CN106946896A - The furans simultaneously amine derivative of [2,3 d] pyrimidine 4 - Google Patents

The furans simultaneously amine derivative of [2,3 d] pyrimidine 4 Download PDF

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CN106946896A
CN106946896A CN201710204740.0A CN201710204740A CN106946896A CN 106946896 A CN106946896 A CN 106946896A CN 201710204740 A CN201710204740 A CN 201710204740A CN 106946896 A CN106946896 A CN 106946896A
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phenyl
compound according
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alkyl
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CN106946896B (en
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王康敏
赵刚
刘继峰
蒲林
陈伟
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Chengdu Zhipulai Biomedicine Technology Co Ltd
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    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses the compound shown in a kind of formula (I) or its stereoisomer or its pharmaceutically acceptable salt or its solvate.Present invention also offers purposes of the aforesaid compound in antineoplastic, angiogenesis inhibitors, EFGR kinase inhibitors or AUR A kinase inhibitors is prepared.

Description

Furans simultaneously [2,3-d] pyrimidine -4- amine derivatives
Technical field
The present invention relates to furans simultaneously [2,3-d] pyrimidine -4- amine derivatives.
Background technology
Along with going from bad to worse for people's living environment, the continuous improvement of stress, global tumor patient increases year by year, But the chemicals poor selectivity of the conventional treatment tumour of tradition, toxic and side effect are by force and resistance problems are than more serious, far from Treatment can be met to require.Therefore, the anti-cancer agent for researching and developing efficient, low toxicity is particularly significant in current medical research and development field.
In recent years, further recognize from cell, molecular level with the development of Protocols in Molecular Biology and to pathogenesis Know, using the key enzyme in tumor development signal path as target spot, find the cancer therapy drug of efficient, low toxicity has turned into important Research direction.The molecular targeted therapy of tumour is different from traditional tumor therapeuticing method, and it is built upon oncomolecularbiology On the basis of research, its key enzyme is blocked using micromolecular compound to the critical path of tumour growth, so as to reach that blocking is swollen The effect of tumor cell growth.Molecular targeted therapy has preferable selectivity, the damage of normal tissue is reduced, and this is exactly Traditional chemical drug therapy is difficult to.
In numerous antineoplastic target spots, EGF-R ELISA (EGFR), that is, a protein-tyrosine Kinases (RTK) acceptor, is regulation cell growth, breeds, the important factor of the signal path of survival and migration.Cancer clinical is studied Show, these acceptors and its part and many tumours have important relation, many cancers occur in that the excess of relevant growth factors Expression, causes the incoming cell nrPTKs in tumor tissues of excessive tyrosine phosphorylation signal to be often activated, reactivation downstream Signal transduction path, promote cell propagation, resistance Apoptosis, promote tumour occurrence and development [Summy, J.M.； Gallick, G.E.Clin.Cancer Rev.2006,12,1398.] the most common activated mutants of show L858R, extron 21 single-point replaces the deletion (delE746-A750) with exons 19.The reversible epidermal growth factor receptor inhibitor of the first generation Gefitinib and Erlotinib.To there is the patient of these specific activated mutants to show significant clinical response in body (50-80%).However, the patient for producing secondary resistance mutation for these medicines can be answered by cancer in some months Hair.Second generation epidermal growth factor receptor inhibitor includes HKI-272, is replaced up to gram in Buddhist nun, the structure of these medicines of Afatinib All contain electrophilic group Michael- acceptors.Wherein so that Afatinib is pharmaceutical representative as an example, allyl amide structure is to Ah method Vital effect is played for the antitumor activity of Buddhist nun, it is used as michael acceptor and EGFR cysteine residues (Cys797) Michael addition reaction occurs for catalytic site (sulfydryl of nucleophilic), makes kinase-dead, irreversibly suppresses junket ammonia The activity of acid kinase, thus with good tolerance.Researchers further demonstrate these by substantial amounts of spectrum analysis The presence of covalent bond, and it was found that Afatinib passes through the Cys803 effects with HER2 Cys805 and HER4 and then strength Suppress these enzymes.Shown to Wild type EGFR testing in vitro, Afatinib is double prominent to Wild type EGFR and L858R/T790M The inhibitory action of modification has more preferable effect compared with Gefitinib, Erlotinib and Lapatinib.In addition, Afatinib 30 times of Lapatinib is higher than to HER4 inhibitory action, higher than 300 times of Gefitinib, higher than 500 times of Erlotinib.
Although Afatinib is better than Gefitinib and Erlotinib etc. in curative effect, its adverse reaction also has by comparison Improved.The adverse reaction of Afatinib is more, wherein diarrhoea, fash, oral inflammation, paronychia, loss of appetite, nosebleed, Itch, dry skin are very common, dehydration, sense of taste change, cystitis, cheilitis, heating, nasal obstruction, Diagnostic value, conjunctivitis, turn ammonia Enzyme rise, hand-foot syndrome, muscle cramp and injury of kidney are common, and keratitis is accidental with pneumonia.
The content of the invention
To solve the above problems, the invention provides the compound shown in formula (I) or its stereoisomer or its pharmacy Upper acceptable salt or its solvate：
Wherein,
R1Selected from A class groups, R2Selected from B class groups；Or, R1Selected from B class groups, R2Selected from A class groups；
The A classes group is selected from phenyl or heteroaryl, wherein the phenyl or heteroaryl are separately optionally further By halogen, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Haloalkyl replaced；
The B classes group is selected from
Wherein m is 0 or 1, n are 0 or 1, and m it is different with n when be 0；
X is representedX phenyl end and the furan nucleus of pyrimido furan nucleus It is connected；
Y is representedWhen m is 0, Y phenyl end is connected with the furan nucleus of pyrimido furan nucleus； When m is not 0, Y phenyl end is connected with X；
Z is selected from hydrogen, halogen, aryl or-N (Ra)(Rb)；
RaAnd RbSeparately it is selected from C1-C6Alkyl；Or, RaAnd RbTogether with the nitrogen-atoms being connected jointly with them Saturated heterocyclyl is formed, the saturated heterocyclyl is optionally further by hydroxyl or C1-C6Alkyl replaced；
R3、R4Hydrogen, phenyl or-C (O) Rc are separately selected from, wherein the phenyl is optionally further one or more Halogen is replaced, RCSelected from C1-C6Alkyl；
R5Selected from hydrogen or-SO2-Rd, wherein RdSelected from C1-C6Alkyl.
Further, R3And R4It is simultaneously hydrogen.
Further, R5For hydrogen.
Further, shown in the compound such as following formula (I a)：
Further, when A classes group is selected from heteroaryl, the heteroaryl is 5 yuan of rings or 6 yuan of rings.
Further, the heteroaryl is selected from pyridine radicals or pyrrole radicals.
Further, when A classes group is selected from the phenyl of substitution, substituent is selected from fluorine, chlorine, bromine, C1-C3Alkyl, methoxy Any of base, trifluoromethyl are a variety of.
Further, in the structure that the X or Y are represented, the substituent on phenyl is located at 3 or 4 of the phenyl.
Further, when A classes group is selected from the phenyl or substituted heteroaryl of substitution, the quantity of substituent is 1~3.
Further, when Z is selected from aryl, the aryl is the phenyl of phenyl, the phenyl that amino replaces or nitro substitution.
Further, R is worked asaAnd RbWhen forming saturated heterocyclyl together with the nitrogen-atoms being connected jointly with them, the saturation Heterocyclic radical is 6 yuan of rings.
Further, the saturated heterocyclyl is piperidyl, morpholinyl or piperazinyl.
Further, R is worked asaAnd RbWhen forming saturated heterocyclyl together with the atom being connected jointly with them, the saturation is miscellaneous Ring group is further by hydroxyl, C1-C6Alkyl or-NH-Pg replaced, wherein Pg represents amino protecting group.
Further, the compound is one of following compound：
Present invention also offers foregoing compound or its stereoisomer or its pharmaceutically acceptable salt or its is molten Use of the agent compound in preparing in antineoplastic, angiogenesis inhibitors, EFGR kinase inhibitors or AUR A kinase inhibitors On the way.
Further, the tumour be liver cancer, lung cancer, neurogliocytoma, astrocytoblast knurl, cervical carcinoma, Colon cancer or breast cancer.
In the present invention：
It is asymmetric for example that " stereoisomer " includes Stereocenter (such as the carbon with 4 different substituents), axle There is the presence of crucial, planar unsymmetrical and its mixture.Stereoisomer includes enantiomer, diastereomer, epimer, outer Raceme and the mesomeric compound with internal symmetry face.
" pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or the salt formed is usual In chemistry or physically with constituting the other compatible into split-phase of certain pharmaceutical dosage form, and physiologically compatible with by body phase.
The C1-C6Alkyl refer to C1、C2、C3、C4、C5、C6Alkyl, i.e., straight chain or branch with 1~6 carbon atom The alkyl of chain, such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, hexyl etc..
" amino protecting group " nitrogen-atoms that may be connected on amino will be referred to so as to protect the amino be not involved in reaction and The group easily removed in the reaction that it can be below.Suitable amino protecting group includes, but are not limited to following protection groups：
Formula-C (O) O-R carbamate groups, wherein R such as methyl, ethyl, the tert-butyl group, benzyl, phenethyl, CH2 =CH-CH2-, etc.；Formula-C (O)-R ' amide group, wherein R ' such as methyl, ethyl, phenyl, trifluoromethyl, etc.； Formula-SO2- R " N- sulfonyl-derivatives-group, wherein R " such as tolyl, phenyl, trifluoromethyl, 2,2,5,7,8- five first Full -6- the bases of primary colours -, 2,3,6- trimethyl -4- methoxybenzenes, etc..
Result of the test shows that the compounds of this invention swashs available for antineoplastic, angiogenesis inhibitors or EFGR is prepared Enzyme inhibitor.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other diversified forms can also be made, replaces or changes.
The embodiment of form, remakes further specifically to the above of the invention by the following examples It is bright.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following example.It is all to be based on the above of the present invention The technology realized belongs to the scope of the present invention.
Brief description of the drawings
Fig. 1 is that the compounds of this invention is as shown in Figure 1 to hepatoma Hep G 2 cells inhibitory activity test result.
Fig. 2 is that the compounds of this invention is as shown in Figure 2 to lung cancer A549 cell inhibitory activity test result
Embodiment
The compounds of this invention and intermediate are prepared essentially according to following routes：
Scheme one：
The synthetic method reference literature Bioorganic＆Medicinal Chemistry Letters of intermediate compound I and II 15(2005)2203–2207。
Intermediate (E) -4- bromine but-2-ene acyl chlorides III synthesis：
(E) -4- bromocrotonic acids methyl esters (6g, 33.5mmol) is dissolved in THF (60mL) is cold to be gone to 0 DEG C, is dripped under N2 protections Add the aqueous solution (20mL) of a hydronium(ion) lithia (1.83g, 43.6mmol).After 15min is dripped off, 0 DEG C of stirring 3h is kept.So Cold water (150mL) and petroleum ether (200mL) are added into the system afterwards to continue to stir 10min at 0 DEG C.Aqueous phase is separated, at 0 DEG C with dense Hydrochloric acid adjusts PH and extracted to 1, then with dichloromethane (80mLx3).Merge and concentrated after organic phase, anhydrous sodium sulfate drying, obtain E- 4- bromocrotonic acid III, yellow solid (4.5g, yield 82%).
Be mixed with E-4- bromocrotonic acids III and 1 drop DMF DCM (3mL) solution in be added dropwise to oxalyl chloride (250mg, 1.96mmol).After dripping, stirring 1h is warmed to room temperature.Reaction terminates, concentrated solvent, obtains intermediate (E) -4- bromine but-2-enes Acyl chlorides IV, without further processing, is directly used in next step reaction.
Scheme two：
Scheme three：
Reference literature WO2005121149A1, which can be synthesized, obtains intermediate X II.
Scheme four：
Scheme five
The compound C-14 of embodiment 1 preparation
Intermediate compound I (1g, 3.01mmol) is dissolved in THF, triethylamine (0.6g, 6.02mmo) is added, is then added dropwise to chloroethene Acyl chlorides (0.37g, 3.31mmol).After liquid phase monitoring reaction completely, instillation 3, which is dripped, is quenched reaction, concentrated solvent.In residue Water is added, dichloromethane extraction merges organic phase.Saturated ammonium chloride washs organic phase, anhydrous sodium sulfate drying, concentrated solvent. Residue carries out pillar layer separation, obtains compound 0.88g, white solid (yield 72%).
1H NMR (400MHz, CDCl3) δ ppm:3.80 (s, 3H), 4.25 (s, 2H), 6.81-6.83 (d, J=9.2Hz, 2H), 7.46-7.51 (m, 4H), 7.73-7.76 (d, J=7.6Hz, 1H), 8.37 (s, 1H), 8.3,9 (s, 1H).
The compound C-13 of embodiment 2 preparation
By potassium carbonate (0.89g, 6.47mmol) plus compound c-14 (0.88g, 2.15mmol) acetonitrile, two are then added Methylamine hydrochloride (0.17g, 2.15mmol), T LC monitoring reactions, stirs 5h.Reaction terminates, and filters, and a small amount of acetonitrile washing is solid Body, concentrated mother liquor.Residue is subjected to pillar layer separation, compound 0.55g (yield 61%) is obtained.
1HNMR(DMSO)δ:9.33 (s, 1H), 8.36 (s, 1H), 7.76-7.78 (m, 2H), 7.45-7.49 (m, 4H), 6.80-6.84(m,2H),4.93(s,2H),3.80(s,3H),3.14(s,2H),2.43(s,6H)；
The compound C-11 of embodiment 3 preparation
Its preparation method is c-14 and N methyl piperazine with reference to embodiment 2, raw material, and product is white solid, yield 60% 。1HNMR(DMSO)δ:9.33 (s, 1H), 8.36 (s, 1H), 7.74-7.76 (m, 2H), 7.46-7.52 (m, 4H), 6.81-6.83 (m,2H),4.92(s,2H),3.80(s,3H),3.20(s,2H),2.51-2.71(m,8H),2.35(s,3H)；
The compound C-5 of embodiment 4 preparation
Intermediate compound I 0.5g (1.08mmol) is dissolved in THF, triethylamine 0.22g (2.18mmol) is added, is then added dropwise to Above-mentioned (the E) -4- bromine but-2-ene acyl chlorides IV 0.195g (1.08mmol) prepared.After liquid phase monitoring reaction completely, concentration Solvent.Water is added in residue, dichloromethane extraction merges organic phase.Saturated ammonium chloride washs organic phase, anhydrous sodium sulfate Dry, concentrated solvent, obtain intermediate compound IV white solid without further handling, be directly used in next step.
In the acetonitrile solution that potassium carbonate 0.60g (4.32mmol) is added to the above-mentioned intermediate V prepared, then add Dimethylamine hydrochloride 0.089g (1.08mmol), T LC monitoring reaction, stir 5h.Reaction terminates, and filters, and a small amount of acetonitrile washing is solid Body, concentrated mother liquor.Residue is subjected to column chromatography separating purification (methylene chloride/methanol makees eluant, eluent), white solid (c- is obtained 5) 0.40g, yield 64%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.45(s,6H),3.44(s,2H),3.75(s,3H),6.38-6.42 (d, J=15.2Hz, 1H), 6.75-6.79 (m, 1H), 6.93-6.95 (d, J=8.8Hz, 1H), 7.37-7.39 (d, J= 8.8Hz, 2H), 7.43-7.45 (d, J=8.4Hz, 2H), 7.84-7.86 (d, J=8.8Hz, 2H), 8.23 (s, 1H), 10.40 (s, 1H).
The compound C-1 of embodiment 5 preparation
Its preparation method is with reference to the intermediate V of embodiment 4 synthesis, and raw material is intermediate compound I and acryloyl chloride, and product is white Solid, yield 72%.
1H NMR (400MHz, DMSO-d6) δ ppm:3.80 (s, 3H), 4.92 (s, 2H), 5.84-5.87 (dd, J= 10.0Hz, 1.2Hz, 1H), 6.31-6.32 (dd, J=16.8Hz, 10.0Hz, 1H), 6.47 (d, J=2.0Hz, 1H), 6.49- 6.51 (dd, J=16.8Hz, 1.2Hz, 1H), 6.80-6.83 (d, J=12.0Hz, 2H), 7.42 (s, 1H), 7.46-7.50 (m, 4H), 7.76-7.78 (d, J=8.8Hz, 2H), 8.36 (s, 1H).
The compound C-6 of embodiment 6 preparation
Its preparation method is with reference to the synthesis of embodiment 4, and raw material is intermediate II and piperidines, and product is white solid, yield 59%.
1H NMR (400MHz, CDCl3) δ ppm:1.47(m,2H),1.61-1.64(m,4H),2.45(s,4H),3.17- 3.19 (dd, J=5.6Hz, 2H), 3.80 (s, 3H), 4.90 (s, 2H), 6.13-6.17 (d, J=15.2Hz, 1H), 6.80- 6.82 (d, J=8.0Hz, 2H), 6.99-7.07 (m, 1H), 7.36 (s, 1H), 7.45-7.49 (m, 4H), 7.73-7.75 (d, J =8.4Hz, 2H), 8.36 (s, 1H).
The compound C-4 of embodiment 7 preparation
Its preparation method is with reference to the intermediate V of embodiment 4 synthesis, and raw material is intermediate II and acryloyl chloride, and product is white Color solid, yield 66%.
1H NMR (400MHz, CDCl3) δ ppm:3.80 (s, 3H), 5.17 (s, 2H), 5.81-5.84 (d, J=11.2Hz, 1H), 6.23-6.29 (dd, J=16.8Hz, 10.0Hz, 1H), 6.44-6.48 (d, J=16.8Hz, 1H), 6.81-6.83 (d, J =8.8Hz, 2H), 7.24 (s, 1H), 7.42 (s, 1H), 7.44-7.51 (m, 4H), 7.65 (s, 1H), 7.74-7.76 (d, J= 7.6Hz, 1H), 8.35 (s, 1H).
The compound C-7 of embodiment 8 preparation
Its preparation method is with reference to the synthesis of embodiment 4, and raw material is intermediate II and N methyl piperazine, and product is solid for white Body, yield 63%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.15bs, 3H), 2.34 (s, 6H), 3.10-3.11 (d, J= 4.8Hz, 2H), 3.75 (s, 3H), 6.24-6.28 (d, J=15.6Hz, 1H), 6.68-6.74 (m, 1H), 6.93-6.95 (d, J =9.2Hz, 2H), 7.15-7.17 (d, J=7.6Hz, 1H), 7.38-7.41 (d, J=9.2Hz, 2H), 7.48-7.52 (d, J= 8.4Hz, 7.6Hz, 1H), 7.78-7.80 (m, 2H), 8.24 (s, 1H), 10.25 (s, 1H).
The compound C-6 of embodiment 9 preparation
Its preparation method is with reference to the synthesis of embodiment 4, and raw material is intermediate II and dimethylamine, and product is white solid, is received Rate 58%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.72 (s, 6H), 3.75 (s, 3H), 3.87-3.88 (d, J= 5.2Hz, 2H), 6.47-6.51 (d, J=15.2Hz, 1H), 6.75-6.80 (m, 1H), 6.93-6.95 (d, J=9.2Hz, 2H), 7.19-7.21 (d, J=7.6Hz, 1H), 7.38-7.41 (d, J=9.2Hz, 2H), 7.51-7.55 (t, J=8.0Hz, 1H), 7.82-7.85 (m, 2H), 8.25 (s, 1H), 10.67 (s, 1H).
The compound C-16 of embodiment 10 preparation
Its preparation method is with reference to the synthesis of embodiment 4, and raw material is intermediate II and piperidines, and product is white solid, yield 58%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.38-1.52 (s, 6H), 2.34 (s, 4H), 3.10-3.11 (d, J= 4.8Hz, 2H), 3.75 (s, 3H), 6.23-6.27 (d, J=15.2Hz, 1H), 6.68-6.72 (m, 1H), 6.93-6.95 (d, J =8.8Hz, 2H), 7.15-7.17 (d, J=7.6Hz, 1H), 7.39-7.41 (d, J=8.8Hz, 2H), 7.48-7.52 (d, J= 8.4Hz, 8.0Hz, 1H), 7.79 (s, 2H), 8.25 (s, 1H), 10.25 (s, 1H).
The compound C-18 of embodiment 11 preparation
Its preparation method is with reference to the synthesis of embodiment 4, and raw material is intermediate II and morpholine, and product is white solid, yield 60%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.40 (s, 6H), 2.34 (s, 2H), 3.10-3.11 (t, J= 4.4Hz, 4H), 3.74 (s, 3H), 6.31-6.35 (d, J=15.6Hz, 1H), 6.74-6.79 (m, 1H), 6.92-6.94 (d, J =8.8Hz, 2H), 7.37-7.38 (d, J=9.2Hz, 2H), 7.42-7.44 (d, J=8.4Hz, 2H), 7.83-7.85 (d, J= 8.8Hz, 2H), 8.23 (s, 2H), 10.30 (s, 1H).
The compound C-21 of embodiment 12 preparation
Its preparation method is with reference to the synthesis of embodiment 4, and raw material is intermediate compound I and morpholine, and product is white solid, yield 61%.
1H NMR (400MHz, DMSO-d6) δ ppm:10.31 (s, 1H), 8.24 (s, 1H), 7.86-7.83 (d, J= 8.4Hz, 2H), 7.44-7.37 (m, 4H), 6.95-6.92 (d, J=8.8Hz, 2H), 6.79-6.74 (m, 1H), 6.35-6.31 (d, J=15.2Hz, 1H), 3.75 (s, 3H), 3.63-3.60 (J=4.4Hz, J=4.4Hz, 4H), 3.15-3.14 (d, J= 5.6Hz,2H),2.41(m,4H)。
The compound C-20 of embodiment 13 preparation
Ethamine 2.53g is sequentially added into tetrahydrofuran (50ml) solution of intermediate (I) (3.32g, 10mmol) (25mmol), m-nitro isocyanates 1.64g (10mmol), is finished, and after room temperature reaction 30min, concentrated solvent obtains crude product. Crude product ethyl acetate is beaten, and is filtered, and is dried, is obtained compound faint yellow solid 4.46g, yield 90%.
1H NMR (400MHz, DMSO-d6) δ ppm:3.75 (s, 3H), 6.96-6.94 (d, J=9.2Hz, 2H), 7.44- 7.40 (m, 4H), 7.61-7.57 (q, J=8.4Hz, J=8.0Hz, 1H), 7.69-7.66 (d, J=8.4Hz, 2H), 7.76- 7.74 (d, J=8.0Hz, 1H), 7.86-7.84 (d, J=8.4Hz, 1H), 8.24 (s, 1H), 8.35 (s, 1H), 8.59-8.58 (q, J=2.4Hz, J=2Hz, 1H), 9.11 (s, 1H), 9.33 (s, 1H)
The compound C-9 of embodiment 14 preparation
Its preparation method is with reference to the synthesis of embodiment 13, and raw material is intermediate II and m-nitro isocyanates, and product is Faint yellow solid, yield 83%.
1H NMR (400MHz, DMSO-d6) δ ppm:3.76 (s, 3H), 6.94-6.96 (d, J=8.8Hz, 2H), 7.06- 7.15 (m, 3H), 7.41-7.63 (m, 4H), 7.70-7.73 (d, J=8.8Hz, 2H), 8.27 (s, 1H), 8.59-8.58 (t, J =2.4Hz, J=2Hz, 1H), 9.07 (s, 1H), 9.29 (s, 1H).
The compound C-22 of embodiment 15 preparation
The compound of embodiment 13 (1.32g, 2.66mmol) is added into 10ml ethanol, the mixing of 10ml water and 1.2ml acetic acid After liquid, 70 DEG C are warming up to, 0.62g iron powders is added and continues to stir 2h in the temperature.Reaction terminates, and filters, and takes mother liquor concentrations.Residual Thing adjusts PH to 9 with sodium hydrate aqueous solution, adds ethyl acetate 50mlx3 extractions.Merge organic phase, saturated sodium-chloride washing is done Dry organic phase, is concentrated to dryness, and obtains crude product.By crude product column chromatography separating purification (methylene chloride/methanol makees eluant, eluent), obtain White solid 0.99g, yield 80%.
1H NMR (400MHz, DMSO-d6) δ ppm:3.75 (s, 3H), 5.05 (s, 2H), 6.21-6.20 (d, J= 8.0Hz, 1H), 6.59-6.57 (d, J=8.0Hz), 6.79 (s, 1H), 6.96-6.89 (m, 3H), 7.42-7.37 (m, 4H), (s, the 1H) of 7.64-7.62 (d, J=8.4Hz, 2H), 8.23 (s, 1H), 8.49 (s, 1H), 8.84
The compound C-10 of embodiment 16 preparation
Its preparation method is with reference to the synthesis of embodiment 15, and raw material is embodiment 14, and product is white solid, yield 71%.
1H NMR (400MHz, DMSO-d6) δ ppm:3.76 (s, 3H), 5.02 (s, 2H), 6.17-6.19 (d, J= 8.0Hz, 1H), 6.52-6.55 (d, J=9.2Hz, 1H), 6.75 (s, 1H), 6.86-6.90 (t, J=8.0Hz, 1H), 6.94- 6.96 (d, J=9.2Hz, 2H), 7.05-7.07 (d, J=7.6Hz, 1H), 7.42-7.47 (m, 3H), 7.54-7.56 (d, J= 8.4Hz, 1H), 7.62 (s, 1H), 8.25 (s, 1H), 8.42 (s, 1H), 8.76 (s, 1H).
The compound C-24 of embodiment 17 preparation
Preparation method is with reference to implementing 4, and raw material is embodiment 15 and dimethylamine, and product is white solid, yield 53%.
1H NMR (400MHz, DMSO-d6) δ ppm:10.15(s,1H),9.30(m,1H),9.15(m,1H),8.24(s, 1H), 7.85 (s, 1H), 7.66-7.64 (d, J=8.8Hz, 2H), 7.42-7.39 (m, 4H), 7.35 (m, 1H), 7.22-7.21 (d, J=5.2Hz, 2H), 6.96-6.94 (d, J=7.6Hz, 2H), 6.77-6.70 (m, 1H), 6.35-6.31 (d, J= 14.4Hz,1H),3.75(s,3H),3,17(s,2H),2.26(s,6H)。
The compound C-23 of embodiment 18 preparation
Preparation method is with reference to implementing 17, and raw material is embodiment 15 and piperidines, and product is white solid, yield 55%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.54-1.40(m,6H),2.37-2.33(m,4H),3.10(s, 2H), 3.75 (s, 3H), 6.31-6.27 (d, J=16.0Hz, 1H), 6.76-6.70 (m, 1H), 6.96-6.94 (d, J= 8.8Hz, 2H), 7.22-7.20 (d, J=6.4Hz, 2H), 7.30 (m, 1H), 7.42-7.39 (m, 4H), 7.66-7.64 (d, J= 8.4Hz,2H),7.89(s,1H),8.24(s,1H),8.96-8.91(m,2H),10.08(s,1H)。
The compound C-19 of embodiment 19 preparation
Preparation method is embodiment 16 and piperidines with reference to embodiment 17, raw material, and product is white solid, yield 53%.
1H NMR (400MHz, DMSO-d6) δ ppm:1H NMR (400MHz, DMSO-d6) δ ppm:1.39-1.52(m,6H), 14.2.39 (s, 4H), 3.07 (s, 2H), 3.75 (s, 3H), 6.24-6.28 (d, J=14.8Hz, 1H), 6.68-6.75 (m, 1H), 6.94-6.96 (d, J=8.8Hz, 2H), 7.07-7.20 (m, 3H), 7.28-7.30 (d, J=14.8Hz, 1H), 7.41- 7.48 (m, 3H), 7.55-7.57 (d, J=8.4Hz, 2H), 7.63 (s, 1H), 7.84 (s, 1H), 8.24 (s, 1H), 8.78- 8.82 (d, J=14Hz, 2H), 10.08 (s, 1H).
The compound C-12 of embodiment 20 preparation
Preparation method is embodiment 16 and acryloyl chloride with reference to embodiment 17, raw material, and product is white solid, yield 53%.
1H NMR (400MHz, DMSO-d6) δ ppm:3.76 (s, 3H), 5.73-5.76 (m, 1H), 6.22-6.27 (dd, J =16.8Hz, 2.0Hz, 1H), 6.41-6.47 (dd, J=16.8Hz, 10.0Hz, 1H), 6.94-6.96 (d, J=7.2Hz, 2H), 6.94-6.96 (d, J=7.6Hz, 1H), 7.14-7.22 (m, 2H), 7.31-7.33 (d, J=7.6Hz, 1H), 7.41- 7.49 (m, 3H), 7.56-7.58 (d, J=9.2Hz, 1H), 7.64 (s, 1H), 7.87 (s, 1H), 7.87 (s, 1H), 8.25 (s, 1H), 8.84-8.87 (d, J=14.8Hz, 2H), 10.12 (s, 1H).
The compound C-45 of embodiment 21 preparation
Method one
This method one is with reference to the synthesis of embodiment 4, and raw material is 4- fluorine bromoacetophenones, raw material 4- fluorine bromoacetophenone and two Methylamine hydrochloride, product is white solid.
1H NMR (400MHz, DMSO-d6) δ ppm:2.22 (s, 6H), 3.09-3.10 (d, J=4.8Hz, 2H), 6.30- 6.34 (d, J=15.2Hz, 1H), 6.74-6.80 (m, 1H), 7.21-7.25 (t, J=9.2,6.8Hz, 2H), 7.43-7.48 (m, 4H), 7.85-7.87 (d, J=8.8Hz, 2H), 8.26 (s, 1H), 10.32 (s, 1H).
Method two
The reference literature W03022852A2 of method two, which can be synthesized, obtains intermediate X I, with reference to the synthetic method of embodiment 4 Synthesized by intermediate X I and obtain embodiment 22.
The compound C-32 of embodiment 22 preparation
Raw material 4- bromoacetyls yl pyridines and dimethylamine hydrochloride, product are white solid, yield 41%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.31 (s, 6H), 3.26 (s, 2H), 6.36-6.40 (d, J= 15.2Hz, 1H), 6.76-6.83 (m, 1H), 7.41-7.44 (m, 1H), 7.46-7.49 (d, J=12.4Hz, 2H), 7.81- 7.84 (m, 1H), 7.88-7.90 (d, J=8.4Hz, 2H), 8.30 (s, 1H), 8.50-8.51 (m, 1H), 8.57-8.58 (d, J =1.6Hz, 1H), 10.45 (s, 1H)；
The compound C-25 of embodiment 23 preparation
Preparation method is with reference to embodiment 21, raw material 4- fluorine bromoacetophenone and 3- t-butoxycarbonyl amino piperidines, and product is White solid, yield 50%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.05-1.178 (m, 2H), 1.38 (s, 9H), 1.49-1.88 (m, 5H), 2.69-2.81 (m, 2H), 3.14-3.15 (d, J=5.2Hz, 2H), 6.28-6.32 (d, J=15.2Hz, 1H), 6.74- 6.80 (m, 2H), 7.21-7.25 (t, J=9.2Hz, 8.8Hz, 1H), 7.49-7.50 (m, 4H), 7.85-7.87 (d, J= 8.4Hz, 2H), 8.26 (s, 1H), 10.31 (s, 1H).
The compound C-27 of embodiment 24 preparation
Preparation method is with reference to embodiment 21, raw material bromoacetophenone and dimethylamine hydrochloride, and product is white solid, yield 50%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.72 (s, 6H), 3.87 (d, J=4.8Hz, 2H), 6.55-6.59 (d, J=15.2Hz, 1H), 6.83-6.87 (m, 1H), 7.32-7.46 (m, 7H), 7.91-7.93 (d, J=8.4Hz, 2H), 8.27 (s, 1H), 10.82 (s, 1H).
The compound C-28 of embodiment 25 preparation
Preparation method is with reference to embodiment 8, raw material bromoacetophenone and piperidines, and product is white solid, yield 51%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.40-1.532(m,6H),2.33-2.36(m,4H),3.10-3.11 (d, J=4.4Hz, 2H), 6.24-6.28 (d, J=15.6Hz, 1H), 6.72-6.76 (m, 1H), 7.17-7.19 (d, J= 7.6Hz, 1H), 7.33-7.37 (m, 3H), 7.46-7.53 (m, 3H), 7.80 (d, J=6.4Hz, 2H), 8.28 (s, 1H), 10.28 (s, 1H).
The compound C-29 of embodiment 26 preparation
Preparation method is with reference to embodiment 8, the bromo- 1- of raw material 2- (1- methyl isophthalic acid H- pyrazoles -4- bases) ethyl ketones and piperidines, and product is White solid, yield 43%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.50-1.70(m,6H),2.87(m,4H),3.65(m,2H),3.83 (s, 3H), 6.46-6.50 (d, J=15.2Hz, 1H), 6.82-6.87 (m, 1H), 7.34 (s, 1H), 7.46-7.48 (d, J= 8.4Hz, 2H), 7.88-7.91 (q, J=4.8Hz, J=4.8Hz, 3H), 8.21 (s, 1H), 10.59 (s, 1H)；
The compound C-37 of embodiment 27 preparation
Preparation method is with reference to embodiment 21, raw material 4- fluorine bromoacetophenone and piperidines, and product is white solid, yield 50%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.42-1.56(m,6H),2.49(s,4H),3.22(s,2H), 6.32-6.35 (d, J=15.2Hz, 1H), 6.76-6.81 (m, 1H), 7.21-7.25 (t, J=8.8Hz, 1H), 7.44-7.48 (m, 4H), 7.85-7.87 (d, J=8.4Hz, 2H), 8.26 (s, 1H), 10.34 (s, 1H).
The compound C-31 of embodiment 28 preparation
Preparation method is with reference to embodiment 8, raw material bromoacetophenone and 4- hydroxy piperidines, and product is white solid, yield 50%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.35-1.45(m,2H),1.65-1.78(m,2H),1.95-2.15 (m, 2H), 2.63-2.75 (m, 2H), 3.16-3.17 (d, J=5.0Hz, 2H), 4.60 (m, 2H), 6.24-6.28 (d, J= 15.6Hz, 1H), 6.71-6.77 (m, 1H), 7.17-7.19 (d, 7.2Hz, 1H), 7.33-7.53 (m, 5H), 7.80-7.81 (m, 2H), 10.28 (s, 1H).
The compound C-30 of embodiment 29 preparation
Preparation method is with reference to embodiment 22, raw material 4- bromoacetyls yl pyridines and piperidines, and product is white solid, yield 43%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.40(m,2H),1.52-1.55(m,4H),2.37(m,4H), 3.10-3.12 (d, J=5.2Hz, 2H), 6.29-6.33 (d, J=15.6Hz, 1H), 6.75-6.82 (m, 1H), 7.41-7.44 (m, 1H), 7.45-7.49 (d, J=12.8Hz, 2H), 7.82-7.84 (m, 1H), 7.86-7.89 (d, J=8.8Hz, 2H), 8.30 (s, 1H), 8.50-8.51 (m, 1H), 8.57-8.58 (d, J=1.6Hz, 1H), 10.33 (s, 1H).
The compound C-33 of embodiment 30 preparation
Preparation method is with reference to embodiment 8, raw material 3- bromoacetophenones and dimethylamine hydrochloride, and product is white solid, receives Rate 41%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.18 (s, 6H), 3.05-3.06 (d, J=4.8Hz, 2H), 3.86 (s, 3H), 6.26-6.30 (d, J=15.6Hz, 1H), 6.54 (s, 1H), 6.70-6.76 (m, 1H), 7.06-7.08 (m, 1H), 7.17-7.19 (d, J=8.8Hz, 2H), 7.25-7.30 (m, 2H), 7.40 (s, 2H), 7.65-7.67 (d, J=8.8Hz, 2H), 8.09(s,1H),10.13(s,1H)。
The compound C-35 of embodiment 31 preparation
Preparation method is with reference to embodiment 22, raw material 3, the trifluoromethyl bromoacetophenones of 5- bis- and piperidines, and product is solid for white Body, yield 41%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.40(m,2H),1.50-1.51(m,4H),2.35(m,4H), 3.08-3.09 (d, J=5.2Hz, 2H), 6.23-6.27 (d, J=15.6Hz, 1H), 6.71-6.76 (m, 1H), 7.22-7.24 (d, J=7.6Hz, 1H), 7.53-7.56 (q, J=7.6Hz, J=8.0Hz, 1H), 7.79-7.81 (d, J=8.4Hz, 1H), 7.91-7.94(m,3H),8.08(s,1H),8.34(s,1H),10.29(s,1H)。
The compound C-43 of embodiment 32 preparation
Preparation method is with reference to embodiment 21, raw material 3,4,5- trimethoxies bromoacetophenone and dimethylamine, and product is white Solid, yield 41%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.19 (s, 6H), 3.07-3.08 (d, J=5.2Hz, 2H), 3.58 (s, 6H), 3.65 (s, 3H), 6.29-6.33 (d, J=15.6Hz, 1H), 6.72 (s, 2H), 6.76-6.80 (m, 1H), 7.47- 7.49 (d, J=8.8Hz, 2H), 7.86-7.88 (d, J=8.4Hz, 2H), 8.25 (s, 1H), 10.30 (s, 1H)；
The compound C-44 of embodiment 33 preparation
Preparation method is with reference to embodiment 21, raw material 3,4,5- trimethoxies bromoacetophenone and piperidines, and product is solid for white Body, yield 41%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.30(m,2H),1.52-1.55(m,4H),2.37(m,4H), 3.10-3.12 (d, J=5.2Hz, 2H), 3.58 (s, 6H), 3.65 (s, 3H), 6.28-6.32 (d, J=15.2Hz, 1H), 6.72 (s, 2H), 6.74-6.81 (m, 1H), 7.47-7.49 (d, J=8.4Hz, 2H), 7.86-7.88 (d, 8.4Hz, 2H), 8.25 (s, 1H),10.29(s,1H)；
The compound C-46 of embodiment 34 preparation
Preparation method is with reference to embodiment 21, raw material bromoacetophenone and piperidines, and product is white solid, yield 50%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.35-1.55 (m, 6H), 2.29-2.39 (m, 4H), 3.11 (d, J= 4.8Hz, 2H), 6.28-6.32 (d, J=15.2Hz, 1H), 6.75-6.80 (m, 1H), 7.32-7.44 (m, 7H), 7.85-7.87 (d, J=8.8Hz, 2H), 8.26 (s, 1H), 10.30 (s, 1H).
The compound C-8 of embodiment 35 preparation
Preparation method is with reference to embodiment 21, raw material 3,4,5- trimethoxies bromoacetophenone and piperidines, and product is solid for white Body, yield 41%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.40-1.70 (m, 6H), 2.87 (m, 4H), 3.58 (s, 6H), 3.66 (s, 3H), 3.88 (s, 2H), 6.43-6.47 (d, J=14.8Hz, 1H), 6.74 (s, 2H), 6.77-6.82 (m, 1H), 7.26- 7.28 (d, J=7.6Hz, 1H), 7.55-7.59 (t, J=8.07.6Hz, 7.6Hz, 1H), 7.80-7.82 (d, J=8.0Hz, 1H), 7.85 (s, 1H), 8.28 (s, 1H), 10.58 (s, 1H).
The compound C-15 of embodiment 36 preparation
Preparation method is with reference to embodiment 22, raw material 3, the trifluoromethyl bromoacetophenones of 5- bis- and dimethylamine hydrochloride, product For white solid, yield 41%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.17 (s, 6H), 3.05-3.06 (d, J=4.8Hz, 2H), 6.24- 6.28 (d, J=15.2Hz, 1H) 6.71-6.75 (m, 1H), 7.22-7.24 (d, J=7.6Hz, 1H), 7.52-7.56 (q, J1= J2=8.0Hz, 1H), 7.78-7.80 (d, J=8.0Hz, 1H), 7.91-7.94 (d, J=12.4Hz, 3H), 8.08 (s, 1H), 8.34(s,1H),10.30(s,1H)。
The compound C-17 of embodiment 37 preparation
Preparation method is with reference to embodiment 22, raw material 3, the trifluoromethyl bromoacetophenones of 5- bis- and piperidines, and product is solid for white Body, yield 41%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.39-1.51(m,6H),2.25-2.39(m,4H),3.07-3.08 (d, J=5.2Hz, 2H), 6.23-6.27 (d, J=15.2Hz, 1H), 6.72-6.75 (m, 1H), 7.22-7.24 (d, J= 7.6Hz, 1H), 7.52-7.56 (q, J=8.0Hz, 7.6Hz, 1H), 7.78-7.80 (d, J=8.4Hz, 1H), 7.90-7.93 (d, J=12.4Hz, 3H), 8.34 (s, 1H), 8.34 (s, 1H), 10.29 (s, 1H).
The compound C-40 of embodiment 38 preparation
Preparation method is with reference to embodiment 22, raw material 3- bromo thiophenes ethyl ketone and piperidines, and product is white solid, yield 41%.
1H NMR (400MHz, DMSO-d6) δ ppm:1.43-1.54(m,6H),2.30-2.40(m,4H),3.14(s, 2H), 6.30-6.34 (d, J=15.2Hz, 1H), 6.75-6.82 (m, 1H), 6.88-6.89 (d, J=5.2Hz, 1H), 7.45- 7.47 (d, J=8.8Hz, 2H), 7.55-7.57 (m, 1H), 7.69-7.70 (m, 1H), 7.86-7.88 (d, J=8.8Hz, 2H), 8.34(s,1H),8.24(s,1H),10.29(s,1H)。
The compound C-2 of embodiment 39 preparation
Preparation method is with reference to embodiment 22, raw material 3- bromo thiophenes ethyl ketone and piperidines, and product is white solid, yield 41%.1H NMR (400MHz, DMSO-d6) δ ppm:1.40-1.65(m,9H),1.91(s,3H),2.20-2.25(m,3H), 2.37-2.46 (m, 4H), 2.99-3.02 (t, J=6.0Hz, 5.2Hz, 3H), 2.56-3.59 (m, 4H), 6.32-6.35 (d, J =15.2Hz, 1H), 6.76-6.85 (m, 1H), 7.42-7.53 (d, J=8.4Hz, 2H), 7.50-7.51 (d, J=9.2Hz, 2H), 7.84-7.86 (d, J=8.4Hz, 1H), 8.14-8.15 (d, J=2.4Hz, 1H), 8.22 (s, 1H), 10.29 (s, 1H).
The compound C-47 of embodiment 40 preparation
Preparation method is with reference to embodiment 21, raw material 3,4- dimethoxy bromo acetophenones and piperidines, and product is white solid, Yield 41%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.19 (s, 6H), 3.08-3.09 (d, J=5.6Hz, 2H), 3.55 (s, 3H), 3.74 (s, 3H), 6.29-6.33 (d, J=15.2Hz, 1H), 6.74-6.79 (m, 1H), 6.94-7.03 (m, 3H), 7.44-7.46 (q, J=8.4Hz, 2H), 7.84-7.86 (d, J=8.4Hz, 2H), 8.24 (s, 1H), 10.31 (s, 1H)；
The compound C-36 of embodiment 41 preparation
Preparation method is with reference to embodiment 21, raw material 3,5- dimethoxy bromo acetophenones and piperidines, and product is white solid, Yield 41%.
The compound C-39 of embodiment 42 preparation
Intermediate X II (100mg, 0.26mmol) is dissolved in after 14mL isopropanols, addition (69mg, 0.31mmol) (R)- (-) -1- benzyl -3- amino-pyrrolidines and (0.66mg, 0.65mmol) triethylamine, heat 80 degree of stirring 2.5h.Liquid phase is detected Reaction is complete, concentrated solvent.Water is added in residue, ethyl acetate extraction merges organic phase.Saturated ammonium chloride washing is organic Phase, anhydrous sodium sulfate drying, concentrated solvent.Residue carries out pillar layer separation, obtains compound 77mg, white solid (yield 62%).
1H NMR (400MHz, DMSO-d6) δ ppm:2.95(s,3H),3.08(s,3H),3.86(s,3H),7.14-7.16 (d, J=8.8Hz, 2H), 7.79 (s, 1H), 8.04-8.06 (d, J=8.8Hz, 2H).
Preparation method is with reference to embodiment 42, raw material ammonia water and intermediate X II, yield 69%.
1H NMR (400MHz, DMSO-d6) δ ppm:2.82 (s, 3H), 3.83 (s, 3H), 7.09-7.11 (dd, J= 6.8Hz, 2.0Hz, 2H), 7.25 (s, 1H), 7.73-7.77 (dd, J=6.8Hz, 2.0Hz, 2H), 7.98 (s, 4H).
The compound C-38 of embodiment 43 preparation
With reference to the synthetic method of embodiment 4, raw material is intermediate X III and dimethylamine hydrochloride.
1H NMR (400MHz, DMSO-d6) δ ppm:2.21 (s, 6H), 3.09-3.10 (d, J=3.6Hz, 2H), 3.76 (s, 3H), 6.31-6.34 (d, J=15.2Hz, 1H), 6.76-6.80 (m, 1H), 6.95-6.97 (d ,=8.8Hz, 2H), 7.40-7.45 (m, 3H), 7.85-7.87 (q, J=8.8Hz, 2H), 10.32 (s, 1H).
The compound C-26 of embodiment 44 preparation
Reference literature W03022852A2, which can be synthesized, obtains intermediate X IV, and the synthetic method for referring again to embodiment 4 is obtained Product.
1H NMR (400MHz, DMSO-d6) δ ppm:10.21 (s, 1H), 8.25 (s, 1H), 7.64-7.62 (d, J= 8.8Hz, 2H), 7.44-7.39 (m, 4H), 7.15-7.13 (d, J=8.8Hz, 2H), 6.76-6.72 (m, 1H), 6.28-6.25 (d, J=15.6Hz, 1H), 3.85 (s, 3H), 3.06-3.05 (d, J=4.8Hz, 2H), 3.17 (s, 6H)；
The compound C-34 of embodiment 45 preparation
Preparation method is with reference to embodiment 44, raw material 4- methoxybromobenzenes ethyl ketone and piperidines, and product is the white solid of class.
1H NMR (400MHz, DMSO-d6) δ ppm:1.40-1.53 (m, 6H), 2.37 (m, 4H), 3.11 (m, 2H), 3.86 (s, 3H), 6.24-6.28 (d, J=15.6Hz, 1H), 6.71-6.77 (m, 1H), 7.13-7.15 (d, J=8.8Hz, 2H), 7.39-7.44 (m, 4H), 7.62-7.64 (d, J=8.8Hz, 2H), 8.25 (s, 1H), 10.22 (s, 1H)；
The compound C-41 of embodiment 46 preparation
Reference literature W03022852A2, which can be synthesized, obtains intermediate X V, and the synthetic method for referring again to embodiment 4 is produced Thing.
1H NMR (400MHz, DMSO-d6) δ ppm:1.41(m,2H),1.51-1.55(m,4H),2.33-2.36(m, 4H), 3.10-3.11 (d, J=4.4Hz, 2H), 3.77 (s, 3H), 6.30-6.33 (d, J=15.6Hz, 1H), 6.75-6.83 (m, 1H), 6.97-6.99 (d, J=8.8Hz, 2H), 7.15-7.18 (m, 1H), 7.25 (s, 1H), 7.34-7.38 (q, J= 9.2Hz, J=8.8Hz, 1H), 7.43-7.46 (d, J=9.2Hz, 2H), 7.53-7.56 (d, J=8.8Hz, 2H), 7.87- 7.90(m,3H),8.52(s,1H),10.32(s,1H)；
The compound C-42 of embodiment 47 preparation
Preparation method is with reference to embodiment 46, raw material 4- methoxybromobenzene ethyl ketones, Resocinol-phenol formaldehyde resin and piperidines, and product is White solid.
1H NMR (400MHz, DMSO-d6) δ ppm:1.38(m,2H),1.50-1.82(m,4H),2.34(m,4H), 3.07-3.08 (d, J=5.2Hz, 2H), 6.24-6.28 (d, J=15.6Hz, 1H), 6.72-6.79 (m, 1H), 6.97-6.99 (d, J=8.8Hz, 2H), 7.22-7.34 (m, 4H), 7.46-7.48 (d, J=8.8Hz, 2H), 7.53-7.57 (q, J= 7.6Hz, J=8.0Hz, 1H), 7.79-7.84 (m, 2H), 7.95 (s, 1H), 8.52 (s, 1H), 10.30 (s, 1H)；
The bioactivity of the compounds of this invention of embodiment 48
Part I
First, experiment material
1st, cell line：Neuroglia cell of human oncocyte U251, human brain astrocytes' blastoma cell U87, cervical carcinoma Cell Hela, human colon cancer cell HCT116, human breast carcinoma cell lines MCF-7, human umbilical vein endothelial HUVEC, this reality Test room preservation.
2nd, experiment reagent：MTT (3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromides), PBS, DMEM culture mediums：Gibco companies, hyclone：Chinese holly company, DMSO：Sigma companies, trypsase：Gibco companies
3rd, laboratory apparatus：Cell culture incubator：SANYO GS Electric company, ELIASA：MOLECULAR companies, optical microphotograph Mirror：LEICA companies, superclean bench：Beijing is big to reach purification techniques research institute.
4th, the preparation of reagent：
(1) PBS solution：NaCl 8g, KCl 0.2g, Na2HPO42H2O 3.62g, KH2PO4 0.24g, will be above-mentioned mixed Compound adds 900ml distillation water dissolves, and regulation pH value is to 7.0, and distilled water is settled to 1000ml.
(2) MTT solution：MTT powder is dissolved in PBS solution (5mg/ml), filtration sterilization, 4 DEG C of preservations.
5th, tested medicine:Embodiment 4, embodiment 5, embodiment 6, embodiment 7, embodiment 12, embodiment 15, embodiment 16, embodiment 18, embodiment 20, embodiment 21, embodiment 22.
2nd, experimental procedure
1. collecting logarithmic phase cell, adjustment concentration of cell suspension is 25000/ml, and 100ul cell suspensions are added per hole (per 2500, hole cell).Typically set 6 multiple holes and control wells are set.
2. cell is put into incubator culture, second day administration (usual noon before that day or the evening bed board, the 2nd after adherent Its morning dose).
3. medication：Medicine is first prepared, then takes out 96 orifice plates, original nutrient solution is discarded, medicine is added.Medicine culture medium Prepare, each medicine sets 0ug/ml, 2ug/ml, 4ug/ml, 6ug/ml, 8ug/ml, 10ug/ml, 20ug/ml, 25ug/ml eight Individual concentration gradient.
4. cell is put into incubator culture 72h.
5. after medicine effect terminates, 20ul---MTT (5mg/ml) is added per hole, 3-4h is cultivated.
6. terminating culture, nutrient solution in hole is carefully sucked.150ul---DMSO, 37 DEG C of incubations 10 minutes are added per hole Or shaking table low-speed oscillation 10 minutes.Detect that OD -490nm (also has and survey 570nm's) absorbance in each hole with ELIASA afterwards.
7. setting zeroing hole (serum free medium, MTT, DMSO) simultaneously, (cell, the medicine of Cmax is molten for control wells Solve medium, serum free medium, MTT, DMSO).
8. cell viability (cell viability)：
Cell viability (cell viability of control)=(medicine group A values-zeroing hole A values)/(control wells A Value-zeroing hole A values) * 100%.
3rd, experimental result
The compound of table 1 is to cancerous cell line MCF-7, cervical cancer cell Hela and 231C IC50 values (μM)
Compound hela MCF7 231C
c-4 100.544 45.527 194.23
c-6 6.585 5.368 26.963
c-16 3.07 4.48 3.65
c-18 Nothing 75.678 Nothing
c-19 9.216 9.3 10.316
c-20 8.567 10.025 11.434
c-21 17.943 50.617 51.998
c-22 9.472 15.984 21.206
c-23 4.052 6.841 7.285
c-24 14.695 10.65 10.931
c-39 9.165 12.063 13.539
IC50 value (μM) of the compound of table 2 to neuroglia cell of human oncocyte U251 and U87 etc.
Compound U87 U251
Afatinib 7.429 6.849
c-3 13.931 3.905
c-5 8.119 4.503
c-7 13.52 9.498
IC50 value (μM) of the compound of table 3 to HCT-116
Compound HCT-116
Afatinib 2.668
c-1 7.715
c-3 0.7882
c-4 61.038
c-5 1.1548
c-7 3.008
c-9 8.959
c-10 15.083
c-11 5.288
c-12 13.677
c-13 6.827
c-14 10.401
c-6 13.984
c-16 4.642
c-18 138.268
c-19 11.729
c-20 10.468
c-21 19.216
c-22 10.165
c-23 3.761
c-24 8.507
c-39 6.508
IC50 value (μM) of the compound of table 4 to A549
Compound A549
Afatinib 3.13
c-3 6.39
c-5 14.59
c-16 10.06
c-25 7.32
c-26 6.6
c-34 7.89
c-35 2.49
c-36 15.46
c-37 2.47
c-41 2.07
c-42 6.25
c-45 3.79
c-46 2.46
Buddhist nun is replaced according to Shandong 61.4
IC50 value (μM) of the compound of table 5 to HepG2
Compound HepG2
Afatinib 1.69
c-3 4.2
c-5 13.43
c-16 8.63
c-25 5.33
c-26 6.6
c-34 7.89
c-35 2.49
c-36 15.83
c-37 2.47
c-41 2.07
c-42 6.25
c-45 2.2
c-46 2.46
Buddhist nun is replaced according to Shandong 61.4
IC50 value (μM) of the compound of table 6 to human umbilical vein endothelial HUVEC
Compound name HUVEC
Afatinib 1.436
c-3 4.283
c-5 4.605
c-7 12.054
c-4 49.671
c-6 11.392
c-16 3.957
c-19 15.902
c-20 12.609
c-21 34.191
c-22 28.036
c-23 11.782
Compound is as shown in Figure 1 to hepatoma Hep G 2 cells inhibitory activity test result.To lung cancer A549 cell inhibitory activity Test result is as shown in Figure 2.
Part II kinase activity is tested
In this experiment, the method that we utilize Mobility Shift Assay, enters to vitro kinase AXL and TRKA The screening of 2 compounds of row, 1 μM of starting, 3 times of dilutions, 10 concentration, single hole test.Mark is used as using compound Afatinib Quasi- control.
Experimental method
I. 1 times of kinase buffer liquid and terminate liquid is prepared
1.1 times of kinase buffer liquids
25Mm HEPES,pH 7.5
0.001%Brij-35
0.01%Triton
0.5Mm EGTA
10Mm MgCl2
2Mm DTT
2. terminate liquid
100mM HEPES,pH 7.5
0.015%Brij-35
0.2%Coating Reagent#3
50mM EDTA
II. compound is prepared
1) diluted chemical compound
3. prepare 50 times of compound：Final concentration of 1 μM of the detection of compound, is configured to 50 times of concentration, i.e., 50 μM, 96 100 μ l 50 μM of compounds are added on orifice plate in second hole, other holes add 60 μ l 100%DMSO.30 are taken from the 2nd hole μ l compounds are added in the 3rd hole, and 3 times of dilutions are down done successively, and 10 concentration are diluted altogether.
2) transferase 45 times compound is to reaction plate
4. in taking 10 μ l to another piece 96 orifice plates from each hole of above-mentioned 96 orifice plate, add 90 μ l kinase buffer liquids.Therefore Second hole is dissolved in the compound in 10%DMSO, the first hole and the 12nd hole being 10%DMSO into 11-holes.
5. 5 μ l to one pieces of 384 hole reaction plates are taken out from above-mentioned 96 orifice plate.Therefore, just have 5 μ l's in 384 hole reaction plates 5 times of compounds of 10%DMSO dissolvings and 5 μ l 10%DMSO.
III. kinase reaction
1) 2.5 times of enzyme solutions are prepared
6. kinases is added into 1 times of kinase buffer liquid, 2.5 times of enzyme solutions are formed.
2) substrate solution of 2.5 times of preparation
7. the FAM polypeptides marked and ATP are added into 1 times of kinase buffer liquid, 2.5 times of substrate solutions are formed.
3) enzyme solutions are added into 384 orifice plates
8. 5 times of compounds of existing 5 μ l 10%DMSO dissolvings in 384 hole reaction plates.
9. 10 μ l 2.5 times of enzyme solutions are added in 384 hole reaction plates.
10. it is incubated 10 minutes at room temperature.
4) substrate solution is added into 384 orifice plates
11. 10 μ l 2.5 times of substrate solutions are added in 384 hole reaction plates.
5) kinase reaction and termination
12. it is incubated 3hr at 28 DEG C.
13. add 25 μ l terminate liquid terminating reactions.
IV.Caliper reads data
The upper reading and converting rate data of 14.Caliper.
V. inhibiting rate is calculated
15. conversion data is replicated from Caliper.
16. a conversion is into inhibiting rate data.Wherein max refers to the conversion ratio of DMSO controls, and min refers to no enzyme activity The conversion ratio of control.
Percent inhibition=(max-conversion)/(max-min) * 100.
17. with XLFit excel add-in version 4.3.1 fitting IC50 values
Fitting formula:Y=Bottom+ (Top-Bottom)/(1+ (IC50/X) ^HillSlope)
As a result it is as shown in the table.
The IC50 results (nM) of table 7
Understand majority of compounds to antitumor cell such as liver cancer, lung cancer, people's knot from the cytoactive test result of gained Colon-cancer cell HCT116 and cervical cancer cell etc. show good activity, or even than replacing Buddhist nun's effect with reference to Afatinib and Yi Lu More preferably；Table 6 shows majority of compounds to the toxicity of human umbilical vein endothelial HUVEC normal cell compared with Afatinib more It is small.Understand to survey compound have good inhibiting effect to EGRF kinases from EGFR and AUR A kinase activities test result, it is right The inhibitory action of AUR A kinases is better than Afatinib.

Claims (16)

1. compound or its stereoisomer or its pharmaceutically acceptable salt or its solvate shown in formula (I)：
Wherein,
R1Selected from A class groups, R2Selected from B class groups；Or, R1Selected from B class groups, R2Selected from A class groups；
The A classes group is selected from phenyl or heteroaryl, wherein the phenyl or heteroaryl are separately optionally further by halogen Element, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Haloalkyl replaced；
The B classes group is selected from
Wherein m is 0 or 1, n are 0 or 1, and m it is different with n when be 0；
X is representedX phenyl end is connected with the furan nucleus of pyrimido furan nucleus；
Y is representedWhen m is 0, Y phenyl end is connected with the furan nucleus of pyrimido furan nucleus；When m not For 0 when, Y phenyl end is connected with X；
Z is selected from hydrogen, halogen, aryl or-N (Ra)(Rb)；
RaAnd RbSeparately it is selected from C1-C6Alkyl；Or, RaAnd RbFormed together with the nitrogen-atoms being connected jointly with them Saturated heterocyclyl, the saturated heterocyclyl is optionally further by hydroxyl or C1-C6Alkyl replaced；
R3、R4Hydrogen, phenyl or-C (O) Rc are separately selected from, wherein the phenyl is optionally further by one or more halogens Replaced, RCSelected from C1-C6Alkyl；
R5Selected from hydrogen or-SO2-Rd, wherein RdSelected from C1-C6Alkyl.
2. compound according to claim 1, it is characterised in that：R3And R4It is simultaneously hydrogen.
3. compound according to claim 1, it is characterised in that：R5For hydrogen.
4. the compound according to claim any one of 1-3, it is characterised in that：Shown in the compound such as following formula (I a)：
5. the compound according to claim any one of 1-4, it is characterised in that：It is described when A classes group is selected from heteroaryl Heteroaryl is 5 yuan of rings or 6 yuan of rings.
6. described compound according to claim 5, it is characterised in that：The heteroaryl is selected from pyridine radicals or pyrroles Base.
7. the compound according to claim any one of 1-4, it is characterised in that：When A classes group is selected from the phenyl of substitution, Substituent is selected from fluorine, chlorine, bromine, C1-C3Alkyl, methoxyl group, any of trifluoromethyl or a variety of.
8. the compound according to claim any one of 1-4, it is characterised in that：In the structure that the X or Y are represented, phenyl On substituent be located at 3 or 4 of the phenyl.
9. the compound according to claim any one of 1-8, it is characterised in that：When A classes group be selected from substitution phenyl or During substituted heteroaryl, the quantity of substituent is 1~3.
10. the compound according to claim any one of 1-9, it is characterised in that：When Z is selected from aryl, the aryl is benzene The phenyl of base, the phenyl of amino substitution or nitro substitution.
11. the compound according to claim any one of 1-10, it is characterised in that：Work as RaAnd RbIt is connected jointly with them Nitrogen-atoms when forming saturated heterocyclyl together, the saturated heterocyclyl is 6 yuan of rings.
12. the compound according to any one of claim 11, it is characterised in that：The saturated heterocyclyl be piperidyl, Quinoline base or piperazinyl.
13. the compound according to claim any one of 1-12, it is characterised in that：Work as RaAnd RbIt is connected jointly with them Atom when forming saturated heterocyclyl together, the saturated heterocyclyl is further by hydroxyl, C1-C6Alkyl or-NH-Pg taken In generation, wherein Pg, represent amino protecting group.
14. compound according to claim 1, it is characterised in that：The compound is one of following compound：
15. compound or its stereoisomer or its pharmaceutically acceptable salt described in claim any one of 1-14 or Its solvate is in antineoplastic, angiogenesis inhibitors, EFGR kinase inhibitors or AUR A kinase inhibitors is prepared Purposes.
16. purposes according to claim 15, it is characterised in that：The tumour is liver cancer, lung cancer, neurogliocytoma, star Shape glioblastoma, cervical carcinoma, colon cancer or breast cancer.
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