Stilbene derivatives as AhR agonists and their use

Abstract

The present invention relates to stilbene derivatives as AhR activators and their use. The compounds of the present invention, their pharmaceutically acceptable salts, tautomers or stereoisomers have excellent AhR activating effects and can be safely used for the treatment of diseases or related conditions mediated by abnormal activation of AhR and related pathway targets. [Chemical 1] JPEG2025516369000086.jpg32169

Description

Detailed description of the invention

[0001] This application claims priority to a prior application filed with the China National Intellectual Property Administration on May 7, 2022, patent application number 202210489648.4, with the title of invention "Stilbene derivatives as AhR agonists and their use." The entire text of said prior application is incorporated herein by reference.

[0002] [Technical Field] This invention relates to the pharmaceutical field, and more specifically to stilbene derivatives as AhR agonists and their use.

[0003] [Background technology] The aromatic hydrocarbon receptor (aryl hydrocarbon receptor, AhR) is a member of the b-HLH-PAS (period-aryl hydrocarbon receptor nuclear translocator-single-minded, Pre-Arnt-Sim) subfamily of the basic helix-loop-helix (b-HLH) superfamily. It is distributed in various tissues and cells of the body, and is most highly expressed in the spleen, stomach, ovaries, and placenta, as well as in immune cells, particularly some hematopoietic stem cells, bone marrow-derived dendritic cells, and CD4 + Several CD4 cells, such as Th17 cells + It is most highly expressed in T cell subpopulations, while in B cells and CD4 + It is expressed at the lowest levels in Treg cells. Overactivation of Th17 cells and increased secretion of IL-17 are associated with various chronic inflammatory and autoimmune diseases in the body, 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 diseases. Studies have demonstrated that the balance of both Th17 and Treg cells plays a vital role in host immunity and resistance. For example, studies have shown that the pathogenesis of ulcerative colitis (UC) is closely related to Th17 / Treg imbalance.

[0004] As the research on AhR progresses intensively, it has been found that the imbalance of Th17 / Treg differentiation may be related to AhR in the body. AhR is a cytoplasmic transcription factor involved in the regulation of drug metabolism, cell growth and differentiation, and is closely related to the onset of immune-responsive diseases and inflammatory diseases in the body. Activated AhR can regulate the differentiation of Th17 and Treg in the body. A number of experiments have demonstrated that AhR is related to the onset of biological immune diseases such as asthma, smoking-related lung inflammatory diseases, atopic dermatitis, chronic kidney diseases, Sjogren's syndrome, and inflammatory bowel diseases.

[0005] Common AhR agonists include ITE, TCDD, and FICZ. Among them, TCDD, as the earliest discovered AhR agonist, can regulate the balance of T cell differentiation, but its clinical application is limited due to its toxicity in the environment and the body. Benvitimod is the first commercially available aromatic hydrocarbon receptor agonist drug. As a new generation of anti-inflammatory drug, it can be used for the treatment of various severe autoimmune diseases such as psoriasis, eczema, ulcerative colitis, and various allergies. As the first commercially available AhR agonist drug, the activity of Benvitimod still has room for improvement. In addition, Benvitimod is easily oxidized under light and difficult to preserve. Therefore, new improved compounds and compositions with improved action effects, bioavailability, and stability are expected for clinical application.

[0006] 〔Summary of the Invention〕 To solve the above technical problems, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0007]

Chemical formula

[0008] Among them, X is selected from halogens, n is an integer from 1 to 5, preferably X is F or Cl, or X is polysubstituted with F and Cl, R is selected from substituted or unsubstituted 3- to 7-membered cycloalkyl or cycloalkenyl groups, or substituted or unsubstituted 3- to 7-membered heterocyclyl groups, and the substituent is, for example, C 1-6 Alkyl alkyl group, C 1-6 Examples include alkoxy groups and halogens.

[0009] In some embodiments, X is one, two, or more of the ortho substitutions, meta substitutions, and para substitutions.

[0010] In some embodiments, X is monosubstituted F, Cl, or Br.

[0011] In some embodiments, X is a disubstituted or trisubstituted F.

[0012] In some embodiments, X is F and n is 1.

[0013] In some embodiments, the substituted or unsubstituted 3- to 7-membered heterocyclyl group is an N-containing heterocyclyl group, and the substitution is C 1-6 Alkyl alkyl group, C 1-6 It is substituted with at least one of an alkoxy group or a halogen.

[0014] In some embodiments, the substituted or unsubstituted 3- to 7-membered cycloalkyl group is a cyclopentyl group or a cyclohexyl group.

[0015] In some specific embodiments, the compound of formula (I) is selected from the following compounds.

[0016] [ka] JPEG0007898766000003.jpg29169

[0017] The present invention further provides compounds of formula (II) or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof.

[0018] [ka]

[0019] The present invention further provides the use of compounds of formula (I), formula (II), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof in the manufacture of drugs for treating cancer, autoimmune deficiency, and other diseases having immunological factors.

[0020] According to embodiments of the present invention, the autoimmune deficiency disease is one or more selected from 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 thrombocytopenia, dry eye, type 1 diabetes mellitus, psoriasis, and arthritis.

[0021] According to embodiments of the present invention, the disease having the above-mentioned immunological factors is one or more selected from asthma, allergy, infectious disease, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, and transplant rejection.

[0022] The present invention further provides the use of compounds of formula (I), formula (II) or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof in the manufacture of drugs for the prevention and / or treatment of diseases or conditions mediated by aryl hydrocarbon acceptors (AhRs).

[0023] The present invention further provides the use of compounds of formula (I), formula (II), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof in the manufacture of drugs for regulating 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, TNFα, TGF-β, IFN-γ, IL-1β, etc., and for preventing and / or treating diseases caused by abnormalities of the above cytokines.

[0024] The present invention further provides pharmaceutical compositions comprising a compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable auxiliary agent such as a carrier or excipient.

[0025] The present invention further provides a method for treating and / or preventing aryl hydrocarbon receptor (AhR)-mediated symptoms or diseases, comprising administering a therapeutically effective amount of a compound represented by formula (I), formula (II) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof to a target.

[0026] The present invention further provides a method for producing the compound represented by formula (I), Compound IMe is reacted with compound SMc to obtain compound IMf, and compound IMf is reacted under acidic conditions to obtain the compound shown in formula (I).

[0027] [ka]

[0028] Among them, X is selected from halogens, and n is an integer from 1 to 5. R is selected from substituted or unsubstituted 3- to 7-membered cycloalkyl or cycloalkenyl groups, or substituted or unsubstituted 3- to 7-membered heterocyclyl groups.

[0029] Furthermore, the manufacturing route for compound IMe is as follows:

[0030] [ka]

[0031] R is selected from substituted or unsubstituted 3- to 7-membered cycloalkyl or cycloalkenyl groups, or substituted or unsubstituted 3- to 7-membered heterocyclyl groups.

[0032] Explanation of terms The "3- to 7-membered cycloalkyl or cycloalkenyl group" described in the present invention includes, but is not limited to, "3- to 7-membered monocyclic cycloalkyl or monocyclic cycloalkenyl groups." Specific examples include, but are not limited to, substituted or unsubstituted cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclopentenyl groups, cyclohexyl groups, cyclohexenyl groups, cycloheptyl groups, cycloheptenyl groups, etc.

[0033] The "3- to 7-membered heterocyclyl group" described in the present invention refers to a saturated or partially saturated monocyclic cyclic group having 3 to 7 ring atoms and containing at least one heteroatom (for example, 1, 2, 3, or 4), wherein the heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom.

[0034] The term "stereoisomer" as used in this invention means that if the compound of the present invention contains one or more chiral centers, it can exist as a racemate and racemic mixture, a single enantiomer, a diastereomer mixture, and a single diastereomer. The compound of the present invention may have chiral centers that independently produce two optical isomers. The scope of this invention includes all possible optical isomers and mixtures thereof.

[0035] "Pharmacopoeia-acceptable carriers (medicinal carriers)" refers to carriers that can be used in the manufacture of pharmaceutical compositions, which are generally compatible with other components of the composition, harmless to the subject, and not biologically undesirable or undesirable in other embodiments. "Pharmacopoeia-acceptable carriers" include one and / or more types of carriers. Embodiments include carriers for topical, ocular, extra-gastrointestinal, intravenous, intramuscular, sublingual, nasal, and oral administration. "Pharmacopoeia-acceptable carriers" further include reagents for manufacturing aqueous dispersions and sterile powders for injection or dispersion.

[0036] As used herein, “excipient” includes physiologically compatible additives that can be used to manufacture pharmaceutical compositions. Examples of pharmaceutically acceptable carriers and excipients can be found, for example, in Remington Pharmaceutical Science (16th edition).

[0037] Beneficial effects Compared to the prior art, the advantages of the present invention are as follows:

[0038] (1) The compounds of the present invention, their pharmaceutically acceptable salts, tautomers, or stereoisomers have excellent AhR agonist activity and can be safely used to treat diseases or related conditions mediated by abnormal AhR activation. When the AhR agonist activity of the compounds of the present invention was tested at concentrations that did not significantly affect HepG2 cell activity, the AhR agonist activity of the compounds of the present invention was 2 to 9 times that of benbitimod or FICZ-positive control agents, demonstrating good efficacy in treating diseases or related conditions mediated by abnormal AhR activation. In a DSS mouse ulcerative colitis model, the recovery effect at a dose of 10 mg / kg after administration of the compounds of the present invention was superior to that of the control group.

[0039] (2) The compounds of the present invention, their pharmaceutically acceptable salts, tautomers, or stereoisomers have good biological and metabolic stability, exhibit good pharmacokinetic properties, and have good prospects for clinical application.

[0040] (3) The compounds of the present invention, their pharmaceutically acceptable salts, or their stereoisomers exhibit relatively low toxicity, excellent drug resistance, and high safety.

[0041] (4) The compounds of the present invention are highly stable, less susceptible to chemical decomposition reactions such as hydrolysis and oxidation, and do not show discoloration or increase in impurities even when left at room temperature for a long time. In particular, there is no need to store them in the dark, and the photodecomposition phenomenon under light irradiation conditions is significantly reduced compared to benbitimod.

[0042] [Brief explanation of the drawing] [Figure 1] This figure shows the results of the effect of the test compound on PBMC cell activity at a concentration of 1 μM.

[0043] [Figure 2] This figure shows the results of the effect of the test compound on HepG2 cell activity at a concentration of 1 μM.

[0044] [Figure 3] Results of the effect of the test compound on colon length in a DSS mouse ulcerative colitis model (comparison with the normal blank group is **p<0.01, and comparison with the model group is #p<0.05).

[0045] [Figure 4] This figure shows the effect of the test compound on the disease activity index in a DSS mouse model of ulcerative colitis (comparison with the normal blank group is **p<0.01, comparison with the model group is #p<0.05, ##p<0.01).

[0046] [Figure 5] Observations of the dorsal surface of each group of mice.

[0047] [Figure 6] This shows the detection results of drug permeability over 24 hours.

[0048] [Figure 7] PASI score chart.

[0049] [Modes for carrying out the invention] The technical aspects of the present invention will be described in more detail below, in accordance with specific embodiments. The embodiments described below are merely illustrative and interpretable to illustrate the present invention, and should not be interpreted as limiting the scope of the claims. Any technology realized based on the above-described aspects of the present invention falls within the scope of the claims according to the present invention.

[0050] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available or can be manufactured by known methods.

[0051] Example 1 The following method provides a detailed explanation of the preparation of the compounds of the present invention, and the compounds of the present invention and the comparative examples can be prepared using raw materials and reagents known or commercially available to those skilled in the field of organic synthesis.

[0052] The following synthesis method is a specific synthesis route for the compound of formula (I) of the present invention.

[0053] [ka]

[0054] Of these, X is selected from halogens, n is an integer from 1 to 5, preferably X is F or Cl, or X is a polysubstituted form of F and Cl. R is selected from substituted or unsubstituted 3- to 7-membered cycloalkyl or cycloalkenyl groups, or substituted or unsubstituted 3- to 7-membered heterocyclyl groups.

[0055] Example 2 Synthesis of 4-cyclopentyl-3,5-dimethoxybenzylphosphonate diethyl (1) Synthesis of 4-cyclopentyl-3,5-dimethoxybenzoic acid

[0056] [ka]

[0057] 20.07 g, 102.29 mmol of methyl 3,5-dimethoxybenzoate was added to a necked flask, and concentrated sulfuric acid (50 mL) was added. The mixture was stirred to dissolve the methyl methyl 3,5-dimethoxybenzoate. Cyclopentanol (21.95 g, 254.82 mmol) was added dropwise to the necked flask using an ice bath. After adding the cyclopentanol, the ice bath was removed, the temperature was raised to 70°C, and the reaction was allowed to proceed for 4 hours. The reaction was monitored using a spotted TLC plate to confirm that the starting materials had reacted completely, and then the reaction was stopped. 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 was complete, the solution was concentrated under reduced pressure to remove ethyl acetate, yielding a brown solid (24.76 g) of crude 4-cyclopentyl-3,5-dimethoxybenzoic acid. The yield was 96.7%.

[0058] (2) Synthesis of methyl 4-cyclopentyl-3,5-dimethoxybenzoate

[0059] [ka]

[0060] 4-cyclopentyl-3,5-dimethoxybenzoic acid (24.76 g, 98.92 mmol) was added to a necked flask, methanol (50 mL) was added, and the mixture was stirred to dissolve. Thionyl chloride (17.65 g, 148.39 mmol) was added dropwise to the necked flask in an ice bath, and white fumes were generated. After adding the thionyl chloride, the ice bath was removed, the temperature was raised to 60°C, and the reaction was allowed to proceed for 1 hour. The reaction was monitored using a spotted TLC plate to confirm that the starting materials had reacted completely, and then the reaction was stopped. 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 ethyl acetate phases were combined, washed with saturated sodium chloride solution (100 mL), and dried over anhydrous sodium sulfate. After drying, the mixture was concentrated under reduced pressure to remove ethyl acetate, yielding a black solid (25.95 g) of crude methyl 4-cyclopentyl-3,5-dimethoxybenzoate. The yield was 99.2%.

[0061] Methyl 4-cyclopentyl-3,5-dimethoxybenzoate was purified by column chromatography using a mobile phase of petroleum ether:ethyl acetate = 15:1. The mobile phase was concentrated until dry to obtain a yellow solid (18.54 g) of pure methyl 4-cyclopentyl-3,5-dimethoxybenzoate. The purification yield was 71.4%.

[0062] (3) Synthesis of 4-cyclopentyl-3,5-dimethoxybenzyl alcohol

[0063] [ka]

[0064] 4-cyclopentyl-3,5-dimethoxybenzoate methyl (18.54 g, 70.14 mmol) was added to a necked flask, tetrahydrofuran (50 mL) was added, and the mixture was stirred to dissolve. In an ice bath, aluminum lithium hydride (3.99 g, 105.21 mmol) was added to the necked flask in several batches, generating a large amount of bubbles. After adding the aluminum lithium hydride, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 1.5 hours. The reaction was monitored using a spotted TLC plate, and after confirming that the starting materials had reacted completely, the reaction was stopped. In an ice bath, water (3.99 mL), 15% sodium hydroxide solution (3.99 mL), and water (11.97 mL) were added dropwise to the necked flask, one drop at a time, and the mixture was stirred for 30 minutes, producing a large amount of white solid. The mixture was filtered through diatomaceous earth to remove the white precipitate, and the filtrate was collected. The precipitate was washed with a small amount of tetrahydrofuran, filtered, and the washing solution was collected. The filtrate and washings were combined and concentrated under reduced pressure to remove tetrahydrofuran. Extraction was performed three times with ethyl acetate (50 mL) and water (50 mL). The ethyl acetate phase was combined, 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 obtain a brown solid (15.37 g) of crude 4-cyclopentyl-3,5-dimethoxybenzyl alcohol. The yield was 92.7%.

[0065] (4) Synthesis of 4-cyclopentyl-3,5-dimethoxybenzyl chloride

[0066] [ka]

[0067] 4-cyclopentyl-3,5-dimethoxybenzyl alcohol (15.37 g, 65.04 mmol) was added to a necked flask, and dichloromethane (30 mL) was added. The mixture was stirred to dissolve. In an ice bath, thionyl chloride (11.61 g, 97.56 mmol) was added dropwise to the necked flask, and white fumes were generated. After adding thionyl chloride, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored using a spotted TLC plate to confirm that the starting materials had reacted completely, and then the reaction was stopped. 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 ethyl acetate phase was combined, 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, and a crude black oily substance (15.14 g) of 4-cyclopentyl-3,5-dimethoxybenzyl chloride was obtained. The yield was 91.4%.

[0068] 4-Cyclopentyl-3,5-dimethoxybenzyl chloride was purified by column chromatography using a mobile phase of petroleum ether:ethyl acetate = 100:1. The mobile phase was concentrated until dry to obtain a yellow solid (12.60 g) of pure 4-cyclopentyl-3,5-dimethoxybenzyl chloride. The purification yield was 83.2%.

[0069] (5) Synthesis of 4-cyclopentyl-3,5-dimethoxybenzylphosphonate diethyl

[0070] [ka]

[0071] 4-cyclopentyl-3,5-dimethoxybenzyl chloride (12.60 g, 49.46 mmol) was added to a necked flask, and triethyl phosphite (49.31 g, 296.76 mmol) was added and stirred until dissolved. The mixture was purged with nitrogen gas three times. The reaction mixture was heated to 160°C and allowed to react for 5 hours. The reaction was monitored using a spotted plate to confirm that the starting materials had reacted completely. After stopping the reaction and removing the solvent, 4-cyclopentyl-3,5-dimethoxybenzylphosphonate diethyl (16.75 g) was obtained. The yield was 95%.

[0072] Example 3 Synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol (1) Synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene

[0073] [ka]

[0074] Diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (1.01 g, 2.83 mmol) was added to a three-necked flask, and tetrahydrofuran (15 mL) was added. The mixture was stirred in an ice bath and dissolved. Under nitrogen gas protection, sodium hydride (452.5 mg, 11.31 mmol) was added to the three-necked flask in several portions. After the addition was complete, the mixture was allowed to react for 1 hour. A solution of benzaldehyde (4.24 mmol) in tetrahydrofuran (450.2 mg of benzaldehyde dissolved in 10 mL of tetrahydrofuran) was gradually added dropwise to the three-necked flask. After the addition was complete, the ice bath was removed, and the temperature was gradually raised to 70°C and the mixture was allowed to react for 4 hours. The reaction was monitored using a spotted TLC plate. After the starting materials had completely reacted, the mixture was cooled to room temperature. Water was added to the three-necked flask in an ice bath and quenched until no more gas was produced. The mixture was then concentrated under reduced pressure to remove the tetrahydrofuran. Extraction was performed three times with ethyl acetate (30 mL) and water (30 mL). The ethyl acetate phase was combined, washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. After drying, the solution was concentrated under reduced pressure to remove the ethyl acetate and obtain a crude yellow oily substance (804.6 mg) which is (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene.

[0075] (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene was purified by column chromatography using a mobile phase of petroleum ether:ethyl acetate = 50:1. The mobile phase was concentrated until dry to obtain a yellow solid (403.2 mg) of pure (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene. The yield was 46.2%.

[0076] (2) Synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol

[0077] [ka]

[0078] (E)-2-Cyclopentyl-1,3-dimethoxy-5-styrylbenzene (403.2 mg, 1.31 mmol) and pyridinium hydrochloride (3.02 g, 26.15 mmol) were added to a one-neck flask. The flask was purged with nitrogen gas three times. The temperature was gradually raised to 210 °C. After pyridinium hydrochloride melted, the mixture was kept at this temperature for 4 h. The reaction was monitored by spotting on a TLC plate. After confirming that the raw material had completely reacted, the reaction was stopped. The reaction solution was cooled to room temperature and extracted 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 solution was concentrated under reduced pressure to remove ethyl acetate, and the crude product (E)-2-cyclopentyl-5-styryl-1,3-benzenediol (305.4 mg) was obtained.

[0079] (E)-2-Cyclopentyl-5-styryl-1,3-benzenediol was purified by column chromatography with a mobile phase of petroleum ether:ethyl acetate = 30:1. The mobile phase was concentrated until dry, and a brown solid (145.1 mg) of pure (E)-2-cyclopentyl-5-styryl-1,3-benzenediol was obtained. The yield was 39.6%.

[0080] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 16.0 Hz, 1H), 6.89 (d, J = 16.0 Hz, 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 [M-H] - .

[0081] Example 4 Synthesis of (E)-2-Cyclopentyl-5-(4-fluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene

[0082] [ka]

[0083] Referring to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the starting materials 4-cyclopentyl-3,5-dimethoxybenzylphosphonate diethyl (1.01 g, 2.83 mmol) and p-fluorobenzaldehyde (525.7 mg, 4.24 mmol) were reacted, and the product (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene (252 mg) was obtained by purification. The yield was 27.2%.

[0084] (2) Synthesis of (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-benzenediol

[0085] [ka]

[0086] Referring to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the starting material (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene (252.5 mg, 0.77 mmol) was reacted, and the product (E)-2-cyclopentyl-5-(4-fluorostyryl)-1,3-benzenediol (103.3 mg) was obtained by purification. The yield was 44.8%.

[0087] 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 2H), 7.64-7.61 (m, 2H), 7.21-7.16 (m, 2H), 6.97 (d, J = 16.0 Hz, 1H), 6.88 (d, J = 16.0 Hz, 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] - .

[0088] Example 5 Synthesis of (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene

[0089] [ka]

[0090] Referring to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the starting material 4-cyclopentyl-3,5-dimethoxybenzylphosphonate diethyl (1.01 g, 2.83 mmol) was reacted with p-chlorobenzaldehyde (593.6 mg, 4.24 mmol), and the product (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene (451.3 mg) was obtained by purification. The yield was 46.5%.

[0091] (2) Synthesis of (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-benzenediol

[0092] [ka]

[0093] Referring to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the starting material (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene (451.3 mg, 1.32 mmol) was reacted, and the product (E)-2-cyclopentyl-5-(4-chlorostyryl)-1,3-benzenediol (251.3 mg) was obtained by purification. The yield was 60.6%.

[0094] 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 16.0 Hz, 1H), 7.88 (d, J = 16.0 Hz, ESI-MS m / z 313.1 [MH] - .

[0095] Example 6 Synthesis of (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-dimethoxybenzene

[0096] [ka]

[0097] Referring to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the starting material 4-cyclopentyl-3,5-dimethoxybenzylphosphonate diethyl (1.01 g, 2.83 mmol) was reacted with p-bromobenzaldehyde (784.4 mg, 4.24 mmol), and the product (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-dimethoxybenzene (521.7 mg) was obtained by purification. The yield was 47.4%.

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

[0099] [ka]

[0100] Referring to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the starting material (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-dimethoxybenzene (521.7 mg, 1.35 mmol) was reacted, and the product (E)-2-cyclopentyl-5-(4-bromostyryl)-1,3-benzenediol (215.2 mg) was obtained by purification. The yield was 44.5%.

[0101] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 7.53 (s, 2H), 7.05 (d, J = 16.0 Hz, 4H), 6.85 (d, J = 16.0 Hz, 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 / z 357.0 [MH] - .

[0102] Example 7 Synthesis of 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1) Synthesis of 4-cyclohexyl-3,5-dimethoxybenzoic acid

[0103] [ka]

[0104] 20.12 g, 102.55 mmol of methyl 3,5-dimethoxybenzoate and 50 mL of concentrated sulfuric acid were added to a necked flask and stirred to dissolve. Cyclohexanol (25.68 g, 256.37 mmol) was added dropwise to the necked flask using an ice bath. After the addition was complete, the ice bath was removed and the temperature was gradually raised to 70°C for 4 hours. The reaction was monitored using a spotted TLC plate to confirm that the starting materials had reacted completely, and then the reaction was stopped. 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 solution 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 solution was concentrated under reduced pressure to remove ethyl acetate, yielding a brown solid (27.10 g) of crude 4-cyclohexyl-3,5-dimethoxybenzoic acid. The yield was 100.0%.

[0105] (2) Synthesis of methyl 4-cyclohexyl-3,5-dimethoxybenzoate

[0106] [ka]

[0107] 4-cyclohexyl-3,5-dimethoxybenzoic acid (27.10 g, 102.53 mmol) and methanol (50 mL) were added to a necked flask and stirred to dissolve. Thionyl chloride (18.29 g, 153.79 mmol) was added dropwise to the necked flask in an ice bath, and white fumes were generated. After adding the thionyl chloride, the ice bath was removed, and the temperature was raised to 60°C and the reaction was allowed to proceed for 1 hour. The reaction was monitored using a spotted plate to confirm that the starting materials had reacted completely, and then the reaction was stopped. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove methanol and excess thionyl chloride. Extraction was performed three times with ethyl acetate (150 mL) and water (150 mL). The ethyl acetate phases were combined, washed with saturated sodium chloride solution (100 mL), and dried over anhydrous sodium sulfate for 5 hours. After drying was complete, the solution was concentrated under reduced pressure to remove ethyl acetate, yielding a black solid (28.23 g) of crude methyl 4-cyclohexyl-3,5-dimethoxybenzoate. The yield was 98.9%.

[0108] Methyl 4-cyclohexyl-3,5-dimethoxybenzoate was purified by column chromatography using a mobile phase of petroleum ether:ethyl acetate = 15:1. The mobile phase was concentrated until dry to obtain a yellow solid (19.51 g) of pure methyl 4-cyclohexyl-3,5-dimethoxybenzoate. The purification yield was 69.1%.

[0109] (3) Synthesis of 4-cyclohexyl-3,5-dimethoxybenzyl alcohol

[0110] [ka]

[0111] 4-cyclohexyl-3,5-dimethoxybenzoate methyl (27.10 g, 97.36 mmol) and tetrahydrofuran (271 mL) were added to a necked flask and stirred until dissolved. In an ice bath, aluminum tetrahydrogen lithium (7.4 g, 194.73 mmol) was gradually added in several portions. After the addition was complete, the ice bath was removed, the temperature was raised to room temperature, and the reaction was allowed to proceed for 1 hour. The reaction was then monitored using a spotted plate to confirm that the starting materials had reacted completely, and the reaction was stopped. Water was added to the reaction solution in an ice bath to quench the aluminum tetrahydrogen lithium until the solution turned grayish-white, and the solution was filtered by suction. The filtrate was extracted three times with ethyl acetate (150 mL) and water (150 mL). The ethyl acetate phase was combined, washed with saturated sodium chloride solution (100 mL), and dried over anhydrous sodium sulfate. After drying was complete, the solution was concentrated under reduced pressure to remove ethyl acetate, yielding a pale yellow solid (20.23 g) of crude 4-cyclohexyl-3,5-dimethoxybenzyl alcohol, with a yield of 83%.

[0112] Methyl 4-cyclohexyl-3,5-dimethoxybenzoate was purified by column chromatography using a mobile phase of petroleum ether:ethyl acetate = 15:1. The mobile phase was concentrated until dry to obtain a white solid (16.13 g) of pure methyl 4-cyclohexyl-3,5-dimethoxybenzoate. The purification yield was 66.2%.

[0113] (4) Synthesis of 4-cyclohexyl-3,5-dimethoxybenzyl chloride

[0114] [ka]

[0115] 4-cyclohexyl-3,5-dimethoxybenzyl alcohol (16.13 g, 64.43 mmol) and dichloromethane (30 mL) were added to a necked flask and stirred until dissolved. Thionyl chloride (11.50 g, 96.65 mmol) was added dropwise to the necked flask in an ice bath, and white fumes were generated. After adding the thionyl chloride, the ice bath was removed and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored using a spotted plate to confirm that the starting materials had reacted completely, and then the reaction was stopped. The reaction mixture was concentrated under reduced pressure to remove dichloromethane and excess thionyl chloride. Extraction was performed three times with ethyl acetate (50 mL) and water (50 mL). The ethyl acetate phases were combined, washed with saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. After drying was complete, the mixture was concentrated under reduced pressure to remove ethyl acetate, yielding a crude 4-cyclohexyl-3,5-dimethoxybenzyl chloride product, a black oily substance (15.22 g), with a yield of 87.9%.

[0116] 4-Cyclohexyl-3,5-dimethoxybenzyl chloride was purified by column chromatography using a mobile phase of petroleum ether:ethyl acetate = 100:1. The mobile phase was concentrated until dry to obtain a yellow solid (11.81 g) of pure 4-cyclohexyl-3,5-dimethoxybenzyl chloride. The purification yield was 77.6%.

[0117] (5) Synthesis of 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl

[0118] [ka]

[0119] 4-cyclohexyl-3,5-dimethoxybenzyl chloride (11.81 g, 43.94 mmol) was added to a necked flask, and triethyl phosphite (43.80 g, 263.63 mmol) was added and stirred until dissolved. The mixture was purged with nitrogen gas three times. The reaction mixture was gradually heated to 160°C and allowed to react for 5 hours. The reaction was monitored on a spotted TLC plate to confirm that the starting materials had reacted completely, after which the reaction was stopped and the mixture was cooled to room temperature. After removing the solvent by concentrating under reduced pressure, the crude product was slurryed three times with n-hexane (100 mL) to obtain a pale yellow solid (15.62 g) of 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl. The yield was 95.9%.

[0120] Example 8 Synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene

[0121] [ka]

[0122] Diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.08 g, 2.92 mmol) and tetrahydrofuran (15 mL) were added to a three-necked flask and stirred to dissolve. The mixture was purged with nitrogen gas three times. 60% sodium hydride (466.5 mg, 11.66 mmol) was added to the three-necked flask in several portions in an ice bath, and the mixture was allowed to react for 1 hour after completion. A solution of benzaldehyde (4.37 mmol) in tetrahydrofuran (464.1 mg of benzaldehyde dissolved in 10 mL of tetrahydrofuran) was gradually added dropwise to the three-necked flask, and after completion, the temperature was gradually raised to 70°C and the mixture was allowed to react for 4 hours. The reaction was monitored using a spotted TLC plate, and after confirming that the starting materials had reacted completely, the reaction was stopped. The reaction was quenched in an ice bath by adding water to the three-necked flask until no more gas was produced, and the mixture was concentrated under reduced pressure to remove the tetrahydrofuran. The solution was extracted three times with ethyl acetate (30 mL) and water (30 mL). The ethyl acetate phase was combined, washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. After drying, the solution was concentrated under reduced pressure to remove the ethyl acetate, yielding a crude yellow oily substance (625.2 mg) which was (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene.

[0123] (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene was purified by column chromatography using a mobile phase of petroleum ether:ethyl acetate = 50:1. The mobile phase was concentrated until dry to obtain a yellow solid (451.1 mg) of pure (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene. The yield was 48.0%.

[0124] (2) Synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol

[0125] [ka]

[0126] (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene (451.1 mg, 1.40 mmol) was added to a necked flask, and pyridine hydrochloride (3.23 g, 27.98 mmol) was added. The mixture was purged with nitrogen gas three times. The temperature was gradually increased to 210°C, and after the pyridine hydrochloride melted, the reaction was allowed to proceed for 4 hours. The reaction was monitored using a spotted TLC plate to confirm that the starting materials had reacted completely, and then the reaction was stopped. The reaction mixture was cooled to room temperature and allowed to solidify, and extracted three times with ethyl acetate (30 mL) and water (30 mL). The ethyl acetate phase was combined, washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. After drying, the mixture was concentrated under reduced pressure to remove the ethyl acetate and obtain the crude product of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol (215.9 mg).

[0127] (E)-2-cyclohexyl-5-styryl-1,3-benzenediol was purified by column chromatography using a mobile phase of petroleum ether:ethyl acetate = 30:1. The mobile phase was concentrated until dry to obtain pure (E)-2-cyclohexyl-5-styryl-1,3-benzenediol (109.3 mg). The yield was 26.5%.

[0128] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 8.0 Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 16.0 Hz, 1H), 6.87 (d, J = 16.0 Hz, 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] - .

[0129] Example 9 (E) Synthesis of 2-2-cyclohexyl-5-(4-fluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene

[0130] [ka]

[0131] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.08 g, 2.92 mmol) and p-fluorobenzaldehyde (525.7 mg, 4.24 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene (483 mg) was obtained by purification. The yield was 48.7%.

[0132] (2) Synthesis of (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-benzenediol

[0133] [ka]

[0134] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene (483.7 mg, 1.42 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(4-fluorostyryl)-1,3-benzenediol (171.8 mg) was obtained by purification. The yield was 38.7%.

[0135] 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 2H), 7.64-7.61 (m, 2H), 7.20-7.17 (m, 2H), 6.96 (d, J = 16.0 Hz, 1H), 6.87 (d, J = 16.0 Hz, 1H), 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] - .

[0136] Example 10 Synthesis of (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene

[0137] [ka]

[0138] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.08 g, 2.92 mmol) and p-chlorobenzaldehyde (593.6 mg, 4.24 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene (475.0 mg) was obtained by purification. The yield was 45.6%.

[0139] (2) Synthesis of (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-benzenediol

[0140] [ka]

[0141] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-dimethoxybenzene (475 mg, 1.33 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(4-chlorostyryl)-1,3-benzenediol (163.6 mg) was obtained by purification. The yield was 37.5%.

[0142] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.87 (d, J = 16.0 Hz, ESI-MS m / z 327.0 [MH] - .

[0143] Example 11 (E) Synthesis of 2-2-cyclohexyl-5-(4-bromostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-dimethoxybenzene

[0144] [ka]

[0145] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.08 g, 2.92 mmol) and p-bromobenzaldehyde (784.4 mg, 4.24 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-dimethoxybenzene (625.3 mg) was obtained by purification. The yield was 53.4%.

[0146] (2) Synthesis of (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-benzenediol

[0147] [ka]

[0148] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-dimethoxybenzene (625.3 mg, 1.56 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(4-bromostyryl)-1,3-benzenediol (194.0 mg) was obtained by purification. The yield was 33.4%.

[0149] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 2H), 7.53 (s, 4H), 7.04 (d, J = 16.0 Hz, 1H), 6.85 (d, J = 16.0 Hz, 1H), 6.47 (s, 2H), 3.08-3.02 (m, ESI-MS m / z 371.0 [MH] - .

[0150] Example 12 Synthesis of (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene

[0151] [ka]

[0152] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 3-fluorobenzaldehyde (502.6 mg, 4.05 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene (470.0 mg) was obtained by purification. The yield was 51.1%.

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

[0154] [ka]

[0155] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene (470 mg, 1.38 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(3-fluorostyryl)-1,3-benzenediol (150 mg) was obtained by purification. The yield was 34.8%.

[0156] 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 2H), 7.80 (t, J = 7.5 Hz, 1H), 7.34 - 7.27 (m, 1H), 7.21 (dd, J = 5.7 Hz, 2H), 7.04 (dd, J = 16.4 Hz, 2H), 6.50 (s, 2H), 3.06 (t, J = 11.5 Hz, 1H), 2.10 (dd, J = 11.5 Hz, 2H), 1.70 (dd, J = 9.2 Hz, 3H), 1.43 (d, J = 11.6 Hz, 2H), 1.36 - 1.12 (m, 3H). ESI-MS m / z 311.1 [MH] - .

[0157] Example 13 (E) Synthesis of 2-2-cyclohexyl-5-(2-fluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene

[0158] [ka]

[0159] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 2-fluorobenzaldehyde (502.6 mg, 4.05 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene (450 mg) was obtained by purification. The yield was 49.0%.

[0160] (2) Synthesis of (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-benzenediol

[0161] [ka]

[0162] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene (450 mg, 1.32 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(2-fluorostyryl)-1,3-benzenediol (170 mg) was obtained by purification. The yield was 41.2%.

[0163] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 7.61 (dd, J = 5.6 Hz, 2H), 7.18 (t, J = 8.8 Hz, 2H), 6.91 (q, J = 16.3 Hz, 2H), 6.46 (s, 2H), 3.05 (t, J = 12.1 Hz, 1H), 2.10 (dd, 12.1 Hz, 2H), 1.70 (dd, J = 10.1 Hz, 4H), 1.42 (d, J = 12.5 Hz, 2H), 1.34 - 1.17 (m, 2H). ESI-MS m / z 311.1 [MH] - .

[0164] Example 14 Synthesis of (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene

[0165] [ka]

[0166] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 2-chlorobenzaldehyde (569.2 mg, 4.05 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene (480 mg) was obtained by purification. The yield was 49.8%.

[0167] (2) Synthesis of (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-benzenediol

[0168] [ka]

[0169] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene (480 mg, 1.34 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(2-chlorostyryl)-1,3-benzenediol (170 mg) was obtained by purification. The yield was 38.4%.

[0170] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 2H), 7.67 (dd, J = 5.6 Hz, 2H), 7.53 (t, J = 8.8 Hz, 2H), 7.37 (q, J = 16.3 Hz, 2H), 7.10 (s, 2H), 3.13 (t, J = 12.1 Hz, 1H), 2.26 (dd, 12.1 Hz, 2H), 2.10 (dd, J = 10.1 Hz, 4H), 1.72 (d, J = 12.5 Hz, 2H), 1.64 - 1.37 (m, 2H). ESI-MS m / z 327.1 [MH] - .

[0171] Example 15 Synthesis of (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene

[0172] [ka]

[0173] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 3-chlorobenzaldehyde (569.2 mg, 4.05 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene (475 mg) was obtained by purification. The yield was 49.3%.

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

[0175] [ka]

[0176] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene (475 mg, 1.33 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(3-chlorostyryl)-1,3-benzenediol (170 mg) was obtained by purification. The yield was 38.8%.

[0177] 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 16.3 Hz, 1H), 6.86 (d, J = 16.3 Hz, 2H), 6.47 (s, 1H), 3.05 (t, J = 12.2 Hz, 1H), 2.10 (dd, J =11.0 Hz, 2H), 1.70 (dd, J = 10.3 Hz, 2H), 1.43 (d, J = 11.7 Hz, 2H), 1.20 (d, J = 13.6 Hz, 4H). ESI-MS m / z 327.1 [MH] - .

[0178] Example 16 Synthesis of (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-dimethoxybenzene

[0179] [ka]

[0180] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 2,4-difluorobenzaldehyde (575.4 mg, 4.05 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-dimethoxybenzene (470 mg) was obtained by purification. The yield was 48.6%.

[0181] (2) Synthesis of (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-benzenediol

[0182] [ka]

[0183] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-dimethoxybenzene (470 mg, 1.31 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(2,4-difluorostyryl)-1,3-benzenediol (170 mg) was obtained by purification. The yield was 39.2%.

[0184] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 7.74 - 7.69 (m, 1H), 7.27 (td, J = 9.6, 4.7 Hz, 1H), 7.20 (d, J = 16.4 Hz, 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 = 12.1 Hz, 1H), 2.20 - 2.02 (m, 2H), 1.73 (dd, J = 31.4, 10.5 Hz, 3H), 1.40 (d, J = 12.2 Hz, 2H), 1.25 (t, J = 13.4 Hz, 3H). ESI-MS m / z 329.1 [MH] - .

[0185] Example 17 Synthesis of (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-dimethoxybenzene

[0186] [ka]

[0187] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 2,6-difluorobenzaldehyde (575.4 mg, 4.05 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-dimethoxybenzene (450 mg) was obtained by purification. The yield was 46.5%.

[0188] (2) Synthesis of (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-benzenediol

[0189] [ka]

[0190] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-dimethoxybenzene (450 mg, 1.26 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(2,6-difluorostyryl)-1,3-benzenediol (150 mg) was obtained by purification. The yield was 36.2%.

[0191] 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 7.35 (d, J = 7.3 Hz, 2H), 7.17 (d, J = 16.3 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H), 6.86 (d, J = 16.3 Hz, 1H), 6.48 (s, 2H), 3.06 (t, J = 12.0 Hz, 1H), 2.10 (dd, J = 11.2 Hz, 2H), 1.70 (dd, J = 10.0 Hz, 3H), 1.43 (d, J = 11.9 Hz, 2H), 1.27 (dd, J =10.6 Hz, 3H). ESI-MS m / z 329.1 [MH] - .

[0192] Example 18 (E) Synthesis of 2-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-dimethoxybenzene

[0193] [ka]

[0194] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 2,5-difluorobenzaldehyde (575.4 mg, 4.05 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-dimethoxybenzene (445 mg) was obtained by purification. The yield was 46.0%.

[0195] (2) Synthesis of (E)-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-benzenediol

[0196] [Chemical]

[0197] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw material (E)-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-dimethoxybenzene (445 mg, 1.24 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(2,5-difluorostyryl)-1,3-benzenediol (168 mg) was obtained by purification. The yield was 41.0%.

[0198] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 2H), 7.86 (dd, J = 7.8 Hz, 1H), 7.30 - 7:23 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 16.4 Hz, 1H), 6.93 (d, J = 16.5 Hz, 1H), 6.48 (s, 2H), 3.11 - 2.98 (m, 1H), 2.10 (dd, J = 12.1 Hz, 2H), 1.70 (dd, J = 8.4 Hz, 3H), 1.43 (d, J = 11.3 Hz, 2H), 1.19 (dd, J =10.7 Hz, 3H). ESI-MS m / z 329.1 [M-H] - .

[0199] Example 19 Synthesis of (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-dimethoxybenzene

[0200] [Chemical]

[0201] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the raw materials diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 3,4-difluorobenzaldehyde (575.4 mg, 4.05 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-dimethoxybenzene (463 mg) was obtained by purification. The yield was 47.9%.

[0202] (2) Synthesis of (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-benzenediol

[0203] [Chemical formula]

[0204] [[ID=?]]Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw material (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-dimethoxybenzene (463 mg, 1.29 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(3,4-difluorostyryl)-1,3-benzenediol (168 mg) was obtained by purification. The yield was 39.4%.

[0205] 1 It should be noted that there seems to be an incorrect "? " in ID=16 in the original text, which is retained as is in the translation. If this is an error in the original, it may need to be corrected for a more accurate translation.H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 2H), 7.77 - 7.68 (m, 1H), 7.27 (td, J = 9.6Hz, 1H), 7.19 (d, J = 16.4 Hz, 1H), 7.12 (dt, J = 11.8,Hz, 1H), 6.95 (d, J = 16.4 Hz, 1H), 6.52 (s, 2H), 3.07 (t, J = 12.1 Hz, 1H), 2.20 - 2.05 (m, 2H), 1.71 (dd, J =10.5 Hz, 3H), 1.44 (d, J = 12.2 Hz, 2H), 1.27 (t, J = 13.4 Hz, 3H). ESI-MS m / z 329.1 [MH] - .

[0206] Example 20 Synthesis of (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-dimethoxybenzene

[0207] [ka]

[0208] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 2,3-difluorobenzaldehyde (575.4 mg, 4.05 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-dimethoxybenzene (468 mg) was obtained by purification. The yield was 48.4%.

[0209] (2) Synthesis of (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-benzenediol

[0210] [ka]

[0211] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-dimethoxybenzene (468 mg, 1.31 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(2,3-difluorostyryl)-1,3-benzenediol (173 mg) was obtained by purification. The yield was 40.1%.

[0212] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 7.72 (ddd, J = 9.5Hz, 1H), 7.27 (td, J = 10.1Hz, 1H), 7.17 (t, J = 10.3 Hz, 1H), 7.18 - 7.08 (m, 1H), 6.94 (d, J = 16.6 Hz, 1H), 6.50 (s, 2H), 3.06 (t, J = 12.1 Hz, 1H), 2.10 (dd, J = 11.2 Hz, 2H), 1.70 (dd, J =10.0 Hz, 3H), 1.43 (d, J = 11.1Hz, 2H), 1.24 - 1.12 (m, 3H). ESI-MS m / z 329.1 [MH] - .

[0213] Example 21 (E) Synthesis of 2-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-dimethoxybenzene

[0214] [ka]

[0215] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the raw materials diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 3,5-difluorobenzaldehyde (575.4 mg, 4.05 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-dimethoxybenzene (470 mg) was obtained by purification. The yield was 48.6%.

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

[0217]

Chemical formula

[0218] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw material (E)-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-dimethoxybenzene (470 mg, 1.31 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(3,5-difluorostyryl)-1,3-benzenediol (165.8 mg) was obtained by purification. The yield was 38.3%.

[0219] 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 2H), 7.43 - 7.27 (m, 2H), 7.13 (dd, J = 18.5, 12.4 Hz, 2H), 6.85 (d, J = 16.8 Hz, 2H), 6.48 (s, 1H), 3.06 (t, J = 11.7 Hz, 1H), 2.10 (dd, J = 13.1 Hz, 2H), 1.70 (dd, J = 9.1 Hz, 3H), 1.42 (d, J = 12.0 Hz, 2H), 1.35 - 1.20 (t, J = 12.0 Hz, 3H). ESI-MS m / z 329.1 [M-H]- .

[0220] Example 22 (E) Synthesis of 2-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-dimethoxybenzene

[0221] [ka]

[0222] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 2,4,5-trifluorobenzaldehyde (648 mg, 4.04 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-dimethoxybenzene (478 mg) was obtained by purification. The yield was 47.0%.

[0223] (2) Synthesis of (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-benzenediol

[0224] [ka]

[0225] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-dimethoxybenzene (478 mg, 1.27 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(2,4,5-trifluorostyryl)-1,3-benzenediol (163 mg) was obtained by purification. The yield was 36.8%.

[0226] 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 2H), 7.63 (dd, J =7.3 Hz, 2H), 6.88 (dd, J = 16.4 Hz, 1H), 6.81 - 6.66 (m,2H), 6.44 (s, 1H), 3.04 (t, J = ESI-MS m / z 347.1 [MH] - .

[0227] Example 23 (E) Synthesis of 2-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-dimethoxybenzene

[0228] [ka]

[0229] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 2,3,4-trifluorobenzaldehyde (648 mg, 4.04 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-dimethoxybenzene (450 mg) was obtained by purification. The yield was 44.3%.

[0230] (2) Synthesis of (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-benzenediol

[0231] [ka]

[0232] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-dimethoxybenzene (450 mg, 1.20 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(2,3,4-trifluorostyryl)-1,3-benzenediol (161 mg) was obtained by purification. The yield was 38.7%.

[0233] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 2H), 7.28 - 7.12 (m, 2H), 6.84 (d, J = 16.2 Hz, 1H), 6.71 (d, J = 16.2 Hz, 1H), 6.41 (s, 2H), 4.75 - 4.69 (m, 1H), 3.09 - 2.98 (m, 2H), 2.09 (dd, J = 12.2 Hz, 2H), 1.69 (dd, J =10.1 Hz, 2H), 1.42 (d, J = 12.4 Hz, 2H), 1.33 - 1.15 (m, 2H). ESI-MS m / z 347.1 [MH] - .

[0234] Example 24 (E) Synthesis of 2-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-dimethoxybenzene

[0235] [ka]

[0236] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 3,4,5-trifluorobenzaldehyde (648 mg, 4.04 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-dimethoxybenzene (463 mg) was obtained by purification. The yield was 45.6%.

[0237] (2) Synthesis of (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-benzenediol

[0238] [ka]

[0239] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-dimethoxybenzene (463 mg, 1.23 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(3,4,5-trifluorostyryl)-1,3-benzenediol (157 mg) was obtained by purification. The yield was 36.6%.

[0240] 1H NMR (400 MHz, DMSO-d6) δ 10.30 (d, J = 16.4 Hz, 1H), 7.55 - 7.31 (m, 1H), 7.32 - 7.17 (m, 1H), 7.17 (s, 1H), 6.96 (t, J = 16.2 Hz, 2H), 6.90 - 6.77 (m, 1H), 6.46 (s, 1H), 3.05 (dt, J = 11.4, 8.3 Hz, 1H), 2.33 - 1.89 (m, 2H), 1.92 - 1.60 (m, 2H), 1.44 (t, J = 12.6 Hz, 1H), 1.42 - 1.19 (m, 5H). ESI-MS m / z 347.1 [MH] - .

[0241] Example 25 (E) Synthesis of 2-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-dimethoxybenzene

[0242] [ka]

[0243] Referring to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8, the starting materials 4-cyclohexyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.70 mmol) and 2,4,6-trifluorobenzaldehyde (648 mg, 4.04 mmol) were reacted, and the product (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-dimethoxybenzene (453 mg) was obtained by purification. The yield was 44.6%.

[0244] (2) Synthesis of (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-benzenediol

[0245] [ka]

[0246] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the starting material (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-dimethoxybenzene (453 mg, 1.20 mmol) was reacted, and the product (E)-2-cyclohexyl-5-(2,4,6-trifluorostyryl)-1,3-benzenediol (158 mg) was obtained by purification. The yield was 37.7%.

[0247] 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 2H), 7.62 (dd, J = 12.3 Hz, 1H), 6.92 (d, J = 16.5 Hz, 2H), 6.91 - 6.79 (m, 1H), 6.74 (dd, J = 10.7 Hz, 1H), 6.44 (s, 1H), 3.04 (dd, J = 10.3 Hz, 1H), 2.09 (dd, J =12.3 Hz, 2H), 1.69 (dd, J = 8.3 Hz, 2H), 1.42 (d, J = 10.4 Hz, 2H), 1.27 (dd, J = 8.3 Hz, 4H). ESI-MS m / z 347.1 [MH] - .

[0248] Example 26 Synthesis of (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene

[0249] [ka]

[0250] Referring to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the starting materials 4-cyclopentyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.81 mmol) and 3-fluorobenzaldehyde (522.4 mg, 4.21 mmol) were reacted, and the product (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene (480 mg) was obtained by purification. The yield was 52.4%.

[0251] (2) Synthesis of (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-benzenediol

[0252] [ka]

[0253] Referring to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the starting material (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-dimethoxybenzene (480 mg, 1.47 mmol) was reacted, and the product (E)-2-cyclopentyl-5-(3-fluorostyryl)-1,3-benzenediol (150 mg) was obtained by purification. The yield was 34.2%.

[0254] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 7.48-7.45 (d, 1H), 7.4-7.38 (d, J = 16.0 Hz, 1H), 7.12-7.01 (m, J = 16.0 Hz, 2H), 6.91-6.87(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] - .

[0255] Example 27 Synthesis of (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene

[0256] [ka]

[0257] Referring to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the starting materials 4-cyclopentyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.81 mmol) and 2-fluorobenzaldehyde (522.4 mg, 4.21 mmol) were reacted, and the product (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene (500 mg) was obtained by purification. The yield was 54.6%.

[0258] (2) Synthesis of (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-benzenediol

[0259] [ka]

[0260] Referring to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the starting material (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-dimethoxybenzene (500 mg, 1.53 mmol) was reacted, and the product (E)-2-cyclopentyl-5-(2-fluorostyryl)-1,3-benzenediol (200 mg) was obtained by purification. The yield was 43.8%.

[0261] 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 2H), 7.83-7.79 (t, J =16.0 Hz 1H), 7.34-7.28 (t, J = 16.0 Hz, 1H), 7.24-7.19 (t, J = 16.0 Hz, 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] - .

[0262] Example 28 Synthesis of (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene

[0263] [ka]

[0264] Referring to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the starting materials 4-cyclopentyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.81 mmol) and 2-chlorobenzaldehyde (591.6 mg, 4.21 mmol) were reacted, and the product (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene (450 mg) was obtained by purification. The yield was 46.8%.

[0265] (2) Synthesis of (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-benzenediol

[0266] [ka]

[0267] Referring to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the starting material (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-dimethoxybenzene (450 mg, 1.31 mmol) was reacted, and the product (E)-2-cyclopentyl-5-(2-chlorostyryl)-1,3-benzenediol (185 mg) was obtained by purification. The yield was 44.8%.

[0268] 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 2H), 7.95-7.92 (d, 1H),7.53-7.50 (m, 1H), 7.42-7.38 (d, J = 16.0 Hz, 1H),7.35-7.31 (m, J = 16.0 Hz, 1H), 7.29-7.25 (d, J = 16.0 Hz, 1H),7.15-7.11 (d, J = 16.0 Hz, 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] - .

[0269] Example 29 Synthesis of (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-benzenediol (1) Synthesis of (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene

[0270] [ka]

[0271] Referring to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the starting materials 4-cyclopentyl-3,5-dimethoxybenzylphosphonate diethyl (1.0 g, 2.81 mmol) and 3-chlorobenzaldehyde (522.4 mg, 4.21 mmol) were reacted, and the product (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene (460 mg) was obtained by purification. The yield was 47.8%.

[0272] (2) Synthesis of (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-benzenediol

[0273] [ka]

[0274] Referring to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the starting material (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-dimethoxybenzene (460 mg, 1.34 mmol) was reacted, and the product (E)-2-cyclopentyl-5-(3-chlorostyryl)-1,3-benzenediol (170 mg) was obtained by purification. The yield was 40.2%.

[0275] 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 2H), 7.74-7.73 (t, 1H), 7.59-7.57 (d, J = 16.0 Hz, 1H), 7.44-7.40 (t, J = 16.0 Hz, 1H), 7.35-7.32 (t, J = 16.0 Hz, 1H), 7.19-7.15 (d, J = 16.0 Hz, 1H), 6.94-6.90 (d, J = 16.0 Hz, 1H), 6.54 (s, J = 16.0 Hz, 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] - .

[0276] Test Example 1 Activity tests were conducted on the compounds of the present invention, and benbitimod, a commercially available aromatic hydrocarbon receptor agonist drug, and FICZ, a common aromatic hydrocarbon receptor agonist compound, were selected as comparative experimental compounds.

[0277] 1. Cytotoxicity test of the test compound 1) Cytotoxicity testing of test compounds in PBMCs The specific test compounds are shown in Table 1.

[0278] (1) Preparation of drugs Preparation of the highest concentration drug solution in the culture medium: 1 μL each of compounds from the 1#~8# series, control 1#, control 2#, and control 3# series, with an initial concentration of 1 mM, was taken and added to 499 μL of culture medium to prepare a 2 μM drug-containing culture medium.

[0279] (2) Preparation of cells (i) Cell information: PBMC 5Million ID#: LP181017 CAT#: PB003F-5M (ii) Cell resuscitation: PBMC cells were removed from the liquid nitrogen bath and quickly thawed in 37°C warm water. The cells were then placed in a centrifuge tube containing culture medium and centrifuged at 1200 rpm for 11 minutes. The centrifuge tube was removed, the culture medium was discarded, and 5 mL of culture medium was drawn up using a titration tube to resuspend the cells. (iii) Cell counting: Launch the cell counting software, set the cell type to PBMC, and the viable cell concentration to 3.47 × 10⁻⁶. 5 Selected as pieces / mL.

[0280] (3) Cell administration Cell seeding and administration: The cell suspension was diluted to 7 mL and seeded into a 96-well plate. 100 μL of cell suspension was added to each well, followed by 100 μL of 2 μM of the 1#-8#, control 1#, control 2#, and control 3# series of drug solutions, with three parallel pores for each group. The final number of viable cells in each well was approximately 2.5 × 10⁶. 4 The sample size was 1 μM, and the drug concentration was 1 μM.

[0281] (4) Cytotoxicity test 24 hours after drug treatment, 10 μL of CCK8 was added to the cells in each well and allowed to react for 3 hours. The absorption wavelength was then read using a microplate reader and was found to be 450 nm. The results are shown in Figure 1.

[0282] The cell activity after treatment with each compound was calculated, with the absorbance of the control group set to 100%.

[0283] 2) Cytotoxicity testing of test compounds in HepG2 (1) Preparation of drugs Preparation of the highest concentration drug solution in the culture medium: 1 μL each of compounds from the 1#~8# series, control 1#, control 2#, and control 3# series, with an initial concentration of 1 mM, was taken and added to 499 μL of culture medium to prepare a 2 μM drug-containing culture medium.

[0284] (2) Preparation of cells Source: HepG2 cells were obtained from the Chinese Academy of Sciences Cell Bank.

[0285] Cell resuscitation: HepG2 cells were removed from the liquid nitrogen bath and quickly thawed in 37°C warm water. The cells were then placed in a centrifuge tube containing culture medium and centrifuged at 1200 rpm for 11 minutes. The centrifuge tube was removed, the culture medium was discarded, and 5 mL of culture medium was aspirated using a titration tube to resuspend the cells.

[0286] (3) Administration of cells The cell suspension was diluted to 7 mL, and cells were seeded in a 96-well plate. 100 μL of the cell suspension was added to each well, and then 100 μL of 2 μM of the 1#-8#, control 1#, control 2#, and control 3# series of reagents was added to each well, resulting in three parallel pores for each group. The final number of viable cells in each well was approximately 2.0 × 10⁶. 4 The sample size was 1 μM, and the drug concentration was 1 μM.

[0287] (4) Cytotoxicity test 24 hours after drug treatment, 10 μL of CCK8 was added to the cells in each well and allowed to react for 3 hours. The absorption wavelength was then read using a microplate reader and was found to be 450 nm. The results are shown in Figure 2.

[0288] As can be seen from Figures 1 and 2, at the test concentrations, none of the compounds had any significant effect on the cellular activity of PBMCs or HepG2.

[0289] 2. Experiments using AhR agonists of compounds Based on the results of the compound in reporter gene experiments, the AhR agonist activity of the compound was evaluated.

[0290] (1) Cell transfection: Inoculate HepG2 cells into a 6 cm cell petri dish and allow them to adhere overnight. When the degree of cell fusion was 80%, the medium was replaced with fresh medium, the transfection working solution was added, and the cells were transfected overnight. The working solution consisted of 1 mL of Opti-MEM + 7.5 μg of pCMV-AHR + 7.5 μg of pTK-3 X DRE-Luc + 30 μL of lipo6000.

[0291] (2) Cell seeding: Digest the cells after transfection and concentrate them to a concentration of 3 × 10 5 A cell suspension was prepared at a concentration of cells / mL, seeded at 100 μL / well in a 96-well plate, and allowed to adhere overnight.

[0292] (3) Preparation of drugs Preparation of the highest concentration drug solution in the culture medium: 1 μL each of compounds from the 1#~16# series, control 1#, control 2#, and control 3# series, at an initial concentration of 1 mM, was taken and added to 499 μL of culture medium to prepare a 2 μM drug-containing medium. Then, 40 μL of this 2 μM drug-containing medium was taken and diluted to 400 μL of a 0.2 μM drug-containing medium.

[0293] (4) Administration of cells The prepared drug-containing medium and blank medium were added to the 96-well plate at a rate of 100 μL / well. After 16 hours of drug treatment, the luciferase reporter gene was detected.

[0294] (5) The experimental statistical results are shown in Table 1.

[0295] [Table 1] JPEG0007898766000071.jpg234169JPEG0007898766000072.jpg82169

[0296] As can be seen from the data in Table 1, all of the compounds 1 to 16 of the present invention possess AhR activity, and of these, all of the test compounds 2 to 16 exhibited good AhR agonist activity.

[0297] 3. Regulatory effect of compounds on PBMC cytokine secretion (1) Cell information: Mononuclear cells derived from bone marrow. (2) Cell seeding and administration: After removing PBMC cells from the liquid nitrogen bath and resuscitating them, 80 μL of medium was added to a 96-well plate at a concentration of 200,000 cells / well. 80 μL of medium containing 2 μM or 0.2 μM of drug solutions #2, #6, and control #1 was aspirated and added to the 96-well plate, respectively, to final drug concentrations of 1 μM and 0.1 μM. Each well was allowed to stand at this concentration for 1 hour for pretreatment. After pretreatment, the drug solutions were removed from the wells, and 80 μL of 1 μM or 0.1 μM solution of 15 μg / mL PHA (plant lectin, Phytohemaggluyinin) was added to the corresponding wells. After 24 hours of stimulation, the cytokine content in the medium was detected. Blank control group: Cells in standard culture medium without any added drugs. PHA group: 80 μL of a culture medium solution containing 15 μg / mL of PHA, without the compound of the present invention added, was added to the corresponding well.

[0298] [Table 2]

[0299] The test results showed that compounds 2# and 6# could suppress the cytokines TNFα and IL4 at two concentrations, 0.1 μM and 1 μM. Furthermore, the inhibitory effect of compounds 2# and 6# on TNFα and IL4 was significantly greater than that of the control compound 1# benbitimod, with both exceeding twice the inhibitory effect at a dose of 1 μM.

[0300] 4. Effects of compounds on colitis caused by DSS (1) Experimental animals: 40 C57BL / 6 mice, male, 8 weeks old, 22-24 g (2) Experimental materials: Dextran sulfate sodium (DSS) (MP. Biomedicals, USA, product number S7102), test compound control #1, compound #6, dimethyl sulfoxide (DMSO), Tween 80, Wahaha purified water (3) Experimental Procedure: 40 mice were randomly divided into four groups of 10 mice each, and designated as a blank group, a model group, a drug control group 1, and a compound group 6. The normal blank group was allowed to drink distilled water freely, while the remaining three groups were allowed to drink a 2.5% DSS aqueous solution freely for 8 consecutive days, with the solution checked daily and replaced with fresh DSS solution. Drug therapy was administered on day 1 of the modeling group. The normal blank group was given the corresponding physiological saline solution, the colitis model group was given a solvent system solution, and the test drug control group 1 and compound group 6 were administered the corresponding drug intragastricly at a dose of 10 mg / kg. The weight of the mice was recorded daily, and the condition of diarrheal stools with blood was observed and scored. On day 9, the mice were killed, and blood and colon samples were collected. The length of the intestines and the presence of occult blood in the cecal contents were also recorded.

[0301] Preparation of the test drug: 1.00 mg of drug powder was weighed, 20 μL of DMSO was added and dissolved thoroughly, then 20 μL of Tween 80 was added and mixed uniformly, and 0.96 mL of Wahaha purified water was added and mixed uniformly to prepare a 1 mg / mL drug solution, which was administered at a dose of 0.1 mL / 10 g (body weight).

[0302] Solvent: 20 μL of DMSO + 20 μL of Tween 80 + 0.96 mL of Wahaha purified water were homogeneously mixed (for the model group).

[0303] (4) Test results: As shown in Figure 3, the statistical results for colon length showed improvement in both the compound 6# and control 1# benbitimod groups, and in terms of actual effect, the compound 6# group was superior to the control 1# benbitimod group.

[0304] As shown in Figure 4, the disease activity index (a comprehensive score based on weight change and stool blood status) data showed that both the compound 6# group and the control 1# benbitimod group exhibited superior therapeutic effects, with the compound 6# group showing an even more pronounced effect.

[0305] 5. Effects on atopic dermatitis (1) Construction of an atopic dermatitis model Fifty-six clean-grade BALB / C mice, 6-8 weeks old, were adaptively reared for five days, and then randomly divided into seven groups of eight mice each. (i) Blank control group (ii) Modeling + Solvents (iii) Modeling + Blank matrix group (iv) Modeling + Positive drug mometasone furoate group (v) Modeling + 1% mass benbitimod group (vi) Modeling + Compound 2# at 1.2% by mass (prepared in a blank matrix) (vii) Modeling + Compound 6# at 1.2% by mass (prepared in a blank matrix)

[0306] [ka]

[0307] As shown in the following steps, after depilation with rosin paraffin, 50 μL of 0.5% (W / V, solvent: acetone-olive oil mixture (acetone:olive oil = 3:1)) 2,4-dinitrofluorobenzene (DNFB) was applied to the back of each mouse, and 50 μL of 0.25% (W / V) DNFB was administered on the mornings of days 4, 6, and 8. The blank control group was applied with an equal volume of solvent control. The animal experiments were conducted in accordance with the Manual of Laboratory Animal Husbandry, Management and Use of China Pharmaceutical University and in compliance with animal ethics guidelines.

[0308] [Table 3]

[0309] Number of days (2) Administration method As shown in the steps above, modeling was performed in the morning by applying a solvent control or DNFB; from the 5th day onward, 50 mg of the drug ointment awaiting measurement was applied daily in the afternoon to ensure uniform application of the drug to the skin surface. The specific administration method was as described above.

[0310] The specific procedures were as follows: Group (ii) received a single application of 50 mg of solvent (acetone:olive oil = 3:1) every afternoon starting from day 5; Group (iii) received a single application of 50 mg of blank matrix every afternoon starting from day 5; and Groups (iv), (v), (vi), and (vii) received 50 mg of the positive agent mometasone furoate, 1% benbitimod, 1.2% compound 2#, or 1.2% compound 6#, respectively, starting from day 5, depending on the group classification.

[0311] The severity of atopic dermatitis was scored using the AD Score criteria.

[0312] The severity of dermatitis was assessed based on four indicators: (i) erythema / hemorrhage, (ii) dryness, (iii) exudation / scabbing, and (iv) edema. Each indicator was scored from 0 to 3 points, and the scores of the four indicators were added together to obtain a total score. The AD Score scoring criteria were as follows: 0 for asymptomatic, 1 for mild symptoms, 2 for moderate symptoms, and 3 for severe symptoms. The dorsal skin of each mouse was photographed and the score recorded on days 0, 4, 6, 8, and 10 of the modeling period.

[0313] [Table 4]

[0314] A surface observation diagram is shown in Figure 5.

[0315] 6. Drug permeability experiment Test Steps Drugs awaiting measurement: 1.2% by mass of compound 2 cream, 1.2% by mass of compound 6 cream, 1.0% by mass of benbitimod cream

[0316] [ka]

[0317] (1) Preparation of the semipermeable membrane: The semipermeable membrane that had been prepared in advance was taken out of the refrigerator.

[0318] (2) Preparation of the receiving solution: 100 mL of polyethylene glycol 400 solution was measured out, and the volume was adjusted to 250 mL using physiological saline. The solution was mixed uniformly and stored at 4°C. Before placing it in the receiving pool, the pool was preheated to 32°C.

[0319] (3) In vitro diffusion test: Using a transdermal drug diffuser, the treated semipermeable membrane was fixed in the center of the supply pool and the receiving pool, and a constant temperature water bath at 32°C was circulated. First, equilibration was performed for 30 minutes, and the receiving solution was replaced to expel the air from the lower layer. Approximately 0.5 g of cream was uniformly added to each of the supply pools and spread evenly. At a magnetic stirring rotation speed of 600 r / min, 1 mL of sample solution was taken from the receiving pool at 0.5, 1, 2, 4, 6, and 24 h, and simultaneously replenished with an equal volume of fresh, isothermal receiving solution.

[0320] Actual sampling times were 0.5, 1, 2, 4, 6, and 24 hours, and the 1 mL sampled was placed directly into the liquid phase vial. Simultaneously, an equal volume of isothermal fresh receiving solution was added. Drug permeability was calculated by liquid phase detection.

[0321] Cream - Diffusion Test - Rabbit Skin Test Steps (1) Exovivo production using rabbit skin (2) Preparation of the receiving solution: 100 mL of polyethylene glycol 400 solution was measured out, and the volume was adjusted to 250 mL using physiological saline. The solution was mixed uniformly and stored at 4°C. Before placing it in the receiving pool, the pool was preheated to 32°C.

[0322] (3) In vitro transdermal test: Using a drug transdermal diffusion test machine, the treated rabbit skin was fixed in the center of the supply pool and receiving pool, with the stratum corneum facing the supply pool, and a constant temperature water bath at 32°C was circulated. First, equilibration was performed for 30 minutes, the receiving solution was changed, air under the skin was expelled, and the liquid on the skin surface was absorbed with filter paper until dry. 0.5 g of cream was uniformly added to each of the supply pools and spread evenly. At a magnetic stirring rotation speed of 600 r / min, 1 mL of sample solution was taken from the receiving pool at 0.5, 1, 2, 3, 4, 5, 7, 9, 12, and 24 h and placed into a liquid phase vial, while simultaneously replenishing with an equal volume of isothermal fresh receiving solution. Drug permeability was calculated by liquid phase detection.

[0323] The detection results for drug permeability over 24 hours are shown in Figure 6.

[0324] As shown in Figure 6, the trends in 24-hour drug permeability of the three creams were consistent in both test systems, with the commercially available control drug benbitimod > 2# > 6# in all cases. The results indicate that the creams prepared with compounds 2# and 6# of the present invention had lower transdermal absorption, lower blood exposure, and lower adverse reactions in the system compared to the commercially available control drug benbitimod.

[0325] 7. Mouse psoriasis test 1. Evaluation of the efficacy of compound 6# against IMQ-induced mouse psoriasis. Structure of the compound:

[0326] [ka]

[0327] 2. Grouping (1) Vaseline + blank matrix group, 10 animals (2) IMQ + blank matrix group, 10 individuals (3) IMQ+ compound 6# group (1.2% by mass drug prepared in a blank matrix), 10 animals.

[0328] IMQ is IMikimodo. 3. Preparation of drugs IMQ is 5% imiquimod (imiquimod is used to induce psoriasis on the surface of modeling mice). A 1.2% compound 6# drug was prepared in a blank matrix. 4. Animals Species and lineage: SPF grade KM mouse, male Weight: 35~40g Source: Beijing Sibifu Biotechnology Co., Ltd. Rearing conditions: Air-conditioned room, temperature 18-26°C, relative humidity 20-60%.

[0329] 5. Examination Steps Skin preparation: The mice were allowed to drink water and eat freely, entered the animal room, and after 5 days of adaptation, the hair on a 2 cm x 2.5 cm area of ​​the mouse's back was removed with clippers, depilatory cream was applied for 30 seconds to 1 minute, and then the depilatory cream was wiped off with a cotton ball.

[0330] Randomization: 24 hours after hair removal, 75 mice were randomly divided into four groups based on body weight: 10 mice in the petrolatum + blank matrix group, 10 mice in the IMQ + blank matrix group, and 10 mice in the IMQ + compound 6# group (where a 1.2% drug was prepared in the blank matrix).

[0331] Modeling administration: In the morning, 5% imiquimod or 62.5 mg of petrolatum was applied. In the afternoon, a blank matrix or 1.2% compound 6# 62.5 mg was applied to the back.

[0332] Experimental Record: Before modeling in the morning, the condition of wrinkles, erythema, and scaling was observed daily, a score was recorded, and photographs were taken to calculate the mouse's PASI score.

[0333] [Table 5]

[0334] [Table 6]

[0335] The test results are shown in Table 5 and Figure 7 above. The IMQ+ compound 6# of the present invention versus the IMQ+ blank matrix showed a statistically significant difference (P-value of 0.0002) on day 7, indicating that compound 6# of the present invention has significantly superior therapeutic effects compared to the IMQ+ blank matrix, which served as the modeling control group. [Brief explanation of the drawing]

[0336] [Figure 1] This figure shows the effect of the test compound on PBMC cell activity at a concentration of 1 μM. [Figure 2] This figure shows the effect of the test compound on HepG2 cell activity at a concentration of 1 μM. [Figure 3] This shows the effect of the test compound on colon length in a DSS mouse model of ulcerative colitis (comparison with the normal blank group is **p<0.01, and comparison with the model group is #p<0.05). [Figure 4] This figure shows the effect of the test compound on the disease activity index in a DSS mouse model of ulcerative colitis (comparison with the normal blank group is **p<0.01, comparison with the model group is #p<0.05, ##p<0.01). [Figure 5] These are observational images of the dorsal surface of mice from each group. [Figure 6] This is the result of detecting drug permeability over 24 hours. [Figure 7] This is a PASI score chart.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, 【Chemistry 1】 Of these, X is selected from halogens, and n is between 1 and 5. R is selected from unsubstituted 3- to 7-membered cycloalkyl groups. A compound or its pharmaceutically acceptable salts, tautomers, or stereoisomers.

2. X is characterized by being F and / or Cl, The compound described in claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

3. The following compounds: 【Chemistry 2】 【change】 Characterized by being selected from, The compound described in claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

4. The compound of formula (II) or its pharmaceutically acceptable salts, tautomers, or stereoisomers. 【Transformation 3】

5. The use of at least one of the compounds of formula (I) described in any one of claims 1 to 3, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and the compounds of formula (II) described in claim 4, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, for the manufacture of a drug, The aforementioned drugs are used to treat cancer, autoimmune deficiencies, and other diseases with immunological factors.

6. Use of at least one of the compounds of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and the compounds of formula (II) according to claim 4, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, The aforementioned drug is used to prevent and / or treat diseases or conditions mediated by aryl hydrocarbon receptors (AhRs).

7. Use of at least one of the compounds of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and the compounds of formula (II) according to claim 4, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, The drug is used to modulate 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, TNFα, TGF-β, IFN-γ, and IL-1β, and to prevent and / or treat diseases caused by abnormalities in the cytokines.

8. The aforementioned autoimmune deficiency disease is one or more selected from 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 thrombocytopenia, dry eye, type 1 diabetes mellitus, psoriasis, and arthritis. The use described in claim 5.

9. The aforementioned immunological conditions are one or more selected from asthma, allergy, infection, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, and transplant rejection. The use described in claim 5.

10. A pharmaceutically acceptable carrier or excipient, a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and at least one of the compound of formula (II) according to claim 4 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, Pharmaceutical composition.

11. A method for producing the compound described in any one of claims 1 to 3, The process includes reacting compound IMe with compound SMc to obtain compound IMf, and then reacting compound IMf under acidic conditions to obtain the compound shown in formula (I). 【Chemistry 4】 A method characterized in that X, n, and R are described in any one of claims 1 to 3.

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