CN102250022A - Substituted quinoxalinamine compounds, and preparation method and application thereof - Google Patents
Substituted quinoxalinamine compounds, and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides N-substituted-3-substituted quinoxaline-2-amine compounds. Quinoxaline compounds are taken as precursors, different substituted amino groups and aryl groups are introduced into the second positions and the third positions of parent nuclei of quinoxalines, and the N-substituted-3-substituted quinoxaline-2-amine compounds are synthesized. Pharmacological tests prove that the compounds and salts thereof have obvious activity of inhibiting tumor cells in vitro, and the IC50 reaches the mu M level; and the pharmacological tests indicate that the antitumor activity of the compounds is related with the inhibition of the compounds on a PI3K/Akt signal path. The design is reasonable, the preparation method is simple and convenient and suitable for practice, and the compounds can be applied to preparation of antitumor medicines. The structural general formula of the compounds is shown as the specifications.
Description
Technical field
The invention belongs to compound, relate to a class
N-replacement-3-substituted quinoxaline-2-aminated compounds and its production and use.
Background technology
Along with the continuous increase of global population and the continuous intensification of aging population trend, also because comprise the extensive existence of the various unhealthy life styles of smoking, tumour has become developed country and has threatened the No.1 killer of human health and developing country to threaten No. second killer of human health simultaneously.（A.?Jemal,?et?al.,?CA?Cancer?J.?Clin.,?2011,?61,?69-90）。Except traditional chemotherapeutic agent such as alkylating agent, metabolic antagonist etc., the antitumor drug that designs at the crucial kinases in the signal path or albumen is just being obtained the effect that the neighbour inspires in the oncotherapy field.From early stage Gleevec, Iressa, Tarceva is to Torisel, Tasigna, the Votrient of listing in recent years, these at the antitumor drug of target spot not only reduced medicine toxicity, improved therapeutic index, and might realize individualized treatment.Therefore development of new with crucial kinases on the signal path or albumen be the antitumor drug of action target spot more and more be subjected to people's attention (W. W. Ma, et al., CA Cancer J. Clin., 2009,59,111-137).
W. Bajjalieh, et al. has reported that a class has antitumor action 2, the dibasic quinoxaline compound of 3-, pharmacologically active shows that this compounds is by suppressing the critical sites on the PI3K signal path, as PI3K, mTOR, thereby (WO 2007/044729 A2) of generation anti-tumor activity.D. T. Aftab, et al have reported the method (WO 2008/021389 A2) that this class quinoxaline PI3K inhibitor and other mek inhibitors are used for oncotherapy of share.Structure activity study shows that the hydrogen bond action that forms between nitrogen, Sauerstoffatom and the corresponding acceptor that nitrogen-atoms on the quinoxaline parent nucleus and molecule two or three-digit exist is to the active vital role that maintains of such Compound P I3K inhibition.Representation compound XL-765 in such quinoxaline PI3K inhibitor and XL-147 are owing to its significant active and good pharmacokinetic property, and this is carrying out various clinical studyes as antitumor drug.
Summary of the invention
The purpose of this invention is to provide a class
N-replacement-3-substituted quinoxaline-2-aminated compounds and salt thereof has following general structure:
Wherein:
R
1Be hydrogen atom or C
1~ C
6Alkoxyl group, be preferably methoxyl group;
R
2Be selected from hydrogen atom, C
1~ C
6Alkyl, C
1~ C
6Alkoxyl group, halogen, nitro, amido, amide group;
R
3And R
4Difference, the phenyl that is selected from hydrogen atom, cyclohexyl, phenyl, replaces by fluorine atom, amino, trifluoromethyl, hydroxyl, perhaps R
3, R
4Form morpholine ring, pyrrolidine ring, pyridine ring, tetrahydroisoquinoline ring, piperazine ring, 3 or 4-methylpiperazine ring, 3 or 4-hydroxy piperidine ring, 4-ethanoyl piperazine, piperidines-4-acid amides ring with nitrogen-atoms;
X is selected from-SO
2-or-NH-NH-SO
2-.
Typical compound of the present invention comprises following compound or their pharmacy acceptable salts, but is not limited to these:
3-(3-(benzene sulfonyl) quinoline-2-base ammonia) phenol (IVa21)
3-(3-(4-bromobenzene sulphonyl) quinoline-2-base ammonia) phenol (IVa23)
3-(4-bromobenzene sulphonyl)-N-cyclohexyl quinoxaline-2-amine (IVa27)
N-cyclohexyl-3-(4-is to the methoxy benzene sulfonyl) quinoxaline-2-amine (IVa28)
N-(4-methoxyphenyl)-3-(4-oil of mirbane sulphonyl) quinoxaline-2-amine (IVa29)
N-(3, the 5-dimethoxy phenyl)-3-(4-oil of mirbane sulphonyl) quinoxaline-2-amine (IVa30)
N
1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) benzene-1,4-diamines (IVa32)
N
1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) benzene-1,3-diamines (IVa33)
3-(4-fluorobenzene sulphonyl)-N-(4-methoxyphenyl) quinoxaline-2-amine (IVa34)
2-(4-methylpiperazine-1-yl)-3-tolysulfonyl quinoxaline (IVa40)
1-(3-(benzenesulfonyl) quinoxaline-2-yl) piperidines-3-alcohol (IVa47)
1-(3-(4-p-toluenesulfonyl) quinoxaline-2-yl) piperidines-3-alcohol (IVa50)
2-(piperazine-1-yl)-3-tolysulfonyl quinoxaline (IVa60)
2-(the 4-methoxy benzene sulfonyl)-3-(quinoxaline (IVa62) of piperazine-1-yl)
4-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) morpholine (IVa67)
2-(4-methylpiperazine-1-yl)-3-(4-oil of mirbane sulphonyl) quinoxaline (IVa68)
1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) piperidines-3-alcohol (IVa73)
2-(4-fluorobenzene sulphonyl)-3-(piperidines-1-yl) quinoxaline (IVa76)
2-(4-fluorobenzene sulphonyl)-3-(tetramethyleneimine-1-yl) quinoxaline (IVa77)
6-methoxyl group-3-(4-methylpiperazine-1-yl)-2-is to methoxy benzenesulfonyl quinoxaline (IVa87)
1-(4-(7-methoxyl group-3-is to methoxy benzene sulfonyl quinoxaline-2-yl) piperazine-1 base) ethyl ketone (IVa88)
N'-(3-(3, the 5-dimethoxyaniline) quinoxaline-2-yl)-4-Methyl benzenesulfonyl hydrazine (IVb1)
Another object of the present invention provides the preparation method of above-mentioned target compound, realizes by following steps: 2, and 3-dichloro-quinoxaline compounds
IWith the benzol sulfohydrazide compounds that replaces
IIIn alcohol excess solution, react 2-chloro-3-(arylsulfonyl) quinoxaline compounds
III, compound
IIIGet target compound with the substitution reaction of various aminated compoundss
IVaOr compound
IGet 2-chloro-3-diazanyl quinoxaline compound with the substitution reaction of hydrazine hydrate
V, compound
VThe substitution reaction that takes place with the aryl chloride compounds gets compound
VI, compound
VIGet target compound with the substitution reaction of various aminated compoundss
IVdThe aniline that described aminated compounds is selected aniline, cyclo-hexylamine for use, replaced by fluorine atom, amino, trifluoromethyl, hydroxyl, methoxyl group; or ring secondary amine compounds, comprise morpholine, tetramethyleneimine, pyridine, tetrahydroisoquinoline, piperazine, 3 or 4-methylpiperazine, 3 or 4-hydroxy piperidine, 4-ethanoyl piperazine, piperidines-4-acid amides.
The preparation method of Compound I va: 2,3-dichloro-quinoxaline compounds
IWith the benzol sulfohydrazide compounds that replaces
IIBack flow reaction gets 2-chloro-3-(arylsulfonyl) quinoxaline compounds in alcohol excess solution
III, compound
IIIAt inert solvent benzene, obtain target compound with benzene-like compounds generation condensation reaction in toluene or the dimethylbenzene
IVa, temperature of reaction is 80-130
oC, the gained target compound
IVaCan get pure products, compound through column chromatography
IVaRefabrication becomes hydrochloride, acetate, and oxalate, reaction formula is:
Perhaps compound
IIIGet target compound at alcoholic solvent neutralizing amine compounds through microwave reaction
Iva
Compound wherein
I(2,3-dichloro-quinoxaline compounds) can make (CN 1958578 for Y. Yu, et al.) by O-Phenylene Diamine and the oxalic acid diethyl ester that replaces.Compound
II(benzol sulfohydrazide of replacement) can benzene sulfonyl chloride and hydrazine hydrate reaction by corresponding replacement make (P. F. Li, et al., Youji Huaxue, 2005,25 (9), 1057-1061).
Compound
IVbThe preparation method: 2,3-dichloro-quinoxaline compounds
IWith hydrazine hydrate at room temperature react 2-chloro-3-diazanyl quinoxaline compound
V, compound
VWith the aryl chloride compounds substitution reaction taking place at room temperature gets compound
VI, compound
VIAt inert solvent benzene, toluene or dimethylbenzene neutralizing amine compounds generation condensation reaction obtain target compound
IVb, temperature of reaction is 80-130
oC, the gained target compound
IVbCan get pure products through column chromatography, and then be prepared into hydrochloride, acetate, oxalate; Reaction formula is:
Compound wherein
IThe same compound of preparation method
IVa
A further object of the present invention provides
NThe application in the preparation tumour medicine of-replacement-3-substituted quinoxaline-2-aminated compounds and physiologically acceptable salt thereof, especially as the active method of a kind of adjusting PI3K/Akt signal path, the purposes in the medicine of preparation treatment and PI3K/Akt signal path diseases associated.Drug prepared also contains preparation allowable pharmaceutical excipients, carrier or other antitumor drugs.
The present invention is on Chinese patent application number is 200910099509.5 basis, and benzenesulfonyl quinoxaline compound is done further to modify and structure of modification, and design has been synthesized a series of
N-replacement-3-substituted quinoxaline-2-aminated compounds is with the structure activity relationship of studying this compounds and obtain the better and active better candidate compound of pharmacokinetic property.The present invention is to provide the brand-new compound of a class formation, synthetic desired raw material is easy to get, and highway route design is reasonable, is suitable for practicality.
N-replacement-3-substituted quinoxaline-2-aminated compounds is to PC3, A549, the remarkable vitro that shown HCT116, tumor cell lines such as HL60 suppresses proliferation function, and the Akt phosphorylation inhibition test of part of compounds has been shown the regulating effect of this compounds to the PI3K/Akt signal path.
Seminar of the present invention is in Chinese patent application numbers 200910099509.5, and design has been synthesized a series of
N-replacement-3-(benzenesulfonyl) quinoxaline-2-aminated compounds.The present invention to substituent improvement in the above-mentioned benzenesulfonyl quinoxaline compound molecule is: further having enriched application number is 2 replacement types that virtue is amino in 200910099509.5 compound structures that provide, or with piperazine ring, 3 or 4-methylpiperazine ring, 3 or 4-hydroxy piperidine ring, 4-ethanoyl piperazine, piperidines-4-acid amides ring, tetrahydroisoquinoline ring replace original morpholine ring or pyridine ring; Perhaps 3 fragrant sulphonyl substituting group is changed into fragrant sulfonyl hydrazino, thereby it is new to obtain this class
N-replacement-3-substituted quinoxaline-2-aminated compounds.
Description of drawings
Fig. 1 is that the part target compound is to suppressing the Western Blot gel electrophoresis figure (I) of AKT (Ser473) protein expression.
Fig. 2 is that the part target compound is to suppressing the Western Blot gel electrophoresis figure (II) of AKT (Ser473) protein expression.
Embodiment
The present invention is further described in conjunction with the embodiments.Following embodiment is that explanation is of the present invention, rather than limits the present invention by any way.
The compound of being mentioned among the present invention
IVaTotal preparation, be to be that raw material makes 2 with the O-Phenylene Diamine and the oxalic acid diethyl ester that replace, 3-dichloro-quinoxaline compounds
I, make fragrant sulfonyl hydrazines compound with benzene sulfonyl chloride and the hydrazine hydrate reaction that replaces
II, 2,3-dichloro-quinoxaline compounds
IWith fragrant sulfonyl hydrazines compound
IIBack flow reaction gets 2-chloro-3-(arylsulfonyl) quinoxaline compound in alcohol excess solution
IIICompound
IIIObtain target compound with various aminated compounds generation condensation reactions
IVa1-88
Embodiment 1:2, the preparation of 3-dichloro-quinoxaline (I)
5.4 (50mmol) O-Phenylene Diamine, 6.8mL oxalic acid diethyl ester and 4mol/L hydrochloric acid 25mL mixing post-heating were refluxed 90 minutes.Get the off-white color needle-like crystal after the cooling, suction filtration, washing gets white needle-like crystals; After the drying, get 2,3-Quinoxalinediones 6.6g, yield 81%, fusing point: 300
oC.
With 6.5g (40mmol) 2, the 3-Quinoxalinediones is dissolved in the 50mL thionyl chloride, adds 2mLDMF, reflux 1 hour, and cooling has solid to separate out.Reaction solution is transferred in the 40mL frozen water, generated a large amount of off-white color needle-like solids, suction filtration, the filter cake distilled water wash after the drying, gets white solid 2,3-dichloro-quinoxaline 7.2g, yield 90%, fusing point: 147-149
oC.
Embodiment 2: the preparation of benzol sulfohydrazide (II)
Hydrazine hydrate and the 16mL of 9mL85% are water-cooled to 0
oC keeps this temperature slowly to add 8.8g (50mmol) benzene sulfonyl chloride, finishes, after at room temperature stirring 2-4 hour, mixture is poured in the 50mL frozen water, and suction filtration is used the cold water washing filter cake, drain, collect solid, infrared lamp oven dry down gets pure product benzol sulfohydrazide 7.7g with ethyl alcohol recrystallization, yield 90%, fusing point: 101-102
oC.
The preparation of embodiment 3:2-chloro-3-(benzenesulfonyl) quinoxaline (III)
The ethanolic soln that 10mL is dissolved with 0.95g (5.5mmol) benzol sulfohydrazide (II) is added drop-wise to 30mL and is dissolved with 1.00g (5.0mmol) 2, and in the ethanolic soln of 3-dichloro-quinoxaline (I), backflow is spent the night.Cooling, decompression and solvent recovery, column chromatography for separation gets yellow solid 0.37g, yield 24.5%.Fusing point: 155-157
oC.
1H?NMR?(500?MHz,?CDCl3):?δ?8.02?(d,?2H,?J?=?8.5?Hz,?aromatic?H),?7.77?(d,?1H,?J?=?8.0?Hz,?aromatic?H),?7.71?(d,?1H,?J?=?8.0?Hz,?aromatic?H),?7.65-7.62?(m,?2H,?aromatic?H),?7.56?(t,?2H,?J?=?8.0?Hz,?aromatic?H),?7.48?(dt,?1H,?J?=?8.0?and?1.0?Hz,?aromatic?H)。
Embodiment 4:
NThe preparation of-(4-fluorophenyl)-3-(benzene sulfonyl) quinoxaline-2-amine (IVa1)
30mg (0.10mmol) 2-chloro-3-(benzenesulfonyl) quinoxaline is dissolved in the 10mL toluene, adds 33mg (0.30mmol) 4-fluoroaniline, is heated to 125
oC reaction 4 hours.Dilute with the 20mL ethyl acetate after being cooled to room temperature, water and saturated common salt water washing successively, anhydrous sodium sulfate drying, decompression and solvent recovery, column chromatography for separation gets red-brown solid 11mg, yield 28%.Fusing point: 212-215
oC.MS?(m/z):?380?[M+H]
+。
1H?NMR?(500?MHz,?CDCl
3):?δ?9.48?(s,?1H,?NH),?8.15?(d,?2H,?
J?=?7.5?Hz,?aromatic?H),?7.85-7.80?(m,?3H,?aromatic?H),?7.75?(d,?1H,
?J?=?8.5?Hz,?aromatic?H),?7.70?(t,?2H,?
J?=?7.5?Hz,?aromatic?H),?7.61?(t,?2H,?
J?=?7.5?Hz,?aromatic?H),?7.47?(t,?1H,?
J?=?7.5?Hz,?aromatic?H),?7.13?(t,?2H,
?J?=?8.5?Hz,?aromatic?H)。
The preparation of embodiment 5:N-(4-fluorophenyl)-3-(tolysulfonyl) quinoxaline-2-amine (IVa2)
Operation has just replaced 2-chloro-3-(benzenesulfonyl) quinoxaline with 2-chloro-3-(p-toluenesulfonyl) quinoxaline with embodiment 1, obtains orange/yellow solid behind the column chromatography.Fusing point: 183-187
oC.MS?(m/z):?394?[M+H]
+。
1H?NMR?(500?MHz,?CDCl
3):?δ?9.50?(s,?1H,?NH),?8.03?(d,?2H,?
J?=?8.5?Hz,?aromatic?H),?7.86-7.80?(m,?3H,?aromatic?H),?7.74?(d,?1H,
?J?=?8.5?Hz,?aromatic?H),?7.69?(dt,?1H,?
J?=?8.5?and?1.5?Hz,?aromatic?H),?7.46?(dt,?1H,?
J?=?8.5?and?1.5?Hz,?aromatic?H),?7.38?(d,?2H,?
J?=?8.5?Hz,?aromatic?H),?7.13?(t,?2H,
?J?=?8.5?Hz,?aromatic?H),?2.44?(s,?3H,?aromatic?CH
3)。
The preparation of embodiment 6:3-(4-bromobenzene sulphonyl)-N-(4-fluorophenyl) quinoxaline-2-amine (IVa3)
Operation has just replaced 2-chloro-3-(benzenesulfonyl) quinoxaline, has obtained yellow solid behind the column chromatography with 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline with embodiment 1.Fusing point: 206-208
oC.MS?(m/z):?459?[M+H]
+。
1H?NMR?(500?MHz,?CDCl
3):?δ?9.38?(s,?1H,?NH),?8.01?(d,?2H,?
J?=?8.5?Hz,?aromatic?H),?7.83-7.80?(m,?3H,?aromatic?H),?7.75-7.73?(m,?3H,?aromatic?H),?7.72?(t,?1H,
?J?=?7.0?Hz,?aromatic?H),?7.748?(t,?1H,?
J?=?8.5?Hz,?aromatic?H),?7.14?(t,?2H,?
J?=?8.5?Hz,?aromatic?H)。
The preparation of embodiment 7:N-(4-fluorophenyl)-3-(4-methoxy benzene sulfonyl) quinoxaline-2-amine (IVa4)
Operation has just replaced 2-chloro-3-(benzenesulfonyl) quinoxaline with 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline with embodiment 1, obtains yellow solid behind the column chromatography.Fusing point: 148-150
oC.MS?(m/z):?409?[M+H]
+。
1H?NMR?(500?MHz,?CDCl
3):?δ?9.50?(s,?1H,?NH),?7.86-7.80?(m,?3H,?aromatic?H),?7.74?(d,?1H,?
J?=?8.0?Hz,?aromatic?H),?7.69?(t,?1H,
?J?=?7.5?Hz,?aromatic?H),?7.46?(t,?1H,?
J?=?7.5?Hz,?aromatic?H),?7.13?(d,?3H,?
J?=?8.0?Hz,?aromatic?H),?7.04?(d,?2H,?
J?=?8.5?Hz,?aromatic?H),?3.88?(s,?3H,?aromatic?OCH
3)。
Example 8:N
1-(3-(tolylsulfonyl) quinoxaline-2-yl) benzene-1, the preparation of 4-diamines (IVa5)
Operation is with embodiment 1, and just with 1, the 4-Ursol D has replaced the 4-fluoroaniline, obtains dark red solid behind the column chromatography.Fusing point: 175
oC.MS?(m/z):?377?[M+H]
+。
Example 9:N
1-(3-(tolysulfonyl) quinoxaline-2-yl) benzene-1, the preparation of 4-diamines (IVa6)
Operation is with embodiment 1, and just with 1, the 4-Ursol D has replaced the 4-fluoroaniline, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains dark red solid behind the column chromatography.Fusing point: 190-191
oC.MS?(m/z):?391?[M+H]
+。
Example 10:N
1-(3-(4-bromobenzene sulphonyl) quinoxaline-2-yl) benzene-1, the preparation of 4-diamines (IVa7)
Operation is with embodiment 1, and just with 1, the 4-Ursol D has replaced the 4-fluoroaniline, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains dark red solid behind the column chromatography.Fusing point: 177-180
oC.MS?(m/z):?456?[M+H]
+。
Example 11:N
1-(3-(4-methoxy benzene sulfonyl) quinoxaline-2-yl) benzene-1, the preparation of 4-diamines (IVa8)
Operation is with embodiment 1, and just with 1, the 4-Ursol D has replaced the 4-fluoroaniline, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains dark red solid behind the column chromatography.Fusing point: 179-182
oC.MS?(m/z):?407?[M+H]
+。
Example 12:N
1-(3-(benzene sulfonyl) quinoxaline-2-yl) benzene-1, the preparation of 3-diamines (IVa9)
Operation is with embodiment 1, and just with 1, the 3-Ursol D has replaced the 4-fluoroaniline, obtains pale brown look solid behind the column chromatography.Fusing point: 158-160
oC.MS?(m/z):?377?[M+H]
+。
Example 13:N
1-(3-tolysulfonyl quinoxaline-2-yl) benzene-1, the preparation of 3-diamines (IVa10)
Operation is with embodiment 1, and just with 1, the 3-Ursol D has replaced the 4-fluoroaniline, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the red-brown solid behind the column chromatography.Fusing point: 129-131
oC.MS?(m/z):?391?[M+H]
+。
Example 14:N
1-(3-(4-brosyl) quinoxaline-2-yl) benzene-1, the preparation of 3-diamines (IVa11)
Operation is with embodiment 1, and just with 1, the 3-Ursol D has replaced the 4-fluoroaniline, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains red solid behind the column chromatography.Fusing point: 178-181
oC.MS?(m/z):456?[M+H]
+。
Example 15:N
1-(3-(4-methoxy benzene sulfonyl) quinoxaline-2-yl) benzene-1, the preparation of 3-diamines (IVa12)
Operation is with embodiment 1, and just with 1, the 3-Ursol D has replaced the 4-fluoroaniline, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the red-brown solid behind the column chromatography.Fusing point: 164-166
oC.MS?(m/z):407?[M+H]
+。
The preparation of example 16:N-phenyl-3-(benzene sulfonyl) quinoxaline-2-amine (IVa13)
Operation has just replaced the 4-fluoroaniline with aniline with embodiment 1, obtains orange/yellow solid behind the column chromatography.Fusing point: 200-203
oC.MS?(m/z):?362?[M+H]
+。
The preparation of example 17:N-phenyl-3-tolysulfonyl quinoxaline-2-amine (IVa14)
Operation is with embodiment 1, and just with 1, the 3-Ursol D has replaced the 4-fluoroaniline, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the glassy yellow solid behind the column chromatography.Fusing point: 162-165
oC.MS?(m/z)：376?[M+H]
+。
The preparation of example 18:3-(4-bromobenzene sulphonyl)-N-phenyl quinoxaline-2-amine (IVa15)
Operation has just replaced the 4-fluoroaniline with aniline with embodiment 1, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 170-173
oC.MS?(m/z)：441?[M+H]
+。
The preparation of example 19:3-(4-methoxy benzene sulfonyl)-N-phenyl quinoxaline-2-amine (IVa16)
Operation has just replaced the 4-fluoroaniline with aniline with embodiment 1, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 150-152
oC.MS?(m/z)：392?[M+H]
+。
The preparation of example 20:3-(benzene sulfonyl)-N-(4-(trifluoromethyl) phenyl) quinoxaline-2-amine (IVa17)
Operation has just replaced the 4-5-trifluoromethylaniline to replace the 4-fluoroaniline with aniline with embodiment 1, obtains the glassy yellow solid behind the column chromatography.Fusing point: 208-209
oC.MS?(m/z)：430?[M+H]
+。
The preparation of example 21:3-tolysulfonyl-N-(4-(trifluoromethyl) phenyl) quinoxaline-2-amine (IVa18)
Operation has just replaced the 4-fluoroaniline with 4-5-trifluoromethylaniline aniline with embodiment 1, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 200-203
oC.MS?(m/z)：444?[M+H]
+。
The preparation of example 22:3-(4-bromobenzene sulphonyl)-N-(4-(trifluoromethyl) phenyl) quinoxaline-2-amine (IVa19)
Operation has just replaced the 4-fluoroaniline with 4-5-trifluoromethylaniline aniline with embodiment 1, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 219-221
oC.MS?(m/z)：509?[M+H]
+。
The preparation of example 23:3-(4-methoxy benzene sulfonyl)-N-(4-(trifluoromethyl) phenyl) quinoxaline-2-amine (IVa20)
Operation has just replaced the 4-fluoroaniline with 4-5-trifluoromethylaniline aniline with embodiment 1, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 206-208
oC.MS?(m/z)：460?[M+H]
+。
The preparation of example 24:3-(3-(benzene sulfonyl) quinoline-2-base ammonia) phenol (IVa21)
Operation has just replaced the 4-fluoroaniline with Metha Amino Phenon with embodiment 1, obtains yellow solid behind the column chromatography.Fusing point: 186-187
oC.MS?(m/z)：378?[M+H]
+。
The preparation of example 25:3-(3-tolysulfonyl quinoline-2-base ammonia) phenol (IVa22)
Operation has just replaced the 4-fluoroaniline with Metha Amino Phenon with embodiment 1, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 188-191
oC.MS?(m/z)：392?[M+H]
+。
The preparation of example 26:3-(3-(4-bromobenzene sulphonyl) quinoline-2-base ammonia) phenol (IVa23)
Operation has just replaced the 4-fluoroaniline with Metha Amino Phenon with embodiment 1, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains orange/yellow solid behind the column chromatography.Fusing point: 208-209
oC.MS?(m/z)：457?[M+H]
+。
The preparation of example 27:3-(3-(4-methoxy benzene sulfonyl) quinoline-2-base ammonia) phenol (IVa24)
Operation has just replaced the 4-fluoroaniline with Metha Amino Phenon with embodiment 1, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains orange/yellow solid behind the column chromatography.Fusing point: 159-161
oC.MS?(m/z)：408?[M+H]
+。
The preparation of example 28:N-cyclohexyl-3-(benzene sulfonyl) quinoxaline-2-amine (IVa25)
Operation has just replaced the 4-fluoroaniline with cyclo-hexylamine with embodiment 1, obtains yellow solid behind the column chromatography.Fusing point: 138-141
oC.MS?(m/z)：368?[M+H]
+。
The preparation of example 29:N-cyclohexyl-3-tolysulfonyl quinoxaline-2-amine (IVa26)
Operation has just replaced the 4-fluoroaniline with cyclo-hexylamine with embodiment 1, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the glassy yellow solid behind the column chromatography.Fusing point: 123-125
oC.MS?(m/z)：382?[M+H]
+。
The preparation of example 30:3-(4-bromobenzene sulphonyl)-N-cyclohexyl quinoxaline-2-amine (IVa27)
Operation has just replaced the 4-fluoroaniline with cyclo-hexylamine with embodiment 1, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the glassy yellow solid behind the column chromatography.Fusing point: 168-170
oC.MS?(m/z)：447?[M+H]
+。
The preparation of example 31:N-cyclohexyl-3-(4-is to the methoxy benzene sulfonyl) quinoxaline-2-amine (IVa28)
Operation has just replaced the 4-fluoroaniline with cyclo-hexylamine with embodiment 1, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the glassy yellow solid behind the column chromatography.Fusing point: 161-163
oC.MS?(m/z)：398?[M+H]
+。
The preparation of example 32:N-(4-methoxyphenyl)-3-(4-oil of mirbane sulphonyl) quinoxaline-2-amine (IVa29)
Operation has just replaced the 4-fluoroaniline with the 4-anisidine with embodiment 1, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains red solid behind the column chromatography.Fusing point: 178-181
oC.MS?(m/z)：437?[M+H]
+。
The preparation of example 33:N-(3, the 5-dimethoxy phenyl)-3-(4-oil of mirbane sulphonyl) quinoxaline-2-amine (IVa30)
Operation is with embodiment 1, and just with 3, the 5-dimethoxyaniline has replaced the 4-fluoroaniline, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 177-179
oC.MS?(m/z)：467?[M+H]
+。
The preparation of example 34:3-(4-oil of mirbane sulphonyl)-N-(3,4,, 5-2,4,5-trimethoxyphenyl) quinoxaline-2-amine (IVa31)
Operation is with embodiment 1, and just with 3,4, the 5-trimethoxy-aniline has replaced the 4-fluoroaniline, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, gets bright orange/yellow solid behind the column chromatography.Fusing point: 146-150
oC.MS?(m/z)：497?[M+H]
+。
Example 35:N
1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) benzene-1, the preparation of 4-diamines (IVa32)
Operation is with embodiment 1, and just with 1, the 4-Ursol D has replaced the 4-fluoroaniline, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains orange red solid behind the column chromatography.Fusing point: 189-191
oC.MS?(m/z)：422?[M+H]
+。
Example 36:N
1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) benzene-1, the preparation of 3-diamines (IVa33)
Operation is with embodiment 1, and just with 1, the 3-Ursol D has replaced the 4-fluoroaniline, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains orange red solid behind the column chromatography.Fusing point: 186-189
oC.MS?(m/z)：422?[M+H]
+。
The preparation of example 37:3-(4-fluorobenzene sulphonyl)-N-(4-methoxyphenyl) quinoxaline-2-amine (IVa34)
Operation has just replaced the 4-fluoroaniline with the 4-anisidine with embodiment 1, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the shiny red solid behind the column chromatography.Fusing point: 159-162
oC.MS?(m/z)：410?[M+H]
+。
Example 38:N-(3, the preparation of 5-dimethoxy-benzene-3-(4-fluorobenzene sulphonyl) quinoxaline-2-amine (IVa35)
Operation is with embodiment 1, and just with 3, the 5-dimethoxyaniline has replaced the 4-fluoroaniline, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 158-160
oC.MS?(m/z)：440?[M+H]
+。
Example 39:N-(3,4, the preparation of 5-trimethoxy benzene-3-(4-fluorobenzene sulphonyl) quinoxaline-2-amine (IVa36)
Operation is with embodiment 1, and just with 3,4, the 5-trimethoxy-aniline has replaced the 4-fluoroaniline, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 234-235
oC.MS?(m/z)：470?[M+H]
+。
Example 40:N
1-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) benzene-1, the preparation of 4-diamines (IVa37)
Operation has just replaced the 4-fluoroaniline with Ursol D with embodiment 1, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains dark red solid behind the column chromatography.Fusing point: 168-169
oC.MS?(m/z)：395?[M+H]
+。
Example 41:N
1-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) benzene-1, the preparation of 3-diamines (IVa38)
Operation has just replaced the 4-fluoroaniline with mphenylenediamine with embodiment 1, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains pale brown look solid behind the column chromatography.Fusing point: 166-168
oC.MS?(m/z)：395?[M+H]
+。
The preparation of example 42:2-(4-methylpiperazine-1-yl)-3-(benzenesulfonyl) quinoxaline (IVa39)
30mg (0.10mmol) 2-chloro-3-(benzenesulfonyl) quinoxaline is dissolved in the 3mL Virahol, adds 50mg (0.50mmol) 4-methylpiperazine, back flow reaction 2 hours or microwave reaction 10min (temperature: 80
oC).Decompression and solvent recovery, column chromatography for separation get yellow solid 27mg, yield 74%.Fusing point: 154-157
oC.
1H?NMR?(500?MHz,?CDCl
3):?δ?8.00?(d,?2H,?
J?=?8.0?Hz,?aromatic?H),?7.77?(d,?1H,
?J?=?8.0?Hz,?aromatic?H),?7.67-7.60?(m,?3H,?aromatic?H),?7.54?(t,?2H,?
J?=?7.5?Hz,?aromatic?H),?3.80?(t,?4H,?
J?=?4.5?H,?piperazine?H),?2.71?(t,?4H,?
J?=?4.5?Hz,?piperazine?H),?2.40?(s,?3H,?pierazine?CH
3).?MS?(m/z)：369?[M+H]
+。
The preparation of example 43:2-(4-methylpiperazine-1-yl)-3-tolysulfonyl quinoxaline (IVa40)
Operation just replaces 2-chloro-3-(benzenesulfonyl) quinoxaline with 2-chloro-3-(p-toluenesulfonyl) quinoxaline with embodiment 39, obtains yellow solid behind the column chromatography.Fusing point: 127-130
oC.MS?(m/z)：383?[M+H]
+。
The preparation of example 44:2-(4-bromobenzenesulfonyl)-3-(4-methylpiperazine-1-yl) quinoxaline (IVa41)
Operation just replaces 2-chloro-3-(benzenesulfonyl) quinoxaline with 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline with embodiment 39, obtains yellow solid behind the column chromatography.Fusing point: 141-142
oC.MS?(m/z)：448?[M+H]
+。
The preparation of example 45:2-(4-methoxy benzenesulfonyl)-3-(4-methylpiperazine-1-yl) quinoxaline (IVa42)
Operation just replaces 2-chloro-3-(benzenesulfonyl) quinoxaline with 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline with embodiment 39, obtains yellow solid behind the column chromatography.Fusing point: 121-124
oC.MS?(m/z)：399?[M+H]
+。
The preparation of example 46:1-(3-(benzenesulfonyl) quinoxaline-2-yl) piperidines-4-alcohol (IVa43)
Operation just replaces the 4-methylpiperazine, obtains yellow solid behind the column chromatography with piperidines-4-alcohol with embodiment 39.Fusing point: 164-167
oC.MS?(m/z)：370?[M+H]
+。
The preparation of example 47:1-(3-tolysulfonyl quinoxaline-2-yl) piperidines-4-alcohol (IVa44)
Operation just replaces the 4-methylpiperazine with piperidines-4-alcohol with embodiment 39, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 130-133
oC.MS?(m/z)：384?[M+H]
+。
The preparation of example 48:1-(3-(4-bromobenzenesulfonyl) quinoxaline-2-yl) piperidines-4-alcohol (IVa45)
Operation just replaces the 4-methylpiperazine with piperidines-4-alcohol with embodiment 39, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 129-133
oC.MS?(m/z)：449?[M+H]
+。
The preparation of example 49:1-(3-(4-methoxy benzenesulfonyl) quinoxaline-2-yl) piperidines-4-alcohol (IVa46)
Operation just replaces the 4-methylpiperazine with piperidines-4-alcohol with embodiment 39, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 148-150
oC.MS?(m/z)：400?[M+H]
+。
The preparation of example 50:1-(3-(benzenesulfonyl) quinoxaline-2-yl) piperidines-3-alcohol (IVa47)
Operation just replaces the 4-methylpiperazine, obtains yellow solid behind the column chromatography with piperidines-3-alcohol with embodiment 39.Fusing point: 118-120
oC.MS?(m/z)：370?[M+H]
+。
The preparation of example 51:1-(3-tolysulfonyl quinoxaline-2-yl) piperidines-3-alcohol (IVa48)
Operation just replaces the 4-methylpiperazine with piperidines-3-alcohol with embodiment 39, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 139-142
oC.MS?(m/z)：384?[M+H]
+。
The preparation of example 52:1-(3-tolysulfonyl quinoxaline-2-yl) piperidines-3-alcohol (IVa48)
Operation just replaces the 4-methylpiperazine with piperidines-3-alcohol with embodiment 39, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 108-112
oC.MS?(m/z)：449?[M+H]
+。
The preparation of example 53:1-(3-(4-p-toluenesulfonyl) quinoxaline-2-yl) piperidines-3-alcohol (IVa50)
Operation just replaces the 4-methylpiperazine with piperidines-3-alcohol with embodiment 39, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 91-94
oC.MS?(m/z)：400?[M+H]
+。
The preparation of example 54:1-(4-(3-(benzenesulfonyl) quinoxaline-2-yl) piperazine-1-yl) ethyl ketone (IVa51)
Operation just replaces the 4-methylpiperazine with 1-(piperazine-1-yl) ethyl ketone with embodiment 39, obtains yellow solid behind the column chromatography.Fusing point: 144-146
oC.MS?(m/z)：397?[M+H]
+。
The preparation of example 55:1-(4-(3-tolysulfonyl quinoxaline-2-yl) piperazine-1-yl) ethyl ketone (IVa52)
Operation just replaces the 4-methylpiperazine with 1-(piperazine-1-yl) ethyl ketone with embodiment 39, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 148-150
oC.MS?(m/z)：411?[M+H]
+。
The preparation of example 56:1-(4-(3-(4-bromobenzene sulphonyl) quinoxaline-2-yl) piperazine-1-yl) ethyl ketone (IVa53)
Operation just replaces the 4-methylpiperazine with 1-(piperazine-1-yl) ethyl ketone with embodiment 39, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 174-178
oC.MS?(m/z)：476?[M+H]
+。
The preparation of example 57:1-(4-(3-(4-methoxy benzene sulfonyl) quinoxaline-2-yl) piperazine-1-yl) ethyl ketone (IVa54)
Operation just replaces the 4-methylpiperazine with 1-(piperazine-1-yl) ethyl ketone with embodiment 39, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 160-162
oC.MS?(m/z)：427?[M+H]
+。
The preparation of example 58:1-(3-(benzene sulfonyl) quinoxaline-2-yl) piperidines-4-carbonyl amine (IVa55)
Operation just replaces the 4-methylpiperazine with piperidines-4-carbonyl amine with embodiment 39, obtains yellow solid % behind the column chromatography.Fusing point: 170-174
oC.MS?(m/z)：397?[M+H]
+。
The preparation of example 59:1-(3-tolysulfonyl quinoxaline-2-yl) piperidines-4-carbonyl amine (IVa56)
Operation just replaces the 4-methylpiperazine with piperidines-4-carbonyl amine with embodiment 39, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 200-203
oC.MS?(m/z)：411?[M+H]
+。
The preparation of example 60:1-(3-(4-bromobenzene sulphonyl) quinoxaline-2-yl) piperidines-4-carbonyl amine (IVa57)
Operation just replaces the 4-methylpiperazine with piperidines-4-carbonyl amine with embodiment 39, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 209-210
oC.MS?(m/z)：476?[M+H]
+。
The preparation of example 61:1-(3-(4-anisole sulphonyl) quinoxaline-2-yl) piperidines-4-carbonyl amine (IVa58)
Operation just replaces the 4-methylpiperazine with piperidines-4-carbonyl amine with embodiment 39, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 185-187
oC.MS?(m/z)：427?[M+H]
+。
The preparation of example 62:2-(benzene sulfonyl)-3-(piperazine-1-yl) quinoxaline (IVa59)
Operation just replaces the 4-methylpiperazine with piperazine with embodiment 39, obtains yellow oil behind the column chromatography.MS?(m/z)：355?[M+H]
+。
Example 63:2-(the preparation of piperazine-1-yl)-3-tolysulfonyl quinoxaline (IVa60)
Operation just replaces the 4-methylpiperazine with piperazine with embodiment 39, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid oily matter behind the column chromatography.MS?(m/z)：369?[M+H]
+。
Example 64:2-(the 4-bromobenzene sulphonyl)-3-(piperazine-1-yl) preparation of quinoxaline (IVa61)
Operation just replaces the 4-methylpiperazine with piperazine with embodiment 39, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 93-96
oC.MS?(m/z)：434?[M+H]
+。
Example 65:2-(the 4-methoxy benzene sulfonyl)-3-(piperazine-1-yl) preparation of quinoxaline (IVa62)
Operation just replaces the 4-methylpiperazine with piperazine with embodiment 39, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 143-144
oC.MS?(m/z)：385?[M+H]
+。
The preparation of example 66:2-(3-methyl piperidine 1-yl)-3-(benzene sulfonyl) quinoxaline (IVa63)
Operation just replaces the 4-methylpiperazine with the 3-methylpiperazine with embodiment 39, obtains yellow oil behind the column chromatography.MS?(m/z)：369?[M+H]
+。
The preparation of example 67:2-(3-methyl piperidine 1-yl)-3-tolysulfonyl quinoxaline (IVa64)
Operation just replaces the 4-methylpiperazine with the 3-methylpiperazine with embodiment 39, uses 2-chloro-3-(p-toluenesulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains orange/yellow solid behind the column chromatography.Fusing point: 136-138
oC.MS?(m/z)：369?[M+H]
+。
The preparation of example 68:2-(4-bromobenzene sulphonyl)-3-(3-methylpiperazine-1-yl) quinoxaline (IVa65)
Operation just replaces the 4-methylpiperazine with the 3-methylpiperazine with embodiment 39, uses 2-(4-bromine alkylsulfonyl)-3-chloro-quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 158-160
oC.MS?(m/z)：448?[M+H]
+。
The preparation of example 69:2-(4-methoxy benzene sulfonyl)-3-(3-methylpiperazine-1-yl) quinoxaline (IVa66)
Operation just replaces the 4-methylpiperazine with the 3-methylpiperazine with embodiment 39, uses 2-chloro-3-(4-anisole alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 130-133
oC.MS?(m/z)：399?[M+H]
+。
The preparation of example 70:4-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) morpholine (IVa67)
Operation is just replaced the 4-methylpiperazine with morpholino with embodiment 39, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the glassy yellow solid behind the column chromatography.Fusing point: 128-132
oC.MS?(m/z)：401?[M+H]
+。
The preparation of example 71:2-(4-methylpiperazine-1-yl)-3-(4-oil of mirbane sulphonyl) quinoxaline (IVa68)
Operation just replaces 2-chloro-3-(benzenesulfonyl) quinoxaline with 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline with embodiment 39, obtains the light beige solid behind the column chromatography.Fusing point: 163-165
oC.MS?(m/z)：414?[M+H]
+。
The preparation of example 72:2-(4-oil of mirbane sulphonyl)-3-(piperidines-1-yl) quinoxaline (IVa69)
Operation just replaces the 4-methylpiperazine with piperidines with embodiment 39, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the glassy yellow solid behind the column chromatography.Fusing point: 147-150
oC.MS?(m/z)：399?[M+H]
+。
The preparation of example 73:2-(4-oil of mirbane sulphonyl)-3-(tetramethyleneimine-1-yl) quinoxaline (IVa70)
Operation just replaces the 4-methylpiperazine with tetramethyleneimine with embodiment 39, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains light yellow solid behind the column chromatography.Fusing point: 129-131
oC.MS?(m/z)：385?[M+H]
+。
The preparation of example 74:1-(4-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) piperazine-1-yl) ethyl ketone (IVa71)
Operation just replaces the 4-methylpiperazine with 1-(piperazine-1-yl) ethyl ketone with embodiment 39, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 159-163
oC.MS?(m/z)：442?[M+H]
+。
The preparation of example 75:1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) piperidines-4-carbonyl amine (IVa72)
Operation just replaces the 4-methylpiperazine with piperidines-4-carbonyl amine with embodiment 39, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the glassy yellow solid behind the column chromatography.Fusing point: 227-229
oC.MS?(m/z)：442?[M+H]
+。
The preparation of example 76:1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) piperidines-3-alcohol (IVa73)
Operation just replaces the 4-methylpiperazine with piperidines-3-alcohol with embodiment 39, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 87-90
oC.MS?(m/z)：415?[M+H]
+。
The preparation of example 77:1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) piperidines-4-alcohol (IVa74)
Operation just replaces the 4-methylpiperazine with piperidines-4-alcohol with embodiment 39, uses 2-chloro-3-(4-oil of mirbane alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 149-151
oC.MS?(m/z)：415?[M+H]
+。
The preparation of example 78:4-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) morpholine (IVa75)
Operation is just replaced the 4-methylpiperazine with morpholino with embodiment 39, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the glassy yellow solid behind the column chromatography.Fusing point: 149-153
oC.MS?(m/z)：374?[M+H]
+。
The preparation of example 79:2-(4-fluorobenzene sulphonyl)-3-(piperidines-1-yl) quinoxaline (IVa76)
Operation just replaces the 4-methylpiperazine with piperidines with embodiment 39, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the glassy yellow solid behind the column chromatography.Fusing point: 155-156
oC.MS?(m/z)：372?[M+H]
+。
The preparation of example 80:2-(4-fluorobenzene sulphonyl)-3-(tetramethyleneimine-1-yl) quinoxaline (IVa77)
Operation just replaces the 4-methylpiperazine with tetramethyleneimine with embodiment 39, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 94-97
oC.MS?(m/z)：358?[M+H]
+。
Example 81:2-(3, the preparation of 4-dihydro-isoquinoline-2 (1H)-yl)-3-(4-fluorobenzene alkylsulfonyl) quinoxaline (IVa78)
Operation is with embodiment 39, and just with 1,2,3, the 4-tetrahydroisoquinoline replaces the 4-methylpiperazine, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 171-175
oC.MS?(m/z)：420?[M+H]
+。
The preparation of example 82:2-(4-fluorobenzene sulphonyl)-3-(4-methylpiperazine-1-yl) quinoxaline (IVa79)
Operation just replaces 2-chloro-3-(benzenesulfonyl) quinoxaline with 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline with embodiment 39, obtains yellow solid behind the column chromatography.Fusing point: 147-148
oC.MS?(m/z)：387?[M+H]
+。
The preparation of example 83:1-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) piperidines-4-alcohol (IVa80)
Operation just replaces the 4-methylpiperazine with piperidines-4-alcohol with embodiment 39, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow oil behind the column chromatography.MS?(m/z)：388?[M+H]
+。
The preparation of example 84:1-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) piperidines-3-alcohol (IVa81)
Operation just replaces the 4-methylpiperazine with piperidines-3-alcohol with embodiment 39, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow oil behind the column chromatography.MS?(m/z)：388?[M+H]
+。
The preparation of example 85:1-(4-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) piperazine-1-yl) ethyl ketone (IVa82)
Operation just replaces the 4-methylpiperazine with 1-(piperazine-1-yl) ethyl ketone with embodiment 39, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 108-112
oC.MS?(m/z)：415?[M+H]
+。
The preparation of example 86:1-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) piperidines-4-carbonyl amine (IVa83)
Operation just replaces the 4-methylpiperazine with piperidines-4-carbonyl amine with embodiment 39, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains the glassy yellow solid behind the column chromatography.Fusing point: 198-202
oC.MS?(m/z)：414?[M+H]
+。
The preparation of example 87:2-(4-fluorobenzene sulphonyl)-3-(piperazine-1-yl) quinoxaline (IVa84)
Operation just replaces the 4-methylpiperazine with piperazine with embodiment 39, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains orange red oily matter behind the column chromatography.MS?(m/z)：373?[M+H]
+。
The preparation of example 88:2-(4-fluorobenzene sulphonyl)-3-(3-methylpiperazine-1-yl) quinoxaline (IVa85)
Operation just replaces the 4-methylpiperazine with the 3-methylpiperazine with embodiment 39, uses 2-chloro-3-(4-fluorobenzene alkylsulfonyl) quinoxaline to replace 2-chloro-3-(benzenesulfonyl) quinoxaline simultaneously, obtains yellow solid behind the column chromatography.Fusing point: 119-123
oC.MS?(m/z)：387?[M+H]
+。
Example 89:6-methoxyl group-3-(piperazine-1-yl)-2-is to the preparation of methoxy benzenesulfonyl quinoxaline (IVa86)
Operation just replaces the 4-methylpiperazine with piperazine with embodiment 39, replaces 2-chloro-3-(benzenesulfonyl) quinoxaline, obtains pale brown look solid behind the column chromatography with 3-chloro-6-methoxyl group-2-p-toluenesulfonyl quinoxaline simultaneously.Fusing point: 160-162
oC.MS?(m/z)：399?[M+H]
+。
Example 90:6-methoxyl group-3-(4-methylpiperazine-1-yl)-2-is to the preparation of methoxy benzenesulfonyl quinoxaline (IVa87)
Operation just replaces 2-chloro-3-(benzenesulfonyl) quinoxaline, obtains yellow solid behind the column chromatography with 3-chloro-6-methoxyl group-2-p-toluenesulfonyl quinoxaline with embodiment 39.Fusing point: 143-146
oC.MS?(m/z)：413?[M+H]
+。
The preparation of example 91:1-(4-(7-methoxyl group-3-is to methoxy benzene sulfonyl quinoxaline-2-yl) piperazine-1 base) ethyl ketone (IVa88)
Operation just replaces the 4-methylpiperazine with 1-(piperazine-1-yl) ethyl ketone with embodiment 39, replaces 2-chloro-3-(benzenesulfonyl) quinoxaline, obtains yellow solid behind the column chromatography with 3-chloro-6-methoxyl group-2-p-toluenesulfonyl quinoxaline simultaneously.Fusing point: 65-68
oC.MS?(m/z)：441?[M+H]
+。
Example 92:2-chloro-3-diazanyl quinoxaline (V
)Preparation
With 5.0g (25mmol) 2, the 3-dichloro-quinoxaline is dissolved in the 75mL ethanol, adds the hydrazine hydrate of 2.5mL85%, and the vigorous stirring reaction is 14 hours under the room temperature.Filter light yellow solid, get compound with the washing with alcohol after drying
V, 2-chloro-3-diazanyl quinoxaline 4.6g (light yellow solid, productive rate: 95%).Fusing point: 182-184
oC.MS?(m/z):?195?[M+H]
+。
The preparation of example 93:N'-(3-chloro-quinoxaline-2-yl)-4-Methyl benzenesulfonyl hydrazine (VI)
1.0g (5mmol) Tosyl chloride is dissolved in the 20mL methylene dichloride, is cooled to 0
oC slowly is added dropwise to the 0.5mL pyridine and gets clarified colorless liquid; The 40mL dichloromethane solution that will be dissolved with 0.4g (2mmol) 2-chloro-3-diazanyl quinoxaline more slowly joins in the reaction system, at room temperature stirs and spends the night.Decompression and solvent recovery, column chromatography for separation get pale pink solid 0.28g, yield 40%.Fusing point: 205-207
oC.MS?(m/z):?349?[M+H]
+。
The preparation of example 94:N'-(3-(3, the 5-dimethoxyaniline) quinoxaline-2-yl)-4-Methyl benzenesulfonyl hydrazine (IVb1)
47mg (0.10mmol) N'-(3-chloro-quinoxaline-2-yl)-4-Methyl benzenesulfonyl hydrazine is dissolved in the 10mL glycol dimethyl ether, adds 31mg (0.20mmol) 3, and the 5-dimethoxyaniline is 120
oC reaction 7 hours.Decompression and solvent recovery, column chromatography for separation get yellow light gray-white solid 25mg, yield 54%.Fusing point: 200-202
oC.
1H?NMR?(500?MHz,?CDCl
3):?δ?9.21?(brs,?1H,?NH),?8.04?(brs,?1H,?NH),?7.85?(d,?2H,?
J?=?8.0?Hz,?aromatic?H),?7.55?(d,?1H,
?J?=?7.5?Hz,?aromatic?H),?7.39?(d,?2H,?
J?=?8.0?Hz,?aromatic?H),?7.20?(dt,?2H,?
J?=?7.5?and?1.5?Hz,?aromatic?H),?7.08-7.06?(m,?3H,?aromatic?H),?6.23?(s,?1H,?aromatic?H),?6.17?(brs,?1H,?NH),?3.83?(s,?6H,?aromatic?OCH
3),?2.47?(s,?3H,?aromatic?CH
3).?MS?(m/z)：466?[M+H]
+。
The preparation of example 95:4-methyl-N'-(3-(3,4,, 5-trimethoxy-aniline) quinoxaline-2-yl)-4-Methyl benzenesulfonyl hydrazine (IVb2)
Operation is with embodiment 90, and just with 3,4, the 5-trimethoxy-aniline replaces 3, and the 5-dimethoxyaniline obtains the light gray-white solid behind the column chromatography.Fusing point: 206
oC.MS?(m/z)：496?[M+H]
+。
The preparation of example 96:N'-(3-(4-chloroaniline) quinoxaline-2-yl)-4-Methyl benzenesulfonyl hydrazine (IVb3)
Operation is just used chloro aniline is replaced 3 with embodiment 90, and the 5-dimethoxyaniline obtains the light beige solid behind the column chromatography.Fusing point: 212-213
oC.MS?(m/z)：440?[M+H]
+。
Embodiment 97: the anti tumor activity in vitro test
Adopt mtt assay to measure this compounds to Human Prostate Cancer Cells PC-3, human lung cancer cell A549, the vitro inhibition effect of human colon cancer cell HCT116 and human leukemia cell HL60, and calculation of half inhibitory concentration (IC
50).The result shows, institute's synthetic
N-replacement-3-substituted quinoxaline-2-aminated compounds all demonstrates good tumors inhibition activity in a plurality of cell strains, the activity of most compounds all obviously is better than positive control LY294002.The results are shown in Table 1-6.
Embodiment 98:PI3K/Akt phosphorylation inhibition test
Adopt Western Blot method, promptly the immune protein marking detects the influence of target compound to the PI3K/AKT signal path.The PI3K kinases can cause a series of cascade reactions and cause the proteic activation of downstream AKT, show as the phosphorylation in AKT Protein S er473 site.Therefore can reflect the PI3K kinase activity indirectly by AKT (Ser473) protein expression level that detects phosphorylation, if compound suppresses the PI3K kinase activity, then p-AKT (Ser473) protein expression reduces.The human prostata cancer PC3 cell strain of PI3K high expression level is selected in experiment for use, selects compound concentration 10 μ M effects 3 hours for use, with confidential reference items albumin A ctin as reference.The result shows, compound IV a45, and IVa65 has the obvious suppression effect to the phosphorylation of 3 of AKT protein 47s; Compound IV a47, IVb2 has certain restraining effect to phosphorylation level; Compound IV a43, IVa51, IVb1, IVa18 has in various degree restraining effect to phosphorylation.The result is referring to Fig. 1 and Fig. 2.Among Fig. 1 and Fig. 2, C is not dosing of control group, the positive control group GDC0941(10 of G μ M), concentration of specimens 10 μ M administrations.
Claims (8)
1. one kind
N-replacement-3-substituted quinoxaline-2-aminated compounds and salt thereof is characterized in that, has following general structure:
Wherein:
R
1Be hydrogen atom or C
1~ C
6Alkoxyl group;
R
2Be selected from hydrogen atom, C
1~ C
6Alkyl, C
1~ C
6Alkoxyl group, halogen, nitro or amide group;
R
3And R
4Difference, the phenyl that is selected from hydrogen atom, cyclohexyl, phenyl, replaces by fluorine atom, amino, trifluoromethyl, hydroxyl, perhaps R
3, R
4Form morpholine ring, pyrrolidine ring, pyridine ring, tetrahydroisoquinoline ring, piperazine ring, 3 or 4-methylpiperazine ring, 3 or 4-hydroxy piperidine ring, 4-ethanoyl piperazine, piperidines-4-acid amides ring with nitrogen-atoms;
X is selected from-SO
2-or-NH-NH-SO
2-.
2. according to the compound of claim 1, be selected from:
N-(4-fluorophenyl)-3-(benzene sulfonyl) quinoxaline-2-amine
N-(4-fluorophenyl)-3-(tolysulfonyl) quinoxaline-2-amine
3-(4-bromobenzene sulphonyl)-N-(4-fluorophenyl) quinoxaline-2-amine
N-(4-fluorophenyl)-3-(4-methoxy benzene sulfonyl) quinoxaline-2-amine
N
1-(3-(tolylsulfonyl) quinoxaline-2-yl) benzene-1, the 4-diamines
N
1-(3-(tolysulfonyl) quinoxaline-2-yl) benzene-1, the 4-diamines
N
1-(3-(4-bromobenzene sulphonyl) quinoxaline-2-yl) benzene-1, the 4-diamines
N
1-(3-(4-methoxy benzene sulfonyl) quinoxaline-2-yl) benzene-1, the 4-diamines
N
1-(3-(benzene sulfonyl) quinoxaline-2-yl) benzene-1, the 3-diamines
N
1-(3-tolysulfonyl quinoxaline-2-yl) benzene-1, the 3-diamines
N
1-(3-(4-brosyl) quinoxaline-2-yl) benzene-1, the 3-diamines
N
1-(3-(4-methoxy benzene sulfonyl) quinoxaline-2-yl) benzene-1, the 3-diamines
N-phenyl-3-(benzene sulfonyl) quinoxaline-2-amine
N-phenyl-3-tolysulfonyl quinoxaline-2-amine
3-(4-bromobenzene sulphonyl)-N-phenyl quinoxaline-2-amine (
3-(4-methoxy benzene sulfonyl)-N-phenyl quinoxaline-2-amine
3-(benzene sulfonyl)-N-(4-(trifluoromethyl) phenyl) quinoxaline-2-amine
3-tolysulfonyl-N-(4-(trifluoromethyl) phenyl) quinoxaline-2-amine
3-(4-bromobenzene sulphonyl)-N-(4-(trifluoromethyl) phenyl) quinoxaline-2-amine
3-(4-methoxy benzene sulfonyl)-N-(4-(trifluoromethyl) phenyl) quinoxaline-2-amine
3-(3-(benzene sulfonyl) quinoline-2-base ammonia) phenol
3-(3-tolysulfonyl quinoline-2-base ammonia) phenol
3-(3-(4-bromobenzene sulphonyl) quinoline-2-base ammonia) phenol
3-(3-(4-methoxy benzene sulfonyl) quinoline-2-base ammonia) phenol
N-cyclohexyl-3-(benzene sulfonyl) quinoxaline-2-amine
N-cyclohexyl-3-tolysulfonyl quinoxaline-2-amine
3-(4-bromobenzene sulphonyl)-N-cyclohexyl quinoxaline-2-amine
N-cyclohexyl-3-(4-is to the methoxy benzene sulfonyl) quinoxaline-2-amine
N-(4-methoxyphenyl)-3-(4-oil of mirbane sulphonyl) quinoxaline-2-amine
N-(3, the 5-dimethoxy phenyl)-3-(4-oil of mirbane sulphonyl) quinoxaline-2-amine
3-(4-oil of mirbane sulphonyl)-N-(3,4,, the 5-2,4,5-trimethoxyphenyl) quinoxaline-2-amine
N
1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) benzene-1, the 4-diamines
N
1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) benzene-1, the 3-diamines
3-(4-fluorobenzene sulphonyl)-N-(4-methoxyphenyl) quinoxaline-2-amine
N-(3,5-dimethoxy-benzene-3-(4-fluorobenzene sulphonyl) quinoxaline-2-amine
N-(3,4,5-trimethoxy benzene-3-(4-fluorobenzene sulphonyl) quinoxaline-2-amine
N
1-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) benzene-1, the 4-diamines
N
1-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) benzene-1, the 3-diamines
2-(4-methylpiperazine-1-yl)-3-(benzenesulfonyl) quinoxaline
2-(4-methylpiperazine-1-yl)-3-tolysulfonyl quinoxaline
2-(4-bromobenzenesulfonyl)-3-(4-methylpiperazine-1-yl) quinoxaline
2-(4-methoxy benzenesulfonyl)-3-(4-methylpiperazine-1-yl) quinoxaline
1-(3-(benzenesulfonyl) quinoxaline-2-yl) piperidines-4-alcohol
1-(3-tolysulfonyl quinoxaline-2-yl) piperidines-4-alcohol
1-(3-(4-bromobenzenesulfonyl) quinoxaline-2-yl) piperidines-4-alcohol
1-(3-(4-methoxy benzenesulfonyl) quinoxaline-2-yl) piperidines-4-alcohol
1-(3-(benzenesulfonyl) quinoxaline-2-yl) piperidines-3-alcohol
1-(3-tolysulfonyl quinoxaline-2-yl) piperidines-3-alcohol
1-(3-(4-bromobenzenesulfonyl) quinoxaline-2-yl) piperidines-3-alcohol
1-(3-(4-p-toluenesulfonyl) quinoxaline-2-yl) piperidines-3-alcohol
1-(4-(3-(benzenesulfonyl) quinoxaline-2-yl) piperazine-1-yl) ethyl ketone
1-(4-(3-tolysulfonyl quinoxaline-2-yl) piperazine-1-yl) ethyl ketone
1-(4-(3-(4-bromobenzene sulphonyl) quinoxaline-2-yl) piperazine-1-yl) ethyl ketone
1-(4-(3-(4-methoxy benzene sulfonyl) quinoxaline-2-yl) piperazine-1-yl) ethyl ketone
1-(3-(benzene sulfonyl) quinoxaline-2-yl) piperidines-4-carbonyl amine
1-(3-tolysulfonyl quinoxaline-2-yl) piperidines-4-carbonyl amine
1-(3-(4-bromobenzene sulphonyl) quinoxaline-2-yl) piperidines-4-carbonyl amine
1-(3-(4-anisole sulphonyl) quinoxaline-2-yl) piperidines-4-carbonyl amine
2-(benzene sulfonyl)-3-(piperazine-1-yl) quinoxaline
2-(piperazine-1-yl)-3-tolysulfonyl quinoxaline
2-(the 4-bromobenzene sulphonyl)-3-(quinoxaline of piperazine-1-yl)
2-(the 4-methoxy benzene sulfonyl)-3-(quinoxaline of piperazine-1-yl)
2-(3-methylpiperazine 1-yl)-3-(benzene sulfonyl) quinoxaline
2-(3-methylpiperazine 1-yl)-3-tolysulfonyl quinoxaline
2-(4-bromobenzene sulphonyl)-3-(3-methylpiperazine-1-yl) quinoxaline
2-(4-methoxy benzene sulfonyl)-3-(3-methylpiperazine-1-yl) quinoxaline
4-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) morpholine
2-(4-methylpiperazine-1-yl)-3-(4-oil of mirbane sulphonyl) quinoxaline
2-(4-oil of mirbane sulphonyl)-3-(piperidines-1-yl) quinoxaline
2-(4-oil of mirbane sulphonyl)-3-(tetramethyleneimine-1-yl) quinoxaline
1-(4-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) piperazine-1-yl) ethyl ketone
1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) piperidines-4-carbonyl amine
1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) piperidines-3-alcohol
1-(3-(4-oil of mirbane sulphonyl) quinoxaline-2-yl) piperidines-4-alcohol
4-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) morpholine
2-(4-fluorobenzene sulphonyl)-3-(piperidines-1-yl) quinoxaline
2-(4-fluorobenzene sulphonyl)-3-(tetramethyleneimine-1-yl) quinoxaline
2-(3,4-dihydro-isoquinoline-2 (1H)-yl)-3-(4-fluorobenzene alkylsulfonyl) quinoxaline
2-(4-fluorobenzene sulphonyl)-3-(4-methylpiperazine-1-yl) quinoxaline
1-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) piperidines-4-alcohol
1-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) piperidines-3-alcohol
1-(4-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) piperazine-1-yl) ethyl ketone
1-(3-(4-fluorobenzene sulphonyl) quinoxaline-2-yl) piperidines-4-carbonyl amine
2-(4-fluorobenzene sulphonyl)-3-(piperazine-1-yl) quinoxaline
2-(4-fluorobenzene sulphonyl)-3-(3-methylpiperazine-1-yl) quinoxaline
6-methoxyl group-3-(piperazine-1-yl)-2-is to the methoxy benzenesulfonyl quinoxaline
6-methoxyl group-3-(4-methylpiperazine-1-yl)-2-is to the methoxy benzenesulfonyl quinoxaline
1-(4-(7-methoxyl group-3-is to methoxy benzene sulfonyl quinoxaline-2-yl) piperazine-1 base) ethyl ketone
N'-(3-(3, the 5-dimethoxyaniline) quinoxaline-2-yl)-4-Methyl benzenesulfonyl hydrazine
4-methyl-N'-(3-(3,4,, the 5-trimethoxy-aniline) quinoxaline-2-yl)-4-Methyl benzenesulfonyl hydrazine
N'-(3-(4-chloroaniline) quinoxaline-2-yl)-4-Methyl benzenesulfonyl hydrazine.
3. claim 1 is described a kind of
NThe preparation method of-replacement-3-substituted quinoxaline-2-aminated compounds and salt thereof is characterized in that compound
IvaRealize by following steps:
2,3-dichloro-quinoxaline compounds
IWith the benzol sulfohydrazide compounds that replaces
IIBack flow reaction gets 2-chloro-3-(arylsulfonyl) quinoxaline compounds in alcohol excess solution
III, compound
IIIAt inert solvent benzene, obtain target compound with benzene-like compounds generation condensation reaction in toluene or the dimethylbenzene
Iva, temperature of reaction is 80-130
OC, target compound IV can get pure products, compound through column chromatography
IVaRefabrication becomes hydrochloride, acetate, and oxalate, reaction formula is:
Wherein, R
1, R
2, R
3, R
4Respectively described in claim 1.
4. claim 3 is described a kind of
NThe preparation method of-replacement-3-substituted quinoxaline-2-aminated compounds is characterized in that compound
IIIGet target compound at alcoholic solvent neutralizing amine compounds through microwave reaction
Iva
5. claim 1 is described a kind of
NThe preparation method of-replacement-3-substituted quinoxaline-2-aminated compounds is characterized in that compound
IVbRealize by following steps: compound
IWith hydrazine hydrate at room temperature react 2-chloro-3-diazanyl quinoxaline compound
V, compound
VWith the aryl chloride compounds substitution reaction taking place at room temperature gets compound
VI, compound
VIAt inert solvent benzene, toluene or dimethylbenzene neutralizing amine compounds generation condensation reaction obtain target compound
IVb, temperature of reaction is 80-130
OC, the gained target compound
IVbCan get pure products through column chromatography, and then be prepared into hydrochloride, acetate, oxalate; Reaction formula is:
Wherein, R
1, R
2, R
3, R
4Respectively described in claim 1.
6. according to claim 4 or 5 described preparation methods; it is characterized in that; the aniline that described aminated compounds is selected aniline, cyclo-hexylamine for use, replaced by fluorine atom, amino, trifluoromethyl, hydroxyl, methoxyl group; or ring secondary amine compounds, comprise morpholine, tetramethyleneimine, pyridine, tetrahydroisoquinoline, piperazine, 3 or 4-methylpiperazine, 3 or 4-hydroxy piperidine, 4-ethanoyl piperazine, piperidines-4-acid amides.
7. the application in the preparation treatment tumour medicine relevant of compound according to claim 1 and salt thereof with the inhibition of PI3K/Akt signal path.
8. application according to claim 7 is characterized in that drug prepared contains preparation allowable pharmaceutical excipients, carrier.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304584A (en) * | 2012-03-06 | 2013-09-18 | 南京大学 | 2-hydrazone-thiazolo[4,5-b]quinoxaline compounds, and preparation method and purpose thereof |
| CN105001169A (en) * | 2015-07-09 | 2015-10-28 | 华侨大学 | Synthetic method for 3-aminoquinoxaline-2(1H)-ketone compound |
| CN109535086A (en) * | 2019-01-29 | 2019-03-29 | 湖南科技学院 | A kind of synthetic method of -2 C-3 carboxylate compounds of (1H) -one of quinoxaline |
| CN109535087A (en) * | 2019-01-29 | 2019-03-29 | 湖南科技学院 | A kind of synthetic method of -2 C-3 aroyl compounds of (1H) -one of quinoxaline |
| CN110981819A (en) * | 2019-12-24 | 2020-04-10 | 广西师范大学 | Quinoxaline signal channel inhibitor and preparation method and application thereof |
| CN114605391A (en) * | 2022-02-21 | 2022-06-10 | 广州六顺生物科技股份有限公司 | Quinoxaline derivative and preparation method and application thereof |
| WO2023217156A1 (en) * | 2022-05-09 | 2023-11-16 | 浙江同源康医药股份有限公司 | Polycyclic compound and use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101068808A (en) * | 2004-11-17 | 2007-11-07 | 瑞恩药品公司 | 1-[(6,7-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives |
| CN101282948A (en) * | 2005-10-07 | 2008-10-08 | 埃克塞里艾克西斯公司 | Phosphatidylinositol 3-kinase inhibitors and methods of their use |
| CN101602737A (en) * | 2009-06-11 | 2009-12-16 | 浙江大学 | Benzenesulfonyl quinoxaline compound and preparation method and purposes |
| WO2011026579A1 (en) * | 2009-09-04 | 2011-03-10 | Bayer Schering Pharma Aktiengesellschaft | Substituted aminoquinoxalines as tyrosine threonine kinase inhibitors |
-
2011
- 2011-05-26 CN CN 201110138834 patent/CN102250022B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101068808A (en) * | 2004-11-17 | 2007-11-07 | 瑞恩药品公司 | 1-[(6,7-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives |
| CN101282948A (en) * | 2005-10-07 | 2008-10-08 | 埃克塞里艾克西斯公司 | Phosphatidylinositol 3-kinase inhibitors and methods of their use |
| CN101602737A (en) * | 2009-06-11 | 2009-12-16 | 浙江大学 | Benzenesulfonyl quinoxaline compound and preparation method and purposes |
| WO2011026579A1 (en) * | 2009-09-04 | 2011-03-10 | Bayer Schering Pharma Aktiengesellschaft | Substituted aminoquinoxalines as tyrosine threonine kinase inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| 李荀,等: "喹喔啉类化合物的生物活性研究进展", 《齐鲁药事》 * |
| 汪进，等: "4-氨基-N-2-喹喔啉基苯磺酰胺的合成", 《化学工程师》 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304584A (en) * | 2012-03-06 | 2013-09-18 | 南京大学 | 2-hydrazone-thiazolo[4,5-b]quinoxaline compounds, and preparation method and purpose thereof |
| CN105001169A (en) * | 2015-07-09 | 2015-10-28 | 华侨大学 | Synthetic method for 3-aminoquinoxaline-2(1H)-ketone compound |
| CN105001169B (en) * | 2015-07-09 | 2017-07-21 | 华侨大学 | A kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds |
| CN109535086A (en) * | 2019-01-29 | 2019-03-29 | 湖南科技学院 | A kind of synthetic method of -2 C-3 carboxylate compounds of (1H) -one of quinoxaline |
| CN109535087A (en) * | 2019-01-29 | 2019-03-29 | 湖南科技学院 | A kind of synthetic method of -2 C-3 aroyl compounds of (1H) -one of quinoxaline |
| CN109535087B (en) * | 2019-01-29 | 2020-07-31 | 湖南科技学院 | Synthetic method of quinoxaline-2 (1H) -ketone C-3 site aroyl compound |
| CN110981819A (en) * | 2019-12-24 | 2020-04-10 | 广西师范大学 | Quinoxaline signal channel inhibitor and preparation method and application thereof |
| CN110981819B (en) * | 2019-12-24 | 2022-07-01 | 广西师范大学 | Quinoxaline signal channel inhibitor and preparation method and application thereof |
| CN114605391A (en) * | 2022-02-21 | 2022-06-10 | 广州六顺生物科技股份有限公司 | Quinoxaline derivative and preparation method and application thereof |
| CN114605391B (en) * | 2022-02-21 | 2024-01-26 | 广州六顺生物科技股份有限公司 | Quinoxaline derivative, preparation method and application thereof |
| WO2023217156A1 (en) * | 2022-05-09 | 2023-11-16 | 浙江同源康医药股份有限公司 | Polycyclic compound and use thereof |
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