CN110790686A - Compound and application thereof in preparing anti-inflammatory and acute lung injury, chronic obstructive lung disease, asthma or pulmonary fibrosis treatment medicines - Google Patents

Compound and application thereof in preparing anti-inflammatory and acute lung injury, chronic obstructive lung disease, asthma or pulmonary fibrosis treatment medicines Download PDF

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CN110790686A
CN110790686A CN201910948949.7A CN201910948949A CN110790686A CN 110790686 A CN110790686 A CN 110790686A CN 201910948949 A CN201910948949 A CN 201910948949A CN 110790686 A CN110790686 A CN 110790686A
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杨诚
杨光
周红刚
李霄鹤
魏玉娇
曹胜
张坤
姜秋燕
高劭妍
刘蕊
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Nankai University
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Abstract

The invention provides a compound and application thereof in preparing anti-inflammatory and treating acute diseasesThe compound has a structural general formula as follows:
Figure DDA0002225124830000011
the compound can effectively inhibit the hydrolase activity of LTA4H, and has high anti-inflammatory and anti-pulmonary fibrosis activity.

Description

Compound and application thereof in preparing anti-inflammatory and acute lung injury, chronic obstructive lung disease, asthma or pulmonary fibrosis treatment medicines
Technical Field
The invention belongs to the field of medicines, and particularly relates to a compound and application thereof in preparing medicines for resisting inflammation and treating acute lung injury, chronic obstructive pulmonary disease, asthma or pulmonary fibrosis.
Background
Leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc finger enzyme that can catalyze the biosynthesis of the endogenous chemotactic agent leukotriene B4(LTB 4). LTB4 is a major member of the leukotriene family, while LTB4 is a potent inflammatory mediator, primarily involved in the chemochemotactic process of neutrophils, eosinophils, monocytes, macrophages, mast cells, dendritic cells, effector T cells, leading to the production of excess inflammatory products, further augmenting local inflammatory responses there is a large body of evidence that LTB4 plays an important role in the expansion of many inflammatory disease states, including inflammatory bowel disease, psoriasis, inflammatory lung disease, etc. LTB4 acts primarily through two G-protein coupled receptors: BLT1 and BLT2, where the affinity of BLT1 for LTB4 (pK d 9.2) is higher than that of BLT2(pK d 7.2). LTB4/BLT1 pathway can also promote the secretion of TGF- β macrophages, further triggering inflammatory disease states.
In addition, the research shows that LTB4 has the functions of promoting lung tissue inflammation, vascular permeability, immune response, pulmonary fibrosis and the like. Garcia J et al found elevated concentrations of LTB4 in alveolar lavage fluid from patients with asbestos-pulmonary fibrosis. The increase of the content of the LTB4 in lung tissues and alveolar lavage fluid is closely related to the occurrence of pulmonary fibrosis, and the LTB4 is involved in the pathogenesis process of pulmonary fibrosis, and blocks the biosynthesis or antagonizes the effect of pulmonary fibrosis, so that the treatment of pulmonary fibrosis is possible to become a new direction.
Leukotriene A4 has aminopeptidase function in addition to hydrolase function, and its aminopeptidase activity is shown in degrading the tripeptide Pro-Gly-Pro (PGP). PGP is a neutrophil chemotactic factor in extracellular matrix collagen, and neutrophils are also the major source of PGP synthase, so uncontrolled PGP activity leads to a vicious cycle of inflammation. LTA4H can promote the resolution of neutrophilic granulocytic inflammation by degrading PGP through aminopeptidase activity, and the abnormal degradation process of LTA4H-PGP leads to the enhancement and persistence of inflammatory reaction, thereby accelerating the disease deterioration. This suggests that LTA4H plays a dual and opposite role during the inflammatory response. Recent studies aimed at the development of potent LTA4H inhibitors, without taking into account the anti-inflammatory physiological significance of LTA4H aminopeptidase activity. In view of the above, the development of selective inhibitors of LTA4H that selectively block the conversion of LTA4 to LTB4 without compromising the hydrolysis of PGP remains a challenging task.
Disclosure of Invention
In view of the above, the present invention aims to provide compounds and applications thereof in preparing anti-inflammatory drugs, and drugs for treating acute lung injury, chronic obstructive pulmonary disease, asthma or pulmonary fibrosis.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a compound having a formula represented by the following formula 1:
Figure BDA0002225124810000011
in the formula:
n＝2-5；
R1is H or CF3；
R2Independently selected from alkyl, alkoxy, heteroatom substituents,
Figure BDA0002225124810000012
-NH-C(O)-R3Said
Figure BDA0002225124810000013
Wherein m is 2-4, said-NH-c (o) -R3R in (1)3Independently selected from alkyl, substituted aryl, -N (R)4R5) said-N (R)4R5) R in (1)4And R5Are independently selected from H, methyl, benzyl, isobutyl, propyl pentyl.
Further, the substituent in the heteroatom substituent is halogen, nitro, amino, methoxy, trifluoromethoxy or methyl.
Further, said R3Independently selected from isopropyl, p-trifluoromethylphenyl, methyl, phenyl, tert-butyl.
Further, the compound is selected from one or more of the following compounds:
Figure BDA0002225124810000021
Figure BDA0002225124810000031
Figure BDA0002225124810000041
the invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing medicaments for resisting inflammation and treating acute lung injury, chronic obstructive pulmonary disease, asthma or pulmonary fibrosis.
Compared with the prior art, the invention has the following advantages:
the invention provides a compound which can be used for specifically inhibiting the hydrolase function of LTA4H by designing and synthesizing a leukotriene A4 hydrolase inhibitor for specifically blocking the hydrolase function of LTA4H and retaining the aminopeptidase function of the hydrolase inhibitor, and researches show that the compound can effectively inhibit the hydrolase activity of LTA4H, has higher activities of resisting inflammation and treating acute lung injury, Chronic Obstructive Pulmonary Disease (COPD), asthma and pulmonary fibrosis, and is expected to be applied to medicaments for treating acute lung injury, Chronic Obstructive Pulmonary Disease (COPD), asthma and pulmonary fibrosis.
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The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIGS. 1-8 are graphs showing that Compound 26 inhibits human lung fibroblast activation and ECM production by inhibiting the TGF- β 1/Smad3 signaling pathway FIG. 1 is a graph of human lung fibroblasts (HFL1 cells) treated with 5ng/ml TGF- β 1 with or without Compound 26(10 μ M) for 24 hours FIG. 1 the expression of α -SMA protein and fibronectin (Fn), collagen type I (Col1) protein in the cells is determined using Western blotting FIG. 2 is a graph showing the relative density of α -SMA strips normalized to GAPDH FIG. 3-5 are the expression of α -SmaSMA (FIG. 3), Fn (FIG. 4) and mRNA of Col1 (FIG. 5) after TGF- β treatment in fibroblasts by qRT-PCR assay, FIG. 6 is a graph of CAGA-NIH3T3 cells treated with 5ng/ml SmaSmad- β with or without Compound 26(10 μ M) for 18 hours, luciferase cells are cleaved with 5ng/ml TGF- β, and the relative density of TGF-Smad 3926, 7 is a graph of 7, 8, 3 μ M, and 3 μ M3-3648, 3-7 is a graph showing the relative density of HFL expression of TGF-7 cells with or no TGF-7.
Fig. 9-20 prophylactic treatment of compound 26 ameliorated BLM-induced lung inflammation fig. 9 is a dosing regimen in a BLM-induced lung injury model C57BL/6J mice treated with pirfenidone (200mg/kg), compound 26(100mg/kg) or SAHA (100 mg) daily, day 0-7 after bleomycin (2mg/kg) treatment, lungs were taken on day 7 for subsequent analysis (n ═ 6 per group), fig. 10 and 11 are H & E staining of lung sections (fig. 10-a-10-E) and inflammatory cells from BALF (fig. 11-a-11-E), fig. 12-16 are total cell numbers in BALF (fig. 16) (fig. 12), macrophage cell numbers (fig. 13), neutrophil cell numbers (fig. 14), lymphocyte numbers (fig. 15) and protein concentrations fig. 17-20 are measured in BALF 4 (fig. 17), IL 1- β), and TNF 6335 levels by ELISA (fig. 19-366335).
Figures 21-28 are compounds 26 that reduced BLM-induced pulmonary fibrosis in mice.
Figure 21 is an early dosing regimen for a pulmonary fibrosis model. On days 0-7 after bleomycin (2mg/kg) treatment, C57BL/6J mice were dosed daily with pirfenidone (200mg/kg), compound 26(100mg/kg) or SAHA (100mg/kg) and lungs were harvested on day 14 for subsequent analysis (n ═ 6 per group). FIG. 22 is the hydroxyproline content in lung tissue. Figure 23 is a percent pulmonary fibrosis analysis of lung sections. FIGS. 24-a-24-E are H & E staining of lung sections. Figure 25 is an interventional dosing regimen for advanced stages of a pulmonary fibrosis model. From day 7-14 after bleomycin treatment, C57BL/6J mice were dosed daily with either pirfenidone (200mg/kg), compound 26(100mg/kg) or SAHA (100mg/kg) (BLM; 2U/kg) and lungs were harvested on day 14 for subsequent analysis (n ═ 6 per group). FIG. 26 is the hydroxyproline content in lung tissue. Figure 27 is a percent pulmonary fibrosis analysis of lung sections. FIGS. 28-a-28-E are H & E staining of lung sections.
Fig. 29-40 are dose regimens for compound 26 to reduce LPS-induced acute lung injury in mice fig. 29 is the dose regimen in the LPS-induced lung injury model C57BL/6J mice were pre-treated 1 hour before administration of LPS (1mg/kg) with dexamethasone (10mg/kg), compound 26(100mg/kg) or SAHA (100mg/kg) and lungs were taken 24 hours later for subsequent analysis (n ═ 6 per group), fig. 30, 31 are lung sections (fig. 30-a-30-E) and H & E staining of inflammatory cells from BALF (fig. 31-a-31-E), fig. 32-36 are H & E staining of total cell number (fig. 32), macrophage number (fig. 33), neutrophil number (fig. 34), lymphocyte number (fig. 35) and protein concentration as described in methods to determine LTB4 (fig. 37), IL-1- β, IL-6 (fig. 38) and TNF levels in lf (fig. 39-40) by ELISA.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The present invention will be described in detail with reference to the following examples and accompanying drawings.
Example 1: preparation of Compound 1
The preparation method comprises the following steps:
(1) preparation of compound a 1:
Figure BDA0002225124810000051
5-Aminopentanoic acid (11.7g, 100mmol) was added to CH3To a solution of OH (100mL) was added thionyl chloride (11mL, 150mmol) slowly dropwise at 0 ℃ to react for 3 hours. The color becomes increasingly clear. Concentration in vacuo afforded 5-aminopentanoic acid methyl ester hydrochloride. Used in the next step without further purification. 5-Aminopentanoic acid methyl ester hydrochloride (200g, 1.31mmol) was added to a solution of anhydrous THF (100mL), triethylamine (0.35mL, 2.4mmol) and 4-chloro-3-trifluoromethylphenyl isocyanate (221mg, 1.00mmol) were added in N2The reaction was carried out for 6 hours under protection and the reaction was complete by TLC. The mixture was concentrated in vacuo. The mixture was then diluted with EtOAc (200mL), washed with saturated NaCl solution (50mL), over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3: 1 to 1: 1) to give compound a1(352mg, yield 78%) as a white solid.
Data characterization of compound a 1:
m.p 109.2-110.1℃；IR(KBr):3389,3358,3040,2943,2874,1688,1591,1537,1482,1462,1447, 1413cm-1.1H NMR(400MHz,CDCl3)δ8.92(s,1H),8.05(s,1H),7.61–7.49(m,2H),6.34(t,J＝5.8Hz, 1H),3.58(s,3H),3.08(q,J＝6.4Hz,2H),2.33(t,J＝7.3Hz,2H),1.54(qd,J＝8.5,7.2,5.5Hz,2H),1.43 (dq,J＝9.1,6.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.3,154.8,140.2,131.8,122.2,121.2,116.1, 116.0,51.2,38.7,32.9,29.0,21.8.HRMS(ESI)calculated for C14H16ClF3N2NaO3 +[M+Na]+:375.0694, found375.0696.
(2) preparation of compound 1:
hydroxylamine hydrochloride (614mg,8.84mmol) was dissolved in 5mL of methanol, KOH (738mg,13.2mmol) was added at 0 deg.C, stirring was carried out for half an hour, and the filtrate obtained by suction filtration was a methanol solution of hydroxylamine. Compound a1(200mg,0.568mmol) was dissolved in the above freshly prepared solution of hydroxylamine in methanol (6mL) at 0 ℃ and stirred at room temperature for 2 h. TLC reaction was complete and methanol was removed by distillation under reduced pressure. Then, column Chromatography (CH) was performed on silica gel2Cl2:CH3OH ═ 7:1) to give compound 1 (yield 81%) as a white solid.
Data characterization of compound 1:
m.p 155.4-156.4℃；IR(KBr):3334,3263,3070,2952,2877,1679,1652,1591,1570,1530,1415cm-1.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.93(s,1H),8.68(s,1H),8.06(d,J＝2.2Hz,1H),7.69– 7.40(m,2H),6.33(t,J＝5.6Hz,1H),3.07(q,J＝6.2Hz,2H),1.97(t,J＝7.2Hz,2H),1.58–1.46(m,2H), 1.40(p,J＝7.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ169.0,154.9,140.2,131.8,122.2,121.2,116.1, 116.0,38.8,32.0,29.3,22.6.HRMS(ESI)calculated for C13H15clF3N3NaO3 +[M+Na]+:376.0646,found 376.0647.
example 2: preparation of Compound 2
The preparation method comprises the following steps:
(1) preparation of compound a 2:
Figure BDA0002225124810000061
4-chloro-3-trifluoromethyl phenyl isocyanate and 6-aminocaproic acid are taken as raw materials to synthesize a2 (yield is 79%) which is a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 2:
m.p 111.3-112.8℃；IR(KBr):3393,3364,3056,2954,2874,1716,1695,1608,1595,1539,1413cm-1.1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.05(d,J＝2.5Hz,1H),7.61–7.44(m,2H),6.30(t,J＝5.7 Hz,1H),3.57(s,3H),3.07(q,J＝6.6Hz,2H),2.29(t,J＝7.4Hz,2H),1.52(q,J＝7.5Hz,2H),1.42(q,J＝ 7.3Hz,2H),1.28(td,J＝8.5,4.2Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.3,154.9,140.2,131.8, 126.7,124.2,122.2,121.5,121.2,116.1,116.0,51.1,39.0,33.2,29.3,25.8,24.2.HRMS(ESI)calculated forC15H18ClF3N2NaO3 +[M+Na]+:389.0850found 389.0851.
(2) preparation of compound 2:
Figure BDA0002225124810000062
compound 2 (77% yield) was synthesized as a white solid from a2 starting material in the same manner as compound 1.
Data characterization of compound 2:
m.p 165.0-165.7℃；IR(KBr):3334,3219,3120,2952,2879,1681,1649,1589,1568,1479,1415cm-1.1H NMR(400MHz,CDCl3)δ10.34(s,1H),8.92(s,1H),8.66(s,1H),8.06(d,J＝2.2Hz,1H),7.54(d,J＝ 7.3Hz,2H),6.31(s,1H),3.06(q,J＝6.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.46(dp,J＝31.3,7.3Hz,4H), 1.25(tt,J＝9.4,6.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ169.1,154.9,140.2,131.8,126.7,124.3, 122.3,121.2,116.1,116.0,32.3,29.4,26.0,24.9.HRMS(ESI)calculated for C14H17ClF3N3NaO3 +[M+Na]+:390.0803,found 390.0805.
example 3: preparation of Compound 3
The preparation method comprises the following steps:
(1) preparation of compound a 3:
Figure BDA0002225124810000063
4-chloro-3-trifluoromethyl phenyl isocyanate and 7-aminoheptanoic acid are taken as raw materials to synthesize a3 (yield is 79%) which is a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 3:
m.p 107.3-107.9℃；IR(KBr):3341,3317,3052,2931,2857,1781,1670,1539,1510,1500,1425cm-1.1H NMR(400MHz,Chloroform-d)δ8.89(s,1H),8.05(d,J＝2.5Hz,1H),7.62–7.45(m,2H),6.29(t,J＝ 5.7Hz,1H),3.56(s,3H),3.06(q,J＝6.6Hz,2H),2.27(t,J＝7.4Hz,2H),1.50(dd,J＝9.2,5.1Hz,2H), 1.40(q,J＝6.9Hz,2H),1.32–1.21(m,4H).13C NMR(100MHz,DMSO-d6)δ173.3,154.9,140.2,131.7, 126.8,124.2,121.2,116.1,116.0,51.1,39.1,33.2,29.5,28.2,26.0,24.4.HRMS(ESI)calculated forC16H20ClF3N2NaO3 +[M+Na]+:403.1007,found 403.1010.
(2) preparation of compound 3:
compound 3 (84% yield) was synthesized as a white solid from a3 as starting material in the same manner as compound 1.
Data characterization of compound 3:
m.p 120.2-122.2℃；IR(KBr):3337,3252,3112,2940,2868,1694,1650,1569,1555,1414cm-1.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.26(s,1H),8.68(s,1H),8.07(s,1H),7.54(t,J＝7.8Hz,2H), 6.49(d,J＝6.2Hz,1H),3.36(d,J＝1.9Hz,3H),3.07(q,J＝6.4Hz,2H),1.95(t,J＝7.4Hz,2H),1.45(dt, J＝29.5,7.2Hz,4H),1.28–1.23(m,4H).13CNMR(100MHz,DMSO-d6)δ169.1,154.9,140.3,131.8, 126.4,122.0,115.9,39.0,32.2,29.5,28.3,26.1,25.1.HRMS(ESI)calculated for C15H19ClF3N3NaO3 +[M+Na]+:404.0959,found 404.0961.
example 4: preparation of Compound 4
The preparation method comprises the following steps:
(1) preparation of compound a 4:
Figure BDA0002225124810000072
4-chloro-3-trifluoromethyl phenyl isocyanate and 8-aminocaprylic acid are used as raw materials to synthesize a4 (yield is 83%) as a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 4:
m.p 113.0-113.9℃；IR(KBr):3378,3329,3087,2980,2857,2774,1674,1632,1537,1517,1423cm-1.1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.06(d,J＝2.5Hz,1H),7.52(t,J＝9.5Hz,2H),6.56(d,J＝ 5.7Hz,1H),3.57(d,J＝1.8Hz,3H),3.06(q,J＝6.6Hz,2H),2.28(t,J＝7.4Hz,2H),1.50(t,J＝7.1Hz, 2H),1.39(q,J＝7.0Hz,2H),1.25(s,6H).13CNMR(100MHz,DMSO-d6)δ173.4,155.0,140.4,131.8, 127.0,126.6,121.0,115.8,51.1,39.0,33.2,29.6,28.4,28.4,26.2,24.4.HRMS(ESI)calculated for C17H22ClF3N2NaO3 +[M+Na]+:417.1163,found 417.1165.
(2) preparation of compound 4:
Figure BDA0002225124810000073
compound 4 (79% yield) was synthesized as a white solid from a4 as a starting material in the same manner as compound 1.
Data characterization of compound 4:
m.p 148.3-149.0℃；IR(KBr):3347,3282,304,2934,2890,1681,1644,1594,1567,1482,1419cm-1.1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.91(s,1H),8.65(s,1H),8.05(d,J＝2.2Hz,1H),7.63– 7.46(m,2H),6.31(s,1H),3.07(q,J＝6.3Hz,2H),1.93(t,J＝7.3Hz,2H),1.45(dt,J＝25.2,6.9Hz,4H), 1.24(d,J＝11.9Hz,6H).13C NMR(100MHz,DMSO-d6)δ169.1,154.9,140.2,131.8,127.0,122.2,121.2, 116.1,39.1,32.3,29.6,28.6,28.5,26.3,25.1.HRMS(ESI)calculated for C16H21ClF3N3NaO3 +[M+Na]+: 418.1116,found 418.1114.
example 5: preparation of Compound 5
The preparation method comprises the following steps:
(1) preparation of compound a 5:
Figure BDA0002225124810000081
the synthesis method is the same as a1, and the synthesis method is the same as a5 (yield is 80%) obtained by using 4-trifluoromethyl phenylisocyanic acid and 5-aminopentanoic acid as raw materials.
Data characterization of compound a 5:
m.p 113.8-114.9℃；IR(KBr):3331,3321,2947,2874,1696,1638,1660,1558,1479,1438cm-1.1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),7.57(d,J＝4.5Hz,4H),6.30(t,J＝5.8Hz,1H),3.59(s,3H), 3.09(q,J＝6.4Hz,2H),2.34(t,J＝7.3Hz,2H),1.61–1.50(m,2H),1.49–1.39(m,2H).13C NMR(100 MHz,DMSO-d6)δ173.3,154.8,144.3,126.0,125.9,120.7,117.1,51.2,38.6,32.9,29.1,21.8.HRMS(ESI) calculated for C14H17F3N2NaO3 +[M+Na]+:341.1083,found 341.1086.
(2) preparation of compound 5:
compound 5 (77% yield) was synthesized as a white solid from a5 as the starting material in the same manner as compound 1.
Data characterization of compound 5:
m.p 153.1-154.0℃；IR(KBr):3315,3302,3011,2932,2877,1654,1632 1530,1514,1505,1417cm-1.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),9.15(s,1H),8.70(d,J＝1.6Hz,1H),7.56(q,J＝8.8Hz, 4H),6.49(t,J＝5.8Hz,1H),3.07(q,J＝6.4Hz,2H),1.97(t,J＝7.2Hz,2H),1.51(dq,J＝11.7,7.1Hz, 2H),1.40(p,J＝6.9Hz,2H).13C NMR(100MHz,DMSO-d6)δ169.1,154.9,144.4,126.0,126.0,125.9, 123.4,121.2,120.9,117.1,38.7,32.0,29.3,22.6.HRMS(ESI)calculated for C13H16F3N3NaO3 +[M+Na]+: 342.1036,found342.1038.
example 6: preparation of Compound 6
The preparation method comprises the following steps:
(1) preparation of compound a 6:
Figure BDA0002225124810000083
the synthesis method is the same as a1, and the synthesis method is the same as a6 (the yield is 81%) obtained by using 4-trifluoromethyl phenylisocyanic acid and 6-aminocaproic acid as raw materials.
Data characterization of compound a 6:
m.p 131.8-132.5℃；IR(KBr):3359,3325,3006,2934,2870,1722,1652,1603,1552,1515,1413cm-1.1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),7.67–7.46(m,4H),6.27(s,1H),3.58(s,3H),3.08(d,J＝ 6.4Hz,2H),2.31(t,J＝7.4Hz,2H),1.61–1.50(m,2H),1.49–1.38(m,2H),1.30(td,J＝8.4,4.2Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.3,154.8,144.3,126.0,125.9,125.8,120.7,117.1,51.2,38.9,33.2, 29.3,25.8,24.2.HRMS(ESI)calculated for C15H19F3N2NaO3 +[M+Na]+:355.1240,found 355.1238.
(2) preparation of compound 6:
Figure BDA0002225124810000084
compound 6 (67% yield) was synthesized as a white solid from a6 as starting material in the same manner as compound 1.
Data characterization of compound 6:
m.p 150.4-151.5℃；IR(KBr):3379,3303,3049,2946,2873,1697,1682,1601,1555,1522,1479, 1412cm-1.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.24(s,1H),8.69(s,1H),7.56(q,J＝8.6Hz, 4H),6.53(t,J＝5.8Hz,1H),3.06(q,J＝6.5Hz,2H),1.95(t,J＝7.4Hz,2H),1.57–1.36(m,4H),1.29– 1.21(m,2H).13C NMR(100MHz,DMSO-d6)δ169.1,154.9,144.4,125.9,125.9,120.6,117.1,39.0,32.3, 29.6,28.6,28.5,26.3,25.0.HRMS(ESI)calculated for C14H18F3N3NaO3 +[M+Na]+:356.1192,found 356.1190.
example 7: preparation of Compound 7
The preparation method comprises the following steps:
(1) preparation of compound a 7:
4-trifluoromethyl phenylisocyanic acid and 7-amino heptanoic acid are taken as raw materials to synthesize a7(85 percent) which is a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 7:
m.p 129.5-130.4℃；IR(KBr):3377,3294,3030,2941,2866,1731,1655,1596,1525,1418cm-1.1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),7.65–7.51(m,4H),6.27(t,J＝5.7Hz,1H),3.58(s,3H),3.08 (q,J＝6.5Hz,2H),2.30(t,J＝7.4Hz,2H),1.60–1.49(m,2H),1.42(q,J＝6.8Hz,2H),1.35–1.24(m, 4H).13C NMR(100MHz,DMSO-d6)δ173.3,154.8,144.3,126.0,125.9,125.8,123.3,121.3,120.6,117.1, 51.1,39.0,33.2,29.4,28.2,26.0,24.4.HRMS(ESI)calculated for C16H21F3N2NaO3 +[M+Na]+:369.1396, found369.1398.
(2) preparation of compound 7:
Figure BDA0002225124810000092
compound 7 (80% yield) was synthesized as a white solid from a7 starting with compound 1.
Data characterization of compound 7:
m.p 150.5-151.1℃；IR(KBr):3370,3357,3080,2993,2875,1792,1677,1629,1530,1511,1421cm-1.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),9.23(s,1H),8.69(s,1H),7.56(q,J＝8.1Hz,4H),6.54(s, 1H),3.07(t,J＝6.5Hz,2H),1.95(t,J＝7.2Hz,2H),1.57–1.36(m,4H),1.26(d,J＝6.9Hz,4H).13C NMR(100MHz,DMSO-d6)δ169.1,154.9,144.4,126.0,125.9,123.3,120.6,117.1,39.0,32.3,29.6,28.5, 26.3,25.1.HRMS(ESI)calculated for C15H20F3N3NaO3 +[M+Na]+:370.1349,found 370.1348.
example 8: preparation of Compound 8
The preparation method comprises the following steps:
(1) preparation of compound a 8:
Figure BDA0002225124810000093
4-trifluoromethyl phenylisocyanic acid and 8-aminocaprylic acid are used as raw materials to synthesize a8 (yield is 80%) as a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 8:
m.p 118.6-119.9℃；IR(KBr):3359,3321,3051,2987,2874,1698,1570,1548,1517,1491,1415cm-1.1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),7.62–7.52(m,4H),6.27(t,J＝5.7Hz,1H),3.58(s,3H), 3.08(q,J＝6.5Hz,2H),2.29(t,J＝7.4Hz,2H),1.53(q,J＝7.2Hz,2H),1.42(t,J＝6.9Hz,2H),1.28(d,J ＝3.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ173.4,154.8,144.3,125.9,123.4,120.80(d,J＝32.0Hz), 117.1,51.2,39.0,33.2,29.5,28.4,28.4,26.2,24.4.HRMS(ESI)calculated for C17H23F3N2NaO3 +[M+Na]+: 383.1553,found 383.1551.
(2) preparation of compound 8:
Figure BDA0002225124810000101
compound 8 (82% yield) was synthesized as a white solid from a8 as starting material in the same manner as compound 1.
Data characterization of compound 8:
m.p 146.9-148.3℃；IR(KBr):3316,3308,3064,2941,2869,16801,1650,1601,1522,1412cm-1.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.86(s,1H),8.69(s,1H),7.68–7.43(m,4H),6.30(t,J＝5.6 Hz,1H),3.07(q,J＝6.5Hz,2H),1.93(t,J＝7.3Hz,2H),1.45(dp,J＝26.5,7.1Hz,4H),1.24(d,J＝12.7 Hz,6H).13C NMR(100MHz,DMSO-d6)δ169.1,154.8,144.4,125.9,123.4,120.7,117.1,39.1,32.3,29.6, 28.4,26.1,25.2.HRMS(ESI)calculated for C16H22F3N3NaO3 +[M+Na]+:384.1505,found 384.1508.
example 9: preparation of Compound 9
The preparation method comprises the following steps:
(1) preparation of compound a 9:
Figure BDA0002225124810000102
p-methoxy phenyl isocyanate and 5-aminovaleric acid are used as raw materials to synthesize a9 (yield is 85%) as a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 9:
m.p 101.3-101.8℃；IR(KBr):3309,3318,2994,2868,1734,1685,1595,1577,1511,1410cm-1.1H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.35–7.20(m,2H),6.89–6.73(m,2H),6.02(d,J＝5.9Hz, 1H),3.68(s,3H),3.58(s,3H),3.05(q,J＝6.5Hz,2H),2.32(t,J＝7.3Hz,2H),1.54(p,J＝7.3Hz,2H), 1.47–1.33(m,2H).13C NMR(100MHz,DMSO-d6)δ173.3,155.4,153.8,133.7,119.3,113.8,55.1,51.2, 38.6,33.0,29.3,21.9.HRMS(ESI)calculated for C14H20N2NaO4 +[M+Na]+:303.1315,found 303.1313.
(2) preparation of compound 9:
compound 9 (79% yield) was synthesized as a white solid from a9 as a starting material in the same manner as compound 1.
Data characterization of compound 9:
m.p 163.0-163.9℃；IR(KBr):3376,3295,3066,2953,2863,1640,1607,1570,1512,1481,1442cm-1.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.70(s,1H),8.18(s,1H),7.27(d,J＝8.4Hz,2H),6.80(d, J＝8.3Hz,2H),6.02(s,1H),3.68(s,3H),3.05(q,J＝5.9Hz,2H),1.97(t,J＝7.2Hz,2H),1.50(q,J＝7.5 Hz,2H),1.39(q,J＝7.3Hz,2H).13C NMR(100MHz,DMSO-d6)δ169.1,155.5,153.1,133.7,119.4, 113.9,55.1,38.8,32.0,29.5,22.6.HRMS(ESI)calculated for C13H19N3NaO4 +[M+Na]+:304.1268,found 304.1265.
example 10: preparation of Compound 10
The preparation method comprises the following steps:
(1) preparation of compound a 10:
Figure BDA0002225124810000104
p-methoxy phenyl isocyanate and 6-aminocaproic acid are used as raw materials to synthesize a10 (85%) white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 10:
m.p 93.5-94.7℃；IR(KBr):3321,3309,2938,2863,1731,1690,1634,1610,1564,1412cm-1.1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.33–7.18(m,2H),6.85–6.73(m,2H),5.98(t,J＝5.7Hz, 1H),3.68(s,3H),3.58(s,3H),3.03(q,J＝6.6Hz,2H),2.30(t,J＝7.4Hz,2H),1.53(p,J＝7.5Hz,2H), 1.39(q,J＝7.1Hz,2H),1.27(qd,J＝9.7,9.0,5.8Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.3,155.4, 153.8,133.7,119.3,113.8,55.1,51.2,38.9,33.2,29.5,25.9,24.2.HRMS(ESI)calculated for C15H22N2NaO4 +[M+Na]+:317.1472,found 317.1474.
(2) preparation of compound 10:
Figure BDA0002225124810000111
compound 10 (yield 78%) was synthesized as a white solid from a10 starting material in the same manner as compound 1.
Data characterization of compound 10:
m.p 171.8-172.2℃；IR(KBr):3274,3208,3065,2927,2854,1641,1606,1567,1511,1479,1441cm-1.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.67(s,1H),8.24(s,1H),7.27(d,J＝8.5Hz,2H),6.79(d, J＝8.4Hz,2H),6.04(t,J＝5.7Hz,1H),3.68(s,3H),3.03(q,J＝6.4Hz,2H),1.95(t,J＝7.3Hz,2H),1.50 (p,J＝7.4Hz,2H),1.40(p,J＝7.2Hz,2H),1.29–1.21(m,2H).13C NMR(100MHz,DMSO-d6)δ169.1, 155.5,153.8,133.8,119.3,113.8,55.1,39.0,32.3,29.6,26.0,24.9.HRMS(ESI)calculated for C14H21N3NaO4 +[M+Na]+:318.1424,found 318.1427.
example 11: preparation of Compound 11
The preparation method comprises the following steps:
(1) preparation of compound a 11:
Figure BDA0002225124810000112
p-methoxy phenyl isocyanate and 7-aminoheptanoic acid are used as raw materials to synthesize a11 (yield is 79%) which is a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 11:
m.p 108.0-108.6℃；IR(KBr):3313,3303,3000,2938,2870,1729,1641,1598,1555,1435cm-1.1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.34–7.19(m,2H),6.89–6.70(m,2H),5.98(t,J＝5.7Hz, 1H),3.69(s,3H),3.58(s,3H),3.04(q,J＝6.5Hz,2H),2.30(t,J＝7.4Hz,2H),1.58–1.47(m,2H),1.40 (p,J＝6.8Hz,2H),1.32–1.23(m,4H).13C NMR(100MHz,DMSO-d6)δ173.3,155.4,153.8,133.7, 119.3,113.8,55.1,51.2,39.0,33.2,29.7,28.2,26.0,24.4.HRMS(ESI)calculated for C16H24N2NaO4 +[M+Na]+:331.1628,found 331.1626.
(2) preparation of compound 11:
compound 11 (86% yield) was synthesized from a11 as the starting material in the same manner as compound 1.
Data characterization of compound 11:
m.p 131.5-132.3℃；IR(KBr):3350,3317,3058,2937,2884,1739,1670,1634,1580,1533,1419cm-1.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.69(s,1H),8.36(s,1H),7.39–7.18(m,2H),6.91–6.72 (m,2H),6.13(d,J＝5.8Hz,1H),3.68(s,3H),3.03(q,J＝6.6Hz,2H),1.95(t,J＝7.4Hz,2H),1.50(t,J＝ 7.6Hz,2H),1.39(q,J＝7.4Hz,2H),1.25(d,J＝10.0Hz,4H).13C NMR(100MHz,DMSO-d6)δ169.5, 155.9,154.3,134.2,119.7,114.3,55.6,39.4,32.7,30.1,26.5,25.4.HRMS(ESI)calculated for C15H23N3NaO4 +[M+Na]+:332.1581,found 332.1583.
example 12: preparation of Compound 12
The preparation method comprises the following steps:
(1) preparation of compound a 12:
Figure BDA0002225124810000114
p-methoxy phenyl isocyanate and 8-aminocaprylic acid are used as raw materials to synthesize a12 (yield is 85%) as a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 12:
m.p 117.5-117.9℃；IR(KBr):3384,3290,3321,2989,2874,1799,1679,1658,1573,1519,1427cm-1.1H NMR(400MHz,CDCl3)δ7.23–7.12(m,2H),6.85(s,1H),6.84–6.77(m,2H),5.08(d,J＝5.9Hz, 1H),3.76(s,3H),3.65(s,3H),3.16(q,J＝6.8Hz,2H),2.28(t,J＝7.6Hz,2H),1.58(t,J＝7.3Hz,2H), 1.43(t,J＝7.3Hz,2H),1.27(s,6H).13C NMR(100MHz,CDCl3)δ174.5,157.0,131.6,124.0,114.6,55.6, 51.6,40.4,34.1,30.2,29.1,29.0,26.8,24.9.HRMS(ESI)calculated for C17H26N2NaO4 +[M+Na]+:345.1785, found345.1787.
(2) preparation of compound 12:
Figure BDA0002225124810000121
compound 12 (79% yield) was synthesized as a white solid from a12 as a starting material in the same manner as compound 1.
Data characterization of compound 12:
m.p 145.5-146.5℃；IR(KBr):3320,3307,3054,2931,2854,1737,1689,1645,1610,1571,1418cm-1.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.70(s,1H),8.18(s,1H),7.27(d,J＝8.7Hz,2H),6.80(d, J＝8.8Hz,2H),6.01(t,J＝5.8Hz,1H),3.68(s,3H),3.04(q,J＝6.4Hz,2H),1.94(t,J＝7.3Hz,2H),1.49 (t,J＝7.0Hz,2H),1.40(t,J＝6.9Hz,2H),1.26(s,6H).13C NMR(100MHz,DMSO-d6)δ169.1,155.5, 153.8,133.8,119.3,113.9,55.1,39.1,32.3,29.9,28.6,28.5,26.3,25.1.HRMS(ESI)calculated for C16H22N3NaO4 +[M+Na]+:346.1737,found 346.1735.
example 13: preparation of Compound 13
The preparation method comprises the following steps:
(1) preparation of compound a 13:
Figure BDA0002225124810000122
the synthesis method is the same as a1, and the synthesis method is the same as a13 (the yield is 85%) white solid obtained by using 4-trifluoromethoxyphenyl isocyanate and 7-aminoheptanoic acid as raw materials.
Data characterization of compound a 13:
m.p 125.5-127.1℃；IR(KBr):3362,3246,3334,2924,2856,1786,1669,1648,1589,1535,1419cm-1.1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),7.63–7.49(m,4H),6.26(t,J＝5.7Hz,1H),3.57(s,3H), 3.07(q,J＝6.5Hz,2H),2.29(t,J＝7.4Hz,2H),1.58–1.48(m,2H),1.41(q,J＝6.8Hz,2H),1.32–1.23 (m,4H).13C NMR(100MHz,DMSO-d6)δ173.3,154.8,144.3,126.0,125.9,125.9,125.8,121.3,120.6, 117.1,51.1,39.0,33.2,29.4,28.2,26.0,24.4.HRMS(ESI)calculated for C17H26N2NaO4 +[M+Na]+: 385.1346,found 385.1347.
(2) preparation of compound 13:
Figure BDA0002225124810000123
compound 13 (75% yield) was synthesized as a white solid from a13 starting material in the same manner as compound 1.
Data for compound 13 characterisation:
m.p 133.2-134.8℃；IR(KBr):3289,2938,1637,1589,1493cm-1.1H NMR(400MHz,Methanol-d4)δ 7.44(d,J＝8.8Hz,2H),7.14(d,J＝8.3Hz,2H),3.18(t,J＝6.9Hz,2H),2.10(t,J＝7.4Hz,2H),1.63(p,J ＝7.1Hz,2H),1.52(q,J＝6.8Hz,2H),1.38(qt,J＝7.6,5.2,3.8Hz,4H).13C NMR(100MHz,Methanol-d4) δ173.0,158.1,144.9,140.4,122.6,120.9,40.7,33.7,31.0,29.8,27.5,26.6.HRMS(ESI)calculated for C19H16NaO6 +[M+Na]+:386.1298,found 386.1299.
example 14: preparation of Compound 14
The preparation method comprises the following steps:
(1) preparation of compound a 14:
Figure BDA0002225124810000131
4-trifluoromethoxyphenyl isocyanate and 8-aminocaprylic acid are used as raw materials to synthesize a14 (yield is 78%) as a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 14:
m.p 117.9-119.3℃；IR(KBr):3321,3202,2933,2856,1621,1577,1489cm-1.1HNMR(400MHz, CDCl3)δ1H NMR(400MHz,CDCl3)δ7.39–7.30(m,2H),7.12(d,J＝8.5Hz,2H),6.99(s,1H),5.05(d, J＝5.9Hz,1H),3.67(d,J＝1.5Hz,3H),3.21(q,J＝7.0,6.5Hz,2H),2.31(td,J＝7.4,1.5Hz,2H),1.60(t, J＝6.9Hz,2H),1.48(t,J＝6.9Hz,2H),1.30(q,J＝5.4Hz,6H).13C NMR(100MHz,CDCl3)δ174.9, 155.8,144.6,138.0,122.0,120.9,119.4,51.7,40.4,34.1,30.0,29.0,28.9,26.6,24.8.HRMS(ESI) calculated for C19H16NaO6 +[M+Na]+:399.1502,found 399.1500.
(2) preparation of compound 14:
Figure BDA0002225124810000132
compound 14 (yield 78%) was synthesized as a white solid from a14 as starting material in the same manner as compound 1.
Data characterization of compound 14:
m.p 123.1-124.4℃；IR(KBr):3288,2938,1690,1578,1495cm-1.1H NMR(400MHz,Methanol-d4)δ 7.44(d,J＝8.8Hz,2H),7.14(d,J＝8.4Hz,2H),3.18(t,J＝6.9Hz,2H),2.09(t,J＝7.4Hz,2H),1.62(t,J ＝7.1Hz,2H),1.52(t,J＝6.9Hz,2H),1.45–1.30(m,6H).13C NMR(100MHz,Methanol-d4)δ173.0, 158.1,144.9,144.9,140.4,122.6,120.8,40.7,33.7,31.0,30.0,30.0,27.7,26.6.HRMS(ESI)calculated for C19H16NaO6 +[M+Na]+:400.1455,found 400.1453.
example 15: preparation of Compound 15
The preparation method comprises the following steps:
(1) preparation of compound a 15:
Figure BDA0002225124810000133
p-nitrobenzene isocyanate and 5-aminopentanoic acid are used as raw materials to synthesize a15 (yield is 62%) as a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 15:
m.p 180.0-180.5℃；IR(KBr):3343,3293,3091,2954,2876,1715,1654,1599,1561,1525,1410cm-1.1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.13(d,J＝9.2Hz,2H),7.61(d,J＝9.2Hz,2H),6.45(t,J＝ 5.8Hz,1H),3.58(s,3H),3.11(d,J＝6.3Hz,2H),2.34(t,J＝7.3Hz,2H),1.55(dd,J＝8.9,6.4Hz,2H), 1.45(dd,J＝8.7,6.2Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.3,154.4,147.2,140.3,125.1,116.7, 51.2,38.7,32.9,28.9,21.8.HRMS(ESI)calculated for C13H17N3NaO5 +[M+Na]+:318.1060,found 318.1061.
(2) preparation of compound 15:
compound 15 (75% yield) was synthesized as a white solid from a15 as starting material in the same manner as compound 1.
Data characterization of compound 15:
m.p 165.8-167.0℃；IR(KBr):3371,3284,3193,2998,2840,1876,1705,1668,1575,1502,1449cm-1.1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.07(s,1H),8.73(s,1H),8.11(d,J＝8.8Hz,2H),7.63(d, J＝8.8Hz,2H),6.95(s,1H),3.08(q,J＝6.3Hz,2H),1.98(t,J＝7.2Hz,2H),1.51(q,J＝7.5Hz,2H),1.41 (q,J＝7.3Hz,2H).13C NMR(100MHz,DMSO-d6)δ169.1,154.7,147.5,140.1,125.1,116.5,38.7,32.0, 29.2,22.6.HRMS(ESI)calculated for C12H16N4NaO5 +[M+Na]+:319.1013,found 319.1012.
example 16: preparation of Compound 16
The preparation method comprises the following steps:
(1) preparation of compound a 16:
p-nitrobenzene isocyanate and 6-aminocaproic acid are used as raw materials to synthesize a16 (yield is 66%) which is a white solid, and the synthesis method is characterized by the data of a1 compound a 16:
m.p 187.1-187.7℃；IR(KBr):3335,3298,3056,2965,2835,1763,1689,1596,1536,1515,1421cm-1.1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.14(d,J＝8.9Hz,2H),7.62(d,J＝8.9Hz,2H),6.44(s, 1H),3.59(s,3H),3.10(q,J＝6.5Hz,2H),2.31(t,J＝7.3Hz,2H),1.61–1.51(m,2H),1.50–1.41(m,2H), 1.34–1.26(m,2H).13C NMR(100MHz,DMSO-d6)δ173.3,154.4,147.3,140.3,125.1,116.7,51.2,38.9, 33.2,29.2,25.8,24.2.HRMS(ESI)calculated for C14H19N3NaO5 +[M+Na]+:332.1217,found 332.1218.
(2) preparation of compound 16:
Figure BDA0002225124810000142
compound 16 (yield 70%) was synthesized as a white solid from a16 starting with compound 1.
Data characterization of compound 16:
m.p.131.5-133.4℃；IR(KBr):3349,3283,3092,2967,2896,1809,1724,1668,1573,1521,1469cm-1.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.11(s,1H),8.70(s,1H),8.13(d,J＝8.8Hz,2H),7.64(d, J＝8.8Hz,2H),6.95(s,1H),3.09(d,J＝6.3Hz,2H),1.97(t,J＝7.3Hz,2H),1.60–1.47(m,2H),1.47– 1.38(m,2H),1.28(dd,J＝11.8,5.3Hz,2H).13CNMR(100MHz,DMSO-d6)δ169.6,155.1,148.0,140.6, 125.6,116.9,45.8,32.7,29.7,26.4,25.3.HRMS(ESI)calculated for C13H18N4NaO5 +[M+Na]+:333.1169, found 333.1167.
example 17: preparation of Compound 17
The preparation method comprises the following steps:
(1) preparation of compound a 17:
Figure BDA0002225124810000143
p-nitrobenzene isocyanate and 7-aminoheptanoic acid are used as raw materials to synthesize a18 (yield is 64%) which is white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 17:
m.p 155.8-156.8℃；IR(KBr):3365,3321,3056,2968,2864,1764,1689,1564,1538,1514,1419cm-1.1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.21–8.00(m,2H),7.68–7.55(m,2H),6.44(d,J＝5.9Hz, 1H),3.08(d,J＝6.6Hz,2H),2.28(t,J＝7.4Hz,2H),1.51(t,J＝7.2Hz,2H),1.42(t,J＝6.9Hz,2H),1.28 (d,J＝5.6Hz,4H).13C NMR(100MHz,DMSO-d6)δ173.3,154.4,147.3,140.3,125.1,116.7,51.1,39.1, 33.2,29.3,28.2,26.0,24.4.HRMS(ESI)calculated for C15H21N3NaO5 +[M+Na]+:346.1373,found 346.1375.
(2) preparation of compound 17:
Figure BDA0002225124810000144
compound 17 (77% yield) was synthesized from a17 as the starting material in the same manner as compound 1.
Data characterization of compound 17:
m.p 130.2-131.9℃；IR(KBr):3225,2984,1673,1522,1468cm-1.1H NMR(400MHz,DMSO-d6)δ 10.44(s,1H),10.13(s,1H),8.69(s,1H),8.11(d,J＝8.8Hz,2H),7.62(d,J＝8.8Hz,2H),6.98(s,1H), 3.08(q,J＝6.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.49(q,J＝7.0,6.5Hz,2H),1.40(q,J＝6.9Hz,2H),1.25 (dt,J＝14.4,8.3Hz,4H).13C NMR(100MHz,DMSO-d6)δ169.2,154.7,147.6,140.1,125.2,116.5,38.9, 32.2,29.4,28.2,26.0,25.0.HRMS(ESI)calculated for C14H20N4NaO5 +[M+Na]+:347.1326,found 347.1325.
example 18: preparation of Compound 18
The preparation method comprises the following steps:
(1) preparation of compound a 18:
p-nitrobenzene isocyanate and 8-aminocaprylic acid are used as raw materials to synthesize a18 (yield is 63%) as a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 18:
m.p 157.6-158.7℃；IR(KBr):3374,3285,3095,2984,2863,1698,1623,1605,1596,1530,1426cm-1.1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.13(d,J＝8.7Hz,2H),7.62(d,J＝8.7Hz,2H),6.42(d,J ＝5.8Hz,1H),3.58(s,3H),3.10(q,J＝6.6Hz,2H),2.29(t,J＝7.5Hz,2H),1.48(dt,J＝33.6,7.1Hz,4H), 1.28(s,6H).13C NMR(100MHz,DMSO-d6)δ173.3,154.3,147.3,140.3,125.1,116.7,51.1,39.1,33.2, 29.4,28.4,28.4,26.1,24.4.HRMS(ESI)calculated for C16H23N3NaO5 +[M+Na]+:360.1530,found 360.1532.
(2) preparation of compound 18:
Figure BDA0002225124810000152
compound 18 (73% yield) was synthesized as a white solid from a18 as starting material in the same manner as compound 1.
Data characterization of compound 18:
m.p 130.6-131.5℃；IR(KBr):3262,2926,1684,1523,1473cm-1.1H NMR(400MHz,DMSO-d6)δ 10.39(s,1H),10.06(d,J＝9.4Hz,1H),8.66(s,1H),8.12(d,J＝8.8Hz,2H),7.62(d,J＝8.9Hz,2H),6.93 (d,J＝7.7Hz,1H),3.08(q,J＝6.5Hz,2H),1.94(t,J＝7.4Hz,2H),1.48(q,J＝7.0Hz,2H),1.41(t,J＝ 7.0Hz,2H),1.31–1.22(m,6H).13C NMR(100MHz,DMSO-d6)δ169.1,154.6,147.5,140.1,125.1, 116.4,38.9,32.2,29.5,28.5,28.4,26.2,25.1.HRMS(ESI)calculated for C15H22N4NaO5 +[M+Na]+: 361.1482,found 361.1480.
example 19: preparation of Compound 19
The preparation method comprises the following steps:
(1) preparation of compound a 19:
Figure BDA0002225124810000153
4-chloro-3-trifluoromethyl phenyl isocyanate and 5-aminopentanoic acid are taken as raw materials to synthesize a19 (yield is 79%) as a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 19:
m.p.130.7-131.9℃；IR(KBr):3383,3156,2897,2874,1816,1795,1668,1654,1579,1493cm-1.1H NMR(400MHz,CDCl3)δ8.53(s,1H),7.43–7.36(m,2H),7.28–7.21(m,2H),6.17(s,1H),3.58(s,3H), 3.07(d,J＝6.3Hz,2H),2.32(t,J＝7.3Hz,2H),1.58–1.49(m,2H),1.42(p,J＝6.9Hz,2H).13C NMR (100MHz,CDCl3)δ173.3,155.0,139.6,128.4,124.4,119.1,51.2,38.6,32.9,29.1,21.8.HRMS(ESI) calculated for C13H17ClN2NaO3 +[M+Na]+:307.0820,found 307.0821.
(2) preparation of compound 19:
Figure BDA0002225124810000154
compound 19 (74% yield) was synthesized as a white solid from a19 as starting material in the same manner as compound 1.
Data for compound 19 characterisation:
m.p 166.9-168.5℃；IR(KBr):3387,3344,3156,3054,2974,1816,1795,1678,1585,1538,1522cm-1..1H NMR(400MHz,CDCl3)δ10.46(s,1H),9.34(s,1H),8.70(s,1H),7.50–7.37(m,2H),7.22(d,J＝ 8.6Hz,2H),6.67(s,1H),3.04(d,J＝6.3Hz,2H),1.97(t,J＝7.2Hz,2H),1.50(t,J＝7.6Hz,2H),1.38(q, J＝7.2Hz,2H).13C NMR(100MHz,CDCl3)δ169.1,155.3,139.9,128.3,124.0,118.7,38.6,32.0,29.3, 22.6.HRMS(ESI)calculatedfor C14H19ClN2NaO3 +[M+Na]+:308.0772,found 308.0773.
example 20: preparation of Compound 20
The preparation method comprises the following steps:
(1) preparation of compound a 20:
Figure BDA0002225124810000161
4-chloro-3-trifluoromethyl phenyl isocyanate and 6-aminocaproic acid are taken as raw materials to synthesize a20 (yield is 79%) which is a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 20:
m.p.131.9-132.8℃；IR(KBr):3282,3056,2894,2845,1819,1795,1728,1589,1545,1496cm-1.1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.40(d,J＝8.9Hz,2H),7.24(d,J＝8.9Hz,2H),6.14(s,1H), 3.58(s,3H),3.05(q,J＝6.6Hz,2H),2.30(t,J＝7.4Hz,2H),1.53(q,J＝7.5Hz,2H),1.41(q,J＝7.2Hz, 2H),1.28(tdd,J＝12.7,7.9,5.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.3,155.0,139.6,128.4, 124.3,119.0,51.1,33.2,29.4,25.8,24.2.HRMS(ESI)calculated for C14H19ClN2NaO3 +[M+Na]+:321.0976, found 321.0973.
(2) preparation of compound 20:
Figure BDA0002225124810000162
compound 20 (yield 79%) was synthesized as a white solid from a20 by the same method as compound 1.
Data characterization of compound 20:
m.p.166.8-168.0℃；IR(KBr):3363,3294,3076,2983,2809,1816,1795,1658,1584,1532,1463cm-1.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.32(s,1H),8.68(s,1H),7.42(d,J＝8.6Hz,2H),7.22(d, J＝8.5Hz,2H),6.64(s,1H),3.03(d,J＝6.3Hz,2H),1.95(t,J＝7.4Hz,2H),1.49(p,J＝7.5Hz,2H),1.39 (p,J＝7.1Hz,2H),1.26(dd,J＝15.8,8.5Hz,2H).13C NMR(100MHz,DMSO-d6)δ169.1,155.3,139.9, 128.3,124.0,118.7,38.8,32.2,29.5,26.0,24.9.HRMS(ESI)calculated for C13H18ClN3NaO3 +[M+Na]+: 322.0929,found 322.0927.
example 21: preparation of Compound 21
The preparation method comprises the following steps:
(1) preparation of compound a 21:
Figure BDA0002225124810000163
4-chloro-3-trifluoromethyl phenyl isocyanate and 7-aminoheptanoic acid are taken as raw materials to synthesize a21 (yield is 89%) which is a white solid and synthesized by the same method as a 1.
Data characterization of compound a 21:
m.p 110.2-111.4℃；IR(KBr):3289,2943,1678,1573,1493cm-1.1H NMR(400MHz,CDCl3)δ7.48 (d,J＝4.9Hz,1H),7.26–7.16(m,4H),5.50(q,J＝5.2Hz,1H),3.67(s,3H),3.15(td,J＝7.0,5.6Hz,2H),2.30(t,J＝7.4Hz,2H),1.57(ddt,J＝10.1,7.5,3.9Hz,2H),1.42(q,J＝7.2Hz,2H),1.32–1.24(m,4H).13C NMR(100MHz,CDCl3)δ174.6,142.1(d,J＝2862.7Hz),137.8,129.1,121.1,51.7,40.3,34.0,29.9, 28.8,26.7,24.8.HRMS(ESI)calculated for C15H21N3NaO5 +[M+Na]+:335.1133,found 335.1132.
(2) preparation of compound 21:
Figure BDA0002225124810000171
compound 21 (77% yield) was synthesized as a white solid from a21 as the starting material in the same manner as compound 1.
Data characterization of compound 21:
m.p 169.1-170.6℃；IR(KBr):3255,2931,1677,1509,1567cm-1.1H NMR(400MHz,DMSO-d6)δ 10.39(s,1H),9.07(s,1H),7.50–7.35(m,2H),7.23(d,J＝8.9Hz,2H),6.49(s,1H),3.04(t,J＝6.3Hz, 2H),1.95(t,J＝7.4Hz,2H),1.48(p,J＝7.0Hz,2H),1.39(q,J＝6.4,5.7Hz,2H),1.30–1.22(m,4H).13C NMR(100MHz,DMSO-d6)δ169.2,154.7,147.6,140.1,125.2,116.5,38.9,32.2,29.4,28.2,26.2,26.0, 25.0.HRMS(ESI)calculated forC19H16NaO6 +[M+Na]+:336.1085,found 336.1083.
example 22: preparation of Compound 22
The preparation method comprises the following steps:
(1) preparation of compound a 22:
4-chloro-3-trifluoromethyl phenyl isocyanate and 8-aminocaprylic acid are used as raw materials to synthesize a22 (yield is 89%) as a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 22:
m.p 114.5-115.1℃；IR(KBr):3289,2943,1678,1573,1493cm-1.1H NMR(400MHz,CDCl3)δ7.25 (d,J＝7.7Hz,4H),6.77(s,1H),4.94(t,J＝5.6Hz,1H),3.67(s,3H),3.21(td,J＝6.9,5.6Hz,2H),2.31(t, J＝7.4Hz,2H),1.60(d,J＝8.4Hz,2H),1.48(t,J＝6.9Hz,2H),1.29(d,J＝4.3Hz,6H).13C NMR(100 MHz,CDCl3)δ174.9,156.2,144.4,138.1,121.9,120.6,51.7,40.3,34.1,30.0,29.8,29.0,26.7,24.8. HRMS(ESI)calculated forC15H21N3NaO5 +[M+Na]+:349.1289,found 349.1288.
(2) preparation of compound 22:
Figure BDA0002225124810000173
compound 22 (71% yield) was synthesized as a white solid from a22 as starting material in the same manner as compound 1.
Data characterization of compound 22:
m.p 121.1-123.4℃；IR(KBr):3289,2938,1678,1582,1439cm-1.1H NMR(400MHz,DMSO-d6)δ 10.39(s,1H),9.15(s,1H),8.66(d,J＝1.7Hz,1H),7.48–7.38(m,2H),7.23(d,J＝8.8Hz,2H),6.55(s, 1H),3.05(q,J＝6.5Hz,2H),1.94(t,J＝7.3Hz,2H),1.49(d,J＝7.2Hz,2H),1.38(d,J＝11.7Hz,2H), 1.26(s,6H).13C NMR(100MHz,DMSO-d6)δ169.1,154.8,144.3,125.9,121.0,117.1,39.0,38.9,32.2, 29.5,28.3,26.1,25.1.HRMS(ESI)calculated for C19H16NaO6 +[M+Na]+:350.1242,found 350.1243.
example 23: preparation of Compound 23
The preparation method comprises the following steps:
(1) preparation of compound a 23:
Figure BDA0002225124810000174
p-methylphenyl isocyanate and 7-aminoheptanoic acid are used as raw materials to synthesize a23 (yield is 81%) which is a white solid and is synthesized by the same method as a 1.
Data characterization of compound a 23:
m.p 108.2-110.1℃；IR(KBr):3333,3265,2932,1686,1572,1454cm-1.1H NMR(400MHz,CDCl3)δ 7.16(d,J＝8.2Hz,2H),7.07(d,J＝8.1Hz,2H),6.94(s,1H),5.21(s,1H),3.66(s,3H),3.26–3.08(m, 2H),2.32–2.23(m,5H),1.61–1.54(m,2H),1.44(t,J＝7.1Hz,2H),1.29(q,J＝3.7Hz,4H).13C NMR (100MHz,CDCl3)δ174.5,156.6,136.2,133.4,129.8,121.4,51.7,40.3,34.0,30.0,28.9,26.7,24.9,20.9. HRMS(ESI)calculated forC19H16NaO6 +[M+Na]+:315,1679,found 315,1677.
(2) preparation of compound 23:
Figure BDA0002225124810000181
compound 23 (80% yield) was synthesized as a white solid from a23 as starting material in the same manner as compound 1.
Data characterization of compound 23:
m.p 144.2-145.8℃；IR(KBr):3279,2977,1690,1532,1483cm-1.1H NMR(400MHz,DMSO-d6)δ 9.59(s,1H),8.32(s,1H),7.25(d,J＝8.0Hz,2H),7.00(d,J＝8.0Hz,2H),6.12(s,1H),3.04(q,J＝6.5Hz, 2H),2.20(s,3H),1.94(t,J＝7.3Hz,2H),1.49(q,J＝7.2Hz,2H),1.39(t,J＝7.1Hz,2H),1.33–1.18(m, 4H).13C NMR(100MHz,DMSO-d6)δ169.1,155.3,138.1,129.5,129.0,117.7,39.0,32.3,29.7,28.4,26.2, 25.2,20.3.HRMS(ESI)calculated for C19H16NaO6 +[M+Na]+:316.1632,found 316.1635.
example 24: preparation of Compound 24
The preparation method comprises the following steps:
(1) preparation of compound a 24:
Figure BDA0002225124810000182
p-methylphenyl isocyanate and 8-aminocaprylic acid are used as raw materials to synthesize a24 (yield is 81%) as a white solid, and the synthesis method is the same as a 1.
Data characterization of compound a 24:
m.p 104.2-105.8℃；IR(KBr):3342,3278,2913,1693,1593,1487cm-1.1H NMR(400MHz,CDCl3)δ 7.51(s,1H),7.37–7.29(m,2H),7.09(d,J＝8.6Hz,2H),5.45(t,J＝5.6Hz,1H),3.67(s,3H),3.17(q,J＝ 6.6Hz,2H),2.30(t,J＝7.4Hz,2H),1.59(p,J＝7.3Hz,2H),1.44(p,J＝6.8Hz,2H),1.35–1.21(m,9H).13C NMR(100MHz,CDCl3)δ174.9,156.2,144.4,138.1,121.9,120.6,51.7,40.3,34.1,30.0,29.8,29.0, 29.0,26.7,24.8.HRMS(ESI)calculated for C19H16NaO6 +[M+Na]+:329.1836,found 329.1838.
(2) preparation of compound 24:
Figure BDA0002225124810000183
compound 24 (74% yield) was synthesized as a white solid from a24 as starting material in the same manner as compound 1.
Data characterization of compound 24:
m.p 129.0-130.1℃；IR(KBr):3293,2932,1690,1529,1472cm-1.1H NMR(400MHz,DMSO-d6)δ 9.42(s,1H),8.63(s,1H),7.26(d,J＝7.9Hz,2H),6.99(d,J＝7.8Hz,2H),6.38(s,1H),3.03(q,J＝6.2Hz, 2H),2.20(s,3H),1.90(t,J＝7.4Hz,2H),1.47(q,J＝7.2Hz,2H),1.38(q,J＝6.8Hz,2H),1.24(s,6H).13C NMR(100MHz,DMSO-d6)δ168.4,155.4,138.3,129.3,129.0,117.6,39.0,32.7,29.7,28.7,28.5, 26.3,25.5,20.3.HRMS(ESI)calculated for C19H16NaO6 +[M+Na]+:330.1788,found 330.1789.
example 25: preparation of Compound 25
The preparation method comprises the following steps:
(1) preparation of Compound a 15-1:
Figure BDA0002225124810000184
intermediate a15(1.18g, 4.00mmol) obtained above was added to CH at 60 deg.C3OH:H2To a solution of O ═ 1:1(40mL), iron (900mg, 16.1mmol) and NH were added4Cl (855mg, 16.0mmol), refluxed for 6 hours. After TLC detection reaction is completed, diatomite is filtered to remove iron, and reduced pressure distillation is carried out to remove CH3OH, diluted with EtOAc (50mL), NaHCO3Basification, EtOAc extraction three times, organic phase with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2: 1 to 1: 1) to give compound a15-1(1,05mg, yield 90%) as a brown solid.
Data characterization of Compound a 15-1:
mp 103.5-104.5℃；IR(KBr):3392,3367,3246,2934,2868,1690,1641,1589,1552,1515,1424,cm-1.1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.14(d,J＝9.2Hz,2H),7.62(d,J＝9.3Hz,2H),6.46(s, 1H),3.59(s,3H),3.12(d,J＝6.2Hz,2H),2.34(t,J＝7.3Hz,2H),1.61–1.52(m,2H),1.50–1.42(m,2H).13C NMR(101MHz,DMSO-d6)δ173.3,154.4,147.2,140.3,125.1,116.7,51.2,38.7,32.9,28.9, 21.8.HRMS(ESI)calculatedfor C13H19N3NaO3 +[M+Na]+:288.1319,found 288.1319.
(2) preparation of compound b 25:
Figure BDA0002225124810000191
a15-1(1g, 3.5mmol) was added to a CH3CN (70mL) solution and K was added2CO3(995mg 7.20mmol),，KI (60.0mg, 0.361mmol) and 1, 4-dibromobutane (755mg, 3.51 mmol). Reflux at 80 ℃ for 6 hours. TLC checked for completion, distilled under reduced pressure to remove CH3CN, diluted with EtOAc (70mL), extracted 3 times, and the organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1 to 1:3) to give compound b25 (895mg, yield 78%) as a brown solid.
Data characterization of compound b 25:
mp 128.8-130.1℃；IR(KBr):3307,3286,3028,2947,2843,1739,1692,1583,1563,1518,1433,cm-1.1H NMR(400MHz,Chloroform-d)δ7.07(d,J＝8.7Hz,2H),6.51(d,J＝8.7Hz,2H),6.10(s,1H), 4.68(s,1H),3.64(s,3H),3.34–3.24(m,4H),3.19(q,J＝6.7Hz,2H),2.30(t,J＝7.3Hz,2H),2.06–1.96 (m,4H),1.65–1.56(m,2H),1.52–1.43(m,2H).13C NMR(101MHz,Chloroform-d)δ174.1,157.8, 146.7,127.3,125.1,112.3,51.7,47.9,39.9,34.4,33.7,29.8,25.6,22.2,20.0.HRMS(ESI) calculated for C17H25N3NaO3 +[M+Na]+:342.1788,found 342.1787.
(3) preparation of compound 25:
Figure BDA0002225124810000192
compound 25 (yield 78%) was synthesized as a brown solid from b25 in the same manner as compound 1.
Data characterization of compound 25:
mp 145.3-146.9℃；IR(KBr):3329,3308,3014,2978,2871,1729,1670,1659,1613,1580,1427,cm-1.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.70(s,1H),8.25(d,J＝4.2Hz,1H),7.17–7.13(m, 2H),6.42(d,J＝8.3Hz,2H),6.20–6.13(m,1H),3.15(d,J＝6.0Hz,4H),3.01(q,J＝6.5Hz,2H),1.98– 1.87(m,6H),1.53–1.46(m,2H),1.37(q,J＝7.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ169.1, 155.8,143.3,129.6,119.9,111.7,47.6,38.7,32.0,29.5,24.8,22.6.HRMS(ESI)calculated for C16H24N4NaO3 +[M+Na]+:343.1741,found 343.1744.
example 26: preparation of Compound 26
The preparation method comprises the following steps:
(1) preparation of Compound a 16-1:
Figure BDA0002225124810000193
using a16 as a raw material, synthesizing to obtain a16-1 (yield is 92%) brown solid, and the synthetic method is the same as a 15-1.
Data characterization of Compound a 16-1:
mp 95.0-95.9℃；IR(KBr):3327,3312,3058,2922,2853,1738,1728,1614,1605,1578,1518,1460, cm-1.1H NMR(400MHz,DMSO-d6)δ7.01(d,J＝8.1Hz,2H),6.72(s,1H),6.60(d,J＝8.1Hz,2H),5.08 (d,J＝5.8Hz,1H),3.64(s,3H),3.13(q,J＝6.8Hz,2H),2.27(t,J＝7.5Hz,2H),1.58(p,J＝7.7Hz,2H), 1.42(p,J＝7.6Hz,2H),1.32–1.24(m,2H).13CNMR(101MHz,Chloroform-d)δ174.2,157.3,143.4, 129.4,124.5,115.7,51.5,40.0,33.9,29.9,26.3,24.6.HRMS(ESI)calculated for C14H21N3NaO3 +[M+Na]+:302.1475,found302.1474.
(2) preparation of compound b 26:
Figure BDA0002225124810000201
b26 (yield: 75%) was synthesized from a16-1 and 1, 4-dibromobutane as starting materials in the same manner as b25 as a brown solid.
Data characterization of compound b 26:
mp 119.8-121.7℃；IR(KBr):3311,3098,3040,2949,2864,1733,1626,1621,1614,1535,1523, 1418,cm-1.1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.15(d,J＝8.5Hz,2H),6.43(d,J＝8.4Hz, 2H),5.88(t,J＝5.7Hz,1H),3.58(s,3H),3.14(d,J＝6.0Hz,4H),3.03(q,J＝6.6Hz,2H),2.30(t,J＝7.4 Hz,2H),1.97–1.87(m,4H),1.53(p,J＝7.5Hz,2H),1.40(p,J＝7.0Hz,2H),1.31–1.23(m,2H).13C NMR(101MHz,DMSO-d6)δ173.3,155.7,143.4,129.4,120.1,111.8,51.2,47.6,38.9,33.3,29.6, 25.9,24.9,24.2.HRMS(ESI)calculated for C18H27N3NaO3 +[M+Na]+:356.1945,found 356.1946.
(3) preparation of compound 26:
Figure BDA0002225124810000202
compound 26 (yield 75%) was synthesized as a brown solid from b26 in the same manner as compound 1.
Data characterization of compound 26:
mp 152.8-153.4℃；IR(KBr):3356,3321,3110,2931,2855,1784,1673,1652,1596,1563,1414cm-1.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.68(s,1H),8.08(s,1H),7.19(d,J＝8.5Hz,2H),6.80 (d,J＝8.5Hz,2H),5.96(s,1H),3.01(dt,J＝20.2,6.0Hz,6H),1.94(t,J＝7.4Hz,2H),1.60(q,J＝5.7Hz, 4H),1.49(q,J＝8.7,7.8Hz,4H),1.38(q,J＝7.4Hz,2H).13C NMR(101MHz,DMSO-d6)δ169.1,155.7, 143.3,129.5,120.0,111.7,47.6,39.0,32.2,29.7,26.0,24.9,24.8.HRMS(ESI)calculated for C17H26N4NaO3 +[M+Na]+:357.1897,found 357.1894.
example 27: preparation of Compound 27
The preparation method comprises the following steps:
(1) preparation of Compound a 17-1:
Figure BDA0002225124810000203
taking a17 as a raw material, synthesizing to obtain a17-1 (yield is 90 percent) brown solid, and the synthetic method is the same as a 15-1.
Data characterization of Compound a 17-1:
mp 94.3-95.7℃；IR(KBr):3425,3311,3035,2930,2857,1735,1730,1675,1631,1610,1570,1434, cm-1.1H NMR(400MHz,Chloroform-d)δ7.15–6.85(m,2H),6.72–6.47(m,2H),6.30(s,1H),4.77(d, J＝6.0Hz,1H),3.17(q,J＝6.8Hz,2H),2.35–2.22(m,2H),1.59(p,J＝7.7,7.2Hz,2H),1.44(p,J＝6.9 Hz,2H),1.34–1.26(m,4H).13C NMR(101MHz,Methanol-d4)δ176.0,159.3,123.6,117.1,52.0,40.8, 34.7,31.1,29.9,27.6,26.0.HRMS(ESI)calculated for C15H23N3NaO3 +[M+Na]+:316.1632,found 316.1635.
(2) preparation of compound b 27:
Figure BDA0002225124810000204
b27 (yield: 75%) was synthesized from a17-1 and 1, 4-dibromobutane as starting materials in the same manner as b25 as a brown solid.
Data characterization of compound b 27:
mp 119.5-120.5℃；IR(KBr):3293,3280,2959,1863,1730,1662,1638,1580,1518,1462,1376cm-1.1H NMR(400MHz,Chloroform-d)δ7.08(d,J＝8.3Hz,2H),6.51(d,J＝8.4Hz,2H),6.30(s,1H),4.78(t, J＝5.8Hz,1H),3.66(s,3H),3.41–3.02(m,6H),2.28(t,J＝7.5Hz,2H),2.10–1.94(m,4H),1.59(t,J＝7.2Hz,2H),1.44(p,J＝7.0Hz,2H),1.29(h,J＝7.5Hz,4H).13C NMR(101MHz,Chloroform-d)δ157.8, 146.4,126.7,112.2,51.6,47.9,40.3,34.1,30.1,28.9,26.6,25.6,24.9.HRMS(ESI)calculated for C19H29N3NaO3 +[M+Na]+:370.2101,found 370.2104.
(3) preparation of compound 27:
Figure BDA0002225124810000211
compound 27 (78% yield) was synthesized as a brown solid from b27 as the starting material in the same manner as compound 1.
Data characterization of compound 27:
mp 174.3-175.3℃；IR(KBr):3350,3320,3196,2932,2854,1650,1591,1553,1515,1462,1417,cm-1.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.67(s,1H),8.02(s,1H),7.15(d,J＝8.4Hz,2H),6.43 (d,J＝8.4Hz,2H),5.97(t,J＝5.6Hz,1H),3.14(d,J＝6.2Hz,4H),3.02(q,J＝6.5Hz,2H),1.93(q,J＝ 7.3,6.7Hz,6H),1.48(p,J＝7.2Hz,2H),1.37(q,J＝7.0Hz,2H),1.28–1.22(m,4H).13C NMR(101 MHz,DMSO-d6)δ169.1,155.7,143.4,129.5,120.0,111.8,47.6,39.1,32.2,29.8,28.3,26.1,25.1, 24.9.HRMS(ESI)calculated forC18H28N4NaO3 +[M+Na]+:371.2054,found.:371.2052.
example 28: preparation of Compound 28
The preparation method comprises the following steps:
(1) preparation of Compound a 18-1:
using a18 as a raw material, synthesizing to obtain a18-1 (the yield is 89%), and obtaining a brown solid with the same synthetic method as a 15-1.
Data characterization of Compound a 18-1:
mp 93.1-94.3℃；IR(KBr):3390,3319,3039,2930,2865,1711,1628,1598,1563,1509,1496,1432,cm-1.1H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.01(d,J＝8.1Hz,2H),6.47(d,J＝8.1Hz,2H),6.05(t,J＝ 5.8Hz,1H),4.87(s,2H),3.58(s,3H),3.01(q,J＝6.5Hz,2H),2.30(t,J＝7.4Hz,2H),1.52(p,J＝7.3Hz, 2H),1.37(q,J＝6.9Hz,2H),1.27(d,J＝4.1Hz,6H).13C NMR(101MHz,DMSO-d6)δ173.3,155.7, 143.0,129.8,120.1,114.2,51.1,39.0,33.3,29.8,28.4,26.2,24.4.HRMS(ESI)calculated for C16H25N3NaO3 +[M+Na]+[M+Na]+:330.1788,found 330.1787
(2) preparation of compound b 28:
Figure BDA0002225124810000213
b28 (yield: 71%) was synthesized from a18-1 and 1, 4-dibromobutane as starting materials in the same manner as b25 as a brown solid.
Data characterization of compound b 28:
mp 113.4-114.4℃；IR(KBr):3312,3096,3041,2927,2854,1738,1628,1560,1522,1490,1418, cm-1.1H NMR(400MHz,Chloroform-d)δ7.12–7.03(m,2H),6.49(d,J＝8.3Hz,2H),6.33(s,1H),4.81 (s,1H),3.64(s,3H),3.25(d,J＝6.1Hz,4H),3.15(q,J＝6.7Hz,2H),2.27(t,J＝7.5Hz,2H),2.04–1.95 (m,4H),1.58(p,J＝7.8Hz,2H),1.40(q,J＝7.0Hz,2H),1.31–1.24(m,6H).13C NMR(101MHz, Chloroform-d)δ174.4,157.8,146.3,126.6,112.2,51.6,47.9,40.3,34.1,30.2,29.1,29.0,26.7, 25.6,24.9.HRMS(ESI)calculated for C20H31N3NaO3 +[M+Na]+:384.2258,found 384.2256.
(3) preparation of compound 28:
Figure BDA0002225124810000214
compound 28 (79% yield) was synthesized as a brown solid from b28 in the same manner as compound 1.
Data characterization of compound 28:
mp 152.0-153.1℃；IR(KBr):3359,3286,3056,2986,2861,1763,1692,1625,1593,1520,1423, cm-1.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.65(s,1H),8.31(s,1H),7.16(d,J＝7.8Hz,2H), 6.43(d,J＝8.0Hz,2H),6.21(s,1H),3.14(d,J＝6.3Hz,4H),3.02(d,J＝6.8Hz,2H),1.93(d,J＝7.1Hz, 4H),1.49(d,J＝9.0Hz,2H),1.38(s,2H),1.25(d,J＝8.6Hz,8H).13C NMR(101MHz,DMSO-d6)δ 169.2,155.8,143.4,129.6,120.0,111.8,47.6,32.3,29.9,28.6,28.5,26.3,25.1,24.9.HRMS(ESI) calculated for C19H30N4NaO3 +[M+Na]+:385.2210,found 385.2208.
example 29: preparation of Compound 29
The preparation method comprises the following steps:
(1) preparation of compound b 29:
Figure BDA0002225124810000221
b29 (yield: 79%) was synthesized from a15-1 and 1, 5-dibromopentane as raw materials in the same manner as b25 as a brown solid.
Data characterization of compound b 29:
mp 117.1-118.1℃；IR(KBr):3313,3097,3033,2996,2854,1738,1687,1585,1564,1516,1426,cm-1.1H NMR(400MHz,Chloroform-d)δ7.33(s,1H),7.10(d,J＝8.5Hz,2H),6.80(d,J＝8.4Hz,2H), 5.62–5.52(m,1H),3.60(s,3H),3.14–2.94(m,6H),2.24(t,J＝7.4Hz,2H),1.66(p,J＝5.7Hz,4H), 1.59–1.49(m,4H),1.40(p,J＝7.1Hz,2H).13C NMR(101MHz,Chloroform-d)δ174.0,157.2,148.8, 130.7,122.8,117.4,51.5,51.2,39.7,29.7,25.9,24.2,22.2.HRMS(ESI)calculated for C18H27N3NaO3 +[M+Na]+:356.1945,found356.1947.
(2) preparation of compound 29:
Figure BDA0002225124810000222
compound 29 (75% yield) was synthesized as a brown solid from b29 in the same manner as compound 1.
Data characterization of compound 29:
mp 169.9-170.7℃；IR(KBr):3151,3058,3055,2954,2832,1731,1692,1611,1555,1513,1439,cm-1.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.72(s,1H),8.36(s,1H),7.21(d,J＝8.3Hz,2H),6.81 (d,J＝8.5Hz,2H),6.18(d,J＝6.1Hz,1H),3.07–2.93(m,6H),1.96(t,J＝7.3Hz,2H),1.68–1.57(m, 4H),1.48(t,J＝7.3Hz,4H),1.37(q,J＝7.5Hz,2H).13C NMR(101MHz,DMSO-d6)δ174.4,155.2, 141.8,135.8,122.0,117.8,56.1,38.6,33.4,29.3,22.9,21.9.HRMS(ESI)calculated for C17H26N4NaO3 +[M+Na]+:357.1897,found357.1895.
example 30: preparation of Compound 30
The preparation method comprises the following steps:
(1) preparation of compound b 30:
b30 (yield: 76%) was synthesized from a16-1 and 1, 5-dibromopentane as starting materials in the same manner as b25 as a brown solid.
Data characterization of compound b 30:
mp 108.0-108.5℃；IR(KBr):3351,3303,3065,2934,2860,1733,1638,1613,1588,1556,1414,cm-1.1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.20(d,J＝9.0Hz,2H),6.83–6.77(m,2H),5.96(t,J＝ 5.7Hz,1H),3.58(s,3H),3.04(q,J＝6.6Hz,2H),2.97(t,J＝5.4Hz,4H),2.30(t,J＝7.4Hz,2H),1.60(p, J＝5.8Hz,4H),1.56–1.45(m,4H),1.39(q,J＝7.2Hz,2H),1.27(qd,J＝10.0,9.2,6.1Hz,2H).13C NMR (101MHz,DMSO-d6)δ173.3,155.5,146.8,132.7,119.0,116.9,51.2,50.7,38.9,33.3,29.6,25.9, 25.5,24.2.HRMS(ESI)calculated for C19H29N3NaO3 +[M+Na]+:370.2101,found 370.2101.
(2) preparation of compound 30:
Figure BDA0002225124810000231
compound 30 (77% yield) was synthesized as a brown solid from b30 in the same manner as compound 1.
Data characterization of compound 30:
mp 153.8-154.5℃；IR(KBr):3354,3235,3160,3086,2939,2872,1731,1686,1651,1605,1553, 1431cm-1.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.68(s,1H),8.08(s,1H),7.19(d,J＝8.5Hz, 2H),6.80(d,J＝8.5Hz,2H),5.96(t,J＝5.6Hz,1H),3.01(dt,J＝20.3,6.0Hz,6H),1.94(t,J＝7.4Hz, 2H),1.60(q,J＝5.7Hz,4H),1.50(t,J＝7.6Hz,4H),1.39(t,J＝7.4Hz,2H),1.25(d,J＝8.5Hz,2H).13C NMR(101MHz,DMSO-d6)δ169.5,156.1,143.9,129.8,120.6,112.2,48.1,39.5,32.7,30.2, 26.5,25.4,25.3.HRMS(ESI)calculated for C18H28N4NaO3 +[M+Na]+:371.2054,found 371.2056.
example 31: preparation of Compound 31
The preparation method comprises the following steps:
(1) preparation of compound b 31:
b31 (yield: 76%) was synthesized from a17-1 and 1, 5-dibromopentane as starting materials in the same manner as b25 as a brown solid.
Data characterization of compound b 31:
mp 127.0-127.3℃；IR(KBr):3311,3203,3097,2926,2853,1739,1688,1634,1583,1565,1414cm-1.1H NMR(400MHz,Chloroform-d)δ7.16–7.06(m,2H),6.88(d,J＝8.3Hz,2H),6.39(s,1H),4.84(d,J＝ 6.1Hz,1H),3.65(d,J＝2.7Hz,3H),3.18(d,J＝6.9Hz,2H),3.10(d,J＝5.5Hz,4H),2.28(dt,J＝7.7,4.6 Hz,2H),1.74–1.66(m,4H),1.63–1.53(m,4H),1.45(t,J＝7.1Hz,2H),1.32–1.26(m,4H).13C NMR (101MHz,Chloroform-d)δ174.4,157.2,149.9,129.6,124.9,117.4,51.6,51.0,40.3,34.1,30.0, 28.9,26.6,25.9,24.9,24.3.HRMS(ESI)calculated for C20H31N3NaO3 +[M+Na]+:384.2258,found 384.2259.
(2) preparation of compound 31:
Figure BDA0002225124810000233
compound 31 (80% yield) was synthesized from b31 as the starting material in the same manner as compound 1.
Data characterization of compound 31:
mp 153.2-154.3℃；IR(KBr):3369,3215,3084,2967,2835,1769,1699,1635,1605,1592,1425,cm-1.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.68(s,1H),8.51(s,1H),7.21(d,J＝8.4Hz,2H),6.80 (d,J＝8.3Hz,2H),6.29(t,J＝5.5Hz,1H),3.00(dt,J＝20.0,5.9Hz,6H),1.95(t,J＝7.3Hz,2H),1.60(q, J＝5.6Hz,4H),1.48(t,J＝6.8Hz,4H),1.37(q,J＝6.9Hz,2H),1.25(dt,J＝8.8,5.2Hz,4H).13C NMR (101MHz,DMSO-d6)δ169.1,155.6,146.6,132.9,118.8,116.9,50.8,38.9,32.2,29.7,28.3,26.1, 25.5,25.0,23.8.HRMS(ESI)calculated for C19H30N4NaO3 +[M+Na]+:385.2210,found 385.2213.
example 32: preparation of Compound 32
The preparation method comprises the following steps:
(1) preparation of compound b 32:
Figure BDA0002225124810000241
b32 (74 percent of yield) is synthesized by using a18-1 and 1, 5-dibromopentane as raw materials, and the synthesis method is the same as b 25.
Data characterization of compound b 32:
mp 132.2-133.4℃；IR(KBr):3356,3298,3062,2988,2865,1795,1763,1692,1652,1534,1429,cm-1.1H NMR(400MHz,Chloroform-d)δ7.18–7.08(m,2H),6.94–6.85(m,2H),6.16(s,1H),4.70(t,J＝ 5.7Hz,1H),3.67(s,3H),3.23–3.15(m,2H),3.16–3.06(m,4H),2.30(t,J＝7.5Hz,2H),1.71(p,J＝5.8 Hz,4H),1.64–1.55(m,4H),1.45(t,J＝7.0Hz,2H),1.29(d,J＝3.0Hz,6H).13C NMR(101MHz, Chloroform-d)δ174.4,157.0,149.6,129.6,124.9,117.4,51.5,51.0,40.3,34.0,30.1,29.0,28.9, 26.6,25.8,24.8,24.1.HRMS(ESI)calculated for C21H33N3NaO3 +[M+Na]+:398.2414,found 398.2417.
(2) preparation of compound 32:
Figure BDA0002225124810000242
compound 32 (83% yield) was synthesized as a brown solid from b32 in the same manner as compound 1.
Data characterization of compound 32:
mp 155.8-157.0℃；IR(KBr):3336,3257,3116,2932,2865,1691,1649,1554,1514,1460,1416,cm-1.1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.65(s,1H),8.06(s,1H),7.19(d,J＝8.5Hz,2H),6.80 (d,J＝8.5Hz,2H),5.96(t,J＝5.7Hz,1H),3.01(dt,J＝23.0,5.9Hz,6H),2.00–1.87(m,2H),1.61(p,J＝ 5.6Hz,4H),1.49(q,J＝6.2Hz,4H),1.39(t,J＝6.7Hz,2H),1.26(s,6H).13C NMR(101MHz,DMSO-d6) δ169.2,155.6,147.8–144.4(m),169.2,155.6,145.6,133.0,118.7,116.9,50.8,39.0,32.3,29.9, 28.6,28.5,26.3,25.5,25.1,23.8.HRMS(ESI)calculated for C20H32N4NaO3 +[M+Na]+:399.2367, found 399.2368.
example 33: preparation of Compound 33
The preparation method comprises the following steps:
(1) preparation of compound b 33:
Figure BDA0002225124810000243
b33 (yield: 72%) was synthesized from a17-1 and 1, 6-dibromohexane as starting materials in the same manner as b25 as a brown solid.
Data characterization of compound b 33:
mp 120.3-121.5℃；IR(KBr):3275,3097,3054,2930,2852,1728,1679,1637,1611,1579,1415,cm-1.1H NMR(400MHz,Chloroform-d)δ7.08–7.00(m,2H),6.67–6.55(m,2H),6.11(s,1H),4.70(s,1H), 3.65(d,J＝1.5Hz,3H),3.43(t,J＝6.1Hz,4H),3.17(d,J＝6.8Hz,2H),2.28(t,J＝7.4Hz,2H),1.77(t,J ＝5.4Hz,4H),1.64–1.52(m,6H),1.44(t,J＝7.0Hz,2H),1.31–1.26(m,4H).13C NMR(101MHz, Chloroform-d)δ174.3,157.7,146.7,125.6,111.7,51.5,49.3,40.2,34.0,30.1,28.8,27.1,26.5, 24.9.HRMS(ESI)calculatedfor C21H33N3NaO3 +[M+Na]+:398.2414,found 398.2412.
(2) preparation of compound 33:
Figure BDA0002225124810000244
compound 33 (82% yield) was synthesized from b33 as the starting material in the same manner as compound 1.
Data characterization of compound 33:
mp 159.3-160.5℃；IR(KBr):3395,3285,3056,2968,2879,1766,1735,1699,1596,1486,1416,cm-1.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.68(s,1H),8.02(s,1H),7.11(d,J＝8.5Hz,2H),6.54 (d,J＝8.5Hz,2H),6.00(t,J＝5.7Hz,1H),3.38(d,J＝6.1Hz,4H),3.02(d,J＝6.4Hz,2H),1.94(t,J＝ 7.4Hz,2H),1.68(q,J＝5.3Hz,4H),1.52–1.41(m,7H),1.38(t,J＝6.9Hz,2H),1.28–1.22(m,4H).13C NMR(101MHz,DMSO-d6)δ169.1,155.8,143.7,129.0,120.4,111.1,48.9,32.2,29.8,28.4,27.1, 26.5,26.1,25.1.HRMS(ESI)calculated for C20H32N4NaO3 +[M+Na]+:385.2210,found 385.2212.
example 34: preparation of Compound 34
The preparation method comprises the following steps:
(1) preparation of compound d 34:
Figure BDA0002225124810000251
the compound d34 (yield: 81%) is synthesized by using a16-1 and isopropanoyl chloride as raw materials, and white solid is synthesized by the same method as the compound d 36.
Data characterization of compound d 34:
m.p 193-195℃；IR(KBr):3342,3252,3041,2968,2954,1730,1650,1631,1606,1561cm-1.1H NMR (400MHz,DMSO-d6)δ9.61(s,1H),8.25(s,1H),7.48–7.32(m,2H),7.30–7.21(m,2H),6.02(t,J＝5.7 Hz,1H),3.54(s,3H),3.01(q,J＝6.5Hz,2H),2.56–2.48(m,1H),2.27(t,J＝7.4Hz,2H),1.50(p,J＝7.5 Hz,2H),1.37(p,J＝7.0Hz,2H),1.24(td,J＝8.4,4.1Hz,2H),1.04(d,J＝6.7Hz,6H).13C NMR(100 MHz,DMSO-d6)δ174.6,173.3,155.2,135.9,133.0,119.7,117.8,51.2,38.8,34.7,33.2,29.5,25.8,24.2, 19.6.HRMS(ESI)calculated for C18H27N3NaO4 +:372.1894,found 372.1895.
(2) preparation of compound 34:
Figure BDA0002225124810000252
compound 34 (82% yield) was synthesized as a white solid from d34 as the starting material in the same manner as compound 1.
Data characterization of compound 34:
m.p 247-249℃；IR(KBr):3256,3041,2969,2930,2863,1651,1634,1567,1513cm-1.1H NMR(400 MHz,DMSO-d6)δ9.38(d,J＝340.1Hz,4H),7.44(d,J＝8.4Hz,2H),7.28(d,J＝8.5Hz,2H),6.54(s, 1H),3.02(q,J＝6.2Hz,2H),2.58(p,J＝6.8Hz,1H),1.95(t,J＝7.3Hz,2H),1.47(q,J＝7.5Hz,2H), 1.37(q,J＝7.2Hz,2H),1.25(dd,J＝14.9,7.6Hz,2H),1.06(d,J＝6.7Hz,6H).13C NMR(100MHz, DMSO-d6)δ174.6,166.8,155.5,136.2,132.8,119.7,117.5,38.8,34.6,32.1,29.5,25.9,24.9,19.6.HRMS (ESI)calculated forC17H26N4NaO4 +:373.1846,found 373.1847.
example 35: preparation of Compound 35
The preparation method comprises the following steps:
(1) preparation of compound d 35:
Figure BDA0002225124810000253
compound d35 (yield: 79%) was synthesized from a16-1 and p-trifluoromethylbenzoyl chloride as starting materials to obtain a white solid, which was synthesized using compound d 36.
Data characterization of compound d 35:
m.p 228-230℃；IR(KBr):3266,3034,2942,1722,1710,1684,1656,1571cm-1.1HNMR(400MHz, DMSO-d6)δ10.35(s,1H),8.51(s,1H),8.14(d,J＝8.0Hz,2H),7.89(d,J＝8.2Hz,2H),7.62(d,J＝8.9 Hz,2H),7.44–7.33(m,2H),6.18(t,J＝5.7Hz,1H),3.58(s,3H),3.06(q,J＝6.5Hz,2H),2.31(t,J＝7.4 Hz,2H),1.54(p,J＝7.5Hz,2H),1.42(p,J＝7.0Hz,2H),1.28(qd,J＝9.3,8.8,5.6Hz,2H).13C NMR (100MHz,DMSO-d6)δ173.3,163.8,155.2,138.9,136.9,132.2,131.3,131.0,128.5,125.3,125.3,122.6, 121.1,117.6,51.2,38.8,33.2,29.5,25.9,24.2.HRMS(ESI)calculated for C22H24F3N3NaO4 +:474.1611,found 474.1613.
(2) preparation of compound 35:
Figure BDA0002225124810000261
compound 35 (77% yield) was synthesized as a white solid from d35 as the starting material in the same manner as compound 1.
Data characterization of compound 35:
m.p 226-228℃；IR(KBr):3266,3045,2965,2940,2873,1651,1631,1565,1518cm-1.1H NMR(400 MHz,DMSO-d6)δ10.35(s,2H),8.55(s,1H),8.14(d,J＝7.9Hz,2H),7.90(d,J＝7.9Hz,2H),7.61(d,J＝ 8.3Hz,2H),7.37(d,J＝8.4Hz,2H),6.21(s,2H),3.05(t,J＝6.7Hz,2H),1.95(t,J＝7.2Hz,2H),1.57– 1.37(m,4H),1.25(dt,J＝13.0,7.0Hz,2H).13CNMR(100MHz,DMSO-d6)δ169.0,163.8,155.2,138.8, 136.9,132.1,131.3,131.0,128.5,125.3,125.3,121.1,117.6,38.9,32.2,29.5,26.0,24.9.HRMS(ESI) calculated forC21H23F3N4NaO4 +:475.1564,found 475.1565.
example 36: preparation of Compound 36
The preparation method comprises the following steps:
(1) preparation of compound d 36:
a16-1(300mg,1.07mmol) was dissolved in dry dichloromethane (10mL) under argon followed by triethylamine (0.448mL,3.22mmol) and the reaction was placed in an ice bath. After 10 minutes, acetyl chloride (0.115mL,1.61mmol) is added, the reaction is continued for 2 hours, after the reaction is completed, the reaction solution is washed by dilute hydrochloric acid, ethyl acetate is used for extraction, the organic phase is washed by saturated salt water once, the obtained organic phase is dried and concentrated by anhydrous sodium sulfate, and finally, the compound d36(293mg, yield 85%, white solid) is obtained after separation and purification by column chromatography.
Data characterization of compound d 36:
m.p 167-169℃；IR(KBr):3332,3257,3044,2958,2944,1733,1660,1639,1626,1548cm-1.1H NMR (400MHz,DMSO-d6)δ9.76(s,1H),8.29(s,1H),7.41(d,J＝8.7Hz,2H),7.28(d,J＝8.7Hz,2H),6.05(t, J＝5.7Hz,1H),3.57(s,3H),3.04(q,J＝6.5Hz,2H),2.30(t,J＝7.4Hz,2H),1.99(s,3H),1.53(p,J＝7.5 Hz,2H),1.40(p,J＝7.0Hz,2H),1.27(tt,J＝9.8,6.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.3, 167.7,155.3,135.9,133.0,119.6,117.9,51.2,38.9,33.2,29.5,25.9,24.2,23.8.HRMS(ESI)calculated for C16H23N3NaO4 +:344.1581,found 344.1583.
(2) preparation of compound 36:
Figure BDA0002225124810000263
compound 36 (88% yield) was synthesized as a white solid from d36 as the starting material in the same manner as compound 1.
Data characterization of compound 36:
m.p 221-223℃；IR(KBr):3276,3037,2965,2943,2873,1658,1635,1569,1516cm-1.1H NMR(400 MHz,DMSO-d6)δ9.82(s,1H),9.33(s,1H),8.75(s,1H),7.45–7.21(m,4H),6.53(s,1H),3.02(q,J＝6.2 Hz,2H),1.99(s,3H),1.89(t,J＝7.4Hz,2H),1.43(dt,J＝36.5,7.4Hz,4H),1.24(q,J＝7.4,7.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ168.0,167.7,155.5,136.3,132.7,119.6,117.7,38.9,32.9,29.4,26.1, 25.4,23.8.HRMS(ESI)calculated for C15H22N4NaO4 +:345.1533,found 345.1532.
example 37: preparation of Compound 37
The preparation method comprises the following steps:
(1) preparation of compound d 37:
Figure BDA0002225124810000271
the compound d37 (yield: 88%) is synthesized by using a16-1 and benzoyl chloride as raw materials, and the synthesis method is the same as that of the compound d 36.
Data characterization of compound d 37:
m.p 137-139℃；IR(KBr):3341,3232,3025,2929,2917,1720,1656,1631,1626,1581cm-1.1H NMR (400MHz,DMSO-d6)δ10.11(s,1H),8.37(s,1H),7.94(dd,J＝8.1,1.4Hz,2H),7.64–7.47(m,5H),7.41 –7.30(m,2H),6.09(t,J＝5.7Hz,1H),3.58(s,3H),3.06(q,J＝6.5Hz,2H),2.31(t,J＝7.4Hz,2H),1.54 (p,J＝7.5Hz,2H),1.42(p,J＝7.0Hz,2H),1.29(td,J＝8.5,3.9Hz,2H).13C NMR(100MHz,DMSO-d6) δ173.35,165.0,155.2,136.6,135.1,132.6,131.3,128.3,127.5,121.0,117.7,51.2,38.9,33.2,29.5,25.9, 24.2.
HRMS(ESI)calculated for C21H25N3NaO4 +:406.1737,found 406.1736.
(2) preparation of compound 37:
Figure BDA0002225124810000272
compound 37 (87% yield) was synthesized as a white solid from d37 as the starting material in the same manner as compound 1.
Data characterization of compound 37:
m.p 235-237℃；IR(KBr):3251,3041,2960,2933,2868,1656,1634,1567,1517cm-1.1H NMR(400 MHz,DMSO-d6)δ10.39–8.64(m,3H),7.94(d,J＝7.5Hz,2H),7.67–7.45(m,5H),7.37(d,J＝8.4Hz, 2H),6.61(s,1H),3.04(d,J＝5.6Hz,2H),1.90(t,J＝7.3Hz,2H),1.44(dt,J＝33.3,7.4Hz,4H),1.26(q,J ＝8.2Hz,2H).13C NMR(100MHz,DMSO-d6)δ168.0,165.0,155.4,136.9,135.1,132.3,131.3,128.3, 127.5,121.0,117.5,39.0,32.9,29.4,26.1,25.4.HRMS(ESI)calculated for C20H24N4NaO4 +:407.1690, found 407.1688.
example 38: preparation of Compound 38
The preparation method comprises the following steps:
(1) preparation of compound d 38:
Figure BDA0002225124810000273
the compound d38 (yield 85%) is synthesized by using a16-1 and tert-butyl chloride as raw materials, and the synthesis method is the same as that of the compound d 36.
Data characterization of compound d 38:
m.p 146-148℃；IR(KBr):3232,3169,3034,2985,1746,1711,1685,1646,1573cm-1.1H NMR(400 MHz,CDCl3)δ7.81(s,1H),7.66(s,1H),7.10–7.04(m,2H),6.91(d,J＝8.6Hz,2H),5.98(t,J＝5.8Hz, 1H),3.63(s,3H),3.12(q,J＝6.5Hz,2H),2.26(t,J＝7.5Hz,2H),1.58(p,J＝7.6Hz,2H),1.47–1.40(m, 2H),1.29(s,11H).13C NMR(100MHz,CDCl3)δ178.0,174.3,156.7,136.5,131.8,123.0,121.0,51.6,39.8, 39.3,34.0,30.1,27.7,26.5,24.7.HRMS(ESI)calculated for C19H29N3NaO4 +:386.2050,found 386.2047.
(2) preparation of compound 38:
Figure BDA0002225124810000281
compound 38 (66% yield) was synthesized as a white solid from d38 as the starting material in the same manner as compound 1.
Data for compound 38 characterisation:
m.p 187-189℃；IR(KBr):3256,3041,2977,2938,2868,1651,1634,1537,1513cm-1.1H NMR(400 MHz,DMSO-d6)δ10.46–10.28(m,1H),9.04(s,1H),8.69(d,J＝1.7Hz,1H),8.39(s,1H),7.52–7.39 (m,2H),7.35–7.22(m,2H),6.13(t,J＝5.7Hz,1H),3.04(q,J＝6.5Hz,2H),1.95(t,J＝7.4Hz,2H),1.50 (p,J＝7.4Hz,2H),1.40(p,J＝7.0Hz,2H),1.20(s,11H).13C NMR(100MHz,DMSO-d6)δ176.0,169.0, 155.3,136.2,132.8,121.0,117.5,38.9,38.8,32.2,29.6,27.3,26.0,24.9.HRMS(ESI)calculated for C18H28N4NaO4 +:387.2003,found 387.2004.
example 39: preparation of Compound 39
The preparation method comprises the following steps:
(1) preparation of compound c 39:
Figure BDA0002225124810000282
a16-1(150mg,0.537mmol) was dissolved in 10mL methanol and formaldehyde solution (0.5mL,6.00mmol, 37%) was added followed by glacial acetic acid (0.1mL) and sodium cyanoborohydride (150mg,2.40mmol) and stirred for 2h to complete the reaction. Quenching the reaction system with a small amount of diluted hydrochloric acid, washing the reaction solution with saturated sodium carbonate solution, extracting with ethyl acetate, washing the organic phase with saturated saline, drying the organic phase with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain c39(118mg, yield 72%, white solid).
Data characterization of compound c 39:
m.p 90-91℃；IR(KBr):3360,3252,3042,2966,2951,1730,16620,1631,1607,1582cm-1.1H NMR (400MHz,CDCl3)δ7.15–7.04(m,2H),6.81(s,1H),6.72–6.60(m,2H),5.16(d,J＝6.6Hz,1H),3.63(s, 3H),3.13(q,J＝6.7Hz,2H),2.88(s,6H),2.26(t,J＝7.5Hz,2H),1.57(p,J＝7.5Hz,2H),1.47–1.38(m, 2H),1.30–1.22(m,2H).13C NMR(100MHz,CDCl3)δ174.2,157.6,148.3,127.4,124.9,113.4,51.5,40.9, 40.0,33.9,29.9,26.4,24.6.HRMS(ESI)calculated for C16H25N3NaO3 +:330.1788,found 330.1787.
(2) preparation of compound 39:
Figure BDA0002225124810000283
compound 39 (yield 62%) was synthesized as a white solid from c39 as the starting material in the same manner as compound 1.
Data characterization of compound 39:
m.p 183-185℃；IR(KBr):3246,3040,2966,2930,2863,1661,1636,1567,1510cm-1.1H NMR(400 MHz,CDCl3)δ10.07(s,1H),8.40(s,1H),7.75(s,1H),6.92–6.85(m,2H),6.40–6.31(m,2H),5.66(t,J ＝5.7Hz,1H),2.73(q,J＝6.5Hz,2H),2.50(s,6H),1.65(t,J＝7.4Hz,2H),1.20(p,J＝7.4Hz,2H),1.10 (p,J＝7.1Hz,2H),0.96(td,J＝8.3,5.4Hz,2H).13C NMR(100MHz,DMSO-d6)δ169.1,155.6,145.9, 130.7,119.5,113.3,40.8,39.0,32.2,29.7,26.0,24.9.HRMS(ESI)calculated for C15H24N4NaO3 +:331.1741, found331.1741.
example 40: preparation of Compound 40
The preparation method comprises the following steps:
(1) preparation of compound c 40:
Figure BDA0002225124810000291
the compound c40 (yield: 64%) is synthesized by using a16-1 and benzaldehyde as raw materials, and the compound c39 is synthesized as a light yellow solid.
Data characterization of compound c 40:
m.p 123-125℃；IR(KBr):3384,3324,3061,2936,2871,1729,1652,1618,1590cm-1.1H NMR(400 MHz,CDCl3)δ7.33–7.27(m,4H),7.22(ddd,J＝8.3,7.0,1.9Hz,6H),7.02(d,J＝8.6Hz,2H),6.76(s, 1H),6.64(d,J＝8.4Hz,2H),5.19(d,J＝6.3Hz,1H),4.58(s,4H),3.61(s,3H),3.13(q,J＝6.7Hz,2H), 2.24(t,J＝7.5Hz,2H),1.57(p,J＝7.5Hz,2H),1.49–1.39(m,2H),1.31–1.22(m,2H).13C NMR (100MHz,CDCl3)δ174.1,157.3,146.5,138.4,128.6,127.8,126.9,126.6,124.6,113.21,54.5,51.5,39.9, 33.9,29.9,26.3,24.6.HRMS(ESI)calculated for C28H33N3NaO3 +:482.2414,found 482.2415.
(2) preparation of compound c 40:
Figure BDA0002225124810000292
compound 40 (67% yield) was synthesized as a white solid from c40 as the starting material in the same manner as compound 1.
Data characterization of compound 40:
m.p 83-85℃；IR(KBr):3256,3051,2939,2931,2863,1651,1634,1567,1523cm- 1.1H NMR(400MHz, DMSO-d6)δ10.39(s,1H),8.72(s,1H),8.00(s,1H),7.27(dq,J＝18.1,10.6,9.1Hz,10H),7.08(d,J＝8.5 Hz,2H),6.59(d,J＝8.6Hz,2H),5.96(s,1H),4.59(s,4H),3.01(q,J＝6.4Hz,2H),1.95(t,J＝7.3Hz, 2H),1.55–1.44(m,2H),1.38(t,J＝7.4Hz,2H),1.24(q,J＝8.1Hz,2H).13C NMR(100MHz,DMSO-d6) δ169.1,155.6,143.4,139.3,130.4,128.4,126.8,126.6,119.9,113.3,54.6,39.0,32.2,29.7,26.0,24.9. HRMS(ESI)calculated for C27H32N4NaO3 +:483.2367,found 483.2368.
example 41: preparation of Compound 41
The preparation method comprises the following steps:
(1) preparation of compound c 41:
compound c41 (yield 92%) is synthesized from a16-1 and isobutyraldehyde as raw materials to obtain a pale yellow solid, and the compound c39 is synthesized.
Data characterization of compound c 41:
m.p 93-95℃；IR(KBr):3374,3325,3060,2936,2881,1727,1655,1628,1595cm- 1.1H NMR(400 MHz,CDCl3)δ7.04(d,J＝8.5Hz,2H),6.71(s,1H),6.55(d,J＝8.4Hz,2H),5.14(d,J＝7.2Hz,1H), 3.62(s,3H),3.20–3.01(m,6H),2.26(t,J＝7.5Hz,2H),2.01(dt,J＝13.6,6.8Hz,2H),1.59(q,J＝7.6Hz, 2H),1.48–1.40(m,2H),1.28(tdd,J＝9.1,6.4,2.4Hz,2H),0.86(d,J＝6.6Hz,12H).13C NMR(100MHz, DMSO-d6)δ173.3,155.6,143.4,129.4,120.1,113.2,59.9,51.1,38.9,33.2,29.6,26.0,25.8,24.2,20.1. HRMS(ESI)calculated for C22H37N3NaO3 +:414.2727,found 414.2726.
(2) preparation of compound 41:
Figure BDA0002225124810000301
compound 41 (yield 79%) was synthesized as a white solid from c41 as the starting material in the same manner as compound 1.
Data characterization of compound 41:
m.p 157-159℃；IR(KBr):3276,3041,2989,2950,2877,1651,1664,1561,1513cm-1.1H NMR(400 MHz,DMSO-d6)δ10.37(s,1H),8.69(s,1H),7.94(s,1H),7.11(d,J＝8.7Hz,2H),6.55(d,J＝8.9Hz, 2H),5.92(t,J＝5.7Hz,1H),3.03(d,J＝7.3Hz,6H),1.93(dt,J＝12.8,7.0Hz,4H),1.49(q,J＝7.5Hz, 2H),1.38(q,J＝7.2Hz,2H),1.28–1.21(m,2H),0.84(d,J＝6.6Hz,12H).13C NMR(100MHz,DMSO-d6)δ169.0,155.7,143.4,129.5,120.1,113.2,60.0,39.0,32.2,29.7,26.0,26.0,24.9,20.1.HRMS(ESI) calculated for C21H36N4NaO3 +:415.2680,found 415.2678.
example 42: preparation of Compound 42
The preparation method comprises the following steps:
(1) preparation of compound c 42:
Figure BDA0002225124810000302
the compound c42 (the yield is 74%) is synthesized by using a16-1 and benzaldehyde as raw materials, and the white solid is synthesized by the same method as the compound c 39.
Data characterization of compound c 42:
m.p 82-84℃；IR(KBr):3364,3298,3062,3030,2955,2860,1721,1683,1621,1598cm-1.1H NMR (400MHz,CDCl3)δ7.38–7.23(m,5H),7.04(ddd,J＝9.3,5.7,2.9Hz,2H),6.57(ddq,J＝9.5,6.4,3.7Hz, 3H),5.01(t,J＝5.9Hz,1H),4.29(d,J＝5.0Hz,2H),4.11(s,1H),3.64(d,J＝5.2Hz,3H),3.15(p,J＝6.1 Hz,2H),2.33–2.22(m,2H),1.64–1.53(m,2H),1.44(dq,J＝12.4,6.5Hz,2H),1.28(dp,J＝14.5,6.0, 4.9Hz,2H).13C NMR(100MHz,CDCl3)δ174.2,157.4,145.8,139.3,128.7,128.1,127.5,127.3,125.3, 113.4,51.5,48.5,40.0,33.9,30.0,26.4,24.6.HRMS(ESI)calculated for C21H27N3NaO3 +:392.1945,found 392.1944.
(2) preparation of compound 42:
Figure BDA0002225124810000303
compound 42 (61% yield) was synthesized as a white solid from c42 as the starting material in the same manner as compound 1.
Data characterization of compound 42:
m.p 87-89℃；IR(KBr):3197,3029,2925,2855,1647,1636,1517,1508cm-1.1H NMR(400MHz, DMSO-d6)δ10.36(s,1H),8.69(s,1H),7.90(s,1H),7.32(dt,J＝14.8,7.2Hz,4H),7.20(t,J＝7.2Hz,1H), 7.02(d,J＝8.4Hz,2H),6.47(d,J＝8.5Hz,2H),5.89(dt,J＝13.7,6.0Hz,2H),4.20(d,J＝5.2Hz,2H), 3.00(q,J＝6.5Hz,2H),1.94(t,J＝7.4Hz,2H),1.48(p,J＝7.5Hz,2H),1.38(q,J＝7.2Hz,2H),1.26– 1.19(m,2H).13C NMR(100MHz,DMSO-d6)δ169.0,155.7,143.7,140.5,129.8,128.2,127.2,126.5, 120.1,112.5,47.0,39.0,32.2,29.7,26.0,24.9.HRMS(ESI)calculated for C20H26N4NaO3 +:393.1897,found393.1898.
example 43: preparation of Compound 43
The preparation method comprises the following steps:
(1) preparation of compound c 43:
Figure BDA0002225124810000311
compound c43 (yield 62%) was synthesized from a16-1 and isobutyraldehyde as starting materials to give compound c39 as a yellow solid.
Data characterization of compound c 43:
m.p 80-82℃；IR(KBr):3366,3298,3052,3033,2955,2868,1721,1688,1636,1588cm-1.1H NMR (400MHz,CDCl3)δ7.14(s,1H),6.95(d,J＝8.2Hz,2H),6.42(d,J＝8.3Hz,2H),5.42(s,1H),3.56(s, 4H),3.02(q,J＝6.7Hz,2H),2.78(d,J＝6.8Hz,2H),2.18(t,J＝7.5Hz,2H),1.77(dp,J＝13.4,6.7Hz, 1H),1.52–1.45(m,2H),1.32(t,J＝7.6Hz,2H),1.17(d,J＝6.5Hz,2H),0.88(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ174.1,157.6,145.6,128.0,124.3,113.0,52.1,51.4,39.9,33.8,29.9,27.9, 26.3,24.5,20.4.HRMS(ESI)calculated for C18H29N3NaO3 +:358.2101,found 358.2103.
(2) preparation of compound 43:
Figure BDA0002225124810000312
compound 43 (66% yield) was synthesized as a white solid from c43 as the starting material in the same manner as compound 1.
Data characterization of compound 43:
m.p 120-122℃；IR(KBr):3193,3039,2915,2875,1637,1626,1534,1511cm-1.1HNMR(400MHz, DMSO-d6)δ10.37(s,1H),8.69(d,J＝1.6Hz,1H),7.89(s,1H),7.03(d,J＝8.4Hz,2H),6.45(d,J＝8.4 Hz,2H),5.90(t,J＝5.6Hz,1H),5.22(s,1H),3.01(q,J＝6.5Hz,2H),2.75(d,J＝6.7Hz,2H),1.94(t,J＝ 7.4Hz,2H),1.80(dt,J＝13.1,6.6Hz,1H),1.49(p,J＝7.5Hz,2H),1.38(p,J＝7.1Hz,2H),1.24(q,J＝ 7.6,5.4Hz,2H),0.91(d,J＝6.6Hz,6H).13C NMR(100MHz,DMSO-d6)δ169.0,155.7,144.3,129.3, 120.3,112.0,51.4,39.0,32.2,29.7,27.3,26.0,24.9,20.5.HRMS(ESI)calculated for C17H28N4NaO3 +:359.2054,found 359.2055.
example 44: preparation of Compound 44
The preparation method comprises the following steps:
(1) preparation of compound c 44:
Figure BDA0002225124810000313
the compound c44 (yield 76%) is synthesized by using a16-1 and valeraldehyde as raw materials, and the white solid is synthesized by the same method as the compound c 39.
Data characterization of compound c 44:
m.p 100-102℃；IR(KBr):3374,3334,3051,2946,2891,1729,1659,1613,1599cm-1.1H NMR(400 MHz,CDCl3)δ7.05(d,J＝8.6Hz,2H),6.55(d,J＝8.1Hz,3H),5.00(t,J＝5.8Hz,1H),3.63(s,3H),3.17 (dt,J＝19.1,7.1Hz,6H),2.26(t,J＝7.4Hz,2H),1.64–1.49(m,6H),1.44(t,J＝7.5Hz,2H),1.34–1.24 (m,10H),0.89(t,J＝7.0Hz,6H).13C NMR(100MHz,CDCl3)δ174.1,157.6,146.2,125.8,125.8,112.4, 51.5,51.2,40.0,33.9,30.0,29.3,26.9,26.4,24.6,22.6,14.1.HRMS(ESI)calculated for C24H41N3NaO3 +: 442.3040,found 442.3041.
(2) preparation of compound 44:
Figure BDA0002225124810000321
compound 44 (yield 72%) was synthesized as a white solid from c44 as the starting material in the same manner as compound 1.
Data characterization of compound 44:
m.p 91-93℃；IR(KBr):3332,3242,3041,2974,2904,1650,1641,1616,1563cm- 1.1H NMR(400 MHz,DMSO-d6)δ10.36(s,1H),8.69(d,J＝1.5Hz,1H),7.93(s,1H),7.12(d,J＝8.5Hz,2H),6.52(d,J＝ 8.5Hz,2H),5.92(t,J＝5.7Hz,1H),3.15(t,J＝7.5Hz,4H),3.02(q,J＝6.5Hz,2H),1.94(t,J＝7.3Hz, 2H),1.47(dt,J＝16.0,7.3Hz,6H),1.39(t,J＝7.3Hz,2H),1.30–1.23(m,10H),0.86(t,J＝6.9Hz,6H).13C NMR(100MHz,DMSO-d6)δ169.0,155.7,143.3,129.4,120.2,112.5,50.6,39.0,32.2,29.7,28.8, 26.5,26.0,24.9,22.1,14.0.HRMS(ESI)calculated for C23H40N4NaO3 +:443.2993,found 443.2991.
example 45: preparation of Compound 45
The preparation method comprises the following steps:
(1) preparation of compound c 45:
the compound c45 (yield 83%) is synthesized by using a16-1 and propionaldehyde as raw materials, and a yellow solid is synthesized by using the compound c 39.
Data characterization of compound c 45:
m.p 89-91℃；IR(KBr):3364,3324,3051,2966,2891,1739,1669,1617,1569cm- 1.1H NMR(400 MHz,CDCl3)δ7.18–6.89(m,2H),6.63–6.46(m,2H),6.39(s,1H),4.90(t,J＝5.7Hz,1H),3.63(s,3H), 3.17(dt,J＝11.9,7.1Hz,6H),2.28(d,J＝7.5Hz,2H),1.64–1.53(m,6H),1.50–1.43(m,2H),1.33– 1.26(m,2H),0.90(t,J＝7.4Hz,6H).13C NMR(100MHz,CDCl3)δ174.2,157.7,146.4,126.2,125.5, 112.4,53.1,51.5,40.0,34.0,30.0,26.4,24.6,20.4,11.5.HRMS(ESI)calculated for C20H33N3NaO3 +: 386.2414,found 386.2413.
(2) preparation of compound 45:
Figure BDA0002225124810000323
compound 45 (73% yield) was synthesized as a white solid from c45 as the starting material in the same manner as compound 1.
Data characterization of compound 45:
m.p 142-144℃；IR(KBr):3242,3202,3040,2969,2951,1656,1631,1606,1529cm-1.1H NMR(400 MHz,DMSO-d6)δ10.37(s,1H),8.70(s,1H),7.94(s,1H),7.12(d,J＝8.6Hz,2H),6.53(d,J＝8.6Hz, 2H),5.91(d,J＝5.8Hz,1H),3.13(t,J＝7.5Hz,4H),3.01(t,J＝6.3Hz,2H),1.95(t,J＝7.3Hz,2H),1.53 –1.45(m,6H),1.39(t,J＝7.5Hz,2H),1.24(t,J＝7.6Hz,2H),0.85(t,J＝7.2Hz,6H).13C NMR(100 MHz,DMSO-d6)δ169.0,155.7,143.3,129.3,120.2,112.4,52.4,39.0,32.2,29.7,26.0,24.9,20.1,11.3. HRMS(ESI)calculated for C19H32N4NaO3 +:387.2367,found 387.2368.
example 46: activity test of Compounds 1-45 against hydrolase and aminopeptidase of LTA4H
LTA4H inhibitor was tested for in vitro enzyme activity, including hydrolase and aminopeptidase activity, at concentrations of 5. mu.M and 50. mu.M. The results are shown in Table 1.
TABLE 1 LTA4H inhibitor in vitro enzyme activity assay results
Figure BDA0002225124810000331
Figure BDA0002225124810000341
The compounds 1-45 can effectively inhibit the activity of leukotriene A4 hydrolase without basically influencing the activity of aminopeptidase, and are expected to be applied to anti-inflammatory and anti-pulmonary fibrosis drugs.
Example 47 inhibition of activation and extracellular matrix production by human lung fibroblasts by Compound 26 through inhibition of the TGF- β 1/Smad3 signaling pathway
The results of Western blot analysis demonstrated that compound 26 was able to inhibit TGF- β induced fibroblast activation (see FIGS. 1-2) in myofibroblasts treated with compound 26, the results of real-time quantitative PCR experiments further demonstrated that compound 26 was able to inhibit TGF- β induced Smad activation (see FIGS. 3-5), and then we examined the effect of compound 26 on the inhibition of TGF- β/Smad signaling pathway in a dose-dependent manner (see FIGS. 7- β. the results of TGF-8 activation and TGF-6858 phosphorylation inhibition of TGF-361 activation) were able to be determined in accordance with the results of assays involving activation of human fibroblasts, extracellular matrix (ECM) deposition at fibrotic foci and TGF- β/Smad3 signaling pathways (see FIGS. 7. TGF- β. TGF-8. activation of human fibroblasts and pathogenesis of pulmonary fibrosis. to further explore the mechanism of compound 26 on Bleomycin (BLM) induced fibrotic changes in Bleomycin (BLM) induced fibrosis.
Example 48 Compound 26 alleviates BLM-induced pulmonary inflammation
To further validate the effect of compound 26 on the reduction of inflammation caused by lung injury, we established a BLM-induced lung injury model with compound 26 administered continuously for 7 days, and using pirfenidone as a positive control (see fig. 9) H & E staining showing that BLM treatment results in accumulation of inflammatory cells in the alveolar space and an increase in alveolar wall thickness, compound 26 treatment significantly reduced infiltration of inflammatory cells and restored BLM-injured alveolar structure (see fig. 10) in alveolar lavage fluid (BALF) of BLM-modeled mice, the total and differential subpopulation inflammatory cell numbers were both significantly up-regulated, compound 26 administration significantly reduced the number of inflammatory cells and was superior to pirfenidone and SAHA (see fig. 11-15) we further tested the protein concentration in BALF, found that BLM group significantly up-regulated total protein in BALF, while compound 26 was able to down-regulate protein amount (see fig. 16) consistent with these results, compound 26 was able to down-regulate protein levels in BLM-modeled mice significantly as measured by ELISA 17-17, TNF-4, TNF-induced protein response to TNF-4 in mice.
Example 49 Compound 26 alleviates BLM-induced pulmonary fibrosis in mice
The bleomycin model is an animal model that can be used for optimal characterization of the IPF preclinical experiments, and the model progression is divided into acute lung injury (days 0-7 after molding), fibroplasia (days 3-14) and fibrosis stage (days 14-28). To test the prophylactic or therapeutic effect of compound 26 on pulmonary fibrosis, we established a BLM-induced animal model of pulmonary fibrosis, and following modeling of BLM, compound 26 was administered by daily gavage from days 0-7 (see fig. 21) or 7-14 (see fig. 22), and mice were sacrificed on day 14 to assess the fibrotic response using pirfenidone as a positive control. Hydroxyproline assay results showed that lung collagen content in the model mice was significantly reduced by compound 26 treatment (see figure 23). The percentage of fiber area after pirfenidone, compound 26, and SAHA treatment was adjusted downward to approximately 36.57%, 68.03%, and 64.01%, respectively (see fig. 24). These pathological changes indicate that treatment with compound 26 significantly ameliorated damage to the alveolar structure of the model mice (see figure 25).
The hydroxyproline assay results showed a reduction in collagen content in the compound 26 treated group when compound 26 was used during the fibrogenic phase (see figures 26-27), a reduction in the area percent fibrosis of approximately 33.83%, 56.56% and 45.88% after pirfenidone, compound 26 and SAHA treatment, respectively (see figure 28), and a restoration of the damaged lung architecture after compound 26 treatment (see figure 29). Briefly, these results demonstrate that compound 26 can reduce BLM-induced pulmonary fibrosis in mice.
Example 50 relief of LPS-induced acute Lung injury by Compound 26
To investigate the anti-inflammatory effect of compound 26 on lung injury, an animal model of LPS-induced Acute Lung Injury (ALI) was established and administered to animals 1 hour before the administration of LPS (see fig. 30). Results of histological analysis showed that LPS caused severe lung injury (e.g. alveolar hemorrhage, interstitial edema, alveolar collapse and significant infiltration of inflammatory cells into the alveolar space). Lung injury was significantly inhibited by pretreatment with compound 26, and the effect of compound 26 was the same as and better than that of the positive drug dexamethasone (see figure 31).
Recruitment of excessive inflammatory cells is critical to the pathogenesis of LPS-induced lung injury. The experimental results show that the total number of BALF inflammatory cells of LPS-treated mice is remarkably up-regulated, and the number of inflammatory cells in BALF can be remarkably down-regulated after the compound 26 is used for treating LPS-modeled mice (refer to fig. 32-33). While we further evaluated the recruitment of inflammatory cell subsets following LPS-induced lung injury, the results demonstrated that compound 26-pretreated mice had reduced recruitment of macrophages, neutrophils and lymphocytes following LPS injury (see fig. 34-36). The concentration of protein in BALF of LPS-modeled mice was also reduced after administration of Compound 26 (see FIG. 37).
As described above, LTB4 is critical for activation and recruitment of neutrophils, and neutrophils accumulate in the BALF of LPS-treated mice. Furthermore, compound 26 specifically targets LTA4H enzyme activity, so we evaluated the concentration of LTB4 in BALF and found that compound 26 significantly inhibited LTB4 biosynthesis in vivo (see figure 38).
IL-1 β -6 and TNF- α are typical proinflammatory mediators in various inflammatory diseases, and to further evaluate the anti-inflammatory properties of compound 26, these three proinflammatory cytokines in BALF were tested, and the experimental results demonstrate that compound 26 significantly down-regulates the protein levels of IL-1 β -6 and TNF- α in LPS-injured mice (see FIGS. 39-40).
The above results indicate that compound 26 can effectively alleviate LPS-induced acute lung injury and inhibit inflammatory responses.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (5)

1. A compound characterized by: the compound has a general formula represented by the following formula 1:
Figure FDA0002225124800000011
in the formula:
n＝2-5；
R1is H or CF3；
R2Independently selected from alkyl, alkoxy, heteroatom substituents,
Figure FDA0002225124800000012
-NH-C(O)-R3Said
Figure FDA0002225124800000013
Wherein m is 2-4, said-NH-c (o) -R3R in (1)3Independently selected from alkyl, substituted aryl, -N (R)4R5) said-N (R)4R5) R in (1)4And R5Are independently selected from H, methyl, benzyl, isobutyl, propyl pentyl.
2. The compound of claim 1, wherein: and the substituent in the heteroatom substituent is halogen, nitryl, amino, methoxyl, trifluoromethoxy or methyl.
3. The compound of claim 1, wherein: said R3Independently selected from isopropyl, p-trifluoromethylphenyl, methyl, phenyl, tert-butyl.
4. The compound of claim 1, wherein: the compound is selected from one or more of the following compounds:
Figure FDA0002225124800000014
Figure FDA0002225124800000021
Figure FDA0002225124800000031
Figure FDA0002225124800000041
5. use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for anti-inflammatory and treatment of acute lung injury, chronic obstructive pulmonary disease, asthma or pulmonary fibrosis.
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