 R 3group replaced;
Z 1for H, C 1-C 12alkyl, C 3-C 12cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, Z 1optionally by 1,2,3,4 or 5 R 4group replaced;
A is indazolyl or Pyrazolopyridine base, and wherein, A is optionally by 1,2,3,4 or 5 R 5group replaced;
W is N;
R 1for H, F, Cl, Br, I, NO 2, N 3, CN, C 1-C 12alkyl, C 1-C 12haloalkyl, C 1-C 12alkoxyl group, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, 3-12 former molecular heterocyclic radical, C 6-C 12aryl, 5-12 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-C (=NR c) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, R 1optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 3be H, F, Cl, Br, I, NO independently 2, CN, N 3, OH, NH 2,-C (=O) CH 2cN, C 1-C 12alkyl, C 1-C 12haloalkyl, C 1-C 12alkoxyl group, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12the individual former molecular heterocyclic radical of aryl, 3-12,5-12 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-S (=O) 2r 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-O (CR 7r 8) n-OR c,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-C (=NR c) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, or the R that two adjacent 3, and together with the atom be connected with them, form C 3-C 12cycloalkyl or 3-12 former molecular heterocycloalkyl, wherein, above-mentioned each substituting group is independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 4and R 5be separately H, F, Cl, Br, I, NO 2, CN, N 3, C 1-C 12alkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl ,-(C 1-C 4alkylidene group)-(C 3-C 12cycloalkyl), C 6-C 12aryl, 3-12 former molecular heterocyclic radical ,-(C 1-C 4alkylidene group)-(3-12 former molecular heterocyclic radical), 5-12 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-C (=NR c) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, above-mentioned each R 4and R 5independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 6be H, C independently 1-C 12alkyl, C 1-C 12haloalkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, wherein, each R 6independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 7and R 8be separately H, F, Cl, Br, I, NO 2, N 3, CN, C 1-C 12alkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, or R 7and R 8, and together with the carbon atom be connected with them, form C 3-C 12cycloalkyl, C 6-C 12aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl groups, wherein, above-mentioned each substituting group is independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 9be F, Cl, Br, I, CN, NO independently 2, N 3, C 1-C 12alkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12the individual former molecular heterocyclic radical of aryl, 3-12,5-12 former molecular heteroaryl, NH 2,-NH (C 1-C 12alkyl) ,-NH (CH 2) n-(C 3-C 12cycloalkyl) ,-NH (CH 2) n-(C 6-C 12aryl) ,-NH (CH 2) n-(3-12 former molecular heterocyclic radical) ,-NH (CH 2) n-(5-12 former molecular heteroaryl) ,-N (C 1-C 12alkyl) 2,-N [(CH 2) n-(C 3-C 12cycloalkyl)] 2,-N [(CH 2) n-(C 6-C 12aryl)] 2,-N [(CH 2) n-(3-12 former molecular heterocyclic radical)] 2,-N [(CH 2) n-(5-12 former molecular heteroaryl)] 2, OH ,-O (C 1-C 12alkyl) ,-O (CH 2) n-(C 3-C 12cycloalkyl) ,-O (CH 2) n-(C 6-C 12aryl) ,-O (CH 2) n-(3-12 former molecular heterocyclic radical) or-O (CH 2) n-(5-12 former molecular heteroaryl);
Each R a, R band R cbe separately H, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl ,-(C 1-C 4alkylidene group)-(C 3-C 6cycloalkyl), 3-6 former molecular heterocyclic radical ,-(C 1-C 4alkylidene group)-(3-6 former molecular heterocyclic radical), C 6-C 10aryl ,-(C 1-C 4alkylidene group)-(C 6-C 10aryl), 5-10 former molecular heteroaryl or-(C 1-C 4alkylidene group)-(5-10 former molecular heteroaryl), or R aand R b, and together with the nitrogen-atoms be connected with them, form 3-8 former molecular heterocyclyl groups, wherein, above-mentioned each substituting group is independent is optionally independently selected from F, Cl, Br, CN, N by 1,2,3 or 4 3, OH, NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group or C 1-C 6the substituting group of alkylamino replaced;
Each m is 1 or 2 independently; With
Each n is 0,1,2,3 or 4 independently.
In other embodiments, Z is C 8-C 11spiral shell bicyclic alkyl, C 8-C 10mix bicyclic group or 8-10 of condensed-bicyclic alkyl, 8-11 former molecular spiral shell formerly molecularly condenses assorted bicyclic alkyl, and wherein, Z is optionally by 1,2,3 or 4 R 3group replaced.
In some embodiments, Z 1for H, C 1-C 6alkyl, C 3-C 6cycloalkyl or 3-6 former molecular heterocyclic radical, wherein, Z 1optionally by 1,2 or 3 R 4group replaced.
In other embodiments, R 1for H, F, Cl, CN, N 3, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 3-C 6cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-(CR 7r 8) nc (=O) NR ar bor-S (=O) 2nR ar b, wherein, R 1optionally by 1,2 or 3 R 9group replaced.
In some embodiments, each R 3be H, F, Cl, CN, N independently 3, NO 2, OH, NH 2,-C (=O) CH 2cN, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6alkoxyl group, C 1-C 6haloalkyl, C 3-C 6the individual former molecular heterocyclic radical of cycloalkyl, phenyl, 3-6,5-6 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-S (=O) 2r 6,-O (CR 7r 8) n-R 6,-O (CR 7r 8) n-OR c,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, or the R that two adjacent 3, and together with the atom be connected with them, form C 3-C 6cycloalkyl or 3-6 former molecular heterocycloalkyl, wherein, above-mentioned each substituting group is independent optionally by 1,2 or 3 R 9group replaced.
In other embodiments, each R 4and R 5be separately H, F, Cl, Br, I, NO 2, N 3, CN, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl ,-(C 1-C 2alkylidene group)-(C 3-C 6cycloalkyl), phenyl, 3-6 former molecular heterocyclic radical ,-(C 1-C 2alkylidene group)-(3-6 former molecular heterocyclic radical), 5-6 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, each R 4and R 5independent optionally by 1,2 or 3 R 9group replaced.
In some embodiments, each R 6be H, C independently 1-C 6alkyl, C 1-C 6haloalkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, wherein, each R 6independent optionally by 1,2 or 3 R 9group replaced.
In other embodiments, each R 7and R 8be separately H, F, Cl, Br, I, CN, N 3, NO 2, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, or R 7and R 8, and form C together with the carbon atom be connected with them 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl groups, wherein, above-mentioned each substituting group is independent optionally by 1,2 or 3 R 9group replaced.
In some embodiments, each R 9be F, Cl, CN, N independently 3, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6the individual former molecular heterocyclic radical of cycloalkyl, phenyl, 3-6,5-6 former molecular heteroaryl, NH 2,-NH (C 1-C 6alkyl) ,-NH (CH 2) n-(C 3-C 6cycloalkyl) ,-NH (CH 2) n-phenyl ,-NH (CH 2) n-(3-6 atom composition heterocyclic radical) ,-NH (CH 2) n-(5-6 former molecular heteroaryl) ,-N (C 1-C 4alkyl) 2,-N [(CH 2) n-(C 3-C 6cycloalkyl)] 2,-N [(CH 2) n-phenyl] 2,-N [(CH 2) n-(3-6 former molecular heterocyclic radical)] 2,-N [(CH 2) n-(5-6 former molecular heteroaryl)] 2, OH ,-O (C 1-C 6alkyl) ,-O (CH 2) n-(C 3-C 6cycloalkyl) ,-O (CH 2) n-phenyl ,-O (CH 2) n-(3-6 former molecular heterocyclic radical) or-O (CH 2) n-(5-6 former molecular heteroaryl).
In other embodiments, each R a, R band R cbe separately H, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 3-C 6cycloalkyl ,-(C 1-C 2alkylidene group)-(C 3-C 6cycloalkyl), 3-6 former molecular heterocyclic radical ,-(C 1-C 2alkylidene group)-(3-6 former molecular heterocyclic radical), phenyl ,-(C 1-C 2alkylidene group)-phenyl, a 5-6 former molecular heteroaryl or-(C 1-C 2alkylidene group)-(5-6 former molecular heteroaryl), or R aand R b, and together with the nitrogen-atoms be connected with them, form 3-6 former molecular heterocyclyl groups, wherein, above-mentioned each substituting group is independent is optionally independently selected from F, Cl, CN, N by 1,2 or 3 3, OH, NH 2, C 1-C 4alkyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group or C 1-C 4the substituting group of alkylamino replaced.
In some embodiments, Z is following subformula:
Or their steric isomer, wherein, each X, X ', X 2and X 3be separately CH 2, NH or O, condition works as X 2when being O, X 3be not O; Each minor structure shown in formula (Z-1) ~ (Z-54) or its steric isomer are independently optionally by 1,2 or 3 R 3group replaced.
In other embodiments, A is following subformula:
Wherein, formula (M), (N), (Q) or the minor structure shown in (T) are independent optionally by 1,2 or 3 R 5group replaced.
In some embodiments, Z 1for H, methyl, ethyl, n-propyl, sec.-propyl or cyclopropyl.
In other embodiments, R 1for H, F, Cl, CN, N 3, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group, C 3-C 6cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-(CR 7r 8) nc (=O) NR ar bor-S (=O) 2nR ar b, wherein, R 1optionally by 1,2 or 3 R 9group replaced.
In some embodiments, each R 3be H, F, Cl, CN, N independently 3, NO 2, OH, NH 2,-C (=O) CH 2cN, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 1-C 4alkoxyl group, C 1-C 4haloalkyl, C 3-C 6the individual former molecular heterocyclic radical of cycloalkyl, phenyl, 3-6,5-6 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-S (=O) 2r 6,-O (CR 7r 8) n-R 6,-O (CR 7r 8) n-OR c,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, each R 3independent optionally by 1,2 or 3 R 9group replaced.
In other embodiments, each R 6be H, C independently 1-C 4alkyl, C 1-C 4haloalkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, wherein, each R 6independent optionally by 1,2 or 3 R 9group replaced.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises compound disclosed by the invention.
In some embodiments, pharmaceutical composition of the present invention comprises pharmaceutically acceptable vehicle, carrier, adjuvant, solvent or their combination further.
In other embodiments, pharmaceutical composition of the present invention, wherein further comprise therapeutical agent, described therapeutical agent is selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 (PDE4) inhibitor, beta-2-adrenoreceptor agonists, reflunomide, nonsteroidal GR agonist, anticholinergic, antihistaminic, anti-inflammatory reagent, immunosuppressor, immunostimulant, is used for the treatment of atherosclerotic medicine, is used for the treatment of the medicine of pulmonary fibrosis and their combination.
On the other hand, the present invention relates to compound disclosed by the invention or pharmaceutical composition is preparing the purposes in medicine, described medicine is for preventing, process, treat or alleviating protein kinase mediated disease.
In some embodiments, protein kinase mediated disease of the present invention is the disease of JAK-, FLT3-or Aurora-mediation.
In other embodiments, protein kinase mediated disease of the present invention is proliferative disease, autoimmune disorders, anaphylactic disease, inflammatory diseases or transplant rejection.
In other embodiments, protein kinase mediated disease of the present invention is cancer, polycythemia vera, primary thrombocytosis, , acute myelocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, acute myelocytic leukemia, chronic granulocytic leukemia, acute lymphoblastic leukemia, chronic obstructive pulmonary disease, asthma, systemic lupus erythematous, skin lupus erythematosus, systemic lupus erythematosus, dermatomyositis, sjogren syndrome, psoriatic, type i diabetes, respiratory anaphylactic disease, sinusitis paranasal sinusitis, eczema, measles, food anaphylaxis, insect venom allergies, inflammatory bowel, Crohn's disease, rheumatoid arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplant rejection.
On the other hand, the present invention relates to compound disclosed by the invention or pharmaceutical composition is preparing the purposes in medicine, described medicine is used for the kinase whose activity of Function protein.
In some embodiments, protein kinase of the present invention is jak kinase, FLT3 kinases, Aurora A or their combination.
Also on the other hand, the present invention relates to the preparation of compound that formula (I) comprises, the method for abstraction and purification.
Biological results shows, compound provided by the invention can be used as good kinases inhibitor.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.
Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will do more specifically complete description below.
Circumstantial letter of the present invention
Definition and general terms
Present detailed description certain embodiments of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with described herein and material can be used in putting into practice the present invention.The present invention is never limited to method as herein described and material.Combined document, patent and (include but not limited to defined term, term application, described technology, etc.) in one or more different from the application or conflicting situations of analogous material, be as the criterion with the application.
Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.
Unless otherwise indicated, this paper institute should be applied and use to obtain following definition.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can with reference to " Organic Chemistry ", ThomasSorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley & Sons, description in New York:2007, its full content is incorporated to herein by reference.
Except as otherwise noted or in context, have obvious conflict, article used herein " ", " one (kind) " and " described " are intended to comprise " at least one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the embodiment of described embodiment and adopt or use.
Term used in the present invention " study subject " refers to animal.Typically described animal is Mammals.Study subject, such as, also refer to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.
Term used in the present invention " patient " refers to people's (comprising adult and children) or other animals.In some embodiments, " patient " refers to people.
Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.
" steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, atropisomer, etc.
" chirality " is that have can not the molecule of overlapping character with its mirror image; And " achirality " refer to can be overlapping with its mirror image molecule.
" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror.
" diastereomer " refers to two or more chiral centres and the steric isomer of its molecule not mirror image each other.Diastereomer has different physical propertiess, as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture is by high resolution analysis operation as electrophoresis and chromatogram, and such as HPLC is separated.
Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-Hill Dictionary of ChemicalTerms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry ofOrganic Compounds ", John Wiley & Sons, Inc., New York, 1994.
Many organic compound exist with optical active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.
The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.
By known method, the method that the racemic modification of any gained end product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by being separated its diastereoisomeric salt obtained.Racemic product also can be separated by chiral chromatography, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, such as, can with reference to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nded.Robert E.Gawley, Jeffrey Aub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H.Tables of ResolvingAgents 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 the constitutional isomer transformed mutually by low energy barrier (low energy barrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropic tautomer)) comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valence tautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.
Generally speaking, term " replacement " represent give the one or more hydrogen atoms be substituted in structure replace by concrete substituting group.Unless other aspects show, a group replaced can have a substituting group to replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.
Term " unsubstituted ", represents and specifies group without substituting group.
Term " optionally by .... replaced ", can " not replace or quilt ... .. replaced " to exchange with term and use, namely described structure is unsubstituted or is replaced by one or more substituting group of the present invention, substituting group of the present invention includes, but are not limited to D, F, Cl, Br, I, CN, N 3,-CN ,-NO 2,-OH ,-SH ,-NH 2,-C (=O) CH 2cN ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-S (=O) 2r 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-O (CR 7r 8) n-OR c,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-C (=NR c) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6,-C (=O) NR ar b, alkyl, haloalkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, cycloalkyl, heterocyclic radical, aryl and heteroaryl etc., wherein, R 6, R 7, R 8, R a, R b, R c, m and n have definition as described in the present invention.
In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different group, did not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect mutually between concrete option expressed between same-sign.
At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C 1-C 6alkyl " refer in particular to independent disclosed methyl, ethyl, C 3alkyl, C 4alkyl, C 5alkyl and C 6alkyl.
At each several part of the present invention, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.
The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In some embodiments, alkyl group contains 1-12 carbon atom; In other embodiments, alkyl group contains 1-6 carbon atom; In other embodiment, alkyl group contains 1-4 carbon atom; Also in some embodiments, alkyl group contains 1-3 carbon atom.The substituting group that described alkyl group can optionally be described by one or more the present invention replace.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr ,-CH (CH 3) 2), normal-butyl (n-Bu ,-CH 2cH 2cH 2cH 3), isobutyl-(i-Bu ,-CH 2cH (CH 3) 2), sec-butyl (s-Bu ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu ,-C (CH 3) 3), n-pentyl (-CH 2cH 2cH 2cH 2cH 3), 2-amyl group (-CH (CH 3) CH 2cH 2cH 3), 3-amyl group (-CH (CH 2cH 3) 2), 2-methyl-2-butyl (-C (CH 3) 2cH 2cH 3), 3-methyl-2-butyl (-CH (CH 3) CH (CH 3) 2), 3-methyl isophthalic acid-butyl (-CH 2cH 2cH (CH 3) 2), 2-methyl-1-butene base (-CH 2cH (CH 3) CH 2cH 3), n-hexyl (-CH 2cH 2cH 2cH 2cH 2cH 3), 2-hexyl (-CH (CH 3) CH 2cH 2cH 2cH 3), 3-hexyl (-CH (CH 2cH 3) (CH 2cH 2cH 3)), 2-methyl-2-amyl group (-C (CH 3) 2cH 2cH 2cH 3), 3-methyl-2-amyl group (-CH (CH 3) CH (CH 3) CH 2cH 3), 4-methyl-2-amyl group (-CH (CH 3) CH 2cH (CH 3) 2), 3-methyl-3-amyl group (-C (CH 3) (CH 2cH 3) 2), 2-methyl-3-amyl group (-CH (CH 2cH 3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (-C (CH 3) 2cH (CH 3) 2), 3,3-dimethyl-2-butyl (-CH (CH 3) C (CH 3) 3), n-heptyl, n-octyl, etc.
Term " alkylidene group " represents the saturated bivalent hydrocarbon radical group removing two hydrogen atoms and obtain from saturated straight or branched alkyl.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In some embodiments, alkylidene group contains 1-6 carbon atom; In other embodiments, alkylidene group contains 1-4 carbon atom; In other embodiment, alkylidene group contains 1-3 carbon atom; Also in some embodiments, alkylidene group contains 1-2 carbon atom.Such example comprises methylene radical (-CH 2-), ethylidene (-CH 2cH 2-), isopropylidene (-CH (CH 3) CH 2-) etc.
Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely has a carbon-to-carbon sp 2double bond, wherein, described alkenyl group can optionally replace by one or more substituting group described in the invention, it comprises " cis " and the location of " tans ", or the location of " E " and " Z ".In some embodiments, alkenyl group comprises 2-8 carbon atom; In other embodiments, alkenyl group comprises 2-6 carbon atom; In other embodiment, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group comprises, but is not limited to, vinyl (-CH=CH 2), allyl group (-CH 2cH=CH 2) etc.The substituting group that described alkenyl group can optionally be described by one or more the present invention replace.
Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely have a carbon-to-carbon sp triple bond, wherein, described alkynyl group can optionally replace by one or more substituting group described in the invention.In some embodiments, alkynyl group comprises 2-8 carbon atom; In other embodiments, alkynyl group comprises 2-6 carbon atom; In other embodiment, alkynyl group comprises 2-4 carbon atom.The example of alkynyl group comprises, but is not limited to, ethynyl (-C ≡ CH), propargyl (-CH 2c ≡ CH), 1-proyl (-C ≡ C-CH 3) etc.
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In some embodiments, alkoxy base contains 1-6 carbon atom; In other embodiments, alkoxy base contains 1-4 carbon atom; In other embodiment, alkoxy base contains 1-3 carbon atom.The substituting group that described alkoxy base can optionally be described by one or more the present invention replace.
The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH 3), oxyethyl group (EtO ,-OCH 2cH 3), 1-propoxy-(n-PrO, n-propoxy-,-OCH 2cH 2cH 3), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH 3) 2), 1-butoxy (n-BuO, n-butoxy ,-OCH 2cH 2cH 2cH 3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH 2cH (CH 3) 2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH 3) CH 2cH 3), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH 3) 3), 1-pentyloxy (n-pentyloxy ,-OCH 2cH 2cH 2cH 2cH 3), 2-pentyloxy (-OCH (CH 3) CH 2cH 2cH 3), 3-pentyloxy (-OCH (CH 2cH 3) 2), 2-methyl-2-butoxy (-OC (CH 3) 2cH 2cH 3), 3-methyl-2-butoxy (-OCH (CH 3) CH (CH 3) 2), 3-methyl-l-butoxy (-OCH 2cH 2cH (CH 3) 2), 2-methyl-l-butoxy (-OCH 2cH (CH 3) CH 2cH 3), etc.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, thiazolinyl or alkoxy base replace by one or more halogen atom, such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy etc.
Term " carbocylic radical " or " carbocyclic ring " expression contain 3-12 carbon atom, nonaromatic saturated or the unsaturated monocycle of part, dicyclo or the three-ring system of unit price or multivalence.Carbon bicyclic group comprises spiral shell carbon bicyclic group, condenses carbon bicyclic group and bridge carbon bicyclic group, and suitable carbocylic radical group comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbocylic radical group comprises further, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc.
Term " cycloalkyl " expression contains 3-12 carbon atom, saturated monocycle, dicyclo or the three-ring system of unit price or multivalence.In some embodiments, cycloalkyl comprises 3-12 carbon atom; In other embodiments, cycloalkyl comprises 3-8 carbon atom; In other embodiments, cycloalkyl comprises 3-6 carbon atom; Also in some embodiments, cycloalkyl is C 7-C 12cycloalkyl, comprises C 7-C 12spiral shell bicyclic alkyl, C 7-C 12condensed-bicyclic alkyl and C 7-C 12bridge bicyclic alkyl; In other embodiment, cycloalkyl is C 8-C 11cycloalkyl, comprises C 8-C 11spiral shell bicyclic alkyl and, C 8-C 11condensed-bicyclic alkyl and C 8-C 11condensed-bicyclic alkyl.Described group of naphthene base can not be substituted independently or replace by one or more substituting group described in the invention.
Term " heterocyclic radical " and " heterocycle " commutative use herein, all refer to comprise 3-12 annular atoms, unit price or multivalence, saturated or part is undersaturated, nonaromatic monocycle, dicyclo or three-ring system, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.Heterocyclic radical comprises saturated heterocyclic radical (that is: Heterocyclylalkyl) and the undersaturated heterocyclic radical of part.The example of heterocyclic radical comprises, but be not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopentyl, two sulphur cyclopentyl, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia suberane base, oxygen azepine base (e.g., Isosorbide-5-Nitrae-oxygen azepine base, 1,2-oxygen azepine base), diaza base (e.g., Isosorbide-5-Nitrae-diaza base, 1,2-diaza base), dioxa base (e.g., Isosorbide-5-Nitrae-dioxa base, 1,2-dioxa base), sulphur azepine base is (as Isosorbide-5-Nitrae-sulphur azepine base, 1,2-sulphur azepine base), indoline base, 1, 2, 3, 4-tetrahydro isoquinolyl, 1, 3-Ben Bing bis-Evil cyclopentadienyl, 2-oxa--5-azabicyclo [2.2.1]-5-in heptan 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-azaspiro [5.5] undecyl, 2-azaspiro [5.5] undecyl, octahydro-1H-pseudoindoyl, octahydro pentamethylene is [c] pyrryl also, hexahydro furyl also [3, 2-b] furyl and ten dihydro-isoquinoline bases, Deng.-CH in heterocyclic radical 2-group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidone base and 3,5-dioxopiperidine base by-C (=O)-alternative example.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to tetramethylene sulfone base, 1,1-dioxothiomorpholinyl, 1,1-dioxotetrahydro thienyl and 1,1-dioxotetrahydro-2H-thiapyran base, etc.Described heterocyclyl groups can optionally replace by one or more substituting group described in the invention.
In some embodiments, heterocyclic radical is 3-8 former molecular heterocyclic radical, refer to comprise 3-8 annular atoms, unit price or multivalence, saturated or part is undersaturated, nonaromatic monocycle, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 3-8 former molecular heterocyclic radical can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 3-8 former molecular heterocyclic radical comprises, but be not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopentyl, two sulphur cyclopentyl, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia suberane base, oxygen azepine base, diaza base, sulphur azepine base, etc.-CH in heterocyclic radical 2-group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidone base and 3,5-dioxopiperidine base by-C (=O)-alternative example, etc.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to tetramethylene sulfone base and 1,1-dioxothiomorpholinyl.Described 3-8 former molecular heterocyclyl groups can optionally replace by one or more substituting group described in the invention.
In other embodiments, heterocyclic radical is 3-6 former molecular heterocyclic radical, refer to comprise 3-6 annular atoms, unit price or multivalence, saturated or part is undersaturated, nonaromatic monocycle, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 3-6 former molecular heterocyclic radical can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 3-6 former molecular heterocyclic radical comprises, but be not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopentyl, two sulphur cyclopentyl, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base is with thioxane base.Described 3-6 former molecular heterocyclyl groups can optionally replace by one or more substituting group described in the invention.
In other embodiments, heterocyclic radical is 7-12 former molecular heterocyclic radical, refer to comprise 7-12 annular atoms, unit price or multivalence, the saturated or undersaturated spiral shell of part mix bicyclic group, condense assorted bicyclic group or bridge and to mix bicyclic group, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 7-12 former molecular heterocyclic radical can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 7-12 former molecular heterocyclic radical includes, but are not limited to: indoline base, 1,2,3,4-tetrahydro isoquinolyl, 1,3-Ben Bing bis-Evil cyclopentadienyl, 2-oxa--5-azabicyclo [2.2.1]-5-in heptan base, 2-azaspiro [4.4] nonyl is (as 2-azaspiro [4.4] nonane-4-base, 2-azaspiro [4.4] nonane-2-base), 1,6-dioxo spiro [4.4] nonyl is (as 1,6-dioxo spiro [4.4] nonane-9-base, 1,6-dioxo spiro [4.4] nonane-4-base), 2-azaspiro [4.5] decyl (e.g., 2-azaspiro [4.5] decane-8-base, 2-azaspiro [4.5] decane-2-base), 7-azaspiro [4.5] decyl is (as 7-azaspiro [4.5] decane-2-base, 7-azaspiro [4.5] decane-8-base), 3-azaspiro [5.5] undecyl (e.g., 3-azaspiro [5.5] undecane-3-base, 3-azaspiro [5.5] undecane-9-base), 2-azaspiro [5.5] undecyl, 8-azaspiro [4.5] decyl, Decahydroisoquinolinpreparation base, octahydro-1H-pseudoindoyl (e.g., octahydro-1H-isoindole-5-base, octahydro-1H-isoindole-7-base), octahydro pentamethylene is [c] pyrryl (e.g., octahydro pentamethylene also [c] pyrroles-5-base also, octahydro pentamethylene is [c] pyrroles-2-base also), hexahydro furyl is [3,2-b] furyl (e.g., hexahydro furyl also [3,2-b] furans-2-base also, hexahydro furyl is [3,2-b] furans-3-base also) and ten dihydro-isoquinoline bases.Described 7-12 former molecular heterocyclyl groups can optionally replace by one or more substituting group described in the invention.
In other embodiment, heterocyclic radical is that 7-12 former molecular spiral shell is mixed bicyclic group, refer to comprise 7-12 annular atoms, unit price or multivalence, saturated or part is undersaturated, nonaromatic spiral shell is mixed bicyclic group, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 7-12 former molecular spiral shell bicyclic group of mixing can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.Described 7-12 former molecular spiral shell bicyclic group of mixing comprises mix bicyclic group (that is: 7-12 former molecular spiral shell mix bicyclic alkyl) and the undersaturated spiral shell of part of 7-12 former molecular saturated spiral shell and to mix bicyclic group.The mix example of bicyclic group of 7-12 former molecular spiral shell comprises, but be not limited to: 2-azaspiro [4.4] nonyl is (as 2-azaspiro [4.4] nonane-4-base, 2-azaspiro [4.4] nonane-2-base), 1, 6-dioxo spiro [4.4] nonyl is (as 1, 6-dioxo spiro [4.4] nonane-9-base, 1, 6-dioxo spiro [4.4] nonane-4-base), 2-azaspiro [4.5] decyl (as, 2-azaspiro [4.5] decane-8-base, 2-azaspiro [4.5] decane-2-base), 7-azaspiro [4.5] decyl is (as 7-azaspiro [4.5] decane-2-base, 7-azaspiro [4.5] decane-8-base), 3-azaspiro [5.5] undecyl (as, 3-azaspiro [5.5] undecane-3-base, 3-azaspiro [5.5] undecane-9-base), 2-azaspiro [5.5] undecyl, 8-azaspiro [4.5] decyl, Deng.Described 7-12 former molecular spiral shell mix bicyclic group group can optionally replace by one or more substituting group described in the invention.
Also in other embodiments, heterocyclic radical is that 8-11 former molecular spiral shell is mixed bicyclic group, refer to comprise 8-11 annular atoms, unit price or multivalence, saturated or part is undersaturated, nonaromatic spiral shell is mixed bicyclic group, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 8-11 former molecular spiral shell bicyclic group of mixing can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.Described 8-11 former molecular spiral shell bicyclic group of mixing comprises mix bicyclic group (8-11 former molecular spiral shell mix bicyclic alkyl) and the undersaturated spiral shell of part of 8-11 former molecular saturated spiral shell and to mix bicyclic group.The mix example of bicyclic group of 8-11 former molecular spiral shell comprises, but be not limited to: 2-azaspiro [4.4] nonyl is (as 2-azaspiro [4.4] nonane-4-base, 2-azaspiro [4.4] nonane-2-base), 1, 6-dioxo spiro [4.4] nonyl is (as 1, 6-dioxo spiro [4.4] nonane-9-base, 1, 6-dioxo spiro [4.4] nonane-4-base), 2-azaspiro [4.5] decyl (as, 2-azaspiro [4.5] decane-8-base, 2-azaspiro [4.5] decane-2-base), 7-azaspiro [4.5] decyl is (as 7-azaspiro [4.5] decane-2-base, 7-azaspiro [4.5] decane-8-base), 3-azaspiro [5.5] undecyl (as, 3-azaspiro [5.5] undecane-3-base, 3-azaspiro [5.5] undecane-9-base), 2-azaspiro [5.5] undecyl, 8-azaspiro [4.5] decyl, Deng.Described 8-11 former molecular spiral shell mix bicyclic group group can optionally replace by one or more substituting group described in the invention.
Also in other embodiment, to be that 7-12 is former molecularly condense assorted bicyclic group to heterocyclic radical, refer to comprise 7-12 annular atoms, unit price or multivalence, saturated or part is undersaturated, nonaromaticly condense assorted bicyclic group, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 7-12 is former, and molecular to condense assorted bicyclic group can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.Described 7-12 is former molecularly to be condensed assorted bicyclic group and comprises 7-12 and formerly molecularly saturated condense assorted bicyclic group (that is: 7-12 former molecular condense assorted bicyclic alkyl) and part is undersaturated condenses assorted bicyclic group.7-12 the former molecular example condensing assorted bicyclic group comprises, but be not limited to: octahydro cyclopentyl is [c] pyrryl, octahydro-1H-pseudoindoyl, indoline base, 1 also, 2,3,4-tetrahydro isoquinolyl, 1,3-Ben Bing bis-Evil cyclopentadienyl, hexahydro furyl be [3,2-b] furyl, hexahydro furyl also [2,3-b] furyl and ten dihydro-isoquinoline bases also.Described 7-12 former molecular condense assorted bicyclic group group can optionally replace by one or more substituting group described in the invention.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " commutative use herein, all refers to unit price or multivalence, saturated or part is unsaturated but nonaromatic member ring systems, and two rings in described member ring systems share a key.Such system can comprise independently or the unsaturated system of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic group can as the substituting group on it).
Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell dicyclo " commutative use herein, refer to unit price or multivalence, the undersaturated member ring systems of saturated or part, one of them ring originates from specific ring carbon atom on another ring.Such as, as below described by formula a, a saturated member ring systems (ring B and B ') is called as " condensed-bicyclic ", and ring A and ring B shares a carbon atom in two saturated member ring systems, is called as " volution " or " spiral shell dicyclo ".Each ring in condensed-bicyclic base and spiral shell bicyclic group can be carbocylic radical or heterocyclic radical, and each ring optionally replace by one or more substituting group described in the invention.
Term " Heterocyclylalkyl " refers to the saturated monocycle of unit price containing 3-12 annular atoms or multivalence, dicyclo or three-ring system, and wherein at least one annular atoms is selected from nitrogen, sulphur or Sauerstoffatom.Unless otherwise indicated, Heterocyclylalkyl can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of assorted bicyclic alkyl comprises, but be not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidyl, pyrazolidyl, imidazolidyl, tetrahydro-thienyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, alkyl dioxin, dithiane base, isoxazolidinyl, isothiazole alkyl, 1,2-oxazinyl, 1,2-thiazines base, hexahydro-pyridazine base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia suberane base, oxygen azepine base (e.g., Isosorbide-5-Nitrae-oxygen azepine base, 1,2-oxygen azepine base), diaza base (e.g., Isosorbide-5-Nitrae-diaza base, 1,2-diaza base), dioxa base (e.g., Isosorbide-5-Nitrae-dioxa base, 1,2-dioxa base), sulphur azepine base (e.g., Isosorbide-5-Nitrae-sulphur azepine base, 1,2-sulphur azepine 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-azaspiro [5.5] undecyl, 2-azaspiro [5.5] undecyl, octahydro cyclopentyl be [c] pyrryl, octahydro-1H-pseudoindoyl, hexahydro furyl also [3 also, 2-b] furyl, hexahydro furyl also [2,3-b] furyl and ten dihydro-isoquinoline bases.Described heterocycloalkyl can optionally replace by one or more substituting group described in the invention.
In some embodiments, Heterocyclylalkyl is 7-12 former molecular Heterocyclylalkyl, refers to containing 7-12 annular atoms, unit price or multivalence, saturated spiral shell mix bicyclic alkyl, condense assorted bicyclic alkyl or bridge and to mix bicyclic alkyl, wherein at least one annular atoms is selected from nitrogen, sulphur or Sauerstoffatom.Unless otherwise indicated, Heterocyclylalkyl can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.Described 7-12 former molecular heterocycloalkyl can optionally replace by one or more substituting group described in the invention.
In some embodiments, Heterocyclylalkyl is 3-6 former molecular Heterocyclylalkyl, refers to containing 3-6 annular atoms, and unit price or multivalence, saturated heterocyclic radical, wherein at least one annular atoms is selected from nitrogen, sulphur or Sauerstoffatom.Unless otherwise indicated, Heterocyclylalkyl can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 3-6 former molecular Heterocyclylalkyl includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidyl, pyrazolidyl, imidazolidyl, piperidyl, piperazinyl, morpholinyl, alkyl dioxin, dithiane base, isoxazolidinyl, isothiazole alkyl and hexahydro-pyridazine base.Described 3-6 former molecular heterocycloalkyl can optionally replace by one or more substituting group described in the invention.
In other embodiments, Heterocyclylalkyl is that 7-12 former molecular spiral shell is mixed bicyclic alkyl, refer to containing 7-12 annular atoms, unit price or multivalence, saturated spiral shell mixes bicyclic alkyl, wherein at least one annular atoms is selected from nitrogen, sulphur or Sauerstoffatom.Unless otherwise indicated, Heterocyclylalkyl can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The mix example of bicyclic alkyl of 7-12 former molecular spiral shell comprises, but be not limited to: 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-azaspiro [5.5] undecyl and 2-azaspiro [5.5] undecyl, etc.Described 7-12 former molecular spiral shell mix bicycloalkyl radicals can optionally replace by one or more substituting group described in the invention.
In other embodiments, to be that 7-12 is former molecularly condense assorted bicyclic alkyl to Heterocyclylalkyl, refer to containing 7-12 annular atoms, unit price or multivalence, saturated condense assorted bicyclic alkyl, wherein at least one annular atoms is selected from nitrogen, sulphur or Sauerstoffatom.Unless otherwise indicated, Heterocyclylalkyl can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.7-12 the former molecular example condensing assorted bicyclic alkyl comprises, but be not limited to: octahydro-1H-pseudoindoyl (as, octahydro-1H-isoindole-5-base, octahydro-1H-isoindole-7-base), octahydro pentamethylene also [c] pyrryl (as, octahydro pentamethylene is [c] pyrroles-5-base also, octahydro pentamethylene is [c] pyrroles-2-base also), hexahydro furyl also [3, 2-b] furyl (as, hexahydro furyl also [3, 2-b] furans-2-base, hexahydro furyl also [3, 2-b] furans-3-base), hexahydro furyl also [2, 3-b] furyl and ten dihydro-isoquinoline bases.Described 7-12 former molecular condense assorted bicycloalkyl radicals can optionally replace by one or more substituting group described in the invention.
In other embodiments, to be that 8-10 is former molecularly condense assorted bicyclic alkyl to Heterocyclylalkyl, refers to containing 8-10 annular atoms, and unit price or multivalence, saturated condenses assorted bicyclic alkyl, and wherein at least one annular atoms is selected from nitrogen, sulphur or Sauerstoffatom.Unless otherwise indicated, 8-10 is former, and molecular to condense assorted bicyclic alkyl can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.8-10 the former molecular example condensing assorted bicyclic alkyl comprises, but be not limited to: octahydro-1H-pseudoindoyl (as, octahydro-1H-isoindole-5-base, octahydro-1H-isoindole-7-base), octahydro pentamethylene also [c] pyrryl (as, octahydro pentamethylene is [c] pyrroles-5-base also, octahydro pentamethylene is [c] pyrroles-2-base also), hexahydro furyl also [3, 2-b] furyl (as, hexahydro furyl also [3, 2-b] furans-2-base, hexahydro furyl also [3, 2-b] furans-3-base), hexahydro furyl also [2, 3-b] furyl and ten dihydro-isoquinoline bases.Described 8-10 former molecular condense assorted bicycloalkyl radicals can optionally replace by one or more substituting group described in the invention.
Term " n former molecular ", wherein n is integer, typically describes the number of ring member nitrogen atoms in molecule, and in described molecule, the number of ring member nitrogen atoms is n.Such as, piperidyl is 6 former molecular Heterocyclylalkyls, and 1,2,3,4-tetralyl is 10 former molecular carbocylic radical groups.
Term " undersaturated " used in the present invention represents in group containing one or more degree of unsaturation.
Term " heteroatoms " refers to O, S, N, P and Si, comprises the form of any oxidation state of N, S and P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, such as, N (N as in 3,4-dihydro-2 h-pyrrole base), NH (NH as in pyrrolidyl) or NR (NR as in the pyrrolidyl that N-replaces).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " azido-" or " N 3" represent a nitrine structure.This group can be connected with other groups, such as, can be connected to form triazonmethane (MeN with a methyl 3), or be connected to form phenylazide (PhN with a phenyl 3).
Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the carbocyclic ring system of the monocycle of 6-10 annular atoms, dicyclo and three rings, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 former molecular ring, and has one or more tie point to be connected with the rest part of molecule.Term " aryl " can exchange with term " aromatic nucleus " and use.The example of aromatic yl group can comprise phenyl, naphthyl and anthryl.Described aromatic yl group can independently optionally replace by one or more substituting group described in the invention.
Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, dicyclo and three-ring system, wherein at least one member ring systems is aromatic, and at least one aromatic ring system comprises one or more heteroatoms, wherein each member ring systems comprises 5-7 former molecular ring, and has one or more tie point to be connected with molecule rest part.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.In some embodiments, heteroaryl is comprise heteroatomic 5-12 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N.In other embodiments, heteroaryl is comprise heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N.Also in some embodiments, heteroaryl is comprise heteroatomic 5-6 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N.Described heteroaryl groups optionally replace by one or more substituting group described in the invention.The example of heteroaryl groups comprises, but be not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyriconyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyrimidine ketone group, pyrimidine dione base, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl is (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo [1, 2-a] pyridyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [4, 3-c] pyridyl, pyrazolo [3, 4-b] pyridyl, pyrazolo [1, 5-a] pyrimidyl, imidazo [1, 2-b] pyridazinyl, [1, 2, 4] triazolo [4, 3-b] pyridazinyl, [1, 2, 4] triazolo [1, 5-a] pyrimidyl, [1, 2, 4] triazolo [1, 5-a] pyridyl, etc..
Term " azoles base " refers to and comprises at least two heteroatomss and wherein have one at least for nitrogen-atoms, by 5 or 9 former molecular heteroaromatic ring systems.The example of azoles base comprises, but be not limited to pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, di azoly, triazolyl, indazolyl, pyrazolo [4,3-c] pyridyl, pyrazolo [3,4-b] pyridyl, imidazo [4,5-b] pyridyl and 1H-benzo [d] imidazolyl.
No matter term " carboxyl ", be used alone or be used in conjunction with other terms, as " carboxyalkyl ", and expression-CO 2h; No matter term " carbonyl ", be used alone or be used in conjunction with other terms, as " aminocarboxyl " or " acyloxy ", represent-(C=O)-.
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group.Some of them embodiment is, alkylamino is one or two C 1-C 6alkyl is connected to the more rudimentary alkylamino group that nitrogen-atoms is formed.Other embodiment is, alkylamino is one or two C 1-C 4alkyl is connected to the more rudimentary alkylamino group that nitrogen-atoms is formed.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
Term " virtue amino " represent amino group replace by one or two aromatic yl group, such example comprises, but is not limited to N-phenylamino.Some of them embodiment is, the aromatic ring on fragrant amino can be substituted further.
Term " aminoalkyl group " comprise the C that replaces by one or more amino 1-C 10straight or branched alkyl group.Some of them embodiment is, aminoalkyl group the C that replaces by one or more amino group 1-C 6" more rudimentary aminoalkyl group ", such example comprises, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
As described in the invention, substituting group is drawn a key and is connected to the member ring systems (shown in b) that the ring at center is formed and represents substituting group any commutable position in this member ring systems and can replace.Such as, formula b represents any position that may be substituted on C ring and D ring, shown in c ~ formula g.
As described in the invention, a connecting key is connected to the member ring systems that Ring current distribution is formed, and (shown in h, wherein, X and X ' is separately CH 2, NH or O) represent connecting key and can be connected with molecule rest part any attachable position in member ring systems.Formula h represents E ring and all can be connected with molecule rest part with the position that may be connected any on F ring.
As described in the invention, two connecting keys are connected to the member ring systems (showing such as formula i) that Ring current distribution is formed and represent two connecting keys and all can be connected with molecule rest part any attachable position in member ring systems.Formula i represents any two positions that may connect on G ring and all can be connected with molecule rest part.
Time term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; t-butyl formate (BOC; Boc), carbobenzoxy-(Cbz) (CBZ, Cbz) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-C 24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al., Prodrugs:Design andClinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al., Prodrugs ofPhosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detailin J.Pharmaceutical Sciences, described in 1977,66:1-19..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-C 4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid and monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Term as used in the present invention " treatment " any disease or illness, some embodiment middle fingers improve disease or illness (namely slow down or stop or palliate a disease or the development of its at least one clinical symptom) wherein.In other embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter may not discovered for patient.In other embodiments, " treatment " refer to from health (such as stablizing perceptible symptom) or physiology (such as stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In other embodiments, " treatment " refer to prevent or postpone the outbreak of disease or illness, generation or deterioration.
" inflammatory diseases " used in the present invention refers to any disease that excessive inflammatory symptoms because inflammatory responses excessive or out of control causes, host tissue infringement or function of organization lose, disorderly or symptom." inflammatory diseases " also refers to by the pathologic state that white corpuscle flows into and/or Neutrophil chemotaxis mediates.
" inflammation " used in the present invention refer to caused by tissue damaged or destruction topical protective response, it for destroy, dilute or separate (completely cut off) be harmful to material and impaired tissue.Inflammation and white corpuscle flow into and/or Neutrophil chemotaxis has and contacts significantly.Inflammation can result from the infection of pathogenic organism and virus and non-infectious mode, as the wound after myocardial infarction or apoplexy or Reperfu-sion, to immunne response and the autoimmune response of exotic antigen.Therefore, can comprise by the inflammatory diseases of the open compounds for treating of the present invention: to react to specificity system of defense and non-specific defense system reacts relevant disease.
" specificity system of defense " refers to that the existence of immune component to specific antigen reacts.The example of inflammation resulting from the reaction of specificity system of defense comprise the classics of exotic antigen replys, autoimmune disease and delayed hypersensitivity reply (cell-mediated by T-).Chronic inflammatory disease, the repulsion (repulsion as kidney and bone marrow transplantation) of transplanting solid tissue and organ and graft versus host disease (GVHD) are other examples of specificity system of defense Inflammatory response.
" autoimmune disorders " used in the present invention refers to and body fluid or the cell-mediated set of health self component being replied to any disease of relevant tissue injury.
" allergy " used in the present invention refers to that producing irritated any symptom, tissue injury or function of organization loses." arthritis disease " refers to be attributable to any disease that various etiologic etiological arthritis damage is feature as used in the present invention." dermatitis " refers to be attributable to any one in the extended familys of the dermatosis that various etiologic etiological skin inflammation is feature as used in the present invention.The antagonism transplanted tissue that " transplant rejection " refers to transplant or the afunction of surrounding tissue, pain, swelling, leukocytosis and thrombopenia are feature as used in the present invention, as any immune response of organ or cell (as marrow).Methods for the treatment of of the present invention comprises the method being used for the treatment of the disease relevant to inflammatory cell activation.
The physiological conditions that term " cancer " and " cancer " refer to or describe is feature with Growth of Cells out of control usually in patient." tumour " comprises one or more cancer cells.The example of cancer includes but not limited to cancer (carcinoma), lymphoma, blastoma, sarcoma and leukemia, or malignant lymph proliferative disease (lymphoid malignancies).The example more specifically of this type of cancer comprises squamous cell carcinoma (as epithelium squamous cell carcinoma), lung cancer (comprises small cell lung cancer, nonsmall-cell lung cancer (NSCLC), adenocarcinoma of lung and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma (hepatocellular cancer), cancer of the stomach (gastric or stomach cancer) (comprising gastrointestinal cancer), carcinoma of the pancreas, glioblastoma, cervical cancer, ovarian cancer, liver cancer (liver cancer), bladder cancer, hepatoma (hepatoma), mammary cancer, colorectal carcinoma, the rectum cancer, colorectal cancer, carcinoma of endometrium or uterus carcinoma, salivary-gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma vulvae, thyroid carcinoma, liver cancer (hepatic carcinoma), anus cancer, penile cancer and head and neck cancer.
The description of compound of the present invention
The invention discloses the compound of a class novelty, can be used as protein kinase activity, particularly the inhibitor of jak kinase, FLT3 kinases and Aurora A activity.Compound as kinases inhibitor can be used for treatment and unsuitable protein kinase activity, particularly the active relevant disease of unsuitable jak kinase, FLT3 kinases and Aurora A, such as, treat and prevent to relate to the disease of the jak kinase of signal path, FLT3 kinases and Aurora A mediation.Such disease comprises proliferative disease, autoimmune disorders, anaphylactic disease, inflammatory diseases, transplant rejection and their complication.Especially, the compounds of this invention can be used for treating following disease, such as cancer, polycythemia vera, primary thrombocytosis, myelofibrosis, acute myelocytic leukemia, acute lymphoblastic leukemia, chronic granulocytic leukemia (CML), chronic obstructive pulmonary disease (COPD), asthma, systemic lupus erythematous, skin lupus erythematosus, systemic lupus erythematosus, dermatomyositis, sjogren syndrome, psoriatic, type i diabetes, respiratory anaphylactic disease, sinusitis paranasal sinusitis, eczema, measles, food anaphylaxis, insect venom allergies, inflammatory bowel, Crohn's disease, rheumatoid arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection, cell transplant rejection, etc..
In some embodiments, the present invention comes into the open compound to the stronger inhibit activities of one or more protein kinases display.
On the one hand, the present invention relates to a kind of steric isomer such as formula compound shown in the compound shown in (I) or formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug,
Wherein, Z, Z 1, A, W and R 1there is implication as described in the present invention.
In some embodiments, Z is C 7-C 12spiral shell bicyclic alkyl, C 7-C 12mix bicyclic group or 7-12 of condensed-bicyclic alkyl, 7-12 former molecular spiral shell formerly molecularly condenses assorted bicyclic alkyl, and wherein, Z is optionally by 1,2,3,4 or 5 R 3group replaced;
Z 1for H, C 1-C 12alkyl, C 3-C 12cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, work as Z 1when not being H, Z 1optionally by 1,2,3,4 or 5 R 4group replaced;
A is indazolyl or Pyrazolopyridine base, and wherein, A is optionally by 1,2,3,4 or 5 R 5group replaced;
W is N;
R 1for H, F, Cl, Br, I, NO 2, N 3, CN, C 1-C 12alkyl, C 1-C 12haloalkyl, C 1-C 12alkoxyl group, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, 3-12 former molecular heterocyclic radical, C 6-C 12aryl, 5-12 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-C (=NR c) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, work as R 1be not H, F, Cl, Br, I, NO 2, N 3during with CN, R 1optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 3be H, F, Cl, Br, I, NO independently 2, CN, N 3, OH, NH 2,-C (=O) CH 2cN, C 1-C 12alkyl, C 1-C 12haloalkyl, C 1-C 12alkoxyl group, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12the individual former molecular heterocyclic radical of aryl, 3-12,5-12 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-S (=O) 2r 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-O (CR 7r 8) n-OR c,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-C (=NR c) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, or the R that two adjacent 3, and together with the atom be connected with them, form C 3-C 12cycloalkyl or 3-12 former molecular heterocycloalkyl, wherein, above-mentioned each substituting group is not H, F, Cl, Br, I, NO 2, CN and N 3time, independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 4and R 5be separately H, F, Cl, Br, I, NO 2, CN, N 3, C 1-C 12alkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl ,-(C 1-C 4alkylidene group)-(C 3-C 12cycloalkyl), C 6-C 12aryl, 3-12 former molecular heterocyclic radical ,-(C 1-C 4alkylidene group)-(3-12 former molecular heterocyclic radical), 5-12 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-C (=NR c) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-C (=O) NR ar b, wherein, as above-mentioned each R 4and R 5be not H, F, Cl, Br, I, NO 2, CN and N 3time, each R 4and R 5respectively optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 6be H, C independently 1-C 12alkyl, C 1-C 12haloalkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, wherein, work as R 6when not being H, each R 6independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 7and R 8be separately H, F, Cl, Br, I, NO 2, N 3, CN, C 1-C 12alkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, or R 7and R 8, and together with the carbon atom be connected with them, form C 3-C 12cycloalkyl, C 6-C 12aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl groups, wherein, above-mentioned each substituting group is not H, F, Cl, Br, I, NO 2, CN and N 3time, independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 9be F, Cl, Br, I, CN, NO independently 2, N 3, C 1-C 12alkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12the individual former molecular heterocyclic radical of aryl, 3-12,5-12 former molecular heteroaryl, NH 2,-NH (C 1-C 12alkyl) ,-NH (CH 2) n-(C 3-C 12cycloalkyl) ,-NH (CH 2) n-(C 6-C 12aryl) ,-NH (CH 2) n-(3-12 former molecular heterocyclic radical) ,-NH (CH 2) n-(5-12 former molecular heteroaryl) ,-N (C 1-C 12alkyl) 2,-N [(CH 2) n-(C 3-C 12cycloalkyl)] 2,-N [(CH 2) n-(C 6-C 12aryl)] 2,-N [(CH 2) n-(3-12 former molecular heterocyclic radical)] 2,-N [(CH 2) n-(5-12 former molecular heteroaryl)] 2, OH ,-O (C 1-C 12alkyl) ,-O (CH 2) n-(C 3-C 12cycloalkyl) ,-O (CH 2) n-(C 6-C 12aryl) ,-O (CH 2) n-(3-12 former molecular heterocyclic radical) or-O (CH 2) n-(5-12 former molecular heteroaryl);
Each R a, R band R cbe separately H, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl ,-(C 1-C 4alkylidene group)-(C 3-C 6cycloalkyl), 3-6 former molecular heterocyclic radical ,-(C 1-C 4alkylidene group)-(3-6 former molecular heterocyclic radical), C 6-C 10aryl ,-(C 1-C 4alkylidene group)-(C 6-C 10aryl), 5-10 former molecular heteroaryl or-(C 1-C 4alkylidene group)-(5-10 former molecular heteroaryl), or R aand R b, and together with the nitrogen-atoms be connected with them, form 3-8 former molecular heterocyclyl groups, wherein, above-mentioned each substituting group, when not being H, is independently optionally independently selected from F, Cl, Br, CN, N by 1,2,3 or 4 3, OH, NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group or C 1-C 6the substituting group of alkylamino replaced;
Each m is 1 or 2 independently; With
Each n is 0,1,2,3 or 4 independently.
In other embodiments, Z is C 8-C 11spiral shell bicyclic alkyl, C 8-C 10mix bicyclic group or 8-10 of condensed-bicyclic alkyl, 8-11 former molecular spiral shell formerly molecularly condenses assorted bicyclic alkyl, and wherein, Z is optionally by 1,2,3 or 4 R 3group replaced.
In other embodiments, Z is following subformula:
Or their steric isomer, wherein, each X, X ', X 2and X 3be separately CH 2, NH or O, condition works as X 2when being O, X 3be not O; Each minor structure shown in formula (Z-1) ~ (Z-54) or its steric isomer are independently optionally by 1,2 or 3 R 3group replaced.
In some embodiments, Z 1for H, C 1-C 6alkyl, C 3-C 6cycloalkyl or 3-6 former molecular heterocyclic radical, wherein, work as Z 1when not being H, Z 1optionally by 1,2 or 3 R 4group replaced.
In other embodiments, Z 1for H, methyl, ethyl, n-propyl, sec.-propyl or cyclopropyl.
In some embodiments, A is following subformula:
Wherein, formula (M), (N), (Q) or the minor structure shown in (T) are independent optionally by 1,2 or 3 R 5group replaced.
In some embodiments, R 1for H, F, Cl, CN, N 3, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 3-C 6cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-(CR 7r 8) nc (=O) NR ar bor-S (=O) 2nR ar b, wherein, work as R 1be not H, F, Cl, N 3during with CN, R 1optionally by 1,2 or 3 R 9group replaced.
In other embodiments, R 1for H, F, Cl, CN, N 3, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group, C 3-C 6cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-(CR 7r 8) nc (=O) NR ar bor-S (=O) 2nR ar b, wherein, work as R 1be not H, F, Cl, N 3during with CN, R 1optionally by 1,2 or 3 R 9group replaced.
In some embodiments, each R 3be H, F, Cl, CN, N independently 3, NO 2, OH, NH 2,-C (=O) CH 2cN, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6alkoxyl group, C 1-C 6haloalkyl, C 3-C 6the individual former molecular heterocyclic radical of cycloalkyl, phenyl, 3-6,5-6 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-S (=O) 2r 6,-O (CR 7r 8) n-R 6,-O (CR 7r 8) n-OR c,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, or the R that two adjacent 3, and together with the atom be connected with them, form C 3-C 6cycloalkyl or 3-6 former molecular heterocycloalkyl, wherein, above-mentioned each substituting group is not H, F, Cl, NO 2, CN and N 3time, independent optionally by 1,2 or 3 R 9group replaced.
In other embodiments, each R 3be H, F, Cl, CN, N independently 3, NO 2, OH, NH 2,-C (=O) CH 2cN, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 1-C 4alkoxyl group, C 1-C 4haloalkyl, C 3-C 6the individual former molecular heterocyclic radical of cycloalkyl, phenyl, 3-6,5-6 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-S (=O) 2r 6,-O (CR 7r 8) n-R 6,-O (CR 7r 8) n-OR c,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, work as R 3be not H, F, Cl, NO 2, CN and N 3time, each R 3independent optionally by 1,2 or 3 R 9group replaced.
In some embodiments, each R 4and R 5be separately H, F, Cl, Br, I, NO 2, N 3, CN, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl ,-(C 1-C 2alkylidene group)-(C 3-C 6cycloalkyl), phenyl, 3-6 former molecular heterocyclic radical ,-(C 1-C 2alkylidene group)-(3-6 former molecular heterocyclic radical), 5-6 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, as above-mentioned each R 4and R 5be not H, F, Cl, Br, I, NO 2, CN and N 3time, each R 4and R 5respectively optionally by 1,2 or 3 R 9group replaced.
In some embodiments, each R 6be H, C independently 1-C 6alkyl, C 1-C 6haloalkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, wherein, work as R 6when not being H, each R 6independent optionally by 1,2 or 3 R 9group replaced.
In other embodiments, each R 6be H, C independently 1-C 4alkyl, C 1-C 4haloalkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, wherein, work as R 6when not being H, each R 6independent optionally by 1,2 or 3 R 9group replaced.
In some embodiments, each R 7and R 8be separately H, F, Cl, Br, I, CN, N 3, NO 2, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, or R 7and R 8, and form C together with the carbon atom be connected with them 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl groups, wherein, above-mentioned each substituting group is not H, F, Cl, Br, I, NO 2, CN and N 3time, independent optionally by 1,2 or 3 R 9group replaced.
In other embodiments, each R 9be F, Cl, CN, N independently 3, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6the individual former molecular heterocyclic radical of cycloalkyl, phenyl, 3-6,5-6 former molecular heteroaryl, NH 2,-NH (C 1-C 6alkyl) ,-NH (CH 2) n-(C 3-C 6cycloalkyl) ,-NH (CH 2) n-phenyl ,-NH (CH 2) n-(3-6 atom composition heterocyclic radical) ,-NH (CH 2) n-(5-6 former molecular heteroaryl) ,-N (C 1-C 4alkyl) 2,-N [(CH 2) n-(C 3-C 6cycloalkyl)] 2,-N [(CH 2) n-phenyl] 2,-N [(CH 2) n-(3-6 former molecular heterocyclic radical)] 2,-N [(CH 2) n-(5-6 former molecular heteroaryl)] 2, OH ,-O (C 1-C 6alkyl) ,-O (CH 2) n-(C 3-C 6cycloalkyl) ,-O (CH 2) n-phenyl ,-O (CH 2) n-(3-6 former molecular heterocyclic radical) or-O (CH 2) n-(5-6 former molecular heteroaryl).
In other embodiments, each R a, R band R cbe separately H, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 3-C 6cycloalkyl ,-(C 1-C 2alkylidene group)-(C 3-C 6cycloalkyl), 3-6 former molecular heterocyclic radical ,-(C 1-C 2alkylidene group)-(3-6 former molecular heterocyclic radical), phenyl ,-(C 1-C 2alkylidene group)-phenyl, a 5-6 former molecular heteroaryl or-(C 1-C 2alkylidene group)-(5-6 former molecular heteroaryl), or R aand R b, and together with the nitrogen-atoms be connected with them, form 3-6 former molecular heterocyclyl groups, wherein, above-mentioned each substituting group, when not being H, is independently optionally independently selected from F, Cl, CN, N by 1,2 or 3 3, OH, NH 2, C 1-C 4alkyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group or C 1-C 4the substituting group of alkylamino replaced.
Also in some embodiments, the present invention relates to following one of them compound or its steric isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, but be never limited to these compounds:
Unless otherwise mentioned, the steric isomer of compound shown in formula (I), tautomer, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug are included in the scope of the invention.
The present invention's compound of coming into the open can contain asymmetric or chiral centre, and stereoisomer form that therefore can be different exists.The present invention is intended to all stereoisomer forms making compound shown in formula (I), include but not limited to diastereomer, enantiomer, atropisomer and geometry (or conformation) isomer, and their mixture is as racemic mixture, become integral part of the present invention.
In structure disclosed by the invention, when the stereochemistry of the chiral atom of any specific does not indicate, then all steric isomers of this structure are all considered within the present invention, and comprise in the present invention as the present invention's compound of coming into the open.When stereochemistry is expressed the real wedge shape line (solid wedge) of particular configuration or dotted line indicates, then the steric isomer of this structure clear and definite and definition at this point.
Shown in formula (I), compound can exist with different tautomeric forms, and all these tautomers, as is described in the claims, be all included in the scope of the present invention.
Shown in formula (I), compound can exist in a salt form.In some embodiments, described salt refers to pharmacy acceptable salt.Term " pharmaceutically acceptable " refer to material or composition must with comprise preparation other composition and/or with its Mammals treated chemically and/or compatible in toxicology.In other embodiments, described salt not necessarily pharmacy acceptable salt, can be for the preparation of and/or purification formula (I) shown in the intermediate of compound and/or the enantiomorph for separating of compound this formula (I) Suo Shi.
Pharmaceutically useful acid salt can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate, muriate/hydrochloride, chloro theophylline salt, Citrate trianion, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, poly-semi-lactosi hydrochlorate, propionic salt, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.
Such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. can be comprised by its derivative mineral acid obtaining salt.
Such as acetic acid, propionic acid, oxyacetic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, sulphosalicylic acid etc. can be comprised by its derivative organic acid obtaining salt.
Pharmaceutically acceptable base addition salt can be formed with mineral alkali and organic bases.
Can be comprised by its derivative mineral alkali obtaining salt, the metal of I race to the XII race of such as ammonium salt and periodictable.In certain embodiments, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; Particularly suitable salt comprises ammonium, potassium, sodium, calcium and magnesium salts.
Can comprise primary amine, secondary amine and tertiary amine by its derivative organic bases obtaining salt, the amine of replacement comprises the amine, cyclic amine, deacidite etc. of naturally occurring replacement.Some organic amine comprises, such as, and Isopropylamine, dibenzylethylenediamine dipenicillin G (benzathine), choline salt (cholinate), diethanolamine, diethylamine, Methionin, meglumine (meglumine), piperazine and Trometamol.
Pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.Generally speaking, such salt can react by making the suitable alkali of the free acid form of these compounds and stoichiometry (oxyhydroxide, carbonate, supercarbonate etc. as Na, Ca, Mg or K), or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared.Such reaction is carried out usually in water or organic solvent or the mixture of the two.Usually, when suitable, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.At such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985); " pharmaceutical salts handbook: character, choice and application (Handbook ofPharmaceutical Salts:Properties; Selection; and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) other can be found to be suitable for the list of salt in.
In addition, compound disclosed by the invention, comprise their salt, also can obtain, for their crystallization with their hydrate forms or the form comprising its solvent (such as ethanol, DMSO, etc.).Compound is come into the open in the present invention can with pharmaceutically acceptable solvent (comprising water) inherently or by design forming solvate; Therefore, the present invention be intended to comprise solvation and the form of non-solvation.
Any structural formula that the present invention provides is also intended to represent these compounds not by the form of the form of isotopic enrichment and isotopic enrichment.The compound of isotopic enrichment has the structure of the general formula description that the present invention provides, except one or more atom is replaced by the atom with selected nucleidic mass or total mass number.The Exemplary isotopes can introduced in the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as 2h, 3h, 11c, 13c, 14c, 15n, 17o, 18o, 18f, 31p, 32p, 35s, 36cl and 125i.
On the other hand, such as, wherein there is radio isotope in the compound that the present invention that compound of the present invention comprises isotopic enrichment defines, as 3h, 14c and 18those compounds of F, or wherein there is non radioactive isotope, as 2h and 13c.The compound of such isotopic enrichment can be used for metabolism research and (uses 14c), reaction kinetics research (uses such as 2h or 3h), detect or imaging technique, as positron emission tomography (PET) or the SPECT (single photon emission computed tomography) (SPECT) comprising medicine or substrate tissue measure of spread, or can be used in the radiotherapy of patient. 18the compound of F enrichment is desirable especially for PET or SPECT research.Use suitable isotope labeling reagent to substitute original used unmarked reagent described by embodiment in the routine techniques that shown in the formula (I) of isotopic enrichment, compound can be familiar with by those skilled in the art or the present invention and preparation process to prepare.
In addition, particularly deuterium is (that is, for higher isotope 2h or D) replacement can provide some treatment advantage, these advantages are brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index improves brings.Should be appreciated that the deuterium in the present invention is counted as the substituting group of compound shown in formula (I).The concentration of such higher isotope particularly deuterium can be defined by the isotopic enrichment factor.Term used in the present invention " the isotopic enrichment factor " refers to specified ratio between isotopic isotopic abundance and natural abundance.If the substituting group of the compounds of this invention is designated as deuterium, this compound has at least 3500 (each deuterium at D atom place 52.5% of specifying mixes) to each D atom of specifying, at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 (deuterium of 82.5% mixes), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), the isotopic enrichment factor of at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuterium of 99.5% mixes).It can be the such as D that isotropic substance replaces that the pharmaceutically useful solvate of the present invention comprises wherein recrystallisation solvent 2o, acetone-d 6, DMSO-d 6those solvates.
On the other hand, the present invention relates to the intermediate of compound shown in preparation formula (I).
On the other hand, the present invention relates to the preparation of compound shown in formula (I), the method for abstraction and purification.
On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises the compounds of this invention.In some embodiments, pharmaceutical composition of the present invention, further comprises pharmaceutically acceptable carrier, vehicle, adjuvant, solvent or their combination.In other embodiments, pharmaceutical composition can be liquid, solid, semisolid, gel or aerosol.
On the other hand, the present invention relates to treatment by one or more protein kinases, the disease regulated as jak kinase, FLT3 kinases and Aurora A or the method for disorder, described methods for the treatment of comprises the present invention giving Mammals significant quantity and to come into the open compound or pharmaceutical composition.In some embodiments, described disease or disorder are selected from proliferative disease, autoimmune disorders, anaphylactic disease, inflammatory diseases or transplant rejection.
On the other hand, the present invention relates to and use the compounds of this invention disclosed by the invention or medicine composite for curing disease or disorder, described disease or disorder are selected from proliferative disease, autoimmune disorders, anaphylactic disease, inflammatory diseases or transplant rejection.
On the other hand, the present invention relates to compound disclosed by the invention or pharmaceutical composition and preparing the purposes of medicine of disease therapy or disorder, described disease is selected from proliferative disease, autoimmune disorders, anaphylactic disease, inflammatory diseases or transplant rejection.
On the other hand, the present invention relates to the purposes using the compounds of this invention disclosed by the invention or pharmaceutical composition to prepare medicine, described medicine is used for the kinase whose activity of Function protein.
The pharmaceutical composition of the compounds of this invention, preparation and administration
The invention provides a kind of pharmaceutical composition, it comprises the present invention and to come into the open compound, or listed compound in embodiment; With pharmaceutically acceptable vehicle, carrier, adjuvant, solvent or their combination.In pharmaceutical composition disclosed by the invention, the amount of compound refers to the amount that effectively can detect and suppress protein kinase in biological specimen or patient body.
Also it should be understood that some compound of the present invention can exist in a free form to be used for the treatment of, if or suitably can exist with the form of its pharmaceutically acceptable derivates.Some nonrestrictive embodiments of pharmaceutically acceptable derivative comprise pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or to directly or indirectly providing any other adducts or the derivative of compound of the present invention or its meta-bolites or residue during patient's administration in need.
Drug pharmaceutical compositions disclosed by the invention can be prepared and be packaged as (bulk) in bulk form, wherein can extract the compound shown in formula (I) of safe and effective amount, then give patient with powder or syrup form.Or pharmaceutical composition disclosed by the invention can be prepared and be packaged as unit dosage, wherein each physically discrete unit contains the compound shown in formula (I) of safe and effective amount.When preparing with unit dosage, pharmaceutical composition disclosed by the invention can contain usually, such as, and the compound disclosed by the invention of 0.5mg to 1g or 1mg to 700mg or 5mg to 100mg.
The present invention's " pharmaceutically acceptable vehicle " used means pharmaceutically acceptable material, mixture or the solvent relevant to form of administration or pharmaceutical composition consistence.Often kind of vehicle must be compatible with other composition of pharmaceutical composition when mixing, with avoid to can greatly reduce during patient's administration the present invention come into the open compound effect interaction and can cause not being the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, often kind of vehicle must be pharmaceutically acceptable, such as, has sufficiently high purity.
Suitable pharmaceutically acceptable vehicle can be different according to selected concrete formulation.In addition, pharmaceutically acceptable vehicle can be selected according to their specific functions in the composition.Such as, some pharmaceutically acceptable vehicle that can contribute to producing equal one dosage type low temperature can be selected.Some pharmaceutically acceptable vehicle that can contribute to administration measure formulation can be selected.Can select to come into the open compound from an organ of health or partly to another organ of health or some pharmaceutically acceptable vehicle of part to contributing to carrying or transport the present invention during patient's administration.Can some pharmaceutically acceptable vehicle of selective enhancement patient compliance.
Suitable pharmaceutically acceptable vehicle comprises the vehicle with Types Below: thinner, weighting agent, tackiness agent, disintegrating agent, lubricant, glidant, granulating agent, Drug coating, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, correctives, odor mask, tinting material, anti-hard caking agent, wetting Agent for Printing Inks, sequestrant, fluidizer, tackifier, antioxidant, sanitas, stablizer, tensio-active agent and buffer reagent.Technician can recognize, some pharmaceutically acceptable vehicle can provide more than a kind of function, and provides alternative function, and this depends in preparation have in how many these vehicle and preparation to there are which other vehicle.
Technician grasps the knowledge and skills of this area, the suitable pharmaceutically acceptable vehicle selecting for appropriate amount of the present invention to make them.In addition, there is the obtainable resource of a large amount of technician, they describe pharmaceutically acceptable vehicle, and for selecting suitable pharmaceutically acceptable vehicle.Example comprises Remington's Pharmaceutical Sciences (Mack Publishing Company), TheHandbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of PharmaceuticalExcipients (the American Pharmaceutical Association and the Pharmaceutical Press).
At Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, LippincottWilliams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, the various carriers for configuring pharmaceutically acceptable composition are disclosed in New York, with the known technology prepared for it, these documents content is separately incorporated to the present invention by reference.Except any such as because producing any less desirable biological action, or occur to interact with other composition any in harmful way and pharmaceutically acceptable composition and come into the open outside the inconsistent any common carrier of compound with the present invention, pay close attention to its application and belong to scope of the present invention.
Pharmaceutical composition disclosed by the invention uses techniques and methods well known by persons skilled in the art to prepare.The description of some common methods of this area can see Remington's Pharmaceutical Sciences (Mack Publishing Company).
Therefore, on the other hand, the present invention relates to the technique of pharmaceutical compositions, described pharmaceutical composition comprises the present invention and to come into the open compound and pharmaceutically acceptable vehicle, carrier, assistant agent, solvent or their combination, and this technique comprises the various composition of mixing.Comprise the present invention to come into the open the pharmaceutical composition of compound, can mix under such as envrionment temperature and normal atmosphere and prepare.
Compound disclosed by the invention is usually formulated into and is adapted to pass through the formulation of required approach to patient's administration.Such as, formulation comprises those formulations being suitable for following route of administration: (1) oral administration, such as tablet, capsule, caplet agent, pill, containing tablet, pulvis, syrup, elixir, suspensoid, solution, emulsion, granule and cachet; (2) parenteral admin, such as sterile solution agent, suspensoid and lyophilized powder agent; (3) transdermal administration, such as percutaneous plaster agent; (4) rectal administration, such as suppository; (5) suck, such as aerosol, solution and dry powder doses; (6) topical, such as ointment, salve, lotion, solution, paste, sprays, foaming agent and gelifying agent.
In some embodiments, compound disclosed by the invention can be mixed with oral dosage form.In other embodiments, compound disclosed by the invention can be mixed with inhalant dosage form.In other embodiments, compound disclosed by the invention can be mixed with nose administration formulation.In other embodiment, compound disclosed by the invention can be mixed with transdermal administration.Also in some embodiments, compound disclosed by the invention can be mixed with Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablet, molded tablet, can chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or enteric coated tablet, sugar-coat or film coated tablet provide.Enteric coated tablet are with can anti-hydrochloric acid in gastric juice effect but dissolve in intestines or the compressed tablet of material dressing of disintegration, thus prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to lipid acid, fat, salol, wax, shellac, ammonification shellac and cellulose acetate phthalate ester.Coated tablet is the compressed tablet that sugar-coat surrounds, and it can be beneficial to covers taste beastly or smell and tablet can be prevented to be oxidized.Thin membrane coated tablet is with the thin layer of water-soluble substances or the compressed tablet of plastic film covering.Film coating includes, but not limited to Natvosol, Xylo-Mucine, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses the general characteristic identical with sweet tablet.Multiple compressed tablet is the compressed tablet through preparing more than a press cycles, comprises multilayer tablet and pressed coated or dry coating tablet.
Tabules can by powder, crystallization or granular activeconstituents independent or one or more carriers of describing with the present invention or the incompatible preparation of vehicle group, described carrier and vehicle comprise tackiness agent, disintegrating agent, controlled release polymer, lubricant, thinner and/or tinting material.Sweetener and sweeting agent are particularly useful when forming chewable tablet and lozenge.
Pharmaceutical composition provided by the invention can provide with soft capsule or hard capsule, and it can be prepared by gelatin, methylcellulose gum, starch or alginate calcium.Described hard gelatin capsule, also referred to as dry-filled capsules (DFC), forms by two sections, and a slug enters in another section, therefore encloses activeconstituents completely.SEC (SEC) is soft, spherical shell, such as gelatin shell, and it is by adding the plasticizing of glycerine, sorbyl alcohol or similar polyvalent alcohol.Soft gelatin shell can comprise sanitas and carry out prophylaxis of microbial growth.Suitable sanitas be as described in the present invention those, comprise Tegosept M and propylben, and Sorbic Acid.Liquid provided by the invention, semisolid and solid dosage can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in solution in propylene carbonate, vegetables oil or triglyceride level and suspensoid.The capsule comprising such solution can as at United States Patent (USP) U.S.Pat.Nos.4, and 328,245; 4,409,239 and 4,410, what describe in 545 prepares.Described capsule also can adopt coating as is known to persons skilled in the art, thus improves or maintain the stripping of activeconstituents.
Pharmaceutical composition provided by the invention can provide with liquid and semisolid dosage form, comprises emulsion, solution, suspensoid, elixir and syrup.Emulsion is two-phase system, and wherein a kind of liquid is dispersed in another kind of liquid in pellet form completely, and it can be oil-in-water-type or water-in-oil-type.Emulsion can comprise pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and sanitas.Suspensoid can comprise pharmaceutically acceptable suspending agent and sanitas.Aqueous alcohol solutions can comprise pharmaceutically acceptable acetal, two (low alkyl group) acetal of such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal; With the water-soluble solvent with one or more hydroxyl, such as propylene glycol and ethanol.Elixir is water-alcohol solution that is transparent, sweet taste.Syrup is the aqueous solution of dense sugar such as sucrose, and can comprise sanitas.For liquid dosage form, such as, the solution in polyoxyethylene glycol can dilute with enough pharmaceutically acceptable liquid vehicles such as water, with accurately administration easily.
Other useful liquid and semisolid dosage form comprise, but be not limited to those formulations comprising activeconstituents provided by the invention and secondary list-or poly-alkylene glycol, described list-or poly-alkylene glycol comprise: 1,2-Methylal(dimethoxymethane), diglyme, triglyme, tetraethylene glycol dimethyl ether, polyoxyethylene glycol-350-dme, polyoxyethylene glycol-550-dme, polyoxyethylene glycol-750-dme, wherein 350,550,750 refer to the approximate molecular-weight average of polyoxyethylene glycol.These preparations may further include one or more oxidation inhibitor, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), Tenox PG, vitamin-E, quinhydrones, Hydroxycoumarin, thanomin, Yelkin TTS, kephalin, xitix, oxysuccinic acid, sorbyl alcohol, phosphoric acid, hydrosulphite, Sodium Pyrosulfite, thio-2 acid and ester thereof and dithiocarbamate.
Time suitable, can by the dosage unit preparations microencapsulation of oral administration.Also can be prepared into the composition extending or maintain release, such as, pass through microparticle material dressing or be embedded in polymkeric substance, wax or analogue.
Combination of oral medication provided by the invention can also provide with the form of liposome, micella, microballoon or nanometer system.Micella formulation can use U.S.Pat.No.6, prepared by 350,458 methods described.
Pharmaceutical composition provided by the invention can provide with the granule of non-effervesce or effervesce and pulvis, to reconstruct liquid dosage form.The pharmaceutically acceptable carrier used in non-effervescent granule or pulvis and vehicle can comprise thinner, sweeting agent and wetting agent.The pharmaceutically acceptable carrier used in effervescent granule or pulvis and vehicle can comprise organic acid and carbon dioxide source.
Tinting material and seasonings can be used in all above-mentioned formulations.
Compound disclosed in this invention also can be combined with the soluble polymer as target medicine carrier.Such polymkeric substance comprises the oxide polylysine of polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or palmitoyl residues replacement.In addition, compound disclosed in this invention can be combined with the class Biodegradable polymeric used in the Co ntrolled release realizing medicine, such as, the crosslinked or amphiphilic block copolymer of poly(lactic acid), poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate and hydrogel.
Pharmaceutical composition provided by the invention can be mixed with immediately or Modified release dosage forms, comprise delay-, slowly-releasing-, pulse-, control-, target-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can with other activeconstituents co-formulation of therapeutic action that can not damage expection, or the material co-formulation of effect with supplementary expection.
Pharmaceutical composition provided by the invention by injection, infusion or can implant administered parenterally, for local or Formulations for systemic administration.The administered parenterally used as the present invention comprises in intravenously, intra-arterial, intraperitoneal, sheath, in ventricle, in urethra, in breastbone, in encephalic, intramuscular, synovial membrane and subcutaneous administration.
Pharmaceutical composition provided by the invention can be mixed with any formulation being suitable for administered parenterally, comprises solution, suspensoid, emulsion, micella, liposome, microballoon, nanometer system and is suitable for making in a liquid before the injection the solid form of solution or suspension.Such formulation can be prepared according to the ordinary method known to the skilled in pharmaceutical science field (see Remington:The Science and Practice of Pharmacy, the same).
The pharmaceutical composition that expection is used for administered parenterally can comprise one or more pharmaceutically acceptable carrier and vehicle; comprise; but be not limited to, containing the sanitas of transporter, water miscibility vehicle, non-transporter, biocide or antimicrobial growth, stablizer, dissolution enhancers, isotonic agent, buffer reagent, oxidation inhibitor, local anesthetic, suspending agent and dispersion agent, wetting agent or emulsifying agent, complexing agent, sequestering agent or sequestrant, frostproofer, cryoprotectant, thickening material, pH adjusting agent and rare gas element.
Suitable includes, but are not limited to containing transporter: water, salt solution, physiological saline or phosphate buffered saline (PBS) (PBS), sodium chloride injection, Ringers injection liquid, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injection liquid.Non-transporter comprises, but be not limited to, the medium chain triglyceride of the fixed oil of plant origin, Viscotrol C, Semen Maydis oil, Oleum Gossypii semen, sweet oil, peanut oil, spearmint oil, Thistle oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and Oleum Cocois and palm seed oil.Water miscibility vehicle comprises, but be not limited to, ethanol, 1,3 butylene glycol, liquid macrogol (such as Liquid Macrogol and poly(oxyethylene glycol) 400), propylene glycol, glycerine, METHYLPYRROLIDONE, N,N-dimethylacetamide and methyl-sulphoxide.
Suitable biocide or sanitas comprise, but be not limited to, phenol, cresols, mercurial, phenylcarbinol, chlorobutanol, methyl p-hydroxybenzoate and propylparaben, Thiomersalate, benzalkonium chloride (such as benzethonium chloride), Tegosept M and propylben and Sorbic Acid.Suitable isotonic agent includes, but not limited to sodium-chlor, glycerine and glucose.Suitable buffer reagent includes, but not limited to phosphoric acid salt and Citrate trianion.Suitable antioxidant be as the present invention describe those, comprise hydrosulphite and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to vovocan.Suitable suspending agent and dispersion agent be as the present invention describe those, comprise Xylo-Mucine, Vltra tears and polyvinylpyrrolidone.Suitable emulsifying agent comprise the present invention describe those, comprise polyoxyethylene sorbitan monolaurate.Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or sequestrant 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 are not limited to cyclodextrin, comprise alpha-cylodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, Sulfobutylether-beta-cyclodextrin and Sulfobutylether 7-beta-cyclodextrin ( cyDex, Lenexa, KS).
Pharmaceutical composition provided by the invention can be mixed with single dose or multiple dose administration.Described single-dose preparations is packaged in ampulla, bottle or syringe.Described multiple doses parenteral administration must comprise biocide that is antibacterial or fungistatic concentrations.All parenteral administrations must be all aseptic, as known in the art with practice.
In some embodiments, pharmaceutical composition provides with instant sterile solution.In other embodiments, pharmaceutical composition provides with aseptic dried soluble product, comprises lyophilized powder agent and hypodermic tablet, and it reconstructs with vehicle before use.In other embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In other embodiment, the aseptic dry insolubility product that pharmaceutical composition reconstructs with vehicle before being formulated into use.Also in some embodiments, pharmaceutical composition is formulated into the aseptic emulsion of instant.
Pharmaceutical composition disclosed in this invention can be configured to immediately or Modified release dosage forms, comprise delay-, slowly-releasing-, pulse-, control-, target-and sequencing releasing pattern.
Pharmaceutical composition can be configured to suspensoid, solid, semisolid or thixotropic fluid, is used as the reservoir administration of implanting.In some embodiments, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, and it is insoluble to body fluid but the outside polymeric membrane allowing the activeconstituents in pharmaceutical composition to diffuse through surrounded.
The internal matrix be applicable to comprises polymethylmethacrylate, poly-butyl methacrylate, plasticising or unplasticizied polyvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, polyisoprene, polyisobutene, polyhutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, dimethione, silicone carbonate copolymer, the hydrogel of the ester of hydrophilic polymer such as vinylformic acid and methacrylic acid, collagen, the polyvinyl acetate of the partial hydrolysis of cross-linking polyvinyl alcohol and coach.
The outside polymeric membrane be applicable to comprises polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate multipolymer, ethylene/vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinatedpolyethylene, polyvinyl chloride, the multipolymer of ethylene chloride and vinyl-acetic ester, vinylidene chloride, ethene and propylene, ionomer polyethylene terephthalate, isoprene-isobutylene rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and ethylene/vinyl ethoxy-ethanol multipolymer.
On the other hand, pharmaceutical composition disclosed in this invention can be mixed with any formulation be suitable for patient's inhalation, such as dry powder doses, aerosol, suspensoid or liquid composite.In some embodiments, pharmaceutical composition disclosed in this invention can be mixed with and be suitable for by the formulation of dry powder doses to patient's inhalation.In other embodiment, pharmaceutical composition disclosed in this invention can be mixed with and be suitable for by the formulation of atomizer to patient's inhalation.Usually fine powdered compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable vehicle are comprised by inhalation delivery to the dry powder composite of lung.Be especially suitable for use as the pharmaceutically acceptable vehicle dawn known to those skilled in the art of dry powder doses, it comprise lactose, starch, N.F,USP MANNITOL and single-, two-and polysaccharide.Fine powder prepares by such as micronization and grinding.In general, (as micronized) compound that size reduces can by the D of about 1 to 10 micron 50value (such as, with laser diffractometry measure) defines.
Aerosol can be prepared by compound disclosed in this invention is suspended or is dissolved in liquefied propellant.The propelling agent be applicable to comprises hydrochloric ether, hydro carbons and other liquefied gas.Representational propelling agent comprises: trichlorofluoromethane (propelling agent 11), dichlorofluoromethane (propelling agent 12), dichloro tetrafluoro ethane (propelling agent 114), Tetrafluoroethane (HFA-134a), 1,1-C2H4F2 C2H4F2 (HFA-152a), methylene fluoride (HFA-32), pentafluoride ethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, perfluorinated butane, perflenapent, butane, Trimethylmethane and pentane.The aerosol comprising compound disclosed in this invention usually by metered dose inhaler (MDI) to patient's administration.Such device dawn known to those skilled in the art
Aerosol can comprise pharmaceutically acceptable vehicle that is extra, that use by MDIs, such as tensio-active agent, lubricant, cosolvent and other vehicle, with improve preparation physical stability, improve valve characteristic, improve solvability or improve taste.
The pharmaceutical composition being suitable for transdermal administration can be prepared into discontinuous paster agent, is intended to the time keeping close contact one elongated segment with the epidermis of patient.Such as, by iontophoretic injection delivering active ingredients from paster agent, as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
The pharmaceutical composition being suitable for topical can be formulated into salve, ointment, suspensoid, lotion, pulvis, solution, paste, gelifying agent, sprays, aerosol or finish.Such as, salve, ointment and gelifying agent can with water or oil matrix, and the thickening material be applicable to and/or gelifying agent and/or solvent configure.Such matrix can comprise, water, and/or oil such as liquid-liquid paraffin and vegetables oil (such as peanut oil or Viscotrol C), or solvent such as polyoxyethylene glycol.The thickening material used according to medium property and gelifying agent comprise soft wax, aluminum stearate, cetostearyl alcohol, polyoxyethylene glycol, lanolin, beeswax, carboxyvinyl polymer and derivatived cellulose, and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
Lotion can be prepared with water or oil matrix, and usually also containing one or more emulsifying agents, stablizer, dispersion agent, suspending agent or thickening material.
Compacted under can be there is in externally-applied powder at the powder matrix such as talcum powder, lactose or the starch that are applicable to arbitrarily.Drops can be formulated with the water or non-aqueous matrix comprising one or more dispersion agents, solubilizing agent, suspending agent or sanitas.
Topical formulations can carry out administration by applying one or many every day in affected part; The impermeable plastic wound dressing covering skin is preferentially used.Adhesivity store system can realize continuously or the administration extended.
Treatment eyes, or other organ as face and skin time, the composition as topical ointment or ointment can be used.When being formulated as salve, compound disclosed in this invention can use together with paraffin or water-soluble salve matrix.Or compound disclosed in this invention can be mixed with ointment 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 invention provides and use compound disclosed in this invention and medicine composite for curing, prevention, or improve by one or more protein kinases, as jak kinase (comprises JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also claiming FLK-2) or Aurora A (comprise Aurora-A, Aurora-B and Aurora C) behavior mediation or the disease that otherwise affects or disorderly or by one or more protein kinases, as jak kinase (comprises JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also claiming FLK-2) or Aurora A (comprise Aurora-A, Aurora-B and Aurora C) method of one or more symptoms of behavior mediation or the disease that otherwise affects or disorder.
FLT3 kinases can be the kinase whose wild-type of FLT3 and/or sudden change.
Jak kinase can be the kinase whose wild-type of JAK1, JAK2, JAK3 or TYK2 and/or sudden change.
In some embodiments, the invention provides class compound disclosed in this invention or comprise the pharmaceutical composition of compound disclosed in the present invention, be used for the treatment of, prevent or improve the disease that to be mediated by unsuitable JAK1 kinases behavior or otherwise affect or disorderly or mediated by unsuitable JAK1 kinases behavior or one or more symptoms of the disease that otherwise affects or disorder.In other embodiments, one or more symptoms of described disease, disorder or disease or disorder are relevant to the behavior of unsuitable JAK2 kinases.Also in some embodiments, one or more symptoms of described disease, disorder or disease or disorder are relevant to the behavior of unsuitable JAK3 kinases.
In some embodiments, the invention provides class compound disclosed in this invention or comprise the pharmaceutical composition of compound disclosed in the present invention, be used for the treatment of, prevent or improve the disease that to be mediated by unsuitable FLT3 kinases behavior or otherwise affect or disorderly or mediated by unsuitable FLT3 kinases behavior or one or more symptoms of the disease that otherwise affects or disorder.
In some embodiments, the invention provides class compound disclosed in this invention or comprise the pharmaceutical composition of compound disclosed in the present invention, be used for the treatment of, prevent or improve the disease that to be mediated by unsuitable Aurora-A kinases behavior or otherwise affect or disorderly or mediated by unsuitable Aurora-A kinases behavior or one or more symptoms of the disease that otherwise affects or disorder.In other embodiments, one or more symptoms of described disease, disorder or disease or disorder are relevant to the behavior of unsuitable Aurora-B kinases.Also in some embodiments, one or more symptoms of described disease, disorder or disease or disorder are relevant to the behavior of unsuitable Aurora C kinases.
" unsuitable jak kinase behavior " refers to the jak kinase behavior occurring in particular patient and depart from normal jak kinase behavior with it.The form of deviation that unsuitable jak kinase behavior can show as such as active abnormal growth or jak kinase time of the act point and control.This unsuitable kinases behavior comes from, such as, and the overexpression of protein kinase or sudden change and the inappropriate or not controlled behavior caused.Therefore, the invention provides these diseases for the treatment of and disorderly method.
Consistent with description above, such disease or disorder include but not limited to: myeloproliferative diseases, such as polycythemia vera (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF), leukemia, such as marrow series leukemia comprises hypotype, the acute megakaryoblastic leukemia (AMKL) of chronic myelogenous leukemia (CML), the CML form of resistance to imatinib, acute myeloid leukemia (AML) and AML, lymphoproliferative disease, such as acute lymphoblastic leukemia (ALL), myelomatosis, cancer comprises incidence cancer, prostate cancer breast cancer, ovarian cancer, melanoma, lung cancer, cerebral tumor, carcinoma of the pancreas and kidney, and with immunologic function disorder, immune deficiency, the diseases associated with inflammation that immunomodulatory is relevant or disorder, autoimmune disorder, tissue transplantation rejection, graft versus host disease (GVH disease), wound healing, ephrosis, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, psoriatic, rhinallergosis, inflammatory bowel comprises Crohn's disease and ulcerative colitis (UC), systemic lupus erythematous (SLE), sacroiliitis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).
On the one hand, the invention provides class compound disclosed in this invention or comprise the pharmaceutical composition of compound disclosed in the present invention, for preventing and/or treating the proliferative disease of Mammals (comprising the mankind), autoimmune disorders, anaphylactic disease, inflammatory diseases or transplant rejection.
On the other hand, the invention provides a kind for the treatment of to suffer from or the risky mammiferous method suffering from disease disclosed herein, described method comprises one or more pharmaceutical composition disclosed herein or compounds of giving effectively to treat illness amount or effectively prevent illness amount.On the other hand, a kind for the treatment of is provided to suffer from herein or the risky mammiferous method suffering from proliferative disease, autoimmune disorders, anaphylactic disease, inflammatory diseases or transplant rejection.
In a kind of method in treatment, the invention provides the mammiferous method treating and/or preventing and easily suffer from or suffer from proliferative disease, described method comprises one or more pharmaceutical composition disclosed herein or compounds of giving effective therapeutic dose or effective preventive dose.In particular instances, proliferative disease is selected from cancer (such as, solid tumor such as leiomyosarcoma of uterus or prostate cancer), polycythemia vera, primary thrombocytosis, myelofibrosis, leukemia (such as, AML, CML, ALL or CLL) and multiple myeloma.
On the other hand, provide a class compound disclosed herein herein, be used for the treatment of and/or prevent proliferative disease.In certain embodiments, proliferative disease is selected from cancer (such as, solid tumor such as leiomyosarcoma of uterus or prostate cancer), polycythemia vera, primary thrombocytosis, myelofibrosis, leukemia (such as, AML, CML, ALL or CLL) and multiple myeloma.
On the other hand, provide a class compound disclosed herein herein, or comprise the pharmaceutical composition of compound of coming into the open herein, for the preparation for the treatment of or the medicine preventing proliferative disease.In particular instances, proliferative disease is selected from cancer (such as, solid tumor, leiomyosarcoma of uterus or prostate cancer), polycythemia vera, primary thrombocytosis, myelofibrosis, leukemia (such as, AML, CML, ALL or CLL) and multiple myeloma.
On the other hand, provide the mammiferous method treating and/or preventing and easily suffer from or suffer from autoimmune disorders herein, described method comprises one or more pharmaceutical composition disclosed herein or compounds of giving effective therapeutic dose or effective preventive dose.In particular instances, autoimmune disorders is selected from COPD, asthma, systemic lupus erythematous, skin lupus erythematosus, systemic lupus erythematosus, dermatomyositis, sjogren syndrome, psoriatic, type i diabetes and inflammatory bowel.
On the other hand, provide a class compound disclosed herein herein, be used for the treatment of and/or prevent autoimmune disorders.In certain embodiments, autoimmune disorders is selected from COPD, asthma, systemic lupus erythematous, skin lupus erythematosus, systemic lupus erythematosus, dermatomyositis, sjogren syndrome, psoriatic, type i diabetes and inflammatory bowel.
On the other hand, provide a class compound disclosed herein herein, or comprise the pharmaceutical composition of compound of coming into the open herein, for the preparation for the treatment of or the medicine preventing autoimmune disorders.In certain embodiments, autoimmune disorders is selected from COPD, asthma, systemic lupus erythematous, skin lupus erythematosus, systemic lupus erythematosus, dermatomyositis, sjogren syndrome, psoriatic, type i diabetes and inflammatory bowel.
On the other hand, provide the mammiferous method treating and/or preventing and easily suffer from or suffer from anaphylactic disease herein, described method comprises one or more pharmaceutical composition disclosed herein or compounds of giving effective therapeutic dose or effective preventive dose.In certain embodiments, anaphylactic disease is selected from respiratory anaphylactic disease, sinusitis paranasal sinusitis, eczema and measles, food anaphylaxis and insect venom allergies.
On the other hand, provide a class compound disclosed herein herein, be used for the treatment of and/or Ammonium Glycyrrhizate disease.In certain embodiments, anaphylactic disease is selected from respiratory anaphylactic disease, sinusitis paranasal sinusitis, eczema and measles, food anaphylaxis and insect venom allergies.
On the other hand, provide a class compound disclosed herein herein, or comprise the pharmaceutical composition of compound of coming into the open herein, for the preparation for the treatment of or the medicine of Ammonium Glycyrrhizate disease.In certain embodiments, anaphylactic disease is selected from respiratory anaphylactic disease, sinusitis paranasal sinusitis, eczema and measles, food anaphylaxis and insect venom allergies.
On the other hand, provide the mammiferous method treating and/or preventing and easily suffer from or suffer from inflammatory diseases herein, described method comprises one or more pharmaceutical composition disclosed herein or compounds of giving effective therapeutic dose or effective preventive dose.In certain embodiments, inflammatory diseases is selected from inflammatory bowel, Crohn's disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.
On the other hand, provide a class compound disclosed herein herein, be used for the treatment of and/or prevent inflammatory diseases.In certain embodiments, inflammatory diseases is selected from inflammatory bowel, Crohn's disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.
On the other hand, provide a class compound disclosed herein herein, or comprise the pharmaceutical composition of compound of coming into the open herein, for the preparation for the treatment of or the medicine preventing inflammatory diseases.In certain embodiments, inflammatory diseases is selected from inflammatory bowel, Crohn's disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.
On the other hand, provide the mammiferous method treating and/or preventing and easily suffer from or suffer from transplant rejection herein, described method comprises one or more pharmaceutical composition disclosed herein or compounds of giving effective therapeutic dose or effective preventive dose.In particular instances, transplant rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, provide a class compound disclosed herein herein, be used for the treatment of and/or prevent transplant rejection.In certain embodiments, transplant rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, provide a class compound disclosed herein herein, or comprise the pharmaceutical composition of compound of coming into the open herein, for the preparation for the treatment of or the medicine preventing transplant rejection.In particular instances, transplant rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, a class is provided to be used as medicine especially as the compound disclosed herein treating and/or preventing disease medicament noted earlier herein.Also use compound manufacture of coming into the open is provided to treat and/or prevent the medicine of disease noted earlier herein.
The present invention that the special projects of present method comprises the study subject significant quantity suffering from inflammation is come into the open compound for some time, and the described time is enough to the level of inflammation reducing study subject, and preferably stops the process of described inflammation.The present invention that the special embodiment of the method comprises the tested patients's significant quantity suffered from or easily suffer from bone rheumatoid arthritis is come into the open compound for some time, the described time is enough to the arthritis reducing or prevent described patient respectively, and preferably stops the process of described inflammation.
The present invention that another special projects of present method comprises the study subject significant quantity suffering from proliferative disease is come into the open compound for some time, the described time is enough to the hyperplasia level reducing study subject, and preferably stops the process of described proliferative disease.The special embodiment of the method comprises coming into the open compound for some time of the tested patients's significant quantity suffering from cancer herein, and the described time is enough to the cancer symptom reducing or prevent described patient respectively, and preferably stops the process of described cancer.
Combination therapy
The compounds of this invention can as independent active agent administration, or can with other therapeutic agent administration, comprise and there is same or similar therapeutic activity and other compound safe and efficient is defined as this type of Combined Preparation.
On the one hand, the invention provides treatment, prevent or improve the method for disease or illness, comprise the present invention that comprises giving safe and effective amount and to come into the open the combination medicine of compound and one or more therapeutic activity agent.In some embodiments, combination medicine comprises one or both other treatment agent.
The example of other therapeutical agent comprises and including but not limited to: carcinostatic agent, comprises chemotherapeutics and antiproliferative; Anti-inflammatory agent; With immunity regulatin remedy agent or immunosuppressor.
On the other hand, the invention provides the product comprising the compounds of this invention and other therapeutical agent of at least one, the combination that can be prepared in the treatment simultaneously, use respectively or sequentially.In some embodiments, treatment is for by one or more protein kinases, as the disease of jak kinase, FLT3 kinases or Aurora A activity mediation or the treatment of symptom.The product that combining preparation provides comprises the composition being present in same pharmaceutical composition and comprising come into the open compound and other treatment agent herein, or come into the open herein compound and the other treatment agent that exist in different forms, such as, and medicine box.
On the other hand, the invention provides a kind of pharmaceutical composition comprising come into the open compound and another or multiple therapeutical agent herein.In some embodiments, pharmaceutical composition can comprise pharmaceutically acceptable vehicle as above, carrier, adjuvant or solvent.
On the other hand, the invention provides the medicine box of the drug alone composition comprising two kinds or more, wherein at least one pharmaceutical composition comprises the present invention and to come into the open compound.In some embodiments, medicine box comprises the instrument keeping separately described composition, such as container, the bottle separated or the paper tinsel box separated.The example of this kind of medicine box is Blister Package, and it is generally used for package troche, capsule etc.
Present invention also offers the purposes of the compounds of this invention in the disease or symptom of the mediation for the treatment of protein kinase activity, wherein patient's previous (such as in 24 hours) treats with other treatment agent.Present invention also offers other treatment agent at treatment protein kinase, as the purposes in the disease of jak kinase, FLT3 kinases and Aurora A activity mediation and symptom, wherein patient previously (such as in 24 hours) treat with the compounds of this invention.
Compound of coming into the open herein as single-activity component applied or as such as adjuvant, can be used with other medicines jointly.Described other medicines comprise, immunosuppressor, immunomodulator, other anti-inflammatory agent, such as, be used for the treatment of or prevent the medicine of allogeneic or xenograft acute or chronic rejection, inflammatory, autoimmune disorder; Or chemotherapeutics, such as malignant cell antiproliferative.Such as, the present invention's compound of coming into the open can be combined with following active ingredient: calcineurin inhibitor, such as cyclosporin A or FK506; MTOR inhibitors, such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9; There is the ascosin of immunosuppressive properties, such as ABT-281, ASM981 etc.; Reflunomide; Endoxan; Imuran; Methotrexate; Leflunomide; Mizoribine; Mycophenolic Acid or salt; Mycophenolate mofetil; 15-Gusperimus or its immunosuppression homologue, analogue or derivative; Pkc inhibitor, such as, described in WO 02/38561 or WO 03/82859, the such as compound of embodiment 56 or 70; Immunosuppression monoclonal antibody, the monoclonal antibody of such as leukocyte receptors, such as, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or its part; Other immunomodulatory compounds, such as there is restructuring binding molecule or its mutant of at least part of extracellular domain of CTLA4, the outer part of at least born of the same parents of the CTLA4 be such as connected with non-CTLA4 protein sequence or its mutant, such as CTLA4Ig (such as called after ATCC 68629) or its mutant, such as LEA29Y; Adhesion molecule inhibitor, such as LFA-1 antagonist, ICAM-1 or-3 antagonist, VCAM-4 antagonist or VLA-4 antagonist; Or chemotherapeutics, such as taxol, gemcitabine, cis-platinum, Dx or 5 FU 5 fluorouracil; Or anti-infection agent.
When the present invention come into the open compound and other immunotherapeutic agent/immunomodulator, anti-inflammatory agent, chemotherapy or anti-infective therapy's Combined Preparation, the dosage of the immunosuppressor of Combined Preparation, immunomodulator, anti-inflammatory agent, chemotherapeutic or anti-infective compounds certainly can according to the type of combination medicine used, such as whether it is steroidal or calcineurin inhibitors, concrete medicine used, illness to be treated etc. and changing.
On the one hand, the invention provides one to comprise the present invention and to come into the open compound and β 2the associating of-adrenoceptor agonists.β 2the example of-adrenoceptor agonists comprises Salmeterol, salbutamol, formoterol, Salmefamol, Partusisten, Ka Moteluo, Yi Tanteluo, naminterol, clenbuterol, pirbuterol, flerobuterol, reproterol, promulgation special sieve, QAB-149, terbutaline, and their salt, the xinafoate (1-hydroxy-2-naphthoic acid salt) of such as Salmeterol, the vitriol of salbutamol or the fumarate of free alkali or formoterol.In some embodiments, long-acting beta 2-adrenoceptor agonists, such as providing effective bronchiectasis to reach 12 hours or compound for more time, is preferred.
β 2-adrenoceptor agonists can form the form of salt with pharmaceutically acceptable acid.Described pharmaceutically acceptable acid is selected from sulfuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (as 1-or 3-hydroxy-2-naphthoic acid), styracin, the styracin of replacement, triphenylacetic acid, thionamic acid, Sulphanilic Acid, 3-(1-naphthyl) vinylformic acid, phenylformic acid, 4-methoxybenzoic acid, 2-or 4-HBA, 4-chloro-benzoic acid and 4-Phenylbenzoic acid.
On the other hand, the invention provides a kind of the present invention of comprising to come into the open the associating of compound and reflunomide.Suitable reflunomide refers to those reflunomides that is oral and that suck, and has the prodrug of anti-inflammatory activity.Example comprises methylprednisolone, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-17-alpha-[(4-methyl isophthalic acid, 3-thiazole-5-carbonyl) oxygen base]-3-oxo-androst-1, 4-diene-17 β-thiocarboxylic acid S-fluorine methyl esters, 6 α, fluoro-17 α of 9 α-two-[(2-furanylcarbonyl) oxygen base]-11 beta-hydroxy-16 Alpha-Methyl-3-oxo-androst-1, 4-diene-17 β-thiocarboxylic acid S-fluorine methyl esters (fluticasone furoate), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-3-oxo-17 α-propionyloxy-androsta-1, 4-diene-17 β-thiocarboxylic acid S-(2-oXo-tetrahydro furans-3S-base) ester, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-3-oxo-17 α-(2, 2, 3, 3-tetramethyl-cyclopropyl carbonyl) oxygen base-androstane-1, 4-diene-17 β-thiocarboxylic acid S-cyano methyl ester and 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-17-alpha-(1-ethyl cyclopropyl carbonyl) oxygen base-3-oxo-androst-1, 4-diene-17 β-thiocarboxylic acid S-methyl fluoride ester, beclomethasone ester is (as 17-propionic ester or 17, 21-dipropionic acid fat), budesonide (budesonide), flunisolide (flunisolide), Mometasone ester (as furoic acid momisone), Triamcinolone Acetonide (triamcinolone acetonide), sieve fluoronaphthalene moral (rofleponide), ciclesonide (ciclesonide) (16 α, 17-[[(R)-cyclohexylmethylene] two (oxygen base)]-11 β, 21-dihydroxyl-pregnant steroid-1, 4-diene-3, 20-diketone), butixocort propionate (butixocort propionate), RPR-106541 and ST-126.Preferred reflunomide comprises fluticasone propionate (fluticasone propionate), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-17-alpha-[(4-methyl isophthalic acid, 3-thiazole-5-carbonyl) oxygen base]-3-oxo-androst-1, 4-diene-17 β-thiocarboxylic acid S-methyl fluoride ester, 6 α, fluoro-17 α of 9 α-two-[(2-furanylcarbonyl) oxygen base]-11 beta-hydroxy-16 Alpha-Methyl-3-oxo-androst-1, 4-diene-17 β-thiocarboxylic acid S-methyl fluoride ester, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-3-oxo-17 α-(2, 2, 3, 3-tetramethyl-cyclopropyl carbonyl) oxygen base-androstane-1, 4-diene-17 β-thiocarboxylic acid S-cyano methyl ester and 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-17-alpha-(1-methylcyclopropyl groups carbonyl) oxygen base-3-oxo-androst-1, 4-diene-17 β-thiocarboxylic acid S-fluorine methyl esters.In some embodiments, reflunomide is 6 α, fluoro-17 α of 9 α-two-[(2-furanylcarbonyl) oxygen base]-11 beta-hydroxy-16 Alpha-Methyl-3-oxo-androst-Isosorbide-5-Nitrae-diene-17 β-thiocarboxylic acid S-methyl fluoride ester.
On the other hand, the invention provides a kind of the present invention of comprising to come into the open the associating of compound and nonsteroidal GR agonist.To Transcription inhibition, there is selectivity (compared with transcriptional activation), the nonsteroidal compound with glucocorticosteroid agonist activity that can be used for combination therapy comprises those and covered in compound in following patent: WO 03/082827, WO 98/54159, WO 04/005229, WO 04/009017, WO 04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO 03/059899, WO 03/101932, WO 02/02565, WO01/16128, WO 00/66590, WO 03/086294, WO 04/026248, WO 03/061651 and WO 03/08277.More nonsteroidal compound is contained in WO 2006/000401, WO 2006/000398 and WO 2006/015870.
On the other hand, the invention provides one to comprise the present invention and to come into the open the associating of compound and nonsteroidal anti-inflammatory drug (NSAID's).The example of NSAID's comprises Sodium Cromoglicate, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor is (as theophylline, PDE4 inhibitor, or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene synthesis inhibitors (as Singulair), iNOS inhibitor, trypsinase and elastase inhibitor, Beta 2 integrin antagonist and adenosine receptor agonist or antagonist (as, adenosine 2a receptor stimulant), cytokine antagonist is (as chemokine receptor anagonists, comprise CCR3 antagonist), cytokine synthesis inhibitor, or 5-LO inhibitor.Wherein, iNOS (iNOS) inhibitor preferred oral administration.The example of iNOS inhibitor comprises those compounds disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875.CCR3 inhibitor comprises those compounds disclosed in WO 02/26722.
In some embodiments, the present invention relates to the present invention come into the open compound with the application in the combining of phosphodiesterase 4 (PDE4) inhibitor, the application especially in inhalant dosage form.PDE4 specific inhibitor for this aspect of the present invention can be known suppression PDE4 enzyme or any compound being found to be used as PDE4 inhibitor, they are only PDE4 inhibitor, not suppress other members in PDE family, as the compound of PDE3 and PDE5.Compound comprises cis-4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl) hexanaphthene-1-carboxylic acid, 2-methoxycarbonyl-4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) hexanaphthene-1-ketone and cis-[4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) hexanaphthene-1-alcohol]; Also cis-4-cyano group-4-[3-(ring propoxy-)-4-p-methoxy-phenyl] hexanaphthene-1-carboxylic acid (also claiming Xi Luosi) and salt thereof is comprised, ester, prodrug or physical form, it was 1996 09 month No. 03 US Patent No. of authorizing 5,552, open in 438, this section of patent and compound disclosed in it are incorporated herein by reference in their entirety.
On the other hand, the invention provides a kind of the present invention of comprising to come into the open the associating of compound and anticholinergic.The example of anticholinergic is that those are used as the compound of muscarinic receptor antagonist, and particularly those are as M1 or M3 receptor antagonist, M 1/ M 3or M 2/ M 3receptor dual antagonist or M 1/ M 2/ M 3the compound of the general antagonist of acceptor.The example compound of inhalation comprise Rinovagos (such as, as bromide, CAS 22254-24-6, with ( ) sell for trade(brand)name), oxygen holder ammonium (such as, as bromide, CAS 30286-75-0) and tiotropium (such as, as bromide, CAS 136310-93-5, with ( ) sell for trade(brand)name); Interested equally also have Revatropate (such as, as hydrobromate, CAS 262586-79-8) and LAS-34273 disclosed in WO01/04118.The example compound of oral administration comprises pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or its hydrobromate CAS 133099-07-7, with for trade(brand)name is sold), Oxybutynin (CAS 5633-20-5, with ( ) sell for trade(brand)name), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or its tartrate CAS124937-52-6, with ( ) sell for trade(brand)name), difficult to understand for ammonium (such as, as bromide, CAS 26095-59-0, with for trade(brand)name is sold), trospium chloride (CAS 10405-02-4) and Solifenacin (CAS 242478-37-1, or its succinate CAS 242478-38-2, i.e. compound YM-905, with ( ) sell for trade(brand)name).
On the other hand, the invention provides a kind of the present invention of comprising to come into the open the associating of compound and H1 antagonist.The example of H1 antagonist includes, but not limited to amlexanox (amelexanox), this imidazoles of west (astemizole), azatadine (azatadine), azelastine (azelastine), acrivastine (acrivastine), Parabromdylamine (brompheniramine), cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine), Cholrtrimeton (chlorpheniramine), clemastine (clemastine), marezine (cyclizine), carebastine (carebastine), Cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), diformazan indenes (dimethindene), ebastine (ebastine), epinastine (epinastine), Efletirizine (efletirizine), fexofenadine (fexofenadine), hydroxyzine (hydroxyzine), ketotifen (ketotifen), Loratadine (loratadine), levocabastine (levocabastine), mizolastine (mizolastine), mequitazine (mequitazine), mianserin (mianserin), Nuo Baisiting (noberastine), meclizine (meclizine), Tecastemizole (norastemizole), Olopatatadine (olopatadine), piperacetazine (picumast), than Lamine (pyrilamine), promethazine (promethazine), terfenadine (terfenadine), tripelennamine (tripelennamine), temelastine (temelastine), nedeltran (trimeprazine) and triprolidine (triprolidine), preferred cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine) and fexofenadine (fexofenadine).In other embodiments, the invention provides one to comprise the present invention and to come into the open the associating of compound and H3 antagonist (and/or inverse agonist).The example of H3 antagonist comprises those compounds disclosed in WO 2004/035556 and WO 2006/045416.Other histamine receptor antagonists that the compound that can be used for coming into the open with the present invention is combined comprise H4 receptor antagonist (and/or inverse agonist), such as compound disclosed in Jablonowski et al., J.Med.Chem.46:3957-3960 (2003).
Another aspect, the invention provides one and comprises the present invention and to come into the open compound, with PDE4 inhibitor and β 2the associating of-adrenoceptor agonists.
Also on the one hand, the invention provides one and comprise the present invention and to come into the open compound, with combining of anticholinergic and PDE-4 inhibitor.
Above-described associating can be prepared into pharmaceutical composition to use easily, and therefore, the pharmaceutical composition comprising combination defined above and pharmaceutically acceptable vehicle or carrier represents another aspect of the present invention.
Each compound of these associatings can with alone or in combination pharmaceutical dosage forms order of administration or administration simultaneously.In one embodiment, each compound component is the pharmaceutical dosage forms administration simultaneously of combining.The applicable dosage of known treatment agent is easy to as those skilled in the art is understood.
Therefore, on the other hand, the invention provides a kind of pharmaceutical composition, comprise combining of compound disclosed by the invention and other treatment promoting agent.
In some embodiments, pharmaceutical composition provided by the invention comprises the present invention and comes into the open combining of compound and phosphodiesterase 4 (PDE4) inhibitor.
In other embodiments, pharmaceutical composition provided by the invention comprises the present invention and comes into the open combining of compound and beta-2-adrenoreceptor agonists.
In other embodiments, pharmaceutical composition provided by the invention comprises the present invention and comes into the open combining of compound and reflunomide.
In other embodiments, pharmaceutical composition provided by the invention comprises the present invention and comes into the open combining of compound and nonsteroidal GR agonist.
In other embodiments, pharmaceutical composition provided by the invention comprises the present invention and comes into the open combining of compound and anticholinergic.
In other embodiment, pharmaceutical composition provided by the invention comprises the present invention and comes into the open combining of compound and antihistaminic.
In medical oncology field, the Therapeutic cancer patient that combines using different form of therapy is conventional means.In medical oncology, one or more other co-therapy forms joining the present composition can be, such as, and operation, radiotherapy, chemotherapy, single transduction inhibitor or conditioning agent (such as, kinase inhibitor or conditioning agent) and/or monoclonal antibody.
The present invention's compound of coming into the open also can be advantageously utilised in the combination with other compounds, or with other treatment agent, in the combination of especially antiproliferative.Such antiproliferative includes, but not limited to aromatase inhibitor; Estrogen antagonist; Topoisomerase I inhibitor; Topoisomerase II inhibitors; Microtubule active agent; Alkylating agent; NSC 630176; The compound of Cell differentiation inducing activity process; Cyclooxygenase-2 inhibitors; MMP inhibitor; MTOR inhibitors; Antitumor antimetabolite; Platinic compound; Target/reduction albumen or the compound of lipid kinase activity and the compound of other angiogenesis inhibitor; The compound of target, reduction or arrestin or lipid phosphate esterase active; Gonadorelin excitomotor; Androgen antagonist; Methionine aminopeptidase inhibitor; Diphosphonate; Biological response modifier; Antiproliferation antibodies; Heparanase inhibitors; The carcinogenic hypotype inhibitor of Ras; Telomerase inhibitor; Proteasome inhibitor; The medicament for the treatment of neoplastic hematologic disorder; Target, reduction or suppress the compound of Flt-3 activity; Hsp90 inhibitor; Temozolomide ( ); And Calciumlevofolinate.
Term used herein " aromatase inhibitor ", refers to the compound suppressing oestrogenic hormon to produce, and namely suppresses substrates androstenedione and testosterone to change into the compound of oestrone and estradiol respectively.This term includes, but are not limited to: steroide, especially Atamestane (atamestane), Exemestane (exemestane) and formestane (formestane); And, particularly non-steroids, especially aminoglutethimide (aminoglutethimide), Rogletimide (roglethimide), Racemic pyridoglutethimide (pyridoglutethimide), Win-24540 (trilostane), testolactone (testolactone), KETOKONAZOL (ketoconazole), fluorine chlorazol (vorozole), fadrozole (fadrozole), Anastrozole (anastrozole) and letrozole (letrozole).Exemestane can with commercially available, as trade mark is ( ) form administration.Formestane (formestane) can with commercially available, as trade mark is ( ) form administration.Fadrozole (fadrozole) can with commercially available, as trade mark is form administration.Anastrozole (anastrozole) can with commercially available, as trade mark is ( ) form administration.Letrozole (letrozole) can with commercially available, as trade mark is ( ) or form administration.Aminoglutethimide (aminoglutethimide) can with commercially available, as trade mark is ( ) form administration.The combination that the present invention includes aromatase inhibitor chemotherapeutic is used in particular for treating the tumour that hormone receptor is positive, as breast tumor.
Term used herein " estrogen antagonist ", refers to the compound in Estrogen Receptor antagonising oestrogen effectiveness.This term comprises, but be not limited to, tamoxifen (tamoxifen), fulvestrant (fulvestrant), raloxifene (raloxifene) and raloxifene hydrochloride (raloxifenehydrochloride).Tamoxifen (tamoxifen) can with commercially available, as trade mark is ( ) form administration.Raloxifene hydrochloride (raloxifene hydrochloride) can with commercially available, as trade mark is ( ) form administration.Fulvestrant (fulvestrant) can with US Patent No. 4, and 659, formulation disclosed in 516, or commercially available, as trade mark is form administration.The combination that the present invention includes estrogen antagonist chemotherapeutic is used in particular for treating the tumour that estrogen receptor is positive, as breast tumor.
Term used herein " androgen antagonist " refers to any material that can suppress male hormone biological action, and it includes, but not limited to bicalutamide (bicalutamide, trade(brand)name ), its formulation can according to US Patent No. 4, and 636,505 prepare.
Term used herein " gonadorelin excitomotor " includes, but not limited to abarelix (abarelix), goserelin (goserelin) and goserelin acetate.Goserelin in US Patent No. 4,100, be disclosed in 274, can with commercially available, as trade mark is ( ) form administration.Abarelix (abarelix) can according to US Patent No. 5, and 843, disclosed in 901, method prepares formulation.
Term used herein " topoisomerase I inhibitor ", include, but are not limited to topotecan (topotecan), gefitinib (gimatecan), irinotecan (irinotecan), camptothecine (camptothecian) and analogue thereof, 9-nitrocamptothecin (9-nitrocamptothecin) and macromolecular camptothecin conjugated compound PNU-166148 (compd A 1 in WO 99/17804).Irinotecan can with commercially available, as trade mark is ( ) form administration.Topotecan can with commercially available, as trade mark is ( ) form administration.
Term used herein " Topoisomerase II inhibitors " includes, but are not limited to anthracycline compound, and as Dx (doxorubicin), its Lipidosome, commodity are called ( ); Daunomycin (daunorubicin); Epirubicin (epirubicin); Idarubicin (idarubicin); The not soft pyrrole star (nemorubicin) of naphthalene; Anthraquinones mitoxantrone (mitoxantrone) and losoxantrone (losoxantrone); Podophillotoxines etoposide (etoposide) and teniposide (teniposide).Etoposide can with commercially available, as trade mark is ( ) form administration.Teniposide can with commercially available, if trade mark is VM form administration.Dx can with commercially available, as trade mark is ( ) or ( ) form administration.Epirubicin can with commercially available, as trade mark is ( ) form administration.Idarubicin can with commercially available, as trade mark is ( ) form administration.Mitoxantrone can with commercially available, as trade mark is ( ) form administration.
Term " microtubule active agent " refers to microtubule stabilizer, microwave destabiliser and microtubule polymerization inhibitor.It includes, but are not limited to taxanes, as taxol (paclitaxel) and Docetaxel (docetaxel); Vinca alkaloids, as vinealeucoblastine(VLB) (vinblastine), especially Vinblastine sulphate, vincristine(VCR), especially vincristine sulphate and vinorelbine (vinorelbine); Discodermolides; Colchicine; And ebormycine and its derivative, as epothilone B or D or derivatives thereof.Taxol can with commercially available, as trade mark is ( ) form administration.Docetaxel can with commercially available, as trade mark is ( ) form administration.Vinblastine sulphate can with commercially available, as trade mark is form administration.Vincristine sulphate can with commercially available, as trade mark is form administration.Discodermolide can according to US Patent No. 5, and 010, disclosed in 099, method obtains.Also be included in ebormycine analog derivative disclosed in WO 98/10121, United States Patent (USP) 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247, especially preferably ebomycin A and/or B.
Term used herein " alkylating agent " comprises, but be not limited to, endoxan (cyclophosphamide), ifosfamide (ifosfamide), melphalan (melphalan) or Nitrosourea (nitrosourea, as BCNU or carmustine).Endoxan can with commercially available, if trade mark is cancer ( ) form administration.Ifosfamide can with commercially available, as trade mark is ( ) form administration.
Term " NSC 630176 " or " hdac inhibitor " refer to inhibition of histone deacetylase, and have the compound of antiproliferative activity.It is included in compound disclosed in WO 02/22577, especially N-hydroxyl-3-[4-[[(2-hydroxyethyl) [2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylamide, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-base)-ethyl]-amino] methyl] phenyl]-2E-2-acrylamide and pharmacy acceptable salt thereof.Especially Vorinostat (SAHA) is comprised.
Term " antineoplastic antimetabolite " includes, but not limited to 5-fluor-uracil (5-fluorouracil) or 5-FU; Capecitabine (capecitabine); Gemcitabine (gemcitabine); DNA demethylation reagent, as U-18496 (5-azacytidine) and Decitabine (decitabine); Methotrexate (methotrexate) and edatrexate (edatrexate); And antifol, as pemetrexed (pemetrexed).Capecitabine can with commercially available, as trade mark is ( ) form administration.Gemcitabine can with commercially available, as trade mark is ( ) form administration.This term also comprises monoclonal antibody Herceptin (trastuzumab), can with commercially available, as trade mark is ( ) form administration.
Term used herein " platinic compound " includes, but are not limited to carboplatin (carboplatin), cDDP (cis-platin), cis-platinum (cisplatinum) and oxaliplatin (oxaliplatin).Carboplatin can with commercially available, as trade mark is form administration.Oxaliplatin can with commercially available, as trade mark is ( ) form administration.
Term used herein " compound of target/reduction albumen or lipid kinase activity or albumen or lipid phosphatase activity; or the compound of other angiogenesis inhibitor " comprise, but be not limited to, protein tyrosine kinase and/or Serine and/or Threonine inhibitor, or lipid kinase inhibitors, such as
A) target, the compound reducing or suppress platelet derived growth factor receptor (PDGFR) active; Target, reduction or suppress the compound of PDGFR activity, especially suppress the compound of pdgf receptor to comprise N-phenyl-2-pyrimidine-amine derivatives, as imatinib (imatinib), and SU101, SU6668, GFB-111 etc.;
B) target, reduce or be suppressed to the active compound of bfgf receptor (FGFR);
C) compound that target, reduction or suppression IGF-1-1 (IGF-1R) are active; Target, reduction or suppress the compound of IGF-1R activity, especially suppress the compound of IGF-1 receptor active to comprise those compounds disclosed in patent WO 02/092599;
D) target, reduction or suppress the compound of Trk receptor tyrosine kinase family active;
E) target, reduction or suppress the compound of Axl family active;
F) target, reduction or suppress the compound of c-Met receptor active;
G) target, reduction or suppress the compound of Kit/SCFR receptor tyrosine kinase activity;
H) compound that target, reduction or suppression C-kit receptor tyrosine kinase (part in PDGFR family) are active; Target, reduction or suppress the compound of C-kit receptor tyrosine kinase family active, especially suppress the compound of c-Kit acceptor, comprise imatinib (imatinib) etc.;
I) target, reduction or suppression c-Abl family and their gene fusion product, as the compound of BCR-Abl kinase activity; Target, reduction or suppress the compound of c-Abl family member and their gene fusion things to comprise N-phenyl-2-pyrimidine-amine derivatives, as imatinib, PD180970, AG957, NSC 680410, PD173955 from ParkeDavis
J) Raf family member in target, reduction or arrestin 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 member, and/or the compound of cell cycle protein dependent kinase family (CDK) member activity; Particularly those are in US Patent No. 5, and 093, staurosporine derivatives disclosed in 330, as midostaurin (midostaurin); More examples of compounds also comprises, UCN-01; Safingol (safingol); BAY 43-9006; Bryostatin 1; Piperazine Li Fuxin (Perifosine); Thio ALP (llmofosine); RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; Isoquinoline compound, those as being disclosed in WO 00/09495; FTIs; PD184352; Or QAN697 (a kind of P13K inhibitor);
K) compound of target, reduction or arrestin tyrosine kinase inhibitor activity, the compound of target, reduction or arrestin tyrosine kinase inhibitor activity comprise Gleevec ( ) or tyrphostin, the preferred lower molecular weight of tyrphostin (Mr<1500) compound, or its pharmacy acceptable salt, especially the compound of this third two eyeball class of benzyl allyl two eyeball class or S-aryl or Double bottom thing quinoline is selected from, further be selected from tyrphostin A23/RG-50810, AG 99, tyrphostin AG 213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44 (+) enantiomorph, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG957 and adaphostin (4-{ [(2, 5-dihydroxy phenyl) methyl] amino-phenylformic acid diamantane ester, NSC 680410, adaphostin), with
I) target, reduction or the compound that suppresses receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, ErbB3, ErbB4 all or heterodimer) active, target, reducing or suppressing the compound of Epidermal Growth Factor Receptor Family to refer in particular to suppress EGF receptor family member (as EGF acceptor, ErbB2, ErbB3, ErbB4, or the material that can be combined with EGF or EGF associated ligands) compound, albumen or antibody, particularly summarized or concrete disclosed compound in the following documents, albumen or monoclonal antibody: WO 97/02266 (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 (as CP358774), WO 96/33980 (as compound ZD 1839), WO 95/03283 (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 the 7H-pyrrolo-be disclosed in WO 03/013541-[2,3-d] pyrimidine derivatives.
In addition, anti-angiogenic compounds comprises the compound with other active mechanisms (such as, suppressing uncorrelated with albumen or lipid kinase), such as Thalidomide ( ) and TNP-470.
The compound of target, reduction or arrestin or lipid kinase activity is Phosphoric acid esterase-1 inhibitor, Phosphoric acid esterase 2A inhibitor, 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-tocotrienols.
Term used herein " cyclooxygenase-2 inhibitors " includes, but not limited to Cox-2 inhibitor, the 2-virtue aminophenyl acetic acid and its derivative that 5-alkyl replaces, as celecoxib ( ), rofecoxib ( ), L-791456, valdecoxib, or 5-alkyl-2-virtue aminophenyl acetic acid, as 5-methyl-2-(the chloro-6'-fluoroanilino of 2'-) phenylacetic acid or Lu meter Kao former times
Term used herein " diphosphonate " includes, but not limited to etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, clinic effect of alendronate, Ibandronic acid, risedronic acid and Zoledronic acid.Etidronic acid can with commercially available, as commodity are called ( ) form administration.Clodronic acid can with commercially available, as commodity are called ( ) form administration.Tiludronic acid can with commercially available, as commodity are called form administration; Pamidronic acid (Pamidronic acid) can with commercially available, as commodity are called Aredia tM(AREDIA tM) form administration; Clinic effect of alendronate can with commercially available, as commodity are called ( ) form administration; Ibandronic acid can with commercially available, as commodity are called ( ) form administration; Risedronic acid can with commercially available, as commodity are called ( ) form administration; Zoledronic acid can with commercially available, as commodity are called ( ) form administration.
Term " mTOR inhibitors " refers to and suppresses Mammals rapamycin (mTOR) target protein, has the compound of antiproliferative activity, such as sirolimus (sirolimus, ), everolimus (CERTICAN tM), CCI-779 and ABT578.
Term used herein " heparanase inhibitors " refers to, target, reduction or suppress the compound of acetylsulfuric acid depolymerized heparin.This term comprises, but does not limit PI-88.
Term used herein " biological response modifier " refers to lymphokine or Interferon, rabbit, such as interferon-gamma.
Term used herein " the carcinogenic hypotype of Ras (as H-Ras, K-Ras or N-Ras) inhibitor " refers to target, reduction or suppresses the compound of Ras carcinogenic activity, such as " farnesyl transferase inhibitor ", as L-744832, DK8G557 or R115777 (Zarnestra).
Term used herein " telomerase inhibitor " refers to target, reduction or suppresses the compound of telomerase activation.Target, reduction or suppress the compound of telomerase activation to refer in particular to the compound suppressing telornerase receptor, such as telomere mycin.
Term used herein " methionine aminopeptidase inhibitor " refers to target, reduction or suppresses the compound of methionine aminopeptidase activity.Target, reduction or suppress the compound of methionine aminopeptidase activity to comprise bengamide or derivatives thereof.
Term used herein " proteasome inhibitor " refers to the compound of target, reduction or proteasome enzyme inhibition activity.The compound of target, reduction or proteasome enzyme inhibition activity comprises PS-341 and MLN 341.
Term used herein " matrix metallo-proteinase inhibitor " or " MMP inhibitor " comprise, but be not limited to, collagen peptide class and non-peptide inhibitor, tetracycline derivant, as hydroxamic acid peptide inhibitor Batimastat (batimastat) and its oral bio equivalence homologue Marimastat (marimastat, BB-2516), Pu Masita (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.
The term used herein reagent of neoplastic hematologic disorder " be used for treat " includes, but not limited to FMS-sample tyrosine kinase inhibitor.Target, reduction or the compound suppressing FMS-sample tyrosine kinase receptor (Flt-3R) active; Interferon, rabbit, 1-b-D-arabinofuranosyl adenin cytosine(Cyt) (ara-c) and bisulfan; With ALK inhibitor, as target, reduction or the compound suppressing Nucleophosmin-anaplastic lymphoma kinase.
Target, reduction or suppress the compound of FMS-sample tyrosine kinase receptor (Flt-3R) especially to suppress the compound of Flt-3 receptor kinase family member, albumen or antibody, such as PKC412, midostaurin (midostaurin), staurosporine derivatives, SU11248 and MLN518.
Term used herein " HSP90 inhibitor " includes, but are not limited to target, reduction or suppresses the compound of Endogenous ATP enzymic activity of HSP90; By the degraded of ubiquitin protein body enzymatic pathway, target, reduction or the compound suppressing HSP90 client protein.Target, reduction or suppress the compound of Endogenous ATP enzymic activity of HSP90 to refer in particular to the compound of the Endogenous ATP enzymic activity suppressing HSP90, albumen or antibody, such as, 17-allyl amino, 17-AAG (17AAG), the compound that other geldanamycin are relevant, red shell rhzomorph and hdac inhibitor.
Term used herein " antiproliferation antibodies " includes, but not limited to Herceptin (HERCEPTIN tM), Herceptin-DM1, Tarceva (TARCEVA tM), rhuMAb-VEGF (AVASTIN tM), Rituximab ( ), PR064553 (anti-CD40) and 2C4 antibody.Antibody means complete monoclonal antibody, polyclonal antibody, the multi-specificity antibody formed by least 2 complete antibody and antibody fragment (as long as they have the biological activity of expectation).For the treatment of acute myeloid leukemia (AML), the leukemia therapy conbined usage of compound and the standard of the present invention can being come into the open, especially with the therapy conbined usage for the treatment of for AML.Specifically, the present invention can be come into the open compound and such as farnesyl tranfering enzyme inhibitor and/or other is used for medicine that AML treats as daunorubicin, Zorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC412 Combined Preparation.
Compound disclosed by the invention also can be advantageously utilised in the combination of other compounds or with the combination of other treatment agent, especially other anti-malarial agents.Such anti-malarial agents includes, but are not limited to chloroguanide (proguanil), M-5943 (chlorproguanil), trimethoprim (trimethoprim), chloroquine (chloroquine), Mefloquine hydrochloride (mefloquine), benzfluorenol (lumefantrine), atovaquone (atovaquone), Pyrimethamine hcl-sulfanilamide (SN) (pyrimethamine-sulfadoxine), Pyrimethamine hcl-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), Quinidine (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfa drugs, Artemisinin, arteflene (arteflene), Artemether, Artesunate, primaquine, suck NO, L-arginine, dipropylenetriamine NONO ester (NO donor), rosiglitazone (PPARy agonist), gac, erythropoietin, LEVAMISOLE HCL, and Malaridine.
Compound disclosed by the invention also can be advantageously used in the combination with the combination of other compounds or other treatment agent, such as, treat the other treatment agent of leishmaniasis, trypanosomiasis, toxoplasmosis and cerebral cysticercosis.Such medicament includes, but are not limited to nivaquin, atovaquone-proguanil, Artemether-lumenfantrine, Quinine Sulphate Di HC, Artesunate, quinine, doxycycline (doxycycline), clindamycin (clindamycin), meglumine antimony (meglumine antimoniate), sodium stibogluconate (sodium stibogluconate), miltefosine (miltefosine), KETOKONAZOL (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposome, paromycin (paromomycine), eflornithine (eflornithine), nifurtimox (nifurtimox), Suramine (suramin), melarsoprol (melarsoprol), prednisolone (prednisolone), benzoglyoxaline, Sulphadiazine Sodium, Pyrimethamine hcl, synergistic sulfonamide methylisoxazole, sulfamethoxazole, Azythromycin (azitromycin), atovaquone, dexamethasone, praziquantel, albendazole (albendazole), beta-lactam, fluoroquinolones medicine, macrolides medicine, aminoglycoside medicine, Sulphadiazine Sodium and Pyrimethamine hcl.
By the structure of the determined activeconstituents of code name, popular name or trade(brand)name and preparation thereof can from the current edition of classic " The Merck Index (the Merck index) " (people such as such as M.J.O ' Neil compiles. ' The MerckIndex ', 13rd edition, Merck ResearchLaboratories, 2001) or know from database (such as Patents International (such as IMS World Publications)).
Above-described, can to come into the open the compound that compound combinationally uses with the present invention, can by those skilled in the art, according to the method preparation described in above-mentioned document and administration.
Compound disclosed by the invention can also be combined with therapeutic process, improves curative effect.Such as, hormonotherapy or special radiotherapy is given.Compound disclosed by the invention is especially used as radiosensitizer, is used in particular for those radiotherapeutic response weak ground oncotherapies.
" associating " represents the medicine box of the fixing joint in single dosage unit form or the part for Combined Preparation, wherein compound disclosed by the invention and associating companion can individual application or can use respectively in certain time interval at one time, particularly make associating companion show cooperation, such as act synergistically." co-administered " or " Combined Preparation " etc. are intended to include the single individuality (such as patient) selected associating companion being applied to and needing it as the term is employed herein, and be intended to comprise wherein material need not by the treatment plan of identical route of administration or administration simultaneously." medication combined " represents the mixing of more than one activeconstituentss or combines the product obtained as the term is employed herein, and the fixing joint both having comprised activeconstituents also comprises on-fixed associating.Term " fixing joint " represents that activeconstituents is as compound disclosed by the invention, and associating companion is applied to patient with the form of single entities or dosage simultaneously.Term " on-fixed associating " represents that activeconstituents is as compound disclosed by the invention, all limit ground successively to patient's administration as separate entity with associating companion, wherein this administering mode provides the treatment level of significance of two kinds of compounds in patient body simultaneously, jointly or without specified time.The latter is also applicable to drug cocktail therapy (treatment), such as, use three kinds or more kind activeconstituents.
Methods for the treatment of
In some embodiments, methods for the treatment of disclosed by the invention comprises and gives the compounds of this invention of safe and effective amount to patient in need or comprise the pharmaceutical composition of the compounds of this invention.Each embodiment disclosed by the invention the present invention comprised by giving safe and effective amount to patient in need is come into the open compound or comprise the present invention and to come into the open the pharmaceutical composition of compound, above treating mention the method for disease.
In some embodiments, the present invention is come into the open compound or comprise the come into the open pharmaceutical composition of compound of the present invention and can carry out administration by any applicable route of administration, comprises Formulations for systemic administration and topical.Formulations for systemic administration comprises oral administration, parenteral admin, transdermal administration and rectal administration.Typical parenteral admin refers to by injection or administered by infusion, comprises intravenously, intramuscular and subcutaneous injection or administered by infusion.Topical comprises and is applied to skin and intraocular, ear, intravaginal, suction and intranasal administration.In one embodiment, the present invention is come into the open compound or to comprise the come into the open pharmaceutical composition of compound of the present invention can be oral administration.In other embodiments, the present invention is come into the open compound or to comprise the come into the open pharmaceutical composition of compound of the present invention can be inhalation.Also have in an embodiment, the present invention is come into the open compound or to comprise the present invention's compound of coming into the open can be intranasal administration.
In some embodiments, the present invention come into the open compound or comprise the present invention come into the open the pharmaceutical composition of compound can once daily, or according to dosage regimen, at the appointed time in section, at different timed interval administration several times.Such as, be administered once every day, twice, three times or four times.In some embodiments, be administered once every day.In other embodiment, every day is administered twice.Can the result for the treatment of wanted of administration until reach or maintain the result for the treatment of wanted indefinitely.The present invention is come into the open compound or comprise the come into the open appropriate dosage regimen of pharmaceutical composition of compound of the present invention and depend on the pharmacokinetic property of this compound, and such as dilute, distribute and the transformation period, these can by determination of technical staff.In addition, the present invention is come into the open compound or comprise the present invention and to come into the open the appropriate dosage regimen of pharmaceutical composition of compound, comprise the time length of implementing the program, depend on the disease be treated, the factor within the scope of technician's knowledge and experience such as the severity being treated disease, the age being treated patient and physical appearance, the character being treated medical history, the simultaneously therapy of patient, the result for the treatment of wanted.Such technician be also to be understood that for the reaction of individual patient to dosage regimen, or along with time lapse individual patient need change time, can require to adjust suitable dosage regimen.
The present invention come into the open compound can with one or more other therapeutical agents simultaneously, or before it or administration afterwards.The compounds of this invention can with other treatment agent by the administration respectively of identical or different route of administration, or with it with pharmaceutical compositions administration.
For the individuality of about 50-70kg, the open pharmaceutical composition of the present invention and combination can be the unit dosage forms containing have an appointment 1-1000mg or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg activeconstituents.The treatment significant quantity of compound, pharmaceutical composition or its combination depends on individual species, body weight, age and individual instances, the disease (disorder) be treated or disease (disease) or its severity.Possesses the significant quantity that the doctor of conventional technical ability, clinicist or animal doctor easily can determine to prevent, treat or suppress required each activeconstituents in disease (disorder) or disease (disease) evolution.
Above quoted Dose Characteristics confirms in the external and in vivo test adopting favourable Mammals (such as mouse, rat, dog, monkey) or its isolated organ, tissue and sample.The present invention comes into the open compound with solution, and such as aqueous solution form uses in vitro, also can in such as suspension or aqueous solution form intestines in vivo, and parenteral, especially intravenously uses.
In some embodiments, the come into the open treatment effective dose of compound of the present invention is be about 0.1mg every day to about 2,000mg.Its pharmaceutical composition should provide about 0.1mg to this compound of about 2,000mg dosage.In a particular, the pharmaceutical dosage unit forms of preparation can provide about 1mg to about 2,000mg, about 10mg is to about 1,000mg, about 20mg are to about 500mg, or the combination of each main component in the main active ingredient of about 25mg to about 250mg or every dosage unit form.In a particular, the pharmaceutical dosage unit forms of preparation can provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active ingredient.
In addition, compound disclosed by the invention can with prodrug form administration.In the present invention, the present invention comes into the open " prodrug " of compound when being to patient's administration, finally can discharge the present invention in vivo and to come into the open the functional derivatives of compound.When giving compound disclosed by the invention with prodrug forms, those skilled in the art can implement one in following manner and more than: onset time in the body of (a) modification compound; Acting duration in the body of (b) modification compound; Conveying or distribution in the body of (c) modification compound; Solubleness in the body of (d) modification compound; And (e) overcomes side effect or other difficult points that compound faces.For the preparation of the typical functional derivatives of prodrug, comprise in vivo chemically or the variant of the compound of the mode cracking of enzyme.Comprising these variants preparing phosphoric acid salt, acid amides, ester, monothioester, carbonate and carbaminate is well-known to those skilled in the art.
General synthesis step
For describing the present invention, below list embodiment.But need be appreciated that and the invention is not restricted to these embodiments, only be to provide and put into practice method of the present invention.
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
The professional in affiliated field will recognize: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as AldrichChemical Company, Arco Chemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemical reagent factory in morning, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao's purchase obtains.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.
1h NMR composes and uses Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer record. 1h NMR composes with CDC1 3, DMSO-d 6, CD 3oD or acetone-d 6for solvent (in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.In time there is multiplet, abbreviation below 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, two triplet).Coupling constant, represents with hertz (Hz).
The condition determination of Algorithm (MS) data is: (pillar model: Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min to Agilent 6120 level Four bar HPLC-M.Moving phase: 5%-95% is (containing the CH of 0.1% formic acid 3cN) (containing the H of 0.1% formic acid 2o) ratio in), adopt electron spray ionisation (ESI), under 210nm/254nm, detect with UV.
The use Agilent 1260pre-HPLC of pure compound or Calesep pump 250pre-HPLC (pillar model: NOVASEP50/80mm DAC), detects at 210nm/254nm UV.
The use of brief word below runs through the present invention:
AcOH, HOAc, CH 3cOOH acetic acid
Ac 2o diacetyl oxide
BOC, Boc tert-butoxycarbonyl
(Boc) 2o tert-Butyl dicarbonate
BH 3.DMS borane dimethylsulf iotade
The two diphenyl phosphine of BINAP 1,1'-dinaphthalene-2,2'-
N-BuOH propyl carbinol
CH 2cl 2, DCM methylene dichloride
CDC1 3deuterochloroform
CH 3i methyl iodide
DIEA, DIPEA, i-Pr 2nEt diisopropyl ethyl amine
DMF DMF
DMP dimethyl phthalate
DMAP DMAP
DMSO dimethyl sulfoxide (DMSO)
DHP 3,4-dihydropyrane
PPTs 4-toluene sulfonic acide pyridine
Et 3n, TEA triethylamine
EtOAc, EA ethyl acetate
EtOH ethanol
Et 2o ether
EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
G gram
H hour
HATU 2-(7-azepine-1H-benzotriazole-1-base)-1,1,3,3-tetramethyl-urea phosphofluoric acid ester
HCl hydrochloric acid
HOAT 1-hydroxyl-7-azepine benzotriazole
KOH potassium hydroxide
KMnO 4potassium permanganate
K 2cO 3salt of wormwood
LiCl lithium chloride
LiHMDS, LHMDS bis-(trimethyl silicon based) Lithamide
LAH lithium aluminium hydride
MeCN, CH 3cN acetonitrile
MsCl methane sulfonyl chloride
(NH 4) 2sO 4ammonium sulfate
NH 4cl ammonium chloride
NaH sodium hydride
NaBH 3cN sodium cyanoborohydride
Na 2cO 3sodium carbonate
NaOH sodium hydroxide
Na 2sO 4sodium sulfate
Na 2s 2o 3sulfothiorine
NaHCO 3sodium bicarbonate
NaOAc ammonium acetate
Ti (Oi-Pr) 4metatitanic acid four isopropyl ester
NBS bromo-succinimide
MeOH methyl alcohol
ML, ml milliliter
Pd (OAc) 2palladium
Pd/C palladium/carbon
PE sherwood oil (60-90 DEG C)
PTSA tosic acid
PDC Pyridinium dichromate
RT, rt, r.t. room temperature
Rt retention time
Raney Ni Raney's nickel
THF tetrahydrofuran (THF)
TFAA trifluoroacetic anhydride
TFA trifluoroacetic acid
TBAF tetrabutyl ammonium fluoride
Ti (Oi-Pr) 4four isopropyl titanates
TsCl 4-toluene sulfonyl chloride
Preparation the present invention comes into the open the typical synthesis step of compound as shown in synthetic schemes 1 ~ synthetic schemes 2 below.Unless otherwise indicated, each Z, Z 1, R 1, R 3and R 5there is definition as described in the present invention, p be 0,1,2,3 or 4, q be 0,1,2 or 3.PG is blocking group, and W is azoles based compound.
Synthetic schemes 1:
Have such as formula ( 6) or ( 7) shown in the present invention of structure general synthetic method that compound can be described by synthetic schemes 1 that comes into the open prepare, concrete steps can reference example.In synthetic schemes 1, the dichloro pyrimidine of replacement ( 1) with the optional replacement of protecting group heterogeneous ring compound ( 2) at alkali, as under the effect of triethylamine, generate optional replace heteroaryl compound ( 3).Compound ( 3) with the Aminoindazole compound optionally replaced ( 4) or its hydrochloride, at alkali, as diisopropyl ethyl amine, triethylamine, or under the katalysis of suitable Pd catalyzer, reacting generating compound ( 5).Compound ( 5) in blocking group can at acidic conditions, as removed in the ethyl acetate solution of trifluoroacetic acid or hydrogenchloride, obtain kinases inhibitor ( 6).Under suitable conditions to compound ( 6) in introduce different substituting group, can obtain having formula ( 7) shown in the kinases inhibitor of structure.
Synthetic schemes 2:
Have such as formula ( 10) or ( 11) shown in the present invention of structure general synthetic method that compound can be described by synthetic schemes 2 that comes into the open prepare, concrete steps can reference example.In synthetic schemes 2, compound ( 3) with the amino azole compound optionally replaced ( 8) or its hydrochloride, at alkali, as diisopropyl ethyl amine, triethylamine or in acid, as the ethyl acetate solution of trifluoroacetic acid, hydrogenchloride, or under the katalysis of suitable Pd catalyzer, reacting generating compound ( 9).Compound ( 9) in blocking group can in acid condition, as the ethyl acetate solution of trifluoroacetic acid, hydrogenchloride, or under the effect of hydrazine hydrate, or remove under otherwise suitable conditions, obtain kinases inhibitor ( 10).Under suitable conditions to compound ( 10) in introduce different substituting group, can obtain having formula ( 11) shown in the kinases inhibitor of structure.
Embodiment
embodiment 1N 2 -(2,3-dimethyl-2H-indazole-6-base)-N 4 -methyl-N 4 -(2-azaspiro [4.5] decane-8-base) pyrimidine-2,4-diamines
step 1) 2-(Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-subunit) ethyl acetate
By NaH, (60% mineral oil suspends, 33.3g, 832.38mmol) be suspended in anhydrous THF (1L), at 0 DEG C, add 1 wherein, anhydrous THF (500mL) solution of 4-dioxo spiro [4.5] decane-8-ketone (100g, 640.29mmol), dripped off in 1 hour.Then, at-20 DEG C, phosphonoacetate (203.23g, 832.38mmol) is added drop-wise in above-mentioned suspending system, drips off in 1 hour.Gained system is moved to room temperature, continues stirring 2 hours, (1L) cancellation that then adds water is reacted, and extracts by ethyl acetate (1L x 3).The organic phase merged, with saturated aqueous common salt (1L) washing, anhydrous Na 2sO 4drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purifying, and obtaining title compound is pale yellow oil (157g, 100%).
1H NMR(600MHz,CDCl 3):δ(ppm)5.64(s,1H),4.12(q,J＝7.1Hz,2H),3.95(s,4H),2.97(m,2H),2.36(m,2H),1.74(m,4H),1.25(t,J＝7.2Hz,4H)。
step 2) 2-(8-(nitre methyl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-base) ethyl acetate
By 2-(1,4-dioxo spiro [4.5] decane-8-subunit) ethyl acetate (157g, 693.86mmol) be dissolved in THF (800mL), under normal temperature, drip Nitromethane 99Min. (55.8mL, 1.04mmol) wherein, then, the tetrahydrofuran solution (1M, 763.25mL, 763.25mmol) of TBAF is dripped in system.Gained reaction solution is heated to backflow, and stirs 20 hours.By reaction mixture concentrating under reduced pressure, gained residue use water (800mL) is diluted, and extracts by ethyl acetate (800mL x 3), and the organic layer of merging washs with saturated aqueous common salt (1L x 3), anhydrous sodium sulfate drying, filters and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying, and obtaining title compound is pale yellow oil (165g, 82.9%).
1H NMR(600MHz,CDCl 3):δ(ppm)4.66(s,2H),4.09(q,J＝7.1Hz,2H),3.88(s,4H),2.49(s,2H),1.64(m,8H),1.21(t,J＝7.2Hz,4H)。
step 3) Isosorbide-5-Nitrae-dioxy-10-azepine-two spiral shell [4.2.4.2] tetradecyl-9-ketone
By 2-(8-(nitre methyl)-1,4-dioxo spiro [4.5] decane-8-base) ethyl acetate (109g, 379.38mmol) be dissolved in ethanol (600mL), add Raney's nickel (10g) wherein.Under normal temperature, gained reaction solution stirs 72 hours in atmosphere of hydrogen, and filter, filter cake washs with the mixing solutions of DCM/MeOH (1/1 (v/v), 500mL).Merging filtrate, concentrating under reduced pressure, the mixed solvent washing of gained residue sherwood oil and ethyl acetate (10/1 (v/v), 800mL), filtering and obtaining title compound is white solid (67g, 83.8%).
MS(ESI,pos.ion)m/z:212.1[M+H] +；
1H NMR(600MHz,CDCl 3):δ(ppm)6.60(s,1H),3.95(s,4H),3.20(s,2H),2.23(s,2H),1.72(m,4H),1.65(m,4H)。
step 4) Isosorbide-5-Nitrae-dioxy-10-azepine-two spiral shell [4.2.4.2] tetradecyl
By LiAlH 4(21g, 558.56mmol) be suspended in anhydrous tetrahydro furan (500mL), at 0 DEG C, add 1 wherein, anhydrous tetrahydro furan (400mL) solution of 4-dioxy-10-azepine-two spiral shell [4.2.4.2] tetradecyl-9-ketone (59g, 279.28mmol).Gained reaction solution is warming up to backflow, reacts 2 hours, and then, drip in system at 0 DEG C and add water to and no longer produce bubble, cancellation is reacted.Filter, filter cake washs with MeOH/DCM (1/1 (v/v), 500mL) mixed solvent.Merging filtrate, concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=10/1) purifying, and obtaining title compound is yellow solid (52g, 94%).
MS(ESI,pos.ion)m/z:198.2[M+H] +；
1H NMR(600MHz,CDCl 3):δ(ppm)3.88(s,4H),2.90(t,J＝7.1Hz,2H),2.65(s,3H),1.56(ddd,J＝29.3,13.4,6.9Hz,10H)。
step 5) 2-azaspiro [4.5] decane-8-ketone
Dioxy-10-azepine-two spiral shell [4.2.4.2] tetradecyl (10g, 50.69mmol) is dissolved in methyl alcohol (100mL), under normal temperature, adds 2M hydrochloric acid (30mL, 60mmol) wherein.Gained reaction solution at normal temperatures, stirring is spent the night, concentrating under reduced pressure, gained residue is dissolved in water (100mL), add saturated aqueous sodium carbonate and be adjusted to pH=10, then, extract with methylene dichloride (200mL x 3), the organic layer merged washs with saturated aqueous common salt (200mL), anhydrous sodium sulfate drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=7/1) purifying, obtaining title compound is yellow solid (10g, 100%).
MS(ESI,pos.ion)m/z:154.2[M+H] +。
step 6) 8-oxo-2-azaspiro [4.5] decane-2-t-butyl formate
2-azaspiro [4.5] decane-8-ketone (10g, 65.26mmol) is dissolved in the mixing solutions (200mL) of water and tetrahydrofuran (THF) (1/3 (v/v)), adds wherein under normal temperature (Boc) 2o (28.48g, 130.53mmol) and sodium carbonate (13.83g, 130.53mmol).Gained reaction solution stirs 2 hours at normal temperatures, and (200mL) cancellation that then, adds water is reacted.Extract with ethyl acetate (300mL x 3), the organic layer merged washs with saturated aqueous common salt (500mL), anhydrous sodium sulfate drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purifying, obtaining title compound is colorless oil (9g, 54.5%).
MS(ESI,pos.ion)m/z:198.1[(M-C 4H 8)+H] +。
step 7) 8-(methylamino)-2-azaspiro [4.5] decane-2-t-butyl formate
By 8-oxo-2-azaspiro [4.5] decane-2-t-butyl formate (4g, 15.80mmol) add in methylamine (33% [w/w] ethanolic soln, 7.42g, 79.0mmol), after gained reaction solution at room temperature stirs and spends the night, then add NaBH wherein 3cN (2.98g, 47.4mmol), adds rear reaction solution and continues to stir 2 hours at normal temperatures.By reaction mixture concentrating under reduced pressure, gained residue use water (50mL) is diluted, and extract with methylene dichloride (80mL x 3), the organic layer merged washs with saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=10/1) purifying, obtaining title compound is yellow oil (3.2g, 75.7%).
MS(ESI,pos.ion)m/z:269.2[M+H] +。
step 8) 8-((2-chloropyrimide-4-base) (methyl) is amino)-2-azaspiro [4.5] decane-2-t-butyl formate
2,4-dichloro pyrimidine (596mg, 4.0mmol) and 8-(methylamino)-2-azaspiro [4.5] decane-2-t-butyl formate (1.29g, 4.8mmol) are dissolved in EtOH (10mL), add Et wherein 3n (0.92g, 9.1mmol), stirs under adding rear reaction mixture normal temperature and spends the night, concentrating under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, and obtaining title compound is faint yellow solid (580mg, 38.1%).
MS(ESI,pos.ion)m/z:381.2[M+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)8.01(d,J＝6.2Hz,1H),6.31(d,J＝5.3Hz,1H),3.41(ddd,J＝20.4,14.0,7.1Hz,2H),3.13(d,J＝25.2Hz,2H),2.93(s,2H),1.81(m,2H),1.65(m,8H),1.48(m,11H)。
step 9) 8-((2-((2,3-dimethyl-2H-indazole-6-base) is amino) pyrimidine-4-yl) (methyl) is amino)-2-azaspiro [4.5] decane-2-t-butyl formate
By 8-((2-chloropyrimide-4-base) (methyl) is amino)-2-azaspiro [4.5] decane-2-t-butyl formate (500.0mg, 1.3mmol) He 2,3-dimethyl-2H-indazole-6-amine hydrochlorate (778.6mg, 3.9mmol) be suspended in n-BuOH (10mL), add DIPEA (1.04g wherein, 8.0mmol), gained reaction system is warming up to 150 DEG C, and tube sealing reaction spends the night.Reaction mixture is cooled to concentrating under reduced pressure after room temperature, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=10/1) purifying, and obtaining title compound is yellow solid (657mg, 100%).
MS(ESI,pos.ion)m/z:506.3[M+H] +。
step 10) N 2 -(2,3-dimethyl-2H-indazole-6-base)-N 4 -methyl-N 4 -(2-azaspiro [4.5] decane-8-base) pyrimidine-2,4-diamines
By 8-((2-((2,3-dimethyl-2H-indazole-6-base) amino) pyrimidine-4-yl) (methyl) amino)-2-azaspiro [4.5] decane-2-t-butyl formate (657mg, 1.3mmol) be dissolved in DCM (10mL), add the ethyl acetate solution (10mL, 40mmol) of hydrogenchloride wherein.By gained reaction mixture concentrating under reduced pressure, in residue water-soluble (30mL), add saturated aqueous sodium carbonate and be adjusted to pH=10, extract with DCM (250mL x 3).The organic phase merged is washed with saturated aqueous common salt (250mL), anhydrous sodium sulfate drying, concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=5/1) purifying, obtaining title compound is brown solid (0.30g, 56.9%).
MS(ESI,pos.ion)m/z:406.2[M+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)9.05(s,1H),8.02(s,1H),7.74(d,J＝6.7Hz,1H),7.37(d,J＝8.9Hz,1H),6.91(d,J＝8.8Hz,1H),5.97(d,J＝6.6Hz,1H),3.96(s,3H),3.32(m,2H),3.00(s,2H),2.91(s,4H),2.49(s,3H),1.93(s,1H),1.87(t,J＝7.4Hz,3H),1.71(m,6H)。
embodiment 2 3-(8-((2-((2,3-dimethyl-2H-indazole-6-base) is amino) pyrimidine-4-yl) (methyl) is amino)-2-azaspiro [4.5] decane-2-base)-3-oxygen for propionitrile
By N 2-(2,3-dimethyl-2H-indazole-6-base)-N 4-methyl-N 4-(2-azaspiro [4.5] decane-8-base) pyrimidine-2,4-diamines (300mg, 0.74mmol) with itrile group acetic acid (156mg, 1.83mmol) be dissolved in mixed solvent (4/1 (v/v) of DCM and DMF, 35mL), add HATU (925.8mg, 2.44mmol) and Et wherein 3n (0.49g, 4.84mmol).After adding, stirring at normal temperature 0.5 hour, add water (30mL), with DCM (100mL x 3) extraction, the organic phase of merging is washed with saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=20/1) purifying, and obtaining title compound is brown solid (210mg, 60.0%).MS(ESI,pos.ion)m/z:473.4[M+H] +；
1H NMR(600MHz,CDCl 3):δ(ppm)8.16(d,J＝9.2Hz,1H),7.99(dd,J＝5.9,3.3Hz,1H),7.45(dd,J＝8.8,4.4Hz,1H),6.98(m,2H),5.96(t,J＝5.5Hz,1H),4.08(d,J＝9.3Hz,3H),3.64(dd,J＝13.4,6.7Hz,2H),3.44(s,3H),3.36(s,1H),2.96(d,J＝7.2Hz,3H),2.59(s,3H),2.02(t,J＝7.1Hz,1H),1.93(t,J＝7.3Hz,1H),1.75(m,6H),1.31(s,2H)。
the chloro-N of embodiment 3 5- 2 -(2,3-dimethyl-2H-indazole-6-base)-N 4 -(octahydro pentamethylene is [c] pyrroles-5-base also) pyrimidine-2,4-diamines
step 1) 3a, 4,7,7a-tetrahydrochysene-1H-isoindole-2 (3H)-t-butyl formate
By LAH (22.80g, 600mmol) be suspended in THF (600mL), at 0 DEG C, gradation adds tetrahydrophthalimide (39.45g wherein, 260.9mmol), add rear reaction system to stir 18 hours at 60 DEG C, then 0 DEG C is cooled to, slowly add water (25mL) successively, the 15%KOH aqueous solution (25mL) and water (75mL), stirring 1 hour is continued under gained mixture normal temperature, diatomite filtration, DCM (500mL) washing leaching cake, filtrate reduced in volume, obtaining product isoindole is yellow oil, this crude product is directly used in next step reaction.
This crude product is dissolved in DCM (300mL), at 0 DEG C, adds Et wherein 3n (39.61g, 391.4mmol) and (Boc) 2o (68.32g, 313.1mmol), adds in 0.5 hour, moves to normal temperature after adding, and continues stirring 21 hours.By reaction mixture concentrating under reduced pressure, gained residue is dissolved in EtOAc (600mL), uses aqueous citric acid solution (1M, 2x 130mL), saturated NaHCO successively 3the aqueous solution (2x 130mL), saturated aqueous common salt (250mL) wash, the organic over anhydrous dried over sodium sulfate merged, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, obtaining title compound is orange oily matter (45.00g, 77.3%)
MS(ESI,pos.ion)m/z:168.2[(M-C 4H 8)+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)5.64(s,2H),3.40(m,2H),3.16(m,1H),3.07(m,1H),2.25(m,4H),1.90(m,2H),1.46(s,9H)。
step 2) 2,2'-(1-(tertbutyloxycarbonyl) Pyrrolidine-3,4-bis-base) diacetyl acetic acid
By 3a, 4,7,7a-tetrahydrochysene-1H-isoindole-2 (3H)-t-butyl formate (4.91g, 22mmol) and (NH 4) 2sO 4(1.55g, 12mmol) is dissolved in H 2in O (40mL), at 5 DEG C, add KMnO wherein in batches 4(8.20g, 52mmol), the joining day is 0.5 hour, after adding, and reaction solution continues stirring 6 hours at 5 DEG C, then filters, and filter cake use water (40mL x 3) rinses, filtrate CH 2cl 2(40mL x 3) extracts, and the water layer 3M HCl aqueous solution is adjusted to pH=2 ~ 3, then uses EtOAc (50mL x 3) to extract, organic phase salt solution (the 50mL x 3) washing of merging, anhydrous Na 2sO 4drying, filters and concentrating under reduced pressure obtains light yellow solid (4.52g, 71.5%).
MS(ESI,pos.ion)m/z:232.2[(M-C 4H 8)+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)3.53(m,2H),3.04(m,2H),2.80(m,2H),2.44(m,4H),1.43(s,9H)。
step 3) 5-oxo six hydrogen pentamethylene also [c] pyrroles-2 (1H)-t-butyl formate
2,2'-(1-(tertbutyloxycarbonyl) tetrahydro pyrrolidine-3,4-bis-base) etheric acid (3.40g, 11.8mmol) is dissolved in Ac 2in O (21mL), and add NaOAc (0.78g, 9.5mmol) wherein.Reaction solution reacts 3 hours at 120 DEG C, then be down to room temperature and filter, filter cake EtOAc (20mL x 2) rinses, by filtrate reduced in volume, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/4) purifying, obtaining title compound is safran oily matter (1.38g, 55.0%).
MS(ESI,pos.ion)m/z:170.2[(M-C 4H 8)+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)3.69(m,2H),3.00(m,4H),2.61(dd,J＝8.2,18.4Hz,2H),2.29(dd,J＝5.8,18.4Hz,2H),1.43(s,9H)。
step 4) 5-(benzyl is amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)-t-butyl formate
By 5-oxo six hydrogen pentamethylene also [c] pyrroles-2 (1H)-t-butyl formate (9.57g, 42.5mmol) be dissolved in DCM (170mL), at 0 DEG C, add BnNH wherein 2(4.56g, 42.5mmol) and AcOH (2.55g, 42.5mmol), after adding, reaction solution stirs 0.5 hour at 0 DEG C.Then, add NaBH (OAc) wherein in batches 3(18.00g, 85.0mmol), gained mixture at room temperature continues stirring 20 hours.Add NaHCO 3the aqueous solution (142mL), with DCM (250mL x 3) extraction, organic phase saturated aqueous common salt (the 250mL x 3) washing of merging, anhydrous Na 2sO 4drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (EtOAc) purifying, and obtaining title compound is yellow solid (7.44g, 55.3%).
MS(ESI,pos.ion)m/z:317.3[M+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)7.31(m,4H),7.26(m,1H),3.79(s,2H),3.46(m,2H),3.28(d,J＝8.8Hz,1H),3.16(tt,J＝9.6,6.9Hz,1H),2.55(m,2H),2.28(s,2H),2.22(m,2H),1.45(s,9H),1.31(m,2H)。
step 5) the amino six hydrogen pentamethylene of 5-also [c] pyrroles-2 (1H)-t-butyl formate
By 5-(benzyl is amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)-t-butyl formate (6.50g, 20.5mmol) with AcOH (1.23g, 20.5mmol) be dissolved in MeOH (150mL), add Pd (OH) wherein 2/ C (10%wt, 1.00g), gained reaction system is warming up to 40 DEG C, stirs and spend the night in atmosphere of hydrogen, and gained reaction mixture is through diatomite filtration, and filtrate reduced in volume, gained residue is dissolved in saturated NaHCO 3in the aqueous solution (70mL), DCM (100mL x 3) extracts, organic phase salt solution (the 100mL x 3) washing of merging, anhydrous Na 2sO 4drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (EtOAc, 100%) purifying, and obtaining title compound is yellow solid (4.00g, 86.2%).
MS(ESI,pos.ion)m/z:227.2[M+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)3.44(m,2H),3.31(m,3H),2.98(br.s,2H),2.57(m,2H),2.22(dt,J＝14.0,7.2Hz,2H),1.44(s,9H)。
step 6) 5-((2,5-dichloro pyrimidine-4-base) is amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)-t-butyl formate
By the amino six hydrogen pentamethylene of 5-also [c] pyrroles-2 (1H)-t-butyl formate (3.11g, 13.74mmol) with 2,4,5-trichloropyrimidine (1.46g, 7.96mmol) be dissolved in EtOH (60mL), add Et wherein 3n (2.21g, 21.84mmol).After adding, reaction mixture stirs at normal temperatures and spends the night, concentrating under reduced pressure, gained residue is dissolved in the mixed solvent of EtOAc (50mL) and water (50mL), extract with EtOAc (150mL x 3), the organic layer merged salt solution (150mL) washing, anhydrous Na 2sO 4drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is faint yellow solid (2.97g, 100%).
MS(ESI,pos.ion)m/z:373.0[M+H] +。
step 7) 5-((the chloro-2-of 5-((2,3-dimethyl-2H-indazole-6-base) is amino) pyrimidine-4-yl) is amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)-formic acid uncle butyl ester
To 5-((2,5-dichloro pyrimidine-4-base) amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)-t-butyl formate (621.8mg, 1.666mmol) and 2,3-dimethyl indazole-6-amine hydrochlorate (999.6mg, DIPEA (1.10g, 8.43mmol) is added in propyl carbinol (6mL) solution 5.057mmol).Reaction system is warming up to 150 DEG C, microwave reaction 2 hours, concentrating under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=2/1) purifying, and obtaining title compound is light tan solid (452.1mg, 54.5%).
MS(ESI,pos.ion)m/z:498.3[M+H] +。
step 8) the chloro-N of 5- 2 -(2,3-dimethyl-2H-indazole-6-base)-N 4 -(octahydro pentamethylene is [c] pyrroles-5-base also) pyrimidine-2,4-diamines
To 5-((the chloro-2-((2 of 5-, 3-dimethyl-2H-indazole-6-base) amino) pyrimidine-4-yl) amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)-t-butyl formate (452.1mg, ethyl acetate solution (the 10mL of hydrogenchloride is added in DCM (10mL) solution 0.908mmol), 40mmol), gained reaction system stirs at normal temperatures and spends the night.React complete, concentrating under reduced pressure, gained residue add water (30mL) dissolve, use saturated Na 2cO 3the aqueous solution is adjusted to pH=10, then thin up, extracts with DCM (250mLx3).The organic phase merged is washed through saturated aqueous common salt (250mL), anhydrous sodium sulfate drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=5/1) purifying, obtaining title compound is brown solid (179.6mg, 49.7%).
MS(ESI,pos.ion)m/z:398.3[M+H] +；
1H NMR(400MHz,DMSO-d 6):δ(ppm)9.14(s,1H),8.10(s,1H),7.96(s,1H),7.47(d,J＝8.9Hz,1H),7.39(d,J＝6.4Hz,1H),7.11(d,J＝8.9Hz,1H),4.45(m,1H),3.96(s,3H),3.17(s,1H),3.05(m,2H),2.92(d,J＝9.8Hz,2H),2.73(br.s,2H),2.53(s,3H),2.30(m,2H),1.492(m,2H)。
embodiment 4 3-(5-((the chloro-2-of 5-((2,3-dimethyl-2H-indazole-6-base) is amino) pyrimidine-4-yl) is amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)- base)-3-oxypropionitrile
To the chloro-N of 5- 2-(2,3-dimethyl-2H-indazole-6-base)-N 4-(octahydro pentamethylene is [c] pyrroles-5-base also) pyrimidine-2,4-diamines (484.7mg, 1.22mmol) with itrile group acetic acid (155.0mg, 1.82mmol) be dissolved in the mixed solvent (40mL/10mL) of DCM and DMF, add HATU (673.2mg wherein, 1.77mmol) with triethylamine (0.60g, 5.90mmol).After adding, stirring at normal temperature 5.5 hours, (30mL) cancellation that adds water is reacted, and extracts with DCM (100mL x 3).The organic phase merged is washed through saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=40/1) purifying, obtaining title compound is brown solid (0.49g, 87%).
MS(ESI,pos.ion)m/z:465.0[M+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)8.09(s,1H),7.94(s,1H),7.47(d,J＝8.9Hz,1H),6.98(m,2H),5.27(d,J＝6.8Hz,1H),4.53(m,1H),4.07(s,3H),3.73(m,2H),3.61(dd,J＝12.8,4.3Hz,1H),3.48(dd,J＝22.5,4.3Hz,1H),3.42(s,2H),2.90(m,2H),2.64(m,2H),2.60(s,3H),1.46(m,2H)。
the chloro-N of embodiment 5 5- 2 -(2,3-dimethyl-2H-indazole-6-base)-N 4 -(3-azaspiro [5.5] undecane-9-base) pyrimidine-2,4-diamines
step 1) 9-oxo-3-azaspiro [5.5] undecane-7-alkene-3-t-butyl formate
To 4-formyl piperidine-1-t-butyl formate (10.0g; 46.9mmol) with KOH (1.3g; in EtOH (200mL) solution 23.5mmol); add fourth-3-alkene-2-ketone (3.9g; 56.3mmol), gained reaction mixture is warming up to 70 DEG C of stirrings 16 hours.After reaction terminates, concentrating under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/4) purifying, and obtaining title compound is light brown oil thing (5.2g, 41.8%).
MS(ESI,pos.ion)m/z:210.2[M-55] +.
step 2) 9-oxo-3-azaspiro [5.5] undecane-3-t-butyl formate
To 9-oxo-3-azaspiro [5.5] undecane-7-alkene-3-t-butyl formate (5.2g, 10%Pd/C (0.5g) is added in DCM (80mL) solution 19.6mmol), at normal temperatures, in atmosphere of hydrogen, stirring reaction spends the night gained suspension.Filtered by reaction mixture, filtrate reduced in volume, gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/4) purifying, and obtaining title compound is light brown oil thing (3.1g, 59.0%).
MS(ESI,pos.ion)m/z:212.1[M-55] +。
step 3) 9-amino-3-azaspiro [5.5] undecane-3-t-butyl formate
Methanol solution (7M, 40mL, 280.0mmol) and the Ti (Oi-Pr) of ammonia is added in EtOH (40mL) solution of 9-oxo-3-azaspiro [5.5] undecane-3-t-butyl formate (5.35g, 20.0mmol) 4(11.30g, 40.0mmol), reaction system at room temperature stirs spends the night.By NaBH 4(1.51g, 40.0mmol) adds in reaction system in batches, and after adding, gained reaction mixture at room temperature stirs 5 hours, and the cancellation that adds water (40mL) is reacted, and stirs after 1 hour and filters.Filtrate reduced in volume, gained residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/25) purifying, and obtaining title compound is faint yellow solid (1.20g, 22.4%).
MS(ESI,pos.ion)m/z:269.3[M+H] +。
step 4) 9-((2,5-dichloro pyrimidine-4-base) is amino)-3-azaspiro [5.5] undecane-3-t-butyl formate
9-amino-3-azaspiro [5.5] undecane-3-t-butyl formate (1.08g, 4.0mmol) and Et is added in ethanol (30mL) solution of 2,4,5-trichloropyrimidine (495.9mg, 2.7mmol) 3n (413.6mg, 4.1mmol).After gained reaction system at room temperature stirs 12 hours, concentrating under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/7) purifying, and obtaining title compound is faint yellow solid (387.1mg, 34.5%).
MS(ESI,pos.ion)m/z:415.0[M+H] +。
step 5) 9-((5-chlorine 2-((2,3-dimethyl-2H-indazole-6-base) is amino) pyrimidine-4-yl) is amino)-3-azaspiro [5.5] undecane-3-t-butyl formate
To 9-((2,5-dichloro pyrimidine-4-base) amino)-3-azaspiro [5.5] undecane-3-t-butyl formate (659.8mg, 1.59mmol) He 2,3-dimethyl indazole-6-amine hydrochlorate (580.6mg, DIPEA (755.5mg, 5.79mmol) is added in butanol solution (6mL) 2.94mmol).Gained reaction system is warming up to 150 DEG C, tube sealing reaction 2 hours, after reaction terminates, is cooled to room temperature, concentrating under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=2/1) purifying, and obtaining title compound is yellow solid (169.7mg, 19.8%).
MS(ESI,pos.ion)m/z:540.4[M+H] +；
1H NMR(600MHz,CDCl 3):δ(ppm)8.02(d,J＝1.2Hz,1H),7.92(s,1H),7.45(d,J＝8.9Hz,1H),7.07(dd,J＝8.9,1.7Hz,1H),7.00(s,1H),5.17(d,J＝7.4Hz,1H),4.06(s,4H),3.42(m,4H),2.59(s,3H),2.02(d,J＝9.5Hz,2H),1.74(m,2H),1.55(br.s,2H),1.49(s,9H),1.44(m,6H)。
step 6) the chloro-N of 5- 2 -(2,3-dimethyl-2H-indazole-6-base)-N 4 -(3-azaspiro [5.5] undecane-9-base) pyrimidine-2,4-diamines
To 9-((5-chlorine 2-((2,3-dimethyl-2H-indazole-6-base) amino) pyrimidine-4-yl) amino)-3-azaspiro [5.5] undecane-3-t-butyl formate (161.5mg, ethyl acetate solution (the 10mL of hydrogenchloride is added in DCM (10mL) solution 0.30mmol), 40mmol), gained reaction system stirs 2 hours at normal temperatures.React complete, concentrating under reduced pressure, gained residue add water (30mL) dissolve, use saturated Na 2cO 3the aqueous solution is adjusted to pH=10, then thin up, extracts with DCM (100mLx3).The organic phase merged is washed through saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=10/1) purifying, obtaining title compound is brown solid (131.6mg, 100%).
MS(ESI,pos.ion)m/z:440.4[M+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)7.99(s,1H),7.91(s,1H),7.46(d,J＝8.9Hz,1H),7.11(dd,J＝8.9,1.5Hz,1H),6.94(s,1H),5.16(d,J＝7.4Hz,1H),4.11(t,J＝6.7Hz,1H),4.07(s,4H),2.85(m,4H),2.59(s,3H),2.00(m,2H),1.78(d,J＝13.3Hz,2H),1.56(d,J＝5.5Hz,2H),1.39(m,6H)。
embodiment 6 3-(9-((the chloro-2-of 5-((2,3-dimethyl-2H-indazole-6-base) is amino) pyrimidine-4-yl) is amino)-3-azaspiro [5.5] undecane-3-base)-3-oxygen for propionitrile
By chloro-for 5-N 2-(2,3-dimethyl-2H-indazole-6-base)-N 4-(3-azaspiro [5.5] undecane-9-base) pyrimidine-2,4-diamines (485.3mg, 1.10mmol) with 2-itrile group acetic acid (137.0mg, 1.61mmol) be dissolved in the mixed solvent of DCM (40mL) and DMF (10mL), add HATU (520.8mg, 1.37mmol) and Et wherein 3n (0.36g, 3.55mmol).After adding, reaction system stirs 6 hours at normal temperatures, and (30mL) cancellation that then adds water is reacted, and extracts with DCM (100mL x 3).The organic phase merged is washed through saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, filter and concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, obtaining title compound is brown solid (171.0mg, 30.6%).
MS(ESI,pos.ion)m/z:507.3[M+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)8.06(d,J＝3.5Hz,1H),7.93(s,1H),7.46(d,J＝8.9Hz,1H),7.03(m,1H),6.96(s,1H),5.16(d,J＝6.8Hz,1H),4.10(m,1H),4.06(s,3H),3.63(m,2H),3.49(2,2H),3.45(m,3H),2.59(s,3H),2.05(m,2H),1.78(m,2H),1.69(m,2H),1.50(m,6H)。
embodiment 7 1-(9-((the chloro-2-of 5-((2,3-dimethyl-2H-indazole-6-base) is amino) pyrimidine-4-yl) is amino)-3-azaspiro [5.5] undecane-3-base) ethyl ketone
By chloro-for 5-N 2-(2,3-dimethyl-2H-indazole-6-base)-N 4-(3-azaspiro [5.5] undecane-9-base) pyrimidine-2,4-diamines (0.10g, in anhydrous DCM (10.0mL) solution 0.23mmol), add triethylamine (0.036g, 0.35mmol) with diacetyl oxide (0.029g, 0.29mmol).Gained reaction system adds DCM (40mL) dilution after at room temperature stirring 30 minutes, then use water (20mL x 2), saturated NaHCO successively 3(20mL) wash with saturated aqueous common salt (20mL), concentrating under reduced pressure.Gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=30/1 to 15/1) purifying, and obtaining title compound is light green solid (75mg, 68%).
MS(ESI,pos.ion)m/z:482.0[M+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)8.03(d,J＝2.8Hz,1H),7.90(s,1H),7.43(d,J＝8.9Hz,1H),7.05-7.02(m,1H),7.01(s,1H),5.19-5.12(m,1H),4.08-4.00(m,4H),3.62-3.54(m,2H),3.45-3.38(m,2H),2.57(s,3H),2.09(s,3H),2.05-1.99(m,2H),1.78-1.71(m,2H),1.58-1.53(m,2H),1.51-1.43(m,6H)。
embodiment 8N 2 -(2,3-methyl-2H-indazole-6-base)-5-methyl-N 4 -(octahydro pentamethylene is [c] pyrroles-5-base also) pyrimidine-2,4-diamines
step 1) 5-((the chloro-5-methylpyrimidine of 2--4-base) is amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)-t-butyl formate
By 2, the chloro-5-methylpyrimidine of 4-bis-(2.00g, 12.3mmol) and the amino six hydrogen pentamethylene of 5-also [c] pyrroles-2 (1H)-t-butyl formate (4.64g, 20.5mmol) be dissolved in EtOH (25mL), and add Et wherein 3n (2.62g, 25.9mmol), reaction mixture stirs and spends the night at 50 DEG C, then concentrating under reduced pressure, residue obtained through silica gel column chromatography (EtOAc/PE (v/v)=1/2) purifying, obtaining title compound is yellow oil (2.42g, 55.9%).
MS(ESI,pos.ion)m/z:353.0[M+H] +；
1H NMR(600MHz,CDCl 3):δ(ppm)7.68(s,1H),5.25(d,J＝7.5Hz,1H),4.48(m,1H),3.42(m,2H),3.26(d,J＝11.1Hz,2H),2.63(m,2H),2.38(m,2H),1.92(s,3H),1.41(s,9H),1.33(m,2H)。
step 2) 5-((2-((2,3-dimethyl-2H-indazole-6-base) is amino)-5-methylpyrimidine-4-base) is amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)-formic acid the tert-butyl ester
By 5-((the chloro-5-methylpyrimidine of 2--4-base) is amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)-t-butyl formate (421.5mg, 1.19mmol) He 2,3-dimethyl indazole-6-amine hydrochlorate (734.5mg, 3.72mmol) be suspended in n-BuOH (10mL), and add DIPEA (795.2mg, 6.09mmol) wherein.Reaction mixture stirs 2 hours at 150 DEG C, then concentrating under reduced pressure, residue obtained through silica gel column chromatography (MeOH/DCM (v/v)=1/10) purifying, and obtaining title compound is brown oil (570.5mg, 100%).
MS(ESI,pos.ion)m/z:478.2[M+H] +。
step 3) N 2 -(2,3-methyl-2H-indazole-6-base)-5-methyl-N 4 -(octahydro pentamethylene is [c] pyrroles-5-base also) pyrimidine-2,4-diamines
By 5-((2-((2,3-dimethyl-2H-indazole-6-base) amino)-5-methylpyrimidine-4-base) amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)-t-butyl formate (597.9mg, 1.25mmol) be dissolved in DCM (15mL), and add the ethyl acetate solution (15mL, 60mmol) of hydrogenchloride wherein.Reaction mixture at room temperature stirs 1 hour, then concentrating under reduced pressure, is dissolved in by residue in water (30mL), the saturated Na of gained mixture 2cO 3the aqueous solution is adjusted to pH=10, then uses DCM (250mL x 3) to extract, organic phase salt solution (250mL) washing of merging, then uses anhydrous Na 2sO 4drying, filters then concentrating under reduced pressure, residue obtained through silica gel column chromatography (MeOH/DCM (v/v)=1/5) purifying, and obtaining title compound is buff white solid (202.4mg, 42.8%).
MS(ESI,pos.ion)m/z:378.3[M+H] +；
1H NMR(400MHz,DMSO-d 6):δ(ppm)9.20(s,1H),9.13(s,1H),7.96(s,1H),7.72(s,1H),7.58(d,J＝8.8Hz,1H),7.04(d,J＝8.8Hz,1H),4.39(m,1H),4.00(s,3H),3.06(m,2H),2.81(m,2H),2.57(s,3H),2.37(m,2H),2.00(s,3H),1.61(m,2H)。
embodiment 9 3-(5-((2-((2,3-methyl-2H-indazole-6-base) is amino)-5-methylpyrimidine-4-base) is amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)- base)-3-oxypropionitrile
By N 2-(2,3-methyl-2H-indazole-6-base)-5-methyl-N 4-(octahydro pentamethylene is [c] pyrroles-5-base also) pyrimidine-2,4-diamines (86.9mg, 0.23mmol) with 2-cyanoacetic acid (31.3mg, 0.37mmol) be dissolved in the mixed solvent of DCM (8mL) and DMF (2mL), and add HOAT (65.5mg wherein, 0.48mmol) with EDCI (77.6mg, 0.40mmol).Reaction mixture stirs 1 hour at 45 DEG C, then uses H 2o (30mL) cancellation is reacted, then uses DCM (100mL x 3) to extract.The organic phase merged salt solution (100mL) washing, then use anhydrous Na 2sO 4drying, filters then concentrating under reduced pressure, and residue is through silica gel column chromatography (MeOH/DCM (v/v)=1/10) purifying, and obtaining title compound is buff white solid (69.8mg, 68.2%).
MS(ESI,pos.ion)m/z:445.0[M+H] +；
1H NMR(600MHz,DMSO-d 6):δ(ppm)8.90(s,1H),8.14(s,1H),7.69(s,1H),7.45(d,J＝8.9Hz,1H),7.11(d,J＝8.9Hz,1H),6.62(s,1H),4.55(m,1H),3.96(s,3H),3.58(dd,J＝10.4,8.1Hz,2H),3.51(dd,J＝12.1,8.5Hz,2H),2.73(m,1H),2.65(m,1H),2.53(s,3H),2.34(m,2H),1.93(s,3H),1.49(m,2H)。
embodiment 10N 2 -(2,3-dimethyl-2H-indazole-6-base)-5-methyl-N 4 -(2-(methylsulfonyl) octahydro pentamethylene is [c] pyrroles-5-base also) pyrimidine-2,4-bis- amine
embodiment 11 1-(5-((2-((2,3-dimethyl-2H-indazole-6-base) is amino)-5-methylpyrimidine-4-base) is amino) six hydrogen pentamethylene also [c] pyrroles-2 (1H)- base) ethyl ketone
By N 2-(2,3-methyl-2H-indazole-6-base)-5-methyl-N 4-(octahydro pentamethylene is [c] pyrroles-5-base also) pyrimidine-2,4-diamines (127.3mg, 0.34mmol) with triethylamine (68.3mg, 0.68mmol) be suspended in DCM (10mL), and add Methanesulfonyl chloride (64.2mg, 0.56mmol) wherein.Reaction mixture at room temperature stirs 2 hours, then uses H 2o (30mL) cancellation is reacted, then uses DCM (100mL x 3) to extract.The organic phase merged salt solution (100mL) washing, then use anhydrous Na 2sO 4dry, filter then concentrating under reduced pressure, residue obtained purification by silica gel column chromatography, first use eluent (MeOH/DCM (v/v)=1/20) wash-out, obtaining embodiment 10 compound is buff white solid (90.5mg, 58.9%), then uses eluent (MeOH/DCM (v/v)=1/10) wash-out instead, obtaining embodiment 11 compound is buff white solid (50.2mg, 35.5%).
Embodiment 10:
MS(ESI,pos.ion)m/z:456.3[M+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)8.15(s,1H),7.75(s,1H),7.44(d,J＝8.9Hz,1H),7.01(dd,J＝8.9,1.5Hz,1H),6.87(br.s,1H),4.77(d,J＝7.5Hz,1H),4.58(m,1H),4.06(s,3H),3.37(s,2H),3.21(dd,J＝9.6,7.0Hz,2H),2.90(m,2H),2.87(s,3H),2.61(m,2H),2.58(s,3H),1.99(s,3H),1.51(m,2H)。
Embodiment 11:
MS(ESI,pos.ion)m/z:420.3[M+H] +；
1H NMR(400MHz,CDCl 3):δ(ppm)8.13(s,1H),7.76(s,1H),7.44(d,J＝8.9Hz,1H),7.02(m,1H),6.86(s,1H),4.59(m,1H),4.50(d,J＝6.7Hz,1H),4.06(s,3H),3.62(m,3H),3.41(dd,J＝10.9,3.4Hz,1H),2.85(m,2H),2.66(m,2H),2.59(s,3H),2.08(s,3H),1.96(s,3H),1.41(m,2H)。
embodiment 12 3-(9-((2-((2,3-dimethyl-2H-indazole-6-base) is amino)-5-methylpyrimidine-4-base) is amino)-3-azaspiro [5.5] undecane-3- base)-3-oxypropionitrile
step 1) 9-((the chloro-5-methylpyrimidine of 2--4-base) is amino)-3-azaspiro [5.5] undecane-3-t-butyl formate
To 2, the chloro-5-methylpyrimidine of 4-bis-(0.58g, 3.60mmol) with 9-amino-3-azaspiro [5.5] undecane-3-t-butyl formate (1.44g, triethylamine (0.86g, 8.50mmol) is added in ethanol (25mL) solution 5.37mmol).Gained reaction system is warming up to 100 DEG C, stirs 25.5 hours, then concentrating under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/2) purifying, and obtaining title compound is yellow solid (332.2mg, 24%).
MS(ESI,pos.ion)m/z:395.4[M+H] +。
step 2) 9-((2-((2,3-dimethyl-2H-indazole-6-base) is amino)-5-methylpyrimidine-4-base) is amino) the tertiary fourth of-3-azaspiro [5.5] undecane-3-formic acid ester
By mixture 9-((the chloro-5-methylpyrimidine of 2--4-base) is amino)-3-azaspiro [5.5] undecane-3-t-butyl formate (1.2g, 3.0mmol), 2, 3-dimethyl indazole-6-amine hydrochlorate (896.5mg, 4.536mmol), palladium (132.4mg, 0.5898mmol), 1, 1'-dinaphthalene-2, two diphenyl phosphine (the 370.3mg of 2'-, 0.5947mmol) with cesium carbonate (2.98g, 9.15mmol) be dissolved in dioxane (10mL), reaction mixture is warming up to 150 DEG C and reacts 2 hours under microwave, then concentrating under reduced pressure, residue is through silica gel column chromatography (DCM/MeOH (v/v)=30/1)) purifying, obtaining title compound is yellow solid (1.04g, 66%).
MS(ESI,pos.ion)m/z:520.1[M+H] +。
step 3) N 2 -(2,3-dimethyl-2H-indazole-6-base)-5-methyl-N 4 -(3-azaspiro [5.5] undecane-9-base) pyrimidine-2,4-diamines
By 9-((2-((2,3-dimethyl-2H-indazole-6-base) amino)-5-methylpyrimidine-4-base) amino)-3-azaspiro [5.5] undecane-3-t-butyl formate (1.04g, 2.00mmol) join the ethyl acetate solution (8mL of hydrogenchloride, 3mol/L), reaction mixture at room temperature stirs and spends the night, then concentrating under reduced pressure.The saturated Na of gained residue 2cO 3the aqueous solution (100mL) dilutes, then uses the mixed extractant solvent of DCM and MeOH (10/1,150mL x3), the organic phase anhydrous Na of merging 2sO 4drying, filters then concentrating under reduced pressure, and obtaining title compound is yellow solid (804mg, 95.8%).
MS(ESI,pos.ion)m/z:420.0[M+H] +。
step 4) 3-(9-((2-((2,3-dimethyl-2H-indazole-6-base) is amino)-5-methylpyrimidine-4-base) is amino)-3-azaspiro [5.5] undecane-3-base)-3-oxygen for propionitrile
By N 2-(2,3-dimethyl-2H-indazole-6-base)-5-methyl-N 4-(3-azaspiro [5.5] undecane-9-base) pyrimidine-2,4-diamines (203.2mg, 0.4843mmol), HOAT (105.8mg, 0.7773mmol) with EDCI (144.5mg, 0.7538mmol) be dissolved in the mixed solvent of DCM and DMF (4mL/1mL), and add triethylamine (209.1mg, 2.066mmol) and 2-cyanoacetic acid (48.1mg, 0.565mmol) wherein.Reaction mixture at room temperature stirs 2.5 hours, then concentrating under reduced pressure.Residue obtained through silica gel column chromatography (DCM/MeOH (v/v)=30/1) purifying, obtain title compound pale pink solid (48.4mg, 20.4%).
MS(ESI,pos.ion)m/z:487.3[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):8.52(s,1H),8.11(s,1H),7.60(s,1H),7.43(d,J＝8.9Hz,1H),7.05(d,J＝7.3Hz,1H),4.84(dd,J＝16.7,7.0Hz,1H),4.11(s,1H),4.03(d,J＝2.2Hz,3H),3.66–3.53(m,2H),3.51-3.34(m,4H),2.57(s,3H),2.05(d,J＝10.9Hz,2H),1.97(s,3H),1.75(d,J＝10.4Hz,2H),1.68-1.41(m,8H)。
embodiment 13 1-(9-((2-((2,3-dimethyl-2H-indazole-6-base) is amino)-5-methylpyrimidine-4-base) is amino)-3-azaspiro [5.5] undecane-3-base) second ketone
By N 2-(2,3-dimethyl-2H-indazole-6-base)-5-methyl-N 4-(3-azaspiro [5.5] undecane-9-base) pyrimidine-2,4-diamines (201.5mg, 0.4802mmol), HOAT (106.4mg, 0.7817mmol) with EDCI (145.7mg, 0.7600mmol) be dissolved in the mixed solvent of DCM and DMF (4mL/1mL), and add triethylamine (207.6mg, 2.052mmol) and acetic acid (36.7mg, 0.611mmol) wherein.Reaction solution at room temperature stirs 2 hours, then concentrating under reduced pressure.Residue obtained through silica gel column chromatography (DCM/MeOH (v/v)=30/1) purifying, obtaining crude product is faint yellow solid (92mg).Crude product is through the mixed solvent recrystallization of acetone and methyl alcohol (6mL/0.5mL), and it is white solid (50.4mg, 21.6%) that purifying obtains title compound.
MS(ESI,pos.ion)m/z:462.4[M+H] +。
Biological test
The LC/MS/MS system analyzed comprises the serial vacuum degassing furnace of Agilent 1200, binary syringe pump, orifice plate automatic sampler, post thermostat container, Agilent G6430 tri-grades of level Four bar mass spectrographs in charged spray ionization (ESI) source.Quantitative analysis is carried out under MRM pattern, and the parameter of MRM conversion is as shown in Table A:
Table A
Many reaction detection scanning 490.2→383.1
Cracked voltage 230V
Capillary voltage 55V
Dryer temperature 350℃
Spraying gun 40psi
Moisture eliminator flow velocity 10L/min
Analyze and use Agilent XDB-C18,2.1x 30mm, 3.5 μMs of posts, inject 5 μ L samples.Analysis condition: moving phase is the aqueous formic acid (A) of 0.1% and the formic acid methanol solution (B) of 0.1%.Flow velocity is 0.4mL/min.Eluent gradient is as shown in tableb:
Table B
Time The gradient of Mobile phase B
0.5min 5％
1.0min 95％
2.2min 95％
2.3min 5％
5.0min Stop
In addition, also have the serial LC/MS/MS spectrograph of Agilent 6330 for what analyze, be equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrograph adopts ESI radioactive source.Use reference liquid carries out suitable positively charged ion models treated to each analyte and best analysis is carried out in MRM conversion.During analyzing, use Capcell MP-C18 post, specification is: 100x 4.6mm I.D., 5 μMs (Phenomenex, Torrance, California, USA).Moving 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 remains on room temperature; Inject 20 μ L samples.
stability in embodiment A people and rat liver microsomes
People or rat liver microsomes are placed in polypropylen tubes duplicate hole hatch.Typically hatch mixed solution and comprise people or rat liver microsomes (0.5mg protein/mL), target compound (5 μMs) and cumulative volume are NADPH (1.0mM) potassium phosphate buffer (PBS of 200 μ L, 100mM, pH value is 7.4), by compound dissolution in DMSO, and using PBS to be diluted, the concentration of the DMSO solution making it final is 0.05%.And hatch in the water-bath communicated with air at 37 DEG C, preincubate adds albumen in backward mixed solution in 3 minutes and starts reaction.In different time point (0,5,10,15,30 and 60min), add same volume ice-cold acetonitrile termination reaction.Preserve until carry out LC/MS/MS analysis at sample Yu – 80 DEG C.
The concentration of compound in people or rat liver microsomes mixtures incubated is measured by the method for LC/MS/MS.The linearity range of concentration range is determined by each test-compound.
Parallelly hatch test and use the microsome of sex change as negative control, hatch at 37 DEG C, react and stop at different time points (0,15 and 60 minute).
Dextromethorphane Hbr (70 μ Μ), as positive control, is hatched at 37 DEG C, reacts and stops at different time points (0,5,10,15,30 and 60 minute).The positive and negative control sample is all comprised, to ensure the integrity of microsome incubation system in each measuring method.
In addition, the stability data of compound of the present invention in people or rat liver microsomes also can be obtained by following test.People or rat liver microsomes are placed in polypropylen tubes duplicate hole hatch.Typical mixtures incubated comprises people or rat liver microsomes (ultimate density: 0.5mg albumen/mL), compound (ultimate density: 1.5 μMs) and cumulative volume are that the K-buffered soln of 30 μ L is (containing 1.0mM EDTA, 100mM, pH 7.4).By compound dissolution in DMSO, and with the dilution of K-buffered soln, the ultimate density of DMSO is made to be 0.2%.Preincubate is after 10 minutes, and add 15 μ L NADPH (ultimate density: 2mM) and carry out enzymatic reaction, whole test is carried out in the incubation tube of 37 DEG C.At different time points (0,15,30 and 60 minute), add 135 μ L acetonitrile (containing IS) termination reactions.With 4000rpm centrifugal 10 minutes, except Deproteinization, collect supernatant liquor, analyze with LC-MS/MS.
In above-mentioned test, ketanserin (1 μM) is selected as positive control, hatches at 37 DEG C, reacts and stops at different time points (0,15,30 and 60 minute).All positive control sample is comprised, to ensure the integrity of microsome incubation system in each measuring method.
data analysis
For each reaction, by the plotted as percentage of the concentration of compound in people or rat liver microsomes are hatched (representing with per-cent) by Relative Zero time point, infer CLint CL in body with this int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.Prediction of human hepatic clearance from vivo animal experiments and in vitrometabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.).Result see table 1, the experimental result of compound stability in people and rat liver microsomes that table 1 provides for the embodiment of the present invention.
The experimental result of the compound that table 1 embodiment of the present invention provides stability in people and rat liver microsomes
As shown in Table 1, when being incubated in by the compounds of this invention in people and rat liver microsomes, compounds exhibit of the present invention goes out suitable stability.
embodiment B mouse, rat, dog and the monkey Pharmacokinetic Evaluation after intravenous injection and oral quantitative the compounds of this invention
The present invention assesses the pharmacokinetic of the compounds of this invention in mouse, rat, dog or monkey body.The compounds of this invention is with the aqueous solution of the aqueous solution or 2%HPMC+1% tween-80, and the salt brine solution of 5%DMSO+5%, 4%MC or capsule form carry out administration.For intravenous administration, animal gives the dosage of 1 or 2mg/kg.For oral dosage (p.o.), rat and mouse is 5 or 10mg/kg, and dog and monkey are 10mg/kg.Be within 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0,12 and 24 hour, get blood (0.3mL) at time point, and under 3,000 or 4,000rpm centrifugal 10 minutes.Collect plasma solutions, and preserve at-20 DEG C or-70 DEG C until carry out above-mentioned LC/MS/MS analysis.Result is see table 2, and the medicine of the compound that table 2 provides for the embodiment of the present invention in rat body is for the experimental result of feature.
The medicine of the compound that table 2 embodiment of the present invention provides in rat body is for the experimental result of feature
As shown in Table 2, during by compound intravenous injection administration provided by the invention or oral administration, compounds exhibit of the present invention goes out good pharmacokinetic property, comprises good absorption, desirable transformation period (T 1/2) oral administration biaavailability (F) of becoming reconciled.
embodiment C Kinase activity assays
The present invention's compound of coming into the open can be evaluated by experiment below as the effectiveness of kinases inhibitor.
The general description of kinase assay
Kinase assay by detection mix γ- 33the myelin basic protein (MBP) of P-ATP has come.Prepare MBP (Sigma#M-1891) Tutofusin tris buffer salt solution (TBS of 20 μ g/ml; 50mM Tris pH 8.0,138mM NaCl, 2.7mM KCl), wrap by white 384 orifice plates (Greiner) of high associativity, every hole 60 μ L.4 DEG C, hatch 24h.Plate is washed 3 times afterwards with 100 μ L TBS.Kinase reaction is kinase buffer liquid (5mM Hepes pH 7.6,15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), the 10mM MgCl of 34 μ L at cumulative volume 2, 1mM DTT, 0.02%TritonX-100) in carry out.By compound dissolution in DMSO, add in each hole, the ultimate density of DMSO is 1%.Each data determination twice, the mensuration of each compound at least carries out twice test.Such as, the ultimate density of enzyme is 10nM or 20nM.Add do not have markd ATP (10 μMs) and γ- 33aTP (every hole 2x 10 of P mark 6cpm, 3000Ci/mmol) start reaction.Reaction at room temperature concussion is carried out 1 hour.The PBS cleaning of 384 orifice plate 7x, then adds the scintillation solution of every hole 50 μ L.By Wallac Trilux counter detected result.To those of ordinary skill in the art, this is only the one in numerous detection method, and other method also can.
The IC that above-mentioned test method can be inhibited 50and/or suppress constant K i.IC 50be defined as under test conditions, suppress compound concentration during 50% enzymic activity.The extension rate of 1/2log is utilized to make the curve comprising 10 concentration point, estimation IC 50value (such as, making a typical curve by following compound concentration: 3 μMs, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM, 0.0003 μM, 0 μM).
JAK1(h)
JAK1 (h) at 20mM Tris/HCl pH 7.5,0.2mM EDTA, 500 μMs of GEEPLYWSFPAKKK, 10mM magnesium acetates and [γ- 33p-ATP] hatch under (specific activity is about 500cpm/pmol, and concentration is determined according to demand) existent condition.Reaction is started after adding MgATP mixture.After incubated at room temperature 40 minutes, add 3% phosphoric acid solution wherein and carry out termination reaction.Be mottled being distributed on P30 strainer by the reaction solution of 10 μ L, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once preserve.
JAK2(h)
JAK2 (h) at 8mM MOPS pH 7.0,0.2mM EDTA, 100 μMs of KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10mM magnesium acetates and [γ- 33p-ATP] hatch under (specific activity is about 500cpm/pmol, and concentration is determined according to demand) existent condition.Reaction is started after adding MgATP mixture.After incubated at room temperature 40 minutes, add 3% phosphoric acid solution wherein and carry out termination reaction.Be mottled being distributed on P30 strainer by the reaction solution of 10 μ L, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once preserve.
JAK3(h)
JAK3 (h) at 8mM MOPS pH 7.0,0.2mM EDTA, 500 μMs of GGEEEEYFELVKKKK, 10mM magnesium acetates and [γ- 33p-ATP] hatch under (specific activity is about 500cpm/pmol, and concentration is determined according to demand) existent condition.Reaction is started after adding MgATP mixture.After incubated at room temperature 40 minutes, add 3% phosphoric acid solution wherein and carry out termination reaction.Be mottled being distributed on P30 strainer by the reaction solution of 10 μ L, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once preserve.
TYK2(h)
TYK2 (h) at 8mM MOPS pH 7.0,0.2mM EDTA, 250 μMs of GGMEDIYFEFMGGKKK, 10mM magnesium acetates and [γ- 33p-ATP] hatch under (specific activity is about 500cpm/pmol, and concentration is determined according to demand) existent condition.Reaction is started after adding MgATP mixture.After incubated at room temperature 40 minutes, add 3% phosphoric acid solution wherein and carry out termination reaction.Be mottled being distributed on P30 strainer by the reaction solution of 10 μ L, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once preserve.
FLT3(h)
FLT3 (h) at 8mM MOPS pH 7.0,0.2mM EDTA, 50 μMs of EAIYAAPFAKKK, 10mM magnesium acetates and [γ- 33p-ATP] hatch under (specific activity is about 500cpm/pmol, and concentration is determined according to demand) existent condition.Reaction is started after adding MgATP mixture.After incubated at room temperature 40 minutes, add 3% phosphoric acid solution wherein and carry out termination reaction.Be mottled being distributed on P30 strainer by the reaction solution of 10 μ L, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once preserve.
Aurora-A(h)
Aurora-A (h) at 8mM MOPS pH 7.0,0.2mM EDTA, 200 μMs of LRRASLG (Kemptide), 10mM magnesium acetate and [γ- 33p-ATP] hatch under (specific activity is about 500cpm/pmol, and concentration is determined according to demand) existent condition.Reaction is started after adding MgATP mixture.After incubated at room temperature 40 minutes, add 3% phosphoric acid solution wherein and carry out termination reaction.Be mottled being distributed on P30 strainer by the reaction solution of 10 μ L, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once preserve.
Aurora-B(h)
Aurora-B (h) at 8mM MOPS pH 7.0,0.2mM EDTA, 30 μMs of AKRRRLSSLRA, 10mM magnesium acetates and [γ- 33p-ATP] hatch under (specific activity is about 500cpm/pmol, and concentration is determined according to demand) existent condition.Reaction is started after adding MgATP mixture.After incubated at room temperature 40 minutes, add 3% phosphoric acid solution wherein and carry out termination reaction.Be mottled being distributed on P30 strainer by the reaction solution of 10 μ L, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once preserve.
Kinase assay in the present invention has been come (Millipore UK Ltd, Dundee Technology Park, Dundee DD21SW, UK) by Millipore company of Britain.
In addition, the kinase activity of compound can pass through KINOMEscan tMdetect, this detection is based on use active-site directed type Competition binding assay method detection by quantitative compound.This test is undertaken by being combined with three kinds of compounds, i.e. DNA marker enzyme, and fixed ligand and detection compound, carry out the competitive capacity of qPCR detection compound and fixed ligands by DNA marker.
Major part experiment is all the T7 phage strains cultivating kinases mark from the escherichia coli host that BL21 bacterial strain derives, be in the intestinal bacteria of logarithmic phase with T7 phage-infect after, 32 DEG C of oscillation incubations are to bacteriolyze, cell debris is removed in lysate centrifuging, and remaining kinases forwards in HEK-293 cell and carries out qPCR detection with DNA marker.The particle of Streptavidin bag quilt, with after biotinylated smaller ligand room temperature treatment 30min, can produce affine resin for kinase assay.Part particle through unnecessary vitamin H close after, through confining liquid (SEABLOCK tM(Pierce), 1% bovine serum albumin, 0.05% tween 20,1mM DTT) clean unconjugated part, reduce non-specific binding.By the binding buffer liquid (20%SEABLOCK at 1x tM, 0.17x phosphate buffer soln, 0.05% polysorbas20, in conjunction with kinases 6mMDTT), part is affine particle and test compounds carry out association reaction, it is all carry out in 96 orifice plates that institute responds, reaction final volume is 0.135mL, shaken at room temperature hatches 1h, add lavation buffer solution (1x phosphate buffer soln, 0.05% polysorbas20) clean affine particle, add resuspended (the 1x phosphate buffer soln of elution buffer, 0.05% polysorbas20, 0.5 μM of non-biotinylated affinity ligand) after, shaken at room temperature hatches 30min, kinase whose concentration in elutriant is detected by qPCR.Kinase activity mensuration described in literary composition is the KINOMEscan at DiscoveRx company of the U.S. (Albrae St.Fremont, CA 94538, USA) tMdepartment, measures.
Kinase activity assays result see table 3 and table 4, the kinase assay result of the compound that table 3 provides for the embodiment of the present invention, JAK3, TYK2, Aurora-A and FLT3 kinase assay result of the compound that table 4 provides for the embodiment of the present invention
JAK1 and the JAK2 kinase assay result of the compound that table 3 embodiment of the present invention provides
NT: test
JAK3, TYK2, Aurora-A and FLT3 kinase assay result of the compound that table 4 embodiment of the present invention provides
NT: test
From table 3 and table 4, compound of the present invention generally demonstrates good activity to JAK1, JAK2, JAK3, TYK2, Aurora-A and FLT3 in kinase assay.
Finally, it should be noted that other modes are used for implementing the present invention in addition.Correspondingly, embodiments of the invention to be illustratively described, but be not limited to content described in the invention, may be also amendment done within the scope of the present invention or equivalents added in the claims.All publications that the present invention quotes or patent all will as reference of the present invention.

Claims (24)

1. a compound, its steric isomer for compound shown in the compound shown in formula (I) or formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug,
Wherein,
Z is C 7-C 12spiral shell bicyclic alkyl, C 7-C 12mix bicyclic group or 7-12 of condensed-bicyclic alkyl, 7-12 former molecular spiral shell formerly molecularly condenses assorted bicyclic alkyl, and wherein, Z is optionally by 1,2,3,4 or 5 R 3group replaced;
Z 1for H, C 1-C 12alkyl, C 3-C 12cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, Z 1optionally by 1,2,3,4 or 5 R 4group replaced;
A is indazolyl or Pyrazolopyridine base, and it is optionally by 1,2,3,4 or 5 R 5group replaced;
W is N;
R 1for H, F, Cl, Br, I, NO 2, N 3, CN, C 1-C 12alkyl, C 1-C 12haloalkyl, C 1-C 12alkoxyl group, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, 3-12 former molecular heterocyclic radical, C 6-C 12aryl, 5-12 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-C (=NR c) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, R 1optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 3be H, F, Cl, Br, I, NO independently 2, CN, N 3, OH, NH 2,-C (=O) CH 2cN, C 1-C 12alkyl, C 1-C 12haloalkyl, C 1-C 12alkoxyl group, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12the individual former molecular heterocyclic radical of aryl, 3-12,5-12 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-S (=O) 2r 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-O (CR 7r 8) n-OR c,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-C (=NR c) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, or the R that two adjacent 3, and together with the atom be connected with them, form C 3-C 12cycloalkyl or 3-12 former molecular heterocycloalkyl, wherein, above-mentioned each substituting group is independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 4and R 5be separately H, F, Cl, Br, I, NO 2, CN, N 3, C 1-C 12alkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl ,-(C 1-C 4alkylidene group)-(C 3-C 12cycloalkyl), C 6-C 12aryl, 3-12 former molecular heterocyclic radical ,-(C 1-C 4alkylidene group)-(3-12 former molecular heterocyclic radical), 5-12 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-C (=NR c) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, above-mentioned each R 4and R 5independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 6be H, C independently 1-C 12alkyl, C 1-C 12haloalkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, wherein, each R 6independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 7and R 8be separately H, F, Cl, Br, I, NO 2, N 3, CN, C 1-C 12alkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, or R 7and R 8, and together with the carbon atom be connected with them, form C 3-C 12cycloalkyl, C 6-C 12aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl groups, wherein, above-mentioned each substituting group is independent optionally by 1,2,3,4 or 5 R 9group replaced;
Each R 9be F, Cl, Br, I, CN, NO independently 2, N 3, C 1-C 12alkyl, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, C 6-C 12the individual former molecular heterocyclic radical of aryl, 3-12,5-12 former molecular heteroaryl, NH 2,-NH (C 1-C 12alkyl) ,-NH (CH 2) n-(C 3-C 12cycloalkyl) ,-NH (CH 2) n-(C 6-C 12aryl) ,-NH (CH 2) n-(3-12 former molecular heterocyclic radical) ,-NH (CH 2) n-(5-12 former molecular heteroaryl) ,-N (C 1-C 12alkyl) 2,-N [(CH 2) n-(C 3-C 12cycloalkyl)] 2,-N [(CH 2) n-(C 6-C 12aryl)] 2,-N [(CH 2) n-(3-12 former molecular heterocyclic radical)] 2,-N [(CH 2) n-(5-12 former molecular heteroaryl)] 2, OH ,-O (C 1-C 12alkyl) ,-O (CH 2) n-(C 3-C 12cycloalkyl) ,-O (CH 2) n-(C 6-C 12aryl) ,-O (CH 2) n-(3-12 former molecular heterocyclic radical) or-O (CH 2) n-(5-12 former molecular heteroaryl);
Each R a, R band R cbe separately H, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl ,-(C 1-C 4alkylidene group)-(C 3-C 6cycloalkyl), 3-6 former molecular heterocyclic radical ,-(C 1-C 4alkylidene group)-(3-6 former molecular heterocyclic radical), C 6-C 10aryl ,-(C 1-C 4alkylidene group)-(C 6-C 10aryl), 5-10 former molecular heteroaryl or-(C 1-C 4alkylidene group)-(5-10 former molecular heteroaryl), or R aand R b, and together with the nitrogen-atoms be connected with them, form 3-8 former molecular heterocyclyl groups, wherein, above-mentioned each substituting group is independent is optionally independently selected from F, Cl, Br, CN, N by 1,2,3 or 4 3, OH, NH 2, C 1-C 6alkyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group or C 1-C 6the substituting group of alkylamino replaced;
Each m is 1 or 2 independently; With
Each n is 0,1,2,3 or 4 independently.
2. compound according to claim 1, wherein, Z is C 8-C 11spiral shell bicyclic alkyl, C 8-C 10mix bicyclic group or 8-10 of condensed-bicyclic alkyl, 8-11 former molecular spiral shell formerly molecularly condenses assorted bicyclic alkyl, and wherein, Z is optionally by 1,2,3 or 4 R 3group replaced.
3. compound according to claim 1, wherein, Z 1for H, C 1-C 6alkyl, C 3-C 6cycloalkyl or 3-6 former molecular heterocyclic radical, wherein, Z 1optionally by 1,2 or 3 R 4group replaced.
4. compound according to claim 1, wherein, R 1for H, F, Cl, CN, N 3, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6haloalkyl, C 1-C 6alkoxyl group, C 3-C 6cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-(CR 7r 8) nc (=O) NR ar bor-S (=O) 2nR ar b, wherein, R 1optionally by 1,2 or 3 R 9group replaced.
5. compound according to claim 1, wherein, each R 3be H, F, Cl, CN, N independently 3, NO 2, OH, NH 2,-C (=O) CH 2cN, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 1-C 6alkoxyl group, C 1-C 6haloalkyl, C 3-C 6the individual former molecular heterocyclic radical of cycloalkyl, phenyl, 3-6,5-6 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-S (=O) 2r 6,-O (CR 7r 8) n-R 6,-O (CR 7r 8) n-OR c,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) NR ar b,-N (R c) C (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, or the R that two adjacent 3, and together with the atom be connected with them, form C 3-C 6cycloalkyl or 3-6 former molecular heterocycloalkyl, wherein, above-mentioned each substituting group is independent optionally by 1,2 or 3 R 9group replaced.
6. compound according to claim 1, wherein, each R 4and R 5be separately H, F, Cl, Br, I, NO 2, N 3, CN, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl ,-(C 1-C 2alkylidene group)-(C 3-C 6cycloalkyl), phenyl, 3-6 former molecular heterocyclic radical ,-(C 1-C 2alkylidene group)-(3-6 former molecular heterocyclic radical), 5-6 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-OC (=O) R 6,-O (CR 7r 8) n-R 6,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) OR c,-(CR 7r 8) nc (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, each R 4and R 5independent optionally by 1,2 or 3 R 9group replaced.
7. compound according to claim 1, wherein, each R 6be H, C independently 1-C 6alkyl, C 1-C 6haloalkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, wherein, each R 6independent optionally by 1,2 or 3 R 9group replaced.
8. compound according to claim 1, wherein, each R 7and R 8be separately H, F, Cl, Br, I, CN, N 3, NO 2, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, or R 7and R 8, and form C together with the carbon atom be connected with them 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl groups, wherein, above-mentioned each substituting group is independent optionally by 1,2 or 3 R 9group replaced.
9. compound according to claim 1, wherein, each R 9be F, Cl, CN, N independently 3, C 1-C 6alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6the individual former molecular heterocyclic radical of cycloalkyl, phenyl, 3-6,5-6 former molecular heteroaryl, NH 2,-NH (C 1-C 6alkyl) ,-NH (CH 2) n-(C 3-C 6cycloalkyl) ,-NH (CH 2) n-phenyl ,-NH (CH 2) n-(3-6 atom composition heterocyclic radical) ,-NH (CH 2) n-(5-6 former molecular heteroaryl) ,-N (C 1-C 4alkyl) 2,-N [(CH 2) n-(C 3-C 6cycloalkyl)] 2,-N [(CH 2) n-phenyl] 2,-N [(CH 2) n-(3-6 former molecular heterocyclic radical)] 2,-N [(CH 2) n-(5-6 former molecular heteroaryl)] 2, OH ,-O (C 1-C 6alkyl) ,-O (CH 2) n-(C 3-C 6cycloalkyl) ,-O (CH 2) n-phenyl ,-O (CH 2) n-(3-6 former molecular heterocyclic radical) or-O (CH 2) n-(5-6 former molecular heteroaryl).
10. compound according to claim 1, wherein, each R a, R band R cbe separately H, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 3-C 6cycloalkyl ,-(C 1-C 2alkylidene group)-(C 3-C 6cycloalkyl), 3-6 former molecular heterocyclic radical ,-(C 1-C 2alkylidene group)-(3-6 former molecular heterocyclic radical), phenyl ,-(C 1-C 2alkylidene group)-phenyl, a 5-6 former molecular heteroaryl or-(C 1-C 2alkylidene group)-(5-6 former molecular heteroaryl), or R aand R b, and together with the nitrogen-atoms be connected with them, form 3-6 former molecular heterocyclyl groups, wherein, above-mentioned each substituting group is independent is optionally independently selected from F, Cl, CN, N by 1,2 or 3 3, OH, NH 2, C 1-C 4alkyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group or C 1-C 4the substituting group of alkylamino replaced.
11. compounds according to claim 1, wherein, Z is following subformula:
Or their steric isomer, wherein, each X, X ', X 2and X 3be separately CH 2, NH or O, condition works as X 2when being O, X 3be not O; Each minor structure shown in formula (Z-1) ~ (Z-54) or its steric isomer are independently optionally by 1,2 or 3 R 3group replaced.
12. compounds according to claim 1, wherein, A is following subformula:
Wherein, formula (M), (N), (Q) or the minor structure shown in (T) are independent optionally by 1,2 or 3 R 5group replaced.
13. compounds according to claim 1, wherein, Z 1for H, methyl, ethyl, n-propyl, sec.-propyl or cyclopropyl.
14. compounds according to claim 1, wherein, R 1for H, F, Cl, CN, N 3, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 1-C 4haloalkyl, C 1-C 4alkoxyl group, C 3-C 6cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-(CR 7r 8) nc (=O) NR ar bor-S (=O) 2nR ar b, wherein, R 1optionally by 1,2 or 3 R 9group replaced.
15. compounds according to claim 1, wherein, each R 3be H, F, Cl, CN, N independently 3, NO 2, OH, NH 2,-C (=O) CH 2cN, C 1-C 4alkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 1-C 4alkoxyl group, C 1-C 4haloalkyl, C 3-C 6the individual former molecular heterocyclic radical of cycloalkyl, phenyl, 3-6,5-6 former molecular heteroaryl ,-(CR 7r 8) n-OR c,-(CR 7r 8) n-NR ar b,-C (=O) R 6,-S (=O) 2r 6,-O (CR 7r 8) n-R 6,-O (CR 7r 8) n-OR c,-N (R c) C (=O) R 6,-(CR 7r 8) nc (=O) NR ar b,-N (R c) S (=O) mr 6or-S (=O) 2nR ar b, wherein, each R 3independent optionally by 1,2 or 3 R 9group replaced.
16. compounds according to claim 1, wherein, each R 6be H, C independently 1-C 4alkyl, C 1-C 4haloalkyl, C 2-C 4thiazolinyl, C 2-C 4alkynyl, C 3-C 6cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, wherein, each R 6independent optionally by 1,2 or 3 R 9group replaced.
17. compounds according to claim 1, have one of them structure following:
or its steric isomer, tautomer, oxynitride, solvate or pharmacy acceptable salt.
18. 1 kinds of pharmaceutical compositions, it comprises the compound described in claim 1-17 any one.
19. pharmaceutical compositions according to claim 18, wherein comprise pharmaceutically acceptable vehicle, carrier, adjuvant, solvent or their combination further.
20. pharmaceutical compositions according to claim 18 or 19, wherein comprise therapeutical agent further, described therapeutical agent is selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 inhibitors, beta-2-adrenoreceptor agonists, reflunomide, nonsteroidal GR agonist, anticholinergic, antihistaminic, anti-inflammatory reagent, immunosuppressor, immunomodulator, is used for the treatment of atherosclerotic medicine, is used for the treatment of the medicine of pulmonary fibrosis and their combination.
Described in compound described in 21. claim 1-17 any one or claim 18-20 any one, pharmaceutical composition is preparing the purposes in medicine, and described medicine is for preventing, processing, treat or alleviate protein kinase mediated disease.
22. purposes according to claim 21, wherein said protein kinase mediated disease is the disease of JAK-mediation, the disease of FLT3-mediation, the disease of Aurora-mediation, proliferative disease, autoimmune disorders, anaphylactic disease, inflammatory diseases, transplant rejection, cancer, polycythemia vera, primary thrombocytosis, myelofibrosis, acute myelocytic leukemia, chronic granulocytic leukemia, acute lymphoblastic leukemia, chronic obstructive pulmonary disease, asthma, systemic lupus erythematous, skin lupus erythematosus, systemic lupus erythematosus, dermatomyositis, sjogren syndrome, psoriatic, type i diabetes, respiratory anaphylactic disease, sinusitis paranasal sinusitis, eczema, measles, food anaphylaxis, insect venom allergies, inflammatory bowel, Crohn's disease, rheumatoid arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplant rejection.
Described in compound described in 23. claim 1-17 any one or claim 18-20 any one, pharmaceutical composition is preparing the purposes in medicine, and described medicine is used for the kinase whose activity of Function protein.
24. purposes according to claim 23, wherein said protein kinase is jak kinase, FLT3 kinases, Aurora A or their combination.
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Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd.

Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei

Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd.

CP03 Change of name, title or address