CN109651355A - 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline and its preparation method and application - Google Patents
3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline and its preparation method and application Download PDFInfo
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Abstract
The present invention provides one kind 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline and its preparation method and application, the general formula of 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline are as follows:
Description
Technical field
The present invention relates to organic chemistry and field of pharmaceutical chemistry technology, and in particular to 3- (the benzo five-membered heterocycle of 2-) -4- (3-
The third amino of dimethylamine) quinoline derivatives and its preparation method and application.
Background technique
It was found that new antitumoral compounds are always a major fields of pharmaceutical chemistry research.4- aminoquinolines chemical combination
Object have extensive biochemistry and quasi-medicated property matter, 4-aminoquinoline compounds such as chloroquine etc. as important anti-malaria medicaments
Through being widely applied clinically.In addition, the benzo five-membered heterocyclic compound such as benzoxazoles, benzothiazole and benzimidazole
It is one of the considerable advantage structure in pharmaceutical chemistry research with extensive bioactivity.We are by by 4- aminoquinoline structure
Unit is combined with the benzo five-membered miscellaneous structural unit such as benzoxazoles, benzothiazole and benzimidazole, and design has synthesized 3- (2- benzo
Five-ring heterocycles) -4- (the third amino of 3- dimethylamine) quinolines, and find that this kind of noval chemical compound has good antitumor work
Property.Currently, there are no document reports for the synthesis of such compound and active report.
Summary of the invention
The present invention provides a kind of derivative with 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline structure
Object and its preparation method and application, such compound have good anti-tumor activity, can apply to prepare anti-tumor drug, be
The research of anti-tumor drug provides broader thinking.
To achieve the above object, the technical solution of the present invention is as follows:
3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline with general formula (I):
Wherein: Y is S, O or NH；R1It is F atom, Cl atom, Br atom, alkyl, alkoxy, trifluoromethyl, nitro respectively
Or hydroxyl.
The present invention provides 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline with general formula (I) to spread out
The preparation method of biology, comprising the following steps:
S1. compound 1 is added into containerCompound 2And diphenyl ether, in nitrogen
Under gas/inert gas shielding, heating reflux reaction is cooled to room temperature after reaction, and a large amount of solids are precipitated, and is filtered, and is washed, and is done
It is dry, it obtains
S2. willPOCl3It is added in container, heating reflux reaction, it is cooling, remove big portion
Divide POCl3, product is poured into ice water, pH to 8~9 is adjusted, is filtered, is washed, drying, column Chromatographic purification obtains faint yellow solid；
By the faint yellow solid, N, N dimethyl propane diamine, dimethylbenzene are added in container, under nitrogen/inert gas shielding, are added
Hot back flow reaction, it is after reaction, cooling, solvent is removed, column Chromatographic purification obtains
Preferably, in the step S1, the temperature of back flow reaction is 210~230 DEG C, and the reaction time is 1.8~2.5h.
Preferably, in the step S1, when washing, petroleum ether is first used, then washed with methylene chloride.
Preferably, in the step S2,And POCl3The time of heating reflux reaction is 4.5
~6h.
Preferably, it in the step S2, when washing, is washed with water.
Invention further provides 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) with general formula (I)
The pharmaceutical composition of quinoline and pharmaceutically acceptable auxiliary material composition.
Invention further provides 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) with general formula (I)
Quinoline is prepared into acceptable dosage form in pharmacy.
Invention further provides 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) with general formula (I)
Quinoline or its pharmaceutical composition application in preparation of anti-tumor drugs.
Preferably, the tumour includes human liver cancer tumour, human gastric cancer tumour, human bladder cancer's tumour, human lung cancer tumour.
The present invention has synthesized a kind of derivative with logical formula (I), and provides preparation method, and raw material is easy to get, preparation
Method is simple, it is only necessary to which two steps provide diversified 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline
Derivative, selectivity is wider, provides more thinkings for the exploitation of anti-tumor drug.
Tests prove that the compound of logical formula (I) is to gastric carcinoma cells MGC-803, human bladder cancer cell T-24, human liver cancer
Cell HepG2, human lung carcinoma cell NCI-H460 all have good inhibitory activity.
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, to tumour cell especially MGC-803 (human gastric cancer
Cell), T-24 (human bladder cancer cell), HepG-2 (human liver cancer cell), NCI-H460 (human lung cancer tumour) have press down well
Active effect is made, it will be in terms of anti-tumor drug with good application prospect.
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 side of 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline with general formula (I)
Method, preparation route are shown in Scheme 1:
S1. under electromagnetic agitation, compound 1,2 near amino thiophenols of compound/neighbour's ammonia are successively added into round-bottomed flask
Base phenol/neighbour's amino aniline and diphenyl ether are heated to 220 DEG C with electric jacket, back flow reaction 2h under nitrogen protection.It is cooled to
A large amount of solids are precipitated in room temperature, filter, and wash with petroleum ether, then with methylene chloride, solid is placed in 60 DEG C of vacuum drying
Dry 3h, respectively corresponds to obtain compound 3/4/5 in case.
S2. under electromagnetic agitation, successively by compound 3/4/5, POCl3It is added in single-necked flask, heating reflux reaction
5h (TLC monitoring reaction, solvent: VPetroleum ether:VEthyl acetate=4:1), it is cooling, most of POCl is removed under reduced pressure3, product is poured into ice
In water, NaHCO is used3Solid adjust pH to 8~9, filter, washed with massive laundering, dry, with silica gel column chromatography purification (eluant, eluent:
VPetroleum ether:VEthyl acetate=8:1) obtain faint yellow solid.
Under electromagnetic agitation, faint yellow solid, the N for successively obtaining upper step, N dimethyl propane diamine, dimethylbenzene are added to
In single-necked flask, heating reflux reaction overnight (react, solvent: V by TLC monitoring under nitrogen protectionPetroleum ether:VEthyl acetate=4:1),
It is cooling, solvent is removed under reduced pressure, purifies (eluant, eluent: V with silica gel column chromatographyMethylene chloride:VEthyl acetate:VMethanol=9:3:1), correspondence is produced
Object 6/7/8.
Specific synthesis step is shown in following example 1~72:
Embodiment 1: the preparation of compound 3a.
Under electromagnetic agitation, successively by compound 1aNear amino thiophenols, diphenyl ether are added to 50mL
In single-necked flask, heating reflux reaction 2h (react, solvent: V by TLC monitoring under nitrogen protectionMethylene chloride:VEthyl acetate:VMethanol=9:
3:1), a large amount of solids are precipitated after the reaction was completed, filters, with petroleum ether (10mL × 5), obtains faint yellow solid (compound
3a), yield 90%.
Embodiment 2: the preparation of compound 3b.
With compound 1bCompound 1a is replaced, synthetic method obtains compound 3b with embodiment 1, produces
Rate: 90%.
Embodiment 3: the preparation of compound 3c.
With compound 1cCompound 1a is replaced, synthetic method obtains compound 3c with embodiment 1, produces
Rate: 81%.
Embodiment 4: the preparation of compound 3d.
With compound 1dCompound 1a is replaced, synthetic method obtains compound 3d, yield with embodiment 1:
91%.
Embodiment 5: the preparation of compound 3e.
With compound 1eCompound 1a is replaced, synthetic method obtains compound 3e with embodiment 1,
Yield: 80%.
Embodiment 6: the preparation of compound 3f.
With compound 1fCompound 1a is replaced, synthetic method obtains compound 3f with embodiment 1,
Yield: 90%.
Embodiment 7: the preparation of compound 3g.
With compound 1gCompound 1a is replaced, synthetic method obtains compound 3g with embodiment 1, produces
Rate: 83%.
Embodiment 8: the preparation of compound 3h.
With compound 1hCompound 1a is replaced, synthetic method obtains compound 3h with embodiment 1, produces
Rate: 94%.
Embodiment 9: the preparation of compound 3i.
With compound 1iCompound 1a is replaced, synthetic method obtains compound 3i, yield with embodiment 1:
85%.
Embodiment 10: the preparation of compound 3j.
With compound 1jCompound 1a is replaced, synthetic method obtains compound 3j with embodiment 1, produces
Rate: 90%.
Embodiment 11: the preparation of compound 3k.
With compound 1kCompound 1a is replaced, synthetic method obtains compound 3k with embodiment 1, produces
Rate: 87%.
Embodiment 12: the preparation of compound 3l.
With compound 1lCompound 1a is replaced, synthetic method obtains compound 3l, yield with embodiment 1:
85%.
Embodiment 13: the preparation of compound 3m.
With compound 1mCompound 1a is replaced, synthetic method obtains compound 3m with embodiment 1, produces
Rate: 90%.
Embodiment 14: the preparation of compound 3n.
With compound 1nCompound 1a is replaced, synthetic method obtains compound 3n with embodiment 1, produces
Rate: 88%.
Embodiment 15: the preparation of compound 3o.
With compound 1oCompound 1a is replaced, synthetic method obtains compound 3o, yield with embodiment 1:
84%.
Embodiment 16: the preparation of compound 3r.
With compound 1rCompound 1a is replaced, synthetic method obtains compound 3r with embodiment 1, produces
Rate: 80%.
Embodiment 17: the preparation of compound 4a.
Under electromagnetic agitation, successively compound 1a, o-aminophenol, diphenyl ether are added in 50mL single-necked flask,
Heating reflux reaction 2h (TLC monitoring reaction, solvent: V under nitrogen protectionMethylene chloride:VEthyl acetate:VMethanol=9:3:1), reaction is completed
After a large amount of solids are precipitated, filter, with petroleum ether (10mL × 5), obtain faint yellow solid (compound 4a), yield 90%.
Embodiment 18: the preparation of compound 4b.
Compound 1a is replaced with compound 1b, synthetic method obtains compound 4b, yield: 90% with embodiment 17.
Embodiment 19: the preparation of compound 4c.
Compound 1a is replaced with compound 1c, synthetic method obtains compound 4c, yield: 86% with embodiment 17.
Embodiment 20: the preparation of compound 4d.
Compound 1a is replaced with compound 1d, synthetic method obtains compound 4d, yield: 86% with embodiment 17.
Embodiment 21: the preparation of compound 4e.
Compound 1a is replaced with compound 1e, synthetic method obtains compound 4e, yield: 85% with embodiment 17.
Embodiment 22: the preparation of compound 4f.
Compound 1a is replaced with compound 1f, synthetic method obtains compound 4f, yield: 88% with embodiment 17.
Embodiment 23: the preparation of compound 4g.
Compound 1a is replaced with compound 1g, synthetic method obtains compound 4g, yield: 83% with embodiment 17.
Embodiment 24: the preparation of compound 4h.
Compound 1a is replaced with compound 1h, synthetic method obtains compound 4h, yield: 94% with embodiment 17.
Embodiment 25: the preparation of compound 4i.
Compound 1a is replaced with compound 1i, synthetic method obtains compound 4i, yield: 85% with embodiment 17.
Embodiment 26: the preparation of compound 4j.
Compound 1a is replaced with compound 1j, synthetic method obtains compound 4j, yield: 85% with embodiment 17.
Embodiment 27: the preparation of compound 4k.
Compound 1a is replaced with compound 1k, synthetic method obtains compound 4k, yield: 87% with embodiment 17.
Embodiment 28: the preparation of compound 4l.
Compound 1a is replaced with compound 1l, synthetic method obtains compound 4l, yield: 85% with embodiment 17.
Embodiment 29: the preparation of compound 4m.
Compound 1a is replaced with compound 1m, synthetic method obtains compound 4m, yield: 90% with embodiment 17.
Embodiment 30: the preparation of compound 4n.
Compound 1a is replaced with compound 1n, synthetic method obtains compound 4n, yield: 86% with embodiment 17.
Embodiment 31: the preparation of compound 4o.
Compound 1a is replaced with compound 1o, synthetic method obtains compound 4o, yield: 84% with embodiment 17.
Embodiment 32: the preparation of compound 4p.
With compound 1pCompound 1a is replaced, synthetic method obtains compound 4p with embodiment 17, produces
Rate: 88%.
Embodiment 33: the preparation of compound 4q.
With compound 1qCompound 1a is replaced, synthetic method obtains compound 4q with embodiment 17,
Yield: 90%.
Embodiment 34: the preparation of compound 4r.
Compound 1a is replaced with compound 1r, synthetic method obtains compound 4r, yield: 80% with embodiment 17.
Embodiment 35: the preparation of compound 5b.
Under electromagnetic agitation, successively 1b, adjacent aminobenzene aniline, diphenyl ether are added in 50mL single-necked flask, in nitrogen
Protect lower heating reflux reaction 2h (TLC monitoring reaction, solvent: VMethylene chloride:VEthyl acetate:VMethanol=9:3:1), it analyses after the reaction was completed
A large amount of solids out are filtered, with petroleum ether (10mL × 5), are obtained faint yellow solid (compound 5b), yield 70%.
Embodiment 36: the preparation of compound 5n.
Compound 1a is replaced with compound 1n, synthetic method obtains compound 5n, yield: 80% with embodiment 35.
Embodiment 37: the preparation of compound 6a.
Under electromagnetic agitation, successively by compound 3a, POCl3It is added in single-necked flask, heating reflux reaction 5h (TLC
Monitoring reaction, solvent: VPetroleum ether:VEthyl acetate=4:1), it is cooling, most of POCl is removed under reduced pressure3,Product is poured into ice water, is used
NaHCO3Solid adjusts pH to 8~9, filters, is washed with massive laundering, dries, and purifies (eluant, eluent: V with silica gel column chromatographyPetroleum ether:
VEthyl acetate=8:1) obtain faint yellow solid.
Under electromagnetic agitation, upper step reaction product and N, N- dimethylated propyl diethylenetriamine, dimethylbenzene are successively added to single port and burnt
In bottle, heating reflux reaction overnight (react, solvent: V by TLC monitoring under nitrogen protectionPetroleum ether:VEthyl acetate=4:1), it is cooling, subtract
Pressure removes solvent, purifies (eluant, eluent: V with silica gel column chromatographyMethylene chloride:VEthyl acetate:VMethanol=9:3:1), obtain compound 6a.
Faint yellow solid 0.071g, yield 59%, m.p.49~51 DEG C,1H NMR(500MHz,CDCl3)δ:10.47(s,
1H, NH), 8.97 (s, 1H, ArH), 8.33 (d, J=8.6Hz, 1H, ArH), 7.97~7.93 (m, 2H, ArH), 7.90~7.87
(m, 1H, ArH), 7.66~7.63 (m, 1H, ArH), 7.49~7.45 (m, 1H, ArH), 7.41~7.35 (m, 2H, ArH),
4.00~3.96 (m, 2H, CH2), 2.52 (t, J=7.2Hz, 2H, CH2), 2.25 (d, J=3.1Hz, 6H, N (CH3)2),2.02
(dd, J=13.9,6.8Hz, 2H, CH2).13C NMR(125MHz,CDCl3)δ:167.5,152.7,152.1,151.0,
149.9,132.8,130.4,129.7,126.3,126.2,125.1,124.2,121.8,121.3,119.7,107.6,57.1,
47.4,45.6,29.1.HRMS(ESI+):C21H23N4S for[M+H]+,calculated 363.1643,found
363.1632.
Embodiment 38: the preparation of compound 6b.
Compound 3a is replaced with compound 3b, synthetic method obtains compound 6b with embodiment 37.
Faint yellow solid 0.088g, yield 73%, m.p.99~101 DEG C,1H NMR(500MHz,CDCl3)δ:10.25(s,
1H, NH), 8.91 (s, 1H, ArH), 8.05 (s, 1H, ArH), 7.94~7.93 (m, 1H, ArH), 7.88~7.84 (m, 2H,
), ArH 7.48~7.44 (m, 2H, ArH), 7.37~7.34 (m, 1H, ArH), 3.92 (dd, J=11.5,6.4Hz, 2H, CH2),
2.52~2.49 (m, 5H, CH2,CH3),2.24(s,6H,N(CH3)2), 2.00~1.95 (m, 2H, CH2).13C NMR
(125MHz,CDCl3)δ:167.6,152.8,151.9,150.3,148.3,133.8,132.9,132.3,129.5,126.3,
125.2,125.0,121.8,121.2,119.8,107.9,57.2,47.4,45.7,29.1,22.0.HRMS(ESI+):
C22H25N4S for[M+H]+,calculated 377.1800,found 377.1782.
Embodiment 39: the preparation of compound 6c.
Compound 3a is replaced with compound 3c, synthetic method obtains compound 6c with embodiment 37.
Faint yellow solid 0.1g, yield 83%, m.p.106~107 DEG C,1H NMR(500MHz,CDCl3)δ:10.42(s,
1H, NH), 8.94 (s, 1H, ArH), 8.22 (d, J=8.7Hz, 1H, ArH), 7.93 (d, J=8.0Hz, 1H, ArH), 7.88 (d,
J=8.0Hz, 1H, ArH), 7.73 (s, 1H, ArH), 7.48~7.45 (m, 1H, ArH), 7.39~7.33 (m, 1H, ArH),
7.21 (dd, J=8.7,1.6Hz, 1H, ArH), 3.98~3.95 (m, 2H, CH2), 2.53~2.50 (m, 5H, CH2,CH3),
2.25(s,6H,N(CH3)2), 2.02~1.99 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:167.7,152.8,
152.0,151.1,150.2,140.8,132.7,129.0,126.2,126.2,126.0,125.0,121.7,121.2,
117.5,107.3,57.1,47.2,45.6,29.1,21.6.HRMS(ESI+):C22H25N4S for[M+H]+,calculated
377.1800,found 377.1780.
Embodiment 40: the preparation of compound 6d.
Compound 3a is replaced with compound 3d, synthetic method obtains compound 6d with embodiment 37.
Yield 87%, yellow solid, m.p.109~111 DEG C；1H NMR(500MHz,CDCl3) δ: 10.28 (t, J=
4.4Hz, 1H, NH), 9.03 (s, 1H, ArH), 8.16 (d, J=8.1Hz, 1H, ArH), 7.96~7.91 (m, 1H, ArH), 7.90
~7.84 (m, 1H, ArH), 7.53~7.49 (m, 1H, ArH), 7.48~7.43 (m, 1H, ArH), 7.38~7.33 (m, 1H,
), ArH 7.30~7.26 (m, 1H, ArH), 3.93 (td, J=6.7,5.0Hz, 2H, CH2),2.75(s,3H,CH3),2.48(t,J
=7.2Hz, 2H, CH2),2.23(s,6H,CH3), 2.01~1.93 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:
167.7,152.9,152.7,149.9,148.9,137.2,133.0,130.9,126.4,125.1,124.2,123.8,
122.0,121.3,119.7,108.0,57.2,47.7,45.7,29.3,19.0.HRMS(ESI)m/z:calcd for
C22H25N4S,(M+H)+377.1800,found 377.1782.
Embodiment 41: the preparation of compound 6e.
Compound 3a is replaced with compound 3e, synthetic method obtains compound 6e with embodiment 37.
Faint yellow solid 0.075g, yield 63%, m.p.47~50 DEG C,1H NMR(500MHz,CDCl3)δ:10.06(s,
1H, NH), 8.88 (s, 1H, ArH), 7.96 (d, J=8.1Hz, 1H, ArH), 7.91~7.89 (m, 2H, ArH), 7.61 (d, J=
2.7Hz, 1H, ArH), 7.50~7.46 (m, 1H, ArH), 7.39~7.36 (m, 1H, ArH), 7.33 (dd, J=9.1,2.7Hz,
1H, ArH), 3.93~3.90 (m, 5H, CH2,OCH3), 2.52~2.49 (m, 2H, CH2),2.23(s,6H,N(CH3)2),2.00
~1.95 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:167.4,156.1,152.8,151.7,148.9,145.3,
133.0,131.0,126.3,125.1,121.9,121.3,120.7,113.9,108.6,105.9,57.1,55.6,47.1,
45.6,29.1.HRMS(ESI+):C22H25ON4S for[M+H]+,calculated 393.1749,found 393.1726.
Embodiment 42: the preparation of compound 6f.
Compound 3a is replaced with compound 3f, synthetic method obtains compound 6f with embodiment 37.
Yield 39%, faint yellow solid, m.p.195~198 DEG C；1H NMR(500MHz,CDCl3) δ: 10.47 (t, J=
4.3Hz, 1H, NH), 8.90 (s, 1H, ArH), 8.23 (d, J=9.4Hz, 1H, ArH), 7.92 (d, J=8.0Hz, 1H, ArH),
7.88 (d, J=7.6Hz, 1H, ArH), 7.49~7.44 (m, 1H, ArH), 7.39~7.34 (m, 1H, ArH), 7.31 (d, J=
2.7Hz, 1H, ArH), 7.02 (dd, J=9.3,2.7Hz, 1H, ArH), 3.98~3.93 (m, 5H, CH2), 2.57~2.53 (m,
2H,CH2),2.27(s,6H,CH3), 2.07~2.00 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:167.8,161.4,
152.8,152.2,152.1,151.2,132.7,127.7,126.4,125.1,121.8,121.4,116.4,114.0,
108.4,107.0,57.2,55.6,47.3,45.6,29.0.HRMS(ESI)m/z:calcd for C22H25N4OS,[M+H]+
393.1749 found 393.1732.
Embodiment 43: the preparation of compound 6g.
Compound 3a is replaced with compound 3g, synthetic method obtains compound 6g with embodiment 37.
Faint yellow solid 0.071g, yield 59%, m.p.124~125 DEG C,1H NMR(500MHz,CDCl3)δ:10.36
(s, 1H, NH), 8.93 (s, 1H, ArH), 7.99~7.89 (m, 4H, ArH), 7.49 (t, J=7.6Hz, 1H, ArH), 7.43~
7.37 (m, 2H, ArH), 3.92 (dd, J=11.6,6.3Hz, 2H, CH2), 2.53 (t, J=7.0Hz, 2H, CH2),2.26(s,
6H,N(CH3)2), 2.03~1.97 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:167.1,159.8,157.9,
152.7,151.5,150.4,146.8,132.9,131.9,126.4,125.3,122.0,121.3,119.9,110.3,
107.9,57.0,47.045.6,28.9.HRMS(ESI+):C21H22FN4S for[M+H]+,calculated 381.1549,
found 381.1532.
Embodiment 44: the preparation of compound 6h.
Compound 3a is replaced with compound 3h, synthetic method obtains compound 6h with embodiment 37.
Faint yellow solid 0.059g, yield 49%, m.p.61~63 DEG C,1H NMR(500MHz,CDCl3)δ:10.58(s,
1H, NH), 8.93 (s, 1H, ArH), 8.32 (dd, J=9.4,5.9Hz, 1H, ArH), 7.92 (d, J=8.0Hz, 1H, ArH),
7.87 (d, J=7.6Hz, 1H, ArH), 7.55 (dd, J=10.1,2.7Hz, 1H, ArH), 7.48~7.45 (m, 1H, ArH),
7.39~7.35 (m, 1H, ArH), 7.15~7.11 (m, 1H, ArH), 3.94 (dd, J=11.4,6.6Hz, 2H, CH2),2.53
(t, J=7.1Hz, 2H, CH2),2.25(s,6H,N(CH3)2), 2.04~1.99 (m, 2H, CH2).13C NMR(125MHz,
CDCl3)δ:167.3,164.5,162.5,152.6,152.0,151.9,132.6,128.6,126.4,125.2,121.8,
116.5,113.9,113.6,113.4,107.3,56.0,47.3,45.6,29.0.HRMS(ESI+):C21H22FN4S for[M+
H]+,calculated 381.1549,found 381.1531.
Embodiment 45: the preparation of compound 6i.
Compound 3a is replaced with compound 3i, synthetic method obtains compound 6i with embodiment 37.
Yield 40%, yellow solid, m.p.108~109 DEG C；1H NMR(600MHz,DMSO-d6) δ: 10.24 (t, J=
4.3Hz, 1H, NH), 8.88 (s, 1H, ArH), 8.19 (d, J=8.6Hz, 1H, ArH), 8.12 (d, J=7.9Hz, 1H, ArH),
7.99 (d, J=8.0Hz, 1H, ArH), 7.54 (dd, J=16.7,9.2Hz, 2H, ArH), 7.47~7.41 (m, 2H, ArH),
3.84 (dd, J=11.3,6.2Hz, 2H, CH2), 2.42 (t, J=6.9Hz, 2H, CH2),2.14(s,6H,CH3), 1.92~
1.85(m,2H,CH2).13C NMR(150MHz,DMSO-d6)δ:166.6,158.4,156.7,152.0,150.8,150.5,
139.3,132.3,126.7,125.5,124.1,122.9,121.9,120.9,114.9,107.3,56.1,46.4,45.0,
27.8.HRMS(ESI)m/z:calcd for C21H22FN4S,[M+H]+381.1550 found 381.1534.
Embodiment 46: the preparation of compound 6j.
Compound 3a is replaced with compound 3j, synthetic method obtains compound 6j with embodiment 37.
Faint yellow solid 0.079g, yield 66%, m.p.129~132 DEG C,1H NMR(500MHz,CDCl3)δ:10.42
(s, 1H, NH), 8.93 (s, 1H, ArH), 8.28 (d, J=2.2Hz, 1H, ArH), 7.95 (d, J=8.0Hz, 1H, ArH), 7.88
(t, J=8.8Hz, 2H, ArH), 7.56 (dd, J=8.9,2.2Hz, 1H, ArH), 7.49~7.47 (m, 1H, ArH), 7.40~
7.37 (m, 1H, ArH), 3.90 (dd, J=11.4,6.5Hz, 2H, CH2), 2.54 (t, J=7.0Hz, 2H, CH2),2.27(s,
6H,N(CH3)2), 2.03~1.97 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:167.0,152.6,151.2,
151.1,148.3,132.9,131.3,130.9,129.7,126.4,125.3,125.1,122.0,121.3,120.5,
108.1,77.3,77.1,76.8,57.0,47.1,45.6,28.8.HRMS (ESI+):C21H22ClN4S for[M+H]+,
calculated 397.1254,found 397.1239.
Embodiment 47: the preparation of compound 6k.
Compound 3a is replaced with compound 3k, synthetic method obtains compound 6k with embodiment 37.
Faint yellow solid 0.067g, yield 52%, mp.128~130 DEG C,1H NMR(500MHz,CDCl3)δ:10.54(s,
1H, NH), 8.94 (s, 1H, ArH), 8.24 (d, J=9.1Hz, 1H, ArH), 7.93~7.87 (m, 3H, ArH), 7.49~7.46
(m, 1H, ArH), 7.39~7.36 (m, 1H, ArH), 7.31 (dd, J=9.1,2.2Hz, 1H, ArH), 3.93 (dd, J=11.5,
6.6Hz,2H,CH2), 2.52 (t, J=7.1Hz, 2H, CH2),2.25(s,6H,N(CH3)2), 2.01 (dd, J=13.8,
6.8Hz,2H,CH2).13C NMR(125MHz,CDCl3)δ:167.2,152.6,151.8,150.7,136.2,132.7,
128.7,127.5,126.4,125.2,124.7,121.9,121.3,118.0,107.7,57.0,47.2,45.6,
29.0.HRMS(ESI+):C21H22ClN4S for[M+H]+,calculated 397.1254,found 397.1233.
Embodiment 48: the preparation of compound 6l.
Compound 3a is replaced with compound 3l, synthetic method obtains compound 6l with embodiment 37.
Faint yellow solid 0.097g, yield 81%, m.p.100~102 DEG C,1H NMR(500MHz,CDCl3)δ:10.51
(s, 1H, NH), 9.10 (s, 1H, ArH), 8.24 (dd, J=8.6,1.2Hz, 1H, ArH), 7.94 (d, J=8.1Hz, 1H,
), ArH 7.89 (d, J=7.9Hz, 1H, ArH), 7.76 (dd, J=7.5,1.2Hz, 1H, ArH), 7.49~7.46 (m, 1H,
), ArH 7.40~7.37 (m, 1H, ArH), 7.29 (dd, J=8.5,7.5Hz, 1H, ArH), 3.95~3.92 (m, 2H, CH2),
2.51 (t, J=7.1Hz, 2H, CH2),2.25(s,6H,N(CH3)2), 2.01~1.99 (m, 2H, CH2).13C NMR(125MHz,
CDCl3)δ:167.0,152.6,152.2,151.3,146.2,133.6,132.9,130.6,126.4,125.3,125.2,
123.7,122.0,121.3,121.1,108.2,57.0,47.5,45.6,29.0.HRMS(ESI+):C21H22ClN4S for[M+
H]+,calculated 397.1254,found 397.1240.
Embodiment 49: the preparation of compound 6m.
Compound 3a is replaced with compound 3m, synthetic method obtains compound 6m with embodiment 37.
Yield 52%, faint yellow solid, m.p.123~126 DEG C；1H NMR(500MHz,CDCl3) δ: 10.42 (t, J=
4.9Hz, 1H, NH), 8.95 (s, 1H, ArH), 8.45 (d, J=1.9Hz, 1H, ArH), 7.97 (d, J=8.1Hz, 1H, ArH),
7.90 (d, J=8.0Hz, 1H, ArH), 7.82 (d, J=8.8Hz, 1H, ArH), 7.72~7.68 (m, 1H, ArH), 7.52~
7.47 (m, 1H, ArH), 7.42~7.37 (m, 1H, ArH), 3.90 (dd, J=11.4,6.3Hz, 2H, CH2), 2.56 (t, J=
7.1Hz,2H,CH2), 2.28 (s, 6H, CH3), 2.04~1.98 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:167.1,
152.7,151.3,151.1,148.5,133.6,133.0,131.5,128.3,126.6,125.4,122.1,121.4,
121.1,117.8,108.2,57.1,47.2,45.5,28.6.HRMS(ESI)m/z:calcd for C21H22BrN4S,[M+H]+
441.0749 found 441.0732.
Embodiment 50: the preparation of compound 6n.
Compound 3a is replaced with compound 3n, synthetic method obtains compound 6n with embodiment 37.
Faint yellow solid 0.071g, yield 61%, m.p.241~244 DEG C,1H NMR(500MHz,DMSO-d6)δ:10.27
(s, 1H, NH), 8.87 (s, 1H, ArH), 8.38 (d, J=9.1Hz, 1H, ArH), 8.12 (dd, J=12.0,7.9Hz, 2H,
), ArH 8.02 (d, J=2.1Hz, 1H, ArH), 7.60~7.55 (m, 2H, ArH), 7.49~7.46 (m, 1H, ArH), 3.93
(dd, J=11.3,6.5Hz, 2H, CH2), 2.98 (t, J=7.3Hz, 2H, CH2),2.59(s,6H,N(CH3)2), 2.19~
2.13(m,2H,CH2).13C NMR(125MHz,DMSO-d6)δ:167.0,152.5,151.9,151.3,150.7,132.7,
131.5,128.8,127.8,127.2,126.0,124.5,122.5,122.3,118.4,107.5,60.2,55.3,46.2,
26.3.HRMS(ESI+):C21H22BrN4S for[M+H]+,calculated 441.0747,found 441.0730.
Embodiment 51: the preparation of compound 6o.
Compound 3a is replaced with compound 3o, synthetic method obtains compound 6o with embodiment 37.
Yield 98%, yellow solid, m.p.186~187 DEG C；1H NMR(600MHz,DMSO-d6) δ: 10.18 (t, J=
4.7Hz, 1H, NH), 8.97 (s, 1H, ArH), 8.43 (dd, J=8.5,1.0Hz, 1H, ArH), 8.16~8.13 (m, 1H,
), ArH 8.10~8.06 (m, 2H, ArH), 7.58~7.54 (m, 1H, ArH), 7.49~7.45 (m, 1H, ArH), 7.39~
7.35 (m, 1H, ArH), 3.87 (dd, J=11.6,6.6Hz, 2H, CH2), 2.75~2.67 (m, 2H, CH2),2.38(s,6H,
CH3), 2.06~2.00 (m, 2H, CH2).13C NMR (151MHz, DMSO-d6)δ:166.4,152.0,151.3,151.1,
146.0,134.3,132.5,126.8,126.1,125.6,124.9,124.4,122.0,121.9,120.5,107.6,55.3,
46.3,43.7,26.6.HRMS(ESI)m/z:calcd for C21H22BrN4S,[M+H]+441.0749 found
441.0735.
Embodiment 52: the preparation of compound 6r.
Compound 3a is replaced with compound 3r, synthetic method obtains compound 6r with embodiment 37.
Yield 64%, yellow solid, m.p.160~162 DEG C；1H NMR(500MHz,CDCl3) δ: 10.45 (t, J=
4.2Hz, 1H, NH), 8.90 (s, 1H, ArH), 8.06 (d, J=11.2Hz, 1H, ArH), 7.98 (d, J=7.5Hz, 1H, ArH),
7.93 (d, J=8.1Hz, 1H, ArH), 7.89~7.87 (m, 1H, ArH), 7.50~7.46 (m, 1H, ArH), 7.40~7.37
(m, 1H, ArH), 3.92~3.86 (m, 2H, CH2), 2.53 (t, J=7.0Hz, 2H, CH2),2.26(s,6H,CH3), 2.03~
1.97(m,2H,CH2).13C NMR(125MHz,CDCl3)δ:167.0,155.2,153.3,152.7,151.4,151.3,
147.2,132.9,131.3,126.6,125.5,122.1,121.4,111.7,111.5,108.0,57.0,46.9,45.7,
28.9.HRMS(ESI)m/z:calcd for C21H21ClFN4S, [M+H]+415.1160 found 415.1141.
Embodiment 53: the preparation of compound 7a.
Compound 3a is replaced with compound 4a, synthetic method obtains compound 7a with embodiment 37.
Light brown solid 0.052g, yield 42%, m.p.84~85 DEG C,1H NMR(500MHz,CDCl3)δ:9.77(s,
1H, NH), 9.29 (s, 1H, ArH), 8.32 (dd, J=8.6,0.8Hz, 1H, ArH), 7.97 (dd, J=8.4,1.1Hz, 1H,
), ArH 7.68~7.59 (m, 3H, ArH), 7.41~7.32 (m, 3H, ArH), 4.00 (dd, J=11.6,6.7Hz, 2H, CH2),
2.55 (t, J=7.2Hz, 2H, CH2),2.28(s,6H,N(CH3)2), 2.08~2.01 (m, 2H, CH2).13C NMR(125MHz,
CDCl3)δ:168.8,162.6,156.8,153.1,151.6,150.8,149.2,141.0,131.1,130.6,129.8,
126.1,124.9,119.5,110.4,102.6,56.9,56.9,47.2,28.9.HRMS(ESI+):C21H23ON4for[M+H
]+,calculated 347.1872,found 347.1856.
Embodiment 54: the preparation of compound 7b.
Compound 3a is replaced with compound 4b, synthetic method obtains compound 7b with embodiment 37.
Faint yellow solid 0.039g, yield 35%, m.p.180~183 DEG C,1H NMR(500MHz,CDCl3)δ:9.05(s,
1H, NH), 8.63 (s, 1H, ArH), 8.01 (d, J=8.0Hz, 1H, ArH), 7.77 (d, J=8.5Hz, 1H, ArH), 7.64 (s,
1H, ArH), 7.42 (d, J=8.5Hz, 1H, ArH), 6.99 (d, J=4.1Hz, 2H, ArH), 6.87~6.85 (m, 1H, ArH),
3.62 (t, J=6.0Hz, 2H, CH2), 2.57 (t, J=6.0Hz, 2H, CH2),2.47(s,3H,CH3),2.34(s,6H,N
(CH3)2), 1.85~1.83 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:167.0,152.1,147.9,145.4,
134.9,132.6,129.7,127.3,125.3,123.2,122.3,120.9,119.8,118.9,116.8,108.9,58.5,
58.4,47.7,26.1,21.9.HRMS(ESI+):C22H25ON4for[M+H]+,calculated 361.20284,found
361.20105.
Embodiment 55: the preparation of compound 7c.
Compound 3a is replaced with compound 4c, synthetic method obtains compound 7c with embodiment 37.
Faint yellow solid 0.052g, yield 57%, m.p.105~107 DEG C,1H NMR(500MHz,CDCl3)δ:9.08(s,
1H, NH), 8.64 (s, 1H, ArH), 8.01 (d, J=7.9Hz, 1H, ArH), 7.78 (d, J=8.5Hz, 1H, ArH), 7.64 (s,
1H, ArH), 7.43 (d, J=8.5Hz, 1H, ArH), 6.99 (d, J=4.0Hz, 2H, ArH), 6.88~6.85 (m, 1H, ArH),
3.62 (t, J=6.0Hz, 2H, CH2), 2.59~2.57 (m, 2H, CH2),2.47(s,3H,CH3),2.35(s,6H,N(CH3)2),
1.85~1.83 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:167.0,152.0,147.9,147.8,135.0,
132.6,127.3,127.1,125.4,122.2,120.9,119.8,116.9,108.9,58.6,47.7,45.4,29.7,
22.0.HRMS(ESI+):C22H25ON4for[M+H]+,calculated 361.2028,found 361.2017.
Embodiment 56: the preparation of compound 7d.
Compound 3a is replaced with compound 4d, synthetic method obtains compound 7d with embodiment 37.
Yield 39%, faint yellow solid, m.p.89~92 DEG C；1H NMR(500MHz,CDCl3) δ 9.61 (t, J=4.2Hz,
1H, NH), 9.35 (s, 1H, ArH), 8.17 (d, J=8.5Hz, 1H, ArH), 7.70~7.66 (m, 1H, ArH), 7.63~7.59
(m, 1H, ArH), 7.55~7.51 (m, 1H, ArH), 7.37~7.32 (m, 2H, ArH), 7.31~7.27 (m, 1H, ArH),
4.00~3.93 (m, 2H, CH2),2.77(s,3H,CH3), 2.51 (t, J=7.2Hz, 2H, CH2), 2.26 (s, 6H, CH3),
2.04~1.97 (m, 2H, CH2).13C NMR (125MHz, CDCl3) δ: 162.9,153.9,149.4,149.2,148.3,
141.2,137.4,131.1,124.9,124.6,124.0,123.8,119.4,119.0,110.6,101.4,57.2,47.7,
45.7,29.3,19.1.HRMS(ESI)m/z:calcd forC22H25N4O,[M+H]+361.2028 found 361.2010.
Embodiment 57: the preparation of compound 7e.
Compound 3a is replaced with compound 4e, synthetic method obtains compound 7e with embodiment 37.
Light brown solid, yield 32%, m.p.52~54 DEG C,1H NMR(500MHz,CDCl3)δ:9.47(s,1H,NH),
9.22 (s, 1H, ArH), 7.93 (d, J=9.1Hz, 1H, ArH), 7.71~7.69 (m, 1H, ArH), 7.62~7.61 (m, 2H,
), ArH 7.38~7.34 (m, 3H, ArH), 3.98 (dd, J=11.8,6.5Hz, 2H, CH2),3.94(s,3H,OCH3),2.57
(t, J=7.3Hz, 2H, CH2),2.30(s,6H,N(CH3)2), 2.08~2.01 (m, 2H, CH2).13C NMR(125MHz,
CDCl3)δ:163.0,161.5,153.1,152.7,149.8,149.1,141.2,127.5,124.9,124.6,118.9,
116.3,113.8,110.5,108.6,100.3,60.7,57.0,55.6,47.0,45.53.HRMS(ESI+):
C22H25N4O2for[M+H]+,calculated 377.1978,found 377.1959.
Embodiment 58: the preparation of compound 7f.
Compound 3a is replaced with compound 4f, synthetic method obtains compound 7f with embodiment 37.
Yield 55%, faint yellow solid, m.p.141~142 DEG C；1H NMR(500MHz,CDCl3) δ: 9.74 (t, J=
4.7Hz, 1H, NH), 9.23 (s, 1H, ArH), 8.24 (d, J=9.4Hz, 1H, ArH), 7.69~7.64 (m, 1H, ArH), 7.61
~7.57 (m, 1H, ArH), 7.37~7.31 (m, 3H, ArH), 7.02 (dd, J=9.3,2.7Hz, 1H, ArH), 4.01~3.93
(m,3H,OCH3), 2.55 (t, J=7.2Hz, 2H, CH2),2.28(s,6H,CH3), 2.08~2.01 (m, 2H, CH2).13C NMR
(125MHz,CDCl3)δ:163.0,161.5,153.1,152.7,149.8,149.1,141.2,127.5,124.9,124.6,
118.9,116.3,113.8,110.5,108.6,100.3,57.1,55.6,47.2,45.7,29.0.HRMS(ESI)m/z:
calcd for C22H25N4O2,[M+H]+377.1978 found 377.1960.
Embodiment 59: the preparation of compound 7g.
Compound 3a is replaced with compound 4g, synthetic method obtains compound 7g with embodiment 37.
White solid 0.068g, yield 57%, m.p.124~127 DEG C,1H NMR(500MHz,CDCl3)δ:9.70(s,
1H, NH), 9.26 (s, 1H, ArH), 7.99~7.95 (m, 2H, ArH), 7.69~7.67 (m, 1H, ArH), 7.61~7.60 (m,
1H, ArH), 7.44~7.40 (m, 1H, ArH), 7.37~7.35 (m, 2H, ArH), 3.97~3.95 (m, 2H, CH2),2.56
(t, J=7.1Hz, 2H, CH2),2.29(s,6H,N(CH3)2), 2.07~2.02 (m, 2H, CH2).13C NMR(125MHz,
CDCl3)δ:162.4,159.8,157.8,152.5,152.5,149.3,148.8,147.3,140.9,132.2,125.1,
124.6,120.2,119.0,110.5,101.3,56.9,46.7,45.6,28.8.HRMS(ESI+):C21H22FON4for[M+H
]+,calculated 365.1778,found 365.1759.
Embodiment 60: the preparation of compound 7h.
Compound 3a is replaced with compound 4h, synthetic method obtains compound 7h with embodiment 37.
White solid 0.068g, yield 57%, m.p.143~146 DEG C,1H NMR(500MHz,CDCl3)δ:9.86(s,
1H, NH), 9.27 (s, 1H, ArH), 8.34 (dd, J=9.4,6.0Hz, 1H, ArH), 7.68~7.66 (m, 1H, ArH), 7.61
~7.57 (m, 2H, ArH), 7.37~7.34 (m, 2H, ArH), 7.17~7.13 (m, 1H, ArH), 3.99~3.96 (m, 2H,
CH2), 2.56 (t, J=7.1Hz, 2H, CH2),2.29(s,6H,N(CH3)2), 2.08~2.03 (m, 2H, CH2).13C NMR
(125MHz, CDCl3) δ: 164.6,162.6,162.5,152.9,152.3,150.3,148.9,140.9,128.4,125.0,
124.6,118.9,116.2,113.9,110.5,100.7,56.9,47.2,45.6,28.9.HRMS (ESI+):
C21H22FON4for[M+H]+,calculated 365.1778,found 365.1763.
Embodiment 61: the preparation of compound 7i.
Compound 3a is replaced with compound 4i, synthetic method obtains compound 7i with embodiment 37.
Faint yellow solid, yield 83%, m.p.136~137 DEG C；1H NMR(500MHz,CDCl3) δ: 9.86 (t, J=
4.0Hz, 1H, NH), 9.31 (s, 1H, ArH), 8.09 (d, J=8.5Hz, 1H, ArH), 7.70~7.63 (m, 1H, ArH), 7.63
~7.54 (m, 1H, ArH), 7.37~7.26 (m, 4H, ArH), 3.97 (dd, J=11.6,6.6Hz, 2H, CH2),2.53(t,J
=7.1Hz, 2H, CH2),2.27(s,6H,CH3), 2.06~1.99 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:
162.4,159.4,157.4,152.7,149.5,149.1,140.9,125.2,124.7,123.6,121.7,119.0,
115.0,114.8,110.6,101.6,57.0,47.2,45.7,29.0.HRMS(ESI)m/z:calcd for C21H22FN4O,
[M+H]+365.1778 found 365.1760.
Embodiment 62: the preparation of compound 7j.
Compound 3a is replaced with compound 4j, synthetic method obtains compound 7j with embodiment 37.
Faint yellow solid 0.043g, yield 36%, m.p.124~126 DEG C,1H NMR(500MHz,CDCl3)δ:9.79(s,
1H), 9.26 (s, 1H, NH), 8.30 (d, J=2.2Hz, 1H, ArH), 7.90 (d, J=8.9Hz, 1H, ArH), 7.70~7.67
(m, J=6.8,1H, ArH), 7.62~7.57 (m, 2H, ArH), 7.38~7.34 (m, 2H, ArH), 3.96 (dd, J=11.5,
6.5Hz,2H,CH2), 2.58 (t, J=7.2Hz, 2H, CH2),2.30(s,6H,N(CH3)2), 2.08~2.02 (m, 2H, CH2)
.13C NMR(125MHz,CDCl3)δ:168.5,162.2,152.2,149.4,149.0,148.6,140.9,131.5,129.7,
125.2,124.9,124.7,120.1,119.0,110.5,101.5,60.8,56.9,47.1,28.7.HRMS (ESI+):
C21H22ClON4for[M+H]+,calculated 381.1482,found 381.1465.
Embodiment 63: the preparation of compound 7k.
Compound 3a is replaced with compound 4k, synthetic method obtains compound 7k with embodiment 37.
Faint yellow solid 0.079g, yield 62%, m.p.139~141 DEG C,1H NMR(500MHz,CDCl3)δ:9.85(s,
1H, NH), 9.28 (s, 1H, ArH), 8.26 (d, J=9.1Hz, 1H, ArH), 7.94 (d, J=2.2Hz, 1H, ArH), 7.67
(dd, J=6.1,3.0Hz, 1H, ArH), 7.61~7.59 (m, 1H, ArH), 7.37~7.31 (m, 3H, ArH), 3.97 (dd, J
=11.6,6.7Hz, 2H, CH2), 2.56 (t, J=7.1Hz, 2H, CH2),2.29(s,6H,N(CH3)2), 2.05 (dd, J=
9.5,4.5Hz,2H,CH2).13C NMR(125MHz,CDCl3)δ:162.3,152.8,151.2,150.2,149.0,140.9,
136.5,128.9,127.4,125.1,124.8,124.6,118.9,117.7,110.5,101.1,56.8,47.1,45.6,
28.8.HRMS(ESI+):C21H22ClON4for[M+H]+,calculated 381.1482,found 381.1471.
Embodiment 64: the preparation of compound 7l.
Compound 3a is replaced with compound 4l, synthetic method obtains compound 7l with embodiment 37.
Light brown solid 0.052g, yield 43%, m.p.81~83 DEG C,1H NMR (500MHz, CDCl3) δ: 9.84 (s,
1H, NH), 9.41 (s, 1H, ArH), 8.25 (dd, J=8.6,1.1Hz, 1H, ArH), 7.79 (dd, J=7.5,1.2Hz, 1H,
ArH), 7.70~7.68 (m, 1H, ArH), 7.63~7.61 (m, 1H, ArH), 7.39~7.35 (m, 2H, ArH), 7.32~
7.29 (m, 1H, ArH), 3.98 (dd, J=11.6,6.6Hz, 2H, CH2), 2.57 (t, J=7.1Hz, 2H, CH2),2.30(s,
6H,N(CH3)2), 2.08~2.03 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:162.1,153.3,152.2,
149.7,149.0,146.6,140.8,133.7,131.3,125.2,124.7,123.7,120.7,119.0,110.6,
101.8,60.9,56.8,47.4,28.8.HRMS(ESI+):C21H22ClON4for[M+H]+,calculated 381.1482,
found 381.1465.
Embodiment 65: the preparation of compound 7m.
Compound 3a is replaced with compound 4m, synthetic method obtains compound 7m with embodiment 37.
Yield 65%, faint yellow solid, m.p.143~146 DEG C；1H NMR(500MHz,CDCl3) δ: 9.75 (t, J=
3.9Hz, 1H, NH), 9.26 (s, 1H, ArH), 8.45 (d, J=2.0Hz, 1H, ArH), 7.82 (d, J=8.9Hz, 1H, ArH),
7.73~7.65 (m, 2H, ArH), 7.62~7.57 (m, 1H, ArH), 7.39~7.32 (m, 2H, ArH), 3.96~3.90 (m,
2H,CH2), 2.55 (t, J=7.1Hz, 2H, CH2),2.29(s,6H,CH3), 2.06~1.98 (m, 2H, CH2).13C NMR
(125MHz,CDCl3)δ:162.4,152.2,149.8,149.2,149.1,141.0,133.7,131.8,128.2,125.2,
124.8,120.8,119.1,117.7,110.6,101.7,57.0,47.1,45.7,28.9.HRMS(ESI)m/z:calcd
for C21H22BrN4O,[M+H]+425.0977 found 425.0967.
Embodiment 66: the preparation of compound 7n.
Compound 3a is replaced with compound 4n, synthetic method obtains compound 7n with embodiment 37.
Faint yellow solid 0.084g, yield 71%, m.p.129~131 DEG C,1H NMR(500MHz,CDCl3)δ:9.82(s,
1H, NH), 9.25 (s, 1H, ArH), 8.16 (d, J=9.1Hz, 1H, ArH), 8.12 (d, J=2.1Hz, 1H, ArH), 7.67~
7.65 (m, 1H, ArH), 7.59~7.58 (m, 1H, ArH), 7.44 (dd, J=9.1,2.1Hz, 1H, ArH), 7.35~7.33
(m, 2H, ArH), 3.95 (dd, J=11.6,6.7Hz, 2H, CH2), 2.56 (t, J=7.2Hz, 2H, CH2),2.29(s,6H,N
(CH3)2), 2.04 (dd, J=13.5,6.5Hz, 2H, CH2).13C NMR(125MHz,CDCl3)δ:162.3,152.8,151.2,
150.1,149.0,140.8,132.1,127.4,127.3,125.1,124.9,124.6,118.9,118.0,110.5,
101.1,56.8,47.0,45.5,28.8.HRMS(ESI+):C21H22BrON4for[M+H]+,calculated 425.0977,
found 425.0953.
Embodiment 67: the preparation of compound 7o.
Compound 3a is replaced with compound 4o, synthetic method obtains compound 7o with embodiment 37.
Faint yellow solid, yield 45%, m.p.179~181 DEG C；1H NMR(600MHz,DMSO-d6) δ: 10.18 (t, J=
4.3Hz, 1H, NH), 8.96 (s, 1H, ArH), 8.43 (d, J=8.5Hz, 1H, ArH), 8.14 (d, J=7.9Hz, 1H, ArH),
8.10~8.05 (m, 1H, ArH), 7.56 (t, J=7.6Hz, 1H, ArH), 7.47 (t, J=7.6Hz, 1H), 7.37 (t, J=
8.0Hz, 1H, ArH), 3.87 (dd, J=11.4,6.3Hz, 2H, CH2), 2.74~2.66 (m, 2H, CH2),2.36(s,6H,
CH3), 2.05~1.99 (m, 2H, CH2).13C NMR(150MHz,DMSO-d6)δ:166.4,152.0,151.3,151.1,
145.9,134.3,132.5,126.7,126.1,125.6,124.9,124.4,122.0,121.9,120.5,107.6,55.4,
46.3,43.8,26.7.HRMS(ESI)m/z:calcd for C21H22BrN4O,[M+H]+425.0977 found
425.0960.
Embodiment 68: the preparation of compound 7p.
Compound 3a is replaced with compound 4p, synthetic method obtains compound 7p with embodiment 37.
Yellow solid, yield 31%, m.p.128~131 DEG C；1H NMR(500MHz,CDCl3) δ: 9.61 (t, J=
4.1Hz, 1H, NH), 9.21 (s, 1H, ArH), 8.03 (s, 1H, ArH), 7.72 (s, 1H, ArH), 7.68~7.63 (m, 1H,
), ArH 7.61~7.55 (m, 1H, ArH), 7.36~7.29 (m, 2H, ArH), 4.01~3.92 (m, 2H, CH2),2.53(t,J
=7.2Hz, 2H, CH2),2.41(s,6H,CH3),2.28(s,6H,CH3), 2.05~1.97 (m, 2H, CH2).13C NMR
(125MHz,CDCl3)δ:163.0,152.9,149.4,149.1,148.7,141.2,140.9,133.7,129.6,125.5,
124.8,124.5,118.9,117.8,110.4,100.8,57.2,47.2,45.8,29.1,20.5,20.3.HRMS(ESI)m/
z:calcd for C23H27N4O,[M+H]+375.2185 found 375.2167.
Embodiment 69: the preparation of compound 7q.
Compound 3a is replaced with compound 4q, synthetic method obtains compound 7q with embodiment 37.
Yield 48%, pale solid, m.p.113~117 DEG C；1H NMR(500MHz,CDCl3) δ: 9.39 (t, J=
4.8Hz, 1H, NH), 9.18 (s, 1H, ArH), 7.69~7.64 (m, 1H, ArH), 7.62~7.58 (m, 1H, ArH), 7.55 (s,
1H, ArH), 7.39 (s, 1H, ArH), 7.37~7.31 (m, 2H, ArH), 4.03 (s, 3H, OCH3),4.01(s,3H,OCH3),
3.98~3.93 (m, 2H, CH2), 2.65~2.59 (m, 2H, CH2),2.31(s,6H,CH3), 2.09~2.03 (m, 2H, CH2)
.13C NMR(125MHz,CDCl3)δ:162.8,153.1,152.7,149.1,147.7,147.5,147.3,141.2,125.0,
124.7,118.9,113.8,110.6,108.8,104.9,101.6,56.7,56.3,56.2,46.9,45.1,28.7.HRMS
(ESI)m/z:calcd for C23H27N4O3,[M+H]+407.2083 found 407.2064.
Embodiment 70: the preparation of compound 7r.
Compound 3a is replaced with compound 4r, synthetic method obtains compound 7r with embodiment 37.
Faint yellow solid, yield 51%, m.p.160~162 DEG C；1H NMR(500MHz,CDCl3) δ: 9.83~9.70 (m,
1H, NH), 9.22 (s, 1H, ArH), 8.08 (d, J=11.2Hz, 1H, ArH), 8.01 (d, J=7.3Hz, 1H, ArH), 7.68~
7.55 (m, 2H, ArH), 7.40~7.30 (m, 2H, ArH), 3.98~3.87 (m, 2H, CH2), 2.55 (t, J=6.6Hz, 2H,
CH2),2.29(s,6H,CH3), 2.07~2.00 (m, 2H, CH2).13C NMR(125MHz,CDCl3)δ:162.2,155.2,
153.2,152.3,149.7,149.1,147.6,140.9,131.4,125.3,124.8,119.1,111.6,111.4,
110.6,101.4,56.9,46.8,45.7,28.9.HRMS(ESI)m/z:calcd for C21H21ClFN4O,[M+H]+
399.1388 found 399.1372.
Embodiment 71: the preparation of compound 8b.
Compound 3a is replaced with compound 5b, synthetic method obtains compound 8b with embodiment 37.
White solid 0.060g. yield 50%, m.p.249~252 DEG C,1H NMR(500MHz,DMSO-d6)δ:10.22
(s, 1H, NH), 9.12 (s, 1H, ArH), 8.15 (s, 1H, ArH), 7.80 (d, J=8.5Hz, 1H, ArH), 7.66 (s, 2H,
), ArH 7.55 (dd, J=8.5,1.6Hz, 1H, ArH), 7.31~7.21 (m, 2H, ArH), 3.87 (t, J=6.6Hz, 2H,
CH2), 2.98~2.91 (m, 2H, CH2),2.54(s,9H,CH3,N(CH3)2), 2.13~2.03 (m, 2H, CH2).HRMS(ESI+):C22H26N5for[M+H]+,calculated 360.21882,found 360.21715.
Embodiment 72: the preparation of compound 8n.
Compound 3a is replaced with compound 5n, synthetic method obtains compound 8n with embodiment 37.
Faint yellow solid 0.043g, yield 35%.1H NMR(500MHz,DMSO-d6) δ: 13.35 (d, J=73.9Hz,
1H, NH), 10.57 (s, 1H, NH), 9.21 (s, 1H, ArH), 8.36 (d, J=9.1Hz, 1H, ArH), 8.06 (s, 1H, ArH),
7.66 (s, 2H, ArH), 7.58 (d, J=9.0Hz, 1H, ArH), 7.31~7.23 (m, 2H, ArH), 3.90 (s, 2H, CH2),
2.97 (d, J=6.7Hz, 2H, CH2),2.56(s,6H,N(CH3)2), 2.17~2.08 (m, 2H, CH2).HRMS(ESI+):
C21H23N5Br for[M+H]+,calculated 424.11368,found 424.11159.
Embodiment 73: test cell and step.
(1) cultivate subject cell HepG2 (liver cancer cells), T-24 (bladder cancer cell), MGC-803 (stomach cancer cell),
It is carried out after A549 (lung carcinoma cell), NCI-H460 (lung carcinoma cell), HL-7702 (liver cell) to logarithmic growth phase with trypsase
Then digestion is made into single cell suspension with the culture solution containing 10% fetal calf serum and is inoculated into 96 orifice plates, is placed in 5%CO2, 37 DEG C thin
It is cultivated in born of the same parents' 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, cultivate 48h in 37 DEG C of cell incubators.
(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 1:
IC of 1 target compound of table to different cell strains50(μM)
As seen from the above table, with 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline derivatives of general formula I
Object, have well external anti-weight activity in anti-cancer agent research and development with good application prospect.
Claims (10)
1. 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline with general formula (I):
(Ⅰ)
Wherein: Y is S, O or NH；R1It is F atom, Cl atom, Br atom, alkyl, alkoxy, trifluoromethyl, nitro or hydroxyl respectively
Base.
2. the preparation method of 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline with general formula (I),
Characterized by the following steps:
S1. compound 1 is added into container, compound 2And diphenyl ether, nitrogen/
Under inert gas shielding, heating reflux reaction is cooled to room temperature after reaction, and a large amount of solids are precipitated, and is filtered, and is washed, dry,
It obtains；
S2. will、POCl3It is added in container, heating reflux reaction, it is cooling, it removes most of
POCl3, product is poured into ice water, pH to 8 ~ 9 is adjusted, is filtered, is washed, drying, column Chromatographic purification obtains faint yellow solid；By institute
Faint yellow solid, N are stated, N dimethyl propane diamine, dimethylbenzene are added in container, under nitrogen/inert gas shielding, are heated back
Stream reaction, it is after reaction, cooling, solvent is removed, column Chromatographic purification obtains。
3. preparation method according to claim 2, it is characterised in that:
In the step S1, the temperature of back flow reaction is 210 ~ 230 DEG C, and the reaction time is 1.8 ~ 2.5h.
4. preparation method according to claim 2, it is characterised in that:
In the step S1, when washing, petroleum ether is first used, then washed with methylene chloride.
5. preparation method according to claim 2, it is characterised in that:
In the step S2,And POCl3The time of heating reflux reaction is 4.5 ~ 6h.
6. preparation method according to claim 2, it is characterised in that:
In the step S2, when washing, washed with water.
7. there is 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of the 3- dimethylamine) quinoline of general formula (I) and pharmaceutically may be used
The pharmaceutical composition of the auxiliary material composition of receiving.
8. 3- (the benzo five-membered heterocycle of 2-) -4- (the third amino of 3- dimethylamine) quinoline with general formula (I) is prepared into medicament
Acceptable dosage form on.
9. derivative described in claim 1 or pharmaceutical composition as claimed in claim 7 answering in the preparation of antitumor drugs
With.
10. application as claimed in claim 9, it is characterised in that: the tumour includes human liver cancer tumour, human gastric cancer tumour, people
Bladder tumor, human lung cancer tumour.
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|---|---|---|---|---|
| CN103153063A (en) * | 2010-07-30 | 2013-06-12 | 肿瘤疗法科学股份有限公司 | Quinoline derivatives and MELK inhibitors containing the same |
| CN108516973A (en) * | 2018-03-30 | 2018-09-11 | 广西师范大学 | 3- benzothiazoles -1- (3- dimethylaminos) propyl quinoline -4- ketone derivatives and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103153063A (en) * | 2010-07-30 | 2013-06-12 | 肿瘤疗法科学股份有限公司 | Quinoline derivatives and MELK inhibitors containing the same |
| CN108516973A (en) * | 2018-03-30 | 2018-09-11 | 广西师范大学 | 3- benzothiazoles -1- (3- dimethylaminos) propyl quinoline -4- ketone derivatives and its preparation method and application |
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|---|---|---|---|---|
| CN114409632A (en) * | 2022-02-22 | 2022-04-29 | 广西师范大学 | 2-substituted amino-3-benzimidazole substituted quinoline derivative and preparation method and application thereof |
| CN114409632B (en) * | 2022-02-22 | 2024-04-30 | 北京鲲达宇科技有限公司 | 2-Substituted amino-3-benzimidazole substituted quinoline derivative, and preparation method and application thereof |
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