CN106946896B - Furans simultaneously [2,3-d] pyrimidine -4- amine derivative - Google Patents
Furans simultaneously [2,3-d] pyrimidine -4- amine derivative Download PDFInfo
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Abstract
The invention discloses a kind of formula (I) compound represented or its stereoisomers or its pharmaceutically acceptable salt or its solvate.The present invention also provides aforesaid compounds to prepare the purposes in anti-tumor drug, angiogenesis inhibitors, EFGR kinase inhibitor or AUR A kinase inhibitor.
Description
Technical field
The present invention relates to furans simultaneously [2,3-d] pyrimidine -4- amine derivatives.
Background technique
Along with the worsening of people's living environment, the continuous improvement of stress, global tumor patient increases year by year,
But chemicals poor selectivity, the toxic side effect of the common treatment tumour of tradition are strong and resistance problems are than more serious, far from
Treatment is able to satisfy to require.Therefore, the anti-cancer agent of research and development efficiently, less toxic is particularly significant in current medical research and development field.
In recent years, further recognize with the development of Protocols in Molecular Biology and to pathogenesis from cell, molecular level
Know, using the key enzyme in tumor development signal path as target spot, the anticancer drug of discovery efficiently, less toxic has become important
Research direction.The molecular targeted therapy of tumour is different from traditional tumor therapeuticing method, it is built upon oncomolecularbiology
On the basis of research, its key enzyme is blocked using small molecule compound to the critical path of tumour growth, so that it is swollen to reach blocking
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 realize.
In numerous anti-tumor drug target spots, EGF-R ELISA (EGFR), that is, a protein-tyrosine
Kinases (RTK) receptor is to adjust cell growth, proliferation, the important factor of the signal path of survival and migration.Cancer clinical research
Show, these receptors and its ligand and many tumours have important relation, and the excess of relevant growth factors occur in many cancers
Expression causes excessive tyrosine phosphorylation signal to be passed to cell nrPTKs in tumor tissues and is often activated, reactivation downstream
Signal transduction path, promote cell Proliferation, resist Apoptosis, promote tumour occurrence and development [Summy, J.M.；
Gallick, G.E.Clin.Cancer Rev.2006,12,1398.] the most common activated mutant of shows L858R, exon
The deletion (delE746-A750) of 21 single-point replacement and exons 19.The reversible epidermal growth factor receptor inhibitor of the first generation
Gefitinib and Erlotinib.Significant clinical response is shown to the patient for there are these specific activated mutants in body
(50-80%).However, the patient for generating secondary resistance mutation for these drugs can be answered within some months by cancer
Hair.Second generation epidermal growth factor receptor inhibitor includes linatinib, Buddhist nun is replaced up to gram, in the structure of these drugs of Afatinib
All contain electrophilic group Michael- receptor.Wherein by taking Afatinib is pharmaceutical representative as an example, allyl amide structure is to Ah method
It is played a crucial role for the anti-tumor activity of Buddhist nun, it is as michael acceptor and EGFR cysteine residue
(Cys797) Michael addition reaction occurs for catalytic site (sulfydryl of nucleophilic), makes kinase-dead, irreversibly inhibits junket ammonia
The activity of acid kinase, thus there is good tolerance.Researchers further demonstrate these by a large amount of spectrum analysis
The presence of covalent bond, and it was found that Afatinib is by the Cys803 of Cys805 and HER4 with HER2 effect and then strongly
Inhibit these enzymes.It is shown to Wild type EGFR testing in vitro, Afatinib is bis- prominent to Wild type EGFR and L858R/T790M
The inhibiting effect of modification has better effect compared with Gefitinib, Erlotinib and Lapatinib.In addition, Afatinib
30 times of Lapatinib are higher than to the inhibiting effect of HER4, is higher than 300 times of Gefitinib, is higher than 500 times of Erlotinib.
Although Afatinib is better than Gefitinib and Erlotinib etc. in curative effect, adverse reaction also has by comparison
It is improved.The adverse reaction of Afatinib is more, wherein diarrhea, fash, oral inflammation, paronychia, loss of appetite, nosebleed,
Itch, dry skin are very common, and dehydration, cystitis, cheilitis, fever, nasal obstruction, Diagnostic value, conjunctivitis, turns ammonia at sense of taste change
Enzyme raising, hand-foot syndrome, muscle cramp and injury of kidney are common, and keratitis is accidental with pneumonia.
Summary of the invention
To solve the above problems, the present invention provides formula (I) compound represented or its stereoisomer or its pharmacy
Upper acceptable salt or its solvate:
Wherein,
R1Selected from A class group, R2Selected from B class group；Alternatively, R1Selected from B class group, R2Selected from A class group；
The A class group is selected from phenyl or heteroaryl, wherein the phenyl or heteroaryl are separately optionally further
By halogen, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl replaced；
The B class group is selected from
Wherein m is 0 or 1, and n is 0 or 1, and m and n are not 0 simultaneously；
X is indicatedThe phenyl end of X and the furan nucleus of pyrimido furan nucleus
It is connected；
Y is indicatedWhen m is 0, the phenyl end of Y is connected with the furan nucleus of pyrimido furan nucleus；
When m is not 0, the phenyl end of Y is connected with X；
Z is selected from hydrogen, halogen, aryl or-N (Ra)(Rb)；
RaAnd RbSeparately it is selected from C1-C6Alkyl；Alternatively, 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、R4It is separately selected from hydrogen, phenyl or-C (O) Rc, wherein the phenyl is optionally further one or more
Replaced halogen, 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 class group is selected from heteroaryl, the heteroaryl is 5 member rings or 6 member rings.
Further, the heteroaryl is selected from pyridyl group or pyrrole radicals.
Further, when A class group is selected from the phenyl replaced, substituent group is selected from fluorine, chlorine, bromine, C1-C3Alkyl, methoxy
Base, trifluoromethyl are any one or more of.
Further, in the structure that the X or Y is indicated, the substituent group on phenyl is located at 3 or 4 of the phenyl.
Further, when A class group is selected from the phenyl or substituted heteroaryl replaced, the quantity of substituent group is 1~3.
Further, when Z is selected from aryl, which is the phenyl of phenyl, the phenyl that amino replaces or nitro substitution.
Further, work as RaAnd RbWhen the nitrogen-atoms being connected jointly with them is formed together saturated heterocyclyl, the saturation
Heterocycle is 6 member rings.
Further, the saturated heterocyclyl is piperidyl, morpholinyl or piperazinyl.
Further, work as RaAnd RbWhen the atom being connected jointly with them is formed together saturated heterocyclyl, the saturation is miscellaneous
Ring group is further by hydroxyl, C1-C6Alkyl or-NH-Pg replaced, wherein Pg indicate amino protecting group.
Further, the compound is one of following compound:
The present invention also provides compound above-mentioned or its stereoisomer or its pharmaceutically acceptable salt or its is molten
Agent close object in preparing anti-tumor drug, angiogenesis inhibitors, EFGR kinase inhibitor or AUR A kinase inhibitor in use
On the way.
Further, the tumour be liver cancer, lung cancer, neurogliocytoma, astrocytoblast tumor, cervical carcinoma,
Colon cancer or breast cancer.
In the present invention:
" stereoisomer " include Stereocenter (such as carbon with 4 different substituents), axis asymmetry for example
There is crucial, planar unsymmetrical and its mixture presence.Stereoisomer includes enantiomer, diastereomer, epimer, outer
Raceme and mesomeric compound with internal symmetry face.
It is described it is " pharmaceutically acceptable " refer to certain carrier, load, diluent, auxiliary material, and/or to be formed by salt usual
In chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with receptor.
The C1-C6Alkyl refer to C1、C2、C3、C4、C5、C6Alkyl, i.e., with 1~6 carbon atom straight chain or branch
Alkyl of chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, sec-butyl, amyl, hexyl etc..
" amino protecting group " will refer to the nitrogen-atoms that can be connected on amino to protect the amino be not involved in reaction and
Its group that can easily remove in reaction below.Suitable amino protecting group includes, but are not limited to following protecting groups:
The carbamate groups of formula-C (O) O-R, wherein R such as methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2
=CH-CH2, etc.；The amide group of formula-C (O)-R ', wherein R ' such as methyl, ethyl, phenyl, trifluoromethyl, etc.；
Formula-SO2N- sulfonyl-derivatives-group of-R ", wherein such as tolyl, phenyl, trifluoromethyl, 2 R ", 2,5,7,8- five first
Primary colours expire -6- base -, 2,3,6- trimethyl -4- methoxybenzenes, etc..
Test result shows that the compounds of this invention can be used for preparing anti-tumor drug, angiogenesis inhibitors or EFGR and swash
Enzyme inhibitor.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
Fig. 1 is that test results are shown in figure 1 to hepatoma Hep G 2 cells inhibitory activity for the compounds of this invention.
Fig. 2 is that test results are shown in figure 2 to lung cancer A549 cell inhibitory activity for the compounds of this invention
Specific 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。
The synthesis of intermediate (E) -4- bromine but-2-ene acyl chlorides III:
(E) -4- bromocrotonic acid methyl esters (6g, 33.5mmol) is dissolved in 0 DEG C of Leng Quzhi of THF (60mL), is dripped under N2 protection
The aqueous solution (20mL) of a hydronium(ion) lithia (1.83g, 43.6mmol) is added.After 15min is dripped off, 0 DEG C of stirring 3h is kept.So
The system is added in cold water (150mL) and petroleum ether (200mL) afterwards to continue to stir 10min at 0 DEG C.Water phase is separated, at 0 DEG C with dense
Hydrochloric acid adjusts PH to 1, then is extracted with methylene chloride (80mLx3).Merge organic phase, is concentrated after anhydrous sodium sulfate is dry, obtains E-
4- bromocrotonic acid III, yellow solid (4.5g, yield 82%).
Be mixed with E-4- bromocrotonic acid III and 1 drop DMF DCM (3mL) solution in be added dropwise to oxalyl chloride (250mg,
1.96mmol).After dripping, it is warmed to room temperature stirring 1h.Reaction terminates, concentrated solvent, obtains intermediate (E) -4- bromine but-2-ene
Acyl chlorides IV is directly used in and reacts in next step without being further processed.
Scheme two:
Scheme three:
Reference literature WO2005121149A1 can synthesize to obtain intermediate X II.
Scheme four:
Scheme five
The preparation of 1 compound C-14 of embodiment
Intermediate compound I (1g, 3.01mmol) is dissolved in THF, is added triethylamine (0.6g, 6.02mmo), is then added dropwise to chloroethene
Acyl chlorides (0.37g, 3.31mmol).After liquid phase monitors fully reacting, instills 3 and drip quenching reaction, concentrated solvent.In residue
Water is added, methylene chloride extraction merges organic phase.Saturated ammonium chloride washs organic phase, and anhydrous sodium sulfate is dry, 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 preparation of 2 compound C-13 of embodiment
By the acetonitrile of potassium carbonate (0.89g, 6.47mmol) plus compound c-14 (0.88g, 2.15mmol), it is then added two
Methylamine hydrochloride (0.17g, 2.15mmol), T LC monitoring reaction, 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, obtains compound 0.55g (yield 61%).
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 preparation of 3 compound C-11 of embodiment
Preparation method is c-14 and N methyl piperazine referring 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 preparation of 4 compound C-5 of embodiment
Intermediate compound I 0.5g (1.08mmol) is dissolved in THF, is added triethylamine 0.22g (2.18mmol), is then added dropwise to
Above-mentioned (the E) -4- bromine but-2-ene acyl chlorides IV 0.195g (1.08mmol) being prepared.After liquid phase monitors fully reacting, concentration
Solvent.Water is added in residue, methylene chloride extraction merges organic phase.Saturated ammonium chloride washs organic phase, anhydrous sodium sulfate
Dry, concentrated solvent obtains intermediate compound IV white solid without being further processed, is directly used in next step.
Potassium carbonate 0.60g (4.32mmol) is added in the acetonitrile solution of the above-mentioned intermediate V being prepared, is then added
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), obtains white solid (c-
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 preparation of 5 compound C-1 of embodiment
Preparation method is referring to the synthesis of 4 intermediate V of embodiment, 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 preparation of 6 compound C-6 of embodiment
Preparation method is referring 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 preparation of 7 compound C-4 of embodiment
Preparation method is referring to the synthesis of 4 intermediate V of embodiment, 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 preparation of 8 compound C-7 of embodiment
Preparation method is referring to the synthesis of embodiment 4, and raw material is intermediate II and N methyl piperazine, and product is that white is solid
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 preparation of 9 compound C-6 of embodiment
Preparation method is referring to the synthesis of embodiment 4, and raw material is intermediate II and dimethylamine, and product is white solid, receives
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 preparation of 10 compound C-16 of embodiment
Preparation method is referring 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 preparation of 11 compound C-18 of embodiment
Preparation method is referring 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 preparation of 12 compound C-21 of embodiment
Preparation method is referring 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 preparation of 13 compound C-20 of embodiment
Ethamine 2.53g is sequentially added into tetrahydrofuran (50ml) solution of intermediate (I) (3.32g, 10mmol)
(25mmol), m-nitro isocyanates 1.64g (10mmol), finishes, and after reacting at room temperature 30min, concentrated solvent obtains crude product.
The mashing of crude product ethyl acetate, filters, dry, obtains 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 preparation of 14 compound C-9 of embodiment
Preparation method is referring to the synthesis of embodiment 13, and raw material is intermediate II and m-nitro isocyanates, product are
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 preparation of 15 compound C-22 of embodiment
10ml ethyl alcohol, the mixing of 10ml water and 1.2ml acetic acid is added in 13 compound of embodiment (1.32g, 2.66mmol)
After liquid, 70 DEG C are warming up to, 0.62g iron powder is added and continues to stir 2h in the temperature.Reaction terminates, and filters, and takes mother liquor concentrations.Residual
Ethyl acetate 50mlx3 extraction is added in object sodium hydrate aqueous solution tune PH to 9.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),
7.64-7.62 (d, J=8.4Hz, 2H), 8.23 (s, 1H), 8.49 (s, 1H), 8.84 (s, 1H)
The preparation of 16 compound C-10 of embodiment
Preparation method is referring 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 preparation of 17 compound C-24 of embodiment
Preparation method is referring 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 preparation of 18 compound C-23 of embodiment
Preparation method is referring 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 preparation of 19 compound C-19 of embodiment
Preparation method is embodiment 16 and piperidines referring 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 preparation of 20 compound C-12 of embodiment
Preparation method is embodiment 16 and acryloyl chloride referring 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 preparation of 21 compound C-45 of embodiment
Method one
For this method one referring to the synthesis of embodiment 4, raw material is 4- fluorine bromoacetophenone, raw material 4- fluorine bromoacetophenone and two
Methylamine hydrochloride, product are 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
Two reference literature W03022852A2 of method can synthesize to obtain intermediate X I, referring to the synthetic method of embodiment 4
It is synthesized to obtain embodiment 22 by intermediate X I.
The preparation of 22 compound C-32 of embodiment
Raw material 4- bromoacetyl 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 preparation of 23 compound C-25 of embodiment
Referring to embodiment 21, raw material 4- fluorine bromoacetophenone and 3- t-butoxycarbonyl amino piperidines, product are preparation method
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 preparation of 24 compound C-27 of embodiment
For preparation method referring to embodiment 21, raw material bromoacetophenone and dimethylamine hydrochloride, product are 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 preparation of 25 compound C-28 of embodiment
For preparation method referring to embodiment 8, raw material bromoacetophenone and piperidines, product are 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 preparation of 26 compound C-29 of embodiment
Referring to embodiment 8, the bromo- 1- of raw material 2- (1- methyl-1 H- pyrazoles -4- base) ethyl ketone and piperidines, product are preparation method
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 preparation of 27 compound C-37 of embodiment
For preparation method referring to embodiment 21, raw material 4- fluorine bromoacetophenone and piperidines, product are 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 preparation of 28 compound C-31 of embodiment
For preparation method referring to embodiment 8, raw material bromoacetophenone and 4- hydroxy piperidine, product are 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 preparation of 29 compound C-30 of embodiment
For preparation method referring to embodiment 22, raw material 4- bromoacetyl yl pyridines and piperidines, product are 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 preparation of 30 compound C-33 of embodiment
For preparation method referring to embodiment 8, raw material 3- bromoacetophenone and dimethylamine hydrochloride, product are white solid, are received
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 preparation of 31 compound C-35 of embodiment
For preparation method referring to embodiment 22, raw material 3, bis- trifluoromethyl bromoacetophenone of 5- and piperidines, product is that white is solid
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 preparation of 32 compound C-43 of embodiment
For preparation method referring to embodiment 21, raw material 3,4,5- trimethoxy bromoacetophenone and dimethylamine, 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 preparation of 33 compound C-44 of embodiment
For preparation method referring to embodiment 21, raw material 3,4,5- trimethoxy bromoacetophenone and piperidines, product is that white is solid
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 preparation of 34 compound C-46 of embodiment
For preparation method referring to embodiment 21, raw material bromoacetophenone and piperidines, product are 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 preparation of 35 compound C-8 of embodiment
For preparation method referring to embodiment 21, raw material 3,4,5- trimethoxy bromoacetophenone and piperidines, product is that white is solid
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 preparation of 36 compound C-15 of embodiment
Preparation method is referring to embodiment 22, raw material 3, bis- trifluoromethyl bromoacetophenone of 5- 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 preparation of 37 compound C-17 of embodiment
For preparation method referring to embodiment 22, raw material 3, bis- trifluoromethyl bromoacetophenone of 5- and piperidines, product is that white is solid
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 preparation of 38 compound C-40 of embodiment
For preparation method referring to embodiment 22, raw material 3- bromo thiophene ethyl ketone and piperidines, product are 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 preparation of 39 compound C-2 of embodiment
For preparation method referring to embodiment 22, raw material 3- bromo thiophene ethyl ketone and piperidines, product are 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 preparation of 40 compound C-47 of embodiment
Preparation method is referring to embodiment 21, and raw material 3,4- dimethoxy bromo acetophenone and piperidines, product are 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 preparation of 41 compound C-36 of embodiment
Preparation method is referring to embodiment 21, and raw material 3,5- dimethoxy bromo acetophenone and piperidines, product are white solid,
Yield 41%.
The preparation of 42 compound C-39 of embodiment
After intermediate X II (100mg, 0.26mmol) is dissolved in 14mL isopropanol, it is added (69mg, 0.31mmol) (R)-
(-) -1- benzyl -3- amino-pyrrolidine and (0.66mg, 0.65mmol) triethylamine heat 80 degree of stirring 2.5h.Liquid phase detection
Fully reacting, concentrated solvent.Water is added in residue, ethyl acetate extraction merges organic phase.Saturated ammonium chloride washing is organic
Phase, anhydrous sodium sulfate is dry, 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 referring 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 preparation of 43 compound C-38 of embodiment
Referring 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 preparation of 44 compound C-26 of embodiment
Reference literature W03022852A2 can synthesize to obtain intermediate X IV, and the synthetic method for referring again to embodiment 4 obtains
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 preparation of 45 compound C-34 of embodiment
For preparation method referring to embodiment 44, raw material 4- methoxybromobenzene ethyl ketone and piperidines, 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 preparation of 46 compound C-41 of embodiment
Reference literature W03022852A2 can synthesize to obtain intermediate X V, and the synthetic method for referring again to embodiment 4 is produced
Object.
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 preparation of 47 compound C-42 of embodiment
Preparation method is referring to embodiment 46, and raw material 4- methoxybromobenzene ethyl ketone, Resocinol-phenol formaldehyde resin and piperidines, product are
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 48 the compounds of this invention of embodiment
First part
One, experimental material
1, cell strain: 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.
2, experiment reagent: MTT (3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromide), PBS buffer solution,
DMEM culture medium: Gibco company, fetal calf serum: Chinese holly company, DMSO:Sigma company, trypsase: Gibco company
3, laboratory apparatus: cell incubator: SANYO GS Electric company, microplate reader: MOLECULAR company, optical microphotograph
Mirror: LEICA company, superclean bench: Beijing is big to reach purification techniques research institute.
4, the preparation of reagent:
(1) PBS solution: NaCl 8g, KCl 0.2g, Na2HPO42H2O 3.62g, KH2PO4 0.24g, it will be above-mentioned mixed
It closes object and the dissolution of 900ml distilled water is added, adjust pH value to 7.0, distilled water is settled to 1000ml.
(2) MTT solution: MTT powder being dissolved in PBS solution (5mg/ml), filtration sterilization, 4 DEG C of preservations.
5, tested medicine: embodiment 4, embodiment 5, embodiment 6, embodiment 7, embodiment 12, embodiment 15, embodiment
16, embodiment 18, embodiment 20, embodiment 21, embodiment 22.
Two, experimental procedure
1. collecting logarithmic phase cell, adjustment concentration of cell suspension is 25000/ml, and 100ul cell suspension is added in every hole
(2500, every hole cell).Generally sets 6 multiple holes and control wells are set.
2. cell is put into incubator culture, be administered within second day after adherent (usual noon before that day or evening bed board, the 2nd
Its morning dose).
3. medication: first preparing medicine, then take out 96 orifice plates, discard original culture solution, drug is added.Drug culture medium
It prepares, 0ug/ml, 2ug/ml, 4ug/ml, 6ug/ml, 8ug/ml, 10ug/ml, 20ug/ml, 25ug/ml eight is arranged in each drug
A concentration gradient.
4. cell is put into incubator culture 72h.
5. after drug effect, 20ul---MTT (5mg/ml) is added in every hole, 3-4h is cultivated.
6. terminating culture, culture solution in hole is carefully sucked.Every hole is added 150ul---DMSO, 37 DEG C incubation 10 minutes
Or shaking table low-speed oscillation 10 minutes.Later with the absorbance value in microplate reader detection OD -490nm (also have and survey 570nm's) each hole.
7. zeroing hole (serum free medium, MTT, DMSO) is arranged simultaneously, (drug of cell, maximum concentration 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 value-zeroing hole A value)/(control wells A
Value-zeroing hole A value) * 100%.
Three, experimental result
1 compound of table is to cancerous cell line MCF-7, the IC50 value (μM) of cervical cancer cell Hela and 231C
| 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 2 compound of table 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 3 compound of table 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 4 compound of table 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 5 compound of table 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 6 compound of table 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 |
Test results are shown in figure 1 to hepatoma Hep G 2 cells inhibitory activity for compound.To lung cancer A549 cell inhibitory activity
Test results are shown in figure 2.
The test of second part kinase activity
In this experiment, we utilize Mobility Shift Assay method, to vitro kinase AXL and TRKA into
The screening of 2 compounds of row, 1 μM of starting, 3 times of dilutions, 10 concentration, single hole test.Using compound Afatinib as mark
Quasi- control.
Experimental method
I. 1 times of kinase buffer liquid and terminate liquid are 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. preparing 50 times of compound: final concentration of 1 μM of the detection of compound, 50 times of concentration, i.e., 50 μM are configured to, 96
50 μM of compounds of 100 μ l are added on orifice plate in second hole, the 100%DMSO of 60 μ l is added in other holes.30 are taken from the 2nd hole
μ l compound is added in the 3rd hole, successively does 3 times of dilutions down, dilutes 10 concentration altogether.
2) 5 times of compounds are shifted to reaction plate
4. taking in 10 μ l to another piece 96 orifice plates from each hole of above-mentioned 96 orifice plate, 90 μ l kinase buffer liquids are added.Therefore
It is 10%DMSO in the compound being dissolved in second Kong Zhi 11-holes in 10%DMSO, the first hole and the 12nd hole.
5. taking out 5 μ l to one pieces of 384 hole reaction plates 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 dissolution and the 10%DMSO of 5 μ l.
III. kinase reaction
1) 2.5 times of enzyme solutions are prepared
6. 1 times of kinase buffer liquid is added in kinases, 2.5 times of enzyme solutions are formed.
2) 2.5 times of substrate solution is prepared
7. 1 times of kinase buffer liquid is added in the polypeptide of FAM label and ATP, 2.5 times of substrate solutions are formed.
3) enzyme solutions are added into 384 orifice plates
8. having 5 times of compounds of the 10%DMSO dissolution of 5 μ l in 384 hole reaction plates.
9. 2.5 times of enzyme solutions of 10 μ l are added in 384 hole reaction plates.
10. being incubated for 10 minutes at room temperature.
4) substrate solution is added into 384 orifice plates
11. 2.5 times of substrate solutions of 10 μ l are added in 384 hole reaction plates.
5) kinase reaction and termination
12. being incubated for 3hr at 28 DEG C.
13. 25 μ l terminate liquids is added to terminate reaction.
IV.Caliper reads data
The upper reading and converting rate data of 14.Caliper.
V. inhibiting rate calculates
15. replicating conversion data from Caliper.
16. conversion is at inhibiting rate data.Wherein max refers to that the conversion ratio of DMSO control, min refer to no enzyme activity
The conversion ratio of control.
Percent inhibition=(max-conversion)/(max-min) * 100.
17. being fitted IC50 value with XLFit excel add-in version 4.3.1
Fitting formula: Y=Bottom+ (Top-Bottom)/(1+ (IC50/X) ^HillSlope)
As a result as shown in the table.
7 IC50 result (nM) of table
From majority of compounds known to resulting cell activity test result to antitumor cell such as liver cancer, lung cancer, people's knot
Colon-cancer cell HCT116 and cervical cancer cell etc. show good activity, or even than replacing Buddhist nun's effect referring to Afatinib and Yi Lu
More preferably；Table 6 shows majority of compounds to the toxicity of the normal cell of human umbilical vein endothelial HUVEC more compared with Afatinib
It is small.There is good inhibiting effect to EGRF kinases from surveyed compound known to EGFR and AUR A kinase activity test result, it is right
The inhibiting effect of AUR A kinases is better than Afatinib.
Claims (3)
1. following compounds or its pharmaceutically acceptable salt:
2. compound described in claim 1 or its pharmaceutically acceptable salt are preparing anti-tumor drug, Agiogenesis inhibition
Purposes in agent, EFGR kinase inhibitor or AUR A kinase inhibitor.
3. purposes according to claim 2, it is characterised in that: the tumour is liver cancer, lung cancer, neurogliocytoma, star
Glioblastoma, cervical carcinoma, colon cancer or breast cancer.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003022852A2 (en) * | 2001-09-11 | 2003-03-20 | Smithkline Beecham Corporation | Furo-and thienopyrimidine derivatives as angiogenesis inhibitors |
| WO2006004658A2 (en) * | 2004-06-29 | 2006-01-12 | Amgen Inc. | Furanopyrimidines |
| CN102264745A (en) * | 2008-11-10 | 2011-11-30 | 财团法人卫生研究院 | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
| CN103405429A (en) * | 2013-08-22 | 2013-11-27 | 中国药科大学 | VEGFR-2 (Vascular Endothelial Growth Factor Receptor-2) inhibitors and use thereof |
| CN104854107A (en) * | 2012-11-15 | 2015-08-19 | 药品循环公司 | Pyrrolopyrimidine compounds as kinase inhibitors |
-
2017
- 2017-03-30 CN CN201710204740.0A patent/CN106946896B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003022852A2 (en) * | 2001-09-11 | 2003-03-20 | Smithkline Beecham Corporation | Furo-and thienopyrimidine derivatives as angiogenesis inhibitors |
| WO2006004658A2 (en) * | 2004-06-29 | 2006-01-12 | Amgen Inc. | Furanopyrimidines |
| CN102264745A (en) * | 2008-11-10 | 2011-11-30 | 财团法人卫生研究院 | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
| CN104854107A (en) * | 2012-11-15 | 2015-08-19 | 药品循环公司 | Pyrrolopyrimidine compounds as kinase inhibitors |
| CN103405429A (en) * | 2013-08-22 | 2013-11-27 | 中国药科大学 | VEGFR-2 (Vascular Endothelial Growth Factor Receptor-2) inhibitors and use thereof |
Non-Patent Citations (3)
| Title |
|---|
| A Three Dimensional Pharmacophore Modeling for KDR and Tie-2 Receptor Tyrosine Kinase Inhibitors and Virtual Screening for New Multikinase Inhibitors;Neha Kansal，等;《QSAR & Combinatorial Science》;20091231;第28卷(第10期);第1130-1147页 |
| Fast-Forwarding Hit to Lead: Aurora and Epidermal Growth Factor Receptor Kinase Inhibitor Lead Identification;Mohane Selvaraj Coumar，等;《J. Med. Chem.》;20100615;第53卷;第4980-4988页 |
| Orally active 4-amino-5-diarylurea-furo[2,3-d]pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2;Yasushi Miyazaki，等;《Bioorganic & Medicinal Chemistry Letters》;20061224;第17卷;第1773-1778页 |
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