CN102329325B - Pyrrolopyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitors - Google Patents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to compounds which are shown as a general formula I and in which pyrrolopyrimidone is taken as a parent nucleus or salts thereof, a method for preparing the compounds, a composition, and use of the compounds as dipeptidyl peptidase-IV (DPP-IV) inhibitors in the prevention or treatment of diseases which benefit from DPP-IV inhibition. The preparation process for the compounds is simple, raw materials are readily available, and the method is suitable for industrialized production; through in-vitro experiments, the compounds have a good effect of selectively inhibiting DPP-IV, and almost do not affect the activities of DPP-VIII and DPP-IX when the activity of the DPP-IV is effectively inhibited; and the compounds are expected to have low toxicity after being developed into medicines, and have outstanding advantages.

Description

Pyrrolopyrimidine ketone DPP-IV inhibitor

Technical field

The invention belongs to medical technical field, relate to particularly and a kind ofly using Pyrrolopyrimidine thion and as dipeptidyl peptidase (DPP-IV) inhibitor, benefit from the purposes in the disease that DPP-IV suppresses in prevention or treatment as compound or its salt, its preparation method, composition and this compounds of parent nucleus.

Background technology

Diabetes (Diabetes Mellitus, DM) are a kind of metabolic diseases of multi-pathogenesis, be due to Regular Insulin definitely or relative deficiency cause blood sugar increasing to cause organism metabolic disorder.It can be divided into insulin-dependent diabetes mellitus (insulindependent diabetes mellitus, IDDM, be type i diabetes) and non insulin dependent diabetes (noninsulindependent diabetes mellitus, NIDDM, be type ii diabetes), wherein type ii diabetes is the most common, accounts for more than 90% of diabetic.Mostly the at present research of Remedies for diabetes is to launch for type ii diabetes.Traditional ofhypoglycemic medicine is of a great variety, mainly contains three major types: euglycemic agent comprises biguanides (as N1,N1-Dimethylbiguanide) and thiazolidinediones (as pioglitazone); The Regular Insulin succagoga, comprise sulfonylurea (as Glipizide); And alpha-glucosidase inhibitor (as acarbose) etc.

Above-mentioned traditional antidiabetic drug is generally all with problems such as the side effect such as body weight increase, hypoglycemia and drug effect reduce gradually, therefore in the urgent need to the medicine of development of new.Dipeptidyl peptidase (Dipeptidyl peptidase-IV, DPP-IV) inhibitor is the antidiabetic medicine of latest generation, be based on the medicine of glucagon-like-peptide-1 (GLP-1), can effectively control blood sugar and not put on weight, do not cause the side effects such as hypoglycemia, for the treatment of diabetes has brought hope.

DPP-IV is a kind of glycoprotein be distributed widely in body, and its function class is similar to serine protease, makes its inactivation by the shearing to polypeptide, thereby reaches the effect of regulation of physiological functions.GLP-1 (Glucagon-like peptide) is a kind of endogenic hormone, and along with postprandial blood sugar raises, the L-cell in small intestine just secretion produces GLP-1, and then stimulates insulin secretion, and reduces blood sugar with this.Treatment plan based on GLP-1 can be controlled blood sugar effectively, but GLP-1 as the substrate of DPP-IV, the transformation period is very short, after secretion, will be sheared rapidly by DPP-IV inactivation within 1-2 minute.Therefore based on the mechanism of action of GLP-1, can adopt the strategy of two kinds of new drug developments: the GLP-1 analogue of exploitation DPP-IV tolerance and exploitation DPP-IV inhibitor.A developing thought after the inventor just is based on, find that heterocycle hepyramine compounds is a kind of effective DPP-IV inhibitor, can effectively reduce blood sugar, do not cause that body weight increases and the hypoglycemia equivalent risk simultaneously, and complete the present invention based on this.

Summary of the invention

One aspect of the present invention relates to a kind of compound of general formula I and enantiomer thereof, diastereomer, pharmacy acceptable salt, solvate, polymorphic form:

Wherein, R ¹Be selected from hydrogen, cyano group, halogen, amino, carboxyl, nitro, alkylsulfonyl, sulfinyl, alkylsulfonyl alkyl, amido, low alkyl group, lower alkoxy, carbonylic alkyl, aryl, aryloxy, Heterocyclylalkyl, heteroaryl, heteroaryloxy, cycloalkyl, cycloalkylalkyl, imido grpup, each replaces naturally or is unsubstituted;

R ⁸, R ⁹, R ¹⁰Be selected from hydrogen, cyano group, halogen, amino, hydroxyl, carboxyl, nitro, alkylsulfonyl, sulfinyl, alkylsulfonyl alkyl, amido, low alkyl group, carbonylic alkyl, lower alkoxy, aryl, aryloxy, Heterocyclylalkyl, heteroaryl, heteroaryloxy, cycloalkyl, cycloalkylalkyl, imido grpup, each replaces naturally or is unsubstituted;

X, Y are not identical, are selected from independently of one another C, N;

R ⁴, R ⁵, R ⁶Be selected from independently of one another hydrogen, halogen, amino, cyano group, nitro, hydroxyl, thiazolinyl, alkynyl, carboxyl, alkylsulfonyl, sulfinyl, alkylsulfonyl alkyl, amido, trifluoromethyl, Heterocyclylalkyl, aryl, heteroaryl, low alkyl group, lower alkoxy, cycloalkyl, cycloalkylalkyl, imido grpup, each replaces naturally or is unsubstituted;

Condition is except following compounds:

In some embodiments, R ¹Be selected from hydrogen, cyano group, halogen, amino, carboxyl, nitro, alkylsulfonyl, sulfinyl, alkylsulfonyl alkyl, amido, low alkyl group, carbonylic alkyl, lower alkoxy, each replaces naturally or is unsubstituted.

Some preferred embodiment in, R ¹Be selected from cyano group.

In some embodiments, R ⁸, R ⁹, R ¹⁰Be selected from hydrogen, cyano group, halogen, amino, hydroxyl, carboxyl, nitro, alkylsulfonyl, sulfinyl, alkylsulfonyl alkyl, amido, low alkyl group, carbonylic alkyl, lower alkoxy, each replaces naturally or is unsubstituted.

Some preferred embodiment in, R ⁸, R ⁹, R ¹⁰Be selected from hydrogen, amino, low alkyl group or hydroxyl.

In some embodiments, R ⁴, R ⁵, R ⁶Be selected from hydrogen, halogen, low alkyl group, amido, trifluoromethyl, aryl, heteroaryl, each replaces naturally or is unsubstituted.

Some preferred embodiment in, R ⁴, R ⁵, R ⁶Be selected from hydrogen, trifluoromethyl, halogen, low alkyl group, heteroaryl, each replaces naturally or is unsubstituted.

Compound of Formula I of the present invention and enantiomer thereof, diastereomer, pharmacy acceptable salt, solvate, polymorphic form, the compound or pharmaceutically acceptable salt thereof of preferred following formula IX or formula XI:

Wherein, R ⁴, R ⁵, R ⁶As the definition in general formula I.

Some preferred embodiment in, R ⁴, R ⁵, R ⁶Be selected from hydrogen, halogen, low alkyl group, amido, trifluoromethyl, aryl, heteroaryl, each replaces naturally or is unsubstituted.

In some preferred embodiment, R ⁴, R ⁵, R ⁶Be selected from hydrogen, trifluoromethyl, halogen, low alkyl group, heteroaryl, each replaces naturally or is unsubstituted.

Term " low alkyl group " refers to the saturated alkyl of the straight or branched be comprised of 1-4 carbon atom, concrete example includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl etc., described low alkyl group can be optionally with substituting group, and substituting group can be selected from halogen, hydroxyl, amino, carboxyl, imido grpup.

Term " lower alkoxy " refer to have that low alkyl group replaces contain the oxygen part, namely-O-low-grade alkyl group, concrete example includes but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert.-butoxy etc., described low alkyl group can be optionally with substituting group, and substituting group can be selected from halogen, hydroxyl, amino, carboxyl, imido grpup.

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, morpholine etc., and substituting group can be selected from cyano group, halogen, hydroxyl, amino, amide group etc.;

Term " aryl " refers to full carbon monocycle or the bicyclic carbocyclic aromatic nucleus system that contains 5-12 carbon atom, has the π-electron system of total conjugated, the limiting examples of aryl such as phenyl, xenyl, naphthyl etc.Aryl can be that replace or unsubstituted, and substituting group is selected from low alkyl group, lower alkoxy, aryl, halogen, amino, hydroxyl, nitro, carboxyl etc.

Term " heteroaryl " refers to the monocyclic aryl with 5 or 6 atoms, contains at least 1 heteroatoms that is selected from N, O or S, and remaining atom is C.Heteroaryl can be that replace or unsubstituted, and substituting group is selected from low alkyl group, lower alkoxy, aryl, hydroxyl, amino etc.The example of heteroaryl such as furans, imidazoles, oxazole, thiophene, pyrroles, pyrazoles, pyridine, pyrimidine, pyrazine, pyridazine, thiazole, thiadiazoles, triazole etc.

" halogen " refers to fluorine, chlorine, bromine, iodine to term.

Term " alkylsulfonyl alkyl " refers to the alkyl of the straight or branched that contains 1-6 carbon atom replaced by alkylsulfonyl; as the alkylsulfonyl methyl; the alkylsulfonyl ethyl; 1-alkylsulfonyl-2-methylethyl etc.; alkyl can be that replace or unsubstituted, and substituting group is selected from low alkyl group, lower alkoxy, aryl, halogen, amino, hydroxyl, nitro, carboxyl etc.

Term " cycloalkyl " refers to the saturated cyclic hydrocarbons that contains 3-7 carbon atom, include but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cycloalkyl can be that replace or unsubstituted, and substituting group is selected from low alkyl group, lower alkoxy, aryl, halogen, amino, hydroxyl, carboxyl, amide group, cyano group etc.

Term " cycloalkylalkyl " refers to the straight or branched alkyl group that contains 1-6 carbon atom be substituted by cycloalkyl, for example as ring the third methyl, cyclopentyl ethyl, 1-cyclohexyl-3-ethyl-butyl etc.

Term " thiazolinyl " refers to the alkyl that contains 2-9 carbon atom and contain at least the straight or branched of 1 two key, such as including but not limited to vinyl, propenyl, 2-propenyl, pseudoallyl, allyl group, n-butene base, positive pentenyl, n-hexylene base etc.

Term " alkynyl " refers to the straight or branched unsaturated alkyl that contains 2-9 carbon atom and at least 1 triple bond, such as including but not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base etc.

Term " carboxyl " refers to and contains-the straight or branched group of the 1-7 carbon atom of COO-group, includes but not limited to HOOC-, CH ₃OOC-or CH ₃CH ₂OOC-etc.

Particular compound provided by the invention is exemplified below, but is not limited to following compounds:

The above-mentioned compound of Formula I the present invention relates to can also exist with the form of its salt, hydrate, and they are converted into compound of Formula I in vivo.For example, within the scope of the invention, according to technique well known in the art, the compounds of this invention is converted into to the form of pharmacy acceptable salt, and uses them with salt form.

When the compounds of this invention possesses the form of free alkali, make free alkali form and the pharmaceutically acceptable inorganic or organic acid reaction of compound, the acid salt that can prepare the compounds of this invention, these salt include but not limited to: hydrochloride, hydrobromate, hydriodate, phosphoric acid salt, vitriol, sulfonate, mesylate, nitrate, esilate, tosylate, benzene sulfonate, acetate, maleate, tartrate, succinate, Citrate trianion, benzoate, ascorbate salt, salicylate, malonate, adipate, hexanoate, arginic acid salt, fumarate, nicotinate, phthalate or oxalate etc.

When the compounds of this invention possesses the form of free acid, make its free acid form react the base addition salt that can prepare the compounds of this invention with pharmaceutically acceptable inorganic or organic bases, this class salt includes but not limited to: lithium, sodium, potassium, barium, calcium, magnesium, aluminium, iron, ferrous iron, copper, zinc salt, or the salt formed with morpholine, diethylamine, triethylamine, Isopropylamine, Trimethylamine 99, Methionin or histidine.

The pharmacologically acceptable salt of compound of the present invention is exemplified below, but is not limited to following salt:

The steric isomer of above general formula compound (enantiomorph, diastereomer and cis-trans-isomer) and the mixture of these steric isomers include within the scope of the present invention.

Further aspect of the present invention relates to the preparation method of compound of Formula I, comprises the steps:

(1) formula A compound reacts production C compound with formula B compound;

(2) formula C compound reacts with formula D compound and generates compound of Formula I;

Wherein, R ¹, R ⁴, R ⁵, R ⁶, R ⁸, R ⁹, R ¹⁰, X, Y be all identical with the definition in general formula I, Hal is chlorine or bromine, Hal ' is chlorine, bromine or iodine.

Further aspect of the present invention relates to a kind of formula A compound:

Wherein, R ⁴, R ⁵, R ⁶, X, Y be all identical with the definition in general formula I; Hal is selected from chlorine or bromine.

Further aspect of the present invention relates to the purposes of formula A compound for the preparation of compound of Formula I.

The present invention relates to the preparation method of above-mentioned formula A compound on the other hand, and it comprises the steps:

(a) compound of the compound of formula F and halide reagent generation halogenating reaction production G;

(b) compound of formula G is hydrolyzed production A compound in organic solvent and alkali aqueous solution or in alkali aqueous solution;

Wherein X, Y, R ⁴, R ⁵, R ⁶With the definition in general formula I, Hal is chlorine or bromine;

Halide reagent described in step (a) is selected from phosphorus oxychloride, tribromo oxygen phosphorus, phosphorus pentachloride or thionyl chloride; Organic solvent described in step (b) is selected from tetrahydrofuran (THF), acetonitrile, alcoholic solvent, dimethyl formamide, Isosorbide-5-Nitrae-dioxane; Alkali aqueous solution is selected from aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, aqueous sodium carbonate etc.Described alcoholic solvent includes but not limited to the alcoholic solvent that this areas such as methyl alcohol, ethanol, propyl alcohol, Virahol, propylene glycol, butanols, the trimethyl carbinol are commonly used.

Specifically, synthetic route of the present invention is as follows, and detailed preparation method can change because of the difference of raw material, synthesis condition, synthetic precursor, completes but substantially all pass through following reaction:

Wherein, R ¹, R ⁴, R ⁵, R ⁶, R ⁸, R ⁹, R ¹⁰, X, Y be identical with the definition in general formula I, Hal is chlorine or bromine, Hal ' is chlorine, bromine or iodine; X-R in formula A ⁶Or Y-R ⁴During for the N-H group, should be first with conventional blocking group, wherein N be protected, and then make to react with formula B compound with the formula A compound of protecting group, by conventional method, slough protecting group subsequently, obtain formula C compound.

Concrete reaction method is exemplified below:

1) formula F compound is joined in halide reagent, reacting by heating 6～10 hours, subsequently that reaction solution is cooling, reduction vaporization is removed most of halide reagent, debris is joined in trash ice, and vigorous stirring, obtain formula G compound by solid filtering the drying separated out;

2) formula G compound is dissolved in organic solvent, add alkali aqueous solution, perhaps directly formula G compound is suspended in alkali aqueous solution, reacting by heating 4～24 hours, then pressure reducing and steaming organic solvent, with Glacial acetic acid, adjust pH to 4～6, carry out subsequently the simple process such as suction filtration or extraction, obtain formula A compound;

3) formula A compound is dissolved in to dry glycol dimethyl ether and N, in the mixed solvent of dinethylformamide (4: 1～0: 1), add wherein 60% sodium hydride, then add anhydrous lithium bromide, then add formula B compound, by mixture reacting by heating 10～18 hours, then cooling, the water that adds subsequently 5～8 times of reaction solution volumes, namely have solid to separate out, and suction filtration drying obtain formula C compound;

4) by the formula C compound of 1 equivalent, 1.05 the D compound of～5 equivalent formulas, the dehydrated alcohol of the sodium bicarbonate of 3～5 equivalents and 5～10 times of volumes mixes, mixed solution is heated to 150 ℃, refluxed 6～15 hours, then cooling, filter, filtrate decompression is concentrated, after purifying, obtain compound of Formula I.

Wherein, the halide reagent described in step (1) is phosphorus oxychloride, tribromo oxygen phosphorus, phosphorus pentachloride or thionyl chloride; Organic solvent described in step (2) is tetrahydrofuran (THF), acetonitrile, alcoholic solvent, dimethyl formamide, Isosorbide-5-Nitrae-dioxane etc.

X-R as formula A ⁶Or Y-R ⁴During for the N-H group, the formula A compound that above-mentioned steps (2) makes after finishing first uses conventional blocking group as (BOC) ₂O etc. protect N wherein, and then carry out the reaction of step (3), make to react with formula B compound with the formula A compound of protecting group; under the condition of step of the present invention (3); along with the carrying out of reaction, blocking group BOC can slough by nature, obtains formula C compound.

In aforesaid method, formula F compound can obtain or buy from the market according to methods known in the art are synthetic.

Further aspect of the present invention relates to compound of Formula I and enantiomer thereof, diastereomer, pharmacy acceptable salt, solvate, polymorphic form and benefits from the purposes in the medicine of the disease that DPP-IV suppresses in treatment or prevention.The disease that the described DPP-IV of benefiting from suppresses is selected from type II diabetes, diabetic dyslipidaemia, glucose tolerance attenuating (IGT) disease, fasting plasma glucose attenuating (IFG) disease, metabolic acidosis, ketosis, appetite stimulator, obesity, various cancer, neurological conditions or disorder of immune system etc., preferably includes type II diabetes or obesity.

Further aspect of the present invention relates to a kind of pharmaceutical composition, comprises compound of Formula I of the present invention and enantiomer thereof, diastereomer, pharmacy acceptable salt, solvate, polymorphic form 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 that is suitable for route of administration used.Composition of the present invention can be according to following administering mode administration: in oral, parenteral, intraperitoneal, intravenously, transdermal, hypogloeeis, 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 pulvis in bulk.These preparations can selectively contain tackiness agent, thinner, disintegrating agent, lubricant, glidant, sweeting agent or 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 or stearic acid; The example of thinner includes but not limited to lactose, sucrose, starch, mannitol or 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 or carboxymethyl cellulose.

With parenteral, give the present composition, generally take injection as main, comprise subcutaneous, intramuscular or intravenous injection.Injection can be made into any conventionally form, as liquor or suspension, be suitable for solid form or emulsion in being dissolved or suspended in liquid before injection.The example that can be used for the pharmaceutically receivable carrier 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 comprise sodium chloride injection, Lin Geshi injection liquid, etc. ooze glucose injection, sterilized water injection liquid, glucose and lactic acid ringer's inj; The example of non-aqueous carrier comprises fixedly oil, Oleum Gossypii semen, Semen Maydis oil, sesame oil and the peanut oil of plant origin; 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 to buffer solution of sodium phosphate, wherein contain glucose or other vehicle be applicable to, subsequently under standard conditions well known by persons skilled in the art by solution sterile filtration, succeeded by lyophilize, obtain required preparation.

Above-mentioned pyrrolopyrimidine ketone compounds preparation technology provided by the invention is simple, raw material is easy to get, be applicable to large-scale industrialization production, and verify through experiment in vitro, the compounds of this invention has extraordinary selective inhibitory to DPP-IV, when effectively suppressing the DPP-IV activity, on the almost not impact of activity of DPP-VIII and DPP-IX, after can predicting the compounds of this invention exploitation patent medicine, toxicity will, far below the contrast medicine, have outstanding advantage.

Embodiment

Compound provided by the invention can synthesize by multiple preparation method, and the exemplary process of synthetic these compounds only is provided in embodiment.Here be noted that free acid and/or alkali form regardless of the compounds of this invention of developing in which way, or the form of salt, scope of the present invention all belonged to.The purpose of specific embodiment is to further illustrate content of the present invention but do not mean that to limit the invention.

The initial feed of using in the specific embodiment of the invention, reaction reagent etc. are commercially available prod.The form of the free alkali prepared can adopt the method for this area salify commonly used to prepare the form of salify, such as, under room temperature, the form of free alkali is dissolved in to methyl alcohol, add wherein hydrogen chloride methanol solution to react, generate hydrochloride; Perhaps add wherein phenylformic acid to react and generate benzoate; Perhaps add trifluoroacetic acid to react and generate trifluoroacetate.Embodiment 26 has enumerated the synthetic method of the hydrochloride of compound 32, and the synthetic of the salt of other compounds can, with reference to the method, also can adopt this area method commonly used to form other salt.

Synthesizing of embodiment 1. compounds 1

Synthetic route:

Synthetic compound 1-2

By urea (1mol, 60g) join in the single necked round bottom flask of 250ml drying, under oil bath, be heated to 160 ℃ to melting, add (0.13mol, 20g) 3-aminothiophene-2-methyl-formiate, mixture was 190-200 ℃ of reacting by heating 3 hours, cooling, the aqueous sodium hydroxide solution that adds 500ml 10%, stir, suction filtration, the 5-10% aqueous sodium hydroxide washes is washed, filtrate is adjusted pH to 6.5 with 2N HCl solution under ice bath, the adularescent solid is separated out, suction filtration, and frozen water is washed, dry white solid 12.5g, the yield 59% of obtaining.

¹H-NMR(400MHz，d ₆-DMSO)：δ6.9(1H，d，J＝5.2Hz)，8.10(1H，d，J＝5.2Hz)，11.60-11.1(2H，br，s)；MS：169.1[M+H ⁺]。

Synthetic compound 1-3

By the compound 1-2 (74.3mmol obtained in upper step, 12.5g) mix with the 200ml phosphorus oxychloride, reflux 8 hours, be chilled to room temperature, the most of phosphorus oxychloride of pressure reducing and steaming, debris slowly is poured in trash ice, vigorous stirring, and the adularescent solid is separated out, suction filtration, cold wash, dry white cotton-shaped solid 10.2g, the yield 67% of obtaining.

¹H-NMR(400MHz，CDCl ₃)：δ7.55(1H，d，J＝5.5Hz)，8.13(1H，d，J＝5.5Hz)；MS：206.9[M+H ⁺]。

Synthetic compound 1-4

By the compound 1-3 (49.7mmol obtained in upper step; 10.2g) be dissolved in the 120ml tetrahydrofuran (THF); under ice bath, add 1N aqueous sodium hydroxide solution 120ml, under nitrogen protection, room temperature reaction is 8 hours, and low-temperature reduced-pressure boils off tetrahydrofuran (THF); Glacial acetic acid is adjusted pH to 5.5; there is solid to separate out, suction filtration, cold wash; dry faint yellow solid 8.4g, the yield 90.5% of obtaining.

¹H-NMR(400MHz，DMSO)：δ7.55(1H，d，J＝5.5Hz)，8.2(1H，d，J＝5.5Hz)，13.47(1H，br，s)；MS：187.0[M+H ⁺]。

Synthetic compound 1-5

By the compound 1-4 (44.9mmol obtained in upper step, 8.4g) dissolve with the mixed solvent of dry 120ml DME and 30ml DMF, under ice bath, add 60% sodium hydride (2.1g, 51.6mmol), stirred 20 minutes, add again anhydrous lithium bromide (7.9g, 89.7mmol), rise to room temperature, stirred 30 minutes, add adjacent cyano group benzyl bromine (10.15g, 51.6mmol), be heated to 65 ℃ of reactions 14 hours, reaction solution is cooling with ice bath, the water that slowly adds 8 times of amounts of reaction solution volume, there is solid to separate out, suction filtration, cold wash, the dry 13.1g compound 1-5 that obtains, yield 96.8%.

¹H-NMR(400MHz，DMSO)：δ5.77(2H，br，s)，7.16(1H，d，J＝8Hz)，7.32(1H，d，J＝5.2Hz)，7.43(1H，t，J＝7.6Hz)，7.55(1H，t，J＝7.6Hz)，7.73(1H，d，J＝7.6Hz)，7.88(1H，d，J＝5.2Hz)；MS：302.0[M+H ⁺]。

Synthetic compound 1

By the compound 1-5 (13.1g obtained in upper step, 43.41mmol), 3-(R)-amino piperidine dihydrochloride (11.5g, 66mmol), sodium bicarbonate (17.4g, 173.6mmol), 300ml dehydrated alcohol and 4g molecular sieve 4A successively add in the 500ml single necked round bottom flask, mixture is heated to 150 ℃, and back flow reaction 12 hours, be chilled to room temperature, filter, filtrate decompression is concentrated, and gained oily matter is through column chromatographic isolation and purification (first ethyl acetate: sherwood oil=1: 1, then methylene dichloride: methyl alcohol=wash at 15: 1) obtain light yellow solid compound 1.

¹H-NMR(400MHz，CD3OD)：δ1.25(1H，m)，1.67(1H，m)，1.76(1H，m)，1.96(1H，m)，2.67(1H，m)，2.88(2H，m)，3.21(1H，m)，3.39(1H，m)，5.56(2H，s)，7.12(1H，d，J＝8Hz)，7.25(1H，d，J＝4.8Hz)，7.42(1H，t，J＝7.6Hz)，7.57(1H，t，J＝7.6Hz)，7.73(1H，d，J＝8Hz)，7.98(1H，dd，J＝2Hz，2Hz)；MS：366.1[M+H ⁺]。

Synthesizing of embodiment 2. compounds 2

With compound 2-1, replace the compound 1-1 in embodiment 1, synthetic method reference example 1, prepare light yellow solid compound 2, yield 45%.

¹H-NMR(400MHz，CD ₃OD)：δ1.25(1H，m)，1.75(1H，m)，1.77(1H，m)，1.96(1H，m)，2.03(1H，m)，2.33(3H，s)，2.71(1H，m)，2.81(1H，s)，2.89(1H，m)，3.21(1H，m)，3.42(2H，m)，5.55(2H，ABq)，7.08(1H，d，J＝8Hz)，7.39(1H，t，J＝7.6Hz)，7.56(1H，t，J＝7.8Hz)，7.59(1H，s)，7.69(1H，d，J＝7.6Hz)；MS：380.1[M+H ⁺]，402.1[M+Na ⁺]。

Synthesizing of embodiment 3. compounds 3

Synthetic route

Synthetic compound 3-2

In the 250ml round-bottomed flask, add compound 3-1 (77.5g, 0.5mol), methyl cyanoacetate (99.1g, 1mol) with 50ml methyl alcohol, under ice bath, splash into respectively 1mlDMF and 5ml triethylamine, be heated to 70 ℃ of reactions 3 hours, remove solvent under reduced pressure, residuum 1L cold water treatment, stirring, obtain the beige precipitation, suction filtration, cold wash, drying obtains 113g gray solid compound 3-2, yield 79.6%.

¹H-NMR(400MHz，CDCl ₃)：δ6.98(1H，d，J＝5.2Hz)，6.30(1H，d，J＝5.2Hz)，4.0(2H，s)，3.80(3H，s)；MS：158.0[M+H ⁺]。

Synthetic compound 3-3

The compound 3-2 (9.5g, 6mmol) obtained in upper step is dissolved in to the methylene dichloride of 300ml drying, is chilled to-60 ℃, under nitrogen protection, drip the 9g Sulfuryl chloride isocyanate, dropwise, rose to room temperature reaction 20 minutes, the TLC demonstration reacts completely.Removal of solvent under reduced pressure, add 200ml water, 75 ℃ are stirred 1 hour to remove excessive Sulfuryl chloride isocyanate, then are chilled to room temperature, the NaOH solution that adds 200ml 10N, be warming up to 85 ℃ and stirred 30 minutes, with dense HCl, adjust pH to 1 under ice bath, produce precipitation, suction filtration, washing, dry 8g pale solid compound 3-3, the yield 78.4% of obtaining.

¹H-NMR(400MHz，DMSO-d6)：δ11.95(1H，s)，11.20(1H，s)，7.12(1H，d，J＝5.6Hz)，7.08(1H，d，J＝5.6Hz)；MS：169.0[M+H ⁺]。

Synthetic compound 3-4

In ice-water bath, by compound 3-3 (8g, 47.6mmol) and 4.2g DMA, 40ml acetonitrile and 200ml POCl ₃Mix, stirred 30 minutes, then reflux is 12 hours, and the TLC demonstration reacts completely.Be chilled to room temperature, slowly in impouring 500ml trash ice, vigorous stirring, have Precipitation, suction filtration, cold wash, dry 8.8g faint yellow solid compound 3-4, the yield 90.2% of obtaining.

¹H-NMR(400MHz，CDCl3)：δ8.15(1H，d，J＝6.4Hz)，7.55(1H，d，J＝6.4Hz)；MS：206.9[M+H ⁺]。

Synthetic compound 3

Adopt the synthetic method of compound 1, prepare compound 3, be light yellow solid, yield 50.5%. ¹H-NMR(400MHz，CD3OD)：δ＝7.73(1H，d，J＝7.6Hz)，7.58(1H，t，J＝7.6Hz)，7.42(1H，t，J＝7.6Hz)，7.28(2H，dd，J＝6.8Hz，6Hz)，7.19(1H，d，J＝8Hz)，5.53(2H，s)，3.49(1H，dd)，3.32(1H，d)，3.25(1H，d)，3.07(1H，s)，2.86(2H，m)，1.80(1H，d，J＝5Hz)，1.71(2H，m)，1.36(2H，m)；MS：366.0[M+H ⁺]。

Synthesizing of embodiment 4. compounds 4

2-amino-4-thiotolene-3-the ethyl formate of take is raw material, the raw material 3-2 in the synthetic route of replacement compound 3, and the synthetic method of all the other step reference compounds 3, prepare compound 4, light yellow solid, yield 50.5%.

¹H-NMR(400MHz，CD3OD)：δ7.71(1H，d，J＝7.6Hz)，7.6(2H，m)，7.44(1H，dd，J＝6.8Hz，6Hz)，6.42(1H，d，J＝4Hz)，5.71(2H，s)，4.54(1H，dd)，4.42(1H，dd)，3.06(1H，m)，2.84(2H，m)，2.46(3H，s)，1.98(1H，m)，1.76(1H，m)，1.54(2H，m)，1.34(2H，m)；MS：380.1[M+H ⁺]，402.1[M+Na ⁺]。

Synthesizing of embodiment 5. compounds 5

Synthetic route:

Synthetic compound 5-2

39.4g bromoacetal di-alcohol is dissolved with 250ml DMF, then add 2.4g NaI, 39.6g methyl-cyanacetate and 55.0g Anhydrous potassium carbonate, be heated to 70 ℃ of reactions and spend the night, and the TLC demonstration reacts completely.Reaction solution is down to room temperature, uses the 500ml water treatment, 300ml extracted with diethyl ether 3 times, and organic phase is washed with saturated common salt, and anhydrous magnesium sulfate drying filters, and concentrated, column chromatography for separation, obtain 24.9g oyster fluid cpds 5-2, yield 57.8%.

¹H-NMR(400MHz，CDCl ₃)：δ4.69(1H，t，J＝5.6Hz)，3.82(3H，s)，3.73(3H，m)，3.54(2H，m)，2.25(2H，m)，1.21(6H，m)；MS：214.1[M-H ⁺]。

Synthetic compound 5-3

2g compound 5-2 and 0.67g urea are joined in the alcohol sodium solution of 0.44g sodium and 50ml anhydrous ethanol preparation, stirring at room 30 minutes, then reflux is 7 hours, steams except ethanol, residuum 30ml water treatment, ether washs and abandons it, and the gained water is adjusted pH to 6.5 with Glacial acetic acid, obtains white precipitate, suction filtration, washing, drying obtains 640mg white solid compound 5-3, yield 28.3%.

¹H-NMR(400MHz，DMSO-d6)：δ10.24(1H，s)，9.95(1H，s)，5.84(2H，s)，4.45(1H，s)，3.58(2H，q)，2.39(2H，d，J＝5.2Hz)，1.07(6H，t，J＝6.8Hz)；MS：266.0[M+Na ⁺]。

Synthetic compound 5-4

630mg compound 5-3 is suspended in the HCl solution of 50ml 0.2N, stirring at room 5 hours, have a large amount of white solids to separate out, suction filtration, washing, dry 350mg pale solid compound 5-4, the yield 81% of obtaining.

¹H-NMR(400MHz，DMSO-d6)：δ11.44(1H，s)，11.09(1H，s)，10.47(1H，s)，6.56(1H，t，J＝2.4Hz)，6.22(1H，t，J＝2.4Hz)；MS：152.1[M+H ⁺]。

Synthetic compound 5-5

3.6g compound 5-4 is dissolved in 10ml toluene, adds the 7ml phosphorus oxychloride, be heated to 70 ℃ and drip DIPEA 8.2ml, drip and finish, 100 ℃ of reactions are spent the night, and the TLC demonstration reacts completely.Be down to room temperature, be poured in the 150ml mixture of ice and water, vigorous stirring, have Precipitation.Suction filtration, cold wash, dry 3.42g deep yellow solid, the yield 77.2% of obtaining.

¹H-NMR(400MHz，DMSO-d6)：δ12.77(1H，s)，7.72(1H，t，J＝2.8Hz)，6.65(1H，dd，J＝2.0Hz，1.6Hz)；MS：190.0[M+H ⁺]。

Synthetic compound 5-6

400mg compound 5-5 is suspended in the KOH aqueous solution of 12ml 2N, reaction is 4 hours under 100 ℃, then is chilled to room temperature.In impouring 50ml cold water, under ice bath, drip Glacial acetic acid and adjust pH=6.5, then use ethyl acetate extraction, organic phase is washed with saturated common salt, and drying is filtered, the concentrated 240mg yellow solid, yield: 80.6% of obtaining.

¹H-NMR(400MHz，DMSO-d6)：δ12.75(1H，br，s)，12.02(1H，s)，7.06(1H，t，J＝2.8Hz)，6.45(1H，t，J＝2.8Hz)；MS：168.0[M+H ⁺]。

Synthetic compound 5-7

240mg compound 5-6 is dissolved in 30mlTHF, then adds respectively the 143mg triethylamine, 320mg (BOC) ₂O and 9mg DMAP, stirring at room 2 hours, the TLC demonstration reacts completely.The reaction mixture concentrating under reduced pressure, residuum obtains the 340mg white solid through column chromatography for separation, yield 89%.

¹H-NMR(400MHz，CD3Cl3)：δ12.76(1H，br，s)，7.37(1H，d，J＝4.0Hz)，6.73(1H，d，J＝3.6Hz)，1.68(9H，t，J＝7.6Hz)；MS：292.0[M+Na ⁺]。

Synthetic compound 5-8

Employing prepares the synthetic method that compound 1-5 is identical, by 310mg compound 5-7, is prepared the compound 5-8 of 144mg white solid form, yield: 44.1%.

¹H-NMR(400MHz，DMSO-d6)：δ12.20(1H，s)，7.90(1H，d，J＝7.6Hz)，7.65(1H，t)，7.50(1H，t)，7.15(2H，m)，6.54(1H，t)，5.58(2H，s)；MS：285.0[M+H ⁺]，307.0[M+Na ⁺]。

Synthetic compound 5

With reference to the method for synthetic compound 1, prepare the compound 5 of light yellow solid form, yield 63%. ¹H-NMR(400MHz，CDCl ₃)：δ10.90(1H，br，s)，7.59(1H，d，J＝7.6Hz)，7.36(1H，t，J＝7.6Hz)，7.25(1H，t，J＝7.6Hz)，6.97(1H，d，J＝7.6Hz)，6.76(1H，d，J＝7.6Hz)，6.59(1H，d，J＝7.6Hz)，5.53(2H，d，J＝5.2Hz)，3.13(1H，t，J＝2.4Hz)，2.96(2H，m)，2.71(2H，t)，1.86(2H，m)，1.69(1H，m)，1.56(1H，m)；MS：349.1[M+H ⁺]，371.1[M+Na ⁺]。

Synthesizing of embodiment 6. compounds 6

The 3-hydroxy piperidine of take is raw material, and the synthetic method of reference compound 4 prepares compound 6, is light yellow solid, yield 85%.

¹H-NMR(CDCl ₃)δ(ppm)：δ7.67(1H，m)，7.53(1H，m)，7.35(1H，m)，6.65(1H，s)，5.52(2H，dd)，3.90(1H，s)，3.26(1H，s)，3.20(2H，m)，3.10(2H，m)，2.50(3H，d)，1.76(1H，m)，1.74(2H，m)，1.72(1H，m)；1.63(1H，m)；MS：381.1[M+H ⁺]。

Synthesizing of embodiment 7. compounds 7

With the 3-2 in the synthetic route of 2-amino-4-thiotolene-3-ethyl formate replacement compound 3, a cyano group benzyl bromine of take is raw material, adjacent cyano group benzyl bromine in the synthetic route of replacement compound 3, the synthetic method of all the other step reference compounds 3, prepare compound 7, light yellow solid, yield 60%.

¹H-NMR(CDCl ₃)δ(ppm)：δ7.54(2H，d，J＝7.6Hz)，7.48(1H，m)，7.42(1H，d，J＝6.8Hz，5.0Hz)，6.66(1H，s)，5.30(2H，s)，3.25(1H，dd)，3.13(1H，dd)，2.98(1H，m)，2.85(1H，m)，2.79(1H，m)，2.51(3H，s)，1.98(1H，m)，1.81(1H，m)，1.75(1H，m)；1.56(4H，m)；MS：380.1[M+H ⁺]，402.1[M+Na ⁺]。

Synthesizing of embodiment 8. compounds 8

Synthetic route

Synthetic compound 8-1

2-amino-4-thiotolene-3-the ethyl formate of take is raw material, the raw material 3-2 in the synthetic route of replacement compound 3, and the synthetic method of all the other step reference compound 3-5, prepare compound 8-1, white solid, yield 56%.

¹H-NMR(400MHz，DMSO-d6)：δ7.85(1H，s)，2.50(3H，s)，2.10(1H，s)；MS：199.1，201.1[M-H ⁺]。

Synthetic compound 8-2

In the single necked round bottom flask of 100ml drying, under nitrogen protection, add 1g (4.984mmol) compound 8-1, DME12ml, DMF3ml, under ice bath to 0 ℃, add NaH (0.25g, 6.23mmol, 1.25eq, 60%oil), add in batches, after 15 minutes, add anhydrous lithium bromide (0.87g, 9.97mmol, 2eq), after 30 minutes, add again a fluorobenzyl bromide (0.99g, 5.23mmol, 1.05eq), under ice bath, stirred 20 minutes, proceed under room temperature and stirred 30 minutes, being heated to 65 ℃ of stirrings spends the night, after the TLC detection reaction is complete, under ice bath, add frozen water 30ml, the adularescent solid is separated out, stirred 1 hour, suction filtration, cold water (20ml) is washed three times, drain, vacuum-drying obtains crude product 1.36g, cross the first sherwood oil of chromatography column: ethyl acetate=15: 1 wash-outs, sherwood oil again: ethyl acetate=12: 1 wash-outs, cross post and obtain white solid 1.0g, yield 65%. ¹H-NMR(400MHz，CDCl ₃)：δ7.28(1H，m)，7.12(1H，d，J＝0.4Hz)，7.01(2H，m)，6.83(1H，br，s)，5.46(1H，br，s)，2.56(3H，s)；MS：309.0[M+H ⁺]。

Synthetic compound 8

With reference to the method for synthetic compound 1, prepare white foam shape solid chemical compound 8, yield 87.5%.

¹H-NMR(400MHz，CD3Cl3)：δ7.13(1H，d，J＝5.6Hz)，6.88(1H，d，J＝3.6Hz)，6.77(2H，m)，6.48(1H，d，J＝1.2Hz)，5.15(1H，d，J＝6Hz)，3.12(1H，dd)，3.07(1H，dd)，2.82(1H，m)，2.68(2H，m)，2.48(1H，m)，2.38(3H，s)，1.81(1H，m)，1.62(1H，m)，1.49(1H，m)，1.2(2H，s)，1.08(1H，m)；MS：373.1[M+H ⁺]。

Synthesizing of embodiment 9. compounds 9

The 4-cyano group benzyl bromine of take is raw material, the stock yard fluorobenzyl bromide in the synthetic route of replacement compound 8, and the synthetic method of all the other step reference compounds 8, prepare compound 9, white foam shape solid, yield 69%.

¹H-NMR(400MHz，CD3Cl3)：δ7.65(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，6.63(1H，br，s)，5.32(2H，br，s)，3.23(1H，dd)，3.09(1H，dd)，2.90(1H，m)，2.76(2H，m)，2.62(1H，m)，2.48(3H，s)，1.93(1H，m)，1.75(1H，m)，1.60(1H，m)，1.38(2H，s)，1.23(1H，m)；MS：380.1[M+H ⁺]。

Synthesizing of embodiment 10. compounds 10

The 2-bromine chloride of take is raw material, the stock yard fluorobenzyl bromide in the synthetic route of replacement compound 8, and the synthetic method of all the other step reference compounds 8, prepare compound 10, white foam shape solid, yield 24.7%.

¹H-NMR(400MHz，CD3Cl3)：δ7.39(1H，d，J＝4Hz)，7.19(2H，s)，6.85(1H，dd)，6.63(1H，d，J＝0.8Hz)，5.34(2H，dd)，3.28(1H，dd)，3.12(1H，m)，2.96(1H，br，s)，2.82(1H，m)，2.58(1H，dd)，2.51(1H，s)，2.18(2H，m)，1.95(1H，m)，1.72(1H，s)，1.58(1H，m)，1.22(1H，m)；MS：389.1[M+H ⁺]。

Synthesizing of embodiment 11. compounds 11

Synthetic route

Synthetic compound 11-2

In the single necked round bottom flask of 250ml drying; sodium sulfhydrate (7.0g, 124.6mmol) is dissolved in 25ml water, in ice bath under agitation condition; slowly drip the 1N NaOH solution of 35ml; and then it is bromo-3,3 slowly to drip 7.5ml 1-, 3-trifluoroacetone (17.0g; diethyl ether solution 89mmol); under nitrogen protection, reaction is 1 hour under 0 ℃ of agitation condition, and reaction mixture is standby.

Under condition of ice bath, methyl-cyanacetate (10.6g, 106.8mmol) is slowly joined in the reaction solution of above-mentioned preparation, and then slowly be added dropwise to triethylamine (10.8g, 106.8mmol), obtain yellow reaction liquid, reaction is 1 hour under condition of ice bath, then under room temperature condition, stirs 1.5 hours, after reacting completely, by reacting liquid filtering, the filter cake washing, vacuum-drying obtains 2-amino-4-hydroxy-4-trifluoromethyl thiophene-3-methyl-formiate crude product.

The gained crude product is heated to 190 ℃ to melting, and stirs 10-15 minute at this temperature, then be cooled to room temperature and obtain 6g brown color product, i.e. compound 11-2.

¹H?NMR(400MHz，CDCl ₃)：δ6.75(1H，s)，6.26(2H，s)，3.84(3H，s)；MS(ES)：223.1[M-H ⁺]。

Synthetic compound 11-3

Under the nitrogen protection condition, by compound 11-2 (4.5g, 20mmol) be dissolved in the 100ml methylene dichloride, and be cooled to-60 ℃, slowly splash into chlorosulfonic acid isocyanate (3.18g, 22.4mmol) dichloromethane solution, control the temperature of reaction solution not higher than-55 ℃, dropwise and maintain this temperature reaction 30 minutes, then slowly rise to room temperature, after detection reaction, be evaporated to dry, in solid residue, add 60ml water, mixture is heated to 75 ℃ under agitation condition, reacted 1 hour, then be cooled to room temperature, the NaOH solution that slowly adds wherein 6ml 10N, under agitation condition, be heated to 85 ℃, reacted 1 hour, then be cooled to room temperature, then with the concentrated hydrochloric acid acidifying, make the pH value reach 1, under normal temperature, stirred 5 hours, mixture filters, the filter cake washing, vacuum-drying obtains white solid 4.7g, yield 99%, be compound 11-3.

¹H?NMR(400MHz，DMSO-d6)：δ12.17(1H，s)，11.28(1H，s)，7.75(1H，s)；MS(ES)：234.9[M-H ⁺]。

Synthetic compound 11

The synthetic method of reference compound 3, prepare compound 11, is white foam shape solid, total recovery 30%.

¹H?NMR(400MHz，CDCl ₃)：δ7.68-7.65(1H，m)，7.55-7.51(2H，m)，7.36(1H，t，J＝7.6Hz)，7.14(1H，d，J＝8.0Hz)，5.50(2H，s)，3.35-3.31(1H，m)，3.22-3.19(1H，m)，3.02-2.95(1H，m)，2.90-2.83(1H，m)，2.67-2.62(1H，m)，1.98-1.94(1H，m)，1.80-1.75(1H，m)，1.70-1.64(1H，m)，1.31-1.20(1H，m)；MS(ES)：435.1[M+H ⁺]。

Synthesizing of embodiment 12. compounds 14

Take 5-8 (50mg) and 4-amino piperidine (40mg) is raw material, with reference to the method for synthetic compound 5, prepares the compound 14 of white solid, yield 59%.

¹H-NMR(CD3OD)δ(ppm)：1.63(m，2H)，1.93(m，2H)，2.92(t，2H)，3.05(m，1H)，3.34(m，1H)，5.56(s，2H)，6.50(d，1H，J＝3.6)，6.93(d，1H，J＝3.6Hz)，7.04(d，1H，J＝7.6Hz)，7.41(t，1H，J＝7.6Hz)，7.56(t，1H，J＝7.6Hz)，7.75(dd，1H，J＝7.6Hz)；MS：349.1[M+H ⁺]，347.1[M-H ⁺]。

Synthesizing of embodiment 13. compounds 19

Take 5-8 (50mg) and 3-hydroxyl piperidine hydrochloric acid salt (55mg) is raw material, with reference to the method for synthetic compound 5, prepares the compound 19 of light yellow oily, yield 61%.

¹H-NMR(CDCl ₃)δ(ppm)：1.45(m，1H)，1.78(m，3H)，2.31(m，2H)，3.07(m，2H)，3.20(d，2H，J＝3.6Hz)，3.88(s，1H)，5.51(q，2H)，6.60(q，1H，J＝3.2Hz)，6.78(q，1H，J＝3.2Hz)，7.19(d，1H，J＝7.6Hz)，7.29(t，1H，J＝7.6Hz)，7.44(t，1H，J＝7.6Hz)，7.61(d，1H，J＝7.6Hz)，10.23(s，1H)；MS：350.0[M+H ⁺]，372.1[M+Na ⁺]，348.1[M-H ⁺]。

Synthesizing of embodiment 14. compounds 20

Synthetic route:

Synthetic compound 20-1

Accurately take 1.7 and digest compound 5-5 50ml anhydrous tetrahydro furan dissolving, condition of ice bath borehole cooling to 0 ℃, the NaH (60%oil) that in batches adds 750mg 2 equivalents under agitation condition, mixture also reacts half an hour under agitation condition in 0 ℃, then slowly drip wherein the 0.675ml methyl iodide, then under room temperature, stir and spend the night, after detection reaction is complete, in reaction mixture, add the 20ml saturated aqueous ammonium chloride, with ethyl acetate (100ml) extraction 2 times, the organic layer anhydrous magnesium sulfate drying, filter, rotary evaporated to dryness obtains crude product, column chromatographic isolation and purification, launch the phase place sherwood oil: ethyl acetate=10: 1～5: 1, obtain white solid 1.52 grams.

¹H-NMR(CDCl ₃)(ppm)：3.89(s，3H)，6.62(d，1H，J＝3.6Hz)，7.22(d，1H，J＝3.6Hz)；MS：202.1[M+H ⁺]。

Synthetic compound 20

The compound 20-1 of take replaces the compound 1-3 in embodiment 1 as raw material, with reference to the method for synthetic compound 1, uses above-mentioned method to prepare the compound 20 of white solid, yield 82%.

¹H-NMR(CDCl ₃)δ(ppm)：1.20(m，1H)，1.44(s，2H)，1.64(m，1H)，1.72(m，1H)，1.92(m，1H)，2.58(m，1H)，2.74(m，1H)，2.92(m，1H)，3.01(m，1H)，3.15(m，1H)，3.71(s，3H)，5.56(s，2H)，6.60(d，1H，J＝3.2Hz)，6.73(d，1H，J＝3.2Hz)，7.00(d，1H，J＝7.6Hz)，7.31(t，1H，J＝7.6Hz)，7.45(d，1H，J＝7.6Hz)，7.64(d，1H，J＝7.6Hz)；MS：363.2[M+H ⁺]，361.2[M-H ⁺]。

Synthesizing of embodiment 15. compounds 21

Synthetic route:

Synthetic compound 21-1

75mg compound 5 is dissolved in to 20mL CH ₂Cl ₂In, and add wherein 80mg K ₂CO ₃And 250mg (Boc) ₂O, react and spend the night under room temperature, the fully rear rotary evaporated to dryness of TLC detection reaction, and crude product is through silica gel column chromatography (PE: EA=8: 3), obtain the compound 21-1 of light yellow solid shape, yield 84.75%.MS：549.3[M+H ⁺]，571.3[M+Na ⁺]。

Synthetic compound 21-2A and 21-2B

100mg compound 21-1 is dissolved in to 20mL CH ₂Cl ₂In, add 31mg NBS, room temperature reaction 4h, the TLC detection reaction is complete, is spin-dried for, and crude product is through silica gel column chromatography separating purification, and launching is CH mutually ₂Cl ₂, obtain solid chemical compound 21-2A and 21-2B.21-2A is white solid, yield 22.89%.The 21-2B white solid, yield 60.62%.

Synthetic compound 21

34mg compound 21-2A is dissolved in to 10mL CH ₂Cl ₂In, adding wherein 0.25mL TFA, reaction is 3 hours under room temperature.The TLC detection reaction is complete, adds saturated K in reaction mixture ₂CO ₃Solution is regulated pH to 7, uses CH ₂Cl ₂Extract this anti-mixed solution, by saturated NaCl washing, organic layer anhydrous Na ₂SO ₄Drying, filter, and filtrate choosing dress is evaporated to dry, and the crude product obtained (launches to be mutually CH through silica gel column chromatography separating purification ₂Cl ₂: MeOH=15: 1), obtain the compound 21 of shallow white solid, yield 16.13%.

¹H-NMR(CDCl ₃)δ(ppm)：1.64(m，4H)，1.75(m，1H)，1.93(m，1H)，2.61(t，1H)，2.76(t，1H)，2.96(m，1H)，3.03(m，1H)，3.21(m，1H)，5.52(q，2H)，7.07(1H，d，J＝7.6Hz)，7.33(t，1H，J＝7.6Hz)，7.49(t，1H，J＝7.6Hz)，7.65(d，1H，J＝7.6Hz)；MS：506.9[M+H ⁺]，504.9[M-H ⁺]。

Synthesizing of embodiment 16. compounds 22

The synthetic method of reference compound 21 be take 21-2B and is raw material, is prepared into white solid compound 22, yield 18.75%.

¹H-NMR(CDCl ₃)δ(ppm)：1.64(m，2H)，1.76(m，2H)，1.93(m，2H)，2.80(m，1H)，2.97(m，1H)，3.06(m，1H)，3.19(m，1H)，5.53(m，2H)，6.58(s，1H)，6.96(d，1H，J＝7.2Hz)，7.30(t，1H，J＝7.6Hz)，7.36(t，1H，J＝7.6Hz)，7.64(dd，1H，J＝7.6Hz)；MS：426.9[M+H ⁺]；

Synthesizing of embodiment 17. compounds 23

The compound 5 of take is raw material, and the synthetic method of reference compound 20 and compound 21, prepare compound 23, yield 59.52%.

¹H-NMR(CDCl ₃)δ(ppm)：1.40(m，2H)，1.65(m，2H)，1.79(m，2H)，2.63(2H，s)，2.99(m，3H)，3.14(s，1H)，3.31(m，1H)，3.71(s，3H)，5.46(s，2H)，7.09(1H，d，J＝7.6Hz)，7.32(t，1H，J＝7.6Hz)，7.48(t，1H，J＝7.6Hz)，7.64(dd，1H，J＝7.6Hz)；MS：521.0[M+H ⁺]。

Synthesizing of embodiment 18. compounds 24

The compound 22 of take is raw material, in reference example 14, prepares the method for compound 20-1, with methyl iodide, compound 22 is methylated, and prepares compound 24, and yield is 62.5%.

¹H-NMR(CDCl ₃)δ(ppm)：1.58(m，1H)，1.65(m，2H)，1.78(m，2H)，3.01(m，3H)，3.17(s，1H)，3.29(m，1H)，3.68(s，3H)，3.80(1H，s)，5.51(s，2H)，6.66(s，1H)，7.04(1H，d，J＝7.6Hz)，7.32(1H，t，J＝7.6Hz)，7.46(1H，t，J＝7.6Hz)，7.65(1H，dd，J＝7.6Hz)；MS：441.0[M+H ⁺]。

Synthesizing of embodiment 19. compounds 25

Synthetic route:

Synthetic compound 25-1

3-amino-2-butylene cyanogen (1.75g) is dissolved in MeOH (50mL), add diethyl aminomalonate hydrochloride (5g), stirring at room 72h, after the TLC detection reaction is complete, the reaction solution rotary evaporated to dryness, (launch is PE: EA=10 to crude product mutually: 1), obtain white solid, yield 97.65% through silica gel column chromatography separating purification.

MS：240.1[M+H ⁺]，239.1[M+Na ⁺]。

Synthetic compound 25-2

Under condition of ice bath, Na (0.57g) gradation is dropped in the EtOH (100ml) heavily steamed, after metal Na is dissolved fully, this solution is splashed in the 30ml EtOH solution of compound 25-1, dripped in 30 minutes and finish, reaction solution is reflux 5h under 60 ℃ of conditions, after the TLC detection reaction is complete, be cooled to room temperature, rotary evaporated to dryness, crude product 100ml water dissolution, regulate pH to 7-8 with glacial acetic acid, then with EtOAc extraction, saturated NaHCO ₃Washing, the organic layer anhydrous Na ₂SO ₄Drying, after filtration, by the filtrate rotary evaporated to dryness, (launch is CH to crude product mutually through silica gel column chromatography separating purification ₂Cl ₂), obtain yellow solid, yield: 58.82%.MS：169.1[M+H ⁺]，167.1[M+Na ⁺]。

Synthetic compound 25-3

Compound 25-2 (2.0g) is dissolved in glacial acetic acid (30mL) and water (3mL), under condition of ice bath, drip 9mL KOCN (2.9g) aqueous solution, drip and finish, stir 23h under room temperature condition, there are a large amount of white solids to separate out, filter, filter cake washes with water, drying, obtain white solid, yield 99.60%.MS：212.1[M+H ⁺]，234.1[M+Na ⁺]，210.1[M-H ⁺]。

Synthetic compound 25-4

Compound 25-3 (2.5g) is dissolved in 6% the NaOH aqueous solution (46mL), be heated to 100 ℃ of backflow 3h, after the TLC detection reaction is complete, be cooled to room temperature, with dense HCl, regulate pH to 6 under condition of ice bath, have a large amount of solids to separate out, filter, filter cake washes with water, after filtration cakes torrefaction, obtains pale solid, yield 99.99%.

MS：166.1[M+H ⁺]，234.1[M+Na ⁺]，164.1[M-H ⁺]。

Synthetic compound 25-5

The compound 25-4 of take is raw material, and the preparation method of reference compound 5-5, prepare yellow solid, yield 88.56%.MS：212.1[M+H ⁺]，202.0[M+Na ⁺]，200.0[M-H ⁺]。

Synthetic compound 25-6

The compound 25-5 (650mg) of take is raw material, adopts the method for preparing compound 5-6, reaction 27h, and crude product is crossed silicagel column (PE: EtOAc=2: 1), obtain white solid, yield 76.27%.

MS：184.0[M+H ⁺]，182.1[M-H ⁺]。

Synthetic compound 25-7

The compound 25-6 of take is raw material, adopts the method for preparing compound 5-7, reaction 18h, and crude product is crossed silicagel column (PE: EtOAc=2: 1), obtain white solid, yield 17.55%.MS：306.0[M+Na ⁺]，282.0[M-H ⁺]。

Synthetic compound 25-8

Compound 25-7 is raw material, adopts the method for preparing compound 5-8, reaction 30h.Crude product is crossed silicagel column (PE: EtOAc=10: 1), obtain white solid, yield 30.47%.MS：399.1[M+H ⁺]。

Compound 25

The compound 25-8 of take is raw material, adopts the method for preparing compound 5, reaction 6-7h, and post separates (CH ₂Cl ₂: MeOH=50: 1) obtain white solid, yield 12.77%.

¹H-NMR(CDCl ₃)δ(ppm)：1.59(m，1H)，1.71(s，2H)，1.90(m，2H)，2.34(s，3H)，2.61(m，1H)，2.88(m，2H)，2.94(m，2H)，3.10(m，1H，5.62(s，2H)，6.14(s，1H)，6.90(d，1H，J＝7.6Hz)，7.32(t，1H，J＝7.6Hz)，7.44(t，1H，J＝7.6Hz)，7.67(dd，1H，J＝7.6Hz)，10.37(s，1H)；MS：363.1[M+H ⁺]，361.1[M-H ⁺]。

Synthesizing of embodiment 20. compounds 26

Synthetic route:

Synthetic compound 26-1

Accurately take 20 gram 2-butylene nitriles and 4.3 gram pyridines and be placed in three mouthfuls of dry round-bottomed flasks, under cryosel bath condition, slowly drip wherein 50 gram bromines, keep simultaneously reacting liquid temperature not higher than 5 ℃, dropwise, under condition of ice bath, stirred 30 minutes, then go under room temperature condition and stir and spend the night, after the TLC demonstration reacts completely, add the 200ml methylene dichloride, filter, filtrate is washed 3 times with 150ml 10% hypo solution, use again the saturated aqueous common salt washed twice, the organic layer anhydrous sodium sulfate drying, filter, filtrate steaming removal solvent is obtained to faint yellow oily thing 58.82 grams, yield 87%, without processing, directly carry out next step.MS：227.1[M+H ⁺]。

Synthetic compound 26-2

With 14.0 gram sodium Metal 99.5s and 200ml anhydrous methanol, make the white solid sodium methylate, in sodium methylate, add the 200ml ether, under condition of ice bath, drip wherein the 100ml diethyl ether solution of 15.6 gram ethyl thioglycolates, drip and finish, maintain this temperature and continued stirring reaction 1 hour, then drip the diethyl ether solution 150ml of compound 26-1, drip and finish, stirred 2 hours, react completely in backward reaction solution and add the 300ml frozen water, twice of extracted with diethyl ether, merge organic layer, use anhydrous magnesium sulfate drying, filter, the filtrate evaporation obtains yellow oil, by recrystallizing methanol, obtain light yellow solid, yield 26%.

¹H-NMR(CDCl ₃)(ppm)：6.25(s，1H)，5.30(bs，2H)，3.81(s，3H)，2.37(s，3H)；MS：156.0[M+H ⁺]。

Synthetic compound 26

With compound 26-2, replace the compound 1-1 in embodiment 1, synthetic method reference example 1, prepare light yellow spumescence solid chemical compound 26, total recovery 35%.

¹H-NMR(400MHz，CDCl ₃)：δ1.41(2H，m)，1.72(1H，m)，1.97(1H，m)，2.54(3H，s)，2.98(3H，m)，4.28(1H，d，J＝13.2Hz)，4.47(1H，d，J＝10.4Hz)，5.60(2H，ABq)，6.73(1H，s)，7.29(1H，m)，7.49(2H，m)，7.57(1H，m)；MS：380.1[M+H ⁺]。

Synthesizing of embodiment 21. compounds 27

Synthetic compound 27

Under room temperature, the compound 1 (510mg, 1.1mmol) in embodiment 1 is dissolved in HOAc (15mL), is added dropwise to methylene dichloride (5mL) solution of NBS (783mg, 4.4mmol), be warming up to reflux state, stirring is spent the night.React complete, be down to room temperature, remove most of solvent under reduced pressure, then add saturated aqueous sodium carbonate (20mL) and methylene dichloride (30mL), extracting and demixing, water layer is used methylene dichloride (30mL) extracting twice again, merge organic layer, use successively saturated aqueous sodium carbonate (20mL), water (20mL) and saturated aqueous common salt (20mL) are washed once, the organic layer anhydrous sodium sulfate drying, filter, after filtrate decompression is steamed and is desolventized, eluent dichloromethane: methyl alcohol=10: 1, 200-300 order silica gel column chromatography separates to such an extent that white foam shape solid is compound 27, 228mg, yield 46.8%. ¹H-NMR(400MHz，CDCl ₃)δ：1.42-1.46(m，1H)，1.65-1.68(m，1H)，1.79-1.80(m，1H)，1.9-2.00(m，1H)，2.88-2.99(m，2H)，3.07(s，2H)，3.12-3.21(m，4H)，3.37-3.41(dd，1H，J＝12Hz，J＝4Hz)，5.50-5.54(dd，2H，J＝8Hz，J＝4Hz)，7.07-7.09(d，1H，J＝8Hz)，7.34-7.38(t，1H，J＝8Hz)，7.48-7.52(m，1H)，7.66-7.68(d，2H，J＝8Hz)，7.72(s，1H)。

Synthesizing of embodiment 22. compounds 28

Synthetic route:

Synthetic compound 28-2

Under room temperature, compound 1 (964mg, 1.97mmol) in embodiment 1 is dissolved in methylene dichloride (30mL), is added dropwise to triethylamine (424mg, 4.2mmol) and Boc-acid anhydrides (479mg, 2.2mmol), stirred overnight at room temperature.React complete, directly use filtered through silica gel, after removing solvent under reduced pressure, the elutriant sherwood oil: ethyl acetate=2: 1,200-300 order silica gel column chromatography are separated to obtain light yellow solid powder compounds 28-2,900mg, yield 96.6%.

Synthetic compound 28-3

Under room temperature, compound 28-2 (890mg, 1.91mmol) is dissolved in methylene dichloride (30mL): in acetic acid (3mL), add 70%mCPBA (3.3g, 13.4mmol), stirred overnight at room temperature.React complete, add saturated aqueous sodium carbonate (20mL) and methylene dichloride (30mL), extracting and demixing.Water layer methylene dichloride (30mL) extracting twice, merge organic layer, use successively saturated aqueous sodium carbonate (20mL), water (20mL) and saturated aqueous common salt (20mL) to wash once, the organic layer anhydrous sodium sulfate drying, filter, after filtrate decompression is steamed and desolventized, elutriant sherwood oil: ethyl acetate=2: 1,200-300 order silica gel column chromatography separates to obtain yellow oil 28-3,240mg, yield 25.3%.

¹H-NMR(400MHz，CDCl ₃)δ：1.38(s，9H)，1.49-1.53(m，1H)，1.67-1.69(m，1H)，1.77-1.80(m，1H)，1.83-1.89(m，1H)，2.91-2.99(m，2H)，3.15(s，1H)，3.39-3.42(d，1H，J＝12Hz)，4.98-4.99(d，1H，J＝4Hz)，5.36(s，2H)，7.00-7.03(d，1H，J＝12Hz)，7.07-7.10(d，1H，J＝12Hz)，7.24-7.26(d，1H，J＝8Hz)，7.35-7.39(t，1H，J＝8Hz)，7.51-7.55(t，1H，J＝8Hz)，7.62-7.64(d，2H，J＝8Hz)。

Synthetic compound 28

Under room temperature, compound 28-3 (240mg, 0.48mmol) is dissolved in saturated HCl/MeOH (20mL), stirred overnight at room temperature.React complete, after removing solvent under reduced pressure, be dissolved in methyl alcohol (20mL), add sodium bicarbonate (84mg, 1.0mmol), stirring at room 2 hours, remove solvent under reduced pressure, acetone solution is separated out salt, removes by filter salt, after the filtrate decompression steaming is desolventized, eluent dichloromethane: methyl alcohol=8: 1,200-300 order silica gel column chromatography separates to obtain yellow foam-like compound 28,180mg, yield 94.0%.

¹H-NMR(400MHz，CD ₃OD)δ：1.32(s，1H)，1.44(s，1H)，1.58(s，1H)，2.64(s，1H)，2.83-2.86(m，2H)，3.16(s，1H)，3.21-3.28(m，1H)，3.32-3.34(d，1H，J＝8Hz)，5.58(s，2H)，6.87-6.90(d，1H，J＝12Hz)，6.94-6.97(d，1H，J＝12Hz)，6.99-7.06(m，2H)，7.12-40(m，3H)，7.46-7.49(d，2H，J＝12Hz)。

Synthesizing of embodiment 23. compounds 29

Synthetic compound 29-1

Take 5.0g 6-amino uracil, the 5.0g sodium acetate adds in 200ml water, under stirring, adds 5mL 1-monochloroacetone, and reflux 72 hours, be cooled to room temperature, filter, and the filter cake washing, vacuum-drying obtains solid 2.0g.Yield 30.7%.MS：166.0[M+H ⁺]。

Synthetic compound 29-2

The compound 29-1 of take is raw material, adopts the method for preparing compound 5-5, obtains yellow solid 400mg, yield 50.1%.MS：202.0[M+H ⁺]。

Synthetic compound 29-3

The compound 29-2 of take is raw material, adopts the method for preparing compound 5-6, obtains white solid 260mg, yield 76.7%.MS：170.1[M+H ⁺]。

Synthetic compound 29-4

Take 900mg compound 29-3 and be dissolved in 10mL DMF, add pyridine (840mg, 2eq), be heated to 80 ℃.After 1 hour, add 2.3g (Boc) in system ₂O, have a large amount of gas to emit, and under 80 ℃, continues to stir 2 hours, and reaction is cooled to room temperature after finishing, and adds 60mL water, ethyl acetate extraction, and anhydrous sodium sulfate drying, revolve and desolventize to obtain white solid. without purification, directly drop into next step reaction.

Synthetic compound 29-5

The compound 29-4 of take is raw material, adopts the method for preparing compound 5-8, obtains white solid 60mg, yield 46.0%.MS：299.1[M+H ⁺]. ¹H-NMR(400MHz，CDCl ₃)δ9.89(s，1H)，7.73(m，1H)，7.68(m，1H)，7.64(m，1H)，7.47(m，1H)，7.26(d，1H，J＝12Hz)，5.75(s，2H)，1.25(s，3H).

Synthetic compound 29

The compound 29-5 of take is raw material, adopts the method for preparing compound 5, obtains white solid 30mg, yield 80.3%.

¹H-NMR(400MHz，CDCl ₃)δ：9.32(s，1H)，7.62(d，2H，J＝8Hz)，7.41(m，1H)，7.29(m，1H)，7.01(d，1H，J＝26Hz)，6.28(s，1H)，5.5(d，2H，J＝6Hz)，3.13(d，1H)，2.96(d，2H)，2.72(d，2H)，2.30(s，1H)，1.90(s，1H)，1.59(s，1H)，1.33(s，1H)，1.24(s，3H).MS：363.2[M+H ⁺].

Synthesizing of embodiment 24 compounds 30

Compound 30-1's is synthetic:

In the 1L eggplant-shape bottle, add the methylene dichloride of 6.58g compound 5 and 200ml drying, after dissolving, add 7.99g salt of wormwood.Under ice bath, agitation condition, drip the dichloromethane solution of the 150ml drying of 20.17g Boc acid anhydrides.Finish, continue to stir 1h under condition of ice bath, after the TLC detection reaction is complete, add saturated sodium bicarbonate aqueous solution, separatory, water ethyl acetate extraction.(petrol ether/ethyl acetate=2/1 is eluent, collects R with column chromatography purification after anhydrous sodium sulfate drying to merge organic phase _f=0.3 component) namely obtain target compound 30-1, yield 74.4%.

¹H-NMR(400MHz，CDCl ₃)：δ9.07(1H，br.s)，7.65(1H，d，J＝7.6Hz)，7.46(1H，t，J＝7.6Hz)，7.31(1H，t，J＝7.6Hz)，7.06(1H，d，J＝7.6Hz)，6.83(1H，d，J＝7.6Hz)，6.64(1H，d，J＝7.6Hz)，5.61(1H，d，J＝16.4Hz)，5.49(1H，d，J＝15.6Hz)，3.77(1H，m)，3.30(1H，m)，2.94(2H，m)，2.78(1H，m)，1.78(2H，m)，1.68(1H，m)，1.51(1H，m)，1.41(9H，m)。MS：449.2[M+H] ⁺。

Compound 30-2's is synthetic:

The methylene dichloride that adds 2.52g compound 30-1 and 50mL drying in the 250mL eggplant-shape bottle, after dissolving, add the dichloromethane solution of the 50ml drying of 1g N-bromo-succinimide under 0 ℃ of condition.Dropwise, under condition of ice bath, continue to stir 30min.After the TLC detection reaction is complete, add saturated sodium-chloride water solution, with the extraction of methylene dichloride separatory, (methylene chloride/methanol=500/1 is eluent to organic phase, collects R with column chromatography purification after anhydrous sodium sulfate drying _f=0.6 component) namely obtain target compound 30-2.

¹H-NMR(400MHz，CDCl ₃)：δ9.14(1H，br.s)，7.65(1H，d，J＝7.6Hz)，7.47(1H，t，J＝7.6Hz)，7.32(1H，t，J＝7.6Hz)，7.07(1H，d，J＝7.6Hz)，6.60(1H，s)，5.60(1H，d，J＝14.8Hz)，5.45(1H，d，J＝15.6Hz)，3.84(1H，m)，3.32(1H，m)，2.96(2H，m)，2.79(1H，m)，1.81(2H，m)，1.68(1H，m)，1.52(1H，m)，1.42(9H，m)。MS：527.0[M+H] ⁺。

Compound 30-3's is synthetic:

After compound 30-2 is dissolved with methylene dichloride, under condition of ice bath, add 10% trifluoroacetic acid/dichloromethane solution, reaction solution at room temperature stirs, after the TLC detection reaction is complete, and the concentrated target compound 30-3 that namely obtains.(C ₂₁H ₂₀BrF ₃N ₆O ₃) C, H, N, test value C46.43, H3.68, N15.38; Theoretical value C46.59, H3.72, N15.53.

Synthesizing of compound 30:

Compound 30-3 is dissolved in methylene dichloride, under room temperature, agitation condition, adds saturated sodium bicarbonate solution approximately to pH 7 left and right, stir 30min, use dichloromethane extraction, filter after the organic phase anhydrous sodium sulfate drying after merging, the concentrated target compound 30 that namely obtains of filtrate.

¹H-NMR(400MHz，CDCl ₃)：δ7.65(1H，d，J＝7.6Hz)，7.44(1H，t，J＝7.6Hz)，7.32(1H，t，J＝7.6Hz)，7.09(1H，d，J＝7.6Hz)，6.57(1H，s)，5.62(1H，d，J＝16Hz)，5.40(1H，d，J＝15.6Hz)，3.23(2H，m)，3.07(2H，m)，2.93(1H，m)，1.74(2H，m)，1.61(2H，m)。

Synthesizing of the hydrochloride of compound 30:

Under room temperature, compound 30 (0.40g, 0.94mmol) is dissolved in to methyl alcohol (10mL), be added dropwise to saturated hydrogen chloride methanol solution (30mL), stirring at room 2 hours, after removing solvent under reduced pressure, add ether under agitation condition, separate out white solid, filter, the ether washing, obtain the white solid compound, the 0.40g that weighs, yield 92%.(C ₁₉H ₂₀BrClN ₆O) C, H, N, test value C49.12, H4.19, N17.11; Theoretical value C49.21, H4.35, N17.23.

Synthesizing of embodiment 25 compounds 31

Compound 31-1's is synthetic:

In 150mL, add 500mg compound 30-2 in pressure pipe, 175mg pyridine-3-boric acid, 77mg tetra-(triphenyl phosphorus) palladium; the 4ml TERTIARY BUTYL AMINE; the mixture of 20ml Virahol and water (2: 1), the system starvation, under nitrogen protection, an oil bath 90-100 ℃ heated and stirred is spent the night.After the TLC detection reaction is complete, the reaction solution concentrated by rotary evaporation, (methylene chloride/methanol=50/1 is eluent to the resistates column chromatography purification, collects R _f=0.3 component) namely obtain target compound 31-1.

¹H-NMR(400MHz，CDCl ₃)：δ10.46(1H，br.s)，9.07(1H，br.s)，8.57(1H，br.s)，8.03(1H，br.s)，7.65(1H，d，J＝7.6Hz)，7.47(3H，m)，7.32(1H，t，J＝15.2Hz，7.6Hz)，7.10(1H，d，J＝7.6Hz)，7.00(1H，s)，5.62(1H，d，J＝16Hz)，5.47(1H，d，J＝14.4Hz)，3.88(1H，br.s)，3.42(1H，m)，3.02(2H，m)，2.79(1H，br.s)，1.81(4H，m)，1.25(9H，m)。

Synthesizing of compound 31:

150mg compound 31-1, with after dissolve with methanol, is dripped to the 0.5ml Acetyl Chloride 98Min. under condition of ice bath.After the TLC detection reaction is complete, add saturated sodium bicarbonate solution to pH 7 left and right, use dichloromethane extraction, merge organic phase, with after anhydrous sodium sulfate drying, filtering, the filtrate concentrated by rotary evaporation namely obtains target compound 31.

¹H-NMR(400MHz，MeOD)：δ9.00(1H，m)，8.69(1H，m)，8.22(1H，m)，8.10(1H，m)，7.72(1H，d，J＝7.6Hz)，7.61(1H，t，J＝7.2Hz)，7.43(1H，t，J＝7.2Hz)，7.28(2H，m)，5.59(1H，d，J＝15.2Hz)，5.50(1H，d，J＝15.2Hz)，3.68(1H，m)，3.54(1H，m)，3.22(2H，m)，3.00(1H，m)，2.16(1H，m)，1.83(1H，m)，1.67(2H，m)。

Synthesizing of the hydrochloride of compound 31:

The synthetic method of the hydrochloride of reference compound 30, prepare the hydrochloride of compound 31.

Synthesizing of embodiment 26 compounds 32

Compound 32-1's is synthetic:

In the 100mL eggplant-shape bottle, add the 520ml vitriol oil, under ice bath, add 140g 6-methyl uracil in batches, keep temperature to be no more than 40 ℃.After all dissolving, slowly drip the 104ml nitrosonitric acid, keep temperature to be no more than 15 ℃.Dropwise, after stirring at room 30min, reaction solution is poured in trash ice, have solid to wash out.Suction filtration, filter cake dries after water, acetone are washed, namely obtain target compound 32-1.

¹H-NMR(400MHz，DMSO-d ₆)：δ11.79(1H，s)，11.76(1H，s)，2.28(3H，s)。

Compound 32-2's is synthetic:

In 1000mL two neck bottles, add 119g compound 32-1 and 400mL N, dinethylformamide, after 80 ℃ of heated and stirred 25min of oil bath, add 160mL N, the dinethylformamide dimethylacetal, after being warming up to 140 ℃ of heated and stirred 30min, ice bath is cooling, separates out solid, suction filtration, filter cake dry after with ethyl acetate, ether, washing successively and obtain target compound 32-2.MS：227.0，228.0[M+1] ⁺。

Compound 32-3's is synthetic:

In the 100mL eggplant-shape bottle, add 1.43g compound 43-2 and 23ml acetic acid, oil bath adds the 2g zinc powder in batches after being heated to 80 ℃.Finish, 80 ℃ of heating of oil bath were cooled to room temperature by reaction solution after 1 hour, had solid to separate out.Suction filtration, filter cake dissolves with 10ml 5% sodium hydroxide solution after acetic acid, washing.After 70 ℃ of heated and stirred 30min of this solution, drip acetic acid to pH 5-6.Suction filtration, filter cake dry and namely obtain target compound 32-3 after cold water, ethanol are washed.

¹H-NMR(400MHz，DMSO-d ₆)：δ11.82(1H，s)，10.75(1H，s)，10.56(1H，s)，7.12-7.13(1H，t，J＝3Hz)，5.83-5.84(1H，t，J＝2Hz)。

Compound 32-4's is synthetic:

In the 100ml eggplant-shape bottle, add 0.38g compound 43-3 and 30ml phosphorus oxychloride, 120 ℃ of oil baths heating is after 6 hours, cool to room temperature, and decompression steams phosphorus oxychloride, and resistates drips ammoniacal liquor that 30mL is cold to pH 8 under condition of ice bath.Finish, continue to stir 30min, suction filtration, filter cake is drying to obtain target compound 32-4 through the cold wash final vacuum.

¹H-NMR(400MHz，DMSO-d ₆)：δ12.72(1H，s)，8.06-8.07(1H，d，J＝4Hz)，6.68-6.69(1H，d，J＝4Hz)。

Compound 32-5's is synthetic:

Under room temperature, compound 32-4 (4.50g, 24.0mmol) is dissolved in methylene dichloride (50mL), is added dropwise to methylene dichloride (15mL) solution of N-bromo-succinimide (4.00g, 24.0mmol), stirring at room 2 hours.React complete, remove by filter insolubles, filtrate adds water (20mL) and DCM (30mL), extracting and demixing, and organic layer water (20mL) and saturated aqueous common salt (20mL) is respectively washed once, the organic layer anhydrous sodium sulfate drying, filter, after filtrate decompression was steamed and desolventized, use sherwood oil: ethyl acetate=recrystallization obtained yellow solid compound 32-5 in 4: 1, the 5.00g that weighs, yield 76.3%.

¹H-NMR(400MHz，DMSO-d ₆)：δ13.25(1H，s)，8.33-8.34(1H，d，J＝1Hz)。。

Compound 32-6's is synthetic:

Under room temperature, compound 32-5 (5.00g, 18.7mmol) is dissolved in the aqueous sodium hydroxide solution (50ml) of 1mol/L, 80 ℃ were stirred 12 hours.React complete, be down to room temperature, under condition of ice bath, drip dilute hydrochloric acid and be adjusted to neutrality, by sedimentation and filtration, the washing filter cake, drain to obtain pale solid compound 32-6, the 4.42g that weighs, yield 95.3%.

¹H-NMR(400MHz，DMSO-d ₆)：δ13.05(1H，s)，12.69(1H，s)，7.61-7.62(1H，d，J＝3Hz)。

Compound 32-7's is synthetic:

Under room temperature, compound 32-6 (4.42g, 17.8mmol) is dissolved in DMF (20mL), adds pyridine (2.11g, 26.7mmol), be added dropwise to Boc ₂The DMF of O (5.82g, 26.7mmol) (5mL) solution, stirring at room 12 hours.React complete, reaction solution directly joins in saturated aqueous common salt, and by sedimentation and filtration, the washing filter cake, drain to such an extent that yellow solid is compound 32-7, the 4.99g that weighs, yield 80.5%.

¹H-NMR(400MHz，DMSO-d ₆)：δ8.07(1H，s)，1.57(3H，s)。

Compound 32-8's is synthetic:

Under room temperature, compound 32-7 (4.99g, 14.3mmol) is dissolved in to N, in dinethylformamide/glycol dimethyl ether=5: 1 (20mL), under condition of ice bath, slowly add 60% sodium hydrogen (0.63g, 15.7mmol), under condition of ice bath, stir after 30 minutes, slowly add anhydrous lithium bromide (2.48g, 28.6mmol), slowly rose to stirring at room 1 hour, then add adjacent cyano group benzyl bromine (3.36g, 17.2mmol), slowly rise to 60 ℃ and stirred 12 hours.React complete, be down to room temperature, directly add water (50ml) and ethyl acetate (50ml), extracting and demixing, water layer is used ethyl acetate (50ml*2) extracting twice again, merge organic layer, each washing of water (20ml) and saturated aqueous common salt (20ml) once successively, anhydrous sodium sulfate drying, filter, after filtrate decompression is steamed and desolventized, with silica gel column chromatography column separating purification (elutriant PE: EA=2: 1), obtain white solid compound 32-8, the 3.58g that weighs, yield 68.8%.

¹H-NMR(400MHz，CDCl ₃)δ：7.35-7.73(4H，m)，7.04-7.06(1H，d，J＝8Hz)，5.68-5.86(2H，m)。

Synthesizing of compound 32:

Under room temperature, by compound 32-8 (0.63g, 1.73mmol) mixing 3-amino piperidine dihydrochloride (0.45g, 2.60mmol), sodium bicarbonate (0.58g, 6.92mmol) and 4A molecular sieve (0.50g), adding dehydrated alcohol is solvent, encloses in reaction tubes, slowly is warming up to 120 ℃ and stirs 12 hours.React complete, be down to room temperature, filter, after filtrate decompression is steamed and desolventized, with silica gel column chromatography column separating purification (elutriant DCM: MeOH=10: 1), obtain colorless oil compound 32, the 0.40g that weighs, yield 54.1%.

¹H-NMR(400MHz，MeOD+DMSO-d ₆)δ：8.04-8.06(1H，d，J＝8Hz)，7.86-7.90(1H，t，J＝8Hz)，7.70-7.74(2H，m)，7.40-7.42(1H，d，J＝8Hz)，5.73-5.91(2H，dd，J＝15Hz，J＝15Hz)，3.75-3.78(1H，m)，3.65-3.71(1H，m)，3.38-3.46(2H，m)，3.15-3.20(1H，m)，2.35-2.37(1H，m)，2.11-2.15(1H，m)，1.92-1.98(2H，m)。。

The synthetic method of the hydrochloride 32-a of compound 32:

Under room temperature, compound 32 (0.40g, 0.94mmol) is dissolved in to methyl alcohol (10mL), be added dropwise to saturated hydrogen chloride methanol solution (30mL), stirring at room 2 hours, after removing solvent under reduced pressure, stir and add ether, separate out white solid, filter, the ether washing, obtain white solid compound 32-a, the 0.40g that weighs, yield 92.1%.(C ₁₉H ₂₀BrClN ₆O) C, H, N, test value C49.01, H4.15, N17.08; Theoretical value C49.21, H4.35, N17.23.

Synthesizing of embodiment 27 compounds 33

Compound 33-1's is synthetic:

Under room temperature, compound 32 (1.67g, 3.60mmol) is suspended in to methylene dichloride (50ml), adds triethylamine (0.91g, 9.0mmol), be added dropwise to Boc ₂The methylene dichloride of O (0.94g, 4.32mmol) (10mL) solution, stirring at room 12 hours.After completion of the reaction, remove by filter insolubles, filtrate water (30ml) and saturated aqueous common salt (30ml) is successively respectively washed once, filter, after filtrate decompression is steamed and is desolventized, recrystallization (sherwood oil: ethyl acetate=2: 1) obtain white solid compound 33-1, the 1.60g that weighs, yield 84.2%.

¹H-NMR(400MHz，CDCl ₃)：δ7.66-7.68(1H，d，J＝8Hz)，7.43-7.47(1H，d，J＝8Hz)，7.31-7.35(1H，t，J＝8Hz)，7.28-7.29(2H，d，J＝8Hz)，6.93-6.95(1H，d，J＝8Hz)，5.57(2H，s)，5.14(1H，s)，3.33-3.37(1H，m)，2.96-3.03(2H，m)，1.78-1.84(2H，m)，1.60-1.69(2H，m)，1.55-1.58(1H，m)，1.42(9H，s)。。

Compound 33-2's is synthetic:

In 150ml, add 500mg compound 33-1 in pressure pipe, 175mg pyridine-3-boric acid, 77mg tetra-(triphenyl phosphorus) palladium; the 4ml TERTIARY BUTYL AMINE; 20ml Virahol and water (2: 1) mixture, the system starvation, under nitrogen protection, an oil bath 90-100 ℃ heated and stirred is spent the night.After the TLC detection reaction is complete, the reaction solution concentrated by rotary evaporation, (methylene chloride/methanol=50/1 is eluent to column chromatography purification, collects R _f=0.3 component) namely obtain target compound 33-2.

¹H-NMR(400MHz，CDCl ₃)：δ12.08(1H，s)，9.24(1H，s)，8.42(1H，s)，8.28-8.30(1H，d，J＝8Hz)，7.64(2H，s)，7.41(1H，，s)，7.28-7.29(2H，d，J＝4Hz)，6.98-7.00(1H，d，J＝8Hz)，5.21-5.66(2H，dd，J＝24Hz，J＝16Hz)，4.90(1H，s)，3.80(1H，s)，2.88-3.01(4H，m)，1.67(1H，s)，1.36(1H，s)，1.36(9H，s)，1.36(9H，s)，0.83(1H，s)。

Synthesizing of compound 33:

150mg compound 33-2, with after dissolve with methanol, is dripped to the 0.5ml Acetyl Chloride 98Min. under ice bath.After the TLC detection reaction is complete, add saturated sodium bicarbonate solution to pH 7 left and right, use dichloromethane extraction, the organic phase after merging is with after anhydrous sodium sulfate drying, filtering, and the filtrate concentrated by rotary evaporation namely obtains target compound 33.

¹H-NMR(400MHz，DMSO-d)：δ12.66(1H，s)，9.55(1H，s)，9.10-9.12(1H，d，J＝8Hz)，8.69-8.70(1H，d，J＝4Hz)，8.34(3H，s)，8.27-8.28(1H，d，J＝4Hz)，7.99-8.03(1H，t，J＝8Hz)，7.83-7.85(1H，d，J＝8Hz)，7.59-7.63(1H，t，J＝8Hz)，7.43-7.47(1H，t，J＝8Hz)，7.11-7.13(1H，d，J＝8Hz)，5.42-5.53(2H，dd，J＝24Hz，J＝16Hz)，3.57(1H，s)，3.60(2H，s)，3.10-3.13(1H，d，J＝8Hz)，2.95(1H，s)，1.99(1H，s)，1.85(1H，s)，1.58-1.60(1H，d，J＝8Hz)。

The preparation of the hydrochloride of compound 33:

The synthetic method of the hydrochloride 32-a of reference compound 32, prepare the hydrochloride of compound 33.

Embodiment 28. external activity experiments

Can measure the inhibiting rate of the compounds of this invention to DPP-IV by the homogeneous luminescent detection system (DPP-IV-Glo Protease Assay, Promega cat#G8350) of DPP-IV-Glo proteolytic ferment.This system contains the Laemmli buffer system Laemmli of the amino luciferin of DPP-IV substrate Gly-Pro-and luciferase activity detection, DPPIV-Glo _TMAfter by DPP-IV, being cut, can activate luciferase and react, produce " glow-type " type luminous signal, then detect with Turner Veritas microwell plate luminometer the activity that luminous signal can characterize DPP-IV.

1, experiment purpose

Measure inhibition activity and the selective inhibitory of the compounds of this invention to the DPP-IV enzyme.

2, experiment material

DPP-IV enzyme, DPP-VIII enzyme, DPP-IX enzyme, GP-AMC (BioMol), black 96 orifice plates, 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/ml BSA.

3, experimental technique

Determining of a, enzymic activity:

GP-AMC is diluted in damping fluid separately, and concentration is 100umol/L, every hole 25ul; Enzyme gradient dilution, initial concentration are respectively DPP-VIII, DPP-IX: 0.01ug/ul, DPP-IV:0.01mU/ul, and by 5 times of dilutions, every hole 25ul, mix; 37 ℃, 360/460nm measures the dynamic change of fluorescent value, measures 30 minutes; The absorbancy of take linearly rises, the enzyme concn of S/B >=5 is working concentration.

B, inhibitor activity are measured:

All enzymes, inhibitor, GP-AMC, all with the analysis buffer preparation, arrange without the compound contrast, contrast without enzyme liquid.

Press the working concentration preparation enzyme liquid of enzyme, every hole 25ul; Gradient dilution inhibitor (10 times or 5 times of dilutions), every hole 25ul, mix; Add the GP-AMC solution 50ul diluted, mix; 37 ℃ were reacted 20 minutes, and 360/460nm measures fluorescent value.

C, data analysis: use the GraphPad-Prism software analysis.

4, experimental result

The compounds of this invention is as shown in table 1 below to the inhibition activity data of three kinds of enzymes.

Table 1 external activity and selective data

Experimental result explanation: with contrast medicine and compare, the compounds of this invention has better selective inhibitory or suitable restraining effect to DPP-IV, when effectively suppressing the DPP-IV activity, the activity almost not impact of the compounds of this invention on DPP-VIII and DPP-IX, after can predicting the compounds of this invention exploitation patent medicine, toxicity will, far below the contrast medicine, have outstanding advantage.

Claims (8)

1. the compound of a formula I and pharmacy acceptable salt thereof:

Formula I

Wherein, R ¹Be selected from hydrogen, cyano group;

R ⁸, R ⁹, R ¹⁰Be selected from hydrogen, amino, hydroxyl;

X, Y are not identical, are selected from independently of one another C, N;

R ⁴, R ⁵, R ⁶Be selected from hydrogen, halogen, C _1-4Alkyl, pyridyl;

Condition is except following compounds:

2. compound claimed in claim 1 and pharmacy acceptable salt thereof are selected from the compound of following formula IX or formula XI:

3. following compounds and pharmacy acceptable salt thereof:

4. following compounds:

5. the preparation method of a generalformulaⅰcompound claimed in claim 1, comprise the steps:

(1) formula A compound reacts production C compound with formula B compound;

(2) formula C compound reacts production I compound with formula D compound;

Wherein, R ¹, R ⁴, R ⁵, R ⁶, R ⁸, R ⁹, R ¹⁰, X, Y be identical with the definition in claim 1, Hal is chlorine or bromine, Hal ' is chlorine, bromine or iodine.

6. in claim 1-4, the described compound of any one and pharmacy acceptable salt thereof are benefited from the purposes in the medicine of the disease that DPP-IV suppresses in preparation treatment or prevention, and the disease that the described DPP-IV of benefiting from suppresses is selected from that type II diabetes, diabetic dyslipidaemia, glucose tolerance lower disease, the fasting plasma glucose lowers disease, metabolic acidosis, ketosis, appetite stimulator, obesity, various cancer, neurological conditions, disorder of immune system.

7. purposes claimed in claim 6, wherein benefit from the disease that DPP-IV suppresses and be selected from type II diabetes.

8. a pharmaceutical composition, comprise the described compound of any one and pharmacy acceptable salt and one or more pharmaceutically acceptable auxiliary materials in claim 1-4.