CN103087077B - Thienopyrimidine and furans miazines derivative, its preparation method and in application pharmaceutically - Google Patents

Thienopyrimidine and furans miazines derivative, its preparation method and in application pharmaceutically Download PDF

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CN103087077B
CN103087077B CN201110342682.0A CN201110342682A CN103087077B CN 103087077 B CN103087077 B CN 103087077B CN 201110342682 A CN201110342682 A CN 201110342682A CN 103087077 B CN103087077 B CN 103087077B
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phenyl
room temperature
piperazine
egfr
compound
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CN103087077A (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 kind of Thienopyrimidine and furans miazines derivative, its preparation method and in application pharmaceutically. Described derivative is the compound with general formula I, general formula I I, general formula III or general formula I V:

Description

Thienopyrimidine and furans miazines derivative, its preparation method and in application pharmaceutically
Technical field
The present invention relates to miazines derivative and its preparation method and application, specifically, relate to one and there is epidermal growthFactor acceptor EGFR and/or Angiogenesis factor receptors VEGFR suppress active Thienopyrimidine and furans miazines and spread outBiological, its preparation method and in application pharmaceutically, belongs to pharmaceutical chemistry technical field.
Background technology
Tumour is one of serious disease threatening human health, and its treatment mainly comprises radiotherapy, chemotherapy and operative treatment. CloselyOver year, along with the development of cell biology and tumor pharmacology, there is huge change in the chemotherapy of tumour. TraditionalThereby chemotherapeutic agent also causes that owing to non-specifically blocking cell division normal cell is dead in killing tumour cellDie and abandoned gradually, meanwhile, using the key node albumen in the signal path of abnormal activation in tumour cell as target spot,The micromolecular inhibitor of finding efficient, low toxicity, high specificity has become the important directions of current antineoplastic research and development.In tumour unconventionality expression activate receptor tyrosine kinase (RTK) due to tumor development, invasion and attack shift, chemotherapy resistanceAll bring into play key effect and become the focus of antineoplastic research Deng links.
EGF-R ELISA (EGFR, epidermalgrowthfactorreceptor claim again HER1 or cerbB1) isIn human cancer, express EGFR-TK HER family member the most widely. EGFR structure comprises three regions: extracellular region,Cross-film district and intracellular region. The amino terminal of extracellular region is made up of 622 amino acid, has 2 of formation ligand binding domain to be rich inCysteine section; Cross-film district is a single α spiral; Intracellular region comprises kinases district and has many Tyr phosphorylation sitesCarboxyl terminal afterbody. EGFR-TK (RTK) is that the γ phosphate transfection of ATP is transported to tyrosine residue. Tying with partAfter closing, there is homology or heterodimer and make TK region form tight connection in EGFR. At carboxyl terminal afterbody RTKMediation Tyr phosphorylation site carries out phosphorylation, created enzyme and connect sub-albumen binding site (Y992, Y1068,Y1086, Y1148 and Y11730), thereby can start Cellular Signaling Transduction Mediated reaction. The conduction of these signals forms different thinBorn of the same parents' reaction, comprises propagation, differentiation, adhesion and vascularization, shifts and apoptosis inhibit.
Research shows, EGFR is at non-small cell lung cancer, prostate cancer, breast cancer, colorectal cancer, head and neck cancer, cancer of the stomach, ovaryIn cancer and cancer of pancreas, have expression, EGFR activation causes sophisticated signal conduction reaction. In dissimilar solid tumor, EGFRThere are propagation and overexpression, cause downstream signal conduction out of control and cause the formation of various tumours. ATP-binding site in EGFRSudden change affect the RTK activity of acceptor, disturb the formation of tumorigenesis signal, meanwhile, EGFR also with progress and the poor prognosis of tumourClosely related.
The unique effect in tumorigenesis due to EGFR and VEGFR, its monoclonal antibody and micromolecular inhibitor becomeThe focus of targeting antineoplastic medicine thing research and development. At present, there is the inhibitor listing of several targeting EGFRs or VEGFR, near20 drug candidates are in clinical each development. Wherein, Gefitinib and Erlotinib representative listing target earlyThe micromolecular inhibitor of EGFR. Gefitinib (Gefitinib claims again ZD1839 or Iressa) is as three line single therapy medicinesFor advanced Non-small cell lung (nonsmallcelllungcancer, NSCLC). (Erlotinib claims again OSI774 to ErlotinibOr Tarceva) two wires or the three line medicines of the advanced NSCLC of failing to respond to any medical treatment as standard scheme.
But, along with the clinical practice of these medicines, it is found that not to be that all high expressed EGFR patients can be to these medicinesThing is effective, and some tumour that initially Gefitinib (Gefitinib) is had to a therapeutic response occurs again that after treatment some months disease entersExhibition. These results show, the EGFR inhibitor antineoplastic using at present has natural or Secondary cases resistance phenomenon, because ofThis, Development of Novel has low drug resistance and maybe can alleviate the medicine of early stage inhibitor drug resistance and become tyrosine kinase inhibitorNew development direction.
Summary of the invention
For the existing the problems referred to above of prior art, the object of this invention is to provide one and there is EGF-R ELISAEGFR and/or Angiogenesis factor receptors VEGFR suppress active Thienopyrimidine and furans miazines derivative, its systemPreparation Method and in application pharmaceutically.
Thienopyrimidine provided by the invention and furans miazines derivative, be have general formula I, general formula I I, general formula III orThe compound of general formula I V:
In above-mentioned general formula:
X is oxygen or sulphur; Z is nitrogen or carbon;
R is hydrogen, containing the alkyl of 1～6 carbon atom or the alkyl of replacement, containing the alkyl acyl of 1～6 carbon atom, containing 3～6The cycloalkyl acyl group of individual carbon atom, containing the alkene acyl group of 2～6 carbon atoms or alkene acyl group, aryl-acyl or the replacement of replacementThe reverse amide groups of amide groups, reverse amide groups or replacement of aryl-acyl, sulfonyl, amide groups or replacement in arbitrarilyA kind of;
Ar1 be phenyl, 2 or 3-fluorine substituted-phenyl, 2 or 3-trifluoromethyl substituted-phenyl, 2 or 3-chlorine substituted-phenyl, 2 or3-itrile group substituted-phenyl, 2-or 3-C1-3Alkyl-substituted phenyl, thienyl, 3-C1-3Thienyl, furyl that alkyl replaces,3-C1-3 alkyl replace furyl, 2 or 3-pyridine radicals in any one;
Ar2For phenyl, the C of phenyl, halogen replacement1-6Xenyl, naphthalene that phenyl, xenyl, the halogen that alkyl replaces replacesThienyl, C that base, pyridine radicals, thienyl, halogen replace1-3The furan that thienyl, furyl, the halogen that alkyl replaces replacesBase, C mutter1-3Any one in the furyl that alkyl replaces.
Further, described Thienopyrimidine and furans miazines derivative, be have general formula I, general formula I I, general formula III orThe compound of general formula I V, and in general formula: X is oxygen or sulphur; Z is nitrogen; Ar1For phenyl; Ar2For phenyl; R is hydrogen, containsThe alkyl of 1～6 carbon atom or the alkyl of replacement, containing the alkyl acyl of 1～6 carbon atom, containing the cycloalkyl of 3～6 carbon atomsAcyl group, containing aryl-acyl, the sulphonyl of the alkene acyl group of 2～6 carbon atoms or alkene acyl group, aryl-acyl or the replacement of replacementAny one in the reverse amide groups of the amide groups of base, amide groups or replacement, reverse amide groups or replacement.
The preparation method of the Thienopyrimidine that general formula I provided by the invention represents and furans miazines derivative, comprises as followsStep 3. or step 1. and 3. step 2. and 3. or step 1.～3.:
The Thienopyrimidine that general formula I I provided by the invention represents and the preparation method of furans miazines derivative, comprise as followsStep 5. or step 2. and 5. step 4. and 5. or step 2. and 4. and 5.:
The preparation method of the Thienopyrimidine that general formula III provided by the invention represents and furans miazines derivative, comprises as followsStep 7. or step 1. and 7. step 6. and 7. or step 1. and 6. and 7.:
The Thienopyrimidine that general formula I V provided by the invention represents and the preparation method of furans miazines derivative, comprise as followsStep 8. or step 4. and 8. step 6. and 8. or step 4. and 6. and 8.:
Further, described general formula I I represents Thienopyrimidine and furans miazines derivative can also be represented by general formula IThienopyrimidine and furans miazines derivative carry out hydrogenation and obtain.
Further, described general formula I V represents Thienopyrimidine and furans miazines derivative can also be represented by general formula IIIThienopyrimidine and furans miazines derivative carry out hydrogenation and obtain.
Because research shows that Thienopyrimidine of the present invention and furans miazines derivative have EGF-R ELISA(EGFR) and/or the inhibition activity of Angiogenesis factor receptors (VEGFR), therefore, thieno of the present invention is phoneticThe dynamic isomer of pyridine and furans miazines derivative or described derivative, racemic modification, enantiomter, non-mapping are differentThe mixture of any one or a few in structure body, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, can answerFor the preparation of tyrosine kinase inhibitor, especially can be applicable to prepare EGFR and/or VEGFR inhibitor.
Furtherly, described inhibitor can be applicable to prepare prevention or treatment and EGF-R ELISA EGFR and/or bloodThe medicine of pipe growth factor receptors VEGFR relevant disease, specifically, can be applicable to prepare prevention or treatment and epidermal growth factorAbnormal cell proliferation, metamorphosis, motor function that sub-Receptor EGFR and/or Angiogenesis factor receptors VEGFR are relevantThe medicine of hyperfunction, angiogenesis and metastases disease.
Furtherly, described inhibitor can be applicable to prepare treatment or prevention and EGF-R ELISA EGFR and/Or the medicine of the relevant growth and metastasis of tumours of Angiogenesis factor receptors VEGFR.
Furtherly, the active component of described inhibitor preferably compound shown in table 1 or shown in the tautomerism of compoundBody, racemic modification, enantiomter, diastereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvent closeThe mixture of any one or a few in thing:
Table 1
Described pharmaceutically acceptable salt comprises without limitation: inorganic acid salt, example hydrochloric acid salt, hydrobromate, nitrate,Sulfate, phosphate etc.; Acylate, as formates, acetate, propionate, benzoate, maleate, rich horseHydrochlorate, succinate, tartrate, citrate etc.; Alkylsulfonate, as metilsulfate, ethyl sulfonate etc.;Arylsulphonate, as benzene sulfonate, tosilate etc.
Described pharmaceutically acceptable solvate comprise without limitation described compound and water, ethanol, isopropyl alcohol,The solvate of ether, acetone etc.
Compared with prior art, the novel structure of Thienopyrimidine provided by the invention and furans miazines derivative, hasIt is active that significantly EGFR inhibition activity, and part of compounds also has obvious inhibition to VEGFR, is expected to be developed as tyrosineKinases EGFR is or/and VEGFR inhibitor, raw for the preparation of prevention or treatment and EGF-R ELISA EGFR and/or blood vesselRelevant disease and and the blood vessels such as abnormal cell proliferation, metamorphosis and hypoerkinesia that growth factor receptor body VEGFR is relevantThe medicine of new life or metastases relevant disease, is especially expected for the preparation for the treatment of or prevention and EGF-R ELISA EGFRAnd/or the medicine of the relevant growth and metastasis of tumours of Angiogenesis factor receptors VEGFR, for Development of Novel have low drug resistance orCan alleviate early stage inhibitor drug resistance tyrosine kinase inhibitor drug provision new developmental direction and approach, have wideApplication prospect and medical value.
Detailed description of the invention
Further set forth the present invention below in conjunction with specific embodiment. Following embodiment is only interpreted as for the present invention is described notFor limiting the scope of the invention. After having read the content of the present invention's record, those skilled in the art can be rightThe present invention makes various changes or modifications, and these equivalences change and modification falls into the claims in the present invention book limited range equally.
In following embodiment the structure of prepared compound be by nuclear magnetic resonance (1HNMR) and mass spectrum (MS) giveDetermine.
1HNMR displacement (δ) with 1,000,000/unit (ppm) provides.1The mensuration of HNMR is to useBrukerAVANCE-400 nuclear magnetic resonance spectrometer, the solvent of mensuration is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3)，Inside be designated as tetramethylsilane (TMS), chemical shift is with 10-6Provide as unit.
The mensuration of MS is by FINNIGANLCQAd (ESI) mass spectrograph (manufacturer: Therm, model: FinniganLCQadvantageMAX)。
The mensuration of IC50 value is with NovoStar ELIASA (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 that use Yantai Huanghai Sea silica gel 200～300 order silica gel are carrier.
HPLC test be use Agilent 1200DAD high pressure liquid chromatograph (SunfireC18150 × 4.6mm chromatographic column) andWaters2695-2996 high pressure liquid chromatograph (GiminiC18150 × 4.6mm chromatographic column).
Microwave reaction is to use CEMDiscover-S908860 type microwave reactor.
In addition, in following examples, without specified otherwise, reaction is all carried out under blanket of nitrogen.
Argon atmospher refers to that reaction bulb connects the argon gas balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 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
The first step:
Under room temperature, will be dissolved in carrene (10ml, 0.16mol) to carboxyl phenyl boric acid pinacol ester (1g, 4.03mmol)And in DMF (1ml, 13.0mmol), add NEP (0.6ml, 4.8mmol), and successivelyAdd 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), stirring at room temperature reaction is until TLC monitoring raw material reactionCompletely, in reactant liquor, add 10ml water, stir 30 minutes, with carrene (50ml*3) extraction, then use saturated chlorineChange sodium solution (50ml*2) washing, organic phase anhydrous magnesium sulfate drying, filters, and reduced pressure concentration, obtains: (4-ethyl-piperazinePiperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-ketone (1.4g, faint yellow solid), directlyFor next step reaction.
Second step:
Wherein the bromo-4-chlorothiophene of 6-[2,3-d] pyrimidine is according to method preparation described in patent WO2007/059257.
Under room temperature by bromo-compound 6-4-chlorothiophene [2,3-d] pyrimidine (1g, 4.0mmol) and L-benzene glycinol (1g, 7.2mmol)Be dissolved in DMF (20ml, 0.259mol), drip 1ml triethylamine (363mg, 7.19mmol),Stirring at room temperature, until TLC monitoring raw material reaction is complete, adds 200ml water, decompress filter, and filter cake washes (100ml*2) with waterObtain: compound 2-(the bromo-thiophene of 6-[2,3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (1.3g, faint yellow solid), productive rate:93％。
MSm/z(ESI)：351[M+1]。
1HNMR(400MHz，DMSO-d6)：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 by compound 2-(the bromo-thiophene of 6-[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 encircle-2-yl)-phenyl]-ketone (982mg, 2.86mmol)Be dissolved in DMF (15ml, 0.194mol), add successively tetra-triphenylphosphine palladium (164mg, 0.143mmol),Sodium carbonate liquor (1mol/L, 2.8ml), nitrogen protection, is heated to 80 DEG C until TLC monitoring raw material reaction is complete, naturally coldBut add water (100ml*3) washing to room temperature, with ethyl acetate (250ml*1) extraction, organic phase saturated aqueous common salt(100ml*2) washing, the organic phase anhydrous magnesium sulfate drying obtaining, filters, and reduced pressure concentration, obtains: (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%.
MSm/z(ESI)：487[M+1]。
1HNMR(400Hz，DMSO-d6)：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, Lithium Aluminium Hydride (27.3mg, 0.718mmol) and anhydrous tetrahydro furan (8ml, 98.63mmol) are mixedStir, to the oxolane (10ml, 0.123mol) that drips Compound I-1 (140mg, 0.287mmol) in reactant liquorSolution, stirring at room temperature reaction 1 hour, is warming up to 50 DEG C of reactions until TLC monitoring raw material reaction is complete, naturally cools to chamberTemperature adds 20ml water in reactant liquor, with ethyl acetate (100ml*3) extraction, then uses saturated nacl aqueous solution (100ml*2)Washing, the organic phase obtaining is filtered with anhydrous magnesium sulfate drying, and reduced pressure concentration is purified gained residue with silica gel column chromatography,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%.
MSm/z(ESI)：473[M+1]。
1HNMR(400Hz，DMSO-d6)：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:
Under room temperature, will be dissolved in carrene (27ml, 0.422mol) to carboxyl phenyl boric acid pinacol ester (3g, 12.10mmol)And in DMF (9ml, 0.116mol), add N methyl piperazine (1.45g, 14.5mmol), and successivelyAdd 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (2.79g, 14.4mmol), N-hydroxy benzo three nitrogenAzoles (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), stirring at room temperature reaction is until TLC monitoring raw material is anti-Should be complete, in reactant liquor, add 30ml water, stir 30 minutes, with carrene (100ml*3) extraction, then use saturatedSodium chloride solution (100ml*2) washing, organic phase anhydrous magnesium sulfate drying, filters, and reduced pressure concentration, obtains: (4-firstBase-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-ketone (1.5g, whiteSolid), productive rate: 37.6%
Second step:
Under room temperature by compound 2-(the bromo-thiophene of 6-[2,3-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (100mg, 0.2857mmol)(4-methyl-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-ketone(188mg, 0.5714mmol) is dissolved in DMF (4ml, 51.7mmol), adds successively four triphensBase phosphine palladium (33mg, 0.0286mmol), sodium carbonate liquor (1mol/L, 0.6ml), nitrogen protection, be heated to 80 DEG C untilTLC monitoring raw material reaction is complete, naturally cools to room temperature and adds water (100ml*3) washing, with ethyl acetate (250ml*1)Extraction, saturated aqueous common salt for organic phase (100ml*2) washing, the organic phase anhydrous magnesium sulfate drying obtaining, filters, and subtractsPress concentratedly, purify gained residue with silica gel column chromatography, 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%.
MSm/z(ESI)：474[M+1]。
1HNMR(400Hz，DMSO-d6)：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, Lithium Aluminium Hydride (100mg, 2.640mmol) and anhydrous tetrahydro furan (10ml, 0.123mol) mixing are stirredMix, molten to the oxolane (10ml, 0.123mol) that drips Compound I-2 (500mg, 1.056mmol) in reactant liquorLiquid, stirring at room temperature reaction 1 hour, is warming up to 50 DEG C of reactions until TLC monitoring raw material reaction is complete, naturally cools to room temperature,In reactant liquor, add 20ml water, with ethyl acetate (100ml*3) extraction, then use saturated nacl aqueous solution (100ml*2)Washing, the organic phase obtaining is filtered with anhydrous magnesium sulfate drying, and reduced pressure concentration is purified gained residue with silica gel column chromatography,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%.
MSm/z(ESI)：460[M+1]。
1HNMR(400Hz，DMSO-d6)：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
The first step:
Under room temperature, will be dissolved in carrene (27ml, 0.422mol) to carboxyl phenyl boric acid pinacol ester (3g, 12.10mmol)And in DMF (9ml, 0.116mol), add 1-cyclopropyl methyl piperazine (2.3g, 14.9mmol),And add successively 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (2.79g, 14.4mmol), N-hydroxy benzenesAnd triazole (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), stirring at room temperature reaction is until TLC monitoringRaw material reaction is complete, in reactant liquor, adds 30ml water, stir 30 minutes, and with carrene (100ml*3) extraction, thenWith saturated nacl aqueous solution (100ml*2) washing, organic phase anhydrous magnesium sulfate drying, filters, and reduced pressure concentration, obtains:(4-cyclopropyl carbonyl-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-ketone(3.5g, white solid), productive rate 61.4%, is used as next step reaction.
Second step:
Under room temperature by compound 2-(the bromo-thiophene of 6-[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 encircle-2-yl)-phenyl]-ketone(1.099g, 2.86mmol) is dissolved in DMF (15ml, 0.194mol), adds successively four triphenylsPhosphine palladium (164mg, 0.143mmol), sodium carbonate liquor (1mol/L, 2.8ml), nitrogen protection, is heated to 80 DEG C until TLCMonitoring raw material reaction is complete, naturally cools to room temperature and adds water (100ml*3) washing, by ethyl acetate (250ml*1) extractionGet, saturated aqueous common salt for organic phase (100ml*2) washing, the organic phase anhydrous magnesium sulfate drying obtaining, filters, decompressionConcentrated, purify gained residue with silica gel column chromatography, obtain: (S)-(4-cyclopropyl methyl-piperazine-1-yl)-{ 4-[4-(2-hydroxylBase-1-phenyl-ethamine)-thieno [2,3-d] pyrimidine-6-yl]-phenyl }-ketone (I-3) (300mg, faint yellow solid), productive rate:60％。
MSm/z(ESI)：528[M+1]。
1HNMR(400Hz，DMSO-d6)：1HNMR(400Hz，DMSO-d6)：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, Lithium Aluminium Hydride (90mg, 2.369mmol) and anhydrous tetrahydro furan (10ml, 0.123mol) mixing are stirredMix, molten to the oxolane (10ml, 0.123mol) that drips Compound I-3 (250mg, 0.474mmol) in reactant liquorLiquid, stirring at room temperature reaction 1 hour, is warming up to 50 DEG C of reactions until TLC monitoring raw material reaction is complete, naturally cools to room temperature,In reactant liquor, add 20ml water, with ethyl acetate (100ml*3) extraction, then use saturated nacl aqueous solution (100ml*2)Washing, the organic phase obtaining is filtered with anhydrous magnesium sulfate drying, and reduced pressure concentration is purified gained residue with silica gel column chromatography,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, off-white color solid), productive rate: 4.3%.
MSm/z(ESI)：500[M+1]。
1HNMR(400Hz，DMSO-d6)：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
The first step:
Under room temperature, will be dissolved in carrene (27ml, 0.422mol) to carboxyl phenyl boric acid pinacol ester (3g, 12.10mmol)And in DMF (9ml, 0.116mol), add N-hydroxyethyl piperazine (2g, 15.36mmol), and comply withInferior 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (2.79g, 14.4mmol), the N-hydroxy benzo three of addingNitrogen azoles (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), stirring at room temperature reaction is until TLC monitoring raw materialReact completely, in reactant liquor, add 30ml water, stir 30 minutes, with carrene (100ml*3) extraction, then with fullAnd sodium chloride solution (100ml*2) washing, organic phase anhydrous magnesium sulfate drying, filters, and reduced pressure concentration, obtains: (4-Ethoxy-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-ketone (3.0g,White solid), productive rate 68.8%, is used as next step reaction.
Second step:
Under room temperature by compound 2-(the bromo-thiophene of 6-[2,3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (500mg, 1.43mmol) and(4-ethoxy-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-ketone(1.029g, 2.86mmol) is dissolved in DMF (15ml, 0.194mol), adds successively four triphenylsPhosphine palladium (164mg, 0.143mmol), sodium carbonate liquor (1mol/L, 2.8ml), nitrogen protection, is heated to 80 DEG C until TLCMonitoring raw material reaction is complete, naturally cools to room temperature and adds water (100ml*3) washing, by ethyl acetate (250ml*1) extractionGet, saturated aqueous common salt for organic phase (100ml*2) washing, the organic phase anhydrous magnesium sulfate drying obtaining, filters, decompressionConcentrated, purify gained residue with silica gel column chromatography, 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), producesRate: 41.7%.
MSm/z(ESI)：504[M+1]。
1HNMR(400Hz，DMSO-d6)：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 by Lithium Aluminium Hydride (90mg, 2.369mmol) and anhydrous tetrahydro furan (10ml) mix and blend, to reactionOxolane (10ml, the 0.123mol) solution that drips Compound I-4 (250mg, 0.496mmol) in liquid, room temperature is stirredMix reaction 1 hour, be warming up to 50 DEG C of reactions until TLC monitoring raw material reaction is complete, naturally cool to room temperature, to reactant liquorIn add 20ml water, with ethyl acetate (100ml*3) extraction, then use saturated nacl aqueous solution (100ml*2) washing,To organic phase filter with anhydrous magnesium sulfate drying, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (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, off-white color solid), productive rate: 4.3%.
MSm/z(ESI)：490[M+1]。
1HNMR(400Hz，DMSO-d6)：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
The first step:
Under room temperature, will be dissolved in carrene (10ml, 0.156mol) to carboxyl phenyl boric acid pinacol ester (0.894g, 4.8mmol)And in DMF (1ml, 17.78mmol), add N-Boc piperazine (1g, 4.03mmol), and successivelyAdd 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.93g, 4.8mmol), N-hydroxy benzo three nitrogenAzoles (0.66g, 4.8mmol), triethylamine (0.84ml, 6.04mmol), stirring at room temperature reaction is until TLC monitoring raw material reactionCompletely, in reactant liquor, add 30ml water, stir 30 minutes, with carrene (100ml*3) extraction, then use saturated chlorineChange sodium solution (100ml*2) washing, organic phase anhydrous magnesium sulfate drying, filters, and reduced pressure concentration, obtains: 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 by compound 2-(the bromo-thiophene of 6-[3,2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (500mg, 1.428mmol) and4-[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 DMF (20ml, 0.65mol), add successively tetra-triphenylphosphine palladium (161.8mg, 0.14mmol),Sodium carbonate liquor (1mol/L, 2.5ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally coldBut add 100ml water washing to room temperature, with ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3)Washing, the organic phase anhydrous magnesium sulfate drying obtaining, filtration, reduced pressure concentration, purifies gained with silica gel column chromatography residualThing, obtains crude product (380mg, faint yellow solid), productive rate: 47.6%. MSm/z (ESI): 560[M+1].
The 3rd step:
Under room temperature, above-mentioned product (168mg, 0.3mmol) is dissolved in carrene (8ml, 0.125mol), addsTrifluoroacetic acid (0.45ml, 0.6mmol), is stirred to TLC monitoring raw material reaction complete under room temperature, reduced pressure concentration, uses saturated carbonAcid hydrogen sodium solution dilution neutralization, with dichloromethane extraction (50ml*3) saturated aqueous common salt for organic layer (50ml*3) washing,Reduced pressure concentration, scrapes large plate, obtains: (S)-and 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%.
MSm/z(ESI)：460[M+1]。
1HNMR(400Hz，DMSO-d6)：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 by Lithium Aluminium Hydride (51.5mg, 1.355mmol) and anhydrous tetrahydro furan (25,0.308mol) mix and blend,To oxolane (25ml, the 0.308mol) solution that drips Compound I-5 (500mg, 0.451mmol) in reactant liquor,Stirring at room temperature reaction 1 hour, is warming up to 50 DEG C of reactions until TLC monitoring raw material reaction is complete, naturally cools to room temperature, toIn reactant liquor, add 20ml water, with ethyl acetate (50ml*3) extraction, then use saturated nacl aqueous solution (100ml*2) to washWash, the organic phase obtaining is filtered with anhydrous magnesium sulfate drying, and reduced pressure concentration is purified gained residue with silica gel column chromatography,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%.
MSm/z(ESI)：446[M+1]。
1HNMR(400Hz，DMSO-d6)：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:
Morpholine (5ml, 57.405mmol) is dissolved in 40ml carrene, under 0 DEG C of ice bath, adds N, N-diisopropylBase ethamine (9.5ml, 57.405mmol), will be dissolved in the triphosgene (6g, 20.69mmol) in carrene (30ml)Slowly drip, drip process temperature and remain on 0 ± 3 DEG C, react 1 hour, under 0 DEG C of ice bath, add N-Boc piperazine(11.8mg, 63.15mmol) and DIPEA (9.5ml, 57.405mmol), stirring reaction under room temperature untilTLC monitoring raw material reaction is complete, and reduced pressure concentration is purified gained residue with silica gel column chromatography, by dissolving crude product in 30mlIn carrene, add stirring reaction under trifluoroacetic acid (14ml, 18.7mmol) room temperature until TLC monitoring raw material reaction is completeEntirely, reduced pressure concentration, adds saturated sodium carbonate solution (50ml*3) washing, with carrene (50ml*6) extraction, decompressionConcentrated, purify gained residue with silica gel column chromatography, obtain: morpholinyl piperazinyl urea (877mg, faint yellow solid),Productive rate: 6%, MSm/z (ESI): 200[M+1].
Second step:
Morpholinyl piperazinyl urea (500mg, 2.51mmol) and 4-formyl phenyl boric acid (396mg, 2.64mmol) are dissolvedIn 20ml oxolane, add acetum (0.5ml, 8.75mmol), stirring at room temperature reaction 1 hour, adds three secondAcyloxy sodium borohydride (798mg, 3.77mmol), is warming up to 60 DEG C of stirring reactions until TLC monitoring raw material reaction is complete,Reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (4-benzyl-piperazine-1-yl)-morpholine-1-base-ketone-boronAcid (330mg, light yellow solid), productive rate: 23%, MSm/z (ESI): 334[M+1].
The 3rd step:
Under room temperature by compound 2-(the bromo-thiophene of 6-[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) is dissolved in DMF(20ml, 0.65mol), adds tetra-triphenylphosphine palladium (52mg, 0.045mmol) successively, sodium carbonate liquor (1mol/L, 3ml),Nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, and naturally cool to room temperature and add 100ml water washing,With ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase obtaining is with anhydrousDried over mgso, filters, and reduced pressure concentration is purified gained residue with silica gel column chromatography, obtains: (S)-(4-{4-[4-(2-hydroxylBase-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%.
MSm/z(ESI)：559[M+1]。
1HNMR(400Hz，DMSO-d6)：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:
Nafoxidine (600mg, 8.436mmol) is dissolved in 15ml carrene, under 0 DEG C of ice bath, adds N, N-Diisopropylethylamine (1.4ml, 8.436mmol), will be dissolved in the triphosgene (801mg, 2.70mmol) in carrene (5ml)Slowly drip, drip process temperature and remain on 0 ± 3 DEG C, react 1 hour, under 0 DEG C of ice bath, add N-Boc piperazine (1.57g,8.436mmol) and DIPEA (1.4ml, 8.436mmol), stirring reaction under room temperature is until TLC monitoring is formerMaterial reacts completely, and dissolving crude product, in 20ml carrene, is added under trifluoroacetic acid (10ml, 0.135mol) room temperature and stirredMix reaction until TLC monitoring raw material reaction is complete, reduced pressure concentration, adds saturated sodium carbonate solution (50ml*3) washing, usesCarrene (50ml*5) extraction, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: nafoxidineBase piperazinyl urea (376mg, faint yellow solid), productive rate: 24%.
MSm/z(ESI)：184[M+1]。
1HNMR(400Hz，DMSO-d6)：3.23(t，5H)，3.05(t，4H)，2.64(t，4H)，1.72(m，4H)。
Second step:
By nafoxidine base piperazinyl urea (370mg, 2.022mmol) and 4-formyl phenyl boric acid (334mg, 2.224mmol)Be dissolved in 10ml oxolane and 10ml methyl alcohol, add acetum (0.5ml, 8.75mmol), stirring at room temperature reaction 1Hour, add sodium triacetoxy borohydride (1.1g, 5.055mmol), be warming up to 60 DEG C of stirring reactions until TLC monitoringRaw material reaction is complete, and reduced pressure concentration is purified gained residue with silica gel column chromatography, obtains: (4-benzyl-piperazine-1-yl)-tetra-Hydrogen pyrroles-1-base-ketone-boric acid (210mg), productive rate: 33%.
MSm/z(ESI)：318[M+1]。
1HNMR(400Hz，DMSO-d6)：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 by compound 2-(the bromo-thiophene of 6-[2,3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (317mg, 0.906mmol) and(4-benzyl-piperazine-1-yl)-nafoxidine-1-base-ketone-boric acid (200mg, 0.604mmol) is dissolved in N, N-dimethyl methylAcid amides (5ml, 65mmol), adds tetra-triphenylphosphine palladium (70mg, 0.0604mmol) successively, sodium carbonate liquor (1mol/L,1ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml waterWashing, with carrene (3*100ml) extraction, saturated aqueous common salt for organic phase (100ml*2) washing, what obtain is organicUse mutually anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (S)-(4-{4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno [2,3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-pyrroles-1-base-firstKetone (II-7) (67mg, white solid), productive rate: 20%.
MSm/z(ESI)：543[M+1]。
1HNMR(400Hz，DMSO-d6)：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
The first step:
Tetramethoxy piperidines (500mg, 4.314mmol) is dissolved in 10ml carrene, under 0 DEG C of ice bath, addsDIPEA (0.72ml, 4.314mmol), will be dissolved in triphosgene in carrene (5ml) (412mg,1.389mmol) slowly drip, drip process temperature and remain on 0 ± 3 DEG C, react 1 hour, under 0 DEG C of ice bath, add N-BocPiperazine (809mg, 4.341mmol) and DIPEA (0.72ml, 4.341mmol), stirring reaction under room temperatureUntil TLC monitoring raw material reaction is complete, reduced pressure concentration, in 20ml carrene, adds trifluoroacetic acid by dissolving crude productStirring reaction under (10ml, 0.135mol) room temperature is until TLC monitoring raw material reaction is complete, and reduced pressure concentration, adds saturated carbonAcid sodium solution (50ml*3) washing, with carrene (50ml*5) extraction, reduced pressure concentration, purifies with silica gel column chromatographyGained residue, obtains: 4-methoxyl group piperidinyl piperazine base urea (414mg, faint yellow solid), and productive rate: 42%, MSm/z (ESI):228[M+1]。
Second step:
By 4-methoxyl group piperidinyl piperazine base urea (414mg, 1.824mmol) and 4-formyl phenyl boric acid (287mg, 1.915mmol)Be dissolved in 5ml oxolane and 5ml methyl alcohol, add acetum (0.2ml, 3.5mmol), it is 1 little that stirring at room temperature is reactedTime, add sodium triacetoxy borohydride (580mg, 2.726mmol), be warming up to 60 DEG C of stirring reactions until TLC monitoringRaw material reaction is complete, and reduced pressure concentration is purified gained residue with silica gel column chromatography, obtains: (4-benzyl-piperazine-1-yl)-4-Methoxyl group piperidin-1-yl-ketone-boric acid (251mg, light yellow solid), productive rate: 38.1%, MSm/z (ESI): 362[M+1].
The 3rd step:
Under room temperature by compound 2-(the bromo-thiophene of 6-[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) is dissolved in N, N-diformazanBase formamide (20ml, 0.65mol), adds tetra-triphenylphosphine palladium (40mg, 0.035mmol) successively, sodium carbonate liquor (1mol/L,3ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml waterWashing, with ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase obtainingWith anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (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)-firstKetone (II-8) (36mg, faint yellow solid), productive rate: 17.7%.
MSm/z(ESI)：587[M+1]。
1HNMR(400Hz，DMSO-d6)：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
Under room temperature, Compound I I-5 (100mg, 0.225mmol) is dissolved in DMF (5ml), adds4-bromo crotonic acid (37.2mg, 0.225mmol) and N-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (43.0mg,0.225mmol), stirring at room temperature reaction is until TLC monitoring raw material reaction is complete, reduced pressure concentration, add oxolane (30ml,0.37mol) and dimethylamine (0.5ml, 3.66mmol), stirring at room temperature reaction, until TLC monitoring raw material reaction is complete, adds secondAcetoacetic ester (200ml*1) extraction, organic layer water (50ml*3) is washed, organic phase anhydrous magnesium sulfate drying, suction filtration, subtractsPress concentratedly, purify gained residue with silica gel column chromatography, obtain: (S)-4-dimethylamino-1-(4-{4-[4-(2-hydroxyl-1-benzeneBase-ethylamino)-thieno [2,3-d] pyrimidine-6-yl]-benzyl }-piperazine-1-yl)-butyl-2-alkene-1-ketone (II-9) (40mg, greyish whiteLook solid), productive rate: 32%.
MSm/z(ESI)：557[M+1]。
1HNMR(400Hz，DMSO-d6)：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:
Piperidines (1g, 11.752mmol) is dissolved in 20ml carrene, under 0 DEG C of ice bath, adds N, N-diisopropylBase ethamine (2ml, 11.752mmol), will be dissolved in the triphosgene (1.1g, 3.761mmol) in carrene (10ml)Slowly drip, drip process temperature and remain on 0 ± 3 DEG C, react 1 hour, under 0 DEG C of ice bath, add N-Boc piperazine (2.2g,11.752mmol) and DIPEA (2ml, 11.752mmol), stirring reaction under room temperature is until TLC monitoring is formerMaterial reacts completely, and reduced pressure concentration in carrene (30ml), adds trifluoroacetic acid (20ml, 0.27mol) by dissolving crude productStirring reaction under room temperature is until TLC monitoring raw material reaction is complete, and reduced pressure concentration, adds saturated sodium carbonate solution (50ml*3)Washing, with carrene (50ml*5) extraction, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains:Piperidinyl piperazine base urea (1.25g, faint yellow solid), productive rate: 36%.
MSm/z(ESI)：198[M+1]。
1HNMR(400Hz，DMSO-d6)：3.59(brs，1H)，3.09(m，8H)，2.78(m，4H)，1.48(m，6H)。
Second step:
Piperidinyl piperazine base urea (1.25g, 6.336mmol) and 4-formyl phenyl boric acid (1.05g, 6.969mmol) are dissolvedIn 15ml oxolane and 15ml methyl alcohol, add acetum (0.7ml, 12.67mmol), stirring at room temperature reaction 1.5Hour, add sodium triacetoxy borohydride (3.36g, 15.84mmol), be warming up to 60 DEG C of stirring reactions until TLC monitoringRaw material reaction is complete, and reduced pressure concentration is purified gained residue with silica gel column chromatography, obtains: (4-benzyl-piperazine-1-yl)-piperazinePyridine-1-base-ketone-boric acid (1.25g, light yellow solid), productive rate: 60%.
MSm/z(ESI)：332[M+1]。
1HNMR(400Hz，DMSO-d6)：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 by compound 2-(the bromo-thiophene of 6-[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) is dissolved in DMF(10ml, 0.325mol), adds tetra-triphenylphosphine palladium (70mg, 0.0604mmol) successively, sodium carbonate liquor (1mol/L,3ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml waterWashing, with ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase obtainingWith anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (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, off-white color solid), productive rate: 20%.
MSm/z(ESI)：557[M+1]。
1HNMR(400Hz，DMSO-d6)：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
The first step:
NEP (1g, 8.77mmol) is dissolved in 15ml carrene, under 0 DEG C of ice bath, adds N, N-bis-Isopropyl ethamine (1.5ml, 8.77mmol), will be dissolved in the triphosgene (833mg, 2.81mmol) in carrene (10ml)Slowly drip, drip process temperature and remain on 0 ± 3 DEG C, react 1 hour, under 0 DEG C of ice bath, add N-Boc piperazine (1.63g,8.77mmol) and DIPEA (1.5ml, 8.77mmol), stirring reaction under room temperature is until TLC monitoring raw materialReact completely, reduced pressure concentration, in carrene (30ml), adds trifluoroacetic acid (10ml, 0.135mol) by dissolving crude productStirring reaction under room temperature is until TLC monitoring raw material reaction is complete, and reduced pressure concentration, adds saturated sodium carbonate solution (50ml*3)Washing, with carrene (50ml*5) extraction, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains:NEP base piperazine urea (1g, weak yellow liquid), productive rate: 34.97%, MSm/z (ESI): 227[M+1].
Second step:
NEP base piperazine urea (1g, 4.40mmol) and 4-formyl phenyl boric acid (729mg, 4.86mmol) are dissolvedIn 10ml oxolane and 10ml methyl alcohol, add acetum (0.7ml, 12.67mmol), stirring at room temperature reaction 1.5Hour, add sodium triacetoxy borohydride (2.33g, 11mmol), be warming up to 60 DEG C of stirring reactions until TLC monitoring is formerMaterial reacts completely, and reduced pressure concentration is purified gained residue with silica gel column chromatography, obtains: (4-benzyl-piperazine-1-yl)-N-secondBase piperazine-1-base-ketone-boric acid (125mg, light yellow solid), productive rate: 8.0%, MSm/z (ESI): 361[M+1].
The 3rd step:
Under room temperature by compound 2-(the bromo-thiophene of 6-[2,3-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (181.8mg, 0.520mmol)(4-benzyl-piperazine-1-yl)-NEP-1-base-ketone-boric acid (125mg, 0.346mmol) is dissolved in N, N-diformazanBase formamide (20ml, 0.65mol), adds tetra-triphenylphosphine palladium (40mg, 0.035mmol) successively, sodium carbonate liquor (1mol/L,3ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml waterWashing, with ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase obtainingWith anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (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%.
MSm/z(ESI)：587[M+1]。
1HNMR(400Hz，DMSO-d6)：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
The first step:
Wherein the bromo-4-chlorothiophene of 6-[3,2-d] pyrimidine is according to method preparation described in patent WO2009/007421.
Under room temperature by bromo-compound 6-4-chlorothiophene [3,2-d] pyrimidine (2g, 8.01mmol) and L-benzene glycinol (1.65g,12.02mmol) be dissolved in DMF (25ml, 0.32mol), dropping 2.8ml triethylamine (2.03g,20.025mmol), be heated to 60 DEG C until TLC monitoring raw material reaction is complete, naturally cool to room temperature, add 100ml waterWashing, with carrene (3*100ml) extraction, saturated aqueous common salt for organic phase (100ml*2) washing, what obtain is organicUse mutually anhydrous magnesium sulfate drying, filter, reduced pressure concentration, obtains: compound 2-(the bromo-thiophene of 6-[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-d6)：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 of wherein (4-ethyl-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-ketoneMethod is with the first step of embodiment 1.
Under room temperature by compound 2-(the bromo-thiophene of 6-[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 encircle-2-yl)-phenyl]-ketone (2.36g, 6.86mmol)Be dissolved in DMF (36ml, 0.465mol), add successively tetra-triphenylphosphine palladium (0.4g, 0.343mmol),Sodium carbonate liquor (1mol/L, 7ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally coolingAdd 100ml water washing to room temperature, with carrene (3*100ml) extraction, saturated aqueous common salt for organic phase (100ml*2)Washing, the organic phase anhydrous magnesium sulfate drying obtaining, filters, and reduced pressure concentration, obtains: (S)-(4-ethyl-piperazine-1-Base)-4-[4-(2-hydroxyl-1-phenyl-ethamine)-thiophene [3,2-d] pyrimidine-6-yl] and-phenyl }-ketone (III-1) (500mg, yellow solid)Productive rate: 30%.
MSm/z(ESI)：487[M+1]。
1HNMR(400Hz，DMSO-d6)：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, Lithium Aluminium Hydride (75mg, 1.95mmol) and anhydrous tetrahydro furan (5ml, 61.27mmol) mixing are stirredMix, in reactant liquor, drip (4-ethyl-piperazine-1-yl)-{ 4-[4-(2-hydroxyl-1-phenyl-ethylamino)-thieno [3,2, d] pyrimidine-6-yl]-phenyl } oxolane (10ml, the 0.123mol) solution of-ketone (370mg, 0.78mmol), stirring at room temperature is anti-Answer 1 hour, be warming up to 55 DEG C of reactions until TLC monitoring raw material reaction is complete, in 0 DEG C of ice bath downhill reaction liquid, add 20mlWater, with ethyl acetate (50ml*2) extraction, then uses saturated nacl aqueous solution (50ml*3) washing, anhydrous sodium sulfate drying.Decompression steams after solvent with silica gel column chromatography purifies gained residue, obtains: (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-d6)：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
The first step:
The preparation method of (4-methyl-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-ketoneWith the first step of embodiment 2.
Under room temperature by compound 2-(the bromo-thiophene of 6-[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 encircle-2-yl)-phenyl]-ketone (226mg, 0.684mmol)Be dissolved in DMF (10ml, 0.13mol), add successively tetra-triphenylphosphine palladium (66mg, 0.057mmol),Sodium carbonate liquor (1mol/L, 0.5ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally coldBut add 100ml water washing to room temperature, with carrene (3*100ml) extraction, saturated aqueous common salt for organic phase (100ml*2)Washing, the organic phase anhydrous magnesium sulfate drying obtaining, filters, and reduced pressure concentration, obtains: (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%.
MSm/z(ESI)：473[M+1]。
1HNMR(400Hz，DMSO-d6)：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, Lithium Aluminium Hydride (20.14mg, 0.53mmol) and anhydrous tetrahydro furan (5ml, 61.27mmol) are mixedStir, to oxolane (10ml, the 0.123mol) solution that drips compound III-2 in reactant liquor, stirring at room temperature reaction 1Hour, be warming up to 55 DEG C of reactions until TLC monitoring raw material reaction is complete, in 0 DEG C of ice bath downhill reaction liquid, add 20ml water, useEthyl acetate (50ml*2) extraction, then use saturated nacl aqueous solution (50ml*3) washing, anhydrous sodium sulfate drying, decompressionSteam after solvent with silica gel column chromatography and purify gained residue, obtain: (S)-2-{6-[4-(4-methyl-piperazine-1-ylmethyl)-benzeneBase]-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-d6)：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
The first step:
Wherein, (4-cyclopropyl carbonyl-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-firstThe preparation method of ketone is with the first step of embodiment 3.
Under room temperature by compound 2-(the bromo-thiophene of 6-[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 encircle-2-yl)-phenyl]-ketone (892mg,2.32mmol) be dissolved in DMF (10ml, 0.13mol), add successively tetra-triphenylphosphine palladium (100mg,0.086mmol), sodium carbonate liquor (1mol/L, 2mL), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reactionCompletely, naturally cool to room temperature and add 100ml water washing, with carrene (3*100ml) extraction, the saturated food of organic phaseSalt solution (100ml*2) washing, the organic phase anhydrous magnesium sulfate drying obtaining, filters, and reduced pressure concentration, uses silica gel column chromatographyMethod purifying gained residue, obtains: (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-d6)：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, Lithium Aluminium Hydride (54mg, 1.423mmol) and anhydrous tetrahydro furan (10ml, 0.123mol) mixing are stirredMix, to oxolane (10ml, the 0.123mol) solution that drips compound III-3 (300mg, 0.57mmol) in reactant liquor,Stirring at room temperature reaction 1 hour, is warming up to 55 DEG C of reactions until TLC monitoring raw material reaction is complete, 0 DEG C of ice bath downhill reaction liquidIn add 100ml water, with ethyl acetate (100ml*2) extraction, then use saturated nacl aqueous solution (50ml*3) washing, useSilica gel column chromatography purifying gained residue, obtains: (S)-2-{6-[4-(4-cyclopropyl methyl-piperazine-1-ylmethyl)-phenyl]-thiopheneAnd [3,2-d] pyrimidine-4-yl amino }-2-phenyl-ethanol (IV-3) (5mg, white solid), productive rate: 1.76%.
MSm/z(ESI)：499[M+1]。
1HNMR(400Hz，DMSO-d6)：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
The first step:
Wherein, (4-ethoxy-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-ketonePreparation method is with the first step of embodiment 4.
Under room temperature by compound 2-(the bromo-thiophene of 6-[3,2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (340mg, 0.97mmol) and (4-Ethoxy-piperazine-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxy boron, penta encircle-2-yl)-phenyl]-ketone (454mg,1.26mmol) be dissolved in DMF (10ml, 0.13mol), add successively tetra-triphenylphosphine palladium (112mg,0.097mmol), sodium carbonate liquor (1mol/L, 1ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is completeEntirely, naturally cool to room temperature and add 100ml water washing, with carrene (3*100ml) extraction, organic phase saturated common saltWater (100ml*2) washing, the organic phase anhydrous magnesium sulfate drying obtaining, filters, and reduced pressure concentration, uses silica gel column chromatographyPurifying gained residue, obtains: (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%.
MSm/z(ESI)：503[M+1]。
1HNMR(400Hz，DMSO-d6)：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 by Lithium Aluminium Hydride (41.8mg, 11mmol) and anhydrous tetrahydro furan (10ml, 0.123mol) mix and blend,To oxolane (10ml, the 0.123mol) solution that drips compound III-4 (220mg, 0.44mmol) in reactant liquor, chamberTemperature stirring reaction 1 hour, is warming up to 55 DEG C of reactions until TLC monitoring raw material reaction is complete, in 0 DEG C of ice bath downhill reaction liquidAdd 100ml water, with ethyl acetate (100ml*2) extraction, then use saturated nacl aqueous solution (50ml*3) washing, obtainOrganic phase anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains:(S)-2-(6-{4-[4-(2-hydroxyl-ethyl)-piperazine-1-ylmethyl]-phenyl }-thieno [3,2-d] pyrimidine-4-yl amino }-2-phenyl-secondAlcohol (IV-4) (30mg, faint yellow solid), productive rate: 14%.
MSm/z(ESI)：490[M+1]。
1HNMR(400Hz，DMSO-d6)：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
The first step:
Wherein the bromo-4-chlorine of 6-furans [3,2-d] pyrimidine synthetic with reference to bromo-4-chlorothiophene [3, the 2-d] pyrimidine of 6-andPreparation method described in W02008/073785.
Under room temperature by bromo-compound 6-4-chlorine furans [3,2-d] pyrimidine (1g, 4.29mmol) and L-benzene glycinol (0.83g,6.06mmol) be dissolved in DMF (25ml, 0.32mol), drip 1.5ml triethylamine, be heated to60 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature, adds 100ml water washing, uses carrene(3*80ml) extraction, saturated aqueous common salt for organic phase (80ml*2) washing, the organic phase anhydrous magnesium sulfate drying obtaining,Filter, reduced pressure concentration, obtains: 2-(the bromo-furans of 6-[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 by compound 2-(the bromo-furans of 6-[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 encircle-2-yl)-phenyl]-ketone (2.36g, 6.86mmol)Be dissolved in 36mlN, dinethylformamide, adds tetra-triphenylphosphine palladium (0.41g, 0.359mmol) successively, and sodium carbonate is moltenLiquid (1Mol/L, 7ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and addsEnter 80ml water washing, with carrene (3*80ml) extraction, saturated aqueous common salt for organic phase (80ml*2) washing, obtainsOrganic phase anhydrous magnesium sulfate drying, filter, reduced pressure concentration, obtains: (4-ethyl-piperazine-1-yl)-{ 4-[4-(2-hydroxyl-1-Phenyl-ethylamino) also [3,2, d] pyrimidine-6-yl of-furans]-phenyl }-ketone (III-5) (475mg, yellow solid), productive rate: 28%.
MSm/z(ESI)：472[M+1]。
1HNMR(400Hz，DMSO-d6)：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 by Lithium Aluminium Hydride (75mg, 1.95mmol) and 5mL anhydrous tetrahydro furan mix and blend, in reactant liquorOxolane (10mL, the 0.123mol) solution that drips compound III-5 (355mg, 0.75mmol), stirring at room temperature is anti-Answer 1 hour, be warming up to 55 DEG C of reactions until TLC monitoring raw material reaction is complete, in 0 DEG C of ice bath downhill reaction liquid, add 20mlWater, with ethyl acetate (50ml*2) extraction, then uses saturated nacl aqueous solution (50ml*3) washing, anhydrous sodium sulfate drying.Decompression steams after solvent with silica gel column chromatography purifies gained residue, obtains: (S)-2-{6-[4-(4-ethyl-piperazine-1-ylmethyl)-Phenyl] also [3,2-d] pyrimidine-4-yl amino of-furans }-2-phenyl-ethanol (IV-5) (48mg, faint yellow solid), productive rate: 14%.
MSm/z(ESI)：458[M+1]。
1HNMR(400Hz，DMSO-d6)：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
The first step:
Under room temperature by compound 2-(the bromo-furans of 6-[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 encircle-2-yl)-phenyl]-ketone (226mg, 0.684mmol)Be dissolved in 10mLN, dinethylformamide, adds tetra-triphenylphosphine palladium (66mg, 0.057mmol), sodium carbonate successivelySolution (1mol/L, 0.5ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to chamberTemperature adds 90ml water washing, with carrene (3*80ml) extraction, saturated aqueous common salt for organic phase (80ml*2) washing,The organic phase anhydrous magnesium sulfate drying obtaining, filters, and reduced pressure concentration, obtains: (S)-and 4-[4-(2-hydroxyl-1-phenyl-ethamine)-Furans is [3,2-d] pyrimidine-6-yl also]-phenyl }-(4-methyl-piperazine-1-yl)-ketone (III-6) (95mg, yellow solid) productive rate: 35.8％。
MSm/z(ESI)：458[M+1]。
1HNMR(400Hz，DMSO-d6)：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, Lithium Aluminium Hydride (20.14mg, 0.53mmol) and anhydrous tetrahydro furan (5ml, 61.27mmol) are mixedStir, molten to the oxolane (10ml, 0.123mol) that drips compound III-6 (90mg, 0.19mmol) in reactant liquorLiquid, stirring at room temperature reaction 1 hour, is warming up to 55 DEG C of reactions until TLC monitoring raw material reaction is complete, under 0 DEG C of ice bath to insteadAnswer in liquid and add 20ml water, with ethyl acetate (40ml*2) extraction, then use saturated nacl aqueous solution (40ml*3) washing,Anhydrous sodium sulfate drying. Decompression steams after solvent with silica gel column chromatography purifies gained residue, obtains: (S)-2-{6-[4-(4-Methyl-piperazine-1-ylmethyl)-phenyl] also [3,2-d] pyrimidine-4-yl amino of-furans }-2-phenyl-ethanol (IV-6) (25mg, faint yellowSolid), productive rate: 28.7%.
MSm/z(ESI)：444[M+1]。
1HNMR(400Hz，DMSO-d6)：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
The first step:
Under room temperature by compound 2-(the bromo-furans of 6-[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 encircle-2-yl)-phenyl]-ketone (445mg,1.16mmol) be dissolved in 5mLN, in dinethylformamide, add successively tetra-triphenylphosphine palladium (50mg, 0.043mmol),Sodium carbonate liquor (1mol/L, 2mL), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally coldBut add 80mL water washing to room temperature, with carrene (3*80mL) extraction, saturated aqueous common salt for organic phase (80ml*2)Washing, the organic phase anhydrous magnesium sulfate drying obtaining, filtration, reduced pressure concentration, purifies gained with silica gel column chromatography residualThing, obtains: (S)-(4-cyclopropyl carbonyl-piperazine-1-yl)-also [3,2-d] pyrimidine-6-yl of 4-[4-(2-hydroxyl-1-phenyl-ethamine)-furans]-Phenyl }-ketone (III-7) (350mg, yellow solid), productive rate: 79%.
MSm/z(ESI)：512[M+1]。
1HNMR(400Hz，DMSO-d6)：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 by Lithium Aluminium Hydride (60mg, 1.578mmol) and 10mL anhydrous tetrahydro furan mix and blend, to reactant liquorThe 10mL tetrahydrofuran solution of middle dropping compound III-7 (290mg, 0.567mmol), stirring at room temperature reaction 1 hour,Be warming up to 55 DEG C of reactions until TLC monitoring raw material reaction is complete, in 0 DEG C of ice bath downhill reaction liquid, add 80ml water, use acetic acidEthyl ester (90ml*2) extraction, then use saturated nacl aqueous solution (60ml*3) washing, purifies gained with silica gel column chromatography residualStay thing, obtain: (S)-2-{6-[4-(4-encircles the third methyl-piperazine-1-methyl)-phenyl] also [3,2-d] pyrimidine-4-amino of-furans }-2-phenyl-Ethanol (IV-7) (75mg, white solid), productive rate: 27.4%.
MSm/z(ESI)：484[M+1]。
1HNMR(400Hz，DMSO-d6)：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: preparation compound III-8
The first step:
Under room temperature, will be dissolved in carrene (27ml, 0.422mol) to carboxyl phenyl boric acid pinacol ester (2.8g, 11.3mmol)And in DMF (9ml, 0.116mol), add 1-Boc-3-methyl piperazine (2.9g, 14.52mmol),Add successively 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (2.79g, 14.55mmol), N-hydroxy benzoTriazole (1.98g, 14.66mmol), triethylamine (2.5ml, 17.99mmol), stirring at room temperature reaction is until TLC monitoringRaw material reaction is complete, in reactant liquor, adds 30ml water, stir 30 minutes, and with carrene (100ml*3) extraction, thenWith saturated nacl aqueous solution (100ml*2) washing, organic phase anhydrous magnesium sulfate drying, filters, and reduced pressure concentration, obtains:Phenyl boric acid pinacol ester (4.1g, white solid), productive rate 85.4%.
MSm/z(ESI)：431[M+1]。
1HNMR(400Hz，DMSO-d6)：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 by compound 2-(the bromo-thiophene of 6-[3,2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (700mg, 2.0mmol) and upperThe phenyl boric acid pinacol ester (1290mg, 3.0mmol) of one step gained be dissolved in DMF (10ml,0.129mol), add successively tetra-triphenylphosphine palladium (115mg, 0.1mmol), sodium carbonate liquor (1mol/L, 2ml), nitrogenProtection, is heated to 80 DEG C until TLC monitoring raw material reaction is complete, and naturally cool to room temperature and add water (100ml*3) washing,With ethyl acetate (250ml*1) extraction, saturated aqueous common salt for organic phase (100ml*2) washing, the organic phase nothing obtainingWater magnesium sulfate is dry, filters, and reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (S)-4-(4-(4-(2-Hydroxyl-1-phenyl ethylamine)-thiophene [3,2-d] pyrimidine-6-yl) benzoyl)-3-methyl piperazine-1-carboxylic acid tert-butyl ester (III-8) (900mg, lightYellow solid), productive rate: 78%.
MSm/z(ESI)：574[M+1]。
1HNMR(400Hz，DMSO-d6)：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: preparation compound III-9
Under room temperature by (S)-4-(4-(4-(2-hydroxyl-1-phenyl ethylamine)-thiophene [3,2-d] pyrimidine-6-yl) benzoyl)-3-methyl piperazine-1-Carboxylic acid tert-butyl ester (III-8) (900mg, 1.57mmol) is dissolved in carrene (10ml, 0.156mol), adds trifluoroAcetic acid (2.4ml, 31.4mmol), is stirred to TLC monitoring raw material reaction complete under room temperature, reduced pressure concentration, uses unsaturated carbonateHydrogen sodium solution dilution neutralization, with dichloromethane extraction (50ml*3) saturated aqueous common salt for organic layer (50ml*3) washing, subtractsPress and concentrate, scrape large plate, obtain: (S)-(4-(4-(2-hydroxyl-1-phenyl ethylamine)-thiophene [3,2-d] pyrimidine-6-yl) phenyl) (2-methyl piperazinePiperazine-1-yl) ketone (III-9) (550mg, white solid), productive rate: 74%.
MSm/z(ESI)：474[M+1]。
1HNMR(400Hz，DMSO-d6)：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: prepare chemical combination materialization IV-8
Under room temperature, Lithium Aluminium Hydride (132mg, 3.479mmol) and anhydrous tetrahydro furan (30ml, 0.369mol) mixing are stirredMix, in reactant liquor, drip (S)-(4-(4-(2-hydroxyl-1-phenyl ethylamine)-thiophene [3,2-d] pyrimidine-6-yl) phenyl) (2-methyl piperazine-1-Base) oxolane (30ml, the 0.369mol) solution of ketone (III-9) (550mg, 116mmol), stirring at room temperature reaction 1Hour, be warming up to 50 DEG C of reactions until TLC monitoring raw material reaction is complete, naturally cool to room temperature, in reactant liquor, add 20mlWater, with ethyl acetate (100ml*3) extraction, then uses saturated nacl aqueous solution (100ml*2) washing, the organic phase obtainingFilter with anhydrous magnesium sulfate drying, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (S)-2-{6-[4-(2-Methyl-piperazine-1-methyl)-phenyl]-thiophene [3,2-d] pyrimidine-4-amino }-2-phenyl-ethanol (IV-8) (142mg, off-white color solid),Productive rate: 26.7%.
MSm/z(ESI)：460[M+1]。
1HNMR(400Hz，DMSO-d6)：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: prepare chemical combination materialization IV-9
Wherein, the preparation method of (4-benzyl-piperazine-1-yl)-nafoxidine-1-base-ketone-boric acid is with described in embodiment 7.
Under room temperature by compound 2-(the bromo-thiophene of 6-[3,2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (174mg, 0.497mmol) and(4-benzyl-piperazine-1-yl)-nafoxidine-1-base-ketone-boric acid (105mg, 0.331mmol) is dissolved in N, N-dimethyl methylAcid amides (5ml, 65mmol), adds tetra-triphenylphosphine palladium (38mg, 0.033mmol) successively, sodium carbonate liquor (1mol/L,1ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml waterWashing, with carrene (3*100ml) extraction, saturated aqueous common salt for organic phase (100ml*2) washing, what obtain is organicUse mutually anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains:(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%.
MSm/z(ESI)：543[M+1]。
1HNMR(400Hz，DMSO-d6)：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: prepare chemical combination materialization IV-10
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 by compound 2-(the bromo-thiophene of 6-[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) is dissolved in N, N-diformazanBase formamide (20ml, 0.65mol), adds tetra-triphenylphosphine palladium (40mg, 0.035mmol) successively, sodium carbonate liquor (1mol/L,3ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml waterWashing, with ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase obtainingWith anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (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)-firstKetone (IV-10) (28mg, white solid), productive rate: 13.8%.
MSm/z(ESI)：587[M+1]。
1HNMR(400Hz，DMSO-d6)：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: prepare 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 by compound 2-(the bromo-thiophene of 6-[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) is dissolved in DMF(20ml, 0.65mol), adds tetra-triphenylphosphine palladium (52mg, 0.045mmol) successively, sodium carbonate liquor (1mol/L, 3ml),Nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, and naturally cool to room temperature and add 100ml water washing,With ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase obtaining is with anhydrousDried over mgso, filters, and reduced pressure concentration is purified gained residue with silica gel column chromatography, obtains: (S)-(4-{4-[4-(2-hydroxylBase-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%.
MSm/z(ESI)：559[M+1]。
1HNMR(400Hz，DMSO-d6)：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: prepare chemical combination materialization IV-12
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 by compound 2-(the bromo-thiophene of 6-[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) is dissolved in DMF(10ml, 0.325mol), adds tetra-triphenylphosphine palladium (70mg, 0.0604mmol) successively, sodium carbonate liquor (1mol/L,3ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml waterWashing, with ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase obtainingWith anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (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, off-white color solid), productive rate: 7.5%.
MSm/z(ESI)：557[M+1]。
1HNMR(400Hz，DMSO-d6)：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: prepare chemical combination materialization IV-13
Wherein (4-benzyl-piperazine-1-yl)-NEP-1-base-ketone-boric acid preparation method is with described in embodiment 11.
Under room temperature by compound 2-(the bromo-thiophene of 6-[3,2-d] pyrimidine-4-yl amine)-2-phenyl 1-ethanol (181.8mg, 0.520mmol)(4-benzyl-piperazine-1-yl)-NEP-1-base-ketone-boric acid (125mg, 0.346mmol) is dissolved in N, N-diformazanBase formamide (20ml, 0.65mol), adds tetra-triphenylphosphine palladium (40mg, 0.035mmol) successively, sodium carbonate liquor (1mol/L,3ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml waterWashing, with ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase obtainingWith anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (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%.
MSm/z(ESI)：587[M+1]。
1HNMR(400Hz，DMSO-d6)：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: prepare chemical combination materialization IV-14
The first step:
N methyl piperazine (1.5g, 10mmol) is dissolved in 15ml carrene, under 0 DEG C of ice bath, adds N, N-bis-Isopropyl ethamine (1.65ml, 10mmol), will be dissolved in the triphosgene (950mg, 3.2mmol) in carrene (10ml)Slowly drip, drip process temperature and remain on 0 ± 3 DEG C, react 1 hour, under 0 DEG C of ice bath, add N-Boc piperazine (1.9g,10mmol) and DIPEA (1.65ml, 10mmol), stirring reaction under room temperature is until TLC monitoring raw material is anti-Should be complete, reduced pressure concentration, in carrene (30ml), adds trifluoroacetic acid (10ml, 0.135mol) by dissolving crude productStirring reaction under room temperature is until TLC monitoring raw material reaction is complete, and reduced pressure concentration, adds saturated sodium carbonate solution (50ml*3)Washing, with carrene (50ml*5) extraction, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains:N methyl piperazine base piperazine urea (2.3g, weak yellow liquid), productive rate: 50%.
MSm/z(ESI)：213[M+1]。
Second step:
By molten to N methyl piperazine base piperazine urea (2.3g, 10.85mmol) and 4-formyl phenyl boric acid (1.9g, 11.93mmol)Solution, in 20ml oxolane and 10ml methyl alcohol, adds acetum (1.2ml, 21.72mmol), stirring at room temperature reaction 1.5Hour, add sodium triacetoxy borohydride (5.8g, 27.12mmol), be warming up to 60 DEG C of stirring reactions until TLC monitoringRaw material reaction is complete, and reduced pressure concentration is purified gained residue with silica gel column chromatography, obtains: (4-benzyl-piperazine-1-yl)-N-Methylpiperazine-1-yl-ketone-boric acid (1.1g, white solid), productive rate: 50%, MSm/z (ESI): 347[M+1].
The 3rd step:
Under room temperature by compound 2-(the bromo-thiophene of 6-[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) is dissolved in N, N-dimethyl formylAmine (20ml, 0.65mol), adds tetra-triphenylphosphine palladium (58mg, 0.05mmol) successively, sodium carbonate liquor (1mol/L,3ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml waterWashing, with ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase obtainingWith anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (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%.
MSm/z(ESI)：572[M+1]。
1HNMR(400Hz，DMSO-d6)：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: prepare chemical combination materialization IV-15
The first step:
N-Boc piperazine (5g, 26.8mmol) and 4-formyl phenyl boric acid (2.68g, 17.9mmol) are dissolved in to 15ml tetra-In hydrogen furans and 15ml methyl alcohol, add acetum (6ml, 43.44mmol), stirring at room temperature reaction 1.5 hours, adds threeAcetoxyl group sodium borohydride (9.49g, 44.7mmol), is warming up to 60 DEG C of stirring reactions until TLC monitoring raw material reaction is complete,Reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: 4-benzyl-piperazine-1-carboxylic acid tert-butyl ester-boric acid 4.98g,White solid), productive rate: 87.4%, MSm/z (ESI): 321[M+1], be directly used in next step reaction.
Second step:
Under room temperature by compound 2-(the bromo-thiophene of 6-[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 DMF (30ml,0.975mol), add successively tetra-triphenylphosphine palladium (323mg, 0.28mmol), sodium carbonate liquor (1mol/L, 5ml), nitrogenProtection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml water washing, uses secondAcetoacetic ester (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase anhydrous slufuric acid obtainingMagnesium is dry, filters, and reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: 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), producesRate: 70.6%, MSm/z (ESI): 546[M+1].
The 3rd step:
By 4-(4-{4-[4-(and 2-hydroxyl-1-phenyl-ethylamino-thieno [3,2-d]-benzyl }-piperazine-1-carbonyl-piperazine-1-carboxylic acidThe tert-butyl ester (1.09g, 2mmol) is dissolved in oxolane, adds trifluoroacetic acid (3ml, 40mmol), stirring at room temperature 2Hour, by the extraction of 400ml ethyl acetate, saturated common salt water washing (100ml*2), the organic phase nothing obtaining for organic phaseWater magnesium sulfate is dry, filters, and reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (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), producesRate: 78.6%.
MSm/z(ESI)：446[M+1]。
1HNMR(400Hz，DMSO-d6)：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: prepare chemical combination materialization IV-16
The first step:
Under room temperature by 1-cyclopropane carbonyl piperazine (2.37g, 15.37mmol) with to formyl phenyl boric acid (1.92g, 12.81mmol)Be dissolved in (40ml) in carrene, stirring at room temperature 1 hour, then add inwards sodium cyanoborohydride (1.77g, 28.18mmol),Stirring at room temperature reacts completely to TLC monitoring, and the 20ml that adds water with dichloromethane extraction, then uses saturated common salt water washing 2 times,Organic phase anhydrous magnesium sulfate drying, reduced pressure concentration, obtains: (4-benzyl boric acid-piperazine-1-yl)-cyclopropyl-ketone, (1.6g,White solid), productive rate: 43.4%, be directly used in next step reaction.
Second step:
Wherein the bromo-4-chloro-2-methyl-thiophene of 6-[3,2-d] pyrimidine can referenced patent WO2009/007421 andMethod preparation described in WO2008/058285.
Under room temperature by bromo-6-4-chloro-2-methyl-thiophene [3,2-d] pyrimidine (830mg, 3.15mmol) and L-benzene glycinol (648mg,4.725mmol) be dissolved in (10ml) in DMF, drip triethylamine (1.1ml, 7.875mol), heatingTo 55 DEG C, react 24 hours, naturally cooling, add 40ml frozen water, decompress filter, decompression after the making beating of 10ml water for filter cakeSuction filtration, then pull an oar with 10ml n-hexane, decompress filter, obtains: 2-(the bromo-2-methyl-thiophene of 6-[3,2-d] pyrimidine-4-amino)-2-Phenyl-ethanol (780mg, faint yellow solid), productive rate: 71%.
MSm/z(ESI)：365[M+1]。
1HNMR(400Hz，DMSO-d6)：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 by compound 2-(the bromo-2-methyl-thiophene of 6-[3,2-d] pyrimidine-4-amino)-2-phenyl-ethanol (364mg,1.0mmol) be dissolved in N, N-dimethyl with (4-benzyl boric acid-piperazine-1-yl)-cyclopropyl-ketone (576mg, 2.0mmol)Formamide (10ml, 0.325mol), adds tetra-triphenylphosphine palladium (70mg, 0.0604mmol) successively, sodium carbonate liquor (1mol/L,2ml), nitrogen protection, is heated to 85 DEG C until TLC monitoring raw material reaction is complete, naturally cools to room temperature and adds 100ml waterWashing, with ethyl acetate (100ml*2) extraction, saturated aqueous common salt for organic phase (50ml*3) washing, the organic phase obtainingWith anhydrous magnesium sulfate drying, filter, reduced pressure concentration, purifies gained residue with silica gel column chromatography, obtains: (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%.
MSm/z(ESI)：528[M+1]。
1HNMR(400Hz，DMSO-d6)：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) 4: 1 use of enzyme reaction substrate Poly (Glu, Tyr) is without PBS (10mM sodium phosphate buffer, the 150mmol/L of potassium ionNaCl, pH=7.2～7.4) be diluted to 20 μ g/ml, 125 μ l/ hole coated elisa plates, put 37 DEG C of reactions 12～16 hours, discard holeMiddle liquid, washes plate, washes plate three times with the T-PBS in 200 μ l/ holes (containing the PBS without potassium ion of 0.1%Tween-20), each5 minutes; Dry ELISA Plate 1～2 hour in 37 DEG C of baking ovens.
(2) every hole adds with reaction buffer (50mmol/LHEPESpH7.4,50mmol/LMgCl2，0.5mmol/LMnCl2，0.2mmol/LNa3VO4, 1mmol/LDTT) dilution ATP solution 50 μ L, final concentration 5 μ mol/L. Every holeIn add the compound solution (1%DMSO dissolve, final concentration is 10 μ mol/L) of 1 μ l, then add 50 μ l reaction bufferingThe c-Met tyrosine-kinase zymoprotein of liquid dilution; Put 37 DEG C of shaking tables (100rpm) reaction 1 hour; Each experiment is established without ATP coupleAccording to two holes, hole and corresponding DMSO solvent control hole (negative control hole); Discard liquid in hole, T-PBS washes plate three times.
(3) add antibody PY99100 μ l/ hole (the T-PBS dilution containing BSA5mg/ml for antibody, concentration is 0.4 μ g/ml),37 DEG C of shaking tables react 0.5 hour; Discard liquid in hole, T-PBS washes plate three times.
(4) add the sheep anti mouse two of horseradish peroxidase-labeled to resist the 100 μ l/ holes (T-PBS containing BSA5mg/ml for antibodyDilution, concentration is 0.5 μ g/ml), 37 DEG C of shaking tables react 0.5 hour, discard liquid in 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%H2O20.1M citric acid-citric acidSodium buffer solution (pH=5.4) dilution), 25 DEG C of lucifuges are reacted 1～10 minute; (need be with ultrasonic when OPD dissolves, nitrite ion need now be joinedNow use).
(6) add 2mol/LH2SO450 μ l/ hole stopped reactions, read with the wavelengthtunable orifice plate ELIASA VERSAmax that declinesNumber, 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 IC50Evaluation experimental
Clearly have EGFR or VEGFR enzyme that above-mentioned screening is obtained live that (compound is 10 for inhibiting compound-5MTo the inhibiting rate > 50% of receptor tyrosine kinase EGFR or VEGFR) be made into gradient concentration, carry out IC50Evaluate. With fourParametric method is calculated the IC of the horizontal CKIs EGFR-TK of each compound molecule50Value, the results are shown in Table shown in 1.
Table 1 embodiment compound is lived and is suppressed experimental result the enzyme of EGFR-TK EGFR and VEGFR
From table 1: in Thienopyrimidine of the present invention and furans miazines derivative, majority of compounds is to epidermisIt is active that growth factor receptors EGFR has obvious inhibition, and part of compounds has good to angiogenesis factor acceptor VEGFRGood inhibitory action, also has part of compounds and to EGF Receptor EGFR and angiogenesis factor acceptor VEGFRAll there is good inhibitory action; And there is the also compound activity of [3,2-d] pyrimidine skeleton and be obviously better than having also [2,3-d] pyrimidineThe compound activity of skeleton; The active order of quality of substituting group on piperazine ring roughly can be arranged as: cyclopropyl > methyl > 2-Ethoxy > ethyl > urea; There is the also EGFR of the majority of compounds of [3,2-d] pyrimidine skeleton and suppress activity and control drugGefitinib Gefitinib quite or better, especially compound III-9 and IV-3, its half-inhibition concentration IC50Value is respectively193nM and 118nM, better than positive control medicine Gefitinib, be worth further exploitation; Compound III-2, III-3, III-8, IV-1, IV-2, IV-3, IV-11 also has obvious VEGFR and suppresses active, its half-inhibition concentration IC50Lower than 1Micromole, has prospect in medicine.

Claims (11)

1. Thienopyrimidine and a furans miazines derivative, is characterized in that, is to have general formula I I:
Compound, in general formula: Ar1、Ar2Be phenyl, X is sulphur, and Z is nitrogen, R be hydrogen,Containing the alkyl of 1～6 carbon atom, containing any one in alkene acyl group, the amide groups of 2～6 carbon atoms; Or,To there is general formula IV:
Compound, in general formula: Ar1、Ar2Be phenyl, X is oxygen or sulphur, and Z is nitrogen, and R isHydrogen, containing the alkyl of 1～6 carbon atom, containing any one in cycloalkyl acyl group, the amide groups of 3～6 carbon atoms.
2. the Thienopyrimidine that the general formula I I described in a claim 1 represents and the preparation side of furans miazines derivativeMethod, is characterized in that, comprise the steps 5. or step 2. and 5. step 4. and 5. or step 2. and 4. and 5.:
3. the Thienopyrimidine that the general formula IV described in a claim 1 represents and the preparation side of furans miazines derivativeMethod, is characterized in that, comprise the steps 8. or step 4. and 8. step 6. and 8. or step 4. and 6. and 8.:
4. an application rights requires the Thienopyrimidine described in 1 and furans miazines derivative or described derivativeAny one in dynamic isomer, racemic modification, enantiomter, diastereoisomer, pharmaceutically acceptable salt orTyrosine kinase inhibitor prepared by several mixtures.
5. tyrosine kinase inhibitor claimed in claim 4 refers to EGFR and/or VEGFR inhibitor.
6. EGFR claimed in claim 5 and/or VEGFR inhibitor are at preparation prevention or treatment and epidermal growth factor receptorApplication in the medicine of body EGFR and/or Angiogenesis factor receptors VEGFR relevant disease.
7. EGFR claimed in claim 5 and/or VEGFR inhibitor are at preparation prevention or treatment and epidermal growth factor receptorAbnormal cell proliferation that body EGFR and/or Angiogenesis factor receptors VEGFR are relevant, metamorphosis, hypoerkinesia,Application in the medicine of angiogenesis and metastases disease.
8. EGFR claimed in claim 5 and/or VEGFR inhibitor are at preparation prevention or treatment and epidermal growth factor receptorApplication in the medicine of the growth and metastasis of tumours that body EGFR and/or Angiogenesis factor receptors VEGFR are relevant.
9. the dynamic isomer with following compound or described compound, racemic modification, enantiomter, non-mapping are differentThe mixture of any one or a few in structure body, pharmaceutically acceptable salt be active fraction preparation EGFR and/orVEGFR inhibitor:
10. the pharmaceutically acceptable salt described in claim 4 or 9, refer in inorganic acid salt or acylate arbitrarilyOne or more.
Pharmaceutically acceptable salt described in 11. claims 4 or 9, refer to hydrochloride, hydrobromate, nitrate,Sulfate, phosphate, formates, acetate, propionate, benzoate, maleate, fumarate, succinate,Any one in tartrate, citrate, metilsulfate, ethyl sulfonate, benzene sulfonate, tosilateOr several.
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Families Citing this family (41)

* Cited by examiner, † Cited by third party
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US11013741B1 (en) 2018-04-05 2021-05-25 Sumitomo Dainippon Pharma Oncology, Inc. AXL kinase inhibitors and use of the same
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1280580A (en) * 1997-11-11 2001-01-17 辉瑞产品公司 Thienopyrimidine and thienopyridine derivatives useful as anti-cancer agents
WO2003022852A2 (en) * 2001-09-11 2003-03-20 Smithkline Beecham Corporation Furo-and thienopyrimidine derivatives as angiogenesis inhibitors
CN1509291A (en) * 2001-05-14 2004-06-30 ��˹��ŵ�� Oxazolo-and-furopyrimidines and their use in medicaments against tumors
WO2006004658A2 (en) * 2004-06-29 2006-01-12 Amgen Inc. Furanopyrimidines
WO2010054285A2 (en) * 2008-11-10 2010-05-14 National Health Research Institutes Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors
WO2010062038A2 (en) * 2008-11-27 2010-06-03 한국과학기술연구원 Tyrosine kinase inhibitor compound, isomer thereof or pharmaceutically allowable salt thereof, and pharmaceutical composition containing the same

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1280580A (en) * 1997-11-11 2001-01-17 辉瑞产品公司 Thienopyrimidine and thienopyridine derivatives useful as anti-cancer agents
CN1509291A (en) * 2001-05-14 2004-06-30 ��˹��ŵ�� Oxazolo-and-furopyrimidines and their use in medicaments against tumors
WO2003022852A2 (en) * 2001-09-11 2003-03-20 Smithkline Beecham Corporation Furo-and thienopyrimidine derivatives as angiogenesis inhibitors
WO2006004658A2 (en) * 2004-06-29 2006-01-12 Amgen Inc. Furanopyrimidines
WO2010054285A2 (en) * 2008-11-10 2010-05-14 National Health Research Institutes Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors
WO2010062038A2 (en) * 2008-11-27 2010-06-03 한국과학기술연구원 Tyrosine kinase inhibitor compound, isomer thereof or pharmaceutically allowable salt thereof, and pharmaceutical composition containing the same

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