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 the priority of a prior application filed with the China National Intellectual Property Administration on May 7, 2022, with patent application number 202210489648.4 and invention title "Stilbene Derivative as an AhR Agonist and Its Use". The full text of the said application is incorporated herein by reference.

[0002] 〔Technical Field〕 The present invention relates to the field of medicine, and specifically to stilbene derivatives as AhR agonists and their use.

[0003] 〔Background Art〕 The 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 living body, and is most highly expressed in the spleen, stomach, ovary and placenta, and at the same time is also highly expressed in immune cells. In particular, some hematopoietic stem cells, bone marrow-derived dendritic cells, CD4 + such as several CD4 + T cell subsets such as Th17 cells are most highly expressed, while on the other hand, it is most lowly expressed in B cells and CD4 + Treg cells. The overactivation of Th17 cells and the increased secretion of IL-17 are related to various chronic inflammatory diseases and autoimmune diseases of the living body such as psoriasis, multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis and asthma. Treg cells play an important role in the suppression of autoimmune diseases, transplantation and graft-versus-host disease. Studies have demonstrated that the balance between both Th17 and Treg plays an important role in the immunity and tolerance of the host. For example, studies have demonstrated that the pathogenesis of UC is closely related to the imbalance of Th17 / Treg.

[0004] As the research on AhR progresses intensively, it has been found that the imbalance in Th17 / Treg differentiation may be related to AhR in the body. AhR is a cytoplasmic transcription factor involved in drug metabolism and the regulation of 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 autoimmune 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〕 In order 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 a polysubstitution of F and Cl, R is selected from a substituted or unsubstituted 3- to 7-membered cycloalkyl group or cycloalkenyl group, and a substituted or unsubstituted 3- to 7-membered heterocyclyl group, and the above substituents are, for example, C 1-6 alkyl group, C 1-6 alkoxy group, halogen, etc.

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

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

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

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

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

[0014] In some embodiments, the above 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]

Chemical formula

[0017] The present invention further provides a compound of formula (II) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0018] [Chemical formula]

[0019] The present invention further provides the use of a compound of formula (I), formula (II) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof in the manufacture of a drug for treating cancer, autoimmune deficiency and other diseases having immunological factors.

[0020] According to an embodiment of the present invention, among them, the autoimmune deficiency diseases are 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, Sjogren's syndrome, polymyositis, vasculitis, polymyalgia rheumatica, immune thrombocytopenia, dry eye, type 1 diabetes, psoriasis and arthritis, etc.

[0021] According to an embodiment of the present invention, among them, the diseases having the above immunological factors are one or more selected from asthma, allergy, infectious disease, osteoporosis, arteriosclerosis, type 2 diabetes, graft-versus-host disease and transplant rejection.

[0022] The present invention further provides the use of a compound of formula (I), formula (II) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof in the manufacture of a drug for preventing and / or treating a disease or disorder mediated by the aryl hydrocarbon receptor (AhR).

[0023] The present invention further provides the use of a compound of formula (I), formula (II) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof in the manufacture of a drug 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 abnormal cytokines.

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

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

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

[0027]

Chemical formula

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

[0029] Furthermore, the production route of compound IMe is as follows:

[0030]

Chemical formula

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

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

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

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

[0035] "Pharmaceutically acceptable carrier (pharmaceutical carrier)" refers to a carrier that can be used in the manufacture of pharmaceutical compositions. Generally, the carrier is compatible with other components of the composition, harmless to the subject, and neither biologically undesirable nor undesirable in other aspects. "Pharmaceutically acceptable carrier" includes one and / or more than one carrier. Embodiments include carriers for topical, ophthalmic, parenteral, intravenous, intraperitoneal, intramuscular, sublingual, nasal and oral administration. "Pharmaceutically acceptable carrier" further includes reagents for producing 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 with 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 for the treatment of diseases or related conditions mediated by abnormal AhR activation. As a result of testing the AhR agonist activity of the compounds of the present invention at a concentration that does not significantly affect HepG2 cell activity, the AhR agonist activity of the compounds of the present invention is 2 to 9 times that of the positive controls of benvitimod or FICZ, indicating that they have a good effect on the treatment of diseases or related conditions mediated by abnormal AhR activation. In the DSS mouse ulcerative colitis model, after administration of the compounds of the present invention, the recovery effect at a dose of 10 mg / kg is 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 stability and metabolic stability, show 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 show relatively low toxicity, are excellent in drug resistance, and have high safety.

[0041] (4) The compounds of the present invention are highly stable, chemical decomposition reactions such as hydrolysis and oxidation are less likely to occur, there is no discoloration or increase in impurities even after long-term storage at room temperature, and it is not particularly necessary to store them in the dark. Compared with benvitimod, the photodegradation phenomenon under light irradiation conditions is significantly reduced.

[0042] 〔Brief Description of the Drawings〕 Figure 1 shows the results of the effect of the test compound on PBMC cell activity at a concentration of 1 μM.

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

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

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

[0046] Figure 5 is an observation diagram of the back surface of mice in each group.

[0047] Figure 6 shows the detection results of the drug permeability rate at 24 h.

[0048] Figure 7 is a PASI score diagram.

[0049] [Mode for Carrying Out the Invention] Hereinafter, in accordance with specific examples, the technical solution of the present invention will be described in more detail. It should be understood that the following examples are merely illustrative explanations of the present invention and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

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

[0051] Example 1 The following method details the production of the compounds of the present invention described above. The compounds of the present invention and the compounds of the comparative examples can be produced using raw materials and reagents that are known or commercially available to those skilled in the field of organic synthesis.

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

[0053] [Chemical formula]

[0054] Among them, X is selected from halogens, n is an integer from 1 to 5. Preferably, X is F or Cl, or X is a polysubstitution of F and Cl. R is selected from a substituted or unsubstituted 3- to 7-membered cycloalkyl group or cycloalkenyl group, and a substituted or unsubstituted 3- to 7-membered heterocyclyl group.

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

[0056] [Chemical formula]

[0057] Methyl 3,5-dimethoxybenzoate (20.07 g, 102.29 mmol) was added to a one-necked flask, and concentrated sulfuric acid (50 mL) was added and stirred until dissolved. In an ice bath, cyclopentanol (21.95 g, 254.82 mmol) was added dropwise to the one-necked flask. After adding cyclopentanol, the ice bath was removed, and the temperature was raised to 70 °C and reacted for 4 h. The reaction was monitored with a spotted TLC plate, and after confirming that the raw materials had completely reacted, 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 value of the reaction solution to 3 - 5. Extraction was performed 3 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, it was concentrated under reduced pressure to remove ethyl acetate, and a brown solid (24.76 g), which was the crude product of 4-cyclopentyl-3,5-dimethoxybenzoic acid, was obtained. The yield was 96.7%.

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

[0059]

Chemical formula

[0060] 4-Cyclopentyl-3,5-dimethoxybenzoic acid (24.76 g, 98.92 mmol) was added to a one-necked flask, and methanol (50 mL) was added and stirred until dissolved. While in an ice bath, thionyl chloride (17.65 g, 148.39 mmol) was added dropwise to the one-necked flask, and white smoke was generated. After adding thionyl chloride, the ice bath was removed, the temperature was raised to 60 °C, and the reaction was carried out for 1 h. The reaction was monitored with a spotted TLC plate, and after confirming that the raw material had completely reacted, 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 carried out 3 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, it was concentrated under reduced pressure to remove ethyl acetate, and a black solid (25.95 g), which was the crude product of methyl 4-cyclopentyl-3,5-dimethoxybenzoate, was obtained. The yield was 99.2%.

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

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

[0063]

Chemical Structure

[0064] Methyl 4-cyclopentyl-3,5-dimethoxybenzoate (18.54 g, 70.14 mmol) was added to a one-necked flask, and tetrahydrofuran (50 mL) was added and stirred to dissolve. Under an ice bath, lithium aluminum hydride (3.99 g, 105.21 mmol) was added to the one-necked flask in several portions, and a large amount of bubbles generated. After adding lithium aluminum hydride, the ice bath was removed and the reaction was carried out at room temperature for 1.5 h. The reaction was monitored with a spotted TLC plate, and after confirming that the raw material had completely reacted, the reaction was stopped. Under an ice bath, water (3.99 mL), 15% sodium hydroxide solution (3.99 mL) and water (11.97 mL) were added drop by drop to the one-necked flask in sequence, stirred for 30 min, and a large amount of white solid was formed. It 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 the washing solution were combined and concentrated under reduced pressure to remove tetrahydrofuran. It was extracted 3 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, it was concentrated under reduced pressure to remove ethyl acetate, and a brown solid (15.37 g), which was the crude product of 4-cyclopentyl-3,5-dimethoxybenzyl alcohol, was obtained. The yield was 92.7%.

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

[0066]

Chemical formula

[0067] 4-Cyclopentyl-3,5-dimethoxybenzyl alcohol (15.37 g, 65.04 mmol) was added to a single-necked flask, and dichloromethane (30 mL) was added. The mixture was stirred until dissolved. While in an ice bath, thionyl chloride (11.61 g, 97.56 mmol) was added dropwise to the single-necked flask, and white smoke was generated. After adding thionyl chloride, the ice bath was removed, and the reaction was carried out at room temperature for 2 h. The reaction was monitored with a spotted TLC plate. After confirming that the raw materials had completely reacted, the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove dichloromethane and excess thionyl chloride. It was extracted 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, it was concentrated under reduced pressure to remove ethyl acetate, and a black oily substance (15.14 g), which was the crude product 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, and the mobile phase was petroleum ether:ethyl acetate = 100:1. The mobile phase was concentrated until dry, and a yellow solid (12.60 g), which was the pure product of 4-cyclopentyl-3,5-dimethoxybenzyl chloride, was obtained. The purification yield was 83.2%.

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

[0070]

Chemical Structure

[0071] 4-Cyclopentyl-3,5-dimethoxybenzyl chloride (12.60 g, 49.46 mmol) was added to a one-necked flask, and triethyl phosphite (49.31 g, 296.76 mmol) was added and stirred until dissolved. The mixture was replaced with nitrogen gas three times. The reaction solution was heated to 160 °C and reacted for 5 h. The reaction was monitored by spotting on a plate. After confirming that the raw materials had completely reacted, the reaction was stopped, the solvent was removed, and diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (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] [Chemical formula]

[0074] Add diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (1.01 g, 2.83 mmol) to a three-necked flask, add tetrahydrofuran (15 mL), and stir and dissolve it in an ice bath. Under nitrogen gas protection, add sodium hydride (452.5 mg, 11.31 mmol) to the three-necked flask in several portions. After the addition is complete, react for 1 h. Then, slowly add dropwise a tetrahydrofuran solution of benzaldehyde (4.24 mmol) (dissolve 450.2 mg of benzaldehyde in 10 mL of tetrahydrofuran) to the three-necked flask. After the dropwise addition is complete, remove the ice bath, slowly raise the temperature to 70 °C, and react for 4 h. Monitor the reaction with a spotted TLC plate. After the raw materials have completely reacted, cool the temperature to room temperature. In an ice bath, add water to the three-necked flask to quench until no gas is generated, and concentrate under reduced pressure to remove tetrahydrofuran. 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 over anhydrous sodium sulfate. After drying, concentrate under reduced pressure to remove ethyl acetate, and obtain a yellow oil (804.6 mg) which is the crude product of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene.

[0075] (E)-2-Cyclopentyl-1,3-dimethoxy-5-styrylbenzene was purified by column chromatography. The mobile phase was petroleum ether:ethyl acetate = 50:1. Concentrate until the mobile phase is dry to obtain a yellow solid (403.2 mg) which is the pure product of (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]

Chemical formula

[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-necked flask. The flask was evacuated and backfilled with nitrogen gas three times. The temperature was gradually raised to 210 °C. After the pyridinium hydrochloride had melted, the mixture was kept at this temperature for 4 h. The reaction was monitored by spotting a TLC plate, and when it was confirmed that the starting material had completely reacted, the reaction was stopped. The reaction mixture was cooled to room temperature and 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 mixture was concentrated under reduced pressure to remove the 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 to obtain a brown solid (145.1 mg) of pure (E)-2-cyclopentyl-5-styryl-1,3-benzenediol. The yield was 39.6%.

[0080] 1 H NMR (400 MHz, DMSO-d 6 ) 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 (E)-2-Cyclopentyl-5-(4-fluorostyryl)-1,3-benzenediol Synthesis (1) Synthesis of (E)-2-Cyclopentyl-5-(4-fluorostyryl)-1,3-dimethoxybenzene

[0082]

Chemical formula

[0083] Referring to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the raw materials diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (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]

Chemical formula

[0086] Referring to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the raw 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] 1 H NMR (400 MHz, DMSO-d 6) 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 [M-H] - 。

[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]

Chemical formula

[0090] With reference to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the raw material diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (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]

Chemical formula

[0093] Referring to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the raw 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-d 6 ) 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, 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 [M-H] - 。

[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]

Chemical formula

[0097] With reference to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the raw material diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (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] [Chemical formula]

[0100] With reference to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the raw 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-d 6 ) 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 [M-H] - .

[0102] Example 7 Synthesis of Diethyl 4-Cyclohexyl-3,5-dimethoxybenzylphosphonate (1) Synthesis of 4-Cyclohexyl-3,5-dimethoxybenzoic Acid

[0103]

Chem.

[0104] Methyl 3,5-dimethoxybenzoate (20.12 g, 102.55 mmol) and concentrated sulfuric acid (50 mL) were added to a one-necked flask and stirred until dissolved. Cyclohexanol (25.68 g, 256.37 mmol) was added dropwise to the one-necked flask in an ice bath. After the addition was complete, the ice bath was removed and the temperature was gradually raised to 70 °C and reacted for 4 h. The reaction was monitored with a spotted TLC plate, and after confirming that the raw materials had completely reacted, 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 value of the reaction solution to 3 - 5. Extraction was performed 3 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, it was concentrated under reduced pressure to remove ethyl acetate, and a brown solid (27.10 g), which was the crude product of 4-cyclohexyl-3,5-dimethoxybenzoic acid, was obtained. The yield was 100.0%.

[0105] (2) Synthesis of Methyl 4-Cyclohexyl-3,5-dimethoxybenzoate

[0106]

Chem.

[0107] 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 until dissolved. While in an ice bath, thionyl chloride (18.29 g, 153.79 mmol) was added dropwise to the single-necked flask, and white smoke was generated. After adding thionyl chloride, the ice bath was removed, the temperature was raised to 60 °C, and the reaction was carried out for 1 h. The reaction was monitored with a spotted plate, and after confirming that the raw materials had completely reacted, 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 carried out 3 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 h. After drying was complete, it was concentrated under reduced pressure to remove ethyl acetate, and a black solid (28.23 g), which was the crude product of methyl 4-cyclohexyl-3,5-dimethoxybenzoate, was obtained. The yield was 98.9%.

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

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

[0110]

Chemical formula

[0111] Methyl 4-cyclohexyl-3,5-dimethoxybenzoate (27.10 g, 97.36 mmol) and tetrahydrofuran (271 mL) were added to a one-necked flask and stirred until dissolved. Lithium aluminum hydride (7.4 g, 194.73 mmol) was gradually added in several portions in an ice bath. After the addition was complete, the ice bath was removed, and the temperature was raised to room temperature. After reacting for 1 h, the reaction was monitored with a spotting plate. After confirming that the raw materials had completely reacted, the reaction was stopped. Water was added to the reaction solution in an ice bath to quench the lithium aluminum hydride until the solution turned grayish white. It was suction filtered, and the filtrate was extracted 3 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 was complete, it was concentrated under reduced pressure to remove ethyl acetate, and a pale yellow solid (20.23 g), which was the crude product of 4-cyclohexyl-3,5-dimethoxybenzyl alcohol, was obtained, with a yield of 83%.

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

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

[0114]

Chemical formula

[0115] 4-Cyclohexyl-3,5-dimethoxybenzyl alcohol (16.13 g, 64.43 mmol) and dichloromethane (30 mL) were added to a one-necked flask and stirred until dissolved. While in an ice bath, thionyl chloride (11.50 g, 96.65 mmol) was added dropwise to the one-necked flask, and white smoke was generated. After adding thionyl chloride, the ice bath was removed and the reaction was carried out at room temperature for 2 h. The reaction was monitored with a spotted plate, and after confirming that the raw materials had completely reacted, the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove dichloromethane and excess thionyl chloride. It was extracted three times with ethyl acetate (50 mL) and water (50 mL). The ethyl acetate phases were combined, washed with a saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. After drying was complete, it was concentrated under reduced pressure to remove ethyl acetate, and a black oily substance (15.22 g), which was the crude product of 4-cyclohexyl-3,5-dimethoxybenzyl chloride, was obtained, and the yield was 87.9%.

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

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

[0118]

Chemical formula

[0119] 4-Cyclohexyl-3,5-dimethoxybenzyl chloride (11.81 g, 43.94 mmol) was added to a one-necked flask, and triethyl phosphite (43.80 g, 263.63 mmol) was added. The mixture was stirred until dissolved. It was replaced with nitrogen gas three times. The reaction solution was gradually heated to 160 °C and reacted for 5 h. The reaction was monitored with a spotted TLC plate. After confirming that the raw materials had completely reacted, the reaction was stopped and cooled to room temperature. After concentration under reduced pressure to remove the solvent, the crude product was slurried three times with n-hexane (100 mL) to obtain a pale yellow solid (15.62 g) of diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate. 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]

Chemical formula

[0122] Add diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.08 g, 2.92 mmol) and tetrahydrofuran (15 mL) to a three-necked flask, stir and dissolve. Replace with nitrogen gas three times. Add 60% sodium hydride (466.5 mg, 11.66 mmol) to the three-necked flask in portions in an ice bath. After the addition is complete, react for 1 h. Slowly add dropwise a solution of benzaldehyde (4.37 mmol) in tetrahydrofuran (dissolve 464.1 mg of benzaldehyde in 10 mL of tetrahydrofuran) to the three-necked flask. After the addition is complete, slowly raise the temperature to 70 °C and react for 4 h. Monitor the reaction with a spotted TLC plate. After confirming that the raw materials have completely reacted, stop the reaction. Add water to the three-necked flask in an ice bath to quench the reaction until no gas is generated, and concentrate under reduced pressure to remove tetrahydrofuran. 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 over anhydrous sodium sulfate. After drying, concentrate under reduced pressure to remove ethyl acetate to obtain a yellow oil (625.2 mg), which is the crude product of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene.

[0123] (E)-2-Cyclohexyl-1,3-dimethoxy-5-styrylbenzene was purified by column chromatography with the mobile phase being petroleum ether:ethyl acetate = 50:1. Concentrate the mobile phase until dry to obtain a yellow solid (451.1 mg), which is the pure product of (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]

Chemical formula

[0126] Add (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene (451.1 mg, 1.40 mmol) to a one-necked flask, and add pyridine hydrochloride (3.23 g, 27.98 mmol). Replace with nitrogen gas three times. Gradually raise the temperature to 210 °C. After pyridine hydrochloride melted, react for 4 h. Monitor the reaction with a spotted TLC plate. After confirming that the raw material had completely reacted, stop the reaction. Cool the reaction solution to room temperature until it solidified, and extract it 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 over anhydrous sodium sulfate. After drying, concentrate under reduced pressure to remove ethyl acetate, and obtain a 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, and the mobile phase was petroleum ether:ethyl acetate = 30:1. Concentrate the mobile phase 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-d 6 ) 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 [M-H] - 。

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

[0130]

Chemical Structure

[0131] 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 (1.08 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]

Chemical Structure

[0134] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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] 1 H NMR (400 MHz, DMSO-d 6) 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 [M-H] - 。

[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]

Chemical formula

[0138] 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 (1.08 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]

Chemical formula

[0141] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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-d 6 ) 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, 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 [M-H] - 。

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

[0144]

Chemical formula

[0145] 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 (1.08 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]

Chemical formula

[0148] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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-d 6 ) 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, 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 [M-H] - 。

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

[0151]

Chemical Structure

[0152] Refer to the synthesis of (E)-2-cyclohexyl-1,3-dimethoxy-5-styrylbenzene in Example 8. React diethyl 4-cyclohexyl-3,5-dimethoxybenzylphosphonate (1.0 g, 2.70 mmol) and 3-fluorobenzaldehyde (502.6 mg, 4.05 mmol). 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]

Chemical Structure

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

[0156] 1 H NMR (400 MHz, DMSO-d 6) 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 [M-H] - 。

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

[0158]

Chemical Structure

[0159] With reference 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 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]

Chemical Structure

[0162] With reference to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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-d 6 ) 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 [M-H] - 。

[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]

Chemical formula

[0166] With reference 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 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] [Chemical formula]

[0169] With reference to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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-d 6 ) 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 [M-H] - .

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

[0172] [Chemical formula]

[0173] 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-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] [Chemical formula]

[0176] Referring to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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] 1 H NMR (400 MHz, DMSO-d 6) 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 [M-H] - 。

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

[0179]

Chemical formula

[0180] With reference 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 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]

Chemical formula

[0183] With reference to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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-d 6 ) 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 [M-H] - 。

[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]

Chemical formula

[0187] With reference 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 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] [Chemical formula]

[0190] With reference to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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] 1 H NMR (400 MHz, DMSO-d 6) 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 [M-H] - 。

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

[0193]

Chem.

[0194] With reference 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 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]

Chem.

[0197] With reference 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-d 6 ) 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 formula

[0201] With reference 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] With reference 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 H NMR (400 MHz, DMSO-d 6) 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 [M-H] - 。

[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]

Chemical formula

[0208] With reference 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 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]

Chemical formula

[0211] With reference to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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-d 6 ) 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 = 11.1 Hz, 2H), 1.24 - 1.12 (m, 3H). ESI-MS m / z 329.1 [M-H] - 。

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

[0214]

Chemical formula

[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-d 6) 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 Synthesis of (E)-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]

Chemical Structure

[0222] With reference 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 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]

Chemical Structure

[0225] With reference to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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-d 6 ) 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 = 9.8 Hz, 1H), 2.09 (dd, J = 13.0 Hz, 2H), 1.70 (dd, J = 9.6 Hz, 3H), 1.42 (d, J = 11.2 Hz, 2H), 1.34 - 1.22 (m, 3H). ESI-MS m / z 347.1 [M-H] - 。

[0227] Example 23 Synthesis of (E)-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]

Chemical formula

[0229] With reference 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 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] [Chemical formula]

[0232] With reference to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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-d 6) 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 [M-H] - 。

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

[0235]

Chemical Structure

[0236] 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 3,4,5-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]

Chemical Structure

[0239] With reference to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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] 1 H NMR (400 MHz, DMSO-d 6 ) 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 [M-H] - 。

[0241] Example 25 Synthesis of (E)-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]

Chemical formula

[0243] With reference 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 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]

Chemical formula

[0246] With reference to the synthesis of (E)-2-cyclohexyl-5-styryl-1,3-benzenediol in Example 8, the raw 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-d 6) 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 [M-H] - 。

[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]

Chemical formula

[0250] With reference to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the raw materials diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (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]

Chemical formula

[0253] With reference to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the raw 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-d 6 ) 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 [M-H] - 。

[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]

Chemical formula

[0257] With reference to the synthesis of (E)-2-cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the raw materials diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (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] [Chemical formula]

[0260] With reference to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the raw 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] 1 H NMR (400 MHz, DMSO-d 6 ) 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 [M-H] - .

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

[0263] [Chemical Structure]

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

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

[0266] [Chemical Structure]

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

[0268] 1 H NMR (400 MHz, DMSO-d 6) 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 [M-H] - 。

[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]

Chemical Structure

[0271] With reference to the synthesis of (E)-2-Cyclopentyl-1,3-dimethoxy-5-styrylbenzene in Example 3, the raw materials diethyl 4-cyclopentyl-3,5-dimethoxybenzylphosphonate (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]

Chemical Structure

[0274] Referring to the synthesis of (E)-2-cyclopentyl-5-styryl-1,3-benzenediol in Example 3, the raw 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] 1 H NMR (400 MHz, DMSO-d 6 ) 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 [M-H] - 。

[0276] Test Example 1 An activity test was conducted on the compounds of the present invention, and benvitimod, an aromatic hydrocarbon receptor agonist drug that has already been commercially available, and FICZ, a general aromatic hydrocarbon receptor agonist compound, were selected as comparative experimental compounds.

[0277] 1. Cytotoxicity test of test compounds 1) Cytotoxicity test of test compounds in PBMC The specific test compounds are shown in Table 1.

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

[0279] (2) Preparation of cells (i) Cell information: PBMC 5 Million ID#: LP181017 CAT#: PB003F-5M (ii) Cell resuscitation: PBMC cells were taken out of the liquid nitrogen tank, quickly melted in warm water at 37°C, placed in a centrifuge tube containing the culture medium, centrifuged at 1200 revolutions for 11 minutes, the centrifuge tube was taken out and the culture medium was discarded, and 5 mL of the culture medium was aspirated with a burette to resuspend the cells. (iii) Cell counting: The cell counting software was launched, and the cell type was selected as PBMC and the viable cell concentration as 3.47×10 5 cells / mL.

[0280] (3) Cell administration Seeding and administration of cells: The cell suspension was diluted to 7 mL, and the cells were seeded in a 96-well plate. 100 μL of the cell suspension was added to each well, and 100 μL of the drug solutions of Series 1# to 8#, Control 1#, Control 2#, and Control 3# with a concentration of 2 μM was further added to each well, with 3 parallel wells in each group. Finally, the number of viable cells in each well was approximately 2.5×10 4 cells, and the drug concentration was 1 μM.

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

[0282] Taking the absorbance of the control group as 100%, the cell viability after the treatment with each compound was calculated.

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

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

[0285] Cell resuscitation: HepG2 cells were taken out of the liquid nitrogen tank, quickly melted in warm water at 37°C, the cells were put into a centrifuge tube containing the culture medium, centrifuged at 1200 revolutions for 11 minutes, the centrifuge tube was taken out and the culture medium was discarded, 5 mL of the culture medium was aspirated with a burette to resuspend the cells.

[0286] (3) Administration of cells The cell suspension was diluted to 7 mL, and the cells were seeded into a 96-well plate. 100 μL of the cell suspension was added to each well, and 100 μL of the drug solutions of Series 1# to 8#, Control 1#, Control 2#, and Control 3# with a concentration of 2 μM was further added to each well, and there were 3 parallel wells in each group. Finally, the number of viable cells in each well was about 2.0×10 4 cells, and the drug concentration was 1 μM.

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

[0288] As can be seen from Figure 1 and Figure 2, at the test concentrations, all the compounds did not have an obvious effect on the cell activity of PBMC and HepG2.

[0289] 2. AhR agonist experiment of the compound Based on the results of the compound in the reporter gene experiment, the AhR agonist effect of the compound was evaluated.

[0290] (1) Cell transfection: HepG2 cells were seeded in 6-cm cell culture dishes and allowed to adhere overnight. When the cell confluence reached 80%, the medium was replaced with fresh medium, and the transfection working solution was added. The cells were transfected overnight. The composition of the working solution was 1 mL of Opti-MEM + 7.5 μg of pCMV-AHR + 7.5 μg of pTK-3X DRE-Luc + 30 μL of lipo6000.

[0291] (2) Cell seeding: The transfected cells were digested and a cell suspension with a concentration of 3×10 5 cells / mL was prepared. The cells were seeded in 96-well plates at 100 μL / well and allowed to adhere overnight.

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

[0293] (4) Administration of drugs The prepared drug-containing medium and blank medium were added to the above 96-well plates at 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

[0296] As can be seen from the data in Table 1, all of the compounds 1# to 16# of the present invention have AhR activity, and among them, all of the test compounds 2# to 16# have a good AhR agonist effect.

[0297] 3. Regulatory effect of the compound on PBMC cytokine secretion (1) Cell information: Mononuclear cells derived from bone marrow. (2) Cell seeding and administration: After taking out PBMC cells from the liquid nitrogen tank and reviving them, 80 μL of medium was added to a 96-well plate at 200,000 cells / well. 80 μL of medium containing 2 μM or 0.2 μM of the drug solutions of Compound 2#, 6#, and Control 1# was aspirated and added to the 96-well plate respectively, and finally the drug concentrations were 1 μM and 0.1 μM. Each well was pre-treated by standing at this concentration for 1 h. After the pre-treatment, the drug solution was removed from the well, and 80 μL of a 1 μM or 0.1 μM solution of 15 μg / mL PHA (phytohemagglutinin) was added to the corresponding well. After 24 h of stimulation, the cytokine content in the medium was detected. Blank control group: Normal medium without any drug added to the cells PHA group: 80 μL of a medium solution containing 15 μg / mL PHA without the compound of the present invention was added to the corresponding well.

[0298]

Table 2

[0299] The test results showed that both Compound 2# and 6# could inhibit cytokines TNFa and IL4 at two concentrations of 0.1 μM and 1 μM, and the inhibitory effects of Compound 2# and 6# on TNFa and IL4 were significantly greater than those of Control 1# (benvitimod), exceeding twice that of Control 1# at a dose of 1 μM.

[0300] 4. Effect of the compound on DSS-induced colitis (1) Experimental animals: 40 male C57BL / 6 mice, 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 protocol: Forty mice were randomly divided into four groups of 10 each, namely the blank group, the model group, the drug control 1# group, and the compound 6# group. The normal blank group was allowed to drink distilled water freely, and the remaining three groups were allowed to drink a 2.5% DSS aqueous solution continuously for 8 days. The solution was checked daily and replaced with fresh DSS solution. On the first day of modeling, drug therapy was administered. The normal blank group was administered the corresponding physiological saline solution, the enteritis model group was administered the solvent-based solution, and the test drug control 1# and compound 6# groups were administered the corresponding drugs intragastrically at a dose of 10 mg / kg. The body weight of the mice was recorded daily, and their diarrhea and bloody stool conditions were observed and scored. On the 9th day, the mice were sacrificed, and blood and colon were collected. Also, the conditions such as intestinal length and occult blood in cecal contents were recorded.

[0301] Preparation method of test drug: Weigh 1.00 mg of drug powder, add 20 μL of DMSO, dissolve it thoroughly, then add 20 μL of Tween 80 and mix uniformly, add 0.96 mL of Wahaha purified water, and mix uniformly to prepare a 1 mg / mL drug solution, which was administered at 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 mixed uniformly (for the model group).

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

[0304] As shown in Figure 4, the disease activity index (comprehensive score based on weight change and blood in stool status) data indicated that both the compound 6# group and the control 1# benvitimod group had excellent therapeutic effects, among which the effect of the compound 6# group was more significant.

[0305] 5. Effects on atopic dermatitis (1) Construction of atopic dermatitis model After adaptively breeding 56 6- to 8-week-old clean-grade BALB / C mice for 5 days, they were randomly divided into 7 groups of 8 mice each. (i) Blank control group (ii) Modeling + solvent group (iii) Modeling + blank matrix group (iv) Modeling + positive drug mometasone furoate group (v) Modeling + 1% (mass percentage) benvitimod group (vi) Modeling + 1.2% (mass percentage) of compound 2# (prepared with blank matrix) (vii) Modeling + 1.2% (mass percentage) of compound 6# (prepared with blank matrix)

[0306]

Chemical formula

[0307] As shown in the following steps, after depilation with rosin paraffin, 50 μL of 2,4-dinitrofluorobenzene (DNFB) at 0.5% (W / V, the solvent was an acetone-olive oil mixture (acetone:olive oil = 3:1)) was applied to the back of each mouse, and 50 μL of 0.25% (W / V) DNFB was administered at midday on the 4th, 6th, and 8th days. The blank control group was applied with an equal amount of solvent control. The animal experiment complied with the Experimental Animal Breeding Management and Use Manual of China Pharmaceutical University and followed the animal ethics regulations.

[0308]

Table 3

[0309] Number of days (2) Administration mode As shown in the above steps, modeling was performed by applying solvent control or DNFB in the morning; starting from the 5th day, the drug ointment to be measured was applied once at 50 mg every afternoon so that the drug was uniformly applied to the skin surface. The specific administration method was as shown above.

[0310] Specific operations were as follows. As shown in the above grouping, group (ii) was applied with 50 mg of solvent (acetone: olive oil = 3:1) once every afternoon starting from the 5th day, group (iii) was applied with 50 mg of blank matrix once every afternoon starting from the 5th day, and groups (iv), (v), (vi), and (vii) were applied with 50 mg of the positive drugs mometasone furoate, 1% benvitimod, 1.2% compound 2#, or 1.2% compound 6# respectively starting from the 5th day according to the grouping.

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

[0312] (i) Erythema / bleeding (ii) Dryness (iii) Exudation / crust (iv) Edema. The severity of the appearance of dermatitis was evaluated from these four indicators. Each indicator was scored from 0 to 3 points, and the scores of the four indicators were added up to obtain the total score. The AD Score scoring criteria were as follows. 0 was asymptomatic, 1 was mild symptoms, 2 was moderate symptoms, and 3 was severe symptoms. On the 0th, 4th, 6th, 8th, and 10th days of modeling, the back skin of each mouse was photographed and the scores were recorded.

[0313]

Table 4

[0314] The surface observation diagram was shown in Figure 5.

[0315] 6. Drug permeability experiment Test steps Drugs awaiting measurement: 2# compound cream with a mass percentage of 1.2%, 6# compound cream with a mass percentage of 1.2%, and bendamod cream with a mass percentage of 1.0%

[0316]

Chem.

[0317] (1) Preparation of semi-permeable membrane: The pre-prepared semi-permeable membrane was taken out of the refrigerator.

[0318] (2) Preparation of receiving solution: Weighed 100 mL of polyethylene glycol 400 solution, made up the volume to 250 mL with physiological saline, mixed uniformly, stored at 4 °C, and preheated to 32 °C before putting it into the receiving pool.

[0319] (3) In vitro diffusion test: Using a drug percutaneous diffusion machine, the treated semi-permeable membrane was fixed in the center of the supply pool and the receiving pool, a constant temperature water bath at 32 °C was circulated, first equilibrated for 30 min, the receiving solution was exchanged to expel the air in the lower layer. Approximately 0.5 g of cream was uniformly added to the supply pool and uniformly applied. At a magnetic stirring rotation speed of 600 r / min, 1 mL of sample solution was taken out from the receiving pool at 0.5, 1, 2, 4, 6, and 24 h respectively, and at the same time, an equal amount and isothermal fresh receiving solution was replenished.

[0320] The actual sampling time points were 0.5, 1, 2, 4, 6, and 24 h. The 1 mL of sample taken was also directly put into the liquid phase vial. At the same time, an equal amount and isothermal fresh receiving solution was replenished. The drug permeation rate was calculated by liquid phase detection.

[0321] Cream - Diffusion Test - Rabbit Skin Test Steps (1) Ex vivo production of rabbit skin (2) Preparation of receiving solution: Weighed 100 mL of polyethylene glycol 400 solution, made up the volume to 250 mL with physiological saline, mixed uniformly, stored at 4 °C, and preheated to 32 °C before putting it into the receiving pool.

[0322] (3) In vitro percutaneous test: Using a drug percutaneous test diffusion tester, the treated rabbit skin was fixed in the center of the supply pool and the receiving pool, with the stratum corneum facing the supply pool. A 32 °C constant temperature water bath was circulated. First, it was equilibrated for 30 min, the receiving solution was exchanged, the air under the skin was expelled, and the liquid on the skin surface was absorbed with filter paper until it dried. 0.5 g of cream was uniformly added to the supply pool and uniformly applied. At a magnetic stirring rotation speed of 600 r / min, 1 mL of sample solution was taken out from the receiving pool at 0.5, 1, 2, 3, 4, 5, 7, 9, 12, and 24 h and placed in a liquid phase vial, and at the same time, an equal amount and isothermal fresh receiving solution was replenished. The drug permeation rate was calculated by liquid phase detection.

[0323] The detection results of the drug permeation rate at 24 h are shown in Figure 6.

[0324] As shown in Figure 6, in the two test systems, the trends of the 24-hour drug permeation rates of the three creams were consistent, and in both cases, the commercially available control drug benvitimod > 2# > 6#. The results indicated that the creams prepared with Compound 2# and 6# of the present invention had low percutaneous absorption, low blood exposure levels, and lower system adverse reactions than the commercially available control drug benvitimod.

[0325] 7. Mouse psoriasis test I. Pharmacodynamic evaluation of Compound 6# against imiquimod (IMQ)-induced mouse psoriasis. Structure of the compound:

[0326] [Chemical formula]

[0327] II. Group setting (1) Vaseline + blank matrix group, 10 mice (2) IMQ + blank matrix group, 10 mice (3) IMQ + Compound 6# group (preparing a drug with a mass percentage of 1.2% in the blank matrix), 10 mice.

[0328] IMQ is imiquimod III. Preparation of Drugs IMQ is 5% imiquimod (imiquimod is used for the development of psoriasis on the surface of modeling mice). A 1.2% compound 6# drug was prepared with a blank matrix. IV. Animals Species and Strain: SPF-grade KM mice, male Body Weight: 35 - 40 g Source: Beijing Speefoo Biotechnology Co., Ltd. Breeding Conditions: Air-conditioned room, temperature 18 - 26°C, relative humidity 20% - 60%.

[0329] V. Test Steps Skin Preparation: The mice were allowed to drink water and eat freely. After entering the animal room and adapting for 5 days, the hair on an area of 2 cm × 2.5 cm on the back of the mice was removed with a clipper. After applying depilatory cream for 30 s - 1 min, the depilatory cream was cleaned with a cotton ball.

[0330] Random Grouping: 24 hours after depilation, 75 mice were randomly divided into 4 groups according to body weight: 10 mice in the Vaseline + Blank Matrix group, 10 mice in the IMQ + Blank Matrix group, and 10 mice in the IMQ + Compound 6# group (a 1.2% drug prepared with a blank matrix).

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

[0332] Experimental Record: Before modeling in the morning, the conditions of wrinkles, erythema, and scales were observed daily, scores were recorded and photographed, and the PASI score of the mice was calculated.

[0333]

Table 5

[0334]

Table 6

[0335] The test results are as shown in Table 5 and Figure 7 above. For the comparison between the IMQ + Compound 6# and the IMQ + blank matrix of the present invention, the significant difference P-value on the 7th day is 0.0002, indicating a significant difference. That is, compared with the IMQ + blank matrix which is the modeling control group, Compound 6# of the present invention has a significantly better therapeutic effect.

Brief Description of the Drawings

[0336]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein 【Chemical 1】 X is selected from halogen, and n is from 1 to 5, R is selected from a substituted or unsubstituted 3- to 7-membered cycloalkyl or cycloalkenyl group, a substituted or unsubstituted 3- to 7-membered heterocyclyl group, The replacement is C 1-6 alkyl group, C 1-6 substituted with at least one of an alkoxy group and a halogen a compound or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. Characterized in that X is F and / or Cl, a compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3. The above-mentioned substituted or unsubstituted C 3 ~C 7 The heterocyclic group is an N-containing heterocyclic group, and the above-mentioned substitution is C 1-6 alkyl group, C 1-6 characterized in that it is substituted with at least one of an alkoxy group and a halogen a compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

4. The following compound: [Chemical 2] Characterized in that it is selected from, a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

5. A compound of formula (II) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. [Chemical Formula 3]

6. Use of at least one of the compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and the compound of formula (II) according to claim 5, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, for the manufacture of a medicament, wherein the medicament is used for treating cancer, autoimmune deficiency and other diseases having immunological factors, or the medicament is used for preventing and / or treating a disease or disorder mediated by the aryl hydrocarbon receptor (AhR), or the medicament is used 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, and for preventing and / or treating diseases caused by abnormal cytokines.

7. The autoimmune deficiency diseases are 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, Sjogren's syndrome, polymyositis, vasculitis, polymyalgia rheumatica, immune thrombocytopenia, dry eye, type 1 diabetes, psoriasis and arthritis, the use according to claim 6. Claim 8 The disease or disorder having the immunological factor is one or more selected from asthma, allergy, infectious disease, osteoporosis, arteriosclerosis, type 2 diabetes, graft-versus-host disease, and transplant rejection, The use according to claim 6. Claim 9 Characterized by comprising at least one of a pharmaceutically acceptable carrier or excipient, the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and the compound of formula (II) according to claim 5 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, Pharmaceutical composition. Claim 10 A method for producing the compound according to any one of claims 1 to 4, comprising reacting compound IMe with compound SMc to obtain compound IMf, and reacting compound IMf under acidic conditions to obtain the compound represented by formula (I), 【Chemical 4】 wherein X is selected from halogens and n is an integer from 1 to 5, R is selected from a substituted or unsubstituted 3- to 7-membered cycloalkyl group or cycloalkenyl group, and a substituted or unsubstituted 3- to 7-membered heterocyclyl group, and the substitution is C 1-6 alkyl group, C 1-6 alkoxy group, or halogen, and is characterized by being substituted with at least one of them.

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