CN102786493A - 2,3-diaryl thiazolidinone compound and analogue, and purpose thereof in preparing antiangiogenic drugs - Google Patents

Abstract

The invention discloses a 2,3-diaryl thiazolidinone compound shown in a structural formula (I), a hydrate and pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing the compound, as well as the application of the compound in preparing drugs capable of treating related diseases caused by all kinds of pathological angiogenesis.

Description

2,3-two aromatic base thiazolinone compounds and analogue and the purposes in the preparation anti-angiogenic drugs thereof

Technical field

The present invention relates to one type 2,3-two aromatic base thiazolinone compounds and analogues, and this compounds or the pharmaceutical composition that contains this compounds can be used as the medicine of the relative disease of treating angiogenesis.The invention still further relates to the preparation method of this thiazolinone compounds.

Background technology

Angiogenesis is meant the process that on the basis of original blood vessel, forms neovascularity, and this is a complex process that multistep is rapid.Angiogenesis not only plays a significant role in physiological processs such as ontogeny and injury repairing, and the diseases such as angiogenic illness in eye, diabetic retinopathy, malignant tumour, psoriasis, rheumatoid arthritis, degenerative osteoarthritis and atherosclerosis that cause after also being destroyed with the newborn balance of pathologic process medium vessels are directly related.

It is the common pathological change of a lot of important eye diseases that new vessel forms, and VEGF (VEGF) is one of startup factor important in the new vessel forming process.Research at present shows that angiogenesis can cause the generation of a series of ophthalmic diseasess unusually.For example; The no blood vessel of cornea itself; But owing to reasons such as eye inflammation, wound, immunodeficient can cause new vessel stimulating factor (for example VEGF) over-expresses; The new vessel inhibitory factor expression reduces, and keeps the avascular balance factor of cornea and is destroyed, and finally brings out pathologic cornea rebirth blood vessel.

Except the vascular keratopathy; The angiogenesis equilibrated destroys also can directly cause other disease such as neovascular retinal diseases; Like diabetic retinopathy) according to statistics; Suffering among the patient of mellitus more than 15 years about 60% patient's eyes blood vessel can be impaired, and wherein a part might be lost one's sight.Newly-increased blood vessel can be grown on retina top layer or the optic nerve.These blood vessels of not growing up are more fragile than normal blood vessels, break easily blood is flowed in the vitreum, cause retinal hemorrhage and make the fuzzy or Loss Of Vision fully of patient's vision.From the disruptive blood vessel, possibly grow scar tissue, cause coming off if contraction can involve retina.

Newly-increased blood vessel also possibly grown and cause neovascular iris disease, neovascular glaucoma, neovascular vitreum illness in eye at other positions of eyes; Or neovascular optic nerve disease; Above-mentioned ophthalmic diseases has a strong impact on human physical and mental health and quality of life, researches and develops the new newborn potential drug of inhibition ocular angiogenesis that has and helps to treat above-mentioned neovascular illness in eye.

Except angiogenic illness in eye causes the very big threat human health, malignant tumour is also directly related with angiogenesis, discovers; Tumour form early stage because the inside tumor blood vessel is less, lack nutritive substance and oxygen supply; Therefore gross tumor volume is less, and it is also slower to grow.Tumour cell can produce some secretory proteins with regulating effect; Like VEGF, bFGF, PDGF etc.; These albumen are through the vascular endothelial cell of different machine-processed activation tranquillization attitudes; The induction of vascular endothelial cell moves to noumenal tumour, finally forms a large amount of new vesseles, thereby makes tumour get into quick growth phase.In addition, tumour cell can also be transferred to other target organs through neonatal blood vessels, causes metastases.The inside tumor blood vessel is abundant more, and tumor growth is fast more, and the rate of transform is also high more.Therefore, tumor growth all depends on angiogenesis with shifting, and angiogenesis inhibiting also is one of available strategy that suppresses tumor development.Technique means such as conventional surgical treatment, radiation and chemotherapy all are to cancer cells itself; And cancer cells and then develops immunity to drugs because genetic instability is very easily undergone mutation, thus traditional treatment often to have a spinoff big; Curative effect is undesirable, defectives such as easy relapse.Compare with traditional oncotherapy means; What the anti-angiogenic rebirth strategy was directed against is vascular endothelial cell rather than tumour cell itself; The vascular endothelial cell mutation probability is little, be difficult for developing immunity to drugs, so the anti-angiogenic rebirth therapy has become more and more important at tumor therapeutic procedure.At present, existing Avastin, Votrient and Sunitinib etc. are used for the clinical treatment of malignant tumour in the world, also have tens of kinds of anti-angiogenic rebirth suppressor factor to be got into clinical study by drugs approved by FDA.

In addition, angiogenesis inhibitors also has the curative effect of anti-other neovascularization disease of potential such as psoriasis, rheumatoid arthritis, degenerative osteoarthritis and atherosclerosis etc.

Micromolecular compound is the important source of new drug development, and therefore, the compound that screening has the anti-angiogenic rebirth effect has significance for the treatment that is destroyed the relative disease that causes owing to the angiogenesis balance.Research premenstruum, screening find 2, and 3-two aromatic base thiazolinone compounds and analogue have the effect of significant angiogenesis inhibiting.Our result of study also shows, 2,3-two aromatic base thiazolinone compounds and analogue can target and the closely-related albumin A rp2/3 of cell migration suppress the migration of vascular endothelial cell.Therefore, such new micromolecular compound has the research and development value of potential treatment neovascularization disease.

Summary of the invention

The object of the present invention is to provide one type 2,3-two aromatic base thiazolinone compounds and related analogs can be used as disease-resistant rational angiogenesis lead compound, comprise its acceptable salts, solvated compounds (hydrate) and ester etc.

The application of the pharmaceutical composition that the present invention also aims to above-claimed cpd to be provided or to contain above-claimed cpd in the medicine of the various disease-resistant rational angiogenesiss of preparation treatment.

The invention provides a kind of 2,3-two aromatic base thiazolinone micromolecular organic cpds or its hydrate or pharmacy acceptable salts, represent by following structural formula (I):

Wherein:

X is S, O or NH;

N is 0,1,2 or 3;

Ar ₁And Ar ₂Substituting group is selected from monocycle aromatic base, many cyclophanes perfume base, many heterocyclic aromatic bases any one, comprises monocycle aromatic base, many cyclophanes perfume base, many heterocyclic aromatic bases; Said monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base.Said many cyclophanes perfume base and many heterocyclic aromatic bases are meant the group that comprises two and plural monocycle aromatic base.

The R substituting group is selected from any in the following groups: hydrogen; Substituted alkyl; Hydroxyl; Methylol; Replace C ₂-C ₆Thiazolinyl; Replace C ₂-C ₆Alkynyl; Substituted cycloalkyl; Any one, two, three, four or five substituted substituted aryls of group; The substituted heterocyclic aryl of one or more groups; Substituted benzyl; The substituted benzene ethyl; Hydrocinnamyl; Replace alkyloyl; Replace aroyl; C ₂-C ₆Enoyl-; C ₃-C ₈The cycloalkanes acyl group; Adamantyl; Cycloalkyloxy; The cycloalkanes amido; Amido; Carboxamido-group; Carbalkoxy; Cycloalkoxycarbonyl; Alkyl amide; The cycloalkanes carboxamido-group; Carboxyl.

Among the present invention, 2, the hydrate of 3-two aromatic base thiazolinone compounds is meant 2, the mixture that 3-two aromatic base thiazolinone compounds and water molecules form.

Among the present invention, 2, the pharmacy acceptable salt of 3-two aromatic base thiazolinone compounds is meant 2,3-two aromatic base thiazolinone compounds are formed on the pharmaceutically form of universally recognized salt with corresponding acid or alkali.

It is a kind of 2 that the present invention also provides, 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt, in the structural formula (I), when n is 0, when R is hydrogen, is represented by following structural formula (II):

Wherein,

X is S, O or NH;

Ar ₁And Ar ₂Substituting group is selected from monocycle aromatic base, many cyclophanes perfume base, many heterocyclic aromatic bases any one; Said monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Said many cyclophanes perfume base and many heterocyclic aromatic bases are meant the group that comprises two and plural monocycle aromatic base.

It is a kind of 2 that the present invention also provides, 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt, and in the structural formula (I), when n is 0, R is a hydrogen, X is S, Ar ₂Be Ar ₃-R ₁The time, represent by following structural formula (III):

Wherein:

Ar ₁And Ar ₃Be selected from monocycle aromatic base, many cyclophanes perfume base, many heterocyclic aromatic bases any one; Said monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Said many cyclophanes perfume base and many heterocyclic aromatic bases are meant the group that comprises two and plural monocycle aromatic base.

R ₁Independently be selected from one or more in the following groups: hydrogen, amino, cyanic acid, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C ₂-C ₁₂Thiazolinyl, C ₂-C ₁₂Alkynyl, C ₃-C ₁₂Naphthenic base, benzyl, alkyl-carbonyl, C ₂-C ₁₂Alkenyl carbonyl, C ₃-C ₁₂Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, carboxamido-group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl.

It is a kind of 2 that the present invention also provides, and 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt in the structural formula (III), are worked as R ₁When replacing, represent by following structural formula (IV) for chain:

Wherein,

M is 0,1,2,3,4,5,6,7,8 or 9 CH ₂

X be O=, S=,=NH ,=N-NH2 ,-OH perhaps-H;

L is O, S, N or NH;

Ar ₁, Ar ₃Be selected from monocycle aromatic base, many cyclophanes perfume base, many heterocyclic aromatic bases any one with the Ar4 substituting group; Said monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Said many cyclophanes perfume base and many heterocyclic aromatic bases are meant the group that comprises two and plural monocycle aromatic base.

It is a kind of 2 that the present invention also provides, and 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt are said 2, the acid salt that 3-two aromatic base thiazolinone compounds and acid form; Wherein, said acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, tartrate, Whitfield's ointment, Hydrocerol A, methylsulfonic acid, tosic acid, lactic acid, pyruvic acid, toxilic acid or succsinic acid.

It is a kind of 2 that the present invention also provides, and 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt are said 2, and 3-two aromatic base thiazolinone compounds combine to form affinity tag with radioactivity group, fluorophor or vitamin H.

The present invention provides 2, and 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt comprise:

2-(3-bromophenyl)-3-(2-p-methoxy-phenyl)-phenyl-4-thiazolinone

2-(3-bromophenyl)-3-phenyl-4-thiazolinone

2-(3-bromophenyl)-3-(2-hydroxy phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone

2-(3-chloro-phenyl-)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-fluorophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2-thiazolyl)-4-thiazolinone

2-phenyl-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-nitrophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-p-methoxy-phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(2-methyl propionate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(1-methyl-formiate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(1-methyl-formiate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(2-methyl acetate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(1-methyl-formiate) phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2-pyrimidyl)-4-thiazolinone

2-(4-pyridyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(2-quinolyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(3-nitrophenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2-p-methoxy-phenyl)-1,3-thiazine-4-ketone

2-(3-bromophenyl)-3-(3-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(4-(diethylin) phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(3-hydroxy phenyl)-4-thiazolinone

2-(4-bromophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(2-bromophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(4-ethoxyl phenenyl)-4-thiazolinone

2-(3-hydroxy phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(4-hydroxy phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2-aminophenyl)-4-thiazolinone

2-(2-furyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(2-thienyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(2-propionyloxy) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-formyloxy phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-formyloxy phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone

2-(4-(2-acetoxyl) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(2-(N-Phenylpropionamide)) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(N, N-diethylbenzene methane amide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(N-(4-fluorophenyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(N-(3-fluorophenyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(N-(4-trifluoromethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N, N-diethylbenzene methane amide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-propyl benzamide) phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone

2-(3-(N-ETHYLE ACETATE BM) phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone

2-(3-(N-(3-hydrocinnamyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-benzene butyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-bromobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-leptodactyline) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-chlorobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-4-anisole ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(phenyl acetanilide,Phenacetylaniline) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-fluorobenzene butyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-fluorobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(2-bromobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(6-benzene hexyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(5-benzene amyl group) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2, the 4-dihydroxy phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(4-hydroxyl-2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(2-phenyl-acetamides)) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(N-(BM)) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(methylol) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(brooethyl) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(4-amino-2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(3-pyridyl) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2-p-methoxy-phenyl)-4-oxazolinyl ketone

2-(3-bromophenyl)-3-(2, the 4-Dimethoxyphenyl)-4-oxazolinyl ketone

2-(3-bromophenyl)-3-(2-(dimethylamino) phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(3-aminophenyl)-4-thiazolinone.

The present invention provides a kind of pharmaceutical composition, wherein contain said 2,3-two aromatic base thiazolinone compounds and related analogs or its hydrate or pharmacy acceptable salt, and pharmaceutically acceptable carrier.

Pharmaceutical composition of the present invention is formulated into injectable fluid, aerosol, emulsifiable paste, gelifying agent, pill, capsule, syrup, transdermal patch or vehicle.

The present invention also provides 2, and 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt are in the application of preparation anti-angiogenic drugs.

The present invention also provides 2, the application in the medicine of preparation treatment arteriosclerosis disease of 3-two aromatic base thiazolinone compounds, hydrate or pharmacy acceptable salt.

The present invention also provides 2, the application of 3-two aromatic base thiazolinone compounds in the medicine of preparation treatment of arthritis.Preferably, the application in the medicine of preparation treatment rheumatoid arthritis.

The present invention also provides 2, the application in the medicine of preparation treatment psoriasis disease of 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt.

The present invention also provides 2, the application in the medicine of preparation treatment mellitus and diabetic syndrome of 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt.

During the present invention uses, 2,3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt can use separately or unite use with other drug.

Description of drawings

Fig. 1 is the synoptic diagram of series compound of the present invention to human umbilical vein's endotheliocyte (HUVEC) inhibited proliferation, and ordinate zou is the per-cent of 490 nanometer absorbance values.

Fig. 2 suppresses the synoptic diagram of human umbilical vein's endotheliocyte (HUVEC) migration for The compounds of this invention;

Fig. 3 suppresses the synoptic diagram of human umbilical vein's endotheliocyte (HUVEC) Boyden cell migration for The compounds of this invention;

Fig. 4 suppresses the synoptic diagram that human umbilical vein's endotheliocyte (HUVEC) becomes pipe for The compounds of this invention;

Fig. 5 suppresses the synoptic diagram that rat artery ring capillary blood vessel is sprouted for The compounds of this invention;

Fig. 6 suppresses the synoptic diagram that the mouse cornea rebirth blood vessel forms for The compounds of this invention;

Fig. 7 suppresses the synoptic diagram that nude mice tumour capillary blood vessel forms for The compounds of this invention;

Fig. 8 suppresses the synoptic diagram that the capillary blood vessel in the solid tumor forms for The compounds of this invention.

Embodiment

In conjunction with following specific embodiment and accompanying drawing, the present invention is done further detailed description, protection content of the present invention is not limited to following examples.Under spirit that does not deviate from inventive concept and scope, variation and advantage that those skilled in the art can expect all are included among the present invention, and are protection domain with the appending claims.The process of embodiment of the present invention, condition, reagent, experimental technique etc. except that the following content of mentioning specially, are the universal knowledege and the common practise of this area, and the present invention does not have special limiting content.

¹H-NMR measures with Bruker300 or Bruker400 type appearance; MS measures with VG ZAB-HS or VG-7070 type appearance, except that indicating, is the ESI method; All through distillation again, employed anhydrous solvent all is to obtain by the standard method drying treatment to all solvents before use; Except that explanation, it all is under argon shield, to carry out and follow the tracks of with TLC that institute responds, during aftertreatment all through saturated common salt washing and anhydrous sodium sulfate drying process; The purifying of product all uses the column chromatography of silica gel (200-300 order) except that explanation; Employed silica gel comprises 200-300 order and GF ₂₅₄Be Haiyang Chemical Plant, Qingdao or the production of the rich silica gel company of Yantai edge.

Embodiment one: the preparation of each compound

Embodiment 1-12-(3-bromophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

Get compound 3-bromobenzaldehyde (185mg, 1.0mmol) and ORTHO ANISIDINE (113 μ L, 1.0mmol) in toluene, under nitrogen atmosphere, stir 5min under the condition of ice bath after, change oil bath into and be heated to backflow, connect water-and-oil separator on the device.To there not being water generates, the postcooling that finishes, add the compound Thiovanic acid (70 μ L 1.0mmol) continue to be heated to backflow, treat to obtain crude product after branch water finishes, behind column chromatography purification, obtain compd A GT001 (309mg, productive rate: 85%): ¹H NMR (400MHz, DMSO) δ 7.52 (s, 1H), 7.34 (d, J=8.0Hz, 1H), 7.19 (dd, J=8.0; 8.0Hz, 1H), 7.09 (dd, J=8.0,8.0Hz, 1H), 6.92 (d; J=8.0Hz, 1H), 6.87-6.80 (m, 2H), 6.02 (s, 1H), 3.94 (AB; J=15.6Hz, 1H), 3.86 (AB, J=15.6Hz, 1H), 3.81 (s, 3H). ¹³C NMR (100MHz, CDCl ₃) δ 171.3,154.9,141.7,132.1,130.9,130.1,130.0,129.8,126.5,125.3,122.5,121.0,112.1,64.1,55.8,33.1.

Embodiment 1-2 is to the preparation of the AGT002-AGT067 thiazoline ketone compounds shown in the 1-67, like following table 1.

Table 1 embodiment 1-1 to embodiment 1-67

Embodiment two: the screening of Human umbilical vein endothelial cells (HUVEC) inhibited proliferation

Purpose and principle: cell proliferation experiment adopts MTS assay.MTS assay is that a kind of colourimetry of in viable cell, using is confirmed the measuring method of cell proliferation quantity.The NADPH desaturase is transformed into MTS tetrazolium salts compound and replaces by a kind of a kind of coloring matter-first moon that is dissolved in tissue culture medium, and its shade and viable cell number be height correlation within the specific limits.Can estimate the influence of medicine on cell proliferation ability through this model.

Method: add Human umbilical vein endothelial cells in 96 orifice plates, control group and application of sample group are set, the application of sample group adds testing compound; Final concentration is 40 micromoles, hatch 60～72 hours after, add the cell proliferation detection reagent; Hatched 1-3 hour, and detected absorbance value at the 490nm place with ELIASA.

Result and evaluation: experimental result is as shown in Figure 1; Compare with control group, the adding of part The compounds of this invention such as AGT006, AGT037, AGT039, AGT049, AGT058, AGT062 and AGT065 etc. is suppressed the multiplication capacity of Human umbilical vein endothelial cells.In addition; With The compounds of this invention with biotin labeling after; Can find through experimental result; With biotin labeled compound tumour cell is had the activity of the inhibition tumor cell proliferation similar with non-labelled compound equally, and vitamin H itself is not have the tumor cell proliferation active (Fig. 4 A) of inhibition.

Embodiment three: the inhibition that The compounds of this invention forms human umbilical vein's endothelial cell migration, one-tenth pipe ability, capillary blood vessel

Embodiment 3-1: The compounds of this invention suppresses human umbilical vein's endotheliocyte (HUVEC) migration

Purpose and principle: under the inducing of serum, human umbilical vein's endotheliocyte can be to acellular scored area migration.Moving into through observation, whether the cell quantity in cut district how much to estimate The compounds of this invention inhibited to the migration of human umbilical vein's endotheliocyte.

Method: human umbilical vein's endotheliocyte is seeded in 12 orifice plates, make it in the substratum that contains 10% serum growth converge to surface-area 80% after, change the hungry 6h of the substratum that contains 0.5% serum into.Carry out the cruciform cut with Tip pair cell and handle, sop up substratum, clean the cell under drawing with PBS; Add different concns (be respectively 1 little rubbing/liter; 5 little rubbing/liter, 10 little rubbing/liter, 20 little rubbing/liter; 40 little rubbing/liter) The compounds of this invention AGT005, in the substratum that contains 10% serum, be cultured to control group and cover with.

Result and evaluation: examine under a microscope and take pictures, experimental result is as shown in Figure 2, compares with control group (not adding The compounds of this invention), and The compounds of this invention AGT005 significantly suppresses the migration of human umbilical vein's endotheliocyte.

Equally; More than add The compounds of this invention AGT017, AGT019, AGT026, AGT037, AGT039, AGT045, AGT056 and AGT067 respectively in the experiment; It is as shown in Figure 2 to obtain experimental result, and these compounds all can significantly suppress the migration of human umbilical vein's endotheliocyte.In addition; With The compounds of this invention with biotin labeling after; Can find through the cell migration experimental result; With biotin labeled compound tumour cell is had the activity of the inhibition tumor cell migration similar with non-labelled compound equally, and vitamin H itself is not have the tumor cell migration active (Fig. 4 B) of inhibition.

Embodiment 3-2: The compounds of this invention suppresses the migration of human umbilical vein's endotheliocyte (HUVEC) Boyden cell

Purpose and principle: the Boyden cell is one type can place 24 porocyte culture plates, has the device of 8 micron pore size poly carbonate filter membranes.During use, cell is received the internal surface of film and is cultivated, and the outside surface of film places the substratum that contains chemokine, and under the inducing of chemokine, the attached cell of film internal surface can be moved to the outside surface of film through the micropore on the film.This experiment can detection compound has the influence of resistance transfer ability to endotheliocyte.

Method: the Boyden cell is encapsulated in 0.1% gelatin, hatched 30 minutes for 37 ℃, discard gelatin, give a baby a bath on the third day after its birth time with PBS.Add in 24 orifice plates in the cell outside substratum that contains 10% serum and respective concentration (be respectively 1 little rubbing/liter; 5 little rubbing/liter; 10 little rubbing/liter, 20 little rubbing/liter, 40 little rubbing/liter) The compounds of this invention AGT007; The inner cell that inserts of cell, the substratum in the cell contain 0.5% the serum and the The compounds of this invention of same concentrations.In 37 ℃ of 5%CO ₂After hatching four hours in the incubator, sop up substratum, with cotton swab the not cell of migration of little chamber internal surface is wiped, PBS washes 3 times; Fix 20 minutes with Paraformaldehyde 96, PBS washes 3 times, and violet staining is spent the night; Sop up Viola crystallina, PBS washes 3 times, dries back microscopically observation and takes pictures.

Result and evaluation: microscopically is observed and is taken pictures; As shown in Figure 3; With control group (not adding The compounds of this invention) ratio; The migration of the endotheliocyte that process The compounds of this invention AGT007 handles has received remarkable inhibition, explains that The compounds of this invention AGT007 can suppress the resistant transfer ability of endotheliocyte.

Equally; More than add The compounds of this invention AGT009, AGT012, AGT015, AGT018, AGT025, AGT029, AGT033, AGT035, AGT037, AGT039, AGT047 and AGT058 etc. respectively in the experiment; It is as shown in Figure 3 to obtain experimental result, and these compounds can significantly suppress the resistant transfer ability of endotheliocyte.

Embodiment 3-3: The compounds of this invention suppresses human umbilical vein's endotheliocyte (HUVEC) and becomes the pipe ability

Purpose and principle: Matrigel is the basilar membrane extract that from murine sarcoma, extracts the solubility that obtains, and is rich in extracellular matrix protein.At room temperature, Matrigel can be condensed into the matrigel of biologically active, and its structure and component and mammalian cell basilar membrane are similar, and the three-dimensional luminal structure of formation can be grown, assembled, merge to human umbilical vein's endotheliocyte in Matrigel.Can utilize endotheliocyte this specific character in Matrigel to study compound to angiopoietic influence.

Method: 50 microlitre Matrigel are taped against in 96 orifice plates, in 37 ℃, 5%CO ₂Hatch in the incubator and treated its cohesion in 30 minutes.50 μ L are comprised 1 * 10 ⁴The cell suspension of individual human umbilical vein's endotheliocyte and 50 μ L respective concentration (be respectively 1 little rubbing/liter, 5 little rubbing/liter, 10 little rubbing/liter, 20 little rubbing/liter, 40 little rubbing/liter) The compounds of this invention AGT004 mix the back and add among the Matrigel, in 37 ° of C CO ₂Hatched in the incubator 6-8 hour, and examined under a microscope the one-tenth pipe situation of human umbilical vein's endotheliocyte and take pictures.

Result and evaluation: as shown in Figure 5, the complete three-dimensional luminal structure of formation is grown, assembled, merges to human umbilical vein's endotheliocyte in the control group in Matrigel.Compare with control group (not adding The compounds of this invention); The one-tenth pipe process of human umbilical vein's endotheliocyte that The compounds of this invention AGT004 handled is affected; The luminal structure that forms is scattered, imperfect, explains that The compounds of this invention AGT004 can suppress human umbilical vein's endotheliocyte and become pipe.

Equally; More than add The compounds of this invention AGT007, AGT011, AGT015, AGT019, AGT023, AGT027, AGT032, AGT034, AGT037, AGT039, AGT045, AGT059 and AGT063 respectively in the experiment; It is as shown in Figure 5 to obtain experimental result, and these compounds can significantly suppress human umbilical vein's endotheliocyte and become pipe.

Embodiment 3-4: The compounds of this invention suppresses rat artery ring capillary blood vessel and sprouts

Purpose and principle: be rich in extracellular matrix protein and growth factor in the collagen; The arterial ring that exsomatizes is coated in the collagen, and the endotheliocyte of arterial ring outer rim can be under the stimulation of growth factor, degrade collagen; Sprout to external migration simultaneously, around arterial ring, form the netted capillary network of dispersing.SD (Sprague-Dawley) rat artery ring model can be used to detect the influence that compound is sprouted capillary blood vessel under the state of exsomatizing.

Method: with male rat anesthesia in 6 ages in week, thoracic aorta is separated, blood remaining in the blood vessel is rinsed well with the MCDB231 substratum of serum-free; Peel off circumvascular reticular tissue at microscopically; Wipe out lateral capillary vessel, thoracic aorta is cut the arterial ring of growing into the 1-1.5 millimeter, with fresh culture rinsing 3 times; Arterial ring is put into 48 orifice plates that are covered with 100 microlitre collagens in advance; Repave into 100 μ L collagens, add the MCDB231 substratum that 1mL contains the compd A GT001 of respective concentration (20 little rubbing/liter) subsequently, in 37 ℃ of CO ₂Cultivate in the incubator and examine under a microscope after 7 days and take pictures.

Result and evaluation: as shown in Figure 6, form radial capillary network around control group (not adding The compounds of this invention) the medium sized artery ring, and the arterial ring that The compounds of this invention AGT001 handled almost can't see microvascular sprouting.It is thus clear that The compounds of this invention AGT001 can sprout at the rat artery ring capillary blood vessel that tissue level suppresses to exsomatize.

Equally; In above-mentioned experiment, add The compounds of this invention AGT003, AGT014, AGT016, AGT017, AGT028, AGT029, AGT033, AGT036, AGT038, AGT040, AGT045, AGT047, AGT052, AGT056, AGT059, AGT062, AGT063 etc. respectively; It is as shown in Figure 6 to obtain experimental result, shows that the invention described above compound can suppress stripped rat artery ring capillary blood vessel in tissue level and sprout.

Embodiment 3-5: The compounds of this invention suppresses the mouse cornea rebirth blood vessel and forms

Purpose and principle: the mouse cornea does not have blood vessel under the physiological status; Between cornea and eyeball, make a micro-capsule bag with syringe needle; Implantation contains the slow-releasing granules of vascular endothelial growth factor (VEGF); The blood vessel that can induce Gong Yuan place, angle is to the growth of slow-releasing granules place, and whether in slow-releasing granules, add compound simultaneously can detection compound form inhibited to the mouse cornea rebirth blood vessel.

Method: with the C57/BL6 mouse anesthesia; Fixing, between cornea and eyeball, make the micro-capsule bag, the implantation slow release particle; Contain VEGF in the slow-releasing granules in the control group; The The compounds of this invention AGT005 that contains VEGF and respective concentration (20 little rubbing/liter) in the dosing group treats that the mouse back of reviving raised for 1 week, examines under a microscope the newborn situation of VEGF induction of vascular after the anesthesia and takes pictures.

Result and evaluation: as shown in Figure 7; VEGF induces and has formed a large amount of blood vessels in the control group (not adding The compounds of this invention); And after adding The compounds of this invention AGT005, new vessel has obviously received inhibition, explains that The compounds of this invention AGT005 can suppress the mouse cornea rebirth blood vessel and form.

Equally; In above-mentioned experiment, add The compounds of this invention AGT015, AGT017, AGT023, AGT029, AGT032, AGT037, AGT039, AGT040, AGT053, AGT057, AGT058, AGT061 and AGT064 etc. respectively; It is as shown in Figure 7 to obtain experimental result, shows that The compounds of this invention can suppress the mouse cornea rebirth blood vessel and form.

Embodiment 3-6: The compounds of this invention suppresses nude mice tumour capillary blood vessel and forms

Purpose and principle: CD31 is as the vascular endothelial cell labelled protein, and therefore high expression level in vascular endothelial cell can detect microvascular distribution situation in the tumor tissues with the CD31 immunohistochemical staining specifically.

Method: will place 4% Paraformaldehyde 96 fixed overnight from the solid tumor that nude mice peels off, it is cut into the paraffin section of 4 μ m behind the paraffin embedding, through dewaxing, carries out antigen retrieval after the rehydration, and preceding paraffin section is changed over to of dyeing contains 3%H ₂O ₂Methanol solution in soaked 10 minutes, to eliminate the catalatic effect of endogenous.Added the CD31 antibody incubation then 30 minutes, PBS washes 3 times, hatches the two anti-of coupling HRP subsequently, and PBS washes 3 times, and the DAB colour developing is redyed with phenodin at last, examines under a microscope after the mounting and takes pictures.Nucleus presents blueness, and capillary blood vessel appears brown.

Result and evaluation: as shown in Figure 8; Compare with control group; Capillary blood vessel in the solid tumor of abdominal injection The compounds of this invention AGT006 is obviously less; Explain that The compounds of this invention can suppress nude mice tumour capillary blood vessel and form, explain that The compounds of this invention AGT006 can suppress metastases through angiogenesis inhibiting.

Equally; Inject The compounds of this invention AGT018, AGT019, AGT025, AGT029, AGT033, AGT037, AGT039, AGT044, AGT056, AGT057, AGT059, AGT062, AGT066 respectively in the abdominal cavity; It is as shown in Figure 8 to obtain experimental result, shows that the invention described above compound can suppress metastases through angiogenesis inhibiting.

Embodiment 4: The compounds of this invention suppresses the sclerosis of rat artery congee shape

In oralbumin abdominal injection to 5 Wistar rat in all ages; And feed Vitamin D3 500,000 I.U/GM to irritate in tail vein injection bovine serum albumin assistant; Feed rat with high lipid food then; And a certain amount of ferrous sulfate joined in the drinking-water, detect lipid level, blood parameters and the pathological change of rat at different time.

Experimental result shows; Compare with control group; After adding The compounds of this invention AGT005, AGT009, AGT015, AGT028, AGT031, AGT036, AGT037, AGT041, AGT045, AGT053, AGT056, AGT061, AGT064; The high-density protein of rat (HDL), low density albumen (LDL) c reactive protein (CRP), myocardium kinases (CK) and myocardium kinase isozyme (CK-Mb) etc. are significantly higher than control group, and dosing group rat aorta plaque deposition is starkly lower than control group.

Embodiment 5: the symptom that The compounds of this invention improves rheumatoid arthritis is dissolved in chicken II Collagen Type VI (Chondrex) among the 0.05M HAc (4mg/ml, the 0.1MTris-HCl balance is to neutral final concentration 2mg/ml), spends the night at 4 ℃, and solution is transparent clear.Then collagen solution and CFA (Sigma contains 1mg/ml Mycobacterium tuberculosis) equal-volume are mixed, emulsification is complete.Then mouse being carried out arthritis model induces: at first carried out first immunisation at the 0th day, tail vein injection 100ug collagenII (CFA adjuvant); At the 21st day second immunisation, tail vein was injected 100ug collagen II (IFA makes solvent) then; From the 23rd day inferior on every Wendesdays (week 1,3,5), carry out scoring of foot outward appearance and sufficient mat thickness and measure.Added The compounds of this invention AGT002, AGT003, AGT006, AGT007, AGT009, AGT010, AGT013, AGT015, AGT019, AGT022, AGT025, AGT027, AGT029, AGT032, AGT036, AGT043, AGT047, AGT051, AGT054, AGT055, AGT061 and AGT064 since the 23rd day; With respect to control group; Dosing group mouse is soaked into intraarticular and surrounding soft tissue's infiltration all has tangible return action; Destructiveness to cartilage has significant inhibition, and bone remodeling is had tangible return action.

Embodiment 5: The compounds of this invention is to the psoriasis treatment effect.

Solubility selects plain level relevant with the patients with psoriasis vulgaris state of an illness in the serum, can be used as a useful indicators judging psoriasis activity property, according to the psoriatic mouse model modeling method of U.S. Schon formulation; The model group mouse is abdominal injection diethylstilbestrol for three days on end all, every 0.2mg/ time, 2 times/day; Make to be in the oestrogenic hormon phase, vaginal epithelial cell was in propagation phase state after the feminisation, in the 10th day; All mouse are put to death behind the abdominal injection NSC-757., get sample, observe and soluble E-selection cellulose content; With the blank control group contrast, increase the modeling success than blank control group.

Administration group injected in mice The compounds of this invention AGT001, AGT004, AGT007, AGT008, AGT009, AGT011, AGT014, AGT017, AGT018, AGT020, AGT022, AGT027, AGT029, AGT032, AGT036, AGT041, AGT045, AGT050, AGT052, AGT057, AGT063 and AGT066, after 6 days, all mouse are put to death behind the abdominal injection NSC-757.; Get the about 1ml of blood, 4 degrees centigrade, 3000r/min with plucking the eyeball method before putting to death; Centrifugal 10min; Get supernatant, sample adds 50ul in reacting hole with sample diluent 1:l dilution back, add the standard substance 50ul of dilution after good in reacting hole, add testing sample 50ul in reacting hole; The biotin labeled antibody that adds 50ul then immediately; Cover lamina membranacea, the mixing that vibrates gently, 37 ℃ of incubation 1h.Get rid of liquid in the hole, washings is filled it up with in every hole, vibrates 30 seconds, gets rid of washings, claps with thieving paper and does, and every hole adds affine chain enzyme one HRP of 80ul, the mixing that vibrates gently, 37% incubation 30min.Get rid of liquid in the hole, washings is filled it up with in every hole, vibrates 30 seconds, gets rid of washings; Do with the thieving paper bat, every hole adds chromogenic substrate liquid 50ul, the mixing that vibrates gently, 37 ℃ of incubations; Avoid illumination, take out enzyme plate, add the 50ul stop buffer rapidly, should measure the result immediately behind the adding stop buffer; Measure serum soluble E one with ELISA method double antibodies sandwich method and select plain content, unit representes that with ng/mL statistics result shows that The compounds of this invention has good therapeutic action to psoriasis.

Embodiment 5: The compounds of this invention is to the result of treatment of mellitus and diabetic syndrome

With seven days mouse (with female mouse) of birth, to raise in 75% oxygen environment, concentration of oxygen can be regulated and monitor.The 12 day; Mouse is exposed in the air again, abdominal injection DMSO every day (control group) or The compounds of this invention AGT002, AGT005, AGT007, AGT009, AGT010, AGT012, AGT015, AGT017, AGT019, AGT022, AGT024, AGT026, AGT027, AGT035, AGT038, AGT043, AGT045, AGT051, AGT053, AGT056, AGT061 and AGT062.The 17 day, abdominal injection carried out fluorescein angiographic.With vetanarcol deep anaesthesia mouse.Then, pour into the VISOSE of high molecular fluorescent mark through left ventricle.After the perfusion, peel off eyeball, 4% formaldehyde fixed 24 hours.Remove cornea and lens, microscopically is peeled off retina, the mounting medium sealing.Microscopically is observed retinal neovascularization and is changed; Find that DMSO group mouse retina is behind hypoxia inducible; A lot of silk ball shape new vesseles occur, and the new vessel that has added in the mouse retina of The compounds of this invention suppressed significantly, and can obviously be reduced the glucose level of mouse.

Following examples 1-2 to embodiment 1-67 shows each compd A GT002-67 preparation method and product qualification result.

Embodiment 1-2,2-(3-bromophenyl)-3-phenyl-4-thiazolinone (AGT002)

Adopt similar method, ORTHO ANISIDINE be replaced into aniline, get compd A GT002, productive rate 78% behind the column chromatography purification with preparation compd A GT001: ¹H NMR (400MHz, DMSO) δ 7.59 (s, 1H), 7.41-7.39 (m, 2H), 7.31-7.30 (m, 4H), 7.25-7.21 (m, 1H), 7.16-7.13 (m, 1H), 6.0 (s, 1H) 4.07 (d, J=14.6Hz, 1H), 3.87 (d, J=14.6Hz, 1H).

Embodiment 1-3,2-(3-bromophenyl)-3-(2-hydroxy phenyl)-4-thiazolinone (AGT003)

Adopt similar method, ORTHO ANISIDINE be replaced into Ortho-Aminophenol with preparation compd A GT001, behind the column chromatography purification compd A GT003, productive rate: 68%:1H NMR (400MHz, DMSO) δ 9.93 (br s, 1H); 7.63 (s, 1H), 7.43-7.41 (m, 2H), 7.24-7.20 (m, 1H); 7.06-7.02 (m, 1H), 6.92 (d, J=7.8Hz, 1H), 6.84 (d; J=7.8Hz, 1H), 6.68-6.64 (m, 1H), 6.0 (br s, 1H); 4.01 (d, J=14.1Hz, 1H), 3.79 (d, J=14.1Hz, 1H).

Embodiment 1-4,2-(3-bromophenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone (AGT004)

Adopt similar method, ORTHO ANISIDINE be replaced into 2 with preparation compd A GT001, the 4-dimethoxyaniline, behind the column chromatography purification compd A GT004, productive rate: 78%:1H NMR (400MHz, DMSO) δ 7.62 (d, J=1.6Hz, 1H), 7.44 (d; J=8.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.24 (dd, J=8.0,8.0Hz; 1H), 6.90 (d, J=8.8Hz, 1H), 6.56 (d, J=2.8Hz, 1H), 6.40 (dd; J=2.4,8.0Hz, 1H), 6.09 (s, 1H), 4.01 (AB, J=1.6,15.6Hz; 1H), 3.80 (AB, J=15.6Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H).

Embodiment 1-5,2-(3-chloro-phenyl-)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT005)

Adopt similar method, the 3-bromobenzaldehyde is replaced into the 3-chlorobenzaldehyde, get compd A GT005 behind the column chromatography purification with preparation compd A GT001, and productive rate 66%:1H NMR (400MHz, CDCl3): δ 7.37 (s, 1H), 7.24-7.20 (m; 2H), 7.18-7.17 (m, 2H), 6.93 (dd, J=8.0,1.6Hz, 1H); 6.88 (dd, J=8.0,0.8Hz, 1H), 6.83 (ddd, J=7.6,7.6; 0.8Hz, 1H), 6.03 (s, 1H), 3.96 (d, J=15.6Hz; 1H), 3.89 (d, J=15.6Hz, 1H), 3.84 (s, 3H).

Embodiment 1-6,2-(3-fluorophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT006)

Adopt similar method, the 3-bromobenzaldehyde is replaced into the 3-fluorobenzaldehyde, get compd A GT006 behind the column chromatography purification with preparation compd A GT001, and productive rate 66%:1H NMR (300MHz, DMSO): δ 7.29-7.27 (m, 2H), 7.20-7.17 (m; 2H), 7.07-7.04 (m, 1H), 7.01 (d, J=7.8Hz, 2H), 6.81 (dd; J=7.8,7.8Hz, 1H), 6.18 (s, 1H), 4.02 (d, J=15.9Hz; 1H), 3.80 (d, J=15.9Hz, 1H), 3.76 (s, 3H).

Embodiment 1-7,2-(3-bromophenyl)-3-(2-thiazolyl)-4-thiazolinone (AGT007)

Adopt similar method, only ORTHO ANISIDINE is replaced into thiazolamine, get compd A GT007 behind the column chromatography purification with preparation compd A GT001, and productive rate 48%:1H NMR (300MHz, DMSO): δ 7.74 (d, J=8.7Hz; 2H), 7.64 (s, 1H), 7.43-7.41 (m, 2H), 7.29 (d; J=8.4Hz, 2H), 7.31-7.28 (m, 1H), 6.63 (s, 1H); 4.09 (d, J=15.9Hz, 1H), 3.91 (d, J=15.9Hz, 1H).

Embodiment 1-8,2-phenyl-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT008)

Adopt similar method, the 3-bromobenzaldehyde is replaced into phenyl aldehyde, ORTHO ANISIDINE is replaced into ORTHO ANISIDINE, get compd A GT008 behind the column chromatography purification with preparation compd A GT001, and productive rate 58%:1H NMR (300MHz, CDCl3): δ 7.34-7.31 (m; 2H), and 7.26-7.23 (m, 3H), 7.21-7.15 (m, 1H); 6.91-6.85 (m, 2H), 6.81-6.76 (m, 1H), 6.08 (s; 1H), 3.99-3.86 (m, 2H), 3.83 (s, 3H).

Embodiment 1-9,2-(3-nitrophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT009)

Adopt similar method, the 3-bromobenzaldehyde is replaced into the 3-nitrobenzaldehyde, get compd A GT009 behind the column chromatography purification with preparation compd A GT001, and productive rate 51%:1H NMR (300MHz, CDCl3): δ 8.24 (s, 1H); 8.11-8.08 (m, 1H), 7.68-7.65 (m, 1H), 7.47-7.42 (m, 1H); 7.24-7.18 (m, 1H), 6.96-6.93 (m, 1H), 6.89-6.80 (m, 2H); 6.20 (s, 1H), 4.02-3.89 (m, 2H), 3.84 (s, 3H).

Embodiment 1-10,2-(3-p-methoxy-phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT010)

Adopt similar method with preparation compd A GT001, with the 3-bromobenzaldehyde be replaced into behind the 3-methoxybenzaldehyde column chromatography purification compd A GT010, productive rate 52%:1H NMR (300MHz, CDCl3): δ 7.23-7.18 (m, 1H), 7.17-7.13 (m; 1H), and 6.94-6.92 (m, 1H), 6.89-6.86 (m, 3H), 6.83-6.81 (m; 1H), 6.78-6.75 (m, 1H), 6.06 (s, 1H); 3.98-3.90 (m, 2H), 3.83 (s, 3H) .3.75 (s, 3H).

Embodiment 1-11,2-(4-(2-methyl propionate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT011)

Adopt similar method, the 3-bromobenzaldehyde is replaced into 2-(4-formyl radical phenyl) methyl propionate, get compd A GT011 behind the column chromatography purification with preparation compd A GT001, and productive rate 42%:1H NMR (400MHz, CDCl3): δ 7.27 (d, J=8.0Hz, 2H), 7.21-7.19 (m; 1H), 7.18 (d, J=8.0Hz, 2H), 6.91 (d, J=7.6Hz, 1H), 6.87 (d; J=7.6Hz, 1H), 6.80 (dd, J=7.6,7.6Hz, 1H), 6.07 (s, 1H); 3.95 (d, J=15.6Hz, 1H), 3.87 (d, J=15.6Hz, 1H), 3.81 (s, 3H); 3.67 (q, J=7.2Hz, 1H), 3.63 (s, 3H), 1.43 (d, J=7.2Hz, 3H).

Embodiment 1-12,2-(3-(1-methyl-formiate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT012)

Adopt similar method, the 3-bromobenzaldehyde is replaced into 3-formyl radical benzoic ether, get compd A GT012 behind the column chromatography purification with preparation compd A GT001, and productive rate 84%:1H NMR (300MHz, CDCl3): δ 8.02 (s, 1H), 7.91 (d; J=7.8Hz, 1H), 7.52 (d, J=7.8Hz, 1H), 7.34 (dd, J=7.8; 7.8Hz, 1H), 7.18 (dd, J=7.8,7.8Hz, 1H); 6.92-6.84 (m, 2H), 6.82-6.77 (m, 1H), 6.14 (s, 1H); 3.95-3.93 (m, 2H), 3.90 (s, 3H), 3.83 (s, 3H).

Embodiment 1-13,2-(4-(1-methyl-formiate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT013)

Adopt similar method, the 3-bromobenzaldehyde is replaced into the 4-acyl radical methyl benzoate, get compd A GT013 behind the column chromatography purification with preparation compd A GT001, and productive rate 66%:1H NMR (300MHz, CDCl3): δ 7.93 (d, J=8.1Hz, 2H); 7.40 (d, J=8.1Hz, 2H), 7.19 (dd, J=8.1,7.8Hz, 1H); 6.90 (d, J=7.8Hz, 1H), 6.85 (d, J=8.1Hz, 1H); 6.80 (dd, J=8.1,7.8Hz, 1H), 6.13 (s, 1H); 3.95-3.93 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H).

Embodiment 1-14,2-(4-(2-methyl acetate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT014)

Adopt similar method, the 3-bromobenzaldehyde is replaced into 4-formyl radical methyl phenylacetate, get compd A GT014 behind the column chromatography purification with preparation compd A GT001, and productive rate 66%:1H NMR (300MHz, CDCl3): δ 7.29-7.27 (m, 2H); 7.18-7.16 (m, 3H), 6.92-6.85 (m, 2H), 6.80 (dd, J=7.8; 7.8Hz, 1H), 6.07 (s, 1H), 3.92-3.90 (m, 2H); 3.82 (s, 3H), 3.66 (s, 3H), 3.55 (s, 2H).

Embodiment 1-15,2-(3-(1-methyl-formiate) phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone (AGT015)

Adopt the similar method with preparation compd A GT001, the 3-bromobenzaldehyde is replaced into 3-formyl radical benzoic ether, ORTHO ANISIDINE is replaced into 2, the 4-dimethoxyaniline gets compd A GT015 behind the column chromatography purification, and productive rate 52%:1H NMR (300MHz, CDCl3): δ 8.01 (s, 1H); 7.92 (d, J=7.8Hz, 1H), 7.51 (d, J=7.8Hz, 1H), 7.35 (dd; J=7.8,7.8Hz, 1H), 6.79-6.76 (m, 1H), 6.40 (d, J=2.4Hz; 1H), 6.29 (dd, J=2.4,8.4Hz), 6.05 (s, 1H), 3.94-3.92 (m; 2H), 3.91 (s, 3H), 3.80 (s, 3H), 3.71 (s, 3H).

Embodiment 1-16,2-(3-bromophenyl)-3-(2-pyrimidyl)-4-thiazolinone (AGT016)

Adopt similar method, only ORTHO ANISIDINE is replaced into the 2-aminopyrimidine, get compd A GT016 behind the column chromatography purification with preparation compd A GT001, and productive rate 30%:1H NMR (300MHz, CDCl3): δ 8.63 (d, J=4.8Hz, 2H), 7.50 (s; 1H), 7.36 (d, J=7.8Hz, 1H), 7.29-7.26 (m, 1H), 7.14 (dd, J=7.8Hz; 7.8Hz, 1H), 7.05 (dd, J=4.8Hz, 4.8Hz, 1H), 6.63 (s; 1H), 4.02 (d, J=16.2Hz, 1H), 3.83 (d, J=16.2Hz, 1H).

Embodiment 1-17,2-(4-pyridyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT0017)

Adopt similar method, the 3-bromobenzaldehyde is replaced into 4-aminopyridine, get compd A GT0017 behind the column chromatography purification with preparation compd A GT001, and productive rate 55%:1H NMR (400MHz, CDCl3): δ 8.52 (dd, J=6.0,1.6Hz, 2H); 7.23 (dd, J=6.0,1.6Hz, 2H), 7.22-7.20 (m, 1H), 6.97-6.95 (m; 1H), 6.89 (dd, J=8.0,1.2Hz, 1H), 6.84 (dd, J=8.0; 1.2Hz, 1H), 6.04 (d, J=1.6Hz, 1H), 3.97 (dd, J=15.6; 1.6Hz, 1H), 3.90 (d, J=15.6Hz, 1H), 3.84 (s, 3H).

Embodiment 1-18,2-(2-quinolyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT018)

Adopt similar method, the 3-bromobenzaldehyde is replaced into the 1-quinolylamine, get compd A GT018 behind the column chromatography purification with preparation compd A GT001, and productive rate 46%:1H NMR (300MHz, CDCl3): δ 8.16 (d, J=8.1Hz, 1H), 7.97 (d, J=8.4Hz; 1H), 7.76 (d, J=8.1Hz, 1H), 7.68 (dd, J=7.2,7.2Hz, 1H), 7.60 (d; J=8.4Hz, 1H), 7.52 (dd, J=7.8,7.2Hz, 1H), 7.18 (dd, J=8.4,7.8Hz; 2H), 6.88 (d, J=8.4Hz, 1H), 6.78 (d, J=7.8Hz, 1H), 6.24 (s, 1H); 4.02 (d, J=15.6Hz, 1H), 3.82 (d, J=15.6Hz, 1H), 3.81 (s, 3H).

Embodiment 1-19,2-(3-bromophenyl)-3-(3-nitrophenyl)-4-thiazolinone (AGT019)

(2.34ml 20mmol) is dissolved in the 50ml THF, adds 3-N-methyl-p-nitroaniline (1.38g to get the 3-bromobenzaldehyde; 10mmol) stir, add after 5 minutes Thiovanic acid (2.27ml, 30mmol); (2.48g 12mmol), reacts under the room temperature after 10 minutes and spends the night after 5 minutes, to add DCC.Suction filtration, with ethyl acetate extraction twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Obtain compd A GT019 (740mg, 54%) through column chromatography purification: 1H NMR (400MHz, CDCl3): δ 8.14-8.13 (m, 1H), 8.06-8.03 (m, 1H), 7.61-7.58 (m; 1H), and 7.52-7.48 (m, 1H), 7.46-7.45 (m, 1H), 7.43-7.40 (m, 1H); 7.25-7.23 (m, 1H), 7.21-7.17 (m, 1H), 6.15 (s, 1H); 4.01 (d, J=15.6Hz, 1H), 3.90 (d, J=15.6Hz, 1H).

Embodiment 1-20,2-(3-bromophenyl)-3-(2-p-methoxy-phenyl)-1,3-thiazine-4-ketone (AGT020)

Adopt similar method, the 3-N-methyl-p-nitroaniline is replaced as ORTHO ANISIDINE, Thiovanic acid is replaced as thiohydracrylic acid, get compd A GT020 behind the column chromatography purification with preparation compd A GT019, and productive rate 54%:1H NMR (400MHz, CDCl3): δ 7.54-7.51 (m, 1H), 7.37 (d; J=8.0Hz, 1H), 7.29 (d, J=7.6Hz, 1H), 7.21 (dd, J=8.0; 7.6Hz, 1H), 7.16 (dd, J=8.0,7.6Hz, 1H), 6.99-6.97 (m; 1H), 6.89 (d, J=7.6Hz, 1H), 6.85-6.83 (m, 1H), 5.83 (s; 1H), 3.86 (s, 3H), 3.02-3.01 (m, 2H), 3.00-2.95 (m, 2H).

Embodiment 1-21,2-(3-bromophenyl)-3-(3-p-methoxy-phenyl)-4-thiazolinone (AGT021)

Adopt similar method, the 3-N-methyl-p-nitroaniline is replaced as m-anisidine, get compd A GT022 behind the column chromatography purification with preparation compd A GT019, and productive rate 74%:1H NMR (400MHz, CDCl3): δ 7.47 (d, J=1.6Hz, 1H), 7.40 (dd; J=7.6,1.6Hz, 1H), 7.24-7.23 (m, 1H), 7.21 (d, J=1.2Hz, 1H); 7.17 (ddd, J=7.6,7.6,1.2Hz, 1H), 6.76 (d, J=1.6Hz; 2H), 6.74 (d, J=1.6Hz, 1H), 6.02 (s, 1H), 4.00 (d; J=15.6Hz, 1H), 3.87 (d, J=15.6Hz, 1H), 3.73 (s, 3H).

Embodiment 1-22,2-(3-bromophenyl)-3-(4-(diethylin) phenyl)-4-thiazolinone (AGT022)

Adopt similar method, the 3-N-methyl-p-nitroaniline be replaced as 4-diethylin aniline, get compd A GT023, productive rate 63% behind the column chromatography purification with preparation compd A GT019: ¹H NMR (300MHz, DMSO): δ 7.56-7.54 (m, 1H), 7.42 (d, J=7.8Hz, 1H), 7.38 (d, J=7.8Hz, 1H); 7.25 (dd, J=7.8,7.8Hz, 1H), 6.98 (d, J=9.0Hz, 2H), 6.51 (d; J=9.0Hz, 2H), 6.27 (s, 1H), 4.02 (d, J=15.6Hz, 1H), 3.79 (d; J=15.6Hz, 1H), 3.24 (q, J=6.9Hz, 4H), 1.00 (t, J=6.9Hz, 6H).

Embodiment 1-23,2-(3-bromophenyl)-3-(3-hydroxy phenyl)-4-thiazolinone (AGT023)

Adopt similar method, the 3-N-methyl-p-nitroaniline be replaced as Metha Amino Phenon, get compd A GT023, productive rate 39% behind the column chromatography purification with preparation compd A GT019: ¹H NMR (400MHz, DMSO): δ 9.57 (br s, 1H), 7.57 (s, 1H), 7.43 (d, J=8.0Hz, 1H); 7.38 (d, J=8.0Hz, 1H), 7.26 (dd, J=8.0,8.0Hz, 1H), 7.07 (dd; J=8.0,8.0Hz, 1H), 6.74-6.71 (m, 2H), 6.57-6.54 (m, 1H), 6.45 (s; 1H), 4.05 (d, J=15.6Hz, 1H), 3.84 (d, J=15.6Hz, 1H).

Embodiment 1-24,2-(4-bromophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT024)

Adopt similar method, the 3-bromobenzaldehyde be replaced as the 4-bromobenzaldehyde, the 3-N-methyl-p-nitroaniline is replaced as ORTHO ANISIDINE, get compd A GT024, productive rate 30% behind the column chromatography purification with preparation compd A GT019: ¹H NMR (400MHz, DMSO): δ 7.45 (d, J=8.4Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.23-7.18 (m, 1H); 7.00 (dd, J=8.0,8.0Hz, 2H), 6.83-6.79 (m, 1H), 6.16 (s, 1H); 4.05 (d, J=16.4Hz, 1H), 3.84 (d, J=16.4Hz, 1H), 3.85 (s, 3H).

Embodiment 1-25,2-(2-bromophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT025)

Adopt similar method, the 3-bromobenzaldehyde be replaced as the 2-bromobenzaldehyde, the 3-N-methyl-p-nitroaniline is replaced as ORTHO ANISIDINE, get compd A GT025, productive rate 28% behind the column chromatography purification with preparation compd A GT019: ¹H NMR (400MHz, DMSO): δ 7.74 (d, J=7.2Hz, 1H), 7.48 (d, J=7.6Hz, 1H), 7.38 (dd, J=7.2; 7.2Hz, 1H), 7.23 (dd, J=7.6,7.6Hz, 1H), 7.18-7.15 (m, 2H), 7.05 (d; J=8.0Hz, 1H), 6.85 (dd, J=8.0,8.0Hz, 1H), 6.59 (s, 1H); 5.08 (d, J=15.6Hz, 1H), 4.49 (d, J=15.6Hz, 1H), 3.71 (s, 3H).

Embodiment 1-26,2-(3-bromophenyl)-3-(4-ethoxyl phenenyl)-4-thiazolinone (AGT026)

Adopt similar method, the 3-N-methyl-p-nitroaniline be replaced as p-ethoxyaniline, get compd A GT026, productive rate 31% behind the column chromatography purification with preparation compd A GT019: ¹H NMR (400MHz, DMSO): δ 7.57 (s, 1H), 7.43-7.38 (m, 2H), 7.24 (dd, J=8.0,8.0Hz; 1H), 7.16 (d, J=8.0Hz, 2H), 6.82 (d, J=8.0Hz, 2H); 6.39 (s, 1H), 4.05 (d, J=15.6Hz, 1H), 3.92 (q, J=7.2Hz; 2H), 3.84 (d, J=15.6Hz, 1H), 1.25 (t, J=7.2Hz, 3H).

Embodiment 1-27,2-(3-hydroxy phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT027)

Adopt similar method, the 3-bromobenzaldehyde be replaced as m-hydroxybenzaldehyde, the 3-N-methyl-p-nitroaniline is replaced as ORTHO ANISIDINE, get compd A GT027, productive rate 39% behind the column chromatography purification with preparation compd A GT019: ¹H NMR (300MHz, DMSO): δ 9.40 (br s, 1H), 7.19 (dd, J=7.2,7.2Hz, 1H); 7.02-6.97 (m, 3H), 6.81 (d, J=7.2Hz, 1H), 6.76-6.74 (m, 2H); 6.59 (d, J=7.5Hz, 1H), 6.04 (s, 1H), 3.94 (d, J=15.3Hz; 1H), 3.89 (d, J=15.3Hz, 1H), 3.76 (s, 3H).

Embodiment 1-28,2-(3-bromophenyl)-3-(4-hydroxy phenyl)-4-thiazolinone (AGT028)

Adopt similar method, the 3-N-methyl-p-nitroaniline be replaced as para hydroxybenzene amine, get compd A GT028, productive rate 38% behind the column chromatography purification with preparation compd A GT019: ¹H NMR (300MHz, DMSO): δ 9.49 (br s, 1H), 7.54 (s, 1H), 7.42-7.35 (m, 2H), 7.32 (dd; J=7.8,7.8Hz, 1H), 7.02 (d, J=8.7Hz, 2H), 6.65-6.62 (m, 2H); 6.30 (s, 1H), 4.03 (d, J=15.3Hz, 1H), 3.80 (d, J=15.3Hz, 1H).

Embodiment 1-29,2-(3-bromophenyl)-3-(2-aminophenyl)-4-thiazolinone (AGT029)

Adopt similar method, the 3-N-methyl-p-nitroaniline be replaced as O-Phenylene Diamine, get compd A GT029, productive rate 32% behind the column chromatography purification with preparation compd A GT019: ¹H NMR (300MHz, DMSO): δ 7.63-7.61 (m, 2H), 7.59-7.55 (m, 1H), 7.35-7.33 (m, 2H); 7.18 (dd, J=7.2Hz, 7.2Hz, 1H), 7.09 (dd, J=7.2Hz; 7.2Hz, 1H), 6.92-6.89 (m, 1H), 6.86 (s, 1H); 4.68 (d, J=14.7Hz, 1H), 4.41 (d, J=14.7Hz, 1H).

Embodiment 1-30,2-(2-furyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT0030)

Adopt similar method, the 3-bromobenzaldehyde be replaced as furans-2-formaldehyde, the 3-N-methyl-p-nitroaniline is replaced as ORTHO ANISIDINE, get compd A GT030, productive rate 65% behind the column chromatography purification with preparation compd A GT019: ¹H NMR (300MHz, CDCl ₃): δ 7.40-7.37 (m, 1H), 7.29-7.24 (m, 1H), 6.94-6.91 (m, 2H), 6.86 (dd, J=7.2,7.2Hz, 1H), 6.21 (d, J=6.9Hz, 2H), 6.05 (s, 1H), 4.02 (d, J=15.6Hz, 1H), 3.85 (s, 3H), 3.78 (d, J=15.6Hz, 1H).

Embodiment 1-31,2-(2-thienyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT031)

Adopt similar method, the 3-bromobenzaldehyde be replaced as thiophene-2-formaldehyde, the 3-N-methyl-p-nitroaniline is replaced as ORTHO ANISIDINE, get compd A GT031, productive rate 31% behind the column chromatography purification with preparation compd A GT019: ¹H NMR (400MHz, DMSO): δ 7.47 (d, J=8.0Hz, 1H), 7.24 (dd, J=8.0,8.0Hz; 1H), 7.04 (d, J=8.0Hz, 1H), 6.95-6.92 (m, 2H), 6.83 (d; J=7.2Hz, 1H), 6.80-6.78 (m, 1H), 6.47 (s, 1H), 3.92 (d; J=15.6Hz, 1H), 3.84 (d, J=15.6Hz, 1H), 3.77 (s, 3H).

Embodiment 1-32,2-(4-(2-propionyloxy) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT032)

(590mg 1.59mmol) is dissolved in the 16ml methyl alcohol, and ice bath dropping Lithium Hydroxide MonoHydrate (spend the night at ambient temperature then for 267mg, aqueous solution 6.35mmol) (4ml) by reaction under nitrogen atmosphere to get compd A GT011.It is acid to add 3M hydrochloric acid furnishing, with ethyl acetate extraction twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Obtain compd A GT032 (370mg, 65%) through column chromatography purification: ¹H NMR (400MHz, CDCl ₃): δ 7.25-7.20 (m, 4H), 7.10 (dd, J=7.6,7.6Hz, 1H), 7.01 (d; J=8.0Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 6.81 (dd, J=7.6; 7.6Hz, 1H), 6.32 (s, 1H), 4.00-3.92 (m, 2H), 3.83 (s; 3H), 3.66 (q, J=7.2Hz, 1H), 1.44 (d, J=7.2Hz, 3H).

Embodiment 1-33,2-(3-formyloxy phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT033)

Adopt similar method, only compd A GT011 be replaced as AGT012, obtain compd A GT033 behind the column chromatography purification, productive rate 69% with preparation compd A GT032: ¹H NMR (300MHz, CDCl ₃): δ 8.07 (s, 1H), 7.97 (d, J=7.8Hz, 1H), 7.59 (d, J=7.8Hz; 1H), 7.38 (dd, J=7.8,7.8Hz, 1H), 7.21-7.16 (m, 1H); 6.94-6.92 (m, 1H), 6.87-6.85 (m, 1H), 6.83-6.78 (m, 1H); 6.17 (s, 1H), 4.03-3.90 (m, 2H), 3.84 (s, 3H).Embodiment 1-34,2-(3-formyloxy phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone (AGT034)

Adopt similar method, only AGT011 be replaced as AGT015, get compd A GT035, productive rate 88% behind the column chromatography purification with preparation compd A GT032: ¹H NMR (300MHz, DMSO): δ 7.94 (s, 1H), 7.81 (d, J=7.5Hz, 1H), 7.64 (d, J=7.5Hz, 1H); 7.41 (dd, J=7.5,7.5Hz, 1H), 6.87 (d, J=8.7Hz, 1H), 6.53 (d; J=2.4Hz, 1H), 6.37 (dd, J=2.4,8.7Hz, 1H), 6.17 (s, 1H); 4.01-3.96 (m, 1H), 3.86-3.81 (m, 1H), 3.73 (s, 3H), 3.68 (s, 3H).

Embodiment 1-35,2-(4-(2-acetoxyl) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT035)

Adopt similar method, only compd A GT011 be replaced as AGT014, get compd A GT035, productive rate 85% behind the column chromatography purification with preparation compd A GT032: ¹H NMR (300MHz, CDCl ₃): δ 7.30-7.28 (m, 2H), 7.22-7.16 (m, 3H), 6.91-6.85 (m, 2H), 6.79-6.76 (m, 1H), 6.08 (m, 1H), 3.98-3.85 (m, 2H), 3.82 (s, 3H), 3.58 (s, 2H).

Embodiment 1-36,2-(4-(2-(N-Phenylpropionamide)) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT036)

Get 2-(4-formyl radical phenyl) propionic acid (267mg, 1.5mmol), EDC (374mg; 1.95mmol) and HOBt (223mg is 1.65mmol) in flask, when 0 ° of C; 5ml DMF is injected in nitrogen protection; (0.18ml, 1.95mmol), 15min recession deicing is bathed normal temperature and was reacted 3 hours down to drip aniline behind the 5min.Concentrating under reduced pressure is the corresponding amides crude product behind the ethyl acetate extraction.With this midbody (152mg, 0.62mmol) and ORTHO ANISIDINE (0.07ml 0.62mmol) prepares compd A GT036 (82mg, 30%) by the method for preparing AGT001: ¹H NMR (300MHz, CDCl ₃): δ 7.35-7.31 (m, 4H), 7.27-7.24 (m, 3H), 7.18-7.06 (m, 3H), 6.92-6.69 (m, 3H), 6.12 (s, 1H), 3.93-3.91 (m, 2H), 3.81 (s, 3H), 3.63 (q, J=6.9Hz, 1H), 1.51 (d, J=6.9Hz, 3H).

Embodiment 1-37,2-(4-(N, N-diethylbenzene methane amide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT037)

Adopt similar method, 2-(4-formyl radical phenyl) propionic acid be replaced as p formyl benzoic acid, aniline is replaced as diethylamine, get compd A GT038, productive rate 56% behind the column chromatography purification with preparation compd A GT036: ¹H NMR (300MHz, CDCl ₃): δ 7.35 (d, J=8.1Hz, 2H), 7.26 (d, J=8.1Hz, 2H), 7.22-7.16 (m; 1H), 6.91-6.84 (m, 2H), 6.79 (dd, J=7.5,7.5Hz, 1H); 6.11 (s, 1H), 3.93-3.90 (m, 2H), 3.83 (s, 3H), 3.49 (br s; 2H), 3.16 (br s, 2H), 1.21 (br s, 3H), 1.05 (br s, 3H).

Embodiment 1-38,2-(4-(N-(4-fluorophenyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT038)

Adopt similar method, 2-(4-formyl radical phenyl) propionic acid be replaced as the 3-carboxyl benzaldehyde, aniline is replaced as the 4-flunamine, get compd A GT038, productive rate 70% behind the column chromatography purification with preparation compd A GT036: ¹H NMR (300MHz, CDCl ₃): δ 7.77 (s, 1H), 7.63 (d, J=7.5Hz, 1H), 7.48 (d, J=7.5Hz, 1H); 7.34-7.27 (m, 3H), 7.20-7.14 (m, 1H), 7.05-6.99 (m, 2H), 6.91-6.88 (m, 1H); 6.85-6.82 (m, 1H), 6.79-6.74 (m, 1H), 6.53-6.50 (m, 1H), 6.13 (s, 1H); 4.55 (d, J=5.7Hz, 2H), 3.97-3.83 (m, 2H), 3.79 (s, 3H).

Embodiment 1-39,2-(4-(N-(3-fluorophenyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT039)

Adopt similar method, 2-(4-formyl radical phenyl) propionic acid be replaced as the 3-carboxyl benzaldehyde, aniline is replaced as the 3-flunamine, get compd A GT039, productive rate 55% behind the column chromatography purification with preparation compd A GT036: ¹H NMR (300MHz, CDCl ₃): δ 7.78 (s, 1H), 7.65 (d, J=7.5Hz, 1H), 7.48 (d, J=7.5Hz, 1H), 7.34-7.29 (m; 2H), and 7.19-7.13 (m, 1H), 7.10-7.07 (m, 1H), 7.02-6.94 (m, 2H), 6.91-6.88 (m; 1H), and 6.85-6.82 (m, 1H), 6.79-6.74 (m, 1H), 6.66 (t, J=5.1Hz, 1H) 6.13 (s; 1H), 4.56 (d, J=5.7Hz, 1H), 3.96-3.82 (m, 2H), 3.78 (s, 3H).

Embodiment 1-40,2-(4-(N-(4-trifluoromethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT040)

Adopt similar method, 2-(4-formyl radical phenyl) propionic acid be replaced as the 3-carboxyl benzaldehyde, aniline is replaced as the 4-trifluoromethyl benzylamine, get compd A GT040, productive rate 56% behind the column chromatography purification with preparation compd A GT036: ¹H NMR (300MHz, CDCl ₃): δ 7.79 (s, 1H), 7.67-7.64 (m, 1H), 7.61-7.58 (m, 2H), 7.51-7.48 (m, 1H); 7.45-7.42 (m, 2H), 7.36-7.31 (m, 1H), 7.20-7.15 (m, 1H), 6.92-6.89 (m, 1H); 6.86-6.83 (m, 1H), 6.80-6.75 (m, 1H), 6.61 (t, J=5.1Hz, 1H), 6.13 (s; 1H), 4.64 (d, J=5.7Hz, 1H), 3.98-3.84 (m, 2H), 3.79 (s, 3H).

Embodiment 1-41,2-(4-(N, N-diethylbenzene methane amide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT041)

Get compd A GT033 (100mg, 0.3mmol), EDC (76mg; 0.4mmol) and HOBt (45mg, 0.33mmol) in flask, the nitrogen protection ice bath injects 3ml DMF down; (0.04ml, 0.4mmol), thorough ice bath normal temperature reacted 3 hours down after 15 minutes to drip diethylamine after 5 minutes.Add the water deactivation, with ethyl acetate extraction twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Obtain compd A GT041 (50mg, 32%) through column chromatography purification: ¹H NMR (300MHz, CDCl ₃): δ 7.41-7.39 (m, 1H), 7.32-7.27 (m, 3H), 7.21-7.15 (m, 1H); 6.90-6.85 (m, 2H), 6.81-6.76 (m, 1H), 6.10 (s, 1H); 3.98-3.87 (m, 2H), 3.83 (s, 3H), 3.56-3.44 (m, 2H); 3.11-3.01 (m, 2H), 1.25-1.16 (m, 3H), 1.06-0.94 (m, 3H).

Embodiment 1-42,2-(4-(N-propyl benzamide) phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone (AGT053)

Adopt similar method, AGT033 be replaced as AGT034, diethylamine is replaced as Tri N-Propyl Amine, get compd A GT042, productive rate 79% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.72 (s, 1H), 7.62 (d, J=7.5Hz, 1H), 7.48 (d, J=7.5Hz, 1H), 7.34 (dd, J=7.5; 7.5Hz, 1H), 6.78 (d, J=8.7Hz, 1H), 6.41 (d, J=2.4Hz, 1H), 6.29 (dd; J=2.4,8.7Hz, 1H), 6.05 (s, 1H), 3.98-3.86 (m, 2H), 3.80 (s, 3H); 3.71 (s, 3H), 3.43-3.36 (m, 2H), 1.64-1.62 (m, 2H), 0.98 (t, J=7.2Hz, 3H).

Embodiment 1-43,2-(4-(N-ETHYLE ACETATE BM) phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone (AGT043)

Adopt similar method, AGT033 be replaced as AGT034, diethylamine is replaced as glycine ethyl ester, get compd A GT043, productive rate 42% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, DMSO): δ 9.01-8.97 (m, 1H), 7.94 (s, 1H), 7.75 (d, J=7.5Hz, 1H), 7.53 (d, J=7.5Hz, 1H); 7.38 (dd, J=7.5,7.5Hz, 1H), 6.90 (d, J=8.7Hz, 1H), 6,54 (d, J=2.4Hz, 1H); 6.37 (dd, J=2.4,8.7Hz, 1H), 6.11 (s, 1H), 4.05-4.02 (m, 1H), 3.99 (s, 2H); 3.86-3.83 (m, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.65 (s, 2H), 1.26-1.24 (m, 3H).

Embodiment 1-44,2-(3-(N-(3-hydrocinnamyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT044)

Adopt similar method, only diethylamine be replaced as amphetamine, get compd A GT044, productive rate 90% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.64 (s, 1H), 7.50-7.47 (m, 2H), 7.33-7.27 (m, 2H), 7.21-7.15 (m, 4H); 6.91-6.88 (m, 1H), 6.86-6.84 (m, 1H), 6.80-6.75 (m, 1H), 6.12 (s; 1H), 6.08 (t, J=5.1Hz, 1H), 3.99-3.87 (m, 2H), 3.82 (s; 3H), and 3.49-3.42 (m, 2H), 2.73-2.68 (m, 2H), 1.99-1.89 (m, 2H).

Embodiment 1-45,2-(3-(N-(4-benzene butyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT056)

Adopt similar method, only diethylamine be replaced as PHENTERMINE, get compd A GT045, productive rate 93% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.69 (s, 1H), 7.58 (d, J=7.5Hz, 1H), 7.49 (d, J=7.5Hz, 1H), 7.35-7.29 (m; 3H), and 7.21-7.15 (m, 4H), 6.91-6.88 (m, 1H), 6.86-6.84 (m, 1H), 6.81-6.76 (m; 1H), 6.13 (s, 1H), 6.03 (t, J=5.1Hz, 1H), 3.99-3.88 (m, 2H); 3.82 (s, 3H), 3.47-3.40 (m, 2H), 2.69-2.64 (m, 2H), 1.75-1.1.64 (m, 4H).

Embodiment 1-46,2-(3-(N-(4-bromobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT046)

Adopt similar method, only diethylamine be replaced as the 4-Bretylium Tosylate, get compd A GT046, productive rate 88% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.67 (s, 1H), 7.54-7.50 (m, 2H), 7.47-7.43 (m, 2H), 7.35-7.30 (m, 1H); 7.22-7.16 (m, 1H), 7.11-7.08 (m, 2H), 6.89-6.84 (m, 2H), 6.81-6.76 (m; 1H), 6.12 (s, 1H), 6.04 (t, J=5.1Hz, 1H), 3.99-3.88 (m; 2H), 3.81 (s, 3H), 3.69-3.62 (m, 2H), 2.90-2.85 (m, 2H).

Embodiment 1-47,2-(3-(N-(4-leptodactyline) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT047)

Adopt similar method, only diethylamine be replaced as the 4-hydroxyphenethylamine, get compd A GT047, productive rate 90% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.64-7.63 (m, 1H), 7.55 (s, 1H), 7.28-7.26 (m, 3H), 7.23-7.18 (m, 1H); 7.11-7.08 (m, 2H), 6.88-6.81 (m, 3H), 6.78-6.75 (m, 1H), 6.05 (s; 1H), 6.00 (t, J=5.1Hz, 1H), 3.99-3.88 (m, 2H), 3.80 (s; 3H), and 3.78-3.71 (m, 1H), 3.61-3.52 (m, 1H), 2.90-2.84 (m, 2H).

Embodiment 1-48,2-(3-(N-(4-chlorobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT048)

Adopt similar method, only diethylamine be replaced as 4-chlorobenzene ethamine, get compd A GT048, productive rate 88% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.67 (s, 1H), 7.54-7.47 (m, 2H), 7.34-7.27 (m, 3H), 7.19-7.13 (m; 3H), and 6.89-6.84 (m, 2H), 6.81-6.76 (m, 1H), 6.12 (s; 1H), 6.06 (t, J=5.1Hz, 1H), 3.99-3.87 (m, 2H); 3.81 (s, 3H), 3.69-3.62 (m, 2H), 2.91-2.87 (m, 2H).

Embodiment 1-49,2-(3-(N-4-anisole ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT049)

Adopt similar method, only diethylamine be replaced as 4-anisole ethamine, get compd A GT049, productive rate 89% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.67 (s, 1H), 7.53-7.45 (m, 2H), 7.33-7.28 (m, 1H), 7.18-7.13 (m; 3H), and 6.89-6.83 (m, 4H), 6.80-6.75 (m, 1H), 6.12 (s; 1H), 6.05 (t, J=5.1Hz, 1H), 3.99-3.85 (m, 2H); 3.80 (s, 3H), 3.68-3.62 (m, 2H), 2.88-2.83 (m, 2H).

Embodiment 1-50,2-(3-(phenyl acetanilide,Phenacetylaniline) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT050)

Adopt similar method, AGT033 be replaced as AGT035, diethylamine is replaced as aniline, get compd A GT050, productive rate 88% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.38-7.35 (m, 2H), 7.32-7.30 (m, 2H), 7.28-7.24 (m, 2H), 7.22-7.17 (m, 2H); 7.11-7.06 (m, 1H), 6.93-6.85 (m, 3H), 6.82-6.77 (m, 1H), 6.14 (s; 1H), 3.40-3.89 (m, 2H), 3.84 (s, 3H), 3.66 (s, 2H).

Embodiment 1-51,2-(3-(N-(4-fluorobenzene butyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT051)

Adopt similar method, only diethylamine be replaced as 4-fluorobenzene butylamine, obtain compd A GT051 (70mg, 86%) through column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.71 (s, 1H), 7.58 (d, J=7.5Hz, 1H), 7.49 (d, J=7.5Hz, 1H), 7.35-7.30 (m; 1H), and 7.21-7.10 (m, 3H), 6.99-6.93 (m, 2H), 6.92-6.84 (m, 2H), 6.81-6.76 (m; 1H), 6.13 (s, 1H), 6.00 (t, J=5.1Hz, 1H), 3.99-3.87 (m, 2H); 3.83 (s, 3H), 3.47-3.41 (m, 2H), 2.66-2.61 (m, 2H), 1.71-1.56 (m, 4H).

Embodiment 1-52,2-(3-(N-(4-fluorobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT052)

Adopt similar method, only diethylamine be replaced as the 4-fluorophenethylamine, obtain compd A GT052 through column chromatography purification, productive rate 89% with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.68 (s, 1H), 7.53-7.46 (m, 2H), 7.34-7.29 (m, 1H), 7.21-7.15 (m; 3H), and 7.03-6.98 (m, 2H), 6.89-6.84 (m, 2H), 6.81-6.76 (m, 1H); 6.12 (s, 1H), 6.09 (t, J=5.1Hz, 1H), 3.99-3.87 (m, 2H); 3.81 (s, 3H), 3.68-3.62 (m, 2H), 2.91-2.87 (m, 2H).

Embodiment 1-53,2-(3-(N-(2-bromobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT053)

Adopt similar method, only diethylamine be replaced as the 2-Bretylium Tosylate, get compd A GT053, productive rate 86% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.69 (s, 1H), 7.5-7.56 (m, 2H), 7.48-7.45 (m, 1H), 7.34-7.29 (m, 1H); 7.26-7.25 (m, 2H), 7.21-7.11 (m, 2H), 6.88-6.84 (m, 2H), 6.80-6.75 (m; 1H), 6.17 (t, J=5.1Hz, 1H), 6.12 (s, 1H), 3.99-3.88 (m; 2H), 3.81 (s, 3H), 3.74-3.68 (m, 2H), 3.11-3.06 (m, 2H).

Embodiment 1-54,2-(3-(N-(6-benzene hexyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT054)

Adopt similar method, only diethylamine be replaced as the benzene hexylamine, get compd A GT054, productive rate 74% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.71 (s, 1H), 7.59 (d, J=7.5Hz, 1H), 7.48 (d, J=7.5Hz, 1H), 7.36-7.25 (m; 4H), and 7.18-7.16 (m, 3H), 6.92-6.85 (m, 2H), 6.82-6.77 (m, 1H), 6.14 (s; 1H), 6.02 (t, J=5.1Hz, 1H), 3.99-3.88 (m, 2H), 3.83 (s, 3H); 3.44-3.37 (m, 2H), 2.63-2.58 (m, 2H), 1.65-1.59 (m, 4H), 1.46-1.34 (m, 4H).

Embodiment 1-55,2-(3-(N-(5-benzene amyl group) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT055)

Adopt similar method, only diethylamine be replaced as the 5-liprodene, get compd A GT055, productive rate 93% behind the column chromatography purification with preparation compd A GT041: ¹H NMR (300MHz, CDCl ₃): δ 7.71 (s, 1H), 7.57 (d, J=7.5Hz, 1H), 7.50 (d, J=7.5Hz, 1H), 7.35-7.30 (m; 1H), and 7.29-7.25 (m, 3H), 7.21-7.16 (m, 3H), 6.92-6.85 (m, 2H), 6.82-6.77 (m, 1H); 6.14 (s, 1H), 6.04 (t, J=5.1Hz, 1H), 3.99-3.88 (m, 2H), 3.83 (s, 3H); 3.44-3.37 (m, 2H), 2.65-2.60 (m, 2H), 1.73-1.58 (m, 4H), 1.45-1.37 (m, 2H).

Embodiment 1-56,2-(3-bromophenyl)-3-(2, the 4-dihydroxy phenyl)-4-thiazolinone (AGT056)

Get compd A GT004 (394mg, 1mmol) and boron tribromide (0.3ml, 3mmol) in the 5ml methylene dichloride, room temperature reaction is 4 hours under nitrogen atmosphere.With ethyl acetate extraction twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Obtain compd A GT056 (322mg, 88%) through column chromatography purification: ¹HNMR (300MHz, DMSO): δ 9.75 (br s, 1H), 9.37 (br s, 1H), 7.63-7.59 (m, 1H), 7.43-7.41 (m, 1H); 7.20 (dd, J=7.8,7.8Hz, 2H), 7.24 (dd, J=7.8,7.8Hz, 1H), 6.64 (d; J=8.7Hz, 1H), 6.28 (d, J=2.4Hz, 1H), 6.08 (s, 1H), 6.07-6.04 (m; 1H), 3.98 (dd, J=15.6,1.8Hz, 1H), 3.76 (d, J=15.6Hz, 1H).

Embodiment 1-57,2-(3-bromophenyl)-3-(4-hydroxyl-2-p-methoxy-phenyl)-4-thiazolinone (AGT057)

(1g is 2.54mmol) in 20ml1, in the 2-ethylene dichloride to get compd A GT004; Ice bath stirs under nitrogen atmosphere, and the adding Aluminum chloride anhydrous (338mg, 2.54mmol); 0.5 hour recession ice bath stirred under the room temperature 0.5 hour, after be warming up to 70 ℃; (2.54mg 2.54mmol), is warming up to 80 ° of C reaction overnight to add Aluminum chloride anhydrous after 4 hours.With ethyl acetate extraction twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Obtain compd A GT057 (340mg, 35%) through column chromatography purification: ¹H NMR (300MHz, DMSO): δ 9.59 (br s, 1H), 7.59-7.54 (m, 1H), 7.43-7.41 (m, 1H), 7.37-7.34 (m; 1H), 7.23 (d, J=7.8Hz, 1H), 6.72 (d, J=8.7Hz, 1H), 6.35 (d; J=2.4Hz, 1H), 6.18 (dd, J=2.4,8.7Hz, 1H), 6.04-6.01 (m, 1H); 3.99 (d, J=15.6Hz, 1H), 3.76 (d, J=15.6Hz, 1H), 3.76 (s, 3H).

Embodiment 1-58,2-(4-(N-(2-phenyl-acetamides)) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT058)

Get 2-(3-aminophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (150mg, 0.5mmol), EDC (125mg; 0.65mmol) and HOBt (74mg; 0.55mmol) in flask, the nitrogen protection ice bath injects 5ml DMF down, adds phenylethylamine (0.08ml after 5 minutes; 0.65mmol), thorough ice bath normal temperature reacted 3 hours down after 15 minutes.Add the water deactivation, with ethyl acetate extraction twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Obtain product A GT058 (110mg, 53%) through column purification: ¹H NMR (300MHz, CDCl ₃): δ 7.86 (s, 1H), 7.35 (s, 1H), 7.23-7.20 (m, 3H), 7.16-7.11 (m, 3H); 7.04 (dd, J=6.6,6.6Hz, 2H), 6.88 (d, J=7.5Hz, 1H), 6.77 (d; J=7.8Hz, 1H), 6.66-6.61 (m, 2H), 5.88 (s, 1H), 3.80 (d, J=15.6Hz; 1H), 3.68 (d, J=15.6Hz, 1H), 3.81 (s, 3H), 3.52 (s, 2H).

Embodiment 1-59,2-(4-(N-(BM)) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT059)

Adopt and prepare the similar method of compd A GT058, phenylethylamine is replaced as aniline, obtain compd A GT059 behind the column chromatography purification, productive rate 76%: ¹H NMR (300MHz, CDCl ₃): δ 8.04 (s, 1H), 7.82 (d, J=7.8Hz, 2H), 7.72 (s, 1H), 7.52 (d, J=7.8Hz, 2H); 7.45 (dd, J=7.5,7.5Hz, 2H), 7.22 (d, J=7.8Hz, 1H), 7.15 (d, J=7.8Hz, 1H); 7.07 (d, J=7.5Hz, 1H), 6.94 (d, J=7.5Hz, 1H), 6.85-6.74 (m, 2H), 6.08 (s; 1H), 3.95 (d, J=15.6Hz, 1H), 3.86 (d, J=15.6Hz, 1H), 3.81 (s, 3H).

Embodiment 1-60,2-(3-(methylol) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT060)

Get 3-methylol phenyl aldehyde (47mg, 0.35mmol) and ORTHO ANISIDINE (0.04ml 0.35mmol) is dissolved in the 5ml toluene, under nitrogen atmosphere, stirs under the condition of ice bath after 5 minutes, changes oil bath into and is heated to backflow, connects water-and-oil separator on the device.To there not being water generates, the postcooling that finishes, add Thiovanic acid (0.05ml 0.7mmol) continues to be heated to backflow, treats that the branch water back concentrating under reduced pressure that finishes obtains crude product, obtains compd A GT060 (80mg, 73%) through column chromatography purification: ¹H NMR (300MHz, CDCl ₃): δ 7.33 (s, 1H), 7.25-7.17 (m, 4H), 6.92-6.86 (m, 2H), 6.80 (dd, J=7.8Hz, 7.8Hz, 1H), 6.10 (s, 1H), 4.63 (s, 2H), 3.99-3.92 (m, 2H), 3.84 (s, 3H).

Embodiment 1-61,2-(3-(brooethyl) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT061)

(100mg 0.32mmol) is dissolved in the 5ml methylene dichloride, and under nitrogen atmosphere, (0.03ml, 0.32mmol), reaction is 4 hours under the room temperature to drip boron tribromide to get compd A GT060.With ethyl acetate extraction twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Obtain product A GT061 (94mg, 78%) through column chromatography purification: ¹H NMR (300MHz, CDCl ₃): 7.38 (s, 1H), 7.25-7.23 (m, 3H), 7.20-7.17 (m, 1H), 6.93-6.86 (m, 2H), 6.83-6.78 (m, 1H), 6.08 (s, 1H), 4.42-4.41 (m, 2H), 3.94-3.93 (m, 2H), 3.84 (s, 3H).

Embodiment 1-62,2-(3-bromophenyl)-3-(4-amino-2-p-methoxy-phenyl)-4-thiazolinone (AGT062)

(263mg, 1.1mmol) (0.13ml 1.1mmol) obtains corresponding thiazoline ketone midbody by the method for preparing AGT001 with the 3-bromobenzaldehyde to get 2-methoxyl group-4-Boc amino-aniline.(527mg 1.1mmol) is dissolved among the 10ml DCM, and ice bath adds the 2ml trifluoroacetic acid under nitrogen atmosphere, reacts 3 hours under the room temperature after 0.5 hour with this midbody.Add 3M Pottasium Hydroxide furnishing alkalescence, with ethyl acetate extraction twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Obtain compd A GT062 (363mg, 87%) through column chromatography purification: ¹H NMR (300MHz, CDCl ₃): δ 7.52 (s, 1H), 7.38-7.35 (m, 1H), 7.21-7.19 (m, 1H), 7.11 (dd; J=7.8Hz, 7.8Hz, 1H), 6.63 (d, J=8.4Hz, 1H), 6.16-6.15 (m; 1H), 6.10-6.07 (m, 1H), 5.89 (s, 1H), 3.96-3.90 (m, 1H); 3.87-3.82 (m, 1H), 3.75 (s, 3H), 3.70-3.67 (m, 2H).

Embodiment 1-63,2-(3-(3-pyridyl) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT063)

Get 3-pyridine phenyl aldehyde (69mg, 0.38mmol) and ORTHO ANISIDINE (0.04ml 0.38mmol) is dissolved in the 5ml toluene, under nitrogen atmosphere, stirs under the condition of ice bath after 5 minutes, changes oil bath into and is heated to backflow, connects water-and-oil separator on the device.To there not being water generates, the postcooling that finishes, add Thiovanic acid (0.05ml 0.76mmol) continues to be heated to backflow, treats that the branch water back concentrating under reduced pressure that finishes gets crude product, obtains compd A GT063 (70mg, 51%) through column chromatography purification: ¹H NMR (300MHz, CDCl ₃): δ 8.73 (s, 1H), 8.59-8.58 (m, 1H), 7.81-7.78 (m, 1H), 7.51 (s, 1H); 7.44-7.35 (m, 4H), 7.23-7.18 (m, 1H), 6.97-6.95 (m, 1H), 6.89-6.87 (m, 1H); 6.85-6.80 (m, 1H), 6.18 (s, 1H), 4.01-3.89 (m, 2H), 3.83 (s, 3H).

Embodiment 1-64,2-(3-bromophenyl)-3-(2-p-methoxy-phenyl)-4-oxazolinyl ketone (AGT064)

Get the 2-oxyacetic acid (990mg, 13mmol), EDC (3.24g; 16.9mmol) and HOBt (1.94g, 14.3mmol) in flask, ice bath injects 20ml DMF under the nitrogen atmosphere; (112ml, 10mmol), thorough ice bath normal temperature reacted 3 hours down after 15 minutes to drip ORTHO ANISIDINE after 5 minutes.Obtain corresponding midbody through ethyl acetate extraction and column chromatography purification.Get this midbody (544mg, 3mmol) and tosic acid (112mg 0.6mmol) is dissolved in the YLENE, stirring at room a little while, add then the 3-bromobenzaldehyde (0.7ml, 6mmol), 140 ℃ of reflux water-dividings 4 hours.Concentrating under reduced pressure gets crude product, obtains compd A GT064 (762mg, 73%) through column chromatography purification: ¹H NMR (300MHz, CDCl ₃): δ 7.54-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.23-7.13 (m, 3H), 6.98-6.95 (m, 1H), 6.90-6.83 (m; 2H), 6.41 (s, 1H), 4.67 (dd, J=14.1,1.2Hz, 1H), 4.56 (dd; J=14.1,1.2Hz, 1H), 3.84 (s, 3H), 3.83 (d, J=15.6Hz, 1H).

Embodiment 1-65,2-(3-bromophenyl)-3-(2, the 4-Dimethoxyphenyl)-4-oxazolinyl ketone (AGT065)

Adopt and prepare the similar method of compd A GT064, ORTHO ANISIDINE is replaced as 2, the 4-dimethoxyaniline obtains compd A GT064 behind column chromatography purification, productive rate 48%: ¹H NMR (300MHz, CDCl ₃): δ 7.55-7.53 (m, 1H), 7.47-7.43 (m, 1H), 7.22-7.14 (m, 2H), 6.81 (d, J=8.7Hz; 1H), 6.44 (d, J=2.4Hz, 1H), 6.35 (dd, J=8.7,2.4Hz, 1H); 6.33-6.28 (m, 1H), 4.67 (dd, J=13.8,1.8Hz, 1H), 4.55 (dd; J=13.8,1.8Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H).

Embodiment 1-66,2-(3-bromophenyl)-3-(2-(dimethylamino) phenyl)-4-thiazolinone (AGT066)

Get AGT029 (150mg, 0.43mmol) and salt of wormwood (297mg, mmol) in 5ml DMF, stirring at room is 0.5 hour under nitrogen atmosphere, add methyl iodide (0.1ml, 1.72mmol), stirred overnight under the room temperature.Add the water deactivation, with ethyl acetate extraction twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Obtain product A GT066 (20mg, 15%) through column chromatography purification: ¹H NMR (300MHz, DMSO): δ 7.52-7.51 (m, 1H), 7.40-7.31 (m, 2H), 7.18 (dd, J=7.5Hz; 7.5Hz, 1H), and 7.15-7.09 (m, 1H), 7.00-6.92 (m, 2H), 6.84 (dd; J=7.5Hz, 7.5Hz, 1H), 6.43 (s, 1H), 4.11 (d, J=15.9Hz; 1H), 3.83 (d, J=15.9Hz, 1H), 2.66 (s, 6H).

Embodiment 1-67,2-(3-bromophenyl)-3-(3-aminophenyl)-4-thiazolinone (AGT067)

Get compd A GT019 (160mg, 0.42mmol), iron powder (118mg; 2.1mmol) and ammonium chloride (45mg is 0.84mmol) in the mixed solvent of 9ml ethanol and 3ml water, under nitrogen atmosphere; Get crude product in 80 ° of C refluxed, obtain product A GT067 (102mg, 70%) through column chromatography purification: ¹H NMR (400MHz, DMSO): δ 7.55 (s, 1H), 7.44 (d, J=8.0Hz, 1H), 7.37 (d, J=8.0Hz; 1H), 7.27 (dd, J=8.0Hz, 8.0Hz, 1H), 6.90 (dd, J=8.0Hz; 8.0Hz, 1H), 6.51 (s, 1H), 6.38-6.33 (m, 3H), 5.16 (s; 2H), 4.03 (d, J=15.6Hz, 1H), 3.81 (d, J=15.6Hz, 1H).

Claims (18)

1. one kind 2,3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt is characterized in that, it is represented by following structural formula (I):

Wherein:

X is S, O or NH;

N is 0,1,2 or 3;

Ar ₁, Ar ₂Be any one in monocycle aromatic base, many cyclophanes perfume base, the many heterocyclic aromatic bases; Said monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Said many cyclophanes perfume base and many heterocyclic aromatic bases are meant the group that comprises two and plural monocycle aromatic base.

R is selected from any in the following groups: hydrogen; Substituted alkyl; Hydroxyl; Methylol; Replace C ₂-C ₆Thiazolinyl; Replace C ₂-C ₆Alkynyl; Substituted cycloalkyl; Any one, two, three, four or five substituted substituted aryls of group; The substituted heterocyclic aryl of one or more groups; Substituted benzyl; The substituted benzene ethyl; Hydrocinnamyl; Replace alkyloyl; Replace aroyl; C ₂-C ₆Enoyl-; C ₃-C ₈The cycloalkanes acyl group; Adamantyl; Cycloalkyloxy; The cycloalkanes amido; Amido; Carboxamido-group; Carbalkoxy; Cycloalkoxycarbonyl; Alkyl amide; The cycloalkanes carboxamido-group; Carboxyl.

2. according to claim 12,3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt is characterized in that, when n be 0, when R is hydrogen, it is represented by following structural formula (II):

Wherein,

X is S, O or NH;

Ar ₁, Ar ₂Be any one in monocycle aromatic base, many cyclophanes perfume base, the many heterocyclic aromatic bases; Said monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Said many cyclophanes perfume base and many heterocyclic aromatic bases are meant the group that comprises two and plural monocycle aromatic base.

3. according to claim 12,3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt is characterized in that, when n is 0, R is a hydrogen, X is S, Ar ₂Be Ar ₃-R ₁The time, it is represented by following structural formula (III):

Wherein:

Ar ₁, Ar ₃Be any in monocycle aromatic base, many cyclophanes perfume base, the many heterocyclic aromatic bases; Said monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Said many cyclophanes perfume base and many heterocyclic aromatic bases are meant the group that comprises two and plural monocycle aromatic base.

R ₁One or more arbitrarily in the following groups: hydrogen, amino, cyanic acid, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C ₂-C ₁₂Thiazolinyl, C ₂-C ₁₂Alkynyl, C ₃-C ₁₂Naphthenic base, benzyl, alkyl-carbonyl, C ₂-C ₁₂Alkenyl carbonyl, C ₃-C ₁₂Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, carboxamido-group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl.

4. according to claim 32,3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt is characterized in that, work as R ₁When replacing for chain, it is represented by following structural formula (IV):

Wherein,

M is 0,1,2,3,4,5,6,7,8 or 9;

X be O=, S=,=NH ,=N-NH2 ,-OH perhaps-H;

L is O, S, N or NH;

Ar ₁, Ar ₃, Ar ₄Be any one in monocycle aromatic base, many cyclophanes perfume base, the many heterocyclic aromatic bases; Said monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Said many cyclophanes perfume base and many heterocyclic aromatic bases are meant the group that comprises two and plural monocycle aromatic base.

5. according to each is described 2 among the claim 1-4,3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt is characterized in that, and be said 2, the acid salt that 3-two aromatic base thiazolinone compounds and acid form; Wherein, said acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, tartrate, Whitfield's ointment, Hydrocerol A, methylsulfonic acid, tosic acid, lactic acid, pyruvic acid, toxilic acid or succsinic acid.

According among the claim 1-5 each described 2; 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt; It is characterized in that said 2,3-two aromatic base thiazolinone compounds combine to form affinity tag with radioactivity group, fluorophor or vitamin H.

7. according to claim 12,3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt is characterized in that, comprising:

2-(3-bromophenyl)-3-(2-p-methoxy-phenyl)-phenyl-4-thiazolinone

2-(3-bromophenyl)-3-phenyl-4-thiazolinone

2-(3-bromophenyl)-3-(2-hydroxy phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone

2-(3-chloro-phenyl-)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-fluorophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2-thiazolyl)-4-thiazolinone

2-phenyl-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-nitrophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-p-methoxy-phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(2-methyl propionate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(1-methyl-formiate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(1-methyl-formiate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(2-methyl acetate) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(1-methyl-formiate) phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2-pyrimidyl)-4-thiazolinone

2-(4-pyridyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(2-quinolyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(3-nitrophenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2-p-methoxy-phenyl)-1,3-thiazine-4-ketone

2-(3-bromophenyl)-3-(3-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(4-(diethylin) phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(3-hydroxy phenyl)-4-thiazolinone

2-(4-bromophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(2-bromophenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(4-ethoxyl phenenyl)-4-thiazolinone

2-(3-hydroxy phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(4-hydroxy phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2-aminophenyl)-4-thiazolinone

2-(2-furyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(2-thienyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(2-propionyloxy) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-formyloxy phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-formyloxy phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone

2-(4-(2-acetoxyl) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(2-(N-Phenylpropionamide)) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(N, N-diethylbenzene methane amide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(N-(4-fluorophenyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(N-(3-fluorophenyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(N-(4-trifluoromethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N, N-diethylbenzene methane amide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-propyl benzamide) phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone

2-(3-(N-ETHYLE ACETATE BM) phenyl)-3-(2, the 4-Dimethoxyphenyl)-4-thiazolinone

2-(3-(N-(3-hydrocinnamyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-benzene butyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-bromobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-leptodactyline) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-chlorobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-4-anisole ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(phenyl acetanilide,Phenacetylaniline) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-fluorobenzene butyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(4-fluorobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(2-bromobenzene ethyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(6-benzene hexyl) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(5-benzene amyl group) BM) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2, the 4-dihydroxy phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(4-hydroxyl-2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(N-(2-phenyl-acetamides)) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(4-(N-(BM)) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(methylol) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(brooethyl) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(4-amino-2-p-methoxy-phenyl)-4-thiazolinone

2-(3-(3-pyridyl) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(2-p-methoxy-phenyl)-4-oxazolinyl ketone

2-(3-bromophenyl)-3-(2, the 4-Dimethoxyphenyl)-4-oxazolinyl ketone

2-(3-bromophenyl)-3-(2-(dimethylamino) phenyl)-4-thiazolinone

2-(3-bromophenyl)-3-(3-aminophenyl)-4-thiazolinone.

8. pharmaceutical composition contains wherein among the claim 1-4 that each is described 2,3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt, and pharmaceutically acceptable carrier.

9. pharmaceutical composition according to claim 8; It is characterized in that said pharmaceutical composition is formulated into injectable fluid, aerosol, emulsifiable paste, gelifying agent, tablet, granule, oral liquid, pill, capsule, syrup, transdermal patch or vehicle.

10. according to each is described 2 among the claim 1-4, the application in the preparation anti-angiogenic drugs of 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt.

11. according to each is described 2 among the claim 1-4, the application in the medicine of preparation treatment neovascular illness in eye of 3-two aromatic base thiazolinone compounds, hydrate or pharmacy acceptable salt.

12. application according to claim 11; It is characterized in that; Said neovascular illness in eye comprises neovascular retinal diseases, neovascular iris disease, neovascular glaucoma, neovascular choroidal diseases, neovascular vitreum illness in eye, or the neovascular optic nerve disease.

13. according to each is described 2 among the claim 1-4,3-two aromatic base thiazolinone compounds, hydrate or pharmacy acceptable salt are suppressing the application in the tumour through anti-angiogenic rebirth.

14. according to each is described 2 among the claim 1-4, the application in the medicine of preparation treatment arteriosclerosis disease of 3-two aromatic base thiazolinone compounds, hydrate or pharmacy acceptable salt.

15. according to each is described 2 among the claim 1-4, the application of 3-two aromatic base thiazolinone compounds in the medicine of preparation treatment of arthritis.

16. according to each is described 2 among the claim 1-4, the application in the medicine of preparation treatment psoriasis disease of 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt.

17. according to each is described 2 among the claim 1-4, the application in the medicine of preparation treatment mellitus and diabetic syndrome of 3-two aromatic base thiazolinone compounds or its hydrate or pharmacy acceptable salt.

18., it is characterized in that said medicine uses separately or unites use with other drug according to each described application among the claim 10-17.

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