Coumarin modified compound as well as preparation method and application thereof

Abstract

The invention provides a coumarin modified compound of which the structural formula is shown as a formula (I), n is equal to 0 or 1, a novel 3-amino coumarin derivative is successfully synthesized, the structural formula is shown as the formula (I), and the structural formula is shown as the formula (II). The compound provided by the invention shows excellent treatment activity in an acute kidney injury (AKI) model: the compound can be used for remarkably repairing kidney tissue injury in a pathological state and promoting the recovery of the damaged renal tubular epithelial cell form to a normal phenotype; the survival ability of kidney injury cells can be effectively improved, and the cell function is improved; meanwhile, the level of renal function impairment markers such as serum creatinine (Scr) can be remarkably reduced, and it is prompted that the traditional Chinese medicine composition can effectively improve the renal function. The compound provides a new candidate drug for treatment of acute kidney injury, and has important clinical development value and application potential.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicinal chemistry, in particular to a preparation method and use of a coumarin-modified compound with acute kidney injury treatment activity. BACKGROUND

[0002] Acute kidney injury is a common critical illness in clinical practice, which is characterized by rapid onset and progression. If not timely and effective intervention, it is easy to lead to irreversible damage to renal function, and even develop into end-stage renal disease, which seriously threatens the life and health of patients. At present, the treatment of acute kidney injury in clinical practice still has limitations, and there is a lack of specific drugs with strong targeting, definite efficacy and high safety.

[0003] Coumarin compounds are a class of natural products with a wide range of biological activities. Their potential effects in anti-inflammatory and antioxidant activities have been confirmed by many studies, and thus they have become an important candidate skeleton for the development of drugs for the treatment of kidney injury. However, traditional coumarin compounds have significant technical defects. On the one hand, they have insufficient therapeutic activity for acute kidney injury, and are difficult to effectively alleviate kidney tissue damage and improve renal function. On the other hand, they have low bioavailability in vivo, which limits their clinical application and conversion, and cannot meet the actual treatment needs. Therefore, it is urgent to develop coumarin derivatives with stronger anti-kidney injury activity, higher bioavailability and better safety through structural modification and optimization, in order to fill the gap in clinical treatment. SUMMARY

[0004] The core purpose of the present application is to overcome the technical defects of traditional coumarin compounds in limited activity and low bioavailability for the treatment of acute kidney injury, and to provide a coumarin-modified compound with significant therapeutic effect, strong targeting and high safety, as well as a preparation method of the compound and its use in the treatment of acute kidney injury, thereby providing a new effective treatment option for clinical practice.

[0005] The present application first provides a coumarin-modified compound, the structural formula of which is shown as formula (I):

[0006] wherein n = 0, 1 or 2, m = 1 or 2; R is a sulfonyl group substituted with C3-C8 alkyl, C3-C8 hydrocarbyl, C3-C8 cycloalkyl, C6-C8 aryl or C5-C8 heteroaryl containing N, O or S; said sulfonyl group substituted with C3-C8 alkyl, C3-C8 hydrocarbyl, C3-C8 cycloalkyl, C5-C8 heterocycloalkyl containing 1 or 2 heteroatoms optionally selected from N, O or S, C6-C8 aryl or C5-C8 heteroaryl containing 1 heteroatom selected from N, O or S is optionally substituted with halo, C1-C6 alkyl, C1-C6 carboxyl, C0-C6 alkyl-hydroxyl, C0-C6 alkyl-NH2-, C2-C6 ester, C2-C6 amide.

[0007] In one embodiment according to the present application, R is trifluoromethanesulfonyl, trichloromethanesulfonyl, fluorothiophenesulfonyl, chlorothiophenesulfonyl, p-toluenesulfonyl, m-toluenesulfonyl, o-toluenesulfonyl or ; said R1 is C1-C6 alkyl-O-, C3-C8 cycloalkyl-O-, C3-C8 cycloalkyl-NH-, C5-C8 heterocycloalkyl containing 1 or 2 heteroatoms optionally selected from N, O or S or C1-C6 alkyl-NH-.

[0008] In one embodiment according to the present application, said R is selected from: .

[0009] In one embodiment according to the present application, said coumarin-modified compound is selected from:

[0010]

[0011]

[0012] In yet another aspect of the present application, there is provided an intermediate compound for preparing a coumarin-modified compound having the structural formula II:

[0013] wherein n = 0, 1 or 2, m = 1 or 2; In one embodiment according to the present application, said intermediate compound is selected from: .

[0014] The present application also provides a method for preparing the above intermediate compound, which comprises:

[0015] wherein the number of carbon atoms n = 0, 1 or 2, and the number of m = 1 or 2; In one embodiment according to the present application, when n = 0 and m = 1, the reaction formula is: ; In one embodiment according to the present application, when n = 1 and m = 1, the reaction formula is: .

[0016] Another aspect of the present application also provides a method for preparing the above-mentioned compound, and the reaction formula is: ; R is trifluoromethanesulfonyl, trichloromethanesulfonyl, fluorothiophenesulfonyl, chlorothiophenesulfonyl, p-toluenesulfonyl, m-toluenesulfonyl or o-toluenesulfonyl; or,

[0017] R is ; the R1 is C1-C6 alkyl-O-, C3-C8 cycloalkyl-O-, C3-C8 cycloalkyl-NH-, C5-C8 heterocycloalkyl containing 1 or 2 heteroatoms optionally selected from N, O or S, or C1-C6 alkyl-NH-.

[0018] In one embodiment according to the present application, the above-mentioned method for preparing includes: In an organic solvent, under the condition of 0°C to 80°C, 3-amino-2 H -chromen-2-one as the starting material, through a series of reactions such as condensation, substitution and / or hydrolysis, through the reaction formula as claimed in claim 8, a novel 3-amino-coumarin restructured derivative is synthesized in 2 to 24 hours; In one embodiment according to the present application, the organic solvent is dichloromethane (DCM), acetonitrile (CH3CN), methanol (MeOH), N,N dimethylformamide (DMF), ethyl acetate (EA), tetrahydrofuran (THF), etc., and the non-polar solvent is petroleum ether (PE).

[0019] The present application also provides a pharmaceutical composition comprising an effective amount of the above-mentioned coumarin restructured compound and a pharmaceutically acceptable excipient.

[0020] The present application further provides the use of the above-mentioned coumarin restructured compound or the pharmaceutical composition in the preparation of a medicament for treating acute kidney injury.

[0021] This invention successfully synthesized a novel class of 3-aminocoumarin derivatives. These compounds exhibited excellent therapeutic activity in an acute kidney injury (AKI) model: they significantly repaired kidney tissue damage under pathological conditions, promoted the restoration of damaged renal tubular epithelial cell morphology to a normal phenotype, effectively enhanced the survival ability of damaged kidney cells, and improved cell function; simultaneously, they significantly downregulated the levels of renal function impairment markers such as serum creatinine (Scr), suggesting their effective ability to improve renal function. These compounds provide new drug candidates for the treatment of acute kidney injury and have significant clinical development value and application potential. Attached Figure Description

[0022] Figure 1 A bar chart comparing the viability of HK-2 cells under different intervention conditions was used to explore the effects of different interventions on the viability of HK-2 cells after HR injury and to screen the coumarin derivatives with the best therapeutic effect. Among them, compounds 6, 7 and 8 had low solubility in DMSO and did not meet the requirements for biological experiments. Figure 2 The images show light microscopic observations of HK2 cell morphology under hypoxia and reoxygenation conditions, illustrating the effects of different treatments on the morphology and growth status of HK-2 cells. The images represent the control group, the HR group (pathological group), and the morphological changes under the intervention of different coumarin compounds (1-18). Compounds 6, 7, and 8 have low solubility in DMSO and do not meet the requirements for biological experiments. Figure 3 These are pathological sections of kidney tissue stained with hematoxylin and eosin (HE) to observe the degree of renal tubular damage in different treatment groups. The groups are: Sham (sham-operated group) and IRI (ischemia-reperfusion injury group); L, M, and R represent low, medium, and high doses of compound 1 (L: 5 mg / kg; M: 25 mg / kg; H: 50 mg / kg). Figure 4 The graph shows the results of the renal function test (Scr); where serum creatinine is measured; L, M, and R represent the low, medium, and high doses of compound 1, respectively: L: 5 mg / kg; M: 25 mg / kg; H: 50 mg / kg. Detailed Implementation

[0023]

[0024] To make the technical problems, technical solutions and advantages of the present invention clearer, a detailed description will be given below in conjunction with the accompanying drawings and specific embodiments.

[0025] Unless otherwise specified, all reagents used in this embodiment are of analytical grade, and the progress of all chemical reactions is detected by thin-layer chromatography.

[0026] Example 1: Synthesis of the compound The reagent described in the present application: 3-amino-2 H - Chromene-2-one, bromoacetyl bromide, anhydrous sodium sulfate, lithium hydroxide, dichloromethane and trifluoromethanesulfonyl chloride, etc. are commercially available analytical pure.

[0028] The water in the present application is distilled water, and the organic solvents are commercially available analytical pure polar solvents or non-polar solvents, such as: dichloromethane (DCM), acetonitrile (CH3CN), methanol (MeOH), dimethylformamide (DMF), petroleum ether (PE), ethyl acetate (EA), etc. N,N - dimethylformamide (DMF), petroleum ether (PE), ethyl acetate (EA), etc.

[0029] Example 1: Preparation of compound 1 3-((4-(2-oxo-2-((2-oxo-2 H - Chromene-3-yl))amino)ethyl)piperazin-1-yl)sulfonyl)thiophene-2-carboxylate:

[0030] Step 1: Synthesis of 2-bromo- N - (2-carbonyl-2 H - Chromene-3-yl)acetamide

[0031] In a clean 100 mL flask, 3-amino-2 H - Chromene-2-one (18.0 mmol) was dissolved in 40 mL of dichloromethane, triethylamine (36.0 mmol) was added at 0°C ice bath, then bromoacetyl bromide (18.0 mmol) was slowly added, after removing the ice bath, stirring at room temperature for 4 hours. TLC monitoring reaction, after the reaction was completed, the excess solvent was removed by reduced pressure distillation, the resulting system was separated by column chromatography to obtain white solid A.

[0032] Step 2: Synthesis of tert-butyl 4-(2-carbonyl-2-((2-carbonyl-2 H - Chromene-3-yl)amino)ethyl)piperazine-1-carboxylate

[0033] In a clean 100 mL flask, 1- B - oc-piperazine (12.0 mmol) was dissolved in 40 mL of dimethylformamide, triethylamine (20.0 mmol) was added, then A (10.0 mmol) was added, stirring at room temperature for 8-12 hours. TLC monitoring reaction, after the reaction was completed, extracted with ethyl acetate and saturated brine, the solvent was removed by reduced pressure distillation, the resulting system was separated by column chromatography to obtain white solid B. N,N - dimethylformamide (DMF), petroleum ether (PE), ethyl acetate (EA), etc. N,NDimethylformamide was used to distill the organic phase under reduced pressure, and the residue was separated by column chromatography to obtain a white solid B.

[0034] Step 3: N -(2-oxo-2) H Synthesis of 2-chromene-3-yl)-2-(piperazin-1-yl)acetamide

[0035] In a clean 100 mL flask, under ice bath conditions, B (9.55 mmol) was dissolved in 30 mL of dichloromethane, followed by the addition of trifluoroacetic acid (95.5 mmol). The ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was complete, excess dichloromethane and trifluoroacetic acid were removed by vacuum distillation, and the solvent was recovered under reduced pressure to obtain a white powdery solid C.

[0036] Step 4: 3-((4-(2-oxo-2-((2-oxo-2) H Synthesis of methyl thiophene-2-carboxylic acid (-chromene-3-yl)amino)ethyl)piperazine-1-yl)sulfonyl)thiophene-2-carboxylic acid

[0037] In a clean 100 mL flask, under ice bath conditions, dissolve A (5.0 mmol) in 20 mL of dichloromethane, and then add... N,N Diisopropylethylamine (10.0 mmol) was added, followed by the addition of methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (6.0 mmol). The ice bath was removed, and the reaction was carried out at room temperature for 2 hours. The reaction was detected by TLC. After the reaction was completed, excess solvent was removed by vacuum distillation, and the residue was separated by column chromatography to obtain a milky white solid 1. 1 H NMR (600 MHz, Chloroform- d ) δ 9.71 (s, 1H), 7.52 (d, J = 5.2 Hz, 1H), 7.50 (dd, J = 7.8, 1.5Hz, 1H), 7.47 (d, J = 5.3 Hz, 1H), 7.46 – 7.43 (m, 1H), 3.92 (s, 3H), 3.50 (s,4H), 3.24 (s, 2H), 2.72 (s, 4H). ESI-MS calculated for [M+H]+: 492.0821, found 492.0827. Example 2: Preparation of Compound 2

[0038] N - cyclobutyl-3-((4-(2-oxo-2-((2-oxo-2 H Synthesis of 3-((4-(2-oxo-2-((2-oxo-2

[0039] In a clean 50 mL flask, D (1.0 mmol), 2-(7-azabenzotriazole) - tetramethylurea hexafluorophosphate (1.0 mmol) and 2,4,6-trimethylpyridine (1.0 mmol) were dissolved in 5 mL of N,N - dimethylformamide at RT for 30 min, then 2,4,6-trimethylpyridine (2.0 mmol) and cyclobutylamine (2.0 mmol) were added to it and the reaction was carried out for 8-12 h. The reaction was monitored by TLC, after completion of the reaction, it was extracted with ethyl acetate and saturated brine, the organic phase was removed and the residue was distilled under reduced pressure, the residue was separated by column chromatography to get 2 as a yellowish solid. N,N 1 H NMR (600 MHz, Chloroform-d) δ 9.54 (s, 1H), 8.60 (s, 1H), 8.49 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 5.3 Hz, 1H), 7.49 (dd, J = 7.7, 1.5 Hz, 1H), 7.46–7.43 (m, 1H), 7.35 (d, J = 5.3 Hz, 1H), 7.33–7.27 (m, 2H), 3.23 (s, 4H), 3.20 (s, 2H), 2.69 (t, J = 4.9 Hz, 4H), 2.42 2.33 (m, 2H), 2.05–1.94 (m, 2H), 1.83–1.69 (m, 2H). ESI-MS calculated for [M+H]+: 531.1294, found 531.1299. Example 3: Preparation of compound 3

[0040] 3-((4-(2-oxo-2-((2-oxo-2 H - cyclobutyl-3-((4-(2-oxo-2-((2-oxo-2 N Synthesis of 3-((4-(2-oxo-2-((2-oxo-2​

[0041] In a clean 50 mL flask, D (1.0 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (1.0 mmol) and 2,4,6-trimethylpyridine (1.0 mmol) were dissolved in 5 mL of dimethylformamide and stirred at RT for 30 min, followed by the addition of 2,4,6-trimethylpyridine (2.0 mmol) and propylamine (2.0 mmol) to it and the reaction was allowed to proceed for 8-12 h. The reaction was monitored by TLC and after completion, the reaction mixture was extracted with ethyl acetate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 3 as a yellow solid. N,N N,N N,N 1 H NMR (600 MHz, Chloroform-d) δ 9.54 (s, 1H), 8.60 (s, 1H), 8.49 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 5.3 Hz, 1H), 7.49 (dd, J = 7.7, 1.5 Hz, 1H), 7.45–7.42 (m, 1H), 7.35 (d, J = 5.3 Hz, 1H), 7.33–7.27 (m, 2H), 3.23 (s, 4H), 3.20 (s, 2H), 2.69 (t, J = 4.9 Hz, 4H), 2.41–2.34 (m, 2H), 2.04–1.96 (m, 2H), 1.81–1.71 (m, 2H). ESI-MS calculated for [M+H]+: 518.1294, found 518.1297. Example 4: Preparation of compound 4

[0042] N Synthesis of 3-((4-(2-oxo-2-((2-oxo-2 H Synthesis of 3-((4-(2-oxo-2-((2-oxo-2

[0043] In a clean 50 mL flask, D (1.0 mmol), 2-(7-azabenzotriazol) ​​​1.0 mmol of tetramethylurea hexafluorophosphate and 1.0 mmol of 2,4,6-trimethylpyridine were dissolved in 5 mL of [a solution / concentrate]. N,N In dimethylformamide, the mixture was stirred at RT for 30 minutes, followed by the addition of 2,4,6-trimethylpyridine (2.0 mmol) and isobutylamine (2.0 mmol), and the reaction was allowed to proceed for 8–12 hours. The reaction was monitored by TLC. After completion, the mixture was extracted with ethyl acetate and saturated brine to remove impurities. N,N -Dimethylformamide, the resulting organic phase was subjected to vacuum distillation, and the residue was separated by column chromatography to obtain a pale yellow solid 4. 1 H NMR(600 MHz, Chloroform-d) δ 9.55 (s, 1H), 8.61 (s, 1H), 8.36 (t,J = 5.7 Hz, 1H), 7.55 (d, J = 5.3 Hz, 1H), 7.49 (dd, J = 7.8, 1.6 Hz, 1H),7.45–7.43 (m, 1H), 7.35 (d, J = 5.3 Hz, 1H), 7.33–7.27 (m, 2H), 3.25 (q, J =5.0, 3.8 Hz, 6H), 3.21 (s, 2H), 2.70 (t, J = 4.9 Hz, 4H), 1.88 (dt, J = 13.4,6.7 Hz, 1H), 0.98 (d, J = 6.7 Hz, 6H). ESI-MS calculated for [M+H]+:532.1450, found 532.1457. Example 5: Preparation of Compound 5

[0044] N -Cyclopropyl-3-((4-(2-oxo-2-((2-oxo-2) H Synthesis of 2-chromene-3-yl)amino)ethyl)piperazine-1-yl)sulfonyl)thiophene-2-carboxamide:

[0045] In a clean 50 mL flask, add D (1.0 mmol), 2-(7-azabenzotriazole)- N,N N,N'-Tetramethylurea hexafluorophosphate (1.0 mmol) and 2,4,6-trimethylpyridine (1.0 mmol) were dissolved in 5 mL of [a solution / concentrate]. N,NIn dimethylformamide, the mixture was stirred at RT for 30 minutes, followed by the addition of 2,4,6-trimethylpyridine (2.0 mmol) and cyclopropylamine (2.0 mmol), and the reaction was allowed to proceed for 8–12 hours. The reaction was monitored by TLC. After completion, the mixture was extracted with ethyl acetate and saturated brine to remove impurities. N,N -Dimethylformamide, the resulting organic phase was subjected to vacuum distillation, and the residue was separated by column chromatography to obtain a pale yellow solid 5. 1 H NMR (600 MHz, Chloroform-d) δ 9.55 (s, 1H), 8.61 (s, 1H), 8.31 (d, J= 3.9 Hz, 1H), 7.55 (d, J = 5.3 Hz, 1H), 7.50 (dd, J = 7.8, 1.5 Hz, 1H),7.46–7.43 (m, 1H), 7.34 (d, J = 5.3 Hz, 1H), 7.33–7.28 (m, 2H), 3.23 (s, 4H),3.21 (s, 2H), 2.95–2.93 (m, 1H), 2.70 (t, J = 4.9 Hz, 4H), 0.88–0.84 (m, 2H),0.64–0.60 (m, 2H). ESI-MS calculated for [M+H]+: 516.1137, found 516.1131. Example 6: Preparation of Compound 6

[0046] N -(2-oxo-2) H Synthesis of 2-(4-((2-(pyrrolidine-1-carbonyl))thiophene-3-yl)sulfonyl)piperazin-1-yl)acetamide:

[0047] In a clean 50 mL flask, add D (1.0 mmol), 2-(7-azabenzotriazole)- N,N N,N'-Tetramethylurea hexafluorophosphate (1.0 mmol) and 2,4,6-trimethylpyridine (1.0 mmol) were dissolved in 5 mL of [a solution / concentrate]. N,N In dimethylformamide, the mixture was stirred at RT for 30 minutes, followed by the addition of 2,4,6-trimethylpyridine (2.0 mmol) and pyrrole (2.0 mmol), and the reaction was allowed to proceed for 8–12 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate and saturated brine to remove impurities. N,N-Dimethylformamide, the resulting organic phase was subjected to vacuum distillation, and the residue was separated by column chromatography to obtain a pale yellow solid 6. 1 H NMR (600 MHz, Chloroform- d ) δ 9.62 (s, 1H), 8.62 (s, 1H), 7.49 (dd, J = 7.7, 1.6 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.22 (d, J = 5.2 Hz, 1H), 3.60 (t, J =6.9 Hz, 2H), 3.33 (s, 4H), 3.28 (t, J = 6.7 Hz, 2H), 3.19 (s, 2H), 2.68 (t, J =4.9 Hz, 4H), 1.98 – 1.86 (m, 4H). ESI-MS calculated for [M+H]+: 530.1294, found 530.1291. Example 7: Preparation of Compound 7

[0048] Synthesis of 2-(4-((2-(morpholin-4-carbonyl)thiophene-3-yl)sulfonyl)piperazin-1-yl)-N-(2-carbonyl-2H-chromene-3-yl)acetamide:

[0049] In a clean 50 mL flask, add D (1.0 mmol), 2-(7-azabenzotriazole)- N,N N,N'-Tetramethylurea hexafluorophosphate (1.0 mmol) and 2,4,6-trimethylpyridine (1.0 mmol) were dissolved in 5 mL of [a solution / concentrate]. N,N In dimethylformamide, the mixture was stirred at RT for 30 minutes, followed by the addition of 2,4,6-trimethylpyridine (2.0 mmol) and morpholine (2.0 mmol), and the reaction was allowed to proceed for 8–12 hours. The reaction was monitored by TLC. After completion, the mixture was extracted with ethyl acetate and saturated brine to remove impurities. N,N -Dimethylformamide, the resulting organic phase was subjected to vacuum distillation, and the residue was separated by column chromatography to obtain a pale yellow solid 7. 1H NMR(600 MHz, Chloroform-d)δ9.63 (s, 1H), 8.63 (s, 1H), 7.51–7.48(m, 2H), 7.45–7.42 (m, 1H), 7.33–7.27 (m, 2H), 7.23 (d, J = 5.1 Hz, ESI-MS calculated for [M+H]+:546.1243, found 546.1248. Example 8: Preparation of Compound 8

[0050] N -(2-carbonyl-2 H Synthesis of (-chromene-3-yl)-2-(4-((2-(piperidin-1-carbonyl)thiophene-3-yl)sulfonyl)piperazin-1-yl)acetamide:

[0051] In a clean 50 mL flask, add D (1.0 mmol), 2-(7-azabenzotriazole)- N,N N,N'-Tetramethylurea hexafluorophosphate (1.0 mmol) and 2,4,6-trimethylpyridine (1.0 mmol) were dissolved in 5 mL of [a solution / concentrate]. N,N In dimethylformamide, the mixture was stirred at RT for 30 minutes, followed by the addition of 2,4,6-trimethylpyridine (2.0 mmol) and piperidine (2.0 mmol), and the reaction was allowed to proceed for 8–12 hours. The reaction was monitored by TLC. After completion, the mixture was extracted with ethyl acetate and saturated brine to remove impurities. N,N -Dimethylformamide, the resulting organic phase was subjected to vacuum distillation, and the residue was separated by column chromatography to obtain a pale yellow solid 8. 1 H NMR (600 MHz, Chloroform- d ) δ 9.64 (s, 1H), 8.63 (s, 1H), 7.50 (dd, J = 7.8, 1.5 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.33 – 7.27 (m, 2H), 7.21 (d, J= 5.2Hz, 1H), 3.69 (s, 2H), 3.34 (s, 4H), 3.22 (t, J = 5.6 Hz, 2H), 3.20 (s, 2H), 2.69 (t, J = 4.9 Hz, 4H), 1.65 (q, J = 3.0 Hz, 5H). ESI-MS calculated for [M+H]+:544.1450, found 544.1455. Example 9: Preparation of Compound 9

[0052] N -(2-oxo-2) H Synthesis of (-chromene-3-yl)-2-(4-p-toluenesulfonylpiperazine-1-yl)acetamide:

[0053] In a clean 50 mL flask, add C (2.0 mmol). N,N - Diisopropylethylamine (6.0 mmol) was dissolved in 20 mL of dichloromethane, and p-toluenesulfonyl chloride (2.0 mmol) was added under ice bath conditions. The ice bath was then removed, and the reaction was allowed to proceed at room temperature for 2–4 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was separated by column chromatography to obtain a pale yellow solid 9. 1 H NMR(600 MHz, Chloroform-d)δ9.54 (s, 1H), 8.64 (s, 1H), 7.66 (d, J= 8.2 Hz, 2H), 7.50 (dd, J = 7.7, 1.5 Hz, 1H), 7.46–7.42 (m, 1H), 7.37 (d, J= 7.8 Hz, 2H), 7.32–7.28 (m, 2H), 3.20 (s, 2H), 3.15 (s, 4H), 2.70 (t, J =4.9 Hz, 4H), 2.47 (s, 3H). ESI-MS calculated for [M+H]+: 441.1358, found441.1354. Example 10: Preparation of Compound 10

[0054] N -(2-oxo-2) HSynthesis of 1-chromene-3-yl)-2-(4-((trifluoromethyl)sulfonyl)piperazin-1-yl)acetamide:

[0055] In a clean 50 mL flask, add C (2.0 mmol). N,N Diisopropylethylamine (6.0 mmol) was dissolved in 20 mL of dichloromethane. Trifluoromethanesulfonyl chloride (2.0 mmol) was added under ice bath conditions. The ice bath was then removed, and the reaction was allowed to proceed at room temperature for 2–4 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was separated by column chromatography to obtain a pale yellow solid, 10. 1 H NMR (600 MHz, Chloroform-d) δ 9.72 (s, 1H), 8.66 (s, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 1H), 7.48–7.45 (m, 1H), 7.36–7.30 (m, 2H), 3.66 (s,5H), 3.28 (s, 2H), 2.74 (s, 4H). ESI-MS calculated for [M+H]+: 419.0763, found 419.0768. Example 11: Preparation of Compound 11

[0056] N -(2-oxo-2) H Synthesis of 1-chromene-3-yl)-2-(4-(thiophene-3-sulfonyl))piperazin-1-yl)acetamide:

[0057] In a clean 50 mL flask, add C (2.0 mmol). N,N Diisopropylethylamine (6.0 mmol) was dissolved in 20 mL of dichloromethane. 3-Thiophenesulfonyl chloride (2.0 mmol) was added under ice bath conditions. The ice bath was then removed, and the reaction was allowed to proceed at room temperature for 2–4 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was separated by column chromatography to obtain a pale yellow solid, 11. 1H NMR (600 MHz, Chloroform-d) δ 9.59 (s, 1H), 8.64 (s, 1H), 7.94 (dd, J = 3.0, 1.4 Hz, 1H), 7.53–7.49 (m, 2H), 7.46–7.43 (m, 1H), 7.33–7.29(m, 3H), 3.22 (d, J = 1.4 Hz, 3H), 2.73 (t, J = 4.9 Hz, 4H). ESI-MScalculated for [M+H]+: 433.0766, found 433.0768. Example 12: Preparation of Compound 12

[0058] 2-(4-(cyclopropylsulfonyl)piperazin-1-yl)- N -(2-carbonyl-2 H Synthesis of 3-chromene-3-yl)acetamide:

[0059] In a clean 50 mL flask, add C (2.0 mmol). N,N - Diisopropylethylamine (6.0 mmol) was dissolved in 20 mL of dichloromethane, and cyclopropanesulfonyl chloride (2.0 mmol) was added under ice bath conditions. The ice bath was then removed, and the reaction was allowed to proceed at room temperature for 2–4 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was separated by column chromatography to obtain a pale yellow solid 12. 1 H NMR (600 MHz, Chloroform-d) δ 9.83 (s, 1H), 8.68 (s, 1H), 7.53 (dd, J = 7.7, 1.6 Hz, 1H), 7.48–7.44 (m, 1H), 7.36–7.30 (m, 2H), 3.45 (t, J =4.7 Hz, 4H), 2.74 (t, J = 4.8 Hz, 4H), 2.35–2.29 (m, 1H), 1.20 (dd, J = 4.8,2.2 Hz, 2H). ESI-MS calculated for [M+H]+: 391.1202, found 391.1205. Example 13: Preparation of Compound 13

[0060] Methyl 3-((4-(2-carbonyl-2-((2-carbonyl-2) H Synthesis of 2-chromene-3-yl)amino)ethyl)-1,4-diazo-heptane-1-yl)sulfonyl)thiophene-2-carboxylic acid ester: Step 1: Synthesis of 4-((2-(methoxycarbonyl)thiophen-3-yl)sulfonyl)-periperazine-1-carboxylic acid tert-butyl ester In a clean 50 mL flask, add 5.0 mmol of 1-Boc-piperazine. N,N Diisopropylethylamine (5.0 mmol) was dissolved in 20 mL of dichloromethane. Methyl 3-(chlorosulfonyl)thiophene-2-carboxylic acid (10.0 mmol) was added under ice bath conditions. The ice bath was then removed, and the reaction was allowed to proceed at room temperature for 2–4 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was separated by column chromatography to give a white solid E.

[0061] Step 2: Synthesis of methyl 3-((1,4-diazo-heptane-1-yl)sulfonyl)thiophene-2-carboxylic acid ester

[0062] In a clean 50 mL flask, under ice bath conditions, E (5.0 mmol) was dissolved in 30 mL of dichloromethane, followed by the addition of trifluoroacetic acid (50.0 mmol). The ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was complete, excess dichloromethane and trifluoroacetic acid were removed by vacuum distillation, and the solvent was recovered under reduced pressure to obtain a white powdery solid F.

[0063] Step 3: Methyl 3-((4-(2-carbonyl-2-((2-carbonyl-2) H Synthesis of 2-chromene-3-yl)amino)ethyl)-1,4-diazo-heptane-1-yl)sulfonyl)thiophene-2-carboxylic acid ester

[0064] In a clean 50 mL flask, under ice bath conditions, F (1.0 mmol) was dissolved in 10 mL of dichloromethane. Triethylamine (2.0 mmol) was then added, followed by A (1.2 mmol). The ice bath was removed, and the reaction was allowed to proceed at room temperature for 8–12 hours. The reaction was monitored by TLC. After completion, the mixture was extracted with ethyl acetate and saturated brine to remove impurities. N,N -Dimethylformamide, the resulting organic phase was subjected to vacuum distillation, and the residue was separated by column chromatography to obtain a white solid 13. 1H NMR(600 MHz, Chloroform-d) δ 9.97 (s, 1H), 8.67 (s, 1H), 7.52–7.49 (m, 2H), 7.47(dd, J = 5.4, 1.1 Hz, 1H), 7.45–7.43 (m, 1H), 7.33–7.28 (m, 2H), 3.92 (d, J =1.2 Hz, 3H), 3.71 (dd, J = 6.6, 3.2 Hz, 2H), 3.63 (t, J = 6.5 Hz, 2H), 3.34(s, 2H), 2.93–2.89 (m, 5H), 2.06–2.00 (m, 2H). ESI-MS calculated for [M+H]+:505.0977, found 505.0972. Example 14: Preparation of Compound 14

[0065] 3-((4-((2-oxo-2) H Synthesis of methyl thiophene-2-carboxylic acid ester: (-chromene-3-yl)carbamoyl)piperazin-1-yl)sulfonyl)thiophene-2-carboxylic acid

[0066] In a clean 50 mL flask, under ice bath conditions, triphosgene (0.4 mmol) was dissolved in dry dichloromethane (10 mL), and then 3-amino-2H-chromene-2-one (1.0 mmol) was added. After the addition was complete, half an equivalent of the solution was added. N,N Add 1.0 mmol of diisopropylethylamine and stir for 30-60 minutes in an ice bath. Then add methyl 3-(piperazine-1-sulfonyl)thiophene-2-carboxylate (1.2 mmol), followed by the remaining half. N,N - Diisopropylethylamine (1.0 mmol) was reacted for 2-8 hours. The reaction was detected by TLC. After the reaction was completed, excess solvent was removed by vacuum distillation. The residue was separated by column chromatography to obtain white solid 14. 1H NMR (600 MHz, Chloroform-d) δ 8.39 (s, 1H), 7.52 (d, J = 5.3 Hz, 1H), 7.49 (d, J = 5.3 Hz, 1H), 7.48–7.46 (m, 2H), 7.41(t, J = 7.9 Hz, 1H), 7.33–7.28 (m, 2H), 3.93 (s, 3H), 3.62 (t, J = 5.1 Hz,5H), 3.43 (t, J = 5.1 Hz, 5H). ESI-MS calculated for [M+H]+: 477.0664, found477.0668. Example 15: Preparation of Compound 15

[0067]

[0068] Step 1: 3-Chloro- N -(2-carbonyl-2 H Synthesis of 3-chromene-3-yl)propionamide In a clean 100 mL flask, 2.0 mmol of 3-amino-2H-chromen-2-one was dissolved in 10 mL of dichloromethane. Triethylamine (4.0 mmol) was added under an ice bath at 0 °C, followed by the slow addition of 4.0 mmol of 3-chloropropionyl chloride. After removing the ice bath, the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, excess solvent was removed by vacuum distillation, and the resulting system was separated by column chromatography to give a white solid G.

[0069] Step 2: Methyl 3-((4-(3-carbonyl-3-((2-carbonyl-2) H Synthesis of 2-chromene-3-yl)amino)propyl)piperazine-1-yl)sulfonyl)thiophene-2-carboxylic acid ester

[0070] In a clean 50 mL flask, under ice bath conditions, methyl 3-(chlorosulfonyl)thiophene-2-carboxylic acid (1.0 mmol) was dissolved in 10 mL of [a solution / concentrate]. Figure 1 - Dimethylformamide, to which... Figure 2 -Diisopropylethylamine (2.0 mmol), followed by G (1.2 mmol), was added. The reaction was carried out at room temperature for 8-12 hours, and the reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate and saturated brine to remove impurities. Figure 3-Dimethylformamide, the resulting organic phase was subjected to vacuum distillation, and the residue was separated by column chromatography to obtain a white solid 15. 1 H NMR(600 MHz, Chloroform-d) δ 9.71 (s, 1H), 8.65(s, 1H), 7.52 (d, J = 5.2 Hz, 1H), 7.50 (dd, J = 7.8, 1.5 Hz, 1H), 7.47 (d, J= 5.3 Hz, 1H), 7.46–7.42 (m, 1H), 7.34–7.28 (m, 2H), 3.92 (s, 3H), 3.54–3.43(m, 4H), 3.24 (s, 2H), 2.72 (s, 4H). ESI-MS calculated for [M+H]+: 505.0977, found 505.0975. Example 16: Preparation of Compound 16

[0071] 3-((4-(2-oxo-2-((2-oxo-2) H Synthesis of 2-chromene-3-yl)amino)ethyl)piperazine-1-yl)sulfonyl)thiophene-2-carboxylic acid:

[0072] In a clean 50 mL flask, compound 1 (1.0 mmol) was dissolved in 10 mL of tetrahydrofuran / water (1:1) solution, and lithium hydroxide (10.0 mmol) was added. The reaction was carried out at room temperature for 20 minutes, and the reaction was detected by TLC. After the reaction was completed, the reaction system was subjected to vacuum distillation to remove water and organic phase. The residue was separated by column chromatography to obtain white solid 16. 1 H NMR(600 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.55 (s, 1H), 7.72 (d, J =7.7 Hz, 1H), 7.69 (s, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 8.2 Hz,1H), 7.33 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 5.1 Hz, 1H), 3.24 (s, 3H), 2.61(s, 2H). ESI-MS calculated for [M+H]+: 477.0664, found 477.0668. Example 17: Preparation of Compound 17

[0073] 3-((4-(2-oxo-2-((2-oxo-2) H Synthesis of propyl 2-thiophene-2-carboxylate: (-chromene-3-yl)amino)ethyl)piperazine-1-yl)sulfonyl)thiophene-2-carboxylate

[0074] In a clean 50 mL flask, compound 17 (1.0 mmol) and n-propanol (3.0 mmol) were added to 2 mL of concentrated sulfuric acid solution and refluxed overnight at 80 °C. The reaction was monitored by TLC. After the reaction was complete, the reaction system was slowly added dropwise to ice water, and then saturated sodium bicarbonate solution was added to adjust the pH to 6-8. Finally, the mixture was extracted with ethyl acetate and saturated brine. The resulting organic phase was subjected to vacuum distillation, and the residue was separated by column chromatography to obtain a white solid, 17. 1 H NMR (600MHz, Chloroform- d ) δ 9.71 (s, 1H), 8.65 (s, 1H), 7.52 – 7.49 (m, 2H), 7.46 –7.42 (m, 2H), 7.33 – 7.28 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.49 (s, 4H), 3.48(s, 2H), 3.21 (s, 2H), 2.69 (t, J = 4.9 Hz, 4H), 1.39 (t, J = 7.1 Hz, 3H). ESI-MScalculated for [M+H]+: 519.1134, found 519.1139. Example 18: Preparation of Compound 18

[0075] 3-((4-(2-oxo-2-((2-oxo-2) H Synthesis of isobutyl 2-thiophene-2-carboxylic acid: (-chromene-3-yl)amino)ethyl)piperazine-1-yl)sulfonyl)thiophene-2-carboxylic acid

[0076] In a clean 50 mL flask, compound 17 (1.0 mmol) was added. - Dicyclohexylcarboimide (2.0 mmol) and 4-dimethylaminopyridine (0.15 mmol) were added to 5 mL of dichloromethane and stirred for 30 minutes. Then, isobutanol (3.0 mmol) was added and stirred overnight at room temperature. The reaction was detected by TLC. After the reaction was completed, the resulting organic phase was distilled under reduced pressure. The residue was separated by column chromatography to obtain a white solid 18. 1 H NMR (600 MHz, Chloroform- d ) δ 9.71 (s, 1H), 8.66 (s, 1H), 7.53 – 7.48 (m, 2H), 7.47 – 7.42(m, 2H), 7.34 – 7.28 (m, 2H), 4.12 (q, J = 7.1 Hz, 3H), 3.22 (s, 2H), 2.70 (t, J = 4.9 Hz, 4H), 2.04 (s, 4H), 1.38 (d, J = 6.2 Hz, 7H). ESI-MS calculated for [M+H]+: 533.1290, found 533.1297. Example 19: (1) Experimental procedure for HK-2 cell HR disease and drug administration model The experiment used HK-2 human renal tubular epithelial cells, which were resuscitated and cultured in DMEM / F12 medium containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin antibiotics. Culture in an incubator. When the cells reach 70%-80% confluence, digest them with 0.25% trypsin and passage them, then seed them into 96-well plates as needed for the experiment. Or 6-hole plate Cells were cultured for 24 hours to allow them to adhere. Before the experiment, the medium was replaced with serum-free DMEM / F12 and the cells were starved for 12 hours to synchronize the cell cycle.

[0077] The cell groups included Control, HR, HR+Drug, Solvent, OGD, and OGD+Drug groups (if an OGD model needed to be constructed simultaneously). Control group cells were cultured normally without hypoxia or oxygen-glucose deprivation treatment, and without drugs or with an equal volume of solvent; HR group cells were transferred to a hypoxic incubator. Cells were cultured for 6 hours (hypoxia time can be adjusted through preliminary experiments), then transferred back to a normal incubator for reoxygenation for 24 hours; OGD group cells were replaced with sugar-free DMEM medium and placed in a hypoxic incubator. After 4 hours of incubation, the culture medium was changed back to normal sugar-containing medium and transferred to a normal incubator for reoxygenation for 24 hours. Different concentrations of the target drug were added to the HR+Drug group and the OGD+Drug group at the beginning of reoxygenation. The Solvent group was given an equal amount of drug solvent (such as DMSO, with a final concentration of <0.1%) to eliminate the interference of solvent toxicity.

[0078] After reoxygenation, various assays were performed: Cell viability was assessed using the CCK-8 assay, with 10 μL of CCK-8 reagent added to each well and cultured for 4 hours. The absorbance at 450 nm was then measured using a microplate reader. Cytotoxicity was assessed using the LDH assay, collecting cell culture supernatant and measuring absorbance at 450 nm according to the kit instructions. Apoptosis was detected using the Annexin V-FITC / PI double staining assay, collecting cells, washing them with PBS, resuspending them in Binding Buffer, adding fluorescent dye, and incubating in the dark for 15 minutes. Apoptosis rate was then detected by flow cytometry. The concentrations of kidney injury markers such as NGAL and KIM-1 in the cell supernatant were detected using ELISA. Morphological observation involved fixing cells in 4% paraformaldehyde and observing morphological changes under a light microscope, or performing HE staining for detailed observation. Cell viability was calculated using the formula: Cell viability (%) = [(Experimental group OD value - Blank well OD value) / (Control group OD value - Blank well OD value)] × 100%.

[0079] (2) Measurement results The effects of different interventions on HK-2 cell viability after HR injury, and the results of screening for the most effective coumarin derivatives are as follows: Figure 4 As shown, compounds 6, 7, and 8 have low solubility in DMSO and do not meet the requirements for biological experiments.

[0080] HR intervention has a significant damaging effect on HK-2 cells: compared with the control group (normal conditions), the cell viability of the HR group was significantly reduced, indicating that HR (such as hypoxia-reoxygenation and other damaging interventions) can lead to a decrease in the viability of HK-2 cells.

[0081] Different HR treatments combined with coumarin derivatives have different effects on cell viability: HR+1 and HR+14 can enhance HK-2 cell viability to varying degrees, suggesting that these treatments have a certain protective or restorative effect on HR-induced cell damage; while other HR combined treatments (such as HR+2, HR+3, HR+9, etc.) did not significantly enhance cell viability, indicating that their protective effect against HR damage is not significant or has no effect.

[0082] In summary, HR can impair the viability of HK-2 cells, and different subsequent interventions show significant differences in their effects on reversing or improving this damage, with compound 1 showing the most significant effect.

[0083] like​ As shown, under a light microscope, the control group cells were oval and spindle-shaped with few protrusions and a high cell density. After HR treatment, significant cell damage was observed, with cells of varying sizes, pseudopodia, indistinct borders, an increased proportion of clear cells, fragmented and indistinct nuclei in some cells, and a significant decrease in the total cell count. After coumarin treatment, cell morphology recovered somewhat; compared to the HR group, the cells and nuclei had more regular edges, and cell growth rate recovered. HR+1 showed the best effect.

[0084] Example 20: (1) Animal (mouse renal ischemia-reperfusion HR) control, disease and drug administration model experimental procedures The experiment used 6-8 week old C57BL / 6 mice, half male and half female, weighing 20-25g, which were acclimatized for one week before the experiment began. First, the mice were divided into groups of 6-8 mice each, including a Control group, a Sham group, a HR group, and an HR+Drug group. Mice in the Control group received no treatment and were fed a standard diet. Mice in the Sham group underwent the same surgical procedure as the HR group, but the renal arteries were not clamped; the kidneys were exposed and then sutured. Mice in the HR group underwent bilateral renal artery clamping to establish an ischemia-reperfusion model. The HR+Drug group received coumarin 1 immediately after surgery, three times daily. Samples were collected after 3 days for observation (low, medium, and high doses: L: 5mg / kg; M: 25mg / kg; H: 50mg / kg). The Sham and HR groups received an equal volume of physiological saline or drug solvent (e.g., DMSO, final concentration <0.1%).

[0085] During the modeling procedure, mice were first anesthetized by intraperitoneal injection of 1% sodium pentobarbital (50 mg / kg). After the corneal reflex disappeared and the muscles relaxed, the mice were fixed prone on a 37°C constant-temperature operating table. The back was shaved, and the surgical area was disinfected alternately with 75% alcohol and povidone-iodine. A sterile drape was applied, and a 1.5 cm incision was made along the midline of the back to separate the subcutaneous tissue and muscles, exposing both kidneys. Both renal arteries were clamped with non-invasive arterial clamps. Successful ischemia was confirmed when the kidneys turned pale. Ischemia was maintained for 30-45 minutes, and the arterial clamps were released. The kidneys quickly returned to a dark red color, indicating successful reperfusion. The muscles and skin were then sutured layer by layer. The incision was disinfected with povidone-iodine, and the mice were placed in a warm environment for recovery. Postoperatively, the mice were allowed free access to food and water, and their mental state, urine output, and incision site for infection were closely monitored for 24 hours.

[0086] Mice were anesthetized again by intraperitoneal injection 24, 48, or 72 hours after modeling (depending on the experimental design). Blood was then collected from the eyeballs to separate serum for detecting renal function indicators such as serum creatinine and blood urea nitrogen. Mice were then euthanized by cervical dislocation, and both kidneys were quickly removed. The renal capsule was removed, and one kidney was fixed in 4% paraformaldehyde for 24 hours, followed by dehydration, paraffin embedding, and 5μm sectioning for HE staining to observe renal tubular morphology and TUNEL staining to detect apoptosis. The other kidney was stored at -80°C for Western blot detection of the expression of inflammatory factors (such as IL-6 and TNF-α) or apoptosis-related proteins (such as Caspase-3 and Bcl-2).

[0087] (2) Measurement results from ​ It is evident that Sham, as a normal control, had intact tissue structure, normal morphology of renal tubules and glomeruli, and no obvious damage; IRI (ischemia-reperfusion injury group): renal tubules showed obvious dilation and deformation, and disordered cell structure, with the most significant damage; IRI+1(L) (low-dose intervention group): there was still a lot of renal tubular damage, but it was reduced compared to the IRI group; IRI+1(M) (medium-dose intervention group): the damage was further reduced, and the tissue structure was relatively closer to normal; IRI+1(H) (high-dose intervention group): the damage improvement was the most obvious, and it was the intervention group closest to the Sham group.

[0088] Kidney function Scr test results as follows ​ As shown, serum creatinine levels decreased after treatment with high concentrations of compound 1, indicating a significant difference.

[0089] Conclusion: This invention successfully synthesized a novel class of 3-aminocoumarin derivatives. These compounds exhibited excellent therapeutic activity in an acute kidney injury (AKI) model: they significantly repaired kidney tissue damage under pathological conditions, promoted the restoration of damaged renal tubular epithelial cell morphology to a normal phenotype, effectively enhanced the survival ability of damaged kidney cells, and improved cell function; simultaneously, they significantly downregulated the levels of renal function impairment markers such as serum creatinine (Scr), suggesting their effective ability to improve renal function. These compounds provide new drug candidates for the treatment of acute kidney injury and have significant clinical development value and application potential.

[0090] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A coumarin restructured compound, having a structural formula as shown in formula (I): ###0001### wherein, n = 0, 1 or 2, m = 1 or 2; R is a sulfonyl group substituted by C3-C8 alkyl, C3-C8 hydrocarbyl, C3-C8 cycloalkyl, C6-C8 aryl or C5-C8 heteroaryl containing N, O or S; the sulfonyl group substituted by C3-C8 alkyl, C3-C8 hydrocarbyl, C3-C8 cycloalkyl, C5-C8 heterocycloalkyl containing 1 or 2 heteroatoms optionally selected from N, O or S, C6-C8 aryl or C5-C8 heteroaryl containing 1 heteroatom selected from N, O or S is substituted by optional halogen, C1-C6 alkyl, C1-C6 carboxyl, C0-C6 alkyl-hydroxyl, C0-C6 alkyl-NH2-, C2-C6 ester, C2-C6 amide. wherein 3. The coumarin restructured compound of claim 1 or 2, wherein R is selected from: ###0003### 2. The coumarin-modified compound of claim 1, wherein, R is trifluoromethanesulfonyl, trichloromethanesulfonyl, fluorothiophenesulfonyl, chlorothiophenesulfonyl, p-toluenesulfonyl, m-toluenesulfonyl, o-toluenesulfonyl or ; said R1is C1-C6alkyl-O-, C3-C8cycloalkyl-O-, C3-C8cycloalkyl-NH-, C5-C8heterocycloalkyl containing 1 or 2 heteroatoms optionally selected from N, O or S or C1-C6alkyl-NH-.

4. The coumarin restructured compound of any one of claims 1-3, which is selected from: ###0004### 。 5. An intermediate compound for preparing the coumarin restructured compound, having a structural formula as shown in formula II: ###0005### wherein, n = 0, 1 or 2, m = 1 or 2. 。 6. A method for preparing the intermediate compound of claim 5, comprising: ###0006### wherein, the number of carbon atoms n = 0, 1 or 2, the number of m = 1 or 2. wherein 7. A method for preparing the compound of any one of claims 1-4, having a reaction formula as shown in formula III: ###0007### wherein, R is trifluoromethanesulfonyl, trichloromethanesulfonyl, fluorothiophenesulfonyl, chlorothiophenesulfonyl, p-toluenesulfonyl, m-toluenesulfonyl or o-toluenesulfonyl; or, 8. The method of claim 7, comprising: ###0008### wherein, 3-amino-2H-chromen-2-one is used as a starting material, a series of reactions of condensation, substitution and / or hydrolysis are carried out in an organic solvent at 0-80 °C, and a novel 3-amino coumarin restructured derivative is synthesized in 2-24 hours. 。 9. A pharmaceutical composition comprising an effective amount of the coumarin restructured compound of any one of claims 1-4 and a pharmaceutically acceptable excipient.

10. Use of the coumarin restructured compound of any one of claims 1-4 or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating acute kidney injury. ​ ； ​ 。 ​ ； ​ R is ; said R1is C1-C6alkyl-O-, C3-C8cycloalkyl-O-, C3-C8cycloalkyl-NH-, C5-C8heterocycloalkyl containing 1 or 2 heteroatoms optionally selected from N, O or S or C1-C6alkyl-NH-. ​ ​ ​ ​ ​

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