CN103044392B - A kind of preparation method of efficient DPP-IV inhibitor - Google Patents

A kind of preparation method of efficient DPP-IV inhibitor Download PDF

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CN103044392B
CN103044392B CN201110309762.6A CN201110309762A CN103044392B CN 103044392 B CN103044392 B CN 103044392B CN 201110309762 A CN201110309762 A CN 201110309762A CN 103044392 B CN103044392 B CN 103044392B
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base
formula
dpp
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CN103044392A (en
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胡文辉
曾丽丽
刘飞
徐宏江
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Guangzhou Institute of Biomedicine and Health of CAS
Lianyungang Runzhong Pharmaceutical Co Ltd
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Guangzhou Institute of Biomedicine and Health of CAS
Lianyungang Runzhong Pharmaceutical Co Ltd
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Abstract

The invention belongs to medical art, relate to a kind of preparation method of efficient DPP-IV inhibitor, relate to particularly a kind of take uracil as the compound or pharmaceutically acceptable salt thereof of parent nucleus, its preparation method, composition and this compounds to benefit from purposes in the disease that DPP-IV suppresses in prevention or treatment as dipeptidyl peptidase (DPP-IV) inhibitor.The compounds of this invention has extraordinary selective inhibitory to DPP-IV, and cardiac toxic is also very low, is very promising DPP-IV inhibitor class medicine.

Description

A kind of preparation method of efficient DPP-IV inhibitor
Technical field
The invention belongs to medical art, relate to particularly a kind of take uracil as the compound or pharmaceutically acceptable salt thereof of parent nucleus, its preparation method, composition and this compounds to benefit from purposes in the disease that DPP-IV suppresses in prevention or treatment as dipeptidyl peptidase (DPP-IV) inhibitor.
Background technology
Diabetes be due to Regular Insulin definitely or relative deficiency cause blood sugar increasing, thus cause serious complication, finally cause patient disable or lethal.Diabetes are divided into I type and II type clinically.Type i diabetes is because pancreaticβ-cell is destroyed, and lack insulin secretion, thus cause blood sugar increasing, this kind of patient can only depend on exogenous insulin; Type ii diabetes is that its sickness rate accounts for more than 90% of all diabetic subject's numbers due to insulin secretion relative deficiency or the unsound initiation hyperglycemia of insulin action link.Current drug research is mainly directed to type ii diabetes expansion.
Traditional ofhypoglycemic medicine is of a great variety, is mainly divided into euglycemic agent (as biguanides, thiazolidinediones etc.) and Insulin secretagogues (as sulfonylurea and non-sulphonyl class medicine), etc.But these medicines can not stop the deterioration of diabetes, and there is body weight increase, the problem that the toxic side effect such as hypoglycemia and drug effect are finally lost.Thus, the antidiabetic medicine of development of new, overcomes above many deficiencies, stops even reverse disease deterioration to be extremely urgent task.
Dipeptidyl peptidase (DPP-IV) is a kind of glycoprotein be distributed widely in human body, and its function class is similar to serine protease, by making its inactivation to the shearing of polypeptide, thus reaches the effect of regulation of physiological functions.The shearing position of DPP-IV to substrate is constant, is proline(Pro) or L-Ala that its N holds penultimate.Glucagon-like-peptide-1 (GLP-1) is a kind of endogenic hormone, along with the rising of postprandial blood sugar, is produced by the L emiocytosis in small intestine, and then stimulates the secretion of Regular Insulin.Therefore, the secretion of GLP-1 and the intake of blood sugar closely related.Treatment plan based on GLP-1 effectively can control blood sugar and not put on weight, and can not produce the untoward reactions such as hypoglycemia.But GLP-1 is as the substrate of DPP-IV, the transformation period is very short, and secretion will be sheared rapidly by DPP-IV within latter 1-2 minute, inactivation.Therefore the mechanism of action based on GLP-1 can adopt the strategy of two kinds of new drug developments: the GLP-1 analogue that exploitation DPP-IV tolerates and exploitation DPP-IV inhibitor.The present inventor, according to this thinking, finds that uracil compound is a kind of effective DPP-IV inhibitor, effectively can reduce blood sugar, not cause body weight to increase and hypoglycemia equivalent risk simultaneously, and complete the present invention based on this.
Summary of the invention
One aspect of the present invention provides the compound or pharmaceutically acceptable salt thereof of a kind of formula I
Wherein, R 1select substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl; Substituting group is selected from alkyl, alkoxyl group, halogen, cyano group, amino, hydroxyl, nitro, carbonyl, Sulfonylalkyl, amido, carbonylic alkyl, aryl, aryloxy, Heterocyclylalkyl, heteroaryl, heteroaryloxy, cycloalkyl, cycloalkylalkyl, alkylsulfonyl or sulfinyl; R 1preferred substituted or unsubstituted aryl or heteroaryl;
R 2be selected from:
(1) hydrogen;
(2) cyano group;
(3) not replace or the alkyl that replaces;
(4) not replace or by 1-5 the independently phenyl that replaces of substituting group separately, substituting group is selected from halogen, cyano group, OH, alkyl, alkoxyl group, NHSO 2r 3, N (alkyl) SO 2r 3, SO 2r 3, SO 2nR 4r 5, NR 4r 5, CONR 4r 5, COOH and carboxyalkyl;
(5)OH；
(6) alkoxyl group;
(7)NR 4R 5；
R 2preferred hydrogen, alkyl or alkoxyl group;
R 3be selected from substituted or unsubstituted alkyl, substituting group is selected from 1-5 respective independently halogen or COOH;
R 4and R 5individually independently to be selected from separately:
(1) hydrogen,
(2) not replace or the phenyl that replaces, substituting group is selected from halogen, OH, alkyl or alkoxyl group,
(3) not replace or by the respective independently C that replaces of substituting group 3-6cycloalkyl, substituting group is selected from halogen, OH, alkyl or alkoxyl group,
(4) not replace or the alkyl that replaces, substituting group is selected from:
(a) halogen, or
B phenyl that () does not replace or replaced by 1-5 respective independently substituting group, substituting group is selected from halogen, OH, alkyl or alkoxyl group.
Formula I of the present invention, R 1preferred substituted or unsubstituted aryl or heteroaryl, substituting group is selected from alkyl, alkoxyl group, halogen, cyano group, amino, hydroxyl, nitro or carbonyl;
R 2preferred hydrogen, alkyl or alkoxyl group, more preferably hydrogen.
Such as formula I provided by the invention is preferred, R 1be selected from substituted or unsubstituted aryl or heteroaryl, substituting group is selected from alkyl, alkoxy or halogen, R 2be selected from hydrogen.
R 1further preferred substituted or unsubstituted phenyl, quinazolyl, benzimidazolyl-, quinolyl, pyrimidyl, indyl, quinoxalinyl, isoquinoline 99.9 or aza-phenanthrenes.
Such as R 1be selected from phenyl, 4-methylquinazolin-2 base, benzimidazolyl-2 radicals-Ji, quinoline-2-base, 6-bromoquinoline-2-base, 6-chloroquinoline-2-base, 6-fluorine quinoline-2-base, 6-toluquinoline-2-base, 7-chloroquinoline-2-base, 7-fluorine quinoline-2-base, 6-methoxy quinoline-2-base, 4-chloroquinoline-2-base, 3-methyl-quinoxaline-2-base, quinolyl-4, quinoline-3-base, pyrimidine-2-base, indol-3-yl, quinoxaline-2-base, isoquinolyl-1 or 1-aza-phenanthrenes-2-base, R 2be selected from hydrogen.
Term " alkyl " refers to the saturated aliphatic hydrocarbon group of the straight or branched be made up of carbon atom and hydrogen atom, and it is connected with the rest part of molecule by singly-bound, and it has 1-6 carbon atom usually also can be expressed as C 1-6alkyl, preferably has the C of 1-4 carbon atom 1-4alkyl.Described alkyl can be non-substituted or by one or more be selected from the substituting group of alkyl, alkoxyl group, aryl, halogen, amino, hydroxyl, nitro or carboxyl etc. replace.The limiting examples of non-substituted alkyl includes but not limited to such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, tert-butyl, n-amyl group, 2-methyl butyl, neo-pentyl, n-hexyl or 2-methylhexyl etc.
Term " alkoxyl group " refer to have that alkyl replaces containing oxygen part, i.e.-O-alkyl group, be usually made up of oxygen and the alkyl containing 1-6 carbon atom, i.e.-O-C 1-6alkyl, preferably-O-C 1-4alkyl, concrete example includes but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, 2-methylbutoxy group, neopentyl oxygen, positive hexyloxy or 2-methyl hexyloxy etc.
Term " Heterocyclylalkyl " refers to heteroatomic five yuan or hexa-atomic replacement or unsubstituted monocycle non-aromatic cyclic groups such as one or two nitrogen, oxygen, sulphur, concrete example includes but not limited to piperazine, piperidines, Pyrrolidine or morpholine etc., and substituting group can be selected from cyano group, halogen, hydroxyl, amino or amido etc.
Term " aryl " refers to full carbon monocycle containing 6-10 carbon atom or bicyclic carbocyclic aromatic ring system, and have the π-electron system of total conjugated, the limiting examples of aryl is as phenyl, xenyl or naphthyl etc.Aryl can be replacement or unsubstituted, and substituting group is selected from alkyl, alkoxyl group, aryl, halogen, amino, hydroxyl, nitro or carboxyl etc.
Term " heteroaryl " refers to the monocycle of 5-14 atom, dicyclo or three cyclophane bases, and it is at least selected from the heteroatoms of N, O or S containing 1, remaining atom is C.Heteroaryl can be replacement or unsubstituted, and substituting group is selected from alkyl, alkoxyl group, aryl, hydroxyl or amino etc.The limiting examples of unsubstituted heteroaryl is as pyrroles, furans, thiophene, imidazoles, oxazole, pyrazoles, pyridine, pyrimidine, indoles, quinoline, isoquinoline 99.9, oxazoline, benzoglyoxaline, quinoxaline, aza-phenanthrenes or quinazoline etc.
" halogen " refers to fluorine, chlorine, bromine or iodine to term.
Term " amino " refers to-NH2 group ,-NH (alkyl) group or-N (alkyl) 2.Amino object lesson includes but not limited to-NH 2,-NHCH 3,-N (CH 3) 2,-NHC 2h 5or-N (C 2h 5) 2deng.
Term " Sulfonylalkyl " refers to the alkyl containing the straight or branched of 1-6 carbon atom replaced by alkylsulfonyl; as sulfonvlmethvl; alkylsulfonyl ethyl or 1-alkylsulfonyl-2-methylethyl etc.; alkyl can be replacement or unsubstituted, and substituting group is selected from alkyl, alkoxyl group, aryl, halogen, amino, hydroxyl, nitro or carboxyl etc.
Term " cycloalkyl " refers to the saturated cyclic hydrocarbons containing 3-6 carbon atom, include but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, cycloalkyl can be replacement or unsubstituted, and substituting group is selected from alkyl, alkoxyl group, aryl, halogen, amino, hydroxyl, carboxyl, amido or cyano group etc.
Term " cycloalkylalkyl " refers to the straight or branched alkyl group containing 1-6 carbon atom be substituted by cycloalkyl, as ring third methyl, ethyl cyclopentane or 1-cyclohexyl-3-ethyl-butyl etc.
Term " thiazolinyl " refers to the unsaturated alkyl containing 2-6 carbon atom and the straight or branched at least containing 1 double bond, thiazolinyl can be non-substituted or be selected from following substituting group and replaced: alkyl, alkoxyl group, hydroxyl, amino or halogen etc., the object lesson of non-substituted thiazolinyl includes but not limited to vinyl, propenyl, 2-propenyl, 1-butylene base, crotyl, 1-pentenyl or 1-hexenyl etc.
Term " alkynyl " refers to the straight or branched unsaturated alkyl containing 2-6 carbon atom and at least 1 triple bond, alkynyl can be non-substituted or be selected from following substituting group and replaced: alkyl, alkoxyl group, hydroxyl, amino or halogen etc., the object lesson of non-substituted alkynyl such as includes but not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base or 2-butyne base etc.
Term " carboxyl " refers to the straight or branched group of the 1-7 carbon atom containing-COO-group, includes but not limited to HOOC-, CH 3oOC-or CH 3cH 2oOC-etc.
Particular compound provided by the present invention is exemplified below, but is not limited to following compounds or its pharmacologically acceptable salt:
Further aspect of the present invention provides the preparation method of formula I, comprises the steps:
(1) formula A compound and formula B compound are in the presence of base, react production C compound in organic solvent:
(2) formula C compound and R-3-amino piperidine dihydrochloride react production I:
Wherein, R 1, R 2identical with the definition in above-mentioned formula I, Hal is chlorine or bromine.
In step (1), alkali is selected from sodium hydride, salt of wormwood or sodium carbonate; Preferred sodium hydride; Organic solvent is selected from the mixed solvent of glycol dimethyl ether and DMF.
In a specific embodiment of the present invention, reaction method is exemplified as:
(1) mixed solvent of alkali with glycol dimethyl ether and DMF is mixed, stir 10 minutes at 0 DEG C, add formula A compound, stir 20 minutes at 0 DEG C, add anhydrous lithium bromide, stirring at room temperature 30 minutes, adds formula B compound, stirred overnight at room temperature.React complete, add trash ice, dichloromethane extraction, gained organic phase is with dry after saturated common salt water washing, concentrated, namely obtains formula C compound after column chromatography purification;
(2) add ethanol after being mixed with R-3-amino piperidine dihydrochloride by formula C compound, after mixing, add sodium bicarbonate, oil bath reflux 6 hours.React complete, concentrated by reaction solution, namely resistates obtains formula I through column chromatography purification.
Wherein, the alkali described in step (1) is selected from sodium hydride, salt of wormwood or sodium carbonate; Preferred sodium hydride; Glycol dimethyl ether and DMF are anhydrous solvent, and the two volume ratio is 2: 1.
Wherein, formula A compound can adopt method conventional in this area to prepare.Such as, R is worked as 2during for H, formula A can prepare from following method:
The concrete preparation method of formula A compound is exemplified as:
Add DMF (DMF) in 6-chlorourea pyrimidine, add DIPEA (DIEA) after dissolving, drip the bromo-2-butyne of 1-after stirring, reaction solution 25 DEG C of stirrings are spent the night.Add water after reacting completely, separate out solid, suction filtration, filter cake drying after water, ether are washed both obtained target compound.
Wherein, 6-chlorourea pyrimidine and the bromo-2-butyne mol ratio of 1-are 1: 1.05-1: 2, preferably 1: 1.1; Reaction times is 3-36 hour, preferably 24 hours; Temperature of reaction 10-40 DEG C, preferably 25 DEG C.
Formula B compound can commercially or adopt method synthesis conventional in this area to obtain, and is exemplified below without limitation:
Concrete reaction method is exemplified as: add Diisopropyl azodicarboxylate (AIBN) after methyl compound that is unsubstituted or that replace mixes with N-bromo-succinimide (NBS), add tetracol phenixin, oil bath reacting by heating.React complete, filtering insolubles, after filtrate is spin-dried for, namely obtain target compound through column chromatography purification.
Wherein, the unsubstituted or methyl compound that replaces and N-bromo-succinimide mol ratio are 1: 1-1: 2, preferably 1: 1; Reaction times is 1-12 hour, preferably 6 hours; Temperature of reaction 50-80 DEG C, preferably 80 DEG C.Unsubstituted or the methyl compound that replaces and Diisopropyl azodicarboxylate mol ratio are 1: 0.01-1: 0.1, preferably 1: 0.02.
In the specific embodiment of the present invention, preparation method is exemplified below:
(1) formula A ' compound and formula B compound are under the existence of sodium hydride, in the mixed solvent of glycol dimethyl ether and DMF, react production C ' compound:
(2) formula C ' compound and R-3-amino piperidine dihydrochloride react production I ' compound:
Wherein, R 1identical with the definition in above-mentioned formula I, Hal is chlorine or bromine.
In a specific embodiment of the present invention, reaction method is exemplified as:
(1) mixed solvent of sodium hydride with glycol dimethyl ether/DMF is mixed, stir 10 minutes at 0 DEG C, add formula A ' compound, stir 20 minutes at 0 DEG C, add anhydrous lithium bromide, stirring at room temperature 30 minutes, adds formula B compound, stirred overnight at room temperature.React complete, add trash ice, dichloromethane extraction, gained organic phase is with dry after saturated common salt water washing, concentrated, namely obtains formula C ' compound after column chromatography purification.
(2) add ethanol after being mixed with R-3-amino piperidine dihydrochloride by formula C ' compound, after mixing, add sodium bicarbonate, oil bath reflux 6 hours.React complete, concentrated by reaction solution, namely resistates obtains formula I ' compound through column chromatography purification.
Wherein, glycol dimethyl ether and DMF are anhydrous solvent, and the two volume ratio is 2: 1.
Uracil compound provided by the invention can form that is free with it or salt exist, when the compounds of this invention possesses the form of free alkali, make the free alkali form of compound and pharmaceutically acceptable inorganic or organic acid reaction, the acid salt of the compounds of this invention can be prepared, these salt include but not limited to: hydrochloride, hydrobromate, hydriodate, phosphoric acid salt, vitriol, nitrate, esilate, tosylate and benzene sulfonate, acetate, maleate, tartrate, succinate, Citrate trianion, benzoate, ascorbate salt and salicylate, malonate, adipate, hexanoate, arginic acid salt, fumarate, nicotinate, phthalate, oxalate etc.
Further aspect of the present invention provides formula I treat in preparation or prevent the purposes in the medicine of the disease benefiting from DPP-IV suppression.The described disease benefiting from DPP-IV suppression is selected from type ii diabetes, diabetic dyslipidaemia, glucose tolerance (IGT) disease, fasted plasma glucose attenuating (IFG) disease, metabolic acidosis, ketosis, appetite stimulator, obesity, various cancer, neurological conditions, disorder of immune system etc., preferably include type ii diabetes and obesity, more preferably comprise type ii diabetes.
Further aspect of the present invention provides a kind of pharmaceutical composition, comprises formula I of the present invention or its pharmacologically acceptable salt and one or more pharmaceutically acceptable auxiliary materials.Composition of the present invention can be liquid, semiliquid or solid form, prepares according to the mode being suitable for route of administration used.Composition of the present invention can according to following administration: in oral, parenteral, intraperitoneal, intravenously, transdermal, sublingual, intramuscular, rectum, oral cavity, nose, the mode such as liposome.
Oral compositions can be solid, gel or liquid.The example of solid preparation includes but not limited to tablet, capsule, granule and bulk powder.These preparations selectively can contain tackiness agent, thinner, disintegrating agent, lubricant, glidant, sweeting agent and correctives etc.The example of tackiness agent includes but not limited to Microcrystalline Cellulose, glucose solution, mucialga of arabic gummy, gelatin solution, sucrose and starch paste; The example of lubricant includes but not limited to talcum, starch, Magnesium Stearate, calcium stearate, stearic acid; The example of thinner includes but not limited to lactose, sucrose, starch, mannitol, Si Liaodengji dicalcium phosphate feed grade; The example of glidant includes but not limited to silicon-dioxide; The example of disintegrating agent includes but not limited to croscarmellose sodium, primojel, alginic acid, W-Gum, yam starch, methylcellulose gum, agar and carboxymethyl cellulose.
Give the present composition with parenteral, generally based on injection, comprise subcutaneous, intramuscular or intravenous injection.Injection can be made into any conventionally form, as liquor or suspension, is suitable for being dissolved or suspended in the solid form in liquid or emulsion before injection.The example that can be used for the carrier of the pharmaceutical acceptable of injection of the present invention includes but not limited to aqueous carrier, non-aqueous carrier, biocide, isotonic agent, buffer reagent, oxidation inhibitor, suspension and dispersion agent, emulsifying agent, sequestrant and other pharmaceutically acceptable material.The example of aqueous carrier comprises sodium chloride injection, Lin Geshi injection liquid, isotonic glucose injection, Sterile Water Injection, glucose and Lactated ringer's inj; The example of non-aqueous carrier comprises the fixing oil of plant origin, Oleum Gossypii semen, Semen Maydis oil, sesame oil and peanut oil; The example of biocide comprises meta-cresol, benzylalcohol, butylene-chlorohydrin, benzalkonium chloride etc.; The example of isotonic agent comprises sodium-chlor and glucose; Buffer reagent comprises phosphoric acid salt and Citrate trianion.
The present composition can also be prepared into aseptic lyophilized injectable powder, compound is dissolved in buffer solution of sodium phosphate, wherein containing glucose or other vehicle be applicable to, under standard conditions well known by persons skilled in the art, solution sterile is filtered subsequently, succeeded by lyophilize, obtain required preparation.
Above-mentioned heterocycle hepyramine compounds preparation technology provided by the invention is simple, raw material is easy to get, be applicable to industrialization scale operation, and through in vitro and in vivo experimental verification, the compounds of this invention has extraordinary selective inhibitory to DPP-IV, while effectively suppressing DPP-IV activity, does not almost affect the activity of DPP-VIII and DPP-IX, after can predicting the compounds of this invention exploitation patent medicine, toxicity is by lower, has extraordinary application prospect.
Embodiment
Compound provided by the invention can be synthesized by multiple preparation method, provide only the exemplary process of these compounds of synthesis in embodiment.Here free acid and/or the alkali form of the compounds of this invention no matter developed in which way is noted that, or the form of salt, all belong to scope of the present invention.The object of specific embodiment further illustrates content of the present invention but do not mean that to limit the invention.
The initial feed used in the specific embodiment of the invention, reaction reagent etc. are commercially available prod.
The phraseology that the reagent abbreviation letter used in the present invention is commonly used for this area, implication is as follows:
DME: glycol dimethyl ether
DMF:N, dinethylformamide
DIEA:N, N-diisopropylethylamine
The synthesis of embodiment 1. compound 4
The synthesis of compound 4-0:
In 500mL eggplant-shape bottle, add 6-chlorourea pyrimidine (15g, 102.4mmol) and 250mL DMF, add 15mL DIEA after dissolving, drip the bromo-2-butyne (9.85mL, 112.64mmol) of 1-after stirring, reaction solution 25 DEG C of stirrings are spent the night.React completely, add frozen water, suction filtration, filter cake dries and is target compound after water, ether are washed.
1H NMR(400MHz，CDCl 3)δ8.85(s，1H)，5.91(s，1H)，4.75(d，J＝2.0Hz，2H)，1.82(t，J＝2.4Hz，3H).MS 199.82[M+H]+.
The synthesis of compound 4-1:
Under nitrogen protection; 60%NaH (54mg is added in 100mL eggplant-shape bottle; 3.78mmol); anhydrous DME/DMF (2: 1) solution is added at 0 DEG C; 0 DEG C is stirred after 10 minutes; add the anhydrous DME/DMF of 10ml (2: the 1) solution of 1-(2-butyne)-6-chlorourea pyrimidine (500mg, 2.52mmol).Finish, 0 DEG C of stirring added anhydrous lithium bromide (263mg, 3.02mmol) after 20 minutes, and stirring at room temperature added 2-chloromethyl-4-methylquinazolin (534mg, 2.77mmol) after 30 minutes, reaction solution stirred overnight at room temperature.React completely, add trash ice, dichloromethane extraction, saturated common salt water washing is used after merging organic phase, organic phase anhydrous sodium sulfate drying after washing, filters, filtrate reduced in volume, namely residue over silica gel column chromatography (petrol ether/ethyl acetate=1/1 wash-out, UV develops the color) purifying obtains compound 4-1.
1H NMR(400MHz，CDCl 3)δ8.03(d，J＝8.0Hz，1H)，7.89(d，J＝8.0Hz，1H)，7.80(t，J＝7.2Hz，1H)，7.55(t，J＝8.0Hz，1H)，6.06(s，1H)，5.47(s，2H)，4.83(d，J＝2.0Hz，2H)，2.90(s，3H)，1.83(t，J＝2.4Hz，3H).MS 355.80[M+H] +.
The synthesis of compound 4:
Compound 4-1 (306mg, 0.86mmol) is added, sodium bicarbonate (361mg in 50mL eggplant-shape bottle, 4.30mmol), R-3-amino piperidine dihydrochloride (224mg, 1.29mmol) and 25mL ethanol, oil bath is heated to return stirring 6 hours.React completely, reaction solution concentrating under reduced pressure, namely residue over silica gel column chromatography (methylene chloride/methanol=15/1+1% ammoniacal liquor wash-out, UV develops the color) purifying obtains compound 4.
1H NMR(400MHz，CDCl 3)δ7.94(d，J＝8.0Hz，1H)，7.81(d，J＝8.4Hz，1H)，7.70(t，J＝7.2Hz，1H)，7.45(t，J＝7.2Hz，1H)，5.41(s，2H)，5.26(s，1H)，4.52(d，J＝1.6Hz，2H)，3.33(m，1H)，3.22(m，1H)，3.00(m，1H)，2.81(s，3H)，2.72(m，1H)，2.50(m，1H)，1.92(m，1H)，1.82(m，1H)，1.74(s，3H)，1.64(m，1H)，1.26(m，1H).MS 419.50[M+H] +.
The synthesis of embodiment 2. compound 3
The synthesis of compound 3-1:
Take cylite as raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 3-1.
1H NMR(400MHz，CDCl 3)δ7.43-7.19(m，5H)，5.97(s，1H)，5.42(s，2H)，4.60(s，2H)，1.77(s，3H).MS 289.07[M+H] +.
The synthesis of compound 3:
With the compound 3-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 3.
1H NMR(400MHz，CDCl 3)δ7.46-7.22(m，5H)，5.33(s，2H)，5.20(s，1H)，4.40(s，2H)，3.22(m，3H)，2.96(m，1H)，2.62(m，1H)，2.42(m，1H)，1.90(m，1H)，1.77(s，3H)，1.60(m，1H)，1.22(m，1H).MS 353.2[M+H] +.
The synthesis of embodiment 3. compound 5
The synthesis of compound 5-1:
With 2-chloromethyl benzimidazole for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 5-1.
1H NMR(400MHz，CDCl 3)δ7.58(m，2H)，7.23(m，2H)，5.99(s，1H)，5.40(s，2H)，4.75(d，J＝2.4Hz，2H)，1.79(t，J＝2.4Hz，3H).MS 329.10[M+H] +.
The synthesis of compound 5:
With the compound 5-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 5.
1H NMR(400MHz，CDCl 3)δ7.47(m，2H)，7.14(m，2H)，5.31(s，2H)，5.18(s，1H)，4.40(s，2H)，3.21(m，3H)，2.95(m，1H)，2.61(m，1H)，2.43(m，1H)，1.92(m，1H)，1.75(s，3H)，1.61(m，1H)，1.21(m，1H).MS 393.45[M+H] +.
The synthesis of embodiment 4. compound 6
The synthesis of compound 6-1:
With 2-chloromethyl quinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 6-1.
1H NMR(400MHz，CDCl 3)δ8.10(d，J＝8.4Hz，1H)，8.00(d，J＝8.4Hz，1H)，7.77(d，J＝8.4Hz，1H)，7.65(m，1H)，7.48(m，1H)，7.32(d，J＝8.4Hz，1H)，6.05(s，1H)，5.43(s，2H)，4.81(m，2H)，1.82(t，J＝2.4Hz，3H).MS 340.90[M+H] +.
The synthesis of compound 6:
With the compound 6-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 6.
1H NMR(400MHz，CDCl 3)δ8.05(d，J＝8.8Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.73(d，J＝8.0Hz，1H)，7.62(t，J＝7.2Hz，1H)，7.44(t，J＝7.2Hz，1H)，7.29(t，J＝8.4Hz，1H)，5.40(s，2H)，5.28(s，1H)，4.53(d，J＝2.4Hz，2H)，3.34(m，1H)，3.23(m，1H)，3.00(m，1H)，2.72(m，1H)，2.50(m，1H)，1.95(m，1H)，1.77(m，1H)，1.72(s，3H)，1.66(m，1H)，1.27(m，1H).MS 404.49[M+H] +.
The synthesis of embodiment 5. compound 7
The synthesis of compound 7-1:
With 2-chloromethyl pyrimidine for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 7-1.
1H NMR(400MHz，CDCl 3)δ8.56(d，J＝4.8Hz，2H)，7.09(t，J＝4.8Hz，1H)，5.94(s，1H)，5.28(s，2H)，4.72(m，2H)，1.73(t，J＝2.4Hz，3H).MS 291.78[M+H] +.
The synthesis of compound 7:
With the compound 7-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 7.
1H NMR(400MHz，CDCl 3)δ8.59(d，J＝4.8Hz，2H)，7.09(t，J＝4.8Hz，1H)，5.32(s，2H)，5.25(s，1H)，4.51(d，J＝2.0Hz，2H)，3.35(m，1H)，3.24(m，1H)，2.99(m，1H)，2.72(m，1H)，2.50(m，1H)，1.95(m，1H)，1.84(m，1H)，1.76(s，3H)，1.64(m，1H)，1.28(m，1H).MS 355.45[M+H] +.
The synthesis of embodiment 6. compound 8
The synthesis of compound 8-1:
With 3-bromomethyl indole for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 8-1. 1h NMR (400MHz, CDCl 3) 7.55 (m, 2H), 7.28 (m, 2H), 7.22 (s, 1H), 5.97 (s, 1H), 5.41 (s, 2H), 4.74 (d, J=2.4Hz, 2H), 1.80 (t, J=2.4Hz, 3H) .MS 328.08 [M+H] +.
The synthesis of compound 8:
With the compound 8-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 8. 1h NMR (400MHz, CDCl 3) 7.46 (m, 2H), 7.22 (m, 2H), 7.20 (s, 1H), 5.34 (s, 2H), 5.19 (s, 1H), 4.41 (s, 2H), 3.25 (m, 3H), 2.97 (m, 1H), 2.61 (m, 1H), 2.42 (m, 1H), 1.93 (m, 1H), 1.73 (s, 3H), 1.62 (m, 1H), 1.25 (m, 1H) .MS 392.2 [M+H] +.
The synthesis of embodiment 7. compound 9
The synthesis of compound 9-1:
With 2-bromomethyl-quinoxaline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 9-1.
1H NMR(400MHz，CDCl 3)δ8.34(s，1H)，8.07(m，1H)，8.00(m，1H)，7.71(m，2H)，6.04(s，1H)，5.47(s，2H)，4.79(m，2H)，1.81(t，J＝2.4Hz，3H).MS 341.78[M+H] +.
The synthesis of compound 9:
With the compound 9-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 9.
1H NMR(400MHz，CDCl 3)δ8.77(s，1H)，7.98(m，2H)，7.64(m，2H)，5.41(s，2H)，5.25(s，1H)，4.49(d，J＝1.2Hz，2H)，3.31(m，1H)，3.20(m，1H)，2.96(m，1H)，2.68(m，1H)，2.47(m，1H)，1.91(m，1H)，1.80(m，1H)，1.74(s，3H)，1.63(m，1H)，1.23(m，1H).MS 405.50[M+H] +.
The synthesis of embodiment 8. compound 10
The synthesis of compound 10-1:
With 4-bromomethyl quinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 10-1.
1H NMR(400MHz，CDCl 3)δ8.82(d，J＝4.8Hz，1H)，8.18(d，J＝8.4Hz，1H)，8.13(d，J＝8.4Hz，1H)，7.73(m，1H)，7.61(m，1H)，7.16(d，J＝4.4Hz，1H)，6.06(s，1H)，5.61(s，2H)，4.79(m，2H)，1.82(t，J＝2.4Hz，3H).MS 340.90[M+H] +.
The synthesis of compound 10:
With the compound 10-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 10.
1H NMR(400MHz，CDCl 3)δ8.78(d，J＝4.4Hz，1H)，8.19(d，J＝8.4Hz，1H)，8.09(d，J＝8.0Hz，1H)，7.69(t，J＝7.2Hz，1H)，7.57(t，J＝7.2Hz，1H)，7.16(d，J＝4.4Hz，1H)，5.58(s，2H)，5.28(s，1H)，4.52(d，J＝2.0Hz，2H)，3.33(m，1H)，3.23(m，1H)，2.99(m，1H)，2.71(m，1H)，2.51(m，1H)，1.95(m，1H)，1.86(m，1H)，1.78(s，3H)，1.67(m，1H)，1.88(m，1H).MS 404.50[M+H] +.
The synthesis of embodiment 9. compound 11
The synthesis of compound 11-1:
With 3-bromomethyl quinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 11-1.
1H NMR(400MHz，CDCl 3)δ9.04(d，J＝2.0Hz，1H)，8.25(d，J＝1.2Hz，1H)，8.06(d，J＝8.4Hz，1H)，7.76(t，J＝8.0Hz，1H)，7.66(m，1H)，7.49(m，1H)，6.00(s，1H)，5.24(s，2H)，4.72(d，J＝2.4Hz，2H)，1.77(t，J＝2.4Hz，3H).MS 340.78[M+H] +.
The synthesis of compound 11:
With the compound 11-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 11.
1H NMR(400MHz，CDCl 3)δ9.05(d，J＝2.0Hz，1H)，8.28(d，J＝1.6Hz，1H)，8.03(d，J＝8.4Hz，1H)，7.76(t，J＝8.0Hz，1H)，7.64(m，1H)，7.47(m，1H)，5.24(s，2H)，5.22(s，1H)，4.48(d，J＝1.6Hz，2H)，3.29(m，1H)，3.18(m，1H)，2.97(m，1H)，2.66(m，1H)，2.47(m，1H)，1.94(m，1H)，1.84(m，1H)，1.77(s，3H)，1.64(m，1H)，1.27(m，1H).MS 404.51[M+H] +.
The synthesis of embodiment 10. compound 12
The synthesis of compound 12-1:
With 1-brooethyl isoquinoline 99.9 for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 12-1.
1H NMR(400MHz，CDCl 3)δ8.34(d，J＝5.6Hz，1H)，8.15(d，J＝8.4Hz，1H)，7.83(d，J＝8.0Hz，1H)，7.69(m，1H)，7.63(m，1H)，7.52(d，J＝6.0Hz，1H)，6.06(s，1H)，5.78(s，2H)，4.82(m，2H)，1.84(t，J＝2.4Hz，3H).MS 340.90[M+H] +.
The synthesis of compound 12:
With the compound 12-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 12.
1H NMR(400MHz，CDCl 3)δ8.32(d，J＝5.6Hz，1H)，8.14(d，J＝8.4Hz，1H)，7.77(d，J＝7.6Hz，1H)，7.63(m，1H)，7.58(m，1H)，7.47(d，J＝5.6Hz，1H)，5.75(s，2H)，5.30(s，1H)，4.54(d，J＝2.4Hz，2H)，3.35(m，1H)，3.25(m，1H)，2.98(m，1H)，2.72(m，1H)，2.49(m，1H)，1.93(m，1H)，1.83(m，1H)，1.77(t，J＝2.0Hz，3H)，1.65(m，1H)，1.26(m，1H).MS 404.49[M+H] +.
The synthesis of embodiment 11. compound 13
The synthesis of compound 13-1:
With 2-brooethyl-6-bromoquinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 13-1.
1H NMR(400MHz，CDCl 3)δ8.01(d，J＝8.8Hz，1H)，7.93(d，J＝2.0Hz，1H)，7.86(d，J＝8.8Hz，1H)，7.71(m，1H)，7.34(d，J＝8.4Hz，1H)，6.05(s，1H)，5.40(s，2H)，4.81(m，2H)，1.82(t，J＝2.4Hz，3H).MS 419.77[M+H] +.
The synthesis of compound 13:
With the compound 13-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 13.
1H NMR(400MHz，CDCl 3)δ7.95(d，J＝8.8Hz，1H)，7.87(m，2H)，7.67(m，1H)，7.31(d，J＝8.4Hz，1H)，5.37(s，2H)，5.28(s，1H)，4.54(d，J＝2.4Hz，2H)，3.35(m，1H)，3.24(m，1H)，3.01(m，1H)，2.72(m，1H)，2.53(m，1H)，1.96(m，1H)，1.86(m，1H)，1.77(t，J＝2.4Hz，3H)，1.69(m，1H)，1.30(m，1H).MS 483.48[M+H] +.
The synthesis of embodiment 12. compound 14
The synthesis of compound 14-1:
With 2-brooethyl-6-chloroquinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 14-1.
1H NMR(400MHz，CDCl 3)δ8.00(d，J＝8.4Hz，1H)，7.92(d，J＝8.8Hz，1H)，7.74(d，J＝2.4Hz，1H)，7.57(m，1H)，7.34(d，J＝8.4Hz，1H)，6.04(s，1H)，5.40(s，2H)，4.80(m，2H)，1.82(t，J＝2.4Hz，3H).MS 357.21[M+H] +.
The synthesis of compound 14:
With the compound 14-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 14.
1H NMR(400MHz，CDCl 3)δ7.95(d，J＝8.8Hz，1H)，7.91(d，J＝8.8Hz，1H)，7.70(d，J＝2.4Hz，1H)，7.53(m，1H)，7.30(d，J＝8.4Hz，1H)，5.37(s，2H)，5.28(s，1H)，4.53(d，J＝2.4Hz，2H)，3.34(m，1H)，3.23(m，1H)，3.00(m，1H)，2.71(m，1H)，2.52(m，1H)，1.95(m，1H)，1.85(m，1H)，1.76(t，J＝2.4Hz，3H)，1.67(m，1H)，1.29(m，1H).MS438.80[M+H] +.
The synthesis of embodiment 13. compound 15
The synthesis of compound 15-1:
With 2-brooethyl-6-fluorine quinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 15-1.
1H NMR(400MHz，CDCl 3)δ8.04(d，J＝8.4Hz，1H)，7.99(dd，J＝5.2Hz，1H)，7.39(m，3H)，6.05(s，1H)，5.41(s，2H)，4.81(m，2H)，1.82(t，J＝2.0Hz，3H).MS 358.78[M+H] +.
The synthesis of compound 15:
With the compound 15-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 15.
1H NMR(400MHz，CDCl 3)δ7.98(m，2H)，7.35(m，3H)，5.37(s，2H)，5.28(s，1H)，4.53(d，J＝2.4Hz，2H)，3.34(m，1H)，3.23(m，1H)，3.01(m，1H)，2.71(m，1H)，2.51(m，1H)，1.95(m，1H)，1.85(m，1H)，1.77(t，J＝2.0Hz，3H)，1.66(m，1H)，1.28(m，1H).MS 422.50[M+H] +.
The synthesis of embodiment 14. compound 16
The synthesis of compound 16-1:
With 2-brooethyl-6-toluquinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 16-1.
1H NMR(400MHz，CDCl 3)δ8.01(d，J＝8.4Hz，1H)，7.95(d，J＝8.8Hz，1H)，7.87(d，J＝1.6Hz，1H)，7.79(m，1H)，7.26(d，J＝8.4Hz，1H)，5.99(s，1H)，5.25(s，2H)，4.72(m，2H)，2.72(s，3H)，1.80(t，J＝2.4Hz，3H).MS 354.89[M+H] +.
The synthesis of compound 16:
With the compound 16-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 16.
1H NMR(400MHz，CDCl 3)δ7.98(d，J＝8.4Hz，1H)，7.89(m，2H)，7.81(m，1H)，7.21(d，J＝8.4Hz，1H)，5.23(m，3H)，4.49(d，J＝1.2Hz，2H)，3.30(m，1H)，3.19(m，1H)，2.98(m，1H)，2.68(s，3H)，2.47(m，1H)，1.94(m，1H)，1.83(m，1H)，1.78(t，J＝2.4Hz，3H)，1.64(m，2H)，1.28(m，1H).MS 418.66[M+H] +.
The synthesis of embodiment 15. compound 17
The synthesis of compound 17-1:
With 2-brooethyl-6-methoxy quinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 17-1.
1H NMR(400MHz，CDCl 3)δ7.98(d，J＝8.4Hz，1H)，7.90(d，J＝9.2Hz，1H)，7.29(m，2H)，7.03(d，J＝2.8Hz，1H)，6.04(s，1H)，5.39(s，2H)，4.80(m，2H)，3.90(s，3H)，1.82(t，J＝2.4Hz，3H).MS 370.89[M+H] +.
The synthesis of compound 17:
With the compound 17-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 17.
1H NMR(400MHz，CDCl 3)δ7.94(d，J＝8.4Hz，1H)，7.89(d，J＝9.2Hz，1H)，7.26(m，2H)，7.00(d，J＝2.4Hz，1H)，5.37(s，2H)，5.28(s，1H)，4.53(d，J＝1.6Hz，2H)，3.86(s，3H)，3.33(m，1H)，3.23(m，1H)，3.01(m，1H)，2.71(m，1H)，2.52(m，1H)，1.96(m，1H)，1.85(m，1H)，1.78(s，3H)，1.67(m，1H)，1.28(m，1H).MS 434.49[M+H] +.
The synthesis of embodiment 16. compound 18
The synthesis of compound 18-1:
With 2-brooethyl-7-fluorine quinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 18-1.
1H NMR(400MHz，CDCl 3)δ8.08(d，J＝8.8Hz，1H)，7.75(m，1H)，7.61(m，1H)，7.27(m，2H)，6.05(s，1H)，5.41(s，2H)，4.82(m，2H)，1.83(t，J＝2.4Hz，3H).MS 358.78[M+H] +.
The synthesis of compound 18:
With the compound 18-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 18.
1H NMR(400MHz，CDCl 3)δ8.05(d，J＝8.8Hz，1H)，7.73(m，1H)，7.63(m，1H)，7.25(m，2H)，5.40(s，2H)，5.31(s，1H)，4.56(d，J＝1.6Hz，2H)，3.37(m，1H)，3.26(m，1H)，3.04(m，1H)，2.75(m，1H)，2.55(m，1H)，1.99(m，1H)，1.88(m，1H)，1.80(s，3H)，1.74(m，1H)，1.32(m，1H).MS 422.50[M+H] +.
The synthesis of embodiment 17. compound 19
The synthesis of compound 19-1:
With 2-brooethyl-7-chloroquinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 19-1.
1H NMR(400MHz，CDCl 3)δ8.06(d，J＝8.4Hz，1H)，8.00(s，1H)，7.69(d，J＝8.8Hz，1H)，7.42(m，1H)，7.32(d，J＝8.4Hz，1H)，6.04(s，1H)，5.40(s，2H)，4.81(m，2H)，1.83(t，J＝2.4Hz，3H).MS 375.21[M+H] +.
The synthesis of compound 19:
With the compound 19-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 19.
1H NMR(400MHz，CDCl 3)δ8.03(d，J＝8.4Hz，1H)，7.99(s，1H)，7.67(d，J＝8.4Hz，1H)，7.40(m，1H)，7.30(d，J＝8.4Hz，1H)，5.39(s，2H)，5.30(s，1H)，4.56(d，J＝2.0Hz，2H)，3.37(m，1H)，3.26(m，1H)，3.04(m，1H)，2.75(s，3H)，2.55(m，1H)，1.98(m，1H)，1.88(m，1H)，1.79(s，3H)，1.73(m，1H)，1.32(m，1H).MS 438.98[M+H] +.
The synthesis of embodiment 18. compound 20
The synthesis of compound 20-1:
With 2-chloromethyl-4-chloroquinoline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 20-1.
1H NMR(400MHz，CDCl 3)δ8.17(d，J＝8.0Hz，1H)，8.02(d，J＝8.4Hz，1H)，7.70(m，1H)，7.58(m，1H)，7.41(s，1H)，6.05(s，1H)，5.39(s，2H)，4.81(m，2H)，1.82(t，J＝2.4Hz，3H).MS 375.21[M+H] +.
The synthesis of compound 20:
With the compound 20-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 20.
1H NMR(400MHz，CDCl 3)δ8.13(d，J＝8.4Hz，1H)，8.02(d，J＝8.4Hz，1H)，7.68(t，J＝7.6Hz，1H)，7.55(t，J＝7.6Hz，1H)，7.38(s，1H)，5.37(s，2H)，5.30(s，1H)，4.55(s，2H)，3.37(m，1H)，3.25(m，1H)，3.03(m，1H)，2.74(m，1H)，2.53(m，1H)，1.97(m，1H)，1.88(m，1H)，1.79(s，3H)，1.70(m，1H)，1.30(m，1H).MS 438.90[M+H] +.
The synthesis of embodiment 19. compound 21
The synthesis of compound 21-1:
With 2-chloromethyl-3-methyl-quinoxaline for raw material, the synthetic method of compound 4-1 in reference example 1, prepares compound 21-1.
1H NMR(400MHz，CDCl 3)δ8.18(d，J＝8.0Hz，1H)，8.06(d，J＝8.4Hz，1H)，7.69(m，1H)，7.57(m，1H)，6.00(s，1H)，5.41(s，2H)，4.82(m，2H)，1.80(t，J＝2.4Hz，3H).MS 354.09[M+H] +.
The synthesis of compound 21:
With the compound 21-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 21.
1H NMR(400MHz，CDCl 3)δ8.16(d，J＝8.4Hz，1H)，8.07(d，J＝8.4Hz，1H)，7.66(m，1H)，7.55(m，1H)，5.37(s，2H)，5.32(s，1H)，4.58(s，2H)，3.37(m，1H)，3.25(m，1H)，3.03(m，1H)，2.74(m，1H)，2.53(m，1H)，2.43(s，3H)，1.95(m，1H)，1.86(m，1H)，1.78(s，3H)，1.73(m，1H)，1.32(m，1H).MS 419.2[M+H] +.
The synthesis of embodiment 20. compound 22
The synthesis of compound 22-1:
Luxuriant and rich with fragrance for raw material with 1-azepine-2-chloromethyl, the synthetic method of compound 4-1 in reference example 1, prepares compound 22-1.
1H NMR(400MHz，CDCl 3)δ8.34(m，1H)，8.21(m，1H)，8.06(m，1H)，7.88(m，1H)，7.69(m，2H)，7.57(m，2H)，5.99(s，1H)，5.38(s，2H)，4.83(m，2H)，1.79(t，J＝2.4Hz，3H).MS 390.10[M+H] +.
The synthesis of compound 22:
With the compound 22-1 obtained in previous step for raw material, the synthetic method of compound 4 in reference example 1, prepares compound 22.
1H NMR(400MHz，CDCl 3)8.35(m，1H)，8.23(m，1H)，8.08(m，1H)，7.89(m，1H)，7.70(m，2H)，7.58(m，2H)，6，00(s，1H)，5.36(s，2H)，4.81(m，2H)，3.37(m，1H)，3.25(m，1H)，3.01(m，1H)，2.76(m，1H)，2.53(m，1H)，2.41(s，3H)，1.94(m，1H)，1.86(m，1H)，1.79(s，3H)，1.72(m，1H)，1.31(m，1H).MS 454.2[M+H] +.
Embodiment 21. external activity is tested
Compound provided by the invention can measure by the homogeneous luminescent detection system (DPP-IV-Glo Protease Assay, Promega cat#G8350) of DPP-IV-Glo proteolytic ferment the inhibiting rate of DPP-IV.This system contains the Laemmli buffer system Laemmli of the amino luciferin of DPP-IV substrate Gly-Pro-and luciferase activity detection, luciferase reaction can be activated after DPPIV-Glo is cut by DPP-IV, " glow-type " type of generation luminous signal, then detect with Turner Ver ita s microwell plate luminometer the activity that luminous signal can characterize DPP-IV.
1, experiment purpose
Measure the compounds of this invention to the inhibit activities of DPP-IV enzyme and selective inhibitory.
2, experiment material
Embodiment of the present invention compound;
DPP-IV enzyme, DPP-VIII enzyme, DPP-IX enzyme, GP-AMC (BioMol), black 96 orifice plate, super microplate reader;
The analysis buffer of DPP-IV and DPP-VIII: 100mmol/l Tris/HCl buffer, pH 8.0,0.1mg/ml BSA;
The analysis buffer of DPP-IX: 100mmol/l Tris/HCl buffer, pH 7.4,0.1mg/mlBSA.
3, experimental technique
The determination of a, enzymic activity:
Be diluted in by GP-AMC in respective damping fluid, concentration is 100umol/L, every hole 25ul; Enzyme gradient dilution, initial concentration is respectively DPP-VIII, DPP-IX:0.01ug/ul, DPP-IV:0.01mU/ul, by 5 times of dilutions, every hole 25ul, mixing; 37 DEG C, 360/460nm measures the dynamic change of fluorescent value, measures 30 minutes; Linearly rise with absorbancy, the enzyme concn of S/B >=5 is working concentration.
B, inhibitor activity measure:
All enzymes, inhibitor, GP-AMC all with analysis buffer preparation, arrange without compound control, contrast without enzyme liquid.
By the working concentration preparation enzyme liquid of enzyme, every hole 25ul; Gradient dilution inhibitor (10 times or 5 times of dilutions), every hole 25ul, mixing; Add the GP-AMC solution 50ul diluted, mixing; 37 DEG C are reacted 20 minutes, and 360/460nm measures fluorescent value.
C, data analysis: use GraphPad-Prism software analysis.
4, experimental result
Embodiment of the present invention compound 3-22 to the inhibit activities data of three kinds of enzymes as shown in following table one.
Table one external activity and selective data
Common DPP-IV inhibitor is while suppression DPP-IV activity, by some DPP-IV relevant enzyme, activity as DPP-II, DPP-VIII, DPP-IX also inhibits, wherein DPP-VIII and DPP-IX is considered to cytosol enzyme, their suppressed toxic action that may cause some DPP-IV inhibitor of effect, as bald, thrombopenia (disease), anaemia, splenomegaly and many lesion tissues etc.More satisfactory state develops to have high selectivity restraining effect to DPP-IV, do not have influential compound to the activity of DPP-VIII and DPP-IX simultaneously.
Experimental result illustrates: embodiment of the present invention compound has extraordinary selective inhibitory to DPP-IV, while effectively suppressing DPP-IV activity, the activity of DPP-VIII and DPP-IX is not almost affected, after can predicting the compounds of this invention exploitation patent medicine, side effect is lower, has extraordinary using value.
The external restraining effect to hERG of embodiment 22.
The prolongation of non-cardiac class medicine likely by suppressing hERG (IKr) passage to cause myocardial action potential time-histories, increases the possibility that life-threatening torsades de pointes (TdP) ventricular arrhythmia occurs.This experiment adopts the HEK293 cell without endogenous IKr electric current to be host cell, and this clone is widely used in the detection of hERG.
HERG clone cellar culture, goes down to posterity in the DMEM substratum containing 10% foetal calf serum and 250g/ml G418.Each experiment taking-up culture dish, with extracellular fluid cleaning twice, is positioned on inverted microscope Stage microscope.Whole-cell patch-clamp experiment is at room temperature carried out, and borosilicate glass microelectrode tip resistance used is 3-5M Ω.
After forming whole-cell recording technique pattern, membrane potential clamped down at-80mV, giving cell+50mV depolarizing voltage every 30s stimulates, and after continuing 2s, repolarization is to-50mV, continues 3s, can draw hERG tail current.Depolarizing voltage first gives cell 50ms ,-50mV repolarization voltage before stimulating, and the electric current recorded under this voltage is as the baseline calculating hERG tail current.Before adding compound, hERG tail current at least stable recording 3 minutes in extracellular fluid.After perfusion administration when the change of hERG tail current amplitude is less than 5%, be considered to drug effect and reach stable state.If electric current did not reach stable state in 6 minutes, then also terminate this concentration compound test.
Testing compound calculates according to following equation the inhibiting rate of hERG electric current: % inhibiting rate={ 1-(electric current residue amplitude)/(contrast current amplitude) } * 100
Obtain the multiple concentration of embodiment of the present invention compound to the inhibiting rate of hERG electric current according to above-mentioned method of calculation, use logistic equation to carry out matching to data, obtain IC 50value.Embodiment of the present invention compound is to the inhibiting rate of hERG and IC 50data as shown in Table 2.
Table two. the external restraining effect to hERG
Compound title Highest detection concentration Maximum concentration inhibiting rate IC 50Value Standard deviation
Compound 4 300μM 79.0±1.2％ 114.2μM 7.3μM
Compound 6 300μM 91.7±1.6％ 47.9μM 4.5μM
Compound 9 300μM 84.9±8.3％ 62.7μM 9.2μM
This research is in the HEK293 cell observation effect of compounds on hERG currents of exogenous expression hERG potassium-channel.Experimental result shows, the suppression of compound 4, compound 6 and compound 9 couples of hERG is more weak, point out the prolongation of each compound by suppressing hERG (IKr) passage to cause myocardial action potential time-histories, the possibility increasing the generation of life-threatening torsades de pointes (TdP) ventricular arrhythmia is very low, namely, after the present invention is developed to the medicine for the treatment of diabetes, cardiac toxic will be lower.

Claims (7)

1. a preparation method for type I compound, comprises the steps:
(1) formula A compound and formula B compound are in the presence of base, react production C compound in organic solvent:
(2) formula C compound and R-3-amino piperidine dihydrochloride react production I:
Wherein, Hal is chlorine or bromine,
R 1be selected from substituted or unsubstituted quinazolyl, benzimidazolyl-, quinolyl, pyrimidyl, indyl, quinoxalinyl, isoquinoline 99.9 or aza-phenanthrenes; Substituting group is selected from alkyl, alkoxyl group, halogen;
R 2be selected from hydrogen.
2. the preparation method of type I compound according to claim 1, wherein, R 1be selected from 4-methylquinazolin-2-base, benzimidazolyl-2 radicals-Ji, quinoline-2-base, 6-bromoquinoline-2-base, 6-chloroquinoline-2-base, 6-fluorine quinoline-2-base, 6-toluquinoline-2-base, 7-chloroquinoline-2-base, 7-fluorine quinoline-2-base, 6-methoxy quinoline-2-base, 4-chloroquinoline-2-base, 3-methyl-quinoxaline-2-base, quinolyl-4, quinoline-3-base, pyrimidine-2-base, indol-3-yl, quinoxaline-2-base, isoquinolyl-1 or 1-aza-phenanthrenes-2-base.
3. the preparation method of the type I compound according to any one of claim 1-2, wherein, in step (1), alkali is selected from sodium hydride, salt of wormwood, sodium carbonate.
4. the preparation method of the type I compound according to any one of claim 1-2, wherein, in step (1), organic solvent is selected from the mixed solvent of glycol dimethyl ether and DMF.
5. the preparation method of the type I compound according to any one of claim 1-2, comprises the steps:
(1) mixed solvent of alkali with glycol dimethyl ether/DMF is mixed, stir 10 minutes at 0 DEG C, add formula A compound, stir 20 minutes at 0 DEG C, add anhydrous lithium bromide, stirring at room temperature 30 minutes, adds formula B compound, stirred overnight at room temperature; React complete, add trash ice, dichloromethane extraction, gained organic phase is with dry after saturated common salt water washing, concentrated, namely obtains formula C compound after column chromatography purification;
(2) add ethanol after being mixed with R-3-amino piperidine dihydrochloride by formula C compound, after mixing, add sodium bicarbonate, oil bath reflux 6 hours; React complete, concentrated by reaction solution, namely resistates obtains formula I through column chromatography purification.
6. the preparation method of type I compound according to claim 5, wherein, in step (1), alkali is selected from sodium hydride, salt of wormwood, sodium carbonate; Glycol dimethyl ether and DMF are anhydrous solvent, and the two volume ratio is 2:1.
7. a preparation method for formula I ' compound, comprises the steps:
(1) formula A ' compound and formula B compound are under the existence of sodium hydride, in the mixed solvent of glycol dimethyl ether and DMF, react production C ' compound:
(2) formula C ' compound and R-3-amino piperidine dihydrochloride react production I ' compound:
Wherein, R 1identical with the definition in claim 1, Hal is chlorine or bromine.
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