Resorcinol compound, preparation method thereof and application of resorcinol compound in nervous system diseases

Abstract

The invention relates to a resorcinol compound as well as a preparation method and application thereof in nervous system diseases. Specifically, the invention provides a resorcinol compound represented by a formula (I), an enantiomer, a diastereoisomer, a raceme, a mixture of the enantiomer, the diastereoisomer and the raceme, and pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates of the resorcinol compound. The invention also provides a preparation method of the compound and application of the compound in preparation of medicines for preventing and / or treating central nervous system diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the fields of pharmaceutical chemistry and chemical synthesis, and in particular to a class of resorcinol compounds with novel structures, a preparation method thereof, and applications thereof in treating central nervous system diseases. Background Art

[0002] Clinical and preclinical studies have found that cannabidiol (CBD) has ameliorative effects on various neuropsychiatric disorders. However, CBD suffers from low oral bioavailability, a low melting point, poor physicochemical properties, and poor target selectivity. Furthermore, low blood concentrations in humans when taken orally as a monotherapy limit its further clinical application.

[0003] Therefore, there is an urgent need in the art to develop a new class of cannabidiol analogs with improved oral bioavailability and stronger efficacy for the treatment of various central nervous system diseases. Summary of the Invention

[0004] The present invention aims to develop cannabidiol analogs with improved oral bioavailability and enhanced efficacy for the treatment of various central nervous system diseases. Specifically, the present invention provides a series of cannabidiol analogs with improved oral bioavailability, good physicochemical properties, and enhanced efficacy, as well as methods for their preparation and use in the preparation of medicaments for the treatment of nervous system diseases.

[0005] In the first aspect of the present invention, a compound or its enantiomers, diastereomers, racemates, and pharmaceutically acceptable inorganic or organic salts, crystalline hydrates, and solvates are provided, wherein the compound is represented by Formula I:

[0006]

[0007] Where,

[0008] R0 is selected from Preferably, R0 is

[0009] R1 is selected from hydroxy C1-C6 alkyl, C1-C6 alkylthio, C3-C 10 Cycloalkyl-substituted formyl, amino, amino substituted by C1-C6 alkyl, amino substituted by C1-C6 alkanoyl, cyano, amino C1-C6 alkyl, cyano C1-C6 alkyl, C1-C6 alkanoyl, sulfonylamino (-SO2NH2), carbamoyl (-CONH2), carbamoyl substituted by C1-C6 alkyl, carbamoyl substituted by hydroxy C1-C6 alkyl (HO-C1-C6 alkyl-NH-CO-), C3-C 10Cycloalkyl-substituted carbamoyl, carboxy C1-C6 alkyl, C1-C6 alkylsulfonyl, amino C1-C6 alkyl substituted by C1-C6 alkyl, amino C1-C6 alkyl substituted by C1-C6 alkanoyl, carbamoyl C1-C6 alkyl, or carbamoyl C1-C6 alkyl substituted by C1-C6 alkyl;

[0010] R2 is selected from C1-C 12 Alkyl, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, substituted C3-C 10 Cycloalkyl, or substituted or unsubstituted -(C1-C3 alkylene)-(C3-C 10 wherein said substitution refers to having 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl; preferably, R2 is a substituted C3-C 10 More preferably, R2 is substituted C3-C 10 Cycloalkyl, the substituted substituent is C1-C6 alkyl; most preferably, R2 is substituted cyclopropyl, the substituted substituent is C1-C6 alkyl;

[0011] R3 is selected from H, hydroxyl, -OC(O)-C1-C6 alkyl, -OC(O)(CH2)nN(C1-C6 alkyl)2; wherein n is any integer from 1 to 6;

[0012] represents a single bond or a double bond;

[0013] And Formula I does not include compounds selected from the group consisting of:

[0014]

[0015] In another preferred embodiment, R1 is selected from hydroxy C1-C4 alkyl, C1-C4 alkylthio, C3-C7 cycloalkyl substituted formyl, amino, amino substituted by C1-C4 alkyl, amino substituted by C1-C4 alkanoyl, cyano, amino C1-C4 alkyl, cyano C1-C4 alkyl, C1-C4 alkanoyl, sulfonylamino (-SO2NH2), carbamoyl (-CONH2), carbamoyl substituted by C1-C4 alkyl, Carbamoyl substituted by hydroxy C1-C4 alkyl (HO-C1-C4 alkyl-NH-CO-), carbamoyl substituted by C3-C7 cycloalkyl, carboxy C1-C4 alkyl, C1-C4 alkylsulfonyl, amino C1-C4 alkyl substituted by C1-C4 alkyl, amino C1-C4 alkyl substituted by C1-C4 alkanoyl, carbamoyl C1-C4 alkyl, or carbamoyl C1-C4 alkyl substituted by C1-C4 alkyl;

[0016] R2 is selected from C1-C 10 Alkyl, C1-C 10 Alkyl, C3-C7 cycloalkyl;

[0017] R3 is selected from H, hydroxyl, -OC(O)-C1-C4 alkyl, -OC(O)(CH2)nN(C1-C4 alkyl)2; wherein n is any integer from 1 to 3.

[0018] In another preferred embodiment, R1 is selected from -CH2OH, -CH2CH2OH, -SCH3, -SCH2CH3, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, cyano, -NHCOCH3, -CH2NH2, -CH2CH2NH2, -CH2CN, -CH2CH2CN, formyl, acetyl, propionyl, sulfonylamino (-SO2NH2), carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N,N-diethylcarbamoyl, -CONHCH2CH2OH, -CH2CO2H, -CH2CH2CO2H, -SO2CH3, -CH2NHMe, -CH2NMe2, -CH2NHCOCH3, -CH2CONH2, -CH2CONHMe or -CH2CONMe2;

[0019] R2 is selected from n-butyl, n-pentyl or cyclopropyl;

[0020] R3 is selected from H, hydroxy or -OC(O)-CH3.

[0021] In another preferred embodiment, the compound of formula (I) is selected from the compounds represented by general formula (IA):

[0022]

[0023] wherein R1, R2, and R3 are as defined above.

[0024] In another preferred embodiment, the compound of formula (I) is selected from the compounds represented by general formula (IA-1):

[0025]

[0026] In another preferred embodiment, the compound of formula (I) is selected from the compounds represented by general formula (IA-1-1):

[0027]

[0028] In another preferred embodiment, the compound of formula (I) is selected from the following compounds:

[0029]

[0030]

[0031]

[0032]

[0033] In a second aspect of the present invention, there is provided a method for preparing a compound of formula I-1, comprising the steps of: providing an aldehyde-substituted compound of formula (II), and subjecting the compound to a reduction reaction in the presence of a reducing agent;

[0034] The steps are shown in Reaction Formula 1:

[0035]

[0036] In formula I-1, R2 and R0 are as defined above.

[0037] In a third aspect of the present invention, a method for preparing a compound of formula I-2 is provided, comprising the steps of providing a compound of formula (III), and reacting NH(R4)2 with ammonolysis to obtain the compound, as shown in Reaction Scheme 2:

[0038]

[0039] In formula I-2,

[0040] R2 and R0 are as defined above;

[0041] R4 are each independently H, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C 10 Cycloalkyl.

[0042] In a fourth aspect of the present invention, a method for preparing a compound of formula I-3 is provided, comprising the steps of: using formula (II) as a raw material, and obtaining a compound of formula (I-3) through a two-step reaction, wherein the steps are shown in Reaction Scheme 3:

[0043]

[0044] In formula I-3,

[0045] R2 and R0 are as defined above.

[0046] In another preferred embodiment, the method specifically comprises the following steps:

[0047] 1) the compound of formula (II) undergoes Henry reaction with nitromethane in the presence of a catalyst in the presence of a base to produce a compound of formula (IV);

[0048] 2) the compound of formula (IV) undergoes a reduction reaction in the presence of a reducing agent to obtain a compound of formula (I-3);

[0049] In another preferred embodiment, the product prepared according to the methods of the second, third and fourth aspects of the present invention is provided and subjected to functional group transformation to obtain the compound of formula I.

[0050] In another preferred embodiment, the functional group conversion reaction is selected from the following group: condensation acylation reaction, reduction reaction, acylation reaction, esterification reaction, or a combination thereof.

[0051] In another preferred embodiment, the condensation acylation reaction is carried out in the presence of a condensing agent.

[0052] In another preferred embodiment, the condensing agent includes but is not limited to: N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU).

[0053] In another preferred embodiment, the reduction reaction is carried out in the presence of a reducing agent.

[0054] In another preferred embodiment, the reducing agent includes but is not limited to: hydrogen, ammonium formate, sodium borohydride, potassium borohydride, diisobutylaluminum hydride (DIBAL), and borane.

[0055] In another preferred embodiment, the acylation reaction is carried out in the presence of an acylating agent.

[0056] In another preferred embodiment, the acylating agent includes but is not limited to: acetyl chloride, acetic anhydride, propionyl chloride, propionic anhydride, and methanesulfonyl chloride.

[0057] In another preferred embodiment, the esterification reaction system includes but is not limited to: thionyl chloride / methanol, thionyl chloride / ethanol.

[0058] In the fifth aspect of the present invention, there is provided a use of the compound as described in the first aspect or its enantiomers, diastereomers, racemates, and pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates, wherein the compound is used to prepare a pharmaceutical composition or preparation for treating, alleviating and / or preventing central nervous system diseases.

[0059] In another preferred embodiment, the pharmaceutical composition or preparation further comprises other drugs for treating central nervous system diseases.

[0060] In another preferred embodiment, the central nervous system disease is selected from the following group: epilepsy, schizophrenia, refractory, intractable or chronic schizophrenia, affective disorders, psychotic disorders, mood disorders, bipolar I disorder, bipolar II disorder, depression, endogenous depression, major depression, refractory depression, dysthymic disorder, cyclothymic disorder, panic attack, panic disorder, social phobia, obsessive-compulsive disorder, impulsive disorder, post-traumatic stress disorder, anxiety disorder, acute stress disorder, hysteria, anorexia nervosa, adjustment disorder, cognitive disorder, autism, pain, mania, Parkinson's disease, Huntington's disease, Alzheimer's disease, various dementias, memory disorders, ADHD, drug addiction, sleep disorders, attention deficit / hyperactivity disorder, tics or a combination thereof.

[0061] In another preferred embodiment, the preparation is an oral preparation or a non-oral preparation.

[0062] In another preferred embodiment, the preparation is selected from the following group: tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, injections or a combination thereof.

[0063] In a sixth aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0064] (1) a compound of formula I as an active ingredient;

[0065] (2) other drugs for treating central nervous system diseases, optionally selected from the group consisting of antipsychotics, antiepileptics, or antidepressants;

[0066] (3) Pharmaceutically acceptable carriers or excipients.

[0067] In another preferred embodiment, the antipsychotic drugs include but are not limited to aripiprazole, risperidone, haloperidol, quetiapine, paliperidone, ziprasidone, asenapine, epiriprazole, olanzapine, clozapine, amisulpride and cariprazine.

[0068] In another preferred embodiment, the anti-epileptic drugs include but are not limited to carbamazepine, lamotrigine, oxcarbazepine, gabapentin, topiramate, zonisamide, lacosamide and valproic acid.

[0069] In another preferred embodiment, the antidepressant drugs include but are not limited to fluoxetine, fluvoxamine, sertraline, escitalopram, amitriptyline, venlafaxine, duloxetine, vortioxetine and citalopram.

[0070] In the seventh aspect of the present invention, a method for treating central nervous system diseases is provided, comprising the step of administering a medically effective amount of the compound of the first aspect of the present invention or the pharmaceutical composition of the sixth aspect to a patient in need.

[0071] In another preferred embodiment, the patient is a patient with a central nervous system disease.

[0072] In another preferred embodiment, the central nervous system disease is as defined above.

[0073] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0074] After extensive and in-depth research, the inventors have discovered for the first time a class of cannabidiol analogs with improved oral bioavailability and stronger efficacy that can effectively treat neurological diseases, and on this basis completed the present invention.

[0075] Specifically, the present invention prepares cannabidiol analogs represented by Formula I. Compared to cannabidiol, these analogs have the advantages of improved oral bioavailability, better physicochemical properties, and stronger efficacy. They are also more effective than CBD in treating neurological diseases and can therefore be better used in the preparation of drugs for preventing, alleviating, and / or treating neurological diseases. The present invention also provides methods for preparing these cannabidiol analogs.

[0076] the term

[0077] As used herein, "compounds of the present invention" and "active ingredients of the present invention" are used interchangeably and refer to cannabidiol analogs of Formula I that have better oral bioavailability, physicochemical properties, and target selectivity than CBD.

[0078] The term "halogen" generally refers to fluorine, chlorine, bromine and iodine; preferably fluorine, chlorine or bromine; more preferably fluorine or chlorine;

[0079] “C1-C 12 "Alkyl" refers to a straight or branched saturated hydrocarbon group containing 1 to 12 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl or n-hexyl, and is preferably methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl;

[0080] "C1-C6 alkylthio" refers to a straight-chain or branched alkylthio group containing 1 to 6 carbon atoms, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, isopentylthio, neopentylthio or n-hexylthio, and is preferably methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio;

[0081] "C1-C6 alkanoyl" refers to a straight or branched chain alkanoyl group containing 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, tert-butyryl or hexanoyl;

[0082] "Carbamoyl substituted by C1-C6 alkyl" means that the hydrogen atom on the carbamoyl group is substituted by one or two identical or different C1-C6 alkyl groups, such as -CONHMe, -CONHEt, -CON(Me)Et, -CONEt2 or -CONMe2;

[0083] "Hydroxy C1-C6 alkyl" refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms with one carbon atom connected to a hydroxy group, such as -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH2CH2CH2OH or -CH2CH(CH3)CH2OH;

[0084] "Amino C1-C6 alkyl" refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms connected to an amino group at one carbon atom, such as -CH2NH2, -CH2CH2NH2, -CH(NH2)CH3, -CH2CH2CH2NH2 or -CH2CH2CH2CH2NH2;

[0085] "Amino C1-C6 alkyl substituted by C1-C6 alkyl" means that the hydrogen atom on the amino group is substituted by one or two identical or different C1-C6 alkyl groups, such as -CH2NHMe or -CH2CH2NEt2;

[0086] "Carbamoyl C1-C6 alkyl" refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, one carbon atom of which is connected to the carbonyl carbon of a carbamoyl group, for example, -CH2CONH2, -CH2CH2CONH2, -CH(CONH2)CH3 or -CH2CH2CH2CONH2;

[0087] "Carbamoyl C1-C6 alkyl substituted by C1-C6 alkyl" means that the amino hydrogen atom on the carbamoyl C1-C6 alkyl group is substituted by one or two identical or different C1-C6 alkyl groups, such as -CH2CONHMe, -CH2CH2CONHEt, -CH2CH2CONMe2 or -CH2CONEt2;

[0088] "Cyano C1-C6 alkyl" refers to a straight-chain or branched alkyl group containing 1 to 6 carbon atoms, one carbon atom of which is connected to a cyano group, such as cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl or 5-cyanopentyl;

[0089] "Carboxy C1-C6 alkyl" refers to a carbon atom of a straight-chain or branched alkyl group containing 1 to 6 carbon atoms connected to a carboxyl group, such as carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl or 5-carboxypentyl;

[0090] "C1-C6 alkanesulfonyl" refers to a straight-chain or branched alkanesulfonyl group containing 1 to 6 carbon atoms, such as methylsulfonyl, ethylsulfonyl or propanesulfonyl;

[0091] "Amino group substituted by C1-C6 alkyl" means that the hydrogen atom on the amino group is substituted by one or two identical or different C1-C6 alkyl groups or C1-C6 alkanoyl groups, such as -NHMe or -NEt2;

[0092] “C3-C 10 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group containing 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.;

[0093] Cannabidiol (CBD)

[0094] Cannabidiol (CBD) is a non-psychoactive component of the cannabis plant that has various pharmacological effects on the nervous system. Its structural formula is as follows:

[0095]

[0096] CBD has a broad spectrum of pharmacological effects. Existing evidence shows that in addition to having certain effects on cannabinoid receptors (CB1 / CB2), CBD can also act on G protein-coupled receptors and ion channels related to neuropsychiatric diseases, such as serotonin (5-HT) receptors, glycine receptors, adenosine receptors and transient receptor potential ion channels (TRP), etc., and can inhibit the synaptic somes' uptake of neurotransmitters such as norepinephrine, dopamine, 5-HT and GABA, as well as the cells' uptake of endogenous cannabinoids. At the same time, it can also affect mitochondrial calcium ion storage and block low-voltage-activated T-type calcium ion channels.

[0097] Pharmaceutical compositions and methods of administration

[0098] The "pharmaceutically acceptable inorganic or organic salts" herein are salts of the compound represented by general formula (I) formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, or phosphoric acid; salts formed with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, maleic acid, tartaric acid, malic acid, fumaric acid, methanesulfonic acid, or citric acid; or sodium, potassium, calcium, or ammonium salts formed with a base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, or aqueous ammonia. "Pharmaceutically acceptable salts" also include solvates thereof, examples of which include hydrates and alcoholates.

[0099] The present invention also provides the use of the compound represented by general formula (I) according to the present invention, its enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts, crystalline hydrates and solvates in the preparation of drugs for preventing and / or treating central nervous system diseases.

[0100] The present invention also provides a method for treating and / or preventing central nervous system diseases, which comprises administering to humans or animals a compound represented by the general formula (I) of the present invention, its enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, or a mixture of more thereof.

[0101] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the above-mentioned general formula (I), its enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts, crystalline hydrates, and solvates thereof, or a mixture thereof, and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition can be used to treat or prevent central nervous system diseases.

[0102] The present invention also provides a method for preparing the pharmaceutical composition, comprising mixing the compound represented by the above general formula (I), its enantiomers, diastereomers, racemates, and a mixture of one or more of their pharmaceutically acceptable salts, crystalline hydrates and solvates with a pharmaceutically acceptable carrier.

[0103] Pharmaceutical compositions include those suitable for oral, nasal, topical (including transdermal, buccal, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration, or administration via implant. The pharmaceutical compositions of the present invention may be administered in a variety of forms, including tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, and injections, depending on the intended treatment.

[0104] For parenteral administration, suitable compositions include aqueous and non-aqueous sterile injections. Compositions can be provided in unit dose or multidose containers, such as sealed vials and ampoules, and can be stored under freeze drying (lyophilization) conditions, only needing to add sterile liquid carriers, such as water, before use. For transdermal administration, it can be expected that such as gel, patch or spray. Compositions or preparations suitable for pulmonary administration such as by nasal inhalation include fine dust or mist that can be produced by means of quantitative pressurized aerosols, sprayers or insufflators. The precise dosage and scheme of the use of compositions must depend on the therapeutic or nutritional effect to be achieved and can be different according to the age and condition of the individual subject to which a particular formulation, route of administration and compositions are applied.

[0105] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0106] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0107] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0108] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0109] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0110] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0111] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0112] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0113] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0114] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0115] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0116] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0117] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0118] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0119] Preparation method

[0120] The present invention also provides a method for preparing the compound of general formula (I) and its intermediates. The compound can be prepared by any of the following methods. The starting materials used in the present invention are commercially available or prepared according to known synthetic methods of similar compounds:

[0121] Method 1: Using the aldehyde-substituted compound (II) as a raw material, a reduction reaction is carried out in the presence of a reducing agent to obtain compound (I-1), as shown in Reaction Formula 1:

[0122]

[0123] Wherein, R2 and R0 are defined as above;

[0124] Method 2: Using formula (III) as the raw material, and reacting with NH(R4)2 through aminolysis to obtain the compound of formula (I-2), as shown in the reaction formula:

[0125]

[0126] Wherein, R2 and R0 are as defined above; R4 are each independently H, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C 10 Cycloalkyl.

[0127] Method 3: Using formula (II) as the raw material, a two-step reaction is performed to obtain a compound of formula (I-3), as shown in the reaction formula:

[0128]

[0129] The method three comprises the following steps:

[0130] 1) the compound of formula (II) undergoes Henry reaction with nitromethane in the presence of a catalyst in the presence of a base to produce a compound of formula (IV);

[0131] 2) the compound of formula (IV) undergoes a reduction reaction in the presence of a reducing agent to obtain a compound of formula (I-3);

[0132] Wherein, R2 and R0 are defined as above;

[0133] Method 4:

[0134] The compound of formula I obtained by methods 1 to 3 is obtained by performing functional group transformation.

[0135] The functional group conversion reaction may be a condensation acylation reaction, a reduction reaction, an acylation reaction, an esterification reaction, or the like.

[0136] The condensation acylation reaction is carried out in the presence of a condensing agent, which includes but is not limited to: N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), etc.

[0137] The reduction reaction is carried out in the presence of a reducing agent, which includes but is not limited to hydrogen, ammonium formate, sodium borohydride, potassium borohydride, diisobutylaluminum hydride (DIBAL), borane, and the like.

[0138] The acylation reaction is carried out in the presence of an acylating agent, which includes but is not limited to acetyl chloride, acetic anhydride, propionyl chloride, propionic anhydride, methanesulfonyl chloride, and the like.

[0139] The esterification reaction system includes but is not limited to: thionyl chloride / methanol, thionyl chloride / ethanol, etc.

[0140] The main advantages of the present invention are:

[0141] 1) The compounds of the present invention have better physicochemical properties and oral bioavailability than cannabidiol (CBD).

[0142] 2) The compounds of the present invention have a good effect on cannabinoid CB1 and CB2 receptors and can be used to treat various diseases related to cannabinoid CB1 and CB2 receptor dysfunction.

[0143] 3) The central nervous system activity of the compound of the present invention is superior to that of cannabidiol (CBD), and it has the characteristics of low onset dose and small toxic side effects. It can be used to treat various central nervous system diseases, such as epilepsy, Parkinson's disease, schizophrenia, bipolar disorder, depression, anxiety, mania, ADHD, drug addiction or neuralgia, and has good clinical application prospects.

[0144] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0145] Example 1 Preparation of the following compound 1

[0146]

[0147] Cannabidiolic acid methyl ester 1-1 was prepared according to the literature (WO 2019033168; WO 2019033164). 1.5 g of cannabidiolic acid methyl ester 1-1 was dissolved in 10 mL of methylamine / ethanol solution and reacted overnight at 100°C in a sealed tube. The reaction was monitored by TLC. After concentration, the reaction solution was separated by column chromatography (petroleum ether / ethyl acetate = 100 / 1 → 20 / 1). The product was slurried with petroleum ether and filtered to obtain the title compound 1 as a solid (212 mg). 1 H NMR(400MHz, CDCl3)δ11.21(br,1H),6.30(br,1H),6.21(s,1H),5.88(br,1H),5.54 (s,1H),4.53(s,1H),4.39(s,1H),4.07(br,1H),2.98(d,3H),2.64(t,2H),2.41–2. 39(m,1H),2.37–2.17(m,1H),2.11–2.05(m,1H),1.82–1.76(m,2H),1.78(s,3H),1. 70(s,3H),1.67–1.56(m,2H),1.37–1.30(m,4H),0.90(t,3H).ESI-MSm / z370.2(MH) - .

[0148] Example 2 Preparation of the following compound 2

[0149]

[0150] Oxalyl chloride (4.1 g, 2 eq) was added dropwise to dichloromethane (40 mL) and DMF (2.35 g, 1.2 eq), the temperature was controlled at -10-0 ° C, and the temperature was kept for 2 minutes. CBD (8.45 g) was dissolved in 40 mL of dichloromethane and added dropwise to the above system at -10 ° C. The reaction was allowed to react for 0.5 hours, and TLC (petroleum ether / ethyl acetate = 20 / 1) monitored the reaction to be complete. The reaction was quenched with saturated sodium bicarbonate solution, the dichloromethane layer was separated, dried over anhydrous sodium sulfate, concentrated and dried through a column, PE → PE / acetone = 100 / 1, and 9.42 g of product 2-a was isolated with a yield of 99%. NMR confirmation was consistent with the literature report (WO 2020031179).

[0151] Compound 2-a was dissolved in methanol, 1 eq of NaBH4 was added, and the mixture was reacted at room temperature overnight. The mixture was concentrated to dryness and directly passed through a column to obtain the title compound in a yield of about 80%. 1H NMR(400MHz,DMSO)δ8.71–8.54(m,2H),6.06(s,1H),5.57(br,1H),5.10(s,1H), 4.55–4.53(m,2H),4.51(m,1H),4.42(m,1H),3.89,3.89–3.86(m,1H),3.04(t,1H ),2.37(t,1H),2.11–2.08(m,1H),1.94–1.90(m,1H),1.61(s,3H),1.59(s,3H), 1.71–1.57(m,3H),1.45–1.38(m,2H),1.33–1.27(m,4H),0.87(t,3H).ESI-MSm / z 343.2 (MH) – .

[0152] Example 3 Preparation of the following compound 3

[0153]

[0154] Compound 2-a (3 g) was dissolved in a mixture of dichloromethane / methanol (50 / 50 mL), and methylamine ethanol solution (10 eq) was added. The mixture was stirred overnight under nitrogen and the starting material disappeared by TLC monitoring. The reaction solution was concentrated to dryness, and 50 mL of methanol was added. A methanol solution of NaBH4 (1 eq) was added dropwise under an ice bath and stirred for 15 minutes. The reaction was complete. Water and ethyl acetate (20 mL / 50 mL) were added, and the pH was adjusted to 8 with HCl. The ethyl acetate layer was separated and concentrated to dryness and passed through a column chromatography (PE / EA = 2 / 1 → EA) to obtain 1.8 g of the title compound 3, with a yield of 40%. 1 HNMR(400MHz, CDCl3)δ6.16(s,1H),5.94(m,1H),5.59(s,1H),4.53(m,1H) ,4.42(m,1H),4.11–4.04(m,1H),3.88(s,2H),2.51–2.41(m,2H),2.41(s,3 H),2.20–2.10(m,1H),2.10–2.05(m,1H),1.81–1.77(m,2H),1.77(s,3H), 1.70(s,3H),1.50–1.43(m,2H),1.32–1.25(m,4H),0.88(t,3H).ESI-MSm / z 358.03(M+H) + .

[0155] Example 4 Preparation of the following compound 4

[0156]

[0157] Cannabidiolic acid methyl ester 1-1 (5 g, 13.4 mmol) was dissolved in ethanolamine, sealed and refluxed for 36 h. The reaction solution was concentrated to dryness and purified by column chromatography to obtain 202 mg of the title compound 4 as a white solid. 1 H NMR(500MHz, CDCl3)δ11.95(s,1H),6.41(s,1H),6.23(s,1H),5.90(br,2H),5 .55(s,1H),4.53(m,1H),4.39(m,1H),4.08(m,1H),2.77–2.70(m,2H),2.40–2. 37(m,1H),2.24–2.20(m,1H),2.12–2.06(m,1H),1.83–1.77(m,2H),1.78(s,3 H),1.71(s,3H),1.65–1.63(m,2H),1.35–1.31(m,4H),0.88(t,3H).ESI-MSm / z 358.13(M+H) + .

[0158] Example 5 Preparation of the following compound 5

[0159]

[0160] Compound 2-a (200 mg, 0.584 mmol) was dissolved in nitromethane, and ammonium acetate (100 mg, 2.2 eq) was added. The mixture was heated under reflux for 12 h. TLC showed that the starting material was completely reacted. The solvent was concentrated and column chromatography was performed to obtain intermediate 5-a (200 mg). 1 H NMR(400MHz,Chloroform-d)δ8.24(d,J=13.3Hz,1H),8.08(d,J=13.2Hz,1H),7.12( s,1H),6.26(s,1H),5.56(s,1H),5.42–5.23(m,1H),4.62(s,1H),4.47(s,1H),3.91( d,J=9.9Hz,1H),2.67(m,2H),2.37(m,1H),2.32–2.21(m,2H),1.83–1.77(m,2H),1.8 5(s,3H),1.66(s,3H),1.66-1.53(m,2H),1.37–1.32(m,4H),0.90(t,3H).ESI-MSm / z 384.08(M–H) – .

[0161] Compound 5-a (200 mg, 0.51 mmol) was dissolved in THF, and lithium aluminum tetrahydride (194 mg, 10 eq) was added. The mixture was heated under reflux for 4 h. TLC indicated complete reaction. The reaction solution was poured into water, and the pH was adjusted to 8-9 with dilute hydrochloric acid. The mixture was extracted with n-butanol, and the organic phase was dried, concentrated, and purified by column chromatography to obtain 70 mg of the title compound. ESI-MS m / z 358.16 (M+H) + ,356.18(M–H) – . 1 H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.65(s,3H),6.10(s,1H),5.18(s,1H) ,4.64–4.30(m,2H),3.87(d,J=10.1Hz,1H),2.94(m,1H),2.71(m,4H),2.38( dd,J=9.0,6.4Hz,2H),2.13(m,1H),2.00–1.91(m,1H),1.71–1.67(m,2H),1 .63(s,3H),1.57(s,3H),1.47–1.39(m,2H),1.33–1.24(m,4H),0.87(t,3H).

[0162] Example 6 Preparation of the following compound 6

[0163]

[0164] Dissolve cannabidiolic acid methyl ester 1-1 (100 mg, 0.27 mmol) in 2 ml of cyclopropylamine solution and react overnight at 110°C in a sealed tube. Concentrate the solvent and column chromatography to obtain 12.7 mg of the title compound. ESI-MS m / z 398.33 (M+H) + ,396.19(M–H) – . 1 H NMR(400MHz,Chloroform-d)δ11.27(s,1H),6.31(br,1H),6.19(s,1H),6.02(s, 1H),5.53(s,1H),4.53(t,J=2.0Hz,1H),4.39(s,1H),4.06(s,1H),2.93–2.86(m 1H),2.72–2.52(m,2H),2.47–2.38(m,1H),2.22–2.17(m,1H),2.12–2.05(m,1H),1.80–1.76(m,2H ),1.78(s,3H),1.70(s,3H),1.62–1.50(m,2H),1.30(m,4H),0.91–0.86(m,5H),0.61–0.57(m,2H).

[0165] Example 7 Preparation of the following compound 7

[0166]

[0167] Cannabidiolic acid methyl ester 1-1 (100 mg, 0.27 mmol) was dissolved in 2 ml of amylamine and heated under reflux overnight. TLC indicated that the starting material had reacted almost completely. The solvent was concentrated to dryness, and column chromatography yielded 40 mg of the title compound. ESI-MS m / z 429.28 (M+2H) + , 426.27 (M–H) – . 1 H NMR(400MHz,Chloroform-d)δ11.18(br,1H)6.40–6.23(m,1H),6.21(s,1H),5.87(s,1H) ),5.54(s,1H),4.53(br,1H),4.40(br,1H),4.17–4.00(m,1H),3.43(p,J=6.6Hz,2H),2. 76–2.57(m,2H),2.43–2.37(m,1H),2.24–2.20(m,1H),2.14–2.02(m,1H),1.82–1.79(m, 2H),1.78(s,3H),1.70(s,3H),1.64–1.57(m,4H),1.42–1.30(m,8H),0.94–0.88(m,6H).

[0168] Example 8 Preparation of the following compound 10

[0169]

[0170] 5 mL (1.7 M) of tert-butylmagnesium chloride was added dropwise to 5 mL (2 M) of dimethylamine tetrahydrofuran solution at 0-10°C, and a tetrahydrofuran solution of cannabidiolic acid methyl ester 1-1 was slowly added dropwise. The tube was sealed and heated to 110°C for 24 h under reflux. TLC showed that a small amount of starting material remained. Column chromatography gave 900 mg of the title compound. 1H NMR(400MHz,DMSO)δ8.99(br,1H),8.02(br,1H),7.28(br,1H),6.15(s,1H),5.19(s,1H),4.41(m,2H),3.84(d,1H),3.00–2.65(m,7H),2.25 –2.13(m,1H),1.97–1.93(m,1H),1.67–1.58(m,2H),1.63(s,3H),1.58(s,3H),1.41–1.40(m,2H),1.30–1.16(m,4H),0.84(t,3H).ESI-MSm / z 384.12(M–H) – .

[0171] Example 9 Preparation of Compound 24

[0172]

[0173] Step 1:

[0174] 3,5-Dimethoxyphenylacetonitrile 24-a (5.0 g, 28.2 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (250 mL) and the atmosphere was replaced with nitrogen three times. Potassium bis(trimethylsilyl)amide (85 mL, 170 mmol, 6.0 eq.) was added to the solution, and 1,2-dibromoethane (15.9 g, 84.7 mmol, 3.0 eq.) was slowly added dropwise to the reaction system. The mixture was stirred at 0°C for 3 h, and the reaction was monitored for completion by TLC. The reaction solution was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain approximately 4 g of compound 24-b in an 80% yield. 1 H NMR (500MHz, CDCl3) δ6.44 (d, J = 2.4Hz, 2H), 6.38 (t, J = 2.4Hz, 1H), 3.80 (s, 6H) ,1.71–1.68(dd,J=7.4Hz,J=5.2Hz,2H), 1.41–1.38(dd,J=7.4Hz,J=5.2Hz,2H).

[0175] Step 2:

[0176] Compound 24-b (355.0 mg, 1.75 mmol, 1.0 eq.) was dissolved in DCM (16 mL), cooled to -67°C, and the atmosphere was replaced with nitrogen three times. DIBAL-H (4.4 mL, 4.4 mmol) was slowly added to the solution and allowed to react at -67 to -62°C for 2 h. Completion was monitored by TLC. The reaction solution was quenched by dropwise addition of saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase dried over anhydrous sodium sulfate and concentrated to afford 24-c as a transparent oil (272 mg, 77% yield).1 H NMR (300MHz, CDCl3) δ9.32 (s, 1H), 6.46 (d, J = 2.4Hz, 2H), 6.40 (t, J = 2.4Hz, 1H), 3.78 (s, 6H), 1.53 (m, 2H), 1.37 (m, 2H).

[0177] Step 3:

[0178] Triphenylpropylphosphonium bromide (8.6 g, 24.3 mmol, 5.0 eq.) was placed in a three-necked flask and the atmosphere was replaced with nitrogen three times. THF (15 mL) was added, and potassium bis(trimethylsilyl)amide (24 mL, 23.8 mmol, 4.9 eq.) was added under ice-cooling. The mixture was stirred for 30 min. Compound 24-c (1 g, 4.85 mmol, 1.0 eq.) was dissolved in 25 mL of THF and slowly added to the reaction system. The reaction was stirred at 0°C for 1 h, and completion was monitored by TLC. The reaction solution was quenched by dropwise addition of saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried, concentrated, and separated by column chromatography to obtain compound 24-d as a light yellow solid (993 mg). 1 H NMR(400MHz, CDCl3)δ6.40(d,2H),6.26(t,1H),5.65–5.62(m,1H),5.53–5.48(m,1H) ,3.77(s,6H),2.12–2.08(m,2H),1.10–1.08(m,2H),0.98–0.96(m,2H),0.91(t,3H).

[0179] Step 4:

[0180] Compound 24-d (375 mg, 1.6 mmol, 1.0 eq.) was dissolved in ethylene glycol dimethyl ether (38.1 mL), and p-toluenesulfonyl hydrazide (3.6 g, 19.2 mmol, 12.0 eq.) was added. The mixture was refluxed, and 37 mL of aqueous sodium acetate (3.1 g, 41.6 mmol, 26.0 eq.) was slowly added. The reaction was stirred at 93°C for 4 h, and completion was monitored by TLC. The reaction solution was quenched by dropwise addition of water, extracted with ethyl acetate, and the organic phase was dried, concentrated, and separated by column chromatography to afford 24-e as an oil (353 mg, 94% yield). 1 H NMR(500MHz, CDCl3)δ6.47(s,1H),6.46(s,1H),6.29(t,1H),3.79(s,6H),1.57–1.50 (m,2H),1.26–1.23(m,4H),0.84–0.81(m,3H),0.78–0.76(m,2H),0.63–0.61(m,2H).

[0181] Step 5:

[0182] Compound 24-e (13.2 g, 56.4 mmol, 1.0 eq.) and NBS (10.54 g, 59.2 mmol, 1.05 eq.) were dissolved in acetonitrile (250 mL). The atmosphere was replaced with nitrogen three times. The reaction system was incubated at 60°C for 4 h, and completion was monitored by TLC. The reaction solution was then added dropwise to a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried, concentrated, and separated by column chromatography to afford compound 24-f, approximately 8 g, in a 61% yield. 1 H NMR (500MHz, CDCl3) δ6.47(d,1H),6.38(d,1H),3.87(s,3H),3.80(s,3H),1.24–1.20(m,5H),0.83–0.78(m,8H).

[0183] Step 6:

[0184] Compound 24-f (500 mg, 1.596 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (16 mL), cooled to -60°C, and the atmosphere was replaced with nitrogen three times. n-BuLi (1.6 mL, 2.5 M, 2.5 eq.) was slowly added to the solution and allowed to react for 2 h. Methyl chloroformate (378 mg, 4 mmol, 2.5 eq.) was then added and the reaction continued for another 2 h. Completion was monitored by TLC. The reaction solution was quenched by dropwise addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to yield 284 mg of 24-g. 1 H NMR (500MHz, CDCl3) δ6.43(d,J=2.3Hz,1H),6.33(d,J=2.2Hz,1H),3.88(s,3H),3.81(s,3H),3.78 (s,3H),1.53–1.50(m,2H),1.25–1.22(m,4H),0.83(t,3H),0.77–0.75(m,2H),0.60–0.58(m,2H).

[0185] Step 7:

[0186] Compound 24-g (670 mg, 2.29 mmol, 1.0 eq.) and potassium hydroxide (1.27 g, 22.9 mmol, 10.0 eq.) were dissolved in 10 ml of DMSO under nitrogen and stirred at 100°C overnight. Completion was monitored by TLC. The reaction solution was quenched by dropwise addition of saturated sodium chloride solution, the pH was adjusted to acidic with 1 M hydrochloric acid, and the product was extracted with methyl tert-butyl ether. The organic phase was dried, concentrated, and purified by column chromatography to yield 24-h (approximately 488 mg). 1H NMR(500MHz,DMSO)δ12.53(s,1H),6.47(d,1H),6.36(d,1H),3.76(s,3H),3.74(s,3H),1.51–1.48 (m,2H),1.19–1.16(m,4H),0.79(t,3H),0.74–0.71(t,J=5.0Hz,2H),0.57–0.55(m,2H).ESI-MSm / z 277.32(M–H) – .

[0187] Step 8:

[0188] Compound 24-h (1.15 g, 4.14 mmol, 1.0 eq) was dissolved in DCM. SOCl2 (984 mg, 8.27 mmol, 2.0 eq) and 2 drops of DMF were added under ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction was monitored for completion by TLC and concentrated to remove the SOCl2. Methylamine hydrochloride (800 mg, 3 eq), 4-dimethylaminopyridine (558 mg, 8.27 mmol, 2.0 eq), and Et3N (1.67 g, 16.5 mmol, 4.0 eq) were added to a separate reaction vessel and stirred for 20 minutes. A solution of the acid chloride in DCM was added under ice-cooling and the reaction was continued under ice-cooling for 30 minutes. The reaction was allowed to proceed at room temperature overnight. Extraction with dichloromethane was performed, and the organic phase was dried, concentrated, and purified by column chromatography to yield approximately 780 mg of compound 24-i. 1 H NMR(500MHz,DMSO)δ7.7(d,1H),6.44(d,1H),6.34(d,1H),3.75(s,3H),3.71(s,3H),2.69(d, 3H),1.48–1.45(m,2H),1.16–1.15(m,4H),0.79(t,3H),0.74–0.72(m,2H),0.50–0.48(m,2H).

[0189] Step 9:

[0190] 24-i (780 mg, 2.68 mmol, 1.0 eq) was placed in a reaction flask, replaced with N2 three times, 30 mL of DCM was added, the temperature was lowered to -65°C, BBr3 (2.01 g, 8.04 mmol, 3.0 eq) was slowly added, the reaction was allowed to proceed for 2 hours, the temperature was naturally raised to react overnight, the reaction was monitored by TLC, saturated brine was added for extraction, the mixture was dried and concentrated, and approximately 440 mg of compound 24-j was obtained by column chromatography. 1H NMR(400MHz,DMSO)δ9.38(s,1H),9.20(s,1H),7.62(d,1H),6.14(d,1H),6.09(d,1H),2.68(d,3H),1.46–1 .43(m,2H),1.24–1.15(m,4H),0.80(t,3H),0.68–0.67(m,2H),0.47–0.45(m,2H).ESI-MSm / z262.35(M–H) – .

[0191] Step 10:

[0192] Compound 24-j (100 mg, 0.38 mmol, 1.0 eq) was placed in a reaction flask, replaced with N2 three times, 30 mL of DCM was added, and the temperature was lowered to 0-5°C. Tf2O (10 mg, 0.04 mmol, 0.1 eq) was slowly added and stirred for 30 minutes. A DCM solution of (+)-limonene (70 mg, 0.46 mmol, 1.35 eq) was slowly added and the reaction was monitored by TLC. The mixture was extracted with saturated brine, dried, concentrated, and purified by column chromatography to obtain approximately 50 mg of the title compound 24. 1 H NMR(400MHz,DMSO)δ11.10(br,1H),9.30(s,1H),7.70(d,1H),6.22(s,1H),5.08(s, 1H),4.48(s,1H),4.42(s,1H),3.88(d,1H),3.00(t,1H),2.82(d,3H),2.12–2.09(m, 1H),1.94–1.90(m,1H),1.75–1.61(m,2H),1.61(s,3H),1.58(s,3H),1.44–1.40(m,2 H),1.17–1.07(m,4H),0.89–0.82(m,2H),0.77(t,3H),0.73–0.62(m,2H).ESI-MSm / z 396.41(M–H) – .

[0193] Example 10 Preparation of Compound 27

[0194]

[0195] Step 1:

[0196] 27-a (100 mg, 0.56 mmol, 1.0 eq.) and NBS (105 mg, 0.59 mmol, 1.05 eq.) were dissolved in acetonitrile (6 mL), and the atmosphere was replaced with N2 three times. The reaction system was reacted at 60°C. The reaction was monitored by TLC. The reaction was quenched, extracted with ethyl acetate, and purified by column chromatography to obtain approximately 95 mg of the target compound 27-b. 1 H NMR (400MHz, CDCl3) δ6.70(d,1H),6.47(d,1H),3.88(s,3H),3.84(s,5H).GC-MSm / z 255.0.

[0197] Step 2:

[0198] Sodium hydride (375 mg, 15.62 mmol, 4.0 eq.) was placed in a three-necked flask and the atmosphere was replaced with nitrogen three times. N,N-dimethylformamide (6 mL) was added and the temperature was cooled to 0°C in an ice-salt bath. 27-b (1.0 g, 3.9 mmol, 1.0 eq.) and iodomethane (0.73 mL, 11.71 mmol, 3.0 eq.) were dissolved in N,N-dimethylformamide (10 mL) and slowly added dropwise to the reaction system, maintaining the temperature between -5°C and 5°C. The reaction was allowed to react for 1 h, and completion was monitored by TLC. The mixture was quenched, extracted with ethyl acetate, and purified by column chromatography to obtain approximately 930 mg of the target compound 27-c. 1 H NMR (500MHz, CDCl3) δ6.71(d,1H),5.51(d,8H),3.93(s,3H),3.86(s,3H),1.92(s,6H).GC-MSm / z 283.1.

[0199] Step 3:

[0200] Compound 27-c (200 mg, 0.7 mmol, 1.0 eq.) was placed in a three-necked flask and the atmosphere was replaced with N2 three times. Dichloromethane (10 mL) was added and the system was cooled to -68°C. 1M diisobutylaluminum hydride (1.77 mL, 1.77 mmol, 2.51 eq.) was slowly added. The reaction was allowed to proceed at -68°C for 1.5 h. The reaction was monitored for completion by TLC. The product was quenched, the insoluble material was filtered, and the product was extracted with dichloromethane. The target compound 27-d (170 mg) was obtained by column chromatography. 1 H NMR (400MHz, CDCl3) δ9.78(s,1H),6.60(d,1H),6.49(d,1H),3.88(s,3H),3.84(s,3H),1.50(s,6H).GC-MSm / z 286.1.

[0201] Step 4:

[0202] Triphenylpropylphosphonium bromide (403 mg, 1.045 mmol, 3.0 eq.) was placed in a three-necked flask and the mixture was purged with nitrogen three times. 5 mL of THF was added, followed by the addition of potassium bis(trimethylsilyl)amide (1 mL, 1.01 mmol, 2.9 eq.) under ice-cooling. The mixture was stirred for 30 minutes. Compound 27-d (100 mg, 0.348 mmol, 1.0 eq.) was dissolved in 5 mL of THF and slowly added to the reaction system. The reaction was stirred at 0°C for 1 hour. The reaction was monitored for completion by TLC. The mixture was quenched, extracted with ethyl acetate, and purified by column chromatography to yield approximately 400 mg of the target compound 27-e. 1 H NMR(400MHz, CDCl3)δ6.74(d,1H),6.40(d,1H),5.74–5.68(m,1H),5.12(dt,1H),3.85(d,6H),1.59–1.53(m,2H),1.52(s,6H),0.66(t,3H).GC-MSm / z 314.1.

[0203] Step 5:

[0204] 27-e (500 mg, 1.596 mmol, 1.0 eq.) was dissolved in 20 mL of ethylene glycol dimethyl ether, and p-toluenesulfonyl hydrazide (3.57 g, 19.15 mmol, 12.0 eq.) was added. The mixture was heated to reflux at 95°C, and aqueous sodium acetate (3.4 g, 41.5 mmol, 26.0 eq.) was slowly added. The reaction was monitored for completion by TLC, quenched, extracted with dichloromethane, and purified by column chromatography to obtain 420 mg of the target compound 27-f. 1 H NMR (400MHz, CDCl3) δ6.60(d,1H),6.39(d,1H),3.87(s,3H),3.81(s,3H),2.07–1.97(m,2H),1.46(s,6H),1.25(m,2H),0.96(m,2H),0.82(t,3H).

[0205] Step 6:

[0206] 27-f (200 mg, 0.634 mmol, 1.0 eq.) was placed in a reaction flask. After nitrogen purge, 5 mL of THF was added and the temperature was lowered to -65°C. n-BuLi (0.38 mL, 0.95 mmol, 1.5 eq.) was slowly added. The reaction was allowed to react at -60 to -65°C for one hour. The reaction system was then replaced with CO2. The reaction was monitored by TLC, quenched, extracted with ethyl acetate, and purified by column chromatography to yield 120 mg of 27-g. 1H NMR(500MHz,DMSO)δ12.61(s,1H),6.51(d,1H),6.44(d,1H),3.77(d,6H),1.67 –1.58(m,2H),1.29(s,6H),1.23–1.15(m,2H),1.06–0.97(m,2H),0.80(t,3H).

[0207] Step 7:

[0208] 27-g (100 mg, 0.36 mmol, 1.0 eq.) was dissolved in 3 mL of dichloromethane. Thionyl chloride (0.1 mL, 1.43 mmol, 4.0 eq.) and 1 drop of DMF were added under ice-cooling (0-2°C). The reaction was then stirred in an ice-cooling bath for 1 hour. TLC confirmed the complete reaction of the starting material, and the solvent and thionyl chloride were removed by concentration. In a separate reaction flask, methylamine hydrochloride (97 mg, 1.44 mmol, 4.0 eq.) was added to 5 mL of dichloromethane. Triethylamine (0.4 mL, 1.43 mmol, 4.0 eq.) was then added. The original reaction solution was slowly added to the reaction system under ice-cooling, and the reaction was allowed to proceed at room temperature (22°C) for 1 hour. The reaction was monitored for completion by TLC. After quenching with ammonium chloride, a small amount of dilute hydrochloric acid was added to acidify the mixture. The mixture was extracted with dichloromethane, dried, concentrated, and purified by column chromatography to obtain the target compound 27-h. 1 H NMR(500MHz,DMSO)δ7.86(m,1H),6.49(d,1H),6.44(d,1H),3.77(s,3H),3.72(s,3H),2. 65(d,3H),1.65–1.56(m,2H),1.26(s,6H),1.22–1.11(m,2H),1.03(m,2H),0.82(t,3H).

[0209] Step 8:

[0210] 27-h (50 mg, 0.17 mmol, 1.0 eq) was replaced with nitrogen and then 2.5 mL of dichloromethane was added. The temperature was cooled to -62°C and then boron tribromide (0.04 mL, 0.43 mmol, 2.5 eq.) was slowly added. The reaction was stirred at -60°C for 3 hours. The reaction was monitored for completion by TLC. The mixture was quenched, extracted, dried, concentrated, and purified by column chromatography to obtain the target compound, 27-i. 1 H NMR(500MHz,DMSO)δ9.12(s,1H),9.07(s,1H),7.71(d,1H),6.18(dd,2H),2.63(d,3H ),1.64–1.50(m,2H),1.23(s,6H),1.20–1.11(m,2H),1.08–0.96(m,2H),0.82(t,3H).

[0211] Step 9:

[0212] 27-i (300 mg, 1.1 mmol, 1.0 eq) was dissolved in 30 mL of DCM, replaced with nitrogen three times, cooled to -10-0°C, and Tf2O (20 mg, 0.11 mmol, 0.1 eq) was slowly added. After stirring for 30 minutes, a DCM solution of (+)-limonene (200 mg, 1.32 mmol, 1.2 eq) was slowly added. The reaction was monitored by TLC, quenched, extracted with dichloromethane, and purified by column chromatography to obtain approximately 100 mg of compound 27. 1 H NMR (400MHz, DMSO) δ8.84(s,1H),7.68(d,1H),6.29(s,1H),5.16(s,1H),4.49(d,2H),3.86(d,1H),2.90(s,1H),2.63 (d,3H),2.14(s,1H),1.94(d,1H),1.58(m,8H),1.20(m,6H),1.17(d,3H),1.00(d,3H),0.90–0.72(t,3H).ESI-MSm / z 398.5(M–H) – .

[0213] Example 11 Preparation of the following compound 9

[0214]

[0215] Step 1:

[0216] To a reaction flask, add 9-a (500 mg, 2.30 mmol, 1.0 eq) and Pd(dppf)Cl2 (169 mg, 0.23 mmol, 0.1 eq). After nitrogen purge, add cyclopropylmagnesium bromide (10 mL, 10 mmol, 5.0 eq). Reflux at 75°C and stir overnight. Monitor the reaction by TLC, quench, extract with ethyl acetate, concentrate, and perform column chromatography to yield approximately 350 mg of 9-b. 1 H NMR (500MHz, CDCl3) δ6.30(d,1H),6.28(d,2H),3.81(s,6H),1.97–1.81(m,1H),0.97(m,2H),0.79–0.63(m,2H).GC-MSm / z178.1.

[0217] Step 2:

[0218] 9-b (100 mg, 0.56 mmol, 1.0 eq) was dissolved in 5 mL of acetonitrile, and NBS (105 mg, 0.59 mmol, 1.05 eq) was added. The reaction was stirred at room temperature for 4 hours and monitored by TLC. The mixture was quenched, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain approximately 60 mg of 9-c. 1 H NMR(500MHz, CDCl3)δ6.37(d,1H),6.16(d,1H),3.90(s,3H),3.81(s,3H),2.27–2.20(m,1H),1.06–1.00(m,2H),0.71–0.66(m,2H).GC-MSm / z 258.0.

[0219] Step 3:

[0220] 9-c (200 mg, 0.78 mmol, 1.0 eq) was placed in a reaction flask, purged with nitrogen, and then 5 mL of tetrahydrofuran was added. The temperature was lowered to -62°C, and n-butyllithium (0.47 mL, 1.17 mmol, 1.5 eq) was slowly added. The reaction temperature was maintained between -62°C and -64°C, and stirred for 1 hour. The atmosphere in the reaction flask was then purged with CO2 and stirred at -60°C to -50°C for another 1 hour. The reaction was monitored by TLC, quenched, extracted with ethyl acetate, concentrated, and purified by column chromatography to yield approximately 130 mg of 9-d. 1 H NMR (400MHz, DMSO) δ12.62(s,1H),6.41(d,1H),6.00(d,1H),3.74(s,6H),2.01–1.78(m,1H),1.04–0.82(m,2H),0.81–0.53(m,2H).ESI-MSm / z 221.2(MH) - .

[0221] Step 4:

[0222] 9-d (50 mg, 0.22 mmol, 1.0 eq) was dissolved in 4 mL of dichloromethane. Thionyl chloride (0.06 mL, 0.9 mmol, 4.0 eq) and 1 drop of DMF were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. TLC monitored the reaction, and the solvent and thionyl chloride were removed by concentration. In a separate single-necked flask, methylamine hydrochloride (61 mg, 0.9 mmol, 4.0 eq) was added to 4 mL of dichloromethane, followed by triethylamine (0.12 mL, 0.9 mmol, 4.0 eq) and DMAP (55 mg, 0.44 mmol, 2.0 eq). A solution of the aforementioned acid chloride in dichloromethane (2.5 mL) was slowly added under ice-cooling, and the mixture was allowed to react at room temperature for 1 hour. The reaction was monitored by TLC, quenched, extracted with dichloromethane, concentrated, and purified by column chromatography to yield approximately 30 mg of 9-e. 1H NMR(500MHz,DMSO)δ7.98(d,1H),6.39(d,1H),5.96(d,1H),3.74(s,3H),3.72(s,3H ),2.71(d,3H),1.89–1.73(m,1H),0.89–0.84(m,2H),0.68–0.64(m,2H).ESI-MSm / z 235.9(M+H) + .

[0223] Step 5:

[0224] 9-e (100 mg, 0.43 mmol, 1.0 eq) was prepared by nitrogen replacement and the addition of 10 mL of dichloromethane. The temperature was lowered to -15 °C and then slowly added with boron tribromide (0.13 mL, 1.3 mmol, 3.0 eq.). The reaction temperature was controlled not to exceed -10 °C and stirred for 30 min. The temperature was naturally raised to react for 3 hours. The reaction was complete after TLC monitoring. The mixture was quenched, extracted with n-butanol, dried, concentrated, and purified by column chromatography to obtain approximately 55 mg of compound 9-f. 1 H NMR(400MHz,DMSO)δ9.65(s,1H),9.26(s,1H),7.81(d,1H),6.10(d,1H),5.72(d,1H),2. 71(d,3H),1.92–1.80(m,1H),0.92–0.76(m,2H),0.60–0.41(m,2H).ESI-MSm / z206.3(MH) - .

[0225] Step 6:

[0226] 9-f (250 mg, 1.2 mmol, 1.0 eq) was dissolved in 30 mL of DCM, replaced with nitrogen three times, cooled to -10-0°C, and Tf2O (34 mg, 0.12 mmol, 0.1 eq) was slowly added. After stirring for 30 minutes, a DCM solution of (+)-limonene (218 mg, 1.44 mmol, 1.2 eq) was slowly added. The reaction was monitored by TLC, quenched, extracted with dichloromethane, and purified by column chromatography to obtain approximately 70 mg of compound 9. 1 H NMR (400MHz, DMSO) δ11.42(s,1H),9.35(s,1H),7.88(s,1H),6.02(s,1H),5.05(s,1H),4.45(d,2H),3.87(d,1H),3.0 3(t,1H),2.09(s,3H),1.97(m,2H),1.68(s,2H),1.68(s,1H),1.65–1.51(m,6H),0.89(m,2H),0.52(d,2H).ESI-MSm / z 340.6(MH)- .

[0227] Example 12 Preparation of the following compound 8

[0228]

[0229] Step 1:

[0230] 9-d (50 mg, 0.22 mmol, 1.0 eq) was dissolved in 4 mL of dichloromethane. Thionyl chloride (0.06 mL, 0.9 mmol, 4.0 eq) and 1 drop of DMF were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. TLC monitored the reaction of the starting material, and the solvent and thionyl chloride were removed by concentration. In a separate single-necked flask, ammonium chloride (48 mg, 0.9 mmol, 4.0 eq) was added to 4 mL of dichloromethane, followed by triethylamine (0.12 mL, 0.9 mmol, 4.0 eq) and DMAP (55 mg, 0.44 mmol, 2.0 eq). A solution of the aforementioned acid chloride in dichloromethane (2.5 mL) was slowly added under ice-cooling, and the mixture was allowed to react at room temperature for 1 hour. The reaction was monitored by TLC, quenched, extracted with dichloromethane, concentrated, and purified by column chromatography to yield approximately 27 mg of 8-a. 1 H NMR(500MHz,DMSO)δ7.53(s,1H),7.28(s,1H),6.38(d,1H),5.95(d,1H),3. 74(t,6H),1.97–1.90(m,1H),0.95–0.80(m,2H),0.75–0.64(m,2H).ESI-MS m / z 222.1(M+H) + .

[0231] Step 2:

[0232] 8-a (50 mg, 0.24 mmol, 1.0 eq) was placed in a reaction flask. After nitrogen replacement, 2.5 mL of dichloromethane was added. The temperature was cooled to -25 to -15°C, and boron tribromide (0.07 mL, 0.72 mmol, 3.0 eq.) was slowly added. Stirring was maintained at this temperature for 2 hours. The reaction was monitored for completion by TLC. The mixture was quenched, extracted with n-butanol, dried, concentrated, and purified by column chromatography to yield approximately 27 mg of compound 8-b. 1 H NMR (400MHz, DMSO) δ10.62(s,1H),9.40(s,1H),7.39(s,2H),6.09(d,1H),5.83(d,1H),2.05(m,1H),0.94–0.81(m,2H),0.67–0.50(m,2H).

[0233] Step 3:

[0234] 8-b (300 mg, 1.6 mmol, 1.0 eq) was dissolved in 30 mL of DCM, replaced with nitrogen three times, cooled to 0-5°C, Tf2O (45 mg, 0.16 mmol, 0.1 eq) was slowly added, and stirred for 30 minutes. A DCM solution of (+)-limonene (292 mg, 1.92 mmol, 1.2 eq) was slowly added. The reaction was monitored by TLC, quenched with saturated sodium bicarbonate, extracted with dichloromethane, and purified by column chromatography to obtain approximately 190 mg of compound 8. 1 H NMR(400MHz,DMSO)δ12.89(s,1H),9.46(s,1H),7.95(s,1H),7.49(s,1H),6.08(s,1H),5.05(s,1H),4.45(d,2H),3.87(d,1 H),3.04(t,1H),2.15(m,2H),1.98(m,2H),1.73–1.64(m,1H),1.63–1.52(m,6H),1.00–0.91(m,2H),0.59(d,2H).ESI-MSm / z 326.4(MH) - .

[0235] Example 13 Preparation of the following compound 34

[0236]

[0237] Step 1:

[0238] Compound 34-b (11.59 g, 48.6 mmol, 1.5 eq.) was placed in a three-necked flask and the atmosphere was replaced with nitrogen three times. Geraniol 34-a (5.0 g, 32.4 mmol, 1.0 eq.) and dichloromethane (150 mL) were added. The temperature was cooled to -20°C, and 8 M boron trifluoride etherate (1.6 mL, 12.96 mmol, 0.4 eq.) was added. The reaction was allowed to react at -20°C for 2 h. The reaction solution was quenched by addition of water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain approximately 4.9 g of product 34-c. 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),6.23(s,1H),5.88(s,1H),5.31–5.2 3(m,1H),5.09–5.01(m,1H),3.91(s,3H),3.43(d,J=7.1Hz,2H),2.84–2.76(m,2H ),2.13–2.02(m,4H),1.83–1.78(m,3H),1.69–1.65(m,3H),1.61–1.56(m,3H),1. 51(dtt,J=10.4,5.2,2.6Hz,2H),1.33(dtt,J=7.4,3.2Hz,4H),0.96–0.86(m,3H).

[0239] Step 2:

[0240] Compound 34-c (2.0 g, 5.34 mmol, 1.0 eq.) was dissolved in a 12.5% ​​(w / w%) methylamine / methyltetrahydrofuran solution (5.3 g, 21.4 mmol, 4.0 eq.), cooled to 0°C, and a 1.7 M tert-butylmagnesium chloride / tetrahydrofuran solution (14.1 mL, 24.03 mmol, 4.5 eq.) was added. The mixture was sealed and refluxed at 110°C overnight. The reaction mixture was slowly added dropwise to a saturated ammonium chloride solution in an ice-water bath to quench the reaction. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and separated by column chromatography to afford 1.0 g of the title compound 34 as a white flocculent solid. 1 H NMR (500MHz, DMSO) δ9.52(s,1H),9.37(d,J=6.4Hz,1H),7.94(d,J=4.7Hz,1H),6.22(d,J=12.1Hz ,1H),5.15(t,J=7.1Hz,1H),5.06(t,J=7.1Hz,1H),3.18(d,J=7.1Hz,2H),2.73(d,J=4.5Hz,3H), 2.55(d,J=7.8Hz,2H),2.01(dt,J=15.5,8.3Hz,2H),1.90(dd,J=9.2,6.2Hz,2H),1.71(s,3H),1. 62(s,3H),1.55(s,3H),1.44(p,J=7.2Hz,2H),1.26(dt,J=9.9,6.5Hz,4H),0.86(t,J=7.0Hz,3H).

[0241] Example 14 Preparation of the following compound 37

[0242]

[0243] Compound 27-i (2.58 g, 9.72 mmol, 1.5 eq.) was placed in a three-necked flask and the atmosphere was purged with nitrogen three times. Geraniol 34-a (1.0 g, 6.48 mmol, 1.0 eq.) and dichloromethane (40 mL) were added. The temperature was cooled to -20°C, and 8 M boron trifluoride etherate (324 μL, 2.59 mmol, 0.4 eq.) was added. The reaction was allowed to proceed at -20°C for 4 h. The reaction solution was added to water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain the title compound 37, approximately 1.3 g. 1 H NMR (500MHz, DMSO) δ9.02 (s, 1H), 7.81 (s, 1H), 7.80 (d, J = 4.8Hz, 1H), 6.37 (s, 1H), 5.17 (t, J = 7. 1Hz,1H),5.07(t,J=7.0Hz,1H),3.21(d,J=7.0Hz,2H),2.65(d,J=4.6Hz,3H),2.02(q,J=7.5Hz, 2H),1.91(dd,J=9.4,6.2Hz,2H),1.71(s,3H),1.63(s,3H),1.56(s,3H),1.27–1.24(m,2H),1.2 3(s,6H),1.20–1.15(m,2H),1.03(dq,J=9.0,4.7,4.1Hz,2H),0.82(t,J=7.3Hz,3H).ESI-MSm / z 400.6(MH) - .

[0244] Example 15 Preparation of the following compound 57

[0245]

[0246] Compound 24-j (200 mg, 0.76 mmol, 1.0 eq.) and 60% NaH (30 mg, 0.76 mmol, 1.0 eq.) were placed in a reaction flask, the atmosphere was purged with nitrogen, and 3 mL of dichloromethane was added for dissolution. The mixture was heated under reflux at 50°C for 4 h, then cooled to 35°C and geranyl bromide 57-a (217 mg, 1.0 mmol, 1.3 eq.) was added and allowed to react overnight. The mixture was quenched with water, extracted with dichloromethane, and purified by column chromatography to yield approximately 30 mg of the title compound 57. 1H NMR(500MHz,DMSO)δ10.50(s,1H),9.42(s,1H),7.74(d,1H),6.29(s,1H),5.15(t,1H),5.05(t,1H),3.18(d,2H),2.81(d,3H),2.03 –1.97(m,2H),1.94–1.86(m,2H),1.71(s,3H),1.61(s,3H),1.54(s,3H),1.45(d,2H),1.16(d,4H),0.80(m,5H),0.68(s,2H).ESI-MS m / z 398.5(MH) - .

[0247] Example 16 Preparation of Compound 43

[0248]

[0249] 9-f (35 mg, 0.17 mmol, 1.0 eq.) was placed in a reaction flask, purged with nitrogen, dissolved in tetrahydrofuran, and cooled to -62°C. 2.5 M n-butyllithium (136 μL, 0.34 mmol, 2.0 eq.) and TMEDA (30 mg, 0.255 mmol, 1.5 eq.) were added and reacted for 60 min. Geranyl bromide 57-a (55 mg, 0.255 mmol, 1.5 eq.) was added and reacted at this temperature for 20 min. The reaction was then allowed to warm to room temperature and then to 60-70°C. The reaction was monitored by TLC. The reaction was quenched with water, extracted with ethyl acetate, and purified by column chromatography to obtain the title compound 43. 1 HNMR(500MHz,DMSO)δ11.28(s,1H),9.56(s,1H),7.91(d,1H),6.10(s,1H),5.14(t,1H),5.05(t,1H),3.17(d,2H),2.82(d,3H),2.12–2.06 (m,1H),2.00(m,2H),1.92–1.87(m,2H),1.70(s,3H),1.61(s,3H),1.54(s,3H),0.94–0.90(m,2H),0.54–0.50(m,2H).ESI-MSm / z342.5(MH) - .

[0250] Example 17 Preparation of Compound 26

[0251]

[0252] Step 1:

[0253] Compound 24-h (1.2 g, 4.32 mmol, 1.0 eq) was dissolved in DCM. SOCl2 (2.06 g, 17.3 mmol, 4.0 eq) and 2 drops of DMF were added under ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC and concentrated to remove the SOCl2. In a separate reaction vessel, dimethylamine hydrochloride (1.41 g, 17.3 mmol, 4.0 eq), 4-dimethylaminopyridine (1.05 g, 8.63 mmol, 2.0 eq), and Et3N (1.75 g, 17.3 mmol, 4.0 eq) were added and stirred for 20 minutes. A solution of the acid chloride in DCM was added under ice-cooling and the reaction was continued under ice-cooling for 30 minutes. The reaction was allowed to proceed at room temperature overnight. Extraction with dichloromethane was performed, and the organic phase was dried, concentrated, and purified by column chromatography to yield approximately 1.17 g of compound 26-a. 1 H NMR(400MHz, CDCl3)δ6.46(d,1H),6.32(d,1H),3.81(s,3H),3.77(s,3H),3.11 (s,3H),2.75(s,3H),1.24(m,6H),0.82(t,4H),0.61(m,2H),0.58–0.52(m,1H).

[0254] Step 2:

[0255] 26-a (1.17 g, 3.84 mmol, 1.0 eq) was placed in a reaction flask, replaced with N2 three times, DCM was added, and the temperature was lowered to -10°C. BBr3 (2.88 g, 11.51 mmol, 3.0 eq) was slowly added and reacted for 20 min. The temperature was naturally raised to react for 2 h. The reaction was monitored by TLC. The reaction solution was slowly added dropwise to ice water to quench the reaction. The mixture was extracted with DCM, dried, concentrated, and purified by column chromatography to obtain compound 26-b. 1 H NMR(400MHz,DMSO)δ9.33(s,1H),9.23(s,1H),6.16(d,1H),6.13(d,1H),2.92(s,3H) ,2.70(s,3H),1.72(d,1H),1.23–1.07(m,5H),0.80(t,3H),0.62(d,1H),0.45(m,3H).

[0256] Step 3:

[0257] Compound 26-b (150 mg, 0.54 mmol, 1.0 eq) was placed in a reaction flask, replaced with N2 three times, and 30 mL of DCM was added. The temperature was lowered to 0-5°C, and Tf2O (15 mg, 0.054 mmol, 0.1 eq) was slowly added. The mixture was stirred for 30 minutes, and a DCM solution containing (+)-limonene (97 mg, 0.73 mmol, 1.35 eq) was slowly added. The reaction was monitored by TLC. The mixture was quenched with saturated brine, extracted, dried, concentrated, and purified by column chromatography to obtain the title compound 26. ESI-MS m / z 410.6 (MH) - ,412.4(M+H) + .

[0258] The following table shows the compounds of Examples 18 to 53. These compounds were prepared using the same methods as in the above examples, except that the starting materials and intermediates corresponding to the final products were used.

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] In vivo efficacy experiments

[0266] 1) Hot Plate Test:

[0267] The test drug was mixed with 5% DMSO and then 5% Mix HS15 and add 90% saline to prepare a solution of appropriate concentration for immediate use. Female ICR mice, 18-22 g.

[0268] The day before the experiment, mice were screened on a hot plate with a screening time of 45 s and a hot plate temperature of 55°C. Mice with similar thermal pain latency were screened out, and mice that were too sensitive or too insensitive to pain were eliminated.

[0269] Before drug administration, a 90-second heat pain latency test was performed at a 55°C hot plate temperature. Heat pain latency was recorded. Animals were randomly divided into a blank control group and each test drug group, with 8 animals per group. Each group received either vehicle or each test drug via intraperitoneal injection. Sixty minutes after drug administration, a 90-second hot plate test was performed at a 55°C hot plate temperature. The time it took for the animal to lick its hind paw or jump was recorded as the heat pain latency. Heat pain latency before and after drug administration, as well as the percentage of MPE, were calculated for each group. The percentage of MPE was calculated using the following formula: [(T1-T0) / T0]*100, where T0 and T1 were the pre- and post-drug latency, respectively. Results are expressed as mean ± SD. Heat pain latency and percentage of MPE were compared before and after drug administration, and the results were analyzed using one-way analysis of variance.

[0270] The drug groups (compounds of Example 1, Example 4 and Example 12) all showed significant analgesic effects, while CBD did not show significant analgesic effects at a dose of 100 mpk.

[0271]

[0272] 2) Forced Swim Test:

[0273] The test drug was mixed with 5% DMSO and then 5% Mix HS15 and then add 90% normal saline to prepare a solution of appropriate concentration for immediate use. Male ICR mice, about 32 g. The animals were randomly divided into a blank control group and each test drug group, with 8 animals in each group. Each group of mice was intraperitoneally injected with the vehicle prescription or each test drug. The water level in the forced swimming apparatus was 45 cm and the water temperature was 25 ° C. The mice were placed in the experimental room to adapt to the environment for 1 hour before the start of the experiment. At the beginning of the experiment, the mice were placed in the apparatus for 6 minutes. The whole process was recorded with a camera. When analyzing the data, only the last 4 minutes of the mice's immobility time were counted.

[0274] The drug groups (compounds of Example 1 and Example 4) showed significant antidepressant-like effects at a low dose of 3 mg / kg, while CBD showed significant antidepressant-like effects only at a dose of 30 mpk.

[0275]

[0276]

[0277] 3) Stress-induced hyperthermia experiment

[0278] The test drug was mixed with 10% DMSO and then 10% Mix HS15 and then add 80% normal saline to prepare a solution of appropriate concentration for immediate use. Male ICR mice, about 35 g. The animals were randomly divided into blank control group and test drug groups, with 8 animals in each group. The mice in each group were subcutaneously injected with vehicle prescription or test drugs. Stress-induced hyperthermia (SIH) is a transient increase in core body temperature in response to stress, a phenomenon that exists in all mammals. Stress can be physical or emotional, or both, causing a rapid increase in body temperature (maximum after 10 to 15 minutes). Depending on the intensity and duration of stress, the temperature returns to basal levels within 60-120 minutes. When mice are pre-treated with anti-anxiety drugs (such as benzodiazepines or 5-HT 1A After administration of a stimulant (e.g., a stimulant to a stimulant receptor agonist), the SIH response decreases, making it a relatively simple procedure for screening anxiolytic drugs. This protocol describes a procedure for quantifying SIH in single-housed mice (n=1 / cage) using rectal temperature measurement as a stressor. Rectal temperature is measured twice every 10 minutes. Due to the stress experienced during the first temperature measurement, the second temperature measurement (T2) is 0.8-1.5 degrees Celsius higher than the first temperature measurement (T1). This temperature difference (dT=T2-T1) is defined as stress-induced hyperthermia (SIH) and is thought to reflect anxiety-related processes. T1, T2, and ΔT values ​​were statistically analyzed (reference: Current Protocols in Pharmacology 5.16.1-5.16.12, June 2009).

[0279] The drug group showed significant antidepressant-like effects at doses of 3-30 mg / kg, while CBD showed significant anxiolytic-like effects only at a dose of 100 mpk.

[0280]

[0281]

[0282] 4) Buried Bead Experiment

[0283] The test drug was mixed with 5% DMSO and then 5% Mix HS15 thoroughly and then add 90% saline to a solution of appropriate concentration for immediate use. Male ICR mice, approximately 32 g, were randomly divided into a blank control group and a test drug group, with 8-10 animals in each group. Each group received either the vehicle formulation or the test drug by intraperitoneal injection.

[0284] Prepare rat cages (6cm x 48cm x 20cm), fresh bedding, and colored glass beads (15mm diameter, approximately 5.2g, washed and dried after each use). Animals should be housed in a room with a 12-hour light-dark cycle, with all mice having free access to food and water. Add 5cm of fresh bedding to the rat cage and smooth it out. Place 20 glass beads in the cage (4 rows x 5 columns). 15 minutes after dosing, place the mouse in a corner as far away from the glass beads as possible, close the cage lid, and carefully return the mouse 30 minutes later. Count the number of buried glass beads in the test cage.

[0285] The compound of the present invention significantly reduced the number of buried beads compared with the blank control group within the dose range of 3-30 mg / kg, showing a significant antidepressant-like effect, while CBD only showed a significant antidepressant-like effect at a dose of 30-60 mg / kg in this experiment.

[0286]

[0287]

[0288] 5) Elevated plus maze test

[0289] The test drug was mixed with 5% DMSO and then 5% Mix HS15 thoroughly and then add 90% saline to a solution of appropriate concentration for immediate use. Male ICR mice, approximately 32 g, were randomly divided into a blank control group and a test drug group, with 8-10 animals in each group. Each group received either the vehicle formulation or the test drug by intraperitoneal injection.

[0290] The elevated plus-maze (EPM) experimental apparatus was constructed from medical organic board and consisted of two opposing open arms (30 cm × 5 cm in length, width, and height, respectively), two opposing enclosed arms (30 cm × 5 cm × 15 cm in length, width, and height, respectively), and a central platform (5 cm × 5 cm) connecting the four arms, forming a cross shape and located 40 cm above the ground. The mouse elevated plus-maze video acquisition system was purchased from Shanghai Yishu Information Technology Co., Ltd. Thirty minutes after intraperitoneal administration, the animal's activity trajectory was recorded for 5 minutes using the Yishu elevated plus-maze video acquisition system. The number of times the mouse entered the open arms and the cumulative time spent in the open arms within 5 minutes were then recorded using the Yishu video analysis system.

[0291] The compound of the present invention significantly increased the open arm residence time compared with the blank control group within the dose range of 3-30 mg / kg, showing a significant anxiolytic effect, while CBD showed a significant effect only at a dose of 30 mg / kg or above in this experiment.

[0292]

[0293] 6) Pharmacokinetic experiments

[0294] The compounds prepared in Example 1 and Example 9 were subjected to in vivo pharmacokinetic studies in mice (ICR mice, oral administration, dose of 25 mg / kg, n=3), with blood drawn at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. The results are shown in the table below.

[0295]

[0296]

[0297] The experimental results show that when R2 in the general formula (I) is substituted C3-C 10 When the compound contains a cycloalkyl group (such as the compound prepared in Example 9), the compound has a higher blood concentration.

[0298] In vitro experiments

[0299] 1) Solubility determination

[0300] The solubility was tested by high performance liquid chromatography external standard method.

[0301] Chromatographic conditions:

[0302] Mobile phase A: 10 mM KH2PO4 pH 2.0

[0303] Mobile phase B: acetonitrile

[0304] Chromatographic column: ZORBAX Bonus-RP Rapid Resolution 150×4.6mm, 3.5μm LC-SH-510

[0305] Wavelength: 220nm

[0306] Column temperature: 30°C

[0307] Flow rate: 1ml / min

[0308] Injection volume: 10 μl

[0309] Diluent: acetonitrile

[0310] Solution Preparation: Test Solution: Place 1 mg of test sample in a 1 ml centrifuge tube, add 1 ml of 10 mM KH2PO4 pH 6.8 solution, and shake in a shaker at 25°C for 30 minutes. Remove and centrifuge for 1.5 minutes, then take the supernatant for injection. Reference Solution: Place approximately 1 mg of reference sample in a 1 ml centrifuge tube, dissolve in 1 ml of acetonitrile, shake well, and place 1 ml of the resulting solution in a 5 ml volumetric flask. Dilute to the mark with acetonitrile and shake well. Solubility results are shown in the table below:

[0311]

[0312]

[0313] Compared with CBD, the solubility of the example compounds is significantly improved, which is beneficial for drug absorption.

[0314] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound or its enantiomers, diastereomers, racemates, and pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates, characterized in that: The compound is represented by formula I: Where, R0 is selected from Preferably, R0 is R1 is selected from hydroxy C1-C6 alkyl, C1-C6 alkylthio, C3-C 10 Cycloalkyl-substituted formyl, amino, amino substituted by C1-C6 alkyl, amino substituted by C1-C6 alkanoyl, cyano, amino C1-C6 alkyl, cyano C1-C6 alkyl, C1-C6 alkanoyl, sulfonylamino (-SO2NH2), carbamoyl (-CONH2), carbamoyl substituted by C1-C6 alkyl, carbamoyl substituted by hydroxy C1-C6 alkyl (HO-C1-C6 alkyl-NH-CO-), C3-C 10 Cycloalkyl-substituted carbamoyl, carboxy C1-C6 alkyl, C1-C6 alkylsulfonyl, amino C1-C6 alkyl substituted by C1-C6 alkyl, amino C1-C6 alkyl substituted by C1-C6 alkanoyl, carbamoyl C1-C6 alkyl, or carbamoyl C1-C6 alkyl substituted by C1-C6 alkyl; R2 is selected from C1-C 12 Alkyl, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, substituted C3-C 10 Cycloalkyl, or substituted or unsubstituted -(C1-C3 alkylene)-(C3-C 10 wherein said substitution refers to having 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl; preferably, R2 is a substituted C3-C 10 Cycloalkyl; R3 is selected from H, hydroxyl, -OC(O)-C1-C6 alkyl, -OC(O)(CH2)nN(C1-C6 alkyl)2; wherein n is any integer from 1 to 6; represents a single bond or a double bond; And Formula I does not include compounds selected from the group consisting of:

2. The compound according to claim 1, wherein The compound of formula (I) is selected from the compounds represented by general formula (IA): wherein R1, R2, and R3 are as defined in claim 1.

3. The compound according to claim 1, wherein The compound of formula (I) is selected from the following compounds:

4. A method for preparing a compound of formula I-1, characterized in that: The method comprises the steps of: providing an aldehyde-substituted compound of formula (II), and subjecting the compound to a reduction reaction in the presence of a reducing agent; The steps are shown in Reaction Formula 1: In formula I-1, R2 and R0 are as defined in claim 1.

5. A method for preparing a compound of formula I-2, characterized in that: The method comprises the steps of providing a compound of formula (III), and subjecting it to an aminolysis reaction with NH(R4)2 to obtain the compound, wherein the steps are shown in Reaction Formula 2: In formula I-2, R2, R0 as defined in claim 1; R4 are each independently H, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C 10 Cycloalkyl.

6. A method for preparing a compound of formula I-3, characterized in that: The method comprises the following steps: using formula (II) as a raw material, and obtaining a compound of formula (I-3) through two-step reaction, wherein the steps are shown in reaction formula 3: In formula I-3, R2 and R0 are as defined in claim 1.

7. A use of the compound according to claim 1 or its enantiomers, diastereomers, racemates, and pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates, characterized in that: The compound is used to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is used to treat, alleviate and / or prevent central nervous system diseases.

8. The use according to claim 7, characterized in that The central nervous system disease is selected from the group consisting of epilepsy, schizophrenia, refractory, intractable or chronic schizophrenia, affective disorders, psychotic disorders, mood disorders, bipolar I disorder, bipolar II disorder, depression, intrinsic depression, major depressive disorder, refractory depression, dysthymic disorder, cyclothymic disorder, panic attacks, panic disorder, social phobia, obsessive-compulsive disorder, impulsive disorder, post-traumatic stress disorder, anxiety disorder, acute stress disorder, hysteria, anorexia nervosa, adjustment disorder, cognitive disorder, autism, pain, mania, Parkinson's disease, Huntington's disease, Alzheimer's disease, various dementias, memory disorders, ADHD, drug addiction, sleep disorders, attention deficit / hyperactivity disorder, tics or a combination thereof.

9. The use according to claim 7, characterized in that The preparation is an oral preparation or a non-oral preparation.

10. A pharmaceutical composition, characterized in that The pharmaceutical composition contains: (1) a compound of formula I as an active ingredient; (2) other drugs for treating central nervous system diseases, optionally selected from the group consisting of antipsychotics, antiepileptics, or antidepressants; (3) Pharmaceutically acceptable carriers or excipients.

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