CN101068808A - 1-[(6,7-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives - Google Patents
1-[(6,7-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives Download PDFInfo
- Publication number
- CN101068808A CN101068808A CNA2005800393565A CN200580039356A CN101068808A CN 101068808 A CN101068808 A CN 101068808A CN A2005800393565 A CNA2005800393565 A CN A2005800393565A CN 200580039356 A CN200580039356 A CN 200580039356A CN 101068808 A CN101068808 A CN 101068808A
- Authority
- CN
- China
- Prior art keywords
- quinoxaline
- piperazine
- methoxyl group
- aminocarboxyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 311
- 238000000034 method Methods 0.000 claims abstract description 206
- 239000000203 mixture Substances 0.000 claims abstract description 92
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- -1 aryl piperazine derivative Chemical class 0.000 claims description 88
- 239000000460 chlorine Substances 0.000 claims description 66
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 64
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 125000006414 CCl Chemical group ClC* 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims description 6
- 150000004885 piperazines Chemical class 0.000 claims description 5
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- 241001465754 Metazoa Species 0.000 claims description 3
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- BRJBOYYVUQVNTG-UHFFFAOYSA-N piperazine;quinoxaline Chemical class C1CNCCN1.N1=CC=NC2=CC=CC=C21 BRJBOYYVUQVNTG-UHFFFAOYSA-N 0.000 abstract 2
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 185
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
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- 238000004440 column chromatography Methods 0.000 description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
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- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 24
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 13
- GLCXJDAMVKPTRX-UHFFFAOYSA-N (3-piperazin-1-ylphenyl)methanamine Chemical compound NCC1=CC=CC(N2CCNCC2)=C1 GLCXJDAMVKPTRX-UHFFFAOYSA-N 0.000 description 12
- VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 238000013019 agitation Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- KIFCSMQTGWVMOD-UHFFFAOYSA-N 1-(3-fluorophenyl)piperazine Chemical compound FC1=CC=CC(N2CCNCC2)=C1 KIFCSMQTGWVMOD-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- XWAJJQBDGFSQLE-UHFFFAOYSA-N (2-piperazin-1-ylphenyl)methanamine Chemical compound NCC1=CC=CC=C1N1CCNCC1 XWAJJQBDGFSQLE-UHFFFAOYSA-N 0.000 description 8
- MRBFGEHILMYPTF-UHFFFAOYSA-N 1-(2-Pyrimidyl)piperazine Chemical compound C1CNCCN1C1=NC=CC=N1 MRBFGEHILMYPTF-UHFFFAOYSA-N 0.000 description 8
- PWZDJIUQHUGFRJ-UHFFFAOYSA-N 1-(2-chlorophenyl)piperazine Chemical compound ClC1=CC=CC=C1N1CCNCC1 PWZDJIUQHUGFRJ-UHFFFAOYSA-N 0.000 description 8
- IVTZRJKKXSKXKO-UHFFFAOYSA-N 1-(2-fluorophenyl)piperazine Chemical compound FC1=CC=CC=C1N1CCNCC1 IVTZRJKKXSKXKO-UHFFFAOYSA-N 0.000 description 8
- KPXVKKBJROCIJB-UHFFFAOYSA-N 1-(4-piperazin-1-ylphenyl)ethanone Chemical compound C1=CC(C(=O)C)=CC=C1N1CCNCC1 KPXVKKBJROCIJB-UHFFFAOYSA-N 0.000 description 8
- FRICBZWJFIRJOB-UHFFFAOYSA-N 2-piperazin-1-ylbenzonitrile Chemical compound N#CC1=CC=CC=C1N1CCNCC1 FRICBZWJFIRJOB-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 8
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 8
- VWOJSRICSKDKAW-UHFFFAOYSA-N 1-(4-nitrophenyl)piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CCNCC1 VWOJSRICSKDKAW-UHFFFAOYSA-N 0.000 description 7
- 239000001640 5-methylquinoxaline Substances 0.000 description 7
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- DOYNABJKDZARLF-UHFFFAOYSA-N 1-(3-bromophenyl)piperazine Chemical compound BrC1=CC=CC(N2CCNCC2)=C1 DOYNABJKDZARLF-UHFFFAOYSA-N 0.000 description 4
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- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 4
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- YVLAWRAOCRZSRV-UHFFFAOYSA-N 3,7-dimethoxyquinoxalin-2-amine Chemical compound N1=C(OC)C(N)=NC2=CC(OC)=CC=C21 YVLAWRAOCRZSRV-UHFFFAOYSA-N 0.000 description 3
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to novel quinoxaline-piperazine compounds, 1-[(6,7-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives and their pharmaceutically acceptable salts, a process for their preparation thereof, and compositions containing such compounds. Therapeutic methods for the treatment of hyperproliferative disorders, including cancers, by administering quinoxalin-piperazine compounds are also included.
Description
Invention field
The present invention relates to new quinoxaline-diethylenediamine compound 1-[(6,7-replaces-2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(mixing) aryl piperazine derivative and its pharmacologically acceptable salt, its preparation method and treat the excess proliferative illness methods of treatment of (comprising cancer) by using quinoxaline-diethylenediamine compound.
Background of invention
The current carcinostatic agent that uses in clinical needs to improve on effect and toxicity, and the new carcinostatic agent that needs exploitation to have better activity and problem still less.
New diethylenediamine compound can be provided for treating for example effective novel therapeutic molecular of cancer of illness.Relevant with the new exploitation of carcinostatic agent, the U.S. Patent Application Publication No. 2003/0092910 that on May 15th, 2003 was presented to people such as Cho has provided the diethylenediamine compound with formula A,
In U.S. Patent Application Publication No. 2003/0092910, provided 1-[(2-alkoxyl group quinoxaline-3-yl) preparation of aminocarboxyl-4-aryl piperazines, wherein R
aAnd R
bCondense and form the unsaturated ring of C3-C4.But the compound of formula A only has hydrogen atom on C-5, C-6, C-7 and the C-8 position of quinoxaline ring.
Promptly, the compound of listing in the U.S. Patent Application Publication No. 2003/0092910 is at 1-[(2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-the C-6 position of the quinoxaline ring of 4-aryl piperazines on except having hydrogen without any other groups, and do not have preparation on the C-6 position of quinoxaline, to have the compound of other groups except hydrogen and test as antineoplastic agent.
The present invention has studied 1-[(2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-the 4-aryl piperazine derivative, because it has outstanding anti-tumor activity and low-down toxicity, and provided new 1-[(6,7-replaces-2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(mixing) aryl piperazine derivative, it is at 1-[(2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-have other functional groups except hydrogen on the C-6 of the quinoxaline ring of 4-aryl piperazine derivative, give the preparation method of these new compounds and strong anti-tumor activity.
Therefore, an object of the present invention is to provide new compound 1-[(6,7-replaces-2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(mixing) aryl piperazine derivative.
Another object of the present invention provides this new compound 1-[(6, and 7-replaces-2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-preparation method of 4-(mixing) aryl piperazine derivative.
Another object of the present invention provides and comprises 1-[(6, and 7-replaces-2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(mixing) aryl piperazine derivative or its pharmacologically acceptable salt be as the pharmaceutical composition of activeconstituents.
Another object of the present invention provides new compound 1-[(6, and 7-replaces-2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-anti-tumor activity of giving prominence to of 4-(mix) aryl piperazine derivative and described compound be as the purposes of antineoplastic agent.
Detailed Description Of The Invention
The present invention includes new quinoxaline-bridged piperazine derivatives or its pharmacologically acceptable salt of general formula (1), the purposes of its preparation method and they treatment excess proliferative illness, disease or situation in experimenter's (for example, human patients or other animal subjects).Method of the present invention comprise to the experimenter use significant quantity according to quinoxaline-diethylenediamine compound of the present invention.This treatment can for example prevent, improves and/or suppress the symptom of excess proliferative situation, and/or can prevent or suppress for example cell proliferation in tumour such as malignant growth or growth.Therapeutic strategy of the present invention is ameliorate tumor load on measurable degree at least, and improves the patient's who suffers from the excess proliferative situation survival rate.Comprise vegetation at these in to disease, illness and situation with the treatment sensitivity that medicament of the present invention carried out, more specifically, the tumour in various sources (lung, colon, stomach, unstriated muscle, oesophagus, non Hodgkin lymphoma, nonsmall-cell lung cancer, or the like).
The compound that is used for the inventive method
The compound that is used for the inventive method comprises the have formula quinoxaline-bridged piperazine derivatives of (1), 1-[(6,7-replaces-2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(mixing) aryl piperazine derivative:
Wherein, X and Y are N or C-R independently
7R
1And R
2Be C independently
1-C
6Alkoxyl group, C
1-C
6Alkyl or halogen; R
3Be C
1-C
6Alkyl; R
4, R
5, R
6And R
7Be hydrogen, C independently
1-C
6Alkoxyl group, C
1-C
6Alkyl, C
1-C
6Haloalkyl, C
1-C
6Alkyl-carbonyl, halogen, cyano group or nitro.
In above-mentioned definition, term " halogen " expression fluorine, chlorine, bromine or iodine.
Term " alkoxyl group " expression C
1-C
6Alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy and tert.-butoxy.
Term " alkyl " expression C
1-C
6Alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, isohexyl and cyclohexyl.
The C of wherein hydrogen and halogen such as fluorine or chlorine exchange represented in term " haloalkyl "
1-C
6Alkyl, for example trifluoromethyl.
Term " alkyl-carbonyl " the expression carbonyl of alkyl ketonize, for example methyl carbonyl or ethyl carbonyl.
Preferred understanding, in the structure of formula (1), X and Y are N, C-H, C-F, C-Cl, C-CN, C-CH independently
3Or C-OCH
3, R
1And R
2Be fluorine, chlorine, methyl or methoxy, R
3Be methyl, R
4, R
5And R
6Be hydrogen, chlorine, nitro, methyl, trifluoromethyl, methoxyl group or acetoxyl group independently, and R
7Be hydrogen, fluorine, chlorine, cyano group, methyl or methoxy.
The present invention gives the method for the compound of preparation general formula (1).The preparation method of formula (1) comprises the two-stage process as shown in scheme 1; Scheme 1 is included in the conventional organic solvent compound 6 with general formula (2), 7-replaces-2-alkoxyl group-3-aminoquinoxaline with provide L-C (=O)-reagent of L ' group reacts in the presence of alkali, obtain the compound of general formula (3), in conventional organic solvent, the compound of general formula (3) and compound 1-(mixing) aryl piperazine derivative of general formula (4) are reacted in the presence of alkali subsequently, obtain the compound of general formula (1).
[scheme 1]
Wherein, X, Y, R
1, R
2, R
3, R
4, R
5And R
6Independently as hereinbefore defined, and L and L ' be imidazoles, chlorine, oxyethyl group, phenoxy group or 4-nitrophenoxy independently.
Two-step reaction in the scheme 1 can carry out continuously, and without the compound of purifying as the general formula (3) of the intermediate in this method.
The preparation method of the compound of scheme 1 formula of (1) can following detailed explanation:
The employed L-C of providing of reaction above being used for (=O)-reagent of L ' group can comprise 1,1-carbonyl dimidazoles, phosgene, carbonyl diurethane phenates, phenyl chloroformate, chloroformic acid 4-nitro phenyl ester and Vinyl chloroformate, and it can be with the 1.0-1.5 equivalent of initial compounds, and the normal amount of preferred 1.0-1.1 is used.
Reaction can be at conventional organic solvent, as carrying out in tetrahydrofuran (THF) (THF), methylene dichloride, acetonitrile, chloroform and the dimethyl formamide.
And, reaction preferably coupling agent such as routine is inorganic or organic bases in the presence of carry out.Be used for the conventional inorganic or organic bases of this type of of described reaction and can comprise sodium hydride, potassium hydride KH, sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, triethylamine, pyridine and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (hereinafter being called DBU).
Reaction can 0 ℃ to the temperature of the boiling point of solvent for use, preferably in room temperature under～100 ℃, carried out preferred 10-24 hour 5-48 hour.
In the scheme 1 second step, promptly compound (3) with compound (4) thus reaction obtains compound (1), can in the presence of conventional organic solvent, under 50-100 ℃ temperature, carry out 5-48 hour.Compound (4) can use with the 1.0-1.5 equivalent.
In addition, reaction is the inorganic or organic bases in routine preferably, for example carries out under the existence such as sodium hydride, potassium hydride KH, sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, triethylamine, pyridine, DBU.
Separating and purifying multicolumn chromatography method (Quad of compound in the scheme 1 (2), (3) and (1)
3+Biotage Co., VA USA) carries out with high speed liquid phase column chromatography (having self-actuated sampler), and the structure of the compound of analysis general formula (1) also confirms with NMR and mass spectrum.
In addition, be used as the compound 6 of the general formula (2) of parent material, the 7-replacement-2-alkoxyl group-3-aminoquinoxaline is new compound, and can prepare by following scheme 2: with the compound and the sodium alkoxide NaOR of general formula (5)
3(R
3Be C
1-C
6Alkyl) thus reaction obtains the compound of general formula (2).
[scheme 2]
Wherein, R
1, R
2And R
3Independently such as in the scheme 1 definition.
Can pass through for example J.Med.Chem.1995,38,3720-3740 or Bull.Chem.Soc.Jpn.1998,71, the currently known methods of describing among the 1125-1135 prepares the compound of general formula (5).
Oxyalkylation reaction in the scheme 2 can be carried out with sodium alkoxide in conventional organic solvent such as THF, and sodium alkoxide can be with the 1.0-10.0 equivalent of initial compounds (being the compound of general formula (5)), and the normal amount of preferred 1.0-1.1 is used.
In addition, the compound of general formula (2) can prepare by following scheme 3: with the compound and 2 of general formula (6), thereby 4-dimethoxybenzylamine reaction obtains the compound of general formula (7), and with the compound of general formula (7) with trifluoroacetic acid (TFA) thus react the compound that obtains general formula (2).
[scheme 3]
Wherein, R
1, R
2And R
3Independently such as in the scheme 1 definition.
The compound of general formula (6) can pass through for example J.Med.Chem.1990, and 33, the currently known methods of describing among the 2240-2254 prepares.
The compound and 2 of scheme 3 formula ofs (6), the reaction of 4-dimethoxybenzylamine can be carried out in conventional organic solvent such as methyl-sulphoxide, and 2, the 4-dimethoxybenzylamine can be with the 1.0-5.0 equivalent of the compound of general formula (6), and the normal amount of preferred 1.0-1.1 is used.
And the compound of general formula (7) and the reaction of trifluoroacetic acid can be carried out in conventional organic solvent such as methylene dichloride, to obtain the compound of general formula (2).Trifluoroacetic acid can be with the 0.5-1.5 equivalent of the compound of general formula (7), and preferred 1.0 normal amounts are used.
Compound of the present invention can have very strong activity for multiple excess proliferative disease (comprising tumour), and can be used as antineoplastic agent.
Compound of the present invention can also mix obtaining pharmaceutical composition by currently known methods with pharmaceutically acceptable carrier, thereby described pharmaceutical composition can be used for prevention or treatment is human or mammiferous various different types of tumors.
Therefore, the present invention includes the compound that contains general formula (1) or its pharmacologically acceptable salt pharmaceutical composition as activeconstituents.
The pharmacologically acceptable salt of the compound of general formula (1) is pharmaceutically useful mineral acid, organic acid, basic metal and ammonium salt; For example, the salt that forms with mineral acid example hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid; The salt that forms with organic acid such as formic acid, acetate, propionic acid, oxalic acid, succsinic acid, phenylformic acid, citric acid, toxilic acid, propanedioic acid, tartrate, oxyacetic acid, lactic acid, fumaric acid, lactobionic acid, Whitfield's ointment, acetylsalicylic acid; The salt that forms with amino acid such as glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, Serine, halfcystine, Gelucystine, aspartic acid, L-glutamic acid, Methionin, arginine, tyrosine, proline(Pro); The salt that forms with sulfonic acid such as methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids; An alkali metal salt is as sodium salt or sylvite; Alkaline earth salt is as calcium salt or magnesium salts; Ammonium salt; The salt that forms with the organic bases that the physiology consistency is provided is as the salt that forms with methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine or the like.
In addition, the novel cpd of general formula (1) and its pharmacologically acceptable salt can with nontoxic pharmaceutically acceptable vehicle such as carrier, adjuvant and excipient composition, this mixture can orally use so that the form of tablet, capsule, lozenge, solution, suspensoid is oral or non-then, with prevention or the treatment mankind or mammiferous various types of tumour.
Compound that preparation comprises general formula (1) can be used for and sweetener, tackiness agent, solvating agent, dissolution aids, wetting agent, emulsifying agent, isotonic agent, sorbent material, degradation agents, antioxidant, sanitas, lubricant, weighting agent, spices or the like can be comprised as the vehicle of the pharmaceutical composition of activeconstituents; For example lactose, glucose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose, glycine, silicon-dioxide, talcum, stearic acid, tristearin, Magnesium Stearate, calcium stearate, neusilin, starch, gelatin, tragacanth gum, glycine, silicon-dioxide, alginic acid, sodiun alginate, methylcellulose gum, Xylo-Mucine, agar, water, ethanol, polyoxyethylene glycol, polyvinylpyrrolidone, sodium-chlor, Repone K, orange essence, strawberry flavour, vanilla flavor or the like.
The per daily dose of the compound of general formula (1) can be according to patient's age, body weight, sex, use type, healthy state, disease degree or the like becomes, and for 70kg grownup, usually according to doctor or pharmacist's suggestion with once to using 0.01mg to 5,000mg several times every day.
Embodiment
Further illustrate the present invention by the reference the following examples, these embodiment are used to illustrate some embodiment preferred, and never are restriction the present invention.
Embodiment 1
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-a) 3-amino-6-fluoro-2-methoxyl group quinoxaline of 4-phenylpiperazine
In room temperature with under stirring, (550mg, (6.01g 27.8mmol), and at room temperature further stirred 1 hour the 3-amino in being dissolved in tetrahydrofuran (THF) (40ml)-2-chloro-6-fluorine quinoxaline to be added in 25wt% sodium methylate in the methyl alcohol among 2.78mmol).The gained mixture under reduced pressure concentrates to remove and desolvates.Use the dichloromethane extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 491mg title compound (productive rate, 91%).
B) N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum
At room temperature, with 3-amino-6-fluoro-2-methoxyl group quinoxaline (580mg, 3.00mmol) and Vinyl chloroformate (391mg 3.60mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (285mg, 3.60mmol).At room temperature stir the mixture 10 hours and concentrating under reduced pressure desolvates to remove, and passes through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 740mg title compound (productive rate, 93%).
C) aminocarboxyl 1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl)]-the 4-phenylpiperazine
At room temperature, with N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum (27mg, 0.10mmol) and the 1-phenylpiperazine (24mg 0.15mmol) is dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (23mg, 0.15mmol).Stirring gained mixture 7 hours and concentrating under reduced pressure desolvate to remove under 70 ℃, and pass through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 34mg title compound (productive rate, 88%).
1H NMR(300MHz，CDCl
3)：δ3.29(s，4H)，3.77(s，3H)，4.14(s，4H)，6.89-6.97(m，4H)，7.24-7.56(m，5H)，7.62-7.71(m，1H)。
Embodiment 2
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-p-methoxy-phenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 8 4%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ3.15(s，4H)，3.79-3.87(m，6H)，4.11(s，4H)，6.86-7.02(m，4H)，7.18-7.22(m，1H)，7.39-7.50(m，1H)，7.65-7.72(m，1H)。
Embodiment 3
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 87%) with embodiment 1.
1H NMR(300MHz，CDCl
3)：δ3.28(s，4H)，3.80(s，6H)，4.13(s，4H)，6.45-6.58(m，3H)，7.01(s，1H)，7.17-7.23(m，2H)，7.37-7.70(m，2H)。
Embodiment 4
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(4-p-methoxy-phenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(4-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 8 0%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ3.18(s，4H)，3.79(s，6H)，4.08-4.15(m，4H)，6.85-6.98(m，4H)，7.22-7.76(m，4H)。
Embodiment 5
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 72%) with embodiment 1.MS(ESI)m/z 442(M+1)。
Embodiment 6
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3,4, the 5-trimethoxyphenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3,4, the 5-trimethoxyphenyl) piperazine are obtained title compound (productive rate, 76%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ3.22(s，4H)，3.79-3.85(m，12H)，4.13(s，4H)，6.19(s，2H)，7.20-7.34(m，1H)，7.35-7.36(m，1H)，7.44(s，1H)，7.67-7.70(m，1H)。
Embodiment 7
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-aminomethyl phenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 73%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ2.35(s，3H)，2.98-3.03(m，4H)，3.73-3.78(m，3H)，4.10-4.14(m，4H)，7.02-7.17(m，2H)，7.19-7.29(m，2H)，7.36(s，1H)，7.48-7.60(m，1H)，7.67-7.74(m，1H)。
Embodiment 8
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 1.
1H NMR (200MHz, CDCl
3): δ 2.33 (s, 3H), 3.26-3.30 (m, 4H), 3.74-3.78 (m, 3H), 4.13 (s, 4H), 6.75-6.78 (m, 3H), 7.14-7.28 (m, 2H), 7.36 (s, 1H), 7.44-7.51 (dd, J=9.8 and 2.4Hz, 1H), 7.67-7.74 (m, 1H).
Embodiment 9
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2, the 6-3,5-dimethylphenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2, the 6-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 65%) with embodiment 1.
1H NMR(300MHz，CDCl
3)：δ2.26(s，3H)，3.20(s，4H)，3.71(s，3H)，4.12-4.18(m，4H)，6.99-7.01(m，3H)，7.26-7.32(m，2H)，7.53-7.81(m，2H)。
Embodiment 10
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 79%) with embodiment 1.
1H NMR(300MHz，CDCl
3)：δ2.29(s，6H)，3.27(s，4H)，3.88(s，3H)，4.14(s，4H)，6.59(s，3H)，7.01-7.10(s，1H)，7.24-7.36(m，2H)，7.47-7.71(m，2H)。
Embodiment 11
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 8 0%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ3.34(s，4H)，3.79(s，3H)，4.10(s，4H)，7.07-7.24(m，3H)，7.35-7.43(m，3H)，7.71(m，1H)。
Embodiment 12
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-fluorophenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-fluorophenyl) piperazine are obtained title compound (productive rate, 91%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ3.18(s，4H)，3.78(s，3H)，4.13(s，4H)，6.93-7.10(m，5H)，7.20-7.34(m，1H)，7.46-7.60(m，1H)，7.67-7.74(m，1H)。
Embodiment 13
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3-fluorophenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluorophenyl) piperazine are obtained title compound (productive rate, 85%) with embodiment 1.
1H NMR(300MHz，CDCl
3)：δ3.19(s，4H)，3.77(s，3H)，4.13(s，4H)，6.88-7.02(m，4H)，7.23-7.27(m，1H)，7.45-7.71(m，3H)。
Embodiment 14
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-chloro-phenyl-) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-chloro-phenyl-) piperazine are obtained title compound (productive rate, 87%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ3.14(s，4H)，3.79(s，3H)，4.13(s，4H)，6.97-7.05(m，2H)，7.22-7.28(m，2H)，7.33-7.40(m，2H)，7.46-7.51(d，J＝10.2 Hz，1H)，7.66-7.73(m，1H)。
Embodiment 15
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 70%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ3.30(s，4H)，3.76(s，3H)，4.13(s，4H)，6.77-6.91(m，3H)，7.15-7.33(m，3H)，7.44-7.58(d，J＝10.0Hz，1H)，7.58-7.75(m，1H)。
Embodiment 16
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(4-chloro-phenyl-) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(4-chloro-phenyl-) piperazine are obtained title compound (productive rate, 95%) with embodiment 1.
1H NMR(300MHz，CDCl
3)：δ3.25(s，4H)，3.78(s，3H)，4.13(s，4H)，6.86(d，J＝8.4 Hz，2H)，7.22-7.26(m，3H)，7.44(m，1H)，7.70(m，1H)。
Embodiment 17
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-cyano-phenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-cyano-phenyl) piperazine are obtained title compound (productive rate, 85%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ3.31(s，4H)，3.73-3.85(m，3H)，4.06-4.16(m，4H)，7.03-7.11(m，3H)，7.20-7.34(m，1H)，7.50-7.62(m，3H)，7.67-7.74(m，1H)。
Embodiment 18
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(4-acetylphenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(4-acetylphenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ2.54(s，3H)，3.42-3.48(m，4H)，3.79(s，3H)，4.14(s，4H)，6.89(d，J＝9.0Hz，2H)，7.10-7.50(m，3H)，7.69-7.80(m，1H)，7.91(d，J＝7.8Hz，2H)。
Embodiment 19
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(4-nitrophenyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluorophenyl) piperazine are obtained title compound (productive rate, 86%) with embodiment 1.
1H NMR(200MHz，DMSO-d
6)：δ3.18(s，4H)，3.62(s，3H)，3.99-4.01(m，4H)，7.01-7.18(m，4H)，7.53-7.57(m，1H)，7.70-7.78(m，1H)，8.06-8.11(m，2H)。
Embodiment 20
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-pyridyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-pyridyl) piperazine are obtained title compound (productive rate, 79%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ3.71(s，7H)，4.11(s，4H)，6.66(d，J＝9.0Hz，2H)，7.10(m，1H)，7.22-7.25(m，1H)，7.38-7.54(m，3H)，7.65-7.68(m，1H)，8.19(d，J＝3.8Hz，1H)。
Embodiment 21
1-[(6-fluoro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-pyrimidyl) piperazine
By the method identical N-(6-fluoro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-pyrimidyl) piperazine are obtained title compound (productive rate, 71%) with embodiment 1.
1H NMR(200MHz，CDCl
3)：δ3.68(s，4H)，3.96(s，3H)，4.12(s，4H)，6.23(t，J＝4.4Hz，1H)，7.02(s，1H)，6.89-7.00(m，1H)，7.36-7.43(m，1H)，7.67(m，1H)，8.32(d，J＝4.4Hz，2H)。
Embodiment 22
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-the 4-phenylpiperazine
A) 3-amino-6-chloro-2-methoxyl group quinoxaline
In room temperature with under stirring, the 3-amino-2 in being dissolved in tetrahydrofuran (THF) (60ml), (1.30g, (13.1g 60.7mmol), and at room temperature further stirred 90 minutes the 6-dichloro-quinoxaline to be added in 25wt% sodium methylate in the methyl alcohol among 6.07mmol).The gained mixture under reduced pressure concentrates to remove and desolvates.Use the dichloromethane extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 1.22g title compound (productive rate, 96%).
B) N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum
At room temperature, with 3-amino-6-chloro-2-methoxyl group quinoxaline (629mg, 3.00mmol) and Vinyl chloroformate (391mg 3.60mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (285mg, 3.60mmol).At room temperature stir gained mixture 10 hours and concentrating under reduced pressure and desolvate, and pass through SiO to remove
2The column chromatography purifying.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 803mg title compound (productive rate, 95%).
C) aminocarboxyl 1-[(6-chloro-2-methoxyl group quinoxaline-3-yl)]-the 4-phenylpiperazine
At room temperature, with N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum (27mg, 0.10mmol) and the 1-phenylpiperazine (24mg 0.15mmol) is dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (23mg, 0.15mmol).Stirring gained mixture 7 hours and concentrating under reduced pressure desolvate to remove under 70 ℃, and pass through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 36mg title compound (productive rate, 91%).
1H NMR(300MHz，CDCl
3)：δ3.22-3.30(m，4H)，3.75-3.78(m，3H)，4.08-4.13(m，4H)，6.89-6.96(m，3H)，7.19-7.44(m，5H)，7.64-7.80(m，1H)。
Embodiment 23
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-p-methoxy-phenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 77%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.10-3.17(m，4H)，3.80-3.89(m，6H)，4.08-4.15(m，4H)，6.88-7.07(m，4H)，7.20-7.32(m，1H)，7.41-7.44(m，1H)，7.50-7.68(m，1H)，7.82(s，1H)。
Embodiment 24
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 70%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.22-3.30(m，4H)，3.76-3.80(m，6H)，4.08-4.14(m，4H)，6.46-6.57(m，3H)，7.20(t，J＝8.1Hz，1H)，7.34-7.44(m，1H)，7.50-7.67(m，1H)，7.80(s，1H)。
Embodiment 25
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(4-p-methoxy-phenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(4-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 81%) with embodiment 22.
1H NMR(200MHz，CDCl
3)：δ3.16(s，4H)，3.78(s，3H)，4.16(s，4H)，6.88-6.93(m，4H)，7.27-7.80(m，4H)。
Embodiment 26
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 81%) with embodiment 22.MS(ESI)m/z 458(M+1)。
Embodiment 27
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3,4, the 5-trimethoxyphenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3,4, the 5-trimethoxyphenyl) piperazine are obtained title compound (productive rate, 84%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.17-3.25(m，4H)，3.81-3.86(m，12H)，4.09-4.16(m，4H)，6.21(s，2H)，7.21-7.30(m，1H)，7.33-7.54(m，1H)，7.58-7.69(m，1H)，7.81(s，1H)。
Embodiment 28
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-aminomethyl phenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 80%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ2.35(s，3H)，2.95-3.02(m，4H)，3.74-3.77(m，3H)，4.08-4.14(m，4H)，7.01-7.57(m，7H)，7.64-7.85(m，1H)。
Embodiment 29
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.20-3.30(m，4H)，3.74-3.77(m，3H)，4.11-4.14(m，4H)，6.74-6.77(m，3H)，7.16-7.25(m，4H)，7.64-7.81(m，1H)。
Embodiment 30
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2, the 6-3,5-dimethylphenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2, the 6-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 67%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ2.33-2.40(m，6H)，3.14-3.22(m，4H)，3.69-3.76(m，3H)，4.06-4.18(m，4H)，6.97-7.04(m，3H)，7.20-7.85(m，4H)。
Embodiment 31
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 79%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ2.29(s，6H)，3.19-3.29(m，4H)，3.73-3.89(m，3H)，4.11-4.14(m，4H)，6.58(s，3H)，7.19-7.25(m，1H)，7.36-7.64(m，2H)，7.67-7.81(m，1H)。
Embodiment 32
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 84%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.27-3.37(m，4H)，3.76-3.80(m，3H)，4.12-4.14(m，4H)，7.08-7.26(m，4H)，7.36-7.45(m，3H)，7.64-7.80(m，1H)。
Embodiment 33
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-fluorophenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-fluorophenyl) piperazine are obtained title compound (productive rate, 80%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.12-3.21(m，4H)，3.77-3.84(m，3H)，4.11-4.15(m，4H)，6.95-7.10(m，4H)，7.20-7.45(m，3H)，7.65-7.82(m，1H)。
Embodiment 34
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3-fluorophenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluorophenyl) piperazine are obtained title compound (productive rate, 77%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.13-3.20(m，4H)，3.77(s，3H)，4.14(s，4H)，6.88-7.02(m，4H)，7.20-7.24(m，1H)，7.36-7.44(m，1H)，7.50-7.67(m，1H)，7.80(s，1H)。
Embodiment 35
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-chloro-phenyl-) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-chloro-phenyl-) piperazine are obtained title compound (productive rate, 76%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.08-3.17(m，4H)，3.78-3.86(m，3H)，4.09-4.15(m，4H)，7.00-7.07(m，2H)，7.20-7.45(m，5H)，7.65-7.84(m，1H)。
Embodiment 36
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 85%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.22-3.32(m，4H)，3.73-3.77(m，3H)，4.11-4.14(m，4H)，6.78-6.90(m，3H)，7.19-7.44(m，4H)，7.64-7.80(m，1H)。
Embodiment 37
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(4-chloro-phenyl-) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(4-chloro-phenyl-) piperazine are obtained title compound (productive rate, 96%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.18-3.26(m，4H)，3.76(s，3H)，4.11-4.14(m，4H)，6.84-6.87(d，J＝8.7Hz，2H)，7.22-7.34(m，3H)，7.41-7.53(m，1H)，7.65-7.66(m，1H)，7.79(s，1H)。
Embodiment 38
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-cyano-phenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-cyano-phenyl) piperazine are obtained title compound (productive rate, 91%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.25-3.32(m，4H)，3.84(s，3H)，4.08-4.15(m，4H)，7.06-7.08(m，2H)，7.21(m，1H)，7.41-7.67(m，4H)，7.82(s，1H)。
Embodiment 39
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(4-acetylphenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(4-acetylphenyl) piperazine are obtained title compound (productive rate, 85%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ2.54(s，3H)，3.50(s，4H)，3.80(s，3H)，4.14(s，4H)，6.89(d，J＝7.7Hz，2H)，7.44(s，1H)，7.66(s，1H)，7.79(s，1H)，7.79(s，1H)，7.91(d，J＝7.7Hz，2H)。
Embodiment 40
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(4-nitrophenyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(4-nitrophenyl) piperazine are obtained title compound (productive rate, 82%) with embodiment 22.
1H NMR(300MHz，DMSO-d
6)：δ3.62-3.66(m，8H)，4.06(s，3H)，7.07(d，J＝9.0Hz，2H)，7.58(d，J＝8.4Hz，1H)，7.76-7.80(m，2H)，8.11(d，J＝9.0Hz，2H)，9.46(s，1H)。
Embodiment 41
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-pyridyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-pyridyl) piperazine are obtained title compound (productive rate, 70%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.63-3.73(m，7H)，4.08-4.15(m，4H)，6.68(d，J＝8.7Hz，2H)，7.20-7.31(m，1H)，7.42-7.53(m，2H)，7.65-7.80(m，2H)，8.21(d，J＝3.6Hz，1H)。
Embodiment 42
1-[(6-chloro-2-methoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(2-pyrimidyl) piperazine
By the method identical N-(6-chloro-2-methoxyl group quinoxaline-3-yl) urethanum and the reaction of 1-(2-pyrimidyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 22.
1H NMR(300MHz，CDCl
3)：δ3.71(s，4H)，3.99(s，3H)，4.15(s，4H)，6.55(s，1H)，7.27-7.43(m，2H)，7.66(s，1H)，7.80(s，1H)，8.35(s，2H)。
Embodiment 43
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-the 4-phenylpiperazine
A) 3-amino-2-methoxyl group-6-methyl-quinoxaline
In room temperature with under stirring, (550mg, (6.14g 28.4mmol), and at room temperature further stirred 60 minutes the 3-amino in being dissolved in tetrahydrofuran (THF) (30ml)-2-chloro-6-methyl-quinoxaline to be added in 25wt% sodium methylate in the methyl alcohol among 2.84mmol).The gained mixture under reduced pressure concentrates to remove and desolvates.Use the dichloromethane extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 467mg title compound (productive rate, 87%).
B) N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum
At room temperature, with 3-amino-2-methoxyl group-6-methyl-quinoxaline (568mg, 3.00mmol) and Vinyl chloroformate (391mg 3.60mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (285mg, 3.60mmol).At room temperature stir gained mixture 10 hours and concentrating under reduced pressure and desolvate, and pass through SiO to remove
2The column chromatography purifying.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 768mg title compound (productive rate, 98%).
C) aminocarboxyl 1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl)]-the 4-phenylpiperazine
At room temperature, with N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum (26mg, 0.10mmol) and the 1-phenylpiperazine (24mg 0.15mmol) is dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (23mg, 0.15mmol).Stirring gained mixture 7 hours and concentrating under reduced pressure desolvate to remove under 70 ℃, and pass through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 34mg title compound (productive rate, 90%).
1H NMR(300MHz，CDCl
3)：δ2.42-2.48(m，3H)，3.22-3.30(m，4H)，3.77(s，3H)，4.12(s，4H)，6.90-7.12(m，4H)，7.25-7.32(m，3H)，7.48-7.65(m，2H)。
Embodiment 44
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(2-p-methoxy-phenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(2-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 66%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.42-2.49(m，3H)，3.10-3.16(m，4H)，3.80-3.89(m，6H)，4.08-4.17(m，4H)，6.88-7.11(m，5H)，7.26-7.32(m，1H)，7.48-7.64(m，2H)。
Embodiment 45
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(3-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 73%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.43-2.48(m，3H)，3.23-3.30(m，4H)，3.76-3.87(m，3H)，4.04-4.13(m，4H)，6.45-6.50(m，2H)，6.57(d，J＝8.4Hz，1H)，7.01-7.12(m，1H)，7.17-7.33(m，3H)，7.48-7.65(m，2H)。
Embodiment 46
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(4-p-methoxy-phenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(4-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 80%) with embodiment 43.
1H NMR(200MHz，CDCl
3)：δ2.48(s，3H)，3.16-3.14(m，4H)，3.78-3.82(m，6H)，4.13(s，4H)，6.84-7.02(m，4H)，7.14-7.33(m，3H)，7.53-7.64(m，1H)。
Embodiment 47
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 94%) with embodiment 43.MS(ESI)m/z 438(M+1)。
Embodiment 48
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(3,4, the 5-trimethoxyphenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(3,4, the 5-trimethoxyphenyl) piperazine are obtained title compound (productive rate, 94%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.44-2.49(m，3H)，3.18-3.25(m，4H)，3.80-3.86(m，12H)，4.04-4.13(m，4H)，6.20(s，2H)，7.02-7.20(m，1H)，7.31-7.40(m，1H)，7.46-7.63(m，2H)。
Embodiment 49
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(2-aminomethyl phenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(2-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 95%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.32-2.56(m，6H)，2.88-3.00(m，4H)，3.77(s，3H)，4.08-4.13(m，4H)，7.02-7.04(m，3H)，7.19-7.39(m，3H)，7.51-7.65(m，2H)。
Embodiment 50
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.33-2.46(m，6H)，3.14-3.37(m，4H)，3.73-3.87(m，3H)，4.05-4.18(m，4H)，6.72-6.78(m，3H)，7.00-7.20(m，2H)，7.30-7.38(m，1H)，7.49-7.62(m，2H)。
Embodiment 51
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(2, the 6-3,5-dimethylphenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(2, the 6-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 88%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.04-2.58(m，9H)，3.14-3.20(m，4H)，3.71-3.76(m，3H)，4.07-4.14(m，4H)，7.00-7.15(m，4H)，7.25-7.76(m，3H)。
Embodiment 52
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 87%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.29(s，6H)，2.42-2.48(m，3H)，3.20-3.28(m，4H)，3.75-3.80(m，3H)，4.10-4.13(m，4H)，6.59(s，3H)，7.00-7.12(m，1H)，7.31(d，J＝8.4Hz，1H)，7.48-7.65(m，2H)。
Embodiment 53
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 82%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.46-2.49(m，3H)，3.18-3.31(m，4H)，3.73-3.80(m，3H)，4.10-4.19(m，4H)，7.10-7.20(m，4H)，7.34-7.39(m，2H)，7.56-7.65(m，2H)。
Embodiment 54
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(2-fluorophenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(2-fluorophenyl) piperazine are obtained title compound (productive rate, 79%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.42-2.49(m，3H)，3.12-3.19(m，4H)，3.79(s，3H)，4.11-4.13(m，4H)，6.97-7.12(m，5H)，7.26-7.33(m，1H)，7.48-7.63(m，2H)。
Embodiment 55
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(3-fluorophenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluorophenyl) piperazine are obtained title compound (productive rate, 70%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.43-2.49(m，3H)，3.13-3.21(m，4H)，3.77(s，3H)，4.11-4.13(m，4H)，6.88-6.99(m，4H)，7.13(m，1H)，7.25(m，1H)，7.48-7.65(m，2H)。
Embodiment 56
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(2-chloro-phenyl-) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(2-chloro-phenyl-) piperazine are obtained title compound (productive rate, 66%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.43-2.49(m，3H)，3.10-3.15(m，4H)，3.81(s，3H)，3.08-4.12(m，4H)，7.00-7.12(m，3H)，7.24-7.40(m，3H)，7.49-7.65(m，2H)。
Embodiment 57
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 72%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.45(s，3H)，3.26(s，4H)，3.77(s，3H)，4.08-4.18(m，4H)，6.78-6.90(m，3H)，7.15-7.38(m，3H)，7.56-7.64(m，2H)。
Embodiment 58
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(4-chloro-phenyl-) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(4-chloro-phenyl-) piperazine are obtained title compound (productive rate, 78%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.44-2.47(m，3H)，3.19-3.26(m，4H)，3.78(s，3H)，4.12(s，4H)，6.87(d，J＝8.9Hz，2H)，7.01-7.11(m，1H)，7.22-7.26(m，3H)，7.52-7.61(m，2H)。
Embodiment 59
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(2-cyano-phenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(2-cyano-phenyl) piperazine are obtained title compound (productive rate, 91%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.46(s，3H)，3.28(s，4H)，3.86(s，3H)，4.08-4.19(m，4H)，7.01-7.08(m，3H)，7.17-7.37(m，1H)，7.49-7.61(m，4H)。
Embodiment 60
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(4-acetylphenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(4-acetylphenyl) piperazine are obtained title compound (productive rate, 87%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.45-2.53(m，6H)，3.47(s，4H)，3.81(s，3H)，3.87-4.13(m，4H)，6.88(d，J＝8.7Hz，2H)，7.22-7.36(m，2H)，7.56-7.76(m，2H)，7.90(d，J＝8.7Hz，2H)。
Embodiment 61
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(4-nitrophenyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(4-nitrophenyl) piperazine are obtained title compound (productive rate, 86%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.46(s，3H)，3.52-3.58(m，4H)，3.82(s，3H)，4.09-4.13(m，4H)，6.85(d，J＝9.2Hz，2H)，7.03-7.15(m，1H)，7.41(m，1H)，7.52-7.58(m，2H)，8.16(d，J＝9.2Hz，2H)。
Embodiment 62
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(2-pyridyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(2-pyridyl) piperazine are obtained title compound (productive rate, 83%) with embodiment 43.
1H NMR (300MHz, CDCl
3): δ 2.43-2.47 (m, 3H), 3.63-3.73 (m, 7H), 4.13 (s, 4H), 6.67 (d, J=8.4Hz, 2H), 7.01-7.12 (m, 1H), 7.30-7.33 (m, 1H), 7.48-7.62 (m, 3H), 8.21 (dd, J=4.8 and 1.5Hz, 1H).
Embodiment 63
1-[(2-methoxyl group-6-methyl-quinoxaline-3-yl) aminocarboxyl]-4-(2-pyrimidyl) piperazine
By the method identical N-(2-methoxyl group-6-methyl-quinoxaline-3-yl) urethanum and the reaction of 1-(2-pyrimidyl) piperazine are obtained title compound (productive rate, 93%) with embodiment 43.
1H NMR(300MHz，CDCl
3)：δ2.47(s，4H)，3.71(s，3H)，3.91-3.99(m，4H)，4.13(s，3H)，6.53(s，1H)，7.01-7.13(m，1H)，7.27-7.30(m，1H)，7.52-7.61(m，2H)，8.33(d，J＝4.8Hz，2H)。
Embodiment 64
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-the 4-phenylpiperazine
A) 3-amino-2,6-dimethoxy quinoxaline
In room temperature with under stirring, 3-amino in being dissolved in tetrahydrofuran (THF) (60ml)-2-chloro-6-methoxyl group quinoxaline (1.50g, 7.16mmol) among be added in 25wt% sodium methylate in the methyl alcohol (15.5g 71.6mmol), and at room temperature further stirred 21 hours.The gained mixture under reduced pressure concentrates to remove and desolvates.Use the dichloromethane extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 1.18g title compound (productive rate, 80%).
B) N-(2,6-dimethoxy quinoxaline-3-yl) urethanum
At room temperature, with 3-amino-2,6-dimethoxy quinoxaline (616mg, 3.00mmol) and Vinyl chloroformate (391mg 3.60mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (285mg, 3.60mmol).At room temperature stir gained mixture 10 hours and concentrating under reduced pressure and desolvate, and pass through SiO to remove
2The column chromatography purifying.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 799mg title compound (productive rate, 96%).
C) 1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-the 4-phenylpiperazine
At room temperature, with N-(2,6-dimethoxy quinoxaline-3-yl) urethanum (28mg, 0.10mmol) and the 1-phenylpiperazine (24mg 0.15mmol) is dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (23mg, 0.15mmol).Stirring gained mixture 7 hours and concentrating under reduced pressure desolvate to remove under 70 ℃, and pass through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 36mg title compound (productive rate, 92%).
1H NMR(300MHz，CDCl
3)：δ3.27(s，4H)，3.73-3.86(m，6H)，4.08-4.11(m，4H)，6.88-7.03(m，4H)，7.15(s，1H)，7.26-7.33(m，3H)，7.57-7.62(m，1H)。
Embodiment 65
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(2-p-methoxy-phenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(2-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 84%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.15(s，4H)，3.83-3.89(m，9H)，4.12-4.17(m，4H)，6.88-6.95(m，3H)，7.02-7.05(m，1H)，7.14(d，J＝8.7Hz，1H)，7.31(s，1H)，7.51(d，J＝8.7Hz，1H)，7.63(d，J＝9.0Hz，1H)。
Embodiment 66
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 80%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.28(s，4H)，3.80-3.87(m，9H)，4.11(s，4H)，6.45-6.49(m，2H)，6.56(d，J＝8.4Hz，1H)，6.91(s，1H)，7.04-7.36(m，3H)，7.53-7.62(m，1H)。
Embodiment 67
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(4-p-methoxy-phenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(4-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 81%) with embodiment 64.
1H NMR(200MHz，CDCl
3)：δ3.16(s，4H)，3.78-3.88(m，9H)，4.12-4.17(m，4H)，6.84-6.97(m，4H)，7.16-7.32(m，3H)，7.62-7.66(m，1H)。
Embodiment 68
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 81%) with embodiment 64.MS(ESI)m/z 454(M+1)。
Embodiment 69
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3,4, the 5-trimethoxyphenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3,4, the 5-trimethoxyphenyl) piperazine are obtained title compound (productive rate, 97%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.55-3.87(m，10H)，4.12(s，4H)，6.67(d，J＝8.4Hz，1H)，7.14(d，J＝9.0Hz，1H)，7.25(s，1H)，7.34(s，1H)，7.51(t，J＝7.2Hz，1H)，7.64(d，J＝9.0Hz，1H)，8.21(d，J＝3.6Hz，1H)。
Embodiment 70
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(2-aminomethyl phenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(2-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ2.35(s，3H)，2.95-3.02(m，4H)，3.75-3.90(m，6H)，4.09-4.13(m，4H)，6.99-7.31(m，7H)，7.50-7.66(m，1H)。
Embodiment 71
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 95%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ2.33(s，3H)，3.26(s，4H)，3.72-3.89(m，6H)，4.09-4.18(m，4H)，6.72-6.78(m，4H)，7.03-7.37(m，3H)，7.57-7.65(m，1H)。
Embodiment 72
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(2, the 6-3,5-dimethylphenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(2, the 6-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 87%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ2.33-2.36(m，6H)，3.14-3.22(m，4H)，3.70-3.90(m，6H)，4.09-4.15(m，4H)，6.67-7.32(m，6H)，7.50-7.65(m，1H)。
Embodiment 73
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 65%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ2.28(s，6H)，3.26(s，4H)，3.76-3.87(m，6H)，4.11(s，4H)，6.59(s，2H)，6.90(m，1H)，7.14(d，J＝8.7Hz，1H)，7.32(s，1H)，7.51(d，J＝7.5Hz，1H)，7.64(d，J＝8.7Hz，1H)。
Embodiment 74
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 77%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.33(s，4H)，3.74-3.90(m，6H)，4.09-4.19(m，4H)，6.92(s，1H)，7.02-7.19(m，5H)，7.38(t，J＝7.5Hz，1H)，7.59-7.66(m，1H)。
Embodiment 75
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(2-fluorophenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(2-fluorophenyl) piperazine are obtained title compound (productive rate, 72%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.18(s，4H)，3.73-3.88(m，6H)，4.11-4.15(m，4H)，6.88-7.15(m，5H)，7.33(s，1H)，7.51(d，J＝8.7Hz，1H)，7.64(d，J＝9.0Hz，1H)。
Embodiment 76
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3-fluorophenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluorophenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.17(s，4H)，3.78-3.89(m，6H)，4.11-4.15(m，4H)，6.88-7.02(m，4H)，7.14-7.36(m，3H)，7.58-7.62(m，1H)。
Embodiment 77
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(2-chloro-phenyl-) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(2-chloro-phenyl-) piperazine are obtained title compound (productive rate, 89%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.09-3.16(m，4H)，3.79-3.90(m，6H)，4.10-4.16(m，4H)，7.00-7.30(m，7H)，7.38-7.66(m，1H)。
Embodiment 78
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 85%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.21-3.32(m，4H)，3.75-3.88(m，6H)，4.10-4.13(m，4H)，6.80-6.90(m，4H)，7.14-7.29(m，3H)，7.63-7.66(m，1H)。
Embodiment 79
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(4-chloro-phenyl-) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(4-chloro-phenyl-) piperazine are obtained title compound (productive rate, 86%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.25(s，4H)，3.77(s，3H)，3.87(s，3H)，4.09-4.12(m，4H)，6.86-7.00(m，3H)，7.12-7.24(m，3H)，7.55-7.65(m，2H)。
Embodiment 80
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(2-cyano-phenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(2-cyano-phenyl) piperazine are obtained title compound (productive rate, 94%) with embodiment 64.
1H NMR(200MHz，CDCl
3)：δ3.30(s，4H)，3.88-3.90(m，6H)，4.07-4.20(m，4H)，6.94-7.07(m，3H)，7.27-7.34(m，2H)，7.53-7.63(m，3H)。
Embodiment 81
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(4-acetylphenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(4-acetylphenyl) piperazine are obtained title compound (productive rate, 87%) with embodiment 64.
1H NMR(200MHz，CDCl
3)：δ2.54-2.58(m，3H)，3.49-3.67(m，4H)，3.87-3.96(m，6H)，4.12-4.16(m，4H)，6.87-7.03(m，2H)，7.19-7.31(m，3H)，7.62-7.66(m，1H)，7.89-7.97(m，2H)。
Embodiment 82
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(4-nitrophenyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(4-nitrophenyl) piperazine are obtained title compound (productive rate, 81%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.57(s，4H)，3.75-3.87(m，6H)，4.09-4.16(m，4H)，6.84(d，J＝9.3Hz，2H)，6.91-7.27(m，3H)，7.56-7.63(m，1H)，8.16(d，J＝9.3Hz，2H)。
Embodiment 83
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(2-pyridyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(2-pyridyl) piperazine are obtained title compound (productive rate, 84%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.87(s，3H)，3.73-3.88(m，6H)，4.11-4.15(m，4H)，6.88-7.15(m，5H)，7.33(s，1H)，7.51(d，J＝8.7Hz，1H)，7.64(d，J＝9.0Hz，1H)。
Embodiment 84
1-[(2,6-dimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(2-pyrimidyl) piperazine
By the method identical N-(2,6-dimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(2-pyrimidyl) piperazine are obtained title compound (productive rate, 80%) with embodiment 64.
1H NMR(300MHz，CDCl
3)：δ3.72(s，3H)，3.87-3.96(m，7H)，4.12-4.15(m，4H)，6.54(t，J＝4.8Hz，1H)，6.92(s，1H)，7.04-7.36(m，3H)，7.62(m，1H)，8.34(d，J＝4.8Hz，2H)。
Embodiment 85
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-the 4-phenylpiperazine
A) 2-(2,4-dimethoxy-benzyl amino)-6-fluoro-3-methoxyl group quinoxaline
In room temperature with under stirring, the 2-chloro-6-fluoro-3-methoxyl group quinoxaline in being dissolved in methyl-sulphoxide (40ml) (4.00g adds 2 among 18.8mmol), and the 4-dimethoxybenzylamine (7.86g, 47.0mmol).Mixture was at room temperature stirred 24 hours, then to wherein adding entry.Use the ethyl acetate extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (6: 1) mixture extraction residue also concentrates, and obtains 4.45g title compound (productive rate, 92%).
B) 2-amino-6-fluoro-3-methoxyl group quinoxaline
At room temperature, (2.70g adds 60ml among 7.86mmol) and is dissolved in 50% trifluoroacetic acid in the methylene dichloride to 2-(2,4-dimethoxy-benzyl amino)-6-fluoro-3-methoxyl group quinoxaline.The gained mixture at room temperature stirs 24 hours, and concentrating under reduced pressure desolvates to remove.Residue neutralizes with saturated sodium bicarbonate solution, then to wherein adding NaCl solution.Use the dichloromethane extraction product, and use MgSO
4Dry organic layer.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (4: 1) mixture extraction residue also concentrates, and obtains 1.27g title compound (productive rate, 84%).
C) N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum
At room temperature, with 2-amino-6-fluoro-3-methoxyl group quinoxaline (580mg, 3.00mmol) and Vinyl chloroformate (391mg 3.60mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (285mg, 3.60mmol).The gained mixture at room temperature stirred 10 hours and concentrating under reduced pressure desolvates to remove, and passed through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 756mg title compound (productive rate, 95%).
D) aminocarboxyl 1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl)]-the 4-phenylpiperazine
At room temperature, with N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum (27mg, 0.10mmol) and the 1-phenylpiperazine (24mg 0.15mmol) is dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (23mg, 0.15mmol).The gained mixture stirred 7 hours under 70 ℃ and concentrating under reduced pressure desolvates to remove, and passed through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 34mg title compound (productive rate, 83%).
1H NMR (300MHz, CDCl
3): δ 3.28-3.31 (m, 4H), 3.75-3.78 (m, 4H), 4.15 (s, 4H), 6.90-6.97 (m, 3H), 7.24-7.42 (m, 5H), 7.80 (dd, J=9.0 and 6.0Hz, 1H).
Embodiment 86
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-p-methoxy-phenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 82%) with embodiment 85.
1H NMR (200MHz, CDCl
3): δ 3.14-3.17 (m, 4H), 3.78-3.81 (m, 4H), 3.88 (s, 3H), 4.14 (s, 3H), 6.88-7.41 (m, 7H), 7.81 (dd, J=9.0 and 5.7Hz.1H).
Embodiment 87
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 77%) with embodiment 85.
1H NMR (300MHz, CDCl
3): δ 3.28-3.31 (m, 4H), 3.74-3.77 (m, 4H), 3.80 (s, 3H), 4.15 (s, 3H), 6.46-6.58 (m, 2H), 7.18-7.28 (m, 4H), 7.40 (dd, J=9.3 and 2.7Hz, 1H), 7.78-7.81 (m, 1H).
Embodiment 88
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(4-p-methoxy-phenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(4-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 84%) with embodiment 85.
1H NMR (200MHz, CDCl
3): δ 3.15-3.18 (m, 4H), 3.78 (s, 4H), 4.15 (s, 3H), 6.85-6.96 (m, 4H), 7.22-7.42 (m, 3H), 7.81 (dd, J=9.0 and 6.0Hz, 1H).
Embodiment 89
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 76%) with embodiment 85.MS(ESI)m/z 442(M+1)。
Embodiment 90
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3,4, the 5-trimethoxyphenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3,4, the 5-trimethoxyphenyl) piperazine are obtained title compound (productive rate, 83%) with embodiment 85.
Embodiment 91
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-aminomethyl phenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 77%) with embodiment 85.
1H NMR(200MHz，CDCl
3)：δ2.95(s，3H)，2.99-3.02(m，4H)，3.74-3.77(m，4H)，4.15(s，3H)，7.01-7.05(m，2H)，7.17-7.42(m，5H)，7.81-7.84(m，1H)。
Embodiment 92
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 87%) with embodiment 85.
1H NMR (200MHz, CDCl
3): δ 2.33 (s, 3H), 3.26-3.30 (m, 4H), 3.74-3.77 (m, 4H), 4.15 (s, 3H), 6.74-6.77 (m, 3H), 7.16-7.29 (m, 3H), 7.40 (dd, J=9.6 and 2.7Hz, 1H), 7.78-7.81 (m, 1H).
Embodiment 93
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2, the 6-3,5-dimethylphenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2, the 6-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 76%) with embodiment 85.
1H NMR(300MHz，CDCl
3)：δ 2.36(s，6H)，3.18-3.21(m，4H)，3.69-3.72(m，4H)，4.15(s，3H)，6.97-7.04(m，3H)，7.22-7.42(m，4H)，7.82-7.87(m，1H)。
Embodiment 94
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 86%) with embodiment 85.
1H NMR(300MHz，CDCl
3)：δ2.29(s，6H)，3.25-3.29(m，4H)，3.73-3.77(m，4H)，4.16(s，3H)，6.55-6.59(m，3H)，7.21-7.43(m，3H)，7.78-7.83(m，1H)。
Embodiment 95
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 85%) with embodiment 85.
1H NMR(200MHz，CDCl
3)：δ3.36(s，4H)，3.78(s，4H)，4.16(s，3H)，7.08-7.41(m，7H)，7.79(t，J＝8.4Hz，1H)。
Embodiment 96
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-fluorophenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-fluorophenyl) piperazine are obtained title compound (productive rate, 85%) with embodiment 85.
1H NMR(200MHz，CDCl
3)：δ3.17-3.20(m，4H)，3.77-3.80(m，4H)，4.13(s，3H)，6.97-7.09(m，4H)，7.24-7.41(m，3H)，7.81-7.82(m，1H)。
Embodiment 97
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3-fluorophenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3-fluorophenyl) piperazine are obtained title compound (productive rate, 82%) with embodiment 85.
1H NMR(300MHz，CDCl
3)：δ3.18-3.21(m，4H)，3.74-3.78(m，4H)，4.14(s，3H)，6.88-6.92(m，4H)，7.25-7.42(m，3H)，7.76-7.81(m，1H)。
Embodiment 98
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-chloro-phenyl-) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-chloro-phenyl-) piperazine are obtained title compound (productive rate, 87%) with embodiment 85.
1H NMR(200MHz，CDCl
3)：δ3.13-3.16(m，4H)，3.78-3.81(m，4H)，4.15(s，3H)，7.02-7.06(m，3H)，7.23-7.42(m，4H)，7.82-7.83(m，1H)。
Embodiment 99
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 82%) with embodiment 85.
1H NMR(200MHz，CDCl
3)：δ3.30(s，4H)，3.91(s，4H)，4.15(s，3H)，6.79-6.91(m，3H)，7.17-7.42(m，4H)，7.79(m，1H)。
Embodiment 100
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(4-chloro-phenyl-) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(4-chloro-phenyl-) piperazine are obtained title compound (productive rate, 86%) with embodiment 85.
1H NMR(300MHz，CDCl
3)：δ3.24-3.27(m，4H)，3.74-3.77(m，4H)，4.15(s，3H)，6.84-6.89(m，2H)，7.14-7.43(m，5H)，7.77-7.82(m，1H)。
Embodiment 101
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-cyano-phenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-cyano-phenyl) piperazine are obtained title compound (productive rate, 88%) with embodiment 85.
1H NMR (200MHz, CDCl
3): δ 3.31 (s, 4H), 3.84 (s, 4H), 4.15 (s, 3H), 7.03-7.10 (m, 2H), 7.25-7.61 (m, 5H), 7.82 (dd, J=8.7 and 5.7Hz, 1H).
Embodiment 102
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(4-acetylphenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(4-acetylphenyl) piperazine are obtained title compound (productive rate, 91%) with embodiment 85.
1H NMR(200MHz，CDCl
3)：δ2.54(s，3H)，3.50(s，4H)，3.90(s，4H)，4.15(s，3H)，6.89(d，J＝8.7Hz，2H)，7.25-7.62(m，3H)，7.79(s，1H)，7.91(d，J＝9.0Hz，1H)。
Embodiment 103
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(4-nitrophenyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(4-nitrophenyl) piperazine are obtained title compound (productive rate, 89%) with embodiment 85.
1H NMR (200MHz, DMSO-d
6): δ 3.57-3.59 (m, 4H), 3.64-3.66 (m, 4H), 4.04 (s, 3H), 7.05 (d, J=9.5Hz, 2H), 7.44 (dt, J=8.9 and 2.9Hz, 1H), 7.54 (dd, J=9.8 and 2.8Hz, 1H), 7.81 (dd, J=9.1 and 5.9Hz, 1H), 8.08 (d, J=9.4Hz, 2H), 9.35 (s, 1H).
Embodiment 104
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-pyridyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-pyridyl) piperazine are obtained title compound (productive rate, 80%) with embodiment 85.
1H NMR (200MHz, CDCl
3): δ 3.72-3.76 (m, 8H), 4.16 (s, 3H), 6.66-6.70 (m, 2H), 7.24-7.52 (m, 4H), 7.80-7.81 (m, 1H), 8.21 (dd, J=5.4 and 1.8Hz, 1H).
Embodiment 105
1-[(6-fluoro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-pyrimidyl) piperazine
By the method identical N-(6-fluoro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-pyrimidyl) piperazine are obtained title compound (productive rate, 79%) with embodiment 85.
1H NMR(200MHz，CDCl
3)：δ3.69(s，4H)，3.98(s，4H)，4.14(s，3H)，6.54(t，J＝4.8Hz，1H)，7.21-7.41(m，3H)，7.79(t，J＝8.4Hz，1H)，8.34(d，J＝4.8Hz，2H)。
Embodiment 106
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-the 4-phenylpiperazine
A) 6-chloro-2-(2,4-dimethoxy-benzyl amino)-3-methoxyl group quinoxaline
In room temperature with under stirring, in being dissolved in methyl-sulphoxide (40ml) 2,6-two chloro-3-methoxyl group quinoxalines (4.00g adds 2 among 17.5mmol), the 4-dimethoxybenzylamine (14.6g, 87.3mmol).Mixture was at room temperature stirred 36 hours, then to wherein adding entry.Use the ethyl acetate extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (30: 1) mixture extraction residue also concentrates, and obtains 4.93g title compound (productive rate, 78%).
B) 2-amino-6-chloro-3-methoxyl group quinoxaline
At room temperature, (4.42g adds 50ml among 12.3mmol) and is dissolved in 50% trifluoroacetic acid in the methylene dichloride to 6-chloro-2-(2,4-dimethoxy-benzyl amino)-3-methoxyl group quinoxaline.The gained mixture at room temperature stirs 18 hours, and concentrating under reduced pressure desolvates to remove.Residue neutralizes with saturated sodium bicarbonate solution, then to wherein adding NaCl solution.Use the dichloromethane extraction product, and use MgSO
4Dry organic layer.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (4: 1) mixture extraction residue also concentrates, and obtains 1.52g title compound (productive rate, 59%).
C) N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum
At room temperature, with 2-amino-6-chloro-3-methoxyl group quinoxaline (629mg, 3.00mmol) and Vinyl chloroformate (391mg 3.60mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (285mg, 3.60mmol).The gained mixture at room temperature stirred 10 hours and concentrating under reduced pressure desolvates to remove, and passed through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 811mg title compound (productive rate, 96%).
D) aminocarboxyl 1-[(6-chloro-3-methoxyl group quinoxaline-2-yl)]-the 4-phenylpiperazine
At room temperature, with N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum (28mg, 0.10mmol) and the 1-phenylpiperazine (24mg 0.15mmol) is dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (23mg, 0.15mmol).The gained mixture stirred 7 hours under 70 ℃ and concentrating under reduced pressure desolvates to remove, and passed through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 36mg title compound (productive rate, 94%).
1H NMR(300MHz，CDCl
3)：δ3.30(s，4H)，3.77(s，4H)，4.15(s，3H)，6.90-6.97(m，3H)，7.28-7.45(m，4H)，7.75-7.76(m，1H)。
Embodiment 107
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-p-methoxy-phenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 92%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.17(s，4H)，3.82(s，4H)，3.89(s，3H)，4.15(s，3H)，6.89-6.97(m，3H)，7.06(m，1H)，7.45(m，1H)，7.75(s，2H)。
Embodiment 108
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 85%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.14-3.16(m，4H)，3.76-3.80(m，7H)，4.14(s，3H)，6.46-6.58(m，3H)，7.14-7.44(m，3H)，7.62-7.74(m，2H)。
Embodiment 109
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(4-p-methoxy-phenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(4-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 106.
1H NMR(200MHz，CDCl
3)：δ3.17(s，4H)，3.78(s，7H)，4.15(m，3H)，6.85-6.96(m，4H)，7.29-7.49(m，2H)，7.74-7.77(m，2H)。
Embodiment 110
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 91%) with embodiment 106.MS(ESI)m/z 458(M+1)。
Embodiment 111
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3,4, the 5-trimethoxyphenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3,4, the 5-trimethoxyphenyl) piperazine are obtained title compound (productive rate, 83%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.24(s，4H)，3.81-3.86(m，12H)，4.15(s，3H)，6.21(s，2H)，7.36-7.45(m，1H)，7.27(s，1H)，7.36-7.45(m，1H)，7.64-7.75(m，2H)。
Embodiment 112
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-aminomethyl phenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 89%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ2.35(s，3H)，3.01(s，4H)，3.76(s，4H)，4.14(s，3H)，7.03-7.52(m，6H)，7.68-7.77(m，2H)。
Embodiment 113
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 97%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.27-3.30(m，4H)，3.74-3.77(m，4H)，4.15(s，3H)，6.75-6.78(m，3H)，7.11-7.45(m，3H)，7.74-7.76(m，2H)。
Embodiment 114
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2, the 6-3,5-dimethylphenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2, the 6-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ2.36(s，3H)，3.14(s，4H)，3.70(s，4H)，4.15(s，3H)，6.95-7.01(m，3H)，7.26-7.46(m，3H)，7.61-7.81(m，2H)。
Embodiment 115
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 85%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ2.29(s，6H)，3.25-3.29(m，4H)，3.73-3.76(m，4H)，4.15(s，3H)，6.59(s，3H)，7.30-7.49(m，3H)，7.74-7.77(m，1H)。
Embodiment 116
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 81%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.37-3.38(m，4H)，3.77-3.80(m，4H)，4.16(s，3H)，7.08-7.45(m，6H)，7.73-7.76(m，2H)。
Embodiment 117
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-fluorophenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-fluorophenyl) piperazine are obtained title compound (productive rate, 93%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.18(s，4H)，3.78(s，4H)，4.14(s，3H)，6.94-7.11(m，4H)，7.35-7.45(m，2H)，7.74-7.77(m，2H)。
Embodiment 118
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3-fluorophenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3-fluorophenyl) piperazine are obtained title compound (productive rate, 88%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.19-3.22(m，4H)，3.75-3.78(m，4H)，4.16(s，3H)，6.89-6.93(m，4H)，7.29-7.46(m，2H)，7.74-7.76(m，1H)。
Embodiment 119
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-chloro-phenyl-) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-chloro-phenyl-) piperazine are obtained title compound (productive rate, 91%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.15(s，4H)，3.79(s，4H)，4.15(s，3H)，6.99-7.06(m，2H)，7.23-7.45(m，4H)，7.74-7.79(m，2H)。
Embodiment 120
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 86%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.30(s，4H)，3.76(s，4H)，4.15(s，3H)，6.79-6.90(m，3H)，7.15-7.45(m，3H)，7.62-7.75(m，2H)。
Embodiment 121
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(4-chloro-phenyl-) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(4-chloro-phenyl-) piperazine are obtained title compound (productive rate, 94%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.25(s，4H)，3.76(s，4H)，4.15(s，3H)，6.86(d，J＝9.0Hz，2H)，7.22-7.45(m，4H)，7.72-7.75(m，2H)。
Embodiment 122
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-cyano-phenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-cyano-phenyl) piperazine are obtained title compound (productive rate, 89%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.30(s，4H)，3.84(s，3H)，4.14(s，3H)，7.02-7.10(m，2H)，7.35-7.89(m，6H)。
Embodiment 123
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(4-acetylphenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(4-acetylphenyl) piperazine are obtained title compound (productive rate, 81%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ2.54(s，3H)，3.50(s，4H)，3.79(s，4H)，4.15(s，3H)，6.89(d，J＝9.0Hz，2H)，7.31-7.50(m，2H)，7.65-7.75(m，2H)，7.90(d，J＝8.7Hz，2H)。
Embodiment 124
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(4-nitrophenyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(4-nitrophenyl) piperazine are obtained title compound (productive rate, 96%) with embodiment 106.
1H NMR (300MHz, DMSO-d
6): δ 3.57-3.65 (m, 8H), 4.17 (s, 3H), 7.05 (d, J=9.5Hz, 2H), 7.55 (dd, J=8.9 and 2.2Hz, 1H), 7.74-7.79 (m, 2H), 8.08 (d, J=9.4Hz, 2H), 9.40 (s, 1H).
Embodiment 125
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-pyridyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-pyridyl) piperazine are obtained title compound (productive rate, 87%) with embodiment 106.
1H NMR (300MHz, CDCl
3): δ 3.73 (m, 8H), 4.15 (s, 3H), 6.68 (d, J=8.4Hz, 2H), 7.11-7.76 (m, 5H), 8.21 (dd, J=3.6 and 0.6Hz, 1H).
Embodiment 126
1-[(6-chloro-3-methoxyl group quinoxaline-2-yl) aminocarboxyl]-4-(2-pyrimidyl) piperazine
By the method identical N-(6-chloro-3-methoxyl group quinoxaline-2-yl) urethanum and the reaction of 1-(2-pyrimidyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 106.
1H NMR(300MHz，CDCl
3)：δ3.69-3.73(m，4H)，3.98(s，4H)，4.16(s，3H)，6.54-6.55(m，1H)，7.28-7.49(m，1H)，7.63-7.75(m，2H)，8.33(d，J＝4.8Hz，2H)。
Embodiment 127
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-the 4-phenylpiperazine
A) 2-(2,4-dimethoxy-benzyl amino)-3-methoxyl group-6-methyl-quinoxaline
In room temperature with under stirring, the 2-chloro-3-methoxyl group-6-methyl-quinoxaline in being dissolved in methyl-sulphoxide (40ml) (3.05g adds 2 among 14.6mmol), and the 4-dimethoxybenzylamine (9.77g, 58.4mmol).Mixture was stirred 45 hours down at 60 ℃, then to wherein adding entry.Use the ethyl acetate extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (13: 1) mixture extraction residue also concentrates, and obtains 4.48g title compound (productive rate, 90%).
B) 2-amino-3-methoxyl group-6-methyl-quinoxaline
At room temperature, (4.48g adds 30ml among 13.2mmol) and is dissolved in 50% trifluoroacetic acid in the methylene dichloride to 2-(2,4-dimethoxy-benzyl amino)-3-methoxyl group-6-methyl-quinoxaline.The gained mixture at room temperature stirs 18 hours, and concentrating under reduced pressure desolvates to remove.Residue neutralizes with saturated sodium bicarbonate solution, then to wherein adding NaCl solution.Use the dichloromethane extraction product, and use MgSO
4Dry organic layer.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 2.01g title compound (productive rate, 81%).
C) N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum
At room temperature, with 2-amino-3-methoxyl group-6-methyl-quinoxaline (1.15g, 6.08mmol) and Vinyl chloroformate (1.32g 12.2mmol) is dissolved in the methylene dichloride (30ml), and under agitation to wherein add pyridine (0.96g, 12.2mmol).The gained mixture at room temperature stirred 24 hours and concentrating under reduced pressure desolvates to remove, and passed through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 1.59g title compound (productive rate, 100%).
D) aminocarboxyl 1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl)]-the 4-phenylpiperazine
At room temperature, with N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum (30mg, 0.11mmol) and the 1-phenylpiperazine (24mg 0.15mmol) is dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (23mg, 0.15mmol).The gained mixture stirred 7 hours under 70 ℃ and concentrating under reduced pressure desolvates to remove, and passed through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 34mg title compound (productive rate, 90%).
1H NMR(300MHz，CDCl
3)：δ2.43(s，3H)，3.22-3.29(m，4H)，3.73-3.87(m，4H)，4.13(s，3H)，6.87-7.74(m，9H)。
Embodiment 128
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(2-p-methoxy-phenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(2-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.49(s，3H)，3.09-3.18(m，4H)，3.77-3.82(m，4H)，3.88(s，3H)，4.13(s，3H)，6.87-7.80(m，8H)。
Embodiment 129
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(3-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 89%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.49(s，3H)，3.19-3.32(m，4H)，3.61-3.90(m，4H)，3.79(s，3H)，4.17(s，3H)，6.44-6.58(m，4H)，7.00-7.65(m，3H)，7.72(d，J＝8.2Hz，1H)。
Embodiment 130
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(4-p-methoxy-phenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(4-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 96%) with embodiment 127.
1H NMR(200MHz，CDCl
3)：δ2.50(s，3H)，3.15-3.17(m，4H)，3.68-3.78(m，4H)，3.78(s，3H)，4.14(s，3H)，6.84-7.75(m，8H)。
Embodiment 131
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 88%) with embodiment 127.MS(ESI)m/z 438(M+1)。
Embodiment 132
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(3,4, the 5-trimethoxyphenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(3,4, the 5-trimethoxyphenyl) piperazine are obtained title compound (productive rate, 91%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.49(s，3H)，3.16-3.23(m，4H)，3.71-3.95(m，4H)，3.80(s，3H)，3.86(s，6H)，4.13(s，3H)，6.19(s，2H)，7.08-7.62(m，3H)，7.72(d，J＝8.6Hz，1H)。
Embodiment 133
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(2-aminomethyl phenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(2-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 84%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.35(s，3H)，2.50(s，3H)，2.89-3.09(m，4H)，3.68-3.88(m，4H)，4.14(s，3H)，6.99-7.78(m，7H)，7.76(d，J＝8.0Hz，1H)。
Embodiment 134
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 91%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.33(s，3H)，2.46(s，3H)，3.21-3.28(m，4H)，3.72-3.86(m，4H)，4.13(s，3H)，6.74-6.78(m，4H)，7.00-8.01(m，4H)。
Embodiment 135
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(2, the 6-3,5-dimethylphenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(2, the 6-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 83%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.33-2.50(m，9H)，3.14-2.20(m，4H)，3.70-3.75(m，4H)，4.14(s，3H)，7.00(s，3H)，7.09-7.78(m，3H)。
Embodiment 136
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 95%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.29(s，6H)，2.50(s，3H)，3.18-3.29(m，4H)，3.73-3.80(m，4H)，4.12(s，3H)，6.58(s，3H)，7.31(d，J＝8.4Hz，1H)，7.43(s，1H)，7.55(s，1H)，7.72(d，J＝8.4Hz，1H)。
Embodiment 137
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 87%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.49(s，3H)，3.27-3.35(m，4H)，3.69-3.89(m，4H)，4.13(s，3H)，7.07-7.60(m，7H)7.71(d，J＝8.2Hz，1H)。
Embodiment 138
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(2-fluorophenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(2-fluorophenyl) piperazine are obtained title compound (productive rate, 98%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.49(s，3H)，3.11-3.18(m，4H)，3.77-3.86(m，4H)，4.12(s，3H)，6.95-7.61(m，7H)，7.73(d，J＝8.6Hz，1H)。
Embodiment 139
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(3-fluorophenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(3-fluorophenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.47(s，3H)，3.07-3.17(m，4H)，3.77-3.87(m，4H)，4.13(s，3H)，6.87-8.01(m，8H)。
Embodiment 140
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(2-chloro-phenyl-) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(2-chloro-phenyl-) piperazine are obtained title compound (productive rate, 85%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.49(s，3H)，3.08-3.17(m，4H)，3.73-3.86(m，4H)，4.13(s，3H)，7.00-7.65(m，7H)，7.74(d，J＝8.0Hz，1H)。
Embodiment 141
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 87%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.46(s，3H)，3.19-3.33(m.4H)，3.72-3.77(m，4H)，4.13(s，3H)，6.79-7.66(m，7H)，7.71(d，J＝8.6Hz，1H)。
Embodiment 142
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(4-chloro-phenyl-) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(4-chloro-phenyl-) piperazine are obtained title compound (productive rate, 91%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.50(s，3H)，3.18-3.28(m，4H)，3.73-3.78(m，4H)，4.14(s，3H)，6.86(dd，J＝12.2Hz，2H)，7.00-7.60(m，5H)，7.71(d，J＝8.2Hz，1H)。
Embodiment 143
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(2-cyano-phenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(2-cyano-phenyl) piperazine are obtained title compound (productive rate, 93%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.47(s，3H)，3.20-3.28(m，4H)，3.76-3.96(m，4H)，4.14(s，3H)，7.02-7.13(m，3H)，7.28(s，1H)，7.49-7.63(m，4H)。
Embodiment 144
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(4-acetylphenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(4-acetylphenyl) piperazine are obtained title compound (productive rate, 97%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.17(s，3H)，2.54(s，3H)，3.39-3.58(m，4H)，3.71-3.90(m，4H)，4.14(s，3H)，6.89(d，J＝6.4Hz，2H)，7.21-7.54(m，4H)，7.90(d，J＝6.4Hz，2H)。
Embodiment 145
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(4-nitrophenyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(4-nitrophenyl) piperazine are obtained title compound (productive rate, 89%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.45(s，3H)，3.45-3.60(m，4H)，3.76-3.88(m，4H)，4.09(s，3H)，6.85(d，J＝6.2Hz，2H)，7.03-7.68(m，4H)，8.16(d，J＝6.0Hz，2H)。
Embodiment 146
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(2-pyridyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(2-pyridyl) piperazine are obtained title compound (productive rate, 88%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.49(s，3H)，3.61-3.71(m，8H)，4.12(s，3H)，6.66(d，J＝8Hz，2H)，7.07-7.74(m，5H)，8.20(dd，J＝5.4，1.8Hz，1H)。
Embodiment 147
1-[(3-methoxyl group-6-methyl-quinoxaline-2-yl) aminocarboxyl]-4-(2-pyrimidyl) piperazine
By the method identical N-(3-methoxyl group-6-methyl-quinoxaline-2-yl) urethanum and the reaction of 1-(2-pyrimidyl) piperazine are obtained title compound (productive rate, 79%) with embodiment 127.
1H NMR(300MHz，CDCl
3)：δ2.45(s，3H)，3.60-3.80(m，4H)，3.80-4.05(m，4H)，4.13(s，3H)，6.52(t，J＝4.5Hz，1H)，7.00-7.69(m，4H)，8.32(d，J＝4.5Hz，2H)。
Embodiment 148
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-the 4-phenylpiperazine
A) 3,6-dimethoxy-2-(2,4-dimethoxy-benzyl amino) quinoxaline
In room temperature with under stirring, the 2-chloro-3 in being dissolved in methyl-sulphoxide (70ml), 6-dimethoxy quinoxaline (3.87g adds 2 among 17.2mmol), and the 4-dimethoxybenzylamine (6.07g, 36.3mmol).Mixture was stirred 118 hours down at 60 ℃, then to wherein adding entry.Use the ethyl acetate extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (6: 1) mixture extraction residue also concentrates, and obtains 4.69g title compound (productive rate, 77%).
B) 2-amino-3,6-dimethoxy quinoxaline
At room temperature, to 3, (4.45g adds 70ml among 12.8mmol) and is dissolved in 50% trifluoroacetic acid in the methylene dichloride 6-dimethoxy-2-(2,4-dimethoxy-benzyl amino) quinoxaline.The gained mixture at room temperature stirs 18 hours, and concentrating under reduced pressure desolvates to remove.Residue neutralizes with saturated sodium bicarbonate solution, then to wherein adding NaCl solution.Use the dichloromethane extraction product, and use MgSO
4Dry organic layer.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: the ethyl acetate mixture extraction leftover also concentrates, and obtains 2.50g title compound (productive rate, 95%).
C) N-(3,6-dimethoxy quinoxaline-2-yl) urethanum
At room temperature, with 3-amino-2,6-dimethoxy quinoxaline (616mg, 3.00mmol) and Vinyl chloroformate (391mg 3.60mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (285mg, 3.60mmol).The gained mixture at room temperature stirred 10 hours and concentrating under reduced pressure desolvates to remove, and passed through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 782mg title compound (productive rate, 94%).
D) 1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-the 4-phenylpiperazine
At room temperature, with N-(3,6-dimethoxy quinoxaline-2-yl) urethanum (28mg, 0.10mmol) and the 1-phenylpiperazine (24mg 0.15mmol) is dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (23mg, 0.15mmol).The gained mixture stirred 7 hours under 70 ℃ and concentrating under reduced pressure desolvates to remove, and passed through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 36mg title compound (productive rate, 91%).
1H NMR(300MHz，CDCl
3)：δ3.27(s，4H)，3.76(s，4H)，3.89(s，3H)，4.12(s，3H)，6.87-6.96(m，3H)，7.13(s，2H)，7.29-7.31(m，2H)，7.72-7.75(s，1H)。
Embodiment 149
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(2-p-methoxy-phenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(2-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 84%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ3.13-3.16(m，4H)，3.66-3.78(m，4H)，3.88(s，3H)，3.90(s，3H)，4.12(s，3H)，6.87-7.14(m，7H)，7.76(d，J＝5.1Hz，1H)。
Embodiment 150
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(3-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ3.27(s，4H)，3.75(s，4H)，3.79(s，3H)，3.89(s，3H)，4.12(s，3H)，6.44-6.57(m，3H)，7.14-7.22(m，4H)，7.72-7.75(m，1H)。
Embodiment 151
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(4-p-methoxy-phenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(4-p-methoxy-phenyl) piperazine are obtained title compound (productive rate, 87%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ3.12-3.15(m，4H)，3.74-3.76(m，7H)，3.89(s，3H)，4.11(s，3H)，6.83-6.93(m，4H)，7.12-7.13(m，2H)，7.33(s，1H)，7.72-7.75(m，1H)。
Embodiment 152
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 86%) with embodiment 148.MS(ESI)m/z 454(M+1)。
Embodiment 153
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(3,4, the 5-trimethoxyphenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(3,4, the 5-trimethoxyphenyl) piperazine are obtained title compound (productive rate, 92%) with embodiment 148.
Embodiment 154
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(2-aminomethyl phenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(2-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 93%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ2.35(s，3H)，2.99-3.02(m，4H)，3.73-3.76(m，4H)，3.91(s，3H)，4.15(s，3H)，7.00-7.22(m，7H)，7.76-7.79(m，1H)。
Embodiment 155
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 86%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ2.33(s，3H)，3.26-3.29(m，4H)，3.73-3.77(m，4H)，3.90(s，3H)，4.13(s，3H)，6.73-6.77(m，3H)，7.13-7.22(m，4H)，7.74(d，J＝9.8Hz，1H)。
Embodiment 156
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(2, the 6-3,5-dimethylphenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(2, the 6-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 91%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ2.36(s，6H)，3.17-3.21(m，4H)，3.68-3.71(m，4H)，3.91(s，3H)，4.14(s，3H)，6.95-7.03(m，3H)，7.14-7.21(m，3H)，7.77-7.80(m，1H)。
Embodiment 157
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 90%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ2.29(s，6H)，3.26(s，4H)，3.75(s，4H)，3.90(s，3H)，4.14(s，3H)，6.59(s，3H)，6.99-7.20(m，3H)，7.73-7.75(m，1H)。
Embodiment 158
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 83%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ3.28-3.34(m，4H)，3.75-3.78(m，4H)，3.90(s，3H)，4.13(s，3H)，7.06-7.14(m，5H)，7.28-7.40(m，2H)，7.73(d，J＝9.9Hz，1H)。
Embodiment 159
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(2-fluorophenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(2-fluorophenyl) piperazine are obtained title compound (productive rate, 95%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ3.18(s，4H)，3.66(s，4H)，3.78(s，3H)，4.15(s，3H)，6.94-7.27(m，7H)，7.73-7.87(m，1H)。
Embodiment 160
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(3-fluorophenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(3-fluorophenyl) piperazine are obtained title compound (productive rate, 92%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ3.17(s，4H)，3.75(s，4H)，3.89(s，3H)，4.12(s，3H)，6.86-7.01(m，4H)，7.13(s，2H)，7.32(s，1H)，7.72-7.74(m，1H)。
Embodiment 161
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(2-chloro-phenyl-) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(2-chloro-phenyl-) piperazine are obtained title compound (productive rate, 89%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ3.13(s，4H)，3.78(s，4H)，3.90(s，3H)，4.12(s，3H)，6.98-7.37(m，7H)，7.76(d，J＝9.9Hz，1H)。
Embodiment 162
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 85%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ2.29(s，4H)，3.74(s，4H)，3.90(s，3H)，4.13(s，4H)，6.78-6.89(m，3H)，7.15-7.27(m，4H)，7.73(d，J＝9.7Hz，1H)。
Embodiment 163
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(4-chloro-phenyl-) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(4-chloro-phenyl-) piperazine are obtained title compound (productive rate, 93%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ3.23(s，4H)，3.75(s，4H)，3.90(s，3H)，4.13(s，3H)，6.85(d，J＝9.0Hz，2H)，7.14(s，2H)，7.20-7.25(m，3H)，7.71-7.74(m，1H)。
Embodiment 164
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(2-cyano-phenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(2-cyano-phenyl) piperazine are obtained title compound (productive rate, 97%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ2.46(s，3H)，3.28(s，4H)，3.86(s，3H)，4.08-4.19(m，4H)，7.01-7.08(m，3H)，7.17-7.37(m，1H)，7.49-7.61(m，4H)。
Embodiment 165
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(4-acetylphenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(4-acetylphenyl) piperazine are obtained title compound (productive rate, 93%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ2.53(s，3H)，3.48(s，4H)，3.77(s，4H)，3.90(s，3H)，4.13(s，3H)，6.86(d，J＝8.7Hz，2H)，7.14-7.28(m，3H)，7.72(d，J＝8.4Hz，1H)，7.89(d，J＝9.0Hz，2H)。
Embodiment 166
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(4-nitrophenyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(4-nitrophenyl) piperazine are obtained title compound (productive rate, 94%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ3.57-3.65(m，8H)，3.90(s，3H)，4.01(s，3H)，7.06(d，J＝9.4Hz，2H)，7.18-7.22(m，2H)，7.69(d，J＝8.6Hz，2H)，8.09(d，J＝9.4Hz，2H)，9.20(s，1H)。
Embodiment 167
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(2-pyridyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(2-pyridyl) piperazine are obtained title compound (productive rate, 94%) with embodiment 148.
1H NMR (300MHz, CDCl
3): δ 3.73 (m, 8H), 3.91 (s, 3H), 4.15 (s, 3H), 6.66-6.70 (m, 2H), 7.13-7.20 (m, 3H), 7.50-7.56 (m, 1H), 7.66 (d, J=9.0Hz, 1H), 8.21 (dd, J=5.1 and 1.5Hz, 1H).
Embodiment 168
1-[(3,6-dimethoxy quinoxaline-2-yl) aminocarboxyl]-4-(2-pyrimidyl) piperazine
By the method identical N-(3,6-dimethoxy quinoxaline-2-yl) urethanum and the reaction of 1-(2-pyrimidyl) piperazine are obtained title compound (productive rate, 86%) with embodiment 148.
1H NMR(300MHz，CDCl
3)：δ3.67-3.70(m，4H)，3.90(s，3H)，3.95-3.97(m，4H)，4.13(s，3H)，6.53(t，J＝4.8Hz，1H)，7.11-7.23(m，4H)，7.30(d，J＝9.3Hz，1H)，8.33(d，J＝4.8Hz，2H)。
Embodiment 169
1-[(6,7-difluoro-2-methoxyl quinoxaline-3-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
A) 2-amino-6,7-two fluoro-3-methoxyl group quinoxalines
In room temperature with under stirring, 2-amino-3-chloro-6 in being dissolved in tetrahydrofuran (THF) (40ml), (610mg is added in the 25wt% sodium methylate (6.12g in the methyl alcohol among 2.83mmol) to 7-difluoro quinoxaline, 28.3mmol), and at room temperature further stirred 1.5 hours.The gained mixture under reduced pressure concentrates to remove and desolvates.Use the ethyl acetate extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 570mg title compound (productive rate, 95%).
B) N-(6,7-difluoro-2-methoxyl quinoxaline-3-yl) urethanum
At room temperature, with 2-amino-6,7-two fluoro-3-methoxyl group quinoxalines (550mg, 2.60mmol) and Vinyl chloroformate (564mg 5.20mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (411mg, 5.20mmol).At room temperature stir the mixture 13 hours and concentrating under reduced pressure desolvates to remove, and passes through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 440mg title compound (productive rate, 60%).
C) 1-[(6,7-difluoro-2-methoxyl quinoxaline-3-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
At room temperature, with N-(6,7-difluoro-2-methoxyl quinoxaline-3-yl) urethanum (25mg, 0.088mmol) and 1-(3-p-methoxy-phenyl) piperazine (35mg, 0.18mmol) be dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (28mg, 0.18mmol).Stir gained mixture and concentrating under reduced pressure down at 70 ℃ and desolvate, and pass through SiO to remove
2The column chromatography purifying.Use normal hexane: ethyl acetate (1: 1) mixture extraction residue also concentrates, and obtains 29mg title compound (productive rate, 76%).
1H NMR(300MHz，CDCl
3)δ3.28-3.30(m，4H)，3.76-3.77(m，4H)，3.81(s，3H)，4.12(s，3H)，6.48-6.49(m，2H)，6.56-6.58(m，1H)，7.20-7.23(m，1H)，7.29-7.30(m，1H)，7.50-7.53(m，1H)，7.60-7.62(m，1H)。
Embodiment 170
1-[(6,7-difluoro-2-methoxyl quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(6,7-difluoro-2-methoxyl quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 70%) with embodiment 169.MS(ESI)m/z 460([M+H]
+)。
Embodiment 171
1-[(6,7-difluoro-2-methoxyl quinoxaline-3-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(6,7-difluoro-2-methoxyl quinoxaline-3-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 66%) with embodiment 169.
1H NMR(300MHz，CDCl
3)δ2.34(s，3H)，3.27-3.29(m，4H)，3.75-3.77(m，4H)，4.15(s，3H)，6.75-6.78(m，4H)，7.18-7.21(m，1H)，7.49-7.53(m，1H)，7.58-7.62(m，1H)。
Embodiment 172
1-[(6,7-difluoro-2-methoxyl quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(6,7-difluoro-2-methoxyl quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 70%) with embodiment 169.
1H NMR(300MHz，CDCl
3)δ2.30(s，6H)，3.26-3.28(m，4H)，3.74-3.76(m，4H)，4.15(s，3H)，6.59(s，3H)，7.29(s，1H)，7.49-7.53(m，1H)，7.52-7.62(m，1H)。
Embodiment 173
1-[(6,7-difluoro-2-methoxyl quinoxaline-3-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(6,7-difluoro-2-methoxyl quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 59%) with embodiment 169.
1H NMR(300MHz，CDCl
3)δ3.33-3.35(m，4H)，3.70-3.80(m，4H)，4.15(s，3H)，7.09-7.11(m，1H)，7.14-7.16(m，2H)，7.26(s，1H)，7.38-7.41(m，1H)，7.49-7.53(m，1H)，7.54(br s，1H)。
Embodiment 174
1-[(6,7-difluoro-2-methoxyl quinoxaline-3-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(6,7-difluoro-2-methoxyl quinoxaline-3-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 67%) with embodiment 169.
1H NMR(300MHz，CDCl
3)δ3.30(m，4H)，3.76(m，4H)，4.15(s，3H)，6.80-6.82(m，1H)，6.87-6.91(m，2H)，7.19-7.22(m，1H)，7.29(br s，1H)，7.49-7.51(m，1H)，7.60(br s，1H)。
Embodiment 175
1-[(6,7-difluoro-2-methoxyl quinoxaline-3-yl) aminocarboxyl]-4-(3-bromophenyl) piperazine
By the method identical N-(6,7-difluoro-2-methoxyl quinoxaline-3-yl) urethanum and the reaction of 1-(3-bromophenyl) piperazine are obtained title compound (productive rate, 58%) with embodiment 169.
1H NMR(300MHz，CDCl
3)δ3.30(m，4H)，3.76(m，4H)，4.15(s，3H)，6.85-6.87(m，1H)，7.02-7.03(m，2H)，7.06-7.07(m，1H)，7.13-7.16(m，1H)，7.30(br s，1H)，7.51-7.53(m，1H)，7.60(br s，1H)。
Embodiment 176
1-[(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
A) 2-amino-6,7-two chloro-3-methoxyl group quinoxalines
In room temperature with under stirring, the 2-amino-3,6 in being dissolved in tetrahydrofuran (THF) (40ml), (1.54g, (2.01g 9.30mmol), and at room temperature further stirred 1 hour 7-three chloro-quinoxalines to be added in 25wt% sodium methylate in the methyl alcohol among 6.20mmol).The gained mixture under reduced pressure concentrates to remove and desolvates.Use the ethyl acetate extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 1.21g title compound (productive rate, 80%).
B) N-(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) urethanum
At room temperature, with 2-amino-6,7-two chloro-3-methoxyl group quinoxalines (1.16g, 4.75mmol) and Vinyl chloroformate (1.03g 9.50mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (751mg, 9.50mmol).At room temperature stir the mixture 24 hours and concentrating under reduced pressure desolvates to remove, and passes through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 1.29g title compound (productive rate, 86%).
C) 1-[(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
At room temperature, with N-(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) urethanum (28mg, 0.089mmol) and 1-(3-p-methoxy-phenyl) piperazine (35mg, 0.18mmol) be dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (27mg, 0.18mmol).Stir gained mixture and concentrating under reduced pressure down at 70 ℃ and desolvate, and pass through SiO to remove
2The column chromatography purifying.Use normal hexane: ethyl acetate (1: 1) mixture extraction residue also concentrates, and obtains 27mg title compound (productive rate, 66%).
1H NMR(300MHz，CDCl
3)δ3.28-3.30(m，4H)，3.74-3.76(m，4H)，3.81(s，3H)，4.19(s，3H)，6.47-6.49(m，3H)，6.53-6.57(m，1H)，7.30(br s，1H)，7.85(s，1H)，7.92(s，1H)。
Embodiment 177
1-[(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 68%) with embodiment 176.
1H NMR(300MHz，CDCl
3)δ3.28-3.30(m，4H)，3.74-3.78(m，4H)，3.79(s，6H)，4.15(s，3H)，6.07(s，1H)，6.11(s，2H)，7.33(br s，1H)，7.85(s，1H)，7.92(s，1H)。
Embodiment 178
1-[(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 71%) with embodiment 176.
1H NMR(300MHz，CDCl
3)δ2.34(s，3H)，3.18-3.21(m，4H)，3.75-3.79(m，4H)，4.14(s，3H)，6.75-6.78(m，4H)，7.32(br s，1H)，7.85(s，1H)，7.92(s，1H)。
Embodiment 179
1-[(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 55%) with embodiment 176.
1H NMR(300MHz，CDCl
3)δ2.30(s，6H)，3.16-3.21(m，4H)，3.75-3.79(m，4H)，4.15(s，3H)，6.52-6.59(m，3H)，7.31(br s，1H)，7.85(s，1H)，7.92(s，1H)。
Embodiment 180
1-[(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 61%) with embodiment 176.
1H NMR(300MHz，CDCl
3)δ3.32-3.35(m，4H)，3.77(m，4H)，4.16(s，3H)，7.05-7.16(m，3H)，7.30(br s，1H)，7.33-7.39(m，1H)，7.86(s，1H)，7.91(s，1H)。
Embodiment 181
1-[(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 61%) with embodiment 176.
1H NMR(300MHz，CDCl
3)δ3.31-3.30(m，4H)，3.75-3.76(m，4H)，4.15(s，3H)，6.80-6.82(m，1H)，6.90-6.91(m，2H)，7.18-7.23(m，1H)，7.32(br s，1H)，7.85(s，1H)，7.91(s，1H)。
Embodiment 182
1-[(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) aminocarboxyl]-4-(3-bromophenyl) piperazine
By the method identical N-(6,7-two chloro-2-methoxyl group quinoxaline-3-yls) urethanum and the reaction of 1-(3-bromophenyl) piperazine are obtained title compound (productive rate, 72%) with embodiment 176.
1H NMR(300MHz，CDCl
3)δ3.29-3.31(m，4H)，3.74-3.76(m，4H)，4.16(s，3H)，6.85-6.87(m，1H)，7.02-7.04(m，1H)，7.06-7.07(m，1H)，7.13-7.15(m，1H)，7.32(br s，1H)，7.86(brs，1H)，7.86(br s，1H)，7.91(br s，1H)。
Embodiment 183
1-[(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
A) 2-amino-3-methoxyl group-6,7-dimethyl quinoxaline
In room temperature with under stirring, 2-amino-3-chloro-6 in being dissolved in tetrahydrofuran (THF) (40ml), (2.59g is added in the 25wt% sodium methylate (4.05g in the methyl alcohol among 12.5mmol) to 7-dimethyl quinoxaline, 18.7mmol), and at room temperature further stirred 1 hour.The gained mixture under reduced pressure concentrates to remove and desolvates.Use the ethyl acetate extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 2.38g title compound (productive rate, 94%).
B) N-(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) urethanum
At room temperature, with 2-amino-3-methoxyl group-6,7-dimethyl quinoxaline (2.34g, 11.5mmol) and Vinyl chloroformate (2.50g 23.0mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (1.82g, 23.0mmol).At room temperature stir the mixture 12 hours and concentrating under reduced pressure desolvates to remove, and passes through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (3: 1) mixture extraction residue also concentrates, and obtains 2.65g title compound (productive rate, 84%).
C) 1-[(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
At room temperature, with N-(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) urethanum (35mg, 0.13mmol) and 1-(3-p-methoxy-phenyl) piperazine (50mg, 0.26mmol) be dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (40mg, 0.26mmol).Stir gained mixture and concentrating under reduced pressure down at 70 ℃ and desolvate, and pass through SiO to remove
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 37mg title compound (productive rate, 68%).
1H NMR(300MHz，CDCl
3)δ2.33(s，3H)，2.39(s，3H)，3.22-3.30(m，4H)，3.75(m，4H)，3.80(s，3H)，4.13(s，3H)，6.46-6.49(m，2H)，6.55-6.58(m，1H)，7.20-7.23(m，1H)，7.52(s，1H)，7.60(s，1H)。
Embodiment 184
1-[(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 75%) with embodiment 183.
1H NMR(300MHz，CDCl
3)δ2.33(s，3H)，2.39(s，3H)，3.21-3.29(m，4H)，3.75(m，4H)，3.79(s，3H)，4.11-4.13(m，3H)，6.06(s，1H)，6.12(s，2H)，7.52(s，1H)，7.59(s，1H)。
Embodiment 185
1-[(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 49%) with embodiment 183.
1H NMR(300MHz，CDCl
3)δ2.33(s，6H)，2.40(s，3H)，3.21-3.31(m，4H)，3.74-4.11(m，3H)，4.13(s，4H)，6.71-6.78(m，3H)，7.16-7.20(m，1H)，7.36(br s，1H)，7.52(s，1H)，7.60(s，1H)。
Embodiment 186
1-[(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 58%) with embodiment 183.
1H NMR(300MHz，CDCl
3)2.29-2.40(m，12H)，3.20-3.29(m，4H)，3.80-3.83(m，3H)，4.10(s，4H)，5，12(br s，1H)，6.59(s，3H)，7.36-7.60(m，2H)。
Embodiment 187
1-[(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 63%) with embodiment 183.
1H NMR(300MHz，CDCl
3)2.33-2.40(m，6H)，3.27-3.38(m，4H)，3.78-3.79(m，3H)，4.13(s，4H)，7.08-7.14(m，2H)，7.36-7.40(m，2H)，7.53(s，1H)，7.59(s，1H)。
Embodiment 188
1-[(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 71%) with embodiment 183.
1H NMR(300MHz，CDCl
3)δ2.33(s，3H)，2.40(s，3H)，3.23-3.30(m，4H)，3.74-3.77(m，3H)，4.13(s，4H)，6.80-6.91(m，3H)，7.15-7.20(m，1H)，7.36(br s，1H)，7.53(s，1H)，7.59(s，1H)。
Embodiment 189
1-[(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) aminocarboxyl]-4-(3-bromophenyl) piperazine
By the method identical N-(2-methoxyl group-6,7-dimethyl quinoxaline-3-yl) urethanum and the reaction of 1-(3-bromophenyl) piperazine are obtained title compound (productive rate, 69%) with embodiment 183.
1H NMR(300MHz，CDCl
3)δ2.33(s，3H)，2.40(s，3H)，3.22-3.31(m，4H)，3.73-3.76(m，3H)，4.13(s，4H)，6.85(m，1H)，7.00-7.20(m，3H)，7.40(br s，1H)，7.53(s，1H)，7.59(s，1H)。
Embodiment 190
1-[(2,6,7-trimethoxy quinoxaline-3-yl) aminocarboxyl]-a) 2-amino-3,6 of 4-(3-p-methoxy-phenyl) piperazine, 7-trimethoxy quinoxaline
In room temperature with under stirring, 2-amino-3-chloro-6 in being dissolved in tetrahydrofuran (THF) (40ml), (3.27g is added in the 25wt% sodium methylate (4.41g in the methyl alcohol among 13.6mmol) to 7-dimethoxy quinoxaline, 20.4mmol), and at room temperature further stirred 2 hours.The gained mixture under reduced pressure concentrates to remove and desolvates.Use the dichloromethane extraction product, wash organic layer with water and use MgSO
4Dry.Behind the concentrating under reduced pressure, pass through SiO
2Column chromatography purifying crude product.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 2.73g title compound (productive rate, 85%).
B) N-(2,6,7-trimethoxy quinoxaline-3-yl) urethanum
At room temperature, with 2-amino-3,6,7-trimethoxy quinoxaline (2.60g, 11.0mmol) and Vinyl chloroformate (2.40g 22.1mmol) is dissolved in the methylene dichloride (50ml), and under agitation to wherein add pyridine (1.75g, 22.1mmol).At room temperature stir the mixture 22 hours and concentrating under reduced pressure desolvates to remove, and passes through SiO
2The column chromatography purifying.Use normal hexane: ethyl acetate (2: 1) mixture extraction residue also concentrates, and obtains 3.04g title compound (productive rate, 90%).
C) 1-[(2,6,7-trimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3-p-methoxy-phenyl) piperazine
At room temperature, with N-(2,6,7-trimethoxy quinoxaline-3-yl) urethanum (28mg, 0.091mmol) and 1-(3-p-methoxy-phenyl) piperazine (27mg 0.18mmol) is dissolved in the tetrahydrofuran (THF) (2ml), and to wherein add DBU (27mg, 0.18mmol).Stir gained mixture and concentrating under reduced pressure down at 70 ℃ and desolvate, and pass through SiO to remove
2The column chromatography purifying.Use normal hexane: ethyl acetate (1: 2) mixture extraction residue also concentrates, and obtains 26mg title compound (productive rate, 64%).
1H NMR(300MHz，CDCl
3)δ3.27-3.29(m，4H)，3.78-3.81(m，7H)，3.94(s，3H)，3.97-3.98(m，1H)，4.00(s，3H)，4.15(s，3H)，6.47-6.49(m，2H)，6.56-6.58(m，1H)，7.11(s，1H)，7.14-7.27(m，3H)。
Embodiment 191
1-[(2,6,7-trimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-Dimethoxyphenyl) piperazine
By the method identical N-(2,6,7-trimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-Dimethoxyphenyl) piperazine are obtained title compound (productive rate, 68%) with embodiment 190.
1H NMR(300MHz，CDCl
3)δ3.28-3.29(m，4H)，3.75-3.79(m，4H)，3.97(s，3H)，4.00(s，3H)，4.13(s，3H)，6.07-6.11(m，3H)，7.14(s，1H)，7.27-7.28(m，2H)。
Embodiment 192
1-[(2,6,7-trimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3-aminomethyl phenyl) piperazine
By the method identical N-(2,6,7-trimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3-aminomethyl phenyl) piperazine are obtained title compound (productive rate, 56%) with embodiment 190.
1H NMR(300MHz，CDCl
3)δ2.34(s，3H)，3.25-3.30(m，4H)，3.76-3.80(m，4H)，3.98(s，3H)，4.02(s，3H)，4.16(s，3H)，6.74-6.78(m，3H)，7.14-7.26(m，4H)。
Embodiment 193
1-[(2,6,7-trimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3, the 5-3,5-dimethylphenyl) piperazine
By the method identical N-(2,6,7-trimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3, the 5-3,5-dimethylphenyl) piperazine are obtained title compound (productive rate, 56%) with embodiment 190.
1H NMR(300MHz，CDCl
3)δ2.28(s，3H)，2.30(s，3H)，3.26(m，4H)，3.77(m，4H)，3.97(s，3H)，4.00(s，3H)，4.13(s，3H)，6.59(s，3H)，7.14(s，1H)，7.27(s，1H)。
Embodiment 194
1-[(2,6,7-trimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3-fluoroform phenyl) piperazine
By the method identical N-(2,6,7-trimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3-fluoroform phenyl) piperazine are obtained title compound (productive rate, 67%) with embodiment 190.
1H NMR(300MHz，CDCl
3)δ3.34(m，4H)，3.81(m，4H)，3.97(s，3H)，4.00(s，3H)，4.13(s，3H)，7.09-7.11(m，2H)，7.14(s，3H)，7.25(m，1H)，7.38-7.41(m，1H)。
Embodiment 195
1-[(2,6,7-trimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3-chloro-phenyl-) piperazine
By the method identical N-(2,6,7-trimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3-chloro-phenyl-) piperazine are obtained title compound (productive rate, 74%) with embodiment 190.
1H NMR(300MHz，CDCl
3)δ3.29-3.31(m，4H)，3.79(m，4H)，3.97(s，3H)，4.00(s，3H)，4.12(s，3H)，6.82(m，1H)，6.86-6.88(m，1H)，6.89-6.91(m，1H)，7.14(s，1H)，7.19-7.22(m，3H)。
Embodiment 196
1-[(2,6,7-trimethoxy quinoxaline-3-yl) aminocarboxyl]-4-(3-bromophenyl) piperazine
By the method identical N-(2,6,7-trimethoxy quinoxaline-3-yl) urethanum and the reaction of 1-(3-bromophenyl) piperazine are obtained title compound (productive rate, 63%) with embodiment 190.
1H NMR(300MHz，CDCl
3)δ3.28-3.30(m，4H)，3.78(m，4H)，3.97(s，3H)，3.99(s，3H)，4.13(s，3H)，6.86(m，1H)，7.01(s，1H)，7.06-7.07(m，1H)，7.13-7.16(m，2H)，7.22-7.28(m，2H)。
The structure of compound 1～196 provides in table 1.
[table 1]
| 38 | Cl | H | Me | H | H | H | C-CN | C-H |
| 39 | Cl | H | Me | H | Ac | H | C-H | C-H |
| 40 | Cl | H | Me | H | NO 2 | H | C-H | C-H |
| 41 | Cl | H | Me | H | H | H | N | C-H |
| 42 | Cl | H | Me | H | H | H | N | N |
| 43 | Me | H | Me | H | H | H | C-H | C-H |
| 44 | Me | H | Me | H | H | H | C-OMe | C-H |
| 45 | Me | H | Me | OMe | H | H | C-H | C-H |
| 46 | Me | H | Me | H | OMe | H | C-H | C-H |
| 47 | Me | H | Me | OMe | H | OMe | C-H | C-H |
| 48 | Me | H | Me | OMe | OMe | OMe | C-H | C-H |
| 49 | Me | H | Me | H | H | H | C-Me | C-H |
| 50 | Me | H | Me | Me | H | H | C-H | C-H |
| 51 | Me | H | Me | H | H | H | C-Me | C-Me |
| 52 | Me | H | Me | Me | H | Me | C-H | C-H |
| 53 | Me | H | Me | CF 3 | H | H | C-H | C-H |
| 54 | Me | H | Me | H | H | H | C-F | C-H |
| 55 | Me | H | Me | H | F | H | C-H | C-H |
| 56 | Me | H | Me | H | H | H | C-Cl | C-H |
| 57 | Me | H | Me | Cl | H | H | C-H | C-H |
| 58 | Me | H | Me | H | Cl | H | C-H | C-H |
| 59 | Me | H | Me | H | H | H | C-CN | C-H |
| 60 | Me | H | Me | H | Ac | H | C-H | C-H |
| 61 | Me | H | Me | H | NO 2 | H | C-H | C-H |
| 62 | Me | H | Me | H | H | H | N | C-H |
| 63 | Me | H | Me | H | H | H | N | N |
| 64 | MeO | H | Me | H | H | H | C-H | C-H |
| 65 | MeO | H | Me | H | H | H | C-OMe | C-H |
| 66 | MeO | H | Me | OMe | H | H | C-H | C-H |
| 67 | MeO | H | Me | H | OMe | H | C-H | C-H |
| 68 | MeO | H | Me | OMe | H | OMe | C-H | C-H |
| 69 | MeO | H | Me | OMe | OMe | OMe | C-H | C-H |
| 70 | MeO | H | Me | H | H | H | C-Me | C-H |
| 71 | MeO | H | Me | Me | H | H | C-H | C-H |
| 72 | MeO | H | Me | H | H | H | C-Me | C-Me |
| 73 | MeO | H | Me | Me | H | Me | C-H | C-H |
| 74 | MeO | H | Me | CF 3 | H | H | C-H | C-H |
| 75 | MeO | H | Me | H | H | H | C-F | C-H |
| 76 | MeO | H | Me | H | F | H | C-H | C-H |
| 77 | MeO | H | Me | H | H | H | C-Cl | C-H |
| 78 | MeO | H | Me | Cl | H | H | C-H | C-H |
| 79 | MeO | H | Me | H | Cl | H | C-H | C-H |
| 80 | MeO | H | Me | H | H | H | C-CN | C-H |
| 81 | MeO | H | Me | H | Ac | H | C-H | C-H |
| 82 | MeO | H | Me | H | NO 2 | H | C-H | C-H |
| 83 | MeO | H | Me | H | H | H | N | C-H |
| 84 | MeO | H | Me | H | H | H | N | N |
| 85 | H | F | Me | H | H | H | C-H | C-H |
| 86 | H | F | Me | H | H | H | C-OMe | C-H |
| 87 | H | F | Me | OMe | H | H | C-H | C-H |
| 88 | H | F | Me | H | OMe | H | C-H | C-H |
| 89 | H | F | Me | OMe | H | OMe | C-H | C-H |
| 90 | H | F | Me | OMe | OMe | OMe | C-H | C-H |
| 91 | H | F | Me | H | H | H | C-Me | C-H |
| 92 | H | F | Me | Me | H | H | C-H | C-H |
| 93 | H | F | Me | H | H | H | C-Me | C-Me |
| 94 | H | F | Me | Me | H | Me | C-H | C-H |
| 95 | H | F | Me | CF 3 | H | H | C-H | C-H |
| 96 | H | F | Me | H | H | H | C-F | C-H |
| 97 | H | F | Me | H | F | H | C-H | C-H |
| 98 | H | F | Me | H | H | H | C-Cl | C-H |
| 99 | H | F | Me | Cl | H | H | C-H | C-H |
| 100 | H | F | Me | H | Cl | H | C-H | C-H |
| 101 | H | F | Me | H | H | H | C-CN | C-H |
| 102 | H | F | Me | H | Ac | H | C-H | C-H |
| 103 | H | F | Me | H | NO 2 | H | C-H | C-H |
| 104 | H | F | Me | H | H | H | N | C-H |
| 105 | H | F | Me | H | H | H | N | N |
| 106 | H | Cl | Me | H | H | H | C-H | C-H |
| 107 | H | Cl | Me | H | H | H | C-OMe | C-H |
| 108 | H | Cl | Me | OMe | H | H | C-H | C-H |
| 109 | H | Cl | Me | H | OMe | H | C-H | C-H |
| 110 | H | Cl | Me | OMe | H | OMe | C-H | C-H |
| 111 | H | Cl | Me | OMe | OMe | OMe | C-H | C-H |
| 112 | H | Cl | Me | H | H | H | C-Me | C-H |
| 113 | H | Cl | Me | Me | H | H | C-H | C-H |
| 114 | H | Cl | Me | H | H | H | C-Me | C-Me |
| 115 | H | Cl | Me | Me | H | Me | C-H | C-H |
| 116 | H | Cl | Me | CF 3 | H | H | C-H | C-H |
| 117 | H | Cl | Me | H | H | H | C-F | C-H |
| 118 | H | Cl | Me | H | F | H | C-H | C-H |
| 119 | H | Cl | Me | H | H | H | C-Cl | C-H |
| 120 | H | Cl | Me | Cl | H | H | C-H | C-H |
| 121 | H | Cl | Me | H | Cl | H | C-H | C-H |
| 122 | H | Cl | Me | H | H | H | C-CN | C-H |
| 123 | H | Cl | Me | H | Ac | H | C-H | C-H |
| 124 | H | Cl | Me | H | NO 2 | H | C-H | C-H |
| 125 | H | Cl | Me | H | H | H | N | C-H |
| 126 | H | Cl | Me | H | H | H | N | N |
| 127 | H | Me | Me | H | H | H | C-H | C-H |
| 128 | H | Me | Me | H | H | H | C-OMe | C-H |
| 129 | H | Me | Me | OMe | H | H | C-H | C-H |
| 130 | H | Me | Me | H | OMe | H | C-H | C-H |
| 131 | H | Me | Me | OMe | H | OMe | C-H | C-H |
| 132 | H | Me | Me | OMe | OMe | OMe | C-H | C-H |
| 133 | H | Me | Me | H | H | H | C-Me | C-H |
| 134 | H | Me | Me | Me | H | H | C-H | C-H |
| 135 | H | Me | Me | H | H | H | C-Me | C-Me |
| 136 | H | Me | Me | Me | H | Me | C-H | C-H |
| 137 | H | Me | Me | CF 3 | H | H | C-H | C-H |
| 138 | H | Me | Me | H | H | H | C-F | C-H |
| 139 | H | Me | Me | H | F | H | C-H | C-H |
| 140 | H | Me | Me | H | H | H | C-Cl | C-H |
| 141 | H | Me | Me | Cl | H | H | C-H | C-H |
| 142 | H | Me | Me | H | Cl | H | C-H | C-H |
| 143 | H | Me | Me | H | H | H | C-CN | C-H |
| 144 | H | Me | Me | H | Ac | H | C-H | C-H |
| 145 | H | Me | Me | H | NO 2 | H | C-H | C-H |
| 146 | H | Me | Me | H | H | H | N | C-H |
| 147 | H | Me | Me | H | H | H | N | N |
| 148 | H | MeO | Me | H | H | H | C-H | C-H |
| 149 | H | MeO | Me | H | H | H | C-OMe | C-H |
| 150 | H | MeO | Me | OMe | H | H | C-H | C-H |
| 151 | H | MeO | Me | H | OMe | H | C-H | C-H |
| 152 | H | MeO | Me | OMe | H | OMe | C-H | C-H |
| 153 | H | MeO | Me | OMe | OMe | OMe | C-H | C-H |
| 154 | H | MeO | Me | H | H | H | C-Me | C-H |
| 155 | H | MeO | Me | Me | H | H | C-H | C-H |
| 156 | H | MeO | Me | H | H | H | C-Me | C-Me |
| 157 | H | MeO | Me | Me | H | Me | C-H | C-H |
| 158 | H | MeO | Me | CF 3 | H | H | C-H | C-H |
| 159 | H | MeO | Me | H | H | H | C-F | C-H |
| 160 | H | MeO | Me | H | F | H | C-H | C-H |
| 161 | H | MeO | Me | H | H | H | C-Cl | C-H |
| 162 | H | MeO | Me | Cl | H | H | C-H | C-H |
| 163 | H | MeO | Me | H | Cl | H | C-H | C-H |
| 164 | H | MeO | Me | H | H | H | C-CN | C-H |
| 165 | H | MeO | Me | H | Ac | H | C-H | C-H |
| 166 | H | MeO | Me | H | NO 2 | H | C-H | C-H |
| 167 | H | MeO | Me | H | H | H | N | C-H |
| 168 | H | MeO | Me | H | H | H | N | N |
| 169 | F | F | Me | OMe | H | H | C-H | C-H |
| 170 | F | F | Me | OMe | H | OMe | C-H | C-H |
| 171 | F | F | Me | Me | H | H | C-H | C-H |
| 172 | F | F | Me | Me | H | Me | C-H | C-H |
| 173 | F | F | Me | CF 3 | H | H | C-H | C-H |
| 174 | F | F | Me | Cl | H | H | C-H | C-H |
| 175 | F | F | Me | Br | H | H | C-H | C-H |
| 176 | Cl | Cl | Me | OMe | H | H | C-H | C-H |
| 177 | Cl | Cl | Me | OMe | H | OMe | C-H | C-H |
| 178 | Cl | Cl | Me | Me | H | H | C-H | C-H |
| 179 | Cl | Cl | Me | Me | H | Me | C-H | C-H |
| 180 | Cl | Cl | Me | CF 3 | H | H | C-H | C-H |
| 181 | Cl | Cl | Me | Cl | H | H | C-H | C-H |
| 182 | Cl | Cl | Me | Br | H | H | C-H | C-H |
| 183 | Me | Me | Me | OMe | H | H | C-H | C-H |
| 184 | Me | Me | Me | OMe | H | OMe | C-H | C-H |
| 185 | Me | Me | Me | Me | H | H | C-H | C-H |
| 186 | Me | Me | Me | Me | H | Me | C-H | C-H |
| 187 | Me | Me | Me | CF 3 | H | H | C-H | C-H |
| 188 | Me | Me | Me | Cl | H | H | C-H | C-H |
| 189 | Me | Me | Me | Br | H | H | C-H | C-H |
| 190 | MeO | MeO | Me | OMe | H | H | C-H | C-H |
| 191 | MeO | MeO | Me | OMe | H | OMe | C-H | C-H |
| 192 | MeO | MeO | Me | Me | H | H | C-H | C-H |
| 193 | MeO | MeO | Me | Me | H | Me | C-H | C-H |
| 194 | MeO | MeO | Me | CF 3 | H | H | C-H | C-H |
| 195 | MeO | MeO | Me | Cl | H | H | C-H | C-H |
| 196 | MeO | MeO | Me | Br | H | H | C-H | C-H |
Embodiment 197
For example understand below to be used for people's the treatment or the representative drugs formulation of preventive use, it contains compound or its pharmacologically acceptable salt (compounds X hereinafter referred to as) of formula (1).Can obtain preparation by known ordinary method in the pharmaceutical field, and it is not limited to described representative drugs formulation.
1) tablet (direct compression)
The compounds X that 5.0mg is sieved mixes with 14.1mg lactose, 0.8mg CrosspovidoneUSNF and 0.1mg Magnesium Stearate, and mixture is pressed into tablet.
2) tablet (Hydroassembling)
The compounds X that 5.0mg is sieved mixes with 16.0mg lactose and 4.0mg starch, and to wherein adding the 0.3mg polysorbate80 that is dissolved in the pure water.Behind this granulating mixture, dried particles sieves, and mixes with 2.7mg silicon dioxide colloid and 2.0mg Magnesium Stearate.Particle is compressed into tablet.
3) pulvis and capsule
The compounds X that 5.0mg is sieved mixes with 14.8mg lactose, 10.0mg polyvinylpyrrolidone and 0.2mg Magnesium Stearate, and uses suitable equipment that mixture is filled in No. 5 gelatine capsules.
4) injection
With 100mg compounds X, 180mg N.F,USP MANNITOL and 26mg Na
2HPO
412H
2O is dissolved in the 2974ml distilled water.
Embodiment 198
The cell growth inhibition of diethylenediamine compound
The growth of cancerous cell line
Being used for this research obtains from following source with the cancer cells of the effect of determining quinazoline compound: from American type culture collection (ATCC, American Type CultureCollection) (Manassas, VA) people OVCAR-3 (ovary), MCF-7 (mammary gland, the dependence hormone), MDA-MB-231 (mammary gland), PC3 (prostate gland), HepG2 (liver), A549 (lung), Caki-1 (kidney), HT-29 (colon), HCT116 (colon) and PANC-1 (pancreas); MKN-45 (stomach) from DSMZ (Germany); From American National ICR (UnitedStates National Cancer Institute) (Bethesda, UMRC2 MD) (kidney); From Korea S clone storehouse (Korean Cell Line Bank) (Seoul, Huvec Korea) (Human umbilical vein endothelial cells), HEK293 (human embryo kidney (HEK)) and SK-OV-3 (ovary).OVCAR-3, MCF-7, PC3, HepG2, A549, HT-29 and MKN-45 are at the RPMI1640 substratum (Invitrogen that is supplemented with 10% foetal calf serum (" FBS "), 1mM Sodium.alpha.-ketopropionate, 10mM HEPES and 100U/ml penicillin and 100 μ g/ml Streptomycin sulphates (" P/S "), Carlsbad, CA) middle growth.(" DMEM " keeps in Invitrogen) at the Eagle substratum of the Dul becco improvement that is supplemented with 10%FBS, P/S, 10mM HEPES and 2mM L-glutaminate for MDA-MB-231, HCT116, UMRC2, Caki-1, PANC-1 and HEK293 cell.HUVEC keeps in the M199 that is supplemented with 3mg/ml Prostatropin (" bFGF "), 100mg/ml Heparn and 20%FBS.All cells all under 37 ℃ in the 5%CO of humidity
2Middle incubation.
CA
Assessed of the growth-inhibiting effect of the quinoxaline-diethylenediamine compound of replacement to the various human tumour cell.Also studied the relative importance of specified substituent to compound.Tested the piperazine derivatives compound of above-mentioned replacement, in contrast with DMSO.
Using sulfo-rhodamine (Sulforhodamine) B (" SRB ") method people such as (, J.National Cancer Institute, 82:1107-1112 (1990)) Skehan to carry out all cpds measures the growth-inhibiting of human tumor cell line.In brief, with the tumour cell of exponential growth with 2-3 * 10
3The density of individual cells/well is inoculated in 96 orifice plates, and handles with quinazoline compound at second day.Handle the in triplicate hole of use for each.5%CO in humidity
2In the atmosphere in 37 ℃ with cell and various compound incubation 96 hours.Behind the incubation 96 hours, cell is fixing with 10% trichoroacetic acid(TCA) (" TCA "), in 4 ℃ of incubations 1 hour, and with tap water washing three times.Subsequently, the 0.4% sulfo-rhodamine B pair cell that is used in 1% acetate dyeed 30 minutes, with 1% acetate washing four times, and air-dry once more.Stir in 10mM Tris solution after 5 minutes, (Bio-RadLaboratories, Hercules is CA) in the absorbancy in the every hole of measurement, 530nm place to use Benchmark Plus Microplate reader.
For with OD
530Value changes into the viable count in every hole, with OD
530Value corresponds to the standard OD that produces for every kind of clone
530Value on the-cell count curve.Use following formula to calculate survival percentage ratio:
% survival=viable count [test]/viable count [contrast] * 100
Calculate IC by nonlinear regression analysis
50Value.
Use QSAR and combinatorial chemistry technique to synthesize a large amount of compounds, comprise the compound that shows in the top table 1.The synthetic compound is screened at least three kinds of clone PANC-1, MDA-MB-231 and UMRC2 with about 1 μ M concentration.Select and show that in these clones at least a active compound is with further screening.From these compounds, select 44 kinds of compounds with further assessment as the wide spectrum antiproliferative, as shown in table 2.
[table 2]
| 172 | 0.70 | 0.56 | 1.00 | ||||||||||||
| 177 | 1.45 | 0.58 | 1.16 | ||||||||||||
| 191 | 0.69 | 0.49 | 0.90 | ||||||||||||
| 193 | 0.65 | 0.47 | 0.69 | ||||||||||||
| 194 | 0.75 | 0.79 | 1.40 | ||||||||||||
| 196 | 0.72 | 0.65 | 1.05 |
Industrial usability
Novel compound of the present invention can provide new quinoxaline-bridged piperazine derivatives or its officinal salt, and it has strong anti-proliferative effect, and can be used for coming overmedication proliferative diseases (comprising cancer) by using quinoxaline-diethylenediamine compound.
Claims (12)
1. the compound 1-[(6 of general formula (1), 7-replaces-2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(mix) aryl piperazine derivative and their pharmacologically acceptable salt,
Wherein, X and Y are N or C-R independently
7R
1And R
2Be C independently
1-C
6Alkoxyl group, C
1-C
6Alkyl or halogen; R
3Be C
1-C
6Alkyl; R
4, R
5, R
6And R
7Be hydrogen, C independently
1-C
6Alkoxyl group, C
1-C
6Alkyl, C
1-C
6Haloalkyl, C
1-C
6Alkyl-carbonyl, halogen, cyano group or nitro.
2. the compound of the formula of claim 1 (1), wherein X and Y are N, C-H, C-F, C-Cl, C-CN, C-CH independently
3Or C-OCH
3
3. the compound of the formula of claim 1 (1), wherein R
1And R
2Be fluorine, chlorine, methyl or methoxy independently.
4. the compound of the formula of claim 1 (1), wherein R
3Be methyl.
5. the compound of the formula of claim 1 (1), wherein R
4, R
5And R
6Be hydrogen, chlorine, nitro, methyl, trifluoromethyl, methoxyl group or acetoxyl group independently.
6. the compound of the formula of claim 1 (1), wherein R
7Be hydrogen, fluorine, chlorine, cyano group, methyl or methoxy.
7. prepare the compound of general formula (1) or the method for its pharmaceutically useful acid salt, described method comprises:
In conventional solvent with the compound 6 of general formula (2), 7-replaces-2-alkoxyl group-3-aminoquinoxaline with provide L-C (=O)-reagent of L ' group reacts in the presence of alkali, obtain the compound of general formula (3), subsequently the compound of general formula (3) and compound 1-(mixing) aryl piperazine derivative of general formula (4) are reacted, obtain the compound of general formula (1)
Wherein, X, Y, R
1, R
2, R
3, R
4, R
5And R
6Independently as defined in claim 1, and L and L ' be imidazoles, chlorine, oxyethyl group, phenoxy group or 4-nitrophenoxy independently.
8. the compound 6 of preparation claim 7 formula of (2), 7-replace-method of 2-alkoxyl group-3-aminoquinoxaline, and described method comprises:
Compound and sodium alkoxide NaOR with general formula (5)
3(R
3Be C
1-C
6Alkyl) react, obtain the compound of general formula (2),
Wherein, R
1And R
2Independently as defined in claim 1.
9. the compound 6 of preparation claim 7 formula of (2), 7-replace-method of 2-alkoxyl group-3-aminoquinoxaline, and described method comprises:
With the compound and 2 of general formula (6), the 4-dimethoxybenzylamine reacts, and obtains the compound of general formula (7), and the compound and the trifluoroacetic acid (TFA) of formula (7) reacted, and obtains the compound of general formula (2),
Wherein, R
1, R
2And R
3Independently as defined in claim 1.
10. the compound 6 of general formula (2), 7-replaces-2-alkoxyl group-3-aminoquinoxaline,
Wherein, R
1, R
2And R
3Independently as defined in claim 1.
11. pharmaceutical composition, it comprises the compound 1-[(6 with the general formula (1) of the combined claim 1 of pharmaceutically acceptable diluent or carrier, and 7-replaces-2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(mix) aryl piperazine derivative and its pharmacologically acceptable salt.
12. for example produce the method for anti-proliferative effect among the people the warm-blooded animal of this type of treatment of needs, described method comprises formula (1) quinoxaline-bridged piperazine derivatives and its pharmacologically acceptable salt of described animal being used the claim 1 of significant quantity, described formula (1) quinoxaline-bridged piperazine derivatives is 1-[(6, and 7-replaces-2-alkoxyl group quinoxaline-3-yl) aminocarboxyl]-4-(mixing) aryl piperazine derivative.
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|---|---|---|---|
| KR1020040094232 | 2004-11-17 | ||
| KR1020040094233A KR100739233B1 (en) | 2004-11-17 | 2004-11-17 | 1-[3-Alkoxy-6-substituted-quinoxalin-2-ylaminocarbonyl]-4-heteroarylpiperazine Derivatives |
| KR1020040094233 | 2004-11-17 |
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| CN102250022A (en) * | 2011-05-26 | 2011-11-23 | 浙江大学 | Substituted quinoxalinamine compounds, and preparation method and application thereof |
| CN102250022B (en) * | 2011-05-26 | 2013-10-16 | 浙江大学 | Substituted quinoxalinamine compounds, and preparation method and application thereof |
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