CN107522700A - A kind of quinazolinone and α, the conjugated derivative of beta unsaturated ketone and its preparation method and application - Google Patents
A kind of quinazolinone and α, the conjugated derivative of beta unsaturated ketone and its preparation method and application Download PDFInfo
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- CN107522700A CN107522700A CN201710658952.6A CN201710658952A CN107522700A CN 107522700 A CN107522700 A CN 107522700A CN 201710658952 A CN201710658952 A CN 201710658952A CN 107522700 A CN107522700 A CN 107522700A
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- 0 CCN(CC)CCC*c(c(F)c1)cc(N=C2N3CCC2=CCC=CC(C=C[*@@](c(cc2)ccc2F)O)=CC#C)c1C3=O Chemical compound CCN(CC)CCC*c(c(F)c1)cc(N=C2N3CCC2=CCC=CC(C=C[*@@](c(cc2)ccc2F)O)=CC#C)c1C3=O 0.000 description 1
- GALCMTDJBJFWDO-UHFFFAOYSA-N Cc(cc(c(N=C1N2CCC1)c1)C2=O)c1NCCCN1CCOCC1 Chemical compound Cc(cc(c(N=C1N2CCC1)c1)C2=O)c1NCCCN1CCOCC1 GALCMTDJBJFWDO-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a kind of quinazolinone and α, the conjugated derivative of beta unsaturated ketone, the quinazolinone and α, shown in the structural formula such as formula (I) or formula (II) of the conjugated derivative of beta unsaturated ketone：Wherein, R1For hydrogen, amido, substituted amido, five yuan or hexa-member heterocycle base；R2For hydrogen, phenyl, substituted-phenyl, Benzoheterocyclic compounds；Substituent is selected from C1‑5Alkyl, C1‑8Alkoxy, halogen, phenyl, amido, five yuan or hexa-member heterocycle base.Quinazolinone and α provided by the invention, the conjugated derivative of beta unsaturated ketone can effectively suppress the growth of kinds of tumor cells, and can significantly inhibit proto-oncogene c MYC transcript and expression, there is wide application space on antineoplastic is prepared.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, more particularly, to a kind of quinazolinone and α, alpha, beta-unsaturated ketone yoke
Close derivative and its preparation method and application.
Background technology
Malignant tumour is to endanger a major class disease of human health, is counted according to the World Health Organization (WHO), and the whole world is annual
There are 8,000,000 people to die from cancer, and China it is annual have close to 2,000,000 people die from cancer.The research and development of anti-malignant tumor medicine in recent years
Important breakthrough is obtained, many newtype drugs enter clinical research, but still suffer from lot of challenges.The problems such as high toxic side effect, resistance
It is still the major obstacle that clinical tumor drug therapy faces.
Proto-oncogene important as one c-MYC, regulate and control the life processes such as cell propagation, differentiation, metabolism, apoptosis.
Research finds that c-MYC has abnormal expression, such as cervical carcinoma, breast cancer, colon cancer, cellule in Several Kinds of Malignancy
Lung cancer, glioblastoma, melanoma, osteosarcoma, marrow row leukaemia etc..The c-MYC of high expression in most of tumour cell
Have benefited from the transcriptional activation of gene, the sequences of c-MYC promoter nucleic acid sensing elements NHE III can form the stranded structures of G- tetra-, and make
Suppress c-MYC transcription for Transcriptional Silencing.Therefore, target the part of the serobilas of c-MYCG- tetra- is developed into antineoplastic
The focus of research and development.
Quinazoline group is widely studied in medicinal chemistry art.Quinazoline alkaloid is present in various plants and animal
In boundary, and quinazoline derivant has multiple biological activities, including the function such as antitumor, antibacterial, anti-inflammatory, hypotensive.Past 15
Nian Lai, quinazoline derivative make substantial progress in anti-tumor aspect, and a large amount of quinazoline compounds are reported, wherein several
Quinazoline compounds are ratified to list by FDA.
Chalcone compounds are widely present in nature, and α is contained in its structure, alpha, beta-unsaturated ketone, aromatic ring, makes its tool
Have and go out appropriate flexibility as hydrogen bond receptor, electrophilicity, lipophilic and whole molecule displays, can be combined from different acceptors, performance
Go out multiple biological activities.Chalcone compounds have remarkable effect to multiple stages of tumorigenesis, including suppress swollen
Generation and transfer of tumor cell proliferation, induced tumor cell differentiation and apoptosis and suppression tumour etc..
The content of the invention
An object of the present invention is to provide a kind of quinazolinone and α, the conjugated derivative of alpha, beta-unsaturated ketone.
Another object of the present invention is to provide the preparation method of said derivative.
It is still another object of the present invention to provide said derivative as proto-oncogene c-MYC transcriptional control blocking agent systems
Application in standby cancer therapy drug.
The present invention is on quinazolinone architecture basics, and α, alpha, beta-unsaturated ketone structure is conjugated obtain new quinazolinone with
α, the conjugated derivative of alpha, beta-unsaturated ketone, the analog derivative have the antitumor action for suppressing c myc transcription and translation.
Further, such quinazolinone and α provided by the present invention, the conjugated derivative of alpha, beta-unsaturated ketone can suppress former
Oncogene c-myc transcription and translations, suppress the propagation of more plants of tumour cells, there is extensive antitumous effect.
The present invention is achieved through the following technical solutions above-mentioned purpose：
The present invention provides a kind of quinazolinone and α, the conjugated derivative of alpha, beta-unsaturated ketone, the quinazolinone and α, β-insatiable hunger
Shown in the structural formula such as formula (I) or formula (II) of the conjugated derivative of ketone：
Wherein, R1For hydrogen, amido, substituted amido, five yuan or hexa-member heterocycle base；R2It is miscellaneous for hydrogen, phenyl, substituted-phenyl, benzo
Cycle compound；
Substituent is selected from C1-5Alkyl, C1-8Alkoxy, halogen, phenyl, amido, five yuan or hexa-member heterocycle base.
Preferably, R1For NH (CH2)n R3, R3It is any in being 1~5 for amido, substituted amido, five yuan or hexa-member heterocycle base, n
One integer, the substituent in substituted amido are selected from C1-5Alkyl, C1-8Alkoxy, five yuan or hexa-member heterocycle base.
Preferably, R3For amido, N, N- diethyl methyl amines base, N, N- dimethyl methyls amido or morpholinyl.
Preferably, R2For phenyl, substituted-phenyl, benzo five-membered or benzo 6-membered heterocyclic compound, taking in substituted-phenyl
Dai Ji is selected from halogen, C1-5Alkoxy, five yuan or hexa-atomic nitrogen heterocycle.
Preferably, R2Luxuriant for phenyl, substituted-phenyl or 1,3- Ben Bing bis- Evil, substituent is halogen, morpholine in substituted-phenyl
Base, C1-5Alkyl or C1-5Alkoxy.
Preferably, substituent is fluorine-based, morpholinyl, the tert-butyl group or methoxyl group in substituted-phenyl.
Present invention simultaneously provides described quinazolinone and α, the preparation method of the conjugated derivative of alpha, beta-unsaturated ketone, including such as
Lower step：
S1.2- amino -4,5- difluoro-benzoic acids react to obtain compound with 2-Pyrrolidone
S2. compoundWith aminated compounds NH-R1Reaction obtains intermediate
S3. compoundReact to obtain intermediate with ketone compounds
S4. gained compound in S2 and gained compound in S3 are reacted, obtains the derivative.
Present invention simultaneously provides described quinazolinone and the conjugated derivative of alpha, beta-unsaturated ketone in cancer therapy drug is prepared
Application.
Further, the quinazolinone and α, the conjugated derivative of alpha, beta-unsaturated ketone are transcribed as proto-oncogene c-MYC
Regulate and control the preparation that blocking agent is applied to cancer therapy drug.
Further, the anticancer be ovarian cancer resistance, cervical carcinoma, breast cancer, adenocarcinoma of lung, colon cancer, liver cancer, leukaemia,
ED-SCLC, cutaneum carcinoma, cell carcinoma, prostate cancer, non-small cell lung cancer, nasopharyngeal carcinoma, glioblastoma, lymthoma or
One or more in melanoma.
Further, medicine of the present invention also include and its pharmaceutically acceptable salt, carrier, stereoisomer or its
Prodrugs.
Further, medicine of the present invention can be injection, tablet, pill, capsule, suspending agent or emulsion.
Derivative provided by the present invention is applied to suppress cancer cell experiment, it is found that it possesses significant inhibition,
Especially compound 3a, 3c, 3h, 3i suppression JEG-3 cultivation effect highly significant.
Compared with prior art, the present invention has advantages below：
The present invention relates to the quinazolinone with logical formula (I) or (II) architectural feature and the conjugated derivative of alpha, beta-unsaturated ketone
The growth of kinds of tumor cells can effectively be suppressed, and proto-oncogene c-MYC transcript and expression can be significantly inhibited, prepared
There is wide application space on antineoplastic.
Brief description of the drawings
Fig. 1 is shadow of the quinazolinone provided by the invention with the conjugated derivative of alpha, beta-unsaturated ketone to c-MYC transcriptional levels
Ring figure.
Fig. 2 is shadow of the quinazolinone provided by the invention with the conjugated derivative of alpha, beta-unsaturated ketone to C-MYC translation skills
Ring figure.
Embodiment
The present invention is further described with reference to specific embodiments and the drawings.Unless stated otherwise, the present invention uses
Reagent, apparatus and method be the art routinely reagent, equipment and conventional use of method purchased in market.
Wherein, the derivative synthetic route of the embodiment of the present invention 14~33 is as follows：
More specifically, the derivative synthetic route of the embodiment of the present invention 14~33 is as follows：
2- amino -4,5- difluoro-benzoic acids react to obtain compound 2 with 2-PyrrolidoneCompound
2 react to obtain intermediate 3 from different amineWith 4
CompoundReact to obtain intermediate with ketone compounds
Intermediate 3,4 again with intermediate a, b, c, d, e, f, g, h, i, j, after being dissolved in DMF, in the effect of trim,ethylchlorosilane
Lower generation substitution reaction, obtains final compound.Obtaining intermediate
Intermediate a, b, c, d, e, f, g, h, i, j preparation method, using to two benzaldehydes or two benzaldehyde and benzene second
Ketone raw material, using NaOH as catalyst, using second alcohol and water as reaction dissolvent in the presence of react, to two benzaldehydes or
Two benzaldehydes and the mol ratio of acetophenones raw material reaction are 1：0.5~1, reaction is first placed in stirring reaction 2h in ice bath, then at
2~6h of reaction is stirred at room temperature.
Further, the preparation method of end-product, in the S4 steps intermediate 3,4 again with the benzaldehyde containing substituent
The mol ratio of mesosome a, b, c, d, e, f, g, h, i, j reaction is 1：(1.05~3.0), reaction temperature is 50~120 DEG C, during reaction
Between be 12~48 hours.
Embodiment 1：The synthesis of compound 2
By 2- amino -4,5- difluoro-benzoic acid (5g, 29mmol), 2-Pyrrolidone (5mL) is as the mono- neck flasks of 100mL
In, 20mL POCl3s (POCl is added dropwise under ice bath stirring3), drip off its 30min, 103 DEG C are heated to reflux 24h, will
Reaction system is added dropwise in 200mL frozen water, is adjusted pH to alkalescent with concentrated NaOH solution, is filtered, obtain crude product, silicagel column
Chromatographic purifying (eluant, eluent：V (petroleum ether)：V (ethyl acetate)=1:1) compound m1,5.4g, yield 85% are obtained.
1H NMR(400MHz,CDCl3)δ8.20–7.85(m,1H),7.60–7.34(m,1H),4.42–4.06(m,2H),
3.19 (td, J=7.9,2.7Hz, 2H), 2.43-2.16 (m, 2H) .LC-MS m/z:223[M+H]+.
Embodiment 2：The synthesis of compound 3
Take compound 2 (2.22g, 10mmol), diethyl amino propylamine (3ml, 24mmol), in heavy wall pressure bottle, 100 DEG C
Heating stirring is stayed overnight, and obtains orange solution, after reaction system is down to room temperature, is had a large amount of pale yellow precipitates to separate out, is filtered, obtain
Filter cake is Off-white solid, vacuumizes drying, obtains Off-white solid 2.3g, yield 69%.
1H NMR(400MHz,CDCl3) δ 7.72 (d, J=11.7Hz, 1H), 6.72 (s, 1H), 6.67 (d, J=7.7Hz,
1H), 4.19-4.12 (m, 2H), 3.31 (dd, J=10.6,5.8Hz, 2H), 3.11 (t, J=7.9Hz, 2H), 2.63-2.59
(m, 2H), 2.55 (q, J=7.1Hz, 4H), 2.30-2.19 (m, 2H), 1.89-1.81 (m, 2H), 1.06 (t, J=7.1Hz,
6H).
Embodiment 3：The synthesis of compound 4
According to 3 synthetic method, 1.8g Off-white solids, yield 52% are obtained.1H NMR(400MHz,CDCl3)δ7.67(d,
J=11.7Hz, 1H), 6.62 (d, J=7.7Hz, 1H), 4.13-4.05 (m, 2H), 3.72-3.67 (m, 2H), 3.66-3.61
(m, 2H), 3.25 (dd, J=11.1,5.8Hz, 2H), 3.04 (t, J=7.9Hz, 4H), 2.51-2.46 (m, 3H), 2.24-
2.12(m,4H),1.86–1.75(m,2H).
Embodiment 4：The synthesis of compound a
Weigh and two benzaldehydes (1.34g, 10mol), 3 ', 4 '-(methylenedioxy) acetophenone (1.64g, 10mol) are burnt with round bottom
Bottle, add 3mL ethanol, 1mL water, 0.01g NaOH be used as catalyst, be placed in stirring reaction 2h in ice bath, then at be stirred at room temperature instead
Answer 2h.After TLC monitoring reactions terminate, filter, take filter cake, silica gel column chromatography separating purification, obtain faint yellow solid 1.21g, yield
43%.
1H NMR (400MHz, DMSO) δ 10.05 (s, 1H), 8.12 (d, J=8.1Hz, 2H), 8.06 (d, J=11.5Hz,
1H), 7.97 (d, J=6.3Hz, 2H), 7.91 (dd, J=8.2,1.8Hz, 1H), 7.77 (d, J=9.3Hz, 1H), 7.69 (s,
1H), 7.11 (d, J=8.2Hz, 1H), 6.18 (s, 2H)
Embodiment 5：Compound b synthesis
According to a synthetic method, 1.78g yellow solids, yield 55% are obtained.
1H NMR (400MHz, DMSO) δ 10.05 (s, 1H), 8.10 (d, J=7.5Hz, 4H), 8.07 (s, 1H), 7.97
(d, J=8.1Hz, 2H), 7.72 (d, J=15.6Hz, 1H), 7.05 (d, J=8.9Hz, 2H), 3.77-3.72 (m, 4H),
3.38–3.33(m,4H).
Embodiment 6：Compound c synthesis
According to a synthetic method, 1.03g Off-white solids, yield 35% are obtained.
1H NMR (400MHz, DMSO) δ 9.01 (s, 3H), 8.12 (d, J=8.5Hz, 1H), 8.02 (d, J=15.7Hz,
2H), 7.99 (m, 2H), 7.76 (d, J=15.6Hz, 1H), 7.60 (d, J=8.5Hz, 1H), 1.34 (s, 9H)
Embodiment 7：Compound d synthesis
According to a synthetic method, 2.11g yellow solids, yield 83% are obtained.
1H NMR(400MHz,CDCl3) δ 10.08 (s, 1H), 8.10 (ddd, J=5.4,4.5,2.1Hz, 2H), 7.96 (d,
J=8.2Hz, 2H), 7.83 (d, J=2.5Hz, 2H), 7.81 (s, 1H), 7.68 (d, J=26.2Hz, 1H), 7.25-7.18 (m,
2H).
Embodiment 8：Compound e synthesis
According to a synthetic method, 1.64g yellow solids, yield 62% are obtained.
1H NMR(400MHz,CDCl3) δ 10.05 (s, 1H), 8.06 (d, J=8.8Hz, 2H), 7.93 (d, J=8.1Hz,
2H), 7.83 (d, J=3.6Hz, 1H), 7.79 (d, J=7.8Hz, 2H), 7.65 (d, J=15.7Hz, 1H), 7.00 (d, J=
8.8Hz,2H),3.90(s,3H).
Embodiment 9：Compound f synthesis
Two benzaldehydes (1.34g, 10mol) between weighing, 3 ', 4 '-(methylenedioxy) acetophenone (1.64g, 10mol) burn with round bottom
Bottle, add 3mL ethanol, 1mL water, 0.01g NaOH be used as catalyst, be placed in stirring reaction 2h in ice bath, then at be stirred at room temperature instead
Answer 2h.After TLC monitoring reactions terminate, filter, take filter cake, silica gel column chromatography separating purification, obtain faint yellow solid 1.01g, yield
36%.
1H NMR(400MHz,CDCl3) δ 10.08 (s, 1H), 8.15 (s, 1H), 7.91 (d, J=7.6Hz, 1H), 7.86
(d, J=8.6Hz, 1H), 7.83 (d, J=15.9Hz, 1H), 7.68 (dd, J=8.1,1.4Hz, 1H), 7.63-7.53 (m,
3H), 6.92 (d, J=8.1Hz, 1H), 6.08 (s, 2H)
Embodiment 10：Compound g synthesis
According to f synthetic method, 1.22g yellow solids, yield 38% are obtained.
1H NMR(400MHz,CDCl3) δ 10.10 (s, 1H), 8.18 (d, J=5.5Hz, 1H), 8.11-8.01 (m, 2H),
7.96–7.79(m,3H),7.73–7.58(m,2H),7.02–6.90(m,2H),3.95–3.85(m,4H),3.42–3.32(m,
4H).
Embodiment 11：Compound h synthesis
According to f synthetic method, 1.20g Off-white solids, yield 41% are obtained.
1H NMR(400MHz,CDCl3) δ 10.08 (s, 1H), 8.17 (s, 1H), 8.00 (d, J=8.4Hz, 2H), 7.94-
7.89 (m, 2H), 7.88 (d, J=7.4Hz, 1H), 7.62 (d, J=5.0Hz, 1H), 7.54 (d, J=8.3Hz, 2H), 7.48
(dd, J=8.5,2.3Hz, 1H), 1.37 (s, 9H)
Embodiment 12：Compound i synthesis
According to f synthetic method, 1.68g yellow solids, yield 66% are obtained.
1H NMR(400MHz,CDCl3) δ 10.09 (s, 1H), 8.12-8.05 (m, 3H), 7.86 (d, J=5.6Hz, 1H),
7.82 (s, 1H), 7.70 (dd, J=7.7,1.5Hz, 1H), 7.56 (d, J=15.7Hz, 1H), 7.50 (t, J=7.7Hz, 1H),
7.23–7.17(m,2H).
Embodiment 13：Compound j synthesis
According to f synthetic method, 1.47g yellow solids, yield 55% are obtained.
1H NMR(400MHz,CDCl3) δ 10.08 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.8Hz, 2H), 7.89
(dd, J=16.9,7.2Hz, 2H), 7.85-7.79 (m, 1H), 7.67 (d, J=8.5Hz, 1H), 7.63-7.60 (m, 1H),
7.00 (d, J=8.6Hz, 2H), 3.91 (s, 3H)
Embodiment 14：Compound 3a synthesis
Compound 3 (0.3323g, 1mmol) and compound a (0.3083g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.4180g, yield 70%.
1H NMR(400MHz,DMSO-d6) δ 8.03 (d, J=6.8Hz, 1H), 8.02-7.97 (m, J=11.4,5.0Hz,
3H), 7.92-7.87 (m, J=8.2,3.8,1.7Hz, 1H), 7.76 (d, J=4.8Hz, 1H), 7.73-7.71 (m, 1H),
7.70-7.68 (m, J=4.9,2.4Hz, 2H), 7.63 (d, J=11.8Hz, 1H), 7.11 (d, J=8.2Hz, 1H), 6.93 (d,
J=7.9Hz, 1H), 6.18 (s, 2H), 4.20-4.12 (m, 2H), 3.40-3.28 (m, 4H), 3.20-3.06 (m, J=11.9,
5.9Hz, 6H), 2.09-1.95 (m, 2H), 1.22 (t, J=7.2Hz, 6H)13C NMR(101MHz,DMSO-d6))δ187.46,
159.73, δ 153.12 (d, J=194.2Hz), 152.07,149.29,148.91,148.52,143.26 (d, J=13.7Hz),
142.94,137.82,135.45,135.05,132.84,130.42,129.72,127.98,125.54,123.26,109.54
(d, J=20.6Hz), 109.11 (d, J=7.5Hz), 108.60,108.41,106.01 (d, J=4.1Hz), 102.54,
51.09,46.96,44.33,41.72,29.42,25.79,24.96,11.55.ESI-HRMS[M+H]+M/z=595.2642,
calcd for C35H35FN4O4,595.2699.Purity:99.6%by HPLC.
Embodiment 15：Compound 3b synthesis
Compound 3 (0.3323g, 1mmol) and compound b (0.3535g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.2961g, yield 46%.
1H NMR(400MHz,CDCl3) δ 8.02 (d, J=8.7Hz, 2H), 7.84-7.75 (m, 3H), 7.71 (d, J=
8.1Hz, 2H), 7.64-7.56 (m, 3H), 6.93 (d, J=8.8Hz, 2H), 6.79 (d, J=7.6Hz, 1H), 4.28 (t, J=
7.0Hz, 2H), 3.91-3.84 (m, 4H), 3.65 (d, J=4.5Hz, 1H), 3.41-3.27 (m, 8H), 2.69-2.50 (m,
6H), 1.94-1.81 (m, 2H), 1.08 (t, J=6.7Hz, 6H)13C NMR(101MHz,CDCl3)δ187.76,160.42,
(154.96,154.26,150.87 d, J=246.3Hz), 148.71,143.46 (d, J=13.8Hz), 142.16,137.38,
135.54,133.32,130.66,130.12,128.79,128.69,122.67,113.40 109.74 (d, J=20.8Hz),
109.42 (d, J=7.6Hz), 105.55 (d, J=4.2Hz), 70.59,66.57,52.72,47.49,46.85,43.78,
25.81,25.12,11.59.
ESI-HRMS[M+H]+M/z=636.3272, calcd for C38H42FN5O3,636.3321.Purity:
97.5%by HPLC.
Embodiment 16：Compound 3c synthesis
Compound 3 (0.3323g, 1mmol) and compound c (0.3216g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.3050g, yield 50%.
1H NMR(400MHz,CDCl3) δ 7.98 (d, J=8.0Hz, 1H), 7.81 (d, J=16.4Hz, 1H), 7.77-
7.68 (m, 5H), 7.59 (d, J=8.6Hz, 2H), 7.53 (d, J=7.6Hz, 3H), 6.78 (d, J=7.5Hz, 1H), 6.65
(s, 1H), 4.30 (t, J=6.7Hz, 2H), 3.41-3.34 (m, 2H), 3.33-3.24 (m, 2H), 2.73-2.55 (m, 6H),
1.96-1.85 (m, 2H), 1.37 (s, 9H), 1.10 (t, J=6.6Hz, 6H)
13C NMR(101MHz,CDCl3) δ 188.75,159.39,156.36 (t, J=273.9Hz), 153.94,
(152.63,151.06,148.62,147.65,142.36 d, J=14.1Hz), 142.20,136.56,134.46,134.22,
132.46,131.30,129.88,129.13,127.81,127.79,127.72,127.49,124.63,121.79,108.76
(d, J=21.0Hz), 108.47 (d, J=6.7Hz), 104.53 (d, J=4.1Hz), 64.54,51.46,45.80,42.89,
34.14,30.10,28.68,24.79,12.70.
ESI-HRMS[M+H]+M/z=607.3370, calcd for C38H43FN4O2,607.3430.Purity:
96.2%by HPLC.
Embodiment 17：Compound 3d synthesis
Compound 3 (0.3323g, 1mmol) and compound d (0.2797g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.2507g, yield 44%.
1H NMR(400MHz,CDCl3) δ 8.03-7.97 (m, 2H), 7.71 (m, 3H), 7.63 (d, J=8.3Hz, 2H),
7.52 (d, J=8.3Hz, 2H), 7.47 (d, J=15.6Hz, 1H), 7.12 (t, J=8.6Hz, 2H), 6.70 (d, J=7.7Hz,
1H), 4.24-4.14 (m, 2H), 3.29 (dd, J=10.6,5.6Hz, 2H), 3.25-3.18 (m, 2H), 2.59 (t, J=
5.9Hz, 2H), 2.53 (q, J=7.0Hz, 4H), 1.84 (dd, J=11.7,5.8Hz, 2H), 1.02 (t, J=7.1Hz, 6H)
.13C NMR(101MHz,CDCl3) δ 187.50,165.94,163.40,159.40,153.87,149.86 (d, J=
245.0Hz), 147.64,142.86,142.41 (d, J=14.0Hz), 136.84,133.92,133.44,132.66,
130.13,130.04,129.14,127.85,127.58,121.16,114.91,114.69 108.74 (d, J=20.7Hz),
108.42 (d, J=7.7Hz), 104.51 (d, J=3.7Hz), 51.60,45.81,42.88,42.48,24.80,23.96,
10.44.
ESI-HRMS[M+H]+M/z=569.2650, calcd for C34H34F2N4O2,569.2722.Purity:
98.2%by HPLC.
Embodiment 18：Compound 3e synthesis
Compound 3 (0.3323g, 1mmol) and compound e (0.2930g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.3011g, yield 52%.
1H NMR(400MHz,CDCl3) δ 8.05 (d, J=8.7Hz, 2H), 7.79 (t, J=14.6Hz, 3H), 7.71 (d, J
=7.9Hz, 2H), 7.64-7.55 (m, 3H), 7.00 (d, J=8.6Hz, 2H), 6.78 (d, J=7.6Hz, 1H), 4.27 (t, J
=6.8Hz, 2H), 3.90 (s, 3H), 3.36 (m, 2H), 3.34-3.27 (m, 2H), 2.70-2.53 (m, J=21.5Hz, 6H),
1.94-1.83 (m, 2H), 1.09 (t, J=6.5Hz, 6H)
13C NMR(101MHz,CDCl3) δ 188.28,163.53,160.37 (d, J=3.3Hz), 153.47 (d, J=
285.4Hz), 149.62,148.66,143.45 (d, J=14.0Hz), 142.77,137.50,135.22,133.44,
(130.94,130.82,130.12,128.74,128.58,122.38,113.89,109.66 d, J=20.8Hz), 109.32
(d, J=7.7Hz), 105.46 (d, J=4.2Hz), 55.51,52.86,46.83,43.89,43.76,25.78,25.05,
11.67.
ESI-HRMS[M+H]+M/z=581.2850, calcd for C35H37FN4O3,581.2900.Purity:
99.1%by HPLC.
Embodiment 19：Compound 3f synthesis
Compound 3 (0.3323g, 1mmol) and compound f (0.3083g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.2106g, yield 35%.
1H NMR(400MHz,CDCl3) δ 7.82-7.77 (m, 1H), 7.76 (d, J=3.4Hz, 1H), 7.73 (d, J=
2.5Hz, 1H), 7.66 (dd, J=8.2,1.6Hz, 1H), 7.62 (d, J=7.5Hz, 1H), 7.57 (d, J=7.3Hz, 1H),
7.55-7.53 (m, 1H), 7.51-7.44 (m, 2H), 6.91 (dd, J=8.1,1.5Hz, 1H), 6.77 (d, J=7.7Hz, 2H),
6.07 (d, J=1.2Hz, 2H), 4.25 (dd, J=9.7,4.5Hz, 2H), 3.38-3.32 (m, 2H), 3.28 (dd, J=8.6,
5.0Hz, 2H), 2.63 (t, J=5.7Hz, 2H), 2.57 (q, J=7.0Hz, 4H), 1.91-1.83 (m, 2H), 1.07 (t, J=
7.1Hz,6H).13C NMR(101MHz,CDCl3) δ 187.99,160.42,154.94,152.10-149.45 (d, J=
187.6Hz), 149.61,148.40,143.45,143.31 (d, J=13.1Hz), 136.44,135.66,133.16,
132.83,131.00,129.88,129.42,128.85,128.04,124.77,122.50 109.82 (d, J=20.8Hz),
109.57 (d, J=7.6Hz), 108.44,107.97,105.61 (d, J=4.3Hz), 101.94,52.18,46.75,43.91,
43.06,29.70,25.66,24.84,11.10.
ESI-HRMS[M+H]+M/z=595.2642, calcd for C35H35FN4O4,595.2711.Purity:
98.1%by HPLC.
Embodiment 20：Compound 3g synthesis
Compound 3 (0.3323g, 1mmol) and compound g (0.3535g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.2360g, yield 37%.
1H NMR(400MHz,CDCl3) δ 8.03 (d, J=9.0Hz, 2H), 7.85-7.76 (m, 4H), 7.65 (d, J=
7.7Hz, 1H), 7.63-7.57 (m, 2H), 7.50 (t, J=7.7Hz, 1H), 6.94 (d, J=9.0Hz, 2H), 6.81 (d, J=
7.7Hz, 1H), 4.31-4.25 (m, 2H), 3.90-3.86 (m, 4H), 3.65 (d, J=4.5Hz, 1H), 3.42 (t, J=
5.4Hz,2H),3.38–3.34(m,4H),3.34–3.29(m,2H),2.83–2.68(m,6H),2.06–1.95(m,2H),
1.17 (t, J=6.7Hz, 6H)13C NMR(101MHz,CDCl3)δ187.58,160.34,154.86,154.22,150.70
(d, J=244.5Hz), 148.58,148.16,143.30 (d, J=14.2Hz), 142.42,136.20,135.75,132.96,
130.80,130.64,129.81,129.31,128.68,128.39,128.00,122.37 113.30,109.60 (d, J=
20.5Hz), 109.28 (d, J=7.6Hz), 105.26 (d, J=35.6Hz), 66.51,52.53,47.32,46.74,43.90,
43.42,25.56,24.85,11.41.
ESI-HRMS[M+H]+M/z=636.3272, calcd for C38H42FN5O3,636.3317.Purity:
98.1%by HPLC.
Embodiment 21：Compound 3h synthesis
Compound 3 (0.3323g, 1mmol) and compound h (0.3216g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.1744g, yield 29%.
1H NMR(400MHz,CDCl3) δ 8.12-8.03 (m, 2H), 7.83 (d, J=15.7Hz, 1H), 7.80-7.72 (m,
3H), 7.64 (d, J=7.4Hz, 1H), 7.60 (d, J=7.5Hz, 1H), 7.57-7.46 (m, 2H), 7.20 (t, J=8.3Hz,
2H), 6.85 (s, 1H), 6.77 (d, J=7.6Hz, 1H), 4.27 (t, J=6.8Hz, 2H), 3.39-3.25 (m, 4H), 2.62
(t, J=5.3Hz, 2H), 2.57 (q, J=7.2Hz, 4H), 1.93-1.81 (m, 2H), 1.25 (s, 9H), 1.07 (t, J=
7.1Hz,6H).13C NMR(101MHz,CDCl3) δ 187.56,166.14,163.61,159.54,156.73 (d, J=
558.3Hz), 151.18,148.75,147.79,143.37,142.62 (d, J=14.1Hz), 135.57,134.50,
133.50,133.47,132.42,130.37,130.27,129.18,128.61,127.63,127.23,121.25,115.12,
114.90,108.80 (d, J=20.8Hz), 108.46 (d, J=7.6Hz), 104.60 (d, J=4.1Hz), 52.00,50.24,
45.97,42.91,34.41,30.93,28.47,24.80,10.82.
ESI-HRMS[M+H]+M/z=607.3370, calcd for C38H43FN4O2,607.3462.Purity:
98.6%by HPLC.
Embodiment 22：Compound 3i synthesis
Compound 3 (0.3323g, 1mmol) and compound i (0.2797g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.3622g, yield 64%.
1H NMR(400MHz,CDCl3) δ 8.12-8.04 (m, 2H), 7.83 (d, J=15.7Hz, 1H), 7.80-7.72 (m,
3H), 7.65 (d, J=7.6Hz, 1H), 7.61 (d, J=7.7Hz, 1H), 7.57-7.47 (m, 2H), 7.20 (t, J=8.3Hz,
2H), 6.85 (s, 1H), 6.78 (d, J=7.6Hz, 1H), 4.27 (t, J=7.0Hz, 2H), 3.39-3.26 (m, 4H), 2.63
(t, J=5.4Hz, 2H), 2.56 (q, J=7.0Hz, 4H), 1.93-1.83 (m, 2H), 1.07 (t, J=7.0Hz, 6H)13C
NMR(101MHz,CDCl3) δ 188.36,166.93,164.40,160.33,160.30,154.75,150.77 (d, J=
244.5Hz), 148.58,144.17,143.41 (d, J=14.1Hz), 136.37,135.30,134.30,134.27,
133.21,131.16,131.07,129.97,129.41,128.43,128.03,122.05,115.91,115.70,109.59
(d, J=20.8Hz), 109.26 (d, J=7.6Hz), 105.39 (d, J=4.1Hz), 52.79,46.77,43.86,43.71,
29.77,25.59,25.00,11.62.
ESI-HRMS[M+H]+M/z=569.2650, calcd for C34H34F2N4O2,569.2705.Purity:
97.9%by HPLC.
Embodiment 23：Compound 3j synthesis
Compound 3 (0.3323g, 1mmol) and compound j (0.2930g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.3140g, yield 54%.
1H NMR (400MHz, DMSO-d6) δ 8.15 (d, J=8.5Hz, 2H), 8.03 (s, 1H), 7.96-7.86 (m,
3H), 7.75 (d, J=15.6Hz, 1H), 7.68 (d, J=7.8Hz, 1H), 7.61 (d, J=11.8Hz, 1H), 7.57 (t, J=
7.7Hz, 1H), 7.09 (d, J=8.5Hz, 2H), 7.01 (d, J=7.3Hz, 1H), 4.17 (t, J=6.9Hz, 2H), 3.88 (s,
3H), 3.41-3.32 (m, 4H), 3.19-3.06 (m, 6H), 2.13-2.03 (m, 2H), 1.26 (t, J=7.2Hz, 6H)13C
NMR (101MHz, DMSO-d6) δ 188.07,163.85,159.34 (d, J=3.1Hz), 153.91 (d, J=427.6Hz),
(149.36,147.15,146.21,143.17 d, J=13.9Hz), 142.91,136.42,136.13,133.83,131.48,
(131.36,131.10,130.46,129.93,129.26,123.78,114.59,109.94 d, J=20.8Hz), 109.15
(d, J=7.4Hz), 105.18 (d, J=3.9Hz), 56.11,49.43,46.96,44.87,34.64,25.61,22.90,
8.95.
ESI-HRMS[M+H]+M/z=581.2850, calcd for C35H37FN4O3,581.2904.Purity:
97.1%by HPLC.
Embodiment 24：Compound 4a synthesis
Compound 4 (0.3462g, 1mmol) and compound a (0.3083g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.2511g, yield 41%.
1H NMR(400MHz,CDCl3) δ 7.82 (d, J=5.7Hz, 1H), 7.80-7.77 (m, 2H), 7.71 (d, J=
8.3Hz, 2H), 7.67 (dd, J=8.1,1.6Hz, 1H), 7.61 (d, J=8.3Hz, 2H), 7.55 (dd, J=8.6,7.0Hz,
2H), 6.92 (d, J=8.1Hz, 1H), 6.82 (d, J=7.7Hz, 1H), 6.08 (s, 2H), 4.32-4.26 (m, 2H), 3.80
(s, 4H), 3.39 (d, J=3.9Hz, 2H), 3.36-3.29 (m, 2H), 2.56 (d, J=20.8Hz, 6H), 1.92 (s, 2H)13C
NMR(101MHz,CDCl3) δ 187.94,160.43 (d, J=3.5Hz), 155.04,152.06,150.85 (d, J=
244.1Hz), 148.68,148.39,143.36 (d, J=13.9Hz), 143.08,137.57,135.25,133.44,
(132.88,130.16,128.80,124.74,122.38,109.83 d, J=20.9Hz), 109.59 (d, J=7.7Hz),
(108.43,107.97,105.63 d, J=3.9Hz), 101.94,66.89,58.10,53.78,43.93,43.45,25.81,
24.02.
ESI-HRMS[M+H]+M/z=608.2435, calcd for C35H33FN4O5,609.2511.Purity:
98.9%by HPLC.
Embodiment 25：Compound 4b synthesis
Compound 4 (0.3462g, 1mmol) and compound b (0.3535g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.3100g, yield 48%.
1H NMR(400MHz,CDCl3) δ 8.02 (d, J=8.8Hz, 2H), 7.80 (dd, J=11.5,4.2Hz, 3H),
(7.71 d, J=8.2Hz, 2H), 7.64-7.58 (m, 3H), 6.93 (d, J=8.7Hz, 2H), 6.82 (d, J=7.7Hz, 1H),
6.50 (s, 1H), 4.28 (t, J=7.2Hz, 2H), 3.91-3.84 (m, 4H), 3.79 (s, 4H), 3.41-3.28 (m, 8H),
2.55 (d, J=22.9Hz, 6H), 1.91 (s, 2H)13C NMR(101MHz,CDCl3) δ 187.74,160.42 (d, J=
3.2Hz), 154.27,152.33 (d, J=545.4Hz), 148.70,143.34 (d, J=13.9Hz), 142.13,137.31,
135.58,133.25,130.66,130.13,128.85,128.69,122.68,113.40 109.81 (d, J=20.9Hz),
109.60 (d, J=7.6Hz), 105.66 (d, J=3.9Hz), 100.00,66.90,66.56,58.08,53.80,47.48,
43.92,43.42,25.79,24.09.
ESI-HRMS[M+H]+M/z=650.3064, calcd forC38H40FN5O4,650.3145.Purity:
99.4%by HPLC.
Embodiment 26：Compound 4c synthesis
Compound 4 (0.3462g, 1mmol) and compound c (0.3216g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.1562g, yield 25%.
1H NMR(400MHz,CDCl3) δ 7.99 (d, J=8.3Hz, 2H), 7.84 (d, J=5.8Hz, 1H), 7.80 (d, J
=11.6Hz, 3H), 7.65 (d, J=7.5Hz, 1H), 7.60 (t, J=3.5Hz, 2H), 7.54 (d, J=8.7Hz, 2H),
7.53-7.47 (m, 1H), 6.83 (d, J=7.7Hz, 1H), 6.50 (s, 1H), 4.29 (t, J=7.1Hz, 2H), 3.87-3.73
(m,4H),3.44–3.36(m,2H),3.35–3.27(m,2H),2.68–2.43(m,6H),1.98–1.84(m,2H),1.38
(s,9H).13C NMR(101MHz,CDCl3) δ 189.69,160.36 (d, J=3.2Hz), 156.75,153.42 (d, J=
298.4Hz), 149.51,148.56,143.50,143.26 (d, J=13.9Hz), 136.29,135.56,135.30,
133.01,131.03,129.72,129.35,128.80,128.43,128.03,125.59 122.77,109.71 (d, J=
20.9Hz), 109.46 (d, J=7.8Hz), 105.52 (d, J=4.0Hz), 66.79,57.99,53.67,43.84,43.34,
35.08,31.02,29.60,23.91.
ESI-HRMS[M+H]+M/z=621.3163, calcd for C38H41FN4O3,621.3209.Purity:
99.0%by HPLC.
Embodiment 27：Compound 4d synthesis
Compound 4 (0.3462g, 1mmol) and compound d (0.2797g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.2961g, yield 51%.
1H NMR(400MHz,CDCl3) δ 8.10 (dd, J=7.8,5.8Hz, 2H), 7.88-7.79 (m, 3H), 7.74 (d, J
=8.1Hz, 2H), 7.63 (d, J=8.0Hz, 2H), 7.57 (d, J=15.6Hz, 1H), 7.22 (t, J=8.4Hz, 2H), 6.84
(d, J=7.6Hz, 1H), 6.54 (s, 1H), 4.31 (t, J=7.0Hz, 2H), 3.89-3.76 (m, 4H), 3.46-3.38 (m,
2H),3.37–3.30(m,2H),2.67–2.46(m,6H),1.99–1.89(m,2H).13C NMR(101MHz,CDCl3)δ
(188.52,166.96,164.43,160.41 d, J=3.4Hz), 152.32 (d, J=537.2Hz), 152.08,148.66,
143.87,143.37 (d, J=14.0Hz), 137.82,134.43 (d, J=2.9Hz), 134.42,133.64,131.16,
(131.07,130.18,128.90,128.68,122.20,115.94,115.73,109.83 d, J=21.0Hz), 109.59
(d, J=7.8Hz), 105.63 (d, J=4.1Hz), 66.89,58.11,53.79,53.49,43.93,25.83,24.00.
ESI-HRMS[M+H]+M/z=583.2422, calcd for C34H32F2N4O3,583.2508.Purity:
98.9%by HPLC.
Embodiment 28：Compound 4e synthesis
Compound 4 (0.3462g, 1mmol) and compound e (0.2930g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.3594g, yield 60%.
1H NMR (400MHz, DMSO) δ 8.20 (d, J=8.2Hz, 2H), 8.07-7.99 (m, 3H), 7.79-7.69 (m,
4H), 7.64 (d, J=11.4Hz, 1H), 7.11 (d, J=7.9Hz, 2H), 6.90 (d, J=7.8Hz, 1H), 4.18-4.13 (m,
2H), 4.00-3.93 (m, 4H), 3.88 (s, 3H), 3.47-3.40 (m, 2H), 3.34 (dd, J=14.4,7.1Hz, 2H),
3.21–3.03(m,6H),2.10–2.02(m,2H).13C NMR(101MHz,DMSO)δ187.96,165.97,163.84,
159.58,151.97 (d, J=774.2Hz), 149.33,143.01 (d, J=14.9Hz), 142.60,137.64,135.73,
134.70,134.67,132.99,131.36,131.09,130.52,129.68,123.62,116.44,114.59,109.84
(d, J=19.9Hz), 105.80 (d, J=6.7Hz), 100.01 (d, J=2.6Hz), 63.65,56.10,54.57,54.47,
51.61,44.61,25.81,22.66.
ESI-HRMS[M+H]+M/z=595.2642, calcd for C35H35FN4O4,595.2690.Purity:
99.5%by HPLC.
Embodiment 29：Compound 4f synthesis
Compound 4 (0.3462g, 1mmol) and compound f (0.3083g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.2530g, yield 41%.
1H NMR(400MHz,MeOD)δ8.13(s,1H),7.82–7.77(m,2H),7.73–7.66(m,3H),7.62
(d, J=3.8Hz, 1H), 7.60 (d, J=6.1Hz, 1H), 7.48 (t, J=7.8Hz, 1H), 7.42 (s, 1H), 7.03 (d, J=
7.3Hz, 1H), 6.86 (d, J=8.1Hz, 1H), 5.98 (s, 2H), 4.33-4.28 (m, 2H), 3.99 (dd, J=13.4,
2.0Hz, 2H), 3.72 (t, J=12.6Hz, 2H), 3.53-3.45 (m, 6H), 3.41-3.34 (m, 4H), 2.15-2.07 (m,
2H).13C NMR (101MHz, MeOD) δ 189.32,163.47,154.06 (d, J=303.1Hz), 151.14,148.56,
143.18 (d, J=13.9Hz), 142.78,141.42,138.63,131.72,130.86,129.57,128.57,125.13,
(122.66,120.36,119.17,117.62,115.38,109.56 d, J=14.6Hz), 109.21 (d, J=8.9Hz),
(107.63,102.15 d, J=8.5Hz), 63.70,56.93,54.92,51.99,30.25,25.32,24.71.
ESI-HRMS[M+H]+M/z=609.2435, calcd for C35H33FN4O5,609.2480.Purity:
98.3%by HPLC.
Embodiment 30：Compound 4g synthesis
Compound 4 (0.3462g, 1mmol) and compound g (0.3535g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.3961g, yield 61%.
1H NMR (400MHz, DMSO) δ 8.07 (d, J=8.4Hz, 2H), 7.92 (d, J=16.1Hz, 2H), 7.84 (d, J
=7.6Hz, 1H), 7.71 (m, 3H), 7.60 (d, J=12.2Hz, 1H), 7.58-7.52 (m, 1H), 7.02 (d, J=8.7Hz,
2H), 6.84 (d, J=7.9Hz, 1H), 6.59 (s, 1H), 4.17-4.10 (m, 2H), 3.78-3.72 (m, 4H), 3.67-3.60
(m,4H),3.37–3.28(m,8H),2.44–2.37(m,6H),1.85–1.77(m,2H).13C NMR(101MHz,CDCl3)δ
188.17,160.85 (d, J=3.1Hz), 154.70,152.76 (d, J=542.4Hz), 149.13,143.77 (d, J=
13.9Hz),142.56,137.74,136.01,133.68,131.09,130.56,129.28,129.12,123.11,
113.83,110.24 (d, J=20.6Hz), 109.99 (d, J=7.4Hz), 106.09 (d, J=3.9Hz), 67.33,66.99,
58.51,54.23,47.91,44.35,43.85,26.22,24.52.
ESI-HRMS[M+H]+M/z=650.3064, calcd for C38H40FN5O4,650.33119.Purity:
99.5%by HPLC.
Embodiment 31：Compound 4h synthesis
Compound 4 (0.3462g, 1mmol) and compound h (0.3216g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.1023g, yield 16%.
1H NMR(400MHz,CDCl3) δ 8.02-7.98 (m, 2H), 7.83-7.80 (m, 1H), 7.78 (d, J=7.3Hz,
2H), 7.65 (d, J=7.6Hz, 1H), 7.59 (d, J=5.6Hz, 1H), 7.57-7.53 (m, 3H), 7.50 (t, J=6.5Hz,
1H), 6.82 (d, J=7.7Hz, 1H), 4.31-4.25 (m, 2H), 3.89-3.77 (m, 4H), 3.44-3.36 (m, 2H), 3.32
(dd, J=9.9,4.3Hz, 2H), 2.69-2.47 (m, 6H), 2.01-1.87 (m, 2H), 1.37 (s, 9H)13C NMR
(101MHz,CDCl3) δ 189.80,160.47 (d, J=3.2Hz), 156.86,153.53 (d, J=298.4Hz), 149.62,
(148.67,143.61,143.37 d, J=13.9Hz), 136.40,135.67,135.41,133.12,131.14,129.83,
(129.46,128.91,128.54,128.14,125.70,122.88,109.82 d, J=20.9Hz), 109.57 (d, J=
7.8Hz), 105.63 (d, J=4.0Hz), 66.90,58.10,53.78,43.95,43.45,35.19,31.13,29.71,
25.68.
ESI-HRMS[M+H]+M/z=621.3163, calcd for C38H41FN4O3,621.3220.Purity:
97.9%by HPLC.
Embodiment 32：Compound 4i synthesis
Compound 4 (0.3462g, 1mmol) and compound i (0.2797g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.4168g, yield 72%.
1H NMR(400MHz,CDCl3) δ 8.08 (t, J=6.8Hz, 2H), 7.86 (d, J=12.0Hz, 2H), 7.80 (d, J
=12.2Hz, 2H), 7.66 (d, J=7.8Hz, 1H), 7.61 (d, J=7.5Hz, 1H), 7.55 (d, J=11.5Hz, 1H),
7.53-7.49 (m, 1H), 7.20 (t, J=8.4Hz, 2H), 6.83 (d, J=7.7Hz, 1H), 6.51 (s, 1H), 4.29 (t, J=
7.0Hz,2H),3.87–3.73(m,4H),3.44–3.36(m,2H),3.35–3.29(m,2H),2.68–2.47(m,6H),
1.91 (dt, J=12.1,6.2Hz, 2H)13C NMR(101MHz,CDCl3)δ188.49,166.98,164.45,160.40,
(154.92,149.55,149.23 d, J=548.0Hz), 148.59,144.23,143.29 (d, J=14.0Hz), 136.37,
135.35,134.29,133.16,131.20,131.11,130.04,129.49,128.69,128.10,122.16,115.97,
115.75,109.76 (d, J=21.0Hz), 109.51 (d, J=8.0Hz), 105.53 (d, J=3.4Hz), 66.71,57.94,
53.65,43.94,43.26,25.62,23.85.
ESI-HRMS[M+H]+M/z=583.2442, calcd for C34H32F2N4O3,583.2500.Purity:
99.1%by HPLC.
Embodiment 33：Compound 4j synthesis
Compound 4 (0.3462g, 1mmol) and compound j (0.2930g, 1.1mmol) are added into rear wall pressure bottle, then added
Enter 2mL DMSO, 10mL trim,ethylchlorosilane, 100 DEG C are heated overnight, and after TLC monitoring reactions terminate, filter, crude product is used
Ethanol/methylene recrystallizes, and obtains faint yellow solid 0.2010g, yield 34%.
1H NMR(400MHz,CDCl3) δ 8.08 (d, J=8.8Hz, 2H), 7.85 (d, J=12.7Hz, 1H), 7.83-
7.79 (m, 2H), 7.68 (d, J=8.1Hz, 1H), 7.64-7.58 (m, 2H), 7.56-7.50 (m, 1H), 7.03 (d, J=
8.8Hz, 2H), 6.84 (d, J=7.7Hz, 1H), 4.35-4.27 (m, 2H), 3.93 (s, 3H), 3.90-3.84 (m, 4H),
3.47–3.40(m,2H),3.38–3.31(m,2H),2.80–2.44(m,6H),2.05–1.92(m,2H).13C NMR
(101MHz, DMSO) δ 187.86,163.83,159.29,154.86 (d, J=246.1Hz), 151.34,147.84,143.21,
143.19 (d, J=3.6Hz), 141.13,136.30,136.04,131.60,131.46,130.91,130.70,129.96,
(129.39,123.42,118.74,114.55,111.77 d, J=10.1Hz), 109.92 (d, J=25.6Hz), 104.63 (d,
), J=7.4Hz 63.61,56.09,54.43,51.51,45.00,34.59,25.61,22.41.
ESI-HRMS[M+H]+M/z=595.2642, calcd for C35H35FN4O4,595.2692.Purity:
98.7%by HPLC.
Embodiment 34：Quinazolinone of the present invention is with the conjugated derivative of alpha, beta-unsaturated ketone to growth of tumour cell
Inhibitory action
Quinazolinone and α of the present invention are chosen, the conjugated derivative of alpha, beta-unsaturated ketone, various tumor cell strains are used
Mtt assay carries out cell in vitro poison measure.The cell of exponential phase adds the quinazolinone and alpha, beta-unsaturated ketone of various concentrations
Conjugated derivative, after acting on 48h, MTT is added, determines its absorbance.Chemical combination when suppressing cell growth 50% is calculated respectively
Thing concentration, represented with IC50 values, as a result as shown in table 1.As a result show this series compound have in vitro to tumor cell line compared with
Strong inhibitory action, available for preparing antineoplastic.
Table 1：Inhibitory action (the IC that quinazolinone grows with the conjugated derivative of alpha, beta-unsaturated ketone to tumor cell line50Value/
μM)
Embodiment 35：The influence of transcriptions and expression of the representation compound 3i to intracellular c-MYC genes
RT-PCR experimental methods：
Cell culture：Seed cells into 6 orifice plates, 200 000/hole, after 24 hour cells are adherent, add chemical combination
Thing, after cultivating 3-24 hours, collect cell, extract RNA, detect RNA concentration, after according to following system do reverse transcription reaction, and
PCR experiment.
PCR primer, primer, the preparation system used is as follows：
10 × Dream Taq Green buffer, 2.5 μ L；DNTP mixture (2.5mM), 0.5 μ L；CDNA, 1 μ L；
Primer (sense), 0.5 μ L；Primer (antisense), 0.5 μ L；Dream Taq DNA polymerases, 0.25 μ L；DdH20,20.25
μL；Total, 25 μ L
Program:95 DEG C of denaturation, 5min；95 DEG C of denaturation, 30s；58 DEG C of annealing, 30s；72 DEG C of extensions, 60s (30cycles)；
72 DEG C, 10min；Finally it is cooled to 10 DEG C.
1.5% agarose electrophoresis 120V, 0.5h, after electrophoresis terminates, gel imaging.
As a result as shown in figure 1, quinazolinone and α, the conjugated derivative 3i of alpha, beta-unsaturated ketone can reduce c-myc transcription water
It is flat.
Western blot experimental methods：
Cell culture：Cell count, inoculation, is cultivated in six orifice plates, after length to 5,000,000 cells, is taken out, cracking, carefully
After born of the same parents are collected, 50 μ L cell pyrolysis liquids are added, extract supernatant total protein liquid.Total protein concentration, rear denaturation are detected using BCA methods
Protein sample, take the albumen loading of phase homogenous quantities, SDS-PAGE gel electrophoresis protein isolate bands.Molecule is calculated according to target protein
Amount, the running gel band of relevant position is cut, wet robin goes to protein band on pvdf membrane.
Configure TBST buffer solutions：25mM NaCl, 100mM Tris, 0.2%Tween-20, pH 7.4, with TBST buffer solutions
5% skimmed milk power solution (w/v) the closing pvdf membrane of dissolving.Mutually it is incubated pvdf membrane, TBST bufferings using primary antibody and secondary antibody respectively
After liquid rinses appropriate number, the super quick luminescence reagent box colour developing imagings of SuperECL Plus are used.
As a result as shown in Fig. 2 quinazolinone and α, the conjugated derivative 3i of alpha, beta-unsaturated ketone can reduce C-MYC expression water
It is flat.
Claims (10)
1. a kind of quinazolinone and α, the conjugated derivative of alpha, beta-unsaturated ketone, it is characterised in that the quinazolinone and α, β-insatiable hunger
Shown in the structural formula such as formula (I) or formula (II) of the conjugated derivative of ketone：
Wherein, R1For hydrogen, amido, substituted amido, five yuan or hexa-member heterocycle base；R2For hydrogen, phenyl, substituted-phenyl, benzheterocycle
Compound；Substituent is selected from C1-5Alkyl, C1-8Alkoxy, halogen, phenyl, amido, five yuan or hexa-member heterocycle base.
2. derivative according to claim 1, it is characterised in that R1For NH (CH2)n R3, R3For amido, substituted amido, five
Member or hexa-member heterocycle base, n are any one integer in 1~5, and the substituent in substituted amido is selected from C1-5Alkyl, C1-8Alkoxy,
Five yuan or hexa-member heterocycle base.
3. derivative according to claim 2, it is characterised in that R3For amido, N, N- diethyl methyl amines base, N, N- diformazans
Base methylamino or morpholinyl.
4. derivative according to claim 1, it is characterised in that R2For phenyl, substituted-phenyl, benzo five-membered or benzo six
Membered heterocyclic compound, the substituent in substituted-phenyl are selected from halogen, C1-5Alkoxy, five yuan or hexa-atomic nitrogen heterocycle.
5. derivative according to claim 4, it is characterised in that R2It is luxuriant for phenyl, substituted-phenyl or 1,3- Ben Bing bis- Evil,
Substituent is halogen, morpholinyl, C in substituted-phenyl1-5Alkyl or C1-5Alkoxy.
6. the derivative according to claim 4 or 5, it is characterised in that in substituted-phenyl substituent be fluorine-based, morpholinyl,
The tert-butyl group or methoxyl group.
7. any described quinazolinone and α in a kind of claim 1 to 6, the preparation method of the conjugated derivative of alpha, beta-unsaturated ketone,
It is characterised in that it includes following steps：
S1.2- amino -4,5- difluoro-benzoic acids react to obtain compound with 2-Pyrrolidone
S2. compoundWith aminated compounds NH-R1Reaction obtains intermediate
S3. compoundReact to obtain intermediate with ketone compounds
S4. gained compound in S2 and gained compound in S3 are reacted, obtains the quinazolinone and α, alpha, beta-unsaturated ketone yoke
Close derivative.
8. any described quinazolinone of claim 1 to 6 is with the conjugated derivative of alpha, beta-unsaturated ketone in cancer therapy drug is prepared
Application.
9. application according to claim 8, it is characterised in that the quinazolinone and α, the conjugated derivative of alpha, beta-unsaturated ketone
It is the preparation for being applied to cancer therapy drug as proto-oncogene c-MYC transcriptional controls blocking agent.
10. application according to claim 8 or claim 9, it is characterised in that the anticancer is ovarian cancer resistance, cervical carcinoma, mammary gland
Cancer, adenocarcinoma of lung, colon cancer, liver cancer, leukaemia, ED-SCLC, cutaneum carcinoma, cell carcinoma, prostate cancer, non-small cell lung
One or more in cancer, nasopharyngeal carcinoma, glioblastoma, lymthoma or melanoma.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101857595A (en) * | 2010-05-21 | 2010-10-13 | 中山大学 | Quinnazolidone derivative, preparation method thereof and purpose of serving as anticarcinogen |
| US20150197492A1 (en) * | 2014-01-13 | 2015-07-16 | National Defense Medical Center | NOVEL INDENO[1,2-c]QUINOLIN-11-ONE DERIVATIVES, PREPARATION METHOD AND APPLICATION THEREOF |
| CN105272986A (en) * | 2015-06-15 | 2016-01-27 | 厦门医学高等专科学校 | A compound for inhibiting acetylcholinesterase activity, and preparation method and uses thereof |
| CN106220631A (en) * | 2016-07-26 | 2016-12-14 | 中山大学 | A kind of 7 fluorine replace Isaindigotone derivant and preparation method thereof and the application in preparing cancer therapy drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101857595A (en) * | 2010-05-21 | 2010-10-13 | 中山大学 | Quinnazolidone derivative, preparation method thereof and purpose of serving as anticarcinogen |
| US20150197492A1 (en) * | 2014-01-13 | 2015-07-16 | National Defense Medical Center | NOVEL INDENO[1,2-c]QUINOLIN-11-ONE DERIVATIVES, PREPARATION METHOD AND APPLICATION THEREOF |
| CN105272986A (en) * | 2015-06-15 | 2016-01-27 | 厦门医学高等专科学校 | A compound for inhibiting acetylcholinesterase activity, and preparation method and uses thereof |
| CN106220631A (en) * | 2016-07-26 | 2016-12-14 | 中山大学 | A kind of 7 fluorine replace Isaindigotone derivant and preparation method thereof and the application in preparing cancer therapy drug |
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| WO2021004391A1 (en) * | 2019-07-08 | 2021-01-14 | 苏州开拓药业股份有限公司 | C-myc protein inhibitor, and preparation method therefor and use thereof |
| CN114072413A (en) * | 2019-07-08 | 2022-02-18 | 苏州开拓药业股份有限公司 | C-Myc protein inhibitor and preparation method and application thereof |
| CN114072413B (en) * | 2019-07-08 | 2024-04-16 | 苏州开拓药业股份有限公司 | c-Myc protein inhibitor and preparation method and application thereof |
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