Phenol derivatives and their applications in medicine

Abstract

The present invention provides a GABAA receptor agonist phenol derivative having a novel structure, better efficacy, effectively reducing side effects, and being more clinically safe, specifically, the compound shown in the following formula (I), its stereoisomer, pharma- ceutically acceptable salt, pharmaceutical composition containing the same, and use of the compound or composition of the present invention in the field of central nervous system. It provides more and better drug selection routes for inducing and / or maintaining anesthesia in animals or humans, promoting sedation-hypnosis, treating and / or preventing anxiety, nausea, vomiting, migraine, convulsions, epilepsy, neurodegenerative diseases, and diseases related to the central nervous system. [Formula 1] JPEG2024504518000055.jpg42148

Description

[Technical field]

[0001] The present invention relates to the field of medicinal chemistry, specifically to phenol derivatives and their stereoisomers, pharma-ceutically acceptable salts, and the use of the compounds of the present invention in the manufacture of drugs for treating central nervous system diseases. [Background technology]

[0002] GABA A The receptor is the major inhibitory neurotransmitter receptor in the central nervous system and is composed of a pentamer of transmembrane polypeptide subunits, with 19 different subunits capable of expressing many different GABA receptors. A Constituting the receptor subtype GABA A The GABA receptor is involved in the pathogenesis and diagnosis and treatment of various diseases such as anesthesia, depression, anxiety, epilepsy, memory disorders, and drug addiction. A Receptors are pharmacologically and clinically important targets of drug action. Propofol and its derivatives bind to the GABA receptors. A It is an important compound that targets

[0003] Propofol acts by inhibiting the action of various GABA A It can activate receptor subtypes and is widely used in the induction and maintenance of general anesthesia. The remarkable pharmacokinetic and pharmacodynamic properties of propofol are rapid onset, short duration and rapid reversibility. After intravenous administration, propofol rapidly enters high perfusion areas such as the heart, lungs and liver from the blood, and its high lipid solubility allows propofol to easily cross the blood-brain barrier and enter the brain to exert its general anesthetic effect.

[0004] As the clinical application of propofol deepens, its not insignificant limitations and drawbacks have been reported one after another. It has been reported that about 70% of patients experience some degree of pain or discomfort when propofol is injected. Propofol has been shown to reduce systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure, so it can cause clinical hypotension. At the same time, respiratory depression is also a non-negligible risk when using propofol. These side effects greatly hinder the use of propofol in some clinical cases, such as cardiovascular disease, brain injury, and chronic hypotension.

[0005] Phosphopropofol sodium is a water-soluble prodrug of propofol that is rapidly hydrolyzed by alkaline phosphatase to release propofol, phosphate and formaldehyde. Phosphopropofol sodium relieves pain at the site of intravenous injection of propofol, but it still exerts its effect in the form of propofol drug substance, so there is a risk of respiratory depression and poor hemodynamic effects, and at the same time, phosphopropofol sodium may cause paresthesia and pruritus.

[0006] In response to the limitations and shortcomings of propofol and linpropofol, new GABA derivatives with better pharmacokinetic and pharmacological properties and fewer side effects are A There is a need to develop receptor agonists.

[0007] Patent US20050032753A1 describes phenol derivatives for anesthesia and sedation, where R 1 and R 2 is independently C 1-8 Alkyl group, C 1-8 cycloalkyl groups; L is a covalent bond; C 1-12 R is selected from hydrocarbyl groups; 3 is -C(=O)OR a where R a is C 1-12 is selected from hydrocarbyl groups, [ka]

[0008] The present invention further discloses the following formula: wherein R4 is a C1-C5 alkyl group, a C2-C5 alkenyl group, or a C2-C5 alkynyl group; R5 is a C1-C6 alkyl group, a C3-C8 cycloalkyl group, and R6 is methyl; or R5 and R6 together with the carbon atom to which they are attached are a C 3-8 forming a cycloalkyl group, and R a is a C1-C8 alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group or a C3-C8 cycloalkyl group. However, none of the compounds disclosed in the patent are included in the general structural formula claimed in the present invention, and the patent does not disclose any efficacy data of any specific compounds, so that a person skilled in the art cannot know from the patent whether the difference of each substituent will cause a difference in efficacy, and the patent does not suggest that a person skilled in the art make further improvements in a certain direction to obtain a specific compound structure with better efficacy. The patent is significantly different from the structure of the compound of the present invention, and the specific description in the patent is not recognized as part of the present invention. [ka]

[0009] Patent CN104507899A discloses a phenol derivative and its preparation method, and its use in the field of central nervous system. It discloses the following general formula. The patent is significantly different from the structure of the compound of the present invention, and the specific description in this patent is not recognized as part of the present invention. [ka]

[0010] Patent CN104507898A discloses a phenol derivative and its preparation method, and its use in the field of central nervous system. It discloses the following general formula. The patent is significantly different from the structure of the compound of the present invention, and the specific description in this patent is not recognized as part of the present invention. [ka] Summary of the Invention

[0011] The object of the present invention is to provide a GABA receptor antagonist having a novel structure, better efficacy, effectively reduced side effects, and greater clinical safety, so as to provide more and better drug choice routes for inducing and / or maintaining anesthesia in animals or humans, promoting sedation-hypnosis, and treating and / or preventing anxiety, nausea, vomiting, migraine, convulsions, epilepsy, neurodegenerative diseases, and diseases related to the central nervous system. A The present invention relates to a receptor agonist phenol derivative, a stereoisomer thereof, and a use thereof in the field of central nervous system.

[0012] According to one aspect of the present invention, a compound of general formula (I): [ka] (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof; Where: X is S, -OC(=O)-, [ka] is selected from R1 is C 1-6 Alkyl groups of C 1-6 Alkenes, C 1-6 wherein the alkyl, alkene, alkyne, heterocycloalkyl group, and cycloalkyl group are optionally further substituted with one or more R; R2 and R3 are independently H, a hydroxyl group, F, or C. 1-6 Alkyl groups of C 1-6 Alkenes, C 1-6 Alkynes, 3-6 membered heterocycloalkyl groups, C 1-6alkoxy groups, CN, NH2, and 3- to 6-membered cycloalkyl groups, wherein the alkyl groups, alkenes, alkynes, heterocycloalkyl groups, alkoxy groups, and cycloalkyl groups can be optionally further substituted with one or more R; or alternatively, R2 and R3 can form (=O); R4 is H, F, Cl, Br, I, hydroxyl group, C 1-6 Alkyl group, C 1-6 is selected from an alkoxy group, a 3- to 5-membered cycloalkyl group, or a 3- to 5-membered heterocyclo group; or alternatively, R1 and R4, together with the atom to which they are attached, form a 4- to 6-membered cycloalkyl or heterocyclo group fused to a benzene ring, said cycloalkyl or heterocyclo group being optionally further substituted with one or more R; R5 is a C2-C5 alkenyl group, a C2-C5 alkynyl group, 1-6 is selected from an alkyl group and a 3- to 6-membered cycloalkyl group, and the alkyl group and cycloalkyl group can be optionally further substituted with one or more R; R6 is C 1-6 is selected from an alkyl group, a 3- to 6-membered cycloalkyl group, and NHR7, and the alkyl group and cycloalkyl group can be optionally further substituted with one or more R; R7 is C 1-6 is selected from the alkyl or cycloalkyl groups Y is H, Na, K, [ka] , -(CH2) m COOR 12 , [ka] , C 1-10 alkyl groups, said alkyl groups being optionally further substituted with one or more R; R8 and R9 are each independently H or C 1-6Alkyl group, C 1-6 selected from an alkoxy group, F, Cl, Br, I, a hydroxyl group, an amino group, a cyano group, and a carboxyl group; or optionally, R8 and R9 together with the atoms to which they are attached form a 5-8 membered ring, said 5-8 membered ring optionally containing 0-4 heteroatoms selected from N, O and S; R 10 and R 11 are independently H, C 1-6 The alkyl group is selected from an alkyl group, an alkali metal ion, an alkaline earth metal ion, a protonated amine, or a protonated amino acid, and the alkali metal ion is selected from Na + , K + , Li + and the alkaline earth metal ion is selected from Be 2+ , Mg 2+ or Ca 2+ wherein the amine is selected from tromethamine, triethanolamine, ethanolamine, triethylamine, or N-methylglycolamine, and the amino acid is selected from arginine or lysine; R 12 are independently H, C 1-6 is selected from an alkyl group, a 3- to 8-membered cycloalkyl group, or a 4- to 8-membered heterocyclo group, and the alkyl group, the cycloalkyl group, and the heterocyclo group can be optionally further substituted with one or more R; R is F, Cl, Br, I, deuterium, hydroxyl, carbonyl, carboxyl, CN, NH2, C 1-6 Alkyl group, C 1-6 is selected from an alkoxy group, a 3- to 5-membered cycloalkyl group, or a 3- to 5-membered heterocyclo group; n is selected from 0, 1, 2, and 3; m is selected from 0, 1, 2, 3, and 4.

[0013] In some preferred embodiments according to the present invention, the compound has the general formula (II): [ka] (II) where X is S, [ka] is selected from.

[0014] In another preferred embodiment according to the present invention, the compound has the general formula (III): [ka] (III) Where: X is S, [ka] is selected from R1, R2, R5, and R6 are each independently C 1-6 and 3- to 6-membered cycloalkyl groups.

[0015] Preferably, R1 is C 1-6 and a 3- to 6-membered cycloalkyl group, R2 is H, hydroxyl group, C 1-6 Alkyl groups of C 1-6 selected from an alkoxy group and a 3- to 6-membered cycloalkyl group; R5 is C 1-6 and a 3- to 6-membered cycloalkyl group, R6 is C 1-6 and 3- to 6-membered cycloalkyl groups, and the alkyl and cycloalkyl groups can be optionally further substituted with one or more R.

[0016] Preferably, R2 is H, hydroxyl group, C 1-6 Alkyl groups of C 1-6 selected from an alkoxy group and a 3- to 6-membered cycloalkyl group; R1 and R4, together with the atom to which they are attached, form a 4- to 6-membered cycloalkyl group or heterocyclo group fused to a benzene ring, and the cycloalkyl group or heterocyclo group can be optionally further substituted with one or more R; R5 is C 1-6 and a 3- to 6-membered cycloalkyl group, R6 is C 1-6 and 3- to 6-membered cycloalkyl groups.

[0017] Preferably, R2 is independently C 1-6 and a 3- to 6-membered cycloalkyl group, R4 is selected from H; R6 is C 1-6 and 3- to 6-membered cycloalkyl groups, wherein the alkyl and cycloalkyl groups can be optionally further substituted with one or more R; R is selected from F, Cl, Br, and I.

[0018] Preferably, R1 and R4 together with the atom to which they are attached form a 4- to 6-membered cycloalkyl group fused to a benzene ring, said cycloalkyl group optionally being further substituted with one or more R; R is C 1-6 Alkyl group, C 1-6 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0019] In another preferred embodiment of the present invention, [ka] [ka] This includes compounds of the formula:

[0020] According to another aspect of the present invention, there is provided a pharmaceutical composition, comprising a compound of the present invention as described above or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable vectors.

[0021] The pharmaceutical composition according to the present invention may be in any pharma- ceutically acceptable dosage form, such as tablets, capsules, dispersible tablets, granules, injections, lipid emulsions, aerosols, powder mists, sprays, oral solutions, oral suspensions, and the like.

[0022] The present invention further provides the use of the compound according to the present invention, or its stereoisomer, or pharma- ceutically acceptable salt, and pharmaceutical composition thereof, in the manufacture of a drug for inducing and / or maintaining anesthesia in animals or humans, promoting sedative-hypnotic sleep in animals or humans, and treating and / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy.

[0023] Unless otherwise stated, terms used in the specification and claims have the following meanings.

[0024] The "alkyl group" is a linear or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, and further preferably an alkyl group having 1 to 4 carbon atoms. Examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

[0025] An "alkoxy group" is an -O-alkyl group, such as a methoxy group, an ethoxy group, an n-propoxy group, or an isopropoxy group.

[0026] The "cycloalkoxy group" is a group in which the above-mentioned cycloalkyl group is bonded via an oxygen atom. Examples of the 3- to 6-membered cycloalkoxy group include a cyclopropyloxy group and a cyclohexyloxy group.

[0027] A "cycloalkyl group" is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 (e.g., 3, 4, 5, or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0028] A "heterocyclo group" is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, in which one or more of the ring atoms is nitrogen, oxygen, or S(O). m (where m is an integer of 0 to 4), but does not include the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 cycloatoms, where 1 to 4 are heteroatoms, preferably it contains 3 to 8 cycloatoms, where 1 to 3 are heteroatoms, preferably it contains 3 to 6 cycloatoms, where 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclo groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, and preferably, it is tetrahydropyranyl, piperidinyl, or pyrrolidinyl. Polycyclic heterocyclo groups include spirocyclic, fused ring, and bridged ring heterocyclic groups.

[0029] "Stereoisomers" are isomers that result from differences in the spatial arrangement of atoms in molecules, and include cis isomers, conformational isomers, and conformational isomers.

[0030] "Optionally," "optionally," or "selectively" means that the event or circumstance after which the said event or circumstance may occur, but does not necessarily occur, and the statement includes instances where the event or circumstance occurs and instances where it does not occur. For example, "a heterocyclo group optionally substituted with an alkyl group" means that the alkyl group may be present, but is not necessarily present, and the statement includes instances where the heterocyclo group is substituted with an alkyl group and instances where the heterocyclo group is not substituted with an alkyl group. [Brief description of the drawings]

[0031] [Figure 1] FIG. 1 is a graph showing changes in heart rate over time after administration of a test compound to a beagle dog. [Diagram 2] FIG. 1 shows the time course of blood pressure changes after administration of a test compound to a beagle dog. [Diagram 3] FIG. 1 is a graph showing changes in body temperature over time after administration of a test compound to a beagle dog. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] The following provides a detailed description of the implementation process of the present invention and the beneficial effects that arise through specific examples, which are intended to help those skilled in the art better understand the essence and characteristics of the present invention and are not intended to limit the scope of the present invention.

[0033] Example 1 Synthesis of compound 1 (2-isopropyl-6-(1-(methylsulfonyl)ethyl)phenol) [ka]

[0034] Step 1: Synthesis of compound 1-2 (2-isopropylphenylacetate) Compound 1-1 (10 g, 73.43 mmol, 1.0 eq) and DMAP (897 mg, 9.34 mmol) were added to 200 mL of dichloromethane, and acetic anhydride (9.74 g, 95.45 mmol, 1.3 eq) was added dropwise at 15°C. After the addition was completed, the temperature was slowly raised to room temperature and the reaction was carried out at 15°C for 16 h. The reaction solution was then neutralized to pH = 6-7 with 1N hydrochloric acid solution, extracted with dichloromethane (150 mL x 3), the organic phases were combined, the solvent was removed by spin evaporation, and the mixture was separated by column. 酢酸エチル :V 石油エーテル Using a 1:10 mixture as an eluent, compound 1-2 (13.16 g, yield: 99.1%) was obtained as a yellow transparent oil.

[0035] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.34-7.31(m,1H),7.24-7.18(m,2H),7.01-6.98(m,1H),3.05-3.01(m,1H),2.33(s,3H),1.23(d,J=8.0Hz,6H).

[0036] Step 2: Synthesis of compound 1-3 (1-(2-hydroxy-3-isopropylphenyl)ethan-1-one)

[0037] Compound 1-2 (13.09 g, 73.45 mmol, 1.0 eq) was mixed with aluminum trichloride (10.58 g, 79.32 mmol, 1.1 eq), and the reaction mixture was then heated to 140° C. and reacted for 5 hours. After monitoring the completion of the reaction by TLC, the reaction mixture was poured into 200 mL of saturated NH4Cl, filtered, separated, the organic phase was removed from the solvent, and column-separated, and the V 石油エーテル :V 酢酸エチル = 50:1 to 20:1 was used as the eluent to obtain a yellow transparent oily compound 1-3 (1.61 g, yield: 12.3%).

[0038] Feature data: 1H NMR(400MHz,CDCl3)δ 12.70(s,1H),7.61-7.59(m,1H),7.43-7.41(m,1H),6.89-6.85(m,1H),3.40-3.35(m,1H),2.64(s,3H),1.26-1.23(m,6H).

[0039] Step 3: Synthesis of compound 1-4 (2-(1-hydroxyethyl)-6-isopropylphenol)

[0040] Compound 1-3 (800 mg, 4.49 mmol, 1.0 eq) was added to 15 mL of dried methanol, and NaBH4 (255 mg, 6.73 mmol, 1.5 eq) was added and reacted at room temperature for 0.5 hours. The reaction solution was poured into 10 mL of saturated aqueous ammonium chloride solution, extracted with DCM (50 mL x 4), and the organic phase was combined and the solvent was removed by spinning to obtain yellow oily compound 1-4 (809 mg, yield: 100%).

[0041] Feature data: 1 H NMR(400MHz,CDCl3)δ 8.13(s,1H),7.15-7.13(m,1H),6.85-6.81(m,2H),5.10-5.04(m,1H),3 .41-3.32(m,1H),2.40(s,1H),1.62(d,J=8.0Hz,3H),1.28-1.20(m,6H).

[0042] Step 4: Synthesis of compound 1-5 (2-isopropyl-6-(1-(methylthio)ethyl)phenol)

[0043] Compound 1-4 (0.75 g, 4.16 mmol) was added to methyl mercaptan (2.40 g, 10% propylene glycol solution, 4.99 mmol, 1.2 eq) under nitrogen gas protection, and hydrochloric acid (230 mg, 6.24 mmol, 1.5 eq) was added dropwise to the reaction solution. The reaction system was stirred at 25°C for 16 hours, and TLC (V ヘキサン :V EA=5:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with H2O, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V n-ヘキサン :V 酢酸エチル = 15:1 to 12:1, and a yellow oily compound 1-5 (440 mg, yield: 50.3%) was obtained.

[0044] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.38(s,1H),7.17-7.15(m,1H),6.92-6.90(m,1H),6.85-6.82(m,1H),4.07-4.02(m,1 H),3.40-3.32(m,1H),1.94(d,J=4.0Hz,3H),1.65(d,J=8.0Hz,3H),1.26-1.21(m,6H).

[0045] Step 5: Synthesis of compound 1 (2-isopropyl-6-(1-(methylsulfonyl)ethyl)phenol)

[0046] Under the protection of nitrogen gas, compound 1-5 (140 mg, 0.666 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (240 mg, 1.332 mmol, 2.0 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 0 to 5 °C for 1.5 hours. TLC (V ヘキサン :V EA =2:1) ​​When it was detected that the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (20 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル = 10:1, and compound 1 (60.0 mg, yield: 37.3%) was obtained as a yellow oil.

[0047] Feature data: 1H NMR(400MHz,CDCl3)δ 7.26-7.24(m,1H),7.12-7.10(m,1H),7.01-6.97(m,1H),6.85(s,1H),4.63-4.58 (m,1H),3.37-3.30(m,1H),2.76(s,3H),1.83(d,J=8.0Hz,3H),1.26-1.23(m,6H).

[0048] Example 2 Synthesis of compound 2 (2-isopropyl-6-(1-(methylsulfinyl)ethyl)phenol) [ka]

[0049] Under the protection of nitrogen gas, compound 1-5 (100 mg, 0.475 mmol) was dissolved in DCM (5 mL), and m-chloroperoxybenzoic acid (48.62 mg, 0.237 mmol, 0.5 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 0 to 5 °C for 0.5 h. TLC (V ヘキサン :V EA =1:1) When it was detected that the raw material had almost completely reacted, the reaction was stopped, the reaction solution was diluted with dichloromethane (20 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル The ratio was 1:1, and compound 2 (28.0 mg, yield: 26.0%) was obtained as a colorless oil.

[0050] Feature data: 1 H NMR(400MHz,CDCl3)δ 9.67(s,1H),7.20-7.18(m,1H),6.86-6.82(m,1H),6.80-6.78(m,1H),3.76-3.70 (m,1H),3.45-3.38(m,1H),2.45(s,3H),1.89(d,J=8.0Hz,3H),1.24-1.21(m,6H).

[0051] Example 3 Synthesis of compound 3 (2-(1-cyclopropylethyl)-6-(1-(methylthio)ethyl)phenol) [ka]

[0052] Step 1: Synthesis of compound 3-2 (1-(2-(but-2-en-1-yloxy)phenyl)ethan-1-one) Compound 3-1 (5.00 g, 73.43 mmol, 1.0 eq) and NaOH (2.94 g, 73.42 mmol) were added to DMF (80 mL) and stirred at 15 ° C for 30 mins, after which 1-chloro-2-butene (a mixture of cis-2, 4.32 g, 47.74 mmol, 1.3 eq) was slowly added dropwise, and after completion of the addition, the system was allowed to react for 16 hours at 15 ° C. After completion of the TLC detection reaction, the reaction solution was further slowly poured into 200 mL of ice water, and further extracted with n-hexane (200 mL × 3), the organic phases were combined, and the solvent was spun off to obtain yellow transparent oily compound 3-2 (6.99 g, yield: 100%).

[0053] Step 2: Synthesis of compound 3-3 (1-(3-(but-3-en-2-yl)-2-hydroxyphenyl)ethyl-1-one)

[0054] Compound 3-2 (6.99 g, 36.72 mmol, 1.0 eq) was added to a 50 mL single-necked vial, and under the protection of nitrogen gas, the air was refluxed and condensed, and the reaction mixture was heated to 210-215 °C and reacted for 3.5 hours. The TLC detection reaction was completed, after which it was diluted with ethyl acetate, mixed, column separated, and V 石油エーテル :V 酢酸エチル =50:1 / 20:1 was used as the eluent to obtain a yellow transparent oily compound 3-3 (1.60 g, yield: 22.9%).

[0055] Feature data: 1H NMR(400MHz,CDCl3)δ 12.70(s,1H),7.63-7.61(m,1H),7.39-7.36(m,1H),6.88-6.85(m,1H),6.05-6.00 (m,1H),5.11-5.05(m,2H),3.98-3.97(m,1H),2.64(s,3H),1.34(d,J=4.0Hz,3H).

[0056] Step 3: Synthesis of compound 3-4 (1-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)ethyl-1-one)

[0057] Under the protection of nitrogen gas, a 100mL three-neck flask was replaced 3 to 5 times, DCM (10mL) was added, the reaction system was cooled to -5 to 0 ° C, diethylzinc (9.46mL, 2.0M, 18.92mmol) was slowly added dropwise to the reaction solution, the addition was completed in about 10 minutes, then trifluoroacetic acid (2.16mg, 18.92mmol) was added (ice ethanol bath) at 5 to 0 ° C, about 5 minutes later, diiodomethane (6.76g, 25.23mmol) was dissolved in DCM (5mL) and added to the reaction solution with a syringe, and the system temperature was maintained at -5 to 0 ° C. After 60 minutes, compound 3-3 (1.2g, 6.31mmol) was dissolved in DCM (5mL) and slowly added dropwise to the reaction, the ice bath was removed after the dropwise addition was completed, the reaction was warmed to 25 ° C, and the reaction was continued with stirring for 48 hours. 1 HNMR and TLC(V ヘキサン :V EA =10:1) When it was detected that the majority of the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (20 mL), and further washed with saturated ammonium chloride solution, the organic phases were combined and washed with saturated saline, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography, the eluent polarity was V. n-ヘキサン :V 酢酸エチル = 60:1 to 15:1, and a yellow oily compound 3-4 (1.1 g, yield: 85.3%) was obtained.

[0058] Feature data: 1H NMR(400MHz,CDCl3)δ 12.63(s,1H),7.63-7.60(m,1H),7.56-7.54(m,1H),6.91-6.87(m,1H),2.64(s,3H),2.52-2.48(m,1H),1.34 -1.27(m,3H),1.03-0.99(m,1H),0.56-0.50(m,1H),0.38-0.30(m,1H),0.24-0.20(m,1H),0.17-0.15(m,1H).

[0059] Step 4: Synthesis of compound 3-5 (2-(1-cyclopropylethyl)-6-(1-hydroxyethyl)phenol)

[0060] Compound 3-4 (1.1 g, 5.39 mmol, 1.0 eq) was added to dry methanol (15 mL), and NaBH4 (265 mg, 7.00 mmol, 1.5 eq) was added little by little and reacted at room temperature for 0.5 hours. The reaction solution was poured into 10 mL of saturated aqueous ammonium chloride solution, extracted with DCM (50 mL x 2), and the organic phases were combined and concentrated to remove the solvent, yielding yellow transparent oily compound 3-5 (1.10 g, yield: 99.1%).

[0061] Feature data: 1 H NMR(400MHz,CDCl3)δ 8.08(s,1H),7.26-7.24(m,1H),7.02-6.98(m,1H),6.86-6.83(m,1H),5.28-5.06(m,1H),2.53-2.46(m,1H),1.62-1.60( m,3H),1.31-1.26(m,3H),1.03-0.99(m,1H),0.56-0.54(m,1H),0.39-0.37(m,1H),0.22-0.20(m,1H),0.17-0.15(m,1H).

[0062] Step 5: Synthesis of compound 3 (2-(1-cyclopropylethyl)-6-(1-(methylthio)ethyl)phenol)

[0063] Compound 3-5 (1.3 g, 6.30 mmol) was added to 15 mL of acetonitrile, and methyl mercaptan (3.94 g, 10% propylene glycol solution, 8.19 mmol, 1.2 eq) was added under nitrogen gas protection. Hydrochloric acid (344 mg, 9.45 mmol, 1.5 eq) was then added dropwise to the reaction solution. The reaction system was stirred at 25°C for 4 hours, and TLC (V ヘキサン :V EA =5:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with H2O, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V n-ヘキサン :V 酢酸エチル = 50:1 to 20:1, and compound 3 (500 mg, yield: 33.6%) was obtained as a yellow oil.

[0064] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.35-7.34(m,1H),7.27-7.25(m,1H),6.93-6.91(m,1H),6.87-6.83(m,1H),4.09-4.02(m,1H),2.57-2.52(m,1H),1.94(d,J=8. 0Hz,3H),1.65(d,J=8.0Hz,3H),1.30-1.24(m,3H),1.04-0.95(m,1H),0.53-0.50(m,1H),0.35-0.30(m,1H),0.20-0.15(m,2H).

[0065] Example 4 Synthesis of compound 4 (2-(1-cyclopropylethyl)-6-(1-(methylsulfonyl)ethyl)phenol) [ka]

[0066] Under the protection of nitrogen gas, compound 3 (100 mg, 0.423 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (165 mg, 0.846 mmol, 2.0 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5°C to 0°C, and the reaction was allowed to proceed at 15°C for 0.5 hours. TLC (V ヘキサン :V EA =1:1) When it was detected that the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル = 1:1, and compound 4 (40.0 mg, yield: 35.4%) was obtained as a yellow oil.

[0067] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.35-7.34(m,1H),7.14-7.12(m,1H),7.02-6.98(m,1H),6.84(s,1H),4.65-4.59(m,1H),2.76(s,3H),2.59-2.54(m,1H) ),1.83(d,J=8.0Hz,3H),1.30-1.25(m,3H),1.06-0.99(m,1H),0.60-0.54(m,1H),0.46-0.40(m,1H),0.26-0.13(m,2H).

[0068] Example 5 Synthesis of compound 5 (2-(1-cyclopropylethyl)-6-(1-(methylsulfinyl)ethyl)phenol) [ka]

[0069] Under the protection of nitrogen gas, compound 3 (100 mg, 0.423 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (77.30 mg, 0.381 mmol, 0.9 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 0 to 5 °C for 0.5 h. TLC (V ヘキサン:V EA =1:1) When it was detected that the majority of the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phases were combined, washed with saturated saline, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography, the eluent polarity was V. n-ヘキサン :V 酢酸エチル = 1:1, and compound 5 (40.0 mg, yield: 37.7%) was obtained as a yellow oil.

[0070] Feature data: 1 H NMR(400MHz,CDCl3)δ 9.61(s,1H),7.32-7.30(m,1H),6.88-6.79(m,2H),3.77-3.71(m,1H),2.59-2.56(m,1H),2.45(s,3H),1.88(d ,J=8.0Hz,3H),1.30-1.28(m,3H),1.04-1.01(m,1H),0.53-0.50(m,1H),0.37-0.32(m,1H),0.21-0.16(m,2H).

[0071] Example 6 Synthesis of compound 6 (2-(1-cyclopropylethyl)-6-(1-(isopropylsulfonyl)ethyl)phenol) [ka] Step 1: Synthesis of compound 6-1 (2-(1-cyclopropylethyl)-6-(1-(isopropylthio)ethyl)phenol)

[0072] Compound 3-5 (1.0 g, 4.85 mmol) was added to 10 mL of acetonitrile, and isopropylthiol (443.0 mg, 5.82 mmol, 1.2 eq) was added under nitrogen gas protection. Hydrochloric acid (230 mg, 6.30 mmol, 1.3 eq) was then added dropwise to the reaction solution. The reaction system was stirred at 15°C for 16 hours, and the TLC ( ヘキサン :V EA=5:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with H2O, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V n-ヘキサン :V 酢酸エチル = 50:1 to 20:1, and a yellow oily compound 6-1 (600 mg, yield: 46.8%) was obtained.

[0073] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.70(d,J=8.0Hz,1H),7.26-7.24(m,1H),6.92-6.90(m,1H),6.86-6.82(m,1H),4.20-4.15(m,1H),2.70-2.63(m,1H),2.58-2.51(m,1H), 1.63(d,J=8.0Hz,3H),1.30-1.24(m,3H),1.17-1.14(m,6H),1.04-0.99(m,1H),0.56-0.52(m,1H),0.39-0.34(m,1H),0.22-0.15(m,2H).

[0074] Step 2: Synthesis of compound 6 (2-(1-cyclopropylethyl)-6-(1-(isopropylsulfonyl)ethyl)phenol)

[0075] Under the protection of nitrogen gas, compound 6-1 (100 mg, 0.378 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (154 mg, 85%, 0.756 mmol, 2.0 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 15 °C for 0.5 h. TLC (V ヘキサン :V EA =1:1) When it was detected that the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル= 1:1, and compound 6 (50.0 mg, yield: 44.6%) was obtained as a yellow oil.

[0076] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.35-7.31(m,1H),7.10-7.08(m,1H),6.97-6.93(m,1H),4.60-4.58(m,1H),3.18-3.10(m,1H),2.60-2.54(m,1H),1.81(d,J= 8.0Hz,3H),1.31-1.27(m,6H),1.26-1.17(m,3H),1.04-0.98(m,1H),0.56-0.52(m,1H),0.37-0.34(m,1H),0.22-0.15(m,2H).

[0077] Example 7 Synthesis of compound 7 (2-(1-cyclopropylethyl)-6-(1-(isopropylsulfinyl)ethyl)phenol) [ka]

[0078] Under the protection of nitrogen gas, compound 6-1 (100 mg, 0.378 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (69.1 mg, 0.341 mmol, 0.9 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 0 to 5 °C for 0.5 h. TLC (V ヘキサン :V EA =1:1) When it was detected that the majority of the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phases were combined, washed with saturated saline, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography, the eluent polarity was V. n-ヘキサン :V 酢酸エチル = 1:1, and compound 7 (30.0 mg, yield: 28.3%) was obtained as a yellow oil.

[0079] Feature data: 1H NMR(400MHz,CDCl3)δ 7.35-7.31(m,1H),7.10-7.08(m,1H),6.97-6.93(m,1H),4.60-4.58(m,1H),2.68-2.63(m,1H),2.45-2.38(m,1H),1.81(d,J= 8.0Hz,3H),1.31-1.27(m,6H),1.26-1.17(m,3H),1.04-0.98(m,1H),0.56-0.54(m,1H),0.39-0.32(m,1H),0.22-0.17(m,2H).

[0080] Example 8 Synthesis of compound 8 (2-(1-cyclopropylethyl)-6-(1-(cyclopropylsulfonyl)ethyl)phenol) [ka] Step 1: Synthesis of compound 8-1 (2-(1-cyclopropylethyl)-6-(1-(cyclopropylthio)ethyl)phenol)

[0081] Compound 3-5 (1.0 g, 4.85 mmol) was added to 10 mL of acetonitrile, and cyclopropylthiol (431.2 mg, 5.82 mmol, 1.2 eq) was added under nitrogen gas protection. Concentrated hydrochloric acid (230 mg, 6.30 mmol, 1.3 eq) was then added dropwise to the reaction solution. The reaction system was stirred at 15°C for 12 hours, and TLC (V ヘキサン :V EA =5:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with H2O, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V n-ヘキサン :V 酢酸エチル = 50:1 to 20:1, and a yellow oily compound 8-1 (490 mg, yield: 38.5%) was obtained.

[0082] Feature data: 1H NMR(400MHz,CDCl3)δ 7.35-7.34(m,1H),7.27-7.25(m,1H),6.93-6.91(m,1H),6.87-6.83(m,1H),4.09-4.02(m,1H),2.57-2.52(m,1H),2.05-2.00(m,1H),1.9 4(d,J=8.0Hz,3H),1.65(d,J=8.0Hz,3H),1.04-0.95(m,2H),0.74-0.58(m,2H),0.59-0.50(m,1H),0.39-0.30(m,2H),0.24-0.12(m,2H).

[0083] Step 2: Synthesis of compound 8 (2-(1-cyclopropylethyl)-6-(1-(cyclopropylsulfonyl)ethyl)phenol)

[0084] Under the protection of nitrogen gas, compound 8-1 (100 mg, 0.381 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (155 mg, 0.762 mmol, 2.0 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 15 °C for 0.5 h. TLC (V ヘキサン :V EA =1:1) When it was detected that the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル = 1:1, and a yellow solid compound 8 (60.0 mg, yield: 53.4%) was obtained.

[0085] Feature data: 1H NMR (400MHz, CDCl3) δ 7.35-7.34(m,1H),7.14-7.12(m,1H),7.02-6.98(m,1H),6.84(s,1H),4.65 -4.59(m,1H),2.59-2.54(m,1H),2.45-2.35(m,1H),1.83(d,J=8.0Hz,3H),1 .30-1.24(m,3H),1.04-0.95(m,1H),0.83-0.80(m,1H),0.65-0.60(m,2H), 0.53-0.50(m,1H),0.45-0.40(m,1H),0.35-0.30(m,1H),0.20-0.15(m,2H).

[0086] Example 9 Synthesis of compound 9 (2-(1-cyclopropylethyl)-6-(1-(cyclopropylsulfinyl)ethyl)phenol) [ka]

[0087] Under nitrogen gas protection, compound 8-1 (100 mg, 0.381 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (69.6 mg, 0.343 mmol, 0.9 eq) was slowly added to the reaction while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 0 to 5 °C for 0.5 hours. TLC (V ヘキサン :V EA =1:1) When it was detected that the majority of the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phases were combined, washed with saturated saline, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography, the eluent polarity was V. n-ヘキサン :V 酢酸エチル = 1:1, and compound 9 (38.0 mg, yield: 35.8%) was obtained as a yellow transparent oil.

[0088] Feature data: 1H NMR(400MHz,CDCl3)δ 9.63(s,1H),7.35-7.32(m,1H),6.89-6.75(m,2H),3.77-3.71(m,1H), 2.59-2.56(m,1H),2.45-2.34(m,1H),1.88(d,J=8.0Hz,3H),1.30-1.24 (m,3H),1.04-0.95(m,1H),0.83-0.80(m,1H),0.65-0.60(m,2H),0.53 -0.50(m,1H),0.45-0.40(m,1H),0.35-0.30(m,1H),0.20-0.15(m,2H).

[0089] Example 10 Synthesis of compound 10 (ethyl 1-(2-hydroxy-3-isopropylphenyl)acetate) [ka]

[0090] Step 1: Synthesis of compound 10-1 (1-(2-(benzyloxy)-3-isopropylphenyl)ethan-1-one)

[0091] Compound 1-3 (2.00 g, 11.22 mmol, 1.0 eq) was added to a 100 mL single-necked vial, dried methanol (40 mL) and potassium carbonate (2.33 g, 16.83 mmol, 1.5 eq) were added, and then benzyl chloride (1.85 g, 14.59 mmol, 1.3 eq) was added. Under the protection of nitrogen gas, the reaction mixture was heated to 30°C and reacted for 2 h. The TLC detection reaction was completed, then diluted with ethyl acetate, mixed, column separated, and V 石油エーテル :V 酢酸エチル = 100:1 to 50:1 as the eluent to obtain yellow oily compound 10-1 (2.5 g, yield: 83.3%).

[0092] Feature data: 1H NMR(400MHz,CDCl3)δ 7.66-7.64(m,1H),7.47-7.43(m,2H),7.37-7.35(m,3H),6.88-6.84(m ,2H),5.06(s,2H),2.46-2.42(m,1H),2.26(s,3H),1.34-1.21(m,6H).

[0093] Step 2: Synthesis of compound 10-2 (1-(2-(benzyloxy)-3-isopropylphenyl)ethan-1-ol)

[0094] Compound 10-1 (2.0 g, 7.45 mmol, 1.0 eq) was added to a 100 mL single-necked vial, dried methanol (30 mL) and sodium borohydride (0.31 g, 8.20 mmol, 1.1 eq) were added, and the reaction mixture was reacted at 15° C. for 0.5 hours. The TLC detection reaction was completed, and then it was diluted with DCM, extracted (100 mL x 2), and purified by column. The elution polarity was V 石油エーテル :V 酢酸エチル = 15:1 to 5:1, and a yellow oily compound 10-2 (2.00 g, yield: 100.0%) was obtained.

[0095] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.65-7.61(m,1H),7.48-7.44(m,2H),7.39-7.35(m,3H),6.88-6.84(m,2H),5.08 (s,2H),3.65(s,1H),2.46-2.42(m,2H),1.91(d,J=8.0Hz,3H),1.34-1.21(m,6H).

[0096] Step 3: Synthesis of compound 10-3 (ethyl 1-(2-(benzyloxy)-3-isopropylphenyl)acetate)

[0097] Compound 10-2 (1.5 g, 5.55 mmol, 1.0 eq) was added to a 100 mL one-neck flask, dried DCM (30 mL) and DMAP (0.678 g, 5.55 mmol, 1.0 eq) were added, followed by acetic anhydride (736.3 mg, 7.21 mmol, 1.3 eq), and the reaction mixture was reacted at 15 ° C for 0.5 h. The TLC detection reaction was completed, and then it was diluted with DCM, extracted (100 mL × 2), washed with 1N hydrochloric acid, extracted, separated, and dried to obtain yellow transparent oily compound 10-3 (1.50 g, yield: 86.7%).

[0098] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.65-7.61(m,1H),7.48-7.44(m,2H),7.39-7.35(m,3H),6.88-6.84(m,2H),6.05-6.00(m, 1H),5.08(s,2H),2.46-2.42(m,1H),2.12(s,3H),1.93(d,J=8.0Hz,3H),1.34-1.21(m,6H).

[0099] Step 4: Synthesis of compound 10 (ethyl 1-(2-hydroxy-3-isopropylphenyl)acetate)

[0100] Under the protection of hydrogen ball (15 psi), compound 10-3 (300 mg, 0.96 mmol, 1.0 eq) was added to dry THF (10 mL) and palladium carbon (200 g, pd: 10%), and the reaction mixture was reacted in hydrogen ball (15 psi) at 15 °C for 5 hours. TLC detection reaction was completed, and the reaction compound was filtered with diatomaceous earth, washed, dried and concentrated to obtain the product, which was purified by column chromatography to obtain pale yellow oily compound 10 (100 mg, yield: 46.9%).

[0101] 1H NMR(400MHz,CDCl3)δ 7.64(s,1H),7.19-7.18(m,2H),6.94-6.90(m,1H),6.05-6.00(m,1H),3 .40-3.33(m,1H),2.08(s,3H),1.65(d,J=8.0Hz,3H),1.24-1.21(m,6H).

[0102] Example 11 Synthesis of compound 11 (2-(1-cyclopropylethyl)-6-(1-(ethylsulfonyl)ethyl)phenol) [ka] Step 1: Synthesis of compound 11-1 (2-(1-cyclopropylethyl)-6-(1-(ethylthio)ethyl)phenol)

[0103] Compound 3-5 (1.0 g, 4.85 mmol) was added to ethanethiol (361 mg, 5.81 mmol, 1.2 eq) under nitrogen gas protection, and hydrochloric acid (229 mg, 6.30 mmol, 1.3 eq) was added dropwise to the reaction solution. The reaction system was stirred at 15°C for 10 hours, and TLC (V ヘキサン :V EA =5:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with H2O, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V n-ヘキサン :V 酢酸エチル = 50:1 to 20:1, and a yellow oily compound 11-1 (700 mg, yield: 57.7%) was obtained.

[0104] Feature data: 1H NMR(400MHz,CDCl3)δ 7.50(d,J=8.0Hz,1H),7.27-7.25(m,1H),6.93-6.91(m,1H),6.86-6.83(m,1H),4.18-4.12(m,1H),2.58-2.52(m,1H),2.40-2.34(m,2H), 1.64(d,J=8.0Hz,3H),1.31-1.28(m,3H),1.19-1.15(m,3H),1.05-0.97(m,1H),0.55-0.54(m,1H),0.35-0.30(m,1H),0.20-0.16(m,2H).

[0105] Step 2: Synthesis of compound 11 (2-(1-cyclopropylethyl)-6-(1-(ethylsulfonyl)ethyl)phenol)

[0106] Under the protection of nitrogen gas, compound 11-1 (200 mg, 0.798 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (325 mg, 1.60 mmol, 2.0 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 15 °C for 0.5 h. TLC (V ヘキサン :V EA =1:1) When it was detected that the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル = 1:1, and pale yellow oily compound 11 (180.0 mg, yield: 82%) was obtained.

[0107] Feature data: 1H NMR(400MHz,CDCl3)δ 7.38-7.33(m,1H),7.12-7.10(m,2H),6.99-6.96(m,1H),4.59-4.55(m,1H),2.94-2.88(m,2H),2.58-2.54(m,1H),1.83(d,J= 8.0Hz,3H),1.34-1.32(m,3H),1.30-1.27(m,3H),1.05-1.01(m,1H),0.58-0.56(m,1H),0.42-0.40(m,1H),0.23-0.15(m,2H).

[0108] Example 12 Synthesis of compound 12 (2-(1-cyclopropylethyl)-6-(1-(ethylsulfinyl)ethyl)phenol) [ka]

[0109] Under the protection of nitrogen gas, compound 11-1 (200 mg, 0.798 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (146 mg, 0.718 mmol, 0.9 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 0 to 5 °C for 0.5 h. TLC (V ヘキサン :V EA =1:1) When it was detected that the majority of the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phases were combined, washed with saturated saline, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography, the eluent polarity was V. n-ヘキサン :V 酢酸エチル = 1:1, and compound 12 (40.0 mg, yield: 18.8%) was obtained as a yellow oil.

[0110] Feature data: 1H NMR(400MHz,CDCl3)δ 9.79(s,1H),7.32-7.29(m,1H),6.86-6.79(m,2H),3.82-3.80(m,1H),2.64-2.56(m,2H),2.40 -2.34(m,1H),1.83(d,J=8.0Hz,3H),1.34-1.29(m,3H),1.24-1.19(m,3H), 1.05-1.00(m,1H),0.54-0.51(m,1H),0.38-0.35(m,1H),0.21-0.16(m,2H).

[0111] Example 13 Synthesis of compound 13 (2-(1-cyclopropylethyl)-6-(1-(methylthio)propyl)phenol) [ka]

[0112] Step 1: Synthesis of compound 13-2 (1-(2-(but-2-en-1-yloxy)phenyl)propan-1-one)

[0113] Compound 13-1 (10.0 g, 66.59 mmol, 1.0 eq) and NaOH (4.0 g, 99.88 mmol, 1.5 eq) were added to anhydrous DMF (150 mL) and stirred at 15 ° C for 30 minutes, after which chlorobutene (cysteine ​​mixture, 7.24 g, 79.91 mmol, 1.3 eq) was added dropwise at 15 ° C. After completion of the addition, the temperature was slowly raised to room temperature (15 ° C.) and the reaction was carried out for 16 hours. The reaction solution was then slowly poured into 500 mL of ice water, and further extracted with n-hexane (400 mL × 3). The organic phases were combined, the solvent was removed by spinning, the crude product was mixed, and the product was purified by column chromatography. The elution polarity was V. n-ヘキサン :V 酢酸エチル = 200:1, and a yellow transparent oily compound 13-2 (7.7 g, yield: 56.6%) was obtained.

[0114] Feature data: 1H NMR(400MHz,CDCl3)δ 7.70-7.66(m,1H),7.43-7.41(m,1H),7.00-6.93(m,2H),5.87-5.71(m,2H),4 .68-4.54(m,2H),3.04-2.98(m,2H),1.78(d,J=8.0Hz,3H),1.18-1.16(m,3H).

[0115] Step 2: Synthesis of compound 13-3 (1-(3-(but-3-en-2-yl)-2-hydroxyphenyl)propan-1-one)

[0116] Compound 13-2 (7.70 g, 37.72 mmol, 1.0 eq) was added to a 50 mL single-necked vial, and under the protection of nitrogen gas, the air was refluxed and condensed, and the reaction mixture was heated to 210-215 °C and reacted for 4.0 hours. The TLC detection reaction was completed, after which it was diluted with ethyl acetate, mixed, column separated, and V 石油エーテル :V 酢酸エチル = 100:1 to 50:1 as the eluent to obtain yellow oily compound 13-3 (6.80 g, yield: 88.3%).

[0117] Feature data: 1 H NMR(400MHz,CDCl3)δ 12.81(s,1H),7.66-7.64(m,1H),7.37-7.35(m,1H),6.88-6.84(m,1H),6.05-6.01(m,1H),5.0 8-5.06(m,2H),4.01-3.97(m,1H),3.06-3.02(m,2H),1.34(d,J=4.0Hz,3H),1.24-1.20(m,3H).

[0118] Step 3: Synthesis of compound 13-4 (1-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)propan-1-one)

[0119] Under the protection of nitrogen gas, replace the atmosphere in a 100mL three-neck flask 3 to 5 times, add DCM (20mL), cool the reaction system to -5 to 0℃, slowly add diethylzinc (14.69mL, 2.0 M, 29.37mmol) dropwise, and complete the addition in about 10 minutes. Then add trifluoroacetic acid (3.35g, 29.37mmol) in an ice-ethanol bath, and after about 5 minutes, dissolve diiodomethane (10.49g, 39.16mmol) in DCM (5mL) and add it to the reaction solution with a syringe, maintaining the system temperature at -5 to 0℃. After 60 min, compound 13-3 (2.00 g, 9.79 mmol) was dissolved in DCM (5 mL) and slowly added dropwise to the reaction. After the addition was complete, the ice bath was removed and the reaction was stirred at -5-0°C for 3 h, after which the reaction was warmed to 15°C and continued to stir for 48 h. 1 H NMR and TLC(V ヘキサン :V EA =10:1) When it was detected that the majority of the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (200 mL), and further washed with saturated ammonium chloride solution, the organic phases were combined and washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography, the eluent polarity was V. n-ヘキサン :V 酢酸エチル = 100:1 to 50:1, and a yellow oily compound 13-4 (1.80 g, yield: 84.1%) was obtained.

[0120] Feature data: 1 H NMR(400MHz,CDCl3)δ 12.73(s,1H),7.66-7.63(m,1H),7.55-7.53(m,1H),6.90(t,J=8.0Hz,1H),3.08-3.03(m,2H),2.52-2.48(m,1H),1.31(d,J=4 .0Hz,3H),1.24-1.20(m,3H),1.03-0.97(m,1H),0.59-0.53(m,1H),0.41-0.35(m,1H),0.26-0.20(m,1H),0.16-0.12(m,1H).

[0121] Step 4: Synthesis of compound 13-5 (2-(1-cyclopropylethyl)-6-(1-hydroxypropyl)phenol)

[0122] Compound 13-4 (3.30 g, 15.14 mmol, 1.0 eq) was added to 50 mL of dried methanol, and NaBH4 (624 mg, 16.49 mmol, 1.1 eq) was added and reacted at room temperature for 0.5 hours. The reaction solution was poured into 10 mL of saturated aqueous ammonium chloride solution, extracted with DCM (200 mL x 3), the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography, with the eluent polarity being V. PE :V EA = 100:1 to 20:1, and a yellow oily compound 13-5 (2.00 g, yield: 60.1%) was obtained.

[0123] Feature data: 1 H NMR(400MHz,CDCl3)δ 8.10(s,1H),7.25-7.23(m,1H),6.82-6.79(m,2H),4.75(t,J=8.0Hz,1H), 2.52-2.45(m,2H),1.98-1.84(m,2H),1.30(dd,J=8.0Hz,2.0Hz,3H),1.05- 1.01(m,1H),0.98(t,J=8.0Hz,3H),0.56-0.52(m,1H),0.41-0.35(m,1H),0.22-0.14(m,2H).

[0124] Step 5: Synthesis of compound 13 (2-(1-cyclopropylethyl)-6-(1-(methylthio)propyl)phenol)

[0125] Compound 13-5 (400 mg, 1.82 mmol) was added to 10 mL of acetonitrile, and methyl mercaptan (1.05 g, 10% propylene glycol solution, 2.18 mmol, 1.2 eq) was added under nitrogen gas protection. Hydrochloric acid (72.82 mg, 2.00 mmol, 1.1 eq) was then added dropwise to the reaction solution, and the reaction system was stirred at 25 °C for 6 hours to react, and TLC (V ヘキサン :V EA=5:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with water, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V. n-ヘキサン :V 酢酸エチル = 1:0 to 100:1, and compound 13 (110 mg, yield: 24.2%) was obtained as a yellow oil.

[0126] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.43(d,J=4.0Hz,1H),7.26-7.25(m,1H),6.87-6.81(m,2H),3.80(t,J=8.0Hz,1H),2.58-2.53(m,1H),2.00-1.92(m,2H),1.88(d,J=2.0H) z,3H),1.30(dd,J=8.0Hz,4.0Hz,3H),1.03-1.00(m,1H),0.98(t,J=8.0Hz,3H),0.54-0.52(m,1H),0.38-0.35(m,1H),0.20-0.14(m,2H).

[0127] Example 14 Synthesis of compound 14 (2-(1-cyclopropylethyl)-6-(1-(methylsulfonyl)propyl)phenol) [ka]

[0128] Under the protection of nitrogen gas, compound 13 (100 mg, 0.439 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (164 mg, 0.878 mmol, 2.0 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 15 °C for 0.5 h. TLC (V ヘキサン :V EA=2:1) ​​When it was detected that the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル = 10:1, and compound 14 (85.0 mg, yield: 75.2%) was obtained as a yellow oil.

[0129] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.35-7.32(m,1H),7.10-7.05(m,1H),7.00-6.96(m,1H),4.48-4.28(m,1H),2.73(s,3H),2.62-2.54(m,1H),2.48-2.42(m,1H),2.32-2.1 8(m,1H),1.30(dd,J=8.0,4.0Hz,3H),1.04-0.99(m,1H),0.95(t,J=8.0Hz,3H),0.59-0.54(m,1H),0.44-0.42(m,1H),0.24-0.12(m,2H).

[0130] Example 15 Synthesis of compound 15 (2-(1-cyclopropylethyl)-6-(1-(isopropylsulfonyl)propyl)phenol) [ka] Step 1: Synthesis of compound 15-1 (2-(1-cyclopropylethyl)-6-(1-(isopropylthio)propyl)phenol)

[0131] Compound 13-5 (200 mg, 0.91 mmol) was added to 5 mL of acetonitrile, and isopropylthiol (82.97 mg, 1.09 mmol, 1.2 eq) was added under nitrogen gas protection. Hydrochloric acid (36.41 mg, 0.998 mmol, 1.1 eq) was then added dropwise to the reaction solution. The reaction system was stirred at 25 °C for 6 hours to react, and TLC (V ヘキサン :V EA=10:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with H2O, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V n-ヘキサン :V 酢酸エチル = 1:0 to 100:1, and a yellow oily compound 15-1 (250 mg, yield: 98.8%) was obtained.

[0132] Feature data: 1 H NMR (400MHz, CDCl3) δ 7.78(d,J=8.0Hz,1H),7.26-7.24(m,1H),6.85-6.79(m,2H),3.91(q,J=12.0 ,8.0,4.0Hz,1H),2.62-2.52(m,2H),1.99-1.84(m,2H),1.30-1.27(m,3H),1. 22(dd,J=8.0,4.0Hz,3H),1.16(dd,J=8.0,4.0Hz,3H),1.05-0.98(m,1H),0.9 6(dt,J=8.0Hz,3H),0.56-0.49(m,1H),0.39-0.31(m,1H),0.21-0.13(m,2H).

[0133] Step 2: Synthesis of compound 15 (2-(1-cyclopropylethyl)-6-(1-(isopropylsulfonyl)propyl)phenol)

[0134] Under the protection of nitrogen gas, compound 15-1 (200 mg, 0.719 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (291 mg, 1.438 mmol, 2.0 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 15 °C for 0.5 h. TLC (V ヘキサン :V EA When it was detected that the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography, the eluent polarity was V. n-ヘキサン :V 酢酸エチル= 15:1, and a white solid compound 15 (160 mg, yield: 71.7%) was obtained.

[0135] Feature data: 1 H NMR(400MHz,CDCl3)δ 8.08(d,J=8.0Hz,1H),7.33-7.31(m,1H),7.00-6.79(m,2H),4.68-4.52(m,1H),3.12-3.06(m,1H),2.63-2.55(m,1H),2.46-2.2 9(m,2H),1.34-1.24(m,9H),1.02-1.00(m,1H),0.89(t,J=8.0Hz,3H),0.57-0.53(m,1H),0.42-0.35(m,1H),0.23-0.12(m,2H).

[0136] Example 16 Synthesis of compound 16 (2-(cyclopropyl(methylsulfonyl)methyl)-6-isopropylphenol) [ka]

[0137] Step 1: Synthesis of compound 16-2 (cyclopropyl(2-hydroxy-3-isopropylphenyl)methanone)

[0138] Compound 16-1 (4.0 g, 29.37 mmol, 1.0 eq) was added to a 100 mL single-necked vial, and then dry DCM (60 mL) and cyclopropane carboxylic acid chloride (3.68 g, 35.24 mmol, 1.2 eq) were added, and then titanium tetrachloride (6.69 g, 35.24 mmol, 1.2 eq) was slowly added to the reaction, and the reaction mixture was kept at -30 ° C for 2 hours under the protection of nitrogen gas. The TLC detection reaction was completed, and then it was diluted with ethyl acetate, mixed, column separated, and V was added. 石油エーテル :V 酢酸エチル = 100:1 to 50:1 as the eluent to obtain yellow oily compound 16-2 (200 mg, yield: 3.3%).

[0139] Feature data: 1H NMR(400MHz,CDCl3)δ 12.96(s,1H),7.86(d,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),6.93(t,J=6.0Hz,1H),3.41-3.32(m,1H) ,2.75-2.68(m,1H),1.32-1.27(m,1H),1.26(d,J=6.0Hz,6H),1.11-1.06(m,1H),1.05-0.99(m,2H).

[0140] Step 2: Synthesis of compound 16-3 (2-(cyclopropyl(hydroxy)methyl)-6-isopropylphenol)

[0141] Compound 16-2 (200 mg, 0.979 mmol, 1.0 eq) was added to a 100 mL single-necked vial, and then dried methanol (8 mL) and sodium borohydride (40.75 mg, 1.08 mmol, 1.1 eq) were added, and the reaction mixture was reacted at 15° C. for 0.5 h. The TLC detection reaction was completed, and then it was diluted with DCM, extracted (30 mL x 2), and column purified, and the eluent polarity was V. 石油エーテル :V 酢酸エチル = 15:1 to 5:1, and reddish brown oily compound 16-3 (200 mg, yield: 99.0%) was obtained.

[0142] Feature data: 1 H NMR(400MHz,CDCl3)δ 8.29(s,1H),7.19(,J=8.0Hz,1H),6.96(d,J=8.0Hz,1H),6.85(t,J=8.0Hz,1H),4.14(d,J=8.0Hz,1H),3 .39(m,1H),2.47(s,1H),1.52-1.41(m,1H),1.27(d,J=6.0Hz,6H),0.74-0.66(m,2H),0.48-0.41(m,2H).

[0143] Step 3: Synthesis of compound 16-4 (2-(cyclopropyl(methylthio)methyl)-6-isopropylphenol)

[0144] Compound 16-3 (200 mg, 0.97 mmol) was added to methyl mercaptan (0.606 g, 10% propylene glycol solution, 1.26 mmol, 1.3 eq) under nitrogen gas protection, and concentrated hydrochloric acid (42.4 mg, 1.16 mmol, 1.2 eq) was added dropwise to the reaction solution. The reaction system was stirred at 25 °C for 4 hours, and TLC (V ヘキサン :V EA =5:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with H2O, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V n-ヘキサン :V 酢酸エチル = 50:1 to 20:1, and a yellow oily compound 16-4 (50 mg, yield: 21.8%) was obtained.

[0145] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.56(s,1H),7.20-7.19(m,1H),6.98-6.95(m,1H),6.89-6.85(m,1H),3.42-3.38(m,1H),3.22-3.19(m,1H),1.94(s,3 H),1.48-1.41(m,1H),1.28-1.25(m,6H),0.79-0.73(m,1H),0.65-0.60(m,1H),0.46-0.41(m,1H),0.36-0.30(m,1H).

[0146] Step 4: Synthesis of compound 16 (2-(cyclopropyl(methylsulfonyl)methyl)-6-isopropylphenol)

[0147] Under the protection of nitrogen gas, compound 16-4 (50 mg, 0.210 mmol) was dissolved in DCM (8 mL), and m-chloroperoxybenzoic acid (84.9 mg, 0.42 mmol, 2.0 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was stirred at 15 °C for 0.5 h. TLC (V ヘキサン :V EA=2:1) ​​When it was detected that the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル = 1:1, and a yellow solid compound 16 (20.1 mg, yield: 35.1%) was obtained.

[0148] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.24-7.22(m,2H),7.03(t,J=8.0Hz,1H),6.85-6.82(m,1H),3.72(d,J=8.0Hz,1H),3.37-3.31(m,1H),2. 92(s,3H),1.75-1.66(m,1H),1.25-1.22(m,6H),1.06-1.02(m,1H),0.78-0.74(m,2H),0.25-0.20(m,1H).

[0149] Example 17 Synthesis of compound 17 (2-(1-(methylsulfonyl)ethyl)-6-(pent-3-yl)phenol) [ka] Step 1: Synthesis of compound 17-2 (2-(pent-2-en-3-yl)phenol)

[0150] Under the protection of nitrogen gas, compound 17-1 (5.0 g, 33.29 mmol, 1.0 eq) was added to a 200 mL three-neck flask, dried THF (60 mL) was added, and ethyl magnesium bromide (19.98 mL, 2.0 M in THF, 39.95 mmol, 1.2 eq) was slowly added to the reaction mixture at -15 °C for 2 hours. The reaction was completed by TLC detection, then diluted with ethyl acetate, mixed, column separated, and V 石油エーテル :V 酢酸エチル = 100:1 to 50:1 as the eluent to obtain yellow oily compound 17-2 (4.0 g, yield: 74.6%).

[0151] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.63(s,1H),7.24-7.16(m,2H),6.97-6.94(m,1H),6.76-6.73(m,1H),6.06-6.00(m,1H),2.06-2.00(m,5H),1.06-1.02(m,3H).

[0152] Step 2: Synthesis of compound 17-3 (2-(pent-3-yl)phenol)

[0153] Under hydrogen gas (15 Psi) protection, compound 17-2 (4.0 g, 24.66 mmol, 1.0 eq) was added to a 250 mL single-necked vial, dried methanol (60 mL) was added, and palladium carbon (800 mg, Pd: 10%) was added to the reaction at 15 °C, and the reaction mixture was placed under hydrogen gas (15 Psi) at 15 °C for 12 hours. The TLC detection reaction was completed, and then it was filtered with diatomaceous earth, washed with methanol, dried, and concentrated to obtain gray oily compound 17-3 (4.0 g, yield: 95.0%).

[0154] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.67(s,1H),7.24-7.16(m,2H),6.97-6.94(m,1H),6.76-6.73(m,1H),2.45-2.42(m,1H),2.06-2.00(m,4H),1.06 -1.02(m,6H).

[0155] Step 3: Synthesis of compound 17-4 (2-(pent-3-yl)phenylacetate)

[0156] Under the protection of nitrogen gas, compound 17-3 (4.0 g, 24.35 mmol, 1.0 eq) was added to a 250 mL single-necked vial, dried DCM (60 mL) was added, and the reaction was allowed to proceed at 15°C. Triethylamine (3.7 g, 36.53 mmol, 1.5 eq) and acetic anhydride (2.98 g, 29.22 mmol, 1.2 eq) were added. The reaction mixture was placed at 15°C and allowed to react for 12 hours. The TLC detection reaction was completed, after which it was neutralized to pH=6-7 with dilute hydrochloric acid, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain colorless oily compound 17-4 (4.5 g, yield: 89.6%).

[0157] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.24 -7.16(m,2H),6.97-6.94(m,1H),6.76-6.73(m,1H),2.45-2.42(m,1H),2.36(s,3H),2.06-2.00(m,4H),1.06-1.02(m,6H).

[0158] Step 4: Synthesis of compound 17-5 (1-(2-hydroxy-3-(pent-3-yl)phenyl)ethan-1-one)

[0159] Under the protection of nitrogen gas, compound 17-4 (4.5 g, 21.81 mmol, 1.0 eq) was added to a 100 mL single-necked vial, dried DCM (60 mL) was added, and aluminum trichloride (3.78 g, 28.36 mmol, 1.3 eq) was added in small portions to the reaction at 15 °C. The reaction mixture was heated to 140 °C and reacted for 4 hours. The TLC detection reaction was completed, after which it was diluted with DCM, filtered, extracted, the organic phase was washed with saturated saline, dried, concentrated, and the crude was purified by column chromatography to obtain yellow oily compound 17-5 (2.26 g, yield: 50.1%).

[0160] 1H NMR(400MHz,CDCl3)δ7.37(s,1H),7.24-7.16(m,1H),6.97-6.94(m,1H),6.76-6. 73(m,1H),2.45-2.42(m,1H),2.18(s,3H),2.06-2.02(m,4H),1.08-1.04(m,6H).

[0161] Step 5: Synthesis of compound 17-6 (2-(1-hydroxyethyl)-6-(pent-3-yl)phenol)

[0162] Under the protection of nitrogen gas, compound 17-5 (2.0 g, 9.70 mmol, 1.0 eq) was added to dry methanol (30 mL), and sodium borohydride (0.440 g, 11.61 mmol, 1.2 eq) was added in portions to the reaction mixture at 15°C. The reaction mixture was reacted at 20°C for 1 h. The TLC detection reaction was completed, after which it was diluted with DCM, extracted, and the organic phase was washed with saturated saline, dried, and concentrated to obtain yellow oily compound 17-6 (2.01 g, yield: 99.0%).

[0163] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.37(s,1H),7.24-7.17(m,1H),6.97-6.94(m,1H),6.76-6.73(m,1H),2.54( s,1H),2.45-2.42(m,1H),2.06-1.98(m,4H),1.91(s,3H),1.24-1.17(m,6H).

[0164] Step 6: Synthesis of compound 17-7 (2-(1-(methylthio)ethyl)-6-(pent-3-yl)phenol)

[0165] Compound 17-6 (2.0 g, 9.60 mmol) was added to methyl mercaptan (5.54 g, 10% propylene glycol solution, 11.52 mmol, 1.2 eq) under nitrogen gas protection, and hydrochloric acid (420 mg, 11.52 mmol, 1.2 eq) was added dropwise to the reaction solution. The reaction system was stirred at 15°C for 12 hours, and the TLC (V ヘキサン :V EA=5:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with H2O, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V n-ヘキサン :V 酢酸エチル = 80:1 to 25:1, and pale yellow oily compound 17-7 (1.1 g, yield: 48.1%) was obtained.

[0166] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.63(s,1H),7.26-7.21(m,1H),7.12-7.06(m,1H),6.96-6.86(m,1H),4.05-4.00(m,1H),2 .45-2.42(m,1H),2.06-1.98(m,4H),1.94(s,3H),1.63(d,J=8.0Hz,3H),1.21-1.14(m,6H).

[0167] Step 7: Synthesis of compound 17 (2-(1-(methylsulfonyl)ethyl)-6-(pent-3-yl)phenol)

[0168] Under nitrogen gas protection, compound 17-7 (400 mg, 1.68 mmol) was dissolved in DCM (12 mL), and m-chloroperoxybenzoic acid (681.3 mg, 3.36 mmol, 2.0 eq) was slowly added to the reaction while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 15 °C for 0.5 hours. TLC (V ヘキサン :V EA =2:1) ​​When it was detected that the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル = 1:1, and compound 17 (100 mg, yield: 22.0%) was obtained as a yellow oil.

[0169] Feature data: 1H NMR(400MHz,CDCl3)δ 7.65(s,1H),7.26-7.18(m,1H),7.12-7.06(m,1H),6.96-6.86(m,1H),4.62-4.58(m,1H),2 .78(s,3H),2.35-2.30(m,1H),2.06-1.98(m,4H),1.83(d,J=8.0Hz,3H),1.21-1.14(m,6H).

[0170] Example 18 Synthesis of compound 18 (2-(1-cyclopropylethyl)-6-(1-(ethylsulfonyl)propyl)phenol) [ka] Step 1: Synthesis of compound 18-1 (2-(1-cyclopropylethyl)-6-(1-(ethylthio)propyl)phenol)

[0171] Compound 13-5 (200 mg, 0.91 mmol) was added to 5 mL of acetonitrile, and ethanethiol (67.7 mg, 1.09 mmol, 1.2 eq) was added under nitrogen gas protection. Hydrochloric acid (36.41 mg, 0.998 mmol, 1.1 eq) was then added dropwise to the reaction solution. The reaction system was stirred at 25 °C for 6 hours to react, and TLC (V ヘキサン :V EA =10:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with H2O, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V n-ヘキサン :V 酢酸エチル = 1:0 to 100:1, and a yellow oily compound 18-1 (210 mg, yield: 87.5%) was obtained.

[0172] Feature data: 1H NMR(400MHz,CDCl3)δ 7.58(d,J=4.0Hz,1H),7.26-7.24(m,1H),6.86-6.80(m,2H),3.90(d,J=8.0Hz ,1H),2.58-2.53(m,1H),2.34-2.28(m,2H),1.99-1.88(m,2H),1.30(dd,J=8.0 ,4.0Hz,3H),1.16-1.12(m,3H),1.04-0.98(m,1H),0.96(t,J=8.0Hz,3H),0.55-0.51(m,1H),0.39-0.33(m,1H),0.21-0.13(m,2H).

[0173] Step 2: Synthesis of compound 18 (2-(1-cyclopropylethyl)-6-(1-(ethylsulfonyl)propyl)phenol): Under nitrogen gas protection, compound 18-1 (200 mg, 0.820 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (306 mg, 1.64 mmol, 2.0 eq) was slowly added to the reaction while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 15 °C for 0.5 hours. TLC (V ヘキサン :V EA =2:1) ​​When it was detected that the raw material had been consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル = 15:1, and compound 18 (200 mg, yield: 89.3%) was obtained as a yellow oil.

[0174] Feature data: 1H NMR(400MHz,CDCl3)δ 7.34-7.31(m,1H),7.03-7.00(m,1H),6.97-6.93(m,1H),4.47-4.05(m,1H),2.90-2.83(m,2H),2.64-2.53(m,1H),2.46-2.28 (m,2H),1.31-1.27(m,6H),1.05-0.98(m,1H),0.92(t,J=8.0Hz,3H),0.59-0.52(m,1H),0.43-0.40(m,1H),0.23-0.10(m,2H).

[0175] Example 19 Synthesis of compound 19 (2-(1-cyclopropylethyl)-6-(1-((2,2,2-trifluoroethyl)sulfonyl)ethyl)phenol) [ka] Step 1: Synthesis of compound 19-1 (2-(1-cyclopropylethyl)-6-(1-((2,2,2-trifluoroethyl)thio)ethyl)phenol)

[0176] Compound 3-5 (1.0 g, 4.85 mmol) was added to 10 mL of acetonitrile, and trifluoroethylthiol (674 mg, 5.81 mmol, 1.2 eq) was added under nitrogen gas protection. Hydrochloric acid (229 mg, 6.30 mmol, 1.3 eq) was then added dropwise to the reaction solution. The reaction system was stirred at 15°C for 10 hours, and TLC (V ヘキサン :V EA =5:1) The reaction was stopped when it was detected that the majority of the raw material had been consumed. The reaction solution was diluted with H2O, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated saline, concentrated, and the crude product was purified by column chromatography, with the eluent polarity being V n-ヘキサン :V 酢酸エチル = 50:1 to 20:1, and a yellow oily compound 19-1 (800 mg, yield: 65.7%) was obtained.

[0177] Feature data: 1H NMR(400MHz,CDCl3)δ 7.50(d,J=8.0Hz,1H),7.27-7.25(m,1H),6.93-6.91(m,1H),6.86-6.83(m,1H),4.16-4.08(m,1H),2.93-2.82(m,2H),2.58-2.5 2(m,1H),1.64(d,J=8.0Hz,3H),1.31-1.28(m,3H),1.05-0.97(m,1H),0.59-0.54(m,1H),0.38-0.33(m,1H),0.20-0.16(m,2H).

[0178] Step 2: Synthesis of compound 19 (2-(1-cyclopropylethyl)-6-(1-((2,2,2-trifluoroethyl)sulfonyl)ethyl)phenol): Under the protection of nitrogen gas, compound 19-1 (200 mg, 0.657 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (265.9 mg, 1.314 mmol, 2.0 eq) was slowly added to the reaction mixture while maintaining the system temperature at -5 to 0 °C, and the reaction was allowed to proceed at 15 °C for 0.5 h. TLC (V ヘキサン :V EA =1:1) The detection raw material was consumed, the reaction was stopped, the reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, the organic phase was combined, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography, the eluent polarity was V n-ヘキサン :V 酢酸エチル = 15:1, and colorless oily compound 19 (185.0 mg, yield: 83.7%) was obtained.

[0179] Feature data: 1 H NMR(400MHz,CDCl3)δ 7.63-7.59(m,1H),7.32-7.27(m,2H),7.10-7.06(m,1H),4.75-4.68(m,1H),3.94-3.88(m,2H),2.56-2.54(m,1H),1 .92(d,J=8.0Hz,3H),1.35-1.24(m,3H),1.05-1.00(m,1H),0.59-0.54(m,1H),0.42-0.40(m,1H),0.28-0.16(m,2H).

[0180] Example 20 Synthesis of compound 20 (2-((R)-1-cyclopropylethyl)-6-((S)-1-(ethylsulfonyl)ethyl)phenol) [ka]

[0181] Feature data: 1 H NMR(400MHz,Chloroform-d)δ 7.36(dd,J=7.6,1.7Hz,1H),7.12(dd,J=7.7,1.7Hz,1H),7.10(s,1H),7. 00(t,J=7.7Hz,1H),4.60(q,J=7.3Hz,1H),2.93(q,J=7.5Hz,2H),2.65-2. 53(m,1H),1.85(d,J=7.2Hz,3H),1.38-1.28(m,6H),1.08-0.99(m,1H),0. 62-0.56(m,1H),0.49-0.38(m,1H),0.28-0.22(m,1H),0.20-0.14(m,1H).

[0182] Example 21 Synthesis of compound 21 (2-((S)-1-cyclopropylethyl)-6-((R)-1-(ethylsulfonyl)ethyl)phenol) [ka]

[0183] Feature data: 1H NMR(400MHz,Chloroform-d)δ 7.36(d,J=7.6Hz,1H),7.13(d,J=8.0Hz,1H),7.11(s,1H),7.01(t,J=7.7Hz,1H),4.60(q,J=7.3Hz,1H),2.94(q,J=7.4Hz,2H),2.69-2.52(m, 1H),1.85(d,J=7.4Hz,3H),1.36-1.30(m,6H),1.09-1.00(m,1H),0.62 -0.56(m,1H),0.49-0.37(m,1H),0.26-0.21(m,1H),0.20-0.15(m,1H).

[0184] Example 22 Synthesis of compound 22 (2-((S)-1-cyclopropylethyl)-6-((S)-1-(ethylsulfonyl)ethyl)phenol) [ka]

[0185] Feature data: 1 H NMR(400MHz,Chloroform-d)δ 7.37(dd,J=7.6,1.7Hz,1H),7.13(dd,J=7.7,1.7Hz,1H),7.11(s,1H),7. 00(t,J=7.7Hz,1H),4.60(q,J=7.3Hz,1H),2.93(q,J=7.5Hz,2H),2.74-2. 46(m,1H),1.85(d,J=7.3Hz,3H),1.41-1.25(m,6H),1.10-0.97(m,1H),0. 62-0.56(m,1H),0.47-0.40(m,1H),0.28-0.22(m,1H),0.20-0.14(m,1H).

[0186] Example 23 Synthesis of compound 23 (2-((R)-1-cyclopropylethyl)-6-((R)-1-(ethylsulfonyl)ethyl)phenol) [ka]

[0187] Feature data: 1 H NMR(400MHz,Chloroform-d)δ 7.36(dd,J=7.7,1.7Hz,1H),7.13(dd,J=7.8,1.6Hz,1H),7.11(s,1H),7. 00(t,J=7.7Hz,1H),4.60(q,J=7.3Hz,1H),2.93(q,J=7.5Hz,2H),2.66-2. 54(m,1H),1.85(d,J=7.3Hz,3H),1.39-1.23(m,6H),1.08-1.00(m,1H),0. 62-0.56(m,1H),0.47-0.41(m,1H),0.27-0.21(m,1H),0.20-0.14(m,1H).

[0188] Preparation method of Examples 20-23: HPLC method was adopted to perform chiral separation of chiral isomer 2-(1-cyclopropylethyl)-6-(1-(ethylsulfonyl)ethyl)phenol) compound 11 (1.5 g, 5.3 mmol) using preparation equipment and chiral column.

[0189] Separation conditions: Chiral column CHIRALCEL OJ-H, mobile phase: V n-ヘキサン :V エタノール =90:10, flow rate 25 mL / min, UV = 214 nm, column temperature 35°C.

[0190] Components with peak out times of 6.908 min, 10.044 min, and 11.829 min were collected and concentrated under reduced pressure.

[0191] Where: (1) The oily product (660 mg) with a peak-out time of 6.908 min was a pair of enantiomers. After one re-resolution, the components with peak-out times of 8.831 min and 10.374 min were collected and concentrated under reduced pressure.

[0192] (1) Compound 20 (350 mg, white solid, HPLC purity: 99.05%, Chiral-HPLC purity: 100.00%, yield 23.3%) having a peak-out time of 8.831 min was obtained. (2) Compound 21 (290 mg, white solid, HPLC purity: 99.47%, Chiral-HPLC purity: 99.94%, yield 19.3%) was obtained, with a peak-out time of 10.374 min.

[0193] (2) Compound 22 (354 mg, white solid, HPLC purity: 97.10%, Chiral-HPLC purity: 99.88%, yield 23.6%) was obtained, with a peak-out time of 10.044 min.

[0194] (3) Compound 23 (322 mg, white solid, HPLC purity: 98.43%, Chiral-HPLC purity: 99.53%, yield 21.5%) was obtained, with a peak-out time of 11.829 min.

[0195] Example 24 Biological Test Example Experiment 1: Anti-specular reflex experiment in mice SPF ICR mice, 18-22g, half male and half female. The general anesthetic effect of the compound of the present invention was studied using a mature mouse anesthesia model. The compound was prepared at the required concentration in a solvent of 10% DMSO, 15% solutol (HS15), and 75% saline. After adapting to the experimental environment, the experimental animals were fasted for 12 hours without water prohibition, and then intravenously injected with a dose volume of 10mL / kg. The anesthesia induction time (the time from administration to the disappearance of the contra-regular reflex) and the duration of anesthesia (the time from the disappearance of the contra-regular reflex to the recovery of the contra-regular reflex) were recorded. The median effective dose (ED 50 ), half-mortal dose (LD 50 ), therapeutic index (TI, i.e., LD 50 / ED 50 The anesthetic effect and safety were evaluated based on the time to induce anesthesia, duration of anesthesia, and maximum tolerable dose. Control group 1 (propofol), control group 2 (cyclopofol, racemic body), and control group 3 (cyclopofol, R-configuration) each have the following structural formulas, and the specific experimental results are shown in Table 1.

[0196] [ka]

[0197] [Table 1]

[0198] Experimental conclusion: The compound of the present invention has a larger therapeutic index, a higher safety factor, and a wider therapeutic range than control group 1, control group 2, and control group 3. Its ED 50 The smaller values ​​explained the lower effective doses and higher activity of these compounds of the present invention, which predicted the effect of avoiding injection pain by lowering the free concentration in the aqueous phase in the corresponding formulations.

[0199] Experiment 2: Anti-specular reflex experiment in rats SD rats were divided into males and females, and fasted for 12 hours without water prohibition. After intravenous administration of 10 mL / kg, the following were recorded: anesthesia induction time (time from administration to disappearance of the contralateral reflex), anesthesia duration (time from disappearance of the contralateral reflex to recovery of the contralateral reflex and awakening), and anesthesia recovery time (time from awakening to complete recovery). 50 ), half-mortal dose (LD 50 ), therapeutic index (TI, i.e., LD 50 / ED 50 ), and its anesthetic effect and safety were evaluated based on anesthesia induction time, duration of anesthesia, and maximum tolerated dose.

[0200] [Table 2]

[0201] Experimental conclusion: Compound 20 of the present invention has a larger therapeutic index, a higher safety factor, and a wider therapeutic range than control group 3. Its ED 50 The smaller value illustrated that the effective dose of compound 20 of the present invention was lower than that of control group 3, but it had higher activity.

[0202] Experiment 3: Stably overexpressed GABA receptor agonists in the present invention using the patch clamp technique A Detection of effects on (α1β2γ2) receptor currents Gamma-aminobutyric acid (GABA) is an important inhibitory amino acid neurotransmitter in the central nervous system, and exerts its functions by binding to GABA receptors. A , GABA B , GABA C There are three subtypes: GABA A The GABA receptor is the most important of the three. A The receptor is an anion-selective ion channel that can increase the permeability of chloride ions and decrease neuronal excitability. A The GABA receptor is involved in the control of general anesthesia and is closely related to neuropsychiatric disorders such as depression, insomnia, anxiety, and epilepsy. A We investigated the allosteric modulation of the α1β2γ2 receptor.

[0203] GABA A We used a HEK293 cell line stably expressing GABA receptors (α1β2γ2) and AThe genetic information of the (α1β2γ2) receptor is as follows: GABA-α1: NM_000806, GABA-β2: NM_021911, GABA-γ2: NM_198904. Whole-cell patch clamp recorded voltage stimulation of GABA receptor current as follows. After forming a whole-cell seal, the cell membrane voltage was clamped at -70 mV. In gap-free mode, the peak value of the current was recorded after sequential injection of low to high concentrations of the test substance and 100 M GABA on the cell surface. Test substance administration method: After administration of each concentration of the test substance 1 to 2 times, the cells were washed with extracellular solution for 1 min to detect the next concentration, and finally 100 μM GABA was administered as a control. The test data was collected by an EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software. A capillary glass tube was stretched using a microelectrode extension device to form a recording electrode. Using an inverted microscope, a microelectrode manipulator was operated to bring the recording electrode into contact with the cell, and negative pressure suction was applied to form a GΩ seal. After the GΩ seal was formed, rapid capacitance compensation (pF) was performed, and then negative pressure was applied to suction-disrupt the cell membrane, forming a whole-cell recording mode. Slow capacitance compensation was then performed to record the membrane capacitance (pF) and series resistance. No leakage compensation was applied. The cover glass on which the cells were laid was placed in the recording bath of an inverted microscope, and the test substance working solution and compound-free external solution were flowed into the recording bath in succession from low to high concentrations by gravity perfusion to act on the cells, and the solution was exchanged using a vacuum pump during recording. Multiple cells were detected independently and repeatedly. All electrophysiological tests were performed at room temperature.

[0204] The GABA receptor agonist activity of the compounds of the present invention was measured in three independent replicates. A Detect allosteric modulation of GABA receptors (α1β2γ2) and measure the GABA receptor activity of the sample by fitting. A The half-activation concentration (EC 50 ) was calculated, and the test results are as follows:

[0205] [Table 3]

[0206] Experimental conclusion: GABA A The half-activating concentration (EC 50 ) is the EC value of the compound 20 of the present invention at 1.556 μM and the EC value of the control group 3. 50 Compared with the control group 3, the compound 20 of the present invention has a GABA A (α1β2γ2) has a stronger allosteric regulatory effect, and GABA A He explained that stimulating (α1β2γ2) can produce an anesthetic effect.

[0207] Experiment 4: Study of the pharmacokinetics of the compound of the present invention in rats Twelve male SD rats (200-300g) were randomly divided into two groups, control group 3 and compound 20 (n=6). 1mg / kg (control group 3) and 1mg / kg (compound 20) were intravenously injected, respectively, with a dose volume of 5mL / kg, and the solvent was 5% DMSO + 10% solutol (HS15) + 85% saline. Blood was collected before administration and 2min, 4min, 8min, 12min, 15min, 30min, 1h, 1.5h and 2h after administration, and plasma was collected by centrifugation and stored in a refrigerator at -80°C until LC-MS analysis was performed for measurement. After sample processing, the substances in the plasma were quantitatively analyzed by LCMS / MS to detect the original compound concentration in the plasma. Pharmacokinetic parameters were calculated using the plasma concentration / time curve obtained in this manner using a validated pharmacokinetic computer program. The experimental results are shown in Table 4.

[0208] [Table 4]

[0209] Experimental conclusion: Compound 20 of the present invention has pharmacokinetic properties similar to those of control group 3, is rapidly eliminated from the body of rats, is consistent with the anesthetic effect, and leads to faster recovery after anesthesia, while avoiding the toxicity of accumulation in the body, and has good pharmacokinetic properties.

[0210] Experiment 5: Study of the pharmacokinetics of the compound of the present invention in beagle dogs Six male beagle dogs (6-10 kg) were randomly divided into two groups, control group 3 and compound 20 (n=3). 0.5 mg / kg (control group 3) and 0.5 mg / kg (compound 20) were intravenously injected, respectively, with a dose volume of 1 mL / kg, and the solvent was 5% DMSO + 10% solutol (HS15) + 85% saline. Blood was collected before administration and 2 min, 5 min, 10 min, 20 min, 30 min, 1 h, 1.5 h, 2 h, and 3 h after administration, and plasma was collected by centrifugation and stored in a refrigerator at -80°C until LC-MS analysis was performed for measurement. After sample processing, the substances in the plasma were quantitatively analyzed by LCMS / MS to detect the original compound concentration in the plasma. Pharmacokinetic parameters were calculated using the plasma concentration / time curve obtained in this manner using a validated pharmacokinetic computer program. The experimental results are shown in Table 5.

[0211] [Table 5]

[0212] Experimental conclusion: Compound 20 of the present invention has pharmacokinetic properties similar to those of control group 3, and is rapidly eliminated from the body in beagle dogs, avoiding accumulation toxicity in the body, and has good pharmacokinetic properties.

[0213] Experiment 6. Study of the hemodynamic effects of the compounds of the invention in beagle dogs. This study employed the emka PACK 4G telemetry system to detect the effects on electrocardiogram, blood pressure, and body temperature in conscious beagle dogs after intravenous injection of control group 3 and compound 20, providing reference information for evaluating the safety of clinical use.

[0214] Four beagle dogs were administered the cross-over drug, and each intravenous injection was administered with a volume of 2mL / kg of the solvent control (5% DMSO + 10% solutol + 85% saline), control group 3 (2mg / kg), compound 20 (0.5mg / kg) and compound 20 (1mg / kg). Observations on the administration day were performed before administration and within 1h after administration, respectively. Anal temperature was measured once before administration, 30min, 1h, 2h and 3h after administration during each administration period, and electrocardiogram parameters were continuously collected from 0.5h before administration to 3h after administration during each administration period. Blood pressure was collected once 15min after the start of collection, and once at 2min, 5min, 10min, 20min, 30min, 1h, 2h and 3h after administration. The electrocardiogram, blood pressure data, body temperature, and clinical observation results on the day of administration were analyzed and evaluated at each time point before administration (30 min after the start of collection) and 2 min, 5 min, 10 min, 20 min, 30 min, 1 h, 2 h, and 3 h after administration. The experimental results are shown in Figures 1, 2, and 3.

[0215] Experimental conclusion: The experimental results showed that the heart rate slowed down within 1 hour after the administration of the control group 3 and compound 20 to the animals, and could be recovered within 1 hour. After administration, the blood pressure indexes of the animals in each group all decreased, but the range was not large, and the decrease in systolic blood pressure was not obvious and was still within the normal range. After administration, no abnormalities were observed in the body temperature indexes of the animals in each group. It was explained that the effect of compound 20 of the present invention on the heart rate, blood pressure and body temperature of beagle dogs was small, and it is predicted that compound 20 of the present invention has excellent safety.

Claims

1. General formula (I): 【Chemistry 1】 (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof, Where: X is 【Chemistry 2】 is selected from R １ is C １－６ Alkyl groups of C １－６ Alkenes of C １－６ wherein the alkyl, alkene, alkyne, heterocycloalkyl, or cycloalkyl group is optionally further substituted with one or more R; R ２ , R ３ are independently H, a hydroxyl group, F, C １－６ Alkyl groups of C １－６ Alkenes of C １－６ alkyne, 3- to 6-membered heterocycloalkyl group, C １－６ Alkoxy groups, CN, NH ２ , 3-6 membered cycloalkyl groups, wherein said alkyl, alkene, alkyne, heterocycloalkyl, alkoxy, and cycloalkyl groups can be optionally further substituted with one or more R; or alternatively, R ２ and R ３ is capable of forming (=O); R ４ is H, or alternatively, R １ and R ４ together with the atom to which they are attached form a 4-6 membered cycloalkyl or heterocyclo group fused to a benzene ring, said cycloalkyl or heterocyclo group optionally being further substituted with one or more R; R ５ is C ２ -C ５ Alkenyl group, C ２ -C ５ Alkynyl, C １－６ an alkyl group, a 3- to 6-membered cycloalkyl group, which may be optionally further substituted with one or more R; R ６ is C １－６ Alkyl group, 3- to 6-membered cycloalkyl group, NHR ７ wherein the alkyl and cycloalkyl groups can be optionally further substituted with one or more R; R ７ is C １－６ is selected from the alkyl or cycloalkyl groups Y is H, R is F, Cl, Br, I, deuterium, hydroxyl group, carboxyl group, CN, NH ２ , C １－６ Alkyl group, C １－６ is selected from an alkoxy group, a 3- to 5-membered cycloalkyl group, or a 3- to 5-membered heterocyclo group; A compound represented by formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof, wherein n is selected from 0, 1, 2, and 3.

2. The compound has the general formula (II): 【Chemistry 3】 (II) Here, X is 【Chemistry 4】 2. The compound of claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof, selected from:

3. The compound has the general formula (III): 【Chemistry 5】 (III) Where: The X is 【Chemistry 6】 is selected from The R １ , R ２ , R ５ , R ６ are each independently C １－６ 2. The compound according to claim 1, wherein the alkyl group is selected from the group consisting of an alkyl group represented by the formula: and a 3- to 6-membered cycloalkyl group.

4. The R １ is C １－６ and 3- to 6-membered cycloalkyl groups; The R ２ is H, a hydroxyl group, C １－６ Alkyl groups of C １－６ selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, The R ５ is C １－６ and 3- to 6-membered cycloalkyl groups; The R ６ is C １－６ and a 3- to 6-membered cycloalkyl group, wherein the alkyl group or cycloalkyl group can be optionally further substituted with one or more R.

5. The R ２ is H, a hydroxyl group, C １－６ Alkyl groups of C １－６ selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, The R １ and R ４ together with the atom to which they are attached form a 4-6 membered cycloalkyl or heterocyclo group fused to a benzene ring, said cycloalkyl or heterocyclo group optionally being further substituted with one or more R; The R ５ is C １－６ and 3- to 6-membered cycloalkyl groups; The R ６ is C １－６ 3. The compound according to claim 2, or a stereoisomer or a pharma- ceutically acceptable salt thereof, wherein the alkyl group is selected from the group consisting of an alkyl group represented by the formula:

6. The R ２ is independently C １－６ and 3- to 6-membered cycloalkyl groups; The R ６ is C １－６ and 3- to 6-membered cycloalkyl groups, which may optionally be further substituted with one or more R; 5. The compound of claim 4, wherein R is selected from F, Cl, Br, I, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

7. The R １ and R ４ together with the atom to which they are attached form a 4- to 6-membered cycloalkyl group fused to a benzene ring, said cycloalkyl group optionally being further substituted with one or more R; The R is C １－６ Alkyl group, C １－６ 6. The compound of claim 5, or a stereoisomer or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of aryl, ...

8. The compound is 【Chemistry 7】 【Chemistry 8】 2. The compound of claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof, selected from:

9. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a stereoisomer or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable vectors.

10. Use of a compound according to any one of claims 1 to 8, or a stereoisomer or a pharma- ceutically acceptable salt thereof, and a pharmaceutical composition according to claim 9 in the manufacture of a medicament for inducing and / or maintaining anesthesia in an animal or human, promoting sedative-hypnotic sleep in an animal or human, and treating and / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy.

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