CN109553604A - 4- aminopyridine derivative makees CXCR4 inhibitor and its application - Google Patents

4- aminopyridine derivative makees CXCR4 inhibitor and its application Download PDF

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CN109553604A
CN109553604A CN201811034891.7A CN201811034891A CN109553604A CN 109553604 A CN109553604 A CN 109553604A CN 201811034891 A CN201811034891 A CN 201811034891A CN 109553604 A CN109553604 A CN 109553604A
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alkyl
atom
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methylene chloride
cxcr4
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CN109553604B (en
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张小虎
郑计岳
马海阔
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Shengshi Taike Biopharmaceutical Technology (Suzhou) Co.,Ltd.
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SUZHOU YUNXUAN PHARMACEUTICAL Co Ltd
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Priority to KR1020207010206A priority Critical patent/KR20200058443A/en
Priority to US16/649,983 priority patent/US11396501B2/en
Priority to JP2020538760A priority patent/JP7282786B2/en
Priority to PCT/US2018/052503 priority patent/WO2019060860A1/en
Priority to EP18859565.6A priority patent/EP3687540A4/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Abstract

The present invention provides a kind of heterocyclic compound and its pharmaceutically acceptable salt, isotope, isomers and crystalline structure with CXCR4 signal path inhibitory activity, the compound have structure shown in general formula I:The present invention also provides the applications of the above-mentioned heterocyclic compound with CXCR4 signal path inhibitory activity.Heterocyclic compound with CXCR4 signal path inhibitory activity of the invention can be used in treating or preventing response in the illness of CXCR4 receptor antagonist as effective antagonist of CXCR4 signal path.

Description

4- aminopyridine derivative makees CXCR4 inhibitor and its application
Technical field
The present invention relates to a kind of heterocyclic compound with CXCR4 inhibitory activity, the composition comprising the compound, use In the purposes of the method and the compound for preparing the compound in medicine, especially for therapeutic response in CXCR4 The illness of receptor antagonist such as cancer, cancer metastasis, HIV, HIV related disease, brain inflammation, diabetic retinopathy, age phase It closes macular degeneration and retina angiocarpy forms the purposes of disease；The invention further relates to the compounds in stem cell collection art method In purposes comprising for example before harvest promote stem cell release and mobilization, the stem cell include candidate stem cell, Non-hematopoietic stem cell and ancestral stem cell.The invention belongs to pharmaceutical technology fields.
Background technique
CXCR4 belongs to 7 transmembrane G-protein coupled receptors (GPCR), and endogenic ligand is chemotactic factor (CF) SDF-1 (matrix Cell derived factor -1), also known as CXCL12.CXCR4 is found to be expressed in T cell earliest, as the co-receptor of T4 antigen, In conjunction with the glycoprotein gp120 of human immunodeficiency virus (HIV), mediate retroviral invades the process of host T cell.Follow-up study Show the release and mobilization that inhibit CXCR4 to peomote stem cell, is combined with granulocyte colony stimulating factor (G-CSF), it can To improve the stem cell mobilization result of candidate stem cell and endothelial progenitor cells.CXCR4/SDF-1 interaction or cancer are dry thin The main adjusting factor that born of the same parents transport in human body, plays a significant role in the progress and transfer of multiple types cancer cell.Due to These important biomolecule functions that CXCR4 is mediated, CXCR4 inhibitor are expected to be used for stem cell transplantation and for treating disease (cancer Disease, HIV, diabetic retinopathy, inflammation etc.).
Hematopoietic stem cell mobilization
Candidate stem cell (HSC) is widely used for treating the disease of hemopoietic system, such as Huppert's disease and non-Hodgkin's Lymthoma.Cell toxicity medicament can also kill hematopoietic cells while killing tumor cell.Candidate stem cell It mobilizes and harvests, stem cell can be fed back after drug therapy in vivo again, be reintroduced back to hemopoietic system.
In general, high expression CXCR4 on stem cell and progenitor cells, and with the SDF-1 of high concentration in marrow.Therefore, it does thin Born of the same parents and progenitor cells can be attracted to marrow and be retained in marrow.The interaction for inhibiting CXCR4 and SDF-1 can make dry thin Born of the same parents or progenitor cells leave marrow, into peripheral blood, so as to dynamic from donor (allograft) or patient's (autotransplantation) Stem cell (Prog Mol Biol Transl Sci.2012 of the member for transplanting；111,243-264.).CXCR4 inhibitor is also It can be combined with another mobilization agent G-CSF, improve it and mobilize efficiency and success rate.
HIV and HIV are ache related
CXCR4 and CCR5 is the accessory receptor (Cell.1996 that HIV enters host cell；87,745-56.).Inhibit CXCR4 can reduce the infectivity of viral X4 strain.Thus CXCR4 inhibitor can effectively treat HIV infection, especially with The combination of CCR5 inhibitor.The inhibition of HIV of X4 preferendum is most pathogenic, and tends to occupy advantage in the late stage of infection, and The stage, neuropathic pain became the problem of getting worse for patients.CXCR4 inhibitor has antiviral and alleviates refreshing Characteristic through property pain can be combined with other HIV therapy drugs and analgesic, and treatment HIV and HIV is ache related.
Pain and inflammation
There is CXCR4 expression in Primary Sensory Neuron, therefore CXCR4 inhibitor can serve as analgestic control pain (J Neurosci.2001,21,5027-35).Inhibit CXCR4 can mitigate allergic respiratory eosinophils and Respiratory response (J.Immunol.2000,165,499-508.).
SDF-1/CXCR4 access passes through the efficient chemotactic to inflammatory cells such as neutrophil leucocyte, lymphocyte, monocytes Effect, the rolling for activating integrin inducing cell and close adhesion promote inflammatory cell to pass through blood in the endothelial cell of activation Endothelial tube reaches inflammation part, thus inducing inflammatory reaction (J.Immunol.2000,164,5035-5040.).Rheumatoid arthrosis Scorching synovial membrane height expresses SDF-1, attracts the memory T cell of expression CXCR4 largely to assemble in intrasynovial, and inhibit withering for the T cell It dies.In addition, SDF-1 is significantly raised in Patients with SLE blood, SpA, rheumatoid arthritis and psoriasis The peripheral blood mononuclear cells expression CXCR4 of arthritic is increased extremely, and polymyositis and patient with dermatomyositis also detect that SDF-1/CXCR4 is abnormal, and SDF-1/CXCR4 is prompted to play a significant role in immune and inflammatory process.Inhibit CXCR4 and SDF- 1 interaction will be helpful to alleviate inflammatory reaction.
Retina neovascular is formed
The main reason for retina neovascular formation is diabetic and age related macular degeneration blindness.SDF- 1/CXCR4 biology axis participates in the neovascularization of eye significantly, is the target for treating related retinopathy.Block CXCR4 by Body can prevent the recruitment of endothelial progenitor cells, to prevent the formation (FASEB J.2007,21,3219-30.) of new capilary. Also, CXCR4 inhibitor and with VEGFR antibody when inhibiting angiogenesis have potential addition.
Cancer and cancer metastasis
SDF-1/CXCR4 plays an important role in the occurrence and development, transfer and recurrence of tumour.SDF-1 and CXCR4 is swollen High expression in tumor tissue.The SDF-1 of tumor microenvironment middle and high concentration can attract the CXCR4 positive immunosuppressant cell Treg and MDSC migration is gathered in tumour, inhibits the effector T cell and M1 type macrophage in tumor microenvironment, it is made not go attack Tumour cell, to realize immunologic escape (Cancer Immunology Research 2014,2,187-193.).In addition, In the tumour such as cancer of pancreas of FAP protein positive, the SDF-1 meeting repelling effect T cell of high concentration enters tumor microenvironment, makes tumour Tissue is not infiltrated by T cell, thus realize immunologic escape (Proc Natl Acad Sci USA.2013,110,20212- 20217.).Inhibit CXCR4 that can assemble in tumour to avoid immunosuppressant cell Treg and MDSC, and enters effector T cell Tumor tissues, to enhance immune system to the killing ability of tumour.CXCR4 inhibitor and other tumour immunotherapies are such as The combinations such as PD-1 antibody or PD-L1 antibody, CTLA-4 antibody have additive effect, can extend being applicable in for the tumour immunotherapy Crowd improves response rate.
SDF-1 activates downstream EGFR, PI3K, MAPK, a plurality of signal path such as Wnt in conjunction with the CXCR4 on tumour cell Promote cell Proliferation, while the expression inhibiting Apoptosis of also activation NF-KB signal path and up-regulation BCL-2 gene, thus directly Connect promotion tumour growth.SDF-1/CXCR4 also passes through the expression of up-regulation VEGF, recruits the various ways such as endothelial progenitor cells rush simultaneously Into Tumor Angiongesis, promote tumour growth indirectly.SDF-1 activates CXCR4 downstream passages, promotes epithelial cell interstitial transition, Enhance the invasive ability of tumour cell.SDF-1 continues in the normal tissues such as marrow, lymph node, liver, lung and brain endothelium simultaneously Height is expressed, and attracts, recruits the tumour cell especially tumor stem cell of the CXCR4 positive to move to these normal tissues.It is clinical It was found that the most common histoorgan of metastases is bone, liver, brain, lung and adrenal gland, it is the tissue of SDF-1 height expression, and And the tumor stem cell ratio of the CXCR4 positive is significantly higher than primary tumor in transfer stove, shows that SDF-1/CXCR4 turns in tumour Play a significant role in shifting.CXCR4 is blocked, the proliferation and transfer (Oncogene2015,1-11.) that inhibit tumour are facilitated.
CXCR4 and SDF-1 also participate in the maintenance of tumor stem cell and tumor recurrence and drug resistance after radiotherapy/chemotherapy.It is putting Treat or while chemotherapy or after, using CXCR4 inhibitor, help to enhance tumour to the sensibility of chemicotherapy, reduce multiple Hair rate (Clinical Cancer Research 2011,17,2074-2080.).
The CXCR4 inhibitor listed has AMD3100, but AMD3100 at physiological ph can be at 4 salt, biological permeable membrane Property is poor, it is caused not have oral administration biaavailability.To AMD3100 structure optimization, a series of tetrahydros with long chain amino are obtained Isoquinoline compound, wherein representative compound be AMD070 (J.Med.Chem.2010,53,3376-3388., WO2004106493).AMD070 has certain oral administration biaavailability, but due to there is a strong basicity center (ammonia in structure Base side chain), having very strong inhibitory activity to liver enzyme (is 100%, Bioorg Med to the inhibiting rate of CYP2D6 at 1 μM Chem Lett.2015,25,4950-4955.).Although AMD070 enters the second stage of clinic, but final because of preclinical laboratory It was found that hepatotoxicity wind agitation and terminate clinical trial.
Summary of the invention
In view of the problems of the above-mentioned prior art, the purpose of the present invention is to propose to a kind of with CXCR4 inhibitory activity Heterocyclic compound and its application, there is the heterocyclic compound of CXCR4 inhibitory activity can effectively inhibit CXCR4 access for this, can For treating or preventing response in the illness of CXCR4 receptor antagonist.
The purpose of the present invention is achieved by the following technical programs:
A kind of heterocyclic compound and its pharmaceutically acceptable salt, isotope, isomers with CXCR4 inhibitory activity And crystalline structure, there is structure shown in general formula I:
Wherein, wherein A1, A2, A3It is respectively and independently selected from N or CR10, and A1, A2, A3A minimum of one is N；
W is
U is
Q is chemical bond or CR23R24；
R1, R2, R3, R4It is respectively and independently selected from hydrogen atom, D-atom, cyano, halogen, hydroxyl, amino, NHC1-6Alkyl, N (C1-6Alkyl)2、NHCOC1-6Alkyl, NHCOOC1-6Alkyl, NHSO2C1-6Alkyl, C1-6Alkyl, C3-6Naphthenic base, C1-8Alkoxy, C2-6Alkenyl, C2-6Alkynyl, the alkyl and alkoxy are unsubstituted or replaced by 1-3 halogen or D-atom；R1, R2, R3, R4 Preferably it is respectively and independently selected from hydrogen atom, D-atom, cyano, halogen, hydroxyl, C1-6Alkyl, C3-6Naphthenic base, C1-8Alkoxy, C2-6Alkenyl, C2-6Alkynyl, the alkyl and alkoxy are unsubstituted or replaced by 1-3 halogen or D-atom；
R5, R6It is respectively and independently selected from hydrogen atom, D-atom, C1-6Alkyl or C3-6Naphthenic base, the alkyl it is unsubstituted or Halogen, D-atom, hydroxyl, amino, NHC are selected from by 1-31-6Alkyl, N (C1-6Alkyl)2、NHCOC1-6Alkyl, NHCOOC1-6Alkane Base, C1-3The substituent group of alkoxy replaces；Or R4With R5And its atom connected can interconnect cyclization；
R7Selected from hydrogen atom, C1-6Alkyl, C3-6Naphthenic base or C3-6Heterocyclylalkyl, the alkyl are unsubstituted or by 1-3 It is a to be selected from halogen, D-atom, C3-6Naphthenic base or C3-6The substituent group of Heterocyclylalkyl replaces, and the Heterocyclylalkyl contains 1 O original Son；
R8, R9It is respectively and independently selected from hydrogen atom, D-atom, cyano, C1-6Alkyl or C3-6Naphthenic base, the alkyl are not taken In generation, is selected from halogen, D-atom, hydroxyl, C by 1-31-3The substituent group of alkoxy replaces；Or R8, R9And its original connected Son can interconnect cyclization；
R10Selected from hydrogen atom, D-atom, halogen, cyano, hydroxyl, amino, C1-6Alkyl, C3-6Naphthenic base, C1-8Alkoxy, NHC1-6Alkyl, N (C1-6Alkyl)2、C(O)NHC1-6Alkyl, C (O) N (C1-6Alkyl)2、SC1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, 4-7 circle heterocyclic ring base, 6 yuan of aryl, 5-6 unit's heteroaryl, the alkyl, alkoxy, heterocycle, aryl, heteroaryl it is unsubstituted or Halogen, D-atom, hydroxyl, C are selected from by 1-31-3The substituent group of alkoxy replaces；
R11Selected from hydrogen atom, C1-6Alkyl, C3-6Naphthenic base, the alkyl are unsubstituted or former selected from halogen, deuterium by 1-3 Son, hydroxyl, amino, NHC1-6Alkyl, N (C1-6Alkyl)2、C1-3The substituent group of alkoxy replaces；
R12, R13, R14, R15, R18, R19, R20, R21, R23, R24Separately it is selected from hydrogen atom, D-atom, cyano, hydroxyl Base, C1-6Alkyl, C3-6Naphthenic base, C1-3Alkoxy, the alkyl and alkoxy are unsubstituted or former selected from halogen, deuterium by 1-3 Son, hydroxyl, amino, NHC1-6Alkyl, N (C1-6Alkyl)2、NHCOC1-6Alkyl, NHCOOC1-6Alkyl, C1-3The substituent group of alkoxy Replace；Or R11With R14And its atom connected can interconnect cyclization；Or R19With R12Or R15And its original connected Son can interconnect cyclization；
R16, R17Separately it is selected from hydrogen atom, C1-6Alkyl, C3-6Naphthenic base, C3-6Heterocyclylalkyl, COC1-6Alkyl, COOC1-6Alkyl, CONHC1-6Alkyl, the alkyl is unsubstituted or is selected from halogen, D-atom, hydroxyl, cyano, C by 1-33-6 Naphthenic base, C1-3Alkoxy, C3-6The substituent group of Heterocyclylalkyl replaces, and the Heterocyclylalkyl contains 1 hetero atom for being selected from O or N； Or R16With R17And its atom connected can be interconnected into 5-7 circle heterocyclic ring；Or R16With R15And its atom connected can It is interconnected into 5-7 circle heterocyclic ring；
R22Selected from hydrogen atom, C1-6Alkyl, C3-6Naphthenic base, C3-8Heterocyclylalkyl, the alkyl, naphthenic base or Heterocyclylalkyl It is unsubstituted or a selected from halogen, D-atom, hydroxyl, cyano, C by 1-33-6Naphthenic base, C1-3Alkoxy, C1-6Sulfuryl, C1-6Acyl Base, C3-6The substituent group of Heterocyclylalkyl replaces, and the Heterocyclylalkyl contains 1 hetero atom for being selected from O or N；Or R22With R15And Its atom connected can interconnect cyclization.
In the above-mentioned heterocyclic compound with CXCR4 inhibitory activity, it is preferred that its W is selected from Wherein, X, Y, Z are separately selected from CR25R26Or O；R25, R26It is separately former selected from hydrogen Son, D-atom, halogen, C1-3Alkyl；Or R25With R26And its carbon atom connected can interconnect cyclization.
In the above-mentioned heterocyclic compound with CXCR4 inhibitory activity, it is preferred that X, Y, Z are separately selected from CH2, O,And X, Y, Z a minimum of one is
In the above-mentioned heterocyclic compound with CXCR4 signal path inhibitory activity, it is preferred that A3It is independently selected from CR10, A1, A2It is respectively and independently selected from N or CR10, and A1, A2A minimum of one is N；
W is
In the above-mentioned heterocyclic compound with CXCR4 inhibitory activity, it is preferred that W is selected from unsubstituted or a by 1-3 Selected from D-atom, cyano, halogen, C1-3Alkyl, C1-3The following groups that the substituent group of alkoxy replaces:
In the above-mentioned heterocyclic compound with CXCR4 inhibitory activity, it is preferred that U is unsubstituted or is independently selected by 1-3 From a D-atom, halogen, hydroxyl, C1-3Alkyl, C1-3Any one of the following groups that the substituent group of alkoxy replaces:
In the above-mentioned heterocyclic compound with CXCR4 inhibitory activity, it is preferred that the heterocyclic compound includes:
The present invention also provides a kind of pharmaceutical composition, described in one or more any of the above-described it includes therapeutically effective amount The heterocyclic compound and its pharmaceutically acceptable salt, isotope, isomers, crystal form with CXCR4 access inhibitory activity, and Further include at least one pharmaceutically acceptable carrier.
The present invention also provides a kind of use in conjunction compositions comprising by above-mentioned with CXCR4 access inhibitory activity It is heterocyclic compound and its pharmaceutically acceptable salt, isotope, isomers or crystal form and anti-tumor drug, antibacterials, disease-resistant The combination of one or more of cytotoxic drug, medicine for central nervous system, diabetes medicament carries out the combination that use in conjunction obtains Object.
The heterocyclic compound and its pharmaceutically acceptable salt that the present invention also provides above-mentioned with CXCR4 inhibitory activity, The application of isotope, isomers or crystal form in the drug for preparing antagonism CXCR4；
According to specific embodiment, in the present invention, it is preferred that isotope includes but is not limited solely to2H,3H,11C,13C,14C ,15N,17O,18O,18F,32P,35S,36Cl etc..Various isomers, including but not limited to stereoisomer, cis-trans-isomer, mutually Tautomeric etc..
Protrusion effect of the invention are as follows:
Heterocyclic compound with CXCR4 inhibitory activity of the invention, be obtained after a large amount of screening compounds it is excellent Choosing is as a result, wherein the link position of U group is particularly significant, when U group changes into and A3When being connected (control compounds B4), it can lose Go the inhibitory activity of CXCR4；Moreover, two N on U group are also particularly significant, remove a N (control compounds B3) or do not have The inhibitory activity of CXCR4 can be lost by having N (control compounds B2) all；Meanwhile on pyrimidine ring N position to the activity ten of CXCR4 Divide key, change pyrimidine ring into pyridine ring (control compounds B5 and B6) or changes the pyrimidine ring (comparison of other connection types into Compound B7 and B8), it can all lose the inhibitory activity of CXCR4.Heterocyclic compound of the present invention is as the effective short of money of CXCR4 Anti-agent can be used in treating or preventing response in the illness of CXCR4 receptor antagonist；It is of the invention with CXCR4 inhibitory activity Heterocyclic compound, it is weak to the rejection ability of CYP liver enzyme, compared to clinical compounds AMD070, there is better drug phase interaction Use safety.
Detailed description of the invention
Fig. 1 is the test result curve graph of heterocyclic compound A42 in embodiment 62；
Fig. 2 is the test result curve graph of heterocyclic compound A43 in embodiment 62；
Fig. 3 is the test result curve graph of heterocyclic compound A78 in embodiment 63；
Fig. 4 is the test result curve graph of heterocyclic compound A83 in embodiment 63.
Specific embodiment
In order to which technical characteristic of the invention, purpose and beneficial effect are more clearly understood, now to skill of the invention Art scheme carries out described further below, but should not be understood as that limiting the scope of the invention.Institute in following embodiments Experimental method is stated, is conventional method unless otherwise specified；The reagent and material unless otherwise specified can be from business ways Diameter obtains.
In following embodiments, solvent for use and drug are that analysis is pure or chemical pure；Solvent is passed through using preceding Re-distillation；Anhydrous solvent is handled according to standard method or literature method.Column chromatography silica gel (100-200 mesh) and thin layer Chromatographic silica gel (GF254) is Haiyang Chemical Plant, Qingdao and Yantai chemical plant product；If not otherwise specified, it is all made of petroleum ether (60- 90 DEG C)/ethyl acetate (v/v) be used as eluant, eluent；The ethanol solution of color developing agent iodine or phosphomolybdic acid；All extractants are without saying It is bright to use anhydrous Na2SO4It is dry.1HNMR is recorded with varian-400 type Nuclear Magnetic Resonance, and TMS is internal standard.The U.S. LC-MS 1100 type HPLC- ESI- MSn combined instrument (LC-MSDTrap) of Agilent company record, Diode Array Detector Device (DAD), Detection wavelength 214nm and 254nm, ion trap mass spectrometry (source ESI).HPLC column is AgelaDurashellC18 (4.6 × 50mm, 3.5 μm)；Mobile phase is 0.1%NH4HCO3 aqueous solution: acetonitrile (from 5: 95 to 95: 5 in 5 minutes)；Flow velocity is 1.8mL/min。
Embodiment 1
Heterocyclic compound A1, synthesizes by the following method:
1) synthesis of intermediate A 1-2:
Intermediate A 1-1 (280mg, 1.9mmol synthesize document see WO2016128529) is dissolved in methylene chloride (10mL), Thionyl chloride (280mg, 2.3mmol) is added dropwise under ice bath, continues to be stirred overnight, sodium bicarbonate solution, methylene chloride is added (50mL) is extracted three times, and mutually drying is spin-dried for methylene chloride, obtains light yellow oil (180mg, 58%).
2) synthesis of intermediate A 1-4:
Intermediate A 1-3 (160mg, 1mmol synthesize document see WO2006026703), intermediate A 1-2 (170mg, 1.05mmol), potassium iodide (16mg, 0.1mmol) and n,N-diisopropylethylamine (320mg, 2.5mmol) are dissolved in 10mL acetonitrile, Stirring at normal temperature is stayed overnight, and the extraction of 100mL methylene chloride 50mL sodium bicarbonate aqueous solution is added, mutually drying is spin-dried for methylene chloride, remaining Object (methylene chloride: methanol=100: 1 to 50: 1), obtains brown oil liquid (200mg, 69%) through column chromatographic purifying.
3) synthesis of product A1:
Intermediate A 1-4 (100mg, 0.35mmol) is dissolved in 4mL ethyl alcohol, is added triethylamine (350mg, 3.5mmol), N- first Base piperazine (40mg, 0.38mmol), 80 DEG C are stirred overnight, and 100mL methylene chloride 50mL sodium bicarbonate aqueous solution is added and extracts, and two Chloromethanes mutually drying is spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol=50: 1), obtain colourless oil liquid (98mg, 80%).
Embodiment 2
According to the synthetic method of embodiment 1, N methyl piperazine is replaced with corresponding amine in final step, synthesis obtains heterocycle Compound A2, A5, A6, A22-A26, A39 and A60.
Embodiment 3
Heterocyclic compound A3, synthesizes by the following method:
1) synthesis of intermediate A 3-2:
4- chloroacetyl acetacetic ester (13g, 79mmol), S- methyl-isourea (20g, 72mmol), is dissolved in 200mL Water is added sodium carbonate (11.5g, 108mmol), and stirring at normal temperature is overnight, and 6N HCl tune PH is added to acidity, and precipitation solid filters, Solid is dry, obtains product (11.1g, 73%), is a white solid.
2) synthesis of intermediate A 3-3:
Intermediate A 3-2 (2.8g, 14.7mmol) is dissolved in 10mL phosphorus oxychloride, and 100 DEG C of stirring 1h are spin-dried for, and 100mL is added The extraction of ethyl acetate 100mL sodium bicarbonate aqueous solution, ethyl acetate phase drying are spin-dried for.Residue is through column chromatographic purifying (acetic acid second Ester: petroleum ether=100: 3), obtaining product (2.4g, 80%), is a yellow oily liquid.
3) synthesis of intermediate A 3-4:
Intermediate A 1-3 (400mg, 2.5mmol), A3-3 (540mg, 2.6mmol), potassium iodide (41mg, 0.25mmol) and N,N-diisopropylethylamine (800mg, 6.2mmol) is dissolved in 20mL acetonitrile, and stirring at normal temperature is overnight, be added 100mL methylene chloride and The extraction of 100mL sodium bicarbonate aqueous solution, mutually drying is spin-dried for methylene chloride.Residue through column chromatographic purifying (methylene chloride: methanol= 200: 1), obtaining product (450mg, 54%), be a brown liquid.
4) synthesis of product A3:
Intermediate A 3-4 (450mg, 1.3mmol) is dissolved in 10mL ethyl alcohol, is added triethylamine (1.3g, 13mmol), N- methyl Piperazine (150mg, 1.4mmol), 80 DEG C are stirred overnight, and 100mL methylene chloride is added and 10mL sodium bicarbonate aqueous solution extracts, and two Chloromethanes mutually drying is spin-dried for, obtain liquid, through column chromatographic purifying (methylene chloride: methanol=50: 1), obtain product (500mg, It 96%), is a brown liquid.
Embodiment 4
Heterocyclic compound A7, synthesizes by the following method:
1) synthesis of intermediate A 7-1:
Intermediate A 1-4 (200mg, 0.7mmol) is dissolved in 10mL ethyl alcohol, and triethylamine (700mg, 7mmol) and N-Boc is added Piperazine (140mg, 0.77mmol), 80 DEG C are stirred overnight.The extraction of 50mL methylene chloride 50mL sodium bicarbonate aqueous solution, dichloro is added Mutually drying is spin-dried for methane.Residue through column chromatographic purifying (methylene chloride: methanol=50: 1 to 25: 1), obtain product (290mg, It 94%), is a colourless oil liquid.
2) synthesis of product A7:
Intermediate A 7-1 (270mg, 0.6mmol) is dissolved in the ethyl acetate solution (5mL) of 5mL methylene chloride and hydrogen chloride, Stirring at normal temperature is stayed overnight, and 50mL methylene chloride and the extraction of 50mL sodium bicarbonate aqueous solution is added, mutually drying is spin-dried for methylene chloride.It is remaining Object (methylene chloride: methanol=50: 1 to 25: 1), obtains colourless oil liquid (180mg, 90%) through column chromatographic purifying.
Embodiment 5
Heterocyclic compound A8, synthesizes by the following method:
A7 (50mg, 0.13mmol) is dissolved in 2mL methanol, be added triethylamine (15mg, 0.13mmol) and acrylonitrile (20mg, 0.26mmol), stirring at normal temperature is overnight.50mL methylene chloride and the extraction of 50mL sodium bicarbonate aqueous solution is added, methylene chloride is relevant It is dry to be spin-dried for.Residue through column chromatographic purifying (methylene chloride: methanol=50: 1 to 25: 1), obtain colourless oil liquid (40mg, 78%).
Embodiment 6
Heterocyclic compound A9, synthesizes by the following method:
1) synthesis of intermediate A 9-2:
A9-1 (300mg, 1.7mmol) and B amidine hydrochloric acid salt (320mg, 3.4mmol) are dissolved in 10mL water, and potassium carbonate is added (940mg, 6.8mmol), stirring at normal temperature is overnight.Acetic acid tune PH is added to acidity, methylene chloride (100mL) extracts three times, organic Mutually drying is spin-dried for.Residue (methylene chloride: methanol=50: 1), obtains white solid (110mg, 35%) through column chromatographic purifying.
2) synthesis of intermediate A 9-3:
A9-2 (110mg, 0.6mmol), triethylamine (600mg, 6mmol), N methyl piperazine (90mg, 0.9mmol) are dissolved in 10mL acetonitrile is added PyBOP (340mg, 0.7mmol), and return stirring is overnight, and 100mL methylene chloride and 100mL bicarbonate is added Sodium water solution extraction, mutually drying is spin-dried for methylene chloride.Residue (methylene chloride: methanol=100: 3), obtains yellow through column chromatographic purifying Color oily liquids (140mg, 88%).
3) synthesis of intermediate A 9-4:
A9-3 (140mg, 0.5mmol) is dissolved in 20% aqueous sulfuric acid of 5mL, and return stirring is overnight, and sodium bicarbonate is added Methylene chloride extraction is added to alkalinity in aqueous solution tune PH, and mutually drying is spin-dried for methylene chloride, obtain yellow oily liquid (110mg, 97%).
4) synthesis of product A9:
A1-3 (37mg, 0.23mmol), A9-4 (46mg, 0.21mmol) and acetic acid (13mg, 0.21mmol) are dissolved in dichloro Ethane (5mL) after stirring at normal temperature 10min, is added acetic acid sodium borohydride (66mg, 0.3mmol), continues to be stirred overnight.It is added 100mL methylene chloride and the extraction of 100mL sodium bicarbonate aqueous solution, mutually drying is spin-dried for methylene chloride.Residue is through column chromatographic purifying (methylene chloride: methanol: ammonium hydroxide=100: 1: 1 to 50: 1: 1), obtain colourless oil liquid (30mg, 39%).
Embodiment 7
According to the synthetic method of embodiment 6, second miaow hydrochloride is replaced with corresponding substrate in step 1, synthesis obtains miscellaneous Cycle compound A10, A11, A28 and A29.
Embodiment 8
According to the synthetic method of embodiment 6, A9-1 is replaced with corresponding substrate in step 1, and with S- methyl isothiourea Sulfate replaces second miaow hydrochloride, and synthesis obtains heterocyclic compound A27.
Embodiment 9
According to the synthetic method of embodiment 6, second miaow hydrochloride is replaced with trifluoro second miaow in step 1, and use in step 4 A42-1 replaces A1-3, and synthesis obtains heterocyclic compound A48.
Embodiment 10
According to the synthetic method of embodiment 6, A1-3 is replaced with corresponding substrate in step 4, synthesis obtains heterocyclic compound Object A57 and A59.
Embodiment 11
Heterocyclic compound A12, synthesizes by the following method:
1) synthesis of intermediate A 12-1:
A9-1 (3g, 17mmol), S- methyl-isourea (9.5g, 34mmol) are dissolved in 100mL water, and carbonic acid is added Potassium (17.6g, 76.5mmol), stirring at normal temperature is overnight, and acetic acid tune PH is added to acidity, methylene chloride (100mL) extraction three is added It is secondary.Organic phase drying is spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol=100: 1), obtain white solid (3.4g, 92%).
2) synthesis of intermediate A 12-2:
A12-1 (3.4g, 16mmol), triethylamine (16g, 160mmol), N methyl piperazine (2.4g, 40mmol) are dissolved in 100mL acetonitrile is added PyBOP (9g, 17.6mmol), and return stirring is overnight, and 200mL methylene chloride and 200mL bicarbonate is added Sodium water solution extraction, mutually drying is spin-dried for methylene chloride.Residue (methylene chloride: methanol=100: 3), obtains yellow through column chromatographic purifying Color oily liquids (2.8g, 59%).
3) synthesis of intermediate A 12-3:
A12-2 (2.8g, 9.4mmol), is dissolved in 90mL tetrahydrofuran and 4.5mL water, and under stirring at normal temperature, Oxone is added 200mL ethyl acetate and the extraction of 200mL sodium bicarbonate aqueous solution is added in (7g, 11mmol), stirring at normal temperature 4h.Ethyl acetate phase Drying is spin-dried for, and obtains yellow oily liquid (2.4g, 78%).
4) synthesis of intermediate A 12-4:
A12-3 (340mg, 1mmol) is dissolved in the tetrahydrofuran solution (5mL) of dimethylamine, and return stirring is stayed overnight in tube sealing, 100mL methylene chloride and the extraction of 100mL sodium bicarbonate aqueous solution is added.Organic phase drying is spin-dried for, and residue is through column chromatographic purifying (methylene chloride: methanol: ammonium hydroxide=100: 1: 1 to 100: 3: 1) obtain yellow oily liquid (260mg, 88%).
5) synthesis of intermediate A 12-5:
A12-4 (260mg, 1.3mmol) is dissolved in 20% aqueous sulfuric acid of 5mL, and return stirring is overnight, and sodium bicarbonate is added Methylene chloride extraction is added to alkalinity in aqueous solution tune PH.Mutually drying is spin-dried for methylene chloride, obtains yellow solid (210mg, 65%).
6) synthesis of product A12:
A1-3 (150mg, 0.9mmol), A12-5 (210mg, 0.84mmol) and acetic acid (50mg, 0.84mmol) are dissolved in two Chloroethanes (5mL) after stirring at normal temperature 10min, is added acetic acid sodium borohydride (270mg, 1.3mmol), continues to be stirred overnight, is added 100mL methylene chloride and the extraction of 100mL sodium bicarbonate aqueous solution.Mutually drying is spin-dried for methylene chloride, and residue is through column chromatographic purifying (methylene chloride: methanol: ammonium hydroxide=100: 1: 1 to 50: 1: 1), obtain colourless oil liquid (60mg, 18%).
Embodiment 12
According to the synthetic method of embodiment 11, dimethylamine is replaced with corresponding amine in step 4, synthesis obtains heterocyclic compound Object A13-A16 and A18-A20.
Embodiment 13
Heterocyclic compound A17, synthesizes by the following method:
1) synthesis of intermediate A 17-1:
In the two-mouth bottle of 25mL, sequentially add A12-2 (298mg, 1.00mmol), phenyl boric acid (244mg, 2.00mmol), thiophene -2-carboxylic acid is cuprous (497mg, 2.60mmol), tetra-triphenylphosphine palladium (115mg, 0.10mmol) and tetrahydro Furans (20mL).After nitrogen displacement three times, in 80 DEG C of reaction 12h.It is spin-dried for solvent, solute chromatographs purification (mobile phase two with column Chloromethanes: methanol=100: 1.5), a colourless oil liquid (240mg, 73%) is obtained.1H NMR (400MHz, CDCl3)δ8.41 (d, J=3.6Hz, 2H), 7.44-7.43 (m, 3H), 6.70 (s, 1H), 5.24 (s, 1H), 3.82-3.80 (m, 4H), 3.47 (s, 6H), 2.53-2.52 (m, 4H), 2.37 (s, 3H)
2) synthesis of intermediate A 17-2:
A17-1 (240mg, 0.73mmol) is dissolved in 20% sulfuric acid solution (10mL).After 80 DEG C of reaction 12h, it is cooled to often Temperature after water phase washes (10mL*1) with ether, after water phase is tuned into pH=10 with the sodium hydroxide solution of 6M again, is extracted with dichloromethane (30mL*3).Organic phase merges, and after anhydrous sodium sulfate drying, is spin-dried for.With the purification of column chromatography, (mobile phase is methylene chloride to solute : methanol=100: 2), obtain a colourless oil liquid (170mg, 82%).
2) synthesis of product A17:
By A17-2 (170mg, 0.605mmol), A1-3 (98mg, 0.605mmol) and acetic acid (36mg, 0.60mmol) are molten In 1mL 1,2- dichloroethanes.After stirring at normal temperature 30min, it is added sodium triacetoxy borohydride (321mg, 1.51mmol). After stirring at normal temperature 12h, it is spin-dried for solvent.With the purification of column chromatography, (mobile phase is methylene chloride to solute: methanol=100: it is colourless 1) to obtain one Oily liquids (52mg, 20%).
Embodiment 14
According to the synthetic method of embodiment 13, phenyl boric acid is replaced with -4 boric acid of 1- methyl-1 H- pyrazoles in step 1, is synthesized Obtain heterocyclic compound A21.
Embodiment 15
Heterocyclic compound A30, synthesizes by the following method:
1) synthesis of intermediate A 30-1:
A12-3 (200mg, 0.61mmol) is dissolved in ethyl alcohol (5mL), is added sodium ethoxide (206mg, 3mmol), return stirring mistake Night.100mL methylene chloride and the extraction of 100mL sodium bicarbonate aqueous solution is added, organic phase drying is spin-dried for.Residue chromatographs pure through column Change and (methylene chloride: methanol: ammonium hydroxide=100: 1: 1 to 100: 3: 1) obtains yellow oily liquid (160mg, 89%).
2) synthesis of intermediate A 30-2:
A30-1 (160mg, 0.5mmol) is dissolved in 20% aqueous sulfuric acid of 5mL, and return stirring is overnight.Sodium bicarbonate is added Aqueous solution tune PH is to alkalinity, methylene chloride extraction.Mutually drying is spin-dried for methylene chloride, obtains yellow solid (100mg, 80%).
3) synthesis of product A30:
A1-3 (36mg, 0.22mmol), A30-2 (50mg, 0.2mmol) and acetic acid (12mg, 0.2mmol) are dissolved in two chloroethenes Alkane (5mL) after stirring at normal temperature 10min, is added acetic acid sodium borohydride (64mg, 0.3mmol), continues to be stirred overnight.100mL is added Methylene chloride and the extraction of 100mL sodium bicarbonate aqueous solution.Mutually drying is spin-dried for methylene chloride, and residue is through column chromatographic purifying (dichloro Methane: methanol: ammonium hydroxide=100: 1: 1 to 50: 1: 1), obtaining colourless oil liquid (40mg, 51%).
Embodiment 16
According to the synthetic method of embodiment 15, ethyl alcohol is replaced with isopropanol in step 1, synthesis obtains heterocyclic compound A31。
Embodiment 17
Heterocyclic compound A32 and A33, synthesize by the following method:
1) synthesis of intermediate A 32-2:
A32-1 (5g, 26mmol), 2,2- dimethyl -1,3- dioxane -4,6- diketone (4.2g, 29mmol) and DMAP (5.0g, 40mmol) is dissolved in 100mL methylene chloride, under ice bath stirring, is added DCC (6g, 29mmol), stirring at normal temperature 48h. 200mL methylene chloride and the extraction of 100mL 1N hydrochloric acid solution is added in filtering, filtrate.Mutually drying is spin-dried for methylene chloride, obtains yellow oil Shape liquid (6g, crude product) is directly used in and operates in next step.
2) synthesis of intermediate A 32-3:
A32-2 (6g, crude product) is dissolved in 100mL dehydrated alcohol, return stirring 2h.It is concentrated under reduced pressure, residue chromatographs pure through column Change (petroleum ether: ethyl acetate=4: 1), obtains yellow oily liquid (640mg, two step yields 10%).
3) synthesis of intermediate A 32-4:
A32-3 (640mg, 2.5mmol) and S- methyl-isourea (696mg, 5mmol) are dissolved in 40mL water, are added Potassium carbonate (1.3g, 10mmol), stirring at normal temperature is overnight.Acetic acid tune PH is added to acidity, methylene chloride (100mL) extracts three times. Organic phase drying is spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol=20: 1), obtain colourless oil liquid (560mg, 74%).
4) synthesis of intermediate A 32-5:
A32-4 (556mg, 1.9mmol), triethylamine (1.9g, 19mmol), N methyl piperazine (280mg, 2.8mmol) are molten In 5mL acetonitrile, it is added PyBOP (1g, 2mmpl), return stirring is overnight.50mL methylene chloride is added and 50mL sodium bicarbonate is water-soluble Liquid extraction.Mutually drying is spin-dried for methylene chloride, and residue (methylene chloride: methanol=100: 1), obtains yellow oily through column chromatographic purifying Liquid (362mg, 52%).
5) synthesis of intermediate A 32-6:
A32-5 (362mg, 1mmol) is dissolved in 5mL ethyl acetate, is added Hydrochloride/ethyl acetate (5mL), room temperature stirs It mixes overnight.It is concentrated under reduced pressure, 100mL methylene chloride and the extraction of 50mL sodium bicarbonate aqueous solution is added.Organic phase is dry, depressurizes dense Contracting, obtains colourless oil liquid (170mg, 64%).1H NMR (400MHz, CDCl3) δ 6.20 (s, 1H), 3.85-3.83 (m, 1H), 3.67 (s, 4H), 2.51 (s, 3H), 2.46 (s, 4H), 2.34 (s, 3H), 1.36 (d, J=6.4Hz, 3H)
6) synthesis of intermediate A 32-8:
The acetic acid of A32-6 (60mg, 0.24mmol), A32-7 (47mg, 0.32mmol) and catalytic amount is dissolved in 1,2-, bis- chloroethene In alkane, it is stirred to react half an hour.It is added sodium triacetoxy borohydride (136mg, 0.64mmol), room temperature reaction is overnight.Add Water quenching is gone out.(10mL*3) three times is extracted with dichloromethane in filtering, filtrate.Merge organic phase, dry, filter, is concentrated under reduced pressure, obtains Yellow oily liquid (90mg, crude product).
7) synthesis of product A32:
A32-8 (80mg, crude product), 37% formaldehyde (33mg, 0.4mmol) and acetic acid (18mg, 0.3mmol) are dissolved in two chloroethenes Alkane (4mL).After being stirred to react half an hour, it is added sodium triacetoxy borohydride (94mg, 0.3mmol), is stirred overnight at room temperature. Add water quenching to go out, filters.(10mL*3) three times is extracted with dichloromethane in filtrate.Merge organic phase, dry, filter, is concentrated under reduced pressure.It is residual Excess (methylene chloride: methanol: ammonium hydroxide=250: 1: 1), obtains product A32 (14mg, 16%) and product A33 through column chromatographic purifying (20mg, 23%), is colourless oil liquid.
Embodiment 18
Heterocyclic compound A34 and A35, synthesize by the following method:
1) synthesis of intermediate A 34-2:
A34-1 (500mg, 2.6mmol) is dissolved in tetrahydrofuran (30mL), addition sodium hydride (60%, 624mg, 15.6mmol), it stirs 10 minutes, is slowly added into iodomethane (3.7g, 26mmol), reacted at room temperature overnight under nitrogen protection.It is added Water (3mL) and ethyl acetate (2mL) quenching reaction.It is concentrated under reduced pressure, ethyl acetate extracts (2*10mL).Water phase 2N HCl tune PH To 3.5, ethyl acetate (3*10mL) extraction merges organic phase, dries, filters, be concentrated under reduced pressure yellow solid (640mg, slightly Product).1H NMR (400MHz, CDCl3) δ 4.78-4.47 (m, 1H), 2.84 (s, 3H), 1.46-1.42 (m, 12H)
2) synthesis of intermediate A 34-3:
A34-2 (640mg, 3.1mmol), 2,2- dimethyl -1,3- dioxane -4,6- diketone (490mg, 3.4mmol) and DMAP (562mg, 4.6mmol) is dissolved in 5mL methylene chloride, under ice bath stirring, be added DCC (701mg, 3.4mmol), stirring at normal temperature 48h.20mL methylene chloride and the layering of 10mL 1N hydrochloric acid solution, extraction is added in filtering, filtrate.Dichloro Mutually drying is spin-dried for methane, and residue is dissolved in 10mL dehydrated alcohol, return stirring 2h.Ethyl alcohol is concentrated under reduced pressure, and residue is chromatographed through column Purifying (petroleum ether: ethyl acetate=4: 1), obtains yellow oily liquid (590mg, 70%).
3) synthesis of intermediate A 34-4:
A34-3 (570mg, 2.1mmol) and S- methyl-isourea (584mg, 4.2mmol) are dissolved in 6mL water, are added Potassium carbonate (1.2g, 8.4mmol), stirring at normal temperature is overnight.Acetic acid tune PH is added to acidity, methylene chloride (20mL) extracts three times. Merge organic phase, drying is spin-dried for.Residue through column chromatographic purifying (methylene chloride: methanol=20: 1), obtain white solid (380mg, 60%).
4) synthesis of intermediate A 34-5:
A34-4 (380mg, 1.2mmol), triethylamine (1.2g, 12mmol), N methyl piperazine (190mg, 1.9mmol) are molten In 5mL acetonitrile, it is added PyBOP (728mg, 1.4mmol), return stirring is overnight.50mL methylene chloride and 50mL bicarbonate is added Sodium water solution extraction.Mutually drying is spin-dried for methylene chloride, and residue (methylene chloride: methanol=100: 1), obtains yellow through column chromatographic purifying Color oily liquids (340mg, 74%).1H NMR (400MHz, CDCl3) δ 6.05 (s, 1H), 5.2-5.0 (m, 1H), 3.63 (s, 4H), 3.16 (s, 1H), 2.78 (s, 3H), 2.49 (s, 3H), 2.46-2.05 (m, 4H), 2.33 (s, 3H), 1.44 (s, 12H)
5) synthesis of intermediate A 34-6:
A34-5 (340mg, 0.89mmol) is dissolved in 5mL ethyl acetate, is added Hydrochloride/ethyl acetate (5mL), room temperature It is stirred overnight.Ethyl acetate is spin-dried for, and 100mL methylene chloride and the extraction of 50mL sodium bicarbonate aqueous solution is added.The dry rotation of organic phase It is dry, obtain yellow oily liquid (170mg, 68%).1H NMR (400MHz, CDCl3) δ 6.20 (s, 1H), 3.68 (s, 4H), 2.50 (s, 3H), 2.47-2.45 (m, 4H), 2.34 (s, 3H), 2.32 (s, 3H), 1.32 (d, J=6.4Hz, 3H)
6) synthesis of product A34 and A35:
A34-6 (100mg, 0.35mmol), A34-7 (117mg, 0.7mmol), potassium iodide (20mg, 0.12mmol), N, N- Diisopropylethylamine (1.4g, 3.5mmol) is dissolved in N-Methyl pyrrolidone (4mL), is reacted overnight at 120 DEG C.It is cooled to room temperature, Ethyl acetate (5*10mL) extraction.Merge organic phase, saturated common salt is washed 5 times, dried, filtered, and is concentrated under reduced pressure.Residue is through column Chromatographic purifying (methylene chloride: methanol: ammonium hydroxide=250: 1: 1), obtains A34 (10mg, 7%) and A35 (20mg, 14%), is nothing Color oily liquids.
Embodiment 19
Heterocyclic compound A37, synthesizes by the following method:
1) synthesis of intermediate A 37-1:
4- chloroacetyl acetacetic ester (16.5g, 100mmol) and ethenylamidine hydrochloride (10g, 106mmol) are successively dissolved in ethyl alcohol In (100mL).It is slowly added under ice-water bath DBU (30.4g, 200mmol), is stirred overnight under room temperature.Solvent is drained, dichloro is added Methane (120mL) dilution, saturated common salt washes (30mL*3), and organic phase is dry afterwards, drains solvent.Residue is dissolved in POCl3 (20mL), the return stirring 30min at 110 DEG C.After being cooled to room temperature, most POCl is pumped3, residue unsaturated carbonate Hydrogen sodium is adjusted to neutrality, and ethyl acetate (30mL*3) extraction merges organic phase and drying.After being spin-dried for solvent, residue passes through silicon Gel column chromatography eluting (PE: EA=5: 1) obtains faint yellow solid (4.0g, 23%).1H NMR (400MHz, CDCl3) δ 7.41 (s, 1H), 4.55 (s, 2H), 2.71 (s, 3H)
2) synthesis of intermediate A 37-3:
2- bromopyridine (1.5g, 9.7mmol) and TMEDA (2.1g, 17.4mmol) are dissolved in 30mL anhydrous tetrahydro furan, displacement After nitrogen, stirred 10 minutes at -78 DEG C.It is added 2.5M n-BuLi (3.2mL, 8.1mmol), after continuing stirring 2 hours, is added 1-Boc-2- pyrrolidones (1g, 5.4mmol), the reaction was continued 2 hours, adds water (10mL) extraction to go out, after restoring room temperature, adds acetic acid second Ester extraction.Ethyl acetate phase is dry, is spin-dried for.Residue (methylene chloride: methanol=250: 1), obtains white through column chromatographic purifying Solid (900mg, 63%).
2) synthesis of intermediate A 37-4:
The tetrahydrofuran solution that A37-3 (500mg, 1.9mmol) is dissolved in methylamine is molten (7.6mL), and tetraethyl titanate is added Sodium borohydride (290mg, 7.6mmol) is added after stirring at normal temperature 30 minutes in (1.1g, 3.8mmol).Continue stirring 2 hours, is added Sodium bicarbonate aqueous solution (100mL) is quenched, and methylene chloride (100mL) extraction is added three times.Organic phase drying is spin-dried for, residue warp Column chromatographic purifying (methylene chloride: methanol=100: 1), obtains colourless oil liquid (270mg, 51%).
3) synthesis of intermediate A 37-5:
A37-4 (100mg, 0.36mmol), A37-1 (70mg, 0.39mmol), potassium iodide (6mg, 0.04mmol) and N, N- Diisopropylethylamine (120mg, 0.9mmol) is dissolved in 5mL acetonitrile, and stirring at normal temperature is overnight.50mL methylene chloride and 50mL carbon is added Sour hydrogen sodium water solution extraction.Methylene chloride mutually drying is spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol=100: 1), It obtains colourless oil liquid (110mg, 63%).
4) synthesis of product A37:
A37-5 (110mg, 0.2mmol), triethylamine (230mg, 2mmol), N methyl piperazine (115mg, 1mmol) are dissolved in 3mL ethyl alcohol, return stirring are overnight.100mL methylene chloride and the extraction of 100mL sodium bicarbonate aqueous solution is added.Methylene chloride is relevant It is dry to be spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol: ammonium hydroxide=100: 1: 1), obtain colourless oil liquid (90mg, 93%).
Embodiment 20
According to the synthetic method of embodiment 19,1-Boc-2- pyrrolidones is replaced with 1-Boc-2- piperidones in step 2, Synthesis obtains heterocyclic compound A36.
Embodiment 21
Heterocyclic compound A38, synthesizes by the following method:
A37 (60mg, 0.12mmol) is dissolved in 3mL ethyl acetate, is added Hydrochloride/ethyl acetate (4mL), room temperature stirs It mixes overnight.Filtering, it is dry, the hydrochloride (90mg) of A38 is obtained, is a white solid.
Embodiment 22
Heterocyclic compound A41, synthesizes by the following method:
1) synthesis of intermediate A 41-1:
Sodium hydride solid (60%, 420mg, 10.5mmol) is added into 50mL two-mouth bottle, is added solvent DMF (10mL). Nitrogen protection and displaced air.Under ice-water bath again by A32-7 (441mg, 3.0mmol) and 1,2- Bromofume (1.95g, It is added sequentially in reaction system after 10.5mmol) being dissolved in DMF.Stir 1h after, be added methylene chloride (40mL) dilution, then with satisfy It is washed with saline solution (40mL).After the dry organic phase of anhydrous sodium sulfate, it is concentrated under reduced pressure.Residue by silica gel column chromatography (PE: EA=10: 3) after purification white solid (110mg, 21%) is obtained.1H NMR (400MHz, CDCl3) δ 8.68 (s, 1H), 7.64 (s, 1H), 7.36 (s, 1H), 3.02 (d, J=4.4Hz, 2H), 2.01 (d, J=4.8Hz, 2H), 1.50 (s, 2H), 0.87 (s, 2H)
2) synthesis of intermediate A 41-2:
A41-1 (110mg, 0.64mmol) is dissolved in the tetrahydrofuran solution (3mL) of methylamine, adds tetraethyl titanate (1.14g, 5mmol) is stirred overnight at 70 DEG C, is added sodium cyanoborohydride (126mg, 1.3mml), stirring at normal temperature 8 small When.Add water quenching reaction, filters.Filtrate adds methylene chloride after (10mL) dilutes and washes (10mL), is spin-dried for, uses after organic phase is dry Silica gel column chromatography (DCM: MeOH=40: 1) purifying, obtains colourless oil liquid (40mg, 30%).
3) synthesis of intermediate A 41-3:
A41-2 (30mg, 0.16mmol) and intermediate A 37-1 (31mg, 0.18mmol) is dissolved in acetonitrile (5mL), according to It is stirred overnight under room temperature after secondary addition potassium iodide (3mg, 0.016mmol), DIPEA (52mg, 0.4mmol).It is spin-dried for solvent, it is residual Excess is purified through silica gel column chromatography (DCM: MeOH=200: 3), obtains yellow oily liquid (30mg, 58%).
4) synthesis of product A41:
A41-3 (35mg, 0.11mmol) and N methyl piperazine (110mg, 1.1mmol) is dissolved in ethyl alcohol (5ml), is added After triethylamine (101mg, 1.1mmol) at 85 DEG C back flow reaction 3h.Methylene chloride (15ml) dilution is added after being cooled to room temperature Afterwards, it then washes (20ml).Organic phase is dry, is spin-dried for, again with silica gel column chromatography (DCM: MeOH: NH4OH=100: 3: 1) obtaining colourless Oily liquids (25mg, 64%).
Embodiment 23
According to the synthetic method of embodiment 22, methylamine is replaced with ethamine in step 2, synthesis obtains heterocyclic compound A44.
Embodiment 24
According to the synthetic method of embodiment 22, N methyl piperazine is replaced with n-ethylpiperazine in step 4, synthesis obtains miscellaneous Cycle compound A45.
Embodiment 25
Heterocyclic compound A40, synthesizes by the following method:
1) synthesis of intermediate A 40-1:
A12-2 (100mg, 0.33mmol) is dissolved in 20% sulfuric acid solution (10mL), 80 DEG C of reaction 12h.It is cooled to room temperature, After water phase washes (10mL) with ether, then with the sodium hydroxide solution of 6M it is tuned into pH=10, (30mL*3) is extracted with dichloromethane.Two Chloromethanes mutually merges, dry with anhydrous sodium sulfate, is concentrated under reduced pressure, obtains a colourless oil liquid (59mg, 71%).
2) synthesis of product A40:
A41-2 (40mg, 0.21mmol) and A40-1 (59mg, 0.23mmol) is dissolved in 1,2- dichloroethanes (3mL), After adding the glacial acetic acid (0.2ml) of catalytic amount, 5h is stirred at room temperature.Add sodium triacetoxy borohydride (90mg, 0.42mmol), it is stirred overnight.Dilution is added in methylene chloride (10mL), and organic phase is washed with saturated sodium bicarbonate aqueous solution (20mL) It washs, drying is spin-dried for.Residue passes through silica gel column chromatography (DCM: MeOH: NH3H2O=100: 1: 1) purifying, obtain colourless oil liquid (49mg, 54%).
Embodiment 26
Heterocyclic compound A42, synthesizes by the following method:
1) synthesis of intermediate A 42-2:
A42-1 (90mg, 0.56mmol), A37-1 (108mg, 0.61mmol), potassium iodide (10mg, 0.06mmol) and N, N- diisopropylethylamine (180mg, 1.4mmol) is dissolved in 10mL acetonitrile, and stirring at normal temperature is overnight, be added 100mL methylene chloride and The extraction of 50mL sodium bicarbonate aqueous solution.Methylene chloride mutually drying is spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol= 100: 1), obtaining pale yellow oily liquid (110mg, 65%).
2) synthesis of product A42:
A42-2 (30mg, 0.1mmol) is dissolved in 2mL ethyl alcohol, is added triethylamine (100mg, 1mmol), N methyl piperazine Overnight, 50mL methylene chloride and the extraction of 50mL sodium bicarbonate aqueous solution is added in (50mg, 0.5mmol), 80 DEG C of reactions.Methylene chloride Mutually drying is spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol=100: 1), obtain yellow oily liquid (36mg, 98%).
Embodiment 27
According to the synthetic method of embodiment 26, N methyl piperazine is replaced with corresponding amine in step 2, synthesis obtains heterocycle Compound A43, A47, A49 and A63-A74.
Embodiment 28
According to the synthetic method of embodiment 26, A42-1 is replaced with corresponding substrate in step 1, synthesis obtains jeterocyclic chemistry Close object A58.
Embodiment 29
According to the synthetic method of embodiment 26, A37-1 is replaced with corresponding substrate in step 1, synthesis obtains jeterocyclic chemistry Close object A61.
Embodiment 30
Heterocyclic compound A46, synthesizes by the following method:
1) synthesis of intermediate A 46-2:
A46-1 (667mg, 6mmol) is dissolved in ethyl alcohol (25mL), propargylamine (1.3g, 24mmol), two water are sequentially added It closes sodium chloraurate (60mg, 0.15mmol).It is stirred 24 hours at 85 DEG C in nitrogen environment.After being cooled to room temperature, it is spin-dried for solvent, Ethyl acetate (30mL) is added to dissolve, saturated sodium bicarbonate solution (15mL), saturated salt solution (15mL) are respectively washed once.It is organic relevant It is dry, be spin-dried for solvent, residue purified by silica gel column chromatography (petroleum ether: ethyl acetate=12: 1) colourless oil liquid (118mg, 12%).1H NMR (400MHz, CDCl3) δ 8.37 (s, 1H), 7.30 (d, J=7.2Hz, 1H), 7.03 (t, J= 4.0Hz, 1H), 3.00 (t, J=6.4Hz, 2H), 2.64 (s, 2H), 1.69 (t, J=6.0Hz, 2H), 0.43 (d, J= 10.0Hz, 4H)
2) synthesis of intermediate A 46-3:
A46-2 (100mg, 0.63mmol) is dissolved in 1,2- methylene chloride, be slowly added to trichloroisocyanuric acid (219mg, 0.95mmol).Be cooled to room temperature after being stirred five hours at 30 DEG C, filter, filtrate be spin-dried for after by silica gel column chromatography purifying (stone Oily ether: ethyl acetate=10: 1) colourless liquid (79mg, 65%) is obtained.1H NMR (400MHz, CDCl3) δ 8.54 (s, 1H), 7.38 (d, J=8.0Hz, 1H), 7.16 (t, J=4.8Hz, 1H), 2.80 (d, J=16Hz, 1H), 2.64 (d, J=16Hz, 1H), 2.44-2.39 (m, 1H), 2.09-2.04 (m, 1H), 0.94-0.85 (m, 1H), 0.65-0.56 (m, 1H), 0.48-0.40 (m, 2H).
3) synthesis of intermediate A 46-4:
A46-3 (30mg, 0.16mmol) is dissolved in the alcoholic solution (5mL) of methylamine.It is stirred overnight at room temperature, then is warming up to 60 DEG C Stirring 5 hours.After being cooled to room temperature, it is spin-dried for solvent and obtains colourless oil liquid (30mg, 99%).1H NMR (400MHz, CDCl3)δ 8.45 (s, 1H), 7.43 (d, J=6.8Hz, 1H), 7.20-7.18 (m, 1H), 4.34-4.24 (m, 1H), 3.27 (d, J= 11.2Hz, 1H), 2.85 (s, 1H), 2.71 (s, 3H), 2.44 (m, J=12.0Hz, 1H), 1.78-1.71 (m, 1H), 0.67- 0.43 (m, 4H)
4) synthesis of intermediate A 46-5:
A46-4 (30mg, 0.17mmol) and A37-1 (33mg, 0.19mmol) is dissolved in acetonitrile (2mL).It sequentially adds It is stirred overnight under room temperature after potassium iodide (3mg, 0.017mmol), DIPEA (55mg, 0.43mmol).After being spin-dried for solvent, obtain Liquid obtains pale yellow oily liquid (50mg, 89%) after purification through column chromatographic purifying (DCM: MeOH=100: 1).
6) synthesis of product A46:
A46-5 (50mg, 0.15mmol) and N methyl piperazine (76mg, 0.76mmol) is dissolved in ethyl alcohol (4ml).It is added After triethylamine (151mg, 1.5mmol) at 85 DEG C back flow reaction 3h.Methylene chloride (15ml) dilution is added after being cooled to room temperature Afterwards, it then washes (20ml).Organic phase is dry, is spin-dried for, and liquid is obtained, through column chromatographic purifying (DCM: MeOH=100: 1 to 50: 1) It obtains colourless oil liquid (25mg, 40%).
Embodiment 31
Heterocyclic compound A50, synthesizes by the following method:
1) synthesis of intermediate A 50-2:
2- methyl -4- chlorine pyrimidine (370mg, 2.9mmol), NBS (566mg, 3.2mmol) and AIBN (50mg, 0.3mmol) It is dissolved in carbon tetrachloride (10mL), return stirring is overnight, and 50mL methylene chloride and the extraction of 50mL sodium bicarbonate aqueous solution is added.Dichloro Methane mutually drying is spin-dried for, residue through column chromatographic purifying (petroleum ether: ethyl acetate=50: 1), obtain white solid (130mg, 22%).
2) synthesis of intermediate A 50-3:
A50-2 (94mg, 0.58mmol), A1-3 (130mg, 0.6mmol), potassium iodide (10mg, 0.06mmol) and N, N- Diisopropylethylamine (740mg, 5.8mmol) is dissolved in 10mL acetonitrile, and 50 DEG C are stirred overnight, and 100mL methylene chloride and 50mL is added Sodium bicarbonate aqueous solution extraction.Methylene chloride mutually drying is spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol=100: 1) brown oil liquid (140mg, 84%), is obtained.
3) synthesis of product A50:
A50-3 (50mg, 0.17mmol) is dissolved in 2mLNMP, is added n,N-diisopropylethylamine (244mg, 1.7mmol), N methyl piperazine (87mg, 0.85mmol), 80 DEG C are stirred overnight, and 50mL methylene chloride and 50mL sodium bicarbonate aqueous solution extraction is added It takes.Mutually drying is spin-dried for methylene chloride, and residue (methylene chloride: methanol=100: 1 to 100: 3), obtains yellowish through column chromatographic purifying Color oily liquids (34mg, 57%).
Embodiment 32
Heterocyclic compound A51, synthesizes by the following method:
1) synthesis of intermediate A 51-2:
NaH (60%, 936mg, 23.4mmol) is added in the ether of 50mL, ethyl fluoroacetate is added dropwise at normal temperature (5g, 47.2mmol) then reacts 4 hours at 40 DEG C.Reaction solution is poured into 2M H2SO4 (15mL) at 0 DEG C, then It is extracted with ether (50mL*3), merges organic phase, after anhydrous sodium sulfate is dry, chromatograph (petroleum ether: ethyl acetate=10: 1 through column To 2: 1) obtaining yellow oil (2g, 25%).
2) synthesis of intermediate A 51-3:
By A51-2 (1.9g, 11.4mmol), ethenylamidine hydrochloride (2.2g, 22.8mmol) and sodium ethoxide (2.3g, 34.2mmol) It is added in ethyl alcohol (40mL), is reacted overnight at 80 DEG C.It is cooled to room temperature, is added 6N HCl (2mL), be concentrated under reduced pressure, through column Chromatographic purifying (petroleum ether: ethyl acetate=3: 1 to 1: 1), obtains yellow solid (800mg, 43%).1H NMR (400MHz, CDCl3) δ 13.07 (br s, 1H), 5.35 (d, J=46.8Hz, 2H), 2.53 (s, 3H)
3) synthesis of intermediate A 51-4:
By A51-3 (800mg, 5mmol), N methyl piperazine (750mg, 7.5mmol), PyBOP (2.9g, 5.5mmol) and Triethylamine (1.5g, 15mmol) is added in the acetonitrile of 40mL, is reacted overnight at 80 DEG C, is concentrated under reduced pressure, the two of 100mL are added Chloromethanes is then washed with saturated salt solution (50mL*3), after anhydrous sodium sulfate is dry, liquid is obtained, through column chromatographic purifying (acetic acid Ethyl ester), obtain yellow oil (1g, 90%).1H NMR (400MHz, CDCl3) δ 5.36 (d, J=47.2Hz, 2H), 3.87- 3.73 (m, 4H), 2.57-2.50 (m, 4H), 2.49 (s, 3H), 2.33 (s, 3H)
4) synthesis of intermediate A 51-5:
By A51-4 (1g, 4.1mmol), 2M methylamine methanol solution (6mL, 12mmol), water (15mL) and isopropanol (15mL) It is added in tube sealing.It is reacted at 80 DEG C overnight, is concentrated under reduced pressure and removes most alcohol, extracted with methylene chloride (30mL*3), Merge organic phase to be spin-dried for after anhydrous sodium sulfate is dry, obtain liquid, through column chromatographic purifying (methylene chloride: methanol: ammonium hydroxide= 400: 10: 1 to 200: 10: 1), obtaining yellow oil (800mg, 76%).1H NMR (400MHz, CDCl3) δ 3.80-3.74 (m, 4H), 3.73 (s, 2H), 2.48-2.46 (m, 4H), 2.44 (s, 6H), 2.31 (s, 3H)
5) synthesis of product A51:
By A51-5 (100mg, 0.4mmol), A34-7 (202mg, 1.2mmol) and DIPEA (155mg, 1.2mmol) are added Into the isopropanol of 5mL, reacted 3 days at 90 DEG C.It is concentrated under reduced pressure, is diluted with methylene chloride (100mL), then use saturated common salt Water (50mL) is washed, organic phase with anhydrous sodium sulfate it is dry after, be spin-dried for, obtain liquid, through column chromatographic purifying (methylene chloride: methanol: Ammonium hydroxide=200: 10: 1), obtaining yellow oil (73mg, 48%).
Embodiment 33
Heterocyclic compound A52, synthesizes by the following method:
1) synthesis of intermediate A 52-2:
A52-1 (5g, 41mmol), methylamine tetrahydrofuran solution (80mL), acetic acid (2.5g, 41mmol) are dissolved in 100mL bis- Chloromethanes, stirring at normal temperature 1h are added acetic acid sodium borohydride (13g, 62mmol), continue to be stirred overnight.It is water-soluble that sodium bicarbonate is added Liquid, layering.Water phase methylene chloride extracts 3 times, merges organic phase, and drying is spin-dried for.Residue through column chromatographic purifying (methylene chloride: Methanol=100: 1), yellow oily liquid (2.7g, 48%) is obtained.
2) synthesis of intermediate A 52-3:
A52-2 (100mg, 0.73mmol), A37-1 (143mg, 0.8mmol), potassium iodide (12mg, 0.07mmol) and N, N- diisopropylethylamine (950mg, 7.3mmol) is dissolved in 10mL acetonitrile, and stirring at normal temperature is overnight, be added 100mL methylene chloride and The extraction of 50mL sodium bicarbonate aqueous solution, mutually drying is spin-dried for methylene chloride.Residue through column chromatographic purifying (methylene chloride: methanol= 100: 1), obtaining pale yellow oily liquid (140mg, 69%).
3) synthesis of product A52:
A52-3 (50mg, 0.18mmol) is dissolved in 2mL ethyl alcohol, is added triethylamine (182mg, 1.8mm0l), N methyl piperazine Overnight, 50mL methylene chloride and the extraction of 50mL sodium bicarbonate aqueous solution is added in (91mg, 0.9mmol), 80 DEG C of reactions.Methylene chloride Mutually drying is spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol=100: 1), obtain yellow oily liquid (63mg, 99%).
Embodiment 34
According to the synthetic method of embodiment 33, A52-1 is replaced with corresponding substrate in step 1, synthesis obtains jeterocyclic chemistry Close object A53-A56.
Embodiment 35
According to the synthetic method of embodiment 33, A37-1 is replaced with corresponding substrate in step 2, synthesis obtains jeterocyclic chemistry Close object A4.
Embodiment 36
Heterocyclic compound A62, synthesizes by the following method:
1) synthesis of intermediate A 62-2:
Intermediate A 62-1 (500mg, 4.8mmol) is dissolved in 10mL toluene and methyl-magnesium-chloride is added under 0 DEG C of stirring (4.8mL, 14.4mmol), reaction solution are heated to reflux 18 hours, are cooled to room temperature, and ammonium hydroxide extraction is added and goes out, filters, and filtrate is dry, Be spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol: ammonium hydroxide=100: 2: 1), obtain yellow oily liquid (390mg, 60%).1H NMR (400MHz, CDCl3) δ 8.56 (d, J=4.4Hz, 1H), 7.64 (t, J=7.8Hz, 1H), 7.45 (d, J= 8.0Hz, 1H), 7.13 (t, J=6.4Hz, 1H), 1.51 (s, 6H)
2) synthesis of intermediate A 62-3:
Intermediate A 62-2 (350mg, 2.6mmol) is dissolved in 10mL toluene, and formic acid (237mg, 5.2mmol) reflux is added and stirs 6h to be mixed, is added sodium bicarbonate aqueous solution (50mL), methylene chloride (50mL) extraction, mutually drying is spin-dried for methylene chloride, liquid is obtained, (methylene chloride: methanol=100: 1 to 100: 3), yellow oily liquid (300mg, 70%) is obtained through column chromatographic purifying.
3) synthesis of intermediate A 62-4:
Intermediate A 62-3 (300mg, 1.8mmol) is dissolved in anhydrous tetrahydro furan, be added portionwise sodium hydride (222mg, 2.7mmol), it after stirring at normal temperature 15 minutes, is added iodomethane (390mg, 5.4mmol), the reaction was continued, and 50mL water extraction is added and goes out, Methylene chloride (50mL) extraction is added three times, organic phase drying is spin-dried for, and liquid is obtained, through column chromatographic purifying (methylene chloride: methanol =100: 1), obtaining yellow oily liquid (280mg, 87%).1H NMR (400MHz, CDCl3) δ 8.59 (d, J=4.4Hz, 1H), 8.55 (s, 1H), 7.69 (t, J=7.4Hz, 1H), 7.26 (d, J=7.7Hz, 1H), 7.21-7.18 (m, 1H), 2.72 (s, 3H), 1.75 (s, 6H)
4) synthesis of intermediate A 62-5:
Intermediate A 62-4 (280mg, 1.6mmol) is dissolved in 5mL methanol 1mL water, be added sodium hydroxide (192mg, 4.8mmol), return stirring is overnight, and the extraction of 50mL methylene chloride 50mL sodium bicarbonate aqueous solution, methylene chloride mutually dry rotation is added It is dry, liquid is obtained, (methylene chloride: methanol=100: 1), obtains yellow oily liquid (216mg, 90%) through column chromatographic purifying.1H NMR (400MHz, CDCl3) δ 8.59 (d, J=4.4Hz, 1H), 7.64 (t, J=7.4Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.13 (dd, J=7.2,4.8Hz, 1H), 2.13 (s, 3H), 1.47 (s, 6H)
5) synthesis of intermediate A 62-6:
Intermediate A 62-5 (50mg, 0.33mmol), intermediate A 37-1 (65mg, 0.36mmol), potassium iodide (6mg, 0.03mmol), n,N-diisopropylethylamine (430mg, 3mmol) is in acetonitrile (1.5mL), and room temperature reaction is overnight.Reaction solution is spin-dried for, 20mL sodium bicarbonate aqueous solution is added, methylene chloride (3*10mL) extraction merges organic phase, dries, filters, be spin-dried for.Obtain liquid Body (methylene chloride: methanol: ammonium hydroxide=100: 1: 1), obtains colourless oil liquid (56mg, 59%) through column chromatographic purifying.
6) synthesis of product A62:
Intermediate A 62-6 (56mg, 0.19mmol), triethylamine (195mg, 1.9mmol), N methyl piperazine (97mg, It 0.95mmol) is dissolved in 1mL ethyl alcohol, 80 DEG C are stirred overnight, and the extraction of 20mL methylene chloride 20mL sodium bicarbonate aqueous solution, dichloro is added Mutually drying is spin-dried for methane, obtains liquid, (methylene chloride: methanol: ammonium hydroxide=100: 1: 1), obtains faint yellow oil through column chromatographic purifying Shape liquid (60mg, 89%).
Embodiment 37
Heterocyclic compound A75, synthesizes by the following method:
1) synthesis of intermediate A 75-1a and A75-1b:
Raw material A 52-1 (605mg, 5mmol) is dissolved in methylene chloride (30mL), acetic acid boron hydrogen is sequentially added at 0 DEG C Change sodium (2.12g, 10mmol) and (S) -1- (4- anisyl) ethamine (755mg, 5mmol), stirring at normal temperature is overnight.Unsaturated carbonate Quenching reaction is added in hydrogen sodium water solution (20mL), separates organic phase, and drying is spin-dried for, and chromatographs (petroleum ether: acetone through silica gel column chromatography : ammonium hydroxide=200: 5: 2) purifying, obtain A75-1a (1.0g, 78%) and A75-1b (70mg, 5.5%), be yellow oily liquid.
A75-1a:1H NMR (400MHz, CDCl3) δ 8.60 (d, J=3.2Hz, 1H), 7.61 (t, J=7.6Hz, 1H), 7.20-7.12 (m, 3H), 7.06 (d, J=7.6Hz, 1H), 6.86 (d, J=8.0Hz, 2H), 3.81 (s, 3H), 3.61-3.55 (m, 1H), 3.46-3.35 (m, 1H), 1.31-1.25 (m, 6H)
A75-1b:1H NMR (400MHz, CDCl3) 68.54 (s, 1H), 7.61-7.50 (m, 1H), 7.26-7.11 (m, 4H), 6.81 (d, J=7.2Hz, 2H), 3.90-3.80 (m, 1H), 3.80-3.70 (m, 4H), 1.42-1.30 (m, 6H)
2) synthesis of intermediate A 75-2:
A75-1a (500mg, 2mmol), 37% formalin (150mg, 5mmol), acetic acid sodium borohydride (636mg, It 3mmol) is dissolved in 30mL methylene chloride, stirring at normal temperature is overnight, and 100mL methylene chloride and 50mL sodium bicarbonate aqueous solution extraction is added It takes.Mutually drying is spin-dried for methylene chloride, and residue (methylene chloride: methanol=100: 1), obtains colourless oil liquid through column chromatographic purifying (400mg, 70%).1H NMR (400MHz, CDCl3) δ 8.56 (d, J=3.6Hz, 1H), 7.66 (t, J=7.2Hz, 1H), 7.49 (d, J=7.6Hz, 1H), 7.33-7.27 (m, 2H), 7.15 (t, J=6.0Hz, 1H), 6.88 (d, J=8.0Hz, 2H), 3.99- 3.93 (m, 1H), 3.87-3.72 (m, 4H), 2.02 (s, 3H), 1.39-1.25 (m, 6H)
3) synthesis of intermediate A 75-3:
A75-2 (400mg, 1.48mmol) is dissolved in methylene chloride (10mL), and trifluoroacetic acid (5mL) is slowly added dropwise to it. Stirring at normal temperature is stayed overnight.It is concentrated under reduced pressure, 1N HCl (15mL) is added in residue, and ethyl acetate washs three times (10mL*3).Water phase is used 1N NaOH aqueous solution tune pH to 9, methylene chloride extract (10mL*4).Merge organic phase, is concentrated under reduced pressure, is obtained colourless after dry Oily liquids (90mg, 45%).1H NMR (400MHz, CDCl3) δ 8.56 (d, J=4.0Hz, 1H), 7.65 (t, J=7.2Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 7.16 (t, J=6.0Hz, 1H), 3.81-3.70 (m, 1H), 2.31 (s, 3H), 1.38 (d, J=6.4Hz, 3H)
4) synthesis of intermediate A 75-4:
A75-3 (50mg, 0.37mmol) and A37-1 (71mg, 0.40mmol) is dissolved in acetonitrile (5mL), is sequentially added Potassium iodide (6mg, 0.037mmol) and DIPEA (119mg, 0.93mmol) are stirred overnight under room temperature.It is concentrated under reduced pressure, through silicagel column Chromatography (methylene chloride: methanol=150: 1) purifies, obtains pale yellow oily liquid (90mg, 88%).
5) synthesis of intermediate A 75-5:
A75-4 (90mg, 0.33mmol) and N methyl piperazine (163mg, 1.6mmol) is dissolved in ethyl alcohol (10mL), is added Enter triethylamine (333mg, 3.3mmol), the back flow reaction 3h at 85 DEG C.It is cooled to room temperature, is concentrated under reduced pressure, through silica gel column chromatography It (methylene chloride: methanol: ammonium hydroxide=100: 2: 1) purifies, obtains colourless oil liquid (70mg, 63%).
Embodiment 38
According to the synthetic method of embodiment 37, A75-1a is replaced with A75-1b in step 2, synthesis obtains heterocyclic compound A76。
Embodiment 39
Heterocyclic compound A77, synthesizes by the following method:
1) synthesis of intermediate A 77-2:
By A77-1 (5.0g, 27mmol), ethenylamidine hydrochloride (3.9g, 41mmol) and potassium carbonate (11.3g, 82mmol) are added To in ethyl alcohol (80mL), stirring at normal temperature is overnight.It is concentrated under reduced pressure and removes ethyl alcohol, 3N HCl tune PH=5 is added, uses extracting n-butyl alcohol (50mL*6) obtains faint yellow solid (3.5g, 87%).
2) synthesis of intermediate A 77-3:
By A77-2 (2.5g, 16.8mmol), N-Boc piperazine (4.7g, 25.2mmol), PyBOP (9.6g, 18.5mmol) It is added in the acetonitrile of 60mL with triethylamine (5.1g, 50.4mmol), is reacted overnight at 80 DEG C.It is concentrated under reduced pressure, residue warp Column chromatographic purifying (petroleum ether: ethyl acetate=5: 1-3: 1), obtains yellow solid (4.3g, 81%).
3) synthesis of intermediate A 77-4:
A77-3 (4.0g, 12.6mmol) is dissolved in CH2Cl2Sym-closene is added portionwise under ice-water bath in (100mL) (2.9g, 12.6mmol) is stirred to react 1h, then rises to room temperature, reacts 6h.Saturated aqueous sodium thiosulfate is added to be quenched instead It answers, is filtered to remove solid.(50mL*3) is extracted with dichloromethane in filtrate layered, water phase.Organic phase merges, and uses saturated salt solution It washes, through anhydrous Na2SO4It is dry, it is concentrated under reduced pressure.Residue (petroleum ether: ethyl acetate=10: 1-5: 1), is obtained through column chromatographic purifying Faint yellow solid (2.4g, 54%).
4) synthesis of intermediate A 77-5:
Intermediate A 1-3 (421mg, 2.6mmol), intermediate A 77-4 (1.0g, 2.8mmol), sodium iodide (45mg, 0.3mmol) and n,N-diisopropylethylamine (671mg, 5.2mmol) is dissolved in 10mL acetonitrile, and stirring at normal temperature is overnight.It is concentrated under reduced pressure, Residue (petroleum ether: ethyl acetate=1: 1-0: 1), obtains weak yellow liquid (800mg, 64%) through column chromatographic purifying.
5) synthesis of intermediate A 77-6:
Intermediate A 77-4 (600mg, 1.3mmol) is dissolved in methylene chloride (2mL), and trifluoroacetic acid (1mL) is added, and room temperature is anti- Answer 2h.It is concentrated under reduced pressure, obtains brown-red oil (700mg, crude product), be directly used in and react in next step.
6) synthesis of product A77:
Intermediate A 77-6 (700mg, crude product) is dissolved in methanol (1mL), order be added 37% formalin (1mL) and Sodium cyanoborohydride (125mg, 2.0mmol).Saturation NaHCO is added in normal-temperature reaction 2h3Aqueous solution (1mL), methylene chloride extraction (10mL*3).Organic phase merges, and is washed with saturated common salt, through anhydrous Na2SO4It is dry, it is concentrated under reduced pressure.Residue chromatographs (alkali through column Property aluminium oxide) purifying (petroleum ether: ethyl acetate=5: 1-1: 0), obtain faint yellow solid (200mg, 39%).
Embodiment 40
According to the synthetic method of embodiment 37, N methyl piperazine is replaced with corresponding amine in final step, synthesis obtains miscellaneous Cycle compound A78, A79.
Embodiment 41
According to the synthetic method of embodiment 37, formaldehyde is replaced with acetaldehyde in step 2, synthesis obtains heterocyclic compound A80.
Embodiment 42
Heterocyclic compound A81, synthesizes by the following method:
1) synthesis of intermediate A 81-1:
By A9-1 (531mg, 3mmol), 2- hydroxyl acetamidine hydrochloride (400mg, 3.6mmol) and potassium carbonate (1.2g, It 9mmol) is added in methanol (20mL), is stirred 16 hours at 70 DEG C.With 36% acetic acid tune pH to about 5-6, add full The sodium bicarbonate aqueous solution tune pH to 8 of sum is concentrated under reduced pressure, and column chromatography (methylene chloride: methanol=50: 1 to 15: 1) purifies yellow Color solid A81-1 (268mg, 31%).1H NMR (400MHz, CDCl3) δ 6.56 (s, 1H), 5.09 (s, 1H), 4.70 (s, 2H), 3.38 (s, 6H)
2) synthesis of intermediate A 81-2:
By intermediate A 81-1 (268mg, 1.34mmol), N methyl piperazine (268mg, 2.68mmol), triethylamine (541mg, 5.36mmol) and hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (766mg, 1.47mmol) are added Into acetonitrile (20mL), it is stirred overnight at 80 DEG C.It is cooled to room temperature, is concentrated under reduced pressure, column chromatography (methylene chloride: methanol=50: 1 to 20: 1) purifying to obtain yellow oil intermediate A 81-2 (355mg, 93%).LC-MS (m/z): 282.9 [M+H]+.
3) synthesis of intermediate A 81-3:
Intermediate A 81-2 (355mg, 1.26mmol) is added in 20% sulfuric acid (10mL), it is stirred at 80 DEG C Night.It is cooled to room temperature, the sodium bicarbonate aqueous solution for adding saturation is adjusted to pH 8, is extracted with methylene chloride (40mL*5), merges Organic phase after being dried over anhydrous sodium sulfate, is concentrated to give yellow oil intermediate A 81-3 (200mg, 67%).LC-MS (m/z): 258.9[M+Na]+.
4) synthesis of product A81:
By intermediate A 81-3 (140mg, 0.6mmol), intermediate A 75-3 (106mg, 0.78mmol) and acetic acid (36mg, It 0.6mmol) is added in methylene chloride (15mL), is stirred 1 hour under room temperature.Sodium triacetoxy borohydride is added under ice-water bath (382mg, 1.8mmol) reacts overnight under room temperature.It is added saturated sodium bicarbonate aqueous solution (5mL), is concentrated under reduced pressure, column chromatography (two Chloromethanes: methanol: ammonium hydroxide=100: 1: 1 to 50: 1: 0.5) purifying to obtain yellow oil product A81 (78mg, 36%).
Embodiment 43
According to the synthetic method of embodiment 42, N- methyl is replaced with (R)-octahydro pyrrolo- [1,2-a] pyrazine in step 2 Piperazine, synthesis obtain heterocyclic compound A82.
Embodiment 44
According to the synthetic method of embodiment 11, dimethylamine is replaced with ammonium hydroxide in step 4, and use in the final step A75-3 replaces A1-3, and synthesis obtains heterocyclic compound A83.
Embodiment 45
Heterocyclic compound A84, synthesizes by the following method:
1) synthesis of intermediate A 84-2:
Intermediate A 75-4 (260mg, 0.95mmol) is dissolved in dehydrated alcohol, sequentially add A84-1 (616mg, 2.85mmol), triethylamine (288mg, 2.85mol) is stirred overnight in 80 DEG C, is concentrated under reduced pressure, is purified by silica gel column chromatography (dichloro Methane: methanol: ammonium hydroxide=100: 1: 1) obtaining yellow oil A84-2 (380mg, 88%).1H NMR (400MHz, CDCl3)δ 8.58 (s, 1H), 7.70 (s, 1H), 7.43 (d, J=7.2Hz, 1H), 7.26-6.68 (m, 2H), 4.52 (s, 1H), 4.20- 3.50 (m, 8H), 3.40-3.00 (m, 4H), 2.80-2.40 (m, 6H), 1.60-1.43 (m, 12H)
2) synthesis of intermediate A 84-3:
A84-2 (200mg, 0.44mmol) is dissolved in methylene chloride, 4mL trifluoroacetic acid is added dropwise under room temperature, is stirred overnight, revolves Dry solvent obtains yellow gel shape solid intermediate A84-3 (crude product 500mg).
3) synthesis of product A84:
Intermediate A 84-3 (crude product 500mg) is dissolved in methanol, is added 37% formalin (356mg, 4.4mmol), Stirring at normal temperature 20min is added sodium cyanoborohydride (82mg, 1.32mmol), and stirring at normal temperature is overnight.Saturated sodium bicarbonate tune is added PH about 7 to 8 is saved, methylene chloride extracts three times (20mL*3), merges organic phase, is concentrated under reduced pressure, is purified by silica gel column chromatography (dichloro Methane: methanol: ammonium hydroxide=50: 1: 0.5), obtaining yellow oil product A84 (80mg, 49%).
Embodiment 46
Heterocyclic compound A85, synthesizes by the following method:
1) synthesis of intermediate A 85-1:
N,N-Dimethylformamide (9.8g, 134.8mmol) is added dropwise to POCl at 0 DEG C3(60.6g, In 396.5mmol), and 1h is reacted at this temperature.2- methyl -3,6- dihydroxy-pyrimidine (10g, 79.3mmol) is added in batches again Enter into above-mentioned reaction solution, 105 DEG C of reactions are warming up to after the reaction was continued at room temperature 1h overnight.Reaction solution is spin-dried for, 100mL is added Glacial acetic acid ethyl ester, then instill in ice water.This suspension is filtered, filtrate is extracted with ethyl acetate (200mL).Organic phase is with anhydrous Sodium sulphate dries, filters, and filtrate is spin-dried for obtaining yellow intermediate A 85-1 (crude product 10g).
2) synthesis of intermediate A 85-2:
Intermediate A 85-1 (10g, 52.3mmol) is dissolved in THF/H2In the mixed solution of O (50mL/10mL), under ice bath By NaBH4(4g, 104.7mmol) is added portionwise, and reacts 30 minutes at this temperature.Water (50mL) is added to quench, ethyl acetate (50mL) extraction, organic phase are dried, filtered with anhydrous sodium sulfate, and filtrate is spin-dried for.Through column chromatography (petroleum ether: ethyl acetate=10: 1) yellow solid intermediate A 85-2 (2g, 20%) is purified to obtain.1H NMR (400MHz, CDCl3) δ 4.91 (s, 2H), 2.69 (s, 3H).
3) synthesis of intermediate A 85-3:
Intermediate A 85-2 (2g, 10.3mmol) and imidazoles (770mg, 11.3mmol) are dissolved in methylene chloride (20mL), TBSCl (1.7g, 11.3mmol) is added portionwise, and room temperature reaction is overnight.It is added water (20mL), methylene chloride (20mL) extraction.Have Machine is mutually dried, filtered with anhydrous sodium sulfate, and filtrate is spin-dried for.(petroleum ether: ethyl acetate=100: 1) purify colourless through column chromatography Oily intermediate A 85-3 (2.6g, 84%).1H NMR (400MHz, CDCl3) δ 4.85 (s, 2H), 2.68 (s, 3H), 0.91 (s, 9H), 0.14 (s, 6H)
4) synthesis of intermediate A 85-4:
By intermediate A 85-3 (1.5g, 4.8mmol), vinyl boron trifluoride sylvite (655mg, 4.88mmol), cesium carbonate (2.4g, 7.32mmol) and four triphenyl phosphorus palladiums (566mg, 0.49mmol) are added to Isosorbide-5-Nitrae-dioxane/water (20mL/4mL) In, the lower 100 DEG C of reactions of nitrogen protection are overnight.Reaction solution is spin-dried for, column chromatography (petroleum ether: ethyl acetate=100: 1) purifies Crude product (900mg).This crude intermediate is dissolved in ethanol/methylene (30mL/7mL) mixed solution again, it is smelly at -65 DEG C Oxygen aoxidizes 4h.After reaction, dimethyl sulphide is quenched for monitoring.Reaction solution is spin-dried for, is added water (20mL), methylene chloride (50mL) extraction It takes.Organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate is spin-dried for obtaining white solid intermediate A 85-4 (crude product 610mg).
5) synthesis of intermediate A 85-5:
By intermediate A 85-4 (610mg, 2.0mmol), A75-3 (544mg, 4.0mmol) and glacial acetic acid (360mg, It 6.0mmol) is added in methylene chloride (10mL), after stirring at normal temperature 1h, by NaBH (OAc)3(1.3g, 6.0mmol) adds in batches Enter, room temperature reaction is overnight.Water quenching is added to go out (10mL), methylene chloride (10mL) extraction.Organic phase is dry with anhydrous sodium sulfate, mistake Filter, filtrate are spin-dried for.(methylene chloride: methanol=100: yellow oily intermediate A 85-5 1/100: 2) is purified to obtain through column chromatography (480mg, 80%).1H NMR (400MHz, CDCl3) δ 8.66-8.55 (m, 1H), 7.82-7.65 (m, 1H), 7.38-7.30 (m, 1H), 7.25-7.18 (m, 1H), 4.77 (s, 2H), 4.15-3.85 (m, 3H), 2.66 (s, 3H), 2.19 (s, 3H), 1.56 (d, J =7.2Hz, 3H)
6) synthesis of product A85:
By intermediate A 85-5 (50mg, 0.16mmol), N methyl piperazine (48mg, 0.48mmol) and triethylamine (80mg, It 0.8mmol) is dissolved in ethyl alcohol (5mL), is warming up to 80 DEG C of reactions overnight.Reaction solution is spin-dried for, column chromatography (methylene chloride: methanol: Ammonium hydroxide=100: 1: 1 to 100: 2: 1) purifying to obtain colorless oil final product A85 (26mg, 80%).
Embodiment 47
According to the synthetic method of embodiment 46, in the final step with corresponding amine (R)-octahydro pyrrolo- [1,2-a] pyrrole Piperazine and (S)-octahydro pyrrolo- [1,2-a] pyrazine replace N methyl piperazine, and synthesis obtains heterocyclic compound A86 and A87.
Embodiment 48
Heterocyclic compound A88, synthesizes by the following method:
1) synthesis of intermediate A 88-2:
The formalin (1.0g, 12.5mmol) of A88-1 (500mg, 2.5mmol) and 37% is added to methylene chloride 1h is reacted at room temperature in (10mL).Again by NaBH (OAc)3(1g, 5.0mmol) is added portionwise, and is stirred overnight at room temperature.Add saturation chlorination Sodium solution is quenched (50mL), methylene chloride (50mL) extraction.Organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate is spin-dried for.By this Residue is dissolved in methylene chloride (5mL) solution, instills trifluoroacetic acid (2mL) at room temperature, stirring at normal temperature is overnight.Reaction solution is revolved It is dry, saturated sodium bicarbonate solution tune pH to 8 is added, is spin-dried for.Column chromatography (methylene chloride: methanol: ammonium hydroxide=10: 1: 1) purifies Yellow oily intermediate A 88-2 (crude product 120mg).1HNMR (400MHz, CDCl3) δ 4.07 (s, 1H), 2.93-2.89 (m, 1H), 2.88-2.82 (m, 1H), 2.78-2.72 (m, 1H), 2.52-2.42 (m, 1H), 2.27 (s, 3H), 2.22-2.10 (m, 1H), 2.05-1.92 (m, 1H), 1.03 (d, J=6.0Hz, 3H)
2) synthesis of product A88:
By intermediate A 85-5 (40mg, 0.13mmol), A88-2 (44mg, 0.39mmol) and triethylamine (66mg, It 0.65mmol) is dissolved in ethyl alcohol (5mL), is warming up to 80 DEG C of reactions overnight.Reaction solution is spin-dried for, column chromatographs (methylene chloride: methanol : ammonium hydroxide=100: 1: 1) purifying to obtain colorless oil final product A88 (40mg, 80%).
Embodiment 49
According to the synthetic method of embodiment 48, A88-1 is replaced with the enantiomter of A88-1 in the first step, is synthesized To heterocyclic compound A89.
Embodiment 50
Heterocyclic compound A90, synthesizes by the following method:
1) synthesis of intermediate A 90-2:
By A90-1 (1.0g, 5.75mmol), cylite (980mg, 5.75mmol), potassium carbonate (1.1g, 7.80mmol) is molten In N-N dimethylformamide (50mL), 110 DEG C of stirring 0.5h are heated.After the reaction was completed, filter residue is filtered out, filtrate is spin-dried for, is added The sodium hydrate aqueous solution for entering 2mL is extracted with the ethyl acetate of 50mL, and organic phase is dried with anhydrous sodium sulfate, rotation Dry solvent obtains yellow oil intermediate A 90-2 (1.4g, 93%).1H NMR (400MHz, CDCl3) δ 8.09-7.88 (m, 1H), 7.47-7.45 (m, 2H), 7.42-7.39 (m, 2H), 7.36-7.34 (m, 1H), 7.21-7.12 (s, 2H), 5.19 (s, 2H).
2) synthesis of intermediate A 90-3:
By cuprous iodide (101mg, 0.53mmol), two triphenylphosphine palladium of dichloro (300mg, 0.43mmol) is put into bottle with two necks In.Replace nitrogen, then the A90-2 (1.4g, 5.34mmol) that acetonitrile will be dissolved in, propargyl alcohol (890mg, 16mmol), triethylamine (2.2g, 21mmol) is injected in bottle with two necks with syringe, is stirred overnight in 50 DEG C.After the reaction was completed, it is spin-dried for solvent, water is added (200mL) is extracted with ethyl acetate (100mL), is merged organic phase, and organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for filtering Liquid, residue pass through column chromatographic purifying (pure ethyl acetate), obtain yellow oil intermediate A 90-3 (1.1g, 85%).1H NMR (400MHz, CDCl3) δ 8.17 (s, 1H), 7.44-7.42 (m, 2H), 7.40-7.36 (m, 2H), 7.34-7.30 (m, 1H), 7.22-7.13 (m, 2H), 5.18 (s, 2H), 4.56 (d, J=2.8Hz, 2H), 3.01 (s, 1H)
3) synthesis of intermediate A 90-4:
A90-3 (800mg, 3.35mmol) is dissolved in 10mL ethyl alcohol, is added palladium carbon (0.2g), is replaced with hydrogen. After the reaction was completed, it filters, is spin-dried for filtrate, residue passes through column chromatographic purifying (pure ethyl acetate), obtains yellow oil intermediate A90-4 (150mg, 29%).1H NMR (400MHz, DMSO-d6) δ 9.68 (s, 1H), 7.91 (d, J=4.4Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 7.05-6.97 (m, 1H), 4.47 (s, 1H), 3.43 (t, J=6.4Hz, 2H), 2.70 (t, J= 7.6Hz, 2H), 1.81-1.72 (m, 2H)
4) synthesis of intermediate A 90-5:
Tributylphosphine (315mg, 1.56mmol) is dissolved in tetrahydrofuran (10mL), with nitrogen protection, is stirred in 0 DEG C, It is added dropwise DIAD (315mg, 1.56mmol), stirs 5min.It is again that the A90-4 (200mg, 1.30mmol) for being dissolved in tetrahydrofuran is slow It instills, reacts 48h.It is spin-dried for solvent, residue obtains yellow oil intermediate A 90-5 by column chromatography (pure ethyl acetate) (48mg, 27%).1H NMR (400MHz, CDCl3) δ 8.10 (s, 1H), 7.11-7.03 (m, 2H), 4.26-4.07 (m, 2H), 3.02-2.85 (m, 2H), 2.17-2.00 (m, 2H)
5) synthesis of intermediate A 90-6:
A90-5 (180mg, 1.33mmol) is dissolved in methylene chloride (20mL), stirring at normal temperature, sym-closene is added (460mg, 1.99mmol) is stayed overnight in stirring at normal temperature.After the reaction was completed, filter residue is filtered out, 20mL saturated sodium bicarbonate water is added Solution is extracted with 30mL dichloromethane solution, and the dry organic phase of anhydrous sodium sulfate is spin-dried for solution.Residue passes through column layer Analysis (petroleum ether: ethyl acetate=4: 1), obtains yellow oil intermediate A 90-6 (40mg, 18%).1H NMR (400MHz, CDCl3) δ 8.23 (s, 1H), 7.17 (s, 2H), 5.25 (m, 1H), 4.55-4.43 (m, 1H), 4.41-4.36 (m, 1H), 2.63- 2.54 (m, 1H), 2.46-2.37 (m, 1H)
6) synthesis of intermediate A 90-7
Chloroacetyl acetacetic ester (16.5g, 100mmol) and ethenylamidine hydrochloride (10g, 106mmol) are successively dissolved in ethyl alcohol In (150mL).It is slowly added to 1,8- diazabicylo, 11 carbon -7- alkene (30.4g, 200mmol) under ice-water bath, is stirred under room temperature Overnight.It is concentrated under reduced pressure and removes solvent, methylene chloride (120mL) dilution is added, saturated common salt washes (30mL*3), anhydrous sodium sulfate Dry organic phase, filtering, filtrate decompression concentration remove solvent, obtain residue intermediate A 90-7 (7.93g, 50%).1H NMR (400MHz, CDCl3) (s, the 3H) .7 of δ 13.01 (s, 1H), 6.53 (s, 1H), 4.37 (s, 2H), 2.50) and intermediate A 90-8 conjunction At
Intermediate A 90-7 (1.7g, 11mmol), methylamine alcohol solution (687mg, 22mmol), diisopropyl ethyl amine (7.1g, 55mmol), potassium iodide (183mg, 0.1mmol) are dissolved in 50mL acetonitrile solution, heat 60 DEG C in tube sealing and are stirred overnight. Acetonitrile is spin-dried for, residue through column chromatographic purifying (methylene chloride: methane=10: 1), obtain yellow solid intermediate A 90-8 (600mg, 35%).1H NMR (400MHz, DMSO-d6) 66.36 (s, 1H), 3.80 (s, 2H), 2.66 (s, 1H), 2.55 (s, 3H), 2.43 (s, 2H)
8) synthesis of intermediate A 90-9
Intermediate A 90-8 (300mg, 1.96mmol), triethylamine (1.9g, 19.6mmol), N methyl piperazine (980mg, 9.8mmol) be dissolved in 20mL acetonitrile, be added hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (1.1g, 2.15mmol), return stirring is overnight.It is spin-dried for acetonitrile, obtains oily liquids, residue is through column chromatographic purifying (methylene chloride: methanol =20: 1), obtaining yellow oil intermediate A 90-9 (300mg, 65%).1H NMR (400MHz, CDCl3) 66.38 (s, 1H), 3.67-3.63 (m, 6H), 2.47-2.45 (m, 10H), 2.32 (s, 3H)
9) synthesis of product A90:
By A90-6 (40mg, 0.24mmol), A90-9 (83mg, 0.36mmol), potassium carbonate (79mg, 0.47mmol) is dissolved in In acetonitrile (10mL), 22h is reacted at 85 DEG C.It is directly spin-dried for solvent, residue passes through column chromatographic purifying (dichloro methanol: methanol =40: 1), obtaining yellow oil product A90 (50mg, 57%).
Embodiment 51
Heterocyclic compound A91, synthesizes by the following method:
1) synthesis of intermediate A 91-2:
By A91-1 (5g, 29mmol), 3- butene-1-ol (2.1g, 29mmol), triphenylphosphine (9.1g, 35mmol) is dissolved in In tetrahydrofuran (50mL), nitrogen, 0 DEG C of stirring are replaced.DIAD (6.5g, 32mmol) is injected with syringe, it is stirred in 60 DEG C Night.After the reaction was completed, it is cooled to room temperature, is spin-dried for tetrahydrofuran, 50mL saturated sodium-chloride water solution is added, with 50mL ethyl acetate It is extracted.Merge organic phase, anhydrous sodium sulfate is dry, be spin-dried for ethyl acetate, residue by column chromatographic purifying (petroleum ether: Ethyl acetate=10: 1), crude yellow oil intermediate A 91-2 (4.8g, 69%) is obtained.
2) synthesis of intermediate A 91-3:
By A91-2 (4.8g, 22.64mmol), triphenylphosphine (1.8g, 6.79mmol), palladium acetate (760mg, 2.26mmol), triethylamine (4.6g, 45mmol), potassium acetate (17.8g, 181mmol) are dissolved in DMF (50mL), stir in 110 DEG C It mixes overnight.After the reaction was completed, 50mL saturated sodium-chloride water solution is added, is extracted with 50mL ethyl acetate, organic phase is merged, Anhydrous sodium sulfate is dry, is spin-dried for ethyl acetate, and residue (petroleum ether: ethyl acetate=10: 1), obtains yellow by column chromatographic purifying Color grease intermediate A 91-3 (1.5g, 48%).1H NMR (400MHz, CDCl3) δ 8.20 (s, 1H), 7.16-7.11 (m, 2H), 5.07 (s, 1H), 4.84 (s, 1H), 4.25 (t, J=5.2Hz, 2H), 2.82 (t, J=6.0Hz, 2H)
3) synthesis of intermediate A 91-4:
A91-3 (1.5g, the 10.2mmol) mixed solution for being dissolved in methanol and chloroform (methanol: chloroform=5: 1), is added 10mg sodium bicarbonate solid stirs in -78 DEG C, is passed through ozone with ozone generator.After the reaction was completed, 20mL is added and is saturated chlorination Sodium water solution is extracted with 20mL methylene chloride, merges organic phase, and anhydrous sodium sulfate is dry, is spin-dried for methylene chloride.Residue By column chromatographic purifying (pure ethyl acetate), yellow solid intermediate A 91-4 (1g, 67%) is obtained.1H NMR (400MHz, CDCl3) δ 8.46 (s, 1H), 7.40 (s, 2H), 4.62 (t, J=6.4Hz, 2H), 2.98 (t, J=6.4Hz, 2H)
4) synthesis of intermediate A 91-5:
A91-4 (1g, 6.71mmol) is dissolved in methylene chloride (50mL), addition acetic acid sodium borohydride (2.62g, 12.40mmol), in 0 DEG C of stirring 10min, be added be dissolved in methylene chloride (S)-(-) -1- (4- methoxybenzene) ethamine (950mg, 6.17mmol), stirring at normal temperature is overnight.After the reaction was completed, be added 40mL saturated sodium bicarbonate aqueous solution, with 50mL methylene chloride into Row extraction is spin-dried for organic phase with the dry organic phase of anhydrous sodium sulfate, and residue is obtained by column chromatography (DCM: MeOH=100: 1) Colorless oil intermediate A 91-5 (800mg, 45%).1H NMR (400MHz, CDCl3) δ 8.16 (s, 1H), 7.40 (d, J= 7.6Hz, 2H), 7.09 (s, 2H), 6.87 (d, J=7.6Hz, 2H), 4.32-4.11 (m, 2H), 4.07-3.96 (m, 1H), 3.93 (t, J=5.2Hz, 1H), 3.81 (s, 3H), 1.82-1.74 (m, 2H), 1.49 (d, J=5.6Hz, 3H)
5) synthesis of intermediate A 91-6:
A91-5 (400mg, 1.41mmol) is dissolved in the methylene chloride of 50mL, is stirred in 0 DEG C, formalin is added (285mg, 3.50mmol) after stirring 10min, is added acetic acid sodium borohydride (746mg, 3.50mmol).After the reaction was completed, it is added 30mL saturated sodium bicarbonate aqueous solution is extracted with 50mL methylene chloride, and organic phase is dry with anhydrous sodium sulfate, is spin-dried for dichloro Methane obtains yellow oil intermediate A 91-6 (330mg, 79%).1H NMR (400MHz, CDCl3) δ 8.22 (s, 1H), 7.40 (d, J=8.4Hz, 2H), 7.06 (s, 2H), 6.86 (d, J=8.4Hz, 2H), 4.41-4.33 (m, 2H), 4.13-4.05 (m, 2H), 3.80 (s, 3H), 2.31-2.22 (m, 1H), 2.04 (s, 3H), 1.93-1.86 (m, 1H), 1.42 (d, J=6.4Hz, 3H).
6) synthesis of intermediate A 91-7:
A91-6 (330mg, 1.11mmol) is dissolved in methylene chloride (10mL), stirring at normal temperature is slowly added to trifluoroacetic acid (6mL), reaction is overnight.After the reaction was completed, it is spin-dried for methylene chloride and trifluoroacetic acid, is added hydrochloric acid (0.5mol/mL, 5mL), is used 10mL methylene chloride is extracted, and is added saturated sodium bicarbonate aqueous solution into water phase, adjusts PH to 8, with 20mL methylene chloride into Row extraction, is dried with anhydrous sodium sulfate, is spin-dried for methylene chloride, obtain yellow oil intermediate A 91-7 (120mg, 66%).1H NMR (400MHz, CDCl3) δ 8.15 (s, 1H), 7.11 (s, 2H), 4.50-4.14 (m, 2H), 3.76 (s, 1H), 2.56 (s, 3H), 2.24-2.20 (m, 2H)
7) synthesis of intermediate A 91-8:
By A91-7 (120mg, 0.73mmol), A37-1 (145mg, 0.80mmol), diisopropyl ethyl amine (188mg, 1.46mmol), potassium iodide (13mg, 0.07mmol) is dissolved in acetonitrile (10mL), is stirred under room temperature.After the reaction was completed, it is spin-dried for Acetonitrile, residue by column chromatographic purifying (dichloro methanol: methanol=70: 1), obtain yellow oil intermediate A 91-8 (120mg, 54%).1H NMR (400MHz, CDCl3) δ 8.21 (s, 1H), 7.53 (s, 1H), 7.09 (s, 2H), 4.51-4.34 (m, 1H), 4.28-4.13 (m, 1H), 4.10-3.97 (m, 1H), 3.81 (s, 2H), 2.65 (s, 3H), 2.42 (s, 3H), 2.32-2.21 (m, 1H), 2.21-2.12 (m, 1H)
8) synthesis of product A91:
By A91-8 (120mg, 0.39mmol), N methyl piperazine (197mg, 1.97mmol), triethylamine (394mg, It 3.94mmol) is dissolved in dehydrated alcohol (20mL), is stirred to react in 80 DEG C overnight.After the reaction was completed, it is spin-dried for ethyl alcohol, residue passes through Column chromatographic purifying (dichloro methanol: methanol=60: 1), obtains yellow oil product A91 (130mg, 94%).
Embodiment 52
Heterocyclic compound A92, synthesizes by the following method:
1) synthesis of intermediate A 92-2:
A92-1 (5g, 41mmol) is dissolved in anhydrous methanol (50mL), is added sodium methoxide (4.4g, 82mmol), in 0 DEG C It is stirred to react overnight.After the reaction was completed, it is spin-dried for methanol, residue is extracted with 50mL ethyl acetate, and residue passes through column layer Analysis purifying (petroleum ether: ethyl acetate=10: 1), obtains yellow oil intermediate A 92-2 (4.6g, 78%).1H NMR (400MHz, CDCl3) δ 8.27 (d, J=2.8Hz, 1H), 7.53-7.45 (m, 1H), 7.39-7.31 (m, 1H), 3.97 (s, 3H).
2) synthesis of intermediate A 92-3:
A92-2 (500mg, 3.73mmol) is dissolved in the tetrahydrofuran of 50mL, is protected with nitrogen, is stirred in 0 DEG C, 3N methyl-magnesium-chloride diethyl ether solution (3.73mL, 11.2mmol) is injected with syringe.After the reaction was completed, 0.5N dilute hydrochloric acid is added (5mL) is extracted with 50mL ethyl acetate.It is spin-dried for ethyl acetate, obtains yellow oil intermediate A 92-3 (400mg, 63%).1H NMR (400MHz, CDCl3) (s, the 3H) of δ 8.25 (s, 1H), 7.61-7.30 (m, 2H), 3.91 (s, 3H), 2.66
3) synthesis of intermediate A 92-4:
A92-3 (450mg, 2.98mmol) is dissolved in 50mL methylene chloride, be added acetic acid sodium borohydride (1.26g, 5.96mmol), it is stirred in 0 DEG C, (S)-(-) -1- (4- methoxybenzene) ethamine for being dissolved in methylene chloride is added after 10min (400mg, 2.65mmol's), stirring at normal temperature is overnight.After the reaction was completed, 50mL sodium bicarbonate aqueous solution is added, with 50mL dichloro Methane is extracted, and methylene chloride is spin-dried for, and residue (dichloro methanol: methanol=50: 1), obtains yellow oil by column chromatographic purifying Shape object intermediate A 92 (300mg, 35%).1H NMR (400MHz, CDCl3) δ 8.27-8.16 (m, 1H), 7.45-7.32 (m, 2H), 7.31-7.27 (m, 1H), 7.21-7.17 (m, 1H), 6.88 (d, J=8.4Hz, 2H), 4.27 (s, 1H), 3.81 (s, 3H), 3.79-3.70 (m, 4H), 1.60-1.38 (m, 6H)
4) synthesis of intermediate A 92-5:
A92-4 (130mg, 0.46mmol) is dissolved in the methylene chloride of 10mL, be added formalin (92mg, 1.14mmol), it stirs, is added acetic acid sodium borohydride (241mg, 1.14mmol), stirring at normal temperature is overnight in 0 DEG C.After the reaction was completed, 50mL saturated sodium bicarbonate aqueous solution is added, is extracted with 40mL methylene chloride, is spin-dried for methylene chloride, obtain crude yellow oily Object intermediate A 92-5 (90mg, 66%).
5) synthesis of intermediate A 92-6:
A92-5 (90mg, 0.30mmol) is dissolved in the methylene chloride of 20mL, the trifluoroacetic acid of 2mL, stirring at normal temperature is added Overnight, after the reaction was completed, it is spin-dried for methylene chloride and trifluoroacetic acid, is added 0.5N hydrochloric acid (0.5mol/mL, 5mL), with 10mL dichloro Saturated sodium bicarbonate aqueous solution is added into water phase for methane wash water phase, adjusts pH to 10, is extracted with 20mL methylene chloride, uses Anhydrous sodium sulfate is dried, and filtering is spin-dried for filtrate, obtains yellow oil intermediate A 92-6 (25mg, 50%).1H NMR (400MHz, CDCl3) δ 8.17 (s, 1H), 7.15 (s, 2H), 4.23 (s, 1H), 3.84 (s, 3H), 2.58 (s, 3H), 2.30 (s, 3H).
6) synthesis of intermediate A 92-7:
By A92-6 (40mg, 0.24mmol), A37-1 (50mg, 0.26mmol), DIPEA (63mg, 0.48mmol) and KI (4mg, 0.24mmol) is dissolved in the acetonitrile of 10mL, and stirring at normal temperature is overnight.After the reaction was completed, it is spin-dried for acetonitrile, residue passes through column Chromatographic purifying (dichloro methanol: methanol=100: 1), obtains yellow oil intermediate A 92-7 (35mg, 47.9%).1H NMR (400MHz, CDCl3) δ 8.18 (s, 1H), 7.45 (s, 1H), 7.18-7.11 (m, 2H), 4.53-4.44 (m, 1H), 3.84 (s, 3H), 3.76 (d, J=16.4Hz, 1H), 3.68 (d, J=16.4Hz, 1H), 2.66 (s, 3H), 2.29 (s, 3H), 1.46 (d, J =6.8Hz, 3H)
7) synthesis of product A92:
By A92-7 (30mg, 0.10mmol), N methyl piperazine (49mg, 0.49mmol), triethylamine (100mg, It 0.98mmol) is dissolved in ethyl alcohol (8mL), is stirred to react in 80 DEG C overnight.After the reaction was completed, it is spin-dried for ethyl alcohol, residue passes through column layer Analysis purifying (dichloro methanol: methanol=60: 1), obtains yellow oil product A92 (30mg, 71.4%).
Embodiment 53
Heterocyclic compound A93, synthesizes by the following method:
1) synthesis of intermediate A 93-1:
By A92-1 (10g, 82mmol), 4- methoxybenzylamine (16.8g, 123.0mmol) and cesium carbonate (40g, It 123.0mmol) is added in DMF (50mL), is warming up to 70 DEG C and is stirred overnight.It is added ethyl acetate (50mL), saturated sodium bicarbonate Solution (20mL*3) is washed three times.Organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate is spin-dried for.(petroleum ether: second is chromatographed through column Acetoacetic ester=20: 1) yellow solid intermediate A 93-1 (crude product 11g) is purified to obtain.1H NMR (400MHz, CDCl3) δ 7.98 (s, 1H), 7.28-7.18 (m, 3H), 7.00 (d, J=8.8Hz, 1H), 6.90 (d, J=8.0Hz, 2H), 5.05 (s, 1H), 4.36 (d, J=5.6Hz, 2H), 3.81 (s, 3H)
2) synthesis of intermediate A 93-2:
A93-1 (11g, 46.0mmol) is dissolved in anhydrous tetrahydro furan in (200mL), by the methyl of 3M concentration at 0 DEG C Magnesium chloride diethyl ether solution (77mL, 230.1mmol) is added dropwise, and stirs 30 minutes at this temperature.It is molten that saturated ammonium chloride is added Liquid is quenched (50mL), and ethyl acetate extracts (100mL).Organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate is spin-dried for.Through column layer Analysis (petroleum ether: ethyl acetate=5: 1) purifies to obtain yellow solid intermediate A 93-2 (4g, 34%).1H NMR (400MHz, CDCl3) δ 9.02 (s, 1H), 8.03-7.90 (m, 1H), 7.28-7.15 (m, 2H), 7.08-6.98 (m, 1H), 6.93-6.83 (m, 2H), 4.50-4.30 (m, 2H), 3.79 (s, 3H), 2.72 (s, 3H)
3) synthesis of intermediate A 93-3:
Intermediate A 93-2 (1.5g, 5.8mmol) is dissolved in trifluoroacetic acid (5mL), reaction is stayed overnight at room temperature.It will reaction Liquid is spin-dried for, and with saturated sodium bicarbonate solution tune pH to 8, methylene chloride extracts (20mL).Organic phase is dry with anhydrous sodium sulfate, mistake Filter, filtrate are spin-dried for.Residue is again dissolved in glacial acetic acid (10mL), is added acetic anhydride (20mL), is stirred overnight at room temperature.It will be anti- Liquid is answered to be spin-dried for, with saturated sodium bicarbonate solution tune pH to 8, methylene chloride extracts (20mL).Organic phase is dry with anhydrous sodium sulfate, Filtering, filtrate are spin-dried for, and obtain white solid intermediate A 93-3 (1g, 97%).1H NMR (400MHz, CDCl3) δ 11.54 (s, 1H), 9.10 (d, J=8.8Hz, 1H), 8.37 (d, J=4.4Hz, 1H), 7.48 (dd, J=8.8Hz, 4.4Hz, 1H), 2.80 (s, 3H), 2.26 (s, 3H)
4) synthesis of intermediate A 93-4:
By intermediate A 93-3 (1g, 5.6mmol), (S)-(-) -1- (4- methoxybenzene) ethamine (1.3g, 8.4mmol) and Tetraethyl titanate (3.8g, 16.8mmol) is added in Isosorbide-5-Nitrae-dioxane (30mL), is reacted for 100 DEG C under nitrogen protection Night.It is cooled to room temperature, is added methanol (30mL), sodium borohydride (638mg, 16.8mmol) is added portionwise at 0 DEG C, react at room temperature 2h.Add diatomite to filter, filtrate is spin-dried for.It adds saturated sodium chloride solution (10mL), methylene chloride extracts (10mL*3).Have Machine is mutually dried, filtered with anhydrous sodium sulfate, and filtrate is spin-dried for.(petroleum ether: ethyl acetate=1: 1) purify white solid through column chromatography Body intermediate A 93-4 (380mg, 22%).1H NMR (400MHz, CDCl3) δ 11.78 (s, 1H), 8.62 (s, 1H), 8.21 (s, 1H), 7.23-7.16 (m, 1H), 7.15-7.04 (m, 2H), 6.87 (d, J=8.0Hz, 2H), 4.10 (s, 1H), 3.79 (s, 3H), 3.61 (s, 1H), 2.20 (s, 3H), 1.50-1.33 (m, 6H)
5) synthesis of intermediate A 93-5:
Intermediate A 93-4 (352mg, 1.1mmol) is dissolved in 20mL methanol, the formalin of 37% content is added (0.9g, 11mmol) and acetic acid (66mg, 1.1mmol), after being stirred at room temperature 1 hour, addition sodium cyanoborohydride (0.69g, 11mmol), room temperature reaction is stayed overnight.Reaction is concentrated to dryness, and DCM (50mL) dissolution is added, and saturated sodium bicarbonate is added and adjusts PH to 8, organic phase is concentrated to dryness, residue chromatograph through column (methylene chloride: methanol=50: 1) purify in yellow solid Mesosome A93-5 (332mg, 92%).1H NMR (400MHz, CDCl3) δ 11.40 (s, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 7.22-7.17 (m, 2H), 7.01-6.85 (m, 3H), 4.17 (s, 1H), 3.94 (s, 1H), 3.81 (s, 3H), 2.21 (s, 3H), 2.00 (s, 3H), 1.50-1.40 (m, 6H)
6) synthesis of intermediate A 93-6:
Intermediate A 93-5 (332g, 1mmol) is dissolved in 5mL DCM, 5mL trifluoroacetic acid is added, stirring at normal temperature is overnight. Reaction system is concentrated to dryness, and obtains yellow oil A93-6 (crude product 600mg).LC-MS (m/z): 194.0 [M+H]+.
7) synthesis of intermediate A 93-7:
By intermediate A 93-6 (crude product 0.6g, 1mmol), intermediate A 37-1 (212mg, 1.2mmol) and potassium iodide (17mg, 0.1mmol) is dissolved in 10mL acetonitrile, is added diisopropyl ethyl amine (0.645g, 5mmol), and room temperature reaction is overnight.Instead It answers system to be concentrated to dryness, saturated sodium bicarbonate is added and adjusts pH to 8, methylene chloride extracts (20mL).Organic phase decompression is dense Contracting, residue chromatograph through column (methylene chloride: methanol: ammonium hydroxide=100: 1: 0.1) purify yellow solid intermediate A 93-7 is (thick Product 190mg).
8) synthesis of product A93:
By intermediate A 93-7 (crude product 170mg, 0.51mmol), N methyl piperazine (204mg, 2.04mmol) and diisopropyl Base ethamine (657mg, 5.1mmol) is dissolved in 10mL ethyl alcohol, is heated 80 DEG C and is stirred 4 hours.Reaction system is concentrated to dryness, residual Excess, which is chromatographed through column, (methylene chloride: methanol: ammonium hydroxide=20: 1: 0..05) purifies to obtain colorless oil A93 (85mg, three step yields 5%).
Embodiment 54
According to the synthetic method of embodiment 53, acetic anhydride acetic acid is replaced with methylsufonyl chloride triethylamine condition in step 3 Condition, synthesis obtain heterocyclic compound A94.
Embodiment 55
Control compounds B1, synthesizes by the following method:
1) synthesis of intermediate B 1-2:
B1-1 (200mg, 1.2mmol), 4-dimethylaminopyridine (14mg, 0.1mmol) and triethylamine (370mg, It 3.6mmol) is dissolved in methylene chloride (15mL), mesyl chloride (210mg, 1.8mmol), which is dissolved at that 0 DEG C of methylene chloride, slowly to be added Enter, stirring at normal temperature 2h, saturated salt solution and methylene chloride extraction is added, liquid separation, mutually drying is spin-dried for methylene chloride.Residue is through column Chromatographic purifying (petroleum ether: ethyl acetate=1: 1), obtains colourless oil liquid (220mg, 76%).
2) synthesis of intermediate B 1-3:
B1-2 (200mg, 0.83mmol) is dissolved in the tetrahydrofuran solution of 5mL methylamine, and n,N-diisopropylethylamine is added (540mg, 4.2mmol), return stirring is overnight, and the extraction of 100mL methylene chloride 100mL sodium bicarbonate aqueous solution, dichloromethane is added Mutually drying is spin-dried for alkane, and residue (methylene chloride: methanol=100: 1 to 25: 1), obtains brown oil liquid through column chromatographic purifying (100mg, 68%).
3) synthesis of intermediate B 1-4:
B1-3 (90mg, 0.5mmol) is dissolved in 3mL ethyl alcohol, is added triethylamine (75mg, 0.8mmol) and 4,6- dichloro pyrimidine (110mg, 0.8mmol), stirring at normal temperature is overnight, and the extraction of 100mL methylene chloride 100mL sodium bicarbonate aqueous solution, dichloromethane is added Alkane mutually drying is spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol=100: 1), obtain brown oil liquid (80mg, 55%).
4) synthesis of product B1:
B1-4 (80mg, 0.28mmol) is dissolved in 3mL ethyl alcohol, is added triethylamine (280mg, 28mmol), N methyl piperazine (30mg, 0.31mmol), 80 DEG C are stirred overnight, and 50mL methylene chloride and the extraction of 50mL sodium bicarbonate aqueous solution, dichloromethane is added Mutually drying is spin-dried for alkane, and residue (methylene chloride: methanol=100: 1 to 50: 1), obtains colourless oil liquid through column chromatographic purifying (20mg, 20%).
Embodiment 56
Control compounds B2, synthesizes by the following method:
A1-4 (70mg, 0.24mmol) is dissolved in 5mL methanol, is added 5% wet palladium carbon (15mg), and after replacing hydrogen, 50 DEG C are stirred It mixes overnight, filtering, filtrate is spin-dried for, and residue (methylene chloride: methanol=100: 1), obtains colourless oil liquid through column chromatographic purifying (50mg, 82%).
Embodiment 57
According to the synthetic method of embodiment 1, N methyl piperazine is replaced with dimethylamine in final step, synthesis obtains comparisonization Close object B3.
Embodiment 58
According to the synthetic method of embodiment 31,2- methyl -4- chlorine pyrimidine is replaced with the chloro- 4- methylpyrimidine of 2- in step 1, Synthesis obtains control compounds B4.
Embodiment 59
Control compounds B6, synthesizes by the following method:
1) synthesis of intermediate B 6-1:
A1-3 (100mg, 0.62mmol), 6- bromopyridine -2- formaldehyde (162mg, 0.68mmol), acetic acid (48mg, It 0.62mmol) is dissolved in 10mL dichloroethanes, stirring at normal temperature after ten minutes, is added acetic acid sodium borohydride (252mg, 0.93mmol), Continue to be stirred overnight, 100mL methylene chloride and the extraction of 50mL sodium bicarbonate aqueous solution is added, mutually drying is spin-dried for methylene chloride, residual Excess (methylene chloride: methanol=100: 1), obtains pale yellow oily liquid (180mg, 87%) through column chromatographic purifying.
2) synthesis of product B6:
B6-1 (50mg, 0.15mmol) is dissolved in 2mL NMP, is added DIPEA (193mg, 1.5mmol), N methyl piperazine (73mg, 0.75mmol), 120 DEG C are stirred overnight, and 50mL methylene chloride and the extraction of 50mL sodium bicarbonate aqueous solution, dichloromethane is added Alkane mutually drying is spin-dried for, residue through column chromatographic purifying (methylene chloride: methanol=100: 1), obtain colourless oil liquid (12mg, 23%).
Embodiment 60
According to the synthetic method of embodiment 59,6- bromopyridine -2- formaldehyde is replaced with 2- chloropyridine -4- formaldehyde in step 1, Synthesis obtains control compounds B5.
Embodiment 61
Control compounds B7 and B8 are to synthesize to obtain according to the operation of patent WO2009121063.
The analytic structure and spectral data of table 1 heterocyclic compound A1-A94 and control compounds B1-B8
Embodiment 62
Combination of the heterocyclic compound A1-A77 and B1-B8 that embodiment 1-61 is prepared in the present embodiment to CXCR4 Ability is measured.
HPB-ALL cell culture is non-containing 10% heat-inactivated fetal bovine serum (Hyclone)+1X penicillin/streptomycin+1X In the RPMI-1640 culture medium of necessary amino acid+1X+50 μM of beta -mercaptoethanols of Sodium Pyruvate.By HPB-ALL cell with ice-cold Measurement buffer (+10% heat-inactivated fetal bovine serum of Du Shi phosphate buffer) is washed once, and cell is then suspended to measurement again and is delayed In fliud flushing, ultimate density 1x106/ml.The above-mentioned cell suspending liquid in 95 holes μ l/ is taken to be added in 96 orifice plates, then in hole 2- The source of people CXCR4 monoclonal antibody 12G5 (SungeneH31841-11H) for being connected to APC fluorescent marker is added in 12, adds in hole 1 Enter the mouse IgG antibody for being connected to APC fluorescent marker of corresponding amount as control.Test compound is diluted step by step with DMSO, then Wanted concentration is diluted to measurement buffer again.The test compound solution of 5 μ l various concentrations is added in the 2-11 of hole, in hole 1 and hole 12 in be added corresponding amount measurement buffer, be then protected from light in 4 DEG C of hatching 3h.100 μ l, 4% poly first is added in every hole Aldehyde solution is protected from light hatching 10 minutes in ice.Cell is washed with test buffer, is then resuspended in test buffer In, fluorescence signal is detected with flow cytometer (GuavaSoft6/8HT, Millipore), according to various concentration compound to hair The suppression result of optical signal calculates the IC of compound50Value.By taking Figure of description 1 as an example, as concentration > 100nM, jeterocyclic chemistry Object A42 is closed to the fluorescence signal inhibiting rate nearly 100% of 12G5, shows compound A42 nearly completely by 12G5 from CXCR4 It is replaced on albumen；When concentration is 0.3nM, fluorescence signal inhibiting rate nearly 0% of the heterocyclic compound A42 to 12G5, table Bright compound A42 almost cannot replace 12G5 from CXCR4 albumen；It can be read from curve, when concentration is When 9.8nM, heterocyclic compound A42 is 50% to the fluorescence signal inhibiting rate of 12G5, shows the heterocyclic compound A42 in the concentration Just the 12G5 of half is replaced from CXCR4 albumen, then the concentration is the half-inhibitory concentration of heterocyclic compound A42 (IC50)。IC50It is worth lower, it is higher to the binding ability of CXCR4 to represent the heterocyclic compound, and activity is better.If IC50> 10000nM shows that the compound all cannot replace 12G5 in 10000nM from CXCR4 albumen, can be regarded as the change It closes object and CXCR4 is not bound with ability, i.e., without activity.
As a result such as table 2 (result of the heterocyclic compound A1-A77 to the binding ability measurement experiment of CXCR4) and (comparison of table 3 Result of the compound B-11-B8 to the binding ability measurement experiment of CXCR4) shown in.
Result of the 2 heterocyclic compound A1-A77 of table to the binding ability measurement experiment of CXCR4
As can be seen from Table 2, the heterocyclic compound in the present invention, there is the ability well in conjunction with CXCR4, it is effective CXCR4 inhibitor can be used in treating or preventing the illness that response inhibits in CXCR4 receptor.
Result of the 3 control compounds B1-B8 of table to the binding ability measurement experiment of CXCR4
Number IC50(nM) Number IC50(nM) Number IC50(nM)
B1 > 10000 B2 > 10000 B3 > 10000
B4 > 10000 B5 > 10000 B6 > 10000
B7 > 10000 B8 > 10000
Seen from table 3, the present invention in heterocyclic compound, the link position of U group is particularly significant, when U group change into A3When being connected (control compounds B4), the inhibitory activity of CXCR4 can be lost；Moreover, two N on U group are also particularly significant, Remove a N (control compounds B3) or can all lose the inhibitory activity of CXCR4 without N (control compounds B2)；Meanwhile it is phonetic The position of N is very crucial to the activity of CXCR4 in phenazine ring, changes pyrimidine ring into pyridine ring (control compounds B5 and B6) or changes At the pyrimidine ring (control compounds B7 and B8) of other connection types, the inhibitory activity of CXCR4 can be all lost.
Embodiment 63
Heterocyclic compound A1, A22, A42, A61, A75 and A78-A94 couple that embodiment 1-61 is prepared in the present embodiment The rejection ability of SDF-1 α inducing T cell calcium ionic current is measured.
People CD4+T cell is separated from people's whole blood, then uses CD3/CD28 amplification kit (Life Technologies it) activates and expands spare.The cell cultivated in advance is taken to be suspended in containing 20mM HEPES, HEPES/ In 0.005% balanced salt solution, cell concentration is made to reach 5x106Cell/mL.In 384 orifice plates, 20 μM of cells are added in every hole (5x106Cell/mL), after so that cell is balanced 10min at room temperature, 20 μM of Fluo-4 fluorescent calcium indicator dyes are added in every hole, Balance 10min at room temperature again, in 37 DEG C, 5%O2/CO2Lower culture 30min.25 μ L (40nM) SDF-1 α, which are added, in every hole stimulates calcium Then test board is added using FLIPR Tetra in untested compound (test concentrations range is 10 μM of -0.035nM) by outflow In hole.Test board is transferred on fluorescence collection photo-forming plate reader (FLIPR), untested compound is detected and calcium ion is changed Become, to measure the antagonistic ability that compound receives CXCR4.Test value relative to untreated control wells by fluorometric investigation value into The processing of row normalization method, by taking compound A78 and A83 as an example (Fig. 3, Fig. 4), 50% inhibition concentration (IC50Value) it is defined as relative to Untreated control wells, untested compound concentration needed for inhibiting the calcium ion of SDF-1 induction to reach 50%.As a result as table 4 is (miscellaneous Inhibition assay result of the cycle compound A78-A94 to the SDF-1 α T cell calcium ionic current induced) shown in.
Table 4 heterocyclic compound A1, A22, A42, A61, A75 and A78-A94 are to the SDF-1 α T cell calcium ionic current induced Inhibition assay result
Number IC50(nM) Number IC50(nM) Number IC50(nM)
A1 4.5 A22 3.4 A42 0.021
A61 0.024 A75 0.090 A78 0.062
A79 0.22 A80 0.18 A81 4.5
A82 2.5 A83 0.93 A84 3.0
A85 0.99 A86 0.13 A87 0.18
A88 0.30 A89 0.13 A90 0.046
A91 0.032 A92 118 A93 20000
A94 20000
Embodiment 64
The present embodiment carries out the heterocyclic compound A1-A94 that embodiment 1-61 is prepared to the rejection ability of CYP liver enzyme Measurement.
Two main CYP isodynamic enzymes and their own probe substrate be respectively as follows: CYP3A4 (midazolam, 1 μM) and CYP2D6 (dextromethorphan, 5 μM).All probes are all to be near or below the use of its KMS concentration.Mixture (200 μ L) is in temperature It educates and is incubated in the thermostat water bath for 37 DEG C.The mixture contains HLM (0.2mg/mL), phosphate buffer (100mM, PH 7.4) in, NADPH (1 μM), test compound (10 μM) and respective CYP probe substrate.Start with reacting for NADPH Before, by mixture preincubate 10 minutes, inhibitor-enzyme interacting is carried out.After 10 minutes, after reaction by addition to 100 μ L contain appropriate cold acetonitrile and are quenched.Be then centrifuged for and by sample to be tested injection LC-MS/MS come quantitative analysis substrate with The concentration of CYP enzyme formation specific metabolite.Each untested compound is at least independently completed to be tested three times.As a result such as 5 (part of table Result of the representative compound to the rejection ability measurement experiment of CYP liver enzyme) shown in, inhibiting rate is lower, shows compound to CYP The rejection ability of liver enzyme is weaker, has better drug interaction safety.
Table 5
Compound number CYP3A4 inhibiting rate CYP2D6 inhibiting rate
A9 52% 53%
A10 45% 39%
A41 58% 28%
A43 48% 56%
By table 5 as it can be seen that the heterocyclic compound in the present invention, shows the inhibiting rate of CYP liver enzyme less than 60% at 10 μM The compound of the present invention has better drug interaction safety, substantially better than clinical compounds AMD070 (at 1 μM pair 100%) inhibiting rate of CYP2D6 is.

Claims (10)

1. a kind of heterocyclic compound and its pharmaceutically acceptable salt with CXCR4 signal path inhibitory activity, isotope, Isomers and crystalline structure have structure shown in general formula I:
Wherein, A1, A2, A3It is respectively and independently selected from N or CR10, and A1, A2, A3A minimum of one is N；
W is
U is
Q is chemical bond or CR23R24；
R1, R2, R3, R4It is respectively and independently selected from hydrogen atom, D-atom, cyano, halogen, hydroxyl, amino, NHC1-6Alkyl, N (C1-6Alkane Base)2、NHCOC1-6Alkyl, NHCOOC1-6Alkyl, NHSO2C1-6Alkyl, C1-6Alkyl, C3-6Naphthenic base, C1-8Alkoxy, C2-6Alkene Base, C2-6Alkynyl, the alkyl and alkoxy are unsubstituted or replaced by 1-3 halogen or D-atom；
R5, R6It is respectively and independently selected from hydrogen atom, D-atom, C1-6Alkyl or C3-6Naphthenic base, the alkyl are unsubstituted or by 1-3 It is a to be selected from halogen, D-atom, hydroxyl, amino, NHC1-6Alkyl, N (C1-6Alkyl)2、NHCOC1-6Alkyl, NHCOOC1-6Alkyl, C1-3The substituent group of alkoxy replaces；Or R4With R5And its atom connected can interconnect cyclization；
R7Selected from hydrogen atom, C1-6Alkyl, C3-6Naphthenic base or C3-6Heterocyclylalkyl, the alkyl is unsubstituted or is selected from by 1-3 Halogen, D-atom, C3-6Naphthenic base or C3-6The substituent group of Heterocyclylalkyl replaces, and the Heterocyclylalkyl contains 1 O atom；
R8, R9It is respectively and independently selected from hydrogen atom, D-atom, cyano, C1-6Alkyl or C3-6Naphthenic base, the alkyl it is unsubstituted or Halogen, D-atom, hydroxyl, C are selected from by 1-31-3The substituent group of alkoxy replaces；Or R8, R9And its atom connected can Interconnect cyclization；
R10Selected from hydrogen atom, D-atom, halogen, cyano, hydroxyl, amino, C1-6Alkyl, C3-6Naphthenic base, C1-8Alkoxy, NHC1-6 Alkyl, N (C1-6Alkyl)2、C(O)NHC1-6Alkyl, C (O) N (C1-6Alkyl)2、SC1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, 4-7 member Heterocycle, 6 yuan of aryl, 5-6 unit's heteroaryl, the alkyl, alkoxy, heterocycle, aryl, heteroaryl are unsubstituted or by 1-3 It is a to be selected from halogen, D-atom, hydroxyl, C1-3The substituent group of alkoxy replaces；
R11Selected from hydrogen atom, C1-6Alkyl, C3-6Naphthenic base, the alkyl it is unsubstituted or by 1-3 selected from halogen, D-atom, Hydroxyl, amino, NHC1-6Alkyl, N (C1-6Alkyl)2、C1-3The substituent group of alkoxy replaces；
R12, R13, R14, R15, R18, R19, R20, R21, R23, R24Separately it is selected from hydrogen atom, D-atom, cyano, hydroxyl, C1-6 Alkyl, C3-6Naphthenic base, C1-3Alkoxy, the alkyl and alkoxy are unsubstituted or a selected from halogen, D-atom, hydroxyl by 1-3 Base, amino, NHC1-6Alkyl, N (C1-6Alkyl)2、NHCOC1-6Alkyl, NHCOOC1-6Alkyl, C1-3The substituent group of alkoxy replaces； Or R11With R14And its atom connected can interconnect cyclization；Or R19With R12Or R15And its atom connected can be mutual Be connected cyclization；
R16, R17Separately it is selected from hydrogen atom, C1-6Alkyl, C3-6Naphthenic base, C3-6Heterocyclylalkyl, COC1-6Alkyl, COOC1-6 Alkyl, CONHC1-6Alkyl, the alkyl is unsubstituted or is selected from halogen, D-atom, hydroxyl, cyano, C by 1-33-6Cycloalkanes Base, C1-3Alkoxy, C3-6The substituent group of Heterocyclylalkyl replaces, and the Heterocyclylalkyl contains 1 hetero atom for being selected from O or N；Or R16With R17And its atom connected can be interconnected into 5-7 circle heterocyclic ring；Or R16With R15And its atom connected can be mutual Connect into 5-7 circle heterocyclic ring；
R22Selected from hydrogen atom, C1-6Alkyl, C3-6Naphthenic base, C3-8Heterocyclylalkyl, the alkyl, naphthenic base or Heterocyclylalkyl not by Replace or is selected from halogen, D-atom, hydroxyl, cyano, C by 1-33-6Naphthenic base, C1-3Alkoxy, C1-6Sulfuryl, C1-6Acyl group, C3-6The substituent group of Heterocyclylalkyl replaces, and the Heterocyclylalkyl contains 1 hetero atom for being selected from O or N；Or R22With R15And its institute The atom of connection can interconnect cyclization.
2. heterocyclic compound according to claim 1 with CXCR4 access inhibitory activity and its pharmaceutically acceptable Salt, isotope, isomers and crystalline structure, W are selected from
Wherein, X, Y, Z are separately selected from CR25R26Or O；
R25, R26Separately it is selected from hydrogen atom, D-atom, halogen, C1-3Alkyl；Or R25With R26And its carbon connected is former Son can interconnect cyclization.
3. heterocyclic compound according to claim 2 with CXCR4 access inhibitory activity and its pharmaceutically acceptable Salt, isotope, isomers and crystalline structure, wherein X, Y, Z are separately selected from CH2, O, orAnd X, Y, Z are minimum Having one is
4. heterocyclic compound according to claim 1 with CXCR4 access inhibitory activity and its pharmaceutically acceptable Salt, isotope, isomers and crystalline structure, it is characterized in that:
A3Selected from CR10；
A1, A2It is respectively and independently selected from N or CR10, and A1, A2A minimum of one is N；
W is
The R1, R2, R3, R4, R5, R6, R10As defined in claim 1.
5. the heterocyclic compound according to claim 1 or 4 with CXCR4 access inhibitory activity, and its can pharmaceutically connect Salt, isotope, isomers and the crystalline structure received, W are selected from unsubstituted or are selected from D-atom, cyano, halogen by 1-3 Element, C1-3Alkyl, C1-3The following groups that the substituent group of alkoxy replaces:
6. the heterocyclic compound according to claim 1-5 with CXCR4 access inhibitory activity, and its pharmaceutically Acceptable salt, isotope, isomers and crystalline structure, it is characterised in that U is unsubstituted or is independently selected from a deuterium original by 1-3 Son, halogen, hydroxyl, C1-3Alkyl, C1-3Any one of the following groups that the substituent group of alkoxy replaces:
7. the heterocyclic compound and its medicine according to claim 1-6 with CXCR4 signal path inhibitory activity Acceptable salt, isotope, isomers and crystalline structure on, it is characterised in that the heterocyclic compound includes:
8. a kind of pharmaceutical composition, it includes the one or more according to claim 1-7 of therapeutically effective amount Heterocyclic compound and its pharmaceutically acceptable salt, isotope, isomers, crystal form with CXCR4 access inhibitory activity, go forward side by side One step includes at least one pharmaceutically acceptable carrier.
9. a kind of use in conjunction composition comprising claim 1-7 is described in any item with CXCR4 access inhibitory activity Heterocyclic compound and its pharmaceutically acceptable salt, isotope, isomers or crystal form and anti-tumor drug, antibacterials, anti- The combination of one or more of virus drugs, medicine for central nervous system, diabetes medicament carries out the group that use in conjunction obtains Close object.
10. the described in any item heterocyclic compounds of claim 1-7 and its pharmaceutically acceptable salt, isotope, isomers or Composition described in crystal form or claim 8 or 9 preparation by antagonism CXCR4 access treat illness, stem cell mobilization, Application in the drug of wound healing and burn treating, the illness include: that HIV infection, myocardial infarction and blood generate Relevant disease, inflammation, anaphylactia, asthma, hylactic pneumonia, interstitial lung disease, lupus erythematosus, tatanic vertebra Inflammation, multiple sclerosis, Systemic sclerosis, polymyositis, rheumatoid arthritis, myasthenia gravis, Juvenile onset sugar It is sick, exedens to urinate disease, glomerulonephritis, autoimmune thyroiditis, graft rejection, inflammatory bowel disease, Crohn Colitis, chorionitis, psoriasis, dermatitis, retinal pigment degeneration, proliferative vitreoretinopathy, bass Te Shi yolk Shape macular degeneration, eczema, nettle rash, vasculitis, eosinophilic fasciitis, moist and Local Electroretinogram (ARMD), diabetic retinopathy, retinopathy of prematurity (ROP), Diabetic Macular redness, uveitis, retina Venous occlusion, cystoid macular edema, glaucoma, branch vein occlusion, breast cancer, lung cancer, bladder cancer, cancer of pancreas, liver cancer, neck Squamous cell carcinoma, thyroid cancer, sarcoma, osteosarcoma, fibroma, melanoma, prostate cancer, colorectal cancer, oophoroma, Cervical carcinoma, the cancer of the esophagus, gastric cancer, myeloma, lymthoma, lymphoma mantle cell, skin T cell lymphoma, chronic and non-progressive Anaemia, spontaneity or primary thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, liver fiber It is change, cirrhosis, diabetic retinopathy, macroglobulinemia, leukaemia, acute leukemia, chronic leukemia, lymphocytic white Blood disease, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferative illness, brain tumor, astrocytoma, medulloblastoma, Outer one of embryoma or the hypophysoma illness or several of schwann's cell tumor, primary nervous.
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