CN105418592B - Substituted pyrimidines carbamide compounds and application thereof - Google Patents

Abstract

The present invention relates to a kind of substituted pyrimidines carbamide compounds and application thereof.The substituted pyrimidines carbamide compounds are compound shown in Formulas I (concrete structure is see specification or claims) or its stereoisomer or pharmaceutically acceptable salt.External activity test shows：Substituted pyrimidines carbamide compounds disclosed by the invention have cholinesterase inhibition, chelated metal ions, the free radical generation for suppressing metal ion induction and suppress the performances such as the A beta peptide aggregations of metal ion induction.Therefore, substituted pyrimidines carbamide compounds provided by the invention are expected to be used to prepare treatment and/or prevention Alzheimer disease drugs.

Description

Substituted pyrimidines carbamide compounds and application thereof

Technical field

The present invention relates to a kind of substituted pyrimidines carbamide compounds and application thereof, belong to pharmaceutical chemistry and pharmacotherapeutics neck Domain.

Background technology

Alzheimer disease (Alzheimer ' s disease, AD) also known as degenerative brain disorder are one kind with senile plaque expelling (Senile Plaque, Sp), neurofibrillary tangles (Neurofibrillary Tangles, NFT) are formed and hippocampal neuron Lose the nerve degenerative diseases for major pathologic features.Main clinical manifestation is memory capability decline and cognition dysfunction Deng, and it is accompanied by a series of psychotic symptoms.With the continuous growth of human longevity, there is aging in population, AD turned into after The fourth-largest epidemiology killer after angiocardiopathy, malignant tumour, cerebral apoplexy.Epidemiology statistics data show, AD The incidence of disease significantly raises with age, and the elderly that the current whole world about has more than 50,000,000 suffers from this disease, it is contemplated that to 2050 Year, global number of patients will be more than 100,000,000.Chinese neurology expert and epidemiological specialist report point out that China is old silly The risky countries of slow-witted disease.At present, China AD patient numbers about 6,000,000 or so, it is predicted that will be increased to 10,000,000 in 2025, occupy generation First, boundary.China is paid much attention to this, will be set to China's senile dementia day on November 3, and carry out the disease extensively in the whole nation Popular science propaganda activity.

Because AD medical expenses are huge, its not only serious threat health of the elderly, also to family numbers of patients and society Heavy economy and mental burden can be brought, tremendous influence is caused to economic development.Shown according to the statistics of U.S.'s announcement, Worldwide, the expense every year for AD diseases has reached 315,000,000,000 dollars, and has the trend of sustainable growth.Alzheimer But up to the present disease has become the focus of world-wide medical circle discussion, not yet finds out its definite cause of disease and effective Prevention and treatment method, therefore, the effective AD medicines of research and development to AD pathogenesis are the tight of current the world of medicine Compel problem and cause the great attention of countries in the world the world of medicine.The research of AD protective agents is also ground as country of China original new drug Study carefully one of key special subjects research.

AD is a kind of multi-pathogenesis influence, complicated central nervous system disease, and the hypothesis that academic circles at present proposes has：Courage Alkali can damage hypothesis, amyloid-beta cascades hypothesis, oxidative stress hypothesis, biological metal ionic homeostasis is unbalance hypothesis, inflammation Hypothesis, Protein tau phosphorylation theory etc..AD pathogenesis is complicated, and connects each other, influences each other between each mechanism, is sending out It is related to the change of various complicated regulated and control networks and regulatory factor during hair tonic exhibition, so the medicine of single target spot is difficult from root Solves problem on this.The focus of Recent study is the multi-functional anti-AD reactive compounds of exploitation, i.e., for different AD pathogenesis In multiple target spots for being related to design micromolecular compound, it is acted on two or more target spots simultaneously, to pass through Number of ways co-therapies improve AD symptoms.

In the numerous pathogenesis of AD, cholinergic damage hypothesis obtains Most scholars and generally accepted, and at present on The treatment AD in city medicine is also mostly the anticholinesterase based on cholinergic damage hypothesis.The anti-AD medicines of FDA approvals at present Thing has five (Fig. 1), is donepezil (Donepezil), Rivastigmine (Rivastigmine), galanthamine respectively (Galantamine), Tacrine (Tacrine), Memantine (Memantine), wherein first four are all acetylcholinesterases (Acetylcholinesterase, AChE) inhibitor, Memantine are NMDA acceptor (NMDAR) antagonisms Agent, Tacrine listing are withdrawn due to side effects such as hepatotoxicity wind agitation in the near future.In addition, huperzine (Huperzine A, table 1) And a kind of efficiently reversible competitive AChE inhibitor, at present the medicine have become domestic more successful treatment AD medicine Thing.

Table 1FDA and the AD medicines of China's approval

It is emphasized that these treatments AD marketed drug can only control or improve cognitive function symptom at present, not Morbid state can fundamentally be improved or terminate disease process.Nevertheless, in view of ground for the medicine of AD novel targets new mechanisms Hair failure in succession, AChE is still nowadays maximally efficient therapy target.Therefore, develop based on cholinesterase inhibition, it is simultaneous The compound for having the anti-AD activity of other approach turns into the new focus of research for having therapeutic potential and value.

Mass data proves the biological metal ion such as Cu of intracerebral²⁺, Fe²⁺, Zn²⁺Oxidative stress (ROS) hair can be promoted Raw and A β aggregation, and study and also found, the excessive enrichment of these metal ions is had been found that in AD patient's later stage brain, is had There is the metal ion of redox, as iron ion and copper ion not only result in ROS generation, and can be by this oxidation The harm Spreading and diffusion of effect.Research shows：A β are not spontaneously to assemble, but with excessive metal (such as Cu in brain²⁺, Fe^{2 +}, Zn²⁺) there occurs a kind of effect of age-dependent, it makes A β be precipitated as the patch rich in metal.Experiment in vitro shows, metal Ion can promote the formation of A beta peptide aggregations body and amyloid plaque, and metal-chelator can make the amyloid plaques histolysis of AD brains, Mitigate the brain A β precipitation loads of APP trangenic mices simultaneously.Based on these researchs, change of the synthesis with the effect of metal ion chelant Compound is expected to turn into a kind of new treatment AD strategy.

In summary, exploitation has the compound of cholinesterase inhibition and metal ion chelating activity to AD's simultaneously Therapy study is significant.

The content of the invention

The present inventor develops a kind of substituted pyrimidines carbamide compounds, and by suppressing to its 1. cholinesterase Activity, 2. chelation of metal ion, the A beta peptide aggregations effect for 3. suppressing metal inducement and the freedom for 4. suppressing metal ion induction One or more characteristics optimize during base produces, and make it have the prospect of preferably treatment Alzheimer disease.

It is an advantage of the invention to provide one kind to have cholinesterase inhibition, metal ion chelating activity, suppression The A beta peptide aggregations of metal inducement processed, the free radical for suppressing metal ion induction produce the substituted pyrimidines carbamide compounds of activity.

Substituted pyrimidines carbamide compounds of the present invention, for compound shown in Formulas I or its stereoisomer or pharmaceutically Acceptable salt：

In Formulas I, R¹For C₁~C₆Chain or cyclic alkyl, the C of phenyl substitution₁~C₆Chain or cyclic alkyl, phenyl take For phenyl,

The substituent of the substituted-phenyl is selected from：Halogen (F, Cl, Br or I, similarly hereinafter), C₁~C₃Alkoxy or cyano group (CN) Middle one kind；

R²And R³It is respectively and independently selected from：Hydrogen (H) or C₁~C₃It is a kind of in straight or branched alkyl；X is oxygen (O) or sulphur (S)；

R⁴Amino, 5~6 circle heterocycles bases or the benzo or 5~6 substituted circle heterocycles bases substituted for amino, benzyl,

The hetero atom of 5~6 circle heterocycles base is selected from：In nitrogen (N) or oxygen (O) it is a kind of or two kinds, hetero atom number be 1~ 3 integer,

The substituent of 5~6 circle heterocycles bases of the substitution is a kind of in following groups：

C₁~C₃The C of alkyl, halogen or hydroxyl substitution₁~C₃Alkyl, nitro, aldehyde radical (Similarly hereinafter), carbomethoxy (Similarly hereinafter) or

Wherein, R⁵And R⁶It is respectively and independently selected from：H、C₁~C₆Chain or cyclic alkyl, the C of phenyl substitution₁~C₃Straight chain or branch It is a kind of in alkyl group, or,

R⁵And R⁶5~7 circle heterocycles bases or 5~7 substituted circle heterocycles bases are combined into N,

The hetero atom of 5~7 circle heterocycles base is selected from：A kind of or two kinds, hetero atom number 1 or 2, described substituted in N or O The substituent of 5~7 circle heterocycles bases is selected from：C₁~C₃It is a kind of in straight or branched alkyl or halogen.

Pharmaceutically acceptable salt of the present invention is：The pharmaceutical salts of suitable substituted pyrimidines carbamide derivative of the present invention are The sufficiently strong substituted pyrimidines carbamide derivative of the present invention of alkalescence is with sour into salt.For example, with inorganic acid or the list or diacid of organic acid Addition salts, the acid can be hydrochloride, phosphate, sulfate, trifluoroacetate, hydrobromate, tartrate, fumaric acid Salt, maleate, citrate, tosilate, mesylate；These salt can be by known salifying method by Formulas I It is prepared by compound.

Another object of the present invention is, disclose above-mentioned substituted pyrimidines carbamide compounds (compound shown in Formulas I or its Pharmaceutically acceptable salt) a kind of purposes, i.e., shown in Formulas I compound or its pharmaceutically acceptable salt is controlled in preparation Treat, improve and/or prevent the application in Alzheimer disease drugs.

The present invention also provides a kind of pharmaceutical composition for being used to treating, improve and/or preventing Alzheimer disease, the medicine Composition includes above-mentioned compound of formula I and pharmaceutically acceptable carrier and/or excipient.

Brief description of the drawings

Fig. 1 are compound, negative control (negative control, NC) and existing gold shown in the Formulas I -45 of the present invention Belong to ion chelating agent (CQ, positive control) and the UV absorption spectrogram after metal mixed；

Wherein, compound shown in (A) Formulas I -45 and the UV absorption spectrogram after metal mixed,

(B) NC and the UV absorption spectrogram after metal mixed,

(C) CQ and the UV absorption spectrogram after metal mixed.

Symbolization distinguishes different metal ions in Fig. 1.

Fig. 2 are the redox system of Cu (II)-ascorbic acid and Cu (II)-compound shown in ascorbic acid-Formulas I -45 Fluorescent value versus time curve.

Fig. 3 is that test sample suppresses Cu²⁺Induce the electron microscope of A beta peptide aggregations；

Wherein, (1) test sample is：Aβ_1-42+Cu²⁺, (2) test sample is：Aβ_1-42+Cu²⁺Chemical combination shown in+Formulas I -45 Thing, (3) test sample are：Aβ_1-42+Cu²⁺+ CQ, (4) test sample are：Aβ_1-42Alone, (5) test sample are：Aβ_{1- 42}fresh。

Embodiment

In a preferred embodiment of the invention, R¹For C₁~C₃Straight or branched alkyl, cyclohexyl, phenyl substitution C₁~C₃Straight or branched alkyl or substituted-phenyl,

The substituent of the substituted-phenyl is selected from：Halogen, C₁~C₃It is a kind of in alkoxy or CN.

Further preferred technical scheme is：R¹For methyl, ethyl, n-propyl, isopropyl, cyclohexyl, benzyl or substitution Phenyl,

The substituent of the substituted-phenyl is selected from：It is a kind of in halogen, methoxyl group or CN.

In another preferred embodiment of the present invention, R⁴ForPyrrole radicals, pyrrolidinyl, pyrazolyl, imidazole radicals, Benzimidazolyl, substituted imidazole base, 1,2,3- triazol radicals, 1,2,4- triazol radicals, morpholinyl, piperazinyl or C₁~C₃Straight chain Or the piperazinyl of branched alkyl substitution,

Wherein, the substituent of the substituted imidazole base is a kind of in following groups：

Methyl, ethyl, trifluoromethyl, methylol (- CH₂OH), Cl, Br, I, nitro (- NO₂), aldehyde radical, carbomethoxy or

Wherein, R⁵And R⁶It is respectively and independently selected from：H、C₁~C₃Straight or branched alkyl, the C of phenyl substitution₁~C₃Straight chain or branch It is a kind of in alkyl group or cyclohexyl, or,

R⁵And R⁶Pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, hexamethylene imino group are combined into NOr Substituted pyrrolidinyl or piperazinyl,

The substituent of the substituted pyrrolidinyl or piperazinyl is selected from：C₁~C₃One in straight or branched alkyl or halogen Kind.

Further preferred technical scheme is：R⁴It is a kind of in following groups：

The present invention also provide one kind prepare substituted pyridines ureas compound (compound shown in Formulas I) of the present invention and its The method of intermediate (compound shown in Formula II), specific synthesis strategy difference are as follows：

Wherein, R¹,R²,R³Definition with X is with described previously identical, R^4aFor amino, benzyl substitute amino, 5~6 yuan it is miscellaneous Ring group or benzo or 5~6 substituted circle heterocycles bases, the hetero atom of 5~6 circle heterocycles base are selected from：One kind or two in N or O Kind, the integer that hetero atom number is 1~3, the substituent of 5~6 circle heterocycles bases of the substitution are selected from：C₁~C₃Alkyl, halogen or The C of hydroxyl substitution₁~C₃It is a kind of in alkyl, nitro, aldehyde radical or carbomethoxy.

Methods described specifically comprises the following steps：

1) the substituted or unsubstituted 4- amino -6- chlorine pyrimidine of raw material and cesium carbonate are added to flask, add people N, N'- diformazans Base formamide makees solvent, adds corresponding fatty amine or substitution or unsubstituted aromatic nitrogen heterocycle, is warming up to 100-120 DEG C, instead It should stay overnight.After question response is complete, suitable quantity of water is added, and is extracted with ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying, Then filter, remove solvent under reduced pressure, residue is purified with silica gel column chromatography, just obtains intermediate (compound shown in Formula II).

2) gained intermediate (compound shown in Formula II) is dissolved in N, in N'- dimethylformamides, adds sodium hydride, room Temperature stirring 5 minutes, corresponding substitution isocyanates or substitution isothiocyanic acid ester are then added, reacts 0.5h, add water quenching anti- Should, it is extracted with ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent, residue silica gel under reduced pressure Column chromatography purifies, and just obtains partial target thing (compound shown in Formulas I a).

The synthesis strategy of another partial target thing (Formulas I b compounds) it is following (using side chain imidazoles have the compound I-X of aldehyde radical as Raw material, with HNR⁵R⁶It is made through reduction amination)：

Wherein, R¹,R²,R³,R⁵R⁶Definition with X with it is described previously identical.

Specifically comprise the following steps：

Compound shown in Formulas I-X is added into flask, with methanol: dichloromethane=1: 1 is solvent, sequentially adds HNR⁵R⁶, cyanogen Base sodium borohydride, acetic acid, room temperature reaction is overnight.Add water quenching reaction, ethyl acetate extraction, saturated common salt washing, anhydrous slufuric acid Sodium is dried, and filtering, removes solvent under reduced pressure, residue is purified with silica gel column chromatography, obtains respective objects thing (chemical combination shown in Formulas I b Thing).

According to the teaching of above-mentioned preparation method, those of ordinary skill in the art are without creative work, you can obtain Formulas I institute Comprising all compounds.

The present invention will be further illustrated below in an example.These embodiments are merely to illustrate the present invention, but It is not in any way limit the scope of the present invention.All parameters and remaining explanation in embodiment, unless otherwise indicated Outside, all it is for unit with quality (milligram).

Embodiment 1

The preparation of 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II -1)

By 518mg (4mmol) 4- amino -6- chlorine pyrimidines, 286mg (4.2mmol) pyrazoles, 1.56g (4.8mmol) cesium carbonate Flask is added, 15mL N, N'- dimethylformamides make solvent, are warming up to 120 DEG C, react 24h.Suitable quantity of water is added, with acetic acid second Ester is extracted, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, and residue is separated pure with silica gel column chromatography Change, ethyl acetate/petroleum ether=1/1 elutes, and obtains yellow solid 405mg, yield 63%.

¹H NMR (400MHz, DMSO) δ 8.66-8.44 (m, 1H), 8.30 (d, J=0.7Hz, 1H), 7.83 (d, J= 0.9Hz, 1H), 7.17 (s, 2H), 6.88 (d, J=0.9Hz, 1H), 6.55 (dd, J=2.6,1.7Hz, 1H)

Embodiment 2

The preparation of 6- (1H- imidazoles -1- bases) pyrimidine -4- amine (intermediate II -2)

By 648mg (5mmol) 4- amino -6- chlorine pyrimidines, 408mg (6mmol) imidazoles, 1.96g (6mmol) cesium carbonate adds Flask, 15mL N, N'- dimethylformamides make solvent, are warming up to 120 DEG C, react 16h.Suitable quantity of water is added, is extracted with ethyl acetate Take, saturated common salt washing, anhydrous sodium sulfate drying, filtering, remove solvent under reduced pressure, residue silica gel column chromatography separating purification, Ethanol/methylene=1/10 elutes, and obtains yellow solid 323mg, yield 40%.

¹H NMR (400MHz, DMSO) δ 8.48-8.43 (m, 1H), 8.33 (d, J=0.8Hz, 1H), 7.82 (t, J= 1.4Hz, 1H), 7.20 (s, 2H), 7.15-7.08 (m, 1H), 6.57 (d, J=1.0Hz, 1H)

Embodiment 3

The preparation of 6- (1H- pyrroles -1- bases) pyrimidine -4- amine (intermediate II -3)

In the N of 335mg (5mmol) pyrroles, N'- dimethylformamides (10mL) solution, 200mg (5mmol) hydrogen is added Change sodium, 10min is stirred at room temperature, add 648mg (5mmol) 4- amino -6- chlorine pyrimidines, room temperature continues to react 1h.Add suitable quantity of water Quenching reaction, is extracted with ethyl acetate, and saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent, residue under reduced pressure With silica gel column chromatography separating purification, ethyl acetate/petroleum ether=1/1 elutes, and obtains white solid 200mg, yield 25%.

¹H NMR(400MHz,DMSO)δ8.27(s,1H),7.54(s,2H),7.00(s,2H),6.48(s,1H),6.30 (s,2H).

Embodiment 4

The preparation of 6- (1H-1,2,3- triazole -1- bases) pyrimidine -4- amine (intermediate II -4)

By 400mg 4- amino -6- chlorine pyrimidines, 188 μ L1,2,3- triazoles, 1.2g (1.2equiv) cesium carbonate, which adds, to be burnt Bottle, 10mLN, N'- dimethylformamides make solvent, are warming up to 120 DEG C, react 12h.Suitable quantity of water is added, is extracted with ethyl acetate, Saturated common salt is washed, anhydrous sodium sulfate drying, filtering, removes solvent, residue silica gel column chromatography separating purification, acetic acid under reduced pressure Ethyl ester/petroleum ether=2/1 elutes, and obtains yellow solid 200mg, yield 40%.

¹H NMR (400MHz, DMSO) δ 8.78 (d, J=1.1Hz, 1H), 8.42 (s, 1H), 7.99 (d, J=1.1Hz, 1H), 7.45 (s, 2H), 7.09 (d, J=0.7Hz, 1H)

Embodiment 5

The preparation of 6- (1H-1,2,4- triazole -1- bases) pyrimidine -4- amine (intermediate II -5)

By 400mg 4- amino -6- chlorine pyrimidines, the triazoles of 214mg (1.0equiv) 1,2,4-, 1.2g (1.2equiv) carbon Sour caesium adds flask, and 10mL N, N'- dimethylformamides make solvent, is warming up to 120 DEG C, reacts 12h.Suitable quantity of water is added, uses second Acetoacetic ester extracts, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent, residue silica gel column chromatography point under reduced pressure From purifying, ethanol/methylene=1/20 elutes, and obtains yellow solid 290mg, yield 58%.

¹H NMR (400MHz, DMSO) δ 9.32 (s, 1H), 8.37 (t, J=5.1Hz, 4H), 8.32 (s, 4H), 7.39 (s, 8H), 6.84 (d, J=0.9Hz, 5H)

Embodiment 6

The preparation of 6- (1H- benzos [d] imidazoles -1- bases) pyrimidine -4- amine (intermediate II -6)

By 200mg 4- amino -6- chlorine pyrimidines, 219mg (1.2equiv) benzimidazole, 604mg (1.2equiv) cesium carbonate Flask is added, 10mL N, N'- dimethylformamides make solvent, are warming up to 120 DEG C, react 12h.Suitable quantity of water is added, with acetic acid second Ester is extracted, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, and residue is separated pure with silica gel column chromatography Change, ethanol/methylene=1/20 elutes, and obtains light yellow solid 173mg, yield 53%.

¹H NMR (400MHz, DMSO) δ 8.89 (s, 1H), 8.45 (d, J=0.7Hz, 1H), 8.20 (t, J=7.7Hz, 1H), 7.87-7.69 (m, 1H), 7.47-7.30 (m, 2H), 7.24 (s, 2H), 6.82 (d, J=0.9Hz, 1H)

Embodiment 7

The preparation of 6- (pyrrolidin-1-yl) pyrimidine -4- amine (intermediate II -7)

By 400mg 4- amino -6- chlorine pyrimidines, 1.51g (1.5equiv) cesium carbonate adds flask, 10mL N, N'- diformazans Base formamide makees solvent, adds 507 μ L (2.0equiv) nafoxidines, is warming up to 100 DEG C, reacts 12h.Suitable quantity of water is added, is used Ethyl acetate extracts, and saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent, residue silica gel column chromatography under reduced pressure Isolate and purify, ethanol/methylene=1/50 elutes, and obtains yellow solid 274mg, yield 54%.

¹H NMR(400MHz,CDCl₃) δ 8.17 (s, 1H), 7.27 (s, 1H), 5.33 (d, J=18.2Hz, 1H), 4.63 (s,2H),3.42(s,4H),1.99(s,4H).

Embodiment 8

The preparation of 6- morpholine pyrimidine -4- amine (intermediate II -8)

By 400mg 4- amino -6- chlorine pyrimidines, 1.51g (1.5equiv) cesium carbonate adds flask, 10mL N, N'- diformazans Base formamide makees solvent, adds 405 μ L (1.5equiv) morpholines, is warming up to 100 DEG C, reacts 12h.Suitable quantity of water is added, uses acetic acid Ethyl ester extracts, and saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, residue is separated with silica gel column chromatography Purifying, ethanol/methylene=1/50 elute, and obtain yellow solid 245mg, yield 44%.

¹H NMR(400MHz,CDCl₃) δ 8.17 (d, J=16.6Hz, 1H), 7.27 (s, 1H), 5.53 (d, J=35.7Hz, 1H),4.78(s,2H),3.89–3.69(m,4H),3.65–3.40(m,4H).

Embodiment 9

The preparation of 6- (4- methylpiperazine-1-yls) pyrimidine -4- amine (intermediate II -9)

By 400mg 4- amino -6- chlorine pyrimidines, 1.51g (1.5equiv) cesium carbonate adds flask, 10mL N, N'- diformazans Base formamide makees solvent, adds 515 μ L (1.5equiv) N methyl piperazines, is warming up to 100 DEG C, reacts 12h.Add suitable quantity of water, It is extracted with ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent, residue silica gel column layer under reduced pressure Analysis isolates and purifies, and ethanol/methylene=1/30 elutes, and obtains yellow solid 382mg, yield 64%.

¹H NMR(400MHz,CDCl₃)δ8.19(s,1H),7.27(s,1H),5.58(s,1H),4.62(s,2H),3.61 (dd, J=16.5,11.5Hz, 4H), 2.59-2.44 (m, 4H), 2.35 (s, 3H)

Embodiment 10

The preparation of N4- benzyl pyrimidines -4,6- diamines (intermediate II -10)

By 400mg 4- amino -6- chlorine pyrimidines, 1.51g (1.5equiv) cesium carbonate adds flask, 10mL N, N'- diformazans Base formamide makees solvent, adds 506 μ L (1.5equiv) benzylamines, is warming up to 100 DEG C, reacts 12h.Suitable quantity of water is added, uses acetic acid Ethyl ester extracts, and saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, residue is separated with silica gel column chromatography Purifying, ethanol/methylene=1/40 elute, and obtain yellow solid 408mg, yield 66%.

¹H NMR(400MHz,CDCl₃) δ 8.12 (s, 1H), 7.33 (m, J=14.5,7.3Hz, 5H), 5.37 (s, 1H), 5.23 (br, 1H), 4.56 (br, 2H), 4.43 (d, J=5.8Hz, 2H)

Embodiment 11

The preparation of 6- (1H- imidazoles -1- bases) -2- methylpyrimidine -4- amine (intermediate II -11)

By 400mg 2- methyl -4,6- dichloro pyrimidines, 184mg (1.1equiv) imidazoles, 1.2g (1.2equiv) cesium carbonate Flask is added, 10mL N, N'- dimethylformamides make solvent, are warming up to 30 DEG C, react 16h.Suitable quantity of water is added, with acetic acid second Ester is extracted, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, and residue is separated pure with silica gel column chromatography Change, ethyl acetate/petroleum ether=1/2 elutes, and obtains white solid 365mg, i.e. intermediate 4- (1H- imidazoles -1- bases) chloro- 2- of -6- Methylpyrimidine.

365mg 4- (1H- imidazoles -1- bases) -6- chloro-2-methyl pyrimidines are added to tube sealing, add 6mL isopropanols and 10mL ammoniacal liquor, 100 DEG C are warming up to, react 34h.Remove solvent, residue silica gel column chromatography separating purification, methanol/bis- under reduced pressure Chloromethanes=1/10 elutes, and obtains yellow solid 270mg, and two step yields are 63%.

¹H NMR (400MHz, DMSO) δ 8.43 (s, 1H), 7.80 (s, 1H), 7.10 (d, J=8.8Hz, 3H), 6.41 (s, 1H),2.37(s,3H).

Embodiment 12

The preparation of 6- (1H- imidazoles -1- bases) -5- methylpyrimidine -4- amine (intermediate II -12)

By 400mg 5- methyl -4,6- dichloro pyrimidines, 184mg (1.1equiv) imidazoles, 1.2g (1.2equiv) cesium carbonate Flask is added, 10mL N, N'- dimethylformamides make solvent, are warming up to 30 DEG C, react 16h.Suitable quantity of water is added, with acetic acid second Ester is extracted, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, and residue is separated pure with silica gel column chromatography Change, ethyl acetate/petroleum ether=1/1 elutes, and obtains white solid 255mg, i.e. intermediate 4- (1H- imidazoles -1- bases) chloro- 5- of -6- Methylpyrimidine.

255mg 4- (1H- imidazoles -1- bases) chloro- 5- methylpyrimidines of -6- are added to tube sealing, add 4mL isopropanols and 7mL Ammoniacal liquor, 100 DEG C are warming up to, react 34h.Remove solvent, residue silica gel column chromatography separating purification, methanol/dichloromethane under reduced pressure Alkane=1/10 elutes, and obtains yellow solid 130mg, and two step yields are 30%.

¹H NMR (400MHz, DMSO) δ 8.22 (d, J=11.7Hz, 1H), 8.05 (s, 1H), 7.57 (d, J=13.2Hz, 1H), 7.16 (s, 2H), 7.09 (d, J=8.5Hz, 1H), 2.01 (s, 3H)

Embodiment 13

The preparation of 6- (2- methyl-1 H-imidazole-1-groups) pyrimidine -4- amine (intermediate II -13)

By 400mg 4- amino -6- chlorine pyrimidines, 279mg (1.1equiv) 2-methylimidazole, 1.2g (1.2equiv) carbonic acid Caesium adds flask, and 10mL N, N'- dimethylformamides make solvent, is warming up to 120 DEG C, reacts 18h.Suitable quantity of water is added, uses acetic acid Ethyl ester extracts, and saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, residue is separated with silica gel column chromatography Purifying, ethanol/methylene=1/30 elute, and obtain yellow solid 173mg, yield 32%.

¹H NMR (400MHz, DMSO) δ 8.36 (d, J=0.7Hz, 1H), 7.51 (d, J=1.5Hz, 1H), 7.20 (s, 2H), 6.90 (d, J=1.5Hz, 1H), 6.48 (d, J=0.9Hz, 1H), 2.52 (d, J=2.6Hz, 3H)

Embodiment 14

The preparation of 6- (2- ethyl -1H- imidazoles -1- bases) pyrimidine -4- amine (intermediate II -14)

By 400mg 4- amino -6- chlorine pyrimidines, 317mg (1.1equiv) 2- ethyl imidazol(e)s, 1.2g (1.2equiv) carbonic acid Caesium adds flask, and 10mL N, N'- dimethylformamides make solvent, is warming up to 120 DEG C, reacts 18h.Suitable quantity of water is added, uses acetic acid Ethyl ester extracts, and saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, residue is separated with silica gel column chromatography Purifying, ethanol/methylene=1/30 elute, and obtain yellow solid 105mg, yield 18%.

¹H NMR (400MHz, DMSO) δ 8.35 (t, J=6.6Hz, 1H), 7.48 (d, J=1.5Hz, 1H), 7.21 (s, 2H), 6.92 (d, J=1.5Hz, 1H), 6.46 (t, J=3.3Hz, 1H), 2.92 (q, J=7.5Hz, 2H), 1.35-1.06 (m, 3H).

Embodiment 15

The preparation of 6- (4- methyl-1 H-imidazole-1-groups) pyrimidine -4- amine (intermediate II -15)

By 200mg (1equiv) 4- amino -6- chlorine pyrimidines, 152mg (1.2equiv) 4-methylimidazole, 604mg (1.2equiv) cesium carbonate adds flask, and 10mL N, N'- dimethylformamides make solvent, is warming up to 120 DEG C, reacts 12h.Add Enter suitable quantity of water, be extracted with ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying, filtering, remove solvent, residue under reduced pressure With silica gel column chromatography separating purification, ethanol/methylene=1/20 elutes, and obtains yellow solid 176mg, yield 65%.

¹H NMR (400MHz, DMSO) δ 8.32 (d, J=1.1Hz, 1H), 8.29 (s, 1H), 7.50 (s, 1H), 7.14 (s, 2H), 6.48 (d, J=0.8Hz, 1H), 2.16 (s, 3H)

Embodiment 16

The preparation of 6- (the chloro- 1H- imidazoles -1- bases of 4-) pyrimidine -4- amine (intermediate II -16)

By 400mg 4- amino -6- chlorine pyrimidines, 317mg (1.0equiv) 4- chlorine imidazoles, 1.2g (1.2equiv) cesium carbonate Flask is added, 10mL N, N'- dimethylformamides make solvent, are warming up to 120 DEG C, react 12h.Suitable quantity of water is added, with acetic acid second Ester is extracted, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, and residue is separated pure with silica gel column chromatography Change, ethanol/methylene=1/20 elutes, and obtains yellow solid 368mg, yield 61%.

¹H NMR (400MHz, DMSO) δ 8.47 (dd, J=19.5,1.5Hz, 1H), 8.33 (d, J=0.6Hz, 1H), 7.98 (d, J=1.6Hz, 1H), 7.29 (s, 2H), 6.57 (d, J=0.9Hz, 1H)

Embodiment 17

The preparation of 6- (the bromo- 1H- imidazoles -1- bases of 4-) pyrimidine -4- amine (intermediate II -17)

By 300mg 4- amino -6- chlorine pyrimidines, 372mg (1.1equiv) 4- bromine imidazoles, 905mg (1.2equiv) cesium carbonate Flask is added, 10mL N, N'- dimethylformamides make solvent, are warming up to 120 DEG C, react 12h.Suitable quantity of water is added, with acetic acid second Ester is extracted, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, and residue is separated pure with silica gel column chromatography Change, ethanol/methylene=1/30 elutes, and obtains yellow solid 250mg, yield 45%.

¹H NMR (400MHz, DMSO) δ 8.45 (d, J=1.4Hz, 1H), 8.33 (s, 1H), 8.03 (d, J=1.4Hz, 1H),7.28(s,2H),6.58(s,1H).

Embodiment 18

The preparation of 6- (the iodo- 1H- imidazoles -1- bases of 4-) pyrimidine -4- amine (intermediate II -18)

By 300mg 4- amino -6- chlorine pyrimidines, 494mg (1.1equiv) 4- iodine imidazoles, 905mg (1.2equiv) cesium carbonate Flask is added, 10mL N, N'- dimethylformamides make solvent, are warming up to 120 DEG C, react 12h.Suitable quantity of water is added, with acetic acid second Ester is extracted, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, and residue is separated pure with silica gel column chromatography Change, ethanol/methylene=1/30 elutes, and obtains yellow solid 180mg, yield 27%.

¹H NMR (400MHz, DMSO) δ 8.40 (d, J=1.1Hz, 1H), 8.32 (s, 1H), 8.05 (d, J=1.1Hz, 1H),7.25(s,2H),6.56(s,1H).

Embodiment 19

The preparation of 6- (the chloro- 1H- imidazoles -1- bases of 4,5- bis-) pyrimidine -4- amine (intermediate II -19)

By 300mg 4- amino -6- chlorine pyrimidines, 347mg (1.1equiv) 4,5- dichloro-imidazoles, 905mg (1.2equiv) carbon Sour caesium adds flask, and 10mL N, N'- dimethylformamides make solvent, is warming up to 120 DEG C, reacts 12h.Suitable quantity of water is added, uses second Acetoacetic ester extracts, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent, residue silica gel column chromatography point under reduced pressure From purifying, ethanol/methylene=1/30 elutes, and obtains yellow solid 64mg, yield 12%.

¹H NMR (400MHz, DMSO) δ 8.41 (s, 1H), 8.29 (d, J=17.2Hz, 1H), 7.47 (s, 2H), 6.69 (s,1H).

Embodiment 20

The preparation of 6- (4- nitro -1H- imidazoles -1- bases) pyrimidine -4- amine (intermediate II -20)

By 1g 4- amino -6- chlorine pyrimidines, 1.05g (1.1equiv) 4- nitroimidazoles, 1.28g (1.2equiv) potassium carbonate Flask is added, 20mL N, N'- dimethylformamides make solvent, are warming up to 100 DEG C, react 12h.Suitable quantity of water is added, with acetic acid second Ester is extracted, saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, and residue is separated pure with silica gel column chromatography Change, ethanol/methylene=1/20 elutes, and obtains yellow solid 500mg, yield 31%.

¹H NMR (400MHz, DMSO) δ 8.99 (d, J=1.4Hz, 1H), 8.63 (d, J=1.4Hz, 1H), 8.40 (s, 1H), 8.32 (d, J=1.0Hz, 1H), 7.85 (s, 1H), 7.43 (s, 2H), 6.80 (s, 1H)

Embodiment 21

The preparation of 1- (6- aminopyrimidine -4- bases) -1H- imidazoles -4- formaldehyde (intermediate II -21)

By 500mg 4- amino -6- chlorine pyrimidines, 445mg (1.2equiv) pyrazoles 4- formaldehyde, 640mg (1.2equiv) carbonic acid Potassium adds flask, and 15mL N, N'- dimethylformamides make solvent, is warming up to 100 DEG C, reacts 12h.Suitable quantity of water is added, uses acetic acid Ethyl ester extracts, and saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent under reduced pressure, residue is separated with silica gel column chromatography Purifying, ethanol/methylene=1/30 elute, and obtain yellow solid 270mg, yield 37%.

¹H NMR (400MHz, DMSO) δ 9.86 (d, J=19.8Hz, 1H), 8.71 (s, 1H), 8.64 (s, 1H), 8.38 (s,1H),7.35(s,2H),6.72(s,1H).

Embodiment 22

The preparation of 6- (4- (trifluoromethyl) -1H- imidazoles -1- bases) pyrimidine -4- amine (intermediate II -22)

By 400mg 4- amino -6- chlorine pyrimidines, 462mg (1.1equiv) 4- trifluoromethyl imidazoles, 1.2g (1.2equiv) Cesium carbonate adds flask, and 10mL N, N'- dimethylformamides make solvent, is warming up to 100 DEG C, reacts 12h.Suitable quantity of water is added, is used Ethyl acetate extracts, and saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent, residue silica gel column chromatography under reduced pressure Isolate and purify, ethanol/methylene=1/20 elutes, and obtains yellow solid 219mg, yield 31%.

¹H NMR (400MHz, DMSO) δ 8.67 (d, J=19.8Hz, 1H), 8.52 (s, 1H), 8.38 (d, J=11.9Hz, 1H),7.34(s,2H),6.71(s,1H).

Embodiment 23

The preparation of 1- (6- aminopyrimidine -4- bases) -1H- imidazoles -4- methyl formates (intermediate II -23)

By 400mg 4- amino -6- chlorine pyrimidines, 428mg (1.1equiv) imidazoles 4- methyl formates, 512mg (1.2equiv) Potassium carbonate adds flask, and 10mL N, N'- dimethylformamides make solvent, is warming up to 120 DEG C, reacts 12h.Suitable quantity of water is added, is used Ethyl acetate extracts, and saturated common salt washing, anhydrous sodium sulfate drying, filtering, removes solvent, residue silica gel column chromatography under reduced pressure Isolate and purify, ethanol/methylene=1/20 elutes, and obtains yellow solid 142mg, yield 21%.

¹H NMR (400MHz, DMSO) δ 8.59 (d, J=28.8Hz, 1H), 8.49 (d, J=1.0Hz, 1H), 8.38 (d, J =16.0Hz, 1H), 7.33 (d, J=28.6Hz, 2H), 6.73 (s, 1H), 3.81 (d, J=11.8Hz, 2H)

Embodiment 24

The preparation of 1- methyl -3- (6- (1H- pyrazol-1-yls) pyrimidine-4-yl) thiocarbamide (compound I-1)

120mg 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II -1) is dissolved in 6mL N, N'- dimethyl formyls Amine, 40mg sodium hydrides are added, 5min is stirred at room temperature, then add methylisothiocyanate ester.Reaction 0.5h is stirred at room temperature, adds water sudden Go out reaction, there is solid precipitation, filter, dry to obtain sterling.Or be extracted with ethyl acetate, remove solvent, residue silica gel under reduced pressure Column chromatographic isolation and purification.Obtain white solid, 110mg, yield 63%.

mp 255-257℃；¹H NMR (400MHz, DMSO) δ 11.22 (d, J=4.4Hz, 1H), 11.16 (s, 1H), 8.72 (d, J=0.9Hz, 1H), 8.63 (d, J=2.6Hz, 1H), 7.94 (d, J=1.1Hz, 1H), 7.62 (d, J=0.9Hz, 1H), 6.64 (dd, J=2.7,1.6Hz, 1H), 3.12 (d, J=4.6Hz, 3H) .HRMS (EI) m/z calcd C₉H₁₀N₆S(M⁺) 234.0688,found 234.0687.

Embodiment 25

The preparation of 1- ethyls -3- (6- (1H- pyrazol-1-yls) pyrimidine-4-yl) thiocarbamide (compound I-2)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II - 1), ethyl isothiocyanate, it is white solid to obtain target product, yield 56%.

mp 201-203℃；¹H NMR (400MHz, DMSO) δ 11.30 (t, J=5.1Hz, 1H), 11.09 (s, 1H), 8.73 (t, J=7.5Hz, 1H), 8.63 (dd, J=2.7,0.5Hz, 1H), 7.94 (d, J=1.0Hz, 1H), 7.64 (d, J= 0.9Hz, 1H), 6.64 (dd, J=2.7,1.6Hz, 1H), 3.79-3.53 (m, 2H), 1.28-1.06 (m, 3H) .HRMS (EI) m/ z calcd C₁₀H₁₂N₆S(M⁺)248.0844,found 248.0845.

Embodiment 26

The preparation of 1- ethyls -3- (6- (1H- pyrazol-1-yls) pyrimidine-4-yl) urea (compound I-3)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II - 1), ethyl isocyanate, it is white solid to obtain target product, yield 58%.

mp 195-197℃；¹H NMR (400MHz, DMSO) δ 9.75 (s, 1H), 8.64 (s, 1H), 8.62 (d, J= 2.7Hz, 1H), 8.09 (s, 1H), 7.93 (d, J=19.3Hz, 1H), 7.49 (s, 1H), 6.62 (dd, J=2.6,1.6Hz, 1H), 3.20 (m, J=14.1,7.1Hz, 2H), 1.10 (t, J=7.2Hz, 2H) .HRMS (EI) m/z calcd C₁₀H₁₂N₆O(M⁺)232.1073,found 232.1074.

Embodiment 27

The preparation of 1- isopropyls -3- (6- (1H- pyrazol-1-yls) pyrimidine-4-yl) thiocarbamide (compound I-4)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II - 1), isopropyl thiocyanates, it is white solid to obtain target product, yield 79%.

mp 180-182℃；¹H NMR (400MHz, DMSO) δ 11.30 (d, J=7.5Hz, 1H), 11.07 (s, 1H), 8.75 (d, J=0.8Hz, 1H), 8.66-8.50 (m, 1H), 7.94 (d, J=1.0Hz, 1H), 7.64 (d, J=0.9Hz, 1H), 6.64 (dd, J=2.7,1.6Hz, 1H), 4.42 (dq, J=13.2,6.6Hz, 1H), 1.28 (d, J=6.6Hz, 6H) .HRMS (EI)m/z calcd C₁₁H₁₄N₆S(M⁺)262.1001,found 262.1002.

Embodiment 28

The preparation of the 1- tert-butyl groups -3- (6- (1H- pyrazol-1-yls) pyrimidine-4-yl) thiocarbamide (compound I-5)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II - 1), tert-butyl group isothiocyanates, it is white solid to obtain target product, yield 66%.

mp 148-151℃；¹H NMR(400MHz,DMSO)δ11.60(s,1H),10.86(s,1H),8.74(s,1H), 8.66-8.48 (m, 1H), 7.93 (t, J=7.6Hz, 1H), 7.62 (d, J=0.9Hz, 1H), 6.64 (dd, J=2.7,1.6Hz, 1H),1.56(s,8H).HRMS(EI)m/z calcd C₁₂H₁₆N₆S(M⁺)276.1157,found 276.1158.

Embodiment 29

The preparation of 1- cyclohexyl -3- (6- (1H- pyrazol-1-yls) pyrimidine-4-yl) thiocarbamide (compound I-6)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II - 1), cyclohexyl isothiocyanate, it is white solid to obtain target product, yield 86%.

mp 195-197℃；¹H NMR (400MHz, DMSO) δ 11.44 (d, J=7.7Hz, 1H), 11.08 (s, 1H), 8.76 (s, 1H), 8.63 (d, J=2.7Hz, 1H), 7.94 (d, J=1.0Hz, 1H), 7.64 (d, J=0.8Hz, 1H), 6.64 (dd, J=2.6,1.6Hz, 1H), 4.21 (s, 1H), 1.98 (m, J=8.6Hz, 2H), 1.69 (m, 2H), 1.56 (m, J= 6.0Hz,1H),1.49–1.22(m,5H).HRMS(EI)m/z calcd C₁₄H₁₈N₆S(M⁺)302.1314,found 302.1313.

Embodiment 30

The preparation of 1- (3- chlorphenyls) -3- (6- (1H- pyrazol-1-yls) pyrimidine-4-yl) thiocarbamide (compound I-7)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II - 1), 3- chlorophenyl isothiocyanates, it is white solid to obtain target product, yield 87%.

mp 191-194℃；¹H NMR (400MHz, DMSO) δ 13.50 (s, 1H), 11.52 (s, 1H), 8.83 (d, J= 24.3Hz, 1H), 8.64 (t, J=15.7Hz, 1H), 8.04-7.89 (m, 2H), 7.74 (s, 1H), 7.65 (d, J=8.2Hz, 1H), 7.46 (t, J=8.1Hz, 1H), 7.29 (dd, J=35.4,19.6Hz, 1H), 6.67 (dd, J=2.6,1.6Hz, 1H) .HRMS(EI)m/z calcd C₁₄H₁₁ClN₆S(M⁺)330.0454,found 330.0452.

Embodiment 31

The preparation of 1- (3- methoxyphenyls) -3- (6- (1H- pyrazoles l-1- yls) pyrimidine-4-yl) thiocarbamide (compound I-8)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II - 1), 3- methoxyphenyls isothiocyanates, it is white solid to obtain target product, yield 83%.

mp 166-168℃；¹H NMR(400MHz,DMSO)δ13.40(s,1H),11.42(s,1H),8.85(s,1H), 8.66 (t, J=4.0Hz, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.40-7.17 (m, 3H), 6.85 (d, J =7.2Hz, 1H), 6.71-6.57 (m, 2H), 3.81-3.76 (s, 3H) .HRMS (EI) m/z calcd C₁₅H₁₄N₆OS(M⁺) 326.0950,found 326.0951.

Embodiment 32

The preparation of 1- (3- cyano-phenyls) -3- (6- (1H- pyrazol-1-yls) pyrimidine-4-yl) thiocarbamide (compound I-9)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II - 1), 3- cyano-phenyls isothiocyanates, it is white solid to obtain target product, yield 79%.

mp 209-212℃；¹H NMR(400MHz,DMSO)δ13.56(s,1H),11.59(s,1H),8.85(s,1H), 8.67 (d, J=2.4Hz, 2H), 8.27-8.23 (m, 1H), 8.07 (dd, J=8.2,1.0Hz, 1H), 7.97 (d, J=1.0Hz, 1H),7.79–7.70(m,2H),7.68–7.59(m,1H),6.72–6.64(m,1H).HRMS(EI)m/z calcd C₁₅H₁₁N₇S (M⁺)321.0797,found 321.0799.

Embodiment 33

The preparation of 1- benzyls -3- (6- (1H- pyrazol-1-yls) pyrimidine-4-yl) thiocarbamide (compound I-10)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrazol-1-yls) pyrimidine -4- amine (intermediate II - 1), BITC, it is white solid to obtain target product, yield 76%.

mp 217-219℃；¹H NMR (400MHz, DMSO) δ 11.74 (t, J=5.5Hz, 1H), 11.28 (s, 1H), 8.71 (d, J=0.9Hz, 1H), 8.65-8.48 (m, 1H), 7.94 (t, J=8.4Hz, 1H), 7.67 (d, J=0.9Hz, 1H), 7.51-7.18 (m, 5H), 6.65-6.53 (m, 1H), 4.93 (d, J=5.6Hz, 2H) .HRMS (EI) m/z calcd C₁₅H₁₄N₆S (M⁺)310.1001,found 310.1002.

Embodiment 34

The preparation of 1- ethyls -3- (6- (1H- imidazoles l-1- yls) pyrimidine-4-yl) thiocarbamide (compound I-11)

Specific implementation step with embodiment 24, required raw material be 6- (1H- imidazoles -1- bases) pyrimidine -4- amine (intermediate II - 2), ethyl isothiocyanate, it is white solid to obtain target product, yield 79%.

mp 221-223℃；¹H NMR (400MHz, DMSO) δ 11.12 (d, J=54.2Hz, 1H), 10.98 (s, 1H), 8.77 (d, J=0.8Hz, 1H), 8.47 (d, J=15.4Hz, 1H), 7.75 (t, J=1.4Hz, 1H), 7.29 (t, J= 16.7Hz,1H),7.23–6.97(m,1H),3.76–3.56(m,1H),1.31–1.08(m,1H).HRMS(EI)m/z calcd C₁₀H₁₂N₆S(M⁺)248.0844,found 248.0845.

Embodiment 35

The preparation of 1- propyl group -3- (6- (1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-12)

Specific implementation step with embodiment 24, required raw material be 6- (1H- imidazoles -1- bases) pyrimidine -4- amine (intermediate II - 2), propyl group isothiocyanates, it is white solid to obtain target product, yield 77%.

mp 193-196℃；¹H NMR (400MHz, DMSO) δ 11.25 (t, J=5.1Hz, 1H), 10.99 (s, 1H), 8.78 (d, J=0.8Hz, 1H), 8.45 (s, 1H), 7.75 (t, J=1.4Hz, 1H), 7.32 (d, J=0.8Hz, 1H), 7.20 (s,1H),3.71–3.47(m,1H),1.76–1.56(m,1H),1.01–0.78(m,1H).HRMS(EI)m/z calcd C₁₁H₁₄N₆S(M⁺)262.1001,found 262.1003.

Embodiment 36

The preparation of 1- ethyls -3- (6- (1H- pyrroles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-13)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrroles -1- bases) pyrimidine -4- amine (intermediate II - 3), ethyl isothiocyanate, it is white solid to obtain target product, yield 90%.

mp 226-229℃；¹H NMR (400MHz, DMSO) δ 11.25 (t, J=5.0Hz, 1H), 10.81 (s, 1H), 8.69 (s, 1H), 7.58-7.44 (m, 2H), 7.24 (d, J=0.7Hz, 1H), 6.54-6.26 (m, 2H), 3.77-3.54 (m, 2H), 1.22 (t, J=7.2Hz, 3H) .HRMS (EI) m/z calcd C₁₁H₁₃N₅S(M⁺)247.0892,found 247.0892.

Embodiment 37

The preparation of 1- propyl group -3- (6- (1H- pyrroles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-14)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrroles -1- bases) pyrimidine -4- amine (intermediate II - 3), propyl group isothiocyanates, it is white solid to obtain target product, yield 86%.

mp 201-204℃；¹H NMR (400MHz, DMSO) δ 11.31 (t, J=5.1Hz, 1H), 10.83 (s, 1H), 8.70(s,1H),7.69–7.40(m,2H),7.24(s,1H),6.52–6.21(m,2H),3.64–3.42(m,2H),1.84– 1.54(m,2H),0.94(t,3H).HRMS(EI)m/z calcd C₁₂H₁₅N₅S(M⁺)261.1048,found 261.1047.

Embodiment 38

The preparation of 1- cyclohexyl -3- (6- (1H- pyrroles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-15)

Specific implementation step with embodiment 24, required raw material be 6- (1H- pyrroles -1- bases) pyrimidine -4- amine (intermediate II - 3), cyclohexyl isothiocyanate, it is white solid to obtain target product, yield 66%.

mp 213-215℃；¹H NMR(400MHz,Acetone)δ11.47(s,1H),9.62(s,1H),8.68(s, 2H),7.57(t,3H),7.25(s,2H),6.37(t,3H),4.44–4.15(m,2H),2.17–2.06(m,2H),1.85– 1.68 (m, 3H), 1.63 (dd, J=11.0,5.7Hz, 2H), 1.56-1.24 (m, 5H) .HRMS (EI) m/z calcd C₁₅H₁₉N₅S(M⁺)301.1361,found 301.1363.

Embodiment 39

The preparation of 1- ethyls -3- (6- (1H-1,2,3- triazole -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-16)

Specific implementation step with embodiment 24, required raw material be 6- (1H-1,2,3- triazole -1- bases) pyrimidine -4- amine (in Mesosome II-4), ethyl isothiocyanate, it is white solid to obtain target product, yield 71%.

mp 252-254℃；¹H NMR(400MHz,DMSO)δ11.26(s,1H),11.22(s,1H),9.17–8.77(m, 2H), 8.06 (d, J=1.0Hz, 1H), 7.88 (s, 1H), 3.90-3.48 (m, 2H), 1.24 (t, J=7.2Hz, 3H) .HRMS (EI)m/z calcd C₉H₁₁N₇S(M⁺)249.0797,found 249.0796.

Embodiment 40

The preparation of 1- ethyls -3- (6- (1H-1,2,4- triazole -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-17)

Specific implementation step with embodiment 24, required raw material be 6- (1H-1,2,4- triazole -1- bases) pyrimidine -4- amine (in Mesosome II-5), ethyl isothiocyanate, it is white solid to obtain target product, yield 55%.

mp 246-247℃；¹H NMR (400MHz, DMSO) δ 11.22 (d, J=10.9Hz, 1H), 9.45 (s, 1H), 8.81 (d, J=0.9Hz, 1H), 8.40 (s, 1H), 7.61 (d, J=0.9Hz, 1H), 3.76-3.56 (m, 1H), 1.23 (t, J= 7.2Hz,1H).HRMS(EI)m/z calcd C₉H₁₁N₇S(M⁺)249.0797,found 249.0796.

Embodiment 41

The preparation of 1- ethyls -3- (6- (1H- benzos [d] imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-18)

Specific implementation step with embodiment 24, required raw material be 6- (1H- benzos [d] imidazoles -1- bases) pyrimidine -4- amine (in Mesosome II-6), ethyl isothiocyanate, it is white solid to obtain target product, yield 64%.

mp 227-230℃；¹H NMR(400MHz,DMSO)δ11.21(s,1H),11.02(s,1H),8.92(s,1H), 8.86 (s, 1H), 8.17 (d, J=8.2Hz, 1H), 7.83 (d, J=7.8Hz, 1H), 7.64 (s, 1H), 7.56-7.09 (m, 3H), 3.81-3.55 (m, 2H), 1.25 (t, J=7.2Hz, 3H) .HRMS (EI) m/z calcd C₁₄H₁₄N₆S(M⁺) 298.1001,found 298.1002.

Embodiment 42

The preparation of 1- ethyls -3- (6- (pyrrolidin-1-yl) pyrimidine-4-yl) thiocarbamide (compound I-19)

Specific implementation step with embodiment 24, required raw material be 6- (pyrrolidin-1-yl) pyrimidine -4- amine (intermediate II - 7), ethyl isothiocyanate, it is white solid to obtain target product, yield 46%.

mp 194-196℃；¹H NMR (400MHz, DMSO) δ 11.57 (t, J=5.0Hz, 1H), 10.27 (s, 1H), 8.29 (d, J=38.6Hz, 1H), 6.06 (s, 1H), 3.73-3.53 (m, 2H), 3.53-2.99 (m, 4H), 1.96 (d, J= 24.4Hz,3H),1.24–1.06(m,3H).HRMS(EI)m/z calcd C₁₁H₁₇N₅S(M⁺)251.1205,found 251.1204.

Embodiment 43

The preparation of 1- ethyls -3- (6- morpholines pyrimidine-4-yl) thiocarbamide (compound I-20)

Specific implementation step is with embodiment 24, and required raw material is 6- morpholine pyrimidine -4- amine (intermediate II -8), the different sulphur of ethyl Cyanate, it is white solid to obtain target product, yield 52%.

mp 168-170℃；¹H NMR(400MHz,DMSO)δ11.46(s,1H),10.32(s,1H),8.31(s,1H), 6.35 (s, 1H), 3.71-3.64 (m, 3H), 3.64-3.53 (m, 2H), 3.52-3.42 (m, 3H), 1.19 (t, J=7.2Hz, 3H).HRMS(EI)m/z calcd C₁₁H₁₇N₅OS(M⁺)267.1154,found 267.1155.

Embodiment 43

The preparation of 1- ethyls -3- (6- (4- methyl piperidine -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-21)

For specific implementation step with embodiment 24, required raw material is 6- (4- methylpiperazine-1-yls) pyrimidine -4- amine (intermediates II-9), ethyl isothiocyanate, it is white solid to obtain target product, yield 48%.

mp 169-172℃；¹H NMR(400MHz,CDCl₃)δ11.52(s,1H),8.33(s,1H),8.27(s,1H), 5.79 (s, 1H), 3.82-3.71 (m, 2H), 3.71 (s, 4H), 2.55 (s, 3H), 2.40 (s, 3H), 1.32 (t, J=7.3Hz, 3H).HRMS(EI)m/z calcd C₁₂H₂₀N₆S(M⁺)280.1470,found 280.1473.

Embodiment 44

The preparation of 1- ethyls -3- (6- (benzyl amino) pyrimidine-4-yl) thiocarbamide (compound I-22)

Specific implementation step is with embodiment 24, and required raw material is N4- benzyl pyrimidines -4,6- diamines (intermediate II -10), second Base isothiocyanates, it is white solid to obtain target product, yield 71%.

mp 207-211℃；¹H NMR (400MHz, DMSO) δ 11.51 (t, J=5.0Hz, 1H), 10.33 (s, 1H), 8.19(s,1H),8.00(s,1H),7.59–6.98(m,5H),6.11(s,1H),4.46(s,2H),3.70–3.40(m,2H), 1.16 (t, J=7.1,2.8Hz, 3H) .HRMS (EI) m/z calcd C₁₄H₁₇N₅S(M⁺)287.1205,found 287.1206.

Embodiment 45

The preparation of 1- ethyls -3- (6- (1H- imidazoles -1- bases) -2- methylpyrimidine -4- bases) thiocarbamide (compound I-23)

Specific implementation step with embodiment 24, required raw material be 6- (1H- imidazoles -1- bases) -2- methylpyrimidine -4- amine (in Mesosome II-11), ethyl isothiocyanate, it is white solid to obtain target product, yield 50%.

mp 237-239℃；¹H NMR(400MHz,DMSO)δ11.33(s,1H),10.90(s,1H),8.41(s,1H), 7.73 (s, 1H), 7.18 (s, 1H), 7.13 (s, 1H), 3.75-3.51 (m, 2H), 2.59 (s, 2H), 1.25 (t, J=7.2Hz, 3H).HRMS(EI)m/z calcd C₁₁H₁₄N₆S(M⁺)262.1001,found 262.1002.

Embodiment 46

The preparation of 1- ethyls -3- (6- (1H- imidazoles -1- bases) -5- methylpyrimidine -4- bases) thiocarbamide (compound I-24)

Specific implementation step with embodiment 24, required raw material be 6- (1H- imidazoles -1- bases) -5- methylpyrimidine -4- amine (in Mesosome II-12), ethyl isothiocyanate, it is white solid to obtain target product, yield 55%.

mp 198-200℃；¹H NMR(400MHz,DMSO)δ11.37(s,1H),9.50(s,1H),8.71(s,1H), 8.14 (s, 1H), 7.63 (s, 1H), 7.14 (s, 1H), 3.79-3.48 (m, 2H), 2.26 (s, 3H), 1.23 (t, J=7.2Hz, 3H).HRMS(EI)m/z calcd C₁₁H₁₄N₆S(M⁺)262.1001,found 262.1002.

Embodiment 47

The preparation of 1- ethyls -3- (6- (2- methyl-1 H-imidazole-1-groups) pyrimidine-4-yl) thiocarbamide (compound I-25)

Specific implementation step with embodiment 24, required raw material be 6- (2- methyl-1 H-imidazole-1-groups) pyrimidine -4- amine (in Mesosome II-13), ethyl isothiocyanate, it is white solid to obtain target product, yield 60%.

mp 201-204℃；¹H NMR(400MHz,DMSO)δ11.29–11.04(m,1H),10.99(s,1H),8.80 (s, 1H), 7.60 (d, J=1.5Hz, 1H), 7.33 (s, 1H), 6.94 (t, J=17.7Hz, 1H), 3.77-3.55 (m, 2H), 2.58(s,3H),1.26–1.17(m,4H).HRMS(EI)m/z calcd C₁₁H₁₄N₆S(M⁺)262.1001,found 262.1002.

Embodiment 48

The preparation of 1- ethyls -3- (6- (2- ethyl -1H- pyrimidine -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-26)

Specific implementation step with embodiment 24, required raw material be 6- (2- ethyl -1H- imidazoles -1- bases) pyrimidine -4- amine (in Mesosome II-14), ethyl isothiocyanate, it is white solid to obtain target product, yield 60%.

mp 166-168℃；¹H NMR (400MHz, DMSO) δ 11.18 (t, J=5.1Hz, 1H), 11.01 (s, 1H), 8.80 (s, 1H), 7.56 (d, J=1.3Hz, 1H), 7.28 (s, 1H), 7.00 (d, J=1.3Hz, 1H), 3.73-3.50 (m, 2H), 2.96 (q, J=7.4Hz, 2H), 1.39-1.10 (m, 6H) .HRMS (EI) m/z calcd C₁₂H₁₆N₆S(M⁺) 276.1157,found 276.1158.

Embodiment 49

The preparation of 1- ethyls -3- (6- (4- methyl-1 H-imidazole-1-groups) pyrimidine-4-yl) thiocarbamide (compound I-27)

Specific implementation step with embodiment 24, required raw material be 6- (4- methyl-1 H-imidazole-1-groups) pyrimidine -4- amine (in Mesosome II-15), ethyl isothiocyanate, it is white solid to obtain target product, yield 54%.

mp 252-255℃；¹H NMR (400MHz, DMSO) δ 11.19 (s, 1H), 10.95 (s, 1H), 8.76 (d, J= 24.7Hz, 1H), 8.34 (d, J=0.7Hz, 1H), 7.38 (d, J=35.7Hz, 1H), 7.23 (s, 1H), 3.79-3.54 (m, 2H), 2.19 (s, 3H), 1.22 (t, J=7.2Hz, 3H) .HRMS (EI) m/z calcd C₁₁H₁₄N₆S(M⁺)262.1001, found 262.1001.

Embodiment 50

The preparation of 1- ethyls -3- (6- (the chloro- 1H- imidazoles -1- bases of 4-) pyrimidine-4-yl) thiocarbamide (compound I-28)

For specific implementation step with embodiment 24, required raw material is that 6- (the chloro- 1H- imidazoles -1- bases of 4-) pyrimidine -4- amine is (middle Body II-16), ethyl isothiocyanate, it is white solid to obtain target product, yield 62%.

mp 241-250℃；¹H NMR (400MHz, DMSO) δ 11.15 (s, 1H), 11.06 (s, 1H), 8.75 (t, J= 17.8Hz, 1H), 8.45 (d, J=1.5Hz, 1H), 7.89 (d, J=1.5Hz, 1H), 7.29 (d, J=0.7Hz, 1H), 3.81- 3.50 (m, 2H), 1.23 (t, J=7.2Hz, 3H) .HRMS (EI) m/z calcd C₁₀H₁₁ClN₆S(M⁺)282.0454,found 282.0459.

Embodiment 51

The preparation of 1- ethyls -3- (6- (the bromo- 1H- imidazoles -1- bases of 4-) pyrimidine-4-yl) thiocarbamide (compound I-29)

For specific implementation step with embodiment 24, required raw material is that 6- (the bromo- 1H- imidazoles -1- bases of 4-) pyrimidine -4- amine is (middle Body II-17), ethyl isothiocyanate, it is white solid to obtain target product, yield 58%.

mp 262-265℃；¹H NMR(400MHz,DMSO)δ11.15(s,1H),11.05(s,1H),8.78(s,1H), 8.45 (s, 1H), 7.93 (d, J=1.0Hz, 1H), 7.29 (s, 1H), 3.79-3.46 (m, 2H), 1.22 (t, J=7.2Hz, 3H).HRMS(EI)m/z calcd C₁₀H₁₁BrN₆S(M⁺)325.9949,found 325.9947.

Embodiment 52

The preparation of 1- ethyls -3- (6- (the iodo- 1H- imidazoles -1- bases of 4-) pyrimidine-4-yl) thiocarbamide (compound I-30)

For specific implementation step with embodiment 24, required raw material is that 6- (the iodo- 1H- imidazoles -1- bases of 4-) pyrimidine -4- amine is (middle Body II-18), ethyl isothiocyanate, it is white solid to obtain target product, yield 46%.

mp 268-270℃；¹H NMR (400MHz, DMSO) δ 11.15 (t, J=5.0Hz, 1H), 11.02 (s, 1H), 8.77 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.27 (s, 1H), 3.72-3.56 (m, 2H), 1.22 (t, J=7.2Hz, 3H).HRMS(EI)m/z calcd C₁₀H₁₁IN₆S(M⁺)373.9811,found 373.9812.

Embodiment 53

The preparation of 1- ethyls -3- (6- (the chloro- 1H- imidazoles -1- bases of 4,5- bis-) pyrimidine-4-yl) thiocarbamide (compound I-31)

For specific implementation step with embodiment 24, required raw material is 6- (4,5- bis- chloro- 1H- imidazoles -1- bases) pyrimidine -4- amine (intermediate II -19), ethyl isothiocyanate, it is white solid to obtain target product, yield 66%.

mp 258-260℃；¹H NMR(400MHz,DMSO)δ11.26(s,1H),11.12(s,1H),8.86(s,1H), 8.45(s,1H),7.60(s,1H),3.80–3.53(m,2H),1.25(t,3H).HRMS(EI)m/z calcd C₁₀H₁₀Cl₂N₆S (M⁺)316.0065,found 316.0060.

Embodiment 54

The preparation of 1- ethyls -3- (6- (4- nitro -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-32)

Specific implementation step with embodiment 24, required raw material be 6- (4- nitro -1H- imidazoles -1- bases) pyrimidine -4- amine (in Mesosome II-20), ethyl isothiocyanate, it is white solid to obtain target product, yield 36%.

mp 243-244℃；¹H NMR(400MHz,DMSO)δ11.16(s,1H),11.12(s,1H),8.86(s,2H), 8.62 (s, 1H), 7.47 (s, 1H), 3.78-3.50 (m, 2H), 1.23 (t, J=7.1Hz, 3H) .HRMS (EI) m/z calcd C₁₀H₁₁N₇O₂S(M⁺)293.0695,found 293.0696.

Embodiment 55

The preparation of 1- ethyls -3- (6- (4- acyls methyl-1 H-imidazole-1-group) pyrimidine-4-yl) thiocarbamide (compound I-33)

For specific implementation step with embodiment 24, required raw material is 1- (6- aminopyrimidine -4- bases) -1H- imidazoles -4- formaldehyde (intermediate II -21), ethyl isothiocyanate, it is white solid to obtain target product, yield 38%.

mp 212-213℃；¹H NMR (400MHz, DMSO) δ 11.14 (t, J=5.1Hz, 1H), 11.10 (s, 1H), 9.88 (s, 1H), 8.83 (s, 1H), 8.62 (s, 2H), 7.43 (s, 1H), 3.72-3.57 (m, 2H), 1.23 (t, J=7.2Hz, 3H).HRMS(EI)m/z calcd C₁₁H₁₂N₆OS(M⁺)276.0793,found 276.0795.

Embodiment 56

The preparation of 1- ethyls -3- (6- (4- (methylol) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-34)

1- ethyls -3- (6- (4- acyls methyl-1 H-imidazole-1-group) pyrimidine-4-yl) thiocarbamide (compound I-33) is added to Flask, answer methanol：Dichloromethane=1:1 makees solvent, adds sodium borohydride, and reaction 6h is stirred at room temperature, removes solvent under reduced pressure, remains Thing silica gel column chromatography separating purification, the elution of ethanol/methylene=1/20, it is white solid to obtain target product, yield 55%.

mp 238-240℃；¹H NMR (400MHz, DMSO) δ 11.19 (t, J=5.0Hz, 1H), 10.93 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.52 (s, 1H), 7.27 (s, 1H), 5.13 (t, J=5.7Hz, 1H), 4.43 (d, J= 5.6Hz,2H),3.75–3.50(m,2H),1.31–1.14(m,3H).HRMS(EI)m/z calcd C₁₁H₁₄N₆OS(M⁺) 278.0950,found 287.0952.

Embodiment 57

The system of 1- ethyls -3- (6- (4- (trifluoromethyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-35) It is standby

For specific implementation step with embodiment 24, required raw material is 6- (4- (trifluoromethyl) -1H- imidazoles -1- bases) pyrimidine -4- Amine (intermediate II -22), ethyl isothiocyanate, it is white solid to obtain target product, yield 45%.

mp 262-264℃；¹H NMR (400MHz, DMSO) δ 11.14 (t, J=5.1Hz, 1H), 11.08 (s, 1H), 8.83(s,1H),8.63(s,1H),8.42(s,1H),7.41(s,1H),3.75–3.51(m,2H),1.37–1.13(m,3H) .HRMS(EI)m/z calcd C₁₁H₁₁F₃N₆S(M⁺)316.0718,found 306.0721.

Embodiment 58

The preparation of 1- (6- (3- ethyl thioureas) pyrimidine -4-yl) -1H- imidazoles -4- methyl formates (compound I-36)

For specific implementation step with embodiment 24, required raw material is 1- (6- aminopyrimidine -4- bases) -1H- imidazoles -4- formic acid first Ester (intermediate II -23), ethyl isothiocyanate, it is white solid to obtain target product, yield 50%.

mp 240-243℃；¹H NMR (400MHz, DMSO) δ 11.15 (d, J=5.4Hz, 1H), 11.04 (s, 1H), 8.82 (s, 1H), 8.54 (d, J=1.2Hz, 1H), 8.36 (d, J=1.2Hz, 1H), 7.40 (s, 1H), 3.82 (s, 3H), 3.72-3.55 (m, 2H), 1.23 (t, J=7.2Hz, 3H) .HRMS (EI) m/z calcd C₁₂H₁₄N₆O₂S(M⁺)306.0899, found 306.0900.

Embodiment 59

1- ethyls -3- (6- (4- ((methylamino) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-37) Preparation

By 100mg 1- ethyls -3- (6- (4- acyls methyl-1 H-imidazole-1-group) pyrimidine-4-yl) thiocarbamide (compound I-33) Flask is added to, with methanol：Dichloromethane=1:1 is solvent, adds the ethanol solution (30-33% of 72 μ L (1.5equiv) methylamines Wt%), 7 μ L (1.0equiv) acetic acid, appropriate anhydrous sodium sulfate are added.It is stirred at room temperature and adds 34.2mg (1.5equiv) in a moment Sodium cyanoborohydride.30 DEG C of reactions are overnight.Reaction solution is evaporated, adds water, ethyl acetate extraction, saturated common salt washing, anhydrous sulphur Sour sodium is dried, and filtering, removes solvent under reduced pressure, and residue is purified with silica gel column chromatography, and ethanol/methylene=1/5 elutes, and obtains yellow Color solid 46mg, yield 42%.

mp 114-117℃；¹H NMR(400MHz,DMSO)δ11.19(s,1H),8.85–8.69(m,1H),8.59– 8.36(m,1H),7.66(s,1H),7.33–7.22(m,1H),3.77(s,2H),3.70–3.57(m,3H),2.40(s,3H), 1.22 (t, J=7.1Hz, 3H) .HRMS (EI) m/z calcd C₁₂H₁₇N₇S(M⁺)291.1266,found 291.1267.

Embodiment 60

1- ethyls -3- (6- (4- ((ethylamino) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-38) Preparation

Specific implementation step is ethamine with embodiment 59, required fatty amine, and it is yellow solid to obtain target product, yield 50%.

mp 105-108℃；¹H NMR (400MHz, DMSO) δ 11.20 (t, J=5.0Hz, 1H), 8.77 (d, J= 15.5Hz,1H),8.53–8.32(m,1H),7.59(s,1H),7.39–7.23(m,1H),3.71(s,2H),3.68–3.59(m, 3H), 2.70-2.58 (m, 2H), 1.23 (t, J=7.1Hz, 3H), 1.13-1.02 (m, 3H) .HRMS (EI) m/z calcd C₁₃H₁₉N₇S(M⁺)305.1423,found 305.1424.

Embodiment 61

1- ethyls -3- (6- (4- ((benzyl amino) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-39) Preparation

Specific implementation step is benzylamine with embodiment 59, required fatty amine, and it is yellow solid to obtain target product, yield 66%.

mp 182-185℃；¹H NMR(400MHz,CDCl₃)δ11.28(s,1H),9.72(s,1H),8.63(s,1H), 8.42 (d, J=20.8Hz, 1H), 7.48 (s, 1H), 7.42-7.30 (m, 4H), 7.25 (d, J=10.7Hz, 2H), 6.82 (s, 1H), 3.89 (s, 2H), 3.84 (s, 2H), 3.81-3.73 (m, 2H), 1.36 (t, J=7.3Hz, 3H) .HRMS (ESI) m/z calcd C₁₈H₂₁N₇S(M⁺+H)368.1657,found 368.1659.

Embodiment 62

1- ethyls -3- (6- (4- ((Cyclohexylamino) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I- 40) preparation

Specific implementation step is cyclo-hexylamine with embodiment 59, required fatty amine, and it is yellow solid to obtain target product, Yield 38%.

mp 171-174℃；¹H NMR (400MHz, DMSO) δ 11.19 (t, J=5.0Hz, 1H), 8.75 (s, 1H), 8.38 (d, J=13.9Hz, 1H), 7.44 (d, J=108.6Hz, 1H), 7.28 (s, 1H), 3.70 (d, J=20.8Hz, 2H), 3.69- 3.58 (m, 2H), 1.87 (d, J=11.5Hz, 2H), 1.75-1.63 (m, 2H), 1.56 (d, J=10.4Hz, 1H), 1.30- 0.98(m,9H).HRMS(ESI)m/z calcd C₁₇H₂₅N₇S(M⁺)359.1892,found 360.1973.

Embodiment 63

1- ethyls -3- (6- (4- ((benzyl (methyl) amino) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (is changed Compound I-41) preparation

Specific implementation step is N- methylbenzylamines with embodiment 59, required fatty amine, obtains target product and consolidates for yellow Body, yield 54%.

mp 153-155℃；¹H NMR(400MHz,DMSO)δ11.19(s,1H),10.92(s,1H),8.76(s,1H), 8.40 (s, 1H), 7.58 (s, 1H), 7.45-7.29 (m, 3H), 7.26 (d, J=6.4Hz, 1H), 3.64 (dt, J=13.8, 7.0Hz, 2H), 3.56 (s, 1H), 3.53 (s, 1H), 2.16 (s, 3H), 1.23 (t, J=7.2Hz, 3H) .HRMS (ESI) m/z calcd C₁₉H₂₃N₇S(M⁺+H)382.1814,found 382.1813.

Embodiment 64

1- ethyls -3- (6- (4- ((dimethylamino) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I- 42) preparation

Specific implementation step is dimethylamine with embodiment 59, required fatty amine, and it is yellow solid to obtain target product, is received Rate 40%.

mp 181-183℃；1H NMR (400MHz, DMSO) δ 11.17 (t, J=5.2Hz, 1H), 11.02 (s, 1H), 8.79(s,1H),8.52(s,1H),7.82(s,1H),7.33(s,1H),3.99(s,1H),3.72–3.58(m,1H),2.57 (s,6H),1.30–1.16(m,3H).HRMS(EI)m/z calcd C₁₃H₁₉N₇S(M⁺)305.1423,found 305.1425.

Embodiment 65

1- ethyls -3- (6- (4- ((lignocaine) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I- 43) preparation

Specific implementation step is diethylamine with embodiment 59, required fatty amine, and it is yellow solid to obtain target product, is received Rate 65%.

mp 152-155℃；¹H NMR (400MHz, DMSO) δ 11.17 (t, J=5.3Hz, 1H), 10.92 (s, 1H), 8.76(s,1H),8.41(s,1H),7.63(s,1H),7.31(s,1H),3.72(s,2H),3.68–3.54(m,2H),2.63 (s, 4H), 1.24 (t, J=7.1Hz, 3H), 1.07 (t, J=6.7Hz, 6H) .HRMS (EI) m/z calcd C₁₅H₂₃N₇S(M⁺) 333.1736,found 333.1738.

Embodiment 66

1- ethyls -3- (6- (4- ((dipropyl amino) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I- 44) preparation

Specific implementation step is di-n-propylamine with embodiment 59, required fatty amine, and it is yellow solid to obtain target product, is received Rate 45%.

mp 158-161℃；¹H NMR(400MHz,CDCl₃)δ11.32(s,1H),9.93(s,1H),8.65(s,1H), 8.40(s,1H),7.51(s,1H),6.96(s,1H),3.91–3.73(m,2H),3.69(s,2H),2.57–2.44(m,4H), 1.63-1.48 (m, 4H), 1.38 (t, J=7.3Hz, 3H), 0.90 (t, J=7.3Hz, 6H) .HRMS (EI) m/z calcd C₁₇H₂₇N₇S(M⁺)361.2049,found 361.2050.

Embodiment 67

1- ethyls -3- (6- (4- (pyrrolidin-1-yl methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I- 45) preparation

Specific implementation step is nafoxidine with embodiment 59, required fatty amine, and it is yellow solid to obtain target product, Yield 76%.

mp 179-180℃；¹H NMR (400MHz, DMSO) δ 11.18 (t, J=5.2Hz, 1H), 10.92 (s, 1H), 8.75(s,1H),8.39(s,1H),7.58(s,1H),7.29(s,1H),3.72–3.58(m,4H),2.60(s,4H),1.71 (s, 4H), 1.23 (t, J=7.2Hz, 3H) .HRMS (EI) m/z calcd C₁₅H₂₁N₇S(M⁺)331.1579,found 331.1581.

Embodiment 68

1- ethyls -3- (6- (4- (piperidin-1-yl methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I- 46) preparation

Specific implementation step is piperidines with embodiment 59, required fatty amine, and it is yellow solid to obtain target product, yield 54%.

mp 156-159℃；¹H NMR (400MHz, DMSO) δ 11.19 (t, J=5.0Hz, 1H), 10.97 (s, 1H), 8.76 (s, 1H), 8.41 (s, 1H), 7.62 (s, 1H), 7.30 (s, 1H), 3.73-3.60 (m, 2H), 3.52 (d, J=41.2Hz, 2H), 2.61 (d, J=52.6Hz, 4H), 1.54 (s, 4H), 1.40 (s, 2H), 1.23 (t, J=7.1Hz, 3H) .HRMS (EI) m/ z calcd C₁₆H₂₃N₇S(M⁺)345.1736,found 345.1738.

Embodiment 69

1- ethyls -3- (6- (4- (hexamethylene imido -1- ylmethyls) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-47 preparation)

Specific implementation step is cycloheximide with embodiment 59, required fatty amine, and it is yellow solid to obtain target product, Yield 40%.

mp 141-144℃；¹H NMR(400MHz,CDCl₃)δ11.27(s,1H),9.74(s,1H),8.64(s,1H), 8.43(s,1H),7.78(s,1H),7.12(s,1H),3.90(s,2H),3.86–3.72(m,2H),3.00–2.89(m,4H), 1.78(s,4H),1.66(s,4H),1.40–1.31(m,3H).HRMS(EI)m/z calcd C₁₇H₂₅N₇S(M⁺)359.1892, found 359.1893.

Embodiment 70

The system of 1- ethyls -3- (6- (4- (morpholine methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (compound I-48) It is standby

Specific implementation step is morpholine with embodiment 59, required fatty amine, and it is yellow solid to obtain target product, yield 56%.

mp 188-190℃；¹H NMR(400MHz,CDCl₃)δ11.24(s,1H),9.46(s,1H),8.65(s,1H), 8.42 (s, 1H), 7.69 (s, 1H), 6.97 (s, 1H), 3.91-3.62 (m, 8H), 2.75 (s, 4H), 1.37 (t, J=7.3Hz, 3H).HRMS(EI)m/z calcd C₁₅H₂₁N₇OS(M⁺)347.1528,found 347.1515.

Embodiment 72

1- ethyls -3- (6- (4- ((4- methylpiperazine-1-yls) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) thiocarbamide (is changed Compound I-49) preparation

Specific implementation step is N methyl piperazine with embodiment 59, required fatty amine, obtains target product and consolidates for yellow Body, yield 32%.

mp 178-179℃；¹H NMR (400MHz, DMSO) δ 11.19 (t, J=5.3Hz, 1H), 10.94 (s, 1H), 8.75(s,1H),8.38(s,1H),7.55(s,1H),7.29(s,1H),3.75–3.56(m,2H),3.46(s,2H),3.41– 3.21 (m, 4H), 2.48-2.30 (m, 4H), 2.21 (s, 3H), 1.23 (t, J=7.2Hz, 3H) .HRMS (EI) m/z calcd C₁₆H₂₄N₈S(M⁺)360.1845,found 360.1847.

Embodiment 73

(R) -1- ethyls -3- (6- (4- ((2- methylpyrrolidin- 1- yls) methyl) -1- imidazoles -1- bases) pyrimidine-4-yl) sulphur The preparation of urea (compound I-50)

Specific implementation step is (R) -2- crassitudes with embodiment 59, required fatty amine, and obtaining target product is Yellow solid, yield 60%.

mp 151-154℃；¹H NMR (400MHz, DMSO) δ 11.19 (t, J=5.1Hz, 1H), 10.93 (s, 1H), 8.76 (s, 1H), 8.40 (s, 1H), 7.59 (s, 1H), 7.30 (s, 1H), 3.93 (d, J=11.6Hz, 1H), 3.76-3.57 (m, 2H), 3.02 (s, 1H), 2.37 (s, 1H), 1.91 (s, 1H), 1.64 (s, 2H), 1.32 (d, J=20.3Hz, 1H), 1.23 (t, J =7.1Hz, 3H), 1.18-1.08 (m, 3H) .HRMS (ESI) m/z calcd C₁₆H₂₃N₇S(M⁺+H)346.1814,found 346.1815.

Embodiment 74

(R) -1- ethyls -3- (6- (4- ((3- fluoropyrrolidine -1- bases) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) sulphur The preparation of urea (compound I-51)

Specific implementation step is (R) -3- fluoropyrrolidines with embodiment 59, required fatty amine, obtains target product as Huang Color solid, yield 58%.

mp 150-153℃；¹H NMR (400MHz, DMSO) δ 11.18 (t, J=5.2Hz, 1H), 10.96 (d, J= 11.2Hz, 1H), 8.76 (s, 1H), 8.42 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H), 5.27 (dt, J=55.2,5.1Hz, 1H), 3.84 (s, 2H), 3.74-3.58 (m, 2H), 3.21-2.86 (m, 3H), 2.72 (dd, J=14.6,8.3Hz, 1H), 2.18 (dtd, J=29.3,14.5,6.7Hz, 1H), 2.07-1.85 (m, 1H), 1.23 (t, J=7.2Hz, 3H) .HRMS (ESI) m/z calcd C₁₅H₂₁FN₇S(M⁺)426.0223,found 426.0216.

Embodiment 75

(R) -1- ethyls -3- (6- (4- ((3- hydroxyl pyrrolidine -1- bases) methyl) -1H- imidazoles -1- bases) pyrimidine-4-yl) The preparation of thiocarbamide (compound I-52)

Specific implementation step is (R) -3- hydroxyl pyrrolidines with embodiment 59, required fatty amine, and obtaining target product is Yellow solid, yield 46%.

mp 158-161℃；¹H NMR(400MHz,CDCl₃) δ 11.21 (t, J=5.1Hz, 1H), 9.55 (s, 1H), 8.63 (d, J=18.7Hz, 1H), 8.50 (s, 1H), 7.86 (s, 1H), 7.09 (s, 1H), 4.56 (s, 1H), 4.04 (s, 2H), 3.84- 3.65(m,2H),3.53–3.35(m,1H),3.36–3.24(m,1H),3.11–2.94(m,2H),2.35–2.18(m,1H), 2.07-1.92 (m, 2H), 1.35 (t, J=7.2Hz, 3H) .HRMS (EI) m/z calcd C₁₅H₂₁N₇OS(M⁺+H)347.1528, found 347.1527.

Embodiment 76

The compound of the present invention is to the activity suppression experiment of acetylcholinesterase (AChE) and Activity Results.

Acetylcholinesterasein measure is slightly changed with reference to Ellman methods：Substituted urea class chemical combination of the present invention to synthesis Thing, rat layer proenzyme is chosen as acetylcholinesterase proenzyme, H is added in 96 orifice plates₂The μ l of 109 μ l, 0.1M PB of O 50, 2mM S-Ach 30 μ l, DTNB 0.2%50 μ l, the μ l of testing compound 1, terminate liquid SDS 3% is added after reacting at room temperature 20min 50 μ l, OD450nm is read, calculate compound to AChE vigor inhibitory action.Activity data is as shown in table 1, and discovery has 1 chemical combination The activity data of thing (I-45) is better than having listed anti-AD medicines huperzine (Hup A) at home.

Table 1：Inhibitory activity data of the substituted pyrimidines carbamide compounds to acetylcholinesterase

In table 1, Hup A are huperzine (as tester, similarly hereinafter)

As can be seen from Table 1, the substitute urea compound with general structure I of the invention is with preferable acetylcholine Esterase inhibition activity, which part compound have listed anti-AD medicines huperzine (Hup A) with quite even better than domestic, The anti-AD medicines of anticholinesterase class can be developed into by illustrating the compound of the present invention.

Embodiment 77

The compound of the present invention is to the activity suppression experiment of butyrylcholine esterase (BuChE) and Activity Results.

The present invention chooses 13 to the preferable compound of AChE inhibitory activity, with big to the substitute urea compound of synthesis The butyrylcholine esterase of mouse serum proenzyme adds H as proenzyme in 96 orifice plates₂99 μ l, 0.1M PB of O 50 μ l, 2mM S- Buch 40 μ l, DTNB 0.2%50 μ l, the μ l of testing compound 1, the μ l of terminate liquid SDS 3%50 are added after reacting at room temperature 20min, OD450nm is read, calculates compound to BuChE vigor inhibitory action.Activity data is as shown in table 2, finds majority of compounds The inhibitory activity of butyrylcholine esterase will be weaker than and listed anti-AD medicines huperzine (Hup A) at home.

Table 2：Inhibitory activity data and selectivity of the substituted pyrimidines carbamide compounds to butyrylcholine esterase

As can be seen from Table 2, suppression of the substitute urea compound with general structure I of the invention to butyrylcholine esterase System activity is poor, and which part compound will be weaker than to butyrylcholine esterase inhibitory activity has listed anti-AD medicines stone China fir at home Alkali first, so that the compounds of this invention has preferable acetylcholine ester enzyme selectivity, illustrating the compound of the present invention can send out Open up as the anti-AD medicines of selective anticholinesterase class.

Embodiment 77

The present invention substituted pyrimidines carbamide compounds there is chelation to metal ion, be a kind of new construction metal from Sub- chelating agent.

The substituted pyrimidines carbamide compounds of the present invention, by taking the best compound I-45 of cholinesterase activity as an example, report should The chelation of class compound and metal ion, while using the compound after I-45 removal thiocarbamide structures as negative control (negative control, NC), using the metal ion chelation agent CQ reported as positive control, with UV absorption spectrophotometric Measurement quantifies compound and changed with the UV absorption after metal mixed, to investigate whether compound has chelation with metal ion.

For water-soluble preferable compound I-45 and NC using HEPES buffer salts as medium, solution compound method is as follows：

20mM pH 7.4HEPES (150mM NaCl) buffer preparation：Weigh hepes 2.383g, NaCl 4.383g Add ultra-pure water and be settled to 500mL, it is 7.4 to adjust PH with a small amount of NaOH solution.

Metal ion solution is prepared：Weigh a certain amount of CuSO₄、FeSO₄And ZnCl₂Being formulated into concentration with ultra-pure water is 10mM.Then 400 μM are diluted to 20mM HEPES cushioning liquid again.

Compound solution is prepared：Weigh a certain amount of compound and be formulated into 10mM with DMSO.Then delayed again with 20mM HEPES Rush solution and be diluted to 50 μM.

Then compound and CuSO are investigated₄、FeSO₄、FeCl₃And ZnCl₂Interaction, take 5 2mL centrifuge tubes, often manage Add 150 μ L HEPES cushioning liquid and 50 μM of 800 μ L compound solution, then be separately added into 50 μ L, 400 μM of CuSO₄、 FeSO₄、FeCl₃And ZnCl₂Solution and 50 μ L HEPES cushioning liquid.Blank is that 4 μ L DMSO solutions add 996 μ L HEPES to buffer Solutions Solution.1h is placed after mixing at room temperature, English ware is poured into and surveys its absorption in 200-500nm, it is each to survey three times, it is averaged Value.

For water-soluble bad CQ, using ethanol as medium, method is as follows：

Weigh a certain amount of CQ to be dissolved with DMSO, be then diluted to 400 μM with ethanol.5 2mL centrifuge tubes are taken, often pipe plus 700 The compound solution of 400 μM of μ L ethanol and 100 μ L, then it is separately added into 200 μ L, 200 μM of CuSO₄、FeSO₄、FeCl₃And ZnCl₂ Solution and 200 μ L ethanol.Blank is that 4 μ L DMSO solutions add 996 μ L ethanol solutions.30min is placed after mixing at room temperature, is fallen Enter silica dish and survey its absorption in 200-500nm, it is each to survey three times, average.

Experimental result is shown in Fig. 1.

As seen from Figure 1, compound of the invention selectively chelating Cu²⁺, and and Fe²⁺、Fe³⁺、Zn²⁺Work is not chelated With.By compared with Fig. 1 (B) negative control, it can be deduced that conclusion, substitute urea compound and Cu of the invention²⁺Chelating Crucial group is (sulphur) urea structure, and after (sulphur) urea fragment is removed (NC), compound will no longer have that metal ion-chelant is made With.Fig. 1 (C) CQ is the metal ion chelation agent reported, has chelation with various metals ion.So present invention Substituted pyrimidines carbamide compounds be a kind of selective Cu²⁺Chelating agent.

Embodiment 78

The substituted pyrimidines carbamide compounds of the present invention are metal ion chelation agent, have the work for suppressing to be induced by metal ion The caused ability of free love base (ROS).

Substituted pyrimidines carbamide compounds of the present invention are tested to the inhibitory action of free radical caused by Cu (I/II), with cholinester Exemplified by the best compound I-45 of enzymatic activity, using the metal ion chelation agent EDTA reported as positive control, experimental method is such as Under：

The preparation of solution：

(1), the phosphate buffer solutions of 20mM pH 7.4 (150mM NaCl) are prepared：Weigh KH₂PO₄1.09g, 2.383g, NaCl 2.34g add ultra-pure water and are settled to 400mL, and it is 7.4 to adjust PH with a small amount of NaOH solution.

(2), the phosphate buffer solutions of 20mM pH 9.0 (150mM NaCl) are prepared：Weigh KH₂PO₄1.09g, 2.383g, NaCl 2.34g add ultra-pure water and are settled to 400mL, and it is 9.0 to adjust pH with a small amount of NaOH solution.

(3), 1mM deferoxamine mesylates solution is prepared：Weigh 65.7mg deferoxamine mesylate 100.0mL 20mM pH 7.4 phosphate buffer solutions dissolve, -20 DEG C of preservations.During test 20 μM are diluted to the phosphate buffer solutions of 20mM pH 7.4.

(4), 5mM coumarin-3-carboxy acids solution is prepared：19.0mg coumarin-3-carboxy acids are weighed with 20.0mL 20mM pH 9.0 phosphate buffer solutions dissolve, then adjust pH to 7.4, -20 DEG C of preservation.Diluted during test with the phosphate buffer solutions of 20mM pH 7.4 To 500 μM.

(5), 10mM ascorbic acid solutions prepare (now with the current)：Weigh 17.6mg ascorbic acid solutions 10.0mL The phosphate buffer solutions of 20mM pH 7.4 dissolve.Then 300 μM are diluted to the phosphate buffer solutions of 20mM pH 7.4 again.

(6), metal ion solution is prepared：Weigh a certain amount of CuSO₄It is 10mM to be formulated into concentration with ultra-pure water.Then again 100 μM are diluted to the phosphate buffer solutions of 20mM pH 7.4.

(7), compound solution is prepared：Weigh a certain amount of compound and be formulated into 5mM with methanol.Then 20mM pH are used again 7.4 phosphate buffer solutions are diluted to 50 μM.

6 holes are chosen in 96 hole blackboards, are sequentially added into 60 μ L, 50 μM of compounds (or 60 μ L 20mM pH 7.4 Phosphate buffer solution), 10 100 μM of μ L CuSO₄Solution, 10 20 μM of μ L deferoxamine mesylate solution, 20 500 μM of μ L tonka-beans Element -3- carboxylic acid solutions, it is then quickly added into 300 μM of 100 μ L, 37 DEG C of ascorbic acid solutions and triggers radical reaction, with excitation wave Long 390nm, launch wavelength 450nm record first order fluorescence value every 30s, record 40min altogether, replace compound to make with 20 μ L bufferings For blank.Per Kong Junhan methanol 0.1%.Experimental result is shown in Fig. 2.

As seen from Figure 2, substituted pyrimidines carbamide compounds of the present invention have the free radical production for suppressing metal ion induction Raw ability, the compounds of this invention a kind of multi-functional anti-AD medicines because dependent interaction can develop into.

Embodiment 79

Substituted pyrimidines carbamide compounds of the present invention have chelation of metal ion, can suppress by metal ion induction The aggregation of amyloid-beta (A β).

Substituted pyrimidines carbamide compounds of the present invention can suppress Cu²⁺A beta peptide aggregations are induced, with the best change of cholinesterase activity Exemplified by compound I-45, using the metal ion chelation agent CQ reported as positive control, in projection electron microscope (TEM) method Test compound is to Cu²⁺Induction A beta peptide aggregation inhibitory activity, experimental method are as follows：

1st, the preparation of solution：

(1), 20 μM of pH 6.6HEPES (150 μM of NaCl) buffer preparations：Weigh hepes 2.38mg, NaCl 4.38mg adds ultra-pure water 500mL dissolvings, and PH to 6.6 is adjusted with a small amount of NaOH solution.

(2)、75μM Aβ_1-42Protein solution is prepared：By 0.1mg protein dissolutions in 10 μ L 1%NH₄In OH solution, add 256 μ 20 μM of pH 6.6HEPES cushioning liquid of L are diluted to 75 μM, and 10 μ L of packing are often managed, and are placed in -80 DEG C and are saved backup.

2nd, sample preparation

Compound sample：The A β for taking 10 μ L to dispense_1-42, add 10 μ L, 75 μM of Cu²⁺, room temperature places 2min, then adds and change Compound or the μ L of CQ (75 μM) 10.Mix 37 DEG C of incubation 24h.

Control sample 1：The A β for taking 10 μ L to dispense_1-42, add 10 μ L, 75 μM of Cu²⁺, room temperature places 2min, then adds 20 μM The μ L of pH 6.6HEPES cushioning liquid 10, mix 37 DEG C of incubation 24h.

Control sample 2：The A β for taking 10 μ L to dispense_1-42, 20 μM of μ L of pH 6.6HEPES cushioning liquid 20 are added, mix 37 DEG C be incubated 24h.

Control sample 3：Take the fresh A β that 10 μ L have been dispensed_1-42, 20 μM of μ L of pH 6.6HEPES cushioning liquid 20 are added, are mixed Even 37 DEG C of incubations 0h.

Take 10 μ L samples to be placed in 2min on copper mesh, unnecessary liquid is then absorbed with filter paper, the sample being placed on copper mesh is again 2min is acted on the phosphotungstic acids of 10 μ L 2%, then absorbs unnecessary liquid with filter paper again.With JEOL JEM-1400 Electronic Speculum to preparing Good observing samples are observed, and are chosen different regions and are taken pictures.Experimental result is shown in Fig. 3.

As seen from Figure 3, substituted pyrimidines carbamide compounds of the invention, which have, suppresses Cu²⁺Induce the ability of A beta peptide aggregations. Figure Fig. 3-1, A β_1-42+Cu²⁺System, which is incubated at 37 DEG C after 24h, assembles very severe, micro- assembles the intensive net that forms in having Shape, and Fig. 3-2, A β_1-42+Cu²⁺+ I-45 systems, after compound incubation has been added, A β_1-42Aggregation extent substantially reduce, explanation The substituted pyrimidines carbamide compounds of the present invention, which have, suppresses Cu²⁺Induce the ability of A beta peptide aggregations.

The substituted pyrimidines carbamide compounds of the present invention are the micromolecular compound of a kind of new construction, and it has cholinesterase suppression System activity, metal ion-chelant property, the free radical for suppressing metal ion induction produce, and suppress metal ion induction A beta peptide aggregations. Its preparation technology is succinct, and production cost is low, therefore is expected to develop into the multi-functional anti-AD medicines of a kind of new construction.

Claims (4)

1. a kind of substituted pyrimidines carbamide derivative, it is compound shown in Formulas I or its pharmaceutically acceptable salt：

In Formulas I, X S, R¹For ethyl, R²And R³It is hydrogen, R⁴For one kind in following groups：

A kind of 2. composition, it is characterised in that the composition include claim 1 described in substituted pyrimidines carbamide derivative and Pharmaceutically acceptable carrier.

3. substituted pyrimidines carbamide derivative as claimed in claim 1 is preparing treatment and/or prevention Alzheimer disease drugs In application.

4. application of the composition as claimed in claim 2 in treatment and/or prevention Alzheimer disease drugs is prepared.