Preparation method of novel aminothiazole derivative containing purine structure and application of novel aminothiazole derivative in promoting plant growth

Abstract

The invention discloses a novel aminothiazole derivative containing a purine structure, which is characterized in that the structural formula of the derivative is as follows: # imgabs0 #, R1 is C3-C4 alkyl, and R2 is mono-substituted or di-substituted hydrogen, methyl and halogen. A biological activity determination result shows that the 2-aminothiazole compound containing the purine part has medium to excellent inhibitory activity on rice bacterial streak pathogen and kiwi fruit bacterial canker pathogen, and the activity of the compound 3A7 is the best; the inhibitory activity on rice bacterial leaf streak germs and kiwi fruit bacterial canker germs is 78.8% and 65.3% respectively, and is far higher than that of control agents thiediazole copper and zinc thiazole.

Description

Technical Field

[0001] The invention relates to the field of chemical technology, in particular to an aminothiazole derivative plant growth regulator containing a purine structure, a preparation method of the compound and use of the composition thereof on rice bacterial leaf streak pathogen, kiwi fruit bacterial canker pathogen and citrus canker pathogen. Background Art

[0002] As the global population continues to grow, the demand for food continues to rise. In order to meet this demand, it is necessary to increase the yield of crops, and pesticides are an important means to ensure the normal growth of crops and increase yields. The occurrence of pests and diseases will seriously affect the yield and quality of crops. High-efficiency pesticides can effectively control pests and diseases, protect crops from harm, and thus increase yields. However, due to the long-term use of the same pesticides, the "3R" problem has gradually become prominent. Therefore, how to develop more environmentally friendly and efficient pesticides while ensuring food production safety has become an important issue.

[0003] Wheat is one of the main food crops for human beings and is of great significance to global food security. There are differences in the growth of caryopsis between different ear and grain positions of wheat. According to their filling conditions, they are divided into strong and weak grains. The poor filling of weak grains has always restricted the improvement of wheat yield. The rational application of plant growth regulators is an effective measure to achieve high-quality and high-yield wheat. Auxin (IAA), gibberellin (GA3) and 6-benzylaminopurine (6-BA) are three types of regulators with growth-promoting effects, which can regulate wheat growth and grain formation. 6-BA is an artificially synthesized active cytokinin, which is an adenine derivative. It can regulate plant seed germination and flowering, root crown development, delay leaf senescence, promote cell division, leaf bud differentiation, metabolite transport and assimilate accumulation. Compared with natural cytokinins, artificial cytokinins are easier to mass produce, have high stability, better rooting effect, and higher bioavailability.

[0004] As a nitrogen-sulfur five-membered heterocyclic ring, the thiazole ring is rich in electrons and can not only form hydrogen bonds, but also coordinate with metal ions and interact with various non-covalent bonds, such as π-π stacking, electrostatic and hydrophobic interactions. These excellent structural characteristics make thiazole compounds have rich properties and are widely used in various fields. In the pharmaceutical field, there are antibiotic drugs such as cefixime, anticancer drugs such as dasatinib, antiparasitic drugs such as nitazoxanide, anti-inflammatory drugs such as meloxicam, etc.; in the pesticide field, there are seed dressing, thiabendazole, and benzathiapyr.

[0005] Zhongshengmycin is a highly effective and low-toxic N-glycoside agricultural antibiotic. It is a protective fungicide with a broad antibacterial spectrum. It has outstanding contact and systemic properties. It inhibits the formation of peptide bonds in pathogenic bacteria, leading to bacterial death. It can also inhibit the growth of fungal hyphae and the germination of spores, playing a role in preventing and controlling bacterial and fungal diseases. Zhongshengmycin was combined with chemical pesticides such as prochloraz, carbendazim, and diniconazole to treat peach blight. Compared with the use of Zhongshengmycin alone, the results showed a synergistic or synergistic effect; Zhongshengmycin and quinoline copper were used to treat tomato canker. After 9 days, the control effect was 6.89%-26.5% higher than that of the corresponding single agent.

[0006] In summary, aminothiazole compounds are an important class of N-cyclic compounds. They have attracted extensive attention from pesticide developers around the world because of their good biological activity, high efficiency, low toxicity and other characteristics. Purine derivatives also show high biological activity, providing a reference for the creation of new and efficient fungicides. Therefore, based on the previous work, the present invention designed and synthesized a new type of aminothiazole derivative containing a purine structure, and selected a chemical agent with a different mechanism of action for coordinated use, reducing the amount of fungicide used while expanding the types of use, striving to use a variety of agents in turn, expanding the prevention and control spectrum, enriching the types of prevention and control, and achieving the effect of increasing the sensitivity of bacteria to commonly used medium and high resistance level chemical agents and reducing the amount of use. Summary of the invention

[0007] The present invention aims to provide a method for preparing a purine structure-containing aminothiazole derivative biological plant growth regulator having fungicidal activity and a composition thereof.

[0008] Another object of the present invention is to provide a novel compound having an inhibitory effect on kiwi fruit bacterial canker, rice bacterial leaf streak pathogen and citrus canker pathogen.

[0009] The technical solution of the present invention is: a novel aminothiazole derivative containing a purine structure, wherein the derivative has the following general formula (I):

[0010]

[0011] Wherein: R1 is C3-C4 alkyl, and R2 is hydrogen, methyl, or halogen, which is monosubstituted or disubstituted.

[0012] Preferably, R1 is isobutyl or cyclopropylmethyl, and R2 is a hydrogen atom, a 2-methyl group, a 3-methyl group, a 4-methyl group, a 2-methoxy group, a 3-methoxy group, a 2-fluoro group, a 3-fluoro group, a 4-fluoro group, a 2-chloro group, a 3-chloro group, a 4-chloro group, a 2-bromo group, a 3-bromo group, a 4-bromo group or a disubstituted group of any combination of the above substituent groups.

[0013] Preferably, R1 is isobutyl or cyclopropylmethyl, and R2 is a hydrogen atom, a 2-methyl group, a 3-methyl group, a 4-methyl group, a 2-methoxy group, a 3-methoxy group, a 2-fluoro group, a 3-fluoro group, a 4-fluoro group, a 2-chloro group, a 3-chloro group, a 4-chloro group, a 2-bromo group, a 3-bromo group, a 4-bromo group or a disubstituted group of any combination of the above substituent groups.

[0014] A novel aminothiazole derivative containing a purine structure, the specific compound is as follows:

[0015] Compound 3A1: 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-phenylthiazol-2-amine;

[0016] Compound 3A2: 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(o-tolyl)thiazol-2-amine;

[0017] Compound 3A3: 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(m-tolyl)thiazol-2-amine;

[0018] Compound 3A4: 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(p-tolyl)thiazol-2-amine;

[0019] Compound 3A5: 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(2-methoxyphenyl)thiazol-2-amine;

[0020] Compound 3A6: 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(3-methoxyphenyl)thiazol-2-amine;

[0021] Compound 3A7: 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(2-fluorophenyl)thiazol-2-amine;

[0022] Compound 3A8: 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(3-fluorophenyl)thiazol-2-amine;

[0023] Compound 3A9: 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)thiazol-2-amine;

[0024] Compound 3A10: N-(2-chlorophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine;

[0025] Compound 3A11: N-(3-chlorophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine;

[0026] Compound 3A12: N-(4-chlorophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine;

[0027] Compound 3A13: N-(2-bromophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine;

[0028] Compound 3A14: N-(3-bromophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine;

[0029] Compound 3A15: N-(4-bromophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine;

[0030] Compound 3A16: 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-phenylthiazol-2-amine; Compound 3A17: 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-(o-tolyl)thiazol-2-amine;

[0031] Compound 3A18: 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-(m-tolyl)thiazol-2-amine;

[0032] Compound 3A19: 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-(p-tolyl)thiazol-2-amine;

[0033] Compound 3A20: 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-(2-methoxyphenyl)thiazol-2-amine;

[0034] Compound 3A21: 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-(3-methoxyphenyl)thiazol-2-amine.

[0035] Compound 3A22: N-(2-fluorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine.

[0036] Compound 3A23: N-(3-fluorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine.

[0037] Compound 3A24: N-(4-fluorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine.

[0038] Compound 3A25: N-(2-chlorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine.

[0039] Compound 3A26: N-(3-chlorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine.

[0040] Compound 3A27: N-(4-chlorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine.

[0041] Compound 3A28: N-(2-bromophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine.

[0042] Compound 3A29: N-(3-bromophenyl)-5-(4-((9-isobutyl-9H-butyl-6-yl)oxy)phenyl)thio-2-amine.

[0043] Compound 3A30: N-(4-bromophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine.

[0044] A method for preparing a purine derivative comprises the following steps:

[0045] (1) 6-chloro-9H-purine: bromomethylcyclopropane or bromoisobutane: potassium carbonate = 1:1-1.2:3, DMF 15mL, react at 50°C for 7h, and after the reaction is complete, add a small amount of saturated brine, extract with dichloromethane, and dry the organic phase with anhydrous sodium sulfate. The crude product of intermediate 1 is purified by silica gel column chromatography using a petroleum ether: ethyl acetate solvent system (v:v = 1:1) to obtain compound 1;

[0046]

[0047] (2) α-Bromo-p-hydroxyacetophenone: various substituted phenylthioureas were added in a ratio of 1:1, 25 mL of acetonitrile, and reacted at 25°C for 9 h. After the reaction was completed, the reaction mixture was cooled to room temperature. The obtained precipitate was filtered, washed with hot acetonitrile solution, and dried to obtain the key intermediate 2;

[0048]

[0049] (3) Add intermediate 2: potassium carbonate: intermediate 1 = 1:2:1, add 30 mL of acetonitrile, and reflux for 7 hours. After the reaction is completed, cool the system to room temperature, wash the reaction mixture with saturated brine three times, and then dry it with anhydrous sodium sulfate. Recrystallize in ethyl acetate to purify the target compound;

[0050]

[0051] The derivative is used in preparing medicines and medicaments for preventing and controlling rice bacterial leaf streak pathogen, kiwi fruit bacterial canker pathogen and citrus canker pathogen.

[0052] A compound pesticide composition, the composition comprising a novel aminothiazole derivative containing a purine structure and Zhongshengmycin. The mass ratio of the derivative to Zhongshengmycin is 1:2-2:1. The derivative is 3A7.

[0053] The composition is used in the preparation of a drug for preventing and treating plant bacterial diseases, wherein the plant bacterial diseases are rice bacterial leaf streak pathogen, citrus canker pathogen and kiwi fruit bacterial canker pathogen.

[0054] A novel plant growth regulator is compound 3A7, a compound of the following formula (II):

[0055]

[0056] Beneficial effects of the present invention: From the results of biological activity assay, it can be seen that the 2-aminothiazole compounds containing a purine moiety have moderate to excellent inhibitory activity against rice bacterial leaf streak pathogen and kiwi fruit bacterial canker pathogen, among which compound 3A7 has the best activity, with inhibitory activities against rice bacterial leaf streak pathogen and kiwi fruit bacterial canker pathogen of 78.8% and 65.3%, respectively, which are much higher than the control agents thiophanate-copper and thiazole zinc.

[0057] From the results of biological activity determination, it can be seen that the activity of the composite composition against rice bacterial leaf streak and kiwifruit bacterial canker is improved compared with the compounds before compounding, and the inhibitory activity of composition 3 (3A7: Zhongshengmycin wettable powder = 2:1) against rice bacterial leaf streak and kiwifruit bacterial canker reached 90.1% and 84.9%, respectively. Therefore, the composite composition of 3A7 and Zhongshengmycin has a synergistic effect on rice bacterial leaf streak and kiwifruit bacterial canker.

[0058] In the wheat germination experiment, some compounds in this series showed good effects in promoting wheat seed germination. Overall, among the five concentrations, 20μg / mL had the highest germination rate. Among them, compound 3A10 showed better wheat seed germination activity than the control drug DA-6 at 20μg / mL.

[0059] The cucumber cotyledon expansion test of some target compounds showed that this series of compounds had certain cytokinin activity, especially compounds 3A1, 3A2 and 3A7, which had better activity than the control drug thiolone at a concentration of 10 μg / mL. DETAILED DESCRIPTION

[0060] Example

[0061] 1. The target compounds were synthesized by the following synthetic route. In short, the process starts with the reaction of 6-chloro-9(H)-purine with bromomethylcyclopropane or bromoisobutane in DMF, using potassium carbonate as a catalyst to generate intermediate 1. In the second step, different substituted phenylthioureas are directly condensed with α-bromo-p-hydroxyacetophenone in acetonitrile solvent to obtain the key intermediate 2. Finally, intermediates 1 and 2 are heated and refluxed in an acetonitrile solution containing potassium carbonate as a catalyst to generate target compounds 3A1-3A30 with a yield of 54% to 70%. All target compounds are prepared using 1 H NMR, 13 The samples were characterized by C NMR and HRMS techniques.

[0062]

[0063] Preparation of intermediate 1:

[0064] 6-Chloro-9H-purine (1.4 g, 9.0 mmol) was dissolved in DMF solution, and potassium carbonate (3.8 g, 27.2 mmol) was added as a catalyst. After stirring at room temperature for 30 minutes, bromomethylcyclopropane or bromoisobutane (10.0 mmol) was added to the reaction mixture, stirred at 50 ° C for 7 hours, and cooled to room temperature after the reaction was completed. A small amount of saturated brine was added, and extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The crude product of intermediate 1 was purified by silica gel column chromatography using a petroleum ether: ethyl acetate solvent system (v:v = 1:1), and the yield was 64.8% to 75.0%.

[0065] Preparation of intermediate 2:

[0066] α-Bromo-p-hydroxyacetophenone (0.8 g, 3.7 mmol) and various substituted phenylthioureas (3.7 mmol) were added to an acetonitrile (25 mL) solution and stirred at 25 °C for 9 hours. After the reaction was completed, the reaction mixture was cooled to room temperature. The resulting precipitate was filtered, washed with hot acetonitrile solution, and dried to obtain the key intermediate 2 with a yield of 70.3% to 86.8%.

[0067] Preparation of target compounds 3A1-3A30:

[0068] A mixture of intermediate 2 (1.0 mmol) and potassium carbonate (2.0 mmol) was placed in an acetonitrile (30 mL) solution and stirred at room temperature for 0.5 h. Then, intermediate 1 (1.0 mmol) dissolved in the acetonitrile solution was slowly added to the above solution and heated under reflux for 7 h. The reaction mixture was washed three times with saturated brine and then dried over anhydrous sodium sulfate. The target compound was purified by recrystallization in ethyl acetate.

[0069] 2. Spectral data of target compounds

[0070]

[0071] 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-phenylthiazol-2-amine(3A1): white solid, mp 211–213℃, yield: 62.8%. 1 H NMR (400MHz, DMSO-d6, ppm) δ: 10.30 (s, 1H), 8.59 (s, 1H), 8.48 (s, 1H), 8.03–7.99 (m, 2H), 7.76–7.74 (m, 2H), 7.38–7.33 (m, 5H), 6.96 (t, J=7.3 Hz,1H),4.15(d,J=7.3 Hz,2H),1.36(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13 C NMR(100 MHz, DMSO-d6, ppm)δ:163.2,159.3,153.2,151.7,151.2,149.5,144.7,141.2,132.0,1 29.0,127.0,122.1,121.2,120.8,116.8,102.8,47.9,11.3,3.8.HRMS(ESI)m / z:[M+Na] + Calculate for C 24 H 20N6OSNa:463.1311,found:463.1292.

[0072]

[0073] 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(o-tolyl)thiazol-2-amine(3A2):white solid,mp 169–170℃,yield:58.5%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:9.37(s,1H),8.59(s,1H),8.47(s,1H),8.03(d,J=7.6 Hz,1H),7.97–7.93(m,2H),7.35–7.31(m,2H),7.28(s,1H),7.25–7.19(m,2H),7.01(t,J=6.8 Hz,1H),4.15(d,J=7.3 Hz,2H),2.31(s,3H),1.35(hept,J=7.5 Hz,1H),0.57–0.46(m,4H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:165.4,159.3,153.2,151.6,151.2,149.3,144.7,139.4,132.2,130.6,128.8,126.9,126.6,123.3,122.0,120.9,120.8,102.9,47.9,18.1,11.3,3.8.HRMS(ESI)m / z:[M+Na] + calcd for C 25 H 22 N6OSNa:477.1468,found:477.1452.

[0074]

[0075] 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(m-tolyl)thiazol-2-amine(3A3):white solid,mp 182–183℃,yield:60.0%. 1H NMR(400 MHz,DMSO-d6,ppm)δ:10.22(s,1H),8.59(s,1H),8.48(s,1H),8.02–7.99(m,2H),7.61(d,J=8.1Hz,1H),7.48(s,1H),7.38–7.34(m,3H),7.23(t,J=7.8 Hz,1H),6.79(d,J=7.3Hz,1H),4.15(d,J=7.3 Hz,2H),2.32(s,3H),1.36(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:163.3,159.3,153.2,151.7,151.2,149.4,144.7,141.2,138.1,132.1,128.9,126.9,122.1,122.0,120.8,117.4,114.1,102.7,47.9,21.4,11.3,3.8.HRMS(ESI)m / z:[M+Na] + calcd forC 25 H 22 N6OSNa:477.1468,found:477.1469.

[0076]

[0077] 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(p-tolyl)thiazol-2-amine(3A4):white solid,mp 216–217℃,yield:64.9%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:10.18(s,1H),8.59(s,1H),8.48(s,1H),8.01–7.98(m,2H),7.63–7.60(m,2H),7.37–7.34(m,2H),7.31(s,1H),7.15(d,J=8.4 Hz,2H),4.15(d,J=7.4 Hz,2H),2.26(s,3H),1.36(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13C NMR(100MHz,DMSO-d6,ppm)δ:163.4,159.3,153.2,151.7,151.2,149.4,144.7,138.8,132.1,130.1,129.4,126.9,122.1,120.8,117.0,102.5,47.9,20.4,11.3,3.8.HRMS(ESI)m / z:[M+H] + calcd forC 25 H 23 N6OS:455.1649,found:455.1629.

[0078]

[0079] 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(2-methoxyphenyl)thiazol-2-amine(3A5):white solid,mp 163–165℃,yield:60.2%. 1 HNMR(400 MHz,DMSO-d6,ppm)δ:9.61(s,1H),8.59(s,1H),8.54(dd,J=7.5,2.1 Hz,1H),8.48(s,1H),8.01–7.97(m,2H),7.37–7.34(m,2H),7.32(s,1H),7.05–6.95(m,3H),4.15(d,J=7.3 Hz,2H),3.88(s,3H),1.36(hept,J=7.5 Hz,1H),0.57–0.46(m,4H); 13 CNMR(100MHz,DMSO-d6,ppm)δ:163.7,159.3,153.2,151.6,151.2,149.0,147.9,144.7,132.2,130.3,126.9,122.0,121.9,120.8,120.7,118.0,110.9,103.5,54.9,47.9,11.3,3.8.HRMS(ESI)m / z:[M+H] + calcd for C 25 H 23 N6O2S:471.1598,found:471.1596.

[0080]

[0081] 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(3-methoxyphenyl)thiazol-2-amine(3A6):white solid,mp 205–206℃,yield:63.2%. 1 HNMR(400 MHz,DMSO-d6,ppm)δ:10.11(s,1H),8.59(s,1H),8.48(s,1H),8.01–7.97(m,2H),7.68–7.64(m,2H),7.37–7.33(m,2H),7.27(s,1H),6.97–6.93(m,2H),4.15(d,J=7.3 Hz,2H),3.73(s,3H),1.35(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:163.8,159.3,154.1,153.2,151.2,149.4,147.4,144.7,134.8,132.1,126.9,122.0,120.8,119.8 118.6,116.5,114.3,102.1,55.2,47.9,11.3,3.8.HRMS(ESI)m / z:[M+Na] + calcd for C 25 H 22 N6O2SNa:493.1417,found:493.1398.

[0082]

[0083] 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(2-fluorophenyl)thiazol-2-amine(3A7):white solid,mp 166–167℃,yield:61.8%. 1HNMR(400 MHz,DMSO-d6,ppm)δ:10.11(s,1H),8.63(t,J=8.5 Hz,1H),8.59(s,1H),8.48(s,1H),8.02–7.98(m,2H),7.39–7.34(m,3H),7.28–7.22(m,2H),7.03–6.98(m,1H),4.15(d,J=7.3 Hz,2H),1.35(hept,J=7.6 Hz,1H),0.57–0.44(m,4H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:163.2,159.3,153.2,151.7,151.6(d, 1 J C-F =250.0 Hz),151.2,149.1,144.7,132.0,129.1(d, 3 J C-F =10.0 Hz),126.9,124.7(d, 4 J C-F =3.0 Hz),122.1,122.0,120.8,119.7,115.1(d, 2 J C-F =18.0 Hz),104.1,47.9,11.3,3.8.HRMS(ESI)m / z:[M+H] + calcd forC 24 H 20 FN6OS:459.1398,found:459.1399.

[0084]

[0085] 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(3-fluorophenyl)thiazol-2-amine(3A8):white solid,mp 176–178℃,yield:63.9%. 1HNMR(400 MHz,DMSO-d6,ppm)δ:10.57(s,1H),8.59(s,1H),8.48(s,1H),8.02–7.99(m,2H),7.83(d,J=12.1 Hz,1H),7.42–7.33(m,5H),6.77(t,J=7.9 Hz,1H),4.15(d,J=7.3 Hz,2H),1.35(hept,J=7.5 Hz,1H),0.57–0.46(m,4H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:162.7,162.6(d, 1 J C-F =240.0 Hz),159.3,153.2,151.8,151.2,149.5,144.7,142.8(d, 3 J C-F =12.0 Hz),131.9,130.5(d, 3 J C-F =10.0 Hz),126.9,122.2,120.8,112.7,107.4(d, 2 J C-F =21.0 Hz),103.5,103.4(d, 2 J C-F =27.0 Hz),47.9,11.3,3.8.HRMS(ESI)m / z:[M+Na] + calcdfor C 24 H 19 FN6OSNa:481.1217,found:481.1213.

[0086]

[0087] 5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)thiazol-2-amine(3A9):white solid,mp 207–209℃,yield:70.5%. 1HNMR(400 MHz,DMSO-d6,ppm)δ:10.33(s,1H),8.59(s,1H),8.48(s,1H),8.02–7.99(m,2H),7.78(dd,J=9.2,4.8 Hz,2H),7.38–7.33(m,3H),7.22–7.16(m,2H),4.15(d,J=7.3Hz,2H),1.35(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:163.3,159.3,156.9(d, 1 J C-F =236.0 Hz),153.2,151.7,151.2,149.4,144.7,137.7(d, 4 J C-F =2.0 Hz),132.0,127.0,122.1,120.8,118.3(d, 3 J C-F =8.0 Hz),115.5(d, 2 J C-F =23.0Hz),102.8,47.9,11.3,3.8.HRMS(ESI)m / z:[M+Na] + calcd for C 24 H 19 FN6OSNa:481.1217,found:481.1213.

[0088]

[0089] N-(2-chlorophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A10):white solid,mp 167–169℃,yield:64.0%. 1H NMR(400MHz,DMSO-d6,ppm)δ:9.73(s,1H),8.59(s,1H),8.51(dd,J=8.3,1.5 Hz,1H),8.47(s,1H),7.99–7.95(m,2H),7.48(dd,J=8.0,1.5 Hz,1H),7.40–7.33(m,4H),7.05(t,J=7.6 Hz,1H),4.15(d,J=7.2 Hz,2H),1.35(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13 C NMR(100MHz,DMSO-d6,ppm)δ:164.2,159.7,153.4,152.1,151.6,149.4,145.1,137.9,132.3,130.0,128.2,127.4,123.9,122.8,122.4,121.3,121.0,104.8,48.4,11.6,4.2.HRMS(ESI)m / z:[M+Na] + calcd for C 24 H 19 ClN6OSNa:497.0922,found:497.0915.

[0090]

[0091] N-(3-chlorophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A11):white solid,mp 170–172℃,yield:65.3.0%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:10.53(s,1H),8.59(s,1H),8.48(s,1H),8.02–7.95(m,3H),7.63(dd,J=8.3,1.3 Hz,1H),7.43(s,1H),7.40–7.35(m,3H),7.00(dd,J=7.9,1.3 Hz,1H),4.15(d,J=7.3 Hz,2H),1.36(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13CNMR(100 MHz,DMSO-d6,ppm)δ:162.7,159.3,153.2,151.8,151.2,149.5,144.7,142.5,133.4,131.9,130.6,126.9,122.2,120.8,120.7,116.1,115.2,103.6,47.9,11.3,3.8.HRMS(ESI)m / z:[M+H] + calcd for C 24 H 20 ClN6OS:475.1102,found:475.1082.

[0092]

[0093] N-(4-chlorophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A12):white solid,mp 205–206℃,yield:66.1%. 1 H NMR(400MHz,DMSO-d6,ppm)δ:10.44(s,1H),8.59(s,1H),8.48(s,1H),8.03–7.99(m,2H),7.81–7.77(m,2H),7.41–7.34(m,5H),4.15(d,J=7.3 Hz,2H),1.35(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:162.8,159.3,153.2,151.8,151.2,149.5,144.7,140.1,131.9,128.8,127.0,124.5,122.1,120.8,118.3,103.3,47.9,11.3,3.8.HRMS(ESI)m / z:[M+Na] + calcd for C 24 H 19 ClN6OSNa:497.0922,found:497.0907.

[0094]

[0095] N-(2-bromophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A13):white solid,mp 167–168℃,yield:59.6%. 1 H NMR(400MHz,DMSO-d6,ppm)δ:9.57(s,1H),8.59(s,1H),8.47(s,1H),8.30(d,J=6.6 Hz,1H),7.97–7.93(m,2H),7.66(d,J=6.5 Hz,1H),7.42(t,J=8.5 Hz,1H),7.38(s,1H),7.35–7.32(m,2H),7.02(t,J=8.0 Hz,1H),4.15(d,J=7.3 Hz,2H),1.35(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:164.2,159.3,153.2,151.7,151.2,149.1,144.7,139.0,133.0,132.0,128.4,126.9,124.5,122.4,122.1,120.7,113.9,104.3,47.9,11.3,3.8.HRMS(ESI)m / z:[M+Na] + calcdfor C 24 H 19 BrN6OSNa:541.0417,found:541.0403.

[0096]

[0097] N-(3-bromophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A14):white solid,mp 189–190℃,yield:57.4%. 1H NMR(400MHz,DMSO-d6,ppm)δ:10.51(s,1H),8.59(s,1H),8.48(s,1H),8.09(t,J=2.0 Hz,1H),8.02–7.98(m,2H),7.69(d,J=7.1 Hz,1H),7.42(s,1H),7.40–7.36(m,2H),7.30(t,J=8.1Hz,1H),7.13(d,J=8.9 Hz,1H),4.15(d,J=7.3 Hz,2H),1.35(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:162.6,159.3,153.2,151.8,151.2,149.5,144.7,142.6,131.9,130.9,126.9,123.6,122.2,121.9,120.8,119.0,115.6,103.6,47.9,11.3,3.8.HRMS(ESI)m / z:[M+Na] + calcdfor C 24 H 19 BrN6OSNa:541.0417,found:541.0411.

[0098]

[0099] N-(4-bromophenyl)-5-(4-((9-(cyclopropylmethyl)-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A15):white solid,mp 203–204℃,yield:62.6%. 1 H NMR(400MHz,DMSO-d6,ppm)δ:10.45(s,1H),8.59(s,1H),8.48(s,1H),8.03–7.99(m,2H),7.76–7.72(m,2H),7.53–7.49(m,2H),7.39(s,1H),7.38–7.34(m,2H),4.15(d,J=7.3 Hz,2H),1.35(hept,J=7.6 Hz,1H),0.57–0.46(m,4H); 13C NMR(100 MHz,DMSO-d6,ppm)δ:162.8,159.3,153.2,151.8,151.2,149.5,144.7,140.5,131.9,131.7,127.0,122.1,120.8,118.7,112.3,103.3,47.9,11.3,3.8.HRMS(ESI)m / z:[M+Na] + calcd for C 24 H 19 BrN6OSNa:541.0417,found:541.0415.

[0100]

[0101] 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-phenylthiazol-2-amine(3A16):whitesolid,mp 159–161℃,yield:55.0%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:10.31(s,1H),8.53(s,1H),8.47(s,1H),8.03–7.99(m,2H),7.76–7.73(m,2H),7.38–7.33(m,5H),6.96(t,J=7.3 Hz,1H),4.11(d,J=7.3 Hz,2H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.7 Hz,6H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:163.2,159.3,153.4,151.7,151.2,149.5,145.2,141.2,132.1,129.0,127.0,122.1,121.2,120.7,116.8,102.8,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcd for C 24 H 22 N6OSNa:465.1468,found:465.1465.

[0102]

[0103] 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-(o-tolyl)thiazol-2-amine(3A17):white solid,mp 158–160℃,yield:54.3%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:9.37(s,1H),8.53(s,1H),8.46(s,1H),8.03(d,J=8.4 Hz,1H),7.97–7.93(m,2H),7.35–7.32(m,2H),7.28(s,1H),7.25–7.20(m,2H),7.00(t,J=8.0 Hz,1H),4.11(d,J=7.3 Hz,2H),2.30(s,3H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.7 Hz,6H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:165.4,159.3,153.4,151.6,151.2,149.3,145.2,139.4,132.2,130.6,128.8,126.9,126.5,123.3,122.0,120.9,120.7,102.8,50.5,28.5,19.6,18.1.HRMS(ESI)m / z:[M+Na] + calcd for C 25 H 24 N6OSNa:479.1624,found:479.1621.

[0104]

[0105] 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-(m-tolyl)thiazol-2-amine(3A18):white solid,mp 191–192℃,yield:59.0%. 1H NMR(400 MHz,DMSO-d6,ppm)δ:10.22(s,1H),8.53(s,1H),8.47(s,1H),8.02–7.98(m,2H),7.61(d,J=10.3 Hz,1H),7.48(s,1H),7.38–7.34(m,3H),7.23(t,J=7.8 Hz,1H),6.78(d,J=7.5 Hz,1H),4.11(d,J=7.2 Hz,2H),2.31(s,3H),2.24(hept,J=7.5 Hz,1H),0.88(d,J=6.7 Hz,6H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:163.3,159.3,153.4,151.7,151.2,149.4,145.2,141.2,138.1,132.1,128.9,126.9,122.1,122.0,120.7,117.4,114.1,102.7,50.5,28.5,21.4,19.6.HRMS(ESI)m / z:[M+Na] + calcd forC 25 H 24 N6OSNa:479.1624,found:479.1620.

[0106]

[0107] 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-(p-tolyl)thiazol-2-amine(3A19):white solid,mp 159–160℃,yield:60.1%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:10.18(s,1H),8.53(s,1H),8.47(s,1H),8.01–7.98(m,2H),7.63–7.60(m,2H),7.38–7.34(m,2H),7.31(s,1H),7.16–7.14(m,2H),4.11(d,J=7.2 Hz,2H),2.29–2.19(m,4H),0.88(d,J=6.8 Hz,6H); 13C NMR(100 MHz,DMSO-d6,ppm)δ:163.4,159.3,153.4,151.7,151.2,149.4,145.2,138.8,132.1,130.1,129.4,126.9,122.1,120.7,117.0,102.5,50.5,28.5,20.4,19.6.HRMS(ESI)m / z:[M+Na] + calcdfor C 25 H 24 N6OSNa:479.1624,found:479.1625.

[0108]

[0109] 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-(2-methoxyphenyl)thiazol-2-amine(3A20):white solid,mp 155–156℃,yield:58.7%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:9.61(s,1H),8.56–8.53(m,2H),8.47(s,1H),8.01–7.97(m,2H),7.37–7.34(m,2H),7.32(s,1H),7.05–6.95(m,3H),4.11(d,J=7.2 Hz,2H),3.87(s,3H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.7 Hz,6H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:163.7,159.3,153.4,151.6,151.2,149.0,147.9,145.2,132.2,130.3,126.9,122.1,121.9,120.7,118.0,110.9,103.5,55.7,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcd forC 25 H 24 N6O2SNa:495.1574,found:495.1568.

[0110]

[0111] 5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)-N-(3-methoxyphenyl)thiazol-2-amine(3A21):white solid,mp 205–207℃,yield:59.6%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:10.09(s,1H),8.53(s,1H),8.47(s,1H),8.01–7.97(m,2H),7.68–7.64(m,2H),7.37–7.34(m,2H),7.27(s,1H),6.97–6.93(m,2H),4.11(d,J=7.3 Hz,2H),3.73(s,3H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.7 Hz,6H); 13 C NMR(100MHz,DMSO-d6,ppm)δ:163.8,159.3,154.1,153.4,151.6,151.2,149.4,145.2,134.7,132.1,126.9,122.0,120.7,118.6,114.3,102.1,55.2,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcd forC 25 H 24 N6O2SNa:495.1574,found:495.1566.

[0112]

[0113] N-(2-fluorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A22):white solid,mp 161–163℃,yield:63.2.0%. 1H NMR(400 MHz,DMSO-d6,ppm)δ:10.11(s,1H),8.63(t,J=8.5 Hz,1H),8.53(s,1H),8.46(s,1H),8.02–7.98(m,2H),7.39–7.34(m,3H),7.28–7.22(m,2H),7.03–6.98(m,1H),4.11(d,J=7.3 Hz,2H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.7 Hz,6H); 13 C NMR(100MHz,DMSO-d6,ppm)δ:163.2,159.3,153.4,151.7,151.6(d, 1 J C-F =242.0 Hz),151.2,149.1,145.2,132.0,129.1(d, 3 J C-F =11.0 Hz),126.9,124.7(d, 4 J C-F =4.0 Hz),122.1,122.0,120.7,119.7,115.1(d, 2 J C-F =19.0 Hz),104.1,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcd forC 24 H 21 FN6OSNa:483.1374,found:483.1373.

[0114]

[0115] N-(3-fluorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A23):white solid,mp 155–156℃,yield:62.5%. 1H NMR(400 MHz,DMSO-d6,ppm)δ:10.55(s,1H),8.53(s,1H),8.46(s,1H),8.02–7.99(m,2H),7.82(d,J=12.1 Hz,1H),7.41–7.33(m,5H),6.77(t,J=8.1 Hz,1H),4.11(d,J=7.3 Hz,2H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.7 Hz,6H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:162.7,159.3,153.4,151.8,151.2,149.6(d, 1 J C-F =371.0 Hz),149.5,145.2,142.8(d, 3 J C-F =11.0Hz),131.9,130.5(d, 3 J C-F =10.0 Hz),126.9,122.2,120.7,112.7(d, 4 J C-F =2.0 Hz),107.4(d, 2 J C-F =21.0 Hz),103.6,103.5(d, 2 J C-F =27.0 Hz),50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcd for C 24 H 21 FN6OSNa:483.1374,found:483.1361.

[0116]

[0117] N-(4-fluorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A24):white solid,mp 216–217℃,yield:68.6%. 1H NMR(400 MHz,DMSO-d6,ppm)δ:10.33(s,1H),8.53(s,1H),8.46(s,1H),8.02–7.98(m,2H),7.80–7.75(m,2H),7.38–7.35(m,3H),7.22–7.16(m,2H),4.11(d,J=7.2 Hz,2H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.7 Hz,6H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:163.3,159.3,156.9(d, 1 J C-F =236.0 Hz),153.4,151.7,151.2,149.4,145.2,137.7(d, 4 J C-F =2.0 Hz),132.0,127.0,122.1,120.7,118.3(d, 3 J C-F =8.0 Hz),115.5(d, 2 J C-F =22.0 Hz),102.8,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcd forC 24 H 21 FN6OSNa:483.1374,found:483.1372.

[0118]

[0119] N-(2-chlorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A25):white solid,mp 159–161℃,yield:60.9%. 1H NMR(400 MHz,DMSO-d6,ppm)δ:9.73(s,1H),8.53(s,1H),8.50(d,J=6.7 Hz,1H),8.46(s,1H),7.99–7.95(m,2H),7.48(d,J=8.0 Hz,1H),7.40–7.33(m,4H),7.05(td,J=7.6,1.5 Hz,1H),4.11(d,J=7.2 Hz,2H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.7 Hz,6H); 13 CNMR(100 MHz,DMSO-d6,ppm)δ:163.7,159.3,153.4,151.7,151.2,149.0,145.2,137.6,132.0,129.6,127.8,126.9,123.4,122.3,122.1,121.0,120.7,104.5,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcd for C 24 H 21 ClN6OSNa:499.1078,found:499.1069.

[0120]

[0121] N-(3-chlorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A26):white solid,mp 157–159℃,yield:65.0%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:10.53(s,1H),8.53(s,1H),8.47(s,1H),8.02–7.95(m,3H),7.63(d,J=8.3Hz,1H),7.42(s,1H),7.40–7.34(m,3H),7.00(d,J=7.9 Hz,1H),4.11(d,J=7.3Hz,2H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.7 Hz,6H); 13C NMR(100 MHz,DMSO-d6,ppm)δ:170.3,162.7,159.3,153.4,151.8,151.2,149.5,145.2,142.5,133.4,131.9,130.6,126.9,122.2,120.7,116.1,115.2,103.6,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcdfor C 24 H 21 ClN6OSNa:499.1078,found:499.1078.

[0122]

[0123] N-(4-chlorophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A27):white solid,mp 204–205℃,yield:64.5%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:10.45(s,1H),8.53(s,1H),8.46(s,1H),8.03–7.99(m,2H),7.81–7.77(m,2H),7.41–7.34(m,5H),4.11(d,J=7.2 Hz,2H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.7 Hz,6H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:162.8,159.3,153.4,151.7,151.2,149.5,145.2,140.1,131.9,128.8,127.0,124.5,122.1,120.7,118.3,103.3,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcd for C 24 H 21 ClN6OSNa:499.1078,found:499.1074.

[0124]

[0125] N-(2-bromophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A28):white solid,mp 156–157℃,yield:59.5%. 1 H NMR(400 MHz,DMSO-d6,ppm)δ:9.57(s,1H),8.53(s,1H),8.46(s,1H),8.30(d,J=8.3 Hz,1H),7.97–7.94(m,2H),7.65(d,J=6.5 Hz,1H),7.42(t,J=7.8 Hz,1H),7.38(s,1H),7.35–7.33(m,2H),7.02(t,J=7.6 Hz,1H),4.11(d,J=7.2 Hz,2H),2.24(hept,J=6.8 Hz,1H),0.88(d,J=6.6 Hz,6H); 13 C NMR(100 MHz,DMSO-d6,ppm)δ:164.2,159.3,153.4,151.7,151.2,149.1,145.2,139.0,133.0,132.0,128.4,126.9,124.5,122.4,122.1,120.7,113.9,104.3,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcd forC 24 H 21 BrN6OSNa:543.0573,found:543.0567.

[0126]

[0127] N-(3-bromophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A29):white solid,mp 156–158℃,yield:57.4%. 1H NMR(400MHz,DMSO-d6,ppm)δ:10.51(s,1H),8.52(s,1H),8.47(s,1H),8.09(t,J=2.0Hz,1H),8.02–7.98(m,2H),7.69(d,J=8.4Hz,1H),7.42(s,1H),7.40–7.36(m,2H),7.30(t,J=8.1Hz,1H),7.13(d,J=9.2Hz,1H),4.10(d,J=7.3Hz,2H),2.24(hept,J=6.8Hz,1H),0.87(d,J=6.7Hz,6H); 13 CNMR(100MHz,DMSO-d6,ppm)δ:162.6,159.3,153.4,151.8,151.2,149.5,145.2,142.6,131.9,130.9,126.9,123.6,122.1,121.9,120.7,119.0,115.6,103.6,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + calcd for C 24 H 21 BrN6OSNa:543.0573,found:543.0565.

[0128]

[0129] N-(4-bromophenyl)-5-(4-((9-isobutyl-9H-purin-6-yl)oxy)phenyl)thiazol-2-amine(3A30):white solid,mp 154–155℃,yield:62.5%. 1 H NMR(400MHz,DMSO-d6,ppm)δ:10.47(s,1H),8.53(s,1H),8.46(s,1H),8.02–7.99(m,2H),7.76–7.72(m,2H),7.53–7.49(m,2H),7.39–7.34(m,4H),4.11(d,J=7.3Hz,2H),2.24(hept,J=6.8Hz,1H),0.88(d,J=6.7Hz,6H); 13C NMR (100MHz, DMSO-d6, ppm) δ: 162.8, 159.3, 153.4, 151.7, 151.2, 149.5, 145.2, 140.5, 131. 9,131.7,127.0,122.1,120.7,118.7,112.3,103.4,50.5,28.5,19.6.HRMS(ESI)m / z:[M+Na] + Calculate for C 24 H 21 BrN6OSNa:543.0573,found:543.0561.

[0130] 3. Antimicrobial data of target compounds

[0131] The turbidity method was used to evaluate the inhibitory activity of the target compounds against kiwifruit bacterial canker (Psa), rice bacterial leaf streak (Xoc) and citrus canker (Xac). First, prepare NB medium (15 g glucose, 7.5 g peptone, 1.5 g yeast powder, 4.5 g beef paste, dissolved in 1500 ml secondary water, pH 7.0-7.2). Take 40 μL of NB solution containing bacteria Psa, Xoc or Xac, mix it with 4 mL of NB solution and 1 mL of 0.1% Tween-20 solution containing the test compound, and incubate at 28°C and 180 rpm for 1-3 days. When the OD value of the blank control is 0.6-0.8, monitor the bacterial growth and determine the OD value of the compound. Turbidity correction value = OD bacterium -OD no bacteria ,I=(C tur -T tur ) / C tur × 100%. Among them, C tur is the turbidity value of the blank control group, T tur is the turbidity value of the drug-treated group, I tur is the inhibition rate.

[0132] Table 1. In vitro antibacterial activity of compounds 3A1-3A30 against Xanthomonas oryzae, Xanthomonas citri var. citri and Xanthomonas avium

[0133]

[0134]

[0135] From the biological activity test results in Table 1, it can be seen that the 2-aminothiazole compounds containing purine moieties have moderate to excellent inhibitory activity against rice bacterial leaf streak fungus and kiwi fruit bacterial canker fungus, among which compound 3A7 has the best activity, with inhibitory activities of 78.8% and 65.3% against rice bacterial leaf streak fungus and kiwi fruit bacterial canker fungus, respectively, which are much higher than the control agents thiophanate-copper and thiazole zinc.

[0136] 4. Preparation of target compound 3A7 composition

[0137] The wettable powder of the target compound 3A7 and Zhongshengmycin is used to prepare a composite composition. In each composition, the ratio of the target compound 3A7 and Zhongshengmycin is calculated according to the mass ratio. The following preparations of the target compound 3A7 and Zhongshengmycin are prepared as needed.

[0138] Composition 1: 3A7: Zhongshengmycin wettable powder = 1:1

[0139] Composition 2: 3A7: Zhongshengmycin wettable powder = 1:2

[0140] Composition 3: 3A7: Zhongshengmycin wettable powder = 2:1

[0141] Anti-rice bacterial leaf streak disease and kiwifruit bacterial canker disease activity of the composition of target compound 3A7

[0142] The antibacterial activity of the combination of target compound 3A7 and zhongshengmycin was tested against oxysporum leaf streak of rice and kiwi fruit bacterial canker using the turbidity method (the antibacterial activity test method mentioned previously).

[0143] Table 2 Inhibitory activity of drugs against bacterial leaf streak pathogen of rice and bacterial canker pathogen of kiwi fruit

[0144]

[0145] The in vitro growth rate method was used to test the activity of the composition against rice bacterial leaf streak pathogen and kiwi fruit bacterial canker pathogen at a concentration of 100 μg / mL. From the biological activity test results in Table 2, it can be seen that the activity of the composite composition against rice bacterial leaf streak pathogen and kiwi fruit canker pathogen was improved compared with the compounds before compounding. The inhibitory activity of composition 3 (3A7: Zhongshengmycin wettable powder = 2:1) against rice bacterial leaf streak pathogen and kiwi fruit bacterial canker pathogen reached 90.1% and 84.9%, respectively. Therefore, the composite composition of 3A7 and Zhongshengmycin has a synergistic effect on rice bacterial leaf streak pathogen and kiwi fruit bacterial canker pathogen.

[0146] 5. Plant growth regulating activity

[0147] (1) Wheat seed germination experiment

[0148] First, the target compound to be tested and the control drug DA-6 (aminoethyl ester) were each prepared into a 5% aqueous solution, and then they were diluted with distilled water to a concentration of 10μg / mL, 20μg / mL, 30μg / mL, 60μg / mL and 120μg / mL of plant growth regulator aqueous solution. Subsequently, wheat seeds with rounded appearance and full grains were carefully selected, and these seeds were cultivated with 5% target compound dilution solution, 5% DA-6 dilution solution and clean water for 8 hours. A total of 240 seeds were treated, and each treatment was repeated three times. After the treatment, the seeds were placed one by one in culture dishes of the same size, and double-layer filter paper was laid in the culture dishes, and the number of wheat seeds in each culture dish was ensured to be the same. The wheat seeds were germinated at a constant temperature of 25°C, and the wheat seeds were kept moist during this period. During the seed germination process, carefully observe the germination status of the wheat seeds. When the embryo length is about 0.5cm, take it as the standard. After one day, count the germination rate of all the wheat seeds in the culture dish. After completing the statistical work, calculate the germination promotion rate of each dilution compared with clean water. The specific test data is shown in the following table.

[0149] Table 3. Wheat germination test of some target compounds

[0150]

[0151]

[0152] In the wheat germination experiment, some compounds in this series showed good effects in promoting wheat seed germination. Overall, among the five concentrations, 20μg / mL had the highest germination rate. Among them, compound 3A10 showed better wheat seed germination activity than the control drug DA-6 at 20μg / mL.

[0153] (2) Cucumber cotyledon expansion experiment

[0154] First, the cucumber seeds required for the biological activity test were soaked, and then sown in an enamel dish with 0.7% agar and a lid, and placed in a dark environment at 26°C for 72 hours, and then carefully selected cucumber seedlings with relatively uniform cotyledon sizes for use. Sample preparation used the filter paper method in the determination of plant hormone active substances. The test concentrations of the samples were set at 10μg / mL and 1μg / mL, and the solvent was DMF. The specific operation process is as follows: first, the samples were prepared into 100μg / mL and 10μg / mL DMF mother solutions, and then 0.3mL of each of the three mother solutions of different concentrations was taken and evenly dripped on a filter paper with a diameter of 6cm. After the solvent was naturally dried, the filter paper containing the sample was placed in a culture dish of the same size as the filter paper, and 3mL of distilled water and 10 cotyledons were added to each culture dish, thus forming a 10μg / mL and 1μg / mL treatment group. The cucumber seeds treated with distilled water were used as the control group. All the culture dishes were placed at 6°C and 3000 Lux for cultivation. After 72 hours, the fresh weight of the cucumber cotyledons in each culture dish was measured. Each treatment was repeated twice to reduce the error. The relevant results were recorded. After the statistics were completed, the expansion promotion rate of the cotyledons of the cucumber seeds treated with the target compound dilution and thidiazuron was calculated compared with the cotyledons of the cucumber seeds treated with water. The detailed experimental results can be found in the table below.

[0155] Table 4. Cucumber cotyledon expansion test of some target compounds

[0156]

[0157]

[0158] The cucumber cotyledon expansion test of some target compounds showed that this series of compounds had certain cytokinin activity, especially compounds 3A1, 3A2 and 3A7, which had better activity than the control drug thiolone at a concentration of 10 μg / mL.

Claims

1. A novel aminothiazole derivative containing a purine structure, characterized in that: The structural formula of the derivative is as follows: Among them, R1 is C3-C4 alkyl, and R2 is hydrogen, methyl, or mono- or di-substituted halogen.

2. A novel aminothiazole derivative containing a purine structure according to claim 1, characterized in that: The R1 is cyclopropylmethyl or isopropyl.

3. The method for preparing a novel aminothiazole derivative containing a purine structure according to claim 1, characterized in that: The reaction formula is as follows:

4. The method for preparing a novel aminothiazole derivative containing a purine structure according to claim 3, characterized in that: The method comprises the following steps: first, 6-chloro-9(H)-purine is reacted with bromomethylcyclopropane or bromoisobutane in DMF, and potassium carbonate is used as a catalyst to generate an intermediate 1; second, phenylthioureas with different substitutions are directly condensed with α-bromo-p-hydroxyacetophenone in an acetonitrile solvent to obtain an intermediate 2; finally, the intermediates 1 and 2 are heated and refluxed in an acetonitrile solution containing potassium carbonate as a catalyst to generate a target compound.

5. Use of a novel aminothiazole derivative containing a purine structure as claimed in claim 1 or 2 in the preparation of drugs and medicaments for preventing and controlling bacterial leaf streak pathogen of rice, bacterial canker pathogen of kiwi fruit and citrus canker pathogen.

6. A compound pesticide composition, characterized in that: The composition comprises the derivative according to claim 1 and zhongshengmycin.

7. The composition according to claim 6, characterized in that: The mass ratio of the derivative to zhongshengmycin is 1:2-2:

1.

8. Use of the composition according to claim 6 in the preparation of a medicament for preventing and controlling bacterial leaf streak pathogen of rice and bacterial canker pathogen of kiwi fruit.

9. The composition according to claim 6, characterized in that: The derivative is 3A7.

10. Application of the novel aminothiazole derivative containing a purine structure as claimed in claim 1 or 2 in the preparation of plant growth regulators.

Images