Oridonin derivative as well as preparation method and application thereof

Abstract

The invention provides an oridonin derivative as well as a preparation method and application thereof, and belongs to the field of medicines. The oridonin derivative or the stereoisomer and the pharmaceutically acceptable salt of the oridonin derivative have a structure as shown in a formula A. A series of oridonin derivatives with novel structures are prepared, and the oridonin derivatives can influence the expression of inflammation-related genes, can be used for treating acute pneumonia, chronic pneumonia, lung injury and peritonitis in the treatment of inflammation and related diseases, and have a better anti-inflammatory function.

Description

Technical Field

[0001] The invention belongs to the field of medicine and relates to an oridonin derivative, and specifically relates to an oridonin derivative and a preparation method and application thereof. Background Art

[0002] Inflammation is the body's defensive response to tissue damage, which helps repair damaged tissues and remove harmful substances, but excessive inflammatory responses can also damage the body and cause disease. Acute inflammation is mainly manifested by redness, swelling, heat, pain, and dysfunction. Inflammation can be divided into infectious inflammation and non-infectious inflammation. The former is often caused by infection with pathogens such as bacteria, viruses, fungi, and parasites, while the latter is mostly aseptic inflammation caused by immunity.

[0003] The inflammatory process mainly includes four stages: vascular response, cell infiltration, cell activation and repair. In the vascular response stage, the body is stimulated, and inflammatory cells release inflammatory mediators to cause vasodilation, increase vascular permeability, and begin to appear red, swollen, hot and painful phenomena; in the cell infiltration stage, inflammatory cells enter the inflammatory site from the blood vessels; in the cell activation stage, inflammatory cells release inflammatory mediators such as histamine, prostaglandins, and interleukins, which activate inflammatory cells, aggravate the inflammatory response, kill and remove harmful substances; in the repair stage, inflammation subsides, parenchymal cells and interstitial cells proliferate, and damaged tissues are repaired. The common molecular mechanism of inflammation is that pathogenic microorganisms stimulate and activate TLR receptors (Toll-like receptor, TLR), and then activate downstream signaling pathways such as NF-κB and NLRP3 inflammasomes, accompanied by the release of inflammatory factors, resulting in an inflammatory response.

[0004] At present, anti-inflammatory drugs are a common means of clinical treatment of inflammation. In the early days, people used steroidal anti-inflammatory drugs to treat inflammation, and long-term use can lead to adrenal cortex dysfunction. Nonsteroidal anti-inflammatory drugs (NSAIDs) began to appear in the 1950s. At present, a variety of nonsteroidal anti-inflammatory drugs have been used in clinical practice. According to different structures, NSAIDs include salicylates, anilines, pyrazolones and other anti-inflammatory organic acids. From the perspective of mechanism of action, NSAIDs are divided into COX-2 selective inhibitors and non-selective inhibitors according to their selective inhibitory effects on COX-1 and COX-2 targets. There are many types of commonly used non-selective NSAIDs, including common aspirin, acetaminophen, diclofenac, etc., all of which have gastrointestinal and renal side effects. Selective COX-2 inhibitors can inhibit COX-2 more specifically, thereby reducing side effects such as gastrointestinal damage, mainly including celecoxib, rofecoxib, etc. Most of the non-steroidal anti-inflammatory drugs currently used in the market are non-selective NSAIDs, which have gastrointestinal and renal side effects. Therefore, the development of new safe and effective anti-inflammatory drugs has more important scientific significance and economic value.

[0005] In the field of traditional Chinese medicine treatment, inflammation is usually related to "getting angry, dampness and heat", and is mainly manifested in syndromes such as "stagnation of qi and blood stasis", "carbuncle, sore, heat and poison".

[0006] Rabdosia rubescens is a widely used traditional Chinese medicine, and its main effects and functions are clearing away heat and detoxifying, relieving sore throat and relieving pain, promoting blood circulation and removing blood stasis, and reducing swelling and dispersing nodules. Rabdosia rubescens A is a kaurane-type tetracyclic diterpenoid compound isolated from Rabdosia rubescens (Hemsl.) Hara.

[0007] The invention patent with the announcement number CN110151749B discloses the use of Rubescensine A in the preparation of drugs for preventing or treating NLRP3 inflammasome-related diseases. Rubescensine A has strong pharmacological effects and can inhibit the activation of NLRP3 inflammasomes in vitro and treat the pathological conditions of NLRP3 inflammasome-related disease models in vivo. Rubescensine A can directly bind to NLRP3 through covalent bonds, thereby inhibiting the interaction between NLRP3 and NEK7, thereby inhibiting the assembly of inflammasomes and achieving the purpose of inhibiting inflammasome activation.

[0008] The invention patent with announcement number CN112704676B discloses the use of Rubescensine A in the preparation of drugs for preventing and / or treating ischemic stroke. Rubescensine A reduces the level of brain oxidative stress after ischemic stroke and inhibits endothelial cell apoptosis, thereby improving the integrity of the blood-brain barrier under ischemia-reperfusion state, reducing the infiltration of peripheral inflammatory cells, and inhibiting neuroinflammation.

[0009] Oridonin has anti-inflammatory effects and has been used as an anti-inflammatory active ingredient in the preparation of Chinese patent medicines. At present, Oridonin tablets, Oridonin capsules and Oridonin oral liquid are anti-inflammatory Chinese patent medicines that have been marketed. They have the effects of clearing away heat and detoxification, promoting blood circulation and relieving pain, and removing wind and resolving phlegm. They are mainly used in clinical practice to treat sore throat, hoarseness, facial paralysis, rheumatism, bleeding gums and other symptoms.

[0010] The invention patent with publication number CN117466906A discloses a Rubescensine A derivative and its preparation method, pharmaceutical composition and application. The Rubescensine A derivative is a compound having a structure shown in formula (I) or (II) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] Wherein: R is selected from any one of hydrogen, deuterium, and substituted or unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl. By comparison, it is found that the inhibition rate of interleukin 1L-1β secretion of the oridonin derivative of the invention is comparable to that of oridonin, indicating that the oridonin derivative of the invention has comparable anti-inflammatory activity to oridonin.

[0013] The invention patent with the announcement number CN114874172B discloses a Rubescensine A derivative and its preparation method and medical use. The Rubescensine A derivative has the structure shown in Formula II:

[0014]

[0015] When R 1 =H, R 2 is the following groups: (A) aromatic hydrocarbons: phenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, benzyl, phenethyl; (B) alkanes: ethyl, propyl, isopropyl, heptyl, hexyl, cyclohexyl, allyl; or R 1 , R 2 The groups are: morpholine, pyrrolidine, piperidine, piperazine, 4-phenylpiperazine, 4-methylsulfonylpiperazine, diphenyl, Boc-piperazine, diethylamino, dimethylamino. The oridonin derivatives of the invention have an inhibitory effect on the inflammatory factor IL-1β.

[0016] As an important source of drug discovery, natural products can continue to develop drugs with anti-inflammatory activity from natural medicines and traditional Chinese medicines. In order to find drugs with higher anti-inflammatory activity, the present invention derives oridonin A with anti-inflammatory effect to obtain compounds with higher anti-inflammatory activity, and at the same time studies the mechanism of action of the compounds, providing a reference for the discovery and research of more innovative natural product drugs. Summary of the invention

[0017] The present invention aims at the problems existing in the prior art and provides a Rubescensine A derivative and a preparation method and application thereof. The present invention derives Rubescensine A to obtain a derivative with anti-inflammatory effect.

[0018] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0019] In a first aspect, the present invention provides a Rubescensine A derivative, wherein the Rubescensine A derivative includes a stereoisomer or a pharmaceutically acceptable salt thereof, and the Rubescensine A derivative has a structure shown in Formula A:

[0020]

[0021] Wherein, Het is any structure shown in the following formula:

[0022] in, The dashed lines shown represent saturated covalent bonds;

[0023] R is selected from any of the following structures:

[0024]

[0025] Preferably, R is selected from any one of the following structures:

[0026]

[0027] In one embodiment, the Rubescensine A derivative has a structure shown in Formula A, wherein Het is a structure shown in the following formula:

[0028] R is selected from any of the following structures:

[0029]

[0030] In one embodiment, the Rubescensine A derivative has a structure shown in Formula A, wherein Het is a structure shown in the following formula:

[0031] R is selected from any of the following structures:

[0032]

[0033] In one embodiment, the Rubescensine A derivative has a structure shown in Formula A, wherein Het is a structure shown in the following formula:

[0034] R is selected from any of the following structures:

[0035]

[0036] In one embodiment, the Rubescensine A derivative has a structure shown in Formula A, wherein Het is a structure shown in the following formula:

[0037] R is selected from any of the following structures:

[0038]

[0039] In one embodiment, the Rubescensine A derivative has a structure shown in Formula A, wherein Het is any one of the following structures:

[0040] R is selected from any of the following structures:

[0041]

[0042] In one embodiment, the Rubescensine A derivative has a structure shown in Formula A, wherein Het is a structure shown in the following formula: R is selected from any of the following structures:

[0043]

[0044] In one embodiment, the Rubescensine A derivative has a structure shown in Formula A, wherein Het is a structure shown in the following formula: R is selected from any of the following structures:

[0045]

[0046] Preferably, the Rubescensine A derivative has any of the following structures:

[0047]

[0048] More preferably, the Rubescensine A derivative has any one of the following structures:

[0049]

[0050] In a second aspect, the present invention provides a method for preparing the oridonin derivatives described in the above technical solution, comprising the following steps:

[0051] subjecting Rubescensine A to one or both of an esterification reaction and a rearrangement reaction to obtain a Rubescensine A derivative;

[0052] Alternatively, the oridonin is subjected to Jones oxidation reaction, esterification reaction or elimination reaction, and then subjected to one or both of esterification reaction and rearrangement reaction to obtain the oridonin derivative.

[0053] In the method for preparing the oridonin derivative, only the esterification reaction may be carried out, or only the rearrangement reaction may be carried out, or the esterification reaction and the rearrangement reaction may be carried out in sequence, or the rearrangement reaction and the esterification reaction may be carried out in sequence, which is not limited here.

[0054] The oridonin is subjected to Jones oxidation reaction, esterification reaction or elimination reaction, and then subjected to one or both of esterification reaction and rearrangement reaction to obtain the oridonin derivative.

[0055] Preferably, the oridonin is subjected to Jones oxidation reaction, esterification reaction or elimination reaction, and then subjected to esterification reaction to obtain the oridonin derivative.

[0056] In one embodiment, the Rubescensine A derivative has a structure shown in the following formula:

[0057]

[0058] Among them, RR 1 Select from any of the following structures:

[0059]

[0060] The preparation method is as follows: Oridonin is reacted with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt) and 4-dimethylaminopyridine (DMAP) to generate a compound shown in Formula 1, or Oridonin is reacted with triethylamine (Et 3 N), EDCI, and HOBt to generate Rubescensine A derivatives:

[0061]

[0062] In one embodiment, the Rubescensine A derivative has a structure shown in the following formula:

[0063]

[0064] Among them, R 2 Select from any of the following structures:

[0065]

[0066] The preparation method is as follows: a Rubescensine A derivative having a structure shown in Formula 1 is reacted with diethylamine sulfur trifluoride (DAST) to generate the Rubescensine A derivative:

[0067]

[0068] Among them, R 1 Selected from the following structures:

[0069]

[0070] In one embodiment, the Rubescensine A derivative has a structure shown in the following formula:

[0071]

[0072] Among them, R 3 Select from any of the following structures:

[0073]

[0074] The preparation method is as follows: Oridonin is subjected to Jones oxidation reaction in the presence of Jones reagent, and then esterification reaction is carried out in the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt) and 4-dimethylaminopyridine (DMAP) to generate Oridonin derivatives:

[0075]

[0076] In one embodiment, the Rubescensine A derivative has a structure shown in the following formula:

[0077]

[0078] Among them, R 4 Select from any of the following structures:

[0079]

[0080] The preparation method is as follows: Oridonin is subjected to Jones oxidation reaction in the presence of Jones reagent, and then esterification reaction is carried out in the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt) and 4-dimethylaminopyridine (DMAP), and finally rearrangement reaction is carried out in the presence of DAST to generate Oridonin derivatives:

[0081]

[0082] Among them, R 3 Select from any of the following structures:

[0083]

[0084] In one embodiment, the Rubescensine A derivative has a structure shown in the following formula:

[0085]

[0086] Among them, R 5 Select from any of the following structures:

[0087]

[0088] The preparation method is as follows: Oridonin is reacted with acetic anhydride (Ac 2 O), DMAP and Et3 N, and then esterification reaction occurs under the action of EDCI, HOBt and DMAP to generate oridonin derivatives:

[0089]

[0090] In one embodiment, the Rubescensine A derivative has a structure shown in the following formula:

[0091]

[0092] Among them, R 5 Select from any of the following structures:

[0093]

[0094] The preparation method is as follows: Oridonin is reacted with acetic anhydride (Ac 2 O), DMAP and Et 3 N, and then EDCI, HOBt and DMAP, and finally rearrangement reaction occurs with the participation of DAST to generate Rubescensine A derivatives:

[0095]

[0096] In one embodiment, the Rubescensine A derivative has a structure shown in the following formula:

[0097]

[0098] Among them, R 6 Select from any of the following structures:

[0099]

[0100] The preparation method comprises the following steps: first, oridonin is subjected to an elimination reaction. Specifically, the elimination reaction comprises: oridonin is protected with the participation of p-toluenesulfonic acid (TsOH) and 2,2-dimethoxypropane (DMP) to prevent the protected hydroxyl sites from undergoing elimination reaction, and then part of the hydroxyl groups are protected with the action of methanesulfonyl chloride (MsCl) and triethylamine (TEA), and then lithium bromide (LiBr) and lithium carbonate (LiCO) are reacted to obtain oridonin. 2 CO 3 ) to undergo an elimination reaction, and finally the hydroxyl protecting group is removed with the participation of a HCl / THF mixed solution. After the elimination reaction, an esterification reaction occurs under the action of EDCI, HOBt and DMAP to produce a Rubescensine A derivative:

[0101]

[0102] In one embodiment, the Rubescensine A derivative has a structure shown in the following formula:

[0103]

[0104] Among them, R 7 Select from any of the following structures:

[0105]

[0106] The preparation method comprises the following steps: first, oridonin is subjected to an elimination reaction. Specifically, the elimination reaction comprises: oridonin is protected with the participation of p-toluenesulfonic acid (TsOH) and 2,2-dimethoxypropane (DMP) to prevent the protected hydroxyl sites from undergoing elimination reaction, and then part of the hydroxyl groups are protected with the action of methanesulfonyl chloride (MsCl) and triethylamine (TEA), and then lithium bromide (LiBr) and lithium carbonate (LiCO) are reacted to obtain oridonin. 2 CO 3 ) with the participation of HCl / THF mixed solution. After the elimination reaction, the hydroxyl protecting group is removed with the participation of EDCI, HOBt and DMAP, and then an esterification reaction occurs with the participation of DAST, and finally a rearrangement reaction occurs with the participation of DAST to generate a Rubescensine A derivative. Alternatively, after the elimination reaction, a rearrangement reaction occurs with the participation of DAST, and finally an esterification reaction occurs with the participation of EDCI, HOBt and DMAP to generate a Rubescensine A derivative:

[0107]

[0108] In a third aspect, the present invention further provides a use of the oridonin derivative described in the above technical solution or the oridonin derivative prepared by the preparation method described in the above technical solution in the preparation of drugs for treating inflammation and related diseases.

[0109] Preferably, the inflammation and its related diseases are acute pneumonia, chronic pneumonia, lung injury or peritonitis.

[0110] Preferably, the drug for treating inflammation and its related diseases is a drug that acts on the inflammatory factor stfa2.

[0111] In one embodiment, the Rubescensine A derivative with the structure shown in the following formula is used in a drug for treating inflammation and related diseases:

[0112]

[0113] The drug for treating inflammation and related diseases is a drug acting on the inflammatory factor stfa2.

[0114] In a fourth aspect, the present invention provides an anti-inflammatory drug, comprising the oridonin derivative described in the above technical solution or the oridonin derivative prepared by the preparation method described in the above technical solution.

[0115] Compared with the prior art, the present invention has the following beneficial effects: the present application prepares a series of novel oridonin derivatives, which can affect the expression of inflammation-related genes and can be used in the treatment of inflammation and related diseases, such as acute pneumonia, chronic pneumonia, lung injury and peritonitis, and have better anti-inflammatory function. BRIEF DESCRIPTION OF THE DRAWINGS

[0116] Figure 1 is the hydrogen spectrum of the compound of formula 1a;

[0117] Figure 2 is the carbon spectrum of the compound of formula 1a;

[0118] Figure 3 is the hydrogen spectrum of the compound of formula 1b;

[0119] Figure 4 is the carbon spectrum of the compound of formula 1b;

[0120] Figure 5 is the hydrogen spectrum of the compound of formula 1c;

[0121] Figure 6 is the carbon spectrum of the compound of formula 1c;

[0122] Figure 7 is the hydrogen spectrum of the compound of formula 1d;

[0123] Figure 8 is the carbon spectrum of the compound of formula 1d;

[0124] Fig. 9 is the hydrogen spectrum of the compound of formula 1e;

[0125] Fig.10 is the carbon spectrum of the compound of formula 1e;

[0126] Fig.11 is the hydrogen spectrum of the compound of formula 1f;

[0127] Fig.12 is the carbon spectrum of the compound of formula 1f;

[0128] Fig.13 is the hydrogen spectrum of the compound of formula 2a;

[0129] Fig.14 is the carbon spectrum of the compound of formula 2a;

[0130] Fig.15 is the hydrogen spectrum of the compound of formula 2b;

[0131] Fig.16 is the carbon spectrum of the compound of formula 2b;

[0132] Fig.17 is the hydrogen spectrum of the compound of formula 3;

[0133] Fig.18 is the carbon spectrum of the compound of formula 3;

[0134] Fig.19 is the hydrogen spectrum of the compound of formula 4a;

[0135] Fig. 20 is the carbon spectrum of the compound of formula 4a;

[0136] Fig.21 is the hydrogen spectrum of the compound of formula 4b;

[0137] Fig. 22 is the carbon spectrum of the compound of formula 4b;

[0138] Fig.23 is the hydrogen spectrum of the compound of formula 4c;

[0139] Fig.24 is the carbon spectrum of the compound of formula 4c;

[0140] Fig.25 is the hydrogen spectrum of the compound of formula 4d;

[0141] Fig.26 is the carbon spectrum of the compound of formula 4d;

[0142] Fig. 27 is the hydrogen spectrum of the compound of formula 4e;

[0143] Fig.28 is the carbon spectrum of the compound of formula 4e;

[0144] Fig.29 is the hydrogen spectrum of the compound of formula 4f;

[0145] Fig.30 is the carbon spectrum of the compound of formula 4f;

[0146] Fig.31 is the hydrogen spectrum of the compound of formula 4g;

[0147] Fig.32 is the carbon spectrum of the compound of formula 4g;

[0148] Fig.33 is the hydrogen spectrum of the compound of formula 4h;

[0149] Fig.34 is the carbon spectrum of the compound of formula 4h;

[0150] Fig.35 is the hydrogen spectrum of the compound of formula 5a;

[0151] Fig.36 is the carbon spectrum of the compound of formula 5a;

[0152] Fig.37 is the hydrogen spectrum of the compound of formula 5b;

[0153] Fig.38 is the carbon spectrum of the compound of formula 5b;

[0154] Fig.39 is the hydrogen spectrum of the compound of formula 5c;

[0155] Fig.40 is the carbon spectrum of the compound of formula 5c;

[0156] Fig.41 is the hydrogen spectrum of the compound of formula 6;

[0157] Fig.42 is the carbon spectrum of the compound of formula 6;

[0158] Fig.43 is the hydrogen spectrum of the compound of formula 7a;

[0159] Fig.44 is the carbon spectrum of the compound of formula 7a;

[0160] Fig.45 is the hydrogen spectrum of the compound of formula 7b;

[0161] Fig.46 is the carbon spectrum of the compound of formula 7b;

[0162] Fig.47 is the hydrogen spectrum of the compound of formula 8a;

[0163] Fig.48 is the carbon spectrum of the compound of formula 8a;

[0164] Fig.49 is the hydrogen spectrum of the compound of formula 8b;

[0165] Fig.50 is the carbon spectrum of the compound of formula 8b;

[0166] Fig.51 is the hydrogen spectrum of the compound of formula 9;

[0167] Fig.52 is the hydrogen spectrum of the compound of formula 10;

[0168] Fig.53 is the hydrogen spectrum of the compound of formula 11;

[0169] Fig.54 is the hydrogen spectrum of the compound of formula 12;

[0170] Fig.55 is the carbon spectrum of the compound of formula 12;

[0171] Fig.56 is the hydrogen spectrum of the compound of formula 13a;

[0172] Fig.57 is the carbon spectrum of the compound of formula 13a;

[0173] Fig.58 is the hydrogen spectrum of the compound of formula 13b;

[0174] Fig.59 is the carbon spectrum of the compound of formula 13b;

[0175] Fig.60 is the hydrogen spectrum of the compound of formula 13c;

[0176] Fig.61 is the carbon spectrum of the compound of formula 13c;

[0177] Fig.62 is the hydrogen spectrum of the compound of formula 13d;

[0178] Fig.63 is the carbon spectrum of the compound of formula 13d;

[0179] Fig.64 is the hydrogen spectrum of the compound of formula 13e;

[0180] Fig.65 is the carbon spectrum of the compound of formula 13e;

[0181] Fig.66 is the hydrogen spectrum of the compound of formula 13f;

[0182] Fig.67 is the carbon spectrum of the compound of formula 13f;

[0183] Fig.68 is the hydrogen spectrum of the compound of formula 13g;

[0184] Fig.69 is the carbon spectrum of the compound of formula 13g;

[0185] Fig.70 is the hydrogen spectrum of the compound of formula 13h;

[0186] Fig.71 is the carbon spectrum of the compound of formula 13h;

[0187] Fig.72 is the hydrogen spectrum of the compound of formula 13i;

[0188] Fig.73 is the carbon spectrum of the compound of formula 13i;

[0189] Fig.74 is the hydrogen spectrum of the compound of formula 14;

[0190] Fig.75 is the carbon spectrum of the compound of formula 14;

[0191] Fig.76 is the hydrogen spectrum of the compound of formula 14a;

[0192] Fig.77 is the carbon spectrum of the compound of formula 14a;

[0193] Fig.78 is the hydrogen spectrum of the compound of formula 14b;

[0194] Fig.79 is the carbon spectrum of the compound of formula 14b;

[0195] Fig.80 is the hydrogen spectrum of the compound of formula 14c;

[0196] Fig.81 is the carbon spectrum of the compound of formula 14c;

[0197] Fig.82 is the hydrogen spectrum of the compound of formula 14d;

[0198] Fig.83 is the carbon spectrum of the compound of formula 14d;

[0199] Fig.84 is the hydrogen spectrum of the compound of formula 14f;

[0200] Fig.85 is the carbon spectrum of the compound of formula 14f;

[0201] Fig.86 This is a graph showing the effect of Rubescensine A derivatives on LPS-induced NO release;

[0202] Fig.87 The graph is a dose-dependent effect diagram of Rubescensine A derivatives (Formulas 1b, 2a, 4d, 5d, 7a and 8a) on inhibiting LPS-induced NO release;

[0203] Fig.88 The graph is a dose-dependent effect diagram of Rubescensine A derivatives (Formulas 13a-13c, 14a-14c) on inhibiting LPS-induced NO release;

[0204] Fig.89 Dose-dependent effect diagram of Rubescensine A derivatives (Formula 13g-13j) in inhibiting LPS-induced NO release;

[0205] Fig.90This is a graph showing that Rubescensine A derivatives inhibit the release of IL-6 and IL-1β induced by LPS;

[0206] Fig.91 The graph shows that Rubescensine A and Rubescensine A derivatives (Formula 4d) inhibit the expression of LPS-induced inflammatory genes; wherein A is the expression of inflammatory genes inhibited by Rubescensine A; and B is the expression of inflammatory genes inhibited by the compound shown in Formula 4d;

[0207] Fig.92 The graph shows that the Rubescensine A derivatives (Formula 13b and Formula 13c) inhibit the expression of LPS-induced inflammatory genes; wherein C is the expression of inflammatory genes inhibited by the compound shown in Formula 13b; and D is the expression of inflammatory genes inhibited by the compound shown in Formula 13c;

[0208] Fig.93 This is a graph showing that Rubescensine A derivatives inhibit the expression of LPS-induced inflammation-related proteins;

[0209] Fig.94 This is a graph showing the therapeutic effect of Rubescensine A derivative (Formula 4d) on acute pneumonia in mice;

[0210] Fig.95 Graph showing the therapeutic effect of Rubescensine A derivative (Formula 13c) on acute pneumonia in mice;

[0211] Fig.96 This is a graph showing the therapeutic effect of Rubescensine A derivative (Formula 4d) on acute peritonitis in mice;

[0212] Fig.97 The volcano map of transcriptome sequencing of Rubescensine A derivatives (Formula 4d) regulating inflammation-related signaling pathways;

[0213] Fig.98 The GO analysis diagram of transcriptome sequencing of Rubescensine A derivatives (Formula 4d) regulating inflammation-related signaling pathways;

[0214] Fig.99 The KEGG analysis diagram of transcriptome sequencing of Rubescensine A derivatives (Formula 4d) regulating inflammation-related signaling pathways;

[0215] Fig.100 The volcano map of transcriptome sequencing of Rubescensine A derivatives (Formula 13c) regulating inflammation-related signaling pathways;

[0216] Fig.101 The GO analysis diagram of transcriptome sequencing of Rubescensine A derivatives (Formula 13c) regulating inflammation-related signaling pathways;

[0217] Fig.102 The KEGG analysis diagram of transcriptome sequencing of Rubescensine A derivatives (Formula 13c) regulating inflammation-related signaling pathways;

[0218] Fig.103 This is a diagram of the inflammatory signaling pathway regulated by Rubescensine A derivatives (Formula 4d). DETAILED DESCRIPTION

[0219] It is worth noting that, unless otherwise specified, the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0220] The abbreviations used in the present invention are well known to those skilled in the art, and the following abbreviations are provided as examples:

[0221] rt: room temperature;

[0222] DMP: 2,2-dimethoxypropane;

[0223] DCM: dichloromethane;

[0224] TsOH: p-toluenesulfonic acid;

[0225] MsCl: methanesulfonyl chloride;

[0226] DMF: N,N-dimethylformamide.

[0227] Example 1

[0228]

[0229] 4-(Bis(2-chloroethyl)amino)benzoic acid (0.1 g, 0.38 mmol) was dissolved in dichloromethane (DCM), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.09 g, 0.52 mmol) and 1-hydroxybenzotriazole (HOBt, 0.05 g, 0.37 mmol) were added. After reacting for 20 min, Rubescensine A (0.12 g, 0.33 mmol) and 4-dimethylaminopyridine (DMAP, 0.01 g, 0.08 mmol) were added, and the reaction was stirred at room temperature for 12 h. The reaction solution was extracted with water and DCM, and the organic layer was separated and precipitated with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 76 mg of the compound of formula 1a with a yield of 38%. The hydrogen spectrum and carbon spectrum of the compound of formula 1a are shown as follows: Figure 1 and Figure 2 shown.

[0230] 1 H NMR (400 MHz, CDCl 3)δ7.70-7.88(m,2H),6.53-6.72(m,2H),6.10-6.37(m,2H),6.02(s,1H),5.47(s,1H),4.27-4.44(m ,2H),4.09(dd,J=1.59,10.15Hz,1H),3.72-3.91(m,5H),3.59-3.68(m,4H),3.47-3.56(m,2H),3.2 9(d,J=10.03Hz,1H),2.66(dd,J=4.65,8.31Hz,1H),2.25-2.43(m,1H),2.03(dd,J=5.75,12.84Hz, 1H),1.56-1.84(m,5H),1.47(td,J=3.18,13.45Hz,1H),1.25-1.32(m,2H),1.12(d,J=4.40Hz,6H).

[0231] 13 C NMR (100 MHz, CDCl 3 )δ206.8,164.7,150.3,150.1,131.9,120.1,111.1,96.3,74.0,73.5,63.4,61. 9,59.9,54.6,53.3,41.4,41.4,40.1,38.7,33.8,32.6,30.5,30.0,21.7,19.9.

[0232] HRMS m / z calculation for [C 31 H 39 Cl 2 NO 7 +H] + 608.2104, found 608.2147.

[0233] Example 2

[0234]

[0235] 1.2 eq of acrylic acid (0.03 g), 1 eq of Rubescensine A (0.12 g), 1.5 eq of EDCI (0.09 g), 1.2 eq of HOBt (0.05 g), and 0.2 eq of DMAP (0.01 g) were added to a 25 ml reaction bottle. Other operations were the same as in Example 1. After purification by chromatographic column, 58 mg of the compound of formula 1b was obtained with a yield of 42%. The hydrogen spectrum and carbon spectrum of the compound of formula 1b are shown as follows: Figure 3 and Figure 4 shown.

[0236] 1H NMR(400MHz,CHLOROFORM-d)d 6.38(dd,J=1.10,17.24Hz,1H),6.16(s,1H),6.01-6.10(m,2H),5.84-5.94(m,2H),5.50 (s,1H),4.32(dd,J=1.22,10.27Hz,1H),4.07-4.13(m,2H),3.78(dd,J=6.72,10.39Hz,1H ),3.48-3.55(m,1H),3.24(d,J=10.27Hz,1H),2.30(s,1H),1.98-2.05(m,1H),1.71-1.79 (m,1H),1.58-1.71(m,3H),1.45-1.51(m,1H),1.26-1.30(m,2H),1.13(d,J=1.71Hz,6H).

[0237] 13 C NMR(100MHz,CHLOROFORM-d)d 206.6,164.4,149.8,132.4,127.7,120.2,96.2,74.0,73.4,63.5,61.9 ,59.8,54.6,53.4,41.4,41.3,38.7,33.8,32.6,30.5,30.0,21.6,19.8.

[0238] HRMS m / z calculation for [C 23 H 30 O 7 +H] + 419.1992, found 419.2118.

[0239] Example 3

[0240]

[0241] Salicylic acid (0.06 g, 0.41 mmol) was dissolved in DCM, 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.09 g, 0.52 mmol) and triethylamine (Et 3 N, 0.05 g, 0.50 mmol), after reacting for 30 min, add Rubescensine A (0.12 g, 0.33 mmol) and 1-hydroxybenzotriazole (HOBt, 0.05 g, 0.37 mmol), and stir at room temperature for 12 h. The reaction solution was washed and diluted with 10% HCl and extracted with DCM. The organic layer was separated and washed with anhydrous Na 2 SO 4The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 48 mg of the compound of formula 1c with a yield of 30%. The hydrogen spectrum and carbon spectrum of the compound of formula 1c are shown as follows: Figure 5 and Figure 6 shown.

[0242] 1 H NMR(400MHz,CHLOROFORM-d)d 10.44(s,1H),7.69(d,J=7.92Hz,1H),7.46(t,J=7.61Hz,1H),6.97(d,J=8.29Hz,1H),6.86(t,J=7.55Hz,1H),6.25( s,1H),6.19(s,1H),6.05-6.10(m,1H),5.58(s,1H),4.40(d,J=10.39Hz,1H),4.13(d,J=10.39Hz,1H),3.87(s,1H), 3.78(dd,J=7.18,10.89Hz,1H),3.52-3.59(m,1H),3.32(d,J=9.53Hz,1H),2.66-2.76(m,1H),2.30-2.38(m,1H),2. 03(dd,J=5.69,12.87Hz,1H),1.81-1.90(m,1H),1.64(br.s.,5H),1.52(d,J=13.61Hz,1H),1.16(d,J=6.31Hz,7H).

[0243] 13 C NMR(101MHz,CHLOROFORM-d)d 136.0,130.2,120.7,119.5,117.7,96.0,77.2,76.3,74.7,73.6,63.5,62 .2,59.3,54.9,41.6,41.4,38.7,33.7,32.7,30.6,30.1,29.7,21.8,20.0.

[0244] HRMS m / z calculation for [C 27 H 32 O 8 +H] + 485.2097, found 485.2103.

[0245] Example 4

[0246]

[0247] In a 25 ml reaction bottle, add 1.2 times the amount of (S)-(+)-ibuprofen (0.08 g), 1 times the amount of Rubescensine A (0.12 g), 1.5 times the amount of EDCI (0.09 g), 1.5 times the amount of Et 3 N (0.05 g), 1.2 times the amount of HOBt (0.05 g). The other operations were the same as in Example 3. After purification by chromatographic column, 64 mg of the compound of formula 1d was obtained with a yield of 35%. The hydrogen spectrum and carbon spectrum of the compound of formula 1d are shown as follows: Figure 7 and Figure 8 shown.

[0248] 1 H NMR(400MHz,CHLOROFORM-d)d ppm 0.84-0.93(m,7H),1.09-1.15(m,7H),1.41-1.52(m,5H),1.61-1.72(m,5H),1.76-1.87(m, 1H),1.97(d,J=5.69Hz,1H),2.42(d,J=7.05Hz,2H),2.96(d,J=10.02Hz,1H),3.42-3.54(m ,1H),3.59(d,J=7.18Hz,1H),3.76(dd,J=10.39,6.43Hz,1H),4.21(s,1H),4.29(d,J=10.3 9Hz,1H),5.07(s,1H),5.79(s,1H),5.85(s,1H)6.06(d,J=10.27Hz,1H),6.96-7.13(m,4H).

[0249] 13 C NMR(101MHz,CHLOROFORM-d)d ppm 14.21,17.64,19.71,21.06,21.59,22.34,30.10,30.21,32.50,33.77,38.65,40.72,41.28,4 4.98,45.36,54.42,60.00,60.41,61.69,73.47,73.72,77.23,96.29,127.04,129.47,172.99.

[0250] HRMS m / z calculation for [C 33 H 44 O 7 +H] + 551.3087, found 551.3029.

[0251] Example 5

[0252]

[0253] In a 25 ml reaction bottle, 1.2 times the amount of probenecid (0.11 g), 1 times the amount of Rubescensine A (0.12 g), 1.5 times the amount of EDCI (0.09 g), 1.5 times the amount of Et 3 N (0.05 g), 1.2 times the amount of HOBt (0.05 g). The other operations were the same as in Example 3. After purification by chromatographic column, 69 mg of the compound of formula 1e was obtained with a yield of 33%. The hydrogen spectrum and carbon spectrum of the compound of formula 1e are shown as follows: Fig. 9 and Fig.10 shown.

[0254] 1 H NMR(400MHz,CHLOROFORM-d)d 8.06-8.12(m,J=8.54Hz,2H),7.82-7.88(m,J=8.66Hz,2H),6.25(s,1H),6.20(s,1H),6.09(d,J=11. 13Hz,1H),5.59(s,1H),5.38(s,1H),4.42(d,J=10.39Hz,1H),4.13(d,J=10.27Hz,1H),3.79(s,1H),3 .74-3.78(m,1H),3.32(d,J=9.65Hz,1H),3.06-3.12(m,4H),2.25(s,1H),2.01-2.08(m,2H),1.64-1. 75(m,3H),1.52-1.58(m,4H),1.15(d,J=8.54Hz,6H),1.11(d,J=3.96Hz,1H),0.89(t,J=7.42Hz,7H).

[0255] 13 C NMR(101MHz,CHLOROFORM-d)d 130.4,126.8,77.2,76.4,74.8,73.6,59.4,54.9,50.0,41.6,41.4,38.7,33.8,30.6,30.1,29.4,22.0,21.8,20.1,11.2.

[0256] HRMS m / z calculation for [C 33 H 45 NO 9 S+H] + 632.2815, found 632.2893.

[0257] Example 6

[0258]

[0259] In a 25 ml reaction bottle, 1.2 times the amount of ketoprofen (0.1 g), 1 times the amount of Rubescensine A (0.12 g), 1.5 times the amount of EDCI (0.09 g), 1.5 times the amount of Et 3 N (0.05 g), 1.2 times the amount of HOBt (0.05 g). The other operations were the same as in Example 3, and after purification by chromatographic column, 77 mg of the compound of formula 1f was obtained with a yield of 39%. The hydrogen spectrum and carbon spectrum of the compound of formula 1f are shown as follows: Fig.11 and Fig.12 shown.

[0260] 1 H NMR(400MHz,CHLOROFORM-d)d 7.78-7.86(m,2H),7.68(dd,J=2.85,4.45Hz,1H),7.60-7.67(m,2H),7.50-7.57(m,2H),7.44-7.48(m,2H),6.11(s,1H),6.0 2(d,J=10.39Hz,1H),5.88(d,J=8.91Hz,1H),5.84(s,1H),5.44(s,1H),5.38(t,J=4.64Hz,1H),4.27(d,J=10.39Hz,1H),4.03 (d,J=10.39Hz,1H),3.77(d,J=7.18Hz,1H),3.66-3.73(m,1H),3.54(s,1H),3.17(d,J=9.77Hz,1H),2.25(t,J=7.67Hz,1H),2 .02-2.08(m,2H),1.63-1.70(m,3H),1.52-1.56(m,4H),1.46(s,1H),1.22-1.27(m,2H),1.14(d,J=9.53Hz,4H),1.08(s,2H).

[0261] 13 C NMR(101MHz,CHLOROFORM-d)d 132.6,130.3,128.4,77.2,73.5,61.8,38.6,30.4,30.1,29.8,29.7,29.4,27.2,21.7,19.8.

[0262] HRMS m / z calculation for [C 36 H 40 O 8 +H] + 601.2723, found 601.2796.

[0263] Example 7

[0264]

[0265] The compound represented by formula 1b (0.12 g, 0.29 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added at -78°C. 2 After 20 min of reaction under protection, the reaction was continued at room temperature for 2 h. The reaction solution was extracted with water and DCM, and the organic layer was washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 52 mg of the compound of formula 2a with a yield of 45%. The hydrogen spectrum and carbon spectrum of the compound of formula 2a are shown as follows: Fig.13 and Fig.14 shown.

[0266] 1 H NMR(400MHz,CHLOROFORM-d)δ6.37(dd,J=1.47,17.36Hz,1H),6.17(s,1H),5.97-6.05(m,1 H),5.81(dd,J=1.47,10.51Hz,1H),5.66-5.71(m,1H),5.46(s,1H),4.77(br.s.,1H),4.18 -4.25(m,2H),3.78(d,J=9.54Hz,1H),3.26(d,J=5.14Hz,1H),2.54-2.62(m,1H),2.38-2.4 6(m,1H),1.92-2.00(m,1H),1.68-1.92(m,6H),1.24-1.36(m,2H),1.01(d,J=1.96Hz,6H).

[0267] 13 C NMR(100MHz,CHLOROFORM-d)δ202.0,199.8,164.9,146.7,132.2,127.7,119.1 ,84.3,69.5,64.7,54.4,53.0,47.0,42.3,32.7,31.1,30.1,24.1,22.6,16.7.

[0268] Example 8

[0269]

[0270] Rubescensine A (0.12 g, 0.33 mmol) was dissolved in DCM, and 1.2 times the amount of adamantane-1-carboxylic acid and 1.5 times the amount of Et 3N and EDCI, 1.2 times the amount of HOBt, react at room temperature for 12 hours to obtain the intermediate. The purified intermediate (0.1 g) was dissolved in DCM, diethylamine sulfur trifluoride (DAST) was added at -78 °C, N 2 After 20 min of reaction under protection, the reaction was continued at room temperature for 2 h. The reaction solution was extracted with water and DCM, and the organic layer was washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 61 mg of the compound of formula 2b with a yield of 63.2%. The hydrogen spectrum and carbon spectrum of the compound of formula 2b are shown as follows: Fig.15 and Fig.16 shown.

[0271] 1 H NMR (400 MHz, CDCl 3 )δ6.15(s,1H),5.56(d,J=1.22Hz,1H),5.37-5.47(m,1H),4.65(br.s.,1H),4.25(s,1H),4.1 8(d,J=9.54Hz,1H),3.77(d,J=9.29Hz,1H),3.08-3.23(m,1H),2.56(s,1H),2.31-2.44(m,1H ),1.93-2.00(m,5H),1.88(s,1H),1.82-1.87(m,1H),1.77(s,3H),1.76(s,3H),1.71-1.75(m ,1H),1.68-1.70(m,1H),1.66(br.s.,6H),1.59(s,2H),1.32(d,J=13.45Hz,1H),1.01(s,6H).

[0272] 13 C NMR (100 MHz, CDCl 3 )δ202.2,199.8,176.5,146.9,118.6,86.9,85.2,84.4,75.8,69.6,64.7,5 4.6,46.9,42.3,40.7,38.4,36.4,32.6,31.2,30.0,27.8,24.3,22.6,16.7.

[0273] HRMS m / z calculation for [C 31 H 40 O 6 +H] + 509.2825, found 509.3046.

[0274] Example 9

[0275]

[0276] Rubescensine A (0.1 g, 0.27 mmol) was dissolved in dichloromethane (DCM), Jones reagent (0.14 g, 1.37 mmol) was added, and the reaction was allowed to proceed at room temperature for 30 min. TLC showed that the reaction of the raw material was complete, and isopropanol was added dropwise to quench the reaction. The reaction solution was diluted with saturated NaCl solution and extracted with DCM. The organic layer was separated and washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 78 mg of the compound of formula 3 with a yield of 81.5%. The hydrogen spectrum and carbon spectrum of the compound of formula 3 are shown as follows: Fig.17 and Fig.18 shown.

[0277] 1 H NMR(400MHz,CHLOROFORM-d)d 6.28(s,1H),5.81(d,J=12.00Hz,1H),5.68(s,1H),5.09(s,1H),4.92(s,1H),4.51(s,1H),4.32(d,J=10.52Hz,1H),4 .05(dd,J=1.42,10.45Hz,1H),3.82(dd,J=9.03,12.00Hz,1H),3.09(d,J=9.16Hz,1H),2.44-2.55(m,2H),2.35-2.40

[0278] (m,1H),2.15(dd,J=4.83,13.86Hz,1H),1.99(d,J=9.53Hz,1H),1.88-1.95(m,1H), 1.72-1.79(m,1H),1.62-1.69(m,3H),1.28(s,2H),1.12-1.16(m,1H),1.02(s,3H).

[0279] 13 C NMR(101MHz,CHLOROFORM-d)d 122.2,77.2,73.2,71.9,65.1,59.1,49.8,42.6,38.1,35.5,32.8,30.4,29.6,23.1,19.0.

[0280] HRMS m / z calculation for [C 20 H 26 O 6 +H] + 363.1729, found 363.1802.

[0281] Example 10

[0282]

[0283] 2-(4-methoxyphenyl)acetic acid (0.06 g, 0.36 mmol) was dissolved in DCM, 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.08 g, 0.42 mmol) and 1-hydroxybenzotriazole (HOBt, 0.04 g, 0.30 mmol) were added, and the compound of formula 3 (0.1 g, 0.28 mmol) and 4-dimethylaminopyridine (DMAP, 0.01 g, 0.08 mmol) were added after reacting for 20 min, and the reaction was continued at room temperature with stirring for 12 h. The reaction solution was extracted with water and DCM, and the organic layer was separated and precipitated with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 76.5 mg of the compound of formula 4a with a yield of 54%. The hydrogen spectrum and carbon spectrum of the compound of formula 4a are shown as follows: Fig.19 and Fig. 20 shown.

[0284] 1 H NMR (400 MHz, CDCl 3 )δ0.93(s,3H),1.12(s,3H),1.24(d,J=7.58Hz,1H),1.51(br.s.,1H),1.67(s,1H),1.78-1 .90(m,3H),2.21-2.30(m,1H),2.35(d,J=4.16Hz,2H),3.00(d,J=9.78Hz,1H),3.44(s,2H), 3.68-3.73(m,4H),3.91-3.99(m,2H),4.20(dd,J=10.51,1.22Hz,1H),5.30(d,J=11.49Hz,1 H),5.46(d,J=0.98Hz,1H),5.76(s,1H),6.14(s,1H),6.71-6.81(m,2H),6.99-7.08(m,2H).

[0285] 13 C NMR (100 MHz, CDCl 3)δ211.6,204.7,170.2,149.3,130.3,125.0,121.9,114.1,97.077.3,77.2,77.0,76.7,75.4,73. 2,64.9,61.2,60.1,55.3,50.8,48.6,41.3,40.7,38.5,35.8,32.9,30.5,29.9,29.7,23.2,19.1.

[0286] HRMS m / z calculation for [C 29 H 34 O 8 +Na] + 533.2254, found 533.2229.

[0287] Embodiment 11

[0288]

[0289] In a 25 ml reaction bottle, add 1.2 times the amount of 2-(3,4-dimethoxyphenyl)acetic acid (0.06 g), 1 times the amount of the compound shown in formula 3 (0.1 g), 1.5 times the amount of EDCI (0.08 g), 1.2 times the amount of HOBt (0.04 g), and 0.2 times the amount of DMAP (0.01 g). The other operations were the same as in Example 10. After purification by chromatographic column, 107 mg of the compound of formula 4b was obtained with a yield of 71%. The hydrogen spectrum and carbon spectrum of the compound of formula 4b are shown as follows: Fig.21 and Fig. 22 shown.

[0290] 1 H NMR (400 MHz, CDCl 3) δ 0.98 (s, 3H), 1.16 - 1.19 (m, 3H), 1.27 - 1.34 (m, 1H), 1.57 (td, J = 13.08, 7.34 Hz, 1H), 1.71 (ddd, J = 13.69, 8.80, 6.60 Hz, 1H), 1.84 - 1.97 (m, 3H), 2.16 - 2.24 (m, 1H), 2.26 - 2.36 (m, 1H), 2.38 - 2.56 (m, 2H), 3.04 (d, J = 9.54 Hz, 1H), 3.45 - 3.52 (m, 2H), 3.76 (dd, J = 11.49, 8.80 Hz, 1H), 3.80 - 3.85 (m, 6H), 3.93 - 4.04 (m, 1H), 4.14 (s, 1H), 4.20 - 4.34 (m, 1H), 5.41 (d, J = 11.49 Hz, 1H) 5.47 - 5.53 (m, 1H), 5.83 (s, 1H), 6.17 (s, 1H), 6.69 - 6.72 (m, 2H), 6.73 - 6.78 (m, 1H).

[0291] 13 C NMR (100 MHz, CDCl 3 ) δ 211.6, 204.8, 170.1, 149.3, 149.0, 148.3, 125.5, 121.9, 121.4, 112.5, 111.3, 97.0, 77.4, 77.1, 76.8, 75.3, 73.2, 64.9, 61.2, 60.0, 55.9, 55.9, 50.7, 48.5, 41.2, 41.2, 38.5, 35.8, 32.9, 30.5, 29.9, 23.2, 19.1.

[0292] HRMS m / z calcd for [C 30 H 36 O 9 +Na] + 563.2259, found 563.2253.

[0293] Example 12

[0294]

[0295] In a 25 ml reaction bottle, 1.2 times the amount of 2-(4-(bis(2-chloroethyl)amino)phenyl)acetic acid (0.09 g), 1 times the amount of the compound shown in formula 3 (0.1 g), 1.5 times the amount of EDCI (0.08 g), 1.2 times the amount of HOBt (0.04 g), and 0.2 times the amount of DMAP (0.01 g) were added. The other operations were the same as in Example 10, and after purification by a chromatographic column, 105.8 mg of the compound of formula 4c was obtained with a yield of 61%. The hydrogen spectrum and carbon spectrum of the compound of formula 4c are shown as follows: Fig.23 and Fig.24 shown.

[0296] 1 H NMR (400 MHz, CDCl 3 )δ7.05-7.10(m,J=8.56Hz,2H),6.59-6.64(m,2H),6.22(s,1H),5.82(s,1H),5.55(s,1H),5.37(d,J=11.49Hz,1H ),4.25-4.29(m,1H),4.01-4.05(m,2H),3.78(dd,J=8.68,11.37Hz,1H),3.68-3.74(m,4H),3.59-3.65(m,4H),3. 10(d,J=9.54Hz,1H),2.51-2.58(m,1H),2.40-2.48(m,1H),2.29-2.37(m,1H),2.22(dd,J=4.28,13.57Hz,1H),1. 92-1.97(m,2H),1.73(ddd,J=6.60,8.68,13.82Hz,1H),1.61(s,4H),1.26-1.35(m,2H),1.20(s,3H),1.01(s,3H).

[0297] 13 C NMR (100 MHz, CDCl 3 )δ211.7,204.7,170.4,149.3,145.3,130.5,121.9,121.9,112.3,97.0,75.5,73.1,64.9 ,61.2,60.1,53.5,50.7,48.6,41.2,40.5,40.4,38.5,35.8,32.9,30.5,29.9,23.3,19.1.

[0298] HRMS m / z calculation for [C 32 H 39 Cl 2 NO 7 +H] +620.2104, found 620.2161.

[0299] Example 13

[0300]

[0301] In a 25 ml reaction bottle, 1.2 times the amount of acrylic acid (0.03 g), 1 times the amount of the compound shown in formula 3 (0.1 g), 1.5 times the amount of EDCI (0.08 g), 1.2 times the amount of HOBt (0.04 g), and 0.2 times the amount of DMAP (0.01 g) were added. The other operations were the same as in Example 10. After purification by chromatographic column, 54.8 mg of the compound of formula 4d was obtained with a yield of 47%. The hydrogen spectrum and carbon spectrum of the compound of formula 4d are shown as follows: Fig.25 and Fig.26 shown.

[0302] 1 H NMR(400MHz,CHLOROFORM-d)δ6.34-6.41(m,1H),6.27(s,1H),5.98-6.09(m,1H),5.93(s,1H),5.83-5.89(m ,1H),5.62(s,1H),5.41(d,J=11.49Hz,1H),4.31(d,J=10.76Hz,1H),4.16(s,1H),4.04(d,J=10.76Hz,1H), 3.80(dd,J=8.80,11.49Hz,1H),3.19(d,J=9.29Hz,1H),2.59(td,J=8.74,13.82Hz,1H),2.42-2.52(m,1H), 2.21-2.39(m,2H),1.86-2.02(m,3H),1.58-1.78(m,3H),1.29-1.38(m,1H),1.20(s,3H),0.99-1.02(m,3H).

[0303] 13 C NMR(101MHz,CHLOROFORM-d)d 211.7,204.9,164.5,149.3,132.4,127.7,122.2,97.0,75.2,73.2,65.0 ,61.3,60.1,50.8,48.6,41.4,38.5,35.8,32.9,30.5,30.0,23.3,19.1.

[0304] HRMS m / z calculation for [C 23 H 28 O 7 +H]+ 620.2104, found 620.2161.

[0305] Embodiment 14

[0306]

[0307] Salicylic acid (0.06 g, 0.41 mmol) was dissolved in dichloromethane (DCM), and 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.1 g, 0.50 mmol) and triethylamine (Et 3 N), react for 20 min, add compound 3 (0.12 g, 0.33 mmol) and 1-hydroxybenzotriazole (HOBt, 0.13 g, 0.52 mmol), and stir at room temperature for 12 h. The reaction solution was washed and diluted with 10% HCl and extracted with DCM. The organic layer was separated and washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 75 mg of the compound of formula 4e with a yield of 47%. The hydrogen spectrum and carbon spectrum of the compound of formula 4e are shown as follows: Fig. 27 and Fig.28 shown.

[0308] 1 H NMR(400MHz,CHLOROFORM-d)d 10.45(s,1H),7.67(dd,J=1.48,8.04Hz,1H),7.46(s,1H),6.98(d,J=8.29Hz,1H),6.86(t,J=7.6 7Hz,1H),6.35(s,1H),6.21(s,1H),5.70(s,1H),5.39(d,J=11.88Hz,2H),4.39(d,J=10.64Hz,1H ),4.09(d,J=10.76Hz,1H),3.90(s,1H),3.80(dd,J=9.09,11.94Hz,1H),3.28(d,J=9.65Hz,1H), 2.27-2.33(m,1H),2.25(s,1H),2.01-2.08(m,4H),1.71(s,1H),1.43-1.47(m,2H),1.04(s,3H).

[0309] 13C NMR(101MHz,CHLOROFORM-d)d 135.9,130.2,122.5,119.4,117.6,77.2,74.8,73.5,65.0,59.6,50.8,48 .6,41.7,38.3,35.7,32.9,30.5,30.1,29.8,29.7,29.3,23.1,19.3,14.1.

[0310] HRMS m / z calculation for [C 27 H 30 O 8 +H] + 483.1941, found 483.1968.

[0311] Embodiment 15

[0312]

[0313] In a 25 ml reaction bottle, add 1.2 times the amount of (S)-(+)-ibuprofen (0.08 g), 1 times the amount of the compound of formula 3 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 1.5 times the amount of Et 3 N (0.05 g), 1.2 times the amount of HOBt (0.05 g). The other operations were the same as in Example 14, and after purification by chromatographic column, 75 mg of the compound of formula 4f was obtained with a yield of 63%. The hydrogen spectrum and carbon spectrum of the compound of formula 4f are shown as follows: Fig.29 and Fig.30 shown.

[0314] 1 H NMR(400MHz,CHLOROFORM-d)d 7.05-7.14(m,4H),6.04(s,1H),5.82(s,1H),5.36-5.44(m,4H),5.30(s,1H),4.23(s,1H),2.46(d,J=7.05 Hz,4H),2.25(d,J=7.05Hz,3H),2.06(br.s.,4H),1.63(br.s.,10H),1.42-1.52(m,4H),1.04(br.s.,3H).

[0315] 13 C NMR(101MHz,CHLOROFORM-d)d 129.9,129.4,127.1,60.3,36.0,35.9,31.9,30.2,29.8,29.7,29.6,29.5,29.5,29.4,29.3,27.2,25.6,22.7,22.4,14.1.

[0316] HRMS m / z calculation for [C 33 H 42 O 7 +H] + 549.2931, found 549.2871.

[0317] Example 16

[0318]

[0319] In a 25 ml reaction bottle, 1.2 times the amount of probenecid (0.11 g), 1 times the amount of compound 3 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 1.5 times the amount of Et 3 N (0.05 g), 1.2 times the amount of HOBt (0.05 g). The other operations were the same as those in Example 14. After purification by chromatographic column, 68.5 mg of the compound of formula 4g was obtained with a yield of 33%. The hydrogen spectrum and carbon spectrum of the compound of formula 4g are shown as follows: Fig.31 and Fig.32 shown.

[0320] 1 H NMR(400MHz,CHLOROFORM-d)d 8.07(d,J=8.54Hz,2H),7.82-7.87(m,2H),6.36(s,1H),6.18-6.23(m,1H),5.70(s,1H),5.42(d,J=12.00Hz,1H),4.39(d,J= 10.39Hz,1H),4.06-4.10(m,1H),3.84(s,1H),3.78(dd,J=8.97,11.94Hz,1H),3.27(d,J=9.53Hz,1H),3.07-3.12(m,4H),2. 61-2.71(m,1H),2.47-2.56(m,1H),2.41(dd,J=4.70,9.03Hz,1H),2.22-2.38(m,2H),2.04-2.16(m,2H),2.01(d,J=8.91Hz, 1H),1.91-1.97(m,1H),1.68-1.82(m,2H),1.61(s,5H),1.56(d,J=7.67Hz,3H),1.37-1.45(m,1H),1.23(s,3H),1.03(s,3H).

[0321] 13C NMR(101MHz,CHLOROFORM-d)d 130.5,127.0,122.4,96.9,77.2,75.0,73.6,65.1,61.6,59.6,50.8,50. 0,48.6,41.7,38.3,35.7,32.9,30.5,30.1,29.7,23.1,22.0,19.3,11.2.

[0322] HRMS m / z calculation for [C 33 H 33 NO 9 S+H] + 628.2659, found 628.2589.

[0323] Embodiment 17

[0324]

[0325] In a 25 ml reaction bottle, add 1.2 times the amount of ketoprofen (0.10 g), 1 times the amount of compound 3 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 1.5 times the amount of Et 3 N (0.05 g), 1.2 times the amount of HOBt (0.05 g). The other operations were the same as those in Example 14. After purification by chromatographic column, 114.5 mg of the compound of formula 4h was obtained with a yield of 58%. The hydrogen spectrum and carbon spectrum of the compound of formula 4h are shown as follows: Fig.33 and Fig.34 shown.

[0326] 1 H NMR(400MHz,CHLOROFORM-d)d 7.79-7.86(m,2H),7.61-7.70(m,3H),7.51-7.56(m,2H),7.40-7.48(m,2H),6.22(s,1H),5.84(s,1H),5. 57(s,1H),5.37-5.40(m,1H),5.32(d,J=11.51Hz,1H),4.27(d,J=10.27Hz,1H),3.99(s,1H),3.72-3.78( m,2H),3.61(s,1H),3.12(d,J=9.40Hz,1H),2.23-2.28(m,1H),2.03-2.08(m,2H),1.92-1.98(m,2H),1.7 1(s,1H),1.64(dd,J=7.42,14.48Hz,2H),1.51-1.55(m,3H),1.20-1.23(m,3H),1.03(s,1H),1.00(s,2H).

[0327] 13 C NMR(101MHz,CHLOROFORM-d)d 130.2,128.8,128.3,77.2,45.7,32.9,30.5,29.7,29.3,23.2.

[0328] HRMS m / z calculation for [C 27 H 30 O 8 +H] + 599.2567, found 599.2636.

[0329] Embodiment 18

[0330]

[0331] The compound of formula 4c (0.1 g, 0.16 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added at -78°C. 2 After 20 min of reaction under protection, the reaction was continued at room temperature for 2 h. The reaction solution was extracted with water and DCM, and the organic layer was washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 70.2 mg of the compound of formula 5a with a yield of 73%. The hydrogen spectrum and carbon spectrum of the compound of formula 5a are shown as follows: Fig.35 and Fig.36 shown.

[0332] 1 H NMR (400 MHz, CDCl 3 )δ7.09-7.11(m,2H),6.59-6.61(m,2H),6.12(s,1H),5.61(s,1H),5.44(s,1H),4.25-4.32(m,2H),3.68-3.72(m,4H),3.59-3.64(m,4 H),2.45(td,1H),2.68-2.78(m,1H),2.28-2.52(m,4H),2.15(s,1H),1.81-1.93(m,3H),1.25-1.36(m,2H),1.20(s,3H),1.06(s,3H).

[0333] 13 C NMR (100 MHz, CDCl 3)δ208.9,201.3,198.7,144.1,129.7,121.6,118.2,82.2,74.8,69.0,63.0,60.2,52.5,40.8,40.0,39.4,38.8,35.3,30.3,29.1,18.2.

[0334] HRMS m / z calculation for [C 28 H 29 B O 6 +Na] + 565.1127, found 565.0859.

[0335] Embodiment 19

[0336]

[0337] The compound of formula 3 (0.12 g, 0.33 mmol) was dissolved in DCM, and 1.2 times the amount of 2-bromophenylacetic acid (0.09 g, 0.42 mmol), 1.5 times the amount of EDCI (0.09 g, 0.47 mmol), 1.2 times the amount of HOBt (0.05 g, 0.37 mmol), and 0.2 times the amount of DMAP (0.01 g, 0.08 mmol) were added. After reacting at room temperature for 12 hours, an intermediate was obtained. The intermediate (0.1 g, 0.18 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added at -78 °C, and N 2 After 20 min of reaction under protection, the reaction was continued at room temperature for 2 h. The reaction solution was extracted with water and DCM, and the organic layer was washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 62.2 mg of the compound of formula 5b with a yield of 64%. The hydrogen spectrum and carbon spectrum of the compound of formula 5b are shown as follows: Fig.37 and Fig.38 shown.

[0338] 1 H NMR (400 MHz, CDCl 3 )δ7.09-7.12(m,2H),6.59-6.62(m,2H),6.13(s,1H),5.62(s,1H),5.45(s,1H), 4.28-4.31(m,2H),3.68-3.74(m,4H),3.59-3.64(m,4H),3.46(s,2H),3.10(d,J=

[0339] 8.31Hz,1H),2.70-2.77(m,1H),2.33-2.54(m,4H),2.16(s,1H),1.85-1.91(m,3H),1.26(s,2H),1.21(s,3H),1.07(s,3H).

[0340] 13 C NMR (100 MHz, CDCl 3 )δ208.9,201.3,198.7,146.7,144.1,129.7,121.6,118.2,111.1,82.3,74.8,69.0,63.0 ,60.2,60.0,52.5,46.1,40.8,40.0,40.0,39.5,38.9,35.3,30.9,30.3,29.1,22.3,18.2.

[0341] HRMS m / z calculation for [C 32 H 37 Cl 2 NO 6 +H] + 602.1998, found 602.2053.

[0342] Embodiment 20

[0343]

[0344] The compound of formula 4d (0.1 g, 0.24 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added at -78°C. The other operations were the same as those in Example 18. After purification by chromatographic column, 57.3 mg of the compound of formula 5c was obtained with a yield of 60%. The hydrogen spectrum and carbon spectrum of the compound of formula 5c are shown as follows: Fig.39 and Fig.40 shown.

[0345] 1H NMR(400MHz,CHLOROFORM-d)δ6.33-6.42(m,1H),6.15(s,1H),5.98-6.08(m,1H),5 .80-5.86(m,1H),5.68(s,1H),5.50(s,1H),4.25-4.39(m,3H),3.21(d,J=8.07Hz, 1H),2.68-2.80(m,1H),2.42-2.57(m,2H),2.35(td,J=4.13,14.73Hz,1H),2.09-2 .20(m,2H),1.81-1.97(m,3H),1.66-1.81(m,1H),1.21(s,3H),1.03-1.08(m,3H).

[0346] 13 C NMR(100MHz,CHLOROFORM-d)δ209.8,202.3,199.5,164.9,147.6,132.2,127.7,119.3,8 3.3,75.8,70.1,64.1,61.5,61.2,47.1,42.0,41.2,36.4,32.0,31.3,30.2,23.2,19.2.

[0347] HRMS m / z calculation for [C 23 H 26 O 6 +H]+399.1729, found 399.1882.

[0348] Embodiment 21

[0349]

[0350] Rubescensine A (0.12 g, 0.33 mmol) was dissolved in DCM, and 1.2 times the amount of acetic anhydride (Ac 2 O, 0.04 g, 0.39 mmol), 1.5 times the amount of Et 3 N (0.05 g, 0.49 mmol), 0.2 times the amount of DMAP (0.01 g, 0.08 mmol), react at room temperature for 2 h. The reaction solution was extracted with dilute hydrochloric acid and DCM, and the organic layer was washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 108.6 mg of the compound of formula 6 with a yield of 81%. The hydrogen spectrum and carbon spectrum of the compound of formula 6 are shown as follows: Fig.41 and Fig.42 shown.

[0351] 1H NMR (400 MHz, CDCl 3 )δ6.30(d,J=11.49Hz,1H),6.19(br.s.,1H),5.57(br.s.,1H),4.98(br.s.,1H),4.87(br.s. ,1H),4.60(dd,J=5.38,10.76Hz,1H),4.45(br.s.,1H),4.27(d,J=10.52Hz,1H),4.19(d,J=1 0.03Hz,1H),3.80(dd,J=7.95,10.88Hz,1H),3.06(d,J=9.78Hz,1H),2.44(br.s.,1H),1.96- 2.02(m,3H),1.72-1.89(m,4H),1.41-1.51(m,3H),1.35(d,J=7.83Hz,2H),1.15(br.s.,6H).

[0352] 13 C NMR(150MHz,CHLOROFORM-d)d 201.2,169.8,151.6,117.4,98.0,75.1,73.1,63.4,60.3,55.5,50.7,41.9,40.2,33.6,31.6,25.1,21.6,21.4,17.6.

[0353] HRMS m / z calculation for [C 22 H 30 O 7 +H] + 407.1992, found 407.2023.

[0354] Embodiment 22

[0355]

[0356] Acrylic acid (0.02 g, 0.28 mmol) was dissolved in acetone, EDCI (0.07 g, 0.37 mmol) and HOBt (0.04 g, 0.30 mmol) were added, and the reaction was continued at room temperature for 20 min. Then, compound 6 (0.1 g, 0.25 mmol) and DMAP (0.006 g, 0.05 mmol) were added, and the reaction was continued by stirring for 12 h. The reaction solution was extracted with water and DCM, and the organic layer was washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 85 mg of the compound of formula 7a with a yield of 72%. The hydrogen spectrum and carbon spectrum of the compound of formula 7a are shown as follows: Fig.43 and Fig.44 shown.

[0357] 1 H NMR(400MHz,CHLOROFORM-d)δ6.40(d,J=17.36Hz,1H),6.01-6.18(m,3H),5.85-5.92(m,2H), 5.52(s,1H),4.65(dd,J=5.50,11.37Hz,1H),4.30(d,J=10.76Hz,1H),4.20(d,J=10.27Hz,1H ),4.14(s,1H),3.80(dd,J=6.60,10.51Hz,1H),3.23(d,J=10.27Hz,1H),2.57(br.s.,1H),2. 00-2.04(m,3H),1.74-1.82(m,1H),1.42-1.63(m,5H),1.31-1.39(m,3H),1.11-1.17(m,6H).

[0358] 13 C NMR(100MHz,CHLOROFORM-d)δ206.2,169.9,164.5,132.7,127.5,120.6,96.1,77.3,77.0 ,76.7,76.6,75.4,73.9,63.6,61.6,60.3,53.7,39.8,32.4,30.2,25.2,21.6,21.5,19.2.

[0359] HRMS m / z calculation for [C 25 H 32 O 8 +H] + 569.3036, found 569.3206.

[0360] Embodiment 23

[0361]

[0362] In a 25 ml reaction bottle, add 1.2 times the amount of adamantane-1-carboxylic acid (0.05 g), 1 times the amount of the compound of formula 6 (0.1 g), 1.5 times the amount of EDCI (0.07 g), 1.2 times the amount of HOBt (0.04 g), and 0.2 times the amount of DMAP (0.006 g). The other operations are the same as those in Example 22. After purification by chromatographic column, 99.5 mg of the compound of formula 7b is obtained with a yield of 70%. The hydrogen spectrum and carbon spectrum of the compound of formula 7b are shown as follows: Fig.45 and Fig.46 shown.

[0363] 1 H NMR (400 MHz, CDCl 3 )δ6.07-6.16(m,2H),5.72(br.s.,1H),5.47(br.s.,1H),4.64(dd,J=5.38,11.00 Hz,1H),4.50(s,1H),4.16-4.29(m,2H),3.83(dd,J=6.24,10.15Hz,1H),3.15(d, J=9.54Hz,1H),2.51(d,J=13.69Hz,1H),2.05(br.s.,1H),2.00(br.s.,6H),1.80 (br.s.,6H),1.60-1.73(m,7H),1.34-1.38(m,2H),1.25(br.s.,2H),1.14(s,6H).

[0364] 13 C NMR (100 MHz, CDCl 3 )δ206.2,169.9,149.5,120.0,77.3,77.2,77.0,76.9,76.7,75.4,73.4,63.5,60.5,53 .7,53.4,40.9,39.8,38.5,38.2,36.1,33.6,32.4,30.0,27.6,25.2,21.6,21.5,17.9.

[0365] HRMS m / z calculation for [C 33 H 44 O 8 +H] + 569.3036, found 569.3206.

[0366] Embodiment 24

[0367]

[0368] The compound of formula 7a (0.1 g, 0.28 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added at -78°C. 2 After 20 min of reaction under protection, the reaction was continued at room temperature for 2 h. The reaction solution was extracted with water and DCM, and the organic layer was washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 85 mg of the compound of formula 8a with a yield of 67.9%. The hydrogen spectrum and carbon spectrum of the compound of formula 8a are shown as follows: Fig.47 and Fig.48 shown.

[0369] 1 H NMR(400MHz,CHLOROFORM-d)δ6.37(dd,J=1.34,17.24Hz,1H),6.12(s,1H),5.97-6.06(m,1H),5.81 (dd,J=1.47,10.51Hz,1H),5.69-5.72(m,1H),5.43(s,1H),4.89(dd,J=6.11,11.00Hz,1H),4.33(d, J=10.03Hz,1H),4.17-4.23(m,2H),3.25(d,J=6.11Hz,1H),2.43(dd,J=6.48,13.57Hz,1H),2.24(t ,J=7.83Hz,1H),1.83-2.03(m,5H),1.60-1.74(m,3H),1.42-1.56(m,2H),1.04(s,3H),0.98(s,3H).

[0370] 13 C NMR(100MHz,CHLOROFORM-d)δ202.7,199.6,170.0,164.8,147.3,132.2,127.7,118.5,83.7,7 6.5,75.9,69.1,65.1,58.2,54.2,51.9,42.2,36.9,32.3,31.2,30.0,24.5,22.0,21.4,18.6.

[0371] HRMS m / z calculation for [C 25 H 30 O 7 +H] + 573.2931, found 573.2927.

[0372] Embodiment 25

[0373]

[0374] The compound of formula 7b (0.1 g, 0.18 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added at -78°C. The other operations were the same as those in Example 24, and 83.2 mg of the compound of formula 8b was obtained after purification by chromatographic column, with a yield of 84%. The hydrogen spectrum and carbon spectrum of the compound of formula 8b are shown as follows: Fig.49 and Fig.50 shown.

[0375] 1 H NMR (400 MHz, CDCl 3)δ6.10(s,1H),5.58(d,J=1.22Hz,1H),5.40(s,1H),4.88(dd,J=6.11,10.76Hz,1H),4.31(d,J=10.03Hz,1 H),4.20(s,2H),3.06-3.20(m,1H),2.32-2.44(m,1H),2.21(t,J=7.70Hz,1H),2.01-2.02(m,3H),1.91-1. 98(m,4H),1.86(dd,J=7.58,15.16Hz,1H),1.77(d,J=2.93Hz,6H),1.72(s,1H),1.66(br.s.,6H),1.53-1. 59(m,1H),1.48-1.51(m,1H),1.41-1.48(m,1H),1.34-1.41(m,1H),1.26(s,1H),1.04(s,3H),0.97(s,3H).

[0376] 13 C NMR (100 MHz, CDCl 3 )δ202.8,199.6,176.5,170.0,147.5,118.0,83.8,76.5,75.1,69.2,65.1,58.5,54.2,5 1.9,42.3,38.4,38.2,36.9,36.4,32.2,31.3,29.8,27.8,27.7,24.5,22.0,21.4,18.6.

[0377] HRMS m / z calculation for [C 33 H 42 O 7 +H] + 573.2931, found 573.2927.

[0378] Embodiment 26

[0379]

[0380] Rubescensine A (0.20 g, 0.55 mmol) was dissolved in acetone, and p-toluenesulfonic acid (TsOH, 0.08 g, 0.05 mmol) and 2,2-dimethoxypropane (DMP, 1.2 mL) were added. The mixture was refluxed for 2 h, diluted with water, extracted with DCM, and washed with saturated NaHCO 3 The organic layer was separated and washed with anhydrous Na 2 SO 4The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 0.17 g of the compound of formula 9 with a yield of 77%. Fig.51 shown.

[0381] 1 H NMR (400 MHz, CDCl 3 )δ6.15(s,1H),5.77(d,J=11.74Hz,1H),5.51-5.61(m,1H),4.79(d,J=1.47Hz,1H),4.24(dd,J=1.59,9.9 0Hz,1H),4.00-4.11(m,1H),3.90(dd,J=7.58,11.74Hz,1H),3.47(dd,J=5.75,11.37Hz,1H),3.06(d,J=9 .54Hz,1H),2.53(td,J=8.59,13.88Hz,1H),1.96(d,J=7.58Hz,1H),1.67-1.82(m,3H),1.66(s,3H),1.58 -1.64(m,2H),1.51-1.57(m,1H),1.45(td,J=3.36,13.82Hz,1H),1.34(s,3H),1.17(s,3H),1.16(s,3H).

[0382] Embodiment 27

[0383]

[0384] The compound of formula 9 (1.0 g, 2.47 mmol) was dissolved in DCM, and tetraethylamine (TEA, 0.90 g, 8.89 mmol) and methanesulfonyl chloride (MsCl, 0.90 g, 7.85 mmol) were slowly added under ice bath, and the reaction was stirred at room temperature for 5 h. The reaction solution was extracted with DCM and saturated NaHCO 3 The solution was washed with brine, and the organic layer was washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 0.57 g of the compound of formula 10 with a yield of 53%. Fig.52 shown.

[0385] 1 H NMR (400 MHz, CDCl 3)δ6.16(s,1H),5.82(d,J=11.74Hz,1H),5.58(s,1H),4.76(d,J=1.47Hz,1H),4.60(dd,J=5 .62,11.98Hz,1H),4.07-4.22(m,2H),3.91(dd,J=7.58,11.74Hz,1H),3.07(d,J=9.29Hz,1 H),3.00(s,3H),2.45-2.62(m,1H),2.02-2.15(m,1H),1.67-1.95(m,5H),1.64(s,3H),1.5 3(td,J=3.48,14.06Hz,1H),1.37(d,J=7.09Hz,1H),1.30-1.35(m,4H),1.17-1.20(m,6H).

[0386] Embodiment 28

[0387]

[0388] The compound of formula 10 (0.50 g, 1.04 mmol) was dissolved in anhydrous dimethylformamide (DMF) solution, lithium carbonate (0.28 g, 3.79 mmol) and lithium bromide (0.34 g, 3.91 mmol) were added, and the mixture was stirred vigorously at 115°C for 2 h and then cooled to room temperature. The reaction solution was diluted with ethyl acetate and saturated NaHCO 3 The organic layer was extracted with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 0.34 g of the compound of formula 11 with a yield of 74%. Fig.53 shown.

[0389] 1 H NMR (400 MHz, CDCl 3)δ6.16(s,1H),5.77(ddd,J=1.96,6.24,10.15Hz,1H),5.53-5.60(m,1H),5.39(d,J=11.74Hz,1H),5 .19(dd,J=2.69,10.27Hz,1H),4.82(d,J=1.22Hz,1H),3.95-4.03(m,1H),3.90(dd,J=8.44,11.86Hz, 1H),3.81(dd,J=1.59,9.90Hz,1H),3.01-3.11(m,1H),2.47-2.61(m,1H),1.91-1.99(m,1H),1.69-1. 86(m,4H),1.65(s,3H),1.59-1.61(m,1H),1.53-1.59(m,1H),1.35(s,3H),1.19(s,3H),1.05(s,3H).

[0390] Embodiment 29

[0391]

[0392] The compound of formula 11 (0.10 g, 0.26 mmol) was dissolved in DMF, 10% HCl / THF (1:1, v / v) was added, and the reaction was stirred for 30 min. The reaction solution was extracted with water and DCM, and the organic layer was washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 0.067 g of the compound of formula 12 with a yield of 75%. The hydrogen spectrum and carbon spectrum of the compound of formula 12 are shown as follows: Fig.54 and Fig.55 shown.

[0393] 1H NMR (400MHz, DMSO-d6) δ7.16(s,1H),6.03(s,1H),5.96(s,1H),5.70-5.77(m,1H),5.63(s,1H),5.53(d,J=1 1.00Hz,1H),5.22(dd,J=2.45,10.27Hz,1H),4.78(s,1H),3.81-3.87(m,1H),3.70-3.76(m,1H),3.59(dd,J= 8.07,11.00Hz,1H),2.93(d,J=9.54Hz,1H),2.42(td,J=8.74,13.57Hz,1H),1.83-1.95(m,2H),1.73-1.83(m ,1H),1.67(dd,J=5.26,13.33Hz,1H),1.45-1.57(m,1H),1.34-1.44(m,2H),1.05(s,3H),0.93-0.98(m,3H).

[0394] 13 C NMR (100 MHz, DMSO-d 6 )d 207.5,152.0,130.0,125.4,121.0,97.9,72.8,72.6,64.8,61.9,58.8,52.1,43.1,41.0,38.3,32.4,31.2,30.1,22.1,17.5.

[0395] HRMS m / z calculation for [C 20 H 26 O 5 +H] + 347.1780, found 347.1859.

[0396] Embodiment 30

[0397]

[0398] 1-Adamantanecarboxylic acid (0.06 g, 0.31 mmol) was dissolved in DCM, 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.1 g, 0.52 mmol) and 0.2 times amount of DMAP (0.008 g) were added, and the reaction was continued for 30 min. Compound 12 (0.12 g, 0.35 mmol) and 1-hydroxybenzotriazole (HOBt, 0.13 g, 0.52 mmol) were added, and the reaction was stirred at room temperature for 12 h. The reaction solution was washed and diluted with 10% HCl and extracted with DCM. The organic layer was washed with anhydrous Na 2 SO 4The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 71 mg of the compound of formula 13a with a yield of 40%. The hydrogen spectrum and carbon spectrum of the compound of formula 13a are shown as follows: Fig.56 and Fig.57 shown.

[0399] 1 H NMR(400MHz,DMSO-d6)δ6.06(s,1H),5.95(s,1H),5.71-5.79(m,2H),5.66(s,1H),5.42(d ,J=11.00Hz,1H),5.27(dd,J=2.45,10.27Hz,1H),3.81(d,J=9.78Hz,1H),3.72(d,J=10.0 3Hz,1H),3.57(dd,J=8.31,11.00Hz,1H),2.88(d,J=9.29Hz,1H),2.41-2.49(m,1H),1.85 -1.98(m,5H),1.52-1.80(m,17H),1.37(d,J=8.31Hz,1H),1.06(s,3H),0.91-0.98(m,3H).

[0400] 13 C NMR(100MHz,DMSO-d6)δ205.8,175.4,151.0,130.1,125.7,96.9,79.7,73.5,73 .2,64.5,61.8,58.2,52.9,42.1,40.6,38.4,38.3,36.5,32.4,30.3,27.7,22.1.

[0401] HRMS m / z calculation for [C 31 H 40 O 6 +H] + 509.2825, found 509.2949.

[0402] Embodiment 31

[0403]

[0404] In a 25 ml reaction bottle, 1.2 times the amount of acrylic acid (0.03 g), 1 times the amount of the compound of formula 12 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 0.2 times the amount of DMAP (0.008 g), and 1.2 times the amount of HOBt (0.06 g) were added. The other operations were the same as in Example 30, and after purification by chromatographic column, 52 mg of the compound of formula 13b was obtained with a yield of 37%. The hydrogen spectrum and carbon spectrum of the compound of formula 13b are shown as follows: Fig.58and Fig.59 shown.

[0405] 1 H NMR(400MHz,CHLOROFORM-d)δ6.38(dd,J=1.22,17.36Hz,1H),6.20-6.22(m,1H),5.98-6.10(m,1H),5.92-5.94(m,1H),5.85(d d,J=1.22,10.52Hz,1H),5.81(ddd,J=2.08,6.24,10.27Hz,1H),5.54-5.58(m,2H),5.21(dd,J=2.57,10.39Hz,1H),4.08-4.10( m,1H),3.96-4.01(m,1H),3.87-3.93(m,1H),3.80(dd,J=8.31,11.49Hz,1H),3.18(d,J=10.03Hz,1H),2.56-2.68(m,1H),1.91- 1.99(m,3H),1.80-1.89(m,1H),1.61-1.71(m,3H),1.52(dd,J=1.22,8.31Hz,1H),1.26(s,1H),1.15-1.18(m,3H),1.04(s,3H).

[0406] 13 C NMR(100MHz,CHLOROFORM-d)δ164.7,149.6,132.2,130.9,127.9,124.2,121.4,96.5 ,75.7,73.5,65.5,61.8,58.2,53.3,41.4,41.0,38.5,32.4,30.8,30.3,21.7,17.8.

[0407] HRMS m / z calculation for [C 23 H 28 O 6 +H] + 401.1919, found 401.2029.

[0408] Embodiment 32

[0409]

[0410] In a 25 ml reaction bottle, 1.2 times the amount of (E)-3-(thiazol-2-yl) acrylic acid (0.06 g), 1 times the amount of the compound of formula 12 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 0.2 times the amount of DMAP (0.008 g), and 1.2 times the amount of HOBt (0.06 g) were added. The other operations were the same as in Example 30, and after purification by a chromatographic column, 72.7 mg of the compound of formula 13c was obtained with a yield of 43%. The hydrogen spectrum and carbon spectrum of the compound of formula 13c are shown as follows: Fig.60 and Fig.61 shown.

[0411] 1 H NMR(600MHz,CHLOROFORM-d)δppm 1.03(s,3H)1.16(s,3H)1.52(d,J=8.36Hz,1H)1.62-1.72(m,2H)1.80-1.90(m,2H)1.92-1.96(m,2H)2.59-2.6 7(m,1H)3.18(d,J=9.26Hz,1H)3.78(dd,J=11.63,8.54Hz,1H)3.90(d,J=10.90Hz,1H)3.99(d,J=10.17Hz,1H)4 .10(s,1H)5.22(dd,J=10.26,2.63Hz,1H)5.58(t,J=5.90Hz,2H)5.80(ddd,J=10.13,6.31,1.54Hz,1H)6.04(s ,1H)6.23(s,1H)6.63(d,J=15.80Hz,1H)7.43(d,J=3.09Hz,1H)7.74(d,J=15.99Hz,1H)7.90(d,J=3.09Hz,1H).

[0412] 13 C NMR(150MHz,CHLOROFORM-d)δ163.2,144.8,136.9,130.9,124.2,122.4,121.7,121.5,9 6.5,75.4,73.7,65.5,62.0,57.9,53.3,41.6,41.0,38.6,32.4,30.8,30.3,21.7,17.9.

[0413] HRMS m / z calculation for [C 26 H 29 NO 6 S+H] + 484.1716, found 484.1761.

[0414] Embodiment 33

[0415]

[0416] In a 25 ml reaction bottle, add 1.2 times the amount of (2E, 4E)-hexa-2,4-dienoic acid (0.05 g), 1 times the amount of the compound of formula 12 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 0.2 times the amount of DMAP (0.008 g), and 1.2 times the amount of HOBt (0.06 g). The other operations were the same as in Example 30, and after purification by chromatographic column, 108 mg of the compound of formula 13d was obtained with a yield of 78%. The hydrogen spectrum and carbon spectrum of the compound of formula 13d are shown as follows: Fig.62 and Fig.63 shown.

[0417] 1 H NMR(600MHz,CHLOROFORM-d)d 7.17(dd,J=10.17,15.26Hz,1H),6.05-6.20(m,3H),5.85(s,1H),5.74-5.82(m,1H),5.67(d,J=15 .26Hz,1H),5.50-5.59(m,2H),5.19(dd,J=2.72,10.17Hz,1H),4.31(s,1H),3.95(d,J=10.17Hz,1 H),3.85-3.90(m,1H),3.76-3.82(m,1H),3.17(d,J=9.45Hz,1H),2.58-2.64(m,1H),1.87-1.99(m ,4H),1.82(d,J=5.99Hz,3H),1.59-1.67(m,2H),1.51(d,J=8.17Hz,1H),1.15(s,3H),1.02(s,3H).

[0418] 13 C NMR(150MHz,CHLOROFORM-d)d 205.1,165.5,149.6,146.7,141.2,130.9,129.5,124.1,121.3,117.7,96.6,76.0, 73.3,65.5,61.7,58.5,53.3,41.3,41.1,38.5,32.4,30.7,30.2,21.7,18.7,17.8.

[0419] Embodiment 34

[0420]

[0421] In a 25 ml reaction bottle, add 1.2 times the amount of 2-(3,4-dimethoxyphenyl)acetic acid (0.08 g), 1 times the amount of compound 12 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 0.2 times the amount of DMAP (0.008 g), and 1.2 times the amount of HOBt (0.06 g). The other operations were the same as in Example 30, and after purification by chromatographic column, 73.5 mg of compound 13e was obtained with a yield of 39%. The hydrogen spectrum and carbon spectrum of compound 13e are shown as follows: Fig.64 and Fig.65 shown.

[0422] 1 H NMR (400 MHz, CDCl 3 )δ6.72-6.80(m,3H),6.15(s,1H),5.86(s,1H),5.80(ddd,J=1.96,6.11,10.27Hz,1H ),5.62(d,J=11.49Hz,1H),5.46(s,1H),5.20(dd,J=2.57,10.39Hz,1H),4.10(br.s. ,1H),3.98(d,J=10.51Hz,1H),3.85(s,6H),3.52(s,2H),3.05(d,J=10.03Hz,1H),1. 85-1.95(m,4H),1.58-1.72(m,5H),1.51(d,J=8.07Hz,1H),1.16(s,3H),1.04(s,3H).

[0423] 13 C NMR (100 MHz, CDCl 3 )δ204.9,170.3,124.2,121.4,111.3,96.5,73.5,65.5,61.8,58.2,55.9,55.9,53.3,41.3,41.3,41.0,38.5,32.3,29.7,22.7,11.0.

[0424] HRMS m / z calculated as [C 30 H 36 O 8 +Na] + 547.2410, found 547.2408.

[0425] Embodiment 35

[0426]

[0427] In a 25 ml reaction bottle, 1.2 times the amount of salicylic acid (0.06 g), 1 times the amount of the compound of formula 12 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 0.2 times the amount of DMAP (0.008 g), and 1.2 times the amount of HOBt (0.06 g) were added. The other operations were the same as in Example 30, and after purification by a chromatographic column, 71.8 mg of the compound of formula 13g was obtained with a yield of 44%. The hydrogen spectrum and carbon spectrum of the compound of formula 13f are shown as follows: Fig.66 and Fig.67 shown.

[0428] 1 H NMR(400MHz,CHLOROFORM-d)d 10.48(s,1H),7.70(dd,J=1.42,7.98Hz,1H),7.42-7.49(m,1H),6.97(d,J=8.41Hz,1H),6.86(t,J=7.42Hz,1H),6.30(s,1H) ,6.21(s,1H),5.86(ddd,J=1.61,6.22,9.99Hz,1H),5.64(s,1H),5.27(dd,J=2.54,10.21Hz,1H),4.05(d,J=10.27Hz,1H),3 .95(d,J=10.14Hz,1H),3.80(br.s.,1H),3.28(d,J=9.28Hz,1H),2.65-2.74(m,1H),2.00(d,J=3.46Hz,1H),1.97(br.s.,1H ),1.91(d,J=6.19Hz,1H),1.74(dd,J=3.96,6.80Hz,1H),1.57(d,J=8.66Hz,1H),1.29(br.s.,4H),1.20(s,3H),1.07(s,3H).

[0429] 13 C NMR(101MHz,DMSO-d6)d ppm 17.44,21.64,29.86,30.74,31.96,37.85,40.44,41.13,52.57,57.97,61.58,72.8 6,75.11,96.30,117.56,119.38,124.88,129.86,130.93,135.49,149.76,158.99.

[0430] HRMS m / z calculation for [C 27 H 30 O 7 +H]+467.1992, found 467.2092.

[0431] Embodiment 36

[0432]

[0433] In a 25 ml reaction bottle, add 1.2 times the amount of (S)-(+)-ibuprofen (0.09 g), 1 times the amount of the compound of formula 12 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 0.2 times the amount of DMAP (0.008 g), and 1.2 times the amount of HOBt (0.06 g). The other operations were the same as in Example 30, and after purification by a chromatographic column, 50.5 mg of the compound of formula 13g was obtained with a yield of 27%. The hydrogen spectrum and carbon spectrum of the compound of formula 13g are shown as follows: Fig.68 and Fig.69 shown.

[0434] 1 H NMR(400MHz,CHLOROFORM-d)d ppm 0.88-0.95(m,13H)1.06(s,2H)1.18(s,2H)1.45-1.51(m,2H)1.54(d,J=7.18Hz,4H)1 .82-1.96(m,3H)2.05(d,J=5.20Hz,1H)2.43-2.50(m,3H)2.92(d,J=9.40Hz,1H)3.71 -3.78(m,1H)3.90(d,J=10.39Hz,1H),4.00(d,J=10.27Hz,1H)5.18-5.26(m,1H)5.80 -5.85(m,1H)5.99(s,1H)7.04-7.09(m,1H)7.10-7.16(m,3H),7.26(d,J=8.04Hz,2H).

[0435] 13 C NMR(101MHz,CHLOROFORM-d)d 173.2,149.3,140.8,130.9,129.4,127.1,124.1,120.8,96.5,75.8,73.3,61.7,58. 3,53.2,45.2,45.0,41.0,40.9,38.4,32.3,30.7,30.1,29.9,22.4,21.7,17.8,17.6.

[0436] HRMS m / z calcd for[C33H42O6-H]+533.2981,found 533.2923.

[0437] Embodiment 37

[0438]

[0439] In a 25 ml reaction bottle, 1.2 times the amount of probenecid (0.12 g), 1 times the amount of compound 12 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 0.2 times the amount of DMAP (0.008 g), and 1.2 times the amount of HOBt (0.06 g) were added. The other operations were the same as in Example 30, and 45 mg of compound 13h was obtained after purification by chromatographic column, with a yield of 21%. The hydrogen spectrum and carbon spectrum of compound 13h are shown as follows: Fig.70 and Fig.71 shown.

[0440] 1 H NMR(400MHz,CHLOROFORM-d)d 8.03-8.09(m,J=8.54Hz,2H),7.79-7.84(m,J=8.54Hz,2H),6.27(s,1H),6.18(s,1H),5.83(ddd,J=1.73,6.15,10.05Hz ,1H),5.58(d,J=11.88Hz,1H),5.24(dd,J=2.29,10.21Hz,1H),4.00(d,J=10.27Hz,1H),3.93(d,J=10.14Hz,1H),3.87(s ,1H),3.75(dd,J=8.66,11.88Hz,1H),3.24(d,J=9.28Hz,1H),3.03-3.09(m,4H),2.62-2.72(m,1H),1.91-2.03(m,3H), 1.81-1.91(m,1H),1.67-1.76(m,2H),1.64(s,2H),1.51-1.57(m,4H),1.16(s,3H),1.03(s,3H),0.86(t,J=7.42Hz,6H).

[0441] 13 C NMR(101MHz,CHLOROFORM-d)d 205.1,164.3,149.8,144.2,133.4,131.0,130.5,127.0,124.2,121.6,96.4,75.4,74.0, 65.6,62.2,57.8,53.4,50.0,41.7,41.0,38.6,32.4,30.8,30.4,22.0,21.7,18.0,11.2.

[0442] HRMS m / z calculation for [C 33 H 43 NO 8S+H] + 614.2709, found 614.2789.

[0443] Embodiment 38

[0444]

[0445] In a 25 ml reaction bottle, 1.2 times the amount of ketoprofen (0.11 g), 1 times the amount of compound 12 (0.12 g), 1.5 times the amount of EDCI (0.10 g), 0.2 times the amount of DMAP (0.008 g), and 1.2 times the amount of HOBt (0.06 g) were added. The other operations were the same as in Example 30, and 40.8 mg of compound 13i was obtained after purification by chromatographic column, with a yield of 20%. The hydrogen spectrum and carbon spectrum of compound 13i are shown as follows: Fig.72 and Fig.73 shown.

[0446] 1 H NMR(400MHz,CHLOROFORM-d)d 7.83-7.86(m,2H),7.66-7.70(m,2H),7.62(d,J=7.42Hz,1H),7.54(d,J=7.79Hz,2H),7.44-7.49(m,2H),6.17(s,1H),5.84(s, 1H),5.51(d,J=2.47Hz,1H),5.47(s,1H),5.38(s,1H),5.22(d,J=2.47Hz,1H),3.94(d,J=10.27Hz,1H),3.85(d,J=10.27Hz,1H) ,3.73-3.78(m,1H),3.58(s,1H),3.11(d,J=10.02Hz,1H),2.24(d,J=7.79Hz,1H),2.05(d,J=5.44Hz,1H),1.93(d,J=4.70Hz,2 H),1.87(d,J=6.06Hz,1H),1.67(s,1H),1.64(d,J=3.34Hz,2H),1.53(d,J=7.18Hz,3H),1.46(s,1H),1.17(s,3H),1.02(s,3H).

[0447] 13C NMR(101MHz,CHLOROFORM-d)d 132.5,131.5,130.9,130.2,129.3,129.1,128.8,128.3,124.1,96.4,77.2, 76.2,73.3,65.4,58.1,53.3,45.8,41.4,41.0,32.3,29.7,29.4,21.7,17.9.

[0448] HRMS m / z calculation for [C 36 H 38 O 7 +H] + 583.2618, found 583.2685.

[0449] Embodiment 39

[0450]

[0451] The compound of formula 11 (0.12 g, 0.31 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added. The reaction was carried out at -78°C for 20 min and then at room temperature for 2 h. The reaction solution was extracted with water and DCM, and the organic layer was washed with anhydrous Na 2 SO 4 The crude product was dried, filtered and concentrated, and purified by chromatography to obtain 55 mg of the compound of formula 14 with a yield of 48%. The hydrogen spectrum and carbon spectrum of formula 14 are shown as follows: Fig.74 and Fig.75 shown.

[0452] 1 H NMR (400 MHz, CDCl 3 )δ6.14(s,1H),5.80(ddd,J=1.96,6.11,10.27Hz,1H),5.66(dd,J=2.93,10.27Hz,1 H),5.54(s,1H),4.64(s,1H),4.32(s,1H),4.08-4.16(m,1H),3.98-4.02(m,1H),3. 73(d,J=9.05Hz,1H),3.14(d,J=8.80Hz,1H),2.43-2.53(m,1H),2.12(dd,J=5.99,1 2.35Hz,1H),1.97-2.02(m,2H),1.66-1.93(m,5H),1.09(s,3H),1.03-1.06(m,3H).

[0453] 13 C NMR (101 MHz, CDCl 3)δ203.1,128.3,124.2,120.2,81.7,73.7,71.6,65.2,53.9,50.0,43.9,39.5,30.4,30.1,29.3,23.1,18.3.

[0454] HRMS m / z calculation for [C 20 H 24 O 4 +H] + 329.1675, found 329.1738.

[0455] Embodiment 40

[0456]

[0457] Compound 13a (0.04 g, 0.076 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added. The other operations were the same as those in Example 39. After purification by chromatographic column, 26 mg of compound 14a was obtained with a yield of 70%. The hydrogen spectrum and carbon spectrum of compound 14a are shown as follows: Fig.76 and Fig.77 shown.

[0458] 1 H NMR (400MHz, DMSO-d6) δ6.74(s,1H),6.57(s,1H),6.36(d,J=5.62Hz,2H),5.05-5.12(m,2H),4.46(d,J=9.29Hz,1H),3.93 (d,J=7.34Hz,1H),2.71-2.86(m,7H),2.68(d,J=5.87Hz,1H),2.35-2.50(m,17H),2.05(s,1H),1.80(s,3H),1.77(s,3H).

[0459] 13 C NMR(100MHz,DMSO-d6)δ202.9,199.8,175.5,148.4,128.3,124.5,82.4,75.4,65.2,56.4,55.4,51.8 ,50.3,42.2,40.6,40.4,40.2,40.0,39.8,39.6,39.4,38.5,36.4,30.4,30.4,30.0,27.6,23.0,17.5.

[0460] HRMS m / z calculation for [C 31 H 38 O 5 +H]+ 491.2719, found 491.2749.

[0461] Embodiment 41

[0462]

[0463] The compound of formula 13b (0.04 g, 0.10 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added. The other operations were the same as those in Example 39. After purification by chromatographic column, 25.9 mg of the compound of formula 14b was obtained with a yield of 68%. The hydrogen spectrum and carbon spectrum of the compound of formula 14b are shown as follows: Fig.78 and Fig.79 shown.

[0464] 1 H NMR (400MHz, CHLOROFORM-d) δ6.38 (dd, J=1.34, 17.24Hz, 1H), 6.13 (s, 1H), 5. 98-6.07(m,1H),5.77-5.85(m,2H),5.63-5.73(m,2H),5.45(s,1H),4.26-4.33 (m,2H),3.83(d,J=9.05Hz,1H),3.25(d,J=7.34Hz,1H),2.47-2.57(m,1H),2. 13-2.19(m,1H),1.84-2.05(m,3H),1.71-1.83(m,3H),1.04(d,J=4.16Hz,6H).

[0465] 13 C NMR(100MHz,CHLOROFORM-d)δ202.8,164.9,147.4,132.1,128.8,127.8,123.6 ,118.9,82.7,76.0,72.1,65.3,56.6,51.5,42.2,39.6,30.4,30.1,22.9,17.7.

[0466] HRMS m / z calculation for [C 23 H 26 O 5 +H] + 383.1814, found 383.1918.

[0467] Embodiment 42

[0468]

[0469] The compound of formula 13c (0.04 g, 0.083 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added. The other operations were the same as those in Example 39. After purification by chromatographic column, 15.1 mg of the compound of formula 14c was obtained with a yield of 39%. The hydrogen spectrum and carbon spectrum of the compound of formula 14c are shown as follows: Fig.80 and Fig.81 shown.

[0470] 1 H NMR(600MHz,CHLOROFORM-d)δppm 0.97(d,J=5.45Hz,7H)1.67-1.71(m,2H)1.75(s,1H)1.82(dd,J=17.62,6.18Hz,1H)1.89-1.96(m ,2H)2.03-2.18(m,1H),2.47(d,J=8.72Hz,1H),3.21(d,J=7.45Hz,1H),3.77(d,J=9.08Hz,1H),4 .18-4.31(m,2H),5.41(s,1H),5.60(dd,J=10.35,2.54Hz,1H),5.67-5.79(m,2H),6.08(s,1H),6 .55(d,J=15.80Hz,1H),7.35(d,J=3.09Hz,1H),7.68(d,J=15.99Hz,1H),7.83(d,J=3.27Hz,1H).

[0471] 13 C NMR(150MHz,CHLOROFORM-d)δ164.7,147.4,144.7,137.0,128.8,123.5,122.1,121.6 ,119.0,82.7,76.4,72.1,65.2,56.5,51.5,50.4,42.3,39.6,30.4,30.1,22.9,17.7.

[0472] HRMS m / z calculation for [C 26 H 27 NO 5 S+H] + 466.1610, found 466.1709.

[0473] Embodiment 43

[0474]

[0475] Compound 13d (0.04 g, 0.091 mmol) was dissolved in DCM, and diethylamine sulfur trifluoride (DAST) was added. The other operations were the same as those in Example 39. After purification by chromatographic column, 24.6 mg of compound 14d was obtained with a yield of 64%. The hydrogen spectrum and carbon spectrum of compound 14d are shown as follows: Fig.82 and Fig.83 shown.

[0476] 1 H NMR (600 MHz, CHLOROFORM-d) 7.20(dd,J=9.54,15.35Hz,1H),6.09-6.17(m,3H),5.80(dd,J=5.90,10.08H z,1H),5.63-5.72(m,3H),5.44(s,1H),4.25-4.35(m,2H),3.82(d,J=9.26Hz ,1H),3.24(d,J=7.45Hz,1H),2.45-2.60(m,1H),2.14(t,J=8.17Hz,1H),1.8 5-2.04(m,4H),1.78-1.84(m,4H),1.70-1.77(m,2H),1.04(d,J=5.81Hz,6H).

[0477] 13 C NMR(150MHz,CHLOROFORM-d)d 203.0,199.6,165.9,147.6,146.3,140.1,129.7,128.7,123.6,118.7,118.2,82 .7,75.7,72.1,65.3,56.7,51.5,50.4,42.3,39.6,30.4,30.1,22.9,18.7,17.7.

[0478] Embodiment 44

[0479]

[0480] In a 25 ml reaction bottle, 1.2 times the amount of 4-(bis(2-chloroethyl)amino)benzoic acid (0.11 g), 1 times the amount of compound 14 (0.12 g, 0.37 mmol), 1.5 times the amount of EDCI (0.11 g), 0.2 times the amount of DMAP (0.009 g), and 1.2 times the amount of HOBt (0.06 g) were added. The other operations were the same as in Example 30, and after purification by chromatographic column, 89 mg of compound 14f was obtained with a yield of 63%. The hydrogen spectrum and carbon spectrum of compound 14f are shown as follows: Fig.84 and Fig.85 shown.

[0481] 1 H NMR (400 MHz, CDCl 3 )δ7.81-7.94(m,2H),6.55-6.69(m,2H),6.13(s,1H),5.76-5.85(m,2H),5 .68(dd,J=2.93,10.27Hz,1H),5.42(s,1H),4.31(t,J=4.52Hz,2H),3.70-3 .88(m,5H),3.58-3.67(m,4H),3.35(d,J=7.09Hz,1H),2.49-2.71(m,1H),2 .10-2.29(m,1H),1.94-2.06(m,2H),1.70-1.93(m,4H),0.98-1.09(m,6H).

[0482] 13 C NMR (100 MHz, CDCl 3 )δ203.2,199.8,165.2,149.9,147.6,132.3,128.8,123.6,118.7,118.2,110.8,82.8,7 6.0,72.2,65.5,56.8,53.3,51.5,50.6,42.4,40.1,39.6,30.5,30.4,30.0,22.9,17.7.

[0483] HRMS m / z calculation for [C 31 H 35 Cl 2 NO 5 +H] + 574.1863, found 574.2014.

[0484] Test Example 1

[0485] (1) Inhibitory effect of compounds represented by formula 1a, 1b, 2a, 2b, 4a-4d, 5a, 5b, 5d, 6, 7a, 7b, 8a, 8b, 13a-13e, 14a-14d and 14f on LPS-induced NO release

[0486] The oridonin derivatives were prepared into 40mM stock solutions with DMSO for later use. NO release was detected using a NO detection kit (Biyuntian S0021M), and the specific method was as follows: RAW 264.7 cells were seeded in a 96-well cell culture plate at 2×104 cells per well, and a cell culture medium containing 1μg / mL LPS was added for pre-incubation for 1 hour after 24 hours, and then a culture medium containing 1μg / mL LPS and oridonin derivatives was added for co-incubation for 24 hours. The cell culture supernatant was mixed with GriessⅠ and GriessⅡ reagents respectively, and the absorbance was detected at a wavelength of 540nm after incubation at room temperature for 10 minutes.

[0487] The results are as follows Fig.86 As shown, Fig.86 The figure shows the effect of oridonin derivatives on LPS-induced NO release (compared with the control group: ####P<0.0001, compared with the LPS group: *P<0.05**P<0.01***P<0.001****P<0.0001). LPS can significantly induce RAW 264.7 cells to release NO. Oridonin, as a positive drug control, can inhibit LPS-induced NO release at a concentration of 5 μM. Oridonin derivatives can significantly inhibit LPS-induced NO release at a concentration of 0.3125 μM. The anti-inflammatory activity of oridonin is significantly improved after structural modification.

[0488] (2) Dose-dependent effects of compounds represented by formula 1b, 2a, 4d, 5d, 7a and 8a on inhibiting LPS-induced NO release

[0489] Select Fig.86 Compounds 1b, 2a, 4d, 5d, 7a and 8a with high NO inhibitory activity were tested for their dose-dependent effects on inhibiting LPS-induced NO release using a NO detection kit (Biyuntian S0021M). The specific method is as follows: RAW264.7 cells were seeded in a 96-well cell culture plate at 2×104 cells per well. After 24 hours, a cell culture medium containing 1μg / mL LPS was added for pre-incubation for 1 hour, and then a culture medium containing 1μg / mL LPS and gradient dilutions of oridonin derivatives was added for co-incubation for 24 hours. The cell culture supernatant was mixed with GriessⅠ and GriessⅡ reagents respectively, incubated at room temperature for 10 minutes, and the absorbance was detected at a wavelength of 540nm.

[0490] The results are as follows Fig.87 As shown, Fig.87 The graph is a dose-dependent effect diagram of Rubescensine A derivatives (Formula 1b, 2a, 4d, 5d, 7a and 8a) on inhibiting LPS-induced NO release (compared with the control group: ###P<0.001, compared with the LPS group: *P<0.05**P<0.01***P<0.001****P<0.0001), the IC50 of the compounds represented by Formula 1b, 2a, 4d, 5d, 7a and 8a for inhibiting LPS-induced NO release are shown in Table 1.

[0491] Table 1 IC of compounds represented by formula 1b, 2a, 4d, 5d, 7a and 8a for inhibiting LPS-induced NO release 50

[0492]

[0493] Fig.87 The results shown in Table 1 indicate that LPS can significantly induce NO release, and the compounds represented by formula 2a, 4d, 5d, 7a and 8a have a dose-dependent inhibitory effect on LPS-induced NO release. The compounds represented by formula 4d and 7a having a 7,20-epoxy-enantio-kaurane diterpenoid skeleton structure have higher NO release inhibitory activity than the compounds represented by formula 5d and 8a having a 6,20-epoxy-enantio-kaurane diterpenoid skeleton structure.

[0494] (3) The dose-dependent effect of the compounds represented by formula 13a-13c and 14a-14c on inhibiting LPS-induced NO release

[0495] Select Fig.86 Compounds with high NO inhibitory activity were selected and the NO detection kit (Biyuntian S0021M) was used to detect the dose-dependent effect of the compounds in inhibiting LPS-induced NO release. The specific method is as follows: RAW 264.7 cells were seeded in a 96-well cell culture plate at 2×104 cells per well. After 24 hours, cell culture medium containing 1μg / mL LPS was added for pre-incubation for 1 hour, and then culture medium containing 1μg / mL LPS and gradient dilutions of oridonin derivatives was added for co-incubation for 24 hours. The cell culture supernatant was mixed with GriessⅠ and GriessⅡ reagents respectively, incubated at room temperature for 10 minutes, and the absorbance was detected at a wavelength of 540nm. The results are as follows Fig.88 As shown in Table 2, Fig.88 The dose-dependent effect diagram of Rubescensine A derivatives (Formulas 13a-13c, 14a-14c) on inhibiting LPS-induced NO release (compared with the control group: ### P<0.001, compared with the LPS group: *P<0.05 **P<0.01 ***P<0.001 ****P<0.0001).

[0496] Table 2 IC of compounds represented by formula 13a-13c, 14a-14c for inhibiting LPS-induced NO release 50

[0497]

[0498]

[0499] Fig.88 The results shown in Table 2 indicate that LPS can significantly induce NO release, and the compounds shown in Formulas 13a-13c and 14a-14c have a dose-dependent inhibitory effect on LPS-induced NO release, and the compounds shown in Formulas 13a-13c having a 7,20-epoxy-enantio-kaurane diterpenoid skeleton structure have higher NO release inhibitory activity than the compounds shown in Formulas 14a-14c having a 6,20-epoxy-enantio-kaurane diterpenoid skeleton structure. The IC50 of the compounds shown in Formulas 13a-13c and 14a-14c for inhibiting LPS-induced NO release is shown in Table 2.

[0500] (3) The dose-dependent effect of the compounds represented by formula 13g-13j on inhibiting LPS-induced NO release

[0501] As shown in Tables 1 and 2, among the above-mentioned structurally modified compounds, the compound represented by Formula 13c has the highest activity in inhibiting NO release. Therefore, the anti-inflammatory activity of the compounds represented by Formulas 13g-13j obtained by further connecting salicylic acid, (s)-(+)-ibuprofen, probenecid, and ketoprofen nonsteroidal anti-inflammatory drug structures on the basis of the structure of the compound represented by Formula 13c was further explored. The dose-dependent effect of the compound on inhibiting LPS-induced NO release was detected using a NO detection kit (Biyuntian S0021M), and the specific method was as follows: RAW 264.7 cells were seeded in a 96-well cell culture plate at 2×104 cells per well, and a cell culture medium containing 1 μg / mL of LPS was added for pre-incubation for 1 hour after 24 hours, and then a culture medium containing 1 μg / mL of LPS and a gradient dilution of a Rubescensine A derivative was added for co-incubation for 24 hours. The cell culture supernatant was mixed with Griess I and Griess II reagents respectively, incubated at room temperature for 10 minutes, and then the absorbance was detected at a wavelength of 540 nm.

[0502] The results are as follows Fig.89 As shown, Fig.89 Dose-dependent effect diagram of Rubescensine A derivatives (Formula 13g-13j) on inhibiting LPS-induced NO release (compared with the control group: #### P<0.0001, compared with LPS group: *P<0.05**P<0.01***P<0.001****P<0.0001). The results showed that LPS could significantly induce NO release, and the compounds represented by Formula 13g-13j had a dose-dependent effect in inhibiting LPS-induced NO release, but the activity of inhibiting NO release was significantly lower than that of the compound represented by Formula 13c.

[0503] (4) The compounds represented by formula 4d, 13b, and 13c inhibit the secretion of IL-6 and IL-1β induced by LPS

[0504] The compounds shown in formula 4d, 13b, and 13c with the highest NO inhibitory activity were selected to further explore the anti-inflammatory activity and mechanism of action. The secretion of IL-6 and IL-1β was detected using Boster ELISA detection kits (EK0394, EK0411). The cell supernatant and HRP-labeled antibody were added to the ELISA plate wells, reacted at 37°C for 60 minutes, washed with PBS, and the substrate TMB was added for color development for 15 minutes, then the stop solution was added, and the absorbance was measured at a wavelength of 450nm.

[0505] The results are as follows Fig.90 As shown in Table 3, Fig.90 This is a graph showing that Rubescensine A derivatives inhibit the release of IL-6 and IL-1β induced by LPS.

[0506] Table 3 IC of compounds represented by formula 4d, 13b, and 13c for inhibiting LPS-induced IL-6 and IL-1β release 50

[0507]

[0508] The results showed that LPS could significantly induce the secretion of IL-6 and IL-1β. Compared with Rubescensine A, the compounds represented by Formulae 4d, 13b and 13c could significantly inhibit the secretion of IL-6 and IL-1β induced by LPS at lower concentrations.

[0509] (5) The compounds represented by formula 4d, 13b, and 13c inhibit the expression of LPS-induced inflammatory genes

[0510] Total RNA from RAW 264.7 cells was extracted using an RNA extraction kit (Solabo R1200), reverse transcribed using a Takara kit (RR036A) to obtain cDNA, and qPCR experiments were performed using Promega reagents (A6002).

[0511] The results are as follows Fig.91 and 92 As shown, Fig.91 The graph shows that Rubescensine A and Rubescensine A derivatives (Formula 4d) inhibit the expression of LPS-induced inflammatory genes; wherein A is the expression of inflammatory genes inhibited by Rubescensine A; and B is the expression of inflammatory genes inhibited by the compound shown in Formula 4d. Fig.92 The graph shows that the Rubescensine A derivatives (Formula 13b and Formula 13c) inhibit the expression of LPS-induced inflammatory genes; wherein, C is the expression of inflammatory genes inhibited by the compound shown in Formula 13b; D is the expression of inflammatory genes inhibited by the compound shown in Formula 13c; compared with the control group:# P<0.05, ## P<0.01, ### P < 0.001, #### P<0.0001, compared with the LPS group: *P<0.05 **P<0.01 ***P<0.001 ****P<0.0001.

[0512] The results showed that LPS could significantly induce the expression of IL-6, COX-2, IL-1β, TNF-α and iNOS inflammatory genes, and the compounds represented by formulas 4d, 13b and 13c could significantly inhibit the expression of IL-6, COX-2 and IL-1β inflammatory genes induced by LPS, but had no significant inhibitory effect on the expression of TNF-α and iNOS genes.

[0513] (6) The compounds represented by formula 4d, 13b, and 13c inhibit the expression of LPS-induced inflammation-related proteins

[0514] Proteins in RAW 264.7 cells were extracted using RIPA lysis buffer and subjected to WB experiments.

[0515] The results are as follows Fig.93 As shown, Fig.93 The figure shows that the oridonin derivatives inhibit the expression of LPS-induced inflammation-related proteins. WB experiments show that LPS can significantly induce the expression of phosphorylated NF-κB, phosphorylated IκBα, COX-2, NLRP3, IL-6 and iNOS proteins. The compound shown in formula 4d can significantly inhibit the expression of phosphorylated NF-κB, COX-2, NLRP3 and iNOS proteins induced by LPS. The compounds shown in formulas 13b and 13c can significantly inhibit the expression of phosphorylated NF-κB, phosphorylated IκBα, COX-2, NLRP3 and IL-6 and proteins induced by LPS. The compound shown in formula 13c can also significantly inhibit the expression of iNOS protein induced by LPS. The above results show that the compounds shown in formulas 4d, 13b, and 13c exert anti-inflammatory effects by inhibiting the NF-κB and NLRP3 inflammasome signaling pathways.

[0516] (7) Therapeutic effect of the compound represented by formula 4d on acute pneumonia in mice

[0517] After the in vitro anti-inflammatory activity and anti-inflammatory mechanism of the compound of Formula 4d were ascertained, the in vivo anti-inflammatory activity was further studied. Female BALB / c mice aged 6-8 weeks were randomly divided into five groups, 3 mice in each group: control group (PBS containing 10% DMSO), LPS model group (LPS 1.25 mg / kg, PBS containing 10% DMSO), positive drug control group (LPS 1.25 mg / kg, oridonin 40 mg / kg), low-dose group of the compound of Formula 4d (LPS 1.25 mg / kg, compound of Formula 4d 20 mg / kg), high-dose group of the compound of Formula 4d (LPS 1.25 mg / kg, compound of Formula 4d 40 mg / kg). Oridonin or the compound of Formula 4d or the solvent were injected intraperitoneally in advance, and LPS was dripped into the nasal cavity 1 hour later to establish the model. The animals were killed 24 hours after nasal instillation, and the lung tissues were removed for HE staining and microscopic photography. The lung tissues were also taken to extract RNA and protein for qPCR and WB experiments.

[0518] The results are as follows Fig.94 As shown, Fig.94 The figure is a graph showing the therapeutic effect of Rubescensine A derivatives on acute pneumonia in mice; wherein, A: the therapeutic effect of the compound shown in Formula 4d on LPS-induced pneumonia in mice; BE: the inhibitory effect of the compound shown in Formula 4d on the expression of inflammatory genes in the lung tissue of mice; F: the inhibitory effect of the compound shown in Formula 4d on the expression of inflammation-related proteins in the lung tissue of mice, β-actin being the internal reference; compared with the control group: # P<0.05, ## P<0.01, ### P<0.001; compared with LPS group: *P<0.05 **P<0.01 ***P<0.001.

[0519] Fig.94 The results in Figure A show that LPS can significantly induce acute pneumonia in mice. Oridonin (40 mg / kg) and low-dose compound of formula 4d (20 mg / kg) have no significant therapeutic effect on acute pneumonia, while high-dose compound of formula 4d (40 mg / kg) can significantly alleviate LPS-induced acute pneumonia. Fig.94 As shown in the BE figure, the qPCR experimental results of lung tissue showed that the high dose of the compound represented by formula 4d (40 mg / kg) can significantly inhibit the expression of inflammatory genes TNF-α, IL-6, IL-1β and COX-2. Fig.94As shown in Figure F, the WB experimental results of lung tissue showed that Russocine A (40 mg / kg), low dose (20 mg / kg) and high dose of the compound represented by Formula 4d (40 mg / kg) could inhibit the expression of inflammatory protein phosphorylation NF-κB and NLRP3, and the inhibitory effect of the high dose of the compound represented by Formula 4d (40 mg / kg) was more significant. The above results show that the compound represented by Formula 4d can effectively treat LPS-induced pneumonia in mice through the NF-κB and NLRP3 inflammasome signaling pathways.

[0520] (8) Therapeutic effect of the compound represented by formula 13c on acute pneumonia in mice

[0521] After the in vitro anti-inflammatory activity and anti-inflammatory mechanism of the compound of Formula 13c were ascertained, the in vivo anti-inflammatory activity was further studied. Female BALB / c mice aged 6-8 weeks were randomly divided into four groups, 3 mice in each group: control group (PBS containing 10% DMSO), LPS model group (LPS 1.25 mg / kg, PBS containing 10% DMSO), positive drug control group (LPS 1.25 mg / kg, oridonin A 20 mg / kg), compound group of Formula 13c (LPS 1.25 mg / kg, compound of Formula 13c 20 mg / kg). Oridonin A or the compound of Formula 13c or the solvent were injected intraperitoneally in advance, and LPS was dripped into the nasal cavity 1 hour later to establish the model. The animals were killed 24 hours after the nasal drip, and the lung tissues were taken for HE staining and microscopic photography, and the lung tissues were taken for RNA and protein extraction for qPCR and WB experiments.

[0522] The results are as follows Fig.95 As shown, Fig.95 The figure is a graph showing the therapeutic effect of Rubescensine A derivative (Formula 13c) on acute pneumonia in mice; wherein, A: the therapeutic effect of the compound shown in Formula 13c on LPS-induced pneumonia in mice; BC: the inhibitory effect of the compound shown in Formula 4d on the expression of inflammatory genes in the lung tissue of mice; D: the inhibitory effect of the compound shown in 4d on the expression of inflammation-related proteins in the lung tissue of mice, with β-actin as the internal reference; compared with the control group: # P<0.05, compared with LPS group: **P<0.01 ***P<0.001.

[0523] like Fig.95 As shown in Figure A, LPS can significantly induce acute pneumonia in mice, and Rubescensine A and the compound shown in Formula 13c can treat acute pneumonia in mice, and the therapeutic effect of the compound shown in Formula 13c is more significant. Fig.95 As shown in Figure BC, the qPCR experimental results of lung tissue showed that Rubescensine A and the compound shown in Formula 13c could significantly inhibit the expression of inflammatory genes IL-6 and TNF-α, and the inhibitory effect of the compound shown in Formula 13c was more significant. Fig.95 As shown in D, the WB experimental results of lung tissue showed that Rubescensine A and the compound represented by Formula 13c could inhibit the expression of inflammation-related proteins NLRP3, phosphorylated NF-κB and IL-6, and the inhibitory effect of the compound represented by Formula 13c was more significant. The above results indicate that the compound represented by Formula 13c can effectively treat LPS-induced pneumonia in mice through the NF-κB and NLRP3 inflammasome signaling pathways.

[0524] (9) Therapeutic effect of the compound represented by formula 4d on acute peritonitis in mice

[0525] After confirming that the compound of formula 4d can effectively treat LPS-induced pneumonia in mice, the therapeutic effect of the compound of formula 4d on acute peritonitis in mice was further explored. Female BALB / c mice of 6-8 weeks were randomly divided into six groups, 12 mice in each group: control group (PBS containing 10% DMSO), LPS model group (LPS 10 mg / kg, PBS containing 10% DMSO), positive drug low-dose control group (LPS 10 mg / kg, oridonin 10 mg / kg), positive drug high-dose control group (LPS 10 mg / kg, oridonin 20 mg / kg), low-dose group of the compound of formula 4d (LPS 10 mg / kg, compound of formula 4d 10 mg / kg), high-dose group of the compound of formula 4d (LPS 10 mg / kg, compound of formula 4d 20 mg / kg). Oridonin or the compound of formula 4d or the solvent was intraperitoneally injected, and 15 minutes later, 10 mg / kg LPS was intraperitoneally injected, and the death of the mice was recorded for seven consecutive days.

[0526] The results are as follows Fig.96 As shown, Fig.96 The figure is a graph showing the therapeutic effect of Rubescensine A derivative (Formula 4d) on acute peritonitis in mice, compared with the control group: #### P<0.0001; compared with the LPS group: *P<0.05.

[0527] The results showed that no mice in the control group died within 7 days of administration, all mice in the LPS model group died within 60 hours, all mice in the positive drug low-dose control group died within 48 hours, and all mice in the positive drug high-dose control group died within 72 hours. 80% of the mice in the low-dose group and high-dose group of the compound shown in formula 4d died within 48 hours, and the remaining 20% ​​of the mice survived, and the peritoneal inflammation was effectively treated. The survival rate of mice in the high-dose group of the compound shown in formula 4d was significantly different from that in the model group. The experimental results show that the compound shown in formula 4d has a therapeutic effect on LPS-induced peritonitis in mice.

[0528] (10) Transcriptome sequencing proves that the compound represented by formula 4d regulates inflammation-related signaling pathways

[0529] After proving that the compound shown in Formula 4d has anti-inflammatory activity in vitro and in vivo, the anti-inflammatory mechanism was further explored by transcriptome sequencing. The specific method is as follows: The experiment was divided into two groups: LPS group and LPS co-incubation group with the compound shown in Formula 4d. RAW264.7 cells were inoculated in a 3-cm cell culture dish, and after 24 hours, a cell culture medium containing 1 μg / mL of LPS was added for pre-incubation for 1 hour, and then a culture medium containing 1 μg / mL of LPS and 0.3125 μM of the compound shown in Formula 4d was added for co-incubation for 24 hours. Total RNA was extracted using Trizol reagent (15596026, Invitrogen), and a library was built and sequenced at Novogene, and differentially expressed genes were determined using p-value < 0.05 and |log2(FoldChange)|>1 as the standard.

[0530] The results are as follows Figures 97-99 As shown, Fig.97 The volcano map of transcriptome sequencing of Rubescensine A derivatives (Formula 4d) regulating inflammation-related signaling pathways. Fig.98 The GO analysis diagram of transcriptome sequencing of Rubescensine A derivatives (Formula 4d) regulating inflammation-related signaling pathways; Fig.99 This is the transcriptome sequencing KEGG analysis diagram of the regulation of inflammation-related signaling pathways by oridonin derivatives (Formula 4d).

[0531] Fig.97 The volcano map of transcriptome sequencing showed that 97 genes were significantly upregulated and 85 genes were significantly downregulated in the group co-incubated with LPS and the compound represented by formula 4d compared with the LPS group. Fig.98 The GO analysis diagram of transcriptome sequencing shows that the compound represented by formula 4d significantly regulates the secretion of polypeptides, cytokines and other pathways. Fig.99 The KEGG analysis diagram of transcriptome sequencing shows that the compound represented by formula 4d significantly regulates signal pathways such as cytokine-cytokine receptor interaction, hematopoietic cell lineage, and malaria.

[0532] (11) Transcriptome sequencing proves that the compound represented by formula 13c regulates inflammation-related signaling pathways

[0533] After proving that the compound shown in Formula 13c has anti-inflammatory activity in vitro and in vivo, the anti-inflammatory mechanism was further explored by transcriptome sequencing. The specific method is as follows: The experiment was divided into two groups: LPS group and LPS co-incubation group with the compound shown in Formula 13c. RAW264.7 cells were inoculated in a 3-cm cell culture dish, and after 24 hours, a cell culture medium containing 1 μg / mL of LPS was added for pre-incubation for 1 hour, and then a culture medium containing 1 μg / mL of LPS and 0.3125 μM of the compound shown in Formula 13c was added for co-incubation for 24 hours. Total RNA was extracted using Trizol reagent (15596026, Invitrogen), and a library was built and sequenced at Novogene, and differentially expressed genes were determined using p-value <0.05 and |log2(FoldChange)|>1 as the standard.

[0534] The results are as follows Figure 100-102 As shown, Fig.100 The volcano map of transcriptome sequencing of Rubescensine A derivatives (Formula 13c) regulating inflammation-related signaling pathways. Fig.101 The GO analysis diagram of transcriptome sequencing of Rubescensine A derivatives (Formula 13c) regulating inflammation-related signaling pathways. Fig.102 This is the transcriptome sequencing KEGG analysis diagram of the regulation of inflammation-related signaling pathways by oridonin derivatives (Formula 13c).

[0535] like Fig.100 The volcano plot of transcriptome sequencing shows that, compared with the LPS group, 303 genes were significantly upregulated and 270 genes were significantly downregulated in the group co-incubated with LPS and the compound represented by formula 13c. Fig.101 This is the GO analysis diagram of transcriptome sequencing. The results show that the compound represented by formula 13c significantly regulates pathways such as inflammatory response, nuclear division, and chromosome separation. Fig.102 The transcriptome sequencing KEGG analysis diagram shows that the compound represented by formula 13c significantly regulates signal pathways such as cytokine-cytokine receptor interaction, hematopoietic cell lineage, and cell cycle.

[0536] (12) The compound represented by formula 4d exerts anti-inflammatory effect through stfa2

[0537] Analysis of transcriptome sequencing results revealed that the gene most significantly upregulated by the compound represented by Formula 4d was stfa2, and molecular biology experiments were used to further verify the regulatory effect of the compound represented by Formula 4d on the stfa2 gene.

[0538] The results are as follows Fig.103 As shown, Fig.103 The diagram is a diagram of the inflammatory signaling pathway regulated by Rubescensine A derivatives (Formula 4d); wherein, A: after induction with LPS, the compound shown in Formula 4d promotes the expression of the stfa2 gene, compared with the control group: #P<0.05, compared with LPS group: *P<0.05**P<0.01; B: Without LPS induction, the compound shown in Formula 4d promoted the expression of stfa2 gene, compared with the control group: ***P<0.001; CD: After knocking down the stfa2 gene, the inhibitory effect of the compound shown in Formula 4d on the expression of IL-6 and IL-1β was significantly reduced, compared with the same drug concentration group of the knockdown (si-stfa2) and the control (NC): *P<0.05**P<0.01; E: After knocking down the stfa2 gene, the inhibitory effect of the compound shown in Formula 4d on the expression of COX-2 and IL-6 was significantly reduced, and GAPDH was used as an internal reference.

[0539] like Fig.103 As shown in Figure AB, qPCR experiments show that the compound shown in Formula 4d can significantly upregulate the expression of the stfa2 gene. Fig.103 As shown in Figures CD, after knocking down the stfa2 gene, the inhibitory effect of the compound shown in Formula 4d on the inflammatory genes IL-6 and IL-1β was significantly reduced. Fig.103 As shown in Figure E, after knocking down the stfa2 gene, the inhibitory effect of the compound represented by Formula 4d on the inflammatory proteins COX-2 and IL-6 was significantly reduced. The above results indicate that the compound represented by Formula 4d exerts an anti-inflammatory effect through stfa2.

[0540] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A Rubescensine A derivative, characterized in that: The Rubescensine A derivatives include stereoisomers or pharmaceutically acceptable salts thereof. The Rubescensine A derivatives have a structure shown in Formula A: Wherein, Het is any structure shown in the following formula: R is selected from any of the following structures:

2. The Rubescensine A derivative according to claim 1, characterized in that: The R is selected from any one of the following structures:

3. The Rubescensine A derivative according to claim 2, characterized in that: Het is a structure shown in the following formula: R is selected from any of the following structures: Alternatively, Het is a structure shown in the following formula: R is selected from any of the following structures: Alternatively, Het is a structure shown in the following formula: R is selected from any of the following structures: Alternatively, Het is a structure shown in the following formula: R is selected from any of the following structures: Alternatively, Het is any of the following structures: R is selected from any of the following structures: Alternatively, Het is a structure shown in the following formula: R is selected from any of the following structures: Alternatively, Het is a structure shown in the following formula: R is selected from any of the following structures:

4. The Rubescensine A derivative according to claim 3, characterized in that: Having any of the following structures:

5. The Rubescensine A derivative according to claim 4, characterized in that: Having any of the following structures:

6. The method for preparing the Rubescensine A derivative according to any one of claims 1 to 5, characterized in that: The following steps are involved: subjecting oridonin to one or both of an esterification reaction and a rearrangement reaction to obtain an oridonin derivative; Alternatively, the oridonin is subjected to Jones oxidation reaction, esterification reaction or elimination reaction, and then subjected to one or both of esterification reaction and rearrangement reaction to obtain the oridonin derivative.

7. Use of the oridonin derivative according to any one of claims 1 to 5 or the oridonin derivative prepared by the preparation method according to claim 6 in the preparation of a drug for treating inflammation and related diseases.

8. The use according to claim 7, characterized in that: The inflammation and related diseases thereof are acute pneumonia, chronic pneumonia, lung injury or peritonitis.

9. The use according to claim 7, characterized in that: The drug is a drug that acts on the inflammatory factor stfa2.

10. An anti-inflammatory drug, characterized in that: The invention comprises the Rubescensine A derivative according to any one of claims 1 to 5 or the Rubescensine A derivative prepared by the preparation method according to claim 6.

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