Stilbene derivatives as ahR agonists and uses thereof

Abstract

The present application relates to stilbene derivatives as AhR activators and uses thereof. The compounds of the present application, pharmaceutically acceptable salts, tautomers or stereoisomers thereof have excellent AhR activation effect, and can be safely used for treating diseases or related conditions mediated by abnormal activity of AhR and related pathway targets.

Description

[0001] This application claims priority to the earlier application filed on May 7, 2022, with the China National Intellectual Property Administration, patent application number 202210489648.4, entitled "Stilbene Derivatives as AhR Agonists and Their Uses Thereof," the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the pharmaceutical field, and more specifically to stilbene derivatives as AhR agonists and their uses. Background Technology

[0003] The aryl hydrocarbon receptor (AhR) belongs to the b-HLH-PAS (period-aryl hydrocarbon receptor nuclear translocator-single-minded, Pre-Arnt-Sim) subfamily within the basic helix-loop-helix (b-HLH) superfamily. It is distributed in various tissues and cells throughout the body, with the highest expression levels in the spleen, stomach, ovary, and placenta. It is also highly expressed in immune cells, particularly in certain CD4+ cells. + T cell subsets, such as some hematopoietic stem cells, bone marrow-derived dendritic cells, and CD4+, etc. + It is most highly expressed in Th17 cells, while it is less expressed in B cells and CD4 cells. + Treg cells express the lowest levels of IL-17. Overactivation of Th17 cells and increased IL-17 secretion are associated with various chronic inflammatory diseases and autoimmune diseases, such as psoriasis, multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, and asthma. Treg cells play a crucial role in suppressing autoimmune diseases, transplantation, and graft-versus-host disease. Studies have demonstrated that the balance between Th17 and Treg cells is vital for host immunity and tolerance. For example, research has shown a close relationship between the pathogenesis of ulcerative colitis (UC) and an imbalance of Th17 / Treg cells.

[0004] Further research into AhR has revealed that the imbalance in Th17 / Treg differentiation may be related to AhR in the body. AhR is a cytoplasmic transcription factor involved in regulating drug metabolism, cell growth and differentiation, and is closely related to the occurrence of immune-mediated and inflammatory diseases. Activated AhR can regulate the differentiation of Th17 and Treg cells in vivo. Numerous experiments have demonstrated that AhR is associated with the occurrence of immune-mediated diseases, such as asthma, smoking-related inflammatory lung diseases, atopic dermatitis, chronic kidney disease, Sjögren's syndrome, and inflammatory bowel disease.

[0005] Common AhR agonists include ITE, TCDD, and FICZ. TCDD, the earliest discovered AhR agonist, can regulate T cell differentiation balance; however, its environmental and in vivo toxicity limits its clinical application. Benvitimod, the first marketed aryl hydrocarbon receptor agonist, is a next-generation anti-inflammatory drug used to treat various major autoimmune diseases, such as psoriasis, eczema, purulent colitis, and various allergic diseases. As the first marketed AhR agonist, benvitimod's activity still needs improvement, and it is easily oxidized under light, making it difficult to store. Clinical application requires novel, improved compounds and compositions with better efficacy, higher bioavailability, and greater stability. Summary of the Invention

[0006] To address the aforementioned technical problems, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0007]

[0008] Wherein, X is selected from halogens, and n is an integer from 1 to 5; preferably, X is F or Cl, or X is a case of multiple substitution of F and Cl;

[0009] R is selected from substituted or unsubstituted 3-7 membered cycloalkyl or cycloalkenyl groups, or substituted or unsubstituted 3-7 membered heterocyclic groups; the substituent is, for example, C. 1-6 Alkyl, C 1-6 Alkoxy groups, halogens, etc.

[0010] In some embodiments, X is one, two, or more of adjacent substitution, meta substitution, and para substitution.

[0011] In some implementations, X is a monosubstituted F, Cl, or Br.

[0012] In some implementations, X is a disubstituted or trisubstituted F.

[0013] In some implementations, X is F and n is 1.

[0014] In some embodiments, the substituted or unsubstituted 3-7 membered heterocyclic group is an N-containing heterocyclic group; the substitution is C-substituted. 1-6 Alkyl, C 1-6 At least one of the following: alkoxy or halogen.

[0015] In some embodiments, the substituted or unsubstituted 3-7 membered cycloalkyl group is cyclopentyl or cyclohexyl.

[0016] In some specific embodiments, the compound of formula (I) is selected from the following compounds:

[0017]

[0018]

[0019] This invention also provides compounds of formula (II) or pharmaceutically acceptable salts, tautomers or stereoisomers thereof:

[0020]

[0021] The present invention also provides the use of compounds of formula (I) and formula (II) or pharmaceutically acceptable salts, tautomers or stereoisomers thereof in the preparation of medicaments for the treatment of cancer, autoimmune disorders and other conditions involving immunological factors.

[0022] According to an embodiment of the present invention, the autoimmune disorder is selected from one or more of the following: psoriasis, eczema, atopic dermatitis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, chronic kidney disease, ankylosing spondylitis, Sjögren's syndrome, polymyositis, vasculitis, polymyalgia rheumatica, immune thrombocytopenic purpura, dry eye syndrome, type 1 diabetes mellitus, psoriasis, and arthritis.

[0023] According to an embodiment of the present invention, the disease with immunological factors is selected from one or more of asthma, allergic reaction, infection, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease and transplant rejection.

[0024] The present invention also provides the use of compounds of formula (I) and formula (II) or pharmaceutically acceptable salts, tautomers or stereoisomers thereof in the preparation of medicaments for the prevention and / or treatment of diseases or conditions mediated by aryl hydrocarbon receptors (AhR).

[0025] The present invention also provides the use of compounds of formula (I) and formula (II) or pharmaceutically acceptable salts, tautomers or stereoisomers thereof in the preparation of medicaments for regulating immune and inflammation-related cytokines, said cytokines being selected from IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-22, IL-23, TNFα, TGF-β, IFN-γ, IL-1β, etc.; and for the prevention and / or treatment of diseases caused by abnormalities of the above cytokines.

[0026] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and a pharmaceutically acceptable excipient, such as a carrier or excipient.

[0027] The present invention also provides a method for treating and / or preventing aryl hydrocarbon receptor (AhR)-mediated symptoms or diseases, the method comprising administering to a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof to a therapeutic subject.

[0028] The present invention also provides a method for preparing the compound represented by formula (I):

[0029] Compound IMe reacts with compound SMC to give compound IMf, and compound IMf reacts under acidic conditions to give the compound shown in formula (I);

[0030]

[0031] Where X is selected from halogens, and n is an integer from 1 to 5;

[0032] R is selected from substituted or unsubstituted 3-7 membered cycloalkyl or cycloalkenyl groups, or substituted or unsubstituted 3-7 membered heterocyclic groups.

[0033] Furthermore, the preparation process route for compound IMe is as follows:

[0034]

[0035] R is selected from substituted or unsubstituted 3-7 membered cycloalkyl or cycloalkenyl groups, or substituted or unsubstituted 3-7 membered heterocyclic groups.

[0036] Terminology Explanation

[0037] The “3-7 membered cycloalkyl or cycloalkenyl” mentioned in this invention includes, but is not limited to, “3-7 membered monocyclic cycloalkyl or monocyclic cycloalkenyl”. Specific embodiments include, but are not limited to, substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, etc.

[0038] The "3-7 membered heterocyclic group" mentioned in this invention refers to a saturated or partially saturated monocyclic cyclic group containing at least one heteroatom (e.g., 1, 2, 3, or 4) and having 3-7 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom;

[0039] The term "stereoisomer" as used in this invention refers to a compound containing one or more asymmetric centers, thus allowing it to exist as a racemic mixture and racemic mixture, a single enantiomer, a mixture of diastereomers, and a single diastereomer. The compounds of this invention may have asymmetric centers, each of which independently produces two optical isomers. The scope of this invention includes all possible optical isomers and mixtures thereof.

[0040] "Pharmaceutically acceptable carriers (pharmaceutical carriers)" refer to carriers that can be used to prepare pharmaceutical compositions, which are generally compatible with the other components of the composition, harmless to the recipient, and neither biologically nor otherwise undesirable. "Pharmaceutically acceptable carriers" include one and / or more carriers. Embodiments include carriers for topical, ocular, parenteral, intravenous, intraperitoneal, intramuscular, sublingual, nasal, and oral administration. "Pharmaceutically acceptable carriers" also include reagents for preparing aqueous dispersions and sterile powders for injection or dispersion.

[0041] As used herein, “excipient” includes physiologically compatible additives that can be used to prepare pharmaceutical compositions. Examples of pharmaceutically acceptable carriers and excipients can be found, for example, in Remington Pharmaceutical Science (16th edition).

[0042] Beneficial effects

[0043] Compared with the prior art, the advantages of this invention are:

[0044] (1) The compounds of this invention, their pharmaceutically acceptable salts, tautomers, or stereoisomers exhibit excellent AhR agonist activity and can be safely used to treat diseases or related conditions mediated by abnormal AhR activity. The compounds of this invention were tested for AhR agonist activity at concentrations that confirmed no significant effect on HepG2 cell viability. The results showed that the AhR agonist activity of the compounds of this invention was 2 to 9 times that of benzenemod or the FICZ positive control drug, demonstrating good efficacy in treating diseases or related conditions mediated by abnormal AhR activity. In a DSS mouse ulcerative colitis model, the recovery at a dose of 10 mg / kg was better than that of the control group after administration of the compounds of this invention.

[0045] (2) The compounds of the present invention, their pharmaceutically acceptable salts, tautomers or stereoisomers have good biological stability and metabolic stability, exhibit good pharmacokinetic properties, and have good clinical application prospects.

[0046] (3) The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers exhibit low toxicity, good drug resistance and high safety.

[0047] (4) The compounds of the present invention have high stability and are not prone to chemical degradation reactions such as hydrolysis and oxidation. No discoloration or impurity growth was observed when stored at room temperature for a long time. No special light-proof storage is required. Compared with benzenemod, the photolysis phenomenon under light conditions is significantly reduced. Attached Figure Description

[0048] Figure 1The graph shows the effect of the test compound at a concentration of 1 μM on the activity of PBMC cells.

[0049] Figure 2 The graph shows the effect of the test compound at a concentration of 1 μM on the activity of HepG2 cells.

[0050] Figure 3 The results show the effect of the test compounds on colon length in a DSS mouse model of ulcerative colitis (**p<0.01 compared with the normal control group; #p<0.05 compared with the model group).

[0051] Figure 4 The figure shows the effect of the test compound on the disease activity index in the DSS mouse ulcerative colitis model (compared with the normal control group, **p<0.01; compared with the model group, #p<0.05, ##p<0.01).

[0052] Figure 5 Images showing the dorsal surface of mice in each group.

[0053] Figure 6 The results are the drug penetration rate test results over 24 hours.

[0054] Figure 7 This is a PASI score chart. Detailed Implementation

[0055] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0056] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0057] Example 1

[0058] The following method describes in detail the preparation of the compounds of the present invention described above. The compounds of the present invention and the comparative compounds can be prepared by those skilled in the art of organic synthesis using known or commercially available raw materials and reagents.

[0059] The following synthetic method is the specific synthetic route for the compound of formula (I) of this invention:

[0060]

[0061] Where X is selected from halogens, and n is an integer from 1 to 5; preferably X is F or Cl, or X is a case of multiple substitution of F and Cl;

[0062] R is selected from substituted or unsubstituted 3-7 membered cycloalkyl or cycloalkenyl groups, or substituted or unsubstituted 3-7 membered heterocyclic groups.

[0063] Example 2

[0064] Synthesis of diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate

[0065] (1) Synthesis of 4-cyclopentyl-3,5-dimethoxybenzoic acid

[0066]

[0067] Methyl 3,5-dimethoxybenzoate (20.07 g, 102.29 mmol) was added to a single-necked flask, followed by concentrated sulfuric acid (50 mL), and stirred until dissolved. Cyclopentanol (21.95 g, 254.82 mmol) was added dropwise to the flask under ice bath conditions. After the addition of cyclopentanol was complete, the ice bath was removed, and the temperature was raised to 70 °C. The reaction was allowed to proceed for 4 h using TLC. The reaction was stopped once the reactants had completely reacted. The reaction solution was cooled to room temperature and poured into a beaker. Saturated sodium bicarbonate solution was added to the beaker to adjust the pH of the reaction solution to 3-5. The mixture was extracted three times with ethyl acetate (200 mL) and water (200 mL). The combined ethyl acetate phases were washed with saturated sodium chloride solution (100 mL) and dried over anhydrous sodium sulfate. After drying, the ethyl acetate was removed by concentration under reduced pressure to obtain a brown solid, crude 4-cyclopentyl-3,5-dimethoxybenzoic acid (24.76 g). Yield: 96.7%.

[0068] (2) Synthesis of methyl 4-cyclopentyl-3,5-dimethoxybenzoate

[0069]

[0070] 4-Cyclopentyl-3,5-dimethoxybenzoic acid (24.76 g, 98.92 mmol) was added to a single-necked flask, followed by methanol (50 mL), and stirred to dissolve. Thionyl chloride (17.65 g, 148.39 mmol) was added dropwise to the flask under ice bath conditions, producing white fumes. After the addition of thionyl chloride was complete, the ice bath was removed, and the temperature was raised to 60 °C, reacting for 1 h. The reaction was monitored by TLC, and the reaction was stopped after confirming the complete reaction of the starting material. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove methanol and excess thionyl chloride. The solution was extracted three times with ethyl acetate (150 mL) and water (150 mL). The combined ethyl acetate phases were washed with saturated sodium chloride solution (100 mL) and dried over anhydrous sodium sulfate. After drying, the ethyl acetate was removed by concentration under reduced pressure to obtain a black solid: crude methyl 4-cyclopentyl-3,5-dimethoxybenzoate (25.95 g). Yield: 99.2%.

[0071] 4-Cyclopentyl-3,5-dimethoxybenzoate was purified by column chromatography using petroleum ether:ethyl acetate in a mobile phase of 15:1. The mobile phase was concentrated to dryness to give a yellow solid: 18.54 g of pure 4-cyclopentyl-3,5-dimethoxybenzoate. Purification yield: 71.4%.

[0072] (3) Synthesis of 4-cyclopentyl-3,5-dimethoxybenzyl alcohol

[0073]

[0074] 18.54 g (70.14 mmol) of methyl 4-cyclopentyl-3,5-dimethoxybenzoate and 50 mL of tetrahydrofuran were added to a single-necked flask and stirred to dissolve. Under ice bath conditions, 3.99 g (105.21 mmol) of lithium aluminum hydride was added in portions to the flask, resulting in the generation of numerous bubbles. After the addition of lithium aluminum hydride was complete, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 1.5 h. The reaction was monitored by TLC, and the reaction was stopped once the reactants were confirmed to have reacted completely. Under ice bath conditions, 3.99 mL of water, 3.99 mL of 15% sodium hydroxide solution, and 11.97 mL of water were added dropwise to the flask sequentially, and the mixture was stirred for 30 min, resulting in the formation of a large amount of white solid. The white precipitate was removed by filtration with diatomaceous earth, and the filtrate was collected. The precipitate was washed with a small amount of tetrahydrofuran, filtered, and the washings were collected. The filtrate and washings were combined and concentrated under reduced pressure to remove the tetrahydrofuran. Extracted three times with ethyl acetate (50 mL) and water (50 mL). The combined ethyl acetate phases were washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. After drying, the ethyl acetate was removed by concentration under reduced pressure to give a brown solid: crude 4-cyclopentyl-3,5-dimethoxybenzyl alcohol (15.37 g). Yield: 92.7%.

[0075] (4) Synthesis of 4-cyclopentyl-3,5-dimethoxybenzyl chloride

[0076]

[0077] 4-Cyclopentyl-3,5-dimethoxybenzyl alcohol (15.37 g, 65.04 mmol) was added to a single-necked flask, followed by dichloromethane (30 mL), and stirred to dissolve. Under ice bath conditions, thionyl chloride (11.61 g, 97.56 mmol) was added dropwise to the flask, producing white fumes. After the addition of thionyl chloride was complete, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored by TLC, and stopped once the reactants had completely reacted. The reaction mixture was concentrated under reduced pressure to remove dichloromethane and excess thionyl chloride. The mixture was extracted three times with ethyl acetate (50 mL) and water (50 mL). The combined ethyl acetate phases were washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. After drying, the mixture was concentrated under reduced pressure to remove ethyl acetate, yielding a black oily substance: crude 4-cyclopentyl-3,5-dimethoxybenzyl chloride (15.14 g). Yield: 91.4%.

[0078] 4-Cyclopentyl-3,5-dimethoxybenzyl chloride was purified by column chromatography using petroleum ether:ethyl acetate (100:1) as the mobile phase. The mobile phase was concentrated to dryness to give a yellow solid, which was 12.60 g of pure 4-cyclopentyl-3,5-dimethoxybenzyl chloride. Purification yield: 83.2%.

[0079] (5) Synthesis of diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate

[0080]

[0081] 4-Cyclopentyl-3,5-dimethoxybenzyl chloride (12.60 g, 49.46 mmol) and triethyl phosphite (49.31 g, 296.76 mmol) were added to a single-necked flask and stirred to dissolve. The mixture was purged with nitrogen three times. The reaction solution was heated to 160 °C and reacted for 5 h. The reaction was monitored by TLC. After confirming complete reaction of the starting material, the reaction was stopped, and the solvent was removed to obtain diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (16.75 g). Yield: 95%.

[0082] Example 3

[0083] Synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol

[0084] (1) Synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrene

[0085]

[0086] Diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (1.01 g, 2.83 mmol) was added to a three-necked flask, followed by tetrahydrofuran (15 mL). The mixture was stirred and dissolved in an ice bath. Under nitrogen protection, sodium hydride (452.5 mg, 11.31 mmol) was added dropwise to the flask. After the addition was complete, the reaction was allowed to proceed for 1 h. Then, a tetrahydrofuran solution of benzaldehyde (4.24 mmol) (450.2 mg benzaldehyde dissolved in 10 mL of tetrahydrofuran) was slowly added dropwise to the flask. After the addition was complete, the ice bath was removed, and the temperature was slowly raised to 70 °C. The reaction was allowed to proceed for 4 h. The reaction was monitored by TLC. After the reactants had reacted completely, the mixture was cooled to room temperature. The mixture was quenched with water in an ice bath until no gas was generated. The tetrahydrofuran was then removed by concentration under reduced pressure. The mixture was extracted three times with ethyl acetate (30 mL) and water (30 mL). The combined ethyl acetate phases were washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. After drying, the product was concentrated under reduced pressure to remove ethyl acetate, yielding a crude yellow oily substance (E)-2-cyclopentyl-1,3-dimethoxy-5-styrene (804.6 mg).

[0087] (E)-2-cyclopentyl-1,3-dimethoxy-5-styrene benzene was purified by column chromatography using petroleum ether:ethyl acetate (50:1) as the mobile phase. The mobile phase was concentrated to dryness to give a yellow solid, which was pure (E)-2-cyclopentyl-1,3-dimethoxy-5-styrene benzene (403.2 mg). Yield: 46.2%.

[0088] (2) Synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol

[0089]

[0090] Add (E)-2-cyclopentyl-1,3-dimethoxy-5-styrene (403.2 mg, 1.31 mmol) and pyridine hydrochloride (3.02 g, 26.15 mmol) to a single-necked flask. Purge with nitrogen three times. Slowly heat to 210 °C, and maintain the temperature for 4 h after the pyridine hydrochloride melts. Monitor the reaction by TLC, and stop the reaction once the reactants have reacted completely. Cool the reaction solution to room temperature and extract three times with ethyl acetate (30 mL) and water (30 mL). Combine the ethyl acetate phases, wash with saturated sodium chloride solution (20 mL), and dry with anhydrous sodium sulfate. After drying, concentrate under reduced pressure to remove ethyl acetate, yielding crude (E)-2-cyclopentyl-5-styrene-1,3-benzenediol (305.4 mg).

[0091] (E)-2-cyclopentyl-5-styryl-1,3-benzenediol was purified by column chromatography using petroleum ether:ethyl acetate in a mobile phase of 30:1. The mobile phase was concentrated to dryness to give a brown solid, which was 145.1 mg of pure (E)-2-cyclopentyl-5-styryl-1,3-benzenediol. Yield: 39.6%.

[0092] 1 H NMR (400MHz, DMSO-d6) δ9.10(s,2H),7.57(d,J=8.0Hz,2H),7.36(t,J=8.0Hz,2H),7.25(t,J=8.0Hz,1H),7.01(d,J=16 .0Hz,1H),6.89(d,J=16.0Hz,1H),3.51-3.42(m,1H),2.02-1.95(m,2H),1.82-1.75(m,2H),1.66-1.55(m,4H).ESI-MS m / z 279.1[MH] - .

[0093] Example 4

[0094] Synthesis of (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-benzenediol

[0095] (1) Synthesis of (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene

[0096]

[0097] Following the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the following starting material was used: diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (1.01 g, 2.83 mmol), reacted with fluorobenzaldehyde (525.7 mg, 4.24 mmol), and purified to obtain the product: (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene (252 mg). Yield: 27.2%.

[0098] (2) Synthesis of (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-benzenediol

[0099]

[0100] Following the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the starting material was (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene (252.5 mg, 0.77 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-benzenediol (103.3 mg). Yield: 44.8%.

[0101] 1H NMR (400MHz, DMSO-d6) δ9.09 (s, 2H), 7.64-7.61 (m, 2H), 7.21-7.16 (m, 2H), 6.97 (d, J=16.0Hz, 1H), 6.88 (d, J= 16.0Hz,1H),6.47(s,2H),3.50-3.41(m,1H),1.99-1.96(m,2H),1.80-1.75(m,2H),1.64-1.55(m,4H).ESI-MS m / z 297.1[MH] - .

[0102] Example 5

[0103] Synthesis of (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-benzenediol

[0104] (1) Synthesis of (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene

[0105]

[0106] Following the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the following reaction was performed using diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (1.01 g, 2.83 mmol) and p-chlorobenzaldehyde (593.6 mg, 4.24 mmol), followed by purification to obtain the product (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene (451.3 mg). Yield: 46.5%.

[0107] (2) Synthesis of (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-benzenediol

[0108]

[0109] Following the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the following starting material was used: (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene (451.3 mg, 1.32 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-benzenediol (251.3 mg). Yield: 60.6%.

[0110] 1H NMR (400MHz, DMSO-d6) δ9.11(s,2H),7.61(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),7.04(d,J=16.0Hz,1H),7.88(d ,J=16.0Hz,1H),6.49(s,2H),3.51-3.42(m,1H),2.00-1.95(m,2H),1.80-1.75(m,2H),1.64-1.55(m,4H).ESI-MS m / z 313.1[MH] - .

[0111] Example 6

[0112] Synthesis of (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-benzenediol

[0113] (1) Synthesis of (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-dimethoxybenzene

[0114]

[0115] Following the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the reactants were diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (1.01 g, 2.83 mmol) and p-bromobenzaldehyde (784.4 mg, 4.24 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-dimethoxybenzene (521.7 mg). Yield: 47.4%.

[0116] (2) Synthesis of (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-benzenediol

[0117]

[0118] Following the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the starting material was (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-dimethoxybenzene (521.7 mg, 1.35 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-benzenediol (215.2 mg). Yield: 44.5%.

[0119] 1H NMR (400MHz, DMSO-d6) δ9.10(s,2H),7.53(s,2H),7.05(d,J=16.0Hz,4H),6.85(d,J=16.0Hz,2H),3.51-3.42(m,1H),1.99 -1.95(m,2H),1.81-1.74(m,2H),1.63-1.54(m,4H).ESI-MS:m / z357.0[MH] - .

[0120] Example 7

[0121] Synthesis of diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate

[0122] (1) Synthesis of 4-cyclohexyl-3,5-dimethoxybenzoic acid

[0123]

[0124] Methyl 3,5-dimethoxybenzoate (20.12 g, 102.55 mmol) and concentrated sulfuric acid (50 mL) were added to a single-necked flask and stirred until dissolved. Cyclohexanol (25.68 g, 256.37 mmol) was added dropwise to the flask under ice bath conditions. After the addition was complete, the ice bath was removed, and the temperature was slowly raised to 70 °C and the reaction was allowed to proceed for 4 h. The reaction was monitored by TLC, and the reaction was stopped once the reactants had completely reacted. The reaction solution was cooled to room temperature and poured into a beaker. Saturated sodium bicarbonate solution was added to the beaker to adjust the pH of the reaction solution to 3-5. The mixture was extracted three times with ethyl acetate (200 mL) and water (200 mL). The ethyl acetate phases were combined, washed with saturated sodium chloride solution (100 mL), and dried over anhydrous sodium sulfate. After drying, the ethyl acetate was removed by concentration under reduced pressure to obtain a crude product as a brown solid: 4-cyclohexyl-3,5-dimethoxybenzoic acid (27.10 g). Yield: 100.0%.

[0125] (2) Synthesis of methyl 4-cyclohexyl-3,5-dimethoxybenzoate

[0126]

[0127] 4-Cyclohexyl-3,5-dimethoxybenzoic acid (27.10 g, 102.53 mmol) and methanol (50 mL) were added to a single-necked flask and stirred to dissolve. Thionyl chloride (18.29 g, 153.79 mmol) was added dropwise to the flask under ice bath conditions, producing white fumes. After the addition of thionyl chloride was complete, the ice bath was removed, and the temperature was raised to 60 °C, reacting for 1 h. The reaction was monitored by TLC, and the reaction was stopped after confirming the complete reaction of the starting materials. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove methanol and excess thionyl chloride. The solution was extracted three times with ethyl acetate (150 mL) and water (150 mL). The combined ethyl acetate phases were washed with saturated sodium chloride solution (100 mL) and dried over anhydrous sodium sulfate for 5 h. After drying, the ethyl acetate was removed by concentration under reduced pressure to obtain a black solid: crude methyl 4-cyclohexyl-3,5-dimethoxybenzoate (28.23 g). Yield: 98.9%.

[0128] 4-Cyclohexyl-3,5-dimethoxybenzoate was purified by column chromatography using petroleum ether:ethyl acetate in a mobile phase of 15:1. The mobile phase was concentrated to dryness to give a yellow solid: 19.51 g of pure 4-cyclohexyl-3,5-dimethoxybenzoate. Purification yield: 69.1%.

[0129] (3) Synthesis of 4-cyclohexyl-3,5-dimethoxybenzyl alcohol

[0130]

[0131] 27.10 g (97.36 mmol) of methyl 4-cyclohexyl-3,5-dimethoxybenzoate and 271 mL of tetrahydrofuran were added to a single-necked flask and stirred until dissolved. Lithium aluminum hydride (7.4 g, 194.73 mmol) was slowly added in portions under ice bath conditions. After the addition was complete, the ice bath was removed, and the mixture was allowed to react at room temperature for 1 hour. The reaction was monitored by TLC, and the reaction was stopped once the reactants were confirmed to have reacted completely. The lithium aluminum hydride was quenched with water under ice bath conditions until the solution turned grayish-white. The mixture was filtered, and the filtrate was extracted three times with ethyl acetate (150 mL) and water (150 mL). The combined ethyl acetate phases were washed with saturated sodium chloride solution (100 mL) and dried over anhydrous sodium sulfate. After drying, the ethyl acetate was removed by concentration under reduced pressure to obtain a pale yellow solid: crude 4-cyclohexyl-3,5-dimethoxybenzyl alcohol (20.23 g), yield: 83%.

[0132] 4-Cyclohexyl-3,5-dimethoxybenzoate was purified by column chromatography using petroleum ether:ethyl acetate in a mobile phase of 15:1. The mobile phase was concentrated to dryness to give a white solid: pure 4-cyclohexyl-3,5-dimethoxybenzoate (16.13 g). Purification yield: 66.2%.

[0133] (4) Synthesis of 4-cyclohexyl-3,5-dimethoxybenzyl chloride

[0134]

[0135] 4-Cyclohexyl-3,5-dimethoxybenzyl alcohol (16.13 g, 64.43 mmol) and dichloromethane (30 mL) were added to a single-necked flask and stirred to dissolve. Thionyl chloride (11.50 g, 96.65 mmol) was added dropwise to the flask under ice bath conditions, resulting in the appearance of white fumes. After the addition of thionyl chloride was complete, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored by TLC, and the reaction was stopped once the reactants had completely reacted. The reaction solution was concentrated under reduced pressure to remove dichloromethane and excess thionyl chloride. The solution was extracted three times with ethyl acetate (50 mL) and water (50 mL). The combined ethyl acetate phases were washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. After drying, the solution was concentrated under reduced pressure to remove ethyl acetate, yielding a black oily substance: crude 4-cyclohexyl-3,5-dimethoxybenzyl chloride (15.22 g), yield: 87.9%.

[0136] 4-Cyclohexyl-3,5-dimethoxybenzyl chloride was purified by column chromatography using petroleum ether:ethyl acetate (100:1) as the mobile phase. The mobile phase was concentrated to dryness to give a yellow solid: 11.81 g of pure 4-cyclohexyl-3,5-dimethoxybenzyl chloride. Purification yield: 77.6%.

[0137] (5) Synthesis of diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate

[0138]

[0139] 4-Cyclohexyl-3,5-dimethoxybenzyl chloride (11.81 g, 43.94 mmol) and triethyl phosphite (43.80 g, 263.63 mmol) were added to a single-necked flask and stirred to dissolve. The mixture was purged with nitrogen three times. The reaction solution was slowly heated to 160 °C and reacted for 5 h. The reaction was monitored by TLC. After confirming that the starting material had reacted completely, the reaction was stopped and cooled to room temperature. After removing the solvent by concentration under reduced pressure, the crude product was slurried three times with n-hexane (100 mL) to obtain a pale yellow solid, diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (15.62 g). Yield: 95.9%.

[0140] Example 8

[0141] Synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol

[0142] (1) Synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrene

[0143]

[0144] Add diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.08 g, 2.92 mmol) and tetrahydrofuran (15 mL) to a three-necked flask and stir to dissolve. Purge with nitrogen three times. Add 60% sodium hydride (466.5 mg, 11.66 mmol) in portions to the three-necked flask under ice bath conditions. After the addition is complete, allow the reaction to proceed for 1 h. Slowly add a tetrahydrofuran solution of benzaldehyde (4.37 mmol) (464.1 mg benzaldehyde dissolved in 10 mL tetrahydrofuran) dropwise to the three-necked flask. After the addition is complete, slowly raise the temperature to 70 °C and allow the reaction to proceed for 4 h. Monitor the reaction by TLC. Once the reactants have reacted completely, stop the reaction. Quench the reaction with water to the three-necked flask under ice bath conditions until no gas is generated. Concentrate under reduced pressure to remove tetrahydrofuran. Extract three times with ethyl acetate (30 mL) and water (30 mL). The ethyl acetate phases were combined, washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. After drying, the ethyl acetate was removed by concentration under reduced pressure to obtain a yellow oily substance: crude (E)-2-cyclohexyl-1,3-dimethoxy-5-styrene (625.2 mg).

[0145] (E)-2-cyclohexyl-1,3-dimethoxy-5-styrene benzene was purified by column chromatography using petroleum ether:ethyl acetate in a mobile phase of 50:1. The mobile phase was concentrated to dryness to give a yellow solid: (E)-2-cyclohexyl-1,3-dimethoxy-5-styrene benzene (451.1 mg). Yield: 48.0%.

[0146] (2) Synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol

[0147]

[0148] Add (E)-2-cyclohexyl-1,3-dimethoxy-5-styrene (451.1 mg, 1.40 mmol) and pyridine hydrochloride (3.23 g, 27.98 mmol) to a single-necked flask. Purge with nitrogen three times. Slowly heat to 210 °C, and after the pyridine hydrochloride melts, react for 4 h. Monitor the reaction by TLC, and stop the reaction once the reactants have reacted completely. Cool the reaction solution to room temperature and allow it to solidify. Extract three times with ethyl acetate (30 mL) and water (30 mL). Combine the ethyl acetate phases, wash with saturated sodium chloride solution (20 mL), and dry with anhydrous sodium sulfate. After drying, concentrate under reduced pressure to remove ethyl acetate, yielding a black solid: crude (E)-2-cyclohexyl-5-styrene-1,3-benzenediol (215.9 mg).

[0149] (E)-2-cyclohexyl-5-styryl-1,3-benzenediol was purified by column chromatography using petroleum ether:ethyl acetate in a mobile phase of 30:1. The mobile phase was concentrated to dryness to give a brown solid: (E)-2-cyclohexyl-5-styryl-1,3-benzenediol (109.3 mg). Yield: 26.5%.

[0150] 1 H NMR (400MHz, DMSO-d6) δ9.04(s,2H),7.56(d,J=8.0Hz,2H),7.35(t,J=8.0Hz,2H),7.24(t,J=8.0Hz,1H),7.00(d,J=16.0Hz,1H),6.87 (d,J=16.0Hz,1H),6.5(s,2H),3.08-3.02(m,1H),2.14-2.06(m,2H),1.75-1.65(m,3H),1.44-1.41(m,2H),1.30-1.23(m,3H).ESI-MS m / z 293.0[MH] - .

[0151] Example 9

[0152] Synthesis of (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-benzenediol

[0153] (1) Synthesis of (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene

[0154]

[0155] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.08 g, 2.92 mmol) and p-fluorobenzaldehyde (525.7 mg, 4.24 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene (483 mg). Yield: 48.7%.

[0156] (2) Synthesis of (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-benzenediol

[0157]

[0158] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene (483.7 mg, 1.42 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-benzenediol (171.8 mg). Yield: 38.7%.

[0159] 1 H NMR (400MHz, DMSO-d6) δ9.06(s,2H),7.64-7.61(m,2H),7.20-7.17(m,2H),6.96(d,J=16.0Hz,1H),6.87(d,J=16.0Hz,1 H),6.46(s,2H),3.08-3.02(m,1H),2.15-2.06(m,2H),1.76-1.65(m,3H),1.44-1.41(m,2H),1.32-1.16(m,3H).ESI-MS m / z 311.1[MH] - .

[0160] Example 10

[0161] Synthesis of (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-benzenediol

[0162] (1) Synthesis of (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene

[0163]

[0164] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.08 g, 2.92 mmol) and p-chlorobenzaldehyde (593.6 mg, 4.24 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene (475.0 mg). Yield: 45.6%.

[0165] (2) Synthesis of (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-benzenediol

[0166]

[0167] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene (475 mg, 1.33 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-benzenediol (163.6 mg). Yield: 37.5%.

[0168] 1 H NMR (400MHz, DMSO-d6) δ9.07(s,2H),7.60(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),7.03(d,J=16.0Hz,1H),6.87(d,J=16.0Hz,1H),6.47(s,2H),3.08 -3.02(m,1H),2.15-2.06(m,4H),1.76-1.65(m,4H),1.44-1.41(m,2H).ESI-MS m / z 327.0[MH] - .

[0169] Example 11

[0170] Synthesis of (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-benzenediol

[0171] (1) Synthesis of (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-dimethoxybenzene

[0172]

[0173] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the reactants were diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.08 g, 2.92 mmol) and p-bromobenzaldehyde (784.4 mg, 4.24 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-dimethoxybenzene (625.3 mg). Yield: 53.4%.

[0174] (2) Synthesis of (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-benzenediol

[0175]

[0176] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-dimethoxybenzene (625.3 mg, 1.56 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-benzenediol (194.0 mg). Yield: 33.4%.

[0177] 1 H NMR (400MHz, DMSO-d6) δ9.06(s,2H),7.53(s,4H),7.04(d,J=16.0Hz,1H),6.85(d,J=16.0Hz,1H),6.47(s, 2H),3.08-3.02(m,1H),2.15-2.06(m,2H),1.75-1.65(m,3H),1.44-1.40(m,2H),1.32-1.19(m,3H).ESI-MS m / z 371.0[MH] - .

[0178] Example 12

[0179] Synthesis of (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-benzenediol

[0180] (1) Synthesis of (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene

[0181]

[0182] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 3-fluorobenzaldehyde (502.6 mg, 4.05 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene (470.0 mg). Yield: 51.1%.

[0183] (2) Synthesis of (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-benzenediol

[0184]

[0185] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene (470 mg, 1.38 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-benzenediol (150 mg). Yield: 34.8%.

[0186] 1 H NMR(400MHz, DMSO-d6)δ9.08(s,2H),7.80(t,J=7.5Hz,1H),7.34–7.27(m,1H),7.21(dd,J=5.7Hz,2H),7.04(dd,J=16.4Hz,2H),6.5 0(s,2H),3.06(t,J=11.5Hz,1H),2.10(dd,J=11.5Hz,2H),1.70(dd,J=9.2Hz,3H),1.43(d,J=11.6Hz,2H),1.36–1.12(m,3H).ESI-MS m / z 311.1[MH] - .

[0187] Example 13

[0188] Synthesis of (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-benzenediol

[0189] (1) Synthesis of (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene

[0190]

[0191] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 2-fluorobenzaldehyde (502.6 mg, 4.05 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene (450 mg). Yield: 49.0%.

[0192] (2) Synthesis of (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-benzenediol

[0193]

[0194] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene (450 mg, 1.32 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-benzenediol (170 mg). Yield: 41.2%.

[0195] 1 H NMR (400MHz, DMSO-d6) δ9.03(s,2H),7.61(dd,J=5.6Hz,2H),7.18(t,J=8.8Hz,2H),6.91(q,J=16.3Hz,2H),6.46(s,2H),3. 05(t,J=12.1Hz,1H),2.10(dd,12.1Hz,2H),1.70(dd,J=10.1Hz,4H),1.42(d,J=12.5Hz,2H),1.34–1.17(m,2H).ESI-MSm / z 311.1[MH] - .

[0196] Example 14

[0197] Synthesis of (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-benzenediol

[0198] (1) Synthesis of (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene

[0199]

[0200] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 2-chlorobenzaldehyde (569.2 mg, 4.05 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(2-chlorostyrene)-1,3-dimethoxybenzene (480 mg). Yield: 49.8%.

[0201] (2) Synthesis of (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-benzenediol

[0202]

[0203] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene (480 mg, 1.34 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-benzenediol (170 mg). Yield: 38.4%.

[0204] 1 H NMR (400MHz, DMSO-d6) δ9.07(s,2H),7.67(dd,J=5.6Hz,2H),7.53(t,J=8.8Hz,2H),7.37(q,J=16.3Hz,2H),7.10(s,2H),3. 13(t,J=12.1Hz,1H),2.26(dd,12.1Hz,2H),2.10(dd,J=10.1Hz,4H),1.72(d,J=12.5Hz,2H),1.64–1.37(m,2H).ESI-MSm / z 327.1[MH] - .

[0205] Example 15

[0206] Synthesis of (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-benzenediol

[0207] (1) Synthesis of (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene

[0208]

[0209] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 3-chlorobenzaldehyde (569.2 mg, 4.05 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene (475 mg). Yield: 49.3%.

[0210] (2) Synthesis of (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-benzenediol

[0211]

[0212] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene (475 mg, 1.33 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-benzenediol (170 mg). Yield: 38.8%.

[0213] 1 H NMR (400MHz, DMSO-d6) δ9.05(s,2H),7.60(d,J=8.5Hz,2H),7.40(d,J=8.5Hz,2H),7.03(d,J=16.3Hz,1H),6.86(d,J=16.3Hz,2H),6.47( s,1H),3.05(t,J=12.2Hz,1H),2.10(dd,J=11.0Hz,2H),1.70(dd,J=10.3Hz,2H),1.43(d,J=11.7Hz,2H),1.20(d,J=13.6Hz,4H).ESI-MS m / z 327.1[MH] - .

[0214] Example 16

[0215] Synthesis of (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-benzenediol

[0216] (1) Synthesis of (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-dimethoxybenzene

[0217]

[0218] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 2,4-difluorobenzaldehyde (575.4 mg, 4.05 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-dimethoxybenzene (470 mg). Yield: 48.6%.

[0219] (2) Synthesis of (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-benzenediol

[0220]

[0221] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-dimethoxybenzene (470 mg, 1.31 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-benzenediol (170 mg). Yield: 39.2%.

[0222] 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 2H), 7.74–7.69 (m, 1H), 7.27 (td, J = 9.6, 4. 7Hz,1H),7.20(d,J=16.4Hz,1H),7.15(dt,J=11.8,Hz,1H),6.98(d,J=16.4 Hz,1H),6.50(s,2H),3.08(t,J=12.1Hz,1H),2.20–2.02(m,2H),1.73(dd,J =31.4,10.5Hz,3H),1.40(d,J=12.2Hz,2H),1.25(t,J=13.4Hz,3H).ESI-MS m / z 329.1[MH] - .

[0223] Example 17

[0224] Synthesis of (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-benzenediol

[0225] (1) Synthesis of (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-dimethoxybenzene

[0226]

[0227] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 2,6-difluorobenzaldehyde (575.4 mg, 4.05 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-dimethoxybenzene (450 mg). Yield: 46.5%.

[0228] (2) Synthesis of (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-benzenediol

[0229]

[0230] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-dimethoxybenzene (450 mg, 1.26 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-benzenediol (150 mg). Yield: 36.2%.

[0231] 1 H NMR (400MHz, DMSO-d6) δ9.10(s,2H),7.35(d,J=7.3Hz,2H),7.17(d,J=16.3Hz,1H),7.07(t,J=9.2Hz,1H),6.86(d,J=16.3Hz,1H),6.48( s,2H),3.06(t,J=12.0Hz,1H),2.10(dd,J=11.2Hz,2H),1.70(dd,J=10.0Hz,3H),1.43(d,J=11.9Hz,2H),1.27(dd,J=10.6Hz,3H).ESI-MS m / z 329.1[MH] - .

[0232] Example 18

[0233] Synthesis of (E)-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-benzenediol

[0234] (1) Synthesis of (E)-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-dimethoxybenzene

[0235]

[0236] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrene as described in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 2,5-difluorobenzaldehyde (575.4 mg, 4.05 mmol). The reaction mixture was then purified to yield (E)-2-cyclohexyl-5-(2,5-difluorostyrene)-1,3-dimethoxybenzene (445 mg). Yield: 46.0%.

[0237] (2) Synthesis of (E)-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-benzenediol

[0238]

[0239] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-dimethoxybenzene (445 mg, 1.24 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-benzenediol (168 mg). Yield: 41.0%.

[0240] 1 H NMR (400MHz, DMSO-d6) δ9.06(s,2H),7.86(dd,J=7.8Hz,1H),7.30–7.23(m,1H),7.12(d,J=8.4Hz,1H),7.05(d,J=16.4Hz,1H),6.93(d,J=16.5H z,1H),6.48(s,2H),3.11–2.98(m,1H),2.10(dd,J=12.1Hz,2H),1.70(dd,J=8.4Hz,3H),1.43(d,J=11.3Hz,2H),1.19(dd,J=10.7Hz,3H).ESI-MS m / z 329.1[MH] - .

[0241] Example 19

[0242] Synthesis of (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-benzenediol

[0243] (1) Synthesis of (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-dimethoxybenzene

[0244]

[0245] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 3,4-difluorobenzaldehyde (575.4 mg, 4.05 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-dimethoxybenzene (463 mg). Yield: 47.9%.

[0246] (2) Synthesis of (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-benzenediol

[0247]

[0248] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-dimethoxybenzene (463 mg, 1.29 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-benzenediol (168 mg). Yield: 39.4%.

[0249] 1 H NMR (400MHz, DMSO-d6) δ9.11(s,2H),7.77–7.68(m,1H),7.27(td,J=9.6Hz,1H),7.19(d,J=16.4Hz,1H),7.12(dt,J=11.8,Hz,1H),6.95(d,J=16. 4Hz,1H),6.52(s,2H),3.07(t,J=12.1Hz,1H),2.20–2.05(m,2H),1.71(dd,J=10.5Hz,3H),1.44(d,J=12.2Hz,2H),1.27(t,J=13.4Hz,3H).ESI-MS m / z 329.1[MH] - .

[0250] Example 20

[0251] Synthesis of (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-benzenediol

[0252] (1) Synthesis of (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-dimethoxybenzene

[0253]

[0254] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 2,3-difluorobenzaldehyde (575.4 mg, 4.05 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-dimethoxybenzene (468 mg). Yield: 48.4%.

[0255] (2) Synthesis of (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-benzenediol

[0256]

[0257] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-dimethoxybenzene (468 mg, 1.31 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-benzenediol (173 mg). Yield: 40.1%.

[0258] 1 H NMR(400MHz, DMSO-d6)δ9.10(s,2H),7.72(ddd,J=9.5Hz,1H),7.27(td,J=10.1Hz,1H),7.17(t,J=10.3Hz,1H),7.18–7.08(m,1H),6.94(d,J=16.6 Hz,1H),6.50(s,2H),3.06(t,J=12.1Hz,1H),2.10(dd,J=11.2Hz,2H),1.70(dd,J=10.0Hz,3H),1.43(d,J=11.1Hz,2H),1.24–1.12(m,3H).ESI-MS m / z 329.1[MH] - .

[0259] Example 21

[0260] Synthesis of (E)-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-benzenediol

[0261] (1) Synthesis of (E)-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-dimethoxybenzene

[0262]

[0263] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 3,5-difluorobenzaldehyde (575.4 mg, 4.05 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-dimethoxybenzene (470 mg). Yield: 48.6%.

[0264] (2) Synthesis of (E)-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-benzenediol

[0265]

[0266] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-dimethoxybenzene (470 mg, 1.31 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-benzenediol (165.8 mg). Yield: 38.3%.

[0267] 1 H NMR (400MHz, DMSO-d6) δ9.13(s,2H),7.43–7.27(m,2H),7.13(dd,J=18.5,12.4Hz,2H),6.85(d,J=16.8Hz,2H),6.48(s,1H),3.06 (t,J=11.7Hz,1H),2.10(dd,J=13.1Hz,2H),1.70(dd,J=9.1Hz,3H),1.42(d,J=12.0Hz,2H),1.35–1.20(t,J=12.0Hz,3H).ESI-MS m / z 329.1[MH] - .

[0268] Example 22

[0269] Synthesis of (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-benzenediol

[0270] (1) Synthesis of (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-dimethoxybenzene

[0271]

[0272] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 2,4,5-trifluorobenzaldehyde (648 mg, 4.04 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-dimethoxybenzene (478 mg). Yield: 47.0%.

[0273] (2) Synthesis of (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-benzenediol

[0274]

[0275] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-dimethoxybenzene (478 mg, 1.27 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-benzenediol (163 mg). Yield: 36.8%.

[0276] 1 H NMR(400MHz, DMSO-d6)δ9.02(s,2H),7.63(dd,J=7.3Hz,2H),6.88(dd,J=16.4Hz,1H),6.81–6.66(m,2H),6.44(s,1H),3 .04(t,J=9.8Hz,1H),2.09(dd,J=13.0Hz,2H),1.70(dd,J=9.6Hz,3H),1.42(d,J=11.2Hz,2H),1.34–1.22(m,3H).ESI-MS m / z347.1[MH] - .

[0277] Example 23

[0278] Synthesis of (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-benzenediol

[0279] (1) Synthesis of (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-dimethoxybenzene

[0280]

[0281] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 2,3,4-trifluorobenzaldehyde (648 mg, 4.04 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-dimethoxybenzene (450 mg). Yield: 44.3%.

[0282] (2) Synthesis of (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-benzenediol

[0283]

[0284] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-dimethoxybenzene (450 mg, 1.20 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-benzenediol (161 mg). Yield: 38.7%.

[0285] 1 H NMR(400MHz, DMSO-d6)δ9.09(s,2H),7.28–7.12(m,2H),6.84(d,J=16.2Hz,1H),6.71(d,J=16.2Hz,1H),6.41(s,2H),4.75–4.69 (m,1H),3.09–2.98(m,2H),2.09(dd,J=12.2Hz,2H),1.69(dd,J=10.1Hz,2H),1.42(d,J=12.4Hz,2H),1.33–1.15(m,2H).ESI-MS m / z 347.1[MH] - .

[0286] Example 24

[0287] Synthesis of (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-benzenediol

[0288] (1) Synthesis of (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-dimethoxybenzene

[0289]

[0290] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 3,4,5-trifluorobenzaldehyde (648 mg, 4.04 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-dimethoxybenzene (463 mg). Yield: 45.6%.

[0291] (2) Synthesis of (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-benzenediol

[0292]

[0293] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-dimethoxybenzene (463 mg, 1.23 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-benzenediol (157 mg). Yield: 36.6%.

[0294] 1 H NMR(400MHz, DMSO-d6)δ10.30(d,J=16.4Hz,1H),7.55–7.31(m,1H),7.32–7.17(m,1H),7.17(s,1H),6.96(t,J=16.2Hz,2H),6.90–6.77(m ,1H),6.46(s,1H),3.05(dt,J=11.4,8.3Hz,1H),2.33–1.89(m,2H),1.92–1.60(m,2H),1.44(t,J=12.6Hz,1H),1.42–1.19(m,5H).ESI-MS m / z 347.1[MH] - .

[0295] Example 25

[0296] Synthesis of (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-benzenediol

[0297] (1) Synthesis of (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-dimethoxybenzene

[0298]

[0299] Following the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the following reactants were used: diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 2,4,6-trifluorobenzaldehyde (648 mg, 4.04 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-dimethoxybenzene (453 mg). Yield: 44.6%.

[0300] (2) Synthesis of (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-benzenediol

[0301]

[0302] Following the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material was (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-dimethoxybenzene (453 mg, 1.20 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-benzenediol (158 mg). Yield: 37.7%.

[0303] 1 H NMR(400MHz, DMSO-d6)δ9.02(s,2H),7.62(dd,J=12.3Hz,1H),6.92(d,J=16.5Hz,2H),6.91–6.79(m,1H),6.74(dd,J=10.7Hz,1H),6.44( s,1H),3.04(dd,J=10.3Hz,1H),2.09(dd,J=12.3Hz,2H),1.69(dd,J=8.3Hz,2H),1.42(d,J=10.4Hz,2H),1.27(dd,J=8.3Hz,4H).ESI-MS m / z 347.1[MH] - .

[0304] Example 26

[0305] Synthesis of (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-benzenediol

[0306] (1) Synthesis of (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene

[0307]

[0308] Following the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the reactants were diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.81 mmol) and 3-fluorobenzaldehyde (522.4 mg, 4.21 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene (480 mg). Yield: 52.4%.

[0309] (2) Synthesis of (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-benzenediol

[0310]

[0311] Following the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol as described in Example 3, the starting material was (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene (480 mg, 1.47 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-benzenediol (150 mg). Yield: 34.2%.

[0312] 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 2H), 7.48-7.45 (d, 1H), 7.4-7.38 (d, J = 16.0Hz, 1H), 7.12-7.01 (m, J = 16.0Hz, 2H), 6.91-6.8 7(d,2H),6.55(s,2H),2.65-2.59(m,1H),2.33-2.29(m,1H),1.99-1.95(m,2H),1.78-1.75(m,1H),1.54-1.50(m,4H).ESI-MS m / z 297.1[MH] - .

[0313] Example 27

[0314] Synthesis of (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-benzenediol

[0315] (1) Synthesis of (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene

[0316]

[0317] Following the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the reactants were diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.81 mmol) and 2-fluorobenzaldehyde (522.4 mg, 4.21 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene (500 mg). Yield: 54.6%.

[0318] (2) Synthesis of (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-benzenediol

[0319]

[0320] Following the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the starting material was (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene (500 mg, 1.53 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-benzenediol (200 mg). Yield: 43.8%.

[0321] 1 H NMR (400MHz, DMSO-d6) δ9.13 (s, 2H), 7.83-7.79 (t, J = 16.0Hz 1H),7.34-7.28(t,J=16.0Hz,1H),7.24-7.19(t,J=16.0Hz,2H),7.13-7.08(d,1H),7.02-6.98( d,1H),6.5(s,2H),3.51-3.42(m,1H),2.0-1.96(t,2H),1.78(s,2H),1.64-1.55(m,4H).ESI-MS m / z 297.1[MH] - .

[0322] Example 28

[0323] Synthesis of (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-benzenediol

[0324] (1) Synthesis of (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene

[0325]

[0326] Following the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the reactants were diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.81 mmol) and 2-chlorobenzaldehyde (591.6 mg, 4.21 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene (450 mg). Yield: 46.8%.

[0327] (2) Synthesis of (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-benzenediol

[0328]

[0329] Following the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol as described in Example 3, the starting material was (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene (450 mg, 1.31 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-benzenediol (185 mg). Yield: 44.8%.

[0330] 1 H NMR (400MHz, DMSO-d6) δ9.21 (s, 2H), 7.95-7.92 (d, 1H), 7.53-7.50 (m, 1H), 7.42-7.38 (d, J = 16.0Hz, 1H), 7.35-7.31 (m, J = 16.0Hz, 1H), 7.29-7.25 (d,J=16.0Hz,1H),7.15-7.11(d,J=16.0Hz,1H),6.56(s,2H),3.57-3.47 (m,1H),1.99-1.96(m,2H),1.86-1.79(m,2H),1.71-1.59(m,4H).ESI-MS m / z 313.1[MH] - .

[0331] Example 29

[0332] Synthesis of (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-benzenediol

[0333] (1) Synthesis of (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene

[0334]

[0335] Following the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the reactants were diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.81 mmol) and 3-chlorobenzaldehyde (522.4 mg, 4.21 mmol). The reaction was followed by purification to obtain the product: (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene (460 mg). Yield: 47.8%.

[0336] (2) Synthesis of (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-benzenediol

[0337]

[0338] Following the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol as described in Example 3, the starting material was (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene (460 mg, 1.34 mmol). The reaction was followed by purification to obtain the product (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-benzenediol (170 mg). Yield: 40.2%.

[0339] 1 H NMR (400MHz, DMSO-d6) δ9.19 (s, 2H), 7.74-7.73 (t, 1H), 7.59-7.57 (d, J = 16.0 Hz,1H),7.44-7.40(t,J=16.0Hz,1H),7.35-7.32(t,J=16.0Hz,1H),7.19-7.15 (d,J=16.0Hz,1H),6.94-6.90(d,J=16.0Hz,1H),6.54(s,J=16.0Hz,2H),3.54 -3.47(m,1H),2.05-1.99(m,2H),1.86-1.78(m,2H),1.69-1.59(m,4H).ESI-MS m / z 313.1 [MH] - .

[0340] Test Example 1

[0341] The compounds of this invention were subjected to activity tests, and the commercially available aromatic hydrocarbon receptor agonist drug benzenemod and the commonly used aromatic hydrocarbon receptor agonist compound FICZ were selected as comparative experimental compounds.

[0342] 1. Cytotoxicity test of the test compound

[0343] 1) Cytotoxicity test of the test compound in PBMC

[0344] The specific test compounds are shown in Table 1:

[0345] (1) Dispensing medicine

[0346] Prepare the highest concentration of drug solution in the culture medium: Take 1 μL of each of the series of compounds 1# to 8# (initial concentration of 1 mM), control 1#, control 2#, and control 3#, and add them to 499 μL of culture medium to prepare a drug-containing culture medium with a concentration of 2 μM.

[0347] (2) Cell preparation

[0348] ① Cell information: PBMC 5 Million ID#:LP181017CAT#:PB003F-5M

[0349] ② Cell resuscitation: Remove PBMC cells from the liquid nitrogen tank and quickly place them in 37°C warm water to thaw. Place the cells in a centrifuge tube containing culture medium and centrifuge at 1200 rpm for 11 minutes. Remove the centrifuge tube, discard the culture medium, and use a dropper to draw 5 mL of culture medium to resuspend the cells.

[0350] ③ Cell counting: Open the cell counting software, select cell type: PBMC, viable cell concentration: 3.47 × 10^ 5 cells / mL;

[0351] (3) Cell-based drug delivery

[0352] Cell seeding and drug administration: Dilute the cell suspension to 7 mL and seed cells in a 96-well plate. Add 100 μL of cell suspension to each well, followed by 100 μL of 2 μM of drug solution #1 to #8, control #1, control #2, and control #3 to each well, with three replicates per group. The final number of viable cells per well is approximately 2.5 × 10^6 cells. 4 One, with a drug concentration of 1 μM.

[0353] (4) Cytotoxicity test

[0354] After 24 hours of drug treatment, 10 μL of CCK8 was added to each well of cells. After 3 hours of reaction, the absorbance was read using a microplate reader at a wavelength of 450 nm. The reading results are as follows. Figure 1 As shown.

[0355] Cell viability was calculated after treatment with each compound, with the absorbance of the control group being 100%.

[0356] 2) Cytotoxicity test of the test compound in HepG2

[0357] (1) Dispensing medicine

[0358] Prepare the highest concentration of drug solution in the culture medium: Take 1 μL of each of the series of compounds 1# to 8# (initial concentration of 1 mM), control 1#, control 2#, and control 3#, and add them to 499 μL of culture medium to prepare a drug-containing culture medium with a concentration of 2 μM.

[0359] (2) Cell preparation

[0360] Source: HepG2 cells were obtained from the Chinese Academy of Sciences Cell Bank.

[0361] Cell resuscitation: Remove HepG2 cells from the liquid nitrogen tank and quickly place them in 37°C warm water to thaw. Place the cells in a centrifuge tube containing culture medium and centrifuge at 1200 rpm for 11 minutes. Remove the centrifuge tube, discard the culture medium, and use a dropper to draw 5 mL of culture medium to resuspend the cells.

[0362] (3) Cell-based drug delivery

[0363] Dilute the cell suspension to 7 mL and seed cells into 96-well plates. Add 100 μL of cell suspension to each well, followed by 100 μL of 2 μM of each of the following drug solutions: #1 to #8, Control #1, Control #2, and Control #3. Each group has three replicates. The final viable cell count per well is approximately 2.0 × 10^6 cells. 4 One, with a drug concentration of 1 μM.

[0364] (4) Cytotoxicity test

[0365] After 24 hours of drug treatment, 10 μL of CCK8 was added to each well of cells. After 3 hours of reaction, the absorbance was read using a microplate reader at a wavelength of 450 nm. The reading results are as follows. Figure 2 As shown.

[0366] Depend on Figure 1 and Figure 2 It can be seen that, at the tested concentrations, none of the compounds had a significant effect on the cell viability of PBMCs or HepG2 cells.

[0367] 2. AhR activating experiment of the compound

[0368] The AhR agonist effect of the compound is evaluated based on the results of its use in reporter gene experiments.

[0369] (1) Cell transfection: HepG2 cells were seeded into 6cm cell culture dishes and allowed to adhere overnight.

[0370] When the cell confluence reaches 80%, replace the medium with fresh medium and add the transfection working solution, then transfect overnight. The working solution is formulated as follows: 1 mL Opti-MEM + 7.5 μg pCMV-AHR + 7.5 μg pTK-3X DRE-Luc + 30 μL lipo6000.

[0371] (2) Cell plating: The transfected cells were digested and prepared into a concentration of 3 x 10^ 5 Cell suspension of 100 μL per cell was seeded into 96-well plates and incubated overnight.

[0372] (3) Dispensing medicine

[0373] Prepare the highest concentration of drug solution in the culture medium: Take 1 μL of each of the series of compounds 1# to 16#, control 1#, control 2#, and control 3# with an initial concentration of 1 mM and add them to 499 μL of culture medium to prepare a drug-containing culture medium with a concentration of 2 μM; then take 40 μL of the 2 μM drug-containing culture medium and dilute it to prepare 400 μL of drug-containing culture medium with a concentration of 0.2 μM.

[0374] (4) Cell-based drug delivery

[0375] Add the prepared drug-containing culture medium and blank culture medium to the above 96-well plates, 100 μL per well. After 16 hours of drug treatment, perform luciferase reporter gene assay.

[0376] (5) The experimental statistical results are shown in Table 1.

[0377] Table 1. Results of AhR activity assays for the tested compounds.

[0378]

[0379]

[0380]

[0381] Note: The AhR receptor activating factor for each group is the ratio of the fluorescence intensity of each group to the blank fluorescence intensity.

[0382] As can be seen from the data in Table 1, all compounds 1-16 of this invention have AhR activity, and all tested compounds 2 to 16 have good AhR activating effects.

[0383] 3. The regulatory effect of the compound on PBMC cytokine secretion

[0384] (1) Cell information: mononuclear cells derived from bone marrow;

[0385] (2) Cell plating and drug administration: After thawing PBMC cells from the liquid nitrogen tank, 80 L of culture medium was added to each well of a 96-well plate, with 200,000 cells per well. 80 μL of culture medium containing 2 μM or 0.2 μM of the drug solution (wells #2, #6, and control #1) was added to each well, resulting in final drug concentrations of 1 μM and 0.1 μM. Each well was pretreated at this concentration for 1 h. After pretreatment, the drug solution was removed from the wells, and 80 μL of a 1 μM or 0.1 μM solution containing 15 μg / mL PHA (phytohemaggluyinin) was added to the corresponding wells. Cytokine levels in the culture medium were measured after 24 h of stimulation.

[0386] Blank control group: ordinary culture medium, with no drugs added to the cells;

[0387] PHA group: Add 80 μL of culture medium solution containing 15 μg / mL PHA without the compound of the present invention to the corresponding well.

[0388] Table 2 Experimental Results

[0389]

[0390]

[0391] The experimental results showed that compounds 2# and 6# could inhibit cytokines TNFα and IL4 at both 0.1 μM and 1 μM concentrations. Furthermore, the inhibitory effects of compounds 2# and 6# on TNFα and IL4 were significantly greater than those of the control compound 1# benzenemod, exceeding twice the inhibitory effect at the 1 μM dose.

[0392] 4. Effects of the compound on DSS-induced colitis

[0393] (1) Experimental animals: 40 male C57BL / 6 mice, 8 weeks old, 22-24g

[0394] (2) Experimental materials: sodium dextran sulfate (DSS) (MP. Biomedicals, USA, catalog number: S7102); test compound control 1#, compound 6#; dimethyl sulfoxide (DMSO); Tween 80; Wahaha purified water

[0395] (3) Experimental protocol: Forty mice were randomly divided into four groups of ten each: a control group, a model group, a drug control group (1#), and a compound control group (6#). The control group had free access to distilled water, while the other three groups had free access to 2.5% DSS aqueous solution for eight consecutive days. The solution was checked daily and replaced with fresh DSS solution. On the first day of modeling, the mice were given drug treatment. The control group was given the corresponding saline solution, the enteritis model group was given the solvent system solution, and the drug control groups (1# and 6#) were administered the corresponding drug by gavage at a dose of 10 mg / kg. The weight of the mice was recorded daily, and their diarrhea and bloody stools were observed and scored. On the ninth day, the mice were sacrificed, and blood and colon samples were collected. The intestinal length and occult blood in the cecal contents were recorded.

[0396] Preparation method of test drug: Weigh 1.00 mg of drug powder, add 20 μL of DMSO, dissolve it completely, add 20 μL of Tween 80 and mix well, add 0.96 mL of Wahaha purified water, mix well to prepare a drug solution of 1 mg / mL, and administer at a dose of 0.1 mL / 10 g (body weight).

[0397] Solvent: Mix 20 μL DMSO + 20 μL Tween 80 + 0.96 mL Wahaha purified water (for the model group).

[0398] (4) Test results: such as Figure 3 As shown, the colon length statistics showed that both compound 6# and the control group 1# benzenemod could improve the colon length, and in terms of actual effect, compound 6# was better than the control group 1# benzenemod.

[0399] like Figure 4 Disease activity index (a comprehensive score based on weight change and rectal bleeding) data showed that both compound 6# group and control group 1# benzenemod had good therapeutic effects, with compound 6# group showing more significant effects.

[0400] 5. Effects on atopic dermatitis

[0401] (1) Construction of an atopic dermatitis model

[0402] Fifty-six clean-grade BALB / c mice, aged 6-8 weeks, were randomly divided into 7 groups of 8 mice each after a 5-day acclimatization period.

[0403] ① Blank control group

[0404] ② Modeling and Solvent Addition Group

[0405] ③ Modeling plus blank matrix group

[0406] ④ Modeling plus positive control drug mometasone furoate group

[0407] ⑤ Modeling with 1% benzene modium by mass

[0408] ⑥ Add 1.2% (by mass) of compound 2# (prepared using a blank matrix) to the model.

[0409] ⑦ Add 1.2% (by mass) of compound 6# (prepared using a blank matrix) to the model.

[0410]

[0411] As shown in the following steps, after hair removal with rosin and paraffin, 50 μL of 0.5% (w / v, solvent was a mixture of acetone and olive oil (acetone: olive oil = 3:1)) 2,4-dinitrofluorobenzene (DNFB) was applied to the back of each mouse. On days 4, 6, and 8, 50 μL of 0.25% (w / v) DNFB was administered in the morning. The blank control group received an equal amount of solvent. Animal experiments were conducted in accordance with the Guidelines for the Management and Use of Laboratory Animals of China Pharmaceutical University and met animal ethics standards.

[0412] Days

[0413] (2) Administration method

[0414] As shown in the steps above, apply the solvent control or DNFB in the morning to establish the model; starting from the 5th day, apply 50mg of the test drug ointment once every afternoon to ensure that the drug can be evenly applied to the skin surface. The specific administration method is as shown above.

[0415] The specific procedures are as shown in the groupings above. Group ② applied 50mg of solvent (acetone: olive oil = 3:1) once a day in the afternoon starting from day 5; Group ③ applied 50mg of blank matrix once a day in the afternoon starting from day 5; Groups ④, ⑤, ⑥, and ⑦ applied 50mg of positive control drug mometasone furoate, 1% benzylmod, 1.2% compound 2#, or 1.2% compound 6# respectively starting from day 5.

[0416] The severity of atopic dermatitis was assessed using the AD Score.

[0417] The severity of dermatitis appearance was evaluated using four indicators: ① erythema / bleeding ② dryness ③ exudation / scab formation ④ edema. Each indicator was scored from 0 to 3, and the scores of the four indicators were added together to obtain the total score. The AD Score scoring criteria are as follows: 0, no symptoms; 1, mild symptoms; 2, moderate symptoms; 3, severe symptoms. Photographs of the dorsal skin of each mouse were taken and scored on days 0, 4, 6, 8, and 10 after modeling.

[0418] Table 3 AD scores of mice in each group

[0419]

[0420]

[0421] Note: **: P < 0.01, vs. blank control group; a P < 0.05, vs solvent group (+DNFB); aa P < 0.01 vs. solvent group (+DNFB); b P < 0.05, vs. blank matrix (+DNFB); bb P < 0.01, vs blank matrix (+DNFB); analysis was performed using two-way ANOVA and Dunnett's double comparison test.

[0422] Surface observation image as follows Figure 5 As shown.

[0423] 6. Drug permeability test

[0424] Test Procedure

[0425] Test drugs: 1.2% (w / w) Compound 2# cream; 1.2% (w / w) Compound 6# cream; 1.0% (w / w) Benzenemod cream;

[0426]

[0427] (1) Preparation of semipermeable membrane: Take the prepared semipermeable membrane out of the refrigerator;

[0428] (2) Preparation of receiving solution: Measure 100 mL of polyethylene glycol 400 solution, add physiological saline to make up to 250 mL, mix well, store at 4℃, and preheat to 32℃ before each addition to the receiving cell.

[0429] (3) In vitro diffusion test: Using a transdermal drug diffusion apparatus, the prepared semipermeable membrane was fixed between the supply and receiving pools and circulated in a constant temperature water bath at 32℃. After equilibration for 30 minutes, the receiving solution was replaced to remove the air in the lower layer. Approximately 0.5g of cream was evenly added to the supply pool and spread evenly. The magnetic stirring speed was 600r / min. 1mL of sample solution was taken from the receiving pool at 0.5, 1, 2, 4, 6, and 24 hours, and an equal amount of isothermal fresh receiving solution was added at the same time.

[0430] The actual sampling times were 0.5, 1, 2, 4, 6, and 24 hours, with 1 mL samples directly placed into the liquid chromatography vial. An equal volume of fresh, isothermal receiving solution was added simultaneously. Drug permeation rate was calculated using liquid chromatography.

[0431] Cream - Diffusion Test - Rabbit Skin

[0432] Test Procedure

[0433] (1) Preparation of isolated rabbit skin

[0434] (2) Preparation of receiving solution: Measure 100 mL of polyethylene glycol 400 solution, add physiological saline to make up to 250 mL, mix well, store at 4℃, and preheat to 32℃ before each addition to the receiving pool.

[0435] (3) In vitro transdermal test: Using a transdermal drug diffusion tester, the treated rabbit skin was fixed between the supply and receiving pools, with the stratum corneum facing the supply pool. The skin was circulated in a constant temperature 32℃ water bath for 30 minutes to equilibrate. The receiving solution was then replaced, and the air under the skin was expelled. The surface liquid was blotted dry with filter paper. 0.5g of cream was added evenly to the supply pool and spread evenly. The mixture was magnetically stirred at 600r / min. At 0.5, 1, 2, 3, 4, 5, 7, 9, 12, and 24 hours, 1mL of sample solution was taken from the receiving pool and placed in a liquid chromatography vial. Simultaneously, an equal volume of fresh, isothermal receiving solution was added. The drug permeation rate was calculated using liquid chromatography.

[0436] The results of the 24-hour drug permeability test are as follows: Figure 6 As shown.

[0437] like Figure 6 As shown, in both experimental systems, the 24-hour drug permeation rates of the three creams showed a consistent trend: the marketed control drug benzenemod > 2# > 6#. The results indicate that the creams prepared from compounds 2# and 6# of this invention have lower transdermal absorption, lower blood exposure, and milder systemic adverse reactions compared to the marketed control drug benzenemod.

[0438] 7. Tests on psoriasis in mice

[0439] I. Evaluation of the efficacy of compound 6# against IMQ-induced psoriasis in mice.

[0440] Compound structure:

[0441]

[0442] II. Group Setup

[0443] (1) Vaseline + blank matrix group, 10 animals;

[0444] (2) IMQ + blank matrix group, 10 animals;

[0445] (3) IMQ+ compound group 6# (1.2% drug by mass fraction prepared with blank matrix), 10 animals.

[0446] IMQ: Imiquimod

[0447] III. Drug Preparation

[0448] IMQ: 5% imiquimod (imiquimod is used to induce psoriasis on the surface of mice).

[0449] Prepare 1.2% of compound 6# drug using a blank matrix.

[0450] IV. Animals

[0451] Species and strain: SPF grade, male KM mouse.

[0452] Weight: 35-40g

[0453] Source: Beijing Spaford Biotechnology Co., Ltd.

[0454] Rearing conditions: Air-conditioned room, temperature 18-26℃, relative humidity 20%-60%.

[0455] V. Experimental Procedure

[0456] Skin preparation: After the mice have free access to water and food and have been acclimatized in the animal room for 5 days, use clippers to remove hair from a 2cm x 2.5cm area on the back of the mice. Apply hair removal cream for 30 seconds to 1 minute, and then clean off the hair removal cream with a cotton ball.

[0457] Randomization: 24 hours after hair removal, 75 mice were randomly divided into 4 groups according to their body weight: Vaseline + blank matrix group (n=10), IMQ + blank matrix group (n=10), and IMQ + compound 6# group (1.2% drug prepared with blank matrix) (n=10).

[0458] Modeling and administration: In the morning, apply 62.5 mg of 5% imiquimod or petroleum jelly. In the afternoon, apply 62.5 mg of blank matrix or 1.2% compound #6 to the back.

[0459] Experimental record: Before modeling in the morning, observe the wrinkles, erythema and scales every day, record the scores and take photos, and calculate the PASI score of the mice.

[0460] Table 4 Scoring Criteria

[0461]

[0462] Table 5 PASI Score (Based on a comprehensive score of wrinkles, scales, and erythema)

[0463]

[0464] The statistical difference between IMQ+ compound 6# and IMQ+ blank matrix was calculated using the T-test method; *P<0.05, **P<0.01, ***P<0.001

[0465] The test results are shown in Table 5 above. Figure 7 As shown, the P-value of the IMQ+compound 6# of the present invention compared with the IMQ+blank matrix on the seventh day was 0.0002, indicating a significant difference. This means that the compound 6# of the present invention has a significantly better therapeutic effect than the modeling control group IMQ+blank matrix.

Claims

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof: （I） in, X is selected from F, and n is 1-3; R is selected from cyclopentyl or cyclohexyl; And when n is 1, X is in the opposite position; And when n is 2, X is a substitution for both positional and intermediate positions; When n is 3, X is either a transposition and a middle position substitution, or an adjacent, transposition and a middle position substitution.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the following compounds: ； ； ； ； 。 3. Use of at least one of the compounds of claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament; The drug is used to treat cancer, autoimmune disorders, and other conditions with immunological factors. Alternatively, the drug may be used to prevent and / or treat diseases or conditions mediated by aryl hydrocarbon receptors; Alternatively, the drug is used to regulate immune and inflammation-related cytokines selected from IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IL-22, IL-23, TNF-α, TGF-β, IFN-γ, and IL-1β; and is used to prevent and / or treat diseases caused by abnormalities of the aforementioned cytokines.

4. The use according to claim 3, wherein, The autoimmune disorders mentioned are selected from one or more of the following: psoriasis, eczema, atopic dermatitis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, chronic kidney disease, ankylosing spondylitis, Sjögren's syndrome, polymyositis, vasculitis, polymyalgia rheumatica, immune thrombocytopenic purpura, dry eye syndrome, type 1 diabetes mellitus, psoriasis, and arthritis.

5. The use according to claim 3, wherein, The diseases with immunological factors are selected from one or more of the following: asthma, allergic reactions, infections, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, and transplant rejection.

6. A pharmaceutical composition, wherein, The pharmaceutical composition comprises at least one of a pharmaceutically acceptable carrier or excipient, the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof.

7. A method for preparing the compound of claim 1 or 2, wherein, include: Compound IMe reacts with compound SMC to give compound IMf; compound IMf reacts under acidic conditions to give the compound shown in formula (I); Wherein X, n and R have the definitions described in claim 1 or 2.

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