Substituted phenol compound, preparation method therefor, and use thereof

Abstract

The present invention provides a substituted phenol compound represented by formula (I), a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, a nitrogen oxide thereof, a solvate thereof, a polymorph thereof, a metabolite thereof, an ester thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof, a preparation method therefor, and use thereof. The substituted phenol compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the isotopically labeled compound thereof, the nitrogen oxide thereof, the solvate thereof, the polymorph thereof, the metabolite thereof, the ester thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof of the present invention significantly improves safety, has an excellent anesthetic effect, can be readily formulated into various formulation forms, and thus can be used for preparing a drug for sedation, hypnosis, analgesia, and anesthesia.

Description

Substituted phenolic compounds, their preparation methods and applications

[0001] This invention claims priority to the prior application filed by the applicant with the China National Intellectual Property Administration on January 22, 2025, with patent application number 202510103332.0 and invention title "Substituted Phenolic Compounds and Preparation Methods and Applications Thereof", the contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to a substituted phenolic compound, its preparation method, and its application. Background Technology

[0003] Propofol (2,6-diisopropylphenol, Propofol, formula A) is a widely used general intravenous anesthetic, particularly suitable for the induction and maintenance of anesthesia in surgical procedures, outpatient biopsies, and various surgical procedures. It can also be used for long-term sedation in cardiac, pediatric, neurosurgical, and intensive care patients.

[0004] Because propofol is a lipid-soluble compound and poorly soluble in water, fat emulsions are currently the most commonly used formulation. However, when fat emulsions are used for intravenous anesthesia, they often cause adverse reactions such as decreased blood pressure, respiratory arrest due to respiratory depression, local pain during injection, hypertriglyceridemia, secondary acute pancreatitis, hyperglycemia, and keturia, thus narrowing its therapeutic window. Furthermore, the lipid component can exacerbate propofol-induced hypotension or lead to bacterial infection and allergic reactions due to contamination, which also limits the clinical application of propofol to some extent. Summary of the Invention

[0005] To address the aforementioned technical problems, the first objective of this invention is to provide a substituted phenolic compound as shown in formula (I), its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs.

[0006] in:

[0007] R 1 R 2 The substituents are independently selected from halogens, substituted C1-C6 alkyl groups, substituted C2-C6 alkenyl groups, substituted C1-C6 alkoxy groups, substituted C3-C6 cycloalkyl groups, substituted C3-C6 cycloalkoxy groups, or three- to seven-membered heterocyclic groups; the substituents are selected from hydrogen, C1-C6 alkyl groups, OH, C1-C6 alkoxy groups, halogens, nitro groups, cyano groups, C3-C6 cycloalkyl groups, or three- to seven-membered heterocyclic groups; the substituents are monosubstituted or polysubstituted.

[0008] X is selected from single bond, carbonyl group, -O- or Where n is 1 or 2; R 3 R 4 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, three- to seven-membered heterocyclic groups, and COOR. a COR b OR e or OCOR d R a R b R c R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or three- to seven-membered heterocyclic groups; R 5 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, three- to seven-membered heterocyclic groups, COR e OCOR f R e R f Selected from C1-C6 alkyl, C3-C6 cycloalkyl, or three- to seven-membered heterocyclic groups;

[0009] A is selected from And A is selected from At that time, X is not a single bond;

[0010] Where p and q are independently selected from 1, 2, or 3, and Y is selected from... -O- or Where R 10 R 11 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C6 cycloalkyl, three- to seven-membered heterocyclic groups, and COOR. g COR h OR i or CH2COOR j ;R g R h R i R j Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or three- to seven-membered heterocyclic groups; R 12 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, three- to seven-membered heterocyclic groups, OCOR k COR l or CH2COOR m ;R k R l R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or three- to seven-membered heterocyclic groups;

[0011] Z is selected from C or N, R 6 Selected from -NR 13 R 14 OR 15 The R 6 It can also be connected to Z to form a ring structure;

[0012] R 13 R 14 R 15 Each is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl;

[0013] R 7 R 8 R 9 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0014] The condition is that the substituted phenolic compounds represented by formula (I) do not include the following compounds:

[0015] In some implementation schemes, R 1 R 2 The groups are independently selected from halogens, substituted C1-C3 alkyl groups, substituted C2-C4 alkenyl groups, substituted C1-C3 alkoxy groups, substituted C3-C5 cycloalkyl groups, substituted C3-C5 cycloalkoxy groups, or three- to five-membered heterocyclic groups; the substituents are selected from hydrogen, methyl, ethyl, OH, methoxy, ethoxy, isopropoxy, F, Cl, B. r I, cyano, cyclopropyl, cyclobutyl, cyclopentyl, azircyclopropane-1-yl, azircyclobutane-1-yl or pyrrolidine-1-yl, wherein the substituent is monosubstituted or polysubstituted.

[0016] In some implementation schemes, R 1 R 2 Each of the following is independently selected from halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, vinyl, propenyl, allyl, propen-2-yl, n-butenyl, 2-methylpropen-1-yl, 2-methylallyl, methoxy, ethoxy, n-propoxy, isopropoxy, 2-methylpropoxy, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, azircyclopropane-1-yl, azircyclobutane-1-yl, or pyrrolidine-1-yl.

[0017] In some implementation schemes, R 1 R 2 Each is independently selected from methyl, ethyl, n-propyl, and isopropyl.

[0018] In some implementation schemes, R 1 R 2Each is independently selected from cyclopropylethyl.

[0019] In some implementation schemes, R 1 R 2 Each is independently selected from 1-cyclopropylethyl.

[0020] In some implementation schemes, R 1 R 2 They are independently selected from (R)-1-cyclopropylethyl and (S)-1-cyclopropylethyl, respectively.

[0021] In some implementations, X is selected from single bonds, carbonyl groups, -O- or Where n is 1 or 2; R 3 R 4 Each is independently selected from hydrogen, halogens (fluorine, chlorine, bromine, iodine), cyano, C1-C6 alkyl, C3-C6 cycloalkyl, COOH, COH, OH, or OCOCH3; R 5 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, COCH3, and OCOCH3;

[0022] In some embodiments, X is selected from single bonds, carbonyl groups, methylene groups, ethylene groups, or...

[0023] In some implementation schemes, A is selected from

[0024] Where p and q are independently selected from 1, 2, or 3, and Y is selected from... -O- or Where R 10 R 11 Each is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, and C1-C6 alkyl groups; R 12 Selected from hydrogen and C1-C6 alkyl groups;

[0025] Z is selected from C or N, R 6 Selected from -NR 13 R 14 OR 15 The R 6 It can also be connected to Z to form a ring structure; where R 13 R 14 R 15 Each is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl;

[0026] R 7 R 8 R 9 They are independently selected from hydrogen and C1 to C6 alkyl groups, respectively.

[0027] In some implementations, p and q are independently selected from 1, 2, or 3, and Y is selected from... -O- or Where R 10 R 11 Each is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, and isopropyl; R 12 Selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl;

[0028] Z is selected from C or N, R 6 Selected from -NR 13 R 14 OR 15 The R 6 It can also be connected with Z to form R 13 R 14 R 15 Each of the following is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, and cyclohexyl;

[0029] R 7 R 8 R 9 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl.

[0030] In some implementations, A is selected from the following structures:

[0031] Where R 10 R 11 R 13 R 14 Each has its own definition as described above;

[0032] In some implementations, A is selected from the following structures:

[0033] The present invention also provides a substituted phenolic compound of formula (I), its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs.

[0034] Among them, R 1 R 2 X has the definition described above, and A is selected from...

[0035] Where r is independently selected from 1, 2 or 3, and s is independently selected from 1, 2, 3, 4 or 5.

[0036] In some implementations, A is selected from the following structures:

[0037] According to embodiments of the present invention, the substituted phenolic compound represented by formula (I), its stereoisomers, tautomers, isotope-labeled compounds, nitrides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs are selected from the substituted phenolic compounds represented by formulas (II), (III), or (IV) below, their stereoisomers, tautomers, isotope-labeled compounds, nitrides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs:

[0038] Among them, R 1 R 2 X and A have the definitions described above.

[0039] According to embodiments of the present invention, the substituted phenolic compounds represented by formulas (II), (III), and (IV), their stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs are respectively selected from the substituted phenolic compounds represented by formulas (II-1), (III-1), (IV-1), and (V-1), their stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs.

[0040] Among them, R 1 R 2 Y, p, and q have the definitions described above;

[0041] Among them, R 1 R 2 R 7 R 8 R 9 It has the definition as described above;

[0042] Where X is a single bond, carbonyl group, or R 1 R 2 R 3 R 4 R 6 Z and n have the definitions described above;

[0043] Where X is R1 R 2 R 3 R 4 r, s, and n have the definitions described above.

[0044] According to an embodiment of the present invention, the substituted phenolic compound represented by formula (II) has the following structure:

[0045] Among them, R 1 R 2 Each of the substituents is independently selected from substituted C1 to C3 alkyl groups, wherein the substituents are selected from hydrogen, cyclopropyl, cyclobutyl, and cyclopentyl;

[0046] A is selected from the following structure:

[0047] Where R 10 R 11 Each is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, and C1-C6 alkyl groups;

[0048] Alternatively, A can be selected from the following structure:

[0049] Where r is independently selected from 1 or 2, and s is independently selected from 1 or 2.

[0050] According to an embodiment of the present invention, the substituted phenolic compound represented by formula (III) has the following structure:

[0051] Among them, R 1 R 2 Each is independently selected from C1 to C3 alkyl groups;

[0052] A is selected from

[0053] R 7 R 8 R 9 They are independently selected from hydrogen and C1 to C6 alkyl groups, respectively.

[0054] According to an embodiment of the present invention, the substituted phenolic compound represented by formula (IV) has the following structure:

[0055] Where X is a single bond, carbonyl group, methylene group, or

[0056] R 1 R 2 Each is independently selected from C1 to C3 alkyl groups;

[0057] A is selected from the following structure:

[0058] R 13 R 14 They are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0059] According to embodiments of the present invention, pharmaceutically acceptable salts of substituted phenolic compounds represented by formula (I) include hydrochloride, hydrobromide, nitrate, carbonate, bicarbonate, phosphate, monohydrogen phosphate, dihydrogen phosphate, sulfate, or hydrogen sulfate of substituted phenolic compounds represented by formula (I).

[0060] Preferably, the substituted phenolic compounds of the present invention are selected from any one of the following compounds:

[0061] This invention provides a method for preparing substituted phenolic compounds of formula (I), their stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs, wherein the preparation method comprises:

[0062] Method 1:

[0063] Compound B-1 was obtained by formylation of compound A-1, followed by reductive amination to prepare compound (II).

[0064] Or method 2:

[0065] Compound C-1 was obtained by halogenation of compound A-1, compound C-2 was obtained by hydroxyl protection of compound C-1, compound C-3 was further prepared by compound C-2, compound C-4 was obtained by coupling of compound C-3, and compound (III) was obtained by dehydroxyl protecting group reaction.

[0066] Where R h It is a hydroxyl protecting group.

[0067] Alternatively, method 3: compound D-1 is obtained by Friedel-Crafts acylation of compound A-1, and compound D-1 is then reduced to obtain compound (IV).

[0068] In some embodiments, compound B-1 is prepared from compound A-1 by dissolving compound A in a solvent and adding a formylation reagent to carry out a substitution reaction. The formylation reagent is selected from 1,1-dichlorodimethyl ether, hexamethylenetetramine, and preferably hexamethylenetetramine. The solvent is selected from glacial acetic acid, trifluoroacetic acid, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or any mixture thereof, preferably trifluoroacetic acid.

[0069] The preparation of compound (I) from compound B-1 involves dissolving compound B-1 in a solvent, adding an acid catalyst and an amine, and then adding a reducing agent to carry out a reductive amination reaction. The acid is selected from hydrochloric acid and glacial acetic acid, preferably glacial acetic acid. The reducing agent is selected from sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride, preferably sodium triacetoxyborohydride. The solvent is selected from methanol, ethanol, acetone, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or any mixture thereof, preferably methanol.

[0070] In some embodiments, C-1 is prepared from compound A-1 by dissolving compound A in a solvent and adding a brominating reagent to carry out a substitution reaction. The brominating reagent is selected from bromine, N-bromosuccinimide (NBS), and dibromohydantoin, preferably NBS. The solvent is selected from methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or any mixture thereof, preferably acetonitrile.

[0071] The preparation of C-2 from compound C-1 involves dissolving compound C-1 in a solvent and adding R. h -X(R h It is obtained by substitution reaction of a hydroxyl protecting group and an acid-binding agent. The R... h -X is selected from Bn-Br, PMB-Cl, TMS-Cl, TES-Cl, TBDMS-Cl, TIPS-Cl, etc., preferably Bn-Br; the acid-binding agent is selected from N,N-diisopropylethylamine (DIEA), triethylamine, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, cesium carbonate or sodium bicarbonate, preferably potassium carbonate; the solvent is selected from acetone, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or any mixture of two solvents, preferably acetone.

[0072] The preparation of C-3 from compound C-2 involves dissolving compound C-2 in a solvent, adding pinacol diborate, a base, and a catalyst, and then reacting the solution under heating via a Miyaura reaction. The base is selected from N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, cesium carbonate, or sodium bicarbonate, preferably potassium acetate. The catalyst is selected from tris(dibenzylideneacetone)palladium, tetra(triphenylphosphine)palladium, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (DPPF palladium dichloride), palladium acetate, preferably tetra(triphenylphosphine)palladium. The solvent is selected from toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or a mixture of any two, preferably 1,4-dioxane. The reaction temperature is preferably 60–80°C.

[0073] The preparation of C-4 from compound C-3 involves dissolving compounds IV and V in a solvent, adding a catalyst and a base, and then subjecting the reaction to a Suzuki coupling reaction under heating. The base is selected from N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, cesium carbonate, or sodium bicarbonate, preferably potassium carbonate; the catalyst is selected from tris(dibenzylacetone)dipalladium, tetra(triphenylphosphine)palladium, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (DPPF palladium dichloride), palladium acetate, or dichlorobis[(1,2,3)-1-phenyl-2-propene]dipalladium, preferably 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (DPPF palladium dichloride); the solvent is selected from toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or a mixture of any two, preferably 1,4-dioxane; the reaction temperature is preferably 60–80°C.

[0074] The preparation of compound (II) from compound C-4 involves dissolving compound C-4 in a solvent and then reacting it with the appropriate deprotecting agent. When R... h When the solvent is Bn, the deprotecting agent is preferably H2 / Pd / C; the solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or any mixture thereof, with methanol being preferred.

[0075] In some embodiments, the preparation of D-1 from compound A-1 involves dissolving compound A-1 in a solvent, adding an acylation reagent and a catalyst, and then performing a Friedel-Crafts acylation reaction. The catalyst is selected from hydrochloric acid, sulfuric acid, ferric chloride, zinc chloride, and aluminum chloride, preferably aluminum chloride; the solvent is selected from methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or a mixture of any two, preferably dichloromethane.

[0076] Compound (IV) is obtained from D-1 through reduction or reduction, substitution, etc. Specifically, when the carbonyl group is reduced to methylene, the solvent is selected from methanol, ethanol, glacial acetic acid, trifluoroacetic acid dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or any mixture of two solvents, preferably trifluoroacetic acid, and the reducing agent is selected from hydrogen, sodium borohydride, lithium aluminum hydride, triethylsilane, preferably triethylsilane.

[0077] The compounds of formulas (II), (III), and (IV) obtained by the above methods are salted with pharmaceutically acceptable acids or bases to obtain the pharmaceutically acceptable salts.

[0078] The present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined in this application as an active ingredient, a stereoisomer thereof, a tautomer thereof, an isotope label thereof, a nitrogen oxide thereof, a solvate thereof, a polymorph thereof, a metabolite thereof, an ester thereof, a pharmaceutically acceptable salt or a prodrug thereof, and another pharmaceutically acceptable carrier.

[0079] The pharmaceutically acceptable carrier can be an excipient widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods to allow the active ingredient to dissolve at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipient can be an inert filler, or it may provide a function such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipient may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0080] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0081] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or sustained-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry powder formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0082] In some embodiments, the pharmaceutical composition according to the invention further comprises additional active ingredients.

[0083] In some embodiments, the dosage of the compound of formula (I), its stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs contained in the pharmaceutical composition may be a therapeutically effective amount.

[0084] The effective dose range of an active compound can be quite wide, and it is usually administered at the pharmaceutically effective dose. However, it is understood that the actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered, the patient's age, weight, and response, and the severity of the patient's symptoms.

[0085] This invention provides the use of compounds of formula (I) as defined in this application, their stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions thereof, in the preparation of a medicament.

[0086] In some implementations, the drug is a drug used for sedation, hypnosis, analgesia, or anesthesia.

[0087] The present invention provides a method for sedation, hypnosis, analgesia, and anesthesia, the method comprising administering to an individual in need a compound of formula (I) according to the present invention, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions thereof. Beneficial effects

[0088] The compound designed in this invention significantly improves safety and has excellent anesthetic effect through structural optimization of propofol. It is easy to prepare into various formulations, which is beneficial for clinical application in multiple administration methods. The structure is novel and the preparation method is simple. Detailed Implementation

[0089] Unless otherwise specified, the terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise specified, all patent and non-patent literature or otherwise disclosed material cited in whole or in part herein is incorporated herein by reference. Unless otherwise specified, the following terms as used herein shall have the meanings as explained below, and their definitions as examples, exemplary definitions, preferred definitions, definitions set forth in tables, definitions of specific compounds in examples, etc., may be freely combined and combined with each other.

[0090] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the connection of the corresponding group to other segments or groups in the compound shown in Formula I through this site.

[0091] In this document, the term "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0092] In this document, the term "halogen" refers to fluorine, chlorine, bromine, and iodine. Accordingly, the term "halogenated" refers to fluorination, chlorination, bromination, or iodination. Within the scope of this document, when a group is halogenated, the group or its atoms may be mono-, di-, or poly-substituted up to fully substituted by a halogen atom.

[0093] In this document, the term "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkyl group contains 1-3 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc., or their isomers.

[0094] In this document, the term “C1-C6 alkoxy” means “-O-C1-C6 alkyl”, where “C1-C6 alkyl” has the definition as described above.

[0095] In this document, the term "C2-C6 alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms, particularly 2, 3, or 4 carbon atoms ("C2-C4 alkenyl"). Examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, and (Z)-pent-2-enyl. (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylpropenyl, 1-methylpropenyl 2-Alkenyl, 2-Methylprop-1-alkenyl, (E)-1-methylprop-1-alkenyl, (Z)-1-methylprop-1-alkenyl, 3-Methylbut-3-alkenyl, 2-Methylbut-3-alkenyl, 1-Methylbut-3-alkenyl, 3-Methylbut-2-alkenyl, (E)-2-methylbut-2-alkenyl, (Z)-2-methylbut-2-alkenyl, (E)-1-methylbut-2-alkenyl, (Z)-1- Methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0096] In this document, the term "C3-C6 cycloalkyl" should be understood as referring to a saturated monovalent monocyclic or polycyclic hydrocarbon ring (bicyclic, tricyclic, etc.) having 3, 4, 5, or 6 carbon atoms. The C3-C6 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or a bicyclic hydrocarbon group.

[0097] In this document, the term “C3-C6 cycloalkoxy” means “-O-C3-C6 cycloalkyl”, where “C3-C6 cycloalkyl” has the definition as described above.

[0098] In this document, the term "three- to seven-membered heterocyclic group" refers to a saturated or unsaturated heterocyclic group containing one to two O, N, or S ring heteroatoms, either saturated or unsaturated. The "three- to seven-membered heterocyclic group" may include, but is not limited to: a 3-membered ring, such as azirropropyl or oxacyclopropyl; a 4-membered ring, such as azirrobutyl or oxacyclobutyl; a 5-membered ring, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or a 7-membered ring, such as diazacycloheptyl. Optionally, the "three- to seven-membered heterocyclic group" may be bicyclic. The nitrogen-containing ring can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl.

[0099] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, etc.); and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid. Acids such as oxalic acid, malic acid, pyruvic acid, ferulic acid, and methanesulfonic acid are included; organic acid salts also include salts of organic acids such as amino acids (e.g., arginine) and glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, thus allowing them to be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, followed by separation of the parent compound, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0100] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.

[0101] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0102] "Enantiomers" refer to two non-overlapping but mirror-image isomers of a compound.

[0103] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0104] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in racemic or enantiomerically enriched forms, such as (R)-, (S)-, or (R, S)- configurations. In some embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.

[0105] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0106] In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomer separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0107] The term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (also called prototro pictautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0108] The term "isotope-labeled" includes, but is not limited to, compounds of the present invention labeled with isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S, and 36Cl). Isotope-labeled compounds of the present invention can be used for the determination of the tissue distribution of the compounds, their prodrugs, and metabolites; preferred isotopes for such determinations include 3H and 14C. Furthermore, in some cases, substitution with a heavier isotope (e.g., deuterium (2H or D)) can provide increased metabolic stability, which offers therapeutic advantages, such as increased in vivo half-life or reduced dose requirements. The isotope-labeled compounds of the present invention can generally be prepared according to the methods described herein by replacing non-isotope-labeled reagents with isotope-labeled reagents.

[0109] The term "nitrogen oxide" in this invention refers to an N-oxide formed by oxidizing one or more nitrogen atoms when the compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen atoms in nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), wherein the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as dichloromethane.

[0110] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0111] In this invention, "ester" refers to an ester that is hydrolyzable in vivo, formed from a compound containing a hydroxyl or carboxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that, upon hydrolysis in a human or animal body, produces a parent alcohol or acid. The compounds of formula (I) of this invention contain a carboxyl group and can form hydrolyzable esters in vivo with suitable groups, including, but not limited to, alkyl, arylalkyl, etc.

[0112] As used in this invention, the term "prodrug" refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; in existing inventions, esters that can serve as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound in this invention contains a hydroxyl group, meaning it can be acylated to obtain the prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent compound. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0113] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0114] Example 1:

[0115] Synthesis of 4-((4,4-difluoropiperidin-1-yl)methyl)-2,6-diisopropylphenol (II-1)

[0116] Synthesis of 4-hydroxy-3,5-diisopropylbenzaldehyde (B-1)

[0117] Propofol (50.00 g, 0.28 mol) was added to a 500 mL three-necked flask, and dissolved in dichloromethane (300 mL). The reaction solution was clear and yellow. The flask was cooled and stirred in an ice bath for 30 min. Titanium tetrachloride (117.6 g, 0.62 mol) was slowly added to the reaction solution over 1 h. The reaction solution gradually changed from clear yellow to reddish-brown. After the addition was complete, the flask was stirred in an ice bath for another 30 min. Then, 1,1-dichlorodimethyl ether (35.60 g, 0.31 mol) was slowly added to the reaction solution over 1 h. After the addition was complete, the flask was stirred in an ice bath for 30 min, then cooled to room temperature and stirred for 2 h. TLC (V 石油醚 V 乙酸乙酯 =10:1) Monitor the reaction of the raw materials to ensure complete reaction, and quench the reaction slowly with water under ice bath. Extract three times with dichloromethane (100mL×3), combine the organic layers, wash three times with water (150mL×3), wash once with saturated sodium chloride aqueous solution (300mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure to remove solvent, (V 正己烷 V 乙酸乙酯 =8:1, 200mL) to obtain 47.32g of reddish-brown solid by pulping. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.80 (s, 1H), 9.32 (s, 1H), 7.58 (s, 2H), 3.36-3.28 (m, 2H), 1.18 (d, J=6.8Hz, 12H).

[0118] Synthesis of 4-((4,4-difluoropiperidin-1-yl)methyl)-2,6-diisopropylphenol (II-1)

[0119] B-1 (500 mg, 2.42 mmol), 4,4-difluoropiperidine hydrochloride (460 mg, 2.91 mmol), and glacial acetic acid (145 mg, 2.42 mmol) were added to a 50 mL round-bottom flask. Dichloromethane (16 mL) was added, and the mixture was cooled and stirred in an ice bath for 15 min. Triethylamine (295 mg, 2.91 mmol) was added, followed by sodium triacetoxyborohydride (2.05 g, 9.68 mmol) in three portions over 3 h in an ice bath. After the addition was complete, the mixture was transferred to room temperature and stirred for 12 h. TLC (V 石油醚 V 乙酸乙酯 =10:1) Monitor the reaction of the starting materials until complete, and quench the reaction slowly with water under ice bath. Extract three times with dichloromethane (10 mL × 3), combine the organic layers, wash three times with water (10 mL × 3), wash once with saturated sodium chloride aqueous solution (40 mL), dry with anhydrous sodium sulfate, and purify by column chromatography (V 石油醚 V 乙酸乙酯 =40:1 to 25:1), the solvent was removed by vacuum concentration, and 32.4 mg of yellowish-white solid was obtained. 1H NMR (400MHz, Chloroform-d) δ (ppm) 6.97 (s, 2H), 6.78 (s, 1H) 3.47 (s, 2H), 3.1 8-3.08(m, 2H), 2.58-2.47(m, 4H), 2.07-1.91(m, 4H), 1.27(d, J=6.9Hz, 12H).

[0120] The synthesis of compounds II-2, II-3, II-4, II-5, and II-6 referenced compound II-1, and the relevant structural confirmation data are as follows:

[0121] Example 2:

[0122] Synthesis of 2,6-diisopropyl-4-(6-(methylamino)pyridin-3-yl)phenol (III-1)

[0123] Synthesis of 4-bromo-2,6-diisopropylphenol (C-1)

[0124] Propofol (25.00 g, 0.14 mol) was dissolved in acetonitrile (200 mL), cooled and stirred at 0 °C for 30 min, and NBS (24.91 g, 0.14 mol) was slowly added in portions. The reaction solution gradually changed from colorless and clear to yellow and turbid. After the addition was complete, the mixture was stirred at 0 °C for 2 h. The reaction solution was analyzed by TLC (V... 石油醚 V 乙酸乙酯 =20:1) After monitoring the reaction of the raw materials to completion, water (100 mL) was added to the reaction system to quench the reaction. The mixture was extracted three times with ethyl acetate (100 mL × 3), washed three times with water (100 mL × 3), and washed once with saturated brine (200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, purified by silica gel column chromatography (petroleum ether), and concentrated under reduced pressure to remove the solvent, yielding 28.37 g of a yellow oil. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 7.74 (s, 1H), 7.14 (s, 2H), 3.17-3.05 (m, 2H), 1.24 (d, J=6.8Hz, 12H).

[0125] Synthesis of 2-benzyloxy-5-bromo-1,3-diisopropylbenzene (C-2)

[0126] C-1 (14.70 g, 0.06 mol) was added to a 250 mL three-necked flask and dissolved in 100 mL of acetone; the reaction solution was clear and yellow. K₂CO₃ (11.80 g, 0.09 mol) was added, and the mixture was stirred at room temperature for 10 min. BnBr (10.26 g, 0.06 mol) was then added to the reaction solution, and the mixture was heated to reflux for 1.5 h. TLC (V1) was performed. 石油醚V 乙酸乙酯 =20:1) Monitor the reaction of the raw materials to ensure completeness, add ethyl acetate (100 mL) to dilute, add water (100 mL) and ethyl acetate (100 mL × 3) to extract three times, combine the organic layers, wash once with saturated brine (300 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure to remove solvent, recrystallize with n-hexane (100 mL), cool to precipitate crystals, filter and dry to obtain 18.98 g of yellow solid. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 8.74 (s, 1H), 7.50-7.32 (m, 5H), 6.47 (s, 2H), 4.66 (s, 2H), 3.66 (t, J=5.0Hz, 2 H), 3.47 (t, J=5.9Hz, 2H), 3.31-3.21 (m, 4H), 3.17-3.10 (m, 2H), 2.11-2.00 (m, 2H), 1.19 (d, J=6.8Hz, 12H).

[0127] Synthesis of 2-(4-(benzyloxy)-3,5-diisopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (C-3)

[0128] C-2 (10.00 g, 28.79 mmol), pinacol diboronate (8.77 g, 34.55 mmol), potassium acetate (5.69 g, 57.58 mmol), and Pd(pddf)Cl2 (1.06 g, 1.44 mmol) were added to a 250 mL three-necked flask. 1,4-dioxane (90 mL) and water (9 mL) were added to dissolve the flask. The air was replaced three times with N2, and the reaction was heated at 80 °C for 7 h. TLC (V1) was performed. 石油醚 V 乙酸乙酯 =20:1) Monitor the reaction of the raw materials to ensure complete reaction. Filter the diatomaceous earth and wash the filter cake three times with ethyl acetate (20 mL). Combine the organic layers and dilute with water (100 mL). Extract three times with ethyl acetate (50 mL × 3). Combine the organic layers and wash three times with water (100 mL × 3). Wash once with saturated sodium chloride aqueous solution (150 mL). Dry with anhydrous sodium sulfate. Concentrate under reduced pressure to remove the solvent. Recrystallize with n-hexane (40 mL), filter, and dry to obtain 8.16 g of brown solid. 1 H NMR (300MHz, Chloroform-d) δ (ppm) 7.63 (s, 2H), 7.53-7.37 (m, 5H), 4.82 (s, 2H), 3.49-3.34 (m, 2H), 1.29 (d, J=7.0Hz, 12H), 0.09 (s, 12H).

[0129] Synthesis of 5-(4-(benzyloxy)-3,5-diisopropylphenyl)-N-methylpyridine-2-amine (C-4-1)

[0130] C-3 (1.76 g, 4.46 mmol), 5-bromo-2-(methylamino)pyridine (1.00 g, 5.35 mmol), potassium carbonate (1.23 g, 57.58 mmol), and tetra(triphenylphosphine)palladium (257 mg, 0.22 mmol) were added to a 100 mL three-necked flask. 1,4-dioxane (10 mL) and water (1 mL) were added to dissolve the flask. The air was replaced three times with N2, and the reaction was heated at 80 °C for 12 h. TLC (V1) was performed. 石油醚 V 乙酸乙酯 =2:1) ​​Monitor the reaction of the raw materials until complete. Filter the diatomaceous earth. Wash the filter cake three times with ethyl acetate (10 mL). Combine the organic layers and dilute with water (40 mL). Extract three times with ethyl acetate (10 mL × 3). Combine the organic layers and wash three times with water (30 mL × 3). Wash once with saturated sodium chloride solution (100 mL). Dry with anhydrous sodium sulfate and purify by column chromatography (V). 石油醚 V 乙酸乙酯 =10:1 to 5:1), the solvent was removed by vacuum concentration, and 0.91 g of yellowish-white solid was obtained. 1 H NMR (300MHz, Chloroform-d) δ (ppm) 8.36 (s, 1H), 7.70 (d, J=8.5, 2.5Hz, 1H), 7.56-7.34 (m, 5H), 6.49 (d, J=8.6 Hz, 1H), 4.84 (s, 2H), 4.62 (d, J=6.2Hz, 1H), 3.51-3.37 (m, 2H), 2.99 (d, J=5.2Hz, 3H), 1.30 (d, J=7.0Hz, 12H).

[0131] Synthesis of 2,6-diisopropyl-4-(6-(methylamino)pyridin-3-yl)phenol (III-1)

[0132] C-4-1 (910 mg, 2.43 mmol) was added to a 50 mL round-bottom flask, dissolved in anhydrous methanol (10 mL), and the reaction solution was yellow and clear. 10% Pd / C (100 mg) was added, and the air was replaced three times with H2. The mixture was stirred at room temperature for 12 hours. TLC (V1) was then performed. 石油醚 V 乙酸乙酯 =1:1) Monitor the reaction of raw materials until complete, filter with diatomaceous earth, wash the filter cake three times with methanol (5mL×3), concentrate under reduced pressure to remove solvent, (V 石油醚 V 乙酸乙酯 =5:1, 10mL) were mixed and filtered to obtain 400mg of white solid. 1H NMR (400MHz, Chloroform-d) δ (ppm) 8.31 (s, 1H), 7.65 (d, J=8.6, 2.5Hz, 1H), 7.18 (s, 2H), 6.46 (d, J= 8.6, 0.9Hz, 1H), 4.64-4.55 (m, 1H), 3.27-3.15 (m, 2H), 2.96 (d, J=5.2Hz, 3H), 1.31 (d, J=6.8Hz, 12H).

[0133] The synthetic reference compound III-1 for compounds III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, and III-12 are shown in the following structural confirmation data:

[0134] Example 3: Synthesis of (6-(dimethylamino)pyridin-3-yl)(4-hydroxy-3,5-diisopropylphenyl)methyl ketone (IV-1)

[0135] Synthesis of (6-chloropyridin-3-yl)(4-hydroxy-3,5-diisopropylphenyl) methyl ketone (D-1)

[0136] Propofol (8.44 g, 47.34 mmol) was added to a 250 mL round-bottom flask, followed by aluminum trichloride (12.63 g, 94.72 mmol), and then dichloromethane (100 mL) to dissolve it. The mixture was cooled and stirred in an ice bath for 30 min. 6-chloropyridine-3-carbonyl chloride (10.00 g, 56.82 mmol) was slowly added. After the addition was complete, the mixture was brought to room temperature and stirred for 8 h. TLC (V 石油醚 V 乙酸乙酯 =8:1) Monitor the reaction of the raw materials to ensure complete reaction, and quench the reaction slowly by adding water under ice bath conditions. Extract three times with dichloromethane (30 mL × 3), combine the organic layers, wash three times with water (50 mL × 3), wash once with saturated sodium chloride aqueous solution (120 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure to remove solvent, (V 正己烷 V 乙酸乙酯 =5:1, 60mL) to obtain 6.38g of brown solid by pulping. 1 H NMR (300MHz, Chloroform-d) δ8.73 (s, 1H), 8.08 (d, J=8.2, 2.4Hz, 1H), 7.57 (s, 2H ), 7.48 (d, J=8.2Hz, 1H), 5.39 (s, 1H), 3.26-3.10 (m, 2H), 1.29 (d, J=6.9Hz, 12H).

[0137] Synthesis of (6-(dimethylamino)pyridin-3-yl)(4-hydroxy-3,5-diisopropylphenyl) ketone (IV-1)

[0138] D-1 (3.00 g, 9.44 mmol), dimethylamine hydrochloride (1.16 g, 14.16 mmol), and triethylamine (2.87 g, 28.32 mmol) were added to a 30 mL sealed tube, dissolved in DMF (8 mL), and reacted at 80 °C for 6 h. TLC (V1) was then performed. 石油醚 V 乙酸乙酯 =5:1) Monitor the reaction of the raw materials until complete, dilute with water (25 mL), extract three times with ethyl acetate (10 mL × 3), combine the organic layers, wash three times with water (20 mL × 3), wash once with saturated sodium chloride aqueous solution (40 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure to remove solvent, (V 正己烷 V 乙酸乙酯 =4:1, 10mL) pulped, filtered, dried, and 2.74g brown solid was obtained. 1 H NMR (400MHz, Chloroform-d) δ8.61 (s, 1H), 8.00 (d, J=9.0, 2.4Hz, 1H), 7.53 (s, 2H), 6.5 6 (d, J=9.0Hz, 1H), 5.34 (s, 1H), 3.21 (s, 6H), 3.20-3.12 (m, 2H), 1.29 (d, J=6.9Hz, 12H). 1 H NMR (400MHz, Chloroform-d) δ8.61 (s, 1H), 8.00 (d, J=9.0, 2.4Hz, 1H), 7.53 (s, 2H), 6.5 6 (d, J=9.0Hz, 1H), 5.34 (s, 1H), 3.21 (s, 6H), 3.20-3.12 (m, 2H), 1.29 (d, J=6.9Hz, 12H).

[0139] Example 4: Synthesis of IV-2 and IV-3:

[0140] IV-1 (0.60 g, 1.84 mmol) was added to a 50 mL three-necked flask, dissolved in trifluoroacetic acid (12 mL), and triethylsilane (2.14 g, 18.38 mmol) was slowly added. After addition, the reaction was carried out at 65 °C for 6 h. The reaction of the raw materials was monitored by TLC (V petroleum ether: V ethyl acetate = 3:1) until completion. The pH was adjusted to 7 - 8 with 4 mol / L sodium hydroxide aqueous solution under ice bath, diluted with water (30 mL), extracted three times with ethyl acetate (25 mL × 3), washed three times with water (35 mL × 3), and washed once with saturated sodium chloride aqueous solution (80 mL). The organic layers were combined, concentrated under reduced pressure to remove the solvent, recrystallized from toluene (5 mL), cooled to crystallize, filtered by suction, and dried to obtain 496 mg of a white solid.

[0141] IV-1 (0.60 g, 1.84 mmol) was added to a 50 mL three-necked flask, dissolved in methanol (10 mL), stirred under ice bath, and sodium borohydride (0.14 g, 3.68 mmol) was slowly added. After addition, the reaction was carried out at rt for 1 h. The reaction of the raw materials was monitored by TLC (V petroleum ether: V ethyl acetate = 1:1) until completion. The reaction was quenched with water (15 mL) under ice bath, the solvent was concentrated under reduced pressure, extracted three times with ethyl acetate (20 mL × 3), washed three times with water (25 mL × 3), and washed once with saturated sodium chloride aqueous solution (50 mL). The organic layers were combined, concentrated under reduced pressure to remove the solvent, slurried with toluene (8 mL), filtered by suction, and dried to obtain 455 mg of a white solid.

[0142] The synthesis of compound IV-4 was referenced to compound IV-1. The confirmation data results of the related structures of compounds IV-2, IV-3 and IV-4 are as follows:

[0143] Example 5: Evaluation of the anesthetic effect of compounds

[0144] 1. Experimental animals

[0145] Grade and strain: SPF-grade ICR mice;

[0146] Animal management: The animals were raised and managed by personnel with the qualification recognition of experimental animal management;

[0147] Age, quantity, and gender at the time of purchase: SPF-grade ICR male mice, 4 - 6 weeks old, 18 - 22 g. Manufacturer: Hangzhou Medical College. Animal quality certificate: SCXK (Su) 2024 - 0001;

[0148] Breeding unit: Experimental Animal Center of China Pharmaceutical University. Use license number: SYXK (Su) 2023 - 0019;

[0149] Quarantine process: Animals are quarantined and observed for 3 to 5 days. During this period, their physical appearance, behavior, weight, and diet are observed.

[0150] 2. Experimental Methods

[0151] Pharmacodynamic studies of the compound and control compound AF in mice: Before the experiment, ICR mice were fasted for 12 hours but allowed free access to water. Propofol and each test compound were dissolved in 5% DMSO, 15% polyethylene glycol-hydroxystearate (HS-15), and 80% physiological saline, with a concentration of 5 mg / mL for propofol and 5 mg / mL for each test compound. The drugs were administered via tail vein injection to mice at a dose of 30 mg / kg, with the injection rate controlled to be completed within 10 seconds. Five mice were used in each group.

[0152] After successful administration via tail vein, the absence of righting reflex (LORR) in mice for more than 30 seconds is considered an induction of anesthesia; if the mouse can right itself twice, it is considered a return of righting reflex (RRR), and is considered a recovery; when the animal awakens and exhibits purposeful exploration, it is considered a complete recovery.

[0153] During the experiment, the behavioral activities, respiratory changes, and significant adverse reactions of the mice were observed. The drug administration time, onset time (the time from the onset of LORR after tail vein injection), duration time (the time from the onset of LORR to the onset of RRR), and recovery time (the time from the onset of RRR to complete recovery) were recorded for ICR mice. The average duration time and average recovery time for each group of mice were calculated.

[0154] 3. Experimental Results

[0155] The onset time, average duration of anesthesia, and average recovery time of propofol and each tested compound are shown in Table 1.

[0156] Table 1. Experimental data on mouse anesthetic activity testing

[0157] The structure of the control compound AF is as follows:

[0158] The results in Table 1 show that several compounds of the present invention have excellent anesthetic effects, and their anesthetic effects are superior to those of the structurally similar compound AF.

[0159] Example 6: Evaluation of the side effects of the compound

[0160] 1. Experimental Methods

[0161] Fifteen male SD rats (SPF grade, weighing 180–220 g, source: Guangdong Provincial Medical Experimental Animal Center) were randomly divided into three groups of five each: A. Propofol raw material biochemical detection group; B. Compound II-2 hydrochloride blood biochemical detection group; and C. Compound IV-2 hydrochloride blood biochemical detection group. Propofol, Compound II-1 hydrochloride, and Compound IV-2 hydrochloride were dissolved in 5% DMSO + 10% Solutol HS 15 + 85% physiological saline, with a concentration of 5 mg / mL for propofol and 5 mg / mL for both Compound II-1 and Compound IV-2 hydrochloride. All administration was intravenous injection. The dosage was set at 15 mg / kg for propofol and II-1, and 40 mg / kg for IV-2. The injection rate was controlled to be consistent (uniform injection rate, controlled to be completed within 210 seconds).

[0162] After fixing each rat in groups A, B, and C, the drug was administered via the tail vein. The animals were observed for injection pain during the administration process. Approximately 1 ml of blood was collected from the orbital venous plexus before administration and at 30 and 60 minutes after administration. Serum was separated to detect high-sensitivity troponin T (cTnT), homocysteine ​​(HCY), creatine kinase isoenzyme MB (CK-MB), creatinine (CR), blood urea nitrogen (UREA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST).

[0163] 2. Data Processing

[0164] Experimental data were statistically processed using GraphPad Prism 7.0 biostatistics software: Quantitative data were expressed as Mean ± SD and analyzed using two-way ANOVA combined with Dunnett's multiple comparison method; ANOVA combined with Dunnett's multiple comparison method was used for analysis; Categorical data were analyzed using the Kruska-Wallis rank-sum test; One-way ANOVA combined with Dunnett's multiple comparison method was used for analysis.

[0165] 3. Experimental Results

[0166] The results of serum biochemical parameters in rats are shown in Table 2. Compared with before drug administration, the levels of high-sensitivity troponin T in the propofol raw material group, compound II-1 hydrochloride group, and IV-2 hydrochloride group were significantly increased at 60 min after drug administration (P < 0.01 or P < 0.001). Among them, propofol raw material showed the highest increase, compound IV-2 hydrochloride showed a smaller increase, and compound II-1 hydrochloride showed the smallest increase.

[0167] Compared with before administration, the homocysteine ​​content in the propofol raw material group and the compound II-1 hydrochloride group did not change significantly at 30 min and 60 min after administration (P>0.05); the homocysteine ​​content in the compound IV-2 hydrochloride group decreased significantly at 30 min and 60 min after administration (P<0.01 or P<0.001).

[0168] Compared with before administration, no significant changes were observed in urea content in the propofol raw material group and the compound II-1 hydrochloride group at 30 min and 60 min after administration (P>0.05); however, urea content in the compound IV-2 hydrochloride group decreased significantly at 30 min and 60 min after administration (P<0.01 or P<0.001).

[0169] Compared with before administration, no significant changes were observed in ALT levels in the propofol raw material group and the compound II-1 hydrochloride group at 30 min and 60 min after administration (P>0.05); however, ALT levels in the compound IV-2 hydrochloride group increased significantly at 60 min after administration (P<0.01 or P<0.001).

[0170] Compared with before administration, no significant changes were observed in CK-MB, CR, and AST in the propofol raw material group, compound II-1 hydrochloride group, and IV-2 hydrochloride group at 30 and 60 min after administration (P>0.05).

[0171] The above results indicate that the side effects of the compounds in this invention are less severe than those of propofol.

[0172] Table 2. Effects on serum biochemical parameters in rats (n=5, )

[0173] Note: Compared with before administration*: P<0.05, **P<0.01, ***<0.001, ****<0.0001.

[0174] Example 7: Evaluation of the solubility of the compound

[0175] The solubility of compound II-1 hydrochloride and propofol at different concentrations were tested in solvent systems of 5% DMSO + 10% Solutol HS 15 + 85% physiological saline, 2% DMSO + 5% Solutol HS 15 + 93% physiological saline, 100% physiological saline, and 1% DMSO + 99% physiological saline. The results are shown in Table 3.

[0176] Table 3: Solubility Test Results

[0177] According to Table 3, in the solvent system of 5% DMSO + 10% Solutol HS 15 + 85% physiological saline, propofol is insoluble at 8 mg / mL, while compound II-1 hydrochloride is soluble at 20 mg / mL. Furthermore, even when the ratio of DMSO and Solutol HS 15 in the solvent system is reduced to 2% DMSO and 5% Solutol HS 15, compound II-1 hydrochloride remains soluble at 20 mg / mL. In the solvent system of 100% physiological saline, compound II-1 hydrochloride is soluble at 2.5 mg / mL, while propofol is insoluble at 1 mg / mL in 100% physiological saline. Therefore, compound II-1 hydrochloride exhibits significantly improved solubility compared to propofol.

[0178] The exemplary embodiments of the present invention have been described above. However, the scope of protection of this application is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A substituted phenolic compound of formula (I), its stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs. in: R 1 R 2 The substituents are independently selected from halogens, substituted C1-C6 alkyl groups, substituted C2-C6 alkenyl groups, substituted C1-C6 alkoxy groups, substituted C3-C6 cycloalkyl groups, substituted C3-C6 cycloalkoxy groups, or three- to seven-membered heterocyclic groups; the substituents are selected from hydrogen, C1-C6 alkyl groups, OH, C1-C6 alkoxy groups, halogens, nitro groups, cyano groups, C3-C6 cycloalkyl groups, or three- to seven-membered heterocyclic groups; the substituents are monosubstituted or polysubstituted. X is selected from single bond, carbonyl group, -O- or Where n is 1 or 2; R 3 R 4 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, three- to seven-membered heterocyclic groups, and COOR. a COR b OR c or OCOR d R a R b R c R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or three- to seven-membered heterocyclic groups; R 5 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, three- to seven-membered heterocyclic groups, COR e OCOR f R e R f Selected from C1-C6 alkyl, C3-C6 cycloalkyl, or three- to seven-membered heterocyclic groups; A is selected from And A is selected from At that time, X is not a single bond; Where p and q are independently selected from 1, 2, or 3, and Y is selected from... -O- or Where R 10 R 11 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C6 cycloalkyl, three- to seven-membered heterocyclic groups, and COOR. g COR h OR i or CH2COOR j ;R g R h R i R j Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or three- to seven-membered heterocyclic groups; R 12 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, three- to seven-membered heterocyclic groups, OCOR k COR 1 or CH2COOR m ;R k R 1 R m Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or three- to seven-membered heterocyclic groups; Z is selected from C or N, R 6 Selected from -NR 13 R 14 OR 15 The R 6 It can also be connected to Z to form a ring structure; R 13 R 14 R 15 Each is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 7 R 8 R 9 Each is independently selected from hydrogen and C1-C6 alkyl groups; The condition is that the substituted phenolic compounds represented by formula (I) do not include the following compounds: Or, R 1 R 2 X has the definition described above, and A is selected from... Where r is independently selected from 1, 2 or 3, and s is independently selected from 1, 2, 3, 4 or 5; Preferably, A is selected from the following structures:

2. The substituted phenolic compound, its stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs according to formula (I) of claim 1, wherein R 1 R 2 The substituents are independently selected from halogens, substituted C1-C3 alkyl groups, substituted C2-C4 alkenyl groups, substituted C1-C3 alkoxy groups, substituted C3-C5 cycloalkyl groups, substituted C3-C5 cycloalkoxy groups, or three- to five-membered heterocyclic groups; the substituents are selected from hydrogen, methyl, ethyl, OH, methoxy, ethoxy, isopropoxy, F, Cl, Br, I, cyano, cyclopropyl, cyclobutyl, cyclopentyl, azircyclopropane-1-yl, azircyclobutane-1-yl, or pyrrolidine-1-yl, and the substituents are monosubstituted or polysubstituted; Preferably, R 1 R 2 Each of the following is independently selected from halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, vinyl, propenyl, allyl, propen-2-yl, n-butenyl, 2-methylpropen-1-yl, 2-methylallyl, methoxy, ethoxy, n-propoxy, isopropoxy, 2-methylpropoxy, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, azicyclopropane-1-yl, azicyclobutane-1-yl, or pyrrolidine-1-yl; More preferably, R 1 R2 is independently selected from methyl, ethyl, n-propyl, and isopropyl, respectively; Preferably, R 1 R 2 Each is independently selected from cyclopropylethyl; More preferably, R 1 R 2 Each is independently selected from 1-cyclopropylethyl, such as R 1 R 2 They are independently selected from (R)-1-cyclopropylethyl and (S)-1-cyclopropylethyl, respectively.

3. The substituted phenolic compound, its stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs according to formula (I) of claim 1 or 2, wherein, X is selected from single bond, carbonyl group, -O- or n is 1 or 2; R 3 R 4 Each is independently selected from hydrogen, halogen (fluorine, chlorine, bromine, iodine), cyano, C1-C6 alkyl, C3-C6 cycloalkyl, COOH, COH, OH or OCOCH3; R 5 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, COCH3, and OCOCH3; Preferably, X is selected from single bonds, carbonyl groups, methylene groups, ethylene groups, etc.

4. The substituted phenolic compound of formula (I) according to any one of claims 1-3, its stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs. in, A is selected from p and q are independently selected from 1, 2, or 3, respectively; Y is selected from -O- or Where R 10 R 11 Each is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, and C1-C6 alkyl groups; R 12 Selected from hydrogen and C1-C6 alkyl groups; Z is selected from C or N, R 6 Selected from -NR 13 R 14 OR 15 The R 6 It can also be connected to Z to form a ring structure; where R 13 R 14 R 15 Each is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 7 R 8 R 9 Each is independently selected from hydrogen and C1-C6 alkyl groups; Preferably, p and q are independently selected from 1, 2, or 3, and Y is selected from... -O- or Where R 10 R 11 Each is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, and isopropyl; R 12 Selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl; Preferably, Z is selected from C or N, R 6 Selected from -NR 13 R 14 OR 15 The R 6 It can also be connected with Z to form R 13 R 14 R 15 Each of the following is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, and cyclohexyl; Preferably, R 7 R 8 R 9 Each of the following is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl; More preferably, A is selected from the following structures: Where R 10 R 11 R 13 R 14 Each has its own definition as described above; More preferably, A is selected from the following structures:

5. A substituted phenolic compound of formula (I) according to any one of claims 1-4, its stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs, wherein, The substituted phenolic compound represented by formula (I) is selected from the substituted phenolic compounds represented by formulas (II), (III) or (IV) below: Among them, R 1 R 2 A and X have the definitions as described in any one of claims 1-4; Preferably, the substituted phenolic compounds represented by formulas (II), (III), and (IV) are selected from the substituted phenolic compounds represented by formulas (II-1), (III-1), (IV-1), and (V-1), respectively: Among them, R 1 R 2 Y, p, and q have the definitions as described in any one of claims 1-4; Among them, R 1 R 2 R 7 R 8 R 9 It has the definition in any one of claims 1-4; Where X is a single bond, carbonyl group, or R 1 R 2 R 3 R 4 R 6 Z and n have the definitions as described in any one of claims 1-4; Where X is R 1 R 2 R 3 R 4 r, s, and n have the definitions as described in any one of claims 1-4; Preferably, the substituted phenolic compound represented by formula (II) has the following structure: Among them, R 1 R 2 Each of the substituents is independently selected from substituted C1 to C3 alkyl groups, wherein the substituents are selected from hydrogen, cyclopropyl, cyclobutyl, and cyclopentyl; A is selected from the following structure: Where R 10 R 11 Each is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, and C1-C6 alkyl groups; Alternatively, A can be selected from the following structure: Where r is independently selected from 1 or 2, and s is independently selected from 1 or 2; Preferably, the substituted phenolic compound represented by formula (III) has the following structure: Among them, R 1 R 2 Each is independently selected from C1 to C3 alkyl groups; A is selected from R 7 R 8 R 9 Each is independently selected from hydrogen and C1-C6 alkyl groups; Preferably, the substituted phenolic compound represented by formula (IV) has the following structure: Where X is a single bond, carbonyl group, methylene group, or R 1 R 2 Each is independently selected from C1 to C3 alkyl groups; A is selected from the following structure: R 13 R 14 They are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

6. A substituted phenolic compound of formula (I) according to any one of claims 1-5, its stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs, wherein, Pharmaceutically acceptable salts of substituted phenolic compounds represented by formula (I) include hydrochloride, hydrobromide, nitrate, carbonate, bicarbonate, phosphate, monohydrogen phosphate, dihydrogen phosphate, sulfate, or hydrogen sulfate of substituted phenolic compounds represented by formula (I).

7. The substituted phenolic compound of formula (I) according to any one of claims 1-6, its stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs, wherein the substituted phenolic compound is selected from any one of the following compounds:

8. A method for preparing a substituted phenolic compound, its stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs according to any one of claims 1-7, wherein the method comprises: Method 1: Compound B-1 was obtained by formylation of compound A-1, followed by reductive amination to prepare compound (II); Or method 2: Compound C-1 was obtained by halogenation of compound A-1, compound C-2 was obtained by hydroxyl protection of compound C-1, compound C-2 was further prepared to obtain compound C-3, compound C-3 was coupled to obtain compound C-4, and compound (III) was obtained by dehydroxyl protecting group reaction. Where R h It is a hydroxyl protecting group; Or method 3: Compound D-1 is obtained by Friedel-Crafts acylation of compound A-1, and compound D-1 is then reduced to obtain compound (IV); 9. A pharmaceutical composition comprising, as an active ingredient, a substituted phenolic compound of formula (I) according to any one of claims 1-7, its stereoisomers, tautomers, isotopic labels, nitrides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, and another pharmaceutically acceptable carrier; the pharmaceutical composition optionally further comprising another active ingredient.

10. The use of a substituted phenolic compound of formula (I) according to any one of claims 1-7, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or the use of the pharmaceutical composition of claim 9 in the preparation of a medicament; for example, the medicament is a sedative-hypnotic, analgesic, or anesthetic medicament.

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