CN1966500B - A class of quinoxaline derivatives, preparation method and use - Google Patents
A class of quinoxaline derivatives, preparation method and use Download PDFInfo
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- CN1966500B CN1966500B CN2005101104831A CN200510110483A CN1966500B CN 1966500 B CN1966500 B CN 1966500B CN 2005101104831 A CN2005101104831 A CN 2005101104831A CN 200510110483 A CN200510110483 A CN 200510110483A CN 1966500 B CN1966500 B CN 1966500B
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- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 title claims abstract 11
- 238000002360 preparation method Methods 0.000 title claims abstract 4
- 230000037361 pathway Effects 0.000 claims abstract 3
- 206010028980 Neoplasm Diseases 0.000 claims abstract 2
- 230000005856 abnormality Effects 0.000 claims abstract 2
- 208000027866 inflammatory disease Diseases 0.000 claims abstract 2
- 208000030159 metabolic disease Diseases 0.000 claims abstract 2
- 230000004770 neurodegeneration Effects 0.000 claims abstract 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 6
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 125000002541 furyl group Chemical group 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims 2
- 125000001544 thienyl group Chemical group 0.000 claims 2
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 102100033992 Dual specificity protein phosphatase 22 Human genes 0.000 abstract 2
- 101001017467 Homo sapiens Dual specificity protein phosphatase 22 Proteins 0.000 abstract 2
- 201000010099 disease Diseases 0.000 abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 2
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 abstract 1
- 102100023332 Dual specificity mitogen-activated protein kinase kinase 7 Human genes 0.000 abstract 1
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 abstract 1
- 101000624594 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 7 Proteins 0.000 abstract 1
- 208000037273 Pathologic Processes Diseases 0.000 abstract 1
- 230000002159 abnormal effect Effects 0.000 abstract 1
- 230000003213 activating effect Effects 0.000 abstract 1
- 230000004071 biological effect Effects 0.000 abstract 1
- 230000033228 biological regulation Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 230000009054 pathological process Effects 0.000 abstract 1
- 238000011144 upstream manufacturing Methods 0.000 abstract 1
- 0 *C(*1)=C(*)*C2=C1C=C(*)C=*=C2 Chemical compound *C(*1)=C(*)*C2=C1C=C(*)C=*=C2 0.000 description 9
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Abstract
本发明公开了一类喹喔啉衍生物、及它的制备和用途，该类化合物经生物活性测试，证明它具有JSP-1抑制作用。JSP-1通过活化JNK的上游激酶MKK4和/或MKK7来实现对JNK的活化。JNK途径的异常与许多疾病的病理过程相关，如在炎症性疾病、神经退行性疾病、代谢疾病以及癌症中都发现JNK活性的异常增加，对JNK途径抑制调节可能预防或治疗相关疾病。The invention discloses a class of quinoxaline derivatives, their preparation and application. The biological activity test of the compounds proves that they have JSP-1 inhibitory effect. JSP-1 activates JNK by activating the upstream kinases MKK4 and/or MKK7 of JNK. The abnormality of JNK pathway is related to the pathological process of many diseases. For example, abnormal increase of JNK activity is found in inflammatory diseases, neurodegenerative diseases, metabolic diseases and cancers. The inhibition and regulation of JNK pathway may prevent or treat related diseases.
Description
Technical field
The present invention relates to use the quinoxaline compound that can be used as JSP-1 protein phosphatase inhibitor to suppress the JNK approach, thus adjusting disease such as diseases associated with inflammation, nerve degenerative diseases, metabolic trouble and the cancer etc. relevant with the JNK path with treatment.
Background technology
Along with the continuous development of related disciplines such as molecular biology and molecular pharmacology, biomacromolecule such as enzyme, acceptor and the ionic channel etc. that play an important role in vital movement that get more and more are found in succession.Carry out the development trend of new drug design having become new drug research exploitation as drug target with the enzyme that plays a crucial role in vivo.JSP-1 is a new protein phosphatase, has three research groups to report respectively in succession.(Shen Y. such as the breadboard Shen of calendar year 2001 U.S. Cold Spring Harbor, Luche R., Wei B., et al.Activation of the Jnk signaling pathway by a dual-specificityphosphatase, JSP-1.Proc.Natl.Acad.Sci U.S.A, 2001,98 (24): 13613-13618) at first reported this protein phosphatase, because of it can activate mitogen-activated protein kinase (the mitogen-activated protein kinase of a kind of JNK of being referred to as (c-JunN-terminal Kinese), MAPK), called after JSP-1 (JNK stimulatory phosphatase-1); (the Chen A.J. such as Belmont of U.S. Baylor medical college in 2002, Zhou G.S., Juan T., et al.The dualspecificity JKAP specifically activates the c-Jun N-terminal kinase pathway.J.Biol.Chem.2002,277 (39): 36592-36601) report that this protein phosphatase also because of relevant with the JNK approach, is referred to as JKAP (JNKpathway-associated phosphatase); Meanwhile, (the AlonsoA. such as Mustelin of California, USA Burnham institute, Merlo J.J., Na S., et al.Inhibition of T Cell Antigen Receptor Signaling by VHR-relatedMKPX (VHX), a New Dual Specificity Phosphatase Related to VH1 Related (VHR) .J.Biol.Chem.2002,277 (7): 5524-5528) report its during to the discovery of this protein phosphatase, according to the base sequence similarity with its called after VHX (VHR-related MKPX).JSP-1 is made up of 184 amino acid, in the multiple tissue of the mankind expression is arranged all, and is maximum in thymus gland.JSP-1 has the feature of DSPs: can hydrolysis pSer/pThr and pTyr residue; Has conserved sequence HCX2GX2R in the 87-94 position.The PDB database will be announced the crystalline structure of JSP-1 in October, 2005, studies show that the JSP-1 overexpression is to JNK (c-JunNH
2Terminal kinases) signal transduction pathway demonstrates the selectivity activation, and JSP-1 realizes activation to JNK by the activation upstream kinases MKK4 of JNK and/or MKK7.And the JNK approach is mitogen-activated protein kinase (mitogen-activated protein kinases, MAPKs) one of signal transduction pathway, it is signal pathway important in the mammalian cell, it participates in cell growth, division and the physiological activity in each stage of apoptosis, is regulating the biological function of a series of complexity.Relative disease may be prevented or treat to JNK approach unusual relevant with the pathologic process of numerous disease as all find the active unusual increase of JNK in diseases associated with inflammation, nerve degenerative diseases, metabolic trouble and cancer, to JNK approach inhibition adjusting.Cutshall research group has reported a class thiazole ketone JSP-1 inhibitor (Cutshall, N.S., O ' Day C., Prezhdo M.Rhodanine derivatives as inhibitors of JSP-1.Bioorg.Med.Chem.Lett.2005,15 (14): 3374-3379).Active strong, the single-minded JSP-1 inhibitor of effect of research and discovery, both can be used as the molecular probe of further investigation JSP-1 and JNK approach biological function, can inquire into JSP-1 again becomes the possibility of the potential drug target spot of relative disease, has very important significance for carrying out original new drug research.
Summary of the invention
The purpose of this invention is to provide quinoxaline derivative.
Another object of the present invention provides the preparation method of this analog derivative.
A further object of the present invention provides the purposes of this analog derivative.
The present invention designs and has synthesized the quinoxaline derivatives that following general formula is arranged:
Wherein R is H, C
1-C
4Alkyl, C
2-C
4Thiazolinyl, C
2-C
4Alkynyl, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
10Alkyl, C
1-C
10Alkoxyl group, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
3-C
8Cycloalkyl, benzyl, perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl and substituted aryl, halogen as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl etc.;
X is :-NHCOY ,-NHCSY ,-OCOY ,-NHC=NHY ,-CH
2COY ,-COY ,-NHSO
2Y ,-N (H) Y;
Y is:
NR
3R
4、OR
3R
4、R
3R
4；
R3, R4 can be identical or different, are H, C
1-C
9Alkyl, C
3-C
8Cycloalkyl, benzyl perhaps contain 0-4 identical or different heteroatomic five Yuans or six Yuans aryl and substituted aryl etc. as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl etc. or R3 forms azaheterocyclyl with R4 with the nitrogen-atoms that they were connected or R3 forms amino acid with R4 with the nitrogen-atoms that they were connected;
Quinoxaline derivatives of the present invention can prepare by the following method:
Reaction formula 1
This reaction formula has provided quinoxaline carbamide derivative synthetic general method.Wherein but compound 1 commercialization is buied or is reoxidized by benzoic condensation by aromatic aldehyde and makes.Compound 1 reacts in polar solvent with compound 2 and obtains compound 3.Here used polar solvent has non-protonic solvent such as tetrahydrofuran (THF) (THF), N, N-diformamide (DMF) etc., and protic solvent such as ethanol (EtOH), methyl alcohol (MeOH), n-propyl alcohol (n-PrOH), propyl carbinol (n-BuOH), Virahol (i-PrOH) etc., be generally methyl alcohol and ethanol.Reaction conditions is generally at the reflux temperature of solvent.Compound 3 reduction can obtain compound 4.General used reductive agent has iron powder (Fe), zinc powder (Zn), tin (Sn), tin protochloride (SnCl
2) and the reductive agent of sulfur-bearing etc.Catalyzer in the catalytic hydrogenation has palladium (Pd), platinum (Pt) and Ranny nickel (Ranny Ni) etc.Resulting compound 4 obtains isocyanic ester 5 with phosgene or the processing of three surpalites in inert solvents such as methylene dichloride, chloroform, benzene, toluene.Compound 5 obtains urea with the amine condensation then.Reaction conditions generally carries out between 0～100 ℃, carries out at ambient temperature usually.The product of gained is purified through methods such as column chromatography or recrystallizations can obtain pure product.
Reaction formula 2
This reaction formula has provided another method of quinoxaline carbamide derivative synthetic.Suc as formula shown in: compound 6 in inert solvents such as methylene dichloride, chloroform, benzene, toluene and organic tertiary amines such as Trimethylamine 99, triethylamine, diisopropylethylamine in the presence of handle with phosgene or three surpalites and to obtain chloroformyl amine compound 7, this compound and compound 4 be at tetrahydrofuran (THF), ether, methylene dichloride, chloroform, benzene, toluene, N, in the inert solvents such as N-diformamide and carry out condensation reaction under the existence of organic tertiary amine such as Trimethylamine 99, triethylamine, diisopropylethylamine and obtain urea.Reaction conditions generally carries out between-78～100 ℃, carries out under 0 ℃ of condition usually.The product of gained is through method purifying such as column chromatography, recrystallizations.
Reaction formula 3
This reaction formula has provided quinoxaline thiourea derivatives synthetic general method.Suc as formula shown in: compound 4 is converted into lsothiocyanates 8 earlier, this can obtain by several different methods, such as compound 4 in inert solvents such as tetrahydrofuran (THF), ether, methylene dichloride, chloroform, benzene, toluene and organic basess such as Trimethylamine 99, triethylamine, diisopropylethylamine in the presence of, earlier with dithiocarbonic anhydride (CS
2) handle and then obtain compound 8 with the processing of acyl chlorides such as phosphorus oxychloride, thionyl chloride and Vinyl chloroformate; Perhaps thiocyanate-and Benzoyl chloride form intermediate earlier and are obtaining lsothiocyanates 8 with compound 4 reactions.This lsothiocyanates 8 obtains thiocarbamide with amine condensation in polar solvent.Here used polar solvent has non-protonic solvent such as tetrahydrofuran (THF), N, and N-diformamide etc., and protic solvent such as ethanol, methyl alcohol, n-propyl alcohol, propyl carbinol, Virahol etc. are generally methyl alcohol and ethanol.Reaction conditions generally carries out between 0～100 ℃, carries out at ambient temperature usually.The product of gained is through method purifying such as column chromatography, recrystallizations.
Reaction formula 4
This reaction formula has provided carboxylamine quinoxaline ester derivative synthetic general method.Suc as formula shown in: at first amine and N, N '-carbonyl dimidazoles (CDI) reaction obtains obtaining 10 after the activation of compound 9,9 usefulness methyl iodide.Compound 11 can be obtained by 3-nitro-4-amino-phenol reduction in addition, and general used reductive agent has iron powder (Fe), zinc powder (Zn), tin (Sn), tin protochloride (SnCl
2) and the reductive agent of sulfur-bearing etc.Catalyzer in the catalytic hydrogenation has palladium (Pd), platinum (Pt) and Ranny nickel (Ranny Ni) etc.Compound 11 is again with 1, and the 2-dicarbonyl compound reacts in polar solvent and obtains compound 12.Here used polar solvent has non-protonic solvent such as tetrahydrofuran (THF) (THF), N, N-diformamide (DMF) etc., and protic solvent such as ethanol (EtOH), methyl alcohol (MeOH), n-propyl alcohol (n-PrOH), propyl carbinol (n-BuOH), Virahol (i-PrOH) etc., be generally methyl alcohol and ethanol.Reaction conditions is generally at the reflux temperature of solvent.Compound 12 obtains carboxylamine quinoxaline ester derivative with compound 10 condensations, carries out at ambient temperature usually.The product of gained is purified through methods such as column chromatography or recrystallizations can obtain pure product.
Reaction formula 5
This reaction formula has provided quinoxaline carbamide derivative synthetic general method.Suc as formula shown in: benzoyl lsothiocyanates 13 by Benzoyl chloride in acetone with the ammonium thiocyanate preparation that refluxes; lsothiocyanates 13 reacts the thiocarbamide 14 that obtains the benzoyl protection with compound 4 in acetone; hydrolysis is sloughed benzoyl and is obtained compound 15 under the alkaline condition, again the methyl-isothiourea hydriodate 16 that methylates and obtain replacing through methyl iodide.Compound 16 reacts in polar solvent with amine and obtains guanidine.Here used polar solvent has non-protonic solvent such as tetrahydrofuran (THF) (THF), N, N-diformamide (DMF) etc., and protic solvent such as ethanol (EtOH), methyl alcohol (MeOH), n-propyl alcohol (n-PrOH), propyl carbinol (n-BuOH), Virahol (i-PrOH) etc., be generally methyl alcohol and ethanol.Reaction conditions adopts the method for microwave-assisted here generally at the reflux temperature of solvent.The product of gained is purified through methods such as column chromatography or recrystallizations can obtain pure product.
Reaction formula 6
This reaction formula has provided quinoxaline amide derivatives synthetic general method.Suc as formula shown in: the p-nitrophenyl acetonitrile can obtain p-aminophenyl acetonitrile 17 through reduction, and general used reductive agent has iron powder (Fe), zinc powder (Zn), tin (Sn), tin protochloride (SnCl
2) and the reductive agent of sulfur-bearing etc.Catalyzer in the catalytic hydrogenation has palladium (Pd), platinum (Pt) and Ranny nickel (Ranny Ni) etc.P-aminophenyl acetonitrile 17 nitrated preceding elder generations obtain acetparaminosalol benzyl cyanide 18 with diacetyl oxide with amido protecting, again with the nitrated 3-nitro that obtains expecting of nitrosonitric acid-4-kharophen benzyl cyanide 19.Hydrolysis obtains corresponding 3-nitro-4-aminophenyl acetic acid 20.Obtain important intermediate 3 through reduction again, 4-diamino-phenylacetic acid 21.Directly carry out next step reaction without separation and purification, with 1, the condensation of 2-dicarbonyl compound obtains compound 22.Compound 22 and amine in inert solvent in the presence of condensing agent and alkali condensation can obtain the quinoxaline amide derivatives.In this reaction, used solvent is generally tetrahydrofuran (THF), ether, methylene dichloride, chloroform, benzene, toluene, N, inert solvents such as N-diformamide; Used condensing agent has carbon imide class condensing agents such as dicyclohexyl carbon imide, di-isopropyl carbon imide, organic-inorganic acyl chlorides such as phosphorus oxychloride, thionyl chloride, p-methyl benzene sulfonic chloride, oxalyl chloride and isobutyl chlorocarbonate; Used alkali is generally organic tertiary amines such as Trimethylamine 99, triethylamine, diisopropylethylamine.Temperature of reaction is between-78 ℃-50 ℃.The product of gained is purified through methods such as column chromatography or recrystallizations can obtain pure product.
Reaction formula 7
This reaction formula has provided quinoxaline benzamide type derivative synthetic general method.Suc as formula shown in: 1,2-dicarbonyl compound and the condensation of O-Phenylene Diamine phenylformic acid obtain compound 23, compound 23 and amine in inert solvent in the presence of condensing agent and alkali condensation can obtain quinoxaline benzamide type derivative.In this reaction, used solvent is generally tetrahydrofuran (THF), ether, methylene dichloride, chloroform, benzene, toluene, N, inert solvents such as N-diformamide; Used condensing agent has carbon imide class condensing agents such as dicyclohexyl carbon imide, di-isopropyl carbon imide, organic-inorganic acyl chlorides such as phosphorus oxychloride, thionyl chloride, p-methyl benzene sulfonic chloride, oxalyl chloride and isobutyl chlorocarbonate; Used alkali is generally organic tertiary amines such as Trimethylamine 99, triethylamine, diisopropylethylamine.Temperature of reaction is between-78 ℃-50 ℃.The product of gained is purified through methods such as column chromatography or recrystallizations can obtain pure product.
Reaction formula 8
This reaction formula has provided 6-sulfonamido quinoxaline derivatives synthetic general method.Suc as formula shown in: compound 4 can obtain target compound with the SULPHURYL CHLORIDE reaction.This reaction can reflux in pyridine solvent and carry out.The product of gained is purified through methods such as column chromatography or recrystallizations can obtain pure product.
Reaction formula 9
This reaction formula has provided quinoxaline amino derivative synthetic general method.Suc as formula shown in: 4-fluoro-2-N-methyl-p-nitroaniline can obtain compound 24 through reduction, and general used reductive agent has iron powder (Fe), zinc powder (Zn), tin (Sn), tin protochloride (SnCl
2) and the reductive agent of sulfur-bearing etc.Catalyzer in the catalytic hydrogenation has palladium (Pd), platinum (Pt) and Ranny nickel (Ranny Ni) etc.Compound 24 and 1, the condensation of 2-dicarbonyl compound obtains 6-fluorine quinoxaline 25.Compound 25 reacts under the alkali effect in polar solvent with amine or nitrogen heterocyclic ring and obtains 6-sulfonamido quinoxaline derivatives.Here used polar solvent has non-protonic solvent such as tetrahydrofuran (THF) (THF), N, N-diformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) etc., and alkali has salt of wormwood, sodium hydroxide etc.
Biological activity determination
Humanization hJSP-1 has similar enzymatic property to the GST-JSP-1 that merges form.Use escherichia expression system express cell mitotic cycle phosphoesterase JSP-1 catalyst structure domain, be present in supernatant with the gst fusion protein form, lysis is after GSH-affinity column purifying obtains recombination human source GST-JSP1 fusion rotein.Utilize this enzyme to carry out the high flux screening of JSP-1 micromolecular inhibitor.
Adopt fluorogenic substrate OMFP, observe of the inhibition of different compounds recombinase active.OMFP hydrolysis substrate OMF can launch the detectable fluorescent signal that wavelength is 535nm after by the 485nm excitation, thereby the activity change of observation enzyme and compound are to its inhibition situation.Primary dcreening operation select for use system be 30nM GST-JSP1 (enzyme storage liquid and diluent are 50mM Tris, 1mM DTT, 1mM EDTA, pH8.0), 10 μ M OMFP, 20 μ g/mL compounds, the solution of survey living is 50mM BisTris, 1mM DTT, 1mM EDTA, pH6.0.At Ex435, under the Em535 wavelength, measure the enzyme reaction performance graph, according to the activity change degree, calculate the compound inhibiting rate, select inhibiting rate and carry out IC greater than 50% compound
50Measure.Choose 7 concentration of compound according to the primary dcreening operation inhibiting rate, the same primary dcreening operation of testing method calculates IC with the enzymic activity value that draws under the compound effects of different concns
50
The biological activity test result
Quinoxaline ureas JSP-1 micromolecular inhibitor
Table5-1 quinoxaline ureas JSP-1 micromolecular inhibitor active testing data
5.2 carboxylamine quinoxaline ester class JSP-1 micromolecular inhibitor
Table5-2 carboxylamine quinoxaline ester class JSP-1 micromolecular inhibitor active testing data
5.3 quinoxaline guanidine class JSP-1 micromolecular inhibitor
Table5-3 quinoxaline guanidine class JSP-1 micromolecular inhibitor active testing data
5.4 quinoxaline ethanamide JSP-1 micromolecular inhibitor
Table5-4 quinoxaline ethanamide JSP-1 micromolecular inhibitor active testing data
5.5 6-amido quinoxaline class JSP-1 micromolecular inhibitor
Table5-5 6-amido quinoxaline class JSP-1 micromolecular inhibitor active testing data
5.6 quinoxaline benzamide type JSP-1 micromolecular inhibitor
Table5-6 quinoxaline benzamide type JSP-1 micromolecular inhibitor active testing data
5.7 quinoxaline amine and 6-nitrogen heterocyclic ring quinoxaline JSP-1 micromolecular inhibitor
Table5-7 quinoxaline amine and 6-nitrogen heterocyclic ring quinoxaline JSP-1 micromolecular inhibitor active testing data
5.8 6-sulfonamido quinoxaline JSP-1 micromolecular inhibitor biological activity and structure activity study
Table5-8 6-sulfonamido quinoxaline JSP-1 micromolecular inhibitor active testing data
Embodiment
Embodiment 1:N-{6-[2,3-two-(2-furyl)-quinoxaline] base }-preparation of 3-diethylamine acylpiperidine-1-methane amide:
1-a:1-tertiary butyloxycarbonyl phenylpiperidines-3-formic acid is added to 20.0g (0.155mol) nipecotic acid in the 180ml aqueous solution of 6.2g (0.155mol) sodium hydroxide, stir 10min under the room temperature, add 24.6g (0.232mol) yellow soda ash again and continue to stir 10min, add the 120ml dioxane, put in the ice-water bath, when treating that temperature is reduced to 0 ℃, in this solution, splash into the 60ml dioxane solution of 41.0g (0.188mmol) uncle fourth oxygen acid anhydrides, drip and finish, continue to stir 30min, at room temperature stir then and spend the night.Adding entry all dissolves the solid of reaction generation, gained solution ethyl acetate: sherwood oil (4:1) extraction three times, water layer is put in the ice bath, added 1N hydrochloric acid adjust pH to 2, use ethyl acetate extraction three times, merge organic layer, anhydrous sodium sulfate drying filters, and obtains 34.3g white powder solid chemical compound after decompression steams solvent, yield: 96.6%, Mp:155-156 ℃.
1H?NMR(400MHz，CDCl
3)：δ4.21(1H，m)，3.85～3.90(1H，m)，3.19(1H，m)，2.82～2.88(1H，m)，2.45～2.50(1H，m)，2.04～2.08(1H，m)，1.60～1.74(2H，m)，1.41～1.49(10H，m)。
1-b:N, N-diethyl-piperidines-3-carboxamide hydrochloride 8.0g (0.035mol) 1-tertiary butyloxycarbonyl phenylpiperidines-3-formic acid is dissolved in the new methylene dichloride that steams of 120ml, add 11.0ml (0.105mol) diethylamine, put and stir 10min in the ice bath, in this solution, drip the 90ml dichloromethane solution of 16.4g (0.037mol) BOP, drip and finish stirring at room 3h.Decompression steams solvent, in debris, add saturated nacl aqueous solution, ethyl acetate extraction three times, merge organic layer, use 10% aqueous citric acid solution successively, saturated sodium bicarbonate washing three times, the saturated nacl aqueous solution washing once, the organic layer anhydrous sodium sulfate drying filters, and obtains the oily matter compound after decompression steams solvent.In this oily matter, add the 5ml ethyl acetate, then this solution is splashed in the ethyl acetate solution of the saturated HCl of 50ml, stir, solid occurs, take out HCl, suction filtration, anhydrous diethyl ether washing, drying, obtain 6.3g white powder solid chemical compound, two step yields: 81.8%, Mp: greater than 250 ℃.
1H?NMR(400MHz，DMSO-d6)：δ3.29～3.33(3H，m)，3.17～3.20(4H，m)，2.79～2.91(2H，m)，1.73～1.77(3H，m)，1.51～1.52(1H，m)，1.13(3H，t)，0.99(3H，t)。
1-c:2,3-difuryl-6-quinoxaline amine
With 20.0g (0.105mol) connection furan acyl and 16.1g (0.105mol) 4-nitro O-Phenylene Diamine reflux 24h in the 420ml dehydrated alcohol.Solid is separated out in cooling, and suction filtration washs solid with small amount of ethanol, and drying obtains 31.1g yellow powder shape solid chemical compound, yield: 96.3%, and Mp:169-171 ℃.
1H?NMR(400MHz，DMSO-d6)：δ8.86(1H，d，J＝2.8Hz)，8.53(1H，dd，J＝2.4Hz，
J＝9.2Hz)，8.29(1H，d，J＝9.2Hz)，7.97～7.99(2H，m)，6.89～6.94(2H，m)，6.76～6.78(2H，m)。
1-d:N-{6-[2,3-two-(2-furyl)-quinoxaline] base }-3-diethylamine acylpiperidine-1-methane amide
Under the nitrogen protection, 170.0mg (0.573mmol) three surpalites are added in the 250ml round-bottomed flask, add the new methylene dichloride that steams of 15ml again, stir 5min under the room temperature.300.0mg (1.082mmol) 2,3-difuryl-6-quinoxaline amine is dissolved in the new methylene dichloride that steams of 80ml, add 0.2ml (1.145mmol) diisopropylethylamine, stir, then this solution is slowly splashed in the above-mentioned solution, drip and finish, continue at room temperature to stir 0.5h, resulting solution directly carries out next step reaction without separating.
0.6ml (3.442mmol) diisopropylethylamine is joined 360.0mg (1.633mmol) compound N, in the 10ml dichloromethane solution of N-diethyl-piperidines-3-carboxamide hydrochloride, stir 10min under the room temperature.To go up resulting compound solution of step and pour into fast in this solution, continue at room temperature to stir 30min.Resulting solution washes with water three times successively, and saturated nacl aqueous solution washs once, the organic layer anhydrous sodium sulfate drying.Filter, decompression steams solvent and obtains oily matter, and column chromatography for separation obtains 370.0mg yellow powder shape solid chemical compound, two step yields: 70.2%, and Mp:118-121 ℃.
1H?NMR(600MHz，CDCl
3)：δ8.04(1H，m)，8.01(1H，m)，7.97(1H，m)，7.80(1H，brs)，7.60(2H，m)，6.60～6.61(2H，m)，6.55(2H，m)，3.94(1H，m)，3.73(1H，m)，3.34～3.49(7H，m)，2.74～2.78(1H，m)，1.78～1.97(3H，m)，1.24(3H，t)，1.13(3H，t)。
IR(KBr，cm
-1)υ
max：3430，1618，1569，1527，1475，1230，744。
EIMS?m/z：487(M
+)，303(100％)。
Similar aforesaid method is synthetic to obtain following compound:
X is-NHCOY;
Y is
Annotate:
*This routine numeral methane amide position on this cycloaliphatic ring
Embodiment 2:N-{6-[2,3-two-(2-furyl)-quinoxaline] base }-preparation of decyl amide:
With 60.0mg (0.217mmol) 2,3-difuryl-6-quinoxaline amine, 54.0 μ l (0.260mmol) decanoyl chloride, 185.0mg (0.648mmol) the new methylene dichloride that steams of triethylamine resin and 2ml adds in the reaction flask of 10ml band screw socket successively, put room temperature vibration 3h on the shaking table, add 62.0mg (0.216mmol) aminoresin then, continue vibration 1h.Leach resin, filtrate adds in the alkaline silica gel post of the immobilized amino of 400mg, methanol-eluted fractions, and decompression steams solvent and obtains 80.0mg scarlet pulverulent solids compound, yield: 85.6%, Mp:145-148 ℃.
1HNMR(300MHz，CDCl
3)：δ8.26(1H，d，J＝2.4Hz)，8.10(1H，d，J＝9.3Hz)，8.03(1H，dd，J＝2.4Hz，J＝9.3Hz)，7.63(2H，m)，7.46(1H，brs)，6.64～6.69(2H，m)，6.57～6.59(2H，m)，2.45～2.50(2H，t)，1.80(2H，m)，1.28～1.38(12H，m)，0.90(3H，t)。
IR(KBr，cm
-1)υ
max：3423，3271，1665，1568，1537，1202，741。
EIMS?m/z：431(M
+)，277(100％)。
HREI：C
26H
29N
3O
3Calculated：431.2209，Found：431.2210。
Similar aforesaid method is synthetic to obtain following compound:
X is-NHCOY;
Y is R3
The preparation of embodiment 3:3-diethylamine acylpiperidine-1-formic acid-6-(2,3-phenylbenzene quinoxaline) ester:
3-a:2,3-phenylbenzene quinoxaline phenol
Under the nitrogen protection, 0.3g10% palladium carbon is added in the 100ml round-bottomed flask, add 50ml dehydrated alcohol and 1.8g (0.012mol) 3-nitro-4-amino-phenol successively, displacement hydrogen, logical hydrogen reaction is to complete under the room temperature, and solution becomes colorless.Remove by filter palladium carbon under the nitrogen protection, absolute ethanol washing obtains 3, the 4-diaminophenol, and this compound is very easily oxidized, so without separation and purification, directly carry out next step reaction.In reaction flask, add 1.4g (6.667mmol) benzil, reflux 24h under the nitrogen protection.Cooling, decompression steams solvent and obtains oily matter, obtains 1.4g purple pulverulent solids 2,3-phenylbenzene-34, two step of 6-quinoxaline phenol yield: 38.9%, Mp:251-253 ℃.
1H?NMR(400MHz，DMSO-d6)：δ10.51(1H，brs)，8.01(1H，d)，7.43～7.47(5H，m)，7.32～7.38(7H，m)。
IR(KBr，cm
-1)υ
max：3381，3057，1618，1498，1203，700。
EIMS?m/z：298(M
+)。
3-b:1-(imidazoles-1-carbonyl)-piperidines-3-formyl diethylamine hydrochloride
8.0g (0.036mol) compound N, N-diethyl-piperidines-3-carboxamide hydrochloride is dissolved in the 120ml methylene dichloride, stirs to add 9.0ml (0.051mol) diisopropylethylamine, 5.9g (0.038mol) N down successively, N '-carbonyl dimidazoles continues to stir 3d under the room temperature.Washing, the organic layer anhydrous magnesium sulfate drying filters, and after decompression steamed solvent, the separation of residue silica gel column chromatography obtained 4.4g yellow oily compounds, two step yields: 44.9%.
1H?NMR(400MHz，CDCl
3)：δ7.85(1H，m)，7.18(1H，m)，7.06(1H，m)，4.06～4.10(1H，m)，3.96～4.00(1H，m)，3.09～3.38(6H，m)，2.68～2.75(1H，m)，1.79～1.95(3H，m)，1.53～1.61(1H，m)，1.21(3H，t)，1.06(3H，t)。
3-c:1-(N-methyl-imidazoles-1-carbonyl)-piperidines-3-formyl diethylamine salt compounded of iodine
3.0g (0.011mol) compound 1-(imidazoles-1-carbonyl)-piperidines-3-formyl diethylamine hydrochloride is dissolved in the 10ml acetonitrile, adds 2.6ml (0.043mol) methyl iodide, stirs under the room temperature and spends the night.Take out excessive methyl iodide, decompression steams solvent and obtains the yellow spumescence solid chemical compound of 4.2g, yield: 91.3%.
1H?NMR(400MHz，DMSO-d6)：δ9.52(1H，s)，8.00(1H，m)，7.82(1H，m)，3.91(3H，s)，3.78(2H，m)，3.28～3.34(4H，m)，3.13～3.18(1H，m)，2.88(1H，m)，2.06(1H，m)，1.95(1H，m)，1.65(3H，m)，1.11(3H，t)，0.99(3H，t)。
ESIMS?m/z：293(M
+)。
3-d:3-diethylamine acylpiperidine-1-formic acid-6-(2,3-phenylbenzene quinoxaline) ester
70.0 μ l DIPEA are added to 150.0mg (0.503mmol) 2, in the 10ml acetonitrile solution of 3-phenylbenzene quinoxaline phenol and 211.0mg (0.502mmol) 1-(N-methyl-imidazoles-1-carbonyl)-piperidines-3-formyl diethylamine salt compounded of iodine, stirred overnight at room temperature.Decompression steams solvent, adds 20ml CH
2Cl
2, wash anhydrous sodium sulfate drying three times.Filter, decompression is spin-dried for solvent and obtains yellow oil.Column chromatography for separation obtains 155.0mg white foam shape solid chemical compound, yield: 60.8%, and Mp:88-90 ℃.
1H?NMR(400MHz，CDCl
3)：δ8.18(1H，d)，7.90～7.93(1H，m)，7.59～7.62(1H，m)，7.51～7.53(4H，m)，7.33～7.41(6H，m)，4.30～4.41(2H，m)，3.34～3.47(5H，m)，3.09～3.10(1H，m)，2.76～2.77(1H，m)，1.87～1.98(3H，m)，1.65(1H，m)，1.25(3H，t)，1.15(3H，t)。
IR(KBr，cm
-1)υ
max：3435，1722，1635，1425，1225，766。
EIMS?m/z：508(M
+)，211(100％)。
Similar aforesaid method is synthetic to obtain following compound:
X is-OCOY;
Y is:
*This routine numeral methane amide position on this cycloaliphatic ring
Embodiment 4:N, the preparation of N-diethyl-N '-{ 6-[2,3-two-(2-furyl)-quinoxaline] base }-guanidine hydriodate:
4-a:1-benzoyl-3-{6-[2,3-two-(2-furyl)-quinoxaline] base } thiocarbamide
3.0ml (0.026mol) Benzoyl chloride is dripped to the 30ml acetone soln of 2.3g (0.030mol) thiocyanic acid amine, reflux 15min, 100ml acetone soln with 2.0g (0.007mol) compound 6 adds in the above-mentioned solution fast then, continue backflow 40mim, cooling, suction filtration, washing with acetone, drying obtains 2.8g yellow solid compound, yield: 87.5%, and Mp:216-218 ℃.
1H?NMR(400MHz，DMSO-d6)：δ8.82(1H，brs)，8.12～8.14(1H，m)，8.02～8.08(4H，m)，7.93～7.95(2H，m)，7.69～7.70(1H，m)，7.57～7.60(2H，m)，6.73～6.77(4H，m)。
EIMS?m/z：440(M
+)，105(100％)。
4-b:6-[2,3-two-(2-furyl)-quinoxaline] basic thiocarbamide
With 2.8g (0.006mol) compound 1-benzoyl-3-{6-[2,3-two-(2-furyl)-quinoxaline] base } thiocarbamide is added in 10% sodium hydroxide solution that 100ml is preheated to 75 ℃ in advance, stirs 20min, cooling down at 80 ℃～90 ℃, suction filtration, filtrate is put in the ice bath, splash into the concentrated hydrochloric acid adjust pH, add saturated sodium bicarbonate and make the pH value to 7-8 to 5-6, suction filtration, washing, drying obtains 1.9g yellow solid compound, yield: 90.5%.Ethyl acetate and tetrahydrofuran (THF) mixed solvent recrystallization obtain the golden yellow solid of 1.2g, yield: 60%, and Mp:209-211 ℃.
1H?NMR(400MHz，DMSO-d6)：δ10.17(1H，s)，8.46(1H，s)，8.01(1H，d)，7.85～7.92(3H，m)，7.84(1H，brs)，6.68～6.71(4H，m)。
IR(KBr，cm
-1)υ
max：3431，3286，3184，1608，1574，1493，1387，756。
ESIMS?m/z：695[M*2+Na]
+。
4-c:1-{6-[2,3-two-(2-furyl)-quinoxaline] base }-2-methyl-isothiourea hydriodate
1.4ml (0.022ml) methyl iodide is added to 5.0g (0.015mol) 6-[2,3-two-(2-furyl)-quinoxaline] in the 25ml THF solution of basic thiocarbamide, stirred overnight at room temperature, take out excessive methyl iodide, suction filtration, tetrahydrofuran (THF) washing, dry, obtain 4.8g yellow solid compound, yield: 66.7%, Mp:187-190 ℃.
1H?NMR(400MHz，DMSO-d6)：δ8.20(1H，d，J＝9.2Hz)，8.05(1H，d，J＝2.4Hz)，7.91～7.93(2H，m)，7.79(1H，dd，J＝8.8Hz，J＝2.4Hz)，6.73～6.79(4H，m)，2.76(3H，s)。
IR(KBr，cm
-1)υ
max：3423，3255，3103，1624，1473，1013，748。
ESIMS?m/z：351[M+1]
+。
4-d:N, N-diethyl-N '-6-[2,3-two-(2-furyl)-quinoxaline] base }-the guanidine hydriodate
100.0mg (0.209mmol) 1-{6-[2,3-two-(2-furyl)-quinoxaline] base }-the 1ml ethanolic soln of 2-methyl-isothiourea hydriodate and 0.22ml (2.110mmol) diethylamine, 160 ℃ of reaction 10min in microwave, decompression steams solvent, obtain 100.0mg yellow powder shape solid chemical compound, yield: 94.8%, Mp:245-247 ℃.
1H?NMR(400MHz，DMSO-d6)：δ9.59(1H，brs)，8.14(1H，d)，7.98(2H，brs)，7.89～7.91(2H，m)，7.85(1H，m)，7.71～7.74(1H，m)，6.71～6.75(4H，m)，3.54～3.59(4H，m)，1.24(6H，m)。
IR(KBr，cm
-1)υ
max：3427，3122，1641，1614，1489，754。
EIMS?m/z：375(M
+)，72(100％)。
Similar aforesaid method is synthetic to obtain following compound:
X is-NHC=NHY;
Y is: NR
3R
4
Embodiment 5:2-{6-[2,3-two-(2-furyl)-quinoxaline] base }-preparation of phenyl acetanilide,Phenacetylaniline:
5-a: p-aminophenyl acetonitrile
5.2g (0.093mol) reduced iron powder is added in the 155ml aqueous solution of 8.3g (0.155mol) ammonium chloride stirring at room 30min.The 150mlTHF solution that in this solution, slowly adds 5.0g (0.031mol) p-nitrophenyl acetonitrile then.Finish vlil 1h.Filtered while hot, with warm THF washing, filtrate is used ethyl acetate extraction three times, and anhydrous sodium sulfate drying filters, and filtrate decompression obtains oily matter after steaming solvent, places after fixing and obtains 4.0g yellow solid compound, yield: 97.6%, Mp:32-34 ℃.
1H?NMR(300MHz，CDCl
3)：δ7.09～7.11(2H，m)，6.67～6.70(2H，m)，3.73(2H，brs)，3.64(2H，s)。
5-b: acetparaminosalol benzyl cyanide
With 4.0g (0.030mol) p-aminophenyl acetonitrile, 3.4ml triethylamine and 3.4ml (0.036mol) diacetyl oxide is added in the 50ml dichloromethane solution successively, stirs 4h under the room temperature.After decompression steams most of solvent surplus solution is poured in the frozen water, separated out solid, suction filtration, washing, drying obtains 4.4g pale powder shape solid chemical compound, yield: 84.6%, Mp:91-93 ℃.
1H?NMR(400MHz，CDCl
3)：δ7.54(1H，m)，7.52(1H，m)，7.30(1H，brs)，7.29(2H，m)，3.72(2H，s)，2.19(3H，s)。
5-c:3-nitro-4-kharophen benzyl cyanide
5.0g (0.029mol) acetparaminosalol benzyl cyanide is joined in advance in the 15ml nitrosonitric acid that is chilled to-30 ℃ in batches, and adding speed makes temperature be no more than-25 ℃.Finish, continue stirring and make temperature rise to 0 ℃, then reaction solution is poured in the 150g trash ice.Separate out solid, suction filtration, washing, drying obtains 5.1g yellow powder shape solid chemical compound, yield: 80.3%, Mp:111-113 ℃.
1H?NMR(400MHz，CDCl
3)：δ10.34(1H，brs)，8.87(1H，d)，8.22(1H，d)，7.62～7.65(1H，m)，3.82(2H，s)，2.33(3H，s)。
5-d:3-nitro-4-aminophenyl acetic acid
5.1g (0.023mol) compound 3-nitro-4-kharophen benzyl cyanide 1h that in the 10ml concentrated hydrochloric acid, refluxes.Cooling is poured reaction solution in the 50ml frozen water into, uses the acetate adjust pH to 6-7, ethyl acetate extraction three times, combining extraction liquid, anhydrous sodium sulfate drying filters, filtrate decompression obtains 4.0g yellow powder shape solid chemical compound, yield after steaming solvent: 88.9%, and Mp:148-150 ℃.
1H?NMR(400MHz，DMSO-d6)：δ7.78(1H，m)，7.30～7.32(1H，m)，7.25(1H，brs)，6.90～6.92(1H，m)，3.13(2H，s)。
5-e:3, the 4-diamino-phenylacetic acid
Under the nitrogen protection, 0.6g10%Pd/C is added in the 250ml round-bottomed flask, add 150ml dehydrated alcohol and 3.0g (0.015mol) 3-nitro-4-aminophenyl acetic acid successively, displacement hydrogen fills hydrogen to reacting completely under the room temperature.Remove by filter Pd/C under the nitrogen protection, absolute ethanol washing, decompression steams solvent and obtains 1.5g pale solid compound, yield: 60%, Mp:101-103 ℃.
1H?NMR(400MHz，DMSO-d6)：δ7.85(1H，m)，7.36(1H，brs)，7.28-7.31(1H，m)，6.95～6.97(1H，m)，3.50(2H，s)。
ESIMS：167[M+1]
+。
5-f:6-[2,3-two-(2-furyl)-quinoxaline] basic toluylic acid
3.0g (0.018mol) compound 3,4-diamino-phenylacetic acid and 3.4g (0.018mol) connection furan acyl reflux 24h in dehydrated alcohol.Cooling, decompression steams solvent and obtains oily matter, adds 100ml water, ethyl acetate extraction three times, combining extraction liquid, decompression steams solvent, adds entry again, sodium hydroxide solution adjust pH to 10 with 10%, ethyl acetate extraction three times, water layer are put in the ice bath and are separated out solid to 3-4, suction filtration with 2N HCl adjust pH, washing, drying obtains 4.0g yellow solid compound.Yield: 69.4%, Mp:177-179 ℃.
1H?NMR(300MHz，DMSO-d6)：δ8.05(1H，d，J＝8.4Hz)，8.00(1H，d，J＝1.6Hz)，7.91～7.92(2H，m)，7.79(1H，dd，J＝8.4Hz，J＝1.6Hz)，6.72～6.73(4H，m)，3.92(2H，s)。
ESIMS?m/z：639[2M-H]
-。
5-g:2-{6-[2,3-two-(2-furyl)-quinoxaline] base }-phenyl acetanilide,Phenacetylaniline
Under the ice bath cooling, 42.0mg (0.344mmol) I-hydroxybenzotriazole is joined 100.0mg (0.313mmol) compound 6-[2,3-two-(2-furyl)-quinoxaline] in the 50ml dichloromethane solution of basic toluylic acid, add 66.0mg (0.344mmol) 1-ethyl-3-(3-dimethylamino-propyl) carbon imide hydrochloride then successively, 136 μ l (0.783mmol) diisopropylethylamine and 34 μ l (0.373mmol) aniline, under ice bath, react 30min, stirred overnight at room temperature.Reaction solution washs three times with 2N HCl successively, the saturated sodium bicarbonate solution washed twice, and saturated nacl aqueous solution washs once, anhydrous sodium sulfate drying.Filter, place after decompression steams most of solvent, separate out solid, suction filtration, drying obtains 109.0mg white powder solid chemical compound D7, yield: 87.9%, Mp:178-180 ℃.
1H?NMR(300MHz，CDCl
3)：δ8.14～8.17(1H，m)，8.11(1H，m)，7.74～7.78(1H，m)，7.63(2H，m)，7.43～7.46(2H，m)，7.28～7.31(2H，m)，7.20(1H，brs)，7.09～7.12(1H，m)，6.70～6.71(2H，m)，6.57～6.59(2H，m)，3.97(2H，s)。
IR(KBr，cm
-1)υ
max：3423，3278，3134，1659，1599，1497，1443，748。
EIMS?m/z：395(M
+)，276(100％)。
Similar aforesaid method is synthetic to obtain following compound:
X is-CH
2COY;
Y is: NR
3R
4
The preparation of embodiment 6:N-phenyl-{ 6-[2,3-two-(2-furyl)-quinoxaline] } base-methane amide:
6-a:6-[2,3-two-(2-furyl)-quinoxaline] basic formic acid
With 4.0g (0.021mol) connection furan acyl and 3.2g (0.021mol) 3, the 4-diaminobenzoic acid is reflux 24h in 60ml ethanol and 60ml glacial acetic acid mixed solvent.Cooling, suction filtration washs solid with small amount of ethanol, and drying obtains 4.3g red-brown pulverulent solids compound, yield: 67.2%, Mp:243-245 ℃.
1H?NMR(300MHz，DMSO-d6)：δ8.58(1H，d)，8.27～8.30(1H，m)，8.17(1H，d)，7.94～7.96(2H，m)，6.83～6.85(1H，m)，6.78～6.79(1H，m)，6.73～6.76(2H，m)。
The 6-b:N-phenyl-and 6-[2,3-two-(2-furyl)-quinoxaline] } base-methane amide
The experimental implementation process is with experiment 5-g, by 100.0mg (0.327mmol) 6-[2,3-two-(2-furyl)-quinoxaline] basic formic acid and 45.0 μ l (0.494mmol) aniline reactions, obtain 102.0mg white powder solid chemical compound, yield: 81.7%, Mp:188-190 ℃.
1H?NMR(300MHz，CDCl
3)：δ8.57(1H，d)，8.21～8.31(2H，m)，8.06(1H，brs)，7.66～7.71(4H，m)，7.39～7.44(2H，m)，7.17～7.23(1H，m)，6.74～6.81(2H，m)，6.59～6.62(2H，m)。
IR(KBr，cm
-1)υ
max：3425，3290，，1651，1597，1489，1336，748。
EIMS?m/z：381(M
+)，289(100％)。
Similar aforesaid method is synthetic to obtain following compound:
X is-COY;
Y is: NR
3R
4
Embodiment 7:N-{6-[2,3-two-(2-furyl)-quinoxaline] base }-preparation of benzsulfamide:
50.0mg (0.180mmol) 2,3-difuryl-6-quinoxaline amine and 30.0 μ l (0.234mmol) benzene sulfonyl chlorides are reflux 3.5h in the new pyridine that steams of 2ml.Cooling is poured reaction solution in the 20ml frozen water into, and no solid is separated out, ethyl acetate extraction three times, combining extraction liquid is washed three times, and anhydrous sodium sulfate drying filters, decompression steams solvent, obtains 67.0mg yellow powder shape solid chemical compound, yield: 89.1%, and Mp:102-105 ℃.
1H?NMR(300MHz，CDCl
3)：δ8.04(1H，d，J＝8.7Hz)，7.88～7.91(2H，m)，7.74(1H，m)，7.59～7.63(3H，m)，7.52～7.55(1H，m)，7.43～7.48(2H，m)，6.65(2H，m)，6.56(2H，m)。
IR(KBr，cm
-1)υ
max：3425，1618，1570，1489，1159，746。
EIMS?m/z：417(M
+)，276(100％)。
HREI：C
22H
15N
3O
4SCalculated：417.0783，Found：417.0783。
Similar aforesaid method is synthetic to obtain following compound:
X is-NHSO
2
Y is: R
3
The preparation of embodiment 9:6-Pyrrolidine quinoxaline:
9-a:6-fluorine quinoxaline
Under the nitrogen protection, 0.8g10%Pd/C is added in the 250ml round-bottomed flask, add 120ml dehydrated alcohol and 2.0g (0.013mol) 2-nitro-4-fluoroaniline successively, displacement hydrogen, room temperature reaction is to complete under the hydrogen effect.Remove by filter Pd/C under the nitrogen protection, absolute ethanol washing, product are easily oxidized, so without separation and purification, directly carry out next step reaction.In reaction flask, add 1.5ml (0.013mol) 40% glyoxal water solution, reflux 24h.Cooling, decompression steams solvent and obtains oily matter, and column chromatography for separation obtains 1.0g faint yellow solid compound.Two step yields: 52.6%, Mp:30-32 ℃
1H?NMR(300MHz，CDCl
3)：δ8.85～8.87(1H，m)，8.12～8.17(1H，m)，7.74～7.78(1H，m)，7.56～7.63(1H，m)。
EIMS?m/z：148(M
+，100％)。
9-b:6-Pyrrolidine quinoxaline
With 50.0mg (0.338mmol) 6-fluorine quinoxaline, 57 μ l (0.681mmol) Pyrrolidines, 93.0mg (0.674mmol) K
2CO
3Reach 1ml DMSO and place the special-purpose reaction tubes of microwave, seal and be placed in the microwave reactor 200 ℃ of reaction 30min, after the cooling reaction solution is poured in the 30ml frozen water into ethyl acetate extraction three times, combining extraction liquid saturated ammonium chloride solution washed twice, saturated sodium chloride solution washing once, anhydrous sodium sulfate drying filters, and obtains oily matter after decompression steams solvent, silica gel thin-layer chromatography separates, obtain the golden yellow solid chemical compound of 62.0mg, yield: 92.5%, Mp:68-71 ℃.
1H?NMR(300MHz，CDCl
3)：δ8.62(1H，d，J＝1.8Hz)，8.46(1H，d，J＝1.8Hz)，7.87～7.91(1H，m)，7.22～7.26(1H，m)，6.90～6.91(1H，m)，3.44～3.49(4H，m)，2.07～2.12(4H，m)。
IR(KBr，cm
-1)υ
max：3036，1616，1510，1252，820。
EIMS?m/z：199(M
+)，198(100％)。
Similar aforesaid method is synthetic to obtain following compound:
X is-N (H) Y;
Y is: R
3R
4
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| DE102007062550A1 (en) * | 2007-12-20 | 2009-06-25 | Westfälische Wilhelms-Universität Münster Körperschaft des öffentlichen Rechts | Perhydroquinoxaline derivatives |
| FR2933977B1 (en) * | 2008-07-18 | 2013-04-26 | Centre Nat Rech Scient | HETEROCYCLIC DERIVATIVES USEFUL IN THE TREATMENT OF NEURODEGENERATIVE DISEASES |
| JP2012517448A (en) * | 2009-02-11 | 2012-08-02 | リアクション バイオロジー コープ． | Selective kinase inhibitor |
| WO2012045196A1 (en) * | 2010-10-09 | 2012-04-12 | Abbott Laboratories | Phosphoglycerate kinase inhibitors |
| US8993758B2 (en) | 2010-11-22 | 2015-03-31 | Board Of Regents Of The University Of Nebraska | Substituted quinoxalines and uses thereof |
| CN102241637A (en) * | 2011-06-29 | 2011-11-16 | 泰山医学院 | 2,3-diphenyl-6-amido quinoxaline compound and preparation method thereof |
| CN102344418A (en) * | 2011-08-17 | 2012-02-08 | 广西师范大学 | Alkyne-containing quinoxalin derivative and preparation method thereof |
| CN103102285B (en) * | 2013-01-30 | 2015-07-29 | 淮阴师范学院 | The preparation method of p-aminophenyl acetonitrile |
| US20150374687A1 (en) * | 2013-02-07 | 2015-12-31 | Merck Patent Gmbh | Substituted quinoxaline derivatives and their use as positive allosteric modulators of mglur4 |
| RU2715236C2 (en) | 2014-03-26 | 2020-02-26 | Астекс Терапьютикс Лтд | Combinations |
| EA201692091A1 (en) * | 2014-04-18 | 2017-04-28 | Милленниум Фармасьютикалз, Инк. | CHINOXALINE COMPOUNDS AND THEIR APPLICATION |
| JOP20200201A1 (en) | 2015-02-10 | 2017-06-16 | Astex Therapeutics Ltd | Pharmaceutical compositions comprising n-(3,5-dimethoxyphenyl)-n'-(1-methylethyl)-n-[3-(1-methyl-1h-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine |
| CN108472298B (en) | 2015-11-24 | 2021-04-20 | 深圳阿拉丁医疗科技有限公司 | selective kinase inhibitor |
| CA3052466A1 (en) * | 2017-02-06 | 2018-08-09 | Case Western Reserve University | Compositions and methods of modulating short-chain dehydrogenase activity |
| CA3120858A1 (en) | 2018-11-21 | 2020-05-28 | Case Western Reserve University | Compositions and methods of modulating short-chain dehydrogenase activity |
| CN110698418B (en) * | 2019-09-11 | 2022-07-01 | 广西师范大学 | 3-arylamino quinoxaline-2-formamide derivative and preparation method and application thereof |
| CN115433173B (en) * | 2021-06-02 | 2025-04-01 | 上海交通大学 | A class of quinoxaline derivatives and their preparation and use |
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| CN1590378A (en) * | 2003-08-29 | 2005-03-09 | 中国科学院上海药物研究所 | A class of quinoxaline derivatives and their preparation and use |
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| CN1590378A (en) * | 2003-08-29 | 2005-03-09 | 中国科学院上海药物研究所 | A class of quinoxaline derivatives and their preparation and use |
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