CN103087077A - Thienopyrimidine and furopyrimidine derivative, its preparation method and application in medicines - Google Patents

Thienopyrimidine and furopyrimidine derivative, its preparation method and application in medicines Download PDF

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CN103087077A
CN103087077A CN2011103426820A CN201110342682A CN103087077A CN 103087077 A CN103087077 A CN 103087077A CN 2011103426820 A CN2011103426820 A CN 2011103426820A CN 201110342682 A CN201110342682 A CN 201110342682A CN 103087077 A CN103087077 A CN 103087077A
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phenyl
piperazine
pyrimidine
hydroxyl
ketone
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CN103087077B (en
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安晓霞
别平彦
刘俊
杨午立
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Jiangsu Disainuo Pharmaceutical Co., Ltd.
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SHANGHAI XIMAI MEDICAL TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Abstract

The invention discloses a thienopyrimidine and furopyrimidine derivative, its preparation method and its application in medicines. The derivative is a compound shown as general formula I, general formula II, general formula III or general formula IV. The thienopyrimidine and furopyrimidine pyrimidine derivative provided in the invention has an obvious EGFR (epidermal growth factor receptor) inhibitory activity, and some of the compounds also have an obvious inhibitory activity on VEGFR (vascular endothelial growth factor receptor), so that the thienopyrimidine and furopyrimidine pyrimidine derivative can be expected to be developed into tyrosine kinase EGFR or/and VEGFR inhibitors, which can be used for preparation of drugs preventing or treating diseases related to EGFR and/or VEGFR. Therefore, the derivative provided in the invention provides a new development direction and approach for developing novel tyrosine kinase inhibitor drugs that have low resistance or can alleviate early inhibitor resistance, and has wide application prospect and medicinal value.

Description

Thienopyrimidine and furo pyridine derivatives, its preparation method and in pharmaceutically application
Technical field
The present invention relates to miazines derivative and its preparation method and application, specifically, relate to a kind ofly have EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR and suppress active Thienopyrimidine and furo pyridine derivatives, its preparation method and in pharmaceutically application, belong to the pharmaceutical chemistry technical field.
Background technology
Tumour is one of serious disease that threatens human health, and its treatment mainly comprises radiotherapy, chemotherapy and operative treatment.Along with the development of cytobiology and tumor pharmacology, huge change has occured in the chemotherapy of tumour in recent years.Thereby traditional chemotherapeutic agent is abandoned gradually owing to non-specifically blocking cell fission also to cause normal cell death in the kill tumor cell, simultaneously, as target spot, find that the micromolecular inhibitor of efficient, low toxicity, high specificity has become the important directions of current antitumor drug research and development with the key node albumen in the signal path of abnormal activation in tumour cell.The receptor tyrosine kinase (RTK) that unconventionality expression activates in tumour has become the focus of antitumor drug research owing to all bringing into play keying action at links such as tumor development, Invasion and Metastasis, chemotherapy resistances.
EGF-R ELISA (EGFR, epidermal growth factor receptor claims again HER1 or cerbB1) is to express Tyrosylprotein kinase HER family member the most widely in human cancer.The EGFR structure comprises Three regions: extracellular region, cross-film district and intracellular region.The amino terminal of extracellular region is comprised of 622 amino acid, has 2 of the formation ligand binding domain to be rich in the halfcystine section; The cross-film district is a single α spiral; Intracellular region comprises the kinases district and the carboxyl terminal afterbody of many Tyr phosphorylation sites is arranged.Tyrosylprotein kinase (RTK) is that the γ phosphate transfection of ATP is transported to tyrosine residues.With ligand binding after, homology or heterodimer occur and the TK zone are formed closely connect in EGFR.Carry out phosphorylation at carboxyl terminal afterbody RTK mediation Tyr phosphorylation site, created the binding site (Y992, Y1068, Y1086, Y1148 and Y11730) of enzyme and the sub-albumen of connection, thereby can begin the Cellular Signaling Transduction Mediated reaction.These signal conduction form different cell responses, comprise propagation, differentiation, adhesion and vascularization, shift and apoptosis inhibit.
Studies show that, EGFR has expression in nonsmall-cell lung cancer, prostate cancer, breast cancer, large bowel cancer, head and neck cancer, cancer of the stomach, ovarian cancer and carcinoma of the pancreas, and the EGFR activation causes sophisticated signal conduction reaction.In dissimilar solid tumor, EGFR has propagation and overexpression, causes downstream signal conduction out of control and cause the formation of various tumours.In EGFR, the sudden change of ATP-binding site affects the RTK activity of acceptor, disturbs the formation of tumorigenesis signal, and simultaneously, EGFR is also closely related with progress and the poor prognosis of tumour.
The unique effect in tumorigenesis due to EGFR and VEGFR, its monoclonal antibody and micromolecular inhibitor have become the focus of targeting antineoplastic medicine thing research and development.At present, the inhibitor listing of several targeting EGFRs or VEGFR has been arranged, nearly 20 drug candidates are in clinical each development.Wherein, the micromolecular inhibitor of Gefitinib and erlotinib representative listing targeting EGFR early.Gefitinib (Gefitinib claims again ZD1839 or Iressa) is used for advanced Non-small cell lung (non small cell lung cancer, NSCLC) as three line single therapy medicines.Two wires or the three line medicines of the advanced NSCLC that erlotinib (Erlotinib claims again OSI774 or Tarceva) is failed to respond to any medical treatment as standard scheme.
Yet, along with the clinical application of these medicines, it is found that not to be that all high expression level EGFR patients can be effective to these medicines, some initially has the tumour of therapeutic response progression of disease to occur again after the treatment some months to Gefitinib (Gefitinib).These results show, the EGFR inhibitor antitumor drug that uses at present has natural or Secondary cases resistance phenomenon, therefore, Development of Novel has low resistance and maybe can alleviate the new development direction that the medicine of early stage inhibitor resistance has become tyrosine kinase inhibitor.
Summary of the invention
For the existing the problems referred to above of prior art, the purpose of this invention is to provide and a kind ofly have that EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR suppress active Thienopyrimidine and furo pyridine derivatives, its preparation method and in pharmaceutically application.
Thienopyrimidine provided by the invention and furo pyridine derivatives are the compounds with general formula I, general formula I I, general formula III or general formula I V:
Figure BDA0000105055160000021
In above-mentioned general formula:
X is oxygen or sulphur; Z is nitrogen or carbon;
R is hydrogen, contain any one in the reverse amide group of amide group, reverse amide group or replacement of aryl-acyl, alkylsulfonyl, amide group or replacement of alkene acyl group, aryl-acyl or replacement of the alkyl of 1～6 carbon atom or the alkyl of replacement, the alkyl acyl that contains 1～6 carbon atom, the cycloalkyl acyl group that contains 3～6 carbon atoms, the alkene acyl group that contains 2～6 carbon atoms or replacement;
A r1 is phenyl, 2 or 3-fluorine substituted-phenyl, 2 or 3-trifluoromethyl substituted-phenyl, 2 or 3-chlorine substituted-phenyl, 2 or 3-itrile group substituted-phenyl, 2-or 3-C 1-3Alkyl-substituted phenyl, thienyl, 3-C 1-3The furyl that the thienyl that alkyl replaces, furyl, 3-C1-3 alkyl replace, 2 or the 3-pyridyl in any one;
Ar 2Phenyl, C for phenyl, halogen replacement 1-6Thienyl, C that the xenyl that the phenyl that alkyl replaces, xenyl, halogen replace, naphthyl, pyridyl, thienyl, halogen replace 1-3Furyl, C that the thienyl that alkyl replaces, furyl, halogen replace 1-3Any one in the furyl that alkyl replaces.
Further, described Thienopyrimidine and furo pyridine derivatives are the compounds with general formula I, general formula I I, general formula III or general formula I V, and in general formula: X is oxygen or sulphur; Z is nitrogen; Ar 1Be phenyl; Ar 2Be phenyl; R is hydrogen, contain any one in the reverse amide group of amide group, reverse amide group or replacement of aryl-acyl, alkylsulfonyl, amide group or replacement of alkene acyl group, aryl-acyl or replacement of the alkyl of 1～6 carbon atom or the alkyl of replacement, the alkyl acyl that contains 1～6 carbon atom, the cycloalkyl acyl group that contains 3～6 carbon atoms, the alkene acyl group that contains 2～6 carbon atoms or replacement.
The preparation method of the Thienopyrimidine that general formula I provided by the invention represents and furo pyridine derivatives, comprise the steps 3. or step 1. and 3. step 2. and 3. or step 1.～3.:
Figure BDA0000105055160000031
The Thienopyrimidine that general formula I I provided by the invention represents and the preparation method of furo pyridine derivatives, comprise the steps 5. or step 2. and 5. or step 4. and 5. or 4. 2. step reach and 5.:
Figure BDA0000105055160000032
The preparation method of the Thienopyrimidine that general formula III provided by the invention represents and furo pyridine derivatives, comprise the steps 7. or step 1. and 7. or step 6. and 7. or 6. 1. step reach and 7.:
Figure BDA0000105055160000033
The Thienopyrimidine that general formula I V provided by the invention represents and the preparation method of furo pyridine derivatives, comprise the steps 8. or step 4. and 8. or step 6. and 8. or 6. 4. step reach and 8.:
Figure BDA0000105055160000041
Further, the Thienopyrimidine and the furo pyridine derivatives that represent of described general formula I I can also be carried out hydrogenation and be got by Thienopyrimidine and the furo pyridine derivatives that general formula I represents.
Further, the Thienopyrimidine and the furo pyridine derivatives that represent of described general formula I V can also be carried out hydrogenation and be got by Thienopyrimidine and the furo pyridine derivatives that general formula III represents.
because studies show that Thienopyrimidine of the present invention and furo pyridine derivatives have the inhibition activity of EGF-R ELISA (EGFR) and/or Angiogenesis factor receptors (VEGFR), therefore, the tautomer of Thienopyrimidine of the present invention and furo pyridine derivatives or described derivative, racemic modification, enantiomer, diastereomer, pharmacy acceptable salt, the mixture of any one or a few in pharmaceutically acceptable solvate, can be applicable to prepare tyrosine kinase inhibitor, especially can be applicable to prepare EGFR and/or VEGFR inhibitor.
Furtherly, described inhibitor can be applicable to prepare the medicine of prevention or treatment and EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR relative disease, specifically, can be applicable to prepare the medicine of prevention or treatment abnormal cell proliferation, metamorphosis, hypoerkinesia, angiogenesis and the metastases disease relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR.
Furtherly, described inhibitor can be applicable to prepare the medicine for the treatment of or the prevention growth and metastasis of tumours relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR.
Furtherly, the activeconstituents of described inhibitor preferably compound shown in table 1 or shown in any one or a few mixture in the tautomer, racemic modification, enantiomer, diastereomer, pharmacy acceptable salt, pharmaceutically acceptable solvate of compound:
Table 1
Figure BDA0000105055160000042
Figure BDA0000105055160000051
Figure BDA0000105055160000071
Figure BDA0000105055160000081
Figure BDA0000105055160000091
Described pharmacy acceptable salt comprises without limitation: inorganic acid salt, example hydrochloric acid salt, hydrobromate, nitrate, vitriol, phosphoric acid salt etc.; Organic acid salt is as formate, acetate, propionic salt, benzoate, maleate, fumarate, succinate, tartrate, Citrate trianion etc.; Alkylsulfonate is as metilsulfate, ethyl sulfonate etc.; Arylsulphonate is as benzene sulfonate, tosilate etc.
Described pharmaceutically acceptable solvate comprises the solvate of described compound and water, ethanol, Virahol, ether, acetone etc. without limitation.
compared with prior art, the novel structure of Thienopyrimidine provided by the invention and furo pyridine derivatives, have obvious EGFR and suppress active, and part of compounds also has obvious inhibition activity to VEGFR, be expected to be developed as Tyrosylprotein kinase EGFR or/and the VEGFR inhibitor, for the preparation of prevention or the treatment abnormal cell proliferation relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR, the relative disease such as metamorphosis and hypoerkinesia reaches the medicine with angiogenesis or metastases relative disease, especially be expected the medicine for the preparation for the treatment of or the prevention growth and metastasis of tumours relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR, for Development of Novel have low resistance maybe can alleviate early stage inhibitor resistance the tyrosine kinase inhibitor drug provision new developmental direction and approach, have broad application prospects and pharmaceutical use.
Embodiment
Further set forth the present invention below in conjunction with specific embodiment.Following embodiment is interpreted as only being used for explanation the present invention rather than being used for restriction protection scope of the present invention.After the content of having read the present invention's record, those skilled in the art can make various changes or modifications the present invention, and these equivalences change and modification falls into claims limited range of the present invention equally.
In following embodiment the structure of prepared compound be by nucleus magnetic resonance ( 1HNMR) and mass spectrum (MS) determined.
1HNMR displacement (δ) provides with 1,000,000/(ppm) unit. 1The mensuration of HNMR is to use the BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and the solvent of mensuration is deuterated dimethyl sulfoxide (DMSO-d 6), deuterochloroform (CDCl 3), in be designated as tetramethylsilane (TMS), chemical shift is with 10 -6Provide as unit.
The mensuration of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Therm, model: Finnigan LCQadvantage MAX).
The mensuration of IC50 value is with NovoStar microplate reader (German BMG company).
Thin layer silica gel is to use Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate.
Silica gel column chromatography is to use Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.
The HPLC test is to use Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 * 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 * 4.6mm chromatographic column).
Microwave reaction is to use CEM Discover-S 908860 type microwave reactors.
In addition, in following examples, without specified otherwise, reaction is all carried out under nitrogen atmosphere.
Argon atmospher refers to that reaction flask connects an approximately argon gas balloon of 1L volume.
Nitrogen atmosphere refers to that reaction flask connects an approximately hydrogen balloon of 1L volume.
In following examples, without specified otherwise, the solution in reaction refers to the aqueous solution.
Embodiment 1: preparation Compound I-1 and Compound I I-1
Figure BDA0000105055160000101
The first step:
will be to carboxyl phenylo boric acid pinacol ester (1g under room temperature, 4.03mmol) be dissolved in methylene dichloride (10ml, 0.16mol) and N, dinethylformamide (1ml, 13.0mmol) in, add NEP (0.6ml, 4.8mmol), and add successively 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.93g, 4.8mmol), N-hydroxy benzo triazole (0.66g, 4.8mmol), triethylamine (0.84ml, 6.04mmol), the stirring at room reaction is until TLC monitoring raw material reaction is complete, add 10ml water in reaction solution, stirred 30 minutes, extract with methylene dichloride (50ml*3), use again saturated nacl aqueous solution (50ml*2) washing, the organic phase anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, obtain: (4-ethyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (1.4g, faint yellow solid), be directly used in next step reaction.
Second step:
Wherein 6-bromo-4-chlorothiophene [2,3-d] pyrimidine is according to the described method preparation of patent WO 2007/059257.
Under room temperature with compound 6-bromo-4-chlorothiophene [2,3-d] pyrimidine (1g, 4.0mmol) and L-benzene glycinol (1g, 7.2mmol) be dissolved in N, dinethylformamide (20ml, 0.259mol) in, drip 1ml triethylamine (363mg, 7.19mmol), stirring at room is until TLC monitoring raw material reaction is complete, add 200ml water, decompress filter, filter cake wash (100ml*2) with water and obtain: compound 2-(6-bromo-thiophene [2,3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (1.3g, faint yellow solid), productive rate: 93%.
MS?m/z(ESI)：351[M+1]。
1HNMR(400MHz，DMSO-d 6)：8.24(s，1H)，8.16(d，J＝8.1Hz，1H)，8.02(s，1H)，7.38-7.40(m，2H)，7.23-7.32(m，2H)，7，20-7.22(m，1H)，5.39(m，1H)，4.98(t，J＝8.1Hz，1H)，3.71(m，2H)。
The 3rd step:
under room temperature with compound 2-(6-bromo-thiophene [2, 3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (500mg, 1.43mmol) and (4-ethyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (982mg, 2.86mmol) be dissolved in N, dinethylformamide (15ml, 0.194mol), add successively tetra-triphenylphosphine palladium (164mg, 0.143mmol), sodium carbonate solution (1mol/L, 2.8ml), nitrogen protection, be heated to 80 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add entry (100ml*3) washing, extract with ethyl acetate (250ml*1), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, obtain: (S)-(4-ethyl-piperazine-1-yl)-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[2, 3-d] pyrimidine-6-yl]-phenyl }-ketone (I-1) (440mg, faint yellow solid), productive rate: 63%.
MS?m/z(ESI)：487[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.30(d，2H)，8.19(d，1H)，7.79(d，2H)，7.51-7.20(m，7H)，5.46(m，1H)，5.01(t，，1H)，3.75(m，2H)，3.55(m，4H)，2.35(m，6H)，0.99(t，J＝8.0Hz，3H)。
The 4th step:
under room temperature with Lithium Aluminium Hydride (27.3mg, 0.718mmol) and anhydrous tetrahydro furan (8ml, 98.63mmol) mix and blend, drip Compound I-1 (140mg in reaction solution, 0.287mmol) tetrahydrofuran (THF) (10ml, 0.123mol) solution, stirring at room reaction 1 hour, be warming up to 50 ℃ of reactions until TLC monitoring raw material reaction is complete, naturally cool to room temperature, add 20ml water in reaction solution, extract with ethyl acetate (100ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase that obtains is filtered with anhydrous magnesium sulfate drying, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-2-{6-[4-(4-ethyl-piperazine-1-ylmethyl)-phenyl]-thieno-[2, 3-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (II-1) (15mg, faint yellow solid), productive rate: 11.0%.
MS?m/z(ESI)：473[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.23-8.18(m，3H)，7.66(d，2H)，7.42-7.23(m，7H)，5.44(m，1H)，5.03(t，，1H)，3.76(m，2H)，3.55(m，6H)，2.41(m，6H)，0.98(t，，3H)。
Embodiment 2: preparation Compound I-2 and Compound I I-2
The first step:
will be to carboxyl phenylo boric acid pinacol ester (3g under room temperature, 12.10mmol) be dissolved in methylene dichloride (27ml, 0.422mol) and N, dinethylformamide (9ml, 0.116mol) in, add N methyl piperazine (1.45g, 14.5mmol), and add successively 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (2.79g, 14.4mmol), N-hydroxy benzo triazole (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), the stirring at room reaction is until TLC monitoring raw material reaction is complete, add 30ml water in reaction solution, stirred 30 minutes, extract with methylene dichloride (100ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, obtain: (4-methyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (1.5g, white solid), productive rate: 37.6%
Second step:
under room temperature with compound 2-(6-bromo-thiophene [2, 3-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (100mg, 0.2857mmol) and (4-methyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (188mg, 0.5714mmol) be dissolved in N, dinethylformamide (4ml, 51.7mmol), add successively tetra-triphenylphosphine palladium (33mg, 0.0286mmol), sodium carbonate solution (1mol/L, 0.6ml), nitrogen protection, be heated to 80 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add entry (100ml*3) washing, extract with ethyl acetate (250ml*1), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[2, 3-d] pyrimidine-6-yl]-phenyl }-(4-methyl-piperazine-1-yl)-ketone (I-2) (71mg, white solid), productive rate: 52.6%.
MS?m/z(ESI)：474[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.30(d，2H)，8.19(d，1H)，7.75(d，2H)，7.51-7.21(m，7H)，5.46(m，1H)，5.02(t，，1H)，3.75(m，2H)，3.55(m，4H)，2.35(m，4H)，2.19(s，3H)。
The 3rd step:
under room temperature with Lithium Aluminium Hydride (100mg, 2.640mmol) and anhydrous tetrahydro furan (10ml, 0.123mol) mix and blend, drip Compound I-2 (500mg in reaction solution, 1.056mmol) tetrahydrofuran (THF) (10ml, 0.123mol) solution, stirring at room reaction 1 hour, be warming up to 50 ℃ of reactions until TLC monitoring raw material reaction is complete, naturally cool to room temperature, add 20ml water in reaction solution, extract with ethyl acetate (100ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase that obtains is filtered with anhydrous magnesium sulfate drying, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-2-{6-[4-(4-methyl-piperazine-1-ylmethyl)-phenyl]-thieno-[2, 3-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (II-2) (42mg, faint yellow solid), productive rate: 8.7%.
MS?m/z(ESI)：460[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.30(d，2H)，8.19(d，1H)，7.75(d，2H)，7.51-7.21(m，7H)，5.46(m，1H)，5.02(t，，1H)，3.75(m，2H)，3.55(m，6H)，2.35(m，4H)，2.19(s，3H)。
Embodiment 3: preparation Compound I-3 and Compound I I-3
Figure BDA0000105055160000131
The first step:
will be to carboxyl phenylo boric acid pinacol ester (3g under room temperature, 12.10mmol) be dissolved in methylene dichloride (27ml, 0.422mol) and N, dinethylformamide (9ml, 0.116mol) in, add 1-cyclopropyl methylpiperazine (2.3g, 14.9mmol), and add successively 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (2.79g, 14.4mmol), N-hydroxy benzo triazole (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), the stirring at room reaction is until TLC monitoring raw material reaction is complete, add 30ml water in reaction solution, stirred 30 minutes, extract with methylene dichloride (100ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, obtain: (4-cyclopropyl carbonyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (3.5g, white solid), productive rate 61.4%, be used as next step reaction.
Second step:
under room temperature with compound 2-(6-bromo-thiophene [2, 3-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (500mg, 1.43mmol) and (4-cyclopropyl carbonyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (1.099g, 2.86mmol) be dissolved in N, dinethylformamide (15ml, 0.194mol), add successively tetra-triphenylphosphine palladium (164mg, 0.143mmol), sodium carbonate solution (1mol/L, 2.8ml), nitrogen protection, be heated to 80 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add entry (100ml*3) washing, extract with ethyl acetate (250ml*1), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-cyclopropyl methyl-piperazine-1-yl)-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[2, 3-d] pyrimidine-6-yl]-phenyl }-ketone (I-3) (300mg, faint yellow solid), productive rate: 60%.
MS?m/z(ESI)：528[M+1]。
1HNMR(400Hz，DMSO-d 6)： 1HNMR(400Hz，DMSO-d 6)：8.44m，2H)，8.26(s，1H)，7.75(d，2H)，7.52-7.28(m，7H)，5.48(m，1H)，5.20(t，1H)，3.87(m，1H)，3.68(s，2H)，3.09(m，8H)，1.23(m，1H)，0.68(m，2H)，0.44(m，2H)。
The 3rd step:
under room temperature with Lithium Aluminium Hydride (90mg, 2.369mmol) and anhydrous tetrahydro furan (10ml, 0.123mol) mix and blend, drip Compound I-3 (250mg in reaction solution, 0.474mmol) tetrahydrofuran (THF) (10ml, 0.123mol) solution, stirring at room reaction 1 hour, be warming up to 50 ℃ of reactions until TLC monitoring raw material reaction is complete, naturally cool to room temperature, add 20ml water in reaction solution, extract with ethyl acetate (100ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase that obtains is filtered with anhydrous magnesium sulfate drying, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-2-{6-[4-(4-cyclopropyl methyl-piperazine-1-ylmethyl)-phenyl]-thieno-[2, 3-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (II-3) (42mg, the off-white color solid), productive rate: 4.3%.
MS?m/z(ESI)：500[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.43(m，2H)，8.26(s，1H)，7.75(d，2H)，7.52-7.28(m，7H)，5.48(m，1H)，5.20(t，1H)，3.87(m，1H)，3.68(s，2H)，3.09(m，10H)，1.23(m，1H)，0.68(m，2H)，0.44(m，2H)。
Embodiment 4: preparation Compound I-4 and Compound I I-4
Figure BDA0000105055160000141
The first step:
will be to carboxyl phenylo boric acid pinacol ester (3g under room temperature, 12.10mmol) be dissolved in methylene dichloride (27ml, 0.422mol) and N, dinethylformamide (9ml, 0.116mol) in, add N-hydroxyethyl piperazine (2g, 15.36mmol), and add successively 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (2.79g, 14.4mmol), N-hydroxy benzo triazole (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), the stirring at room reaction is until TLC monitoring raw material reaction is complete, add 30ml water in reaction solution, stirred 30 minutes, extract with methylene dichloride (100ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, obtain: (4-hydroxyethyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (3.0g, white solid), productive rate 68.8%, be used as next step reaction.
Second step:
under room temperature with compound 2-(6-bromo-thiophene [2, 3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (500mg, 1.43mmol) and (4-hydroxyethyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (1.029g, 2.86mmol) be dissolved in N, dinethylformamide (15ml, 0.194mol), add successively tetra-triphenylphosphine palladium (164mg, 0.143mmol), sodium carbonate solution (1mol/L, 2.8ml), nitrogen protection, be heated to 80 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add entry (100ml*3) washing, extract with ethyl acetate (250ml*1), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[2, 3-d] pyrimidine-6-yl]-phenyl }-ketone (I-4) (300mg, faint yellow solid), productive rate: 41.7%.
MS?m/z(ESI)：504[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.37-8.27(m，3H)，7.77(d，2H)，7.51-7.22(m，7H)，5.45(m，1H)，5.14(t，1H)，4.46(m，1H)，3.75(m，2H)，3.61(m，2H)，3.49(m，2H)，3.36(m，4H)，2.43(m，4H)。
The 3rd step:
under room temperature with Lithium Aluminium Hydride (90mg, 2.369mmol) and anhydrous tetrahydro furan (10ml) mix and blend, drip Compound I-4 (250mg in reaction solution, 0.496mmol) tetrahydrofuran (THF) (10ml, 0.123mol) solution, stirring at room reaction 1 hour, be warming up to 50 ℃ of reactions until TLC monitoring raw material reaction is complete, naturally cool to room temperature, add 20ml water in reaction solution, extract with ethyl acetate (100ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase that obtains is filtered with anhydrous magnesium sulfate drying, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-2-(6-{4-[4-(2-hydroxyl-ethyl)-piperazine-1-ylmethyl]-phenyl }-thieno-[2, 3-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (II-4) (48mg, the off-white color solid), productive rate: 4.3%.
MS?m/z(ESI)：490[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.37-8.29(m，3H)，7.77(d，2H)，7.51-7.22(m，7H)，5.45(m，1H)，5.14(t，1H)，4.46(m，1H)，3.75(m，2H)，3.68(s，2H)，3.61(m，2H)，3.49(m，2H)，3.36(m，4H)，2.43(m，4H)。
Embodiment 5: preparation Compound I-5 and Compound I I-5
Figure BDA0000105055160000151
The first step:
will be to carboxyl phenylo boric acid pinacol ester (0.894g under room temperature, 4.8mmol) be dissolved in methylene dichloride (10ml, 0.156mol) and N, dinethylformamide (1ml, 17.78mmol) in, add N-Boc piperazine (1g, 4.03mmol), and add successively 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.93g, 4.8mmol), N-hydroxy benzo triazole (0.66g, 4.8mmol), triethylamine (0.84ml, 6.04mmol), the stirring at room reaction is until TLC monitoring raw material reaction is complete, add 30ml water in reaction solution, stirred 30 minutes, extract with methylene dichloride (100ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, obtain: 4-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxygen boron 2-yl) benzoyl-]-piperazine-1-tert-butyl ester (1.6g, white solid), productive rate 95.4%.
Second step:
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (500mg, 1.428mmol) and 4-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxygen boron 2-yl) benzoyl-]-piperazine-1-tert-butyl ester (1.189g, 2.857mmol) be dissolved in N, dinethylformamide (20ml, 0.65mol), add successively tetra-triphenylphosphine palladium (161.8mg, 0.14mmol), sodium carbonate solution (1mol/L, 2.5ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain crude product (380mg, faint yellow solid), productive rate: 47.6%.MS?m/z(ESI)：560[M+1]。
The 3rd step:
under room temperature with above-mentioned product (168mg, 0.3mmol) be dissolved in methylene dichloride (8ml, 0.125mol) in, add trifluoroacetic acid (0.45ml, 0.6mmol), be stirred to TLC monitoring raw material reaction under room temperature complete, concentrating under reduced pressure, with saturated sodium bicarbonate solution dilution neutralization, wash with saturated aqueous common salt (50ml*3) with dichloromethane extraction (50ml*3) organic layer, concentrating under reduced pressure, scrape large plate, obtain: (S)-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-(2, 3-d) pyrimidine-6-yl]-phenyl }-piperazine-1-base-ketone (I-5) (50mg, white solid), productive rate: 36%.
MS?m/z(ESI)：460[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.40(m，1H)，8.24(m，2H)，7.79(d，2H)，7.45(m，4H)，7.21(m，3H)，5.45(m，1H)，5.04(t，1H)，3.55(s，2H)，2.74(m，4H)，2.39(m，4H)。
The 4th step:
under room temperature with Lithium Aluminium Hydride (51.5mg, 1.355mmol) and anhydrous tetrahydro furan (25, 0.308mol) mix and blend, drip Compound I-5 (500mg in reaction solution, 0.451mmol) tetrahydrofuran (THF) (25ml, 0.308mol) solution, stirring at room reaction 1 hour, be warming up to 50 ℃ of reactions until TLC monitoring raw material reaction is complete, naturally cool to room temperature, add 20ml water in reaction solution, extract with ethyl acetate (50ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase that obtains is filtered with anhydrous magnesium sulfate drying, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-2-phenyl-2-[6-(4-piperazine-1-ylmethyl-phenyl)-thieno-[2, 3-d] pyrimidine-4-yl amino]-ethanol (II-5) (100mg, white solid), productive rate: 20.7%.
MS?m/z(ESI)：446[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.41(m，1H)，8.26(m，2H)，7.78(d，2H)，7.46(m，4H)，7.22(m，3H)，5.48(m，1H)，5.06(t，1H)，3.84(m，2H)，3.57(s，2H)，2.76(m，4H)，2.40(m，4H)。
Embodiment 6: preparation Compound I I-6
The first step:
with morpholine (5ml, 57.405mmol) be dissolved in the 40ml methylene dichloride, add N under 0 ℃ of ice bath, N-diisopropylethylamine (9.5ml, 57.405mmol), to be dissolved in the triphosgene (6g in methylene dichloride (30ml), 20.69mmol) slowly drip, drip process temperature and remain on 0 ± 3 ℃, reacted 1 hour, add N-Boc piperazine (11.8mg under 0 ℃ of ice bath, 63.15mmol) and N, N-diisopropylethylamine (9.5ml, 57.405mmol), stirring reaction under room temperature is until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, with dissolving crude product in the 30ml methylene dichloride, add trifluoroacetic acid (14ml, 18.7mmol) under room temperature stirring reaction until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, add saturated sodium carbonate solution (50ml*3) washing, extract with methylene dichloride (50ml*6), concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: morpholinyl piperazinyl urea (877mg, faint yellow solid), productive rate: 6%, MS m/z (ESI): 200[M+1].
Second step:
with morpholinyl piperazinyl urea (500mg, 2.51mmol) and 4-formyl phenylo boric acid (396mg, 2.64mmol) be dissolved in the 20ml tetrahydrofuran (THF), add acetum (0.5ml, 8.75mmol), stirring at room reaction 1 hour, add sodium triacetoxy borohydride (798mg, 3.77mmol), be warming up to 60 ℃ of stirring reactions until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (4-benzyl-piperazine-1-yl)-morpholine-1-base-ketone-boric acid (330mg, light yellow solid), productive rate: 23%, MS m/z (ESI): 334[M+1].
The 3rd step:
under room temperature with compound 2-(6-bromo-thiophene [2, 3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (189mg, 0.540mmol) and (4-benzyl-piperazine-1-yl)-morpholine-1-base-ketone-boric acid (150mg, 045mmol) be dissolved in N, dinethylformamide (20ml, 0.65mol), add successively tetra-triphenylphosphine palladium (52mg, 0.045mmol), sodium carbonate solution (1mol/L, 3ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2, 3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-morpholine-4-yl)-ketone (II-6) (15mg, white solid), productive rate: 6%.
MS?m/z(ESI)：559[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.28-8.20(m，3H)，7.69(d，2H)，7.46-7.23(m，7H)，5.45(m，1H)，5.05(t，1H)，3.76(m，2H)，3.55(m，6H)，3.25-3.08(m，8H)，2，39(m，4H)。
Embodiment 7: preparation Compound I I-7
The first step:
with Pyrrolidine (600mg, 8.436mmol) be dissolved in the 15ml methylene dichloride, add N under 0 ℃ of ice bath, N-diisopropylethylamine (1.4ml, 8.436mmol), to be dissolved in the triphosgene (801mg in methylene dichloride (5ml), 2.70mmol) slowly drip, drip process temperature and remain on 0 ± 3 ℃, reacted 1 hour, add N-Boc piperazine (1.57g under 0 ℃ of ice bath, 8.436mmol) and N, N-diisopropylethylamine (1.4ml, 8.436mmol), stirring reaction under room temperature is until TLC monitoring raw material reaction is complete, with dissolving crude product in the 20ml methylene dichloride, add trifluoroacetic acid (10ml, 0.135mol) under room temperature stirring reaction until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, add saturated sodium carbonate solution (50ml*3) washing, extract with methylene dichloride (50ml*5), concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: Pyrrolidine base piperazinyl urea (376mg, faint yellow solid), productive rate: 24%.
MSm/z(ESI)：184[M+1]。
1HNMR(400Hz，DMSO-d 6)：3.23(t，5H)，3.05(t，4H)，2.64(t，4H)，1.72(m，4H)。
Second step:
with Pyrrolidine base piperazinyl urea (370mg, 2.022mmol) and 4-formyl phenylo boric acid (334mg, 2.224mmol) be dissolved in 10ml tetrahydrofuran (THF) and 10ml methyl alcohol, add acetum (0.5ml, 8.75mmol), stirring at room reaction 1 hour, add sodium triacetoxy borohydride (1.1g, 5.055mmol), be warming up to 60 ℃ of stirring reactions until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (4-benzyl-piperazine-1-yl)-Pyrrolidine-1-base-ketone-boric acid (210mg), productive rate: 33%.
MSm/z(ESI)：318[M+1]。
1HNMR(400Hz，DMSO-d 6)：7.99(s，2H)，7.74(d，2H)，7.25(d，2H)，3.47(s，2H)，3.23(m，4H)，3.16(m，4H)，2.33(m，4H)，1.72(m，4H)。
The 3rd step:
under room temperature with compound 2-(6-bromo-thiophene [2, 3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (317mg, 0.906mmol) and (4-benzyl-piperazine-1-yl)-Pyrrolidine-1-base-ketone-boric acid (200mg, 0.604mmol) be dissolved in N, dinethylformamide (5ml, 65mmol), add successively tetra-triphenylphosphine palladium (70mg, 0.0604mmol), sodium carbonate solution (1mol/L, 1ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with methylene dichloride (3*100ml), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2, 3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-pyrroles-1-base-ketone (II-7) (67mg, white solid), productive rate: 20%.
MSm/z(ESI)：543[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.28-8.19(m，3H)，7.69(d，2H)，7.46-7.23(m，7H)，5.45(m，1H)，5.05(t，1H)，3.76(m，2H)，3.53(s，2H)，3.25-3.08(m，8H)，2，39(m，4H)，1.74(s，4H)。
Embodiment 8: preparation Compound I I-8
Figure BDA0000105055160000191
The first step:
with tetramethoxy piperidines (500mg, 4.314mmol) be dissolved in the 10ml methylene dichloride, add N under 0 ℃ of ice bath, N-diisopropylethylamine (0.72ml, 4.314mmol), to be dissolved in the triphosgene (412mg in methylene dichloride (5ml), 1.389mmol) slowly drip, drip process temperature and remain on 0 ± 3 ℃, reacted 1 hour, add N-Boc piperazine (809mg under 0 ℃ of ice bath, 4.341mmol) and N, N-diisopropylethylamine (0.72ml, 4.341mmol), stirring reaction under room temperature is until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with dissolving crude product in the 20ml methylene dichloride, add trifluoroacetic acid (10ml, 0.135mol) under room temperature stirring reaction until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, add saturated sodium carbonate solution (50ml*3) washing, extract with methylene dichloride (50ml*5), concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: 4-methoxyl group piperidinyl piperazine base urea (414mg, faint yellow solid), productive rate: 42%, MS m/z (ESI): 228[M+1].
Second step:
with 4-methoxyl group piperidinyl piperazine base urea (414mg, 1.824mmol) and 4-formyl phenylo boric acid (287mg, 1.915mmol) be dissolved in 5ml tetrahydrofuran (THF) and 5ml methyl alcohol, add acetum (0.2ml, 3.5mmol), stirring at room reaction 1 hour, add sodium triacetoxy borohydride (580mg, 2.726mmol), be warming up to 60 ℃ of stirring reactions until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (4-benzyl-piperazine-1-yl)-4-methoxyl group piperidin-1-yl-ketone-boric acid (251mg, light yellow solid), productive rate: 38.1%, MS m/z (ESI): 362[M+1].
The 3rd step:
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (181mg, 0.520mmol) and (4-benzyl-piperazine-1-yl)-4-methoxyl group piperidin-1-yl-ketone-boric acid (125mg, 0.346mmol) be dissolved in N, dinethylformamide (20ml, 0.65mol), add successively tetra-triphenylphosphine palladium (40mg, 0.035mmol), sodium carbonate solution (1mol/L, 3ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2, 3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-(4-methoxyl group-piperidin-1-yl)-ketone (II-8) (36mg, faint yellow solid), productive rate: 17.7%.
MS?m/z(ESI)：587[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.31-8.19(m，3H)，7.67(d，2H)，7.46-7.44(m，4H)，7.35-7.22(m，3H)，5.46(m，1H)，5.06(t，1H)，3.77(m，2H)，3.52(s，2H)，3.35(m，7H)，3.20(s，3H)，2.89(m，2H)，2.44(m，4H)，1.81(m，2H)，1.35(m，2H)。
Embodiment 9: preparation Compound I I-9
Figure BDA0000105055160000201
under room temperature with Compound I I-5 (100mg, 0.225mmol) be dissolved in N, in dinethylformamide (5ml), add 4-bromo β-crotonic acid (37.2mg, 0.225mmol) and N-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (43.0mg, 0.225mmol), the stirring at room reaction is until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, add tetrahydrofuran (THF) (30ml, 0.37mol) and dimethylamine (0.5ml, 3.66mmol), the stirring at room reaction is until TLC monitoring raw material reaction is complete, add ethyl acetate (200ml*1) extraction, organic layer water (50ml*3) is washed, the organic phase anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-4-dimethylamino-1-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2, 3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-butyl-2-alkene-1-ketone (II-9) (40mg, pale solid), productive rate: 32%.
MS?m/z(ESI)：557[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.36-8.30(m，3H)，7.74(d，2H)，7.53-7.29(m，7H)，6.87(d，1H)，6.64(dd，1H)，5.52(m，1H)，5.12(t，1H)，3.83(m，2H)，3.60(s，2H)，3.58(m，6H)，2.60(s，6H)，2.45(m，4H)。
Embodiment 10: preparation Compound I I-10
The first step:
with piperidines (1g, 11.752mmol) be dissolved in the 20ml methylene dichloride, add N under 0 ℃ of ice bath, N-diisopropylethylamine (2ml, 11.752mmol), to be dissolved in the triphosgene (1.1g in methylene dichloride (10ml), 3.761mmol) slowly drip, drip process temperature and remain on 0 ± 3 ℃, reacted 1 hour, add N-Boc piperazine (2.2g under 0 ℃ of ice bath, 11.752mmol) and N, N-diisopropylethylamine (2ml, 11.752mmol), stirring reaction under room temperature is until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with dissolving crude product in methylene dichloride (30ml), add trifluoroacetic acid (20ml, 0.27mol) under room temperature stirring reaction until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, add saturated sodium carbonate solution (50ml*3) washing, extract with methylene dichloride (50ml*5), concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: piperidinyl piperazine base urea (1.25g, faint yellow solid), productive rate: 36%.
MS?m/z(ESI)：198[M+1]。
1HNMR(400Hz，DMSO-d 6)：3.59(brs，1H)，3.09(m，8H)，2.78(m，4H)，1.48(m，6H)。
Second step:
with piperidinyl piperazine base urea (1.25g, 6.336mmol) and 4-formyl phenylo boric acid (1.05g, 6.969mmol) be dissolved in 15ml tetrahydrofuran (THF) and 15ml methyl alcohol, add acetum (0.7ml, 12.67mmol), stirring at room reaction 1.5 hours, add sodium triacetoxy borohydride (3.36g, 15.84mmol), be warming up to 60 ℃ of stirring reactions until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (4-benzyl-piperazine-1-yl)-piperidin-1-yl-ketone-boric acid (1.25g, light yellow solid), productive rate: 60%.
MS?m/z(ESI)：332[M+1]。
1HNMR(400Hz，DMSO-d 6)：7.97(s，2H)，7.74(d，2H)，7.25(d，2H)，3.47(s，2H)，3.09(m.8H)，2.33(m，4H)，1.45(m，6H)。
The 3rd step:
under room temperature with compound 2-(6-bromo-thiophene [2, 3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (317mg, 0.906mmol) and (4-benzyl-piperazine-1-yl)-piperidin-1-yl-ketone-boric acid (200mg, 0.604mmol) be dissolved in N, dinethylformamide (10ml, 0.325mol), add successively tetra-triphenylphosphine palladium (70mg, 0.0604mmol), sodium carbonate solution (1mol/L, 3ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2, 3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-piperidin-1-yl)-ketone (II-10) (67mg, the off-white color solid), productive rate: 20%.
MS?m/z(ESI)：557[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.28(m，3H)，7.68(d，2H)，7.44(d，4H)，7.31-7.24(m，3H)，5.45(m，1H)，5.06(t，1H)，3.80(m，2H)，3.54(s，2H)，3.12(m，8H)，2.39(m，4H)，1.19(m，6H)。
Embodiment 11: preparation Compound I I-11
Figure BDA0000105055160000221
The first step:
with NEP (1g, 8.77mmol) be dissolved in the 15ml methylene dichloride, add N under 0 ℃ of ice bath, N-diisopropylethylamine (1.5ml, 8.77mmol), to be dissolved in the triphosgene (833mg in methylene dichloride (10ml), 2.81mmol) slowly drip, drip process temperature and remain on 0 ± 3 ℃, reacted 1 hour, add N-Boc piperazine (1.63g under 0 ℃ of ice bath, 8.77mmol) and N, N-diisopropylethylamine (1.5ml, 8.77mmol), stirring reaction under room temperature is until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with dissolving crude product in methylene dichloride (30ml), add trifluoroacetic acid (10ml, 0.135mol) under room temperature stirring reaction until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, add saturated sodium carbonate solution (50ml*3) washing, extract with methylene dichloride (50ml*5), concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: NEP base piperazine urea (1g, weak yellow liquid), productive rate: 34.97%, MS m/z (ESI): 227[M+1].
Second step:
with NEP base piperazine urea (1g, 4.40mmol) and 4-formyl phenylo boric acid (729mg, 4.86mmol) be dissolved in 10ml tetrahydrofuran (THF) and 10ml methyl alcohol, add acetum (0.7ml, 12.67mmol), stirring at room reaction 1.5 hours, add sodium triacetoxy borohydride (2.33g, 11mmol), be warming up to 60 ℃ of stirring reactions until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (4-benzyl-piperazine-1-yl)-NEP-1-base-ketone-boric acid (125mg, light yellow solid), productive rate: 8.0%, MS m/z (ESI): 361[M+1].
The 3rd step:
under room temperature with compound 2-(6-bromo-thiophene [2, 3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (181.8mg, 0.520mmol) and (4-benzyl-piperazine-1-yl)-NEP-1-base-ketone-boric acid (125mg, 0.346mmol) be dissolved in N, dinethylformamide (20ml, 0.65mol), add successively tetra-triphenylphosphine palladium (40mg, 0.035mmol), sodium carbonate solution (1mol/L, 3ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2, 3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-N-ethyl-piperazine-1-yl)-ketone (II-11) (120mg, white solid), productive rate: 59%.
MS?m/z(ESI)：587[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.38(m，2H)，8.27(s，1H)，7.70(d，2H)，7.47(m，4H)，7.26(m，3H)，5.45(m，1H)，5.13(t，1H)，3.80(m，2H)，3.60(s，2H)，3.40-3.05(m，14H)，2.43(m，4H)，1.21(m，3H)。
Embodiment 12: preparation compound III-1 and compound IV-1
Figure BDA0000105055160000231
The first step:
Wherein 6-bromo-4-chlorothiophene [3,2-d] pyrimidine is according to the described method preparation of patent WO 2009/007421.
under room temperature with compound 6-bromo-4-chlorothiophene [3, 2-d] pyrimidine (2g, 8.01mmol) and L-benzene glycinol (1.65g, 12.02mmol) be dissolved in N, dinethylformamide (25ml, 0.32mol) in, drip 2.8ml triethylamine (2.03g, 20.025mmol), be heated to 60 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature, add the 100ml water washing, extract with methylene dichloride (3*100ml), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, obtain: compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (1.7g, faint yellow solid), productive rate: 61%.
MSm/z(ESI)：351[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.39(s，1H)，8.230(d，1H)，7.60(d，1H)，7.46(m，2H)，7.24(m，3H)，5.48(m，1H)，5.03(t，1H)，3.78(m，2H)。
Second step:
The preparation method of wherein (4-ethyl-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-phenyl]-ketone is with the first step of embodiment 1.
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (1.2g, 3.43mmol) and (4-ethyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (2.36g, 6.86mmol) be dissolved in N, dinethylformamide (36ml, 0.465mol), add successively tetra-triphenylphosphine palladium (0.4g, 0.343mmol), sodium carbonate solution (1mol/L, 7ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with methylene dichloride (3*100ml), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, obtain: (S)-(4-ethyl-piperazine-1-yl)-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-thiophene [3, 2-d] pyrimidine-6-yl]-phenyl }-ketone (III-1) (500mg, yellow solid) productive rate: 30%.
MSm/z(ESI)：487[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.42(s，1H)，8.22(d，1H)，7.89(d，2H)，7.85(s，1H)，7.82(m，4H)，7.20-7.46(m，3H)，5.48(m，1H)，5.00(t，1H)，3.83(m，2H)，3.40(m，4H)，2.45(m，4H)，2.27(q，2H)，0.99(t，3H)。
The 3rd step:
under room temperature with Lithium Aluminium Hydride (75mg, 1.95mmol) and anhydrous tetrahydro furan (5ml, 61.27mmol) mix and blend, drip (4-ethyl-piperazine-1-yl)-{ 4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3 in reaction solution, 2, d] pyrimidine-6-yl]-phenyl }-ketone (370mg, 0.78mmol) tetrahydrofuran (THF) (10ml, 0.123mol) solution, stirring at room reaction 1 hour, be warming up to 55 ℃ of reactions until TLC monitoring raw material reaction is complete, add 20ml water in 0 ℃ of ice bath downhill reaction liquid, extract with ethyl acetate (50ml*2), use again saturated nacl aqueous solution (50ml*3) washing, anhydrous sodium sulfate drying.Decompression is used silica gel column chromatography purifying gained residue after steaming solvent, obtain: (S)-2-{6-[4-(4-ethyl-piperazine-1-ylmethyl)-phenyl]-thieno-[3,2-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (IV-1) (17mg, faint yellow solid), productive rate: 18.4%.
MSm/z(ESI)：473[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.37(s，1H)，8.19(d，1H)，7.82(d，2H)，7.79(s，1H)，7.82(m，4H)，7.20-7.46(m，3H)，5.47(m，1H)，5.00(t，1H)，3.83(m，2H)，3.52(s，2H)，2.40(brs，8H)，2.27(q，2H)，0.98(t，3H)。
Embodiment 13: preparation compound III-2 and compound IV-2
Figure BDA0000105055160000241
The first step:
The preparation method of (4-methyl-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-phenyl]-ketone is with the first step of embodiment 2.
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (200mg, 0.57mmol) and (4-methyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (226mg, 0.684mmol) be dissolved in N, dinethylformamide (10ml, 0.13mol), add successively tetra-triphenylphosphine palladium (66mg, 0.057mmol), sodium carbonate solution (1mol/L, 0.5ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with methylene dichloride (3*100ml), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, obtain: (S)-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[3, 2-d] pyrimidine-6-yl]-phenyl }-(4-methyl-piperazine-1-yl)-ketone (III-2) (100mg, yellow solid), productive rate: 37%.
MS?m/z(ESI)：473[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.41(s，1H)，8.30(d，1H)，7.87(d，2H)，7.84(s，1H)，7.50(m，4H)，7.27-7.39(m，3H)，5.49(m，1H)，5.10(t，1H)，3.83(s，2H)，3.65-3.60(m，4H)，2.40(m，4H)，2.25(s，3H)。
Second step:
under room temperature with Lithium Aluminium Hydride (20.14mg, 0.53mmol) and anhydrous tetrahydro furan (5ml, 61.27mmol) mix and blend, drip the tetrahydrofuran (THF) (10ml of compound III-2 in the reaction solution, 0.123mol) solution, stirring at room reaction 1 hour, be warming up to 55 ℃ of reactions until TLC monitoring raw material reaction is complete, add 20ml water in 0 ℃ of ice bath downhill reaction liquid, extract with ethyl acetate (50ml*2), use again saturated nacl aqueous solution (50ml*3) washing, anhydrous sodium sulfate drying, decompression is used silica gel column chromatography purifying gained residue after steaming solvent, obtain: (S)-2-{6-[4-(4-methyl-piperazine-1-ylmethyl)-phenyl]-thieno-[3, 2-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (IV-2) (30mg, faint yellow solid), productive rate: 31%.
MSm/z(ESI)：458[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.42(s，1H)，8.31(d，1H)，7.87(d，2H)，7.85(s，1H)，7.50(m，4H)，7.27-7.39(m，3H)，5.49(m，1H)，5.10(t，1H)，3.78(m，2H)，3.63(s，2H)，2.84-2.62(m，4H)，2.45(s，3H)，2.52-2.56(m，4H)。
Embodiment 14: preparation compound III-3 and compound IV-3
Figure BDA0000105055160000251
The first step:
The preparation method of wherein, (4-cyclopropyl carbonyl-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-phenyl]-ketone is with the first step of embodiment 3.
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (600mg, 1.72mmol) and (4-cyclopropyl carbonyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (892mg, 2.32mmol) be dissolved in N, dinethylformamide (10ml, 0.13mol), add successively tetra-triphenylphosphine palladium (100mg, 0.086mmol), sodium carbonate solution (1mol/L, 2mL), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with methylene dichloride (3*100ml), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-cyclopropyl carbonyl-piperazine-1-yl)-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[3, 2-d] pyrimidine-6-yl]-phenyl }-ketone (III-3) (862mg, yellow solid), productive rate: 95%.
MSm/z(ESI)：528[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.39(s，1H)，8，17(d，1H)，7.84-7.78(m，3H)，7.47-7.43(m，4H)，7.34-7.22(m，3H)，5.46(m，1H)，5.00(t，1H)，3.80-3.76(m，2H)，3.61-3.50(m，8H)，2.0(m，1H)，0.70(m，4H)。
Second step:
under room temperature with Lithium Aluminium Hydride (54mg, 1.423mmol) and anhydrous tetrahydro furan (10ml, 0.123mol) mix and blend, drip compound III-3 (300mg in reaction solution, 0.57mmol) tetrahydrofuran (THF) (10ml, 0.123mol) solution, stirring at room reaction 1 hour, be warming up to 55 ℃ of reactions until TLC monitoring raw material reaction is complete, add 100ml water in 0 ℃ of ice bath downhill reaction liquid, extract with ethyl acetate (100ml*2), use again saturated nacl aqueous solution (50ml*3) washing, with silica gel column chromatography purifying gained residue, obtain: (S)-2-{6-[4-(4-cyclopropyl methyl-piperazine-1-ylmethyl)-phenyl]-thieno-[3, 2-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (IV-3) (5mg, white solid), productive rate: 1.76%.
MS?m/z(ESI)：499[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.39(s，1H)，8，17(d，1H)，7.84-7.78(m，3H)，7.47-7.43(m，4H)，7.34-7.22(m，3H)，5.46(m，1H)，5.00(t，1H)，3.81-3.76(m，2H)，3.55(brs，2H)，2.50(m，10H)，0.90(m，1H)，0.5(m，4H)。
Embodiment 15: preparation compound III-4 and compound IV-4
Figure BDA0000105055160000261
The first step:
The preparation method of wherein, (4-hydroxyethyl-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-phenyl]-ketone is with the first step of embodiment 4.
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (340mg, 0.97mmol) and (4-hydroxyethyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (454mg, 1.26mmol) be dissolved in N, dinethylformamide (10ml, 0.13mol), add successively tetra-triphenylphosphine palladium (112mg, 0.097mmol), sodium carbonate solution (1mol/L, 1ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with methylene dichloride (3*100ml), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[3, 2-d] pyrimidine-6-yl]-phenyl }-ketone (III-4) (45mg, yellow solid), productive rate: 9.2%.
MS?m/z(ESI)：503[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.43(s，1H)，8.21(d，1H)，7.92(m，3H)，7.43(m，4H)，7.26(m，3H)，5.49(m，1H)，5.02(t，1H)，3.83(m，4H)，3.56(s，2H)，3.10-3.01(m，6H)，2.78(m，2H)。
Second step:
under room temperature with Lithium Aluminium Hydride (41.8mg, 11mmol) and anhydrous tetrahydro furan (10ml, 0.123mol) mix and blend, drip compound III-4 (220mg in reaction solution, 0.44mmol) tetrahydrofuran (THF) (10ml, 0.123mol) solution, stirring at room reaction 1 hour, be warming up to 55 ℃ of reactions until TLC monitoring raw material reaction is complete, add 100ml water in 0 ℃ of ice bath downhill reaction liquid, extract with ethyl acetate (100ml*2), use again saturated nacl aqueous solution (50ml*3) washing, the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-2-(6-{4-[4-(2-hydroxyl-ethyl)-piperazine-1-ylmethyl]-phenyl }-thieno-[3, 2-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (IV-4) (30mg, faint yellow solid), productive rate: 14%.
MS?m/z(ESI)：490[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.37(s，1H)，8.20(d，1H)，7.90(m，3H)，7.45(m，4H)，7.25(m，3H)，5.48(m，1H)，5.01(t，1H)，3.85(m，4H)，3.58(s，2H)，3.10(m，8H)，2.80(m，2H)。
Embodiment 16: preparation compound III-5 and compound IV-5
Figure BDA0000105055160000271
The first step:
Wherein 6-bromo-4-chlorine furans [3,2-d] pyrimidine is synthetic with reference to 6-bromo-4-chlorothiophene [3,2-d] pyrimidine and the described preparation method of W02008/073785.
under room temperature with compound 6-bromo-4-chlorine furans [3, 2-d] pyrimidine (1g, 4.29mmol) and L-benzene glycinol (0.83g, 6.06mmol) be dissolved in N, dinethylformamide (25ml, 0.32mol) in, drip the 1.5ml triethylamine, be heated to 60 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature, add the 100ml water washing, extract with methylene dichloride (3*80ml), organic phase is washed with saturated aqueous common salt (80ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, obtain: 2-(6-bromo-furans [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (0.7g, faint yellow solid), productive rate: 49%, MSm/z (ESI): 335[M+1], be directly used in next step reaction.
Second step:
under room temperature with compound 2-(6-bromo-furans [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (1.2g, 3.59mmol) and (4-ethyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (2.36g, 6.86mmol) be dissolved in 36ml N, dinethylformamide, add successively tetra-triphenylphosphine palladium (0.41g, 0.359mmol), sodium carbonate solution (1Mol/L, 7ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 80ml water washing, extract with methylene dichloride (3*80ml), organic phase is washed with saturated aqueous common salt (80ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, obtain: (4-ethyl-piperazine-1-yl)-{ 4-[4-(2-hydroxyl-1-phenyl-ethylamino)-furo [3, 2, d] pyrimidine-6-yl]-phenyl }-ketone (III-5) (475mg, yellow solid), productive rate: 28%.
MS?m/z(ESI)：472[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.40(s，1H)，8.22(d，1H)，7.89(d，2H)，7.48(s，1H)，7.82(m，4H)，7.20-7.46(m，3H)，5.48(m，1H)，5.01(t，1H)，3.83(m，2H)，3.40(m，4H)，2.45(m，4H)，2.27(q，2H)，1.03(t，3H)。
The 3rd step:
Under room temperature with Lithium Aluminium Hydride (75mg, 1.95mmol) and 5mL anhydrous tetrahydro furan mix and blend, drip compound III-5 (355mg in reaction solution, 0.75mmol) tetrahydrofuran (THF) (10mL, 0.123mol) solution, stirring at room reaction 1 hour, be warming up to 55 ℃ of reactions until TLC monitoring raw material reaction is complete, add 20ml water in 0 ℃ of ice bath downhill reaction liquid, extract with ethyl acetate (50ml*2), use again saturated nacl aqueous solution (50ml*3) washing, anhydrous sodium sulfate drying.Decompression is used silica gel column chromatography purifying gained residue after steaming solvent, obtain: (S)-2-{6-[4-(4-ethyl-piperazine-1-ylmethyl)-phenyl]-furo [3,2-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (IV-5) (48mg, faint yellow solid), productive rate: 14%.
MS?m/z(ESI)：458[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.38(s，1H)，8.20(d，1H)，7.82(d，2H)，7.47(s，1H)，7.82(m，4H)，7.23-7.47(m，3H)，5.46(m，1H)，5.01(t，1H)，3.83(m，2H)，3.52(s，2H)，2.40(brs，8H)，2.28(q，2H)，0.99(t，3H)。
Embodiment 17: preparation compound III-6 and compound IV-6
Figure BDA0000105055160000281
The first step:
under room temperature with compound 2-(6-bromo-furans [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (198mg, 0.59mmol) and (4-methyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (226mg, 0.684mmol) be dissolved in 10mL N, dinethylformamide, add successively tetra-triphenylphosphine palladium (66mg, 0.057mmol), sodium carbonate solution (1mol/L, 0.5ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 90ml water washing, extract with methylene dichloride (3*80ml), organic phase is washed with saturated aqueous common salt (80ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, obtain: (S)-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-furo [3, 2-d] pyrimidine-6-yl]-phenyl }-(4-methyl-piperazine-1-yl)-ketone (III-6) (95mg, yellow solid) productive rate: 35.8%.
MS?m/z(ESI)：458[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.43(s，1H)，8.30(d，1H)，7.88(d，2H)，7.48(s，1H)，7.50(m，4H)，7.27-7.41(m，3H)，5.50(m，1H)，5.03(t，1H)，3.83(s，2H)，3.65-3.60(m，4H)，2.40(m，4H)，2.27(s，3H)。
Second step:
Under room temperature with Lithium Aluminium Hydride (20.14mg, 0.53mmol) and anhydrous tetrahydro furan (5ml, 61.27mmol) mix and blend, drip compound III-6 (90mg in reaction solution, 0.19mmol) tetrahydrofuran (THF) (10ml, 0.123mol) solution, stirring at room reaction 1 hour, be warming up to 55 ℃ of reactions until TLC monitoring raw material reaction is complete, add 20ml water in 0 ℃ of ice bath downhill reaction liquid, with ethyl acetate (40ml*2) extraction, then use saturated nacl aqueous solution (40ml*3) washing, anhydrous sodium sulfate drying.Decompression is used silica gel column chromatography purifying gained residue after steaming solvent, obtain: (S)-2-{6-[4-(4-methyl-piperazine-1-ylmethyl)-phenyl]-furo [3,2-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (IV-6) (25mg, faint yellow solid), productive rate: 28.7%.
MS?m/z(ESI)：444[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.43(s，1H)，8.32(d，1H)，7.87(d，2H)，7.49(s，1H)，7.50(m，4H)，7.27-7.39(m，3H)，5.49(m，1H)，5.11(t，1H)，3.78(m，2H)，3.63(s，2H)，2.84-2.62(m，4H)，2.47(s，3H)，2.52-2.56(m，4H)。
Embodiment 18: preparation compound III-7 and compound IV-7
Figure BDA0000105055160000291
The first step:
under room temperature with compound 2-(6-bromo-furans [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (290mg, 0.868mmol) and (4-cyclopropyl carbonyl-piperazine-1-yl)-[4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxy boron penta ring-2-yl)-phenyl]-ketone (445mg, 1.16mmol) be dissolved in 5mLN, in dinethylformamide, add successively tetra-triphenylphosphine palladium (50mg, 0.043mmol), sodium carbonate solution (1mol/L, 2mL), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 80mL water washing, extract with methylene dichloride (3*80mL), organic phase is washed with saturated aqueous common salt (80ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-cyclopropyl carbonyl-piperazine-1-yl)-{ 4-[4-(2-hydroxyl-1-phenyl-ethamine)-furo [3, 2-d] pyrimidine-6-yl]-phenyl }-ketone (III-7) (350mg, yellow solid), productive rate: 79%.
MS?m/z(ESI)：512[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.41(s，1H)，8.19(d，1H)，7.86-7.75(m，3H)，7.49-7.40(m，4H)，7.36-7.22(m，3H)，5.48(m，1H)，5.01(t，1H)，3.80-3.78(m，2H)，3.67-3.52(m，8H)，2.01(m，1H)，0.70(m，4H)。
Second step:
under room temperature with Lithium Aluminium Hydride (60mg, 1.578mmol) and 10mL anhydrous tetrahydro furan mix and blend, drip compound III-7 (290mg in reaction solution, 0.567mmol) the 10mL tetrahydrofuran solution, stirring at room reaction 1 hour, be warming up to 55 ℃ of reactions until TLC monitoring raw material reaction is complete, add 80ml water in 0 ℃ of ice bath downhill reaction liquid, extract with ethyl acetate (90ml*2), use again saturated nacl aqueous solution (60ml*3) washing, with silica gel column chromatography purifying gained residue, obtain: (S)-2-{6-[4-(4-encircles the third methyl-piperazine-1-methyl)-phenyl]-furo [3, 2-d] pyrimidine-4-amino }-2-phenyl-ethanol (IV-7) (75mg, white solid), productive rate: 27.4%.
MS?m/z(ESI)：484[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.37(s，1H)，8.17(d，1H)，7.83-7.78(m，3H)，7.47-7.43(m，4H)，7.34-7.19(m，3H)，5.45(m，1H)，5.02(t，1H)，3.81-3.76(m，2H)，3.56(brs，2H)，2.59(m，10H)，2.02(m，1H)，0.68(m，4H)。
Embodiment 19: prepare compound III-8
Figure BDA0000105055160000301
The first step:
will be to carboxyl phenylo boric acid pinacol ester (2.8g under room temperature, 11.3mmol) be dissolved in methylene dichloride (27ml, 0.422mol) and N, dinethylformamide (9ml, 0.116mol) in, add 1-Boc-3-methylpiperazine (2.9g, 14.52mmol), add successively 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (2.79g, 14.55mmol), N-hydroxy benzo triazole (1.98g, 14.66mmol), triethylamine (2.5ml, 17.99mmol), the stirring at room reaction is until TLC monitoring raw material reaction is complete, add 30ml water in reaction solution, stirred 30 minutes, extract with methylene dichloride (100ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, obtain: phenylo boric acid pinacol ester (4.1g, white solid), productive rate 85.4%.
MS?m/z(ESI)：431[M+1]。
1HNMR(400Hz，DMSO-d 6)：7.79(d，2H)，7.43(d，2H)，3.79(m，3H)，3.36(m，4H)，1.52(s，9H)，1.40(s，12H)，1.18(d，3H)。
Second step:
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (700mg, 2.0mmol) and the phenylo boric acid pinacol ester (1290mg of previous step gained, 3.0mmol) be dissolved in N, dinethylformamide (10ml, 0.129mol), add successively tetra-triphenylphosphine palladium (115mg, 0.1mmol), sodium carbonate solution (1mol/L, 2ml), nitrogen protection, be heated to 80 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add entry (100ml*3) washing, extract with ethyl acetate (250ml*1), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-4-(4-(4-(2-hydroxyl-1-phenylethylamine)-thiophene [3, 2-d] pyrimidine-6-yl) benzoyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (III-8) (900mg, faint yellow solid), productive rate: 78%.
MS?m/z(ESI)：574[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.39(s，1H)，8.24(d，1H)，7.92(m，3H)，7.54(d，2H)，7.45(d，2H)，7.25(m，3H)，5.46(m，1H)，4.99(t，1H)，3.82(m，2H)，3.20-2.90(m，7H)，1.42(s，9H)，1.16(d，3H)。
Embodiment 20: prepare compound III-9
Figure BDA0000105055160000311
under room temperature with (S)-4-(4-(4-(2-hydroxyl-1-phenylethylamine)-thiophene [3, 2-d] pyrimidine-6-yl) benzoyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (III-8) (900mg, 1.57mmol) be dissolved in methylene dichloride (10ml, 0.156mol) in, add trifluoroacetic acid (2.4ml, 31.4mmol), be stirred to TLC monitoring raw material reaction under room temperature complete, concentrating under reduced pressure, with saturated sodium bicarbonate solution dilution neutralization, wash with saturated aqueous common salt (50ml*3) with dichloromethane extraction (50ml*3) organic layer, concentrating under reduced pressure, scrape large plate, obtain: (S)-(4-(4-(2-hydroxyl-1-phenylethylamine)-thiophene [3, 2-d] pyrimidine-6-yl) phenyl) (2-methylpiperazine-1-yl) ketone (III-9) (550mg, white solid), productive rate: 74%.
MS?m/z(ESI)：474[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.44(s，1H)，8.32(d，1H)，8.00(m，3H)，7.65(d，2H)，7.49(d，2H)，7.34(m，3H)，5.51(m，1H)，5.06(t，1H)，3.84(m，2H)，3.44-3.08(m，7H)，1.41(d，3H)。
Embodiment 21: preparation chemical combination materialization IV-8
Figure BDA0000105055160000312
under room temperature with Lithium Aluminium Hydride (132mg, 3.479mmol) and anhydrous tetrahydro furan (30ml, 0.369mol) mix and blend, drip (S)-(4-(4-(2-hydroxyl-1-phenylethylamine)-thiophene [3 in reaction solution, 2-d] pyrimidine-6-yl) phenyl) (2-methylpiperazine-1-yl) ketone (III-9) (550mg, tetrahydrofuran (THF) (30ml 116mmol), 0.369mol) solution, stirring at room reaction 1 hour, be warming up to 50 ℃ of reactions until TLC monitoring raw material reaction is complete, naturally cool to room temperature, add 20ml water in reaction solution, extract with ethyl acetate (100ml*3), use again saturated nacl aqueous solution (100ml*2) washing, the organic phase that obtains is filtered with anhydrous magnesium sulfate drying, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-2-{6-[4-(2-methyl-piperazine-1-methyl)-phenyl]-thiophene [3, 2-d] pyrimidine-4-amino }-2-phenyl-ethanol (IV-8) (142mg, the off-white color solid), productive rate: 26.7%.
MS?m/z(ESI)：460[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.37(s，1H)，8.34(d，1H)，7.83(m，3H)，7.47(m，4H)，7.25(m，3H)，5.44(m，1H)，5.14(t，1H)，3.78(m，2H)，3.56(brs，2H)，3.44-3.08(m，7H)，1.32(d，3H)。
Embodiment 22: preparation chemical combination materialization IV-9
Figure BDA0000105055160000321
Wherein, the preparation method of (4-benzyl-piperazine-1-yl)-Pyrrolidine-1-base-ketone-boric acid is with described in embodiment 7.
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (174mg, 0.497mmol) and (4-benzyl-piperazine-1-yl)-Pyrrolidine-1-base-ketone-boric acid (105mg, 0.331mmol) be dissolved in N, dinethylformamide (5ml, 65mmol), add successively tetra-triphenylphosphine palladium (38mg, 0.033mmol), sodium carbonate solution (1mol/L, 1ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with methylene dichloride (3*100ml), organic phase is washed with saturated aqueous common salt (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3, 2-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-pyrroles-1-base-ketone (IV-9) (7mg, white solid), productive rate: 3.9%.
MS?m/z(ESI)：543[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.36(s，1H)，8.15(d，1H)，7.83-7.77(m，3H)，7.47-7.42(m，4H)，7.24-7.21(m，3H)，5.44(m，1H)，4.97(t，1H)，3.75(m，2H)，3.54(s，2H)，3.25-3.17(m，8H)，2.40-2.38(m，4H)，1.75(m，4H)。
Embodiment 23: preparation chemical combination materialization IV-10
Figure BDA0000105055160000322
Wherein, the preparation method of (4-benzyl-piperazine-1-yl)-4-methoxyl group piperidin-1-yl-ketone-boric acid is with described in embodiment 8.
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (181mg, 0.520mmol) and (4-benzyl-piperazine-1-yl)-4-methoxyl group piperidin-1-yl-ketone-boric acid (125mg, 0.346mmol) be dissolved in N, dinethylformamide (20ml, 0.65mol), add successively tetra-triphenylphosphine palladium (40mg, 0.035mmol), sodium carbonate solution (1mol/L, 3ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3, 2-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-(4-methoxyl group-piperidin-1-yl)-ketone (IV-10) (28mg, white solid), productive rate: 13.8%.
MS?m/z(ESI)：587[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.37(s，1H)，8，18(d，1H)，7.84-7.79(m，3H)，7.47-7.44(m，4H)，7.32-7.22(m，3H)，5.45(m，1H)，4.99(t，1H)，3.81-3.72(m，2H)，3.52(s，2H)，3.37(s，1H)，3.35(s，3H)，3.14(m，4H)，2.90(m，2H)，2.40(m，4H)，1.80(m，2H)，1.36(m，4H)。
Embodiment 24: preparation chemical combination materialization IV-11
Wherein, the preparation method of (4-benzyl-piperazine-1-yl)-morpholine-1-base-ketone-boric acid is with described in embodiment 6.
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (189mg, 0.540mmol) and (4-benzyl-piperazine-1-yl)-morpholine-1-base-ketone-boric acid (150mg, 045mmol) be dissolved in N, dinethylformamide (20ml, 0.65mol), add successively tetra-triphenylphosphine palladium (52mg, 0.045mmol), sodium carbonate solution (1mol/L, 3ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3, 2-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-morpholine-4-yl)-ketone (IV-11) (25mg, white solid), productive rate: 14%.
MS?m/z(ESI)：559[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.37(s，1H)，8.21(d，1H)，7.84-7.79(m，3H)，7.45-7.41(m，4H)，7.29-7.22(m，3H)，5.42(m，1H)，5.00(t，1H)，3.78(m，2H)，3.53(m.6H)，3.20-3.10(m，8H)，2.41-2.39(m，4H)。
Embodiment 25: preparation chemical combination materialization IV-12
Figure BDA0000105055160000341
Wherein the preparation method of (4-benzyl-piperazine-1-yl)-piperidin-1-yl-ketone-boric acid is with described in embodiment 10.
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (317mg, 0.906mmol) and (4-benzyl-piperazine-1-yl)-piperidin-1-yl-ketone-boric acid (200mg, 0.604mmol) be dissolved in N, dinethylformamide (10ml, 0.325mol), add successively tetra-triphenylphosphine palladium (70mg, 0.0604mmol), sodium carbonate solution (1mol/L, 3ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3, 2-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-piperidin-1-yl)-ketone (IV-12) (25mg, the off-white color solid), productive rate: 7.5%.
MS?m/z(ESI)：557[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.37(s，1H)，8.16(d，1H)，7.84-7.78(m，3H)，7.47-7.22(m，7H)，5.45(m，1H)，4.97(t，1H)，3.7(m，2H)，3.55(s，2H)，3.11(m，8H)，2.39(m，4H)，1.49(m，6H)。
Embodiment 26: preparation chemical combination materialization IV-13
Figure BDA0000105055160000342
Wherein (4-benzyl-piperazine-1-yl)-NEP-1-base-ketone-boric acid preparation method is with described in embodiment 11.
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (181.8mg, 0.520mmol) and (4-benzyl-piperazine-1-yl)-NEP-1-base-ketone-boric acid (125mg, 0.346mmol) be dissolved in N, dinethylformamide (20ml, 0.65mol), add successively tetra-triphenylphosphine palladium (40mg, 0.035mmol), sodium carbonate solution (1mol/L, 3ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3, 2-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-N-ethyl-piperazine-1-yl)-ketone (IV-13) (110mg, white solid), productive rate: 54%.
MS?m/z(ESI)：587[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.38(s，1H)，8.22(m，1H)，7.85(m，3H)，7.50(m，4H)，7.31(m，3H)，5.47(m，1H)，5.00(m，1H)，3.78(m，2H)，3.59(s，2H)，3.40-2.95(m，14H)，2.43(m，4H)，1.25(m，3H)。
Embodiment 27: preparation chemical combination materialization IV-14
Figure BDA0000105055160000351
The first step:
with N methyl piperazine (1.5g, 10mmol) be dissolved in the 15ml methylene dichloride, add N under 0 ℃ of ice bath, N-diisopropylethylamine (1.65ml, 10mmol), to be dissolved in the triphosgene (950mg in methylene dichloride (10ml), 3.2mmol) slowly drip, drip process temperature and remain on 0 ± 3 ℃, reacted 1 hour, add N-Boc piperazine (1.9g under 0 ℃ of ice bath, 10mmol) and N, N-diisopropylethylamine (1.65ml, 10mmol), stirring reaction under room temperature is until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with dissolving crude product in methylene dichloride (30ml), add trifluoroacetic acid (10ml, 0.135mol) under room temperature stirring reaction until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, add saturated sodium carbonate solution (50ml*3) washing, extract with methylene dichloride (50ml*5), concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: N methyl piperazine base piperazine urea (2.3g, weak yellow liquid), productive rate: 50%.
MS?m/z(ESI)：213[M+1]。
Second step:
with N methyl piperazine base piperazine urea (2.3g, 10.85mmol) and 4-formyl phenylo boric acid (1.9g, 11.93mmol) be dissolved in 20ml tetrahydrofuran (THF) and 10ml methyl alcohol, add acetum (1.2ml, 21.72mmol), stirring at room reaction 1.5 hours, add sodium triacetoxy borohydride (5.8g, 27.12mmol), be warming up to 60 ℃ of stirring reactions until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (4-benzyl-piperazine-1-yl)-N methyl piperazine-1-base-ketone-boric acid (1.1g, white solid), productive rate: 50%, MS m/z (ESI): 347[M+1].
The 3rd step:
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (195mg, 0.75mmol) and (4-benzyl-piperazine-1-yl)-N methyl piperazine-1-base-ketone-boric acid (174mg, 0.5mmol) be dissolved in N, dinethylformamide (20ml, 0.65mol), add successively tetra-triphenylphosphine palladium (58mg, 0.05mmol), sodium carbonate solution (1mol/L, 3ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2, 3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-N-methyl-piperazine-1-yl)-ketone (IV-14) (28mg, white solid), productive rate: 10%.
MS?m/z(ESI)：572[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.38(s，1H)，8.30(d，1H)，7.80(m，3H)，7.44(m，4H)，7.24(m，3H)，5.45(m，1H)，5.10(m，1H)，3.78(m，2H)，3.60(s，2H)，3.52-3.18(m，12H)，2.42(m，4H)，2.38(s，3H)。
Embodiment 28: preparation chemical combination materialization IV-15
Figure BDA0000105055160000361
The first step:
with N-Boc piperazine (5g, 26.8mmol) and 4-formyl phenylo boric acid (2.68g, 17.9mmol) be dissolved in 15ml tetrahydrofuran (THF) and 15ml methyl alcohol, add acetum (6ml, 43.44mmol), stirring at room reaction 1.5 hours, add sodium triacetoxy borohydride (9.49g, 44.7mmol), be warming up to 60 ℃ of stirring reactions until TLC monitoring raw material reaction is complete, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: 4-benzyl-piperazine-1-carboxylic acid tert-butyl ester-boric acid 4.98g, white solid), productive rate: 87.4%, MS m/z (ESI): 321[M+1], be directly used in next step reaction.
Second step:
under room temperature with compound 2-(6-bromo-thiophene [3, 2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (1g, 2.856mmol) and 4-benzyl-piperazine-1-carboxylic acid tert-butyl ester-boric acid (1.83g, 5.714mmol) be dissolved in N, dinethylformamide (30ml, 0.975mol), add successively tetra-triphenylphosphine palladium (323mg, 0.28mmol), sodium carbonate solution (1mol/L, 5ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: 4-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino-thieno-[3, 2-d]-benzyl }-piperazine-1-carbonyl-piperazine-1-carboxylic acid tert-butyl ester (1.1g, white solid), productive rate: 70.6%, MS m/z (ESI): 546[M+1].
The 3rd step:
with 4-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino-thieno-[3, 2-d]-benzyl }-piperazine-1-carbonyl-piperazine-1-carboxylic acid tert-butyl ester (1.09g, 2mmol) be dissolved in tetrahydrofuran (THF), add trifluoroacetic acid (3ml, 40mmol), stirring at room 2 hours, use the 400ml ethyl acetate extraction, organic phase saturated common salt water washing (100ml*2), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-2-phenyl-2-[6-(4-piperazine-1-ylmethyl-phenyl)-thieno-[3, 2-d] pyrimidine-4-yl amino]-ethanol (IV-15) (700mg, faint yellow solid), productive rate: 78.6%.
MS?m/z(ESI)：446[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.39(s，1H)，8.18(d，1H)，7.80(m，3H)，7.43(m，4H)，7.27(m，2H)，7.22(m，1H)，5.45(m，1H)，5.00(m，1H)，3.83(m，2H)，3.51(s，2H)，2.71(m，4H)，2.27(m，4H)。
Embodiment 29: preparation chemical combination materialization IV-16
Figure BDA0000105055160000371
The first step:
under room temperature with 1-cyclopropane carbonyl piperazine (2.37g, 15.37mmol) and to formyl phenylo boric acid (1.92g, 12.81mmol) be dissolved in (40ml) in methylene dichloride, stirring at room 1 hour, add inwards again sodium cyanoborohydride (1.77g, 28.18mmol), stirring at room is complete to the TLC monitoring reaction, add water 20ml, use dichloromethane extraction, use again the saturated common salt water washing 2 times, the organic phase anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain: (4-benzyl boron dihydroxide-piperazine-1-yl)-cyclopropyl-ketone, (1.6g, white solid), productive rate: 43.4%, be directly used in next step reaction.
Second step:
Wherein 6-bromo-4-chloro-2-methyl-thiophene [3,2-d] but the preparation of the described method of pyrimidine referenced patent WO 2009/007421 and WO2008/058285.
under room temperature with 6-bromo-4-chloro-2-methyl-thiophene [3, 2-d] pyrimidine (830mg, 3.15mmol) and L-benzene glycinol (648mg, 4.725mmol) be dissolved in N, in dinethylformamide (10ml), drip triethylamine (1.1ml, 7.875mol), be heated to 55 ℃, reacted 24 hours, naturally cooling, add the 40ml frozen water, decompress filter, decompress filter after filter cake is pulled an oar with 10ml water, again with the making beating of 10ml normal hexane, decompress filter, obtain: 2-(6-bromo-2-methyl-thiophene [3, 2-d] pyrimidine-4-amino)-2-phenyl-ethanol (780mg, faint yellow solid), productive rate: 71%.
MS?m/z(ESI)：365[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.12(d，1H)，7.46(m，3H)，7.29-7.19(m，3H)，5.45(m，1H)，4.98(t，1H)，3，75(m，2H)，2.38(s，3H)。
The 3rd step:
under room temperature with compound 2-(6-bromo-2-methyl-thiophene [3, 2-d] pyrimidine-4-amino)-2-phenyl-ethanol (364mg, 1.0mmol) and (4-benzyl boron dihydroxide-piperazine-1-yl)-cyclopropyl-ketone (576mg, 2.0mmol) be dissolved in N, dinethylformamide (10ml, 0.325mol), add successively tetra-triphenylphosphine palladium (70mg, 0.0604mmol), sodium carbonate solution (1mol/L, 2ml), nitrogen protection, be heated to 85 ℃ until TLC monitoring raw material reaction is complete, naturally cool to room temperature and add the 100ml water washing, extract with ethyl acetate (100ml*2), organic phase is washed with saturated aqueous common salt (50ml*3), the organic phase anhydrous magnesium sulfate drying that obtains, filter, concentrating under reduced pressure, with silica gel column chromatography purifying gained residue, obtain: (S)-cyclopropyl-(4-{4-[4-(2-hydroxyl-1-phenyl-ethamine)-2-methyl-thiophene [3, 2-d] pyrimidine-6-yl]-phenyl }-piperazine-1-yl)-ketone (IV-16) (110mg, white solid), productive rate: 21%.
MS?m/z(ESI)：528[M+1]。
1HNMR(400Hz，DMSO-d 6)：8.05(d，1H)，7.81(d，2H)，7.70(s，1H)，7.46(m，5H)，7.31-7.21(m，3H)，5.52(m，1H)，4.99(m，1H)，3.80(m，2H)，3.68(s，2H)，3.56(m，4H)，2.52(s，3H)，2.41(m，4H)，1.96(m，1H)，0.73(m，4H)。
Biological assessment
1. receptor tyrosine kinase EGFR, VEGFR molecular level enzyme are lived and are suppressed preliminary assessment
(1) enzyme reaction substrate Poly (Glu, Tyr) 4: 1 use is without PBS (the 10mM sodium phosphate buffer of potassium ion, 150mmol/LNaCl, pH=7.2～7.4) be diluted to 20 μ g/ml, 125 μ l/ hole coated elisa plates, put 37 ℃ of reactions 12～16 hours, discard liquid in the hole, wash plate, T-PBS (PBS without potassium ion that contains 0.1%Tween-20) with 200 μ l/ holes washes plate three times, each 5 minutes; Dry enzyme plate is 1～2 hour in 37 ℃ of baking ovens.
(2) every hole adds with reaction buffer (50mmol/L HEPES pH 7.4,50mmol/L MgCl 2, 0.5mmol/LMnCl 2, 0.2mmol/L Na 3VO 4, 1mmol/L DTT) dilution ATP solution 50 μ L, final concentration 5 μ mol/L.The compound solution (1%DMSO dissolving, final concentration is 10 μ mol/L) that adds 1 μ l in every hole, then the c-Met tyrosine-kinase zymoprotein that adds 50 μ l to dilute with reaction buffer; Put 37 ℃ of shaking tables (100rpm) reaction 1 hour; Each experiment is established without ATP control wells two holes and corresponding DMSO solvent control hole (negative control hole); Discard liquid in the hole, T-PBS washes plate three times.
(3) add antibody PY99100 μ l/ hole (antibody dilutes with the T-PBS that contains BSA 5mg/ml, and concentration is 0.4 μ g/ml), 37 ℃ of shaking tables reacted 0.5 hour; Discard liquid in the hole, T-PBS washes plate three times.
(4) add the anti-100 μ l/ holes (antibody dilutes with the T-PBS that contains BSA 5mg/ml, and concentration is 0.5 μ g/ml) of sheep anti mouse two of horseradish peroxidase-labeled, 37 ℃ of shaking tables reacted 0.5 hour, discarded liquid in the hole, and T-PBS washes plate three times.
(5) add the OPD nitrite ion 100 μ l/ holes of 2mg/ml (with containing 0.03%H 2O 20.1M citric acid-sodium citrate damping fluid (pH=5.4) dilution), 25 ℃ of lucifuges reactions 1～10 minute; (need be with ultrasonic during the OPD dissolving, nitrite ion needs now with the current).
(6) add 2mol/L H 2SO 450 μ l/ hole stopped reactions, with the wavelengthtunable orifice plate microplate reader VERSAmax reading that declines, wavelength is 490nm.
(7) inhibiting rate of sample is tried to achieve by following formula:
Test result is shown in Table 1.
2, receptor tyrosine kinase EGFR, VEGFR enzyme are lived and are suppressed IC 50Evaluation experimental
clearly have EGFR or VEGFR enzyme that above-mentioned screening obtains are lived that (compound is 10 for inhibiting compound -5M is to the inhibiting rate of receptor tyrosine kinase EGFR or VEGFR＞50%) be made into gradient concentration, carry out IC 50Estimate.Calculate the IC of the horizontal arrestin Tyrosylprotein kinase of each compound molecule with four parameter methods 50Value the results are shown in Table shown in 1.
Table 1 embodiment compound is lived to the enzyme of Tyrosylprotein kinase EGFR and VEGFR and is suppressed experimental result
Figure BDA0000105055160000391
Figure BDA0000105055160000401
By as seen from Table 1: in Thienopyrimidine of the present invention and furo pyridine derivatives, that the Urogastron Receptor EGFR is had an obvious inhibition is active for majority of compounds, part of compounds has good restraining effect to angiogenesis factor acceptor VEGFR, also has part of compounds and Urogastron Receptor EGFR and angiogenesis factor acceptor VEGFR are all had good restraining effect; And has the compound activity that the compound activity of [3,2-d] pyrimidine skeleton also obviously is better than having also [2,3-d] pyrimidine skeleton; The active order of excellence of substituting group on piperazine ring roughly can be arranged as: cyclopropyl＞methyl＞2-hydroxyethyl＞ethyl＞urea; EGFR with majority of compounds of [3,2-d] pyrimidine skeleton also suppresses active and control drug Gefitinib Gefitinib quite or better, especially compound III-9 and IV-3, its half-inhibition concentration IC 50Value is respectively 193nM and 118nM, and is better than positive control medicine Gefitinib, is worth further exploitation; Compound III-2, III-3, III-8, IV-1, IV-2, IV-3, IV-11 also have obvious VEGFR and suppress active, its half-inhibition concentration IC 50Lower than 1 micromole, has prospect in medicine.

Claims (17)

1. a Thienopyrimidine and furo pyridine derivatives, is characterized in that, is the compound with general formula I, general formula I I, general formula III or general formula I V:
Figure FDA0000105055150000011
In above-mentioned general formula:
X is oxygen or sulphur; Z is nitrogen or carbon;
R is hydrogen, contain any one in the reverse amide group of amide group, reverse amide group or replacement of aryl-acyl, alkylsulfonyl, amide group or replacement of alkene acyl group, aryl-acyl or replacement of the alkyl of 1～6 carbon atom or the alkyl of replacement, the alkyl acyl that contains 1～6 carbon atom, the cycloalkyl acyl group that contains 3～6 carbon atoms, the alkene acyl group that contains 2～6 carbon atoms or replacement;
Ar 1Be phenyl, 2 or 3-fluorine substituted-phenyl, 2 or 3-trifluoromethyl substituted-phenyl, 2 or 3-chlorine substituted-phenyl, 2 or 3-itrile group substituted-phenyl, 2-or 3-C 1-3Alkyl-substituted phenyl, thienyl, 3-C 1-3Thienyl, furyl, 3-C that alkyl replaces 1-3The furyl that alkyl replaces, 2 or the 3-pyridyl in any one;
Ar 2Phenyl, C for phenyl, halogen replacement 1-6Thienyl, C that the xenyl that the phenyl that alkyl replaces, xenyl, halogen replace, naphthyl, pyridyl, thienyl, halogen replace 1-3Furyl, C that the thienyl that alkyl replaces, furyl, halogen replace 1-3Any one in the furyl that alkyl replaces.
2. Thienopyrimidine according to claim 1 and furo pyridine derivatives is characterized in that: be the compound with general formula I, general formula I I, general formula III or general formula I V, and in general formula: X is oxygen or sulphur; Z is nitrogen; Ar 1Be phenyl; Ar 2Be phenyl; R is hydrogen, contain any one in the reverse amide group of amide group, reverse amide group or replacement of aryl-acyl, alkylsulfonyl, amide group or replacement of alkene acyl group, aryl-acyl or replacement of the alkyl of 1～6 carbon atom or the alkyl of replacement, the alkyl acyl that contains 1～6 carbon atom, the cycloalkyl acyl group that contains 3～6 carbon atoms, the alkene acyl group that contains 2～6 carbon atoms or replacement.
3. the Thienopyrimidine that represents of the general formula I described in a claim 1 and the preparation method of furo pyridine derivatives, is characterized in that, comprise the steps 3. or step 1. and 3. step 2. and 3. or step 1.～3.:
Figure FDA0000105055150000021
4. the Thienopyrimidine that represents of the general formula I I described in a claim 1 and the preparation method of furo pyridine derivatives, is characterized in that, comprise the steps 5. or step 2. and 5. or step 4. and 5. or 4. 2. step reach and 5.:
Figure FDA0000105055150000022
5. the Thienopyrimidine that represents of the general formula I I described in a claim 1 and the preparation method of furo pyridine derivatives, it is characterized in that: the Thienopyrimidine and the furo pyridine derivatives that are represented by general formula I carry out hydrogenation and get.
6. the Thienopyrimidine that represents of the general formula III described in a claim 1 and the preparation method of furo pyridine derivatives, is characterized in that, comprise the steps 7. or step 1. and 7. or step 6. and 7. or 6. 1. step reach and 7.:
Figure FDA0000105055150000023
7. the Thienopyrimidine that represents of the general formula I V described in a claim 1 and the preparation method of furo pyridine derivatives, is characterized in that, comprise the steps 8. or step 4. and 8. or step 6. and 8. or 6. 4. step reach and 8.:
Figure FDA0000105055150000031
8. the Thienopyrimidine that represents of the general formula I V described in a claim 1 and the preparation method of furo pyridine derivatives, is characterized in that, the Thienopyrimidine and the furo pyridine derivatives that are represented by general formula III carry out hydrogenation and get.
9. an application rights requires any one or a few the tyrosine kinase inhibitor of mixture preparation in the tautomer, racemic modification, enantiomer, diastereomer, pharmacy acceptable salt, pharmaceutically acceptable solvate of the Thienopyrimidine described in 1 and furo pyridine derivatives or described derivative.
10. tyrosine kinase inhibitor claimed in claim 9 refers to EGFR and/or VEGFR inhibitor.
11. EGFR claimed in claim 10 and/or the VEGFR inhibitor application in the medicine of preparation prevention or treatment and EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR relative disease.
12. EGFR claimed in claim 10 and/or the VEGFR inhibitor application in the medicine for preparing prevention or treatment abnormal cell proliferation, metamorphosis, hypoerkinesia, angiogenesis and the metastases disease relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR.
13. EGFR claimed in claim 10 and/or the VEGFR inhibitor application in the medicine for preparing prevention or the treatment growth and metastasis of tumours relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR.
14. the activeconstituents of EGFR claimed in claim 10 and/or VEGFR inhibitor is selected from any one or a few the mixture in the tautomer, racemic modification, enantiomer, diastereomer, pharmacy acceptable salt, pharmaceutically acceptable solvate of following compound or described compound:
(S)-(4-ethyl-piperazine-1-yl)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[2,3-d] pyrimidine-6-yl]-phenyl }-ketone,
(S)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[2,3-d] pyrimidine-6-yl]-phenyl }-(4-methyl-piperazine-1-yl)-ketone,
(S)-(4-cyclopropyl methyl-piperazine-1-yl)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[2,3-d] pyrimidine-6-yl]-phenyl }-ketone,
(S)-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[2,3-d] pyrimidine-6-yl]-phenyl }-ketone,
(S)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[2,3-d] pyrimidine-6-yl]-phenyl }-piperazine-1-base-ketone,
(S)-2-{6-[4-(4-ethyl-piperazine-1-ylmethyl)-phenyl]-thieno-[2,3-d] pyrimidine-4-yl is amino }-2-phenyl-ethanol,
(S-2-{6-[4-(4-methyl-piperazine-1-ylmethyl)-phenyl]-thieno-[2,3-d] pyrimidine-4-yl is amino }-2-phenyl-ethanol,
(S-2-{6-[4-(4-cyclopropyl methyl-piperazine-1-ylmethyl)-phenyl]-thieno-[2,3-d] pyrimidine-4-yl is amino }-2-phenyl-ethanol,
(S)-2-(6-{4-[4-(2-hydroxyl-ethyl)-piperazine-1-ylmethyl]-phenyl }-thieno-[2,3-d] pyrimidine-4-yl is amino }-2-phenyl-ethanol,
(S)-2-phenyl-2-[6-(4-piperazine-1-ylmethyl-phenyl)-thieno-[2,3-d] pyrimidine-4-yl is amino]-ethanol,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2,3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-morpholine-4-yl)-ketone,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2,3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-pyrroles-1-base-ketone,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2,3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-(4-methoxyl group-piperidin-1-yl)-ketone,
(S)-4-dimethylamino-1-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2,3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-butyl-2-alkene-1-ketone,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2,3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-piperidin-1-yl)-ketone,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2,3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-N-ethyl-piperazine-1-yl)-ketone,
(S)-(4-ethyl-piperazine-1-yl)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-thiophene [3,2-d] pyrimidine-6-yl]-phenyl }-ketone,
(S)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[3,2-d] pyrimidine-6-yl]-phenyl }-(4-methyl-piperazine-1-yl)-ketone,
(S)-(4-cyclopropyl carbonyl-piperazine-1-yl)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[3,2-d] pyrimidine-6-yl]-phenyl }-ketone,
(S)-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-4-[4-(2-hydroxyl-1-phenyl-ethamine)-thieno-[3,2-d] pyrimidine-6-yl]-phenyl }-ketone,
(S)-(4-ethyl-piperazine-1-yl)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-furans [3,2-d] pyrimidine-6-yl]-phenyl }-ketone,
(S)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-furo [3,2-d] pyrimidine-6-yl]-phenyl }-(4-methyl-piperazine-1-yl)-ketone,
(S)-(4-cyclopropyl carbonyl-piperazine-1-yl)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-furo [3,2-d] pyrimidine-6-yl]-phenyl }-ketone,
(S)-4-(4-(4-(2-hydroxyl-1-phenylethylamine)-thiophene [3,2-d] pyrimidine-6-yl) benzoyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester,
(S)-(4-(4-(2-hydroxyl-1-phenylethylamine)-thiophene [3,2-d] pyrimidine-6-yl) phenyl) (2-methylpiperazine-1-yl) ketone,
(S)-2-{6-[4-(4-ethyl-piperazine-1-ylmethyl)-phenyl]-thieno-[3,2-d] pyrimidine-4-yl is amino }-2-phenyl-ethanol,
(S)-2-{6-[4-(4-methyl-piperazine-1-ylmethyl)-phenyl]-thieno-[3,2-d] pyrimidine-4-yl is amino }-2-phenyl-ethanol,
(S)-2-{6-[4-(4-cyclopropyl methyl-piperazine-1-ylmethyl)-phenyl]-thieno-[3,2-d] pyrimidine-4-yl is amino }-2-phenyl-ethanol,
(S)-2-(6-{4-[4-(2-hydroxyl-ethyl)-piperazine-1-ylmethyl]-phenyl }-thieno-[3,2-d] pyrimidine-4-yl is amino }-2-phenyl-ethanol,
(S)-2-{6-[4-(4-ethyl-piperazine-1-ylmethyl)-phenyl]-furo [3,2-d] pyrimidine-4-yl is amino }-2-phenyl-ethanol,
(S)-2-{6-[4-(4-methyl-piperazine-1-ylmethyl)-phenyl]-furo [3,2-d] pyrimidine-4-yl is amino }-2-phenyl-ethanol,
(S)-2-{6-[4-(4-encircles the third methyl-piperazine-1-methyl)-phenyl]-furo [3,2-d] pyrimidine-4-is amino }-2-phenyl-ethanol,
(S)-2-{6-[4-(2-methyl-piperazine-1-methyl)-phenyl]-thiophene [3,2-d] pyrimidine-4-is amino }-2-phenyl-ethanol,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3,2-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-pyrroles-1-base-ketone,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3,2-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-(4-methoxyl group-piperidin-1-yl)-ketone,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3,2-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-morpholine-4-yl)-ketone,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3,2-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-piperidin-1-yl)-ketone,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[3,2-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-N-ethyl-piperazine-1-yl)-ketone,
(S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno-[2,3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-N-methyl-piperazine-1-yl)-ketone,
(S)-2-phenyl-2-[6-(4-piperazine-1-ylmethyl-phenyl)-thieno-[3,2-d] pyrimidine-4-yl is amino]-ethanol,
(S)-cyclopropyl-(4-{4-[4-(2-hydroxyl-1-phenyl-ethamine)-2-methyl-thiophene [3,2-d] pyrimidine-6-yl]-phenyl }-piperazine-1-yl)-ketone.
15. the pharmacy acceptable salt described in claim 9 or 14 refers to any one or a few in inorganic acid salt, organic acid salt, alkylsulfonate, arylsulphonate.
16. the pharmacy acceptable salt described in claim 9 or 14 refers to any one or a few in hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, formate, acetate, propionic salt, benzoate, maleate, fumarate, succinate, tartrate, Citrate trianion, metilsulfate, ethyl sulfonate, benzene sulfonate, tosilate.
17. the pharmaceutically acceptable solvate described in claim 9 or 14, refer to water, ethanol, Virahol, ether, acetone in the solvate that forms of any one or a few solvent.
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