embodiment
In conjunction with following specific embodiments and the drawings, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Do not deviating under the spirit and scope of inventive concept, variation and advantage that those skilled in the art can expect are all included in the present invention, and take appending claims as protection domain.Implement process of the present invention, condition, reagent, experimental technique etc., except the content of mentioning specially below, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
1h-NMR measures with Bruker300 or Bruker400 type instrument; MS measures with VG ZAB-HS or VG-7070 type instrument, except indicating, is ESI method; All solvents all pass through re-distillation before use, and the anhydrous solvent using is all to obtain by standard method drying treatment; Except explanation, it is all under argon shield, carry out and follow the tracks of with TLC that institute responds, and during aftertreatment, all through saturated common salt, washes and anhydrous sodium sulfate drying process; The purifying of product is all used the column chromatography of silica gel (200-300 order) except explanation; The silica gel using, comprises 200-300 order and GF
254for Haiyang Chemical Plant, Qingdao or the production of Yantai Yuan Bo silica gel company.
Embodiment mono-: 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, under condition of ice bath, stir after 5min, change oil bath into and be heated to reflux, on device, connect water-and-oil separator.To without water generates, after cooling, add compound Thiovanic acid (70 μ L, 1.0mmol) to continue to be heated to reflux, treat to obtain crude product after minute water, after 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 1-67, as following table 1.
Table 1 embodiment 1-1 to embodiment 1-67
Embodiment bis-: the screening of Human umbilical vein endothelial cells (HUVEC) inhibited proliferation
Object and principle: cell proliferation experiment adopts MTS assay.MTS assay is a kind of measuring method that uses colorimetry to determine cell proliferation quantity in viable cell.NADPH desaturase is transformed into a kind of replacing by a kind of coloring matter-first moon of tissue culture medium that be dissolved in by MTS tetrazolium salts compound, and its shade and viable cell number be height correlation within the specific limits.By this model, can evaluate the impact of medicine on cell proliferation ability.
Method: add Human umbilical vein endothelial cells in 96 orifice plates, control group and application of sample group are set, application of sample group adds testing compound, final concentration is 40 micromoles, hatches after 60~72 hours, adds cell proliferation detection reagent, hatch 1-3 hour, by microplate reader, at 490nm place, detect absorbance value.
Result and evaluation: experimental result as shown in Figure 1, compare with control group, part the compounds of this invention is as being suppressed the multiplication capacity of Human umbilical vein endothelial cells adding of AGT006, AGT037, AGT039, AGT049, AGT058, AGT062 and AGT065 etc.In addition, by the compounds of this invention with after biotin labeling, result can be found by experiment, with biotin labeled compound, tumour cell is there is equally the activity of the inhibition tumor cell propagation similar to non-labelled compound, and vitamin H itself is (Fig. 4 A) without inhibition tumor cell proliferation activity.
Embodiment tri-: 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
Object and principle: under the induction of serum, human umbilical vein's endotheliocyte can be to acellular scored area migration.By observation, moving into, whether the cell quantity in cut district how much to evaluate 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 containing growth in the substratum of 10% serum, converge to surface-area 80% after, change the hungry 6h of substratum containing 0.5% serum into.With Tip head, cell is carried out to cruciform scratching, sop up substratum, with PBS, clean the cell under drawing, add different concns (be respectively 1 micro-rubbing/liter, 5 micro-rubbing/liter, 10 micro-rubbing/liter, 20 micro-rubbing/liter, 40 micro-rubbing/liter) the compounds of this invention AGT005, containing being cultured to control group in the substratum of 10% serum, covering with.
Result and evaluation: examine under a microscope and take pictures, experimental result as shown in Figure 2, is compared 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 in experiment, add respectively the compounds of this invention AGT017, AGT019, AGT026, AGT037, AGT039, AGT045, AGT056 and AGT067, obtain experimental result as shown in Figure 2, these compounds all can significantly suppress the migration of human umbilical vein's endotheliocyte.In addition, by the compounds of this invention with after biotin labeling, by cell migration experimental result, can find, with biotin labeled compound, tumour cell is there is equally the activity of the inhibition tumor cell migration similar to non-labelled compound, and vitamin H itself is (Fig. 4 B) without inhibition tumor cell migratory activity.
Embodiment 3-2: the compounds of this invention suppresses the migration of human umbilical vein's endotheliocyte (HUVEC) Boyden cell
Object and principle: Boyden cell is that a class can be placed in 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 is placed in the substratum containing chemokine, and under the induction of chemokine, the attached cell of film internal surface can move to by the micropore on film the outside surface of film.This experiment can detection compound Human Umbilical Vein Endothelial Cells has the impact of resistance transfer ability.
Method: Boyden cell is coated in 0.1% gelatin, hatches 30 minutes for 37 ℃, discard gelatin, wash three times with PBS.In 24 orifice plates in cell outside, add the substratum that contains 10% serum and respective concentration (be respectively 1 micro-rubbing/liter, 5 micro-rubbing/liter, 10 micro-rubbing/liter, 20 micro-rubbing/liter, 40 micro-rubbing/liter) the compounds of this invention AGT007, the inner access of cell cell, the substratum in cell is containing 0.5% serum and the compounds of this invention of same concentrations.In 37 ℃ of 5%CO
2in incubator, hatch after four hours, sop up substratum, with cotton swab, the not cell of migration of little chamber internal surface is wiped, PBS washes 3 times, with paraformaldehyde, fix 20 minutes, PBS washes 3 times, and violet staining is spent the night, sop up Viola crystallina, PBS washes 3 times, dries rear micro-Microscopic observation and takes pictures.
Result and evaluation: micro-Microscopic observation is also taken pictures, as shown in Figure 3, with control group (not adding the compounds of this invention) ratio, the migration of the endotheliocyte of processing through the compounds of this invention AGT007 has been subject to remarkable inhibition, illustrates that the compounds of this invention AGT007 can suppress the resistant transfer ability of endotheliocyte.
Equally, more than in experiment, add respectively the compounds of this invention AGT009, AGT012, AGT015, AGT018, AGT025, AGT029, AGT033, AGT035, AGT037, AGT039, AGT047 and AGT058 etc., obtain experimental result as shown in Figure 3, 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 pipe ability
Object and principle: Matrigel extracts the basilar membrane extract of the solubility obtaining from murine sarcoma, is rich in extracellular matrix protein.At room temperature, Matrigel can be condensed into has bioactive matrigel, and its structure and component and mammalian cell basilar membrane are similar, and formation three-dimensional tube cavity configuration can be grown, be assembled, merge to human umbilical vein's endotheliocyte in Matrigel.Can utilize endotheliocyte this specific character in Matrigel to study compound to angiopoietic impact.
Method: 50 microlitre Matrigel are taped against in 96 orifice plates, in 37 ℃, 5%CO
2in incubator, hatch and within 30 minutes, treat its cohesion.50 μ L are comprised to 1 * 10
4the cell suspension of individual human umbilical vein's endotheliocyte and 50 μ L respective concentration (be respectively 1 micro-rubbing/liter, 5 micro-rubbing/liter, 10 micro-rubbing/liter, 20 micro-rubbing/liter, 40 micro-rubbing/liter) the compounds of this invention AGT004 add in Matrigel after mixing, in 37 ° of C CO
2in incubator, hatch 6-8 hour, examine 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, in control group, the complete three-dimensional tube cavity configuration of formation is grown, assembled, merges to human umbilical vein's endotheliocyte 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 processed is affected, the luminal structure forming is scattered, imperfect, illustrates that the compounds of this invention AGT004 can suppress human umbilical vein's endotheliocyte and become pipe.
Equally, more than in experiment, add respectively the compounds of this invention AGT007, AGT011, AGT015, AGT019, AGT023, AGT027, AGT032, AGT034, AGT037, AGT039, AGT045, AGT059 and AGT063, obtain experimental result as shown in Figure 5, 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
Object and principle: in collagen, be rich in extracellular matrix protein and somatomedin, in vitro arterial ring is coated in collagen, and the endotheliocyte of arterial ring outer rim can be under the stimulation of somatomedin, degrade collagen, to external migration, sprout simultaneously, at arterial ring, form the netted capillary network of dispersing around.SD(Sprague-Dawley) rat artery ring model can be used to detect the impact that under in vitro state, compound is sprouted capillary blood vessel.
Method: by male rat anesthesia in 6 week age, thoracic aorta is separated, with the MCDB231 substratum of serum-free, blood remaining in blood vessel is rinsed well, peel off under the microscope circumvascular reticular tissue, wipe out the capillary vessel of adnation, thoracic aorta is cut to the arterial ring of growing into 1-1.5 millimeter, with fresh culture rinsing 3 times, arterial ring is put into 48 orifice plates that are covered with in advance 100 microlitre collagens, repave into 100 μ L collagens, add subsequently 1mL to contain the MCDB231 substratum of the compd A GT001 of respective concentration (20 micro-rubbing/liter), in 37 ℃ of CO
2in incubator, cultivate after 7 days and examine under a microscope and take pictures.
Result and evaluation: as shown in Figure 6, control group (not adding the compounds of this invention) medium sized artery ring forms radial capillary network around, and the arterial ring that the compounds of this invention AGT001 processed almost be can't see microvascular sprouting.Visible the compounds of this invention AGT001 can stabilize the in vitro rat artery ring capillary blood vessel of system in tissue water and sprout.
Equally, in above-mentioned experiment, add respectively the compounds of this invention AGT003, AGT014, AGT016, AGT017, AGT028, AGT029, AGT033, AGT036, AGT038, AGT040, AGT045, AGT047, AGT052, AGT056, AGT059, AGT062, AGT063 etc., obtain experimental result as shown in Figure 6, show that the invention described above compound can stabilize the in vitro rat artery ring capillary blood vessel of system in tissue water and sprout.
Embodiment 3-5: the compounds of this invention suppresses mouse cornea new vessel and forms
Object and principle: under physiological status, mouse cornea does not have blood vessel, of syringe needle, between cornea and eyeball, make a micro-capsule bag, the slow-releasing granules that implantation contains vascular endothelial growth factor (VEGF), can induce the blood vessel at Gong Yuan place, angle to the growth of slow-releasing granules place, in slow-releasing granules, add compound detection compound whether inhibitedly to form to mouse cornea new vessel simultaneously.
Method: by C57/BL6 mouse anesthesia, fixing, between cornea and eyeball, make micro-capsule bag, implantation slow release particle, in slow-releasing granules in control group, contain VEGF, the compounds of this invention AGT005 that contains VEGF and respective concentration (20 micro-rubbing/liter) in dosing group raises 1 week after mouse revives, and examines under a microscope VEGF induction of vascular new life's situation and take pictures after anesthesia.
Result and evaluation: as shown in Figure 7, in control group (not adding the compounds of this invention), VEGF induction has formed a large amount of blood vessels, and add after the compounds of this invention AGT005, new vessel has obviously been subject to inhibition, illustrates that the compounds of this invention AGT005 can suppress mouse cornea new vessel and form.
Equally, in above-mentioned experiment, add respectively the compounds of this invention AGT015, AGT017, AGT023, AGT029, AGT032, AGT037, AGT039, AGT040, AGT053, AGT057, AGT058, AGT061 and AGT064 etc., obtain experimental result as shown in Figure 7, show that the compounds of this invention can suppress mouse cornea new vessel and form.
Embodiment 3-6: the compounds of this invention suppresses nude mice tumor-microvessel and forms
Object and principle: CD31 is as vascular endothelial cell labelled protein, and high expression level in vascular endothelial cell, therefore can detect microvascular distribution situation in tumor tissues with CD31 immunohistochemical staining specifically.
Method: the solid tumor of peeling off from nude mice is placed in to 4% paraformaldehyde and fixedly spends the night, after paraffin embedding, it is cut into the paraffin section of 4 μ m, through dewaxing, carries out antigen retrieval after rehydration, before dyeing, paraffin section is proceeded to containing 3%H
2o
2methanol solution in soak 10 minutes, to eliminate the catalatic effect of endogenous.Then add CD31 antibody incubation 30 minutes, PBS washes 3 times, hatches subsequently two of coupling HRP and resists, and PBS washes 3 times, and DAB colour developing, finally redyes with phenodin, examines under a microscope and take pictures after mounting.Nucleus presents blueness, and capillary blood vessel presents 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, illustrate that the compounds of this invention can suppress nude mice tumor-microvessel and form, illustrate that the compounds of this invention AGT006 can suppress metastases by angiogenesis inhibiting.
Equally, in abdominal cavity, inject respectively the compounds of this invention AGT018, AGT019, AGT025, AGT029, AGT033, AGT037, AGT039, AGT044, AGT056, AGT057, AGT059, AGT062, AGT066, obtain experimental result as shown in Figure 8, show that the invention described above compound can suppress metastases by angiogenesis inhibiting.
Embodiment 4: the compounds of this invention suppresses the sclerosis of rat artery atherosclerotic
By in oralbumin abdominal injection to 5 Wistar rat in all ages, and help to fill with hello Vitamin D3 500,000 I.U/GM at tail vein injection bovine serum albumin, then with high lipid food, feed rat, and a certain amount of ferrous sulfate is joined in drinking-water, detect rat in blood lipid level, blood parameters and the pathological change of different time.
Experimental result shows, compare with control group, add after 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 0.05M HAc(4mg/ml by chicken II Collagen Type VI (Chondrex), and 0.1MTris-HCl balance is to neutral final concentration 2mg/ml) in, at 4 ℃, spending the night, solution is transparent clear.Then by collagen solution and CFA(Sigma, containing 1mg/ml Mycobacterium tuberculosis) equal-volume mixing, emulsification is complete.Then mouse is carried out to arthritis model induction: first at the 0th day, carry out first immunisation, tail vein injection 100ug collagenII(CFA adjuvant); Then at the 21st day second immunisation, tail vein injection 100ug collagen II(IFA made solvent); From the 23rd day on every Wendesdays time (week 1,3,5), carry out the scoring of foot outward appearance and the measurement of sufficient mat thickness.Since the 23rd day, add 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, with respect to control group, dosing group mouse infiltrates intraarticular and surrounding soft tissue's infiltration has obvious return action, the destructiveness of cartilage is had to significant inhibition, bone remodeling is had to obvious return action.
Embodiment 5: the compounds of this invention is to psoriasis treatment effect.
In serum, solubility selects plain level relevant to the patients with psoriasis vulgaris state of an illness, can be used as a useful indicators judging psoriasis activity, the psoriatic mouse model modeling method of formulating according to U.S. Schon, model group mouse is abdominal injection diethylstilbestrol for three days on end all, every 0.2mg/ time, 2 times/day, make in the oestrogenic hormon phase, after feminisation, vaginal epithelial cell is in proliferation period state, in the 10th day, all mouse are put to death after abdominal injection colchicine, label taking originally, observe and Soluble E-selectin, contrast with blank group, more blank group is increased, modeling success.
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 after abdominal injection colchicine, before putting to death, with plucking eyeball method, get the about 1ml of blood, 4 degrees Celsius, 3000r/min, centrifugal 10min, get supernatant, sample is with adding 50ul in reacting hole after sample diluent 1:l dilution, standard substance 50ul after adding dilution good is in reacting hole, add testing sample 50ul in reacting hole, then the biotin labeled antibody that adds immediately 50ul, cover lamina membranacea, vibration mixes gently, 37 ℃ of incubation 1h.Get rid of liquid in hole, washings is filled it up with in every hole, vibrates 30 seconds, gets rid of washings, with thieving paper, pats dry, and every hole adds affine chain enzyme one HRP of 80ul, and vibration mixes gently, 37% incubation 30min.Get rid of liquid in hole, washings is filled it up with in every hole, vibrates 30 seconds, get rid of washings, with thieving paper, pat dry, every hole adds chromogenic substrate liquid 50ul, vibration mixes gently, and 37 ℃ of incubations, avoid illumination, take out enzyme plate, add rapidly 50ul stop buffer, add after stop buffer measurement result immediately, by ELISA method double antibodies sandwich method, measure serum soluble E one and select plain content, unit represents with ng/mL, and statistics result shows, the compounds of this invention has good therapeutic action to psoriasis.
Embodiment 5: the result for the treatment of of the compounds of this invention to diabetes and diabetic syndrome
By the birth mouse (with female mouse) of seven days, to raise in 75% oxygen environment, the concentration of oxygen can regulate and monitor.The 12 day, mouse is exposed in air again, every day abdominal injection DMSO(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, by left ventricle, pour into the dextran of high molecular fluorescent mark.After perfusion, peel off eyeball, 4% formaldehyde is fixed 24 hours.Remove cornea and lens, under microscope, peel off retina, mounting medium sealing.Micro-Microscopic observation retinal neovascularization changes, find that DMSO group Mouse Retina is after hypoxia inducible, occur a lot of silk ball shape new vesseles, and the new vessel having added in the Mouse Retina of the compounds of this invention significantly suppressed, 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 Identification result.
Embodiment 1-2,2-(3-bromophenyl)-3-phenyl-4-thiazolinone (AGT002)
Adopt and prepare the similar method of compd A GT001, ORTHO ANISIDINE is replaced into aniline, after column chromatography purification, obtaining compd A GT002, productive rate 78%:
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 and prepare the similar method of compd A GT001, ORTHO ANISIDINE is replaced into Ortho-Aminophenol, after column chromatography purification, obtaining 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-(2,4-Dimethoxyphenyl)-4-thiazolinone (AGT004)
Adopt and prepare the similar method of compd A GT001, ORTHO ANISIDINE is replaced into 2, 4-dimethoxyaniline, after column chromatography purification, obtain 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 and prepare the similar method of compd A GT001,3-bromobenzaldehyde is replaced into 3-chlorobenzaldehyde, after column chromatography purification, obtaining compd A GT005, 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 and prepare the similar method of compd A GT001,3-bromobenzaldehyde is replaced into 3-fluorobenzaldehyde, after column chromatography purification, obtaining compd A GT006, 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 and prepare the similar method of compd A GT001, only ORTHO ANISIDINE being replaced into thiazolamine, after column chromatography purification, obtaining compd A GT007, 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 and prepare the similar method of compd A GT001,3-bromobenzaldehyde is replaced into phenyl aldehyde, ORTHO ANISIDINE is replaced into ORTHO ANISIDINE, after column chromatography purification, obtain compd A GT008, productive rate 58%:1H NMR (300MHz, CDCl3): δ 7.34-7.31 (m, 2H), 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 and prepare the similar method of compd A GT001,3-bromobenzaldehyde is replaced into 3-nitrobenzaldehyde, after column chromatography purification, obtaining compd A GT009, 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 and prepare the similar method of compd A GT001,3-bromobenzaldehyde is replaced into after m-methoxybenzaldehyde column chromatography purification to obtain to compd A GT010, productive rate 52%:1H NMR (300MHz, CDCl3): δ 7.23-7.18 (m, 1H), 7.17-7.13 (m, 1H), 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 and prepare the similar method of compd A GT001, 3-bromobenzaldehyde is replaced into 2-(4-formyl radical phenyl) methyl propionate, after column chromatography purification, obtain compd A GT011, 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 and prepare the similar method of compd A GT001,3-bromobenzaldehyde is replaced into 3-formyl radical benzoic ether, after column chromatography purification, obtaining compd A GT012, 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 and prepare the similar method of compd A GT001,3-bromobenzaldehyde is replaced into 4-acyl radical methyl benzoate, after column chromatography purification, obtaining compd A GT013, 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 and prepare the similar method of compd A GT001,3-bromobenzaldehyde is replaced into 4-formyl radical methyl phenylacetate, after column chromatography purification, obtaining compd A GT014; 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-(2,4-Dimethoxyphenyl)-4-thiazolinone (AGT015)
Adopt and prepare the similar method of compd A GT001, 3-bromobenzaldehyde is replaced into 3-formyl radical benzoic ether, ORTHO ANISIDINE is replaced into 2, 4-dimethoxyaniline, after column chromatography purification, obtain compd A GT015, 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 and prepare the similar method of compd A GT001, only ORTHO ANISIDINE being replaced into 2-aminopyrimidine, after column chromatography purification, obtaining compd A GT016, 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 and prepare the similar method of compd A GT001,3-bromobenzaldehyde is replaced into 4-aminopyridine, after column chromatography purification, obtaining compd A GT0017, 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 and prepare the similar method of compd A GT001, 3-bromobenzaldehyde is replaced into 1-quinolylamine, after column chromatography purification, obtain compd A GT018, 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)
Get 3-bromobenzaldehyde (2.34ml, 20mmol) be dissolved in 50ml tetrahydrofuran (THF), add 3-N-methyl-p-nitroaniline (1.38g, 10mmol) stir, after 5 minutes, add Thiovanic acid (2.27ml, 30mmol), after 5 minutes, add DCC (2.48g, 12mmol), after 10 minutes, under room temperature, react and spend the night.Suction filtration, is extracted with ethyl acetate twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Through column chromatography purification, obtain compd A GT019 (740mg, 54%): 1H NMR (400MHz, CDCl3): δ 8.14-8.13 (m, 1H), 8.06-8.03 (m, 1H), 7.61-7.58 (m, 1H), 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 and prepare the similar method of compd A GT019, 3-N-methyl-p-nitroaniline is replaced as to ORTHO ANISIDINE, Thiovanic acid is replaced as to thiohydracrylic acid, after column chromatography purification, obtain compd A GT020, 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 and prepare the similar method of compd A GT019,3-N-methyl-p-nitroaniline is replaced as to m-anisidine, after column chromatography purification, obtain compd A GT022, 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 and prepare the similar method of compd A GT019,3-N-methyl-p-nitroaniline is replaced as to 4-diethylin aniline, after column chromatography purification, obtaining compd A GT023, productive rate 63%:
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 and prepare the similar method of compd A GT019,3-N-methyl-p-nitroaniline is replaced as to Metha Amino Phenon, after column chromatography purification, obtaining compd A GT023, productive rate 39%:
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 and prepare the similar method of compd A GT019,3-bromobenzaldehyde is replaced as to 4-bromobenzaldehyde, 3-N-methyl-p-nitroaniline is replaced as to ORTHO ANISIDINE, after column chromatography purification, obtaining compd A GT024, productive rate 30%:
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 and prepare the similar method of compd A GT019,3-bromobenzaldehyde is replaced as to 2-bromobenzaldehyde, 3-N-methyl-p-nitroaniline is replaced as to ORTHO ANISIDINE, after column chromatography purification, obtaining compd A GT025, productive rate 28%:
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 and prepare the similar method of compd A GT019,3-N-methyl-p-nitroaniline is replaced as to p-ethoxyaniline, after column chromatography purification, obtaining compd A GT026, productive rate 31%:
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 and prepare the similar method of compd A GT019,3-bromobenzaldehyde is replaced as to m-hydroxybenzaldehyde, 3-N-methyl-p-nitroaniline is replaced as to ORTHO ANISIDINE, after column chromatography purification, obtaining compd A GT027, productive rate 39%:
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 and prepare the similar method of compd A GT019,3-N-methyl-p-nitroaniline is replaced as to para hydroxybenzene amine, after column chromatography purification, obtaining compd A GT028, productive rate 38%:
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 and prepare the similar method of compd A GT019,3-N-methyl-p-nitroaniline is replaced as to O-Phenylene Diamine, after column chromatography purification, obtaining compd A GT029, productive rate 32%:
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 and prepare the similar method of compd A GT019,3-bromobenzaldehyde is replaced as to furans-2-formaldehyde, 3-N-methyl-p-nitroaniline is replaced as to ORTHO ANISIDINE, after column chromatography purification, obtaining compd A GT030, productive rate 65%:
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 and prepare the similar method of compd A GT019,3-bromobenzaldehyde is replaced as to thiophene-2-formaldehyde, 3-N-methyl-p-nitroaniline is replaced as to ORTHO ANISIDINE, after column chromatography purification, obtaining compd A GT031, productive rate 31%:
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)
Get compd A GT011 (590mg, 1.59mmol) and be dissolved in 16ml methyl alcohol, under nitrogen atmosphere, ice bath drips the aqueous solution (4ml) of lithium hydroxide (267mg, 6.35mmol), and then reaction is spent the night at ambient temperature.Add 3M hydrochloric acid furnishing acid, be extracted with ethyl acetate twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Through column chromatography purification, obtain compd A GT032 (370mg, 65%):
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 and prepare the similar method of compd A GT032, only compd A GT011 being replaced as to AGT012, after column chromatography purification, obtaining compd A GT033, productive rate 69%:
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-(2,4-Dimethoxyphenyl)-4-thiazolinone (AGT034)
Adopt and prepare the similar method of compd A GT032, only AGT011 being replaced as to AGT015, after column chromatography purification, obtaining compd A GT035, productive rate 88%:
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 and prepare the similar method of compd A GT032, only compd A GT011 being replaced as to AGT014, after column chromatography purification, obtaining compd A GT035, productive rate 85%:
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, 1.65mmol) in flask, when 0 ° of C; 5ml DMF is injected in nitrogen protection; after 5min, drip aniline (0.18ml, 1.95mmol), 15min recession deicing is bathed under normal temperature and is reacted 3 hours.After ethyl acetate extraction, concentrating under reduced pressure is corresponding amides crude product.This intermediate (152mg, 0.62mmol) and ORTHO ANISIDINE (0.07ml, 0.62mmol) are prepared to 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-(DEET) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT037)
Adopt and prepare the similar method of compd A GT036,2-(4-formyl radical phenyl) propionic acid is replaced as to p formyl benzoic acid, aniline is replaced as to diethylamine, after column chromatography purification, obtaining compd A GT038, productive rate 56%:
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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT038)
Adopt and prepare the similar method of compd A GT036,2-(4-formyl radical phenyl) propionic acid is replaced as to 3-carboxyl benzaldehyde, aniline is replaced as to 4-flunamine, after column chromatography purification, obtaining compd A GT038, productive rate 70%:
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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT039)
Adopt and prepare the similar method of compd A GT036,2-(4-formyl radical phenyl) propionic acid is replaced as to 3-carboxyl benzaldehyde, aniline is replaced as to 3-flunamine, after column chromatography purification, obtaining compd A GT039, productive rate 55%:
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), 7.19-7.13 (m, 1H), 7.10-7.07 (m, 1H), 7.02-6.94 (m, 2H), 6.91-6.88 (m, 1H), 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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT040)
Adopt and prepare the similar method of compd A GT036,2-(4-formyl radical phenyl) propionic acid is replaced as to 3-carboxyl benzaldehyde, aniline is replaced as to 4-trifluoromethyl benzylamine, after column chromatography purification, obtaining compd A GT040, productive rate 56%:
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-(DEET) 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, under nitrogen protection ice bath, inject 3ml DMF, after 5 minutes, drip diethylamine (0.04ml; 0.4mmol), after 15 minutes, under thorough ice bath normal temperature, react 3 hours.Add water deactivation, be extracted with ethyl acetate twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Through column chromatography purification, obtain compd A GT041 (50mg, 32%):
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-(2,4-Dimethoxyphenyl)-4-thiazolinone (AGT053)
Adopt and prepare the similar method of compd A GT041, AGT033 is replaced as to AGT034, diethylamine is replaced as to Tri N-Propyl Amine, after column chromatography purification, obtaining compd A GT042, productive rate 79%:
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-ethyl acetate benzamide) phenyl)-3-(2,4-Dimethoxyphenyl)-4-thiazolinone (AGT043)
Adopt and prepare the similar method of compd A GT041, AGT033 is replaced as to AGT034, diethylamine is replaced as to glycine ethyl ester, after column chromatography purification, obtaining compd A GT043, productive rate 42%:
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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT044)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to amphetamine, after column chromatography purification, obtaining compd A GT044, productive rate 90%:
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), 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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT056)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to PHENTERMINE, after column chromatography purification, obtaining compd A GT045, productive rate 93%:
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), 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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT046)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to 4-Bretylium Tosylate, after column chromatography purification, obtaining compd A GT046, productive rate 88%:
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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT047)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to 4-hydroxyphenethylamine, after column chromatography purification, obtaining compd A GT047, productive rate 90%:
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), 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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT048)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to 4-chlorobenzene ethamine, after column chromatography purification, obtaining compd A GT048, productive rate 88%:
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), 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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT049)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to 4-anisole ethamine, after column chromatography purification, obtaining compd A GT049, productive rate 89%:
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), 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 and prepare the similar method of compd A GT041, AGT033 is replaced as to AGT035, diethylamine is replaced as to aniline, after column chromatography purification, obtaining compd A GT050, productive rate 88%:
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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT051)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to 4-fluorobenzene butylamine, through column chromatography purification, obtaining compd A GT051 (70mg, 86%):
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), 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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT052)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to 4-fluorophenethylamine, through column chromatography purification, obtaining compd A GT052, productive rate 89%:
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), 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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT053)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to 2-Bretylium Tosylate, after column chromatography purification, obtaining compd A GT053, productive rate 86%:
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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT054)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to benzene hexylamine, after column chromatography purification, obtaining compd A GT054, productive rate 74%:
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), 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) benzamide) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT055)
Adopt and prepare the similar method of compd A GT041, only diethylamine being replaced as to 5-liprodene, after column chromatography purification, obtaining compd A GT055, productive rate 93%:
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), 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-(2,4-dihydroxy phenyl)-4-thiazolinone (AGT056)
Get compd A GT004 (394mg, 1mmol) and boron tribromide (0.3ml, 3mmol) in 5ml methylene dichloride, under nitrogen atmosphere, room temperature reaction is 4 hours.Be extracted with ethyl acetate twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Through column chromatography purification, obtain compd A GT056 (322mg, 88%):
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)
Get compd A GT004 (1g, 2.54mmol) in 20ml1, in 2-ethylene dichloride, under nitrogen atmosphere, ice bath stirs, add Aluminum chloride anhydrous (338mg, 2.54mmol), 0.5 hour recession ice bath, stirs under room temperature 0.5 hour, after be warming up to 70 ℃, after 4 hours, add Aluminum chloride anhydrous (2.54mg, 2.54mmol), be warming up to 80 ° of C reaction overnight.Be extracted with ethyl acetate twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Through column chromatography purification, obtain compd A GT057 (340mg, 35%):
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, under nitrogen protection ice bath, inject 5ml DMF, after 5 minutes, add phenylethylamine (0.08ml; 0.65mmol), after 15 minutes, under thorough ice bath normal temperature, react 3 hours.Add water deactivation, be extracted with ethyl acetate twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Through column purification, obtain product A GT058 (110mg, 53%):
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-(benzamide)) phenyl)-3-(2-p-methoxy-phenyl)-4-thiazolinone (AGT059)
Adopt and prepare the similar method of compd A GT058, phenylethylamine is replaced as to aniline, after column chromatography purification, obtaining compd A GT059, 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)
Getting 3-methylol phenyl aldehyde (47mg, 0.35mmol) and ORTHO ANISIDINE (0.04ml, 0.35mmol) is dissolved in 5ml toluene, under nitrogen atmosphere, under condition of ice bath, stir after 5 minutes, change oil bath into and be heated to reflux, on device, connect water-and-oil separator.To without water generates, after cooling, add Thiovanic acid (0.05ml, 0.7mmol) to continue to be heated to reflux, treat minute water after concentrating under reduced pressure obtain crude product, through column chromatography purification, obtain compd A GT060 (80mg, 73%):
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)
Get compd A GT060 (100mg, 0.32mmol) and be dissolved in 5ml methylene dichloride, under nitrogen atmosphere, drip boron tribromide (0.03ml, 0.32mmol), under room temperature, react 4 hours.Be extracted with ethyl acetate twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Through column chromatography purification, obtain product A GT061 (94mg, 78%):
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)
Get 2-methoxyl group-4-Boc amino-aniline (263mg, 1.1mmol) and 3-bromobenzaldehyde (0.13ml, 1.1mmol) and obtain corresponding thiazoline ketone intermediate by the method for preparing AGT001.This intermediate (527mg, 1.1mmol) is dissolved in 10ml DCM, and under nitrogen atmosphere, ice bath adds 2ml trifluoroacetic acid, after 0.5 hour, reacts 3 hours under room temperature.Add 3M potassium hydroxide furnishing alkalescence, be extracted with ethyl acetate twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Through column chromatography purification, obtain compd A GT062 (363mg, 87%):
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) and be dissolved in 5ml toluene, under nitrogen atmosphere, under condition of ice bath, stir after 5 minutes, change oil bath into and be heated to reflux, on device, connect water-and-oil separator.To without water generates, after cooling, add Thiovanic acid (0.05ml, 0.76mmol) to continue to be heated to reflux, treat minute water after concentrating under reduced pressure obtain crude product, through column chromatography purification, obtain compd A GT063 (70mg, 51%):
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-oxazoline ketone (AGT064)
Get 2-oxyacetic acid (990mg, 13mmol), EDC (3.24g, 16.9mmol) and HOBt (1.94g, 14.3mmol) in flask, under nitrogen atmosphere, ice bath injects 20ml DMF, drips ORTHO ANISIDINE (112ml after 5 minutes, 10mmol), after 15 minutes, under thorough ice bath normal temperature, react 3 hours.Through ethyl acetate extraction and column chromatography purification, obtain corresponding intermediate.Get this intermediate (544mg, 3mmol) and tosic acid (112mg, 0.6mmol) and be dissolved in dimethylbenzene, stirring at room a little while, then adds 3-bromobenzaldehyde (0.7ml, 6mmol), 140 ℃ of reflux water-dividings 4 hours.Concentrating under reduced pressure obtains crude product, through column chromatography purification, obtains compd A GT064 (762mg, 73%):
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-(2,4-Dimethoxyphenyl)-4-oxazoline ketone (AGT065)
Adopt and prepare the similar method of compd A GT064, ORTHO ANISIDINE is replaced as to 2,4-dimethoxyaniline, after column chromatography purification, obtaining compd A GT064, 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, under nitrogen atmosphere, stirring at room is 0.5 hour, adds methyl iodide (0.1ml, 1.72mmol), under room temperature, stirs and spends the night.Add water deactivation, be extracted with ethyl acetate twice, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Through column chromatography purification, obtain product A GT066 (20mg, 15%):
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), 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, 0.84mmol) in the mixed solvent of 9ml ethanol and 3ml water, under nitrogen atmosphere, crude product refluxes to obtain under 80 ° of C, through column chromatography purification, obtain product A GT067 (102mg, 70%):
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).