Glycyrrhetinic acid derivative and use thereof

Abstract

Provided in the present disclosure is a glycyrrhetinic acid derivative as shown in formula (A) or a pharmaceutically acceptable salt thereof. The compound of the present disclosure can be used in the treatment of inflammatory diseases or autoimmune diseases.

Description

Glycyrrhetinic acid derivatives and uses thereof Technical Field

[0001] The present disclosure belongs to the field of medical technology, and in particular relates to a glycyrrhetinic acid derivative and its use, including but not limited to treatment of dermatitis, eczema, atopic dermatitis, seborrheic dermatitis, hormone-dependent dermatitis, photosensitive dermatitis, chloasma, psoriasis, urticaria, prurigo nodularis, pityriasis rosea, inflammatory bowel disease, lupus erythematosus, alopecia areata, pemphigus, bullous pemphigoid, chronic nephritis, asthma, rhinitis, skin damage caused by radiotherapy, burns or scalds. Background Art

[0002] Glycyrrhetinic acid is a triterpenoid saponin derived from the natural product glycyrrhizic acid, a traditional Chinese medicine, and is the primary pharmacologically active component of licorice. Glycyrrhetinic acid belongs to the pentacyclic triterpenoid family, with a C=O residue at position 11, similar to an 18-H-oleanane structure. Glycyrrhetinic acid exists in different optical isomers: 18α and 18β (as shown in the figure below).

[0003] Studies have shown that glycyrrhetinic acid and its derivatives have a wide range of pharmacological activities, including anti-inflammatory, anti-ulcer, antiviral, lipid-lowering, free radical scavenging, and anti-tumor activities. Regarding anti-inflammatory properties, glycyrrhetinic acid and its derivatives can directly inhibit the production of inflammatory cytokines and inflammatory mediators through multiple targets, and can also indirectly exert their anti-inflammatory functions through mechanisms such as enhancing the activity of steroid hormones. However, the biological activity of glycyrrhetinic acid is generally weak, with its anti-inflammatory activity being approximately 1 / 10 that of hydrocortisone, which limits its clinical application. Therefore, the development of compounds with better biological activity is urgently needed.

[0004] In view of this, the present disclosure is proposed. Summary of the Invention

[0005] The main purpose of the present disclosure is to provide a glycyrrhetinic acid derivative and its use, in order to at least partially solve at least one of the above technical problems.

[0006] In general, the present disclosure provides a compound represented by formula (A) or a pharmaceutically acceptable salt thereof:

[0007] Among them, R a -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different and are independently selected from hydrogen, C1-C6 alkyl or R 21 and R 22Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which may optionally contain one or more other heteroatoms selected from O, N or NH, where n is an integer from 1 to 6;

[0008] R c is selected from hydrogen, halogen, hydroxy, cyano, methoxy, amino or haloalkyl;

[0009] R b is selected from carbonyl or methine;

[0010] is a single bond or a double bond;

[0011] R d For oxygen;

[0012] Indicates that the H connected to C is α-type or β-type;

[0013] or,

[0014] R a is hydrogen; R b is a carbonyl group; R c represents Br or Cl; R d For oxygen; is a single bond or a double bond; Indicates that the H connected to C is α-type or β-type;

[0015] or

[0016] R a Selected from hydrogen or -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different and are independently selected from hydrogen, C1-C6 alkyl or R 21 and R 22 Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which may optionally contain one or more other heteroatoms selected from O, N or NH, where n is an integer from 1 to 6;

[0017] R b is a carbonyl group;

[0018] R c and R d Each is independently selected from N, O or S, and together with the carbon atom to which they are attached form a 5-6 membered aromatic heterocyclic group, the aromatic heterocyclic group is optionally substituted by NR 11 R 12 Replacement, R 11 and R 12 Each is independently selected from C1-C6 alkyl;

[0019] is a single bond or a double bond;

[0020] Indicates that the H connected to C is α-type or β-type;

[0021] Provided that the compound represented by formula (A) is not

[0022] The present disclosure provides a glycyrrhetinic acid derivative having a structure represented by formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof:

[0023] Wherein, in the compound of formula (I), R1 is selected from hydrogen, halogen, hydroxyl, cyano, methoxy, amino or haloalkyl;

[0024] R2 is selected from -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different and are independently selected from hydrogen, C1-C6 alkyl or R 21 and R 22 Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which may optionally contain one or more other heteroatoms selected from O, N or NH, where n is an integer from 1 to 6;

[0025] R3 is selected from carbonyl or methine;

[0026] is a single bond or a double bond;

[0027] Indicates that the H attached to the C18-position is α-type or β-type;

[0028] or,

[0029] Wherein, in the compound of formula (II), R1' represents Br or Cl;

[0030] Indicates that the H attached to the C18-position is α-type or β-type;

[0031] or,

[0032] Wherein, in the compound of formula (III), R 11 ' and R 12 ' are each independently selected from C1-C6 alkyl;

[0033] R2' is selected from hydrogen or -(CH2) n -NR 21 'R 22 ', R 21 ' and R 22 ' may be the same or different, and are independently selected from hydrogen, C1-C6 alkyl or R 21 ' and R 22 'Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which may optionally contain one or more other heteroatoms selected from O, N or NH, where n is an integer of 1-6;

[0034] Indicates that the H attached to the C18-position is α-type or β-type;

[0035] Wherein, the compound of formula (I) cannot be selected from

[0036] Furthermore, in the compound of formula (I), R1 is selected from hydrogen or cyano;

[0037] R2 is selected from -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different, and are independently selected from C1-C3 alkyl or R 21 and R 22 Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which may optionally contain one or more other heteroatoms selected from O, where n is an integer of 2-5;

[0038] R3 is selected from carbonyl or methine;

[0039] is a single bond or a double bond;

[0040] Indicates that the H attached to the C18-position is α-type or β-type;

[0041] Preferably, in the compound of formula (I), R1 is selected from hydrogen or cyano;

[0042] R2 is selected from -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different and are independently selected from methyl, ethyl or R 21 and R 22 Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, n=an integer from 2 to 5;

[0043] R3 is selected from carbonyl or methine;

[0044] is a single bond or a double bond;

[0045] It represents that the H attached to the C18-position is of α-type or β-type.

[0046] In some embodiments, in the compound of formula (I), when R1 is hydrogen, R2 is -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different, and are independently selected from C2-C3 alkyl or R 21 and R 22 Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group (e.g., a 5-6 membered heterocycloalkyl group), n=an integer of 2-5, the heterocyclic group may optionally additionally contain one or more (e.g., 1-2) heteroatoms selected from O or N, R3 is a carbonyl group, is a single bond, Indicates that the H attached to the C18-position is α-type or β-type;

[0047] Alternatively, when R1 is hydroxy, cyano or amino (preferably cyano), R2 is -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different, and are independently selected from C1-C3 alkyl, n=an integer of 2-5 (preferably n=2 or 3; preferably, R2 is -(CH2)2-N(C1-C2 alkyl)(C1-C2 alkyl)), R3 is a methine or carbonyl group, is a single bond or a double bond, It represents that the H attached to the C18-position is of α-type or β-type.

[0048] In some embodiments, in the compound of formula (I), when R1 is hydrogen, R2 is -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different, and are independently selected from C2-C3 alkyl or R 21 and R 22Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocycloalkyl group, n=an integer of 2-5, wherein the heterocycloalkyl group may optionally contain one or more (e.g., 1-2) heteroatoms selected from O or N, R3 is a carbonyl group, is a single bond, Indicates that the H attached to the C18-position is α-type or β-type;

[0049] Alternatively, when R1 is cyano or amino (preferably cyano), R2 is -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different, and are independently selected from C1-C3 alkyl, n=an integer of 2-5 (preferably n=2 or 3; preferably, R2 is -(CH2)2-N(C1-C2 alkyl)(C1-C2 alkyl)), R3 is a methine or carbonyl group, is a single bond or a double bond (preferably, is a single bond, and the other is a double bond), It represents that the H attached to the C18-position is of α-type or β-type.

[0050] Furthermore, in the compound of formula (I), R1 is selected from hydrogen or cyano;

[0051] R2 is selected from -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different and are independently selected from methyl, ethyl or R 21 and R 22 Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, n=an integer from 2 to 5;

[0052] R3 is selected from carbonyl;

[0053] is a single bond or a double bond;

[0054] Indicates that the H attached to the C18-position is α-type or β-type;

[0055] Preferably, in the compound of formula (I), R1 is selected from hydrogen or cyano;

[0056] R2 is selected from -(CH2) n -NR 21 R 22 , R 21 and R22 may be the same or different, and are independently selected from ethyl, n=2;

[0057] R3 is selected from carbonyl;

[0058] is a single bond or a double bond;

[0059] It represents that the H attached to the C18-position is of α-type or β-type.

[0060] Further, in the compound of formula (I), R1 is selected from cyano;

[0061] R2 is selected from -(CH2) n -NR 21 R 22 , R 21 and R 22 May be the same or different, and are independently selected from methyl, ethyl, n=2;

[0062] R3 is selected from methine;

[0063] is a double bond;

[0064] It represents that the H attached to the C18-position is of α-type or β-type.

[0065] In some embodiments, in the compound of formula (I), when R1 is hydrogen, R2 is -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different and are independently selected from C2-C3 alkyl (e.g. ethyl, propyl) or R 21 and R 22 Together with the nitrogen atoms to which they are attached, n=an integer of 2-5, R3 is a carbonyl group, is a single bond, Indicates that the H attached to the C18-position is α-type or β-type;

[0066] Alternatively, when R1 is cyano, R2 is -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different, and are independently selected from C1-C3 alkyl (e.g., methyl, ethyl, propyl), n=2 or 3 (preferably, R2 is -(CH2)2-N(C1-C2 alkyl)(C1-C2 alkyl)), R3 is a carbonyl group, is a single bond or a double bond (preferably, is a single bond, and the other is a double bond), It represents that the H attached to the C18-position is of α-type or β-type.

[0067] In some embodiments, in the compound of formula (I), R1 is hydrogen or cyano, R2 is -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different, and are independently selected from C2-C3 alkyl (e.g., ethyl, propyl), n=2 or 3 (preferably, R2 is -(CH2)2-N(C1-C2 alkyl)(C1-C2 alkyl), e.g., -(CH2)2-N(CH2CH3)2), R3 is a carbonyl group, is a single bond or a double bond (preferably, is a single bond, and the other is a single bond or a double bond), It represents that the H attached to the C18-position is of α-type or β-type.

[0068] In some embodiments, in the compound of formula (III), R 11 ' and R 12 'are each independently selected from C1-C5 alkyl, C1-C4 alkyl or C1-C3 alkyl (eg methyl, ethyl, propyl);

[0069] R2' is selected from hydrogen or -(CH2) n -NR 21 'R 22 ', R 21 ' and R 22 ' may be the same or different, and are each independently selected from C1-C5 alkyl (preferably C1-C4 alkyl or C1-C3 alkyl, such as methyl, ethyl, propyl), n = an integer of 1-3 (preferably n = 2 or 3; preferably, R2' is -(CH2)2-N(C1-C2 alkyl)(C1-C2 alkyl), such as -(CH2)2-N(CH2CH3)2);

[0070] It represents that the H attached to the C18-position is of α-type or β-type.

[0071] Furthermore, in the compound of formula (III), R 11 ' and R 12 ' are each independently selected from C1-C3 alkyl;

[0072] R2' is selected from hydrogen or -(CH2) n-NR 21 'R 22 ', R 21 ' and R 22 ' may be the same or different, and are independently selected from C1-C3 alkyl, n = an integer of 1-3;

[0073] Indicates that the H attached to the C18-position is α-type or β-type;

[0074] Preferably, in the compound of formula (III), R 11 ' and R 12 ' are each independently selected from methyl, ethyl or propyl;

[0075] R2' is selected from hydrogen or -(CH2) n -NR 21 'R 22 ', R 21 ' and R 22 ' may be the same or different, and are independently selected from methyl, ethyl or propyl, preferably ethyl, n=2;

[0076] Indicates that the H attached to the C18-position is α-type or β-type;

[0077] More preferably, in the compound of formula (III), R 11 ' and R 12 ' are each independently selected from methyl, ethyl or propyl;

[0078] R2' is selected from hydrogen;

[0079] It represents that the H attached to the C18-position is of α-type or β-type.

[0080] Furthermore, the compound of formula (I) is selected from the following compounds:

[0081] Preferably, compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 13, compound 14, and compound 15;

[0082] More preferred are Compound 1, Compound 2, Compound 3, and Compound 9.

[0083] Furthermore, the compound of formula (II) is selected from the following compounds:

[0084] Preferred are Compound 16, Compound 17, and Compound 18.

[0085] Furthermore, the compound of formula (III) is selected from the following compounds:

[0086] Preferred are Compound 21, Compound 22, and Compound 23.

[0087] The present disclosure also provides a pharmaceutical composition comprising the above-mentioned glycyrrhetinic acid derivative (i.e., a compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof) and optionally one or more pharmaceutically acceptable carriers, diluents, excipients or adjuvants.

[0088] Furthermore, the pharmaceutical composition is a solid oral preparation, a liquid oral preparation, an injection or a topical preparation.

[0089] Furthermore, the solid oral preparation is selected from tablets, capsules, dry suspensions or granules; the liquid oral preparation is selected from syrups, oral solutions, oral suspensions or oral emulsions; the injection is selected from injection solutions, sterile powders for injection or concentrated solutions for injection; the topical preparation is selected from ointments, creams, gels, latexes, pastes, liniments, paints, tinctures, lotions, coatings, sprays, suppositories, foams or enemas.

[0090] The present disclosure also provides the use of the above-mentioned glycyrrhetinic acid derivatives (i.e., compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof) or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating inflammatory or autoimmune diseases. Alternatively, the present disclosure also provides the above-mentioned glycyrrhetinic acid derivatives (i.e., compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof) or the above-mentioned pharmaceutical compositions for use in drugs for treating inflammatory or autoimmune diseases. Alternatively, the present disclosure also provides a method for treating inflammatory or autoimmune diseases, comprising administering a therapeutically effective amount of the above-mentioned glycyrrhetinic acid derivatives (i.e., compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof) or the above-mentioned pharmaceutical compositions to a subject in need.

[0091] Furthermore, the disease is selected from dermatitis, eczema, atopic dermatitis, seborrheic dermatitis, hormone-dependent dermatitis, photosensitive dermatitis, chloasma, psoriasis, urticaria, prurigo nodularis, pityriasis rosea, inflammatory bowel disease, lupus erythematosus, alopecia areata, pemphigus, bullous pemphigoid, chronic nephritis, asthma, rhinitis, skin damage caused by radiotherapy (including but not limited to radiation dermatitis), burns, scalds or solar dermatitis.

[0092] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that can produce a desired response (including preventing or slowing the occurrence of a disease, reducing the severity of a disease, improving the patient's condition, inducing an immune response, delaying or at least slowing the progression of a disease, or curing the disease) in a patient or individual in need thereof, and can be determined by those skilled in the art based on the patient's or individual's age, sex, weight, physical condition, family history, risk of disease, etc. in combination with the contents of this disclosure.

[0093] Compared with the prior art, the present invention has the following beneficial effects:

[0094] The compounds disclosed herein exhibit significant inhibitory activity in RAW264.7 cell inflammation models, ear swelling models, atopic dermatitis models, radiation dermatitis models, and pruritus models, with significant anti-inflammatory effects. They also exhibit prominent drug distribution in the colon and significantly reduce intracellular ROS levels in ROS release assays, suggesting potential applications in the treatment of various inflammatory or autoimmune diseases. Furthermore, as topical preparations, the compounds disclosed herein exhibit significant benefits, such as minimal skin irritation and high safety. DETAILED DESCRIPTION

[0095] definition

[0096] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. A particular term should not be considered ambiguous or unclear if it is not specifically defined, but should be understood according to its ordinary meaning in the art.

[0097] "Alkyl" refers to a saturated hydrocarbon group, which can be straight or branched. As used herein, C1-C6 alkyl refers to a straight or branched alkyl group consisting of 1-6 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, or a range consisting of any two of the aforementioned values). Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, and the like.

[0098] "Heteroatom" refers to any atom other than carbon and hydrogen atoms that can be covalently bonded to a carbon atom. Common heteroatoms include but are not limited to O, S, N, etc.

[0099] "Heterocyclic group" refers to a fully saturated or partially unsaturated (but not fully unsaturated, e.g., having 1 or 2 double bonds) monocyclic, bridged, or spirocyclic monovalent group, wherein at least one (e.g., 1, 2, 3, or 4) ring atom is a heteroatom selected from N, O, and S, and the remaining ring atoms are C, for example, a 5-6 membered heterocyclic group includes a heterocycloalkyl or heterocycloalkenyl group containing 1-2 heteroatoms (selected from N, O, and S). "Heterocycloalkyl" refers to a saturated heterocyclic group.

[0100] "Aromatic heterocycle" is also called "heteroaryl", which refers to an aromatic cyclic structure formed by replacing carbon atoms in an aromatic ring with one or more heteroatoms. For example, a 5-6 membered aromatic heterocycle refers to an aromatic cyclic group containing heteroatoms and composed of 5 or 6 ring atoms.

[0101] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0102] "Oxo" means =0.

[0103] "Haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen atom. For example, a C1-C6 haloalkyl group refers to a straight-chain or branched-chain alkyl group consisting of 1 to 6 carbon atoms, in which at least one hydrogen atom is replaced by any halogen atom.

[0104] "Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted" includes substituted or unsubstituted, and "optionally comprising" encompasses comprising or not comprising.

[0105] "Pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0106] Unless otherwise indicated, the terms "comprise, comprise, and comprising" or their equivalents (contain, contains, containing, include, includes, including) used herein are open-ended expressions and mean that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included.

[0107] Unless otherwise indicated, all numbers used herein expressing amounts of ingredients, measurements, or reaction conditions are to be understood as modified in all instances by the term "about." When used in conjunction with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%.

[0108] Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

[0109] As used herein, and unless otherwise indicated, the term "treat," ...

[0110] The term "subject" encompasses any vertebrate, e.g., mammals and non-mammals, such as humans, non-human primates (e.g., chimpanzees, rhesus monkeys, cynomolgus monkeys, etc.), sheep, dogs, cats, horses, cows, chickens, pigs, mice, etc., preferably humans.

[0111] Herein, unless otherwise specified, "C18-position" refers to the carbon atom located at the C18 position in the structure of the corresponding glycyrrhetinic acid in the compound of formula (I), formula (II) or formula (III) of the present disclosure.

[0112] Example

[0113] The embodiments of the present disclosure will be described in detail below with reference to the examples. However, it will be understood by those skilled in the art that the following examples are merely illustrative of the present disclosure and should not be construed as limiting the scope of the present disclosure. Where specific conditions are not specified in the examples, conventional conditions were used. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0114] Wherein, DMAP: 4-dimethylaminopyridine, EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, IBX: 2-iodobenzoic acid, DMSO: dimethyl sulfoxide, DMF: dimethylformamide.

[0115] Preparation of a specific compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0116] Example 1

[0117] 2-(Diethylamino)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylamine-2-carboxylate

[0118] Synthesis method:

[0119] Preparation of Intermediate 1a: 18β-glycyrrhetinic acid (10 g, 21 mmol) was dissolved in acetone (120 mL). 12 mL of Jones reagent was slowly added dropwise in an ice bath. The reaction was allowed to proceed in an ice bath. TLC was monitored until the 18β-glycyrrhetinic acid disappeared. The reaction solution was then poured into 300 mL of water. A large amount of white precipitate formed. The filter cake was filtered and washed with copious amounts of water several times until the pH of the washings reached approximately 6-7. The filter cake was then dried under reduced pressure to yield Intermediate 1a (9 g, 90% yield). MS m / z (ESI): 469.42 [M+H] + .

[0120] Preparation of Compound 1: Intermediate 1a (5 g, 11 mmol), diethylaminoethanol (1.5 g, 13 mmol), DMAP (0.26 g, 2.1 mmol), and EDCI (2.5 g, 13 mmol) were dissolved in dichloromethane (85 mL) and reacted at room temperature. TLC monitoring was performed until the intermediate 1a disappeared. Dichloromethane (100 mL) was then added to the reaction solution, and the mixture was washed with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The concentrate was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to obtain Compound 1 (4 g, 66% yield). MS m / z (ESI): 568.47 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ5.52(s,1H),4.13(m,2H),2.70(m,1H),2.60(m,2H),2.54(m,2H),2,46(m,2H),2.30(m,1H), 2.09(m,2H),1.73(m,5H),1.47(m,4H),1.36(m,6H),1.29(m,2H),1.13(m,4H),1.09(m,6H),0.96(m,14H),0.75(s,3H).

[0121] Example 2

[0122] 2-(Diethylamino)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bS)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylamine-2-carboxylate

[0123] Synthesis method:

[0124] Preparation of Intermediate 2a: Refer to the preparation method of Intermediate 1a in Example 1, except that 18-β-glycyrrhetinic acid was replaced with 18-α-glycyrrhetinic acid. The remaining steps were the same. MS m / z (ESI): 469.42 [M+H] + .

[0125] Preparation of Compound 2: Refer to the preparation method of Compound 1 in Example 1, replacing Intermediate 1a with Intermediate 2a, and the remaining steps are the same. MS m / z (ESI): 568.47 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ5.52(s,1H),4.13(m,2H),2.70(m,1H),2.58(m,2H),2.51(m,2H),2,43(m,2H),2.28(m,1H), 2.04(m,3H),1.73(m,4H),1.47(m,4H),1.36(m,6H),1.29(m,2H),1.13(m,4H),1.09(m,6H),0.96(m,14H),0.75(s,3H).

[0126] Example 3

[0127] 2-(Diethylamino)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-11-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-2-carboxylate

[0128] Synthesis method:

[0129] Preparation of Intermediate 3a: 18β-glycyrrhetinic acid (10 g, 21 mmol) and IBX (17.6 g, 63 mmol) were dissolved in DMSO (100 mL) and reacted at 85°C. TLC was monitored until 18β-glycyrrhetinic acid disappeared. After cooling to room temperature, the reaction solution was poured into 800 mL of water. A large amount of white precipitate formed. The filter cake was filtered, washed three times with water, and dried under reduced pressure to obtain Intermediate 3a (9 g, 91% yield). MS m / z (ESI): 467.42 [M+H] + .

[0130] Preparation of Intermediate 3b: Intermediate 3a (4 g, 8.6 mmol) was dissolved in tetrahydrofuran (100 mL), followed by the addition of I2 (13 g, 51 mmol) and pyridine (6.1 g, 77 mmol). The reaction was refluxed and monitored by TLC until the intermediate 3a disappeared. The mixture was cooled to room temperature, and most of the tetrahydrofuran was evaporated under reduced pressure. The mixture was washed with sodium thiosulfate solution until golden yellow. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The concentrate was purified by silica gel column chromatography (tetrahydrofuran) to obtain intermediate 3b (4.5 g, 88% yield). MS m / z (ESI): 593.56 [M+H] + .

[0131] Preparation of Intermediate 3c: Intermediate 3b (4 g, 6.8 mmol) was dissolved in DMF (50 mL), followed by the addition of cuprous cyanide (1.2 g, 13 mmol). The reaction was allowed to proceed at 140°C, and the reaction mixture was monitored by TLC until the presence of intermediate 3b was eliminated. After cooling to room temperature, water (100 mL) was added to the reaction mixture to precipitate a solid, which was filtered and extracted with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was purified by silica gel column chromatography (tetrahydrofuran) to afford intermediate 3c (2.5 g, 75% yield). MS m / z (ESI): 492.31 [M+H] + .

[0132] Preparation of compound 3: Intermediate 3c (2 g, 4.1 mmol), diethylaminoethanol (0.57 g, 4.9 mmol), DMAP (0.1 g, 0.8 mmol), and EDCI (0.93 g, 4.9 mmol) were dissolved in dichloromethane (30 mL) and reacted at room temperature. TLC monitoring was performed until intermediate 3c disappeared. Dichloromethane (40 mL) was then added to the reaction solution, and the mixture was washed with 10% citric acid solution (40 mL), saturated sodium bicarbonate solution (40 mL), and water (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The concentrate was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to obtain compound 3 (1.5 g, 62% yield). MS m / z (ESI): 591.45 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ8.47(s,1H),5.63(s,1H),4.17(m,2H),2.96(m,1H),2.62(m,2H),2.48(m,2H), 2.13(m,2H),1.77(m,7H),1.57(m,2H),1.37(m,9H),1.29(m,2H),1.17(m,13H),0.99(m,7H),0.76(s,3H).

[0133] Example 4

[0134] 2-(Dimethylamino)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-11-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-2-carboxylate

[0135] Synthesis method:

[0136] Preparation of Compound 4: Refer to the preparation method of Compound 3 in Example 3, replacing diethylaminoethanol with dimethylaminoethanol. The remaining steps are the same. The concentrate is purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to obtain Compound 4 (1.3 g, 57% yield). MS m / z (ESI): 563.36 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ8.43(s,1H),5.60(s,1H),3.95(m,2H),2.94(m,1H),2.03(m,2H), 1.74(m,7H),1.56(m,2H),1.36(m,9H),1.27(m,2H),1.14(m,13H),0.97(m,7H),0.86(s,3H).

[0137] Example 5

[0138] 5-(Diethylamino)pentyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylate

[0139] Synthesis method:

[0140] Preparation of Compound 5: Refer to the preparation method of Compound 1 in Example 1, replacing diethylaminoethanol with diethylaminopentanol. The remaining steps are the same. The concentrate is purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to obtain Compound 5 (2.1 g, 32% yield). MS m / z (ESI): 610.42 [M+H] + . 1H-NMR (400MHz, DMSO-d6): δ5.62(s,1H),4.63(m,2H),2.75(m,1H),2,41(m,2H),2.28(m,1H),2.19(m,2H), 1.64(m,5H),1.40(m,4H),1.32(m,6H),1.23(m,2H),1.13(m,8H),1.03(m,12H),0.86(m,14H),0.70(s,3H).

[0141] Example 6

[0142] 2-(Piperidin-1-yl)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylate

[0143] Synthesis method:

[0144] Preparation of Compound 6: Refer to the preparation method of Compound 1 in Example 1, substituting diethylaminoethanol for 2-piperidinylethanol; the remaining steps were the same. The concentrate was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to give Compound 6 (2.0 g, 32% yield). MS m / z (ESI): 580.41 [M+H]+. 1 H-NMR (400MHz, DMSO-d6): δ5.62(s,1H),4.07(m,2H),2.82(m,1H),2.68(m,2H),2.49(m,4H),2.36(m,1H), 2.18(m,2H),1.97(m,5H),1.45(m,8H),1.38(m,8H),1.31(m,2H),1.16(m,4H),1.03(m,14H),0.75(s,3H).

[0145] Example 7

[0146] 2-Morpholinoethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylate

[0147] Synthesis method:

[0148] Preparation of Compound 7: Refer to the preparation method of Compound 1 in Example 1, replacing diethylaminoethanol with 2-morpholinoethanol. The remaining steps are the same. The concentrate is purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to obtain Compound 7 (2.4 g, 38% yield). MS m / z (ESI): 582.43 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ5.98(s,1H),4.13(m,2H),3.57(m,4H),3.03(m,2H),2.82(m,1H),2.50(m,4H),2.41( m,1H),2.27(m,2H),1.99(m,5H),1.64(m,4H),1.41(m,6H),1.35(m,2H),1.23(m,4H),1.05(m,14H),0.89(s,3H).

[0149] Example 8

[0150] 2-(Pyrrolidin-1-yl)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylate

[0151] Synthesis method:

[0152] Preparation of Compound 8: Refer to the preparation method of Compound 1 in Example 1, replacing diethylaminoethanol with 2-tetrahydropyrrolylethanol. The remaining steps are the same. The concentrate is purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to obtain Compound 8 (2.2 g, 36% yield). MS m / z (ESI): 566.45 [M+H] + . 1H-NMR (400MHz, DMSO-d6): δ5.92(s,1H),4.06(m,2H),3.01(m,2H),2.72(m,1H),2.51(m,4H),2.41(m,1H), 2.21(m,2H),1.92(m,5H),1.64(m,8H),1.43(m,6H),1.39(m,2H),1.22(m,4H),1.09(m,14H),0.88(s,3H).

[0153] Example 9

[0154] 2-(Diethylamino)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylamine-2-carboxylate hydrochloride

[0155] Synthesis method:

[0156] Preparation of compound 9: Compound 1 (2 g, 3.5 mmol) was dissolved in 200 mL of dichloromethane, and hydrochloric acid in isopropanol was added dropwise. The mixture was reacted at room temperature for 24 h, and concentrated to give compound 9 (1.9 g, 89% yield). MS m / z (ESI): 568.43 [M+H] + .

[0157] Example 10

[0158] 2-(Pyrrolidin-1-yl)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylamine-2-carboxylate hydrochloride

[0159] Synthesis method:

[0160] Preparation of compound 10: Compound 8 (1.5 g, 2.6 mmol) was dissolved in 20 mL of dichloromethane, and hydrochloric acid in isopropanol was added dropwise. The mixture was reacted at room temperature for 24 h and concentrated to give compound 10 (1.3 g, 81% yield). MS m / z (ESI): 566.45 [M+H] + .

[0161] Example 11

[0162] 2-(Diethylamino)ethyl (2S,4aS,6aR,6bS,8aR,12aS,14bR)-11-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14b-hexahydro-2-carboxylate

[0163] Synthesis method:

[0164] Preparation of Intermediate 11a: Dissolve 18β-glycyrrhetinic acid (20 g, 42 mmol) in tetrahydrofuran (200 mL) and slowly add dropwise 64 mL of a solution of sodium borohydride (16.1 g, 425 mmol) in sodium hydroxide (8.4 g, 210 mmol). After complete addition, reflux the mixture and monitor by TLC until the absence of 18β-glycyrrhetinic acid. Cool to room temperature, pour the reaction solution into 10% sodium dihydrogen phosphate solution (800 mL), extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain Intermediate 11a (19 g, 96% yield). MS m / z (ESI): 473.46 [M+H] + .

[0165] Preparation of Intermediate 11b: Dissolve Intermediate 11a (18 g, 38 mmol) in tetrahydrofuran (200 mL) and slowly add a catalytic amount of concentrated hydrochloric acid dropwise. After the addition is complete, reflux the reaction and monitor by TLC until the intermediate 11a disappears. Cool to room temperature, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain Intermediate 11b (13.8 g, 80% yield). MS m / z (ESI): 455.32 [M+H] + .

[0166] Preparation of Intermediate 11c: Intermediate 11b (13 g, 28 mmol) and IBX (32 g, 114 mmol) were dissolved in DMSO (450 mL) and reacted at 85°C. TLC monitoring indicated the disappearance of Intermediate 11b. After cooling to room temperature, the reaction solution was poured into 2000 mL of water. A large amount of white precipitate formed. The filter cake was filtered and washed with copious amounts of water several times. The filter cake was then dried under reduced pressure to afford Intermediate 11c (11.6 g, 90% yield). MS m / z (ESI): 451.29 [M+H] + .

[0167] Preparation of Intermediate 11d: Intermediate 11c (11 g, 24.4 mmol) was dissolved in tetrahydrofuran (800 mL), followed by the addition of I2 (35.7 g, 140 mmol) and pyridine (16.8 g, 212 mmol). The mixture was refluxed and monitored by TLC until the intermediate 11c disappeared. The mixture was cooled to room temperature, and most of the tetrahydrofuran was evaporated under reduced pressure. The mixture was washed with sodium thiosulfate solution until golden yellow. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The concentrate was purified by silica gel column chromatography (tetrahydrofuran) to obtain intermediate 11d (12.5 g, 89% yield). MS m / z (ESI): 577.26 [M+H] + .

[0168] Preparation of Intermediate 11e: Intermediate 11d (12 g, 20.4 mmol) was dissolved in DMF (200 mL), followed by the addition of cuprous cyanide (3.5 g, 39 mmol). The reaction was allowed to proceed at 140°C, and the reaction mixture was monitored by TLC until the presence of intermediate 11d was eliminated. The mixture was cooled to room temperature, and water (600 mL) was added to the reaction mixture to precipitate a solid. The solid was filtered, and the filtrate was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The concentrate was purified by silica gel column chromatography (tetrahydrofuran) to afford Intermediate 11e (8.0 g, 81% yield). MS m / z (ESI): 476.32 [M+H] + .

[0169] Preparation of Compound 11: Intermediate 11e (4 g, 8.4 mmol), diethylaminoethanol (1.2 g, 10.1 mmol), DMAP (0.21 g, 1.7 mmol), and EDCI (1.93 g, 10.1 mmol) were dissolved in dichloromethane (50 mL) and reacted at room temperature. TLC monitoring was performed until intermediate 11e disappeared. Dichloromethane (30 mL) was then added to the reaction solution, which was then washed with 10% citric acid solution (80 mL), saturated sodium bicarbonate solution (80 mL), and water (80 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The concentrate was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to afford Compound 11 (2.1 g, 43% yield). MS m / z (ESI): 575.43 [M+H] + . 1H-NMR (400MHz, DMSO-d6): δ7.82(s,1H),5.66(d,1H,J=5.67Hz),5.52(d,1H,J=5.52Hz),4.87(m,2H),2.96(m,4H),2.08(m, 3H),1.96(m,1H),1.78(m,5H),1.55(m,4H),1.29(m,4H),1.18(s,3H),1.10(s,3H),1.06(m,13H),0.98(m,6H),0.79(s,3H).

[0170] Example 12

[0171] 2-(Dimethylamino)ethyl (2S,4aS,6aR,6bS,8aR,12aS,14bR)-11-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14b-hexahydro-2-carboxylate

[0172] Synthesis method:

[0173] Preparation of Compound 12: Refer to the preparation method of Compound 11 in Example 11, replacing diethylaminoethanol with dimethylaminoethanol. The remaining steps are the same. The concentrate is purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to obtain Compound 12 (1.8 g, 39% yield). MS m / z (ESI): 547.37 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ7.81(s,1H),5.96(d,1H,J=5.61Hz),5.62(d,1H,J=5.22Hz),4.82(m,2H),2.95(m,6H),2.10(m, 3H),1.91(m,1H),1.75(m,5H),1.49(m,4H),1.22(m,4H),1.14(s,3H),1.08(s,3H),1.01(m,7H),0.94(m,6H),0.73(s,3H).

[0174] Example 13

[0175] 2-(Piperidin-1-yl)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bS)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydroquinone-2-carboxylate

[0176] Synthesis method:

[0177] Refer to the preparation method of compound 6 in Example 6, replacing intermediate 1a with intermediate 2a, and the remaining steps are the same. MS m / z (ESI): 580.41 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ5.62(s,1H),4.07(m,2H),2.94(m,1H),2.71(m,2H),2.46(m,4H),2.32(m,1H), 2.14(m,2H),1.95(m,5H),1.42(m,8H),1.35(m,8H),1.31(m,2H),1.16(m,4H),1.03(m,14H),0.75(s,3H).

[0178] Example 14

[0179] 2-Morpholinoethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bS)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylate

[0180] Synthesis method:

[0181] Refer to the preparation method of compound 7 in Example 7, replacing intermediate 1a with intermediate 2a, and the remaining steps are the same. MS m / z (ESI): 582.43 [M+H] + . 1H-NMR (400MHz, DMSO-d6): δ5.98(s,1H),4.13(m,2H),3.57(m,4H),3.03(m,2H),2.82(m,1H),2.47(m,4H),2.38( m,1H),2.21(m,2H),1.89(m,5H),1.62(m,4H),1.43(m,6H),1.31(m,2H),1.25(m,4H),1.05(m,14H),0.89(s,3H).

[0182] Example 15

[0183] 2-(Pyrrolidin-1-yl)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bS)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylamine-2-carboxylate

[0184] Synthesis method:

[0185] Refer to the preparation method of compound 8 in Example 8, replace intermediate 1a with intermediate 2a, and the rest of the steps are the same. MS m / z (ESI): 566.45 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ5.92(s,1H),4.06(m,2H),3.01(m,2H),2.72(m,1H),2.62(m,4H),2.48(m,1H), 2.34(m,2H),2.02(m,5H),1.72(m,8H),1.54(m,6H),1.35(m,2H),1.24(m,4H),1.05(m,14H),0.88(s,3H).

[0186] Comparative Example 1

[0187] 2-(Dimethylamino)ethyl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylate

[0188] Synthesis method:

[0189] Preparation of control compound 1: refer to the preparation method of compound 1 in Example 1, except that diethylaminoethanol is replaced by dimethylaminoethanol, and the remaining steps are the same.

[0190] Comparative Example 2

[0191] 2-(Dimethylamino)ethyl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylate

[0192] Synthesis method:

[0193] Preparation of control compound 2: refer to the preparation method of compound 1 in Example 1, except that intermediate 1a is replaced by 18β-glycyrrhetinic acid, and the remaining steps are the same.

[0194] Comparative Example 3

[0195] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid

[0196] Intermediate 1a was used as control compound 3.

[0197] Preparation of a specific compound having a structure represented by formula (II) or a pharmaceutically acceptable salt thereof:

[0198] Example 16

[0199] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-11-chloro-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-2-carboxylic acid

[0200] Synthesis method:

[0201] Preparation of Intermediate 16a: Intermediate 3a (10 g, 21 mmol) was dissolved in tetrahydrofuran (200 mL) and 2 M sodium hydroxide solution (100 mL) was slowly added dropwise. After the addition was complete, a 30% hydrogen peroxide solution (25 mL) in methanol (100 mL) was added dropwise to the system. The reaction was allowed to proceed at room temperature. TLC was monitored until the intermediate 3a disappeared. Most of the solvent was evaporated under reduced pressure, and the mixture was adjusted to neutral with 5% hydrochloric acid solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford Intermediate 16a (10 g, 97% yield). MS m / z (ESI): 483.31 [M+H] + .

[0202] Preparation of Compound 16: Intermediate 16a (10 g, 21 mmol) was dissolved in 200 mL of glacial acetic acid. Concentrated hydrochloric acid (30 mL) was added dropwise and allowed to react at room temperature. TLC was monitored until the reaction was complete. The reaction solution was poured into 1000 mL of water. A large amount of white precipitate formed. This was filtered and the filter cake was washed with copious amounts of water several times to obtain a white solid. The solid was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) and concentrated to dryness to obtain Compound 16 (5.1 g, 48% yield). MS m / z (ESI): 501.16 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ12.19(s,1H),7.92(s,1H),5.52(s,1H),2.87(s,1H), 2.13(m,2H),1.81(m,6H),1.55(m,2H),1.38(m,11H),1.07(m,13H),0.75(s,3H).

[0203] Example 17

[0204] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bS)-11-chloro-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-2-carboxylic acid

[0205] Synthesis method:

[0206] Preparation of Intermediate 17a: Refer to the preparation method of Intermediate 3a in Example 3, except that 18β-glycyrrhetinic acid was replaced with 18α-glycyrrhetinic acid. The remaining steps were the same. MS m / z (ESI): 467.34 [M+H] + .

[0207] Preparation of Intermediate 17b: Refer to the preparation method of Intermediate 16a in Example 16, replacing Intermediate 3a with Intermediate 17a, and the rest of the steps are the same. MS m / z (ESI): 483.31 [M+H] + .

[0208] Preparation of Compound 17: Refer to the preparation method of Compound 16 in Example 16, replacing Intermediate 16a with Intermediate 17b, and the remaining steps are the same. MS m / z (ESI): 501.28 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ12.19(s,1H),7.92(s,1H),5.52(s,1H),2.74(s,1H), 2.05(m,2H),1.76(m,6H),1.53(m,2H),1.36(m,11H),1.07(m,13H),0.75(s,3H).

[0209] Example 18

[0210] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-11-chloro-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-11-carboxylic acid, triethanolamine salt

[0211] Preparation of compound 18: Compound 16 was dissolved in dichloromethane, an equivalent amount of triethanolamine was added, the mixture was reacted at room temperature for 24 h, and the mixture was concentrated to obtain compound 18. MS m / z (ESI): 501.31 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.19(s,1H),7.92(s,1H),5.52(s,1H),4.16(s,3H),3.42(m,6H),2.87(s ,1H), 2.57(m,6H),2.13(m,2H),1.81(m,6H),1.55(m,2H),1.38(m,11H),1.07(m,13H),0.75(s,3H).

[0212] Example 19

[0213] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-11-bromo-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-2-carboxylic acid

[0214] Synthesis method:

[0215] Preparation of Compound 19: Refer to the preparation method of Compound 16 in Example 16, replacing concentrated hydrochloric acid with hydrobromic acid. The remaining steps are the same. The white solid is purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to obtain Compound 19 (5.5 g, 49% yield). MS m / z (ESI): 545.23 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ12.09(s,1H),7.83(s,1H),5.32(s,1H),2.72(s,1H), 2.01(m,2H),1.89(m,6H),1.65(m,2H),1.43(m,11H),1.21(m,13H),0.72(s,3H).

[0216] Example 20

[0217] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bS)-11-bromo-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-2-carboxylic acid

[0218] Synthesis method:

[0219] Preparation of Compound 20: Refer to the preparation method of Compound 17 in Example 17, except that concentrated hydrochloric acid was replaced with hydrobromic acid. The remaining steps were the same. MS m / z (ESI): 545.36 [M+H] + . 1H-NMR (400MHz, DMSO-d6): δ12.09(s,1H),7.83(s,1H),5.32(s,1H),2.65(s,1H), 2.12(m,2H),1.74(m,6H),1.63(m,2H),1.45(m,11H),1.21(m,13H),0.72(s,3H).

[0220] Comparative Example 4

[0221] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-11-iodo-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-2-carboxylic acid

[0222] Intermediate 3b was used as control compound 4.

[0223] Comparative Example 5

[0224] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-11-fluoro-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-2-carboxylic acid

[0225] Synthesis method:

[0226] Preparation of Reference Compound 5: Intermediate 16a (10 g, 21 mmol) was dissolved in 60 mL of chloroform. A mixture of hydrofluoric acid (27 mL) in tetrahydrofuran (46 mL) and chloroform (27 mL) was slowly added dropwise at 70°C. After the addition was complete, the reaction was allowed to proceed at room temperature. TLC monitoring indicated the disappearance of intermediate 16a. The reaction mixture was poured into 1000 mL of 5% potassium carbonate solution, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. Purification by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) afforded reference compound 5 (2.1 g, 21% yield).

[0227] Comparative Example 6

[0228] (2S,4aS,6aS,6bR,8aR,12aR,12bR,14bR)-11-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-2-carboxylic acid

[0229] Synthesis method:

[0230] Preparation of Reference Compound 6: Compound 1a (5 g, 10.7 mmol) was dissolved in 300 mL of tert-butanol, and potassium tert-butoxide (24 g, 213.3 mmol) was added. The reaction was allowed to proceed at 45°C. TLC monitoring was performed until the intermediate 1a disappeared. The mixture was cooled to room temperature, and the pH was adjusted to a weakly acidic state using 5N hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The concentrate was separated by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) to afford Reference Compound 6 (2 g, 39% yield).

[0231] Comparative Example 7

[0232] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-11-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydro-2-carboxylic acid

[0233] Intermediate 3c was used as control compound 7.

[0234] Comparative Example 8

[0235] (2S,4aS,6aR,6bS,8aR,12aS,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14b-octahydro-2-carboxylic acid

[0236] Synthesis method:

[0237] Preparation of reference compound 8: refer to the preparation method of intermediate 1a in Example 1, except that 18β-glycyrrhetinic acid was replaced by intermediate 11b, and the remaining steps were the same.

[0238] Comparative Example 9

[0239] (2S,4aS,6aR,6bS,8aR,12aS,14bR)-11-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14b-hexahydro-2-carboxylic acid

[0240] Intermediate 11e was used as control compound 9.

[0241] Comparative Example 10

[0242] (2S,4aS,6aR,6bS,8aR,12aR,14bR)-11-chloro-2,4a,6a,6b,9,9,12a-heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14b-hexahydro-2-carboxylic acid

[0243] Synthesis method:

[0244] Preparation of intermediate reference compound 10a: Refer to the preparation method of intermediate 16a in Example 16, replacing intermediate 3a with intermediate 11c, and the remaining steps are the same. MS m / z (ESI): 467.65 [M+H] + .

[0245] Preparation of reference compound 10: Refer to the preparation method of compound 16 in Example 16, replacing intermediate 16a with intermediate reference compound 10a, and the remaining steps are the same. MS m / z (ESI): 485.27 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ12.13(s,1H),7.31(s,1H),6.07(s,1H),5.66(s,1H),2.36(m,2H),2.14(m,2H),1.98 (m,2H),1.80(m,1H),1.52(m,3H),1.44(m,8H),1.11(m,1H),1.06(m,3H),1.02(m,6H),0.96(m,6H),0.83(s,3H).

[0246] Preparation of a specific compound having a structure represented by formula (III) or a pharmaceutically acceptable salt thereof:

[0247] Example 21

[0248] (2S,4aS,6aS,6bR,8aR,13aS,13bR,15bR)-11-(dimethylamino)-2,4a,6a,6b,9,9,13a-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,13,13a,13b,14,15b-octahydropyro[3,2-d]thiazole-2-carboxylic acid

[0249] Synthesis method:

[0250] Preparation of Intermediate 21b: Intermediate 1a (18 g, 38 mmol) was dissolved in acetic acid (200 mL). 3-Bromopyridine (6.7 g, 42 mmol) was slowly added dropwise at room temperature. The mixture was allowed to react at room temperature and monitored by TLC until the presence of intermediate 1a was eliminated. The solvent was evaporated under reduced pressure, and the mixture was added to 200 mL of ethyl acetate. The mixture was washed with saturated sodium carbonate solution (200 mL) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography (tetrahydrofuran) to obtain intermediate 21b (9 g, 43% yield). MS m / z (ESI): 547.24 [M+H] + .

[0251] Preparation of compound 21: Intermediate 21b (9 g, 16 mmol) and 1,1-dimethylthiourea (1.7 g, 16 mmol) were dissolved in ethanol (100 mL) and refluxed. TLC monitoring was performed until intermediate 21b disappeared. The solvent was concentrated under vacuum to obtain a yellow solid. The product was slurried three times with ethyl acetate (50 mL) to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether: tetrahydrofuran = 10:1) and concentrated to obtain compound 21 (4 g, 44%). MS m / z (ESI): 553.39 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ12.08(s,1H),5.48(s,1H),3.50(m,1H),3.21(s,6H),2.61(m,1H) ,2.10(m,2H),1.72(m,6H),1.60(m,8H),1.44(m,3H),1.37(m,14H),1.09(m,2H),0.77(s,3H).

[0252] Example 22

[0253] (2S,4aS,6aS,6bR,8aR,13aS,13bR,15bR)-11-(diethylamino)-2,4a,6a,6b,9,9,13a-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,13,13a,13b,14,15b-octahydropyro[3,2-d]thiazole-2-carboxylic acid

[0254] Synthesis method:

[0255] Preparation of compound 22: Intermediate 21b (9 g, 16 mmol) and 1,1-diethylthiourea (2.2 g, 16 mmol) were dissolved in ethanol (100 mL) and refluxed. TLC monitoring was performed until intermediate 21b disappeared. The solvent was concentrated under vacuum to obtain a yellow solid. The product was beaten three times with ethyl acetate (50 mL) to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether: tetrahydrofuran = 10:1) and concentrated to obtain compound 22 (3.5 g, 37%). MS m / z (ESI): 581.35 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ12.08(s,1H),5.77(s,1H),3.46(m,1H),3.12(m,4H),2.54(m,1H) ,2.13(m,2H),1.67(m,6H),1.58(m,8H),1.37(m,3H),1.29(m,14H),1.07(m,8H),0.72(s,3H).

[0256] Example 23

[0257] (2S,4aS,6aS,6bR,8aR,13aS,13bR,15bR)-11-(dipropylamino)-2,4a,6a,6b,9,9,13a-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,13,13a,13b,14,15b-octahydropyro[3,2-d]thiazole-2-carboxylic acid

[0258] Synthesis method:

[0259] Preparation of compound 23: Intermediate 21b (9 g, 16 mmol) and 1,1-dipropylthiourea (2.6 g, 16 mmol) were dissolved in ethanol (100 mL) and refluxed. TLC monitoring was performed until the intermediate 21b disappeared. The solvent was concentrated under vacuum to obtain a yellow solid. The product was slurried three times with ethyl acetate (50 mL) to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 10:1) and concentrated to obtain compound 23 (3.8 g, 38%). MS m / z (ESI): 609.40 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ12.08(s,1H),5.75(s,1H),3.52(m,1H),3.49(m,4H),2.45(m,1H),2.17( m,2H),1.76(m,6H),1.57(m,12H),1.32(m,3H),1.25(m,14H),1.06(m,2H),0.87(m,6H),0.70(s,3H).

[0260] Example 24

[0261] (2S,4aS,6aS,6bR,8aR,13aS,13bR,15bR)-11-(dimethylamino)-2,4a,6a,6b,9,9,13a-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,13,13a,13b,14,15b-octahydropyro[3,2-d]thiazole-2-carboxylic acid hydrochloride

[0262] Synthesis method:

[0263] Preparation of Compound 24: Compound 21 (2 g, 3.2 mmol) was dissolved in 20 mL of dichloromethane, and hydrochloric acid in isopropanol was added dropwise. The mixture was reacted at room temperature for 24 h, and concentrated to give Compound 24 (1.9 g, 89% yield). MS m / z (ESI): 553.39 [M+H] + .

[0264] Example 25

[0265] (2S,4aS,6aS,6bR,8aR,13aS,13bR,15bR)-11-(diethylamino)-2,4a,6a,6b,9,9,13a-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,13,13a,13b,14,15b-octahydropyro[3,2-d]thiazole-2-carboxylic acid hydrochloride

[0266] Synthesis method:

[0267] Preparation of Compound 25: Compound 22 (2 g, 3.4 mmol) was dissolved in 20 mL of dichloromethane, and hydrochloric acid in isopropanol was added dropwise. The mixture was reacted at room temperature for 24 h and concentrated to give Compound 25 (1.8 g, 86% yield). MS m / z (ESI): 581.35 [M+H] + .

[0268] Example 26

[0269] (2S,4aS,6aS,6bR,8aR,13aS,13bR,15bR)-11-(dipropylamino)-2,4a,6a,6b,9,9,13a-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,13,13a,13b,14,15b-octahydropyro[3,2-d]thiazole-2-carboxylic acid hydrochloride

[0270] Synthesis method:

[0271] Preparation of Compound 26: Compound 23 (2 g, 3.3 mmol) was dissolved in 20 mL of dichloromethane, and hydrochloric acid in isopropanol was added dropwise. The mixture was reacted at room temperature for 24 h, and concentrated to give Compound 26 (1.9 g, 90% yield). MS m / z (ESI): 609.40 [M+H] + .

[0272] Example 27

[0273] 2-(Diethylamino)ethyl (2S,4aS,6aS,6bR,8aR,13aS,13bR,15bR)-11-(dimethylamino)-2,4a,6a,6b,9,9,13a-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,13,13a,13b,14,15b-octahydropyro[3,2-d]thiazole-2-carboxylate

[0274] Synthesis method:

[0275] Preparation of Compound 27: Refer to the preparation method of Compound 1 in Example 1, replacing Intermediate 1a with Compound 21, and the remaining steps are the same. MS m / z (ESI): 652.45 [M+H] + . 1H-NMR (400MHz, DMSO-d6): δ5.72(s,1H),4.27(m,2H),3.58(m,1H),3.10(s,6H),2.72(m,2H),2.61(m,2H), 2.53(m,3H),2.23(m,2H),1.84(m,6H),1.67(m,8H),1.51(m,3H),1.41(m,14H),1.16(m,8H),0.73(m,3H).

[0276] Experimental Example 1: Cellular Anti-inflammatory Activity Study

[0277] 1.1 Cells: RAW264.7 cells were purchased from PROCELL, batch number: JYBR1POD9R.

[0278] 1.2 Reagents: Lipopolysaccharide (LPS) was purchased from SIGMA; DMEM cell culture medium was purchased from GIBCO; and mouse IL-1β ELISA kit was purchased from Ruixin Biotechnology.

[0279] 1.3 Methods

[0280] RAW264.7 cells were collected at 1×10 5 Cells were inoculated into 96-well plates at 100 μL / well. 100 μL of cell suspension was added to each well. 50 μL of drugs with corresponding gradient concentrations (0.00128, 0.0064, 0.032, 0.16, 0.8, 4, 20, and 100 μM, respectively) were added to the wells of the test group (compound 1-27) and the control drug group (glycyrrhetinic acid, control compound 1-10). Corresponding volumes of culture medium were added to the wells of the blank control group and the model group. After 1 hour of culture, 50 μL of LPS (the final concentration of LPS was 100 ng / mL) was added to the wells of the model group, the control drug group, and the test group. After culturing for 24 hours in an incubator at 37°C and 5% CO2, the supernatant was centrifuged at 1000 rpm for 5 minutes to detect the IL-1β content. The IC was calculated according to the instructions of the kit. 50 value.

[0281] 1.4 Experimental Results

[0282] Note: A is less than or equal to 0.02 μM; B is greater than 0.02 μM and less than or equal to 0.1 μM; C is greater than 0.1 μM and less than or equal to 1 μM; D is greater than 1 μM.

[0283] Test Example 2 Study on the inhibitory activity against guinea pig ear swelling

[0284] 2.1 Animal: Ordinary guinea pig, approximately 300g.

[0285] 2.2 Reagents: The inflammatory agent was prepared from 80% dimethyl sulfoxide (DMSO) and 20% anhydrous ethanol; DMSO and anhydrous ethanol were of analytical grade.

[0286] 2.3 Methods

[0287] Guinea pigs were randomly divided into 10 groups, each consisting of 50 males and 50 females. The inner and outer sides of the left and right ears were shaved, and four points were marked on the inner edge of the left ear. The thickness of the auricle at these four points was measured with a vernier caliper, and the average value was used as the pre-drug standard. The corresponding drug was dripped into the auricle of the guinea pigs in each test group (Compound 1, Compound 2, Compound 3, Compound 9, Compound 16, Compound 17, Compound 18, Compound 21) and the glycyrrhetinic acid group, with 200 μL of the corresponding drug added to each ear. The blank control group and the model group received only the corresponding volume of anhydrous ethanol. The positive drug hydrocortisone butyrate group received an equal volume of hydrocortisone butyrate cream. 30 minutes after drug administration, the drug was removed. The model group and the treatment group received an inflammatory agent applied to both sides of the left auricle (50 μL / ear). The blank control group received only the corresponding volume of normal saline. 45 minutes after modeling, the thickness of the four points was measured with a vernier caliper, and the average value was calculated. The difference was used to calculate the guinea pig ear swelling value. Swelling value inhibition rate = (swelling value of model group - swelling value of sample group) / swelling value of model group × 100%, wherein the sample group includes each test group, glycyrrhetinic acid group and positive drug hydrocortisone butyrate group.

[0288] 2.4 Source of preparation

[0289] The test compound and glycyrrhetinic acid were dissolved in anhydrous ethanol to prepare a solution with a concentration of 40 mg / mL.

[0290] Positive drug: commercially available hydrocortisone butyrate cream (from Hubei Hengan Fulin Pharmaceutical Co., Ltd., specification: 1 mg / g).

[0291] 2.5 Experimental Results

[0292] Note: A is greater than 70%; B is greater than 40% and less than or equal to 70%; C is less than 40%.

[0293] It can be seen that the compounds of the present disclosure can exhibit good anti-inflammatory effects on subjects with inflammatory diseases.

[0294] Experimental Example 3 Study on the inhibitory activity against ear swelling in ICR mice

[0295] 3.1 Animals:

[0296] ICR mice, male, 20 ± 2 g.

[0297] 3.2 Reagents: Inflammatory agent (phorbol ester (TPA)).

[0298] 3.3 Methods

[0299] ICR mice were randomly divided into groups of 8 per group. The thickness of the right ear of each animal was measured using a micrometer. Then, all mice in the blank control group were smeared with 20 μL of 0.03% TPA on both sides of the right ear to induce inflammation (10 μL on each side). Drugs were administered once 1 hour before and 1 hour after modeling. The test groups (Compound 1 and Compound 16) received 50 μL of each dose. The blank control group and the model (with matrix) group received the corresponding volume of blank matrix (pimecrolimus cream matrix). The positive drug group received an equal volume of pimecrolimus cream or compound dexamethasone acetate cream. Before modeling, the ears should be cleaned before applying TPA. Ear thickness measurement: The right ear thickness was measured at 0, 2, 4, and 6 hours after TPA induction.

[0300] 3.4 Source of preparation

[0301] Test compound: The formulation was prepared with reference to pimecrolimus cream (from MEDA Manufacturing) (test compound concentration was 3%).

[0302] Positive drugs: commercially available compound dexamethasone acetate cream (from China Resources Sanjiu Pharmaceutical, specification: 0.75 mg / g), commercially available pimecrolimus cream (from MEDA Manufacturing, specification: 10 mg / g).

[0303] 3.5 Experimental Results Note: Compared with the blank control group: ## P<0.01, ### P<0.001; compared with the model (with matrix) group: * P<0.05, ** P<0.01, *** P<0.001.

[0304] The experimental results showed that compounds 1 and 16 of the present disclosure had significant inhibitory activity against the phorbol ester-induced mouse ear swelling and inflammation model (P<0.001), which was significantly better than the model group.

[0305] According to the above method, compounds 2, 3, 9, 17, 18 and 21 of the present disclosure also have significant inhibitory activity on the phorbol ester-induced mouse ear swelling and inflammation model.

[0306] Test Example 4 Atopic Dermatitis Test

[0307] 4.1 Animals: BALB / c female mice, 20 ± 2 g.

[0308] 4.2 Reagent: 2,4-dinitrofluorobenzene (DNFB).

[0309] 4.3 Methods

[0310] The backs of BALB / c mice were shaved. Except for the blank control group, all mice were topically smeared with DNFB solution (the solvent was a mixture of acetone and olive oil, with a volume ratio of 4:1) for sensitization. No treatment was given on the 3rd to 6th day. Starting from the 7th day, the mice were smeared every 2 days for a total of 10 times. The model was completed after the 10th application. After modeling, mice were evenly divided into groups of 8 based on the skin lesion observation score. The test group (Compound 1, Compound 16) was then given the corresponding drug at 150 μL / time, twice a day. The model group was given the corresponding volume of blank matrix (Pimecrolimus cream matrix) at the same dosing frequency. Skin lesion observation and scoring were performed on days 3, 6, and 10 (scores were scored for six items: erythema / darkening, edema / papule, exudation / scab, erosion, lichenification / prurigo, and dryness at the lesion site, and the sum of the six scores was the total score; the score was scored according to the SCORAD score standard: 0-3 points, 0 points: none; 1 point: mild; 2 points: moderate; 3 points: severe). Body weight was recorded on days 0, 3, 6, and 10 after modeling.

[0311] 4.4 Source of preparation

[0312] Test compound: The preparation formula was prepared with reference to pimecrolimus cream (test compound concentration was 3%).

[0313] 4.5 Experimental Results

[0314] 4.5.1 SCORAD Note: Compared with the blank control group: ## P<0.01, ### P<0.001; compared with the model (with matrix) group: * P<0.05, ** P<0.01, *** P<0.001.

[0315] The experimental results showed that the compounds 1 and 16 of the present disclosure were able to significantly reduce the SCORAD score in the mouse atopic dermatitis test compared with the model group (P<0.001).

[0316] According to the above method, compounds 2, 3, 9, 17, 18, and 21 of the present disclosure were able to significantly reduce the SCORAD score in the mouse atopic dermatitis model.

[0317] 4.5.2 Weight

[0318] The experimental results showed that compounds 1 and 16 of the present disclosure had no significant effect on the body weight of mice, demonstrating good safety.

[0319] According to the above method, compounds 2, 3, 9, 17, 18, and 21 of the present disclosure had no significant effect on the body weight of mice in the mouse atopic dermatitis model, demonstrating good safety.

[0320] Test Example 5: Radiation Dermatitis Test

[0321] 5.1 Animals: SD rats, SPF grade, male, 230-250 g.

[0322] 5.2 Equipment: RS2000·Pro 225 Rad Source X-ray irradiator, SpectraMax i3 multi-function microplate reader.

[0323] 5.3 Methods

[0324] Eighty SD rats were randomly divided into 10 groups. All groups, except the blank control group, were irradiated using a Rad Source X-ray irradiator to establish the model. Twenty-four hours before irradiation, the irradiated area was depilated and skinned. On the day of irradiation, the rats were anesthetized and received a single X-ray irradiation of the buttocks at a dose of 25 Gy at a dose rate of 4 Gy / min, with an irradiation area of ​​2 × 2 square centimeters. On the second day of irradiation, each test group (Compound 1, Compound 16, and Compound 21) was administered the corresponding drug, 100 mg per dose, once daily for 28 consecutive days. The blank control group and the model (with matrix) group were given the corresponding weight of blank matrix (triethanolamine cream matrix). The positive drug groups were applied with the corresponding weight of triethanolamine cream or hydrocortisone butyrate cream. After the administration, the damaged skin areas were scored according to the atopic dermatitis criteria based on erythema / darkening, edema / papules, exudation / scabs, and erosion. After the scoring, the skin of the damaged area was collected, homogenized, and the ELISA kit was used to detect the content of inflammatory cells in the skin. Another piece of skin was fixed and stained with HE to observe the number of inflammatory cells.

[0325] 5.4 Source of Preparation

[0326] Test compound: The preparation formula was prepared with reference to triethanolamine cream (test compound concentration was 0.5%).

[0327] Positive drugs: commercially available triethanolamine cream (from JOHNSON & JOHNSON SANTE BEAUTE FRANCE, specification: 0.67%), hydrocortisone butyrate cream (from Hubei Hengan Fulin Pharmaceutical Co., Ltd., specification: 1 mg / g).

[0328] 5.5 Experimental Results

[0329] 5.5.1 Number of inflammatory cells Note: Compared with the blank control group:## P<0.01, ### P<0.001; compared with the model (with matrix) group: * P<0.05, ** P<0.01, *** P<0.001.

[0330] The experimental results showed that compounds 1, 16, and 21 of the present disclosure had significant anti-inflammatory effects on the rat radiation dermatitis model and could significantly reduce the number of inflammatory cells (P<0.001).

[0331] According to the above method, compounds 2, 3, 9, 17, and 18 disclosed herein also have significant anti-inflammatory effects in the rat radiation dermatitis model and can significantly reduce the number of inflammatory cells.

[0332] In addition, the experimental results determined according to the above method showed that compounds 1, 2, 3, 9, 16, 17, 18, and 21 of the present disclosure all had significant anti-inflammatory effects in the rat radiation dermatitis model, and were able to significantly reduce the release of the inflammatory cytokine TNF-α and the content of the cytokine TGF-β1.

[0333] 5.5.2 Radiation dermatitis lesion scoring Note: Compared with the blank control group: ## P<0.01, ### P<0.001; compared with the model group (with matrix): * P<0.05, ** P<0.01, *** P<0.001.

[0334] The experimental results showed that compounds 1, 16, and 21 of the present disclosure had significant anti-inflammatory effects on the rat radiation dermatitis model and were able to significantly reduce the skin lesion scores (P<0.001, P<0.01).

[0335] According to the above method, the compounds 2, 3, 9, 17 and 18 disclosed herein all have significant anti-inflammatory effects in the rat radiation dermatitis model and can significantly reduce the skin lesion score.

[0336] In addition, the experimental results determined according to the above method showed that compounds 1, 2, 3, 9, 16, 17, 18, and 21 of the present disclosure all had significant anti-inflammatory effects in the rat radiation dermatitis model and were able to significantly reduce the area of ​​skin lesions.

[0337] At the same time, skin pathological observations of rats showed that compounds 1, 2, 3, 9, 16, 17, 18, and 21 of the present disclosure significantly increased the number of capillaries and new granulations in the dermis of the skin, indicating that the compounds of the present disclosure can promote epidermal regeneration.

[0338] Experimental Example 6: Experiment on the effect of chloroquine on itching in mice

[0339] 6.1 Animals: Balb / c female mice.

[0340] 6.2 Reagents: Chloroquine, normal saline.

[0341] 6.3 Methods

[0342] Fifty female Balb / c mice were acclimated for 3 days and then randomly divided into 10 groups. A 2×3 square centimeter area of ​​hair on the back of each group of mice was completely removed using a depilatory cream. Except for the blank control group, each test group (Compound 1, Compound 16) and the model group were treated with the corresponding drug or base (Pimecrolimus Cream Base) at the depilatory site, 100 mg each time, once a day for 3 consecutive days. The positive drug group was treated with the corresponding weight of Pimecrolimus Cream and subcutaneously injected with chloroquine (40 mg / kg) 30 minutes after the last administration. The blank control group was subcutaneously injected with the corresponding volume of normal saline. The number of scratches within 20 minutes after the chloroquine injection was measured.

[0343] 6.4 Source of Preparation

[0344] Test compound: The preparation formula was prepared with reference to pimecrolimus cream (test compound concentration was 3%).

[0345] Positive drug: commercially available pimecrolimus cream (from MEDA Manufacturing, specification: 10 mg / g).

[0346] 6.5 Experimental Results Note: Compared with the blank control group: ## P<0.01, ### P<0.001; compared with the model (with matrix) group: * P<0.05, **P<0.01, *** P<0.001.

[0347] The experimental results showed that compounds 1 and 16 of the present disclosure had a significant anti-itch effect on the chloroquine-induced pruritus model in mice and could significantly reduce the number of scratching in mice (P<0.05).

[0348] According to the above method, the compounds 2, 3, 9, 17, 18, and 21 of the present disclosure also have anti-itch effects in the chloroquine-induced itch model in mice, and can significantly reduce the number of scratching times in mice.

[0349] Test Example 7 In vitro ROS release inhibition test

[0350] 7.1 Cells: HaCaT cells

[0351] 7.2 Reagents

[0352] Culture medium: DMEM containing 10% FBS;

[0353] Test sample: Compound 16, control drugs: triethanolamine and hydrocortisone butyrate;

[0354] Reagents: ROS kit (Biyuntian);

[0355] Instruments: RS2000·Pro 225 Rad Source X-ray irradiator, flow cytometer.

[0356] 7.3 Methods

[0357] 7.3.1 Cell culture, grouping, and drug administration

[0358] The cells were divided into a blank control group, a model group, a compound 16 group, a triethanolamine group, and a hydrocortisone butyrate group. Each group had three replicates and was cultured in DMEM containing 10% FBS at 37°C in a 5% CO2 incubator. The blank control group and the model group received only the corresponding volume of blank solvent (DMSO). The compound 16 group received 0.5 μM compound 16, the triethanolamine group received 0.5 μM triethanolamine, and the hydrocortisone butyrate group received 10 nM hydrocortisone butyrate.

[0359] 7.3.2 Cellular X-ray Irradiation and ROS Level Detection

[0360] After administration, cells in the model, compound 16, triethanolamine, and hydrocortisone butyrate groups were irradiated with 8 Gy of X-rays. The blank control group was not irradiated. Flow cytometry was used to measure intracellular ROS levels in each group 24 hours after irradiation. ROS content in each group was determined according to the instructions of the ROS detection kit.

[0361] 7.4 ROS detection experimental results Note: Compared with the blank control group: ### P<0.001; compared with the model group: *** P<0.001.

[0362] The experimental results showed that compound 16 of the present disclosure could significantly reduce the intracellular ROS level (P<0.001).

[0363] According to the above method, compounds 1, 2, 3, 9, 17, 18, and 21 of the present disclosure can also significantly reduce the level of ROS in cells.

[0364] Test Example 8 Tissue Distribution Test

[0365] 8.1 Animals: ICR mice.

[0366] 8.2 Methods

[0367] 3 mg of compound 16 was accurately weighed and added to a solvent (5% DMSO + 5% Tween 80 + 20% PEG400 + 70% double-distilled water) and sonicated until completely dissolved to prepare a 3 mg / mL dosing solution. ICR mice were fasted for 16 hours prior to dosing and had free access to food and water during the experiment. A 30 mg / kg dose was administered by gavage. Sampling sites and points were as follows:

[0368] 8.3 Experimental Results

[0369] The experimental results show that the compounds of the present disclosure have a prominent drug distribution in the colon and have the potential to treat colonic inflammation. According to the above method, the tissue distribution of compounds 17 and 18 of the present disclosure is similar to that of compound 16.

[0370] For the purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present application. All statements regarding the dates of these documents or the representations of their contents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications become part of the common general knowledge in the art in any country.

[0371] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present disclosure, rather than to limit them. Although the present disclosure has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present disclosure.

Claims

1. A glycyrrhetinic acid derivative having a structure represented by formula (II), formula (I) or formula (III) or a pharmaceutically acceptable salt thereof: Among them, In the compound of formula (II), R1’ represents Br or Cl; represents that the H connected to the C18-position is of the α-form or the β-form; Or, wherein, in the compound of formula (I), R1 is selected from hydrogen, halogen, hydroxyl, cyano, methoxy, amino or haloalkyl; R2 is selected from -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different and are each independently selected from hydrogen, C1-C6 alkyl or R 21 and R 22 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group which may optionally contain one or more other heteroatoms selected from O, N or NH, and n is an integer from 1 to 6; R3 is selected from carbonyl or methylene; is a single bond or a double bond; represents that the H connected to the C18-position is of the α-form or the β-form; Or, Among them, in the compound of formula (III), R 11 ’ and R 12 ’ are each independently selected from C1-C6 alkyl groups; R2’ is selected from hydrogen or -(CH2) n -NR 21 ’R 22 ’,R 21 ’ and R 22 ’ may be the same or different and are each independently selected from hydrogen, C1-C6 alkyl or R 21 ’ and R 22 ’ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group which may optionally contain one or more other heteroatoms selected from O, N or NH, and n is an integer from 1 to 6; represents that the H connected to the C18-position is of the α-form or the β-form; Among them, the compound of formula (I) cannot be selected from 2. The glycyrrhetinic acid derivative according to claim 1, wherein, In the compound of formula (I), R1 is selected from hydrogen or cyano; R2 is selected from -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different and are each independently selected from C1-C3 alkyl or R 21 and R 22 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group which may optionally contain one or more other heteroatoms selected from O, and n is an integer from 2 to 5; R3 is selected from carbonyl or methylene; is a single bond or a double bond; represents that the H connected to the C18-position is of the α-form or the β-form; Preferably, in the compound of formula (I), R1 is selected from hydrogen or cyano; R2 is selected from -(CH2) n -NR 21 R 22 ,R 21 and R 22 may be the same or different and are each independently selected from methyl, ethyl or R 21 and R 22 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group, n is an integer of 2 - 5; R3 is selected from carbonyl or methylene; is a single bond or a double bond; represents that the H connected to the C18-position is of the α-form or the β-form.

3. The glycyrrhetinic acid derivative according to claim 1 or 2, wherein, In the compound of formula (I), R1 is selected from hydrogen or cyano; R2 is selected from -(CH2) n -NR 21 R 22 ,R 21 and R 22 may be the same or different and are each independently selected from methyl, ethyl or R 21 and R 22 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group, n is an integer of 2 - 5; R3 is selected from carbonyl; is a single bond or a double bond; represents that the H connected to the C18-position is of the α-form or the β-form; Preferably, in the compound of formula (I), R1 is selected from hydrogen or cyano; R2 is selected from -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different and are each independently selected from ethyl, n = 2; R3 is selected from carbonyl; is a single bond or a double bond; represents that the H connected to the C18-position is of the α-form or the β-form.

4. The glycyrrhetinic acid derivative according to any one of claims 1 to 3, wherein, In the compound of formula (I), R1 is selected from cyano; R2 is selected from -(CH2) n -NR 21 R 22 , R 21 and R 22 may be the same or different and are each independently selected from methyl, ethyl, and n = 2; R3 is selected from methylene; is a double bond; represents that the H connected to the C18-position is of the α-form or the β-form.

5. The glycyrrhetinic acid derivative according to claim 1 or 2, wherein In the compound of formula (I), when R1 is hydrogen, R2 is -(CH2) n -NR 21 R 22 ,R 21 and R 22 may be the same or different and are each independently selected from C2-C3 alkyl or R 21 and R 22 together with the nitrogen atom to which they are attached form a 5-6 membered heterocycloalkyl group, n is an integer from 2-5, and the heterocycloalkyl group may optionally further contain one or more heteroatoms selected from O or N, R3 is a carbonyl group, is a single bond, represents that the H attached to the C18-position is of the α or β type; Alternatively, when R1 is a cyano group or an amino group, R2 is -(CH2) n -NR 21 R 22 ,R 21 and R 22 may be the same or different and are each independently selected from C1-C3 alkyl groups, n is an integer from 2 to 5, and R3 is a methylene group or a carbonyl group, is a single bond or a double bond, represents that the H connected to the C18-position is of the α-form or the β-form.

6. The glycyrrhetinic acid derivative according to any one of claims 1, 2 and 5, wherein, In the compound of formula (I), when R1 is hydrogen, R2 is -(CH2) n -NR 21 R 22 ,R 21 and R 22 may be the same or different and are each independently selected from C2-C3 alkyl or R 21 and R 22 together with the nitrogen atom to which they are attached form an integer of n = 2-5, R3 is a carbonyl group, is a single bond, represents that the H attached to the C18-position is of the α-type or β-type; Alternatively, when R1 is a cyano group, R2 is -(CH2) n -NR 21 R 22 ,R 21 and R 22 may be the same or different and are each independently selected from C1-C3 alkyl groups, n = 2 or 3, and R3 is a carbonyl group, is a single bond or a double bond, represents that the H connected to the C18-position is of the α-form or the β-form.

7. The glycyrrhetinic acid derivative according to any one of claims 1, 2, 5 and 6, wherein, In the compound of formula (I), R1 is hydrogen or cyano, R2 is -(CH2) n -NR 21 R 22 where R 21 and R 22 may be the same or different and are each independently selected from C2-C3 alkyl, n = 2 or 3, R3 is carbonyl, is a single bond or a double bond, represents that the H connected to the C18-position is of the α-type or the β-type.

8. The glycyrrhetinic acid derivative according to claim 1, wherein, In the compound of formula (III), R 11 ’ and R 12 ’ are each independently selected from C1-C5 alkyl groups; R2’ is selected from hydrogen or -(CH2) n -NR 21 ’R 22 ’,R 21 ’ and R 22 ’ may be the same or different and are each independently selected from C1-C5 alkyl, and n is an integer from 1 to 3; represents that the H connected to the C18-position is of the α-form or the β-form.

9. The glycyrrhetinic acid derivative according to claim 1 or 8, wherein, In the compound of formula (III), R 11 ’ and R 12 ’ are each independently selected from C1-C3 alkyl; R2’ is selected from hydrogen or -(CH2) n -NR 21 ’R 22 ’,R 21 ’ and R 22 ’ may be the same or different and are each independently selected from C1-C3 alkyl groups, and n is an integer from 1 to 3; represents that the H connected to the C18-position is of the α-form or the β-form; Preferably, in the compound of formula (III), R 11 ’ and R 12 ’ are each independently selected from methyl, ethyl or propyl; R2’ is selected from hydrogen or -(CH2) n -NR 21 ’R 22 ’,R 21 ’ and R 22 ’ may be the same or different and are each independently selected from methyl, ethyl or propyl, preferably ethyl, and n = 2; represents that the H connected to the C18-position is of the α-form or the β-form; Further preferably, in the compound of formula (III), R 11 ’ and R 12 ’ are each independently selected from methyl, ethyl or propyl; R2’ is selected from hydrogen; represents that the H connected to the C18-position is of the α-form or the β-form.

10. The glycyrrhetinic acid derivative according to any one of claims 1-7, wherein, The compound of formula (I) is selected from the following compounds: Preferably, they are Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 13, Compound 14, Compound 15; More preferably, they are Compound 1, Compound 2, Compound 3, Compound 9.

11. The glycyrrhetinic acid derivative according to claim 1, wherein, The compound of formula (II) is selected from the following compounds: Preferably, they are Compound 16, Compound 17, Compound 18.

12. The glycyrrhetinic acid derivative according to any one of claims 1, 8, and 9, wherein, The compound of formula (III) is selected from the following compounds: Preferably, they are Compound 21, Compound 22, Compound 23.

13. A pharmaceutical composition comprising the glycyrrhetinic acid derivative according to any one of claims 1 - 12 and optionally one or more pharmaceutically acceptable carriers, diluents, excipients or adjuvants.

14. The pharmaceutical composition according to claim 13, wherein, The pharmaceutical composition is a solid oral preparation, a liquid oral preparation, an injection or a topical preparation; preferably, the solid oral preparation is selected from tablets, capsules, dry suspensions or granules; the liquid oral preparation is selected from syrups, oral solutions, oral suspensions or oral emulsions; the injection is selected from injections, sterile powders for injection or concentrated solutions for injection; the topical preparation is selected from ointments, creams, gels, latexes, pastes, liniments, paints, tinctures, lotions, film-forming agents, sprays, suppositories, foams or enemas.

15. The glycyrrhetinic acid derivative according to any one of claims 1 - 12 or the pharmaceutical composition according to claim 13 or 14 for treating inflammatory or autoimmune diseases; Preferably, the disease is selected from dermatitis, eczema, atopic dermatitis, seborrheic dermatitis, hormone-dependent dermatitis, photosensitive dermatitis, melasma, psoriasis, urticaria, prurigo nodularis, pityriasis rosea, inflammatory bowel disease, lupus erythematosus, alopecia areata, pemphigus, bullous pemphigoid, chronic nephritis, asthma, rhinitis, skin damage caused by radiotherapy, burns, scalds or solar dermatitis.

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