CN103360407B - A kind of Thienopyrimidine analog derivative, its preparation method and in application pharmaceutically - Google Patents
A kind of Thienopyrimidine analog derivative, its preparation method and in application pharmaceutically Download PDFInfo
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- 0 C*1CC(CN(C2)CC(I)[U]C2I)CC1 Chemical compound C*1CC(CN(C2)CC(I)[U]C2I)CC1 0.000 description 11
- RFUHDYFJGHCVME-UHFFFAOYSA-N C=C(C(c1ccc(CN(CC2)CCS2(=N)=O)nc1)=C1)c2c1ncnc2NCc1ccccc1 Chemical compound C=C(C(c1ccc(CN(CC2)CCS2(=N)=O)nc1)=C1)c2c1ncnc2NCc1ccccc1 RFUHDYFJGHCVME-UHFFFAOYSA-N 0.000 description 1
- VRSSNZKEQVGCKR-BRUPJXTFSA-N CC(C)C(N1CCC(Cc(nc2)ccc2-c2cc(N=C)c(C(N(C)[C@H](CO)c3ccccc3)=N)[s]2)CCCC1)=C Chemical compound CC(C)C(N1CCC(Cc(nc2)ccc2-c2cc(N=C)c(C(N(C)[C@H](CO)c3ccccc3)=N)[s]2)CCCC1)=C VRSSNZKEQVGCKR-BRUPJXTFSA-N 0.000 description 1
- KSTFGONYLMJMGB-UHFFFAOYSA-N CC1(C)OB(B2[U]C(C)(C)C(C)(C)O2)OC1(C)C Chemical compound CC1(C)OB(B2[U]C(C)(C)C(C)(C)O2)OC1(C)C KSTFGONYLMJMGB-UHFFFAOYSA-N 0.000 description 1
- WGCYRFWNGRMRJA-UHFFFAOYSA-N CCN1CCNCC1 Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- OPWDOUVOKQLQST-YUMQZZPRSA-N CC[C@H]([C@@H](C)CNC=N)C=N Chemical compound CC[C@H]([C@@H](C)CNC=N)C=N OPWDOUVOKQLQST-YUMQZZPRSA-N 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N CCc1ccccc1 Chemical compound CCc1ccccc1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- XCSVWHNZINSGJT-UHFFFAOYSA-N CN(CC1)CCN1O Chemical compound CN(CC1)CCN1O XCSVWHNZINSGJT-UHFFFAOYSA-N 0.000 description 1
- UNZVPFYFWJEQJX-UHFFFAOYSA-N CN1CC[IH]CC1 Chemical compound CN1CC[IH]CC1 UNZVPFYFWJEQJX-UHFFFAOYSA-N 0.000 description 1
- LLQBISLCBNUUBO-UHFFFAOYSA-N CNCCCc(nc1)ccc1-c1cc2ncnc(NC(CO)C3C=CC=CC3)c2[s]1 Chemical compound CNCCCc(nc1)ccc1-c1cc2ncnc(NC(CO)C3C=CC=CC3)c2[s]1 LLQBISLCBNUUBO-UHFFFAOYSA-N 0.000 description 1
- DWBOYSSIXWZMDX-UHFFFAOYSA-N C[BrH]c1ccc(C(O)=O)nc1 Chemical compound C[BrH]c1ccc(C(O)=O)nc1 DWBOYSSIXWZMDX-UHFFFAOYSA-N 0.000 description 1
- WXFXYLMXXCSPAU-GFCCVEGCSA-N Cc1ccc([C@@H](CO)Nc2ncnc3c2[s]c(Br)c3)cc1 Chemical compound Cc1ccc([C@@H](CO)Nc2ncnc3c2[s]c(Br)c3)cc1 WXFXYLMXXCSPAU-GFCCVEGCSA-N 0.000 description 1
- IJXJGQCXFSSHNL-UHFFFAOYSA-N NC(CO)c1ccccc1 Chemical compound NC(CO)c1ccccc1 IJXJGQCXFSSHNL-UHFFFAOYSA-N 0.000 description 1
- KFLGIWROPQWBLV-BRFYHDHCSA-N N[C@H](CO)C1C=CC=CC1 Chemical compound N[C@H](CO)C1C=CC=CC1 KFLGIWROPQWBLV-BRFYHDHCSA-N 0.000 description 1
Abstract
The invention discloses a kind of Thienopyrimidine analog derivative, its preparation method and in application pharmaceutically。Described derivant is the compound with formula I or formula II or general formula III:In above-mentioned formula: Ar is phenyl, the phenyl of halogen substiuted, C1-6The phenyl of alkyl replacement, xenyl, the xenyl of halogen substiuted, naphthyl, pyridine radicals, thienyl, the thienyl of halogen substiuted, C1-3The thienyl of alkyl replacement, furyl, the furyl of halogen substiuted, C1-3Alkyl replace furyl in any one;A, D, E respectively carbon atom or nitrogen-atoms, but be carbon atom during A, D, E difference;R is R1——NH——、
Description
Technical field
The present invention relates to Thienopyrimidine analog derivative and its preparation method and application, specifically, relate to a kind of there is EGF-R ELISA EGFR and/or the Thienopyrimidine analog derivative of Angiogenesis factor receptors VEGFR inhibitory activity, its preparation method and in application pharmaceutically, belong to field of pharmaceutical chemistry technology。
Background technology
Tumor is one of most serious disease threatening human health, and its treatment mainly includes radiotherapy, chemotherapy and operative treatment。Recently as the development of cytobiology and tumor pharmacology, the chemotherapy of tumor there occurs huge change。Traditional chemotherapeutic agent owing to non-specifically blocking cell division thus also causing Normal cell death while killing tumor cell and being abandoned gradually, simultaneously, in tumor cell, the key node albumen in the signal path of abnormal activation is as target spot, it has been found that efficiently, the micromolecular inhibitor of low toxicity, high specificity become the important directions of current antitumor drug research and development。The receptor tyrosine kinase (RTK) that unconventionality expression activates in tumor has become the focus of antitumor drug research owing to all playing pivotal role at links such as tumor development, Invasion and Metastasis, chemoresistant。
EGF-R ELISA (EGFR, epidermalgrowthfactorreceptor, also known as HER1 or cerbB1) expresses tyrosine kinase HER family member the most widely in human cancer。EGFR structure includes three regions: extracellular region, cross-film district and intracellular region;The N-terminal of extracellular region is made up of 622 aminoacid, has 2 that form ligand binding domain rich in cysteine section;Cross-film district is a single α spiral;Intracellular region includes kinases district and has the carboxy-terminal afterbody of many Tyr phosphorylation sites。Tyrosine kinase (RTK) is that the γ phosphate transfection of ATP is transported to tyrosine residue, and after being combined with part, EGFR occurs homology or heterodimer to make TK region form compact siro spinning technology。Mediate Tyr phosphorylation site at carboxy-terminal afterbody RTK and carry out phosphorylation, create enzyme and couple the binding site (Y992, Y1068, Y1086, Y1148 and Y11730) of sub-albumen, it is thus possible to start Cellular Signaling Transduction Mediated reaction。The cell effect that the conduction formation of these signals is different, including propagation, differentiation, adhesion and vascularization, transfer and suppression apoptosis。
Research shows, EGFR has expression in nonsmall-cell lung cancer, carcinoma of prostate, breast carcinoma, colorectal cancer, head and neck cancer, gastric cancer, ovarian cancer and cancer of pancreas, and EGFR activation causes sophisticated signal conduction reaction。In different types of solid tumor, EGFR has propagation and overexpression, causes that downstream signal conduction is out of control and causes the formation of various tumor。In EGFR, the sudden change of ATP-binding site affects the RTK activity of receptor, and the formation of interference tumorigenesis signal, meanwhile, EGFR is also closely related with the progress of tumor and poor prognosis。
Due to EGFR and VEGFR unique effect in tumorigenesis, its monoclonal antibody and micromolecular inhibitor have become as the focus of targeting antineoplastic medicine thing research and development。At present, having had the inhibitor of several targeting EGFR or VEGFR to list, nearly 20 drug candidates are in each development clinical。Wherein, gefitinib and erlotinib represent the micromolecular inhibitor listing targeting EGFR earlier。Gefitinib (Gefitinib, also known as ZD1839 or Iressa) is used for advanced Non-small cell lung (nonsmallcelllungcancer, NSCLC) as three line single therapy medicines。The two wires of the advanced NSCLC that erlotinib (Erlotinib, also known as OSI774 or Tarceva) is failed to respond to any medical treatment as standard scheme or three line medicines。
But, along with the clinical practice of these medicines, it has been found that and not all high expressed EGFR patient can be effective to these medicines, gefitinib (Gefitinib) is initially had the tumor of therapeutic response progression of disease occur again after treatment some months by some。These are it is shown that currently used EGFR inhibitor antitumor drug has natural or secondary resistance phenomenon, and therefore, Development of Novel has low drug resistance and maybe can alleviate the medicine of early stage inhibitor drug resistance and have become as the new development direction of tyrosine kinase inhibitor。
Summary of the invention
The problems referred to above existing for prior art, it is an object of the invention to provide and a kind of have EGF-R ELISA EGFR and/or the Thienopyrimidine analog derivative of Angiogenesis factor receptors VEGFR inhibitory activity, its preparation method and in application pharmaceutically。
Thienopyrimidine analog derivative provided by the invention, is the compound with formula I or formula II or general formula III:
In above-mentioned formula:
Ar is phenyl, the phenyl of halogen substiuted, C1-6The phenyl of alkyl replacement, xenyl, the xenyl of halogen substiuted, naphthyl, pyridine radicals, thienyl, the thienyl of halogen substiuted, C1-3The thienyl of alkyl replacement, furyl, the furyl of halogen substiuted, C1-3Alkyl replace furyl in any one;
A, D, E respectively carbon atom or nitrogen-atoms, but be carbon atom during A, D, E difference;
R is R1——NH——、 Wherein: R1For hydrogen, C1~C6Alkyl, C3~C6Cycloalkyl, C1~C6The acyl group of alkyl replacement, C3~C6The acyl group of cycloalkyl substituted, C1~C6The ester group of alkyl replacement or C3~C6The ester group of cycloalkyl substituted;R2For hydrogen, C1~C6Alkyl, C3~C6The C that cycloalkyl, hydroxyl replace1~C6Alkyl, C1~C6The acyl group of alkyl replacement, C1~C6The acyl group of alkane hydroxyl replacement, C3~C6The acyl group of cycloalkyl substituted, C1~C6The ester group of alkyl replacement, C3~C6The ester group of cycloalkyl substituted, sulfonyl or C1~C6The sulfonyl that alkyl replaces;R3、R4、R5Respectively hydrogen, C1~C6Alkyl, C3~C6The C that cycloalkyl or hydroxyl replace1~C6Alkyl。
As a kind of preferred version, described Thienopyrimidine analog derivative, is the compound with formula I or formula II or general formula III, and in formula: Ar is phenyl;A, D, E respectively carbon atom or nitrogen-atoms, but be carbon atom during A, D, E difference;R is R1——NH——、 Wherein: R1For hydrogen or C1~C6The ester group that alkyl replaces;R2For hydrogen, C1~C6The C that alkyl, hydroxyl replace1~C6Alkyl, C1~C6The acyl group of alkyl replacement, C1~C6The acyl group of alkane hydroxyl replacement, C3~C6The acyl group of cycloalkyl substituted or C1~C6The sulfonyl that alkyl replaces;R3、R4、R5Respectively hydrogen or C1~C6Alkyl。
As it is preferred that scheme, described Thienopyrimidine analog derivative, it is the compound with following chemical structural formula:
The preparation method of the Thienopyrimidine analog derivative that a kind of formula I of the present invention represents, including the step in following route 3. or step 1. and 3. step 2. and 3. or step 1.~3.:
The definition of Ar, A, D, E and R in described route is all as described above。
The preparation method of the Thienopyrimidine analog derivative that a kind of formula II of the present invention represents, including the step in following route 5. or step 2. and 5. step 4. and 5. or step 2., 4. and 5.:
The definition of Ar, A, D, E and R in described route is all as described above。
The preparation method of the Thienopyrimidine analog derivative that a kind of general formula III of the present invention represents, including the step in following route 6. or step 2. and 6.:
The definition of Ar, A, D, E and R in described route is all as described above。
As a kind of preferred version, described step 3., step be 5. 6. all the Suzuki coupling reaction carried out under Pd-catalyst action with step。
As it is preferred that scheme, described Pd-catalyst is double; two (triphenylphosphine) palladium of dichloro, tetrakis triphenylphosphine palladium or [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride。
The preparation method of the Thienopyrimidine analog derivative that another kind of formula II of the present invention represents, is that the Thienopyrimidine analog derivative represented by formula I carries out reduction of amide reaction and obtains。
As a kind of preferred version, the reducing agent carrying out reduction of amide reaction is LiAlH4, red aluminum (Red-Al) or borane complex。
Because research shows that Thienopyrimidine analog derivative of the present invention has EGF-R ELISA (EGFR) and/or the inhibitory activity of Angiogenesis factor receptors (VEGFR), therefore, any one or a few mixture in Thienopyrimidine analog derivative of the present invention or the tautomer of described derivant, racemic modification, enantiomer, diastereomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, can be applicable to prepare tyrosine kinase inhibitor, be particularly applicable to preparation EGFR and/or VEGFR inhibitor。
Meanwhile, described inhibitor can be applicable to the medicine of preparation prevention or treatment and EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR relevant disease;Specifically, can be applicable to the medicine of preparation prevents or treatment is relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR abnormal cell proliferation, metamorphosis, hypoerkinesia, angiogenesis and neoplasm metastasis disease。
It addition, described inhibitor can be applicable to preparation treatment or prevents the medicine of the growth and metastasis of tumours relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR。
Furtherly, compound shown in the preferred table of the active component of inhibitor described in this patent 1 or any one or a few the mixture in the tautomer of shown compound, racemic modification, enantiomer, diastereomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate:
Table 1
Described pharmaceutically acceptable salt includes without limitation: inorganic acid salt, example hydrochloric acid salt, hydrobromate, nitrate, sulfate, phosphate etc.;Acylate, such as formates, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate etc.;Alkylsulfonate, such as metilsulfate, ethyl sulfonate etc.;Arylsulphonate, such as benzene sulfonate, tosilate etc.。
Described pharmaceutically acceptable solvate includes the solvate of described compound and water, ethanol, isopropanol, ether, acetone etc. without limitation。
Compared with prior art, the novel structure of Thienopyrimidine analog derivative provided by the invention, there is obvious EGFR inhibitory activity, and VEGFR is also had obvious inhibitory activity by part of compounds, it is expected exploitation for tyrosine kinase EGFR or/and VEGFR inhibitor, for preparing prevention or treating the abnormal cell proliferation relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR, the relevant disease such as metamorphosis and hypoerkinesia and the medicine with angiogenesis or neoplasm metastasis relevant disease, especially it is expected for preparing treatment or preventing the medicine of the growth and metastasis of tumours relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR, for Development of Novel have low drug resistance maybe can alleviate early stage inhibitor drug resistance tyrosine kinase inhibitor medicine provide new developmental direction and approach, have broad application prospects and medical value。
Detailed description of the invention
The present invention is expanded on further below in conjunction with specific embodiment。Following embodiment is interpreted as being merely to illustrate the present invention rather than for limiting the scope of the invention。
The structure of compound obtained in following embodiment be by nuclear magnetic resonance, NMR (1HNMR) determined with mass spectrum (MS)。
1HNMR displacement (δ) provides with the unit of 1/1000000th (ppm)。1The mensuration of HNMR is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and the solvent of mensuration is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), inside it being designated as tetramethylsilane (TMS), chemical shift is to provide using 10-6 as unit。
The mensuration of MS is with FINNIGANLCQAd (ESI) mass spectrograph (manufacturer: Therm, model: FinniganLCQadvantageMAX)。
IC50The mensuration of value is with NovoStar microplate reader (BMG company of Germany)。
Thin layer silica gel is to use Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate。
Silica gel column chromatography is use Yantai Huanghai Sea silica gel 200~300 order silica gel is carrier。
HPLC test is to use Agilent 1200DAD high pressure liquid chromatograph (SunfireC18150 × 4.6mm chromatographic column) and Waters2695-2996 high pressure liquid chromatograph (GiminiC18150 × 4.6mm chromatographic column)。
Microwave reaction is to use CEMDiscover-S908860 type microwave reactor。
It addition, without specified otherwise in following example, reaction carries out all under nitrogen atmosphere。
Argon atmospher refers to that reaction bulb connects the argon balloon of an about 1L volume。
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume。
Without specified otherwise in following example, the solution in reaction refers to aqueous solution。
Embodiment 1: the preparation of compound I-1
The first step:
Under room temperature, by 5-bromo-2-pyridyl formic acid (2.02g, 10mmol) with N methyl piperazine (1g, 10mmol) it is dissolved in dichloromethane (50ml), then I-hydroxybenzotriazole (2.03g it is sequentially added into, 15mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (2.88g, 15mmol) and N, N-diisopropylethylamine (3.88g, 30mmol), it is stirred at room temperature 24 hours, water (200ml) is added in reactant liquor, dichloromethane (100ml*3) extracts, again with saturated sodium-chloride (100ml*3) washing, organic facies anhydrous sodium sulfate dries, filter, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (5-bromo-pyridine-2-base)-(4-thyl-piperazin-1-base)-ketone (1.7g, orange red grease), yield: 60%;It is directly used in next step reaction。
Second step:
Under room temperature, by (5-bromo-pyridine-2-base)-(4-thyl-piperazin-1-base)-ketone (400mg, 1.41mmol) with connection boric acid pinacol ester (393mg, 1.55mmol) it is dissolved in dioxane (10ml), it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (57mg, 0.07mmol), potassium acetate (414mg, 4.23mmol), nitrogen is replaced, heat to 120 DEG C of reactions 24 hours, reactant liquor concentrating under reduced pressure, residue is dissolved in methanol, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (300mg, brown solid), yield: 64%;It is directly used in next step reaction。
3rd step:
By corresponding pyridine substituted boracic acid (300mg under room temperature, 1.2mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (220mg, 0.63mmol) it is dissolved in N, in dinethylformamide (8ml), it is subsequently adding tetrakis triphenylphosphine palladium (73mg, 0.063mmol), sodium carbonate liquor (1N, 2.0ml), 85 DEG C are reacted 2 hours, cool down addition 200ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-{ 5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-(4-thyl-piperazin-1-base)-ketone (260mg, brown solid), yield 87.5%。
MSm/z (ESI): 475.6 [M+1];
1HNMR (400Hz, DMSO-d6): 9.10 (s, 1H), 8.39 (m, 3H), 8.04 (s, 1H), 7.75 (d, 1H), 7.46 (m, 2H), 7.30 (m, 2H), 7.24 (m, 1H), 5.48 (m, 1H), 5.03 (m, 1H), 3.80 (m.2H), 3.69 (m, 4H), 2.47 (m, 4H), 2.19 (s, 3H)。
Embodiment 2: the preparation of compound I-2
The first step:
Under room temperature, by 5-bromo-2-pyridyl formic acid (303mg, 1.5mmol) with NEP (172mg, 1.5mmol) it is dissolved in dichloromethane (15ml), then I-hydroxybenzotriazole (244mg it is sequentially added into, 1.8mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (346mg, 1.8mmol) and N, N-diisopropylethylamine (582mg, 4.5mmol), it is stirred at room temperature 24 hours, water (100ml) is added in reactant liquor, dichloromethane (50ml*3) extracts, again with saturated sodium-chloride (100ml*2) washing, organic facies anhydrous sodium sulfate dries, filter, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (5-bromo-pyridine-2-base)-(4-ethyl-piperazin-1-base)-ketone (400mg, yellow oil), yield: 89%;It is directly used in next step reaction。
Second step:
Under room temperature, by (5-bromo-pyridine-2-base)-(4-ethyl-piperazin-1-base)-ketone (400mg, 1.34mmol) with connection boric acid pinacol ester (381mg, 1.5mmol) it is dissolved in dioxane, it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (33mg, 0.04mmol), potassium acetate (395mg, 4.02mmol), nitrogen is replaced, heat to 120 DEG C of reactions 24 hours, reactant liquor concentrating under reduced pressure, residue is dissolved in methanol, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (313mg, brown solid), yield: 67%;It is directly used in next step reaction。
3rd step:
By corresponding pyridine substituted boracic acid (313mg under room temperature, 1.19mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (378mg, 1.08mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding tetrakis triphenylphosphine palladium (124.8mg, 0.108mmol), sodium carbonate liquor (1N, 3.0ml), nitrogen is replaced, 85 DEG C are reacted 2 hours, cool down addition 200ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-{ 5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-(4-ethyl-piperazin-1-base)-ketone (454mg, brown solid), yield 86%。
MSm/z (ESI): 489.6 [M+1];
1HNMR (400Hz, DMSO-d6): 9.10 (s, 1H), 8.39 (m, 3H), 8.04 (s, 1H), 7.76 (d, 1H), 7.46 (m, 2H), 7.30 (m, 2H), 7.24 (m, 1H), 5.47 (m, 1H), 5.02 (m, 1H), 3.81 (m.2H), 3.65 (m, 4H), 2.43 (m, 4H), 2.35 (m, 2H), 1.01 (t, 3H)。
Embodiment 3: the preparation of compound I-3
The first step:
Under room temperature, by 5-bromo-2-pyridyl formic acid (2.02g, 10mmol) with NEP (1.30g, 10mmol) it is dissolved in dichloromethane (50ml), then I-hydroxybenzotriazole (2.03g it is sequentially added into, 15mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (2.88g, 15mmol) and N, N-diisopropylethylamine (3.88g, 30mmol), it is stirred at room temperature 24 hours, water (200ml) is added in reactant liquor, dichloromethane (100ml*3) extracts, again with saturated sodium-chloride (100ml*2) washing, organic facies anhydrous sodium sulfate dries, filter, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (5-bromo-pyridine-2-base)-(4-ethoxy-piperazine-1-base)-ketone (2.2g, white solid), yield: 88%。
1HNMR (400Hz, CDCl3): 8.64 (s, 1H), 7.94 (m, 1H), 7.59 (m, 1H), 3.83 (m, 2H), 3.66 (m, 4H), 2.63 (m, 6H)。
Second step:
Under room temperature, by (5-bromo-pyridine-2-base)-(4-ethoxy-piperazine-1-base)-ketone (628mg, 2.0mmol) with connection boric acid pinacol ester (1014mg, 4mmol) it is dissolved in dioxane, it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (81.6mg, 0.1mmol), potassium acetate (588mg, 6mmol), nitrogen is replaced, heat to 120 DEG C of reactions 24 hours, reactant liquor concentrating under reduced pressure, residue is dissolved in methanol, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (350mg, brown solid), yield: 62%;It is directly used in next step reaction。
3rd step:
By corresponding pyridine substituted boracic acid (216.6mg under room temperature, 0.77mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (105mg, 0.3mmol) it is dissolved in N, in dinethylformamide (6ml), it is subsequently adding tetrakis triphenylphosphine palladium (35mg, 0.03mmol), sodium carbonate liquor (95mg, 0.9mmol), nitrogen is replaced, 85 DEG C are reacted 2 hours, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (50ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-4-(2-hydroxy-ethyl)-piperazine-1-base]-{ 5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-ketone (50mg, yellow solid), yield 33%。
MSm/z (ESI): 538.98 [M+1];
1HNMR (400Hz, DMSO-d6): 9.07 (s, 1H), 8.47-8.25 (m, 3H), 8.01 (s, 1H), 7.72 (d, 1H), 7.42 (d, 2H), 7.29 (t, 2H), 7.19 (t, 1H), 5.43 (d, 1H), 5.07 (s, 1H), 4.58 (s, 1H), 3.86-3.60 (m, 4H), 3.52 (d, 4H), 3.02 (m, 3H), 2.54 (s, 6H)。
Embodiment 4: the preparation of compound I-4
The first step:
Under room temperature, by 5-bromo-2-pyridyl formic acid (2.02g, 10mmol) with 1-methanesulfonylpiperazin (2.46g, 15mmol) it is dissolved in dichloromethane (50ml), then I-hydroxybenzotriazole (2.7g it is sequentially added into, 20mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (3.83g, 20mmol) and N, N-diisopropylethylamine (6.46g, 50mmol), it is stirred at room temperature 24 hours, water (200ml) is added in reactant liquor, dichloromethane (100ml*3) extracts, again with saturated sodium-chloride (100ml*2) washing, organic facies anhydrous sodium sulfate dries, filter, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (5-bromo-pyridine-2-base)-(4-methanesulphonyl-piperazine-1-base)-ketone (3.05g, white solid), yield: 87.6%。
MSm/z (ESI): 349 [M+1];
1HNMR (400Hz, DMSO-d6): 8.74 (s, 1H), 8.22 (d, 1H), 7.60 (d, 1H), 3.75 (m, 2H), 3.54 (m, 2H), 3.22 (m, 2H), 3.12 (m, 2H), 2.91 (s, 3H)。
Second step:
Under room temperature, by (5-bromo-pyridine-2-base)-(4-methanesulphonyl-piperazine-1-base)-ketone (696mg, 2mmol) with connection boric acid pinacol ester (1016mg, 4mmol) it is dissolved in dioxane, it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (163.2mg, 0.2mmol), potassium acetate (588mg, 6mmol), nitrogen is replaced, heat to 120 DEG C of reactions 24 hours, reactant liquor concentrating under reduced pressure, residue is dissolved in ethyl acetate, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (237mg, brown solid);It is directly used in next step reaction。
3rd step:
By corresponding pyridine substituted boracic acid (237mg under room temperature, 0.75mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (105mg, 0.3mmol) it is dissolved in N, in dinethylformamide (6ml), it is subsequently adding tetrakis triphenylphosphine palladium (35mg, 0.03mmol), sodium carbonate (95mg, 0.9mmol), nitrogen is replaced, 85 DEG C are reacted 2 hours, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (50ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-{ 5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]--pyridine-2-base }-(4-methanesulphonyl-piperazine-1-base)-ketone (40mg, yellow solid), yield 26%。
MSm/z (ESI): 504.6 [M+1];
1HNMR (400Hz, DMSO-d6): 9.07 (d, 1H), 8.44 (m, 3H), 8.06 (s, 1H), 7.79 (d, 1H), 7.44 (d, 2H), 7.31 (d, 2H), 7.24 (d, 1H), 5.46 (s, 1H), 5.04 (s, 1H), 3.79 (s, 1H), 3.62 (s, 2H), 3.25 (s, 2H), 3.16 (s, 2H), 2.93 (s, 3H)。
Embodiment 5: the preparation of compound I-5
The first step:
Under room temperature, by 5-bromo-2-pyridyl formic acid (2.5g, 12.4mmol) and morpholine (11g, 12.4mmol) be dissolved in dichloromethane (50ml), then I-hydroxybenzotriazole (2.5g it is sequentially added into, 18.6mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (3.6g, 18.6mmol) and N, N-diisopropylethylamine (4.8g, 37.2mmol), it is stirred at room temperature 24 hours, water (200ml) is added in reactant liquor, dichloromethane (100ml*3) extracts, again with saturated sodium-chloride (100ml*2) washing, organic facies anhydrous sodium sulfate dries, filter, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (5-bromo-pyridine-2-base)-morpholine-4-base-ketone (2.13g, white solid), yield: 64%。
MSm/z (ESI): 272 [M+1];
1HNMR (400Hz, DMSO-d6): 8.74 (s, 1H), 8.22 (m, 1H), 7.59 (m, 1H), 3.55 (m, 4H), 3.43 (m, 4H)。
Second step:
Under room temperature, by (5-bromo-pyridine-2-base)-morpholine-4-base-ketone (271mg, 1mmol) with connection boric acid pinacol ester (330mg, 1.3mmol) it is dissolved in dioxane, it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (40.8mg, 0.04mmol), potassium acetate (294mg, 3mmol), nitrogen is replaced, heat to 120 DEG C of reactions 24 hours, reactant liquor concentrating under reduced pressure, residue is dissolved in ethyl acetate, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (218mg, brown solid);It is directly used in next step reaction。
3rd step:
By corresponding pyridine substituted boracic acid (218mg under room temperature, 0.92mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (200mg, 0.57mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding tetrakis triphenylphosphine palladium (33mg, 0.108mmol), sodium carbonate liquor (1N, 3.0ml), nitrogen is replaced, 85 DEG C are reacted 2 hours, cool down addition 200ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-{ 5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-morpholine-4-base-ketone (80mg, brown solid), yield 26%。
MSm/z (ESI): 461.89 [M+1];
1HNMR (400Hz, DMSO-d6): 9.10 (s, 1H), 8.41 (m, 3H), 8.04 (s, 1H), 7.77 (d, 1H), 7.45 (m, 2H), 7.32 (m, 2H), 7.22 (m, 1H), 5.47 (m, 1H), 5.04 (m, 1H), 3.81 (m.2H), 3.69 (m, 4H), 3.59 (m, 4H)。
Embodiment 6: the preparation of compound I-6
The first step:
Under room temperature, by 5-bromo-2-pyridyl formic acid (2.0g, 9.9mmol) He 2, 6-thebaine (1.14g, 9.9mmol) it is dissolved in dichloromethane (50ml), then I-hydroxybenzotriazole (2.0g it is sequentially added into, 14.9mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (2.85g, 14.9mmol) and N, N-diisopropylethylamine (3.8g, 29.7mmol), it is stirred at room temperature 24 hours, water (200ml) is added in reactant liquor, dichloromethane (100ml*3) extracts, again with saturated sodium-chloride (100ml*2) washing, organic facies anhydrous sodium sulfate dries, filter, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (5-bromo-pyridine-2-base)-(2, 6-thebaine-4-base)-ketone (2.18g, white solid), yield: 75%。
1HNMR (400Hz, DMSO-d6): 8.75 (s, 1H), 8.21 (d, 1H), 7.59 (d, 1H), 4.35 (d, 1H), 3.55 (m, 4H), 2.78 (t, 1H), 1.16 (d, 3H), 0.99 (d, 3H)。
Second step:
Under room temperature, by (5-bromo-pyridine-2-base)-(2, 6-thebaine-4-base)-ketone (299.2mg, 1mmol) with connection boric acid pinacol ester (330mg, 1.3mmol) it is dissolved in dioxane, it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (40.8mg, 0.04mmol), potassium acetate (294mg, 3mmol), nitrogen is replaced, heat to 120 DEG C of reactions 24 hours, reactant liquor concentrating under reduced pressure, residue is dissolved in ethyl acetate, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (320mg, brown solid);It is directly used in next step reaction。
3rd step:
By corresponding pyridine substituted boracic acid (320mg under room temperature, 1.2mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (250mg, 0.71mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding tetrakis triphenylphosphine palladium (41mg, 0.036mmol), sodium carbonate (225mg, 2.13mmol), nitrogen is replaced, 85 DEG C are reacted 2 hours, cool down addition 200ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-(2, 6-Dimethyl-morpholin-4-base)-{ 5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-ketone (85mg, brown solid), yield 24%。
MSm/z (ESI): 489.98 [M+1];
1HNMR (400Hz, DMSO-d6): 9.09 (s, 1H), 8.42 (m, 3H), 8.02 (s, 1H), 7.73 (d, 1H), 7.42 (d, 2H), 7.30 (t, 2H), 7.21 (d, 1H), 5.45 (d, 1H), 4.98 (s, 1H), 4.39 (d, 1H), 3.72 (d, 3H), 3.55 (s, 2H), 2.90-2.75 (m, 1H), 1.20-1.09 (m, 3H), 1.00 (d, 3H)。
Embodiment 7: the preparation of compound I-7
The first step:
Under room temperature, by 5-bromo-2-pyridyl formic acid (1.0g, 4.95mmol) with nafoxidine (0.35g, 4.95mmol) it is dissolved in dichloromethane (30ml), then I-hydroxybenzotriazole (0.8g it is sequentially added into, 5.94mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (1.14g, 5.94mmol) and N, N-diisopropylethylamine (1.92g, 14.85mmol), it is stirred at room temperature 24 hours, water (100ml) is added in reactant liquor, dichloromethane (50ml*3) extracts, again with saturated sodium-chloride (100ml*2) washing, organic facies anhydrous sodium sulfate dries, filter, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (5-bromo-pyridine-2-base)-pyrrolidinyl-piperazine-1-base)-ketone (800mg, white solid), yield: 61.5%。
1HNMR (400Hz, DMSO-d6): 8.76 (s, 1H), 8.22 (d, 1H), 7.70 (d, 1H), 3.50-3.63 (d, 4H), 1.87 (s, 4H).
Second step:
Under room temperature, by (5-bromo-pyridine-2-base)-pyrrolidinyl-piperazine-1-base)-ketone (300mg, 118mmol) with connection boric acid pinacol ester (388mg, 1.53mmol) it is dissolved in dioxane, it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (43mg, 0.059mmol), potassium acetate (347mg, 3.54mmol), nitrogen is replaced, heat to 120 DEG C of reactions 24 hours, reactant liquor concentrating under reduced pressure, residue is dissolved in ethyl acetate, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (340mg, brown solid);It is directly used in next step reaction。
3rd step:
By corresponding pyridine substituted boracic acid (340mg under room temperature, 1.54mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (200mg, 0.57mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding tetrakis triphenylphosphine palladium (40mg, 0.034mmol), sodium carbonate (181mg, 1.71mmol), nitrogen is replaced, 85 DEG C are reacted 2 hours, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-{ 5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-pyrrolidin-1-yl-ketone (56mg, off-white color solid), yield 22%。
MSm/z (ESI): 445.96;
1HNMR (400Hz, DMSO-d6): 9.05 (s, 1H), 8.38 (m, 3H), 8.05 (s, 1H), 7.88 (d, 1H), 7.45 (d, 2H), 7.32 (m, 2H), 7.25 (m, 1H), 5.47 (m, 1H), 4.99 (m, 1H), 3.79 (m, 2H), 3.75 (m, 2H), 3.54 (m, 2H), 1.88 (m, 4H)。
Embodiment 8: the preparation of Compound II per-1
The first step:
Under room temperature, by 5-bromo-2-pyridyl carboxylic acid (1.65g, 8.19mmol) it is dissolved in methanol solution (30ml), then concentrated sulphuric acid (2.5ml) is dripped, heating, condensing reflux, react 12 hours, reactant liquor is slowly added dropwise in saturated sodium bicarbonate solution (200ml), extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, organic facies anhydrous magnesium sulfate dry filter, concentrating under reduced pressure, obtain the bromo-2 pyridinecarboxylate's (white solids of 5-, 1.39g), yield: 79%。
Second step:
5-bromo-2-pyridyl carboxylate methyl ester (648mg, 3mmol) is dissolved in methanol solution (10ml), under ice bath, is slowly added to sodium borohydride (340mg, 9mmol), add recession deicing bath, be warming up to room temperature, stirring reaction 12 hours;The HCl being subsequently adding 1N adjusts pH value to 1, then adds saturated sodium bicarbonate solution tune pH value inwards to 8, is then extracted with ethyl acetate, organic facies anhydrous magnesium sulfate dry filter, concentrating under reduced pressure, obtain 5-bromo-2-pyridyl methanol (535mg, white solid), yield: 94.8%。
3rd step:
Under room temperature, 5-bromo-2-pyridyl methanol (500mg, 2.66mmol) is dissolved in thionyl chloride (5ml), it is stirred at room temperature, reacts 12 hours, concentrating under reduced pressure, obtain the bromo-2-chloromethylpyridine of 5-(635mg, white solid), yield: 98%。
4th step:
By bromo-for 5-2-chloromethylpyridine (2.43g, 10mmol) with N-Boc piperazine (2.8g, 15mmol) it is dissolved in N, in dinethylformamide (20ml), it is subsequently adding potassium carbonate (4.84g, 35mmol), reaction 12 hour is stirred at room temperature, cool down addition 200ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, obtain 4-(5-bromo-pyridine-2-methyl)-piperazine-1-carboxylic acid tert-butyl ester (3g, off-white color solid), yield: 84%。
5th step:
By 4-(5-bromo-pyridine-2-methyl)-piperazine-1-carboxylic acid tert-butyl ester (3g under room temperature, 8.42mmol) with connection boric acid pinacol ester (2.56g, 10.1mmol) it is dissolved in N, in dinethylformamide (15ml), it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (0.308g, 0.42mmol) with potassium acetate (1g, 10.1mmol), nitrogen is replaced, react 12 hours at 85 DEG C, reactant liquor concentrating under reduced pressure, residue is dissolved in ethyl acetate, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (1.97g, brown solid), yield: 73%;It is directly used in next step reaction。
6th step:
By corresponding pyridine substituted boracic acid (1.97g under room temperature, 6.13mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (1.95g, 5.57mmol) it is dissolved in N, in dinethylformamide (15ml), it is subsequently adding tetrakis triphenylphosphine palladium (0.644g, 0.56mmol), sodium carbonate (1.77g, 16.7mmol), nitrogen is replaced, 85 DEG C are reacted 2 hours, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-4-{5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-methyl }-piperazine-1-carboxylic acid tert-butyl ester (2.3g, red solid), yield 76%。
MSm/z (ESI): 547.6。
7th step:
Under ice bath, by the hydrochloric acid solution (1.1N of ethyl acetate, 70ml) it is slowly added to (S)-4-{5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-methyl-piperazine-1-carboxylic acid tert-butyl ester dichloromethane solution in, add and remove ice bath, it is stirred at room temperature, react 4 hours, concentrating under reduced pressure, it is subsequently adding saturated sodium carbonate solution (100ml), extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, obtain product 2-phenyl-2-[6-(6-piperazine-1-methvl-pyridinium-3-base)-thiophene [3, 2-d] pyrimidine-4-amino]-ethanol (1.69g, brown solid), yield: 89.9%。
Embodiment 9: the preparation of Compound II per-2
The first step:
By N methyl piperazine (301mg under room temperature, 3mmol) with the bromo-2-pyrimidinecarboxylic acid (507mg of 5-, 2.5mmol) it is dissolved in dichloromethane (10ml), then I-hydroxybenzotriazole (405mg it is sequentially added into, 3mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (575mg, 3mmol), triethylamine (0.8ml), it is stirred at room temperature, react 12 hours, add water (100ml) inwards, extract with dichloromethane (100ml*2), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous sodium sulfate obtained dries, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (the bromo-pyrimidine-2-base of 5-)-(4-thyl-piperazin-1-base)-ketone (320mg, yellow solid), yield: 45%。
MSm/z (ESI): 285.96;
1HNMR (400Hz, DMSO-d6): 9.11 (s, 2H), 3.64 (m, 2H), 3.17 (m, 2H), 2.51 (m, 2H), 2.37 (m, 2H), 2.25 (s, 3H)。
Second step:
By (the bromo-pyrimidine-2-base of 5-)-(4-thyl-piperazin-1-base)-ketone (300mg under room temperature, 1.05mmol) with connection boric acid pinacol ester (321mg, 1.26mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (38mg, 0.053mmol) with potassium acetate (308mg, 3.15mmol), nitrogen is replaced, react 12 hours at 85 DEG C, reactant liquor concentrating under reduced pressure, residue is dissolved in ethyl acetate, filter, filtrate reduced in volume, obtain corresponding pyrimidine substituted boracic acid (200mg, brown solid), yield: 76%;It is directly used in next step reaction。
3rd step:
By corresponding pyridine substituted boracic acid (200mg under room temperature, 0.80mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (223mg, 0.67mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding tetrakis triphenylphosphine palladium (39mg, 0.034mmol), sodium carbonate (213mg, 2.01mmol), nitrogen is replaced, 85 DEG C are reacted 4 hours, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-(4-thyl-piperazin-1-base)-{ 5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyrimidine-2-base }-ketone (120mg, white solid), yield: 37%。
MSm/z (ESI): 475.98;
1HNMR (400Hz, DMSO-d6): 9.10 (s, 2H), 8.30 (m, 1H), 7.95 (s, 1H), 7.63 (s, 1H), 7.45 (m, 2H), 7.33 (m, 2H), 7.24 (m, 1H), 5.45 (m, 1H), 5.00 (m, 1H), 3.79 (m, 2H), 3.64 (m, 2H), 3.18 (m, 2H), 2.51 (m, 2H), 2.38 (m, 2H), 2.26 (s, 3H)。
Embodiment 10: the preparation of Compound II per-3
The first step:
By NEP (274mg under room temperature, 2.4mmol) with the bromo-2-pyrimidinecarboxylic acid (406mg of 5-, 2mmol) it is dissolved in dichloromethane (10ml), then I-hydroxybenzotriazole (324mg it is sequentially added into, 2.4mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (460mg, 2.4mmol), triethylamine (0.8ml), it is stirred at room temperature, react 12 hours, add water (100ml) inwards, extract with dichloromethane (100ml*2), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous sodium sulfate obtained dries, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (the bromo-pyrimidine-2-base of 5-)-(4-ethyl-piperazin-1-base)-ketone (287mg, white solid), yield: 48%。
MSm/z (ESI): 300.06;
1HNMR (400Hz, DMSO-d6): 9.11 (s, 2H), 3.64 (m, 2H), 3.18 (m, 2H), 2.28-2.24 (m, 6H), 1.00 (m, 3H)。
Second step:
By (the bromo-pyrimidine-2-base of 5-)-(4-ethyl-piperazin-1-base)-ketone (280mg under room temperature, 0.94mmol) with connection boric acid pinacol ester (285mg, 1.12mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (34mg, 0.047mmol) with potassium acetate (276mg, 2.82mmol), nitrogen is replaced, react 12 hours at 85 DEG C, reactant liquor concentrating under reduced pressure, residue is dissolved in ethyl acetate, filter, filtrate reduced in volume, obtain corresponding pyrimidine substituted boracic acid (194mg, brown solid), yield: 78%;It is directly used in next step reaction。
3rd step:
By corresponding pyridine substituted boracic acid (194mg under room temperature, 0.73mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (214mg, 0.61mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding tetrakis triphenylphosphine palladium (35mg, 0.031mmol), sodium carbonate (194mg, 1.83mmol), nitrogen is replaced, 85 DEG C are reacted 4 hours, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-(4-ethyl-piperazin-1-base)-{ 5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyrimidine-2-base }-ketone (87mg, white solid), yield: 29%。
MSm/z (ESI): 490.23;
1HNMR (400Hz, DMSO-d6): 9.11 (s, 2H), 8.29 (m, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 7.45 (m, 2H), 7.33 (m, 2H), 7.24 (m, 1H), 5.46 (m, 1H), 5.01 (m, 1H), 3.79 (m, 2H), 3.64 (m, 2H), 3.18 (m, 2H), 2.28-2.24 (m, 6H), 1.01 (m, 3H)。
Embodiment 11: the preparation of Compound II per-4
The first step:
By 2-phenyl-2-[6-(6-piperazine-1-methvl-pyridinium-3-base)-thiophene [3 under room temperature, 2-d] pyrimidine-4-amino]-ethanol (334mg, 0.6mmol) with bromoethanol (113mg, 0.9mmol) it is dissolved in N, in dinethylformamide (15ml), it is subsequently adding potassium carbonate (497mg, 3.6mmol), stirred overnight at room temperature, add water (100ml) more inwards, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous sodium sulfate obtained dries, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-(6-{6-[4-(2-hydroxy-ethyl)-piperazine-1-methyl]-pyridin-3-yl }-thiophene [3, 2-d] pyrimidine-4-amino)-2-phenyl-ethanol (25mg, white powder), yield: 8%。
MSm/z (ESI): 490.92;
1HNMR (400Hz, DMSO-d6): 9.03 (d, 1H), 8.43 (s, 1H), 8.37 (m, 1H), 8.28 (m, 1H), 7.96 (s, 1H), 7.63 (d, 1H), 7.49 (d, 2H), 7.35 (m, 2H), 7.28 (m, 1H), 5.49 (m, 1H), 5.07 (m, 1H), 3.84 (m, 2H), 3.75 (s, 2H), 3.46 (m, 6H), 2.55 (m, 6H)。
Embodiment 12: the preparation of Compound II per-5
The first step:
Wherein the preparation of the bromo-2-chloromethylpyridine of 5-is with described in embodiment 8。
By bromo-for 5-2-chloromethylpyridine (243mg, 2mmol) with N-isobutyryl piperazine (289mg, 3mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding potassium carbonate (691mg, 10mmol), reaction 12 hour is stirred at room temperature, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (50ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, obtain 1-[4-(5-bromo-pyridine-2-methyl)-piperazine-1-base]-2-methyl-propan-1-ketone (282mg, grease), yield: 86%。
Second step:
By 1-[4-(5-bromo-pyridine-2-methyl)-piperazine-1-base]-2-methyl-propan-1-ketone (280mg under room temperature, 0.86mmol) with connection boric acid pinacol ester (262mg, 1.03mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (32mg, 0.43mmol) with potassium acetate (102mg, 1.03mmol), nitrogen is replaced, react 12 hours at 85 DEG C, reactant liquor concentrating under reduced pressure, residue is dissolved in ethyl acetate, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (204mg, brown solid), yield: 82%;It is directly used in next step reaction。
3rd step:
By corresponding pyridine substituted boracic acid (204mg under room temperature, 0.7mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (223mg, 0.64mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding tetrakis triphenylphosphine palladium (74mg, 0.064mmol), sodium carbonate (203mg, 1.92mmol), nitrogen is replaced, 85 DEG C are reacted 2 hours, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-1-(4-{5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-methyl }-piperazine-1-base)-2-methyl-propan-1-ketone (192mg, faint yellow solid), yield: 58%。
MSm/z (ESI): 517.6;
1HNMR (400Hz, DMSO-d6): 9.01 (s, 1H), 8.39 (s, 1H), 8.29 (m, 2H), 7.94 (s, 1H), 7.63 (d, 1H), 7.45 (d, 2H), 7.33 (m, 2H), 7.24 (m, 1H), 5.46 (m, 1H), 5.01 (m, 1H), 3.79 (m, 2H), 3.72 (s, 2H), 3.51 (m, 4H), 2.86 (m, 1H), 2.41 (m, 4H), 0.99 (d, 6H)。
Embodiment 13: the preparation of Compound II per-6
The first step:
Under room temperature, by 2-phenyl-2-[6-(6-piperazine-1-methvl-pyridinium-3-base)-thiophene [3, 2-d] pyrimidine-4-amino]-ethanol (166mg, 0.3mmol) with glycolic (35mg, 0.45mmol) it is dissolved in N, in dinethylformamide (8ml), it is subsequently adding O-BTA-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid (145mg, 0.45mmol) and N, N-diisopropylethylamine (388mg, 3mmol), reaction 30 minute is stirred at room temperature, add water (100ml) inwards, extract by ethyl acetate (100ml*2), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous sodium sulfate obtained dries, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-hydroxyl-1-(4-{5-[4-(2-hydroxyl-1-Phenyl-ethylamino)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-methyl }-piperazine-1-base)-ethyl ketone (80mg, pale solid), yield: 53%。
MSm/z (ESI): 504.9;
1HNMR (400Hz, DMSO-d6): 9.00 (d, 1H), 8.39 (s, 1H), 8.26 (m, 2H), 7.93 (s, 1H), 7.62 (d, 1H), 7.44 (d, 2H), 7.27 (m, 2H), 7.21 (m, 1H), 5.46 (m, 1H), 4.98 (m, 1H), 3.80 (m, 2H), 3.70 (s, 2H), 3.46 (m, 4H), 3.33 (s, 2H), 2.47 (m, 4H)。
Embodiment 14: the preparation of Compound II per-7
The first step:
Under room temperature, by 2-phenyl-2-[6-(6-piperazine-1-methvl-pyridinium-3-base)-thiophene [3, 2-d] pyrimidine-4-amino]-ethanol (166.8mg, 0.3mmol) with 2-hydroxy-iso-butyric acid (46.8mg, 0.45mmol) it is dissolved in N, in dinethylformamide (8ml), it is subsequently adding O-BTA-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid (144.5mg, 0.45mmol) and N, N-diisopropylethylamine (388.5mg, 3mmol), reaction 30 minute is stirred at room temperature, add water (100ml) inwards, extract by ethyl acetate (100ml*2), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous sodium sulfate obtained dries, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-hydroxyl-1-(4-{5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-yl]-pyridine-2-methyl }-piperazine-1-yl)-2-methyl-propan-1-ketone (70mg, pale solid), yield: 43.8%。
MSm/z (ESI): 533.0;
1HNMR (400Hz, DMSO-d6): 9.01 (d, 1H), 8.39 (s, 1H), 8.27 (m, 2H), 7.94 (s, 1H), 7.63 (d, 1H), 7.45 (d, 2H), 7.29 (m, 2H), 7.22 (m, 1H), 5.45 (m, 1H), 5.03 (m, 1H), 3.80 (m, 4H), 3.71 (m, 4H), 2.45 (m, 4H), 1.32 (s, 6H)。
Embodiment 15: the preparation of Compound II per-8
The first step:
Wherein the preparation of the bromo-2-chloromethylpyridine of 5-is with described in embodiment 8。
By bromo-for 5-2-chloromethylpyridine (500mg, 2.06mmol) with 1-methanesulfonylpiperazin (440mg, 2.68mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding potassium carbonate (996mg, 7.21mmol), reaction 12 hour is stirred at room temperature, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, obtain 1-(5-bromo-pyridine-2-methyl)-4-methanesulphonyl-piperazine (520mg, off-white color solid), yield: 75.6%。
Second step:
By 1-(5-bromo-pyridine-2-methyl)-4-methanesulphonyl-piperazine (334mg under room temperature, 1mmol) with connection boric acid pinacol ester (330mg, 1.3mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (40mg, 0.05mmol) with potassium acetate (294mg, 3mmol), nitrogen is replaced, react 12 hours at 85 DEG C, reactant liquor concentrating under reduced pressure, residue is dissolved in ethyl acetate, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (230mg, brown solid), yield: 76%。
3rd step:
By corresponding pyridine substituted boracic acid (230mg under room temperature, 0.77mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (170mg, 0.48mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding tetrakis triphenylphosphine palladium (28mg, 0.024mmol), sodium carbonate (153mg, 1.44mmol), nitrogen is replaced, 85 DEG C are reacted 2 hours, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (50ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-2-{6-[6-(4-methanesulphonyl-piperazine-1-methyl)-pyridin-3-yl]-thiophene [3, 2-d] pyrimidine-4-amino }-2-phenyl-ethanol (50mg, yellow solid), yield 20%。
MSm/z (ESI): 524.98;
1HNMR (400Hz, DMSO-d6): 9.04 (d, 1H), 8.40 (s, 1H), 8.27 (m, 2H), 7.95 (s, 1H), 7.56 (d, 1H), 7.43 (d, 2H), 7.30 (m, 2H), 7.22 (m, 1H), 5.46 (m, 1H), 5.24 (s, 2H), 4.96 (m, 1H), 3.77 (m, 2H), 3.56 (m, 4H), 3.16 (m, 4H), 2.91 (s, 3H)。
Embodiment 16: the preparation of Compound II per-9
The first step:
Wherein the preparation of the bromo-2-chloromethylpyridine of 5-is with described in embodiment 8。
By bromo-for 5-2-chloromethylpyridine (486mg, 2mmol) with thiomorpholine 1, 1-dioxide (406mg, 3mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding potassium carbonate (986mg, 7mmol), reaction 12 hour is stirred at room temperature, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, obtain 1-(5-bromo-pyridine-2-methyl)-(1, 1-dioxido-thiomorpholine)-piperazine (499mg, off-white color solid), yield: 81.8%。
Second step:
By 1-(5-bromo-pyridine-2-methyl)-(1 under room temperature, 1-dioxido-thiomorpholine)-piperazine (152mg, 0.5mmol) with connection boric acid pinacol ester (153mg, 0.6mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (21mg, 0.025mmol) with potassium acetate (59mg, 0.6mmol), nitrogen is replaced, react 12 hours at 85 DEG C, reactant liquor concentrating under reduced pressure, residue is dissolved in ethyl acetate, filter, filtrate reduced in volume, obtain corresponding pyridine substituted boracic acid (118mg, brown solid), yield: 87%。
3rd step:
By corresponding pyridine substituted boracic acid (118mg under room temperature, 0.44mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (140mg, 0.40mmol) it is dissolved in N, in dinethylformamide (10ml), it is subsequently adding tetrakis triphenylphosphine palladium (47mg, 0.04mmol), sodium carbonate (85mg, 0.8mmol), nitrogen is replaced, 85 DEG C are reacted 2 hours, cool down addition 100ml water in backward reactant liquor, extract by ethyl acetate (50ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain (S)-2-{6-[6-(1, 1-dioxido-thiomorpholine-4-methyl)-pyridin-3-yl]-thiophene [3, 2-d] pyrimidine-4-amino }-2-phenyl-ethanol (60mg, yellow solid), yield 30%。
MSm/z (ESI): 496.63;
1HNMR (400Hz, DMSO-d6): 9.00 (d, 1H), 8.39 (s, 1H), 8.23 (m, 2H), 7.92 (s, 1H), 7.66 (d, 1H), 7.43 (d, 2H), 7.31 (m, 2H), 7.23 (m, 1H), 5.45 (m, 1H), 4.94 (m, 1H), 3.86 (s, 2H), 3.76 (m, 2H), 3.14 (m, 4H), 2.99 (m, 4H)。
Embodiment 17: the preparation of compound III-1
Under room temperature, by { 5-[4-(2-hydroxyl-1-phenyl l-ethamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-t-butyl carbamate is dissolved in dichloromethane (2ml), it is subsequently adding trifluoroacetic acid (257.4mg, 2.58mmol), room temperature reaction 2 hours, add saturated sodium carbonate solution (100ml) inwards, extract with dichloromethane (50ml*2), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-[6-(6-amino-pyridine-3-base)-thiophene [3, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (30mg, white solid), yield: 76%。
MSm/z (ESI): 363.92 [M+1];
1HNMR (400Hz, DMSO-d6): 8.47 (m, 3H), 7.92 (d, 1H), 7.64 (s, 1H), 7.53 (d, 2H), 7.46 (m, 3H), 6.81 (m, 3H), 5.48 (m, 1H), 5.10 (m, 1H), 3.86 (m, 2H)。
Embodiment 18: the preparation of compound III-2
The first step:
Under room temperature, 2-amino-5-bromopyridine (5g, 29mmol) and Bis(tert-butoxycarbonyl)oxide (6.9g, 32mmol) are dissolved in oxolane (28ml), heating is to 70 DEG C, condensing reflux, reacts 24 hours, concentrating under reduced pressure, the crude product ether obtained: petroleum ether (1: 1) washs, concentrating under reduced pressure obtains 2-Boc amino-5-bromopyridine (5g, white solid), yield: 63%。
1HNMR (400Hz, DMSO-d6): 9.99 (s, 1H), 8.36 (s, 1H), 7.80 (d, 1H), 7.77 (d, 1H), 1.47 (d, 9H)。
Second step:
Under room temperature, by 2-Boc amino-5-bromopyridine (150mg, 0.55mmol) with connection boric acid pinacol ester (181mg, 0.71mmol) it is dissolved in N, in dinethylformamide (5ml), it is subsequently adding potassium acetate (161mg, 1.65mmol), [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (23mg, 0.028mmol), 100 DEG C of microwave reacts 15 minutes, 200ml water is added in reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-Boc amino-5-and join boric acid pinacol ester pyridine (17mg, white solid), yield: 20%。
1HNMR (400Hz, DMSO-d6): 9.99 (s, 1H), 8.47 (s, 1H), 7.93 (m, 2H), 1.48 (s, 9H), 1.28 (m, 12H)。
3rd step:
Under room temperature, 2-Boc amino-5-is joined boric acid pinacol ester pyridine (96.7mg, 0.3mmol) with 2-(the bromo-thiophene [3 of 6-, 2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (70mg, 0.2mmol) it is dissolved in N, in dinethylformamide (3ml), it is subsequently adding tetrakis triphenylphosphine palladium (23mg, 0.02mmol), sodium carbonate liquor (1N, 0.6ml), 85 DEG C are reacted 2 hours, cool down addition 200ml water in backward reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain { 5-[4-(2-hydroxyl-1-phenyl l-ethamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-t-butyl carbamate (60mg, off-white color solid), yield 67%。
MSm/z (ESI): 463.76 [M+1];
1HNMR (400Hz, DMSO-d6): 10.1 (s, 1H), 8.77 (s, 1H), 8.39 (s, 1H), 8.23 (m, 2H), 7.99 (d, 1H), 7.83 (s, 1H), 7.47 (d, 2H), 7.35 (t, 2H), 7.26 (t, 1H), 5.50 (m, 1H), 4.99 (m, 1H), 3.76 (m, 2H), 1.52 (s, 9H)。
Embodiment 19: the preparation of compound III-3
The first step:
By 2-[6-(the fluoro-pyridin-3-yl of 6-)-thiophene [3 under room temperature, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (146mg, 0.4mmol) with N-Boc piperazine (223mg, 1.2mmol) it is dissolved in N, in dinethylformamide (5ml), it is stirred at room temperature 20 hours, 100ml water is added in reactant liquor, extract by ethyl acetate (100ml*2), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 4-{5-[4-(2-hydroxyl-1-phenyl l-ethamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-piperazine-1-carboxylic acid tert-butyl ester (200mg, light yellow solid), yield: 94%;It is directly used as next step reaction。
Second step:
By 4-{5-[4-(2-hydroxyl-1-phenyl l-ethamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.38mmol) it is dissolved in dichloromethane (10ml), it is subsequently adding trifluoroacetic acid (0.6ml, 0.008mmol), stirring reaction under room temperature is until TLC monitoring raw material reaction is complete, add 200ml ethyl acetate, it is stirred for down being slowly added dropwise saturated sodium bicarbonate, extract, organic facies saturated nacl aqueous solution (100ml*2) washs, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-phenyl-2-[6-(6-piperazine-1-base-pyridine-3-yl)-thiophene [3, 2-d] pyrimidine-4-yl amine]-ethanol (13mg, yellow solid), yield: 8%。
MSm/z (ESI): 433.15 [M+1];
1HNMR (400Hz, DMSO-d6): 8.61 (d, 1H), 8.34 (s, 1H), 8.09 (d, 1H), 8.03 (dd, 1H), 7.68 (s, 1H), 7.45 (d, 2H), 7.24 (m, 3H), 7.01 (d, 1H), 5.45 (m, 1H), 4.99 (m, 1H), 3.80 (m, 2H), 3.55 (m, 9H)。
Embodiment 20: the preparation of compound III-4
By 2-[6-(the fluoro-pyridin-3-yl of 6-)-thiophene [3 under room temperature, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (96mg, 0.26mmol) with N methyl piperazine (79mg, 0.79mmol) it is dissolved in N, in dinethylformamide (3ml), it is stirred at room temperature 20 hours, 100ml water is added in reactant liquor, extract by ethyl acetate (100ml*2), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-{6-[6-(4-thyl-piperazin-1-base)-pyridin-3-yl]-thiophene [3, 2-d] pyrimidine-4-yl amine }-2-phenyl-ethanol (23mg, greenish yellow solid), yield: 20%。
MSm/z (ESI): 447.07 [M+1];
1HNMR (400Hz, DMSO-d6): 8.60 (d, 1H), 8.35 (s, 1H), 8.08 (d, 1H), 8.01 (dd, 1H), 7.66 (s, 1H), 7.46 (d, 2H), 7.29 (m, 3H), 6.96 (d, 1H), 5.44 (m, 1H), 4.97 (m, 1H), 3.78 (m, 2H), 3.62 (m, 4H), 2.41 (m, 4H), 2.23 (s, 3H)。
Embodiment 21: the preparation of Compound II per I-5
The first step:
By 2-fluorine pyridine-5-boric acid (282mg under room temperature; 2.0mmol) it is dissolved in N with 2-(6-bromo-thiophene [3,2-d] pyrimidine-4-yl amine)-2-phenyl l-ethanol (800.8mg, 2.2mmol); in dinethylformamide (20ml); then tetra-triphenylphosphine palladium (231mg, 0.2mmol), potassium carbonate (828mg it are sequentially added into; 6mmol); nitrogen protection, heating, to 85 DEG C, is reacted 12 hours。200ml water is added in reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, purify gained residue with silica gel column chromatography, obtain 2-[6-(the fluoro-pyridin-3-yl of 6-)-thiophene [3,2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (580mg, off-white color solid), yield: 79%。
MSm/z (ESI): 367.13 [M+1]。
Second step:
By 2-[6-(the fluoro-pyridin-3-yl of 6-)-thiophene [3 under room temperature, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (146mg, 0.4mmol) with NEP (88mg, 0.6mmol) it is dissolved in N, in dinethylformamide (3ml), it is stirred at room temperature 20 hours, 100ml water is added in reactant liquor, extract by ethyl acetate (100ml*2), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-{6-[6-(4-ethyl-piperazin-1-base)-pyridin-3-yl]-thiophene [3, 2-d] pyrimidine-4-yl amine }-2-phenyl-ethanol (100mg, light yellow solid), yield: 54%。
MSm/z (ESI): 461.64 [M+1];
1HNMR (400Hz, DMSO-d6): 8.60 (s, 1H), 8.34 (s, 1H), 8.09 (d, 1H), 8.01 (d, 1H), 7.66 (s, 1H), 7.40 (d, 2H), 7.24 (m, 3H), 6.98 (d, 1H), 5.44 (m, 1H), 4.98 (m, 1H), 3.79 (m, 2H), 3.64 (m, 4H), 2.47 (m, 6H), 1.07 (t, 3H)。
Embodiment 22: the preparation of compound III-6
By 2-[6-(the fluoro-pyridin-3-yl of 6-)-thiophene [3 under room temperature, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (96mg, 0.26mmol) with N-hydroxyethyl piperazine (102mg, 0.79mmol) it is dissolved in N, in dinethylformamide (3ml), it is stirred at room temperature 20 hours, 100ml water is added in reactant liquor, extract by ethyl acetate (100ml*2), again with saturated nacl aqueous solution (100ml*2) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-{6-[6-(4--(2-hydroxy-ethyl)-piperazine-1-base)-pyridin-3-yl]-thiophene [3, 2-d] pyrimidine-4-yl amine }-2-phenyl-ethanol (38mg, greenish yellow solid), yield: 31%。
MSm/z (ESI): 477.06 [M+1];
1HNMR (400Hz, DMSO-d6): 8.59 (d, 1H), 8.35 (s, 1H), 8.06 (d, 1H), 7.99 (dd, 1H), 7.66 (s, 1H), 7.46 (d, 2H), 7.29 (m, 3H), 6.97 (d, 1H), 5.44 (m, 1H), 4.97 (m, 1H), 4.46 (m, 1H), 3.76 (m, 2H), 3.58 (m, 8H), 2.39 (m, 4H)。
Embodiment 23: the preparation of compound III-7
By 2-[6-(the fluoro-pyridin-3-yl of 6-)-thiophene [3 under room temperature, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (110mg, 0.3mmol) with N-cyclopropyl carbonyl piperazine (138mg, 0.9mmol) it is dissolved in N, in dinethylformamide (5ml), it is stirred at room temperature 20 hours, 200ml water is added in reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain cyclopropyl-(4-{5-[4-(2-hydroxyl-1-phenyl-ethylamine)-thiophene [3, 2-d] pyrimidine-6-base]-pyridine-2-base }-piperazine-1-base)-ketone (15mg, faint yellow solid), yield: 10%。
MSm/z (ESI): 501.19 [M+1];
1HNMR (400Hz, DMSO-d6): 8.63 (d, 1H), 8.35 (s, 1H), 8.09 (d, 1H), 8.02 (dd, 1H), 7.68 (s, 1H), 7.45 (d, 2H), 7.32 (m, 3H), 7.01 (d, 1H), 5.45 (m, 1H), 4.97 (m, 1H), 3.79 (m, 2H), 3.69 (m, 8H), 2.01 (m, 1H), 0.77 (m, 4H)。
Embodiment 24: the preparation of compound III-8
By 2-[6-(the fluoro-pyridin-3-yl of 6-)-thiophene [3 under room temperature, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (100mg, 0.27mmol) with 1-sulfonyl methane piperazine (44.8mg, 0.27mmol) it is dissolved in N-Methyl pyrrolidone (3ml), it is subsequently adding potassium carbonate (138mg, 0.410mmol), it is stirred at room temperature 20 hours, 200ml water is added in reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-{6-[6-(4-methylsulfonyl-piperazine-1-base)-pyridin-3-yl]-thiophene [3, 2-d] pyrimidine-4-yl amine }-2-phenyl-ethanol (35mg, greenish yellow solid), yield: 25%。
MSm/z (ESI): 510.76 [M+1];
1HNMR (400Hz, DMSO-d6): 8.60 (d, 1H), 8.40 (s, 1H), 8.10 (d, 1H), 8.07 (dd, 1H), 7.75 (s, 1H), 7.48 (d, 2H), 7.30 (m, 3H), 7.11 (d, 1H), 5.48 (m, 1H), 5.08 (m, 1H), 3.89 (m, 6H), 3.21 (m, 4H), 2.97 (s, 3H)。
Embodiment 25: the preparation of compound III-9
By 2-[6-(the fluoro-pyridin-3-yl of 6-)-thiophene [3 under room temperature, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (150mg, 0.4mmol) with morpholine (52mg, 0.6mmol) it is dissolved in N, in dinethylformamide (5ml), it is stirred at room temperature 20 hours, 200ml water is added in reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-[6-(6-morpholine-4-base-pyridin-3-yl)-thiophene [3, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (70mg, greenish yellow solid), yield: 40%。
MSm/z (ESI): 434.16 [M+1];
1HNMR (400Hz, DMSO-d6): 8.63 (s, 1H), 8.36 (s, 1H), 8.09 (d, 1H), 8.01 (d, 1H), 7.68 (s, 1H), 7.45 (d, 2H), 7.34 (m, 3H), 6.98 (d, 1H), 5.46 (m, 1H), 4.98 (m, 1H), 3.72 (m.2H), 3.65 (m, 4H), 3.57 (m, 4H)。
Embodiment 26: the preparation of compound III-10
By 2-[6-(the fluoro-pyridin-3-yl of 6-)-thiophene [3 under room temperature, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (110mg, 0.3mmol) with 2-methyl-octahydro-pyrroles [3, 4-c] pyrroles (113mg, 0.9mmol) it is dissolved in N, in dinethylformamide (5ml), it is stirred at room temperature 20 hours, 200ml water is added in reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-{6-[6-(5-methyl-hexahydro-pyrroles [3, 4-c] pyrroles's-2-base)-pyridin-3-yl]-thiophene [3, 2-d] pyrimidine-4-yl amine }-2-phenyl-ethanol (34mg, greenish yellow solid), yield: 24%。
MSm/z (ESI): 473.15 [M+1];
1HNMR (400Hz, DMSO-d6): 8.60 (d, 1H), 8.35 (s, 1H), 8.08 (d, 1H), 8.01 (dd, 1H), 7.66 (s, 1H), 7.46 (d, 2H), 7.29 (m, 3H), 6.96 (d, 1H), 5.44 (m, 1H), 4.97 (m, 1H), 3.78 (m.2H), 3.52 (m, 8H), 2.91 (m, 2H), 2.83 (s, 3H)。
Embodiment 27: the preparation of compound III-11
By 2-[6-(the fluoro-pyridin-3-yl of 6-)-thiophene [3 under room temperature, 2-d] pyrimidine-4-yl amine]-2-phenyl-ethanol (109.8mg, 0.3mmol) with thiomorpholine 1, 1-dioxide (60.8mg, 0.45mmol) it is dissolved in N, in dinethylformamide (3ml), it is stirred at room temperature 20 hours, 200ml water is added in reactant liquor, extract by ethyl acetate (100ml*3), again with saturated nacl aqueous solution (100ml*3) washing, the organic facies anhydrous magnesium sulfate dry filter obtained, concentrating under reduced pressure, gained residue is purified with silica gel column chromatography, obtain 2-{6-[6-(1, double, two oxo-thiomorpholin-4-the base of 1-)-pyridin-3-yl]-thiophene [3, 2-d] pyrimidine-4-yl amine }-2-phenyl-ethanol (30mg, greenish yellow solid), yield: 21%。
MSm/z (ESI): 482.03 [M+1];
1HNMR (400Hz, DMSO-d6): 8.61 (d, 1H), 8.28 (s, 1H), 8.25 (d, 1H), 8.04 (dd, 1H), 7.68 (s, 1H), 7.39 (d, 2H), 7.27 (m, 2H), 7.16 (m, 2H), 5.37 (m, 1H), 5.14 (m, 1H), 3.78 (m, 2H), 3.21 (m, 4H), 2.95 (m, 4H)。
Biological assessment
1. receptor tyrosine kinase EGFR, VEGFR molecular level enzyme is lived and is suppressed preliminary assessment
(1) enzyme reaction substrate Poly (Glu, Tyr) PBS (10mM sodium phosphate buffer without potassium ion is used at 4: 1,150mmol/LNaCl, pH=7.2~7.4) it is diluted to 20 μ g/ml, 125 μ l/ hole coated elisa plates, put 37 DEG C to react 12~16 hours, discard liquid in hole, wash plate, plate is washed three times with the T-PBS (PBS without potassium ion containing 0.1%Tween-20) in 200 μ l/ holes, each 5 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) and the ATP solution 50 μ L, 5 μm of ol/L of final concentration that dilute。Every hole adds the compound solution (1%DMSO dissolves, final concentration of 10 μm of ol/L) of 1 μ l, adds the c-Met protein tyrosine kinase of 50 μ l reaction buffer dilutions;Put 37 DEG C of shaking tables (100rpm) and react 1 hour;Experiment sets without ATP control wells holes and corresponding DMSO solvent control hole (negative control hole) every time;Discarding liquid in hole, T-PBS washes plate three times。
(3) adding antibody PY99100 μ l/ hole (antibody T-PBS containing BSA5mg/ml dilutes, and concentration is 0.4 μ g/ml), 37 DEG C of shaking tables react 0.5 hour;Discarding liquid in hole, T-PBS washes plate three times。
(4) adding the anti-100 μ l/ holes (antibody T-PBS containing BSA5mg/ml dilutes, and concentration is 0.5 μ g/ml) of sheep anti mouse two of horseradish peroxidase-labeled, 37 DEG C of shaking tables react 0.5 hour, discard liquid in hole, and T-PBS washes plate three times。
(5) the OPD nitrite ion 100 μ l/ hole of 2mg/ml is added (with containing 0.03%H2O20.1M citric acid-sodium citrate buffer (pH=5.4) dilution), 25 DEG C of lucifuges are reacted 1~10 minute;(need to ultrasonic when OPD dissolves, nitrite ion needs now with the current)。
(6) 2mol/LH is added2SO450 μ l/ hole stopped reactions, decline orifice plate microplate reader VERSAmax reading with wavelengthtunable, and wavelength is 490nm。
(7) suppression ratio of sample is tried to achieve by following equation:
2, receptor tyrosine kinase EGFR enzyme is lived and is suppressed IC50Evaluation experimental
(compound is 10 for EGFR or the VEGFR enzyme inhibiting compound alive that clearly has above-mentioned screening obtained-5The M suppression ratio > 50% to receptor tyrosine kinase EGFR or VEGFR) it is made into gradient concentration, carry out IC50(half-inhibition concentration) is evaluated。
Passing a test, the activity display of the chemical compound lot according to the present invention of measurement is in Table 1。In these tables, according to test, " a " represents less than the inhibitory activity of 50 nanomolar concentrations (nM);" b " represents >=50 but the inhibitory activity of < 250 nanomolar concentration (nM);" c " represents >=250 but the inhibitory activity of < 500 nanomolar concentration (nM), and " d " represents the inhibitory activity of >=500 nanomolar concentrations (nM);" e " represents do not have activity。
3. the IC of extracorporeal anti-tumor cell proliferation50Measure
Detect the candidate compound cytotoxicity to application on human skin epidermoid carcinoma cell strain A431 by CCK-8 detection kit and suppress IC50Value。
(1). material and method
Cell strain: A431 application on human skin epidermoid carcinoma cell strain (Chinese Academy of Sciences's Shanghai cell bank)
Reagent and consumptive material:
CellCountingKit-8 (Cat#CK04-13, Dojindo)
96 well culture plates (Cat#3599, CorningCostar)
Hyclone (Cat#10099-141, GIBCO)
Culture medium (Invitrogen)
Desk-top microplate reader SpectraMaxM5MicroplateReader (MolecularDevices)
(2). experimental procedure
Preparation of reagents
The preparation of culture medium
Cell line: A431
Culture medium: DMEM+10%FBS
The preparation of compound: make final concentration of 10mM by DMSO diluted compounds。
Cell is cultivated
A) exponential phase cell is collected, counting, with complete medium Eddy diffusion cell,
B) adjusting cell concentration to suitable concn, inoculate 96 orifice plates, 100 μ l cell suspension are inoculated in every hole。
C) cell is at 37 DEG C, 100% relative humidity, 5%CO2Incubator is hatched 24 hours。
IC50Experiment
A) exponential phase cell is collected, counting, with complete medium Eddy diffusion cell, adjust cell concentration to suitable concn (determining according to cell density optimization Test result), inoculate 96 orifice plates, every hole adds 100 μ l cell suspension。Cell at 37 DEG C, 100% relative humidity, 5%CO2Incubator is hatched 24 hours。
B) gradient dilution 8 times after testing compound being diluted to 500 μMs by culture medium。Cell is added by 25 μ l/ holes。23 candidate compound effect final concentrations from 100 μMs to 0 μM, 5 times of gradient dilutions, totally 10 concentration point。
C) cell is placed in 37 DEG C, 100% relative humidity, 5%CO2Incubator is hatched 72 hours。
D) culture medium is abandoned in suction, and the addition complete medium containing 10%CCK-8 is placed in 37 DEG C of incubators hatches 2-4 hour。
E) on SpectraMaxM5MicroplateReader, measure the absorbance at 450nm wavelength place after shaking gently, using 650nm place absorbance as reference, calculate suppression ratio。
Data process
It is calculated as follows the suppression ratio of drug on tumor Growth of Cells: growth of tumour cell suppression ratio %=[(Ac-As)/(Ac-Ab)] × 100%
As: the OA (cell+CCK-8+ testing compound) of sample
Ac: the OA (cell+CCK-8+DMSO) of negative control
Ab: the OA (culture medium+CCK-8+DMSO) of positive control
Adopt software GraphpadPrism5 matching IC50 curve and calculate IC50Value
This experiment test candidate compound to application on human skin epidermoid carcinoma cell strain A431 anti-increment effect。Compound effects final concentration from 100 μMs to 0 μM, 5 times of gradient dilutions, totally 10 points。
Experimental result is as shown in table 2。
Table 2
From table 2: Thienopyrimidine analog derivative of the present invention has good tyrosine kinase EGFR inhibitory activity, especially Compound II per-2, II-5, II-6, III-3, III-4, III-5, III-6, III-7, III-10 have better more active than marketed drug gefitinib in 10 nanomole levels;At cellular level, Compound II per-1, II-2, II-3, II-5, II-6, III-3, III-5, III-6, III-10 also show that and significantly suppress A431 cytoactive;It is expected exploitation for tyrosine kinase inhibitor, has broad application prospects and medical value。
Claims (18)
1. a Thienopyrimidine analog derivative, it is characterised in that be that there is formula I:
Compound, in formula: Ar is phenyl;A is nitrogen-atoms, and D, E are carbon atom, and R isR therein2For C1~C6The C that alkyl, hydroxyl replace1~C6Alkyl or C1~C6The sulfonyl that alkyl replaces, R3、R4Respectively hydrogen or C1~C6Alkyl;Or,
It is that there is formula II:
Compound, in formula: Ar is phenyl;A is nitrogen-atoms, and D is carbon atom or nitrogen-atoms, and E is carbon atom, and R isR therein2For hydrogen, C1~C6The C that alkyl, hydroxyl replace1~C6Alkyl, C1~C6The acyl group of alkyl replacement, C1~C6The acyl group of alkane hydroxyl replacement or C1~C6The sulfonyl that alkyl replaces;Or,
It is that there is general formula III:
Compound, in formula: Ar is phenyl;A is nitrogen-atoms, and D, E are carbon atom, and R is R1-NH-、 Wherein: R1For hydrogen or C1~C6The ester group that alkyl replaces;R2For hydrogen, C1~C6The C that alkyl, hydroxyl replace1~C6Alkyl, C3~C6The acyl group of cycloalkyl substituted or C1~C6The sulfonyl that alkyl replaces;R3、R4It is hydrogen;R5For C1~C6Alkyl。
2. Thienopyrimidine analog derivative according to claim 1, it is characterised in that be the compound with following chemical structural formula:
3. the preparation method of the Thienopyrimidine analog derivative that the formula I described in a claim 1 represents, it is characterised in that include the step in following route 3. or step 1. and 3. step 2. and 3. or step 1.~3.:
The definition of Ar, A, D, E and R in described route is all as described in the appended claim 1。
4. the preparation method of the Thienopyrimidine analog derivative that formula I according to claim 3 represents, it is characterised in that: 3. described step is the Suzuki coupling reaction carried out under Pd-catalyst action。
5. the preparation method of the Thienopyrimidine analog derivative that the formula II described in a claim 1 represents, it is characterised in that include the step in following route 5. or step 2. and 5. step 4. and 5. or step 2., 4. and 5.:
The definition of Ar, A, D, E and R in described route is all as described in the appended claim 1。
6. the preparation method of the Thienopyrimidine analog derivative that formula II according to claim 5 represents, it is characterised in that: 5. described step is the Suzuki coupling reaction carried out under Pd-catalyst action。
7. the preparation method of the Thienopyrimidine analog derivative that the general formula III described in a claim 1 represents, it is characterised in that include the step in following route 6. or step 2. and 6.:
The definition of Ar, A, D, E and R in described route is all as described in the appended claim 1。
8. the preparation method of the Thienopyrimidine analog derivative that general formula III according to claim 7 represents, it is characterised in that: 6. described step is the Suzuki coupling reaction carried out under Pd-catalyst action。
9. the preparation method of the Thienopyrimidine analog derivative according to claim 4,6 or 8, it is characterized in that: described Pd-catalyst is double; two (triphenylphosphine) palladium of dichloro, tetrakis triphenylphosphine palladium or [1,1'-double; two (diphenylphosphine) ferrocene] palladium chloride。
10. the preparation method of the Thienopyrimidine analog derivative that the formula II described in a claim 1 represents, it is characterised in that: the Thienopyrimidine analog derivative represented by formula I carries out reduction of amide reaction。
11. the preparation method of the Thienopyrimidine analog derivative that formula II according to claim 10 represents, it is characterised in that: the reducing agent carrying out reduction of amide reaction is LiAlH4, red aluminum or borane complex。
12. a tyrosine kinase inhibitor, it is characterised in that: comprise the Thienopyrimidine analog derivative described in claim 1 or described derivant pharmaceutically acceptable salt。
13. tyrosine kinase inhibitor as claimed in claim 12, it is characterised in that: described inhibitor refers to EGFR and/or VEGFR inhibitor。
14. the application that EGFR and/or the VEGFR inhibitor described in claim 13 is in the medicine of preparation prevention or treatment and EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR relevant disease。
15. apply as claimed in claim 14, it is characterised in that: described medicine is the medicine of the abnormal cell proliferation relevant to EGF-R ELISA EGFR and/or Angiogenesis factor receptors VEGFR, metamorphosis, hypoerkinesia, angiogenesis, tumor growth and/or transfer。
16. tyrosine kinase inhibitor as claimed in claim 13, it is characterised in that: the active component in inhibitor is selected from compound or its pharmaceutically acceptable salt in detail below:
17. the tyrosine kinase inhibitor as described in claim 12 or 16, it is characterised in that: described Thienopyrimidine analog derivative pharmaceutically acceptable salt is inorganic acid salt or acylate。
18. tyrosine kinase inhibitor as claimed in claim 17, it is characterised in that: described Thienopyrimidine analog derivative pharmaceutically acceptable salt refers to any one or a few in hydrochlorate, hydrobromate, nitrate, sulfate, phosphate, formates, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, metilsulfate, ethyl sulfonate, benzene sulfonate, tosilate。
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