A glycyrrhetinic acid derivative, pharmaceutical composition and application thereof

Abstract

The application provides a glycyrrhetinic acid derivative, a pharmaceutical composition and application thereof, relates to the technical field of medicinal chemistry, and the main skeleton of the glycyrrhetinic acid derivative prepared by the application is glycyrrhetinic acid with a urea group; the 3th position, the 11th position, the 18th position and the 30th position of the glycyrrhetinic acid are modified, so that the glycyrrhetinic acid derivative has nanomolar level inhibitory activity on soluble epoxide hydrolase. Different urea group substituents are introduced into the 30th position on the basis of 18alpha / 18beta-glycyrrhetinic acid, and the activity difference between different substituents is small, but when different urea group substituents are connected to the 20th position of 18alpha / 18beta-glycyrrhetinic acid, the inhibitory effect of the glycyrrhetinic acid derivative on soluble epoxide hydrolase is greatly reduced. The glycyrrhetinic acid derivative prepared by the application has high inhibitory effect on soluble epoxide hydrolase, so that the inhibitory effect on inflammation can be realized by inhibiting soluble epoxide hydrolase, and the glycyrrhetinic acid derivative has good application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and in particular to a glycyrrhetinic acid derivative, a pharmaceutical composition, and its application. Background Technology

[0002] Inflammation is an evolutionarily conserved, tightly regulated protective mechanism that includes immune, vascular, and cellular biochemical responses. Normal inflammatory responses are time-limited and generally beneficial to the host. However, long-term, chronic inflammation can continuously damage human organs and tissues, and may even lead to cancer, threatening human life and health.

[0003] Licorice is a traditional Chinese herbal medicine containing various bioactive natural compounds such as glycyrrhizic acid (GL) and glycyrrhetinic acid (GA). The 3β and 18β stereoconfigurations are the main products (Formulas 1-2), exhibiting anti-inflammatory, antiviral, hepatoprotective, and antitumor effects. Glycyrrhetinic acid is the triterpenoid aglycone of the natural product glycyrrhizic acid, abundant in licorice roots. Glycyrrhizic acid exerts its anti-inflammatory effect by inhibiting the production of reactive oxygen species (ROS) by neutrophils and can also promote the production of interleukin (IL)-10 by dendritic cells in the liver of hepatitis-infected mice. In addition, glycyrrhizic acid reduces the expression levels of iNOS, TNF-α, IL-1β and IL-6 by regulating the p38 mitogen-activated protein kinase (p38-MAPK) and c-Jun N-terminal kinase (p-JNK) signaling pathways in brain vascular cells, and by inhibiting the p38-MAPK, p-JNK and NF-κB signaling pathways in lung cells, thereby preventing oxidative stress and alleviating inflammation. Glycyrrhetinic acid is the main bioactive hydrolysis product of glycyrrhizic acid and can be used to treat various inflammatory diseases, including hepatitis. Studies have shown that glycyrrhetinic acid can significantly inhibit the production of nitric oxide (NO), prostaglandin E2 (PGE2), and reactive oxygen species (ROS) induced by LPS (lipopolysaccharides), and reduce the protein and mRNA (messenger RNA) levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in macrophages induced by LPS. Glycyrrhetinic acid may also exert its anti-inflammatory effects by inhibiting the production of excess NO, PGE2, and ROS, as well as inhibiting the activity of NF-kappa B and PI3K. Although studies have demonstrated that glycyrrhetinic acid has multiple mechanisms of action in anti-inflammation, it suffers from limitations such as unclear target, low activity, and poor water solubility, making further rational design and improvement of its drug formulation difficult.

[0004]

[0005] Soluble epoxide hydrolase (sEH) is an important hydrolytic enzyme in mammals. Recent studies have revealed its crucial role in the development of inflammation in humans, classifying it as a key enzyme regulating inflammation. SEH catalyzes the hydrolysis of arachidonic acid's lipid intermediate, epioxyeicosatrienoic acids (EETs), via the cytochrome P450 enzyme system (CYP450) cyclooxygenase pathway, converting EETs into dihydroxyeicosatrienoic acid. Endogenous EETs (ethyl acetate-containing acids, DHETs) are derived from arachidonic acid (AA) via cytochrome P450 oxidation. They are important signaling molecules in organisms, regulating ion transport and gene expression, vasodilation, and anti-inflammation. In animals, EETs are degraded through various pathways, with sEH (saturated EET-H) metabolism of EETs into DHETs being the most significant, leading to decreased EET concentration and physiological activity. Numerous studies have shown that inhibiting sEH to stabilize EETs can significantly reduce inflammation and pain; therefore, sEH inhibitors are an effective treatment for various inflammatory diseases.

[0006] To date, AR9281, GSK2256294, and EC5026 have entered clinical trials, but no sEH inhibitor drugs are currently on the market. Numerous compounds in natural products have also shown inhibitory effects on sEH, such as natural ureas, triterpenoids, flavonoids, and phenylpropionic acid. Unfortunately, many compounds reported as sEH inhibitors have IC50 values ​​at the micromolar level, which are not valuable for further preclinical studies.

[0007] Therefore, there is an urgent need for novel skeletal soluble epoxide hydrolase inhibitory compounds with IC50 values ​​in the nanomolar range, targeting the anti-inflammatory target soluble epoxide hydrolase. Summary of the Invention

[0008] This invention provides a glycyrrhetinic acid derivative, a pharmaceutical composition, and its application, in order to address the problem of how to provide an inhibitor of a novel scaffold of soluble epoxide hydrolase to reduce its IC50 value for soluble epoxide hydrolase.

[0009] In a first aspect, embodiments of the present invention provide a glycyrrhetinic acid derivative, the glycyrrhetinic acid derivative having the following general structural formula (Formula I):

[0010]

[0011] In Formula I, Y is selected from any one of CH-OH or carbonyl groups;

[0012] X is selected from either carbonyl or methylene groups;

[0013] R 1 Selected from C 1-4 Alkyl, tetrahydropyranyl, N-(C 1-4 alkylformyl)piperidinyl, N-(halogenated C) 1-4 The R group is selected from any one of alkylformyl, piperidinyl, pyridinyl, or substituted phenyl (R-Ph); wherein R is selected from any one of methoxy, trifluoromethoxy, aminosulfonyl, or methanesulfonyl groups.

[0014] The 18-position hydrogen is selected from either the α-position or the β-position stereoconfiguration.

[0015] Preferably, the Y is selected as a CH-OH group.

[0016] Preferably, X is selected as a carbonyl group.

[0017] Preferably, the R 1 It is selected from any one of the following groups: isopropyl, isobutyl, tetrahydropyranyl, N-acetylpiperidinyl, N-propionylpiperidinyl, pyridyl, methoxyphenyl, difluoromethoxyphenyl, trifluoromethoxyphenyl, aminosulfonylphenyl, and methanesulfonylphenyl.

[0018] Preferably, Y is selected as a CH-OH group, X is selected from any one of carbonyl or methylene groups, and R... 1 It is selected from any one of the following groups: isopropyl, isobutyl, tetrahydropyranyl, N-acetylpiperidinyl, N-propionylpiperidinyl, 4-pyridinyl, 4-methoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-aminosulfonylphenyl, and 4-methanesulfonylphenyl.

[0019] Preferably, X is selected as a carbonyl group, and R 1 It is selected from any one of the following groups: isopropyl, tetrahydropyranyl, N-propionylpiperidinyl, 4-pyridyl, 4-methoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-aminosulfonylphenyl, and 4-methanesulfonylphenyl.

[0020] Preferably, the specific structural formula of the glycyrrhetinic acid derivative is as follows:

[0021]

[0022]

[0023] In a second aspect, embodiments of the present invention provide a glycyrrhetinic acid derivative pharmaceutical composition comprising at least one of the following: a glycyrrhetinic acid derivative as described in any one of the first aspects above, an isotope label thereof, a solvate, a polymorph thereof, a pharmaceutically acceptable salt thereof, or a prodrug compound thereof.

[0024] Thirdly, embodiments of the present invention provide a glycyrrhetinic acid derivative as described in the first aspect above, or a glycyrrhetinic acid derivative pharmaceutical composition as described in the second aspect above, for use in the preparation of anti-inflammatory drugs.

[0025] Preferably, the anti-inflammatory drug is used to inhibit inflammation caused by soluble epoxide hydrolase.

[0026] This invention has the following advantages:

[0027] (1) The main skeleton of the glycyrrhetinic acid derivative provided by the present invention is glycyrrhetinic acid with urea group. By modifying the 3, 11, 18 and 30 positions of glycyrrhetinic acid, it can have nanomolar level inhibitory activity against sEH enzyme.

[0028] (2) The glycyrrhetinic acid derivatives provided by the present invention are based on 18α-glycyrrhetinic acid or 18β-glycyrrhetinic acid, with different urea substituents introduced at the 30 position. The activity difference between different substituents is small, among which (tetrahydropyran-4-yl)methyl)urea and (pyridin-4-yl)methyl)urea have the best effects.

[0029] (3) The present invention provides a novel soluble epoxide hydrolase inhibitory compound by introducing the glycyrrhetinic acid skeleton described in general formula I. It has a good inhibition rate against soluble epoxide hydrolase, with an IC50 of about 3 nM.

[0030] (4) The glycyrrhetinic acid derivative in the embodiments of the present invention has a highly efficient inhibitory effect on soluble epoxide hydrolase, thereby inhibiting inflammation by inhibiting soluble epoxide hydrolase, and has good application prospects. Detailed Implementation

[0031] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0032] Specific experimental steps or conditions are not specified in the examples; they can be performed according to conventional experimental procedures or conditions described in the prior art. Reagents and other instruments used, unless otherwise specified, are all commercially available conventional reagents. All chemicals used in this invention are commercially available, and the nuclear magnetic resonance and mass spectrometry instruments used to determine the structures of the following compounds were provided by the Analysis and Testing Center of Beijing Institute of Technology.

[0033] The first aspect of this invention provides a glycyrrhetinic acid derivative having the following general structural formula (Formula I):

[0034]

[0035] In Formula I, Y is selected from any one of CH-OH or carbonyl groups;

[0036] X is selected from either carbonyl or methylene groups;

[0037] R 1 Selected from C 1-4 Alkyl, tetrahydropyranyl, N-(C 1-4 alkylformyl)piperidinyl, N-(halogenated C) 1-4 The R group is selected from any one of alkylformyl, piperidinyl, pyridinyl, or substituted phenyl (R-Ph); wherein R is selected from any one of methoxy, trifluoromethoxy, aminosulfonyl, or methanesulfonyl groups.

[0038] The 18th hydrogen atom is selected from either the α-position or the β-position stereoconfiguration;

[0039] Preferably, Y is selected as a CH-OH group with a β-position stereoconfiguration, and the hydrogen at position 18 is selected as having a β-position stereoconfiguration;

[0040] Preferably, Y is selected as a CH-OH group with a β-position stereoconfiguration, and the hydrogen at position 18 is selected as an α-position stereoconfiguration.

[0041] The above C 1-4 Alkyl groups represent straight-chain or branched saturated monovalent hydrocarbon groups having 1 to 4 carbon atoms. For example, C 1-4 Alkyl means a straight-chain or branched alkyl group having 1, 2, 3, or 4 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, or tert-butyl.

[0042] The above C 1-4 alkylformyl group is represented by RC (=O)-, where R is C 1-4 Alkyl group. The alkyl formyl group is, for example, acetyl, propionyl, butyryl, valeryl, or isobutyryl.

[0043] In this invention, the halogen refers to fluorine, chlorine, bromine, and / or iodine. Correspondingly, halogenation refers to fluorination, chlorination, bromination, and / or iodination. Within the scope of this invention, when an atom, residue, group, or part is halogenated, the atom at the halogenated position can be monosubstituted, disubstituted, or polysubstituted up to fully substituted by the halogen atom, for example, halogenating C. 1-4 Alkylformyl, halomethoxy, halomethanesulfonyl, such as trifluoroacetyl, trifluoromethoxy, difluoromethoxy, trifluoromethanesulfonyl.

[0044] A second aspect of the present invention provides a glycyrrhetinic acid derivative pharmaceutical composition comprising at least one of the glycyrrhetinic acid derivatives described in any one of the first aspects above, an isotope label thereof, a solvate, a polymorph thereof, a pharmaceutically acceptable salt thereof, or a prodrug compound thereof.

[0045] A third aspect of the present invention provides the use of a glycyrrhetinic acid derivative as described in any of the first aspects above, or a glycyrrhetinic acid derivative pharmaceutical composition as described in the second aspect above, in the preparation of an anti-inflammatory drug;

[0046] The anti-inflammatory drug is used to inhibit inflammation caused by soluble epoxide hydrolase.

[0047] This invention also provides a method for preventing and / or treating inflammation-related diseases, comprising administering to a patient a preventive or therapeutically effective amount of at least one of a compound of Formula I, its racemic, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt, its prodrug compound, or the pharmaceutical composition thereof.

[0048] In some alternative implementations, the patient is a mammal, preferably a human.

[0049] The pharmaceutical compositions in the embodiments of this invention also include any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption delay agents for pharmaceutically active substances, which are reagents and materials known in the art. The use of any conventional media or reagents in the pharmaceutical compositions is contemplated, except for any conventional media or reagents incompatible with the compound, and complementary compounds may also be added to the compositions.

[0050] In embodiments of the present invention, various pharmaceutically acceptable acids can form pharmaceutically acceptable salts on the basic nitrogen of the compound. The acid can be an inorganic or organic acid; the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, or phosphoric acid; the organic acid is acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, maleic acid, fumaric acid, malic acid, or citric acid.

[0051] The prodrug compounds in this specification are compounds that, although not disclosed in structure, are administered to the human body but are metabolized or converted into the compounds disclosed herein, and exert their pharmacological effects as active ingredients. Conventional methods for the preparation of prodrugs are described in *Design of Prodrugs* (H. Bundgaad, Elsevier, 1985).

[0052] The term "patient" refers to any animal, including mammals. In this embodiment of the invention, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates are preferred, with humans being the most preferred.

[0053] The therapeutically effective amount refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response, and includes one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder, or condition in individuals who are susceptible to disease, disorder, or symptom but have not yet experienced or developed the pathology or symptoms of the disease. (2) suppression of disease: for example, suppression of disease, disorder, or symptom in individuals who are experiencing or developing the pathology or symptoms of the disease (i.e., preventing further development of the pathology and / or symptoms). (3) relief of disease: for example, relief of disease, disorder, or symptom in individuals who are experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms).

[0054] To enable those skilled in the art to further understand the technical solution of the present invention, the following specific embodiments are used to further illustrate the glycyrrhetinic acid derivative, pharmaceutical composition and its application provided by the present invention.

[0055] The following is a brief description of the synthesis method of the compounds of the present invention. In the synthesis examples listed below, the synthesis of intermediates mainly involves Clemens reduction, acid-amine condensation, amide reduction, urea group construction, oxidation reaction, etc.

[0056] Specifically, the following provides methods for synthesizing representative compounds of the present invention.

[0057] Synthesis Example 1 - Synthesis of Compound C1:

[0058]

[0059] The synthetic route for compound 2 is as follows:

[0060]

[0061] 18β-Glycyrrhetinic acid (0.55 g, 1.17 mmol) was dissolved in 10 mL of 1,4-dioxane, and zinc powder (1.5 g, 22.9 mmol, 20 eq) was added. HCl (2.5 mL of 12 M concentrated hydrochloric acid + 5 mL of dioxane) was added dropwise under an ice-water bath. The reaction was completed within 5 h. The mixture was filtered through diatomaceous earth, washed and extracted with dichloromethane and saturated brine, and separated three times. The organic phase was collected and rotary evaporated. The mixture was recrystallized from ethyl acetate to give a white solid (compound 2) (0.24 g, 0.53 mmol, yield 55%).

[0062] HRMS(ESI)[MH] - m / z calcd for C 30 H 47 O3:455.3531; found:455.3542.

[0063] 1 H NMR(400MHz, Methanol-d4)δ5.27(t,J=3.7Hz,1H),3.15(dd,J=11.4,4.9Hz,1H),2.10–1.76(m,7H),1.62(m,7H),1.51–1.42(m,1H),1.41 –1.27(m,5H),1.15(d,J=16.1Hz,6H),1.07–0.95(m,10H),0.89(ddt,J=13.4,4.5,2.3Hz,1H),0.79(d,J=4.0Hz,6H),0.75(d,J=1.9Hz,1H)

[0064] The synthetic route for compound 3 is as follows:

[0065]

[0066] Compound 2 (0.5 g, 1.09 mmol) was dissolved in dry dichloromethane. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (HATU) (0.456 g, 1.199 mmol, 1.1 eq) and diisopropylethylamine (DIEA) (0.95 mL, 2.398 mmol, 2.2 eq) were added. After reacting for 20 min, 25% ammonia water (0.2 mL, 2.725 mmol, 2.5 eq) was added. The reaction was essentially complete after 4 h. The solution was washed three times with saturated ammonium chloride solution and purified by silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v) to give a white solid (compound 3) (0.359 g, 0.79 mmol, yield 72%). HRMS(ESI)[M+H] + m / zcalcd for C 30 H 50NO2:456.3836; found:456.3835.

[0067] 1H NMR (CDCl3, 400MHz) δ: 5.64 (s, 1H), 5.45 (s, 1H), 5.27 (t, J = 3.7Hz, 1H), 3.22 (dd, J = 10.9, 4.7Hz, 1H), 2.80 (s, 1H), 2.04–1.28 (m, 19H), 1.15 (d, J = 3. 5Hz, 6H), 1.00 (s, 3H), 0.98 (s, 1H), 0.95 (d, J=10.0Hz, 6H), 0.89 (ddd, J=1 4.4,5.0,2.8Hz,1H),0.80(d,J=5.0Hz,6H),0.74(dd,J=11.6,1.9Hz,1H).

[0068] The synthetic route for compound 4 is as follows:

[0069]

[0070] Compound 3 (0.225 g, 0.495 mmol) was dissolved in 10 mL of DME, and aluminum trichloride (0.52 g, 3.96 mmol, 8 eq) was added. Sodium borohydride (0.187 g, 4.95 mmol, 10 eq) was added in portions over 30 min under an ice-water bath. After reacting for 24 h, the reaction was quenched with water, and the pH was adjusted to 9 with 1 N sodium hydroxide. The mixture was extracted with dichloromethane and then subjected to column chromatography (first with mobile phase: dichloromethane / ethanol, 10 / 0.2 v / v, then dichloromethane / ethanol / ammonia, 10 / 0.2 / 0.1 v / v / v) to give a white solid (compound 4) (55 mg, 0.124 mmol, 25%).

[0071] HRMS(ESI)[M+H] + m / z calcd for C 30 H 50 NO2:442.4043; found:442.4036.

[0072] 1H NMR(Methanol-d4,400MHz)δ:5.30(t,J=3.6Hz,1H),3.15(dd,J=11.3,4.9Hz,1 H),3.05(d,J=13.1Hz,1H),2.86(d,J=13.1Hz,1H),2.08(td,J=13.6,4.4Hz,1H ),2.01–1.77(m,5H),1.70–1.47(m,8H),1.51–1.19(m,6H),1.18(s,3H),1.08– 0.96(m,13H),0.96–0.85(m,1H),0.89(s,3H),0.79(s,3H),0.83–0.72(m,1H).

[0073] The synthetic route for compound C1 is as follows:

[0074]

[0075] CDI (81 mg, 0.504 mmol, 2.4 eq) and aminomethyltetrahydropyran (0.07 mL, 0.57 mmol, 2.7 eq) were dissolved in anhydrous dichloromethane and reacted for 2–3 h. Then, compound 4 (100 mg, 0.21 mmol) was dissolved in anhydrous dichloromethane and added dropwise to the reaction mixture. After 24 h, the organic phase was washed three times with saturated ammonium chloride. The organic phase was collected and evaporated under vacuum. Silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v) gave a white solid 5 (compound C1) (32 mg, 0.055 mmol, yield 26%). Melting point: 149–152 °C.

[0076] HRMS(ESI)[M+H] + m / z calcd for C 37 H 63 N2O3:583.4833; found:583.4826.

[0077] 1H NMR(CDCl3,400MHz)δ:5.18(t,J=3.6Hz,1H),4.81(t,J=6.2Hz,1H),4.55(t,J=6.1Hz,1H ),3.97(ddd,J=11.7,4.6,1.8Hz,2H),3.36(td,J=11.8,2.0Hz,2H),3.21(dt,J=10.4,5. 0Hz,2H),3.16–3.01(m,3H),1.99–1.68(m,6H),1.66–1.57(m,6H),1.56–1.49(m,5H),1. 40–1.16(m,9H),1.13(s,3H),1.02–0.89(m,10H),0.86–0.79(m,9H),0.77–0.69(m,1H).

[0078] 13 C NMR(CDCl3,100MHz)δ:158.6,144.7,122.2,79.0,67.7,55.2,47.7,46.4,44.8,43.0,41.7,39.8,38.8,3 7.0,36.5,35.9,34.8,32.7,32.4,31.1,30.7,28.4,28.1,27.3,27.1,26.1,23.6,18.4,16.8,15.6,15.5

[0079] Synthesis Example 2 - Synthesis of Compound C2:

[0080]

[0081] The synthetic route for compound C2 is as follows:

[0082]

[0083] CDI (81 mg, 0.504 mmol, 2.4 eq) and isobutylamine (0.04 mL, 0.42 mmol, 2 eq) were dissolved in anhydrous dichloromethane and reacted for 2 h. Compound 4 (90 mg, 0.21 mmol) was dissolved in dichloromethane and added dropwise to the reaction solution. The reaction was allowed to proceed for 4–6 h until complete. The organic phase was washed three times with saturated ammonium chloride. The organic phase was collected and rotary evaporated under vacuum. Column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v) yielded a white solid 6 (compound C2) (27 mg, 0.0504 mmol, yield 24%). Melting point: 148–150 °C.

[0084] HRMS(ESI)[M+H] + m / z calcd for C 35 H61 N2O2:541.4728; found:541.4727.

[0085] 1H NMR(CDCl3,400MHz)δ:5.19(t,J=3.6Hz,1H),4.63(t,J=5.8Hz,1H),4.45(t,J= 6.0Hz,1H),3.27–3.09(m,3H),2.99(q,J=5.9,4.8Hz,2H),2.06–1.88(m,4H),1. 87–1.68(m,2H),1.67–1.37(m,12H),1.37–1.17(m,3H),1.14(s,3H),1.00(s,3 H),0.93(dd,J=15.2,7.7Hz,14H),0.84(s,6H),0.79(s,3H),0.77–0.69(m,1H).

[0086] 13C NMR(CDCl3,100MHz)δ:158.7,144.6,122.3,79.0,55.2,48.1,47.7,46.4,44.7,43.1,41.7,39.8,38.8,3 7.0,36.5,34.7,32.7,32.4,31.0,29.7,29.0,28.4,28.2,27.3,27.2,26.1,23.5,20.1,18.4,16.8,15.6

[0087] Synthesis Example 3 - Synthesis of Compound C3:

[0088]

[0089] The synthetic route for compound 7 is as follows:

[0090]

[0091] 18β-Glycyrrhetinic acid (2 g, 4.25 mM, 1 eq) was dissolved in 100 mL of dichloromethane. HATU (1.78 g, 4.675 mM, 1.1 eq) and DIEA (1.55 mL, 9.35 mM, 2.2 eq) were added to the reaction solution in sequence. The solution changed from turbid to clear. Then, ammonia water (0.82 mL, 10.63 mM, 2.5 eq) was added, and the reaction was allowed to proceed for 6-8 h until complete. The organic phase was washed three times with saturated ammonium chloride, collected, and rotary evaporated. Recrystallization from anhydrous methanol gave a white solid 7 (compound 7) (1.9 g, 4.08 mmol, yield 96%).

[0092] The synthetic route for compound 8 is as follows:

[0093]

[0094] Nickel chloride ethylene glycol dimethyl ether complex (80 mg, 0.364 mmol, 0.2 eq) and compound 7 (0.3 g, 0.639 mmol, 1.0 eq) were dissolved in 50 mL of dry toluene. The container was evacuated for 5 minutes and backfilled three times with argon gas. The mixture was then refluxed and placed in a preheated oil bath at 115 °C. After 10 minutes, benzyl silane (0.5 mL, 4.05 mmol, 6.3 eq) was added. The reaction changed from orange to black. The reaction was carried out in an oil bath at 115 °C for 24 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate and the pH was adjusted to 9 with 1 N NaOH. The reaction solvent was evaporated to dryness, and the mixture was extracted with ethyl acetate and water. The organic layer was filtered through diatomaceous earth and subjected to column chromatography (mobile phase: dichloromethane / ethanol / ammonia, 10 / 0.2 / 0.1 v / v) to give a white solid 8 (compound 8) (216 mg, 0.47 mmol, yield 74%).

[0095] HRMS(ESI)[M+H] + m / z calcd for C 30 H 50 NO2:456.3836; found:456.3843.

[0096] 1H NMR (MeOD, 400MHz) δ: 5.69 (s, 1H), 3.22 (dd, J = 11.0, 5.3Hz, 1H), 2.81–2.72 ( m,3H),2.32(s,1H),2.09–1.90(m,J=4.3Hz,2H),1.82(td,J=13.8,4.6Hz,1H ),1.69–1.62(m,4H),1.50–1.28(m,7H),1.36(s,3H),1.28–1.14(m,2H),1.1 2(m,4H),1.05–0.90(m,9H),0.84(d,J=29.5Hz,7H),0.69(d,J=11.5Hz,1H).

[0097] The synthetic route for compound C3 is as follows:

[0098]

[0099] CDI (120 mg, 0.74 mmol, 2.2 eq) and 4-aminomethyltetrahydropyran (0.06 mL, 0.5 mmol, 1.51 eq) were dissolved in dry dichloromethane and reacted for 2–3 h. Compound 8 (150 mg, 0.329 mmol) was dissolved in dichloromethane and added dropwise to the reaction mixture. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, and evaporated under vacuum. The resulting solution was then subjected to silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10:0.1 v / v) to give a white solid 9 (compound C3) (110 mg, 0.184 mmol, yield 56%). Melting point: 141–142 °C.

[0100] HRMS(ESI)[M+H] + m / z calcd for C 37 H 61 N2O4:597.4626; found:597.4625.

[0101] 1H NMR (CDCl3, 400MHz) δ: 5.52 (s, 1H), 4.69 (t, J = 6.0Hz, 1H), 4.43 (t, J = 6.3Hz, 1H), 3.89 (dd, J = 11.3, 4.4Hz ,2H),3.29(tt,J=11.8,2.6Hz,2H),3.19–2.98(m,5H),2.72(dt,J=13.6,3.6Hz,1H),2.24(s,1H),2.17(d d,J=14.1,4.5Hz,1H),1.99(td,J=13.6,4.4Hz,1H),1.81–1.63(m,2H),1.63–1.50(m,10H),1.37–1.29(m ,3H),1.29–1.27(s,3H),1.22–1.07(m,6H),1.05(s,6H),0.96–0.71(m,12H),0.62(d,J=11.4Hz,1H).13C NMR(CDCl3,100MHz)δ:200.4,170.4,158.5,128.3,78.8,67.7,61.9,55.0,46.7,46.2,45.4,44.3,43.4,41.1,39.2,3 9.2,37.2,35.9,34.9,32.7,32.2,31.1,30.6,29.7,28.6,28.3,28.1,27.3,26.6,26.4,23.6,18.7,17.5,16.4,15.6.

[0102] Synthesis Example 4 - Synthesis of Compound C4:

[0103]

[0104] The synthetic route for compound C4 is as follows:

[0105]

[0106] N,N′-carbonyldiimidazole CDI (81 mg, 0.504 mmol, 1.5 eq) and isobutylamine (0.04 mL, 0.42 mmol, 1.27 eq) were dissolved in anhydrous dichloromethane (DCM) and reacted for 2–3 h. Compound 8 (150 mg, 0.329 mmol) was dissolved in dichloromethane and added dropwise to the reaction mixture. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, and evaporated under vacuum. The resulting solution was then subjected to silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v) to give a white solid 10 (compound C4) (98 mg, 0.181 mmol, yield 55%). Melting point: 145–147 °C.

[0107] HRMS(ESI)[M+H] + m / z calcd for C 35 H 61 N2O2:555.4520; found:555.4518.

[0108] 1 H NMR (CDCl3, 400MHz) δ: 5.52 (s, 1H), 4.81 (d, J = 7.7Hz, 1H), 4.62 (s, 1H), 3.19–3.12 (m, 2H), 3.12 (d, J = 6.9Hz, 1H), 2.92 (t, J = 5.8Hz, 2H), 2. 72(dt,J=13.7,3.7Hz,1H),2.25(s,1H),2.15(dd,J=14.0,4.4Hz,1H),1.99(td,J=13.6,4.4Hz,1H),1.75(dt,J=14.0,7.0Hz,1H),1.66–1.5 3(m,3H),1.53(d,J=10.1Hz,3H),1.50–1.39(m,1H),1.36(d,J=11.2Hz,1H),1.29(s,3H),1.26(d,J=3.5Hz,1H),1.25–1.06(m,4H),1.05(s ,6H),0.93(d,J=4.5Hz,4H),0.91–0.83(m,1H),0.81(dd,J=15.2,6.7Hz,12H),0.74(d,J=15.9Hz,1H),0.73(s,3H),0.62(d,J=11.0Hz,1H).

[0109] 13C NMR (CDCl3, 100MHz) δ: 200.5, 170.5, 170.5, 158.8, 128.2, 78.8, 61.9, 55.0, 48.0, 46.7, 45.4, 44.2, 43.4, 41. 2,39.2,38.9,37.2,35.9,34.9,32.7,31.0,28.6,28.1,27.3,26.6,23.5,20.2,20.0,18.7,17.5,16.4,15.6.

[0110] Synthesis Example 5 - Synthesis of Compound C5:

[0111]

[0112] The synthetic route for compound C5 is as follows:

[0113]

[0114] Compound 8 (220 mg, 0.48 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane, and DIEA (0.16 mL, 0.96 mM, 2 eq) was added. The reaction system was placed in an ice-water bath at 0 °C. Triphosgene (43 mg, 0.144 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system through a constant pressure dropping funnel. After the addition was complete, p-trifluoromethoxybenzylamine (0.07 mL, 0.48 mM, 1 eq) was immediately added. The reaction was allowed to proceed for 30-60 min. The organic phase was washed three times with saturated brine, and the organic phase was collected and rotary evaporated. The solution was then passed through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v) to give a white solid 11 (compound C5) (150 mg, 0.223 mM, yield 46%). Melting point: 162-164 °C

[0115] HRMS(ESI)[M+H] + m / z calcd for C 39 H 56 F3N2O4:673.4187; found:673.4186.

[0116] 1H NMR (400MHz, Methanol-d4) δ7.40(d,J=8.6Hz,2H),7.21(d,J=7.7Hz,2H),5.65(s,1H),4.44–4.30(m,2H),3.48(dd,J= 13.6,5.8Hz,1H),3.19(dd,J=11.8,4.6Hz,1H),2.93(dd,J=13.7,4.8Hz,1H),2.77(dt,J=13.4,3.6Hz,1H),2.45(s,1H ),2.40(dd,J=13.6,4.3Hz,1H),2.17(td,J=13.6,4.4Hz,1H),1.89(td,J=13.6,4.5Hz,1H),1.80–1.44(m,9H),1.42(s ,3H),1.35–1.18(m,5H),1.16(s,6H),1.10–0.96(m,6H),0.92(s,3H),0.87(s,3H),0.82(s,3H),0.78(d,J=9.8Hz,1H).

[0117] 13 C NMR (100MHz, CDCl3) δ200.4,170.4,158.4,148.3,138.4,128.8,128.2,121.2,78.8,61.9,55.0,46.7,45.4,44.4,43.8,43 .3,41.0,39.2,39.2,37.1,35.8,34.8,32.7,32.2,31.1,28.6,28.2,28.1,27.3,26.6,26.4,23.5,18.7,17.5,16.4,15.6.

[0118] Synthesis Example 6 - Synthesis of Compound C6:

[0119]

[0120] The synthetic route for compound C6 is as follows:

[0121]

[0122] Compound 8 (280 mg, 0.62 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane, and DIEA (0.2 mL, 1.23 mM, 2 eq) was added. The reaction system was placed in an ice-water bath at 0 °C. Triphosgene (54 mg, 0.186 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system through a constant pressure dropping funnel. After the addition was complete, 4-aminomethylpropionylpiperidine (104 mg, 0.62 mM, 1 eq) was immediately added. The reaction was allowed to proceed for 30-60 min. The organic phase was washed three times with saturated brine, and the organic phase was collected and rotary evaporated. The solution was then passed through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.15 v / v) to give a white solid 12 (compound C6) (150 mg, 0.23 mM, yield 38%). Melting point: 174-176 °C

[0123] HRMS(ESI)[M+H] + m / z calcd for C 40 H 66 N3O4:652.5048; found:652.5058.

[0124] 1 H NMR (400MHz, Chloroform-d) δ5.52(s,1H),4.99(s,1H),4.77(d,J=6.0Hz,1H),4.52(d,J=13.2Hz,1H),3.79(d,J=13. 4Hz,1H),3.27(m,1H),3.15(dd,J=11.0,5.1Hz,2H),2.94(m,3H),2.72(dt,J=13.9,4.1Hz,1H),2.45(m,J=12.7,2.9Hz ,1H),2.33–2.19(m,4H),1.99(td,J=13.7,4.4Hz,1H),1.80–1.44(m,10H),1.42–1.31(m,3H),1.29(s,3H),1.25–1.10 (m,5H),1.09–1.01(m,10H),0.93(s,3H),0.87(m,2H),0.81(s,3H),0.77(s,3H),0.73(s,3H),0.62(d,J=12.1Hz,1H).

[0125] 13C NMR (100MHz, CDCl3) δ200.3,172.4,170.5,158.7,128.2,78.8,61.9,55.0,46.5,45.6,45.4,44.3,43.3,41.8,41.0,40.8,39.2, 37.1,37.0,35.9,35.0,32.7,32.2,31.3,30.4,29.7,28.7,28.3,28.1,27.3,26.6,26.6,26.5,23.6,18.7,17.5,16.4,15.6,9.7.

[0126] Synthesis Example 7 - Synthesis of Compound C7:

[0127]

[0128] The synthetic route for compound C7 is as follows:

[0129]

[0130] Compound 7 (250 mg, 0.55 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane, and DIEA (0.18 mL, 1.10 mM, 2 eq) was added. The reaction system was placed in an ice-water bath at 0 °C. Triphosgene (50 mg, 0.165 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system through a constant pressure dropping funnel. After the addition was complete, 4-pyridinemethylamine (0.06 mL, 0.55 mM, 1 eq) was immediately added. The reaction was allowed to proceed for 1–2 h. The organic phase was washed three times with saturated brine, collected, and rotary evaporated. The solution was then passed through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.2 v / v) to give a white solid 13 (compound C7) (180 mg, 0.31 mM, yield 55%). Melting point: 174.1–175.4 °C.

[0131] HRMS(ESI)[M+H] + m / z calcd for C 37 H 56 N3O3:590.4316; found:590.4315.

[0132] 1H NMR(400MHz,Chloroform-d)δ8.53(d,J=5.0Hz,2H),7.27(s,2H),5.55(s,1H),5.44(t,J=6.0Hz,1H),4.91–4.75(m,1H),4.40(d,J=6.0Hz,2 H),3.33(dd,J=13.6,6.5Hz,1H),3.21(dd,J=11.1,5.1Hz,1H),3.07(dd,J=13.6,5.9Hz,1H),2.76(dt,J=13.5,3.6Hz,1H),2.31(s,1H),2.24 (dd,J=14.1,4.6Hz,2H),2.04(td,J=13.6,4.3Hz,1H),1.81(td,J=13.5,4.4Hz,1H),1.59(m,5H),1.44–1.37(m,2H),1.35(s,3H),1.28(d,J= 16.1Hz,3H),1.22–1.13(m,2H),1.11(d,J=2.2Hz,6H),1.00(s,3H),0.95(s,2H),0.85(d,J=6.9Hz,6H),0.80(s,3H),0.68(d,J=11.3Hz,1H).

[0133] 13 C NMR (175MHz, CDCl3) δ200.4,170.6,158.4,149.1,128.2,122.5,78.7,61.9,55.0,46.6,45.4,44.4,43.3,40.8, 39.2,39.2,37.1,35.8,34.9,32.7,32.2,31.2,28.6,28.3,28.1,27.3,26.5,26.4,23.6,18.7,17.5,16.4,15.6.

[0134] Synthesis Example 8 - Synthesis of Compound C8:

[0135]

[0136] The synthetic route for intermediate 1 is as follows:

[0137]

[0138] Methylsulfonyl benzylamine (0.5 g, 2.7 mM, 1 eq) was dissolved in tetrahydrofuran and dichloromethane (v / v = 1:1) and placed in an ice-water bath. Triethylamine (0.32 mL, 1 eq) was added, and p-nitrophenyl chloroformate (0.54 g, 1 eq) was dissolved in tetrahydrofuran and dichloromethane (v / v = 1:1) and added dropwise to the reaction system. The addition time was controlled at about 30 min. After 1 h, the reaction was complete. The mixture was filtered with diatomaceous earth, and the original solvent was rotary evaporated. The mixture was extracted three times with dichloromethane and saturated brine. The organic phase was collected and rotary evaporated to give intermediate 1 (0.61 g, yield 65%).

[0139] The synthetic route for compound C8 is as follows:

[0140]

[0141] Compound 8 (140 mg, 0.31 mM) was dissolved in 2 mL of dichloromethane, followed by the addition of 10 mL of acetonitrile, intermediate 1 (130 mg, 1.2 eq), and pyridine (0.13 mL, 5 eq). The mixture was refluxed at 80 °C for 1 h. The original solvent was evaporated, and the solution was purified by silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.2 v / v) to give a white solid powder 14 (compound C8) (120 mg, yield 58%). Melting point: 189-191 °C

[0142] HRMS(ESI)[M+H] + m / z calcd for C 39 H 59 N2O5S:667.4139; found:667.4144.

[0143] 1H NMR (400MHz, Chloroform-d) δ7.77(d,J=8.0Hz,2H),7.39(d,J=8.1Hz,2H),5.60(s,1H),5.44(t,J=6.1Hz,1H),4.87(t,J=6.2Hz,1H),4.42(d,J=5.9 Hz,2H),3.33(dd,J=13.7,6.4Hz,1H),3.22(dd,J=10.7,5.5Hz,1H),3.08( d,J=6.0Hz,1H),3.05(s,3H),2.77(dt,J=13.3,3.6Hz,1H),2.33(s,1H),2. 30–2.21(m,1H),2.05(td,J=13.5,4.4Hz,1H),1.81(td,J=13.8,4.4Hz,1H ),1.59(dd,J=11.8,4.8Hz,4H),1.55–1.46(m,2H),1.45–1.38(m,2H),1.36 (s,3H),1.33–1.25(m,3H),1.18(td,J=14.2,13.8,3.7Hz,2H),1.11(s,6H ),1.00(s,5H),0.86(d,J=8.7Hz,6H),0.80(s,3H),0.69(d,J=11.4Hz,1H).

[0144] 13 C NMR (100MHz, CDCl3) δ200.5,170.7,158.4,146.8,138.8,128.2,127.9,127.6,78.8,61.9,55.0,46.6,45.4,44.5,44.3,43.6 ,43.4,40.8,39.2,39.2,37.2,35.9,34.9,32.7,32.2,31.3,28.7,28.3,28.1,27.3,26.6,26.4,23.6,18.7,17.5,16.4,15.6.

[0145] Synthesis Example 9 - Synthesis of Compound C9:

[0146]

[0147] The synthetic route for intermediate 2 is as follows:

[0148]

[0149] Aminosulfonyl benzylamine (0.6 g, 2.7 mM, 1 eq) was dissolved in tetrahydrofuran and dichloromethane (v / v = 1:1) and placed in an ice-water bath. Triethylamine (0.32 mL, 1 eq) was added, and p-nitrophenyl chloroformate (0.54 g, 1 eq) dissolved in tetrahydrofuran and dichloromethane (v / v = 1:1) was added dropwise to the reaction system. The addition time was controlled at about 30 min. After 1 h, the reaction was complete. The mixture was filtered through diatomaceous earth, and the original solvent was rotary evaporated. The mixture was extracted three times with dichloromethane and saturated brine. The organic phase was collected and rotary evaporated to give intermediate 2 (0.45 g, yield 35%).

[0150] The synthetic route for compound C9 is as follows:

[0151]

[0152] Compound 8 (210 mg, 0.46 mM) was dissolved in 2 mL of dichloromethane, followed by the addition of 10 mL of acetonitrile, intermediate 2 (194 mg, 1.2 eq), and pyridine (0.13 mL, 5 eq). The mixture was refluxed at 80 °C for 1 h. The original solvent was evaporated, and the solution was purified by silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.3 v / v) to give a white solid powder 15 (compound C9) (130 mg, yield 41%). Melting point: 196-198 °C

[0153] HRMS(ESI)[M+H] + m / z calcd for C 38 H 58 N3O5S:668.4092; found:668.4102.

[0154] 1 H NMR(400MHz,Chloroform-d)δ7.61(d,J=7.9Hz,2H),7.20(d,J=7.9Hz,2H),6.00(s,2H),5.76(s,1H),5.63 (s,1H),5.23(s,1H),4.31(m,2H),3.38(s,1H),3.17(d,J=9.7Hz,1H),3.03–2.89(m,1H),2.62(d,J=12.2Hz ,1H),2.31(s,1H),2.26–2.17(m,1H),2.03(m,1H),1.69–1.45(m,7H),1.38(m,6H),1.27(m,3H),1.16(d,J =10.5Hz,1H),1.06(d,J=15.7Hz,6H),0.98(s,4H),0.91–0.80(m,7H),0.76(s,3H),0.66(d,J=11.4Hz,1H).

[0155] 13 C NMR (175MHz, CDCl3) δ201.5,172.0,158.8,145.3,140.6,128.0,127.4,126.4,78.6,61.9,54.9,53.4,46.8,45.6,44.0,43 .5,40.2,39.2,39.1,37.1,35.8,35.0,32.7,32.2,31.8,28.7,28.3,28.1,27.2,26.6,26.4,23.5,18.7,17.4,16.4,15.7.

[0156] Synthesis Example 10 - Synthesis of Compound C10:

[0157]

[0158] The synthetic route for compound C10 is as follows:

[0159]

[0160] DMP (85 mg, 0.2 mM, 1.2 eq) was dissolved in 10 mL of anhydrous dichloromethane. Compound C3 (0.1 g, 0.17 mM) was dissolved in 5 mL of anhydrous dichloromethane and added dropwise to the reaction system. Argon gas was used to fill the entire system throughout the reaction. After the reaction was complete, the organic phase was washed three times with saturated sodium bicarbonate solution. The organic phase was collected and rotary evaporated. The solution was then subjected to silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.15 v / v) to give a white solid 16 (compound C10) (66 mg, 0.111 mM, yield 65%). Melting point: 90.5-92.5 °C

[0161] HRMS(ESI)[M+H] + m / z calcd for C 37 H 59 N2O4:595.4469; found:595.4470.

[0162] 1H NMR (400MHz, Methanol-d4) δ5.67(s,1H),3.98–3.87(m,2H),3.52–3.33(m,3H),3.11(dd,J=13.6,6.5Hz,1H),2.97(dd, J=13.6,6.7Hz,1H),2.90–2.80(m,2H),2.64–2.53(m,2H),2.47–2.35(m,2H),2.17(td,J=13.6,4.4Hz,1H),1.90(td,J= 13.7,4.6Hz,1H),1.82–1.67(m,2H),1.65–1.57(m,5H),1.55–1.45(m,3H),1.43(s,3H),1.40–1.35(m,1H),1.34–1.26( m,4H),1.25(s,4H),1.21(d,J=4.1Hz,1H),1.19(s,3H),1.08(d,J=12.7Hz,6H),1.01(m,1H),0.92(s,3H),0.86(s,3H).

[0163] 13 C NMR (175MHz, CDCl3) δ217.4,199.6,170.8,158.3,128.2,67.7,61.1,55.5,47.8,46.6,46.3,45.2,44.4,43.4,41.1,39. 8,36.7,35.9,35.8,34.9,34.3,32.2,32.1,31.0,30.6,29.7,28.7,28.3,26.5,26.5,26.4,23.5,21.4,18.8,18.6,15.7.

[0164] Synthesis Example 11 - Synthesis of Compound C11:

[0165]

[0166] The synthetic route for compound 18 is as follows:

[0167]

[0168] 18α-Glycyrrhetinic acid 17 (2.0 g, 4.25 mM, 1 eq) was dissolved in 100 mL of dichloromethane. HATU (1.78 g, 4.675 mM, 1.1 eq) and DIEA (1.55 mL, 9.35 mM, 2.2 eq) were added sequentially to the reaction solution. The solution changed from turbid to clear. Then, ammonia water (0.82 mL, 10.63 mM, 2.5 eq) was added, and the reaction was allowed to proceed for 6-8 h until complete. The organic phase was washed three times with saturated ammonium chloride, collected, and rotary evaporated. Recrystallization from anhydrous methanol yielded a white solid 18 (compound 18) (1.9 g, 4.26 mmol, yield 96%).

[0169] The synthetic route for compound 19 is as follows:

[0170]

[0171] Nickel chloride ethylene glycol dimethyl ether complex (80 mg, 0.364 mmol, 0.2 eq) and compound 18 (0.3 g, 0.639 mmol, 1.0 eq) were dissolved in 50 mL of dry toluene. The container was evacuated for 5 minutes and backfilled three times with argon gas. The mixture was then refluxed and placed in a preheated oil bath at 115 °C. After 10 minutes, benzyl silane (0.5 mL, 4.05 mmol, 6.3 eq) was added. The reaction changed from orange to black. The reaction was carried out in the oil bath at 115 °C for 24 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate and the pH was adjusted to 9 with 1N NaOH. The reaction solvent was evaporated to dryness, and the mixture was extracted with ethyl acetate and water. The organic layer was filtered through diatomaceous earth and subjected to column chromatography (mobile phase: dichloromethane / ethanol / ammonia, 10 / 0.2 / 0.1 v / v) to give a white solid 19 (compound 19) (158 mg, 0.35 mmol, yield 54%).

[0172] HRMS(ESI)[M+H] + m / z calcd for C 30 H 50 NO2:456.3836; found:456.3835.

[0173] 1H NMR(400MHz,Chloroform-d)δ5.57(d,J=1.9Hz,1H),3.24(dd,J=11.3,5.0Hz,1H),2.71 (dt,J=13.4,3.6Hz,1H),2.50(s,2H),2.31–2.22(m,2H),2.00(td,J=13.7,5.0Hz,1H), 1.73–1.40(m,10H),1.37(s,3H),1.35–1.24(m,3H),1.22(s,3H),1.19(d,J=11.7Hz,2H ),1.16(s,3H),1.02(s,3H),1.00–0.93(m,1H),0.92(s,3H),0.83(s,3H),0.69(s,4H). 13 CNMR(175MHz, CDCl3)δ200.0,166.8,124.0,78.8,60.7,56.3,55.0,45.0,43.9,40.8,39.1,39.1,37.8 ,36.9,36.5,36.0,35.5,33.8,32.9,29.4,28.1,27.3,26.8,21.0,20.8,18.5,17.6,16.6,16.1,15.7.

[0174] The synthetic route for compound C11 is as follows:

[0175]

[0176] CDI (120 mg, 0.74 mmol, 2.2 eq) and 4-aminomethyltetrahydropyran (0.06 mL, 0.5 mmol, 1.51 eq) were dissolved in dry dichloromethane and reacted for 2-3 h. Compound 19 (150 mg, 0.329 mmol) was dissolved in dichloromethane and added dropwise to the reaction mixture. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, and evaporated under vacuum. The resulting solution was then subjected to silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10:0.1 v / v) to give a white solid 20 (compound C11) (127 mg, 0.214 mmol, yield 65%). Melting point: 152.5-154 °C

[0177] HRMS(ESI)[M+H] + m / z calcd for C 37 H 61 N2O4:597.4626; found:597.4622.

[0178] 1H NMR(400MHz,Chloroform-d)δ5.45(d,J=1.8Hz,1H),5.05–4.82(m,2H),3.88(dd,J=11.7,4.3Hz,2H),3.28(tt,J=11.6,1.8H z,2H),3.15(dd,J=11.2,5.0Hz,1H),3.01(q,J=6.0Hz,3H),2.87(dd,J=13.4,6.0Hz,1H),2.60(dt,J=13.4,3.5Hz,1H),2.19( s,1H),2.17–2.09(m,1H),1.89(td,J=13.7,4.9Hz,1H),1.68–1.33(m,14H),1.26(s,3H),1.24–1.16(m,4H),1.10(d,J=5.9Hz ,5H),1.05(s,3H),0.93(s,3H),0.88(dd,J=13.2,4.0Hz,1H),0.82(s,3H),0.74(s,3H),0.62(d,J=11.5Hz,1H),0.58(s,3H). 13 C NMR (100MHz, CDCl3) δ200.5,167.3,159.0,123.7,78.8,67.7,60.8,55.0,53.3,46.2,45.0,44.0,40.8,39.2,39.1,3 7.7,36.9,36.3,35.9,35.9,35.6,33.8,33.0,30.7,29.7,28.1,27.3,26.8,21.3,20.8,18.5,17.6,16.6,16.1,15.7.

[0179] Synthesis Example 12 - Synthesis of Compound C12:

[0180]

[0181] The synthetic route for compound C12 is as follows:

[0182]

[0183] CDI (81 mg, 0.504 mmol, 1.5 eq) and isobutylamine (0.04 mL, 0.42 mmol, 1.27 eq) were dissolved in anhydrous dichloromethane and reacted for 2–3 h. Compound 19 (150 mg, 0.329 mmol) was dissolved in dichloromethane and added dropwise to the reaction mixture. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, and evaporated under vacuum. The resulting solution was then subjected to silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v) to give a white solid 21 (compound C12) (112 mg, 0.188 mmol, yield 57%). Melting point: 166.1–167.9 °C

[0184] HRMS(ESI)[M+H] + m / z calcd for C 35 H 59 N2O3:555.4520; found:555.4524.

[0185] 1 H NMR(400MHz,Chloroform-d)δ5.46(d,J=1.8Hz,1H),4.68(s,1H),4.64(s,1H),3. 15(dd,J=11.2,5.0Hz,1H),3.01(dd,J=13.5,5.8Hz,1H),2.93(t,J=5.9Hz,3H),2. 61(dt,J=13.4,3.6Hz,1H),2.19(s,1H),2.17–2.10(m,1H),1.90(td,J=13.7,4.9H z,1H),1.72–1.33(m,11H),1.26(s,3H),1.25–1.17(m,4H),1.12(s,4H),1.05(s,3 H),0.93(s,3H),0.84(d,J=6.5Hz,10H),0.74(s,3H),0.62(dd,J=11.7,1.8Hz,1H) ,0.58(s,3H).13CNMR(175MHz,CDCl3)δ200.3,167.0,158.8,123.8,78.8,60.7,55 .0,53.3,48.1,44.9,43.9,40.7,39.2,39.1,37.7,36.9,36.3,35.9,35.6,33.8,33.0,29.6,29.0,28.1,27.3,26.7,21.2,20.8,20.2,18.5,17.6,16.6,16.0,15.7.

[0186] Synthesis Example 13 - Synthesis of Compound C13:

[0187]

[0188] The synthetic route for compound C13 is as follows:

[0189]

[0190] Compound 19 (220 mg, 0.48 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane. DIEA (0.16 mL, 0.96 mM, 2 eq) was added, and the reaction system was placed in an ice-water bath at 0 °C. Triphosgene (43 mg, 0.144 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system using a constant-pressure dropping funnel. After the addition was complete, p-trifluoromethoxybenzylamine (0.07 mL, 0.48 mM, 1 eq) was immediately added. The reaction was allowed to proceed for 30-60 min. The organic phase was washed three times with saturated brine. The organic phase was collected and rotary evaporated. The solution was then perfused through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v) to give a white solid 22 (compound C13) (129 mg, 0.192 mM, yield 40%). Melting point: 156.5-157.7 °C.

[0191] HRMS(ESI)[M+H] + m / z calcd for C 39 H 56 F3N2O4:673.4187; found:673.4183.

[0192] 1H NMR(400MHz,Chloroform-d)δ7.30(d,J=8.6Hz,2H),7.13(d,J=8.6Hz,2H),5.47(d,J=1.8Hz,1H),5.20(t,J=5.9Hz,1H),4.86(t,J=6.4Hz,1H), 4.36(dd,J=5.9,2.5Hz,2H),3.21(dd,J=11.2,5.0Hz,1H),3.09(dd,J=13.4,6.8Hz,1H),2.93(dd,J=13.4,6.0Hz,1H),2.66(dt,J=13.4,3.5Hz, 1H),2.24(s,1H),2.21–2.13(m,1H),1.95(td,J=13.7,5.0Hz,1H),1.72 –1.35(m,8H),1.31(s,3H),1.30–1.22(m,2H),1.18(s,3H),1.16–1.12( m,2H),1.11(s,3H),1.09–1.01(m,2H),0.99(s,3H),0.91(dd,J=14.9,5 .6Hz,2H),0.85(s,3H),0.80(s,3H),0.68(d,J=9.8Hz,1H),0.62(s,3H).

[0193] 13 C NMR (175MHz, CDCl3) δ200.4,167.0,158.5,148.3,138.4,128.8,123.7,121.1,78.8,60.8,55.0,53.3,44.9,43.9,43.7,40 .7,39.2,39.1,37.7,36.9,36.3,35.9,35.6,33.8,32.9,29.6,28.1,27.3,26.7,21.1,20.8,18.5,17.6,16.6,16.0,15.7.

[0194] Synthesis Example 14 - Synthesis of Compound C14:

[0195]

[0196] The synthetic route for compound C14 is as follows:

[0197]

[0198] Compound 19 (280 mg, 0.62 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane. DIEA (0.2 mL, 1.23 mM, 2 eq) was added, and the reaction system was placed in an ice-water bath at 0 °C. Triphosgene (54 mg, 0.186 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system using a constant-pressure dropping funnel. After the addition was complete, 4-aminomethylpropionylpiperidine (104 mg, 0.62 mM, 1 eq) was immediately added. The reaction was allowed to proceed for 30-60 min. The organic phase was washed three times with saturated brine. The organic phase was collected and rotary evaporated. The solution was then perfused through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.15 v / v) to give a white solid 23 (compound C14) (161 mg, 0.248 mM, yield 40%). Melting point: 169.5-170.5 °C.

[0199] HRMS(ESI)[M+H] + m / z calcd for C 40 H 66 N3O4:652.5048; found:652.5055.

[0200] 1 H NMR(400MHz,Chloroform-d)δ5.50(d,J=1.8Hz,1H),5.07–4.88(m,2H),4.60(d,J=13.2Hz,1H),3.85(d,J=13.5Hz,1H),3.19(tt,J=13.0,5 .6Hz,2H),3.02(m,4H),2.66(dt,J=13.3,3.6Hz,1H),2.57–2.46(m,1H),2.33(qd,J=7.5,2.4Hz,2H),2.25(s,1H),2.23–2.16(m,1H),1.96 (td,J=13.9,5.0Hz,1H),1.72(td,J=14.0,13.6,7.3Hz,4H),1.63–1.54(m,4H),1.53–1.37(m,5H),1.33(s,3H),1.29(m,2H),1.16(d,J=16 .0Hz,7H),1.12(d,J=2.5Hz,6H),1.00(s,3H),0.95(dd,J=13.1,4.3Hz,2H),0.89(s,3H),0.80(s,3H),0.68(d,J=10.7Hz,1H),0.64(s,3H). 13C NMR (100MHz, CDCl3) δ200.3,172.3,167.1,158.8,123.7,78.8,60.8,55.0,53.3,45.6,45.5,45.0,43.9,41.7,40.7,39.2,39.1, 37.7,37.1,36.9,36.3,35.9,35.7,33.8,33.0,30.4,29.6,28.1,27.3,26.8,26.6,21.3,20.8,18.5,17.6,16.6,16.1,15.7,9.7.

[0201] Synthesis Example 15 - Synthesis of Compound C15:

[0202]

[0203] The synthetic route for compound C15 is as follows:

[0204]

[0205] Compound 19 (250 mg, 0.55 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane. DIEA (0.18 mL, 1.10 mM, 2 eq) was added, and the reaction system was placed in an ice-water bath at 0 °C. Triphosgene (50 mg, 0.165 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system using a constant-pressure dropping funnel. After the addition was complete, 4-pyridinemethylamine (0.06 mL, 0.55 mM, 1 eq) was immediately added. The reaction was allowed to proceed for 1–2 h. The organic phase was washed three times with saturated brine, collected, and rotary evaporated. The solution was then perfused through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.2 v / v) to give a white solid 24 (compound C15) (168 mg, 0.286 mM, yield 52%). Melting point: 178–180 °C.

[0206] HRMS(ESI)[M+H] + m / z calcd for C 37 H 56 N3O3:590.4316; found:590.4326.

[0207] 1H NMR (400MHz, Methanol-d4) δ8.63–8.33(m,2H),7.37(d,J=4.9Hz,2H),5.53(s,1H),4.40(s,2H),3.19(dd,J=11.7,4.6H z,1H),3.04(d,J=2.8Hz,2H),2.66(dt,J=13.4,3.7Hz,1H),2.39(s,1H),2.34(dd,J=11.0,4.3Hz,1H),2.05(td,J=13.8 ,4.8Hz,1H),1.75(m,2H),1.69–1.61(m,2H),1.55(m,3H),1.51(s,1H),1.46(d,J=13.1Hz,2H),1.40(s,3H),1.37–1.29 (m,3H),1.23(d,J=7.9Hz,5H),1.17(s,4H),1.01(s,5H),0.95(s,3H),0.82(s,3H),0.78(d,J=11.6Hz,1H),0.72(s,3H). 13 C NMR (100MHz, CDCl3) δ200.5,167.2,158.6,149.9,149.1,123.6,122.2,78.8,60.8,55.0,53.3,45.0,43.9,43.3,40.7, 39.2,39.1,37.6,36.9,36.3,35.9,35.6,33.8,32.9,29.6,28.1,27.3,26.8,21.2,20.8,18.5,17.6,16.6,16.1,15.7.

[0208] Synthesis Example 16 - Synthesis of Compound C16:

[0209]

[0210] The synthetic route for compound C16 is as follows:

[0211]

[0212] Compound 19 (140 mg, 0.31 mM) was dissolved in 2 mL of dichloromethane, followed by the addition of 10 mL of acetonitrile, intermediate 1 (130 mg, 1.2 eq), and pyridine (0.13 mL, 5 eq). The mixture was refluxed at 80 °C for 1 h. The original solvent was evaporated, and the solution was purified by silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.2 v / v) to give white solid powder 25 (compound C16) (103 mg, 0.155 mM, 50% yield). Melting point: 185-187 °C

[0213] HRMS(ESI)[M+H] + m / z calcd for C 39 H 59 N2O5S:667.4139; found:667.4150.

[0214] 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J=8.0Hz,2H),7.39(d,J=8.1Hz,2H),5.79(s,1H),5.50(s,1H),5.39(d,J=6.3Hz,1H),4.42(s,2H), 3.21(dd,J=11.2,5.1Hz,1H),3.08(dd,J=13.5,6.0Hz,1H),3.04(s,3H),2.93(dd,J=13.5,5.4Hz,1H),2.63(dt,J=13.3,3.4Hz,1H),2.25 (s,1H),2.19(d,J=10.6Hz,1H),1.96(td,J=13.7,5.0Hz,1H),1.73–1.54(m,6H),1.53–1.38(m,5H),1.33(s,3H),1.30–1.23(m,2H),1.15 (d,J=10.9Hz,5H),1.11(s,3H),0.99(s,3H),0.93(dd,J=13.2,3.7Hz,1H),0.87(s,3H),0.79(s,3H),0.68(d,J=11.6Hz,1H),0.64(s,3H).

[0215] 13 C NMR (175MHz, CDCl3) δ200.5,167.4,158.8,146.8,138.8,127.9,127.6,123.6,78.7,60.8,55.0,53.2,45.0,44.5,43.9,43.6 ,40.7,39.2,39.1,37.6,36.9,36.3,35.9,35.7,33.8,32.8,29.7,28.1,27.2,26.8,21.2,20.8,18.5,17.5,16.6,16.1,15.7.

[0216] Synthesis Example 17 - Synthesis of Compound C17:

[0217]

[0218] The synthetic route for compound C17 is as follows:

[0219]

[0220] Compound 19 (210 mg, 0.46 mM) was dissolved in 2 mL of dichloromethane, followed by the addition of 10 mL of acetonitrile, intermediate 2 (194 mg, 1.2 eq), and pyridine (0.13 mL, 5 eq). The mixture was refluxed at 80 °C for 1 h. The original solvent was evaporated, and the solution was purified by silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.3 v / v) to obtain a white solid powder 26 (compound C17, 153 mg, 0.23 mM, yield 50%). Melting point: 201-203 °C

[0221] HRMS(ESI)[M+H] + m / z calcd for C 38 H 58 N3O5S:668.4092; found:668.4100.

[0222] 1 H NMR (400MHz, Methanol-d4) δ7.83(d,J=8.3Hz,2H),7.44(d,J=8.1Hz,2H),5.51(d,J=1.9Hz,1H),4.40(s,2H),3.17(dd,J=11.7, 4.5Hz,1H),3.08–2.95(m,2H),2.62(dt,J=13.5,3.7Hz,1H),2.38(s,1H),2.31(dt,J=11.3,2.7Hz,1H),2.02(td,J=13.8,4.8Hz ,1H),1.77–1.66(m,2H),1.66–1.57(m,2H),1.57–1.40(m,6H),1.38(s,3H),1.31(d,J=11.8Hz,2H),1.23(d,J=11.6Hz,1H),1.2 0(s,3H),1.15(s,4H),1.03(dd,J=13.2,3.7Hz,1H),0.99(s,3H),0.91(s,3H),0.80(s,3H),0.75(d,J=11.6Hz,1H),0.71(s,3H).

[0223] 13C NMR(175MHz,MeOD)δ201.1,168.5,159.8,145.1,142.1,127.0,126.0,123.1,78.0,60.6,54.9,44.9,43.8,42.8,40.7, 38.9,38.8,37.3,36.7,36.0,35.6,35.6,33.5,32.4,29.2,27.3,26.5,26.4,20.3,19.8,17.8,17.3,15.8,15.1,15.0.

[0224] Synthesis Example 18 - Synthesis of Compound C18:

[0225]

[0226] The synthetic route for compound C18 is as follows:

[0227]

[0228] DMP (85 mg, 0.2 mM, 1.2 eq) was dissolved in 10 mL of anhydrous dichloromethane. Compound 11 (0.1 g, 0.17 mM) was dissolved in 5 mL of anhydrous dichloromethane and added dropwise to the reaction system. Argon gas was used to fill the entire system throughout the reaction. After the reaction was complete, the organic phase was washed three times with saturated sodium bicarbonate solution. The organic phase was collected and rotary evaporated. The solution was then subjected to silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.15 v / v) to give white solid 27 (compound C18) (67 mg, 0.112 mM, yield 66%). Melting point: 87.7-89.0 °C

[0229] HRMS(ESI)[M+H] + m / z calcd for C 37 H 59 N2O4:595.4469; found:595.4457.

[0230] 1H NMR(400MHz,Chloroform-d)δ5.49(d,J=1.8Hz,1H),5.03(dt,J=21.4,6.2Hz,2H),3.92–3.84(m,2H),3.28 (m,2H),3.02(dq,J=6.7,3.9Hz,3H),2.88(dd,J=13.5,6.0Hz,1H),2.77(m,1H),2.56(m,1H),2.34–2.23(m, 2H),2.19–2.10(m,1H),1.92(m,1H),1.78–1.58(m,3H),1.57–1.43(m,4H),1.41–1.29(m,4H),1.27(s,3H), 1.24(s,4H),1.23–1.16(m,4H),1.10(d,J=8.2Hz,5H),1.03(s,4H),1.00(s,3H),0.82(s,3H),0.59(s,3H). 13 C NMR (100MHz, CDCl3) δ217.2,199.7,167.7,159.0,123.6,67.7,60.0,55.4,53.3,47.7,46.1,45.1,43.8,40.8,39. 7,37.6,36.5,36.3,36.0,35.6,34.2,33.1,33.0,30.7,29.7,26.8,26.4,21.5,21.2,20.8,18.9,18.4,16.1,15.9.

[0231] The following demonstrates the technical effects and advantages of the present invention by applying the glycyrrhetinic acid derivative of the present invention to the inhibition of soluble epoxide hydrolases.

[0232] Specifically, the verification method for the glycyrrhetinic acid derivative in this embodiment of the invention involves co-incubating the glycyrrhetinic acid derivative prepared in this invention with a sample containing soluble epoxide hydrolase and the endogenous hydrolysis substrate 14,15-EET of the hydrolase, detecting the content of the hydrolysis product 14,15-DHET, and using its relative amount to reflect the inhibitory effect of the compound on soluble epoxide hydrolase. The specific steps are as follows:

[0233] Add 1:10 (mg / μL) pre-cooled PBS (phosphate buffer saline) (pH=7.4) to the collected brain tissue samples of adult (25-30g) male C57BL / 6J mice, homogenize for 30 seconds (4℃, 4500rpm) using a BertinPrecellys 24-Dual homogenizer, and then centrifuge at 9000g for 15 minutes at 4℃ using a small low-temperature centrifuge. Take the supernatant and dilute it 20 times. Add 160 μL of PBS, 20 μL of tissue fluid diluted 20 times, and 2 μL of compounds with concentration gradients of 10000, 5000, 1000, 500, 100, 50, 10, 1, 0.1, and 0.01 μg / mL (final concentrations of 100, 50, 10, 5, 1, 0.5, 0.1, 0.01, 0.001, and 0.0001 μg / mL) to an EP (Eppendorf) tube. Incubate at room temperature for 15 minutes. The negative control is PBS without tissue dilution but with added solvent (180 μL PBS plus 2 μL DMSO). The positive control is the same concentration of sample dilution plus an equal volume of solvent (160 μL PBS plus 20 μL of tissue fluid diluted 20 times plus 2 μL DMSO). After incubation at room temperature, all samples were placed on ice, and the enzyme reaction substrate (10 μL of 14,15-EET (10 μg / mL)) was quickly added and mixed. The mixture was then incubated at 37°C in a shaker. After incubation, the samples were placed on ice, and 10 μL of 800 nM t-TUCB (No. 6757, Tocris Bioscience, UK, Bristol) was quickly added to terminate the reaction, resulting in a final reaction volume of 200 μL. To detect enzyme activity, the concentration of the reaction product 14,15-DHET was determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS). The pretreatment process was as follows: 1. Add an equal volume (200 μL) of a 50 / 50, v / v mixture of methanol and acetonitrile to the sample. The mixture contained 0.4% acetic acid and internal standards 11,12-EET-d11 and 11,12-DHET-d11 (20 ng / mL); 2. Homogenize at 4500 rpm for 10 minutes and incubate at -20°C for 2 hours to precipitate the protein; 3. Centrifuge the sample for 10 minutes (14000 rpm) and collect the supernatant for UPLC-MS / MS analysis. The relative enzyme activity of sEH was calculated by comparing the amount of 14,15-DHET produced at a certain concentration of the tested compound with that produced without inhibitor. The inhibition rate was 100% minus the relative enzyme activity.

[0234] Wherein, the inhibition rate % (5 μg / mL) is the inhibition rate of the tested compound against sEH at a concentration of 5 μg / mL.

[0235] The positive control compounds were TPPU and EC5026.

[0236] The verification results of the glycyrrhetinic acid derivatives prepared in this invention are shown in Table 1:

[0237] Table 1: Inhibitory activity of the glycyrrhetinic acid derivative prepared in this invention against soluble epoxide hydrolase.

[0238]

[0239]

[0240]

[0241] The results for the positive control compounds are shown in Table 2:

[0242] Table 2. Inhibitory activity of positive control compounds against soluble cyclooxide enzymes under the same conditions.

[0243]

[0244] The results for the negative control compounds are shown in Table 3:

[0245] Table 3. Inhibitory activity of negative control compounds against soluble cyclooxide enzymes under the same conditions.

[0246]

[0247] As shown in Tables 1 and 2, 18β-glycyrrhetinic acid had no inhibitory effect on soluble epoxide hydrolase (sEH) at a dose of 5 μg / mL. The positive control compounds TPPU and EC5026 showed inhibition rates of 99.5% and 99.74% against sEH, respectively, with IC50 values ​​of 44 nM and 19 nM. The glycyrrhetinic acid derivatives prepared in this invention exhibit comparable or superior sEH inhibitory activity (IC50 values ​​of compounds C3, C11, C5, C6, C7, C14, and C15 are less than 10 nM), indicating that the compounds synthesized based on the glycyrrhetinic acid skeleton in this invention can enhance the interaction with sEH. As can be seen from the data of the negative control compounds in Table 3, compounds C19, C20, C21, and C22 exhibited inhibition rates of approximately 8%, 1%, 38%, and 43% for sEH, respectively. The negative control compounds showed a low inhibition rate for sEH because the urea group is directly attached to the 20th carbon of the E ring, indicating that attaching a urea group at the 20th position of glycyrrhetinic acid does not improve its inhibitory activity against sEH. However, when a urea group is attached to the 30th position of glycyrrhetinic acid, i.e., a methylene group is retained between the 20th carbon and the urea group, it exhibits excellent sEH inhibitory activity and a very low IC50. Therefore, this invention, by introducing the glycyrrhetinic acid skeleton described in Formula I, yields a novel sEH inhibitory compound with a good inhibition rate against sEH and an IC50 as low as approximately 3 nM.

[0248] In summary, the main skeleton of the glycyrrhetinic acid derivative prepared in this invention is glycyrrhetinic acid with a urea group. Modification of the 3, 11, 18, and 30 positions of glycyrrhetinic acid resulted in nanomolar-level inhibitory activity against sEH. Based on 18α / 18β-GA, the introduction of different urea substituents at the 30 position showed superior activity compared to the positive control compound TPPU in inhibiting sEH. However, when different urea substituents were attached to the 20 position of 18α / 18β-GA, the inhibitory effect on sEH was significantly reduced. The configuration of the hydrogen at the 18-position of glycyrrhetinic acid and the reduction of the carbonyl group at the 11-position did not have a decisive effect on sEH inhibition. Changing the 3-position to a carbonyl group slightly reduced the activity compared to retaining the hydroxyl group. The glycyrrhetinic acid derivative prepared in this invention exhibits highly efficient inhibitory activity against sEH, thus achieving an anti-inflammatory effect by inhibiting sEH, and has promising application prospects.

[0249] The foregoing has provided a detailed description of a glycyrrhetinic acid derivative, a pharmaceutical composition, and its applications. Specific examples have been used to illustrate the principles and implementation methods of the present invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of the present invention. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the ideas of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A glycyrrhetinic acid derivative, characterized by, The glycyrrhetinic acid derivative has a general structural formula of Formula I as follows: Formula I In Formula I, Y is selected from any one of CH-OH, carbonyl; X is selected from any one of carbonyl, methylene; R 1 selected from C 1-4 alkyl, tetrahydropyranyl, N-(C 1-4 alkylcarbonyl)piperidinyl, pyridinyl, substituted phenyl (R-Ph); wherein R is selected from haloalkoxy, aminosulfonyl, methylsulfonyl. 18 hydrogen is selected from α or β stereoisomer.

2. The glycyrrhetinic acid derivative according to claim 1, characterized by Y is selected as CH-OH group.

3. The glycyrrhetinic acid derivative according to claim 1, characterized by X is selected as carbonyl group.

4. The glycyrrhetinic acid derivative according to claim 1, characterized by The R 1 is selected from any one of isopropyl, isobutyl, tetrahydropyranyl, N-acetylpiperidinyl, N-propionylpiperidinyl, pyridinyl, difluoromethoxyphenyl, trifluoromethoxyphenyl, aminosulfonylphenyl, methylsulfonylphenyl.

5. The glycyrrhetinic acid derivative according to claim 1, characterized by said Y is selected as a CH-OH group, said X is selected as any one of a carbonyl group, a methylene group, said R 1 is selected as any one of an isopropyl group, an isobutyl group, a tetrahydropyranyl group, a N-acetylpiperidinyl group, a N-propionylpiperidinyl group, a 4-pyridyl group, a 4-difluoromethoxyphenyl group, a 4-trifluoromethoxyphenyl group, a 4-aminosulfonylphenyl group, a 4-methanesulfonylphenyl group.

6. The glycyrrhetinic acid derivative according to claim 5, characterized by said X is selected from a carbonyl group, said R 1 is selected from any one of isopropyl, tetrahydropyranyl, N-propionylpiperidinyl, 4-pyridyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-aminosulfonylphenyl, 4-methanesulfonylphenyl.

7. The glycyrrhetinic acid derivative according to claim 1, characterized by The specific structural formula of the glycyrrhetinic acid derivative is as follows: 。 8. A pharmaceutical composition of a glycyrrhetinic acid derivative, characterized by, The glycyrrhetinic acid derivative pharmaceutical composition comprises at least one of the glycyrrhetinic acid derivative or pharmaceutically acceptable salt according to any one of claims 1-7.

9. Use of the glycyrrhetinic acid derivative according to any one of claims 1-7, or the glycyrrhetinic acid derivative pharmaceutical composition according to claim 8 in the preparation of sEH inhibitors.

10. Use according to claim 9, characterized in that, The sEH inhibitor is used for inhibiting inflammation caused by soluble epoxide hydrolase.

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