CN109651354A - - 4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) and its preparation method and application - Google Patents
- 4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) and its preparation method and application Download PDFInfo
- Publication number
- CN109651354A CN109651354A CN201910068653.6A CN201910068653A CN109651354A CN 109651354 A CN109651354 A CN 109651354A CN 201910068653 A CN201910068653 A CN 201910068653A CN 109651354 A CN109651354 A CN 109651354A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- reaction
- propyl
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention provides one kind 3- (2-[4-morpholinodithio base) -4 (1H) qualone derivative and its preparation method and application, such compound has 3- (2-[4-morpholinodithio base) -4 (1H) quinolinone structure, general formula is
Description
Technical field
The present invention relates to organic chemistry and field of pharmaceutical chemistry technology, and in particular to -4 (1H) quinoline of 3- (2-[4-morpholinodithio base)
Quinoline ketone derivatives and its preparation method and application.
Background technique
The apoptosis that Caspase is relied on, usually also referred to as Apoptosis are study at present the most deep thin
Born of the same parents' programmed death mode.And cell foaminess is dead, commonly known as other apoptosis, is the apoptosis of different apoptosis
Mode and a kind of apoptosis mode of Caspase dependent/non-dependent.It can induce tumour cell and foaminess death occur
Compound, have a good application prospect in terms of coping with tumor drug resistance (Nat.Cell Biol.2017,19,1014-
1015.).In recent years, many Antitumor Natural Products (Pharmacol.Ther.2016,162,120-133.), including Japanese yew
Alcohol (Paclitaxel), curcumin (Curcumin), Ophiobolin A (ophiobolin A), Celastrol (Celastrol)
Foaminess death occurs Deng inducible cancer cell is found successively.With going deep into for research, apoptosis is closed by some inducible cells
At small organic molecule (J.Med.Chem.2016,59,5063-5076；PLoS One 2015,10,e0120709/1-
e0120709/14；Cancer Sci.2017,108,1032-1041；Cell Death Dis.2017,8,e2807；Cancer
Cell 2015,28,240-252.), metal complex (Chem.Sci.2017,8,6865-6870；
Eur.J.Pharmacol.2017,815,147-155；J.Am.Chem.Soc.2017,139,14302-14314；
Chem.Sci.2016,7,6115-6124；Metallomics 2016,8,286-297.), nanoparticle (Small 2018,
Xx-xxDOI:10.1002/smll.201702446.) and viral (EMBO is J.2017,36,1653-1668.) etc. is sent out successively
Now have the function of inducing cancer cell that foaminess death occurs.
We have found this kind of compound when studying 3- (2-[4-morpholinodithio base) -4 (1H)-quinolinones compound early period
With good antitumor action, and the new method that this kind of compound is prepared using arylamine as starting material is developed
(Scheme 1), correlative study find that we have applied for patent protection (number of patent application: 201810289152.6).
Due to being synthesized in the reaction of E in Scheme 1 by D, need to use halogenated aminated compounds, but be suitble to our needs
The compound commercialization product there was only N, N- dimethyl chloride ethamine and N, N- dimethyl chloride propylamine so that we can not obtain
The product of more structure diversifications, the especially diversified product of side-chain structure.
For this purpose, -4 (1H) qualone derivative of more 3- (2-[4-morpholinodithio base) is studied, to prepare new antineoplastic
Object is the emphasis that we study.
Summary of the invention
The present invention provides one kind 3- (2-[4-morpholinodithio base) -4 (1H) qualone derivative and its preparation method and application, should
Class compound has 3- (2-[4-morpholinodithio base) -4 (1H) quinolinone structure, has good anti-tumor activity, part of compounds is also
It can induce tumour cell and foaminess death occur, show good antitumous effect in vitro and in vivo.
To achieve the above object, the technical solution of the present invention is as follows:
- 4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) with general formula (I):
Wherein: R1Indicate F atom, Cl atom, Br atom, I atom, alkyl, alkoxy, nitro or hydroxyl.
R2Be alkyl, hydroxyalkyl, aryl, substituted aryl, 2- (N, N- dimethyl) ethyl, 3- (N, N- dimethyl) propyl,
4- (N, N- dimethyl) butyl, 2- (N, N- diethyl) ethyl, 3- (N, N- diethyl) propyl, 2- (N, N- diisopropyl) second
Base, 3- (N, N- diisopropyl) propyl, 2- (1- nafoxidine base) ethyl, 3- (1- nafoxidine base) propyl, 2- (1- piperidines
Base) ethyl, 3- (1- piperidyl) propyl, 2- (4- morpholinyl) ethyl, 3- (4- morpholinyl) propyl, 2- (1- imidazole radicals) ethyl,
3- (1- imidazole radicals) propyl, 2- (4- methyl piperazine base) ethyl, 3- (4- methyl piperazine base) propyl, 2- (4- piperazinyl) ethyl or
3- (4- piperazinyl) propyl.
The present invention also provides the preparation method of -4 (1H) qualone derivative of the 3- of general formula (I) (2-[4-morpholinodithio base),
The following steps are included:
S1. compound 2 is added into containerTriethylamine, acetonitrile and 2,4- difluoro benzoyl chloride,
N2Under/inert gas shielding and stirring, water is added in heating reflux reaction after the reaction was completed, is filtered, and is washed, and drying is slightly produced
Object 1；
The crude product 1, morpholine and methanol are added into container, in N2Under/inert gas shielding and stirring, it is heated to reflux
Water is added in reaction after the reaction was completed, and solid is precipitated；It filters, washs, drying obtains compound 3
S2. compound 3 and DMFDMA are added into container, in N2Under/inert gas shielding and stirring, heating reaction, instead
Solvent, the isolated solid chemical compound 4 of silica gel column chromatography should be removed after the completion
S3. compound 4, methanol and compound 5R are added into container2NH2, it is stirred to react, removes solvent after the reaction was completed,
Obtain crude product 2；
K is added into the container equipped with crude product 22CO3And DMF, then in N2Under/inert gas shielding and stirring, heating
Reaction removes solvent after the reaction was completed, and water is added, there is solid precipitation, filters, and washs, and drying obtains chemical combination through column Chromatographic purification
Object 6, i.e., with -4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) of general formula (I).
Preferably, in the step S1, compound 2, triethylamine, acetonitrile and 2,4- difluoro benzoyl chloride heating reflux reaction
0.8~1.5h of time.
Preferably, in the step S1,0.8~1.5h of time of crude product 1, morpholine and methanol heating reflux reaction.
Preferably, in the step S2, the time for heating reaction is 0.4~1h.
Preferably, in the step S3, the time that compound 4, methanol and compound 5 react is 0.4~1h.
Preferably, in the step S3, crude product 2, K2CO3Time with DMF reaction is 2h.
Invention further provides -4 (1H) qualone derivatives of 3- (2-[4-morpholinodithio base) and medicine with general formula (I)
The pharmaceutical composition of acceptable auxiliary material composition on.
Invention further provides -4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) preparations with general formula (I)
At dosage form acceptable in pharmacy.
Invention further provides with general formula (I) -4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) or its
Pharmaceutical composition application in preparation of anti-tumor drugs.
The present invention has synthesized a kind of derivative with logical formula (I), and provides preparation method, and raw material sources are richer
Richness, and preparation method is simple, provides -4 (1H) qualone derivative of the more diversified 3- of structure (2-[4-morpholinodithio base), selection
Property is wider, provides more thinkings for the exploitation of anti-tumor drug.
Tests prove that the derivative of logical formula (I) is to human bladder cancer cell T-24, gastric carcinoma cells MGC-803, human liver cancer
Cell HepG2, human lung carcinoma cell NCI-H460 and human cervical carcinoma cell Hela all have good inhibitory activity.Further,
The derivative of logical formula (I) can induce tumour cell that foaminess death occurs, i.e. other apoptosis occurs for induction tumour cell, in addition,
Also have induction tumour cell mitochondrial membrane potential decline, generate active oxygen (ROS), endocytoplasmic reticulum stress, mitochondria hair
The effect of raw swelling.
The compound of logical formula (I) and pharmaceutically acceptable auxiliary material are formed into pharmaceutical composition, due to the pharmaceutical composition
It is added to the logical formula (I) compound that there is fine inhibitory activity to tumour cell, therefore also there is the work of inhibitory activity well
With will be in terms of anti-tumor drug with good application prospect.
Detailed description of the invention
Fig. 1 a, Fig. 1 b, Fig. 1 c are the concentration of compound 6ah respectively when being respectively 0 μM, 10.0 μM, 20.0 μM it is caused by
Try the light field figure of the metamorphosis of tumour cell.
Fig. 2 a, Fig. 2 b are Hoechst33258 dense to Control group, compound 6ah after tumour cell HepG2 dyeing respectively
Spend the microscope figure of 10.0 μM of groups.
Induction that Fig. 3 is the concentration of compound 6ah when be respectively 0 μM, 5.0 μM, 10.0 μM and Doc concentration being 5.0 μM is swollen
The microscope figure of oncocyte HepG2 generation foaminess death.
Fig. 4 is that the concentration of compound 6ah is respectively 0 μM, 1.0 μM, 5.0 μM, 10.0 μM of induction HepG2 cell mitochondrial films
The diagram that current potential reduces.
Fig. 5 is that the concentration of compound 6ah is respectively 0 μM, 1.0 μM, 5.0 μM, 10.0 μM of induction HepG2 cell ROS levels
The diagram of rising.
Fig. 6 is that the concentration of compound 6ah acts on HepG2 cell through ER when being respectively 0 μM, 1.0 μM, 5.0 μM, 10.0 μM
Cellular morphology figure after Tracker Red dyeing.
Fig. 7, which is the concentration of compound 6ah, induces HepG2 cell mitochondrial when being respectively 0 μM, 1.0 μM, 5.0 μM, 10.0 μM
The diagram of swelling.
Specific embodiment
Below in conjunction with specific embodiment, the present invention is further described, but protection scope of the present invention is not limited to following implementation
Example.
The preparation method of -4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) with general formula (I), preparation route are shown in
Scheme 2:
Specifically:
S1. under electromagnetic agitation, compound 2 is sequentially added into the round-bottomed flask of 100mLThree
Ethamine, acetonitrile and 2,4- difluoro benzoyl chloride, in N2Under/inert gas shielding and stirring, heating reflux reaction 1h (TLC monitoring
Reaction, solvent: VEA:VPE=1:10), it is slowly added to water after the reaction was completed, filters, be washed with a small amount, dries, obtains thick
Product 1；
Under electromagnetic agitation, crude product 1, morpholine and methanol are sequentially added into round-bottomed flask, in N2/ inert gas shielding
Under stirring, heating reflux reaction 1h (TLC monitoring reaction, solvent: VEA:VPE=1:10), water is added after the reaction was completed, analyses
A large amount of solids out；It filters, is washed with a small amount, dry, obtain compound 3
S2. under electromagnetic agitation, compound 3 and DMFDMA are sequentially added into round-bottomed flask, in N2/ inert gas shielding
Under stirring, heating reaction 0.5h (TLC monitoring reaction, solvent: VEA:VPE=1:2), solvent is removed under reduced pressure after the reaction was completed,
Gained crude product separates (eluant, eluent: V through silica gel column chromatographyEA:VPE=1:6) obtain compound 4
S3. under electromagnetic agitation, compound 4, methanol and compound 5R are sequentially added into the round-bottomed flask of 25mL2NH2,
Reaction 0.5h (TLC monitoring reaction, solvent: V is stirred at room temperatureDCM:VEA:VMeOH=9:3:1), decompression removes after the reaction was completed
Solvent is removed, crude product 2 is obtained；
K is added into the round-bottomed flask equipped with crude product 2 under electromagnetic agitation2CO3And DMF, then in N2/ inert gas
Under protection and stirring, heating reaction 2h (TLC monitoring reaction, solvent: VDCM:VEA:VMeOH=9:3:1), it depressurizes after the reaction was completed
Solvent is removed, water is slowly added in round-bottomed flask, there is solid precipitation during Jia Shui, filters, is washed with a small amount, is dried
Dry, gained crude product purifies (eluant, eluent V through silica gel column chromatographyDCM:VEA:VMeOH=9:3:1) obtain compound 6, that is, there is general formula
(I) -4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base).
The following table 1 is -4 (1H) qualone derivative of typical 3- (2-[4-morpholinodithio base) that the present embodiment is related to:
The derivative and number that 1 the present embodiment of table is related to
Specific synthesis step is shown in following example 1~42:
Embodiment 1: the preparation of compound 3a.
Under electromagnetic agitation, sequentially added into the round-bottomed flask of 100mL 2- methylbenzothiazole, triethylamine, acetonitrile and
2,4- difluoro benzoyl chlorides, in N2Protect lower heating stirring back flow reaction 1h (TLC monitoring reaction, solvent: VEA:VPE=1:
10).It is slowly added to water after the reaction was completed, filters, be washed with a small amount, dries, obtains crude product, thick yield is 66%,
m.p.178–179℃。
Under electromagnetic agitation, above-mentioned crude product, morpholine and methanol (80mL) are sequentially added into round-bottomed flask, in N2Protection
Lower heating stirring back flow reaction 1h (TLC monitoring reaction, solvent: VEA:VPE=1:10), it is slowly added to water after the reaction was completed, analyses
A large amount of yellow solids out are filtered, are washed with a small amount, and drying obtains the crude product of compound 3a, yield 85%, m.p.107-
109 DEG C, m/z:290 ([M+H]+)。
Embodiment 2: the preparation of compound 3b.
With2- methylbenzothiazole is replaced, compound 3b is made with embodiment 1 in synthetic method,
Yield: 90%；Fusing point: 115-117 DEG C.
Embodiment 3: the preparation of compound 3c.
With2- methylbenzothiazole is replaced, compound 3c is made with embodiment 1 in synthetic method,
Yield: 81%；Fusing point: 120-121 DEG C.
Embodiment 4: the preparation of compound 4a.
Under electromagnetic agitation, sequentially added into the round-bottomed flask of 25mL compound 3a (0.50g, 1.73mmol) and
DMFDMA (7mL, 51.90mmol), in N2Protect lower heating stirring reaction 0.5h (TLC monitoring reaction, solvent: VEA:VPE=1:
2) solvent, is removed under reduced pressure after the reaction was completed, gained crude product separates (eluant, eluent: V through silica gel column chromatographyEA:VPE=1:6) it obtains
0.25g faint yellow solid 4a, yield 42%.
1H NMR(400MHz,CDCl3) δ 7.96 (d, J=8.0Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.58 (s,
1H), 7.47~7.40 (m, 2H), 7.31 (t, J=7.5Hz, 1H), 6.90~6.85 (m, 1H), 6.80~6.75 (m, 1H),
3.02(s,6H).
Embodiment 5: the preparation of compound 4b.
Compound 3a is replaced with compound 3b, compound 4b, yield: 40% is made with embodiment 4 in synthetic method.
Embodiment 6: the preparation of compound 4c.
Compound 3a is replaced with compound 3c, compound 4c, yield: 45% is made with embodiment 4 in synthetic method.
Embodiment 7: the preparation of compound 6aa.
Under electromagnetic agitation, compound 4a, methanol and N, N- dimethyl-ethylenediamine, in room are sequentially added into round-bottomed flask
0.5h (TLC monitoring reaction, solvent: V are stirred to react under temperatureDCM:VEA:VMeOH=9:3:1), it is removed under reduced pressure after the reaction was completed molten
Agent, resulting crude product is not purified directly to carry out next step reaction.
K is sequentially added into round-bottomed flask under electromagnetic agitation2CO3And DMF, then in N2Protect lower heating stirring reaction
2h (TLC monitoring reaction, solvent: VDCM:VEA:VMeOH=9:3:1), solvent is removed under reduced pressure after the reaction was completed, in round-bottomed flask
It is slowly added to water (15mL), there is solid precipitation during Jia Shui, filters, is washed with a small amount, is dried, gained crude product warp
Silica gel column chromatography purifies (eluant, eluent VDCM:VEA:VMeOH=9:3:1) obtain 0.12g yellow solid compound 6aa, yield 49%.
3-(Benzo[d]thiazol-2-yl)-1-(2-(dimethylamino)ethyl)-7-fluoroquinolin-
4 (1H)-one (6aa) .Yellow crystalline, yield 49%, m.p.214~215 DEG C；1H NMR(600MHz,
CDCl3) δ: 9.00 (s, 1H), 8.60 (s, 1H), 7.95 (s, 2H), 7.46 (s, 1H), 7.35 (d, J=6.2Hz, 1H), 7.18
(d, J=5.6Hz, 2H), 4.30 (t, J=6.7Hz, 2H), 2.78 (t, J=6.7Hz, 2H), 2.33 (s, 6H)13C NMR
(150MHz,CDCl3)δ:173.7,166.0(d,JCF=252.3Hz), 164.34,161.4,151.6,144.0,140.1 (d,
JCF=11.2Hz), 135.9,130.6 (d, JCF=10.7Hz), 125.8,124.1,123.9,121.6 (d, JCF=8.6Hz),
114.5,113.7(d,JCF=22.5Hz), 102.2 (d, JCF=27Hz), 57.2,52.4045.8.HRMS (ESI) calcd
for C20H19FN3OS[M+H]+:368.1233；found 368.1217.
Embodiment 8: the preparation of compound 6ab.
With N, N- diethyl ethylenediamine replaces N, N- dimethyl-ethylenediamine, and synthetic method obtains compound 6ab with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-1-(2-(diethylamino)ethyl)-7-fluoroquinolin-4
(1H)-one (6ab) .Yellow crystalline, yield 70%, m.p.143~144 DEG C1H NMR(400MHz,
CDCl3) δ: 9.05 (s, 1H), 8.66~8.62 (m, 1H), 8.03~7.88 (m, 2H), 7.53~7.41 (m, 1H), 7.40~
7.30 (m, 1H), 7.26~7.16 (m, 2H), 4.28 (t, J=5.9Hz, 2H), 2.86 (t, J=5.9Hz, 2H), 2.54 (q, J
=7.0Hz, 4H), 0.92 (t, J=7.0Hz, 6H)13C NMR(100MHz,CDCl3)δ:173.7,165.2(d,JCF=
252.6Hz),161.6,151.7,144.8,140.1(d,JCF=11.2Hz), 135.9,130.6 (d, JCF=10.6Hz),
125.8,124.0,123.9(d,JCF=1.5Hz), 121.7,121.6,114.1,113.8 (d, JCF=22.9Hz), 102.2
(d,JCF=26.8Hz), 53.1,51.4,47.5,12.1.HRMS (ESI) calcd for C22H23FN3OS[M+H]+
396.1546；found 396.1537.
Embodiment 9: the preparation of compound 6ac.
Use i-Pr2N(CH2)2NH2N, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6ac with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-1-(2-(diisopropylamino)ethyl)-7-
Fluoroquinolin-4 (1H)-one (6ac) .Yellow crystalline, yield 87%, m.p.212~214 DEG C1H
NMR(400MHz,CDCl3) δ: 9.00 (s, 1H), 8.66~8.62 (m, 1H), 8.01~7.88 (m, 2H), 7.48~7.45 (m,
1H), 7.36~7.32 (m, 1H), 7.25~7.13 (m, 2H), 4.20 (t, J=5.7Hz, 2H), 3.04~3.00 (m, 2H),
2.88 (t, J=5.7Hz, 2H), 0.87 (d, J=6.6Hz, 12H)13C NMR(100MHz,CDCl3)δ:173.7,165.2(d,
JCF=252.3Hz), 161.7,151.8,145.3,140.1 (d, JCF=11.2Hz), 136.0,130.7 (d, JCF=
10.6Hz),125.8,124.0(d,JCF=2.7Hz), 121.8,121.6,113.8,113.5 (d, J=22.8Hz), 102.1
(d,JCF=26.7Hz), 53.8,48.1,43.2,20.8.HRMS (ESI) calcd for C24H27FN3OS[M+H]+
424.1859；found 424.1849.
Embodiment 10: the preparation of compound 6ad.
WithN, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6ad with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-7-fluoro-1-(2-(pyrrolidin-1-yl)ethyl)
Quinolin-4 (1H)-one (6ad) .Yellow crystalline, yield 70%, m.p.155~157 DEG C1H NMR
(400MHz,CDCl3) δ: 9.10 (s, 1H), 8.67~8.64 (m, 1H), 7.99~7.97 (m, 2H), 7.53~7.44 (m,
1H), 7.38~7.34 (m, 1H), 7.30 (s, 1H), 7.25~7.19 (m, 1H), 4.41 (t, J=6.9Hz, 2H), 3.03 (t, J
=6.9Hz, 2H), 2.66 (t, J=3.5Hz, 4H), 1.83~1.78 (m, 4H)13C NMR(100MHz,CDCl3)δ:173.7,
165.2(d,JCF=252.9Hz), 161.4,151.6,144.0,140.1 (d, JCF=11.3Hz), 135.9,130.5 (d, JCF
=10.6Hz), 125.9,124.1,123.9 (d, JCF=1.6Hz), 121.7,121.6,114.6,113.6 (d, JCF=
22.9Hz),102.2(d,JCF=26.8Hz), 54.4,53.9,53.2,23.7.HRMS (ESI) calcd for C22H21FN3OS
[M+H]+394.1389；found 394.1380.
Embodiment 11: the preparation of compound 6ae.
WithN, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6ae with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-7-fluoro-1-(2-(piperidin-1-yl)ethyl)
Quinolin-4 (1H)-one (6ae) .Yellow crystalline, yield 72%, m.p.171~173 DEG C1H NMR
(400MHz,CDCl3) δ: 9.04 (s, 1H), 8.63~8.58 (m, 1H), 8.02~7.87 (m, 2H), 7.51~7.42 (m,
1H), 7.40~7.31 (m, 1H), 7.25~7.13 (m, 2H), 4.30 (t, J=6.2Hz, 2H), 2.75 (t, J=6.2Hz,
2H), 2.52~2.41 (m, 4H), 1.56~1.54 (m, 4H), 1.41~1.40 (m, 2H)13C NMR(100MHz,CDCl3)δ:
173.7,165.2(d,JCF=250.0Hz), 161.5,152.0,144.5,140.2 (d, JCF=11.3Hz), 135.9,130.5
(d,JCF=10.6Hz), 125.8,124.0,123.9 (d, JCF=1.0Hz), 121.7,121.6,114.3,113.6 (d, JCF=
22.9Hz),102.2(d,JCF=26.8Hz), 56.7,54.9,51.8,25.9,24.0.HRMS (ESI) calcd for
C23H23FN3OS[M+H]+408.1546；found 408.1537.
Embodiment 12: the preparation of compound 6af.
WithN, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6af with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-7-fluoro-1-(2-(piperazin-1-yl)ethyl)
Quinolin-4 (1H)-one (6af) .Yellow crystalline, yield 42%, m.p.89~91 DEG C1H NMR
(400MHz,CDCl3) δ: 9.06 (s, 1H), 8.64~8.60 (m, 1H), 7.98~7.94 (m, 2H), 7.48~7.45 (m,
1H), 7.37~7.33 (m, 1H), 7.24~7.14 (m, 2H), 4.31 (t, J=6.4Hz, 2H), 2.85 (t, J=6.4Hz,
4H), 2.80 (t, J=6.4Hz, 2H), 2.50 (t, J=6.4Hz, 4H), 1.24 (s, 1H)13C NMR(100MHz,CDCl3)δ:
173.8,165.2(d,JCF=250.0Hz), 161.6,151.7,144.6,140.1 (d, JCF=11.3Hz), 135.9,130.7
(d,JCF=10.7Hz), 125.9,124.0,123.9 (d, JCF=1.0Hz), 121.7,121.6,114.3,113.7 (d, JCF=
22.8Hz),102.1(d,JCF=26.8Hz), 56.5,54.6,51.6,46.0.HRMS (ESI) calcd for C22H22FN4OS
[M+H]+409.1498；found 409.1491.
Embodiment 13: the preparation of compound 6ag.
WithN, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6ag with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-7-fluoro-1-(2-morpholinoethyl)quinolin-4
(1H)-one (6ag) .Yellow crystalline, yield 72%, m.p.171~173 DEG C1H NMR(400MHz,
CDCl3) δ: 9.02 (s, 1H), 8.61~8.60 (m, 1H), 7.98~7.94 (m, 2H), 7.50~7.43 (m, 1H), 7.36~
7.33 (m, 1H), 7.22~7.13 (m, 2H), 4.29 (t, J=6.0Hz, 2H), 3.67 (t, J=8.2Hz, 4H), 2.80 (t, J
=6.0Hz, 2H), 2.52 (t, J=8.2Hz, 4H)13C NMR(100MHz,CDCl3)δ:173.7,165.2(d,JCF=
252.6Hz),161.6,151.7,144.8,140.1(d,JCF=11.2Hz), 135.9,130.6 (d, JCF=10.6Hz),
125.8,124.0,123.9(d,JCF=1.5Hz), 121.7,121.6,114.1,113.8 (d, JCF=22.9Hz), 102.2
(d,JCF=26.8Hz), 66.8,56.3,53.7,51.3.HRMS (ESI) calcd for C22H21FN3O2S[M+H]+
410.1339；found 410.1331.
Embodiment 14: the preparation of compound 6ah.
With N, N- dimethylated propyl diethylenetriamine replaces N, N- dimethyl-ethylenediamine, and synthetic method obtains compound 6ah with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-1-(3-(dimethylamino)propyl)-7-
Fluoroquinolin-4 (1H)-one (6ah) .Yellow crystalline, yield 52%, m.p.179~180 DEG C；1H
NMR(600MHz,CDCl3) δ: 9.14 (s, 1H), 8.65~8.53 (m, 1H), 7.94 (dd, J=12.0Hz, 8.2Hz, 2H),
7.45 (t, J=7.5Hz, 1H), 7.33 (dd, J=13.5Hz, 8.9Hz, 2H), 7.16 (t, J=8.2Hz, 1H), 4.35 (t, J
=6.6Hz, 2H), 2.30 (t, J=5.9Hz, 2H), 2.25 (s, 6H), 2.03~2.02 (m, 2H)13C NMR(150MHz,
CDCl3)δ:173.7,166.0(d,JCF=252.6Hz), 164.4,161.5,151.7,144.3,140.3 (d, JCF=
11.4Hz),135.9,130.5(d,JCF=10.5Hz), 125.8,124.0 (d, JCF=14.9Hz), 121.7 (d, JCF=
11.6Hz),114.5,113.7,113.5,102.5(d,JCF=27Hz), 55.2,51.4,45.3,26.8.HRMS (ESI)
calcd for C21H21FN3OS[M+H]+:382.1389；found 382.1373.
Embodiment 15: the preparation of compound 6ai.
With N, N- diethyl propyldiamine replaces N, N- dimethyl-ethylenediamine, and synthetic method obtains compound 6ai with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-1-(3-(diethylamino)propyl)-7-fluoroquinolin-
4 (1H)-one (6ai) .Yellow crystalline, yield 67%, m.p.150~152 DEG C1H NMR(400MHz,
CDCl3) δ: 9.12 (s, 1H), 8.67~8.59 (m, 1H), 7.97~7.93 (m, 2H), 7.51~7.41 (m, 1H), 7.39~
7.30 (m, 2H), 7.22~7.12 (m, 1H), 4.36 (t, J=7.1Hz, 2H), 2.58 (q, J=7.1Hz, 4H), 2.51 (t, J
=6.2Hz, 2H), 2.11~1.97 (m, 2H), 1.06 (t, J=7.1Hz, 6H)13C NMR(100MHz,CDCl3)δ:173.7,
165.2(d,JCF=252.6Hz), 161.6,151.7,144.8,140.1 (d, JCF=11.2Hz), 135.9,130.6 (d, JCF
=10.6Hz), 125.8,124.0,123.9 (d, JCF=1.5Hz), 121.7,121.6,114.1,113.8 (d, JCF=
22.9Hz),102.2(d,JCF=26.8Hz), 52.0,49.3,46.4,26.5,11.3.HRMS (ESI) calcd for
C23H25FN3OS[M+H]+410.1702；found 410.1694.
Embodiment 16: the preparation of compound 6aj.
N, N- dimethyl-ethylenediamine are replaced with n-butylamine, synthetic method obtains compound 6aj with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-1-butyl-7-fluoroquinolin-4(1H)-one(6aj)
.Yellow crystalline, yield 43%, m.p.191~193 DEG C1H NMR(400MHz,CDCl3)δ:9.07(s,
1H), 8.65~8.62 (m, 1H), 7.98~7.96 (m, 2H), 7.50~7.45 (m, 1H), 7.39~7.33 (m, 1H), 7.24
~7.14 (m, 2H), 4.25 (t, J=7.7Hz, 2H), 2.01~1.88 (m, 2H), 1.56~1.43 (m, 2H), 1.03 (t, J=
7.4Hz,3H).13C NMR(100MHz,CDCl3)δ:173.6,165.2(d,JCF=252.6Hz), 161.6,151.7,144.8,
140.1(d,JCF=11.2Hz), 135.9,130.6 (d, JCF=10.6Hz), 125.8,124.0,123.9 (d, JCF=
1.5Hz),121.7,121.6,114.1,113.8(d,JCF=22.9Hz), 102.2 (d, JCF=26.8Hz), 54.3,30.9,
20.0,13.6.HRMS(ESI)calcd for C20H18FN2OS[M+H]+353.1124；found 353.1115.
Embodiment 17: the preparation of compound 6ak.
With HO (CH2)3NH2N, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6ak with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-7-fluoro-1-(3-hydroxypropyl)quinolin-4(1H)-
One (6ak) .Yellow crystalline, yield 70%, m.p.145~147 DEG C1H NMR(400MHz,DMSO-d6)δ:
9.27 (s, 1H), 8.47~8.43 (m, 1H), 8.11~8.09 (m, 1H), 7.98~7.96 (m, 1H), 7.85~7.82 (m,
1H), 7.55~7.46 (m, 1H), 7.46~7.33 (m, 2H), 4.58 (t, J=7.0Hz, 2H), 3.51 (t, J=5.5Hz,
2H), 2.05~1.91 (m, 2H) (the resonance of O-H was not observed in DMSO-d6).13C NMR
(100MHz,DMSO-d6)δ:173.0,165.1(d,JCF=247.0Hz), 161.6,151.7,145.6,140.7 (d, JCF=
12.1Hz),135.5,130.0(d,JCF=11.0Hz), 126.5,124.5,123.9,122.4,121.9,114.2 (d, JCF=
23.4Hz),113.4,104.3(d,JCF=27.0Hz), 57.9,51.3,31.8.HRMS (ESI) calcd for
C19H16FN2O2S[M+H]+355.0917；found 355.0910.
Embodiment 18: the preparation of compound 6al.
WithN, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6al with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-7-fluoro-1-(3-(pyrrolidin-1-yl)propyl)
quinolin-4(1H)-
- one (6al) .Yellow crystalline, yield 56%, m.p.150~152 DEG C1H NMR(400MHz,
CDCl3) δ: 9.20 (s, 1H), 8.61~8.58 (m, 1H), 7.99~7.90 (m, 2H), 7.47~7.45 (m, 1H), 7.39~
7.29 (m, 2H), 7.19~7.14 (m, 1H), 4.39 (t, J=6.7Hz, 2H), 2.52~2.51 (m, 4H), 2.49~2.48
(m, 2H), 2.11~2.04 (m, 2H), 1.86~1.82 (m, 3.2Hz, 4H)13C NMR(100MHz,CDCl3)δ:173.6,
165.2(d,JCF=252.6Hz), 161.6,151.7,144.8,140.1 (d, JCF=11.2Hz), 135.9,130.6 (d, JCF
=10.6Hz), 125.8,124.0,123.9 (d, JCF=1.5Hz), 121.7,121.6,114.1,113.8 (d, JCF=
22.9Hz),102.2(d,JCF=26.8Hz), 53.9,51.5,27.4,23.6.HRMS (ESI) calcd for C23H23FN3OS
[M+H]+408.1546；found 408.1537.
Embodiment 19: the preparation of compound 6am.
WithN, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6am with embodiment 7.
1-(3-(1H-imidazol-1-yl)propyl)-3-(benzo[d]thiazol-2-yl)-7-
Fluoroquinolin-4 (1H)-one (6am) .Yellow crystalline, yield 67%, m.p.150~152 DEG C1H
NMR(400MHz,DMSO-d6) δ: 9.25 (s, 1H), 8.46~8.42 (m, 1H), 8.10 (d, J=7.8Hz, 1H), 7.96 (d, J
=8.0Hz, 1H), 7.78~7.76 (m, 1H), 7.70 (s, 1H), 7.53~7.46 (m, 1H), 7.44~7.34 (m, 2H),
7.25 (s, 1H), 6.93~6.92 (m, 1H), 4.51 (t, J=7.3Hz, 2H), 4.17 (t, J=7.3Hz, 2H), 2.41~
2.23(m,2H).13C NMR(100MHz,DMSO-d6)δ:173.1,165.2(d,JCF=247.0Hz), 161.6,151.7,
145.4,140.6(d,JCF=12.0Hz), 137.7,135.5,130.0 (d, JCF=10.9Hz), 128.9,126.5,124.6,
123.9,122.4,121.9,119.8,114.2(d,JCF=23.4Hz), 113.7,104.2 (d, JCF=27.2Hz), 51.4,
43.8,30.5.HRMS(ESI)calcd for C22H18FN4OS[M+H]+405.1185；found 405.1178.
Embodiment 20: the preparation of compound 6an.
WithN, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6an with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-7-fluoro-1-(3-(piperazin-1-yl)propyl)
quinolin-4(1H)-
- one (6an) .Yellow crystalline, yield 91%, m.p.218~220 DEG C1H NMR(400MHz,
DMSO-d6) δ: 9.42 (s, 1H), 8.46~8.42 (m, 1H), 8.09 (d, J=7.6Hz, 1H), 8.03 (d, J=8.0Hz,
1H), 7.89 (dd, J=11.3,2.1Hz, 1H), 7.55~7.45 (m, 1H), 7.45~7.35 (m, 2H), 4.60 (t, J=
6.0Hz, 2H), 3.18 (t, J=4.5Hz, 4H), 2.51 (t, J=1.8Hz, 4H), 2.28 (t, J=6.0Hz, 2H), 2.06~
1.92(m,2H)(the resonance of N–H was not observed in DMSO-d6).13C NMR(100MHz,
DMSO-d6)δ:173.0,165.1(d,JCF=240Hz), 161.8,151.7,146.4,140.7 (d, JCF=12.1Hz),
135.5,129.9(d,JCF=10.9Hz), 126.5,124.5,123.9 (d, JCF=1.0Hz), 122.3,121.9,114.1
(d,JCF=23.5Hz), 112.9,104.3 (d, JCF=27.0Hz), 53.1,51.1,49.6,43.5,24.5.HRMS (ESI)
calcd for C23H24FN4OS[M+H]+423.1655；found 423.1649.
Embodiment 21: the preparation of compound 6ao.
WithN, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6ao with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-7-fluoro-1-(3-morpholinopropyl)quinolin-4
(1H)-one (6ao) .Yellow crystalline, yield 73%, m.p.211~213 DEG C1H NMR(400MHz,
CDCl3) δ: 9.31 (s, 1H), 8.68~8.64 (m, 1H), 7.99~7.95 (m, 2H), 7.52~7.43 (m, 1H), 7.38~
7.33 (m, 2H), 7.24~7.19 (m, 1H), 4.45 (t, J=6.4Hz, 2H), 3.85 (t, J=4.6Hz, 4H), 2.45 (t, J
=4.6Hz, 4H), 2.34 (t, J=6.0Hz, 2H), 2.16~2.01 (m, 2H)13C NMR(100MHz,CDCl3)δ:173.7,
165.2(d,JCF=250.9Hz), 161.4,151.7,144.7,140.1 (d, JCF=11.3Hz), 135.9,130.5 (d, JCF
=9.5Hz), 125.9,124.0,123.9 (d, JCF=1.5Hz), 121.7,121.6,114.2,113.6 (d, JCF=
23.3Hz),102.2(d,JCF=26.8Hz), 67.0,53.7,53.4,50.9,24.7.HRMS (ESI) calcd for
C23H23FN3O2S[M+H]+424.1495；found 424.1483.
Embodiment 22: the preparation of compound 6ap.
N, N- dimethyl-ethylenediamine are replaced with Putriscine, synthetic method obtains compound 6ap with embodiment 7.
1-(4-Aminobutyl)-3-(benzo[d]thiazol-2-yl)-7-fluoroquinolin-4(1H)-one
(6ap) .Yellow crystalline, yield 59%, m.p.225~227 DEG C1H NMR(400MHz,CD3OD)δ:8.92
(s, 1H), 8.24~8.20 (m, 1H), 7.83~7.81 (m, 1H), 7.69~7.65 (m, 1H), 7.37~7.32 (m, 2H),
7.27~7.23 (m, 1H), 7.09~7.04 (m, 1H), 4.28 (t, J=7.4Hz, 2H), 2.74 (t, J=7.2Hz, 2H),
1.97~1.84 (m, 2H), 1.65~1.58m, 2H) (the resonance of N-H was not observed in
CD3OD).13C NMR(100MHz,CD3OD)δ:173.3,165.2(d,JCF=250.0Hz), 161.2,151.0,144.3,
140.0(d,JCF=11.8Hz), 135.1,129.1 (d, JCF=10.8Hz), 125.6,123.9,123.1,121.1,121.0,
113.5,113.3,102.9(d,JCF=27.3Hz), 53.8,40.3,28.5,26.0.HRMS (ESI) calcd for
C20H19FN3OS[M+H]+368.1233；found 368.1227.
Embodiment 23: the preparation of compound 6aq.
With N, N- diamine dimethyl butyrate replaces N, N- dimethyl-ethylenediamine, and synthetic method obtains compound 6aq with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-1-(4-(dimethylamino)butyl)-7-fluoroquinolin-
4 (1H)-one (6aq) .Yellow crystalline, yield 65%, m.p.170~171 DEG C1H NMR(400MHz,
CDCl3) δ: 8.99 (s, 1H), 8.59~8.55 (m, 1H), 7.98~7.85 (m, 2H), 7.46~7.42 (m, 1H), 7.35~
7.31 (m, 2H), 7.17~7.12 (m, 1H), 4.23 (t, J=7.8Hz, 2H), 2.35 (t, J=6.9Hz, 2H), 2.23 (s,
6H), 2.02~1.89 (m, 2H), 1.67~1.55 (m, 2H)13C NMR(100MHz,CDCl3)δ:173.7,165.3(d,JCF
=250.0Hz), 161.5,151.6,143.5,140.1 (d, JCF=11.5Hz), 135.9,130.4 (d, JCF=10.6Hz),
125.9,124.1,123.9(d,JCF=1.5Hz), 121.7,121.6,114.5,113.6 (d, JCF=23.0Hz), 102.7
(d,JCF=27.1Hz), 58.4,54.2,45.4,26.7,24.2.HRMS (ESI) calcd for C22H23FN3OS[M+H]+
396.1546；found 396.1536.
Embodiment 24: the preparation of compound 6ar.
WithN, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound 6aq with embodiment 7.
3-(Benzo[d]thiazol-2-yl)-1-(4-chlorophenyl)-7-fluoroquinolin-4(1H)-
One (6ar) .Yellow crystalline, yield 38%, m.p.282~284 DEG C1H NMR(400MHz,CDCl3)δ:
9.07 (s, 1H), 8.63~8.60 (m, 1H), 7.99~7.93 (m, 1H), 7.92~7.85 (m, 1H), 7.70~7.62 (m,
2H), 7.52~7.47 (m, 2H), 7.47~7.43 (m, 1H), 7.37~7.33 (m, 1H), 7.20~7.15 (m, 1H), 6.71
~6.69 (m, 1H)13C NMR(100MHz,CDCl3)δ:173.9,165.0(d,JCF=260.0Hz), 161.0,151.6,
143.1,141.7,141.6,138.9,136.6,136.0,130.9,130.3(d,JCF=10.5Hz), 128.9,126.0,
124.3,123.2,121.7,121.6,115.2,114.2(d,JCF=23.0Hz), 103.7 (d, JCF=27.0Hz) .HRMS
(ESI)calcd for C22H13ClFN2OS[M+H]+407.0421；found 407.0413.
Embodiment 25: the preparation of compound 6ba.
4a is replaced with 4b, synthetic method obtains compound 6ba with embodiment 7.
1-(2-(Dimethylamino)ethyl)-7-fluoro-3-(5-fluorobenzo[d]thiazol-2-yl)
quinolin-
- 4 (1H)-one (6ba) .Yellow crystalline, yield 68%, m.p.199~201 DEG C1H NMR
(400MHz,CDCl3) δ: 9.04 (s, 1H), 8.70~8.56 (m, 1H), 7.95~7.85 (m, 1H), 7.64~7.61 (m,
1H), 7.24~7.22 (m, 2H), 7.14~7.10 (m, 1H), 4.35 (t, J=6.7Hz, 2H), 2.81 (t, J=6.7Hz,
2H),2.35(s,6H).13C NMR(100MHz,CDCl3)δ:173.7,165.3(d,JCF=251.0Hz), 164.0,161.9
(d,JCF=240.0Hz), 152.7 (d, JCF=12.0Hz), 144.2,140.2 (d, JCF=11.3Hz), 131.5,130.7 (d,
JCF=10.6Hz), 123.9,122.3 (d, JCF=9.9Hz), 114.4,113.9 (d, JCF=22.0Hz), 112.8 (d, JCF=
25.0Hz),107.6(d,JCF=23.4Hz), 102.2 (d, JCF=26.8Hz), 57.3,52.5,45.8.HRMS (ESI)
calcd for C20H18ClF2N3OS[M+H]+386.1139；found 386.1131.
Embodiment 26: the preparation of compound 6bb.
4a, N are replaced with 4b, N- diethyl ethylenediamine replaces N, N- dimethyl-ethylenediamine, and synthetic method is obtained with embodiment 7
Compound 6bb.
1-(2-(Diethylamino)ethyl)-7-fluoro-3-(5-fluorobenzo[d]thiazol-2-yl)
quinolin-
- 4 (1H)-one (6bb) .Yellow crystalline, yield 65%, m.p.166~167 DEG C1H NMR
(400MHz,CDCl3) δ: 9.04 (s, 1H), 8.66~8.62 (m, 1H), 7.90~7.87 (m, 1H), 7.67~7.57 (m,
1H), 7.24~7.20 (m, 2H), 7.14~7.05 (m, 1H), 4.29 (t, J=5.6Hz, 2H), 2.87 (t, J=5.6Hz,
2H), 2.54 (q, J=7.0Hz, 4H), 0.91 (t, J=7.0Hz, 6H)13C NMR(100MHz,CDCl3)δ:173.7,165.3
(d,JCF=250.0Hz), 164.0,161.9 (d, JCF=240.0Hz), 152.8 (d, JCF=12.3Hz), 145.1,140.2
(d,JCF=11.2Hz), 131.5,130.7 (d, JCF=10.5Hz), 123.9,122.3 (d, JCF=10.0Hz), 113.8,
113.7,112.6(d,JCF=25.1Hz), 107.6 (d, JCF=23.3Hz), 102.2 (d, JCF=26.8Hz), 53.2,51.4,
47.6,12.2.HRMS(ESI)calcd for C22H22F2N3OS[M+H]+414.1452；found 414.1443.
Embodiment 27: the preparation of compound 6bc.
4a, i-Pr are replaced with 4b2N(CH2)2NH2N, N- dimethyl-ethylenediamine are replaced, synthetic method must be changed with embodiment 7
Close object 6bb.
1-(2-(Diisopropylamino)ethyl)-7-fluoro-3-(5-fluorobenzo[d]thiazol-2-
yl)quino-
- lin-4 (1H)-one (6bc) .Yellow crystalline, yield 58%, m.p.231~233 DEG C1H
NMR(500MHz,CDCl3) δ: 8.97 (s, 1H), 8.65~8.62 (m, 1H), 7.89~7.86 (m, 1H), 7.63~7.56 (m,
1H), 7.21~7.19 (m, 2H), 7.12~7.09 (m, 1H), 4.21 (t, J=5.4Hz, 2H), 3.01~2.99 (m, 2H),
2.88 (t, J=5.4Hz, 2H), 0.87 (d, J=6.5Hz, 12H)13C NMR(125MHz,CDCl3)δ:173.6,165.2(d,
JCF=250.0Hz), 164.1,161.9 (d, JCF=237.5Hz), 152.8 (d, JCF=12.3Hz), 145.5,140.1 (d, JCF
=11.2Hz), 131.4,130.7 (d, JCF=10.6Hz), 123.9,122.2 (d, JCF=10.0Hz), 113.7,113.5 (d,
JCF=11.3Hz), 112.5 (d, JCF=24.9Hz), 107.6 (d, JCF=23.3Hz), 102.1 (d, JCF=26.7Hz),
53.8,48.0,43.1,20.8.HRMS(ESI)calcd for C24H26F2N3OS[M+H]+422.1759；found
422.1740.
Embodiment 28: the preparation of compound 6bh.
4a, N are replaced with 4b, N- dimethylated propyl diethylenetriamine replaces N, N- dimethyl-ethylenediamine, and synthetic method is obtained with embodiment 7
Compound 6bh.
1-(3-(Dimethylamino)propyl)-7-fluoro-3-(5-fluorobenzo[d]thiazol-2-yl)
Quinolin--4 (1H)-one (6bh) .Yellow crystalline, yield 76%, m.p.152~154 DEG C1H NMR
(400MHz,CDCl3) δ: 9.11 (s, 1H), 8.60~8.56 (m, 1H), 7.89~7.83 (m, 1H), 7.59~7.55 (m,
1H), 7.33~7.30 (m, 1H), 7.19~7.14 (m, 1H), 7.11~7.06 (m, 1H), 4.36 (t, J=6.8Hz, 2H),
2.30 (t, J=6.2Hz, 2H), 2.25 (s, 6H), 2.06~2.00 (m, 2H)13C NMR(100MHz,CDCl3)δ:173.6,
165.3(d,JCF=250.0Hz), 163.9,161.9 (d, JCF=241.0Hz), 152.7 (d, JCF=12.2Hz), 144.4,
140.3(d,JCF=11.5Hz), 131.4,130.4 (d, JCF=10.6Hz), 123.9,122.2 (d, JCF=10.0Hz),
113.7,113.5,112.6(d,JCF=24.9Hz), 107.6 (d, JCF=23.3Hz), 102.5 (d, JCF=27.0Hz),
55.1,51.4,45.3,26.6.HRMS(ESI)calcd for C21H20F2N3OS[M+H]+400.1295；found
400.1295.
Embodiment 29: the preparation of compound 6bi.
4a, N are replaced with 4b, N- diethyl propyldiamine replaces N, N- dimethyl-ethylenediamine, and synthetic method is obtained with embodiment 7
Compound 6bi.
1-(3-(Diethylamino)propyl)-7-fluoro-3-(5-fluorobenzo[d]thiazol-2-yl)
quinolin-
- 4 (1H)-one (6bi) .Yellow crystalline, yield 66%, m.p.156~158 DEG C1H NMR
(400MHz,CDCl3) δ: 9.11 (s, 1H), 8.68~8.50 (m, 1H), 7.88~7.85 (m, 1H), 7.59~7.56 (m,
1H), 7.34 (d, J=10.5Hz, 1H), 7.22~7.15 (m, 1H), 7.13~7.08 (m, 1H), 4.37 (t, J=7.0Hz,
2H), 2.57 (q, J=7.1Hz, 4H), 2.49 (t, J=6.0Hz, 2H), 2.11~1.91 (m, 2H), 1.06 (t, J=7.1Hz,
6H).13C NMR(100MHz,CDCl3)δ:173.7,165.3(d,JCF=250.0Hz), 164.0,161.9 (d, JCF=
250.0Hz),152.7(d,JCF=12.1Hz), 144.4,140.2 (d, JCF=11.4Hz), 131.4,130.5 (d, JCF=
10.6Hz),123.9,122.3(d,JCF=10.0Hz), 114.2,113.9 (d, JCF=22.0Hz), 112.6 (d, JCF=
24.9Hz),107.6(d,JCF=23.3Hz), 102.6 (d, JCF=26.8Hz), 52.1,49.3,46.4,26.5,
11.3.HRMS(ESI)calcd for C23H24F2N3OS[M+H]+428.1608；found 428.1602.
Embodiment 30: the preparation of compound 6bj.
4a is replaced with 4b, n-butylamine replaces N, N- dimethyl-ethylenediamine, and synthetic method obtains compound 6bj with embodiment 7.
1-Butyl-7-fluoro-3-(5-fluorobenzo[d]thiazol-2-yl)quinolin-4(1H)-one
(6bj) .Yellow crystalline, yield 71%, m.p.185~187 DEG C1H NMR(400MHz,CDCl3)δ:9.04
(s, 1H), 8.64~8.60 (m, 1H), 7.89~7.86 (m, 1H), 7.63~7.60 (m, 1H), 7.23~7.09 (m, 3H),
4.26 (t, J=7.6Hz, 2H), 2.03~1.74 (m, 2H), 1.72~1.23 (m, 2H), 1.02 (t, J=7.3Hz, 3H)13C
NMR(100MHz,CDCl3)δ:173.6,165.3(d,JCF=250Hz), 164.0,161.9 (d, JCF=241.0Hz), 160.7,
143.8,140.0(d,JCF=11.2Hz), 131.4,130.7 (d, JCF=10.7Hz), 123.9,122.4 (d, JCF=
9.9Hz),114.3,113.9(d,JCF=22.9Hz), 112.8 (d, JCF=24.9Hz), 107.6 (d, JCF=23.4Hz),
102.3(d,JCF=26.7Hz), 54.4,30.9,20.0,13.7.HRMS (ESI) calcd for C20H17F2N3O2S[M+H]+
371.1030；found 371.1024.
Embodiment 31: the preparation of compound 6bk.
4a, HO (CH are replaced with 4b2)3NH2N, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound with embodiment 7
6bk。
7-Fluoro-3-(5-fluorobenzo[d]thiazol-2-yl)-1-(3-hydroxypropyl)
quinolin-4(1H)-
- one (6bk) .Yellow crystalline, yield 67%, m.p.145~147 DEG C1H NMR(400MHz,
DMSO-d6) δ: 9.21 (s, 1H), 8.43~8.39 (m, 1H), 8.13~8.09 (m, 1H), 7.80 (d, J=11.1Hz, 1H),
7.71~7.68 (m, 1H), 7.43~7.39 (m, 1H), 7.27~7.22 (m, 1H), 4.56 (t, J=6.9Hz, 2H), 3.51
(t, J=5.6Hz, 2H), 2.05~1.92 (m, 2H) (the resonance of O-H was not observed in
DMSO-d6).13C NMR(100MHz,DMSO-d6)δ:172.9,165.1(d,JCF=248.0Hz), 164.4,161.7 (d, JCF
=239.0Hz), 152.7 (d, JCF=12.4Hz), 145.7,140.6 (d, JCF=12.1Hz), 131.3,129.9 (d, JCF=
10.8Hz),123.8,123.6(d,JCF=15.6Hz), 114.2 (d, JCF=23.4Hz), 113.1,113.0 (d, JCF=
19.0Hz),107.5(d,JCF=23.3Hz), 104.4 (d, JCF=27.0Hz), 57.9,51.3,31.8.HRMS (ESI)
calcd for C19H15F2N2OS[M+H]+373.0822；found 373.0820.
Embodiment 32: the preparation of compound 6bl.
4a is replaced with 4b,N, N- dimethyl-ethylenediamine are replaced, synthetic method obtains chemical combination with embodiment 7
Object 6bl.
7-Fluoro-3-(5-fluorobenzo[d]thiazol-2-yl)-1-(3-(pyrrolidin-1-yl)
Propyl) quinolin-4 (1H)-one (6bl) .Yellow crystalline, yield 49%, m.p.184~186 DEG C
.1H NMR(400MHz,CDCl3) δ: 9.23 (s, 1H), 8.64~8.60 (m, 1H), 7.89~7.86 (m, 1H), 7.61~7.58
(m, 1H), 7.39~7.36 (m, 1H), 7.24~7.15 (m, 1H), 7.13~7.08 (m, 1H), 4.42 (t, J=6.5Hz,
2H), 2.51~2.50 (m, 4H), 2.48 (t, J=6.0Hz, 2H), 2.10~2.06 (m, 2H), 1.88~1.83 (m, 4H)13C
NMR(100MHz,CDCl3)δ:173.6,165.3(d,JCF=251.0Hz), 164.0,161.9 (d, JCF=240.0Hz),
152.7(d,JCF=12.1Hz), 144.8,140.3 (d, JCF=11.5Hz), 131.5,130.5 (d, JCF=10.6Hz),
123.9,122.3(d,JCF=10.0Hz), 114.1,113.6 (d, JCF=23.0Hz), 112.6 (d, JCF=24.9Hz),
107.6(d,JCF=23.2Hz), 102.6 (d, JCF=27.0Hz), 53.8,51.5,51.4,27.4,23.6.HRMS (ESI)
calcd for C23H22F2N3OS[M+H]+426.1452；found 426.1443.
Embodiment 33: the preparation of compound 6bo.
4a is replaced with 4b,N, N- dimethyl-ethylenediamine are replaced, synthetic method must be changed with embodiment 7
Close object 6bo.
7-Fluoro-3-(5-fluorobenzo[d]thiazol-2-yl)-1-(3-morpholinopropyl)
quinolin-
- 4 (1H)-one (6bo) .Yellow crystalline, yield 63%, m.p.236~237 DEG C1H NMR
(400MHz,CDCl3) δ: 9.22 (s, 1H), 8.62~8.58 (m, 1H), 7.88~7.85 (m, 1H), 7.56 (dd, J=9.7,
2.4Hz, 1H), 7.30 (dd, J=9.7,2.4Hz, 1H), 7.22~7.14 (m, 1H), 7.13~7.08 (m, 1H), 4.42 (t, J
=6.3Hz, 2H), 3.83 (t, J=4.5Hz, 4H), 2.43 (t, J=4.5Hz, 4H), 2.33 (t, J=5.9Hz, 2H), 2.12
~2.02 (m, 2H)13C NMR(100MHz,CDCl3)δ:173.6,165.3(d,JCF=251.0Hz), 163.9,161.9 (d,
JCF=241.0Hz), 152.7 (d, JCF=12.1Hz), 144.8,140.2 (d, JCF=11.3Hz), 131.4,130.6 (d, JCF
=10.6Hz), 123.9,122.3 (d, JCF=10.0Hz), 114.1,113.8 (d, JCF=23.0Hz), 112.7 (d, JCF=
24.9Hz),107.6(d,JCF=23.3Hz), 102.3 (d, JCF=26.8Hz), 67.0,53.8,53.5,51.1,
24.8.HRMS(ESI)calcd for C23H22F2N3O2S[M+H]+442.1401；found 442.1396.
Embodiment 34: the preparation of compound 6ca.
4a is replaced with 4c, synthetic method obtains compound 6ca with embodiment 7.
3-(5-Chlorobenzo[d]thiazol-2-yl)-1-(2-(dimethylamino)ethyl)-7-
fluoroquinolin-
- 4 (1H)-one (6ca) .Yellow crystalline, yield 82%, m.p.190~191 DEG C1H NMR
(400MHz,CDCl3) δ: 8.95 (s, 1H), 8.59~8.55 (m, 1H), 7.86~7.82 (m, 2H), 7.30~7.27 (m,
1H), 7.20~7.13 (m, 2H), 4.29 (t, J=6.8Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.34 (s, 6H)13C
NMR(100MHz,CDCl3)δ:173.6,165.3(d,JCF=251.0Hz), 163.3,152.6,144.3,140.1 (d, JCF=
11.3Hz),134.2,131.8,130.6(d,JCF=10.6Hz), 124.4,123.8,122.3,121.5,114.2,113.9
(d,JCF=28.0Hz), 102.2 (d, JCF=26.8Hz), 57.2,52.5,45.8.HRMS (ESI) calcd for
C20H18ClFN3OS[M+H]+402.0843；found 402.0837.
Embodiment 35: the preparation of compound 6cb.
4a, N are replaced with 4c, N- diethyl ethylenediamine replaces N, N- dimethyl-ethylenediamine, and synthetic method is obtained with embodiment 7
Compound 6cb.
3-(5-Chlorobenzo[d]thiazol-2-yl)-1-(2-(diethylamino)ethyl)-7-
fluoroquinolin-
- 4 (1H)-one (6cb) .Yellow crystalline, yield 68%, m.p.187~188 DEG C1H NMR
(400MHz,CDCl3) δ: 9.00 (s, 1H), 8.63~8.60 (m, 1H), 7.90~7.84 (m, 2H), 7.30 (dd, J=8.4,
2.0Hz, 1H), 7.22~7.18 (m, 2H), 4.26 (t, J=5.9Hz, 2H), 2.85 (t, J=5.9Hz, 2H), 2.53 (q, J=
7.0Hz, 4H), 0.90 (t, J=7.0Hz, 6H)13C NMR(100MHz,CDCl3)δ:173.7,165.3(d,JCF=
251.0Hz),163.5,152.7,145.1,140.1(d,JCF=11.3Hz), 134.3,131.7,130.6 (d, JCF=
10.6Hz),124.4,123.8,122.4,121.5,113.8,113.7(d,JCF=17.0Hz), 102.2 (d, JCF=
26.8Hz),53.2,51.4,47.5,12.2.HRMS(ESI)calcd for C22H22ClFN3OS[M+H]+430.1156；
found 430.1153.
Embodiment 36: the preparation of compound 6cc.
4a, i-Pr are replaced with 4c2N(CH2)2NH2N, N- dimethyl-ethylenediamine are replaced, synthetic method must be changed with embodiment 7
Close object 6cc.
3-(5-Chlorobenzo[d]thiazol-2-yl)-1-(2-(diisopropylamino)ethyl)-7-
fluoroquino-
- lin-4 (1H)-one (6cc) .Yellow crystalline, yield 63%, m.p.212~214 DEG C1H
NMR(400MHz,CDCl3) δ: 8.99 (s, 1H), 8.67~8.63 (m, 1H), 7.93~7.86 (m, 2H), 7.31 (dd, J=
8.4,1.9Hz, 1H), 7.24~7.20 (m, 2H), 4.23 (t, J=5.8Hz, 2H), 3.08~2.95 (m, 2H), 2.89 (t, J
=5.8Hz, 2H), 0.88 (d, J=6.6Hz, 12H)13C NMR(100MHz,CDCl3)δ:173.6,165.3(d,JCF=
251.0Hz),163.5,152.8,145.6,140.0(d,JCF=11.2Hz), 134.2,131.6,130.7 (d, JCF=
10.6Hz),124.3,123.8,122.3,121.5,113.7,113.5(d,JCF=22.0Hz), 102.1 (d, JCF=
26.7Hz),53.7,48.0,43.1,20.8.HRMS(ESI)calcd for C24H26ClFN3OS[M+H]+458.1469；
found 458.1467.
Embodiment 37: the preparation of compound 6ch.
4a, N are replaced with 4c, N- dimethylated propyl diethylenetriamine replaces N, N- dimethyl-ethylenediamine, and synthetic method is obtained with embodiment 7
Compound 6ch.
3-(5-Chlorobenzo[d]thiazol-2-yl)-1-(3-(dimethylamino)propyl)-7-
Fluoroquinolin-4 (1H)-one (6ch) .Yellow crystalline, yield 78%, m.p.220~222 DEG C1H
NMR(400MHz,CDCl3) δ: 9.13 (s, 1H), 8.61~8.60 (m, 1H), 7.88~7.83 (m, 2H), 7.34~7.28 (m,
2H), 7.22~7.15 (m, 1H), 4.38 (t, J=6.8Hz, 2H), 2.30 (t, J=6.2Hz, 2H), 2.26 (s, 6H), 2.07
~2.00 (m, 2H)13C NMR(100MHz,CDCl3)δ:173.7,165.3(d,JCF=251.0Hz), 163.4,152.7,
144.6,140.3(d,JCF=11.4Hz), 134.2,131.7,130.5 (d, JCF=10.6Hz), 124.1,123.9,122.3,
121.4,114.1,113.9(d,JCF=24.0Hz), 102.5 (d, JCF=27.0Hz), 55.1,51.4,45.3,26.5.HRMS
(ESI)calcd for C21H20ClFN3OS[M+H]+416.1000；found 416.0989.
Embodiment 38: the preparation of compound 6ci.
4a, N are replaced with 4c, N- diethyl propyldiamine replaces N, N- dimethyl-ethylenediamine, and synthetic method is obtained with embodiment 7
Compound 6ci.
3-(5-Chlorobenzo[d]thiazol-2-yl)-1-(3-(diethylamino)propyl)-7-
fluoroquinolin-
- 4 (1H)-one (6ci) .Yellow crystalline, yield 52%, m.p.158~160 DEG C1H NMR
(400MHz,CDCl3) δ: 9.11~9.08 (m, 1H), 8.60~8.56 (m, 1H), 7.92~7.80 (m, 2H), 7.38~7.27
(m, 2H), 7.23~7.15 (m, 1H), 4.36 (t, J=6.0Hz, 2H), 2.57 (q, J=7.0Hz, 4H), 2.49~2.46 (m,
2H), 2.04~2.03 (m, 2H), 1.05 (t, J=7.0Hz, 6H)13C NMR(100MHz,CDCl3)δ:173.7,165.3(d,
JCF=251.0Hz), 163.3,152.7,144.5,140.2 (d, JCF=9.3Hz), 134.2,131.7,130.4 (d, JCF=
10.6Hz),124.4,123.9,122.3,121.4,114.1,113.9(d,JCF=18.0Hz), 102.6 (d, JCF=
26.8Hz),52.1,49.3,46.4,26.5,11.4.HRMS(ESI)calcd for C23H24ClFN3OS[M+H]+
444.1313；found 444.1305.
Embodiment 39: the preparation of compound 6cj.
4a is replaced with 4c, n-butylamine replaces N, N- dimethyl-ethylenediamine, and synthetic method obtains compound 6cj with embodiment 7.
1-Butyl-3-(5-chlorobenzo[d]thiazol-2-yl)-7-fluoroquinolin-4(1H)-one
(6cj) .Yellow crystalline, yield 64%, m.p.237~238 DEG C1H NMR(400MHz,CDCl3)δ:8.97
(s, 1H), 8.60~8.56 (m, 1H), 7.86~7.83 (m, 2H), 7.29 (dd, J=8.4,1.9Hz, 1H), 7.21~7.15
(m, 1H), 7.12~7.10 (m, 1H), 4.22 (t, J=7.6Hz, 2H), 1.96~1.88 (m, 2H), 1.53~1.44 (m,
2H), 1.02 (t, J=7.4Hz, 3H)13C NMR(100MHz,CDCl3)δ:173.6,165.3(d,JCF=251.0Hz),
163.3,152.5,143.8,140.0(d,JCF=11.3Hz), 134.1,131.8,130.5 (d, JCF=10.6Hz), 124.5,
123.8,122.4,121.4,114.2,113.9(d,JCF=21.0Hz), 102.3 (d, JCF=26.7Hz), 54.4,30.9,
20.0,13.7.HRMS(ESI)calcd for C20H17ClFN2OS[M+H]+387.0734；found 387.0726.
Embodiment 40: the preparation of compound 6ck.
4a, HO (CH are replaced with 4c2)3NH2N, N- dimethyl-ethylenediamine are replaced, synthetic method obtains compound with embodiment 7
6ck。
3-(5-Chlorobenzo[d]thiazol-2-yl)-7-fluoro-1-(3-hydroxypropyl)
quinolin-4(1H)-
- one (6ck) .Yellow crystalline, yield 30%, m.p.270~272 DEG C1H NMR(400MHz,
DMSO-d6) δ: 9.15 (s, 1H), 8.40~8.37 (m, 1H), 8.09 (d, J=8.5Hz, 1H), 7.87 (d, J=1.5Hz,
1H), 7.77 (dd, J=11.3,1.9Hz, 1H), 7.41~7.35 (m, 2H), 4.55 (t, J=7.1Hz, 2H), 3.53 (t, J=
5.8Hz, 2H), 2.02~1.96 (m, 2H) (the resonance of O-H was not observed in DMSO-d6)
.13C NMR(100MHz,DMSO-d6)δ:172.9,165.0(d,JCF=247.9Hz), 163.8,152.7,145.6,140.6
(d,JCF=12.1Hz), 134.2,131.1,129.9 (d, JCF=10.9Hz), 124.4,123.7,121.0,114.2 (d, JCF
=23.3Hz), 113.0,104.4,104.2,57.9,51.4,31.8.HRMS (ESI) calcd for C19H15ClFN2O2S[M+
H]+389.0527；found 389.0523.
Embodiment 41: the preparation of compound 6cl.
4a is replaced with 4c,N, N- dimethyl-ethylenediamine are replaced, synthetic method obtains chemical combination with embodiment 7
Object 6cl.
3-(5-Chlorobenzo[d]thiazol-2-yl)-7-fluoro-1-(3-(pyrrolidin-1-yl)
Propyl) quinolin-4 (1H)-one (6cl) .Yellow crystalline, yield 35%, m.p.181~182 DEG C
.1H NMR(400MHz,CDCl3) δ: 9.20 (s, 1H), 8.59 (dd, J=8.7,6.7Hz, 1H), 7.89~7.80 (m, 2H),
7.35 (dd, J=10.6,1.7Hz, 1H), 7.30 (dd, J=8.4,2.0Hz, 1H), 7.22~7.15 (m, 1H), 4.41 (t, J
=6.5Hz, 2H), 2.50~2.46 (m, 4H), 2.47 (t, J=6.3, Hz, 2H), 2.13~2.02 (m, 2H), 1.86~1.84
(m,4H).13C NMR(100MHz,CDCl3)δ:173.7,165.3(d,JCF=251.0Hz), 163.5,152.7,145.0,
140.3(d,JCF=11.4Hz), 134.3,131.7,130.4 (d, JCF=10.6Hz), 124.4,123.8,122.4,121.4,
114.0,113.8(d,JCF=13.0Hz), 102.5 (d, JCF=27.0Hz), 53.8,51.6,51.4,27.4,23.6.HRMS
(ESI)calcd for C23H22ClFN3OS[M+H]+442.1156；found 442.1148.
Embodiment 42: the preparation of compound 6co.
4a is replaced with 4c,N, N- dimethyl-ethylenediamine are replaced, synthetic method must be changed with embodiment 7
Close object 6co.
3-(5-Chlorobenzo[d]thiazol-2-yl)-7-fluoro-1-(3-morpholinopropyl)
quinolin-
- 4 (1H)-one (6co) .Yellow crystalline, yield 64%, m.p.212~214 DEG C1H NMR
(400MHz,CDCl3) δ: 9.21 (s, 1H), 8.62~8.58 (m, 1H), 7.86~7.84 (m, 2H), 7.35~7.27 (m,
2H), 7.22~7.14 (m, 1H), 4.42 (t, J=6.3Hz, 2H), 3.83 (t, J=4.6Hz, 4H), 2.44 (t, J=4.6Hz,
4H), 2.33 (t, J=5.8Hz, 2H), 2.12~2.00 (m, 2H)13C NMR(100MHz,CDCl3)δ:173.6,165.3(d,
JCF=251.0Hz), 163.3,152.7,144.9,140.1 (d, JCF=11.3Hz), 134.2,131.8,130.6 (d, JCF=
10.6Hz),124.5,123.9,122.4,121.4,114.0,113.9(d,JCF=13.0Hz), 102.3 (d, JCF=
26.8Hz),67.0,53.8,53.4,51.1,24.7.HRMS(ESI)calcd for C23H22ClFN3OS[M+H]+
458.1105；found 458.1100.
Embodiment 43: pharmacological experiment.
1. the cytotoxicity of compound.
This experimental test cytotoxicity of the part of compounds to cell.
Testing procedure is as follows:
(1) subject cell T-24 (bladder cancer cell) is cultivated, MGC-803 (stomach cancer cell), HepG2 (liver cancer cells),
After Hela (cervical cancer cell), NCI-H460 (lung carcinoma cell), HL-7702 (liver cell) to logarithmic growth phase with trypsase into
Row digestion, is then made into single cell suspension with the culture solution containing 10% fetal calf serum and is inoculated into 96 orifice plates, be placed in 5%CO2, 37 DEG C
It is cultivated in cell incubator.
(2) compound of concentration gradient (1.25,2.5,5,10,20 μM) is added, if 5 multiple holes ensure to reflect true feelings
Condition.
(3) continue to be placed in 5%CO2, 37 DEG C of cell incubators are interior to cultivate 48h.
(4) 10 μ L MTT solution (5mg/mL) are added in every hole, continue 4~6h of culture.
(5) culture is terminated, liquid in hole is carefully sucked.
(6) 100 μ L dimethyl sulfoxides are added in every hole, set micro vibrator low-speed oscillation 10min, keep crystal sufficiently molten
Solution.The light absorption value in each hole is measured in enzyme-linked immunosorbent assay instrument, setting test wavelength is 570nm, reference wavelength 630nm.
(7) inhibiting rate and IC50The calculating of value
Inhibiting rate/%=(1-sample sets mean OD value/control group mean OD value) × 100%, IC50Value is by SPSS software meter
Calculate gained.
Experimental result statisticallys analyze institute by statistic software SPSS 17.0 by 3 independent repetition experiment gained, experimental data
, data are indicated with mean+SD.
Test result is shown in Table 2.
IC of 2 part of compounds of table to tumor cell line50(μM)
2. compound 6ah can induced hepatocellular carcinoma cell HepG2 foaminess death.
We are detecting some target compounds synthesized to the proliferation inhibition activity process of tumor cell line with mtt assay
In, it is found that certain compounds respectively with 10.0 μM of concentration, after 20.0 μM act on tumour cell, apparent sky occur into the cell
Bubble, as shown in Fig. 1 a, 1b, 1c, the concentration of respectively compound 6ah is caused tested when being respectively 0 μM, 10.0 μM, 20.0 μM
The light field figure of the metamorphosis of tumour cell, and cell death finally occurs.
Further with Hoechst33258 to showing after tumour cell HepG2 dyeing, as shown in Figure 2 a, Control group is (empty
White control group) cellular morphology is full and uniformly distributes the fluorescence of disperse, into the cell without cavity；And with compound 6ah with 10 μM
After concentration induces HepG2 cell, in fluorescence microscopy microscopic observation, as shown in Figure 2 b, shrinkage and born of the same parents are all had occurred in the form of cell
Apparent cavity is inside produced, this phenomenon is consistent with the cell foaming observed before.
In order to which further foaminess death occurs for detailed research and the inducible tumour cell of confirmation compound, we are further
The tested time is tested to the form of subject cell and the influence of life, as shown in the result of Fig. 3, compound 6ah can be with the time
It is dead that foaminess occurs for the mode inducing cell of dependence.Vacuole formation is detected by inverted microscope, compound is being added
After 6ah acts on 4h, cell starts apparent vacuolation occur, and with the increase of administration time, the size and quantity of vacuole
Increase.After administration for 24 hours, Vacuole formation reaches peak, at this time the equal dead of cell, and no longer adherent.
3. compound 6ah inducing mitochondrial film potential declines.
Rhodamine 123 (Rhodamine 123, Rho 123) is a kind of cationic fluorescent dyestuff, can pass through cell membrane, across
Mitochondrial membrane potential enters mitochondrial matrix, and fluorescence intensity weakens.In Apoptosis, mitochondrial membrane potential collapse, mitochondria
The permeability transhipment hole of film is opened, and Rho 123 discharges mitochondrial again, to issue strong yellow-green fluorescence.It is thin by streaming
The power of born of the same parents' instrument detection fluorescence signal occurs to detect mitochondrial membrane potential variation and apoptosis, is that a kind of mitochondrial transmembrane potentials refer to
Show agent.
After Rhodamine 123 is to cell dyeing, carried out shown in testing result Fig. 4 using flow cytometer, the peak on the left side in figure
What is represented is hot spot, and what the peak on the right represented is negative area.It is handled respectively with 1 μM, 5 μM, the compound 6ah of 10 μM of concentration
HepG2 cell for 24 hours after, as shown in figure 4, compound 6ah can be such that significantly HepG2 mitochondrial membrane potential in anoxic collapses, with
The concentration of compound increase, the degree of the mitochondrial membrane potential of cell collapse is all the more obvious.Shared by the hot spot of control group
Ratio is 0.9%, and the shared ratio of mitochondrial membrane potential collapse is respectively when compound 6ah concentration is 1 μM, 5 μM, 10 μM
5.5%, 22.4% and 42.8%, the ratio that compound 6ah collapses mitochondrial membrane potential in the case where concentration is 10 μM of effects is about 5
μM when twice, show significant dose-dependence.
4. compound 6ah induces HepG2 cell to generate active oxygen (ROS).
Active oxygen (Reactive Oxygen Species, ROS), be by-product during mitochondria aerobic metabolism such as
Oxonium ion, peroxide and oxygen radical etc..The excess of Apoptosis and reactive oxygen species (ROS) generates closely related.
Active oxygen detection is carried out using fluorescence probe DCFH-DA (2 ', 7 '-dichlorofluorescein diacetate).Compound is mutual with cell
The release of intracellular ROS and mitochondria have close relationship after effect, and ROS also has highly important work in Apoptosis
With.By experimental result Fig. 5 it is found that abscissa indicates fluorescence intensity in figure, if signal peak can occur when fluorescence intensity changes
Variation.Respectively with 1 μM, 5 μM, the compound 6ah of 10 μM of concentration to HepG2 cytosis for 24 hours after, with compound concentration
Increase, the sample sets fluorescence intensity for blank control group after each concentration effect has significant change, with Control group
Comparison, after compound 6ah is added, the fluorescence intensity curves of DCF are gradually turned right offset, and as the increase of concentration is turned right offset
It is more obvious, illustrates that intracellular reactive oxygen species increase after compound 6ah is added, the permeability changes of mitochondrial membrane, finally
Induce HepG2 apoptosis.
5. compound 6ah induces HepG2 endocytoplasmic reticulum stress.
Can be seen that by the above results, vacuole mainly appears on around core and in cytoplasm, prompt we may vacuole may be with
Endoplasmic reticulum is related.So endoplasmic reticulum is dyed red whether to study the vacuole of endochylema by interior with ER Tracker Red by us
Matter net.Experimental result is as shown in fig. 6, disperse red, compound 6ah is presented in the cell of untreated fish group after endoplasmic reticulum dyeing
After acting on HepG2 cell with gradient concentration (1,5,10 μM), ER Tracker Red can to endoplasmic reticulum dye and cannot be right
Vacuole in cytoplasm is dyed, as the fluorescence intensity of the incremental ER Tracker Red of compound concentration gradually increases.
However after compound 6ah is with 5 μM or 10 μM of inducing cells, cell cytoplasm vacuolization, fluorescence intensity is dramatically increased, together
When around the endoplasmic reticulum of swelling can be observed, above-mentioned phenomenon shows that intracytoplasmic vacuole is probably derived from endoplasmic reticulum.Endoplasmic reticulum is come
The vacuole in source is usually related to er stress, according to this it is presumed that vacuolation caused by compound 6ah may be derived from endoplasmic reticulum
Stress, show occur er stress phenomenon.
6. compound 6ah induces HepG2 cell mitochondrial that swelling occurs.
Compound 6ah acts on HepG2 cell with gradient concentration (1,5,10 μM), dyes through Mito Tracker Green
Result is as shown in fig. 7, according to the experimental results after liquid dyeing, Mito Tracker Green mitochondria can be dyed and cannot
Vacuole in cytoplasm is dyed.Disperse green fluorescence, compound is presented after mitochondria dyeing in the cell of untreated fish group
After 6ah acts on HepG2 cell with gradient concentration (1,5,10 μM), Mito Tracker Green can to mitochondria dye and
Vacuole in cytoplasm cannot be dyed, with the fluorescence intensity of the incremental Mito Tracker Green of compound concentration
It gradually increases, however after compound 6ah is with 5 μM or 10 μM of inducing cells, cell cytoplasm vacuolization, fluorescence intensity is shown
It writes and increases, while the mitochondria of swelling can be observed in surrounding.
Claims (10)
1. the 3- (2-[4-morpholinodithio base) -4 (1 with general formula (I)H) qualone derivative:
(Ⅰ)
Wherein: R1Indicate F atom, Cl atom, Br atom, I atom, alkyl, alkoxy, nitro or hydroxyl；
R2Be alkyl, hydroxyalkyl, aryl, substituted aryl, 2- (N, N- dimethyl) ethyl, 3- (N, N- dimethyl) propyl, 4- (N,
N- dimethyl) butyl, 2- (N, N- diethyl) ethyl, 3- (N, N- diethyl) propyl, 2- (N, N- diisopropyl) ethyl, 3-
(N, N- diisopropyl) propyl, 2- (1- nafoxidine base) ethyl, 3- (1- nafoxidine base) propyl, 2- (1- piperidyl) second
Base, 3- (1- piperidyl) propyl, 2- (4- morpholinyl) ethyl, 3- (4- morpholinyl) propyl, 2- (1- imidazole radicals) ethyl, 3- (1-
Imidazole radicals) propyl, 2- (4- methyl piperazine base) ethyl, 3- (4- methyl piperazine base) propyl, 2- (4- piperazinyl) ethyl or 3- (4-
Piperazinyl) propyl.
2. the 3- (2-[4-morpholinodithio base) -4 (1 with general formula (I)H) qualone derivative preparation method, it is characterised in that packet
Include following steps:
S1. compound 2 is added into container, triethylamine, acetonitrile and 2,4- difluoro benzoyl chloride, in N2/
Under inert gas shielding and stirring, water is added in heating reflux reaction after the reaction was completed, is filtered, and is washed, and drying obtains crude product
1；
The crude product 1, morpholine and methanol are added into container, in N2Under/inert gas shielding and stirring, heating reflux reaction,
Water is added after the reaction was completed, solid is precipitated；It filters, washs, drying obtains compound 3；
S2. compound 3 and DMFDMA are added into container, in N2Under/inert gas shielding and stirring, heating reaction has been reacted
At rear removing solvent, the isolated solid chemical compound 4 of silica gel column chromatography；
S3. compound 4, methanol and compound 5R are added into container2NH2 ,It is stirred to react, removes solvent after the reaction was completed, obtain
Crude product 2；
K is added into the container equipped with crude product 22CO3And DMF, then in N2Under/inert gas shielding and stirring, heating is anti-
It answers, removes solvent after the reaction was completed, water is added, there is solid precipitation, filter, wash, drying obtains compound through column Chromatographic purification
6, i.e., with the 3- (2-[4-morpholinodithio base) -4 (1 of general formula (I)H) qualone derivative.
3. preparation method according to claim 2, it is characterised in that:
In the step S1, compound 2, triethylamine, acetonitrile and 2, time 0.8 of 4- difluoro benzoyl chloride heating reflux reaction ~
1.5h。
4. preparation method according to claim 2, it is characterised in that:
In the step S1,0.8 ~ 1.5h of time of crude product 1, morpholine and methanol heating reflux reaction.
5. preparation method according to claim 2, it is characterised in that:
In the step S2, the time for heating reaction is 0.4 ~ 1h.
6. preparation method according to claim 2, it is characterised in that:
In the step S3, the time that compound 4, methanol and compound 5 react is 0.4 ~ 1h.
7. preparation method according to claim 2, it is characterised in that:
In the step S3, crude product 2, K2CO3Time with DMF reaction is 2h.
8. the 3- (2-[4-morpholinodithio base) -4 (1 with general formula (I)H) qualone derivative and pharmaceutically acceptable auxiliary material composition
Pharmaceutical composition.
9. the 3- (2-[4-morpholinodithio base) -4 (1 with general formula (I)H) qualone derivative is prepared into pharmacy acceptable dose
Type.
10. derivative described in claim 1 or pharmaceutical composition according to any one of claims 8 answering in the preparation of antitumor drugs
With.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910068653.6A CN109651354A (en) | 2019-01-24 | 2019-01-24 | - 4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910068653.6A CN109651354A (en) | 2019-01-24 | 2019-01-24 | - 4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) and its preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109651354A true CN109651354A (en) | 2019-04-19 |
Family
ID=66121357
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910068653.6A Pending CN109651354A (en) | 2019-01-24 | 2019-01-24 | - 4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109651354A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483418A (en) * | 2019-09-11 | 2019-11-22 | 广西师范大学 | 3- substituted quinazoline ketone -2- carboxamides derivatives and its preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1473827A (en) * | 2003-08-11 | 2004-02-11 | 中国药科大学 | 3-position substituted quinolone derivativers and its use in pharmacy |
| TW201011008A (en) * | 2008-08-01 | 2010-03-16 | Sanofi Aventis | Thiophene-2-carboxamide derivatives, their preparation and their therapeutic application |
| CN102617568B (en) * | 2012-03-06 | 2014-06-25 | 天津市汉康医药生物技术有限公司 | Stable moxifloxacin hydrochloride compound and preparation method thereof |
-
2019
- 2019-01-24 CN CN201910068653.6A patent/CN109651354A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1473827A (en) * | 2003-08-11 | 2004-02-11 | 中国药科大学 | 3-position substituted quinolone derivativers and its use in pharmacy |
| TW201011008A (en) * | 2008-08-01 | 2010-03-16 | Sanofi Aventis | Thiophene-2-carboxamide derivatives, their preparation and their therapeutic application |
| CN102617568B (en) * | 2012-03-06 | 2014-06-25 | 天津市汉康医药生物技术有限公司 | Stable moxifloxacin hydrochloride compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| GH CIURDARU ET AL.: "The acylation of 2-methylbenzazoles", 《JOURNAL FUER PRAKTISCHE CHEMIE(LEIPZIG)》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483418A (en) * | 2019-09-11 | 2019-11-22 | 广西师范大学 | 3- substituted quinazoline ketone -2- carboxamides derivatives and its preparation method and application |
| CN110483418B (en) * | 2019-09-11 | 2022-09-20 | 广西师范大学 | 3-substituted quinazolinone-2-formamide derivative and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105153122B (en) | [(indol-3-yl) pyrimidine -2-base] aminophenyl propyl- 2- alkenylamide derivatives and salt, preparation method, application | |
| Ali et al. | Facile synthesis of indole heterocyclic compounds based micellar nano anti-cancer drugs | |
| CN104292170B (en) | There is quinazoline-Arylurea derivatives and the application thereof of antitumor action | |
| CN106810536A (en) | A kind of kinases inhibitor and preparation method thereof and medical usage | |
| Zhang et al. | Novel multi-substituted benzyl acridone derivatives as survivin inhibitors for hepatocellular carcinoma treatment | |
| CN103224496B (en) | Tricyclic antidepressants PI3K and/or mTOR inhibitors | |
| CN106220641B (en) | Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure | |
| JP2019507779A (en) | Urea-based compound, method for producing the same and pharmaceutical use thereof | |
| Ali et al. | Antitumor studies. Part 1: Design, synthesis, antitumor activity, and AutoDock study of 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides as a new class of antitumor agents | |
| Ibrahim et al. | Synthesis and biological evaluation of some novel thiobenzimidazole derivatives as anti-renal cancer agents through inhibition of c-MET kinase | |
| CN112125911B (en) | CDK9 inhibitor and preparation method and application thereof | |
| CN109476672A (en) | New type heterocycle derivative compound and application thereof | |
| CN104447765A (en) | Tricyclic compound and pharmaceutical compositions thereof and application thereof | |
| Yan et al. | Design, synthesis, and biological evaluation of novel diphenylamine derivatives as tubulin polymerization inhibitors targeting the colchicine binding site | |
| CN110128367A (en) | A kind of indoles amine -2,3- dioxygenase inhibitor and its preparation method and application | |
| CN109651354A (en) | - 4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) and its preparation method and application | |
| Fouda et al. | Discovery of pyran annulated heterocyclic scaffolds linked to carboxamide fragments: Anticancer evaluation, topoisomerase I/II, tyrosine kinase receptor inhibition and molecular docking studies | |
| CN104059053B (en) | One class amide side chains contains synthesis and the application thereof of the naphthalimide derivative of 1,2,3-triazoles | |
| CA2939687A1 (en) | Aminopyrazolone derivative | |
| CN106866642B (en) | Quinazoline compound containing aryl acylhydrazone structure and application thereof | |
| CN109988120A (en) | A kind of indoles amine -2,3- dioxygenase inhibitor and its preparation method and application | |
| CN106467498A (en) | N-（Thiazol-2-yl）Aminoamide derivatives and preparation method and application | |
| CN109438437A (en) | Anticancer compound of the one kind containing thiazole ring | |
| CN115160277A (en) | Apigenin derivative and application thereof | |
| CN105859684B (en) | Fused ring compound and preparation method, application and intermediate compound thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190419 |