Synthesis method and activity research of antibacterial drugs containing mannose structure
阅读说明：本技术 一组含有甘露糖结构的抗菌药物的合成方法及活性研究 (Synthesis method and activity research of antibacterial drugs containing mannose structure ) 是由 吕廷洪 冯峰 于 2020-06-11 设计创作，主要内容包括：本发明提供了一种O-糖苷甘露糖修饰的化合物制备以及活性测试。通过改变6-位取代基甘露糖和双靶点甘露糖与致病性大肠杆菌黏附素上的FimH结合力,进而发现设计了双靶点甘露糖抗生素活性效果更优,其活性效果HAI提高上百倍,反应整体收率较高,过程中使用的试剂廉价易得,且合成过程中步骤简单,操作容易,可以广泛应用于工业,其优良的生物活性,为治疗尿路感染提供了物质基础和技术路线。(The invention provides preparation and activity test of an O-glycoside mannose modified compound. Through changing the 6-position substituent mannose, the double-target mannose and the FimH binding force on the pathogenic escherichia coli adhesin, the double-target mannose antibiotic is found and designed to have better activity effect, the activity effect HAI is improved by hundreds of times, the overall reaction yield is higher, the reagents used in the process are cheap and easy to obtain, the steps in the synthesis process are simple, the operation is easy, the double-target mannose antibiotic can be widely applied to the industry, the excellent biological activity of the double-target mannose antibiotic provides a material basis and a technical route for treating urinary tract infection.)
1. The invention relates to application of the following four mannose micromolecules as antibiotics in preparation of medicines for preventing and treating urinary tract infection.
2. The molecular structural feature of claim 1 having:
wherein R is1The group can be selected from any one of guanidyl, amide, hydrazine, azide, fluorine, amino and hydroxylamine,
wherein R is2The group can be selected from any one of tert-butylamide carbonate, amino and 1-methylpiperazine,
wherein n in the molecules A, B and C can be any one of 0, 2, 3, 4, 6, 8 and 10.
3. 1-1, a, B, C according to claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable drug loaded form.
4. 1-1, a, B, C according to claim 1, wherein any one of the compounds is used for killing microorganisms.
Technical Field
The invention designs and synthesizes a group of antibiotic drug molecules containing mannose structures, and performs activity test on bacterial uremia infection on the group of compounds, belonging to the field of pharmaceutical chemistry.
Background
Urinary Tract Infections (UTIs) are a serious public health problem worldwide, causing not only great economic loss, but also a reduction in the quality of life of women. UTIs are often caused by uropathogenic E.coli (UPEC), and current antibiotics have difficulty eradicating the bacterium and its spores. In addition, the development of UPEC-resistant drugs is restricted by factors such as bacterial mutation and antibiotic resistance, so that new strategies are needed to develop corresponding antibiotics. UPEC survive in the intestine and colonize around and invade the urinary tract through the urethra, thereby inducing urinary tract infections. UPEC encodes up to 16 flagella, each of which is capable of invading a host cell in a different environment. The first-type flagellar FimH fibronectin binds to mannose of high mannose glycoprotein of human epithelial cells, and further invades epithelial cells. Although UPEC has specific proteins, there are no antibiotics to date that act on such specific protein targets.
The patent therefore intends to overcome urinary tract infections caused by UPEC by designing and synthesizing a group of molecules of antibacterial drugs containing mannose structures. Compared with lead compounds, the component has the advantage of higher activity.
Disclosure of Invention
One of the purposes of the invention is to synthesize an antibacterial drug molecule containing a mannose structure by aiming at UTIs.
One of the objectives of the present invention is to synthesize an antibacterial drug molecule containing a 6-substituted mannose.
One of the objectives of the present invention is to design an antibacterial drug molecule with a dual-target effect by a fusion strategy.
The invention performs activity test on the synthesized antibacterial drug molecules, finds out the antibiotic with excellent activity, and can be used for treating UTIs.
Wherein R is1The group can be selected from any one of guanidino, amide, hydrazine, azide, fluorine, amino and hydroxylamine.
Wherein R is2The group can be selected from any one of tert-butylamide carbonate, amino and 1-methylpiperazine.
Wherein n in the molecules A, B and C can be any one of 0, 2, 3, 4, 6, 8 and 10.
The preparation method of 1-1 (when R is amino) described in the patent is as follows.
The preparation method of A, B and C described in the patent is as follows.
Wherein when F is a, the A molecule can be obtained by the above synthesis method.
Wherein when F is B, B molecule can be obtained by the above synthesis method.
Wherein when F is C, the C molecule can be obtained by the synthesis method.
Wherein when F is d, the C molecule can be obtained by the synthesis method.
The activity test is carried out on the synthesized molecules, the test effect of partial molecules is excellent, and the specific test result is shown in the following part.
Specific experimental scheme
The foregoing and other aspects of the present invention will become more apparent from the following detailed description, given by way of example only, for purposes of illustrating the invention. This is not to be construed as limiting the invention.
Example 1: synthesis of Compounds 1-8
The compounds 1-8 of the invention are synthesized by the following steps:
synthesis of Compounds 1-8: argon gas stripNext, mannose (54.9mmol), imidazole (77.8mmol), triphenylphosphine (110.6mmol) and iodine (83.1mmol) as raw materials were dissolved in DMF and reacted at 50 ℃ for a certain period of time. After the reaction is finished, a large amount of DMF is removed by spinning, water is added, and excessive iodine simple substance is washed by dichloromethane. The aqueous phase was spun dry and directly taken to the next step. The crude product was dissolved in DMF and sodium azide (166,1mmol) was added and reacted at 60 ℃ until the starting material disappeared. After the reaction, DMF is removed by spinning, and an intermediate product is obtained by column chromatography. And (2) reacting the intermediate product obtained in the step (1), acetic anhydride (505mmol) and a catalytic amount of iodine at room temperature for 10 minutes. Extraction with ethyl acetate, washing with 1N hydrochloric acid solution to remove excess pyridine, washing with saturated sodium bicarbonate solution, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, spin-drying the organic phase, and purification by column chromatography. The purified product was dissolved in dry dichloromethane, 4-bromo-2-methylphenol (101mmol) and boron trifluoride etherate (151.5mmol) were added, after a certain time of reflux reaction, quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, spun dry and purified by column chromatography (78% yield). The purified product was dissolved in a solution of 1,4 dioxane and water (5:1), 3- (N-methylcarboxamide) phenylboronic acid (59 mmol), cesium carbonate (118.2mmol), and palladium tetratriphenylphosphine (3.9mmol) were added in this order and reacted at 80 ℃ for a certain period of time. After the reaction, 1,4 dioxane is removed by rotation, ethyl acetate is extracted for three times, organic phases are combined, dried by anhydrous sodium sulfate, dried by rotation and purified by column chromatography to obtain an intermediate, and the intermediate is dissolved in MeOH, K2CO3(6.6mmol) to give an intermediate, which is then dissolved in THF/H2To O (4/1), triphenylphosphine (33.1 mmol) was added, the reaction was carried out at 50 ℃ until the TLC detection reaction was completed, and the reaction mixture was subjected to dry column chromatography to obtain compounds 1 to 8 (87% yield).
Example 2: synthesis of Compounds 1-9
The compounds 1-9 of the invention are synthesized by the following steps:
synthesis of Compounds 1-9S-methylisothiouronium sulfate (0.079mmol) was dissolved in water at 0 deg.C and a defined amount of concentrated ammonia was added, after stirring for 1h, compounds 1-8(0.017mmol) were added, reacted at 85 deg.C for a defined time and after reaction purified by preparative HPLC to give compounds 1-9 (yield 70%).
Example 3: synthesis of Compounds 1-10
The compounds 1-10 of the invention are synthesized by the following steps:
synthesis of Compounds 1-10 Compounds 1-8(0.025mmol) were dissolved in water and an aqueous solution of hydroxylamine sulfonic acid (0.042mmol) was slowly added dropwise at room temperature and reacted for a certain period of time at room temperature. After the reaction was complete, spin-dried and purified by preparative HPLC to give compounds 1-10 (55% yield).
Example 4: synthesis of Compounds 1-11
The compounds 1-11 of the invention are synthesized by the following steps:
synthesis of Compounds 1-11 Compounds 1-8(0.05mmol) were added to 0.04mL of ethyl formate and reacted for a period of time under reflux. After the reaction was complete, spin-dried and purified by preparative HPLC to give compounds 1-11 (50% yield).
Example 5 Synthesis of 1-15
The compounds 1-15 of the invention are synthesized by the following steps:
synthesis of Compounds 1-15: raw material mannose (54.9mmol), acetic anhydride (545mmol) and a catalytic amount of iodine are reacted for 10 minutes at room temperature under the argon condition. Extracting with ethyl acetate, washing with 1N hydrochloric acid solution to remove excessive pyridine, washing with saturated sodium bicarbonate solution, washing with saturated sodium chloride solution, and washing with anhydrous sulfuric acidSodium was dried and the organic phase was spin dried and purified by column chromatography. The purified product was dissolved in dry dichloromethane, 4-bromo-2-methylphenol (109mmol) and boron trifluoride etherate (151.5mmol) were added, after a certain time of reflux reaction, quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, spin dried and purified by column chromatography. The purified intermediate (0.97mmol) was dissolved in a solution of 1,4 dioxane and water (5:1), 3- (N-methylcarboxamide) phenylboronic acid (1.46mmol), cesium carbonate (2.91mmol), and palladium tetrakistriphenylphosphine (0.097mmol) were added in this order and reacted at 80 ℃ for a certain period of time. After the reaction, 1,4 dioxane is removed by rotation, ethyl acetate is extracted for three times, organic phases are combined, dried by anhydrous sodium sulfate, dried by rotation and purified by column chromatography to obtain the compound which is added with MeOH and K2CO3Hydrolysis (0.19 mmol) gave compounds 1-15 (82% yield).
Example 6 Synthesis of 1-14
The synthesis method of the compounds 1-14 is the same as that of the example 5, and only the direct deacetylation protection is skipped over the Suzuki reaction. Compounds 1-14 (85% yield).
Example 7 Synthesis of 1-16
The synthesis of compounds 1 to 14 according to the invention is the same as in example 5, only 3-sulfonylfluorobenzeneboronic acid replacing 3- (N-methylcarboxamide) phenylboronic acid. Compounds 1-16 (80% yield).
Example 8 Synthesis of 1-17
The synthesis of compounds 1 to 17 according to the invention is carried out in the same manner as in example 5, except that 2-methyl-3- (N-methylcarboxamide) phenylboronic acid is used instead of 3- (N-methylcarboxamide) phenylboronic acid. Compounds 1-17 (88% yield).
Example 9 Synthesis of 1-21
The compounds 1-21 of the invention are synthesized by the following steps:
synthesis of Compounds 1-21: 1-18(0.02mmol,1equiv.) and 1-19(0.024mmol) were condensed with 1.2 equivalents of Katt condensation agent (0.024mmol) in DMF at room temperature for a period of time, and the product was isolated by column chromatography as 1-21 (51% yield).
Example 10 Synthesis of 1-20
The compounds 1-20 of the invention are synthesized by the following steps:
the synthesis of compounds 1-20 of the present invention was the same as in example 9. Wherein n in the compound a is 0. Compounds 1-20 (43% yield).
Example 11 Synthesis of 1-22
The compounds 1-22 of the present invention are synthesized by the following steps:
the synthesis of compounds 1-22 according to the invention is the same as in example 9. Wherein n in the compound A is 6. Compounds 1-22 (49% yield).
Example 12 Synthesis of 1-23
The compounds 1-23 of the invention are synthesized by the following steps:
the synthesis of compounds 1-23 of the present invention was the same as in example 9. Wherein n in the compound a is 10. Compounds 1-23 (52% yield).
Example 13 Synthesis of 1-27
The compounds 1-27 of the present invention were synthesized by the following steps:
compounds 1-27: 1-18(0.024mmol) and 1-24(0.02mmol), CDI (0.024mmol) in dichloromethane, and after stirring for a period of time at room temperature, the product was isolated by column chromatography (53% yield).
Example 14 Synthesis of 1-25
The compounds 1-25 of the invention are synthesized by the following steps:
the synthesis of compounds 1-25 of the present invention was the same as in example 13. Wherein n is 2 in the compound A. Compounds 1-25 (51% yield).
Example 15 Synthesis of 1-26
The compounds 1-26 of the present invention are synthesized by the following steps:
the synthesis of compounds 1-26 of the present invention was the same as in example 13. Wherein n is 3 in the compound A. Compounds 1-26 (51% yield).
Example 16 Synthesis of 1-28
The compounds 1-28 of the present invention were synthesized by the following steps:
the synthesis of compounds 1-28 of the present invention was the same as in example 13. Wherein n in the compound A is 6. Compounds 1-28 (50% yield).
Example 17 Synthesis of 1-29
The compounds 1-29 of the invention are synthesized by the following steps:
the synthesis of compounds 1-29 according to the invention is the same as in example 13. Wherein n in the compound A is 8. Compounds 1-29 (51% yield).
Example 18 Synthesis of 1-33
The compounds 1-33 of the present invention are synthesized by the following steps:
examples 1 to 33: 1-18(0.024mmol) and 1-31(0.02mmol), CDI (0.024mmol) in dichloromethane, and after stirring for a period of time at room temperature, the product was isolated by column chromatography 1-33 (53% yield).
Example 19 Synthesis of 1-32
The compounds 1-32 of the invention are synthesized by the following steps:
the synthesis of compounds 1-32 according to the invention is the same as in example 18. Wherein n is 2 in the compound A. Compounds 1-32 (48% yield).
Example 20 Synthesis of 1-34
The compounds 1-34 of the present invention are synthesized by the following steps:
the synthesis of compounds 1-34 of the present invention was the same as in example 18. Wherein n in the compound A is 6. Compounds 1-34 (50% yield).
Example 21 Synthesis of 1-36
The compounds 1 to 36 of the present invention were synthesized by the following steps:
compounds 1-33: 1-18(0.024mmol) and 1-35(0.02mmol), CDI (0.024mmol) in dichloromethane, and after stirring for a period of time at room temperature, the product was isolated by column chromatography (55% yield).
Example 22 Synthesis of 1-37
The compounds 1-37 of the present invention are synthesized by the following steps:
the synthesis of compounds 1-37 of the present invention was the same as in example 21. Wherein n in the compound A is 6. Compounds 1-37 (52% yield).
Example 23 Synthesis of 1-38
The compounds 1-38 of the present invention were synthesized by the following steps:
the synthesis of compounds 1-38 of the present invention was the same as in example 21. Wherein n is 4 in the compound A. Compounds 1-38 (47% yield).
Example 24 Synthesis of 1-39
The compounds 1-39 of the invention are synthesized by the following steps:
the synthesis of compounds 1-39 of the present invention was performed in the same manner as in example 21. Wherein n in the compound A is 6. Compounds 1-39 (43% yield).
Example 25 Synthesis of 1-19
The compounds 1-19 of the invention are synthesized by the following steps:
synthesis of Compounds 1-19: starting from the ciprofloxacin, methyl esterification protects the carboxyl of the ciprofloxacin; next, methyl ester protected ciprofloxacin was linked with carbonate mono protected diamine using a condensing agent to give intermediates, and decarbonylation under the acidity of trifluoroacetic acid gave intermediates 1-19.
Example 26 Synthesis of 1-24
The compounds 1-24 of the invention are synthesized by the following steps:
synthesis of Compounds 1-24: protecting methyl ester of ciprofloxacin, then carrying out alkylation reaction on alkane bromide with amino protected by phthalamide and an intermediate, and removing the phthalamide by hydrazine hydrate to obtain the intermediate 1-24.
Example 27 Synthesis of 1-31
The compounds 1-31 of the invention are synthesized by the following steps:
synthesis of Compounds 1-31: starting from N-methyl piperazine, carrying out alkylation reaction with alkane bromide of the phthalamide for protecting amino, and removing the phthalamide protection from hydrazine hydrate to obtain an intermediate 1-31.
The synthesized O-mannases were tested for activity and the results were as follows:
TABLE 1 Structure-activity relationship of O-mannases double-target embodiment
TABLE 2 Structure-activity relationship of O-mannases double target embodiments
Nuclear magnetic and mass spectral data for the synthesis of O-mannoside
1-8 (FIG. 1):1HNMR(300MHz,DMSO-d6)δ7.48(s,1H),7.34(d,J＝7.6Hz,1H), 7.23(d,J＝7.9Hz,1H),7.12(t,J＝7.8Hz,1H),7.00(d,J＝8.9Hz,2H),6.81(d,J＝ 8.3Hz,1H),5.33(s,1H),3.93(t,J＝2.5Hz,1H),3.82(dd,J＝9.3,3.3Hz,1H),3.55 –3.34(m,2H),2.91(d,J＝12.7Hz,1H),2.82–2.70(m,1H),2.69(s,3H),1.91(s, 3H).
1-9 (FIG. 2):1HNMR(300MHz,DMSO-d6)δ7.50(s,1H),7.36(d,J＝7.7Hz,1H), 7.25(d,J＝8.1Hz,1H),7.21–7.08(m,1H),7.01(d,J＝8.9Hz,2H),6.88–6.75(m, 1H),5.34(s,1H),4.02–3.89(m,1H),3.84(dd,J＝9.2,3.3Hz,1H),3.58–3.35(m, 2H),2.93(d,J＝13.0Hz,1H),2.85–2.74(m,1H),2.74–2.63(m,3H),1.92(s,3H). MS(ESI)[M+H]+Calcd.for C22H28O6N4:444.2,found:444.1.
1-10 (FIG. 4):1HNMR(300MHz,DMSO-d6)δ7.61(s,1H),7.51(d,J＝7.8Hz,1H), 7.42(d,J＝7.7Hz,1H),7.34–7.17(m,3H),6.97(d,J＝8.5Hz,1H),5.49(s,1H), 4.01(s,1H),3.87(d,J＝5.5Hz,1H),3.47(d,J＝7.8Hz,2H),3.04(d,J＝12.8Hz, 1H),2.82(dd,J＝13.6,7.4Hz,1H),2.75–2.61(m,3H),2.04(s,3H).MS(ESI)[M +H]+Calcd.for C21H27O6N3:417.2,found:417.4.
1-11 (fig. 3)1HNMR(300MHz,DMSO-d6)δ7.82(s,2H),7.69–7.53(m,2H),7.52 –7.24(m,4H),7.08(dd,J＝10.6,8.3Hz,1H),5.53–5.45(m,1H),4.06(dd,J＝3.4, 1.8Hz,1H),3.92(dd,J＝8.8,3.3Hz,1H),3.53(d,J＝5.6Hz,3H),3.22(p,J＝1.7 Hz,1H),2.85(s,3H),2.16(s,3H).MS(ESI)[M+H]+Calcd.for C22H26O7N2: 430.1,found:430.3.
1-14 (FIG. 5):1H NMR(400MHz,CDCl3)δ7.22–7.17(m,1H),7.15–7.10(m,1H), 6.94(d,J＝8.7Hz,1H),5.50(dd,J＝10.1,3.4Hz,1H),5.46–5.40(m,2H),5.36– 5.30(m,1H),4.26(dt,J＝12.2,5.8Hz,1H),4.09–4.00(m,2H),2.23(s,3H).MS (ESI)[M+H]+Calcd.for C13H17O6Br:348.0,found:348.3.
1-15：1H NMR(400MHz,D2O)δ7.49(d,J＝7.8Hz,1H),7.41–7.19(m,4H),7.08 (dd,J＝39.7,8.1Hz,2H),5.41(s,1H),3.94(s,2H),3.56–3.45(m,4H),2.83(d,J＝ 35.1Hz,6H),2.05(s,3H).MS(ESI)[M+H]+Calcd.for C22H27O7N4:417.1,found: 417.2.
1-16 (FIG. 6):1HNMR(600MHz,DMSO-d6)δ7.63–7.55(m,2H),7.46(d,J＝2.4 Hz,1H),7.41(td,J＝8.8,7.5,5.6Hz,2H),7.28(t,J＝7.4Hz,1H),7.20(d,J＝8.5 Hz,1H),5.40(d,J＝1.8Hz,1H),5.10(s,1H),4.92(d,J＝34.2Hz,2H),4.46(s,1H), 3.86(s,1H),3.71(d,J＝9.3Hz,1H),3.58(d,J＝11.5Hz,1H),3.48(d,J＝21.9Hz, 3H),2.22(s,3H).MS(ESI)[M+H]+Calcd.for C19H21O8SF 428.0, found 428.4.1-17 (FIG. 7):1HNMR(300MHz,D2O)δ7.61(s,1H),7.47(dd,J＝25.9,7.7Hz,2H), 7.36–7.14(m,3H),6.97(d,J＝8.5Hz,1H),5.49(s,1H),4.01(s,1H),3.96–3.73 (m,1H),3.47(d,J＝7.6Hz,2H),3.04(d,J＝12.8Hz,1H),2.83(dd,J＝13.7,7.2Hz, 1H),2.76–2.61(s,3H),2.04(s,3H),1.68(s,J＝0.8Hz,3H).MS(ESI)[M+H]+ Calcd.for C22H27O7N:417.1,found:417.4.
1-20 (FIG. 8):1HNMR(300MHz,DMSO-d6)δ8.66(s,1H),7.93(d,J＝12.7Hz,1H), 7.77–7.65(m,2H),7.51(dd,J＝13.8,6.3Hz,4H),7.39(d,J＝7.6Hz,1H),7.24(d, J＝8.6Hz,1H),5.44(d,J＝1.7Hz,1H),5.05(d,J＝4.5Hz,1H),4.86(d,J＝5.6Hz, 1H),4.77(d,J＝5.8Hz,1H),4.45(t,J＝5.8Hz,1H),3.88(s,2H),3.78(m,13H), 2.25(s,3H),1.32(d,J＝6.9Hz,2H),1.17(d,J＝4.0Hz,2H).MS(ESI)[M+H]+ Calcd.for C37H38O10N3F:703.2,found:703.1.
1-21:1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.05(s,1H),7.75(t,J＝6.0Hz, 2H),7.59–7.44(m,4H),7.25(d,J＝8.6Hz,1H),6.63(s,1H),5.44(s,1H),5.05(d, J＝4.5Hz,1H),4.80(dd,J＝30.9,5.8Hz,2H),4.47(t,J＝5.8Hz,1H),3.89(s,2H), 3.78(m,17H),2.25(s,3H),1.54(s,2H),1.44(s,2H),1.27(d,J＝32.3Hz,4H).MS (ESI)[M+H]+Calcd.for C42H48O11N5F:817.3,found:817.4.
1-22 (fig. 9):1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.05(s,1H),7.75(t,J＝ 6.0Hz,2H),7.59–7.44(m,4H),7.25(d,J＝8.6Hz,1H),6.63(s,1H),5.44(s,1H), 5.06(d,J＝4.5Hz,1H),4.83(dd,J＝30.9,5.8Hz,2H),4.47(t,J＝5.8Hz,1H),3.89 (s,2H),3.78(m,17H),2.25(s,3H),1.54(s,2H),1.44(s,2H),1.27(d,J＝32.3Hz, 8H).MS(ESI)[M+H]+Calcd.for C44H52O11N5F:845.3,found:845.1.
1-23 (fig. 10):1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.04(s,1H),7.99–7.64 (m,3H),7.56–7.45(m,3H),7.25(d,J＝8.6Hz,1H),6.60(s,1H),5.44(s,1H),5.15 –4.93(m,1H),4.83(dd,J＝30.7,5.9Hz,2H),4.47(t,J＝5.9Hz,1H),3.92–3.39 (m,19H),2.25(s,3H),1.53(s,2H),1.40(s,2H),1.28(d,J＝14.6Hz,16H).MS(ESI) [M+H]+Calcd.for C48H60O11N5F:901.4,found:901.1.
1-25 (fig. 11):1H NMR(400MHz,CD3OD)δ8.30(s,1H),7.85(d,J＝1.8Hz,1H), 7.54(ddd,J＝13.4,8.3,1.7Hz,3H),7.32–7.21(m,3H),7.18(d,J＝7.2Hz,1H), 7.06(d,J＝8.5Hz,1H),5.32(s,1H),3.84(dd,J＝3.4,1.8Hz,1H),3.71(dd,J＝9.4, 3.4Hz,1H),3.64–3.03(m,18H),2.07(s,3H),1.35–0.65(m,6H).MS(ESI)[M+ H]+Calcd.for C40H45O10N4F:760.3,found:760.2.
1-26 (fig. 12):1HNMR(600MHz,CD3OD)δ8.41(d,J＝5.4Hz,1H),7.96–7.89(m, 1H),7.68–7.56(m,3H),7.41–7.31(m,3H),7.22–7.06(m,2H),5.40–5.29(m, 1H),3.92(dd,J＝3.4,1.9Hz,1H),3.79(dd,J＝9.4,3.4Hz,1H),3.75–3.08(m, 18H),2.12(d,J＝3.6Hz,3H),1.76(dq,J＝11.6,6.3,5.7Hz,2H),1.26–1.08(m, 4H),1.07–0.96(m,2H).MS(ESI)[M+H]+Calcd.for C41H47O10N4F:774.3, found:774.1.
1-27 (fig. 13):1H NMR(400MHz,CD3OD)δ8.70(s,1H),7.95(t,J＝1.9Hz,1H), 7.89(d,J＝13.2Hz,1H),7.67(dd,J＝7.7,1.9Hz,2H),7.51(d,J＝7.3Hz,1H), 7.47–7.32(m,3H),7.20(d,J＝8.6Hz,1H),5.44(d,J＝2.0Hz,1H),3.94(dd,J＝ 3.5,1.9Hz,1H),3.82(dd,J＝9.4,3.3Hz,1H),3.72–3.51(m,18H),2.20(s,3H), 1.86–1.56(m,4H),1.33–0.99(m,6H).MS(ESI)[M+H]+Calcd.for C42H49O10N4F:788.3,found:788.1.
1-28 (FIG. 14):1HNMR(400MHz,DMSO-d6)δ8.58(t,J＝5.5Hz,1H),8.07(dd,J＝ 3.8,2.2Hz,1H),7.81–7.68(m,2H),7.57–7.37(m,5H),7.25(d,J＝8.6Hz,1H), 5.45(d,J＝1.9Hz,1H),3.89(dd,J＝3.4,1.9Hz,1H),3.73(s,1H),3.67–3.18(m, 18H),2.25(s,3H),1.61–1.40(m,4H),1.41–1.17(m,8H),1.13–1.02(m,2H).MS (ESI)[M+H]+Calcd.for C44H53O10N4F:816.3,found:816.1.
1-29 (fig. 15):1HNMR(400MHz,DMSO-d6)δ8.57(t,J＝5.5Hz,1H),8.46(d,J＝ 1.4Hz,1H),8.06(d,J＝2.2Hz,1H),7.80–7.70(m,2H),7.59–7.44(m,4H),7.26 (d,J＝8.6Hz,1H),5.45(d,J＝1.7Hz,1H),3.90(dd,J＝3.4,1.7Hz,1H),3.85– 3.34(m,11H),3.35–3.11(m,8H),2.26(s,3H),1.69(s,2H),1.59–1.48(m,2H), 1.38–1.18(m,12H),1.11(dd,J＝6.5,3.9Hz,2H).MS(ESI)[M+H]+Calcd.for C46H57O10N4F:844.4,found:844.3.
1-32 (FIG. 17):1H NMR(400MHz,CD3OD)δ8.03(t,J＝1.8Hz,1H),7.83–7.63(m, 2H),7.58–7.39(m,3H),7.30(d,J＝8.5Hz,1H),5.56(d,J＝1.8Hz,1H),4.08(dd, J＝3.4,1.9Hz,1H),3.98(dd,J＝9.4,3.4Hz,1H),3.84–3.70(m,3H),3.64–3.59 (m,1H),3.57(t,J＝6.7Hz,2H),2.75–2.38(m,10H),2.30(d,J＝9.2Hz,6H).MS (ESI)[M+H]+Calcd.for C27H37O7N3:515.3,found:515.1.
1-33 (FIG. 16):1H NMR(400MHz,CD3OD)δ8.02(t,J＝1.8Hz,1H),7.74(dd,J＝ 7.7,1.8Hz,2H),7.56–7.41(m,3H),7.31(d,J＝8.4Hz,1H),5.56(d,J＝1.9Hz, 1H),4.08(dd,J＝3.4,1.8Hz,1H),3.98(dd,J＝9.5,3.4Hz,1H),3.82–3.72(m,3H), 3.60(ddd,J＝9.9,4.7,2.9Hz,1H),3.43(t,J＝6.5Hz,2H),3.00–2.07(m,10H), 1.73–1.21(m,10H).MS(ESI)[M+H]+Calcd.for C29H41O7N3:543.3,found: 543.1.
1-34 (fig. 18):1H NMR(400MHz,CD3OD)δ8.02(t,J＝1.8Hz,1H),7.73(dq,J＝ 6.7,1.7Hz,2H),7.55–7.40(m,3H),7.30(d,J＝8.5Hz,1H),5.56(d,J＝1.8Hz, 1H),4.12–4.03(m,1H),3.98(dd,J＝9.4,3.4Hz,1H),3.78(ddd,J＝15.1,6.4,4.0 Hz,3H),3.61(ddt,J＝7.1,4.8,2.4Hz,1H),3.40(t,J＝7.1Hz,2H),2.35(dd,J＝9.4, 6.4Hz,10H),2.31(s,3H),2.26(s,3H),1.64(q,J＝7.1Hz,2H),1.52(q,J＝7.3Hz, 3H),1.44–1.33(m,3H).MS(ESI)[M+H]+Calcd.for C31H45O7N3:571.3,found: 571.4.
1-36 (fig. 19):1H NMR(600MHz,CD3OD)δ8.02(d,J＝2.1Hz,1H),7.72(t,J＝8.8 Hz,2H),7.51–7.42(m,3H),7.29(d,J＝8.5Hz,1H),5.55(d,J＝1.7Hz,1H),4.09 –4.07(m,1H),3.98(dd,J＝9.5,3.4Hz,1H),3.83–3.69(m,3H),3.65–3.56(m, 1H),3.41(t,J＝7.0Hz,2H),3.08(t,J＝6.9Hz,2H),2.30(s,3H),1.65(p,J＝7.2Hz, 2H),1.55(p,J＝7.2Hz,2H),1.42(s,9H).MS(ESI)[M+H]+Calcd.for C29H40O9N2:560.3,found:560.1.
1-37 (fig. 20):1H NMR(600MHz,CD3OD)δ8.00(s,1H),7.70(dd,J＝18.1,7.7Hz, 2H),7.48–7.40(m,3H),7.26(d,J＝8.4Hz,1H),5.55(s,1H),4.08(d,J＝2.9Hz, 1H),3.97(dd,J＝9.5,3.3Hz,1H),3.83–3.69(m,3H),3.63–3.55(m,1H),3.38(t, J＝7.2Hz,2H),3.02(t,J＝7.1Hz,2H),2.29(s,3H),1.63(p,J＝7.4Hz,2H),1.48 (p,J＝7.2Hz,2H),1.40(s,13H).MS(ESI)[M+H]+Calcd.for C31H44O9N2:588.3, found:588.1.
1-38 (FIG. 21):1HNMR(400MHz,DMSO-d6)δ8.05(d,J＝1.9Hz,1H),7.77(dt,J＝ 8.0,2.0Hz,2H),7.56–7.46(m,3H),7.26(d,J＝8.5Hz,1H),5.45(d,J＝1.8Hz, 1H),3.94–3.84(m,1H),3.73(dd,J＝9.2,3.4Hz,1H),3.65–3.57(m,3H),2.82(q, J＝6.1Hz,2H),2.26(s,3H),1.65–1.51(m,5H),1.33–1.18(m,3H).MS(ESI)[M +H]+Calcd.for C24H32O7N2:460.2,found:460.3.
1-39 (FIG. 22):1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝1.8Hz,1H),7.77(dt,J＝ 8.0,2.0Hz,2H),7.56–7.46(m,3H),7.27(d,J＝8.5Hz,1H),5.45(d,J＝1.8Hz, 1H),3.90(dd,J＝3.3,1.9Hz,1H),3.74(dd,J＝9.2,3.4Hz,3H),3.29(q,J＝6.6Hz, 4H),2.83–2.72(m,2H),2.27(s,3H),1.55(tq,J＝12.2,7.2,5.3Hz,4H),1.42–1.18 (m,6H).MS(ESI)[M+H]+Calcd.for C26H36O7N2:488.3,found:488.4.