A class of resorcinol compounds, their preparation methods and applications in nervous system diseases

Abstract

The present invention relates to a class of resorcinol compounds, their preparation methods, and their applications in nervous system diseases. Specifically, the present invention provides a resorcinol compound represented by formula (I), its enantiomers, diastereomers, racemates, and mixtures thereof, as well as its pharmaceutically acceptable inorganic or organic salts, hydrates, and solvates. The present invention also provides a method for preparing the compound and its application in the preparation of drugs for preventing and / or treating central nervous system diseases.

Description

Technical Field

[0001] The present invention relates to the fields of medicinal chemistry and chemical synthesis. Specifically, the present invention relates to a novel class of resorcinol compounds, their preparation methods, and their applications in central nervous system diseases. Background Art

[0002] In 1940, researchers isolated cannabidiol (CBD) from the plant Cannabis, and its chemical structure was identified in 1963, containing resorcinol and terpene modules. Among more than 500 natural compounds derived from the plant Cannabis, CBD has received increasing attention due to its wide range of pharmacological effects and efficacy.

[0003] In 2005, the (oral mucosal spray with a THC / CBD content ratio of 1) developed by GW Pharmaceuticals was approved for marketing for the treatment of multiple sclerosis and the relief of cancer-related pain. In June 2018, the FDA approved the marketing of GW Pharmaceuticals' CBD oral solution, with the trade name for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome in patients two years of age and older. In addition to its applications in the field of neuropsychiatric diseases, CBD also shows potential clinical application value in the fields of cardiovascular and oncology diseases.

[0004] Clinical and preclinical studies have found that CBD has an improving effect on a variety of neuropsychiatric diseases. However, CBD has problems such as low oral bioavailability, low melting point, poor physicochemical properties, and poor target selectivity, and its low human blood drug concentration when taken orally as a single therapy limits its further clinical application.

[0005] Therefore, there is an urgent need in the art to develop a novel class of cannabidiol analogs with improved oral bioavailability and stronger efficacy for the treatment of various central nervous system diseases. Summary of the Invention

[0006] The object of the present invention is to develop a novel class of cannabidiol analogs with improved oral bioavailability and stronger 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 stronger efficacy, their preparation methods, and their applications in the preparation of drugs for the treatment of nervous system diseases.

[0007] In a first aspect of the present invention, there is provided a compound or its enantiomers, diastereomers, racemates, and its pharmaceutically acceptable inorganic or organic salts, crystal hydrates, and solvates, wherein the compound is represented by Formula I:

[0008]

[0009] In the formula,

[0010] R0 is selected from Preferably, R0 is

[0011] 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-), carbamoyl substituted by C3-C 10 cycloalkyl, carboxy C1-C6 alkyl, C1-C6 alkanesulfonyl, 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;

[0012] R2 is selected from C1-C 12 alkyl, C1-C alkyl substituted by one or more halogens 12 alkyl, C3-C 10 cycloalkyl, substituted C3-C 10 cycloalkyl, or substituted or unsubstituted -(C1-C3 alkylene)-(C3-C 10 cycloalkyl); wherein, the said substitution means having 1-3 substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl; Preferably, R2 is substituted C3-C 10 cycloalkyl; More preferably, R2 is substituted C3-C 10 cycloalkyl, the substituent of the said substitution is C1-C6 alkyl; Most preferably, R2 is substituted cyclopropyl, the substituent of the said substitution is C1-C6 alkyl;

[0013] R3 is selected from H, hydroxy, -OC(O)-C1-C6 alkyl, -OC(O)(CH2)nN(C1-C6 alkyl)2; wherein n is any integer from 1 to 6;

[0014] represents a single bond or a double bond;

[0015] And the compound represented by formula I does not include the compounds selected from the group consisting of:

[0016]

[0017] In another preferred example, R1 is selected from hydroxy C1-C4 alkyl, C1-C4 alkylthio, formyl substituted by C3-C7 cycloalkyl, 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 alkanesulfonyl, 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;

[0018] R2 is selected from C1-C 10 alkyl, C1-C alkyl substituted by one or more halogens, 10 C3-C7 cycloalkyl;

[0019] R3 is selected from H, hydroxy, -OC(O)-C1-C4 alkyl, -OC(O)(CH2)nN(C1-C4 alkyl)2; where n is any integer from 1 to 3.

[0020] In another preferred example, 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;

[0021] R2 is selected from n-butyl, n-pentyl or cyclopropyl;

[0022] R3 is selected from H, hydroxy or -OC(O)-CH3.

[0023] In another preferred embodiment, the compound of formula (I) is selected from the compounds represented by general formula (I-A):

[0024]

[0025] Wherein, R1, R2, and R3 are as defined above.

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

[0027]

[0028] In another preferred embodiment, the compound of formula (I) is selected from the compounds represented by general formula (I-A-1-1):

[0029]

[0030] In another preferred embodiment, the compound of formula (I) is selected from the following compounds:

[0031]

[0032]

[0033]

[0034]

[0035] In the second aspect of the present invention, a method for preparing the compound of formula I-1 is provided, including the steps of: providing an aldehyde group-substituted compound of formula (II), and performing a reduction reaction in the presence of a reducing agent to obtain the compound;

[0036] The above steps are shown in Reaction Scheme 1:

[0037]

[0038] In formula I-1, R2 and R0 are as defined above.

[0039] In the third aspect of the present invention, a method for preparing the compound of formula I-2 is provided, including the steps of: providing a compound of formula (III), and performing an ammonolysis reaction with NH(R4)2 to obtain the compound, and the above steps are shown in Reaction Scheme 2:

[0040]

[0041] Reaction Scheme 2;

[0042] In formula I-2,

[0043] R2 and R0 are as defined above;

[0044] Each R4 is independently H, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C 10 cycloalkyl.

[0045] In the fourth aspect of the present invention, there is provided a method for preparing a compound of formula I-3, comprising the steps of: using a compound of formula (II) as a raw material, and obtaining a compound of formula (I-3) through two-step reaction, and the said steps are as shown in Reaction Scheme 3:

[0046]

[0047] In formula I-3,

[0048] R2 and R0 are as defined above.

[0049] In another preferred embodiment, the said method specifically comprises the following steps:

[0050] 1) The compound of formula (II) undergoes a Henry reaction with nitromethane in the presence of a base and a catalyst to generate a compound of formula (IV);

[0051] 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);

[0052] In another preferred embodiment, there is provided a product prepared by the method according to the second, third and fourth aspects of the present invention, and functional group transformation is carried out to obtain a compound of formula I.

[0053] In another preferred embodiment, the said functional group transformation reaction is selected from the group consisting of: condensation acylation reaction, reduction reaction, acylation reaction, esterification reaction, or a combination thereof.

[0054] In another preferred embodiment, the said condensation acylation reaction is carried out in the presence of a condensing agent.

[0055] In another preferred embodiment, the said condensing agent includes but is not limited to: N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU).

[0056] In another preferred embodiment, the said reduction reaction is carried out in the presence of a reducing agent.

[0057] In another preferred embodiment, the said reducing agent includes but is not limited to: hydrogen, ammonium formate, sodium borohydride, potassium borohydride, diisobutylaluminum hydride (DIBAL), borane.

[0058] In another preferred embodiment, the said acylation reaction is carried out in the presence of an acylation reagent.

[0059] In another preferred example, the acylating agent includes but is not limited to: acetyl chloride, acetic anhydride, propionyl chloride, propionic anhydride, methanesulfonyl chloride.

[0060] In another preferred example, the esterification reaction system includes but is not limited to: thionyl chloride / methanol, thionyl chloride / ethanol.

[0061] In a fifth aspect of the present invention, there is provided a use of a compound as described in the first aspect or its enantiomers, diastereomers, racemates, and pharmaceutically acceptable inorganic or organic salts, hydrates and solvates thereof, wherein the compound is used to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is used for treating, alleviating and / or preventing central nervous system diseases.

[0062] In another preferred example, the pharmaceutical composition or preparation further comprises other drugs for treating central nervous system diseases.

[0063] In another preferred example, the central nervous system diseases are selected from the group consisting of: epilepsy, schizophrenia, intractable, refractory or chronic schizophrenia, affective disorder, mental disorder, mood disorder, bipolar disorder type I, bipolar disorder type II, depression, endogenous depression, major depressive disorder, intractable 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 disorder, attention deficit / hyperactivity disorder, drug addiction, sleep disorder, attention deficit / hyperactivity disorder, tic disorder or a combination thereof.

[0064] In another preferred example, the preparation is an oral preparation or a non-oral preparation.

[0065] In another preferred example, the preparation is selected from the group consisting of: tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, injections or a combination thereof.

[0066] In a sixth aspect of the present invention, there is provided a pharmaceutical composition, the pharmaceutical composition comprising:

[0067] (1) a compound of formula I as an active ingredient;

[0068] (2) optionally other drugs for treating central nervous system diseases selected from the group consisting of: antipsychotic drugs, antiepileptic drugs or antidepressant drugs;

[0069] (3) a pharmaceutically acceptable carrier or excipient.

[0070] In another preferred example, the antipsychotic drugs include, but are not limited to, aripiprazole, risperidone, haloperidol, quetiapine, paliperidone, ziprasidone, asenapine, brexpiprazole, olanzapine, clozapine, amisulpride, and cariprazine.

[0071] In another preferred example, the antiepileptic drugs include, but are not limited to, carbamazepine, lamotrigine, oxcarbazepine, gabapentin, topiramate, zonisamide, lacosamide, and valproic acid.

[0072] In another preferred example, the antidepressant drugs include, but are not limited to, fluoxetine, fluvoxamine, sertraline, escitalopram, amitriptyline, venlafaxine, duloxetine, vilazodone, and citalopram.

[0073] In the seventh aspect of the present invention, there is provided a method for treating a central nervous system disease, comprising the step of administering to a patient in need thereof a medicinally effective amount of the compound according to the first aspect of the present invention or the pharmaceutical composition according to the sixth aspect of the present invention.

[0074] In another preferred example, the patient is a patient with a central nervous system disease.

[0075] In another preferred example, the central nervous system disease is as defined above.

[0076] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described hereinafter (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Detailed Description of the Invention

[0077] The inventors of the present invention have, through extensive and in-depth research, first discovered that a class of cannabidiol analogs with improved oral bioavailability and stronger efficacy can effectively treat nervous system diseases, and on this basis, the present invention has been completed.

[0078] Specifically, the present invention has prepared cannabidiol analogs represented by Formula I, which have the advantages of improved oral bioavailability, good physicochemical properties, and stronger efficacy compared to cannabidiol, and are also superior to CBD in the treatment of nervous system diseases. Therefore, they can be better used to prepare drugs for preventing, alleviating, and / or treating nervous system diseases. And the present invention provides methods for preparing these cannabidiol analogs.

[0079] Terms

[0080] As used herein, "the compounds of the present invention" and "the active ingredients of the present invention" can be used interchangeably, and both refer to the cannabidiol analogs represented by Formula I, which have better oral bioavailability, physicochemical properties, and target selectivity compared to CBD.

[0081] The term "halogen" generally refers to fluorine, chlorine, bromine and iodine; preferably fluorine, chlorine or bromine; more preferably fluorine or chlorine;

[0082] “C1-C 12 "alkyl" means a straight-chain or branched-chain saturated hydrocarbon group containing 1-12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl or n-hexyl, etc., preferably methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl;

[0083] "C1-C6 alkylthio" means a straight-chain or branched-chain alkylthio group containing 1-6 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, isopentylthio, neopentylthio or n-hexylthio, etc., preferably methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio;

[0084] "C1-C6 alkanoyl" means a straight-chain or branched-chain alkanoyl group containing 1-6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, tert-butyryl or hexanoyl, etc.;

[0085] "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, etc.;

[0086] "hydroxy C1-C6 alkyl" means that one carbon atom of a straight-chain or branched-chain alkyl group containing 1-6 carbon atoms is connected to a hydroxyl group, such as -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH2CH2CH2OH or -CH2CH(CH3)CH2OH, etc.;

[0087] "amino C1-C6 alkyl" means that one carbon atom of a straight-chain or branched-chain alkyl group containing 1-6 carbon atoms is connected to an amino group, such as -CH2NH2, -CH2CH2NH2, -CH(NH2)CH3, -CH2CH2CH2NH2 or -CH2CH2CH2CH2NH2, etc.;

[0088] "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, etc.;

[0089] "Carbamoyl C1-C6 alkyl" means that one carbon atom of a straight-chain or branched-chain alkyl group containing 1-6 carbon atoms is connected to the carbonyl carbon of the carbamoyl group, such as -CH2CONH2, -CH2CH2CONH2, -CH(CONH2)CH3 or -CH2CH2CH2CONH2, etc.;

[0090] "Carbamoyl C1-C6 alkyl substituted by C1-C6 alkyl" means that one or two hydrogen atoms of the amino group on the carbamoyl C1-C6 alkyl are substituted by the same or different C1-C6 alkyl groups, such as -CH2CONHMe, -CH2CH2CONHEt, -CH2CH2CONMe2 or -CH2CONEt2, etc.;

[0091] "Cyano C1-C6 alkyl" means that one carbon atom of a straight-chain or branched-chain alkyl group containing 1-6 carbon atoms is connected to the cyano group, such as cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl or 5-cyanopentyl, etc.;

[0092] "Carboxy C1-C6 alkyl" means that one carbon atom of a straight-chain or branched-chain alkyl group containing 1-6 carbon atoms is connected to the carboxy group, such as carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl or 5-carboxypentyl, etc.;

[0093] "C1-C6 alkanesulfonyl" means a straight-chain or branched-chain alkanesulfonyl group containing 1-6 carbon atoms, such as methanesulfonyl, ethanesulfonyl or propanesulfonyl, etc.;

[0094] "Amino group substituted by C1-C6 alkyl" means that the hydrogen atom on the amino group is substituted by one or two same or different C1-C6 alkyl groups or C1-C6 alkanoyl groups, such as -NHMe or -NEt2, etc.;

[0095] "C3-C 10 cycloalkyl" means a saturated cycloalkyl group containing 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.;

[0096] Cannabidiol (CBD)

[0097] Cannabidiol (CBD) is a non-psychoactive component derived from the cannabis plant and has various pharmacological effects on the nervous system. Its structural formula is as follows:

[0098]

[0099] CBD has a broad spectrum of pharmacological effects. Existing evidence shows that in addition to having a certain effect 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 (TRP) ion channels, etc. Moreover, it can inhibit the uptake of neurotransmitters such as norepinephrine, dopamine, 5-HT, and GABA by synaptic vesicles and the uptake process of endogenous cannabinoids by cells. At the same time, it can also affect the calcium storage in mitochondria and block the low-voltage-activated T-type calcium channels.

[0100] Drug Compositions and Administration Methods

[0101] The "pharmaceutically acceptable inorganic or organic salts" described in the present invention are salts formed by the compound represented by the general formula (I) and inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, or phosphoric acid, salts formed by organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, maleic acid, tartaric acid, malic acid, fumaric acid, methanesulfonic acid, citric acid, etc., or sodium, potassium, calcium, or ammonium salts formed by bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, or ammonia. The "pharmaceutically acceptable salts" also include their solvates, and examples of solvates are hydrates, alcoholates, etc.

[0102] The present invention also provides the use of the compound represented by the general formula (I) according to the present invention, its enantiomers, diastereomers, racemates, and its pharmaceutically acceptable salts, crystalline hydrates, and solvates in the preparation of drugs for preventing and / or treating central nervous system diseases.

[0103] The present invention also provides a method for treating and / or preventing central nervous system diseases, which includes administering to a human or an animal a mixture of one or more of the compound represented by the general formula (I) according to the present invention, its enantiomers, diastereomers, racemates, and its pharmaceutically acceptable salts, crystalline hydrates, and solvates.

[0104] The present invention also provides a drug composition, which contains a therapeutically effective amount of a mixture of one or more of the compound represented by the general formula (I) according to the present invention, its enantiomers, diastereomers, racemates, and its pharmaceutically acceptable salts, crystalline hydrates, and solvates, and an optional pharmaceutically acceptable carrier. The drug composition can be used for treating or preventing central nervous system diseases.

[0105] The present invention also provides a method for preparing the pharmaceutical composition, which comprises mixing one or several mixtures of the compounds represented by the above general formula (I), their enantiomers, diastereomers, racemates, and their pharmaceutically acceptable salts, crystal hydrates and solvates with a pharmaceutically acceptable carrier.

[0106] 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 by implants. In the pharmaceutical compositions of the present invention, various pharmaceutical dosage forms can be selected according to the therapeutic purpose, generally including: tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols and injections, etc.

[0107] For parenteral administration, suitable compositions include aqueous and non-aqueous sterile injectables. The compositions can be provided in unit-dose or multi-dose containers, such as sealed vials and ampoules, and can be stored under lyophilized (freeze-dried) conditions, and only need to add a sterile liquid carrier, such as water, before use. For transdermal administration, gels, patches or sprays can be expected. Compositions suitable for pulmonary administration, such as by nasal inhalation, or formulations include fine dusts or mists that can be generated by means of metered-dose pressurized aerosols, nebulizers or insufflators. The precise dosage and regimen of administration of the composition will have to depend on the therapeutic or nutritional effect to be achieved and can vary depending on the specific formulation, route of administration and the age and condition of the individual subject to whom the composition is administered.

[0108] The pharmaceutical composition of the present invention contains the compound of the present invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier within a safe and effective amount range. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0109] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatible" here means that the components in the composition can be admixed 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 are 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), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0110] The pharmaceutical composition is an injection, capsule, tablet, pill, powder or granule.

[0111] There is no particular limitation on the mode of administration of the compounds or pharmaceutical compositions of the present invention. Representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0112] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or calcium phosphate, or admixed with the following components: (a) fillers or bulking agents, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxypropylmethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizing agents, for example, paraffin wax; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

[0113] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and casings, such as enteric coatings and other materials well 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 manner such that they are released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric materials and wax-like materials. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0114] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

[0115] In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and fragrances.

[0116] In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum monostearate and agar or mixtures of these substances, etc.

[0117] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstituting into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and their suitable mixtures.

[0118] Dosage forms of the compounds of the present invention for topical administration 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 if necessary.

[0119] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0120] The treatment methods of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.

[0121] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), wherein the dosage during administration is an effective dosage considered pharmaceutically. For a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also consider factors such as the administration route and the health status of the patient, which are all within the scope of the skills of a skilled physician.

[0122] Preparation method

[0123] 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 purchased or prepared according to the known synthesis methods of similar compounds:

[0124] Method 1: Using the aldehyde group-substituted formula (II) as the raw material, a reduction reaction occurs in the presence of a reducing agent to obtain the compound (I-1), as shown in Reaction Scheme 1:

[0125]

[0126] Among them, the definitions of R2 and R0 are the same as described above;

[0127] Method 2: Using the formula (III) as the raw material, and reacting with NH(R4)2 through an ammonolysis reaction to obtain the compound of formula (I-2), as shown in the reaction formula:

[0128]

[0129] Reaction Scheme 2

[0130] Among them, the definitions of R2 and R0 are the same as described above; R4 are each independently H, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C 10 cycloalkyl.

[0131] Method 3: Using the formula (II) as the raw material, and obtaining the compound of formula (I-3) through two-step reactions, as shown in the reaction formula:

[0132]

[0133] The Method 3 includes the following steps:

[0134] 1) The compound of formula (II) undergoes a Henry reaction with nitromethane in the presence of a base and a catalyst to generate the compound of formula (IV);

[0135] 2) The compound of formula (IV) undergoes a reduction reaction in the presence of a reducing agent to obtain the compound of formula (I-3);

[0136] Among them, the definitions of R2 and R0 are the same as described above;

[0137] Method 4:

[0138] Obtained by performing functional group transformation on the compound of formula I obtained from Methods 1 to 3.

[0139] The said functional group transformation reaction is such as through condensation acylation reaction, reduction reaction, acylation reaction, esterification reaction, etc.

[0140] The condensation acylation reaction is carried out in the presence of a condensing agent, and the condensing agent includes but is not limited to: N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), O-benzotriazol-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), etc.

[0141] The reduction reaction is carried out in the presence of a reducing agent, and the reducing agent includes but is not limited to: hydrogen, ammonium formate, sodium borohydride, potassium borohydride, diisobutylaluminum hydride (DIBAL), borane, etc.

[0142] The acylation reaction is carried out in the presence of an acylating agent, and the acylating agent includes but is not limited to: acetyl chloride, acetic anhydride, propionyl chloride, propionic anhydride, methanesulfonyl chloride, etc.

[0143] The esterification reaction system includes but is not limited to: thionyl chloride / methanol, thionyl chloride / ethanol, etc.

[0144] The main advantages of the present invention are as follows:

[0145] 1) The compounds of the present invention have better physical and chemical properties and oral bioavailability compared with cannabidiol (CBD).

[0146] 2) The compounds of the present invention have good effects on cannabinoid CB1 and CB2 receptors and can be used to treat various diseases related to the dysfunction of cannabinoid CB1 and CB2 receptors.

[0147] 3) The central nervous system activity of the compounds of the present invention is superior to that of cannabidiol (CBD), and has the characteristics of low effective dose and small toxic and 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, attention deficit hyperactivity disorder, drug addiction or neuralgia, and has good clinical application prospects.

[0148] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0149] Example 1 Preparation of Compound 1 of the following formula

[0150]

[0151] Cannabidolic acid methyl ester 1-1 was prepared according to the reference documents (WO 2019033168; WO 2019033164). Take cannabidolic acid methyl ester 1-1 (1.5 g) and dissolve it in 10 mL of methylamine / ethanol solution. React at 100 °C overnight in a sealed tube, and monitor the reaction by TLC until it is completed. After concentrating the reaction solution, separate the product 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, 212 mg of solid. 1 H NMR (400 MHz, CDCl3) δ 11.21 (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-MS m / z 370.2 (M-H) - .

[0152] Example 2 Preparation of compound 2 of the following formula

[0153]

[0154] Drop oxalyl chloride (4.1 g, 2 eq) into dichloromethane (40 mL) and DMF (2.35 g, 1.2 eq), control the temperature at -10 - 0 °C, keep warm for 2 minutes. Dissolve CBD (8.45 g) in 40 mL of dichloromethane and drop CBD into the above system at -10 °C. React for 0.5 hour and monitor the reaction by TLC (petroleum ether / ethyl acetate = 20 / 1) until it is complete. Quench the reaction with saturated sodium bicarbonate solution, separate the dichloromethane layer, dry it over anhydrous sodium sulfate, concentrate and dry, and pass through a column, PE → PE / acetone = 100 / 1, to separate 9.42 g of product 2-a, with a yield of 99%. NMR confirmation is consistent with the literature report (WO 2020031179).

[0155] Dissolve compound 2-a in methanol, add 1 eq of NaBH4, react at room temperature overnight, concentrate and dry directly through a column to obtain the title compound, with a yield of about 80%. 11H NMR (400 MHz, DMSO) δ 8.71–8.54 (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-MS m / z 343.2 (M-H) – .

[0156] Example 3 Preparation of Compound 3 of the following formula

[0157]

[0158] Dissolve compound 2-a (3 g) in a mixed system of dichloromethane / methanol (50 / 50 mL), add methylamine ethanol solution (10 eq), stir overnight under nitrogen, and monitor the disappearance of the raw materials by TLC. Concentrate the reaction solution to dryness, add 50 mL of methanol, dropwise add a methanol solution of NaBH4 (1 eq) under ice bath, stir for 15 minutes, and the reaction is complete. Add water and ethyl acetate (20 mL / 50 mL), adjust the pH = 8 with HCl, separate the ethyl acetate layer, concentrate to dryness and column chromatograph, PE / EA = 2 / 1 → EA, to obtain 1.8 g of the title compound 3 with a yield of 40%. 1 1H NMR (400 MHz, CDCl3) δ 6.16 (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, 3H), 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-MS m / z 358.03 (M + H) + .

[0159] Example 4 Preparation of Compound 4 of the following formula

[0160]

[0161] Methyl cannabidiolate 1-1 (5 g, 13.4 mmol) was dissolved in ammonia ethanol, and the reaction mixture was refluxed in a sealed tube for 36 h. The reaction solution was concentrated to dryness, and column chromatography gave 202 mg of the title compound 4 as a white solid. 1 H NMR (500 MHz, CDCl3) δ 11.95 (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, 3H), 1.71 (s, 3H), 1.65–1.63 (m, 2H), 1.35–1.31 (m, 4H), 0.88 (t, 3H). ESI-MS m / z 358.13 (M + H) + .

[0162] Example 5 Preparation of the following compound 5

[0163]

[0164] Compound 2-a (200 mg, 0.584 mmol) was dissolved in nitromethane, ammonium acetate (100 mg, 2.2 eq) was added, and the mixture was refluxed for 12 h. TLC showed that the starting material had completely reacted. The solvent was concentrated to dryness, and column chromatography gave intermediate 5-a (200 mg). 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 13.3 Hz, 1H), 8.08 (d, J = 13.2 Hz, 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 = 9.9 Hz, 1H), 2.67 (m, 2H), 2.37 (m, 1H), 2.32–2.21 (m, 2H), 1.83–1.77 (m, 2H), 1.85 (s, 3H), 1.66 (s, 3H), 1.66 - 1.53 (m, 2H), 1.37–1.32 (m, 4H), 0.90 (t, 3H). ESI-MS m / z 384.08 (M – H) – .

[0165] Compound 5-a (200 mg, 0.51 mmol) was dissolved in THF, and lithium aluminum hydride (194 mg, 10 eq) was added. The mixture was heated under reflux for 4 h. TLC showed complete reaction. The reaction mixture was poured into water, and the pH was adjusted to 8 - 9 with dilute hydrochloric acid. It was extracted with n-butanol. The organic phase was dried and concentrated, and column chromatography gave 70 mg of the title compound. ESI-MS m / z 358.16 (M+H) + , 356.18 (M–H) – . 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.65 (s, 3H), 6.10 (s, 1H), 5.18 (s, 1H), 4.64–4.30 (m, 2H), 3.87 (d, J = 10.1 Hz, 1H), 2.94 (m, 1H), 2.71 (m, 4H), 2.38 (dd, J = 9.0, 6.4 Hz, 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).

[0166] Example 6 Preparation of the following compound 6

[0167]

[0168] Methyl cannabidiolic acid 1-1 (100 mg, 0.27 mmol) was dissolved in 2 ml of cyclopropylamine solution, and the reaction was carried out in a sealed tube at 110 °C overnight. The solvent was concentrated to dryness, and column chromatography gave 12.7 mg of the title compound. ESI-MS m / z 398.33 (M+H) + , 396.19 (M–H) – . 1 H NMR (400 MHz, Chloroform-d) δ 11.27 (s, 1H), 6.31 (br, 1H), 6.19 (s, 1H), 6.02 (s, 1H), 5.53 (s, 1H), 4.53 (t, J = 2.0 Hz, 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).

[0169] Example 7 Preparation of Compound 7 of the following formula

[0170]

[0171] Methyl cannabidiolate 1-1 (100 mg, 0.27 mmol) was dissolved in 2 ml of pentylamine and heated under reflux overnight. TLC showed that the raw material had basically completely reacted. The solvent was concentrated to dryness, and the title compound (40 mg) was obtained by column chromatography. ESI-MS m / z 429.28 (M+2H) + , 426.27 (M–H) – . 1 1H NMR (400 MHz, Chloroform-d) δ 11.18 (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=6.6 Hz, 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).

[0172] Example 8 Preparation of Compound 10 of the following formula

[0173]

[0174] 5 mL (1.7 M) of tert-butylmagnesium chloride was added dropwise to 5 mL (2 M) of a solution of dimethylamine in tetrahydrofuran at 0-10 °C. A solution of methyl cannabidiolate 1-1 in tetrahydrofuran was slowly added dropwise. The reaction mixture was sealed and heated to 110 °C under reflux for 24 h. TLC showed a small amount of the raw material remaining. The title compound (900 mg) was obtained by column chromatography. 11H NMR (400 MHz, DMSO) δ 8.99 (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-MS m / z 384.12 (M–H) – .

[0175] Example 9 Preparation of Compound 24 of the following formula

[0176]

[0177] Step 1:

[0178] Dissolve 3,5-dimethoxybenzyl cyanide 24-a (5.0 g, 28.2 mmol, 1.0 eq.) in tetrahydrofuran (250 mL), displace with nitrogen three times, add potassium bis(trimethylsilyl)amide (85 mL, 170 mmol, 6.0 eq.) to the solution, and slowly add 1,2-dibromoethane (15.9 g, 84.7 mmol, 3.0 eq.) dropwise to the reaction system. Stir at 0 °C for 3 h, and monitor the reaction by TLC until completion. Quench the reaction mixture by dropping it into saturated ammonium chloride solution, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain about 4 g of compound 24-b, with a yield of 80%. 1 1H NMR (500 MHz, CDCl3) δ 6.44 (d, J = 2.4 Hz, 2H), 6.38 (t, J = 2.4 Hz, 1H), 3.80 (s, 6H), 1.71–1.68 (dd, J = 7.4 Hz, J = 5.2 Hz, 2H), 1.41–1.38 (dd, J = 7.4 Hz, J = 5.2 Hz, 2H).

[0179] Step 2:

[0180] Dissolve compound 24-b (355.0 mg, 1.75 mmol, 1.0 eq.) in DCM (16 mL), cool to -67 °C, displace with nitrogen three times, slowly add DIBAL-H (4.4 mL, 4.4 mmol) to the solution, and react at -67 to -62 °C for 2 h. Monitor the reaction by TLC until completion. Quench the reaction mixture by dropping it into saturated ammonium chloride solution, extract with dichloromethane, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain 24-c, a transparent oil, 272 mg, with a yield of 77%.1 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 6.46 (d, J = 2.4 Hz, 2H), 6.40 (t, J = 2.4 Hz, 1H), 3.78 (s, 6H), 1.53 (m, 2H), 1.37 (m, 2H).

[0181] Step 3:

[0182] Triphenylpropylphosphonium bromide (8.6 g, 24.3 mmol, 5.0 eq.) was placed in a three-necked flask, purged 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 an ice bath. 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 monitored by TLC until completion. The reaction mixture was quenched by dropping into saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated by column chromatography to obtain compound 24-d, 993 mg of pale yellow solid. 1 1H NMR (400 MHz, CDCl3) δ 6.40 (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).

[0183] Step 4:

[0184] Compound 24-d (375 mg, 1.6 mmol, 1.0 eq.) was dissolved in ethylene glycol dimethyl ether (38.1 mL), and then p-toluenesulfonylhydrazide (3.6 g, 19.2 mmol, 12.0 eq.) was added. The mixture was refluxed, and 37 mL of aqueous sodium acetate solution (3.1 g, 41.6 mmol, 26.0 eq) was slowly added. The reaction was stirred at 93 °C for 4 h and monitored by TLC until completion. The reaction mixture was quenched by dropping into water, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated by column chromatography to obtain 24-e, 353 mg of oily substance, yield 94%. 1 1H NMR (500 MHz, CDCl3) δ 6.47 (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).

[0185] Step 5:

[0186] 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 reaction system was purged with N₂ three times and then reacted at 60 °C for 4 h. The reaction was monitored by TLC until completion. The reaction solution was dropped into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried and concentrated, and compound 24-f was obtained by column chromatography, about 8 g, with a yield of 61%. 1 H NMR (500 MHz, CDCl₃) δ 6.47 (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).

[0187] Step Six:

[0188] Compound 24-f (500 mg, 1.596 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (16 mL). The temperature was lowered to -60 °C, and the reaction system was purged with N₂ three times. n-BuLi (1.6 mL, 2.5 M, 2.5 eq) was slowly added to the solution. After reacting for 2 h, methyl chloroformate (378 mg, 4 mmol, 2.5 eq.) was added and the reaction continued for 2 h. The reaction was monitored by TLC until completion. The reaction solution was quenched by dropping it into saturated ammonium chloride solution and then extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain 284 mg of 24-g. 1 H NMR (500 MHz, CDCl₃) δ 6.43 (d, J = 2.3 Hz, 1H), 6.33 (d, J = 2.2 Hz, 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).

[0189] Step Seven:

[0190] 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 N₂ protection, the mixture was stirred and reacted at 100 °C overnight. The reaction was monitored by TLC until completion. The reaction solution was quenched by dropping it into saturated sodium chloride solution, adjusted to acidic pH with 1 M hydrochloric acid, and then extracted with methyl tert-butyl ether. The organic phase was dried and concentrated, and 24-h was obtained by column chromatography, about 488 mg. 11H NMR (500 MHz, DMSO) δ 12.53 (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 = 5.0 Hz, 2H), 0.57–0.55 (m, 2H). ESI-MS m / z 277.32 (M–H) – .

[0191] Step 8:

[0192] Dissolve compound 24-h (1.15 g, 4.14 mmol, 1.0 eq) in DCM, add SOCl2 (984 mg, 8.27 mmol, 2.0 eq) and 2 drops of DMF under ice bath, stir at room temperature for 1 hour, monitor the reaction by TLC until completion, and concentrate to remove SOCl2. Take another reaction vessel, add 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), stir for 20 minutes, add the DCM solution of acyl chloride under ice bath, continue to react under ice bath for 30 minutes, and react overnight at room temperature. Extract with dichloromethane, dry and concentrate the organic phase, and obtain about 780 mg of compound 24-i by column chromatography. 1 1H NMR (500 MHz, DMSO) δ 7.7 (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).

[0193] Step 9:

[0194] Place 24-i (780 mg, 2.68 mmol, 1.0 eq) in a reaction flask, displace with N2 three times, add 30 mL of DCM, cool down to -65 °C, slowly add BBr3 (2.01 g, 8.04 mmol, 3.0 eq), react for 2 hours, allow to warm up to room temperature and react overnight, monitor the reaction by TLC, add saturated brine for extraction, dry and concentrate, and obtain about 440 mg of compound 24-j by column chromatography. 11H NMR (400 MHz, DMSO) δ 9.38 (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-MS m / z 262.35 (M–H) – .

[0195] Step Ten:

[0196] Place compound 24-j (100 mg, 0.38 mmol, 1.0 eq) in a reaction flask, displace with N2 three times, add 30 mL of DCM, cool to 0 - 5 °C, slowly add Tf2O (10 mg, 0.04 mmol, 0.1 eq), stir for 30 minutes, slowly add a DCM solution of (+)-limonene (70 mg, 0.46 mmol, 1.35 eq), monitor the reaction by TLC, extract with saturated brine, dry and concentrate, and obtain about 50 mg of the title compound 24 by column chromatography. 1 1H NMR (400 MHz, DMSO) δ 11.10 (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, 2H), 1.17–1.07 (m, 4H), 0.89–0.82 (m, 2H), 0.77 (t, 3H), 0.73–0.62 (m, 2H). ESI-MS m / z 396.41 (M–H) – .

[0197] Example 10 Preparation of Compound 27 of the Following Formula

[0198]

[0199] Step One:

[0200] 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). After three replacements with N2, the reaction system was reacted at 60 °C. The reaction was monitored by TLC until completion, quenched, extracted with ethyl acetate, and purified by column chromatography to obtain approximately 95 mg of the target compound 27-b. 1 H NMR (400 MHz, CDCl3) δ 6.70 (d, 1H), 6.47 (d, 1H), 3.88 (s, 3H), 3.84 (s, 5H). GC-MS m / z 255.0.

[0201] Step 2:

[0202] Sodium hydride (375 mg, 15.62 mmol, 4.0 eq.) was placed in a three-necked flask. After three replacements with N2, N,N-dimethylformamide (6 mL) was added, and the temperature was lowered 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 while maintaining the system temperature between -5 °C and 5 °C. The reaction was carried out for 1 h and monitored by TLC until completion. It 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 (500 MHz, CDCl3) δ 6.71 (d, 1H), 5.51 (d, 8H), 3.93 (s, 3H), 3.86 (s, 3H), 1.92 (s, 6H). GC-MS m / z 283.1.

[0203] Step 3:

[0204] Compound 27-c (200 mg, 0.7 mmol, 1.0 eq.) was placed in a three-necked flask. After three replacements with N2, dichloromethane (10 mL) was added, and the system temperature was lowered to -68 °C. 1 M diisobutylaluminum hydride (1.77 mL, 1.77 mmol, 2.51 eq.) was slowly added. The reaction was carried out at -68 °C for 1.5 h and monitored by TLC until completion. It was quenched, the insoluble matter was filtered off, extracted with dichloromethane, and separated by column chromatography to obtain 170 mg of the target compound 27-d. 1 H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 6.60 (d, 1H), 6.49 (d, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 1.50 (s, 6H). GC-MS m / z 286.1.

[0205] Step 4:

[0206] Triphenylpropylphosphonium bromide (403 mg, 1.045 mmol, 3.0 eq.) was placed in a three-necked flask, and the flask was purged with N2 three times. Then 5 mL of THF was added, and potassium bis(trimethylsilyl)amide (1 mL, 1.01 mmol, 2.9 eq.) was added under an ice bath. The mixture was stirred at ice bath temperature for 30 min. 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 h. After the reaction was completed as monitored by TLC, it was quenched, extracted with ethyl acetate, and the target compound 27-e was obtained by column chromatography, about 400 mg. 1 1H NMR (400 MHz, CDCl3) δ 6.74 (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-MS m / z 314.1.

[0207] Step Five:

[0208] 27-e (500 mg, 1.596 mmol, 1.0 eq.) was dissolved in 20 mL of ethylene glycol dimethyl ether, and then p-toluenesulfonylhydrazide (3.57 g, 19.15 mmol, 12.0 eq.) was added. The mixture was heated under reflux at 95 °C, and an aqueous solution of sodium acetate (3.4 g, 41.5 mmol, 26.0 eq) was slowly added. After the reaction was completed as monitored by TLC, it was quenched, extracted with dichloromethane, and the target compound 27-f was obtained by column chromatography, 420 mg. 1 1H NMR (400 MHz, CDCl3) δ 6.60 (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).

[0209] Step Six:

[0210] 27-f (200 mg, 0.634 mmol, 1.0 eq.) was placed in a reaction flask. After purging with nitrogen, 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, and the reaction was carried out at -60 to -65 °C for one hour. Then the reaction system was purged with CO2. After the reaction was monitored by TLC, it was quenched, extracted with ethyl acetate, and purified by column chromatography to obtain 27-g, 120 mg. 11H NMR (500 MHz, DMSO) δ 12.61 (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).

[0211] Step 7:

[0212] 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 an ice bath (0 - 2 °C), and then the reaction was stirred in the ice bath for 1 hour. The reaction of the starting material was monitored by TLC and was found to be complete. The solvent and thionyl chloride were removed by concentration. Another reaction flask was charged with methylamine hydrochloride (97 mg, 1.44 mmol, 4.0 eq.) in 5 mL of dichloromethane, and triethylamine (0.4 mL, 1.43 mmol, 4.0 eq.) was added. The original reaction solution was slowly added to the reaction system under an ice bath, and the reaction was carried out at room temperature (22 °C) for 1 h. The reaction was monitored by TLC. After quenching with ammonium chloride, the mixture was adjusted to acidic with a small amount of dilute hydrochloric acid, extracted with dichloromethane, dried and concentrated, and purified by column chromatography to obtain the target compound 27 - h. 1 1H NMR (500 MHz, DMSO) δ 7.86 (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).

[0213] Step 8:

[0214] 27 - h (50 mg, 0.17 mmol, 1.0 eq) was purged with nitrogen and then 2.5 mL of dichloromethane was added. After cooling to - 62 °C, boron tribromide (0.04 mL, 0.43 mmol, 2.5 eq.) was slowly added, and the reaction was stirred at - 60 °C for 3 hours. The reaction was monitored by TLC and was found to be complete. After quenching, extraction, drying and concentration, purification by column chromatography gave the target compound, 27 - i. 1 1H NMR (500 MHz, DMSO) δ 9.12 (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).

[0215] Step Nine:

[0216] Dissolve 27-i (300 mg, 1.1 mmol, 1.0 eq) in 30 mL of DCM, displace with nitrogen three times, cool to -10 - 0 °C, slowly add Tf2O (20 mg, 0.11 mmol, 0.1 eq), stir for 30 minutes, slowly add a DCM solution of (+)-limonene (200 mg, 1.32 mmol, 1.2 eq), monitor the reaction by TLC, quench, extract with dichloromethane, and obtain about 100 mg of compound 27 by column chromatography. 1 H NMR (400 MHz, DMSO) δ 8.84 (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-MS m / z 398.5 (M–H) – .

[0217] Example 11 Preparation of Compound 9 of the following formula

[0218]

[0219] Step One:

[0220] Add 9-a (500 mg, 2.30 mmol, 1.0 eq) and Pd(dppf)Cl2 (169 mg, 0.23 mmol, 0.1 eq) to a reaction flask, displace with nitrogen, 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 obtain about 350 mg of 9-b by column chromatography. 1 H NMR (500 MHz, CDCl3) δ 6.30 (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-MS m / z 178.1.

[0221] Step Two:

[0222] Dissolve 9-b (100 mg, 0.56 mmol, 1.0 eq) in 5 mL of acetonitrile, add NBS (105 mg, 0.59 mmol, 1.05 eq), react under stirring at room temperature for 4 hours, monitor the reaction by TLC, quench, extract with ethyl acetate, concentrate, and obtain about 60 mg of 9-c by column chromatography. 1 1H NMR (500 MHz, CDCl3) δ 6.37 (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-MS m / z 258.0.

[0223] Step 3:

[0224] Place 9-c (200 mg, 0.78 mmol, 1.0 eq) in a reaction flask, replace the gas with nitrogen, and then add 5 mL of tetrahydrofuran. Cool down to -62 °C, slowly add n-butyllithium (0.47 mL, 1.17 mmol, 1.5 eq), control the reaction temperature to stir between -62 °C and -64 °C for 1 hour. Then replace the gas in the reaction flask with CO2 and continue to stir at -60 °C to -50 °C for 1 hour. Monitor the reaction by TLC, quench, extract with ethyl acetate, concentrate, and obtain about 130 mg of 9-d by column chromatography. 1 1H NMR (400 MHz, DMSO) δ 12.62 (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-MS m / z 221.2 (M-H) - .

[0225] Step 4:

[0226] Dissolve 9-d (50 mg, 0.22 mmol, 1.0 eq) in 4 mL of dichloromethane, add thionyl chloride (0.06 mL, 0.9 mmol, 4.0 eq) and 1 drop of DMF under ice bath, and stir at ice bath for 1 hour. Monitor the reaction by TLC until the raw materials react completely, concentrate to remove the solvent and thionyl chloride. Take another single-necked flask, add methylamine hydrochloride (61 mg, 0.9 mmol, 4.0 eq) to 4 mL of dichloromethane, add triethylamine (0.12 mL, 0.9 mmol, 4.0 eq) and DMAP (55 mg, 0.44 mmol, 2.0 eq), and slowly add the dichloromethane (2.5 mL) solution of the aforementioned acyl chloride under ice bath, and react at room temperature for 1 hour. Monitor the reaction by TLC, quench, extract with dichloromethane, concentrate, and obtain about 30 mg of 9-e by column chromatography. 11H NMR (500 MHz, DMSO) δ 7.98 (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-MS m / z 235.9 (M+H) + .

[0227] Step Five:

[0228] 9-e (100 mg, 0.43 mmol, 1.0 eq), after purging with nitrogen, 10 mL of dichloromethane was added. After cooling to -15 °C, boron tribromide (0.13 mL, 1.3 mmol, 3.0 eq.) was slowly added. The reaction temperature was controlled not to exceed -10 °C and stirred for 30 min, then allowed to warm to room temperature naturally and reacted for 3 h. The reaction was monitored by TLC until completion, quenched, extracted with n-butanol, dried and concentrated, and purified by column chromatography to obtain about 55 mg of compound 9-f. 1 1H NMR (400 MHz, DMSO) δ 9.65 (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-MS m / z 206.3 (M-H) - .

[0229] Step Six:

[0230] 9-f (250 mg, 1.2 mmol, 1.0 eq) was dissolved in 30 mL of DCM. After purging with nitrogen three times, the temperature was cooled to -10 - 0 °C, and trifluoromethanesulfonic anhydride (34 mg, 0.12 mmol, 0.1 eq) was slowly added. Stirred for 30 min, then 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 about 70 mg of compound 9. 1 1H NMR (400 MHz, DMSO) δ 11.42 (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), 3.03 (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-MS m / z 340.6 (M-H)- .

[0231] Example 12 Preparation of Compound 8 of the following formula

[0232]

[0233] Step 1:

[0234] 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 an ice bath, and the mixture was stirred for 1 hour under the ice bath. TLC monitored the complete reaction of the raw materials, and the solvent and thionyl chloride were removed by concentration. Another single-necked flask was charged with ammonium chloride (48 mg, 0.9 mmol, 4.0 eq) in 4 mL of dichloromethane, triethylamine (0.12 mL, 0.9 mmol, 4.0 eq) and DMAP (55 mg, 0.44 mmol, 2.0 eq) were added, and the dichloromethane (2.5 mL) solution of the aforementioned acyl chloride was slowly added under an ice bath, and the reaction was carried out at room temperature for 1 hour. TLC monitored the reaction, quenched, extracted with dichloromethane, concentrated, and column chromatography gave about 27 mg of 8-a. 1 H NMR (500 MHz, DMSO) δ 7.53 (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) + .

[0235] Step 2:

[0236] 8-a (50 mg, 0.24 mmol, 1.0 eq) was placed in a reaction flask. After purging with nitrogen, 2.5 mL of dichloromethane was added. After cooling to -25 to -15 °C, boron tribromide (0.07 mL, 0.72 mmol, 3.0 eq.) was slowly added, and the mixture was stirred at this temperature for 2 hours. TLC monitored the complete reaction, quenched, extracted with n-butanol, dried and concentrated, and column chromatography gave about 27 mg of compound 8-b. 1 H NMR (400 MHz, DMSO) δ 10.62 (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).

[0237] Step 3:

[0238] Dissolve 8-b (300 mg, 1.6 mmol, 1.0 eq) in 30 mL of DCM, displace with nitrogen three times, cool to 0 - 5 °C, slowly add Tf2O (45 mg, 0.16 mmol, 0.1 eq), stir for 30 minutes, slowly add a DCM solution of (+)-limonene (292 mg, 1.92 mmol, 1.2 eq), monitor the reaction by TLC, quench with saturated sodium bicarbonate, extract with dichloromethane, and obtain about 190 mg of compound 8 by column chromatography. 1 1H NMR (400 MHz, DMSO) δ 12.89 (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, 1H), 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-MS m / z 326.4 (M-H) - .

[0239] Example 13 Preparation of Compound 34 of the following formula

[0240]

[0241] Step 1:

[0242] Place compound 34-b (11.59 g, 48.6 mmol, 1.5 eq.) in a three-necked flask, displace with N2 three times, add geraniol 34-a (5.0 g, 32.4 mmol, 1.0 eq.), dichloromethane (150 mL), cool to -20 °C, and add 8M boron trifluoride diethyl etherate (1.6 mL, 12.96 mmol, 0.4 eq.). React at -20 °C for 2 h. Quench the reaction solution with water, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography to obtain about 4.9 g of product 34-c. 11H NMR (400 MHz, Chloroform-d) δ 12.01 (s, 1H), 6.23 (s, 1H), 5.88 (s, 1H), 5.31–5.23 (m, 1H), 5.09–5.01 (m, 1H), 3.91 (s, 3H), 3.43 (d, J = 7.1 Hz, 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, 2.6 Hz, 2H), 1.33 (dt, J = 7.4, 3.2 Hz, 4H), 0.96–0.86 (m, 3H).

[0243] Step 2:

[0244] Compound 34-c (2.0 g, 5.34 mmol, 1.0 eq.) was dissolved in 12.5% (w / w%) methylamine / methyltetrahydrofuran solution (5.3 g, 21.4 mmol, 4.0 eq.). The temperature was lowered to 0 °C, and 1.7 M tert-butylmagnesium chloride / tetrahydrofuran solution (14.1 mL, 24.03 mmol, 4.5 eq.) was added. The reaction tube was sealed and refluxed at 110 °C overnight. Under ice-water bath conditions, the reaction solution was slowly added dropwise to saturated ammonium chloride solution for quenching, extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate; filtered, concentrated, and separated by column chromatography to obtain the title compound 34, 1.0 g of white flocculent solid. 1 1H NMR (500 MHz, DMSO) δ 9.52 (s, 1H), 9.37 (d, J = 6.4 Hz, 1H), 7.94 (d, J = 4.7 Hz, 1H), 6.22 (d, J = 12.1 Hz, 1H), 5.15 (t, J = 7.1 Hz, 1H), 5.06 (t, J = 7.1 Hz, 1H), 3.18 (d, J = 7.1 Hz, 2H), 2.73 (d, J = 4.5 Hz, 3H), 2.55 (d, J = 7.8 Hz, 2H), 2.01 (dt, J = 15.5, 8.3 Hz, 2H), 1.90 (dd, J = 9.2, 6.2 Hz, 2H), 1.71 (s, 3H), 1.62 (s, 3H), 1.55 (s, 3H), 1.44 (p, J = 7.2 Hz, 2H), 1.26 (dt, J = 9.9, 6.5 Hz, 4H), 0.86 (t, J = 7.0 Hz, 3H).

[0245] Example 14 Preparation of the following compound 37

[0246]

[0247] Compound 27-i (2.58 g, 9.72 mmol, 1.5 eq.) was placed in a three-necked flask. The flask was purged with N2 three times, then 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 diethyl etherate (324 μL, 2.59 mmol, 0.4 eq.) was added. The reaction was carried out at -20 °C for 4 h. The reaction mixture was added to water, 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, about 1.3 g. 1 H NMR (500 MHz, DMSO) δ 9.02 (s, 1H), 7.81 (s, 1H), 7.80 (d, J = 4.8 Hz, 1H), 6.37 (s, 1H), 5.17 (t, J = 7.1 Hz, 1H), 5.07 (t, J = 7.0 Hz, 1H), 3.21 (d, J = 7.0 Hz, 2H), 2.65 (d, J = 4.6 Hz, 3H), 2.02 (q, J = 7.5 Hz, 2H), 1.91 (dd, J = 9.4, 6.2 Hz, 2H), 1.71 (s, 3H), 1.63 (s, 3H), 1.56 (s, 3H), 1.27–1.24 (m, 2H), 1.23 (s, 6H), 1.20–1.15 (m, 2H), 1.03 (dq, J = 9.0, 4.7, 4.1 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H). ESI-MS m / z 400.6 (M-H) - .

[0248] Example 15 Preparation of the following compound 57

[0249]

[0250] 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, purged with nitrogen, dissolved in 3 mL of dichloromethane, heated under reflux at 50 °C for 4 h, cooled to 35 °C, and geranyl bromide 57-a (217 mg, 1.0 mmol, 1.3 eq.) was added. The reaction was carried out overnight. The reaction was quenched with water, extracted with dichloromethane, and purified by column chromatography to obtain the title compound 57, about 30 mg. 11H NMR (500 MHz, DMSO) δ 10.50 (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 (M-H) - .

[0251] Example 16 Preparation of Compound 43 of the following formula

[0252]

[0253] Place 9-f (35 mg, 0.17 mmol, 1.0 eq.) in a reaction flask, displace with nitrogen, dissolve in tetrahydrofuran, cool to -62 °C, add 2.5 M n-butyllithium (136 μL, 0.34 mmol, 2.0 eq.) and TMEDA (30 mg, 0.255 mmol, 1.5 eq.), react for 60 min, add geranyl bromide 57-a (55 mg, 0.255 mmol, 1.5 eq.), react at this temperature for 20 min, naturally warm to room temperature, then warm to 60 - 70 °C, monitor the reaction by TLC. Quench with water, extract with ethyl acetate, and obtain the title compound 43 by column chromatography. 1 1H NMR (500 MHz, DMSO) δ 11.28 (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-MS m / z 342.5 (M-H) - .

[0254] Example 17 Preparation of Compound 26 of the following formula

[0255]

[0256] Step 1:

[0257] 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 an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After completion of the reaction, SOCl2 was removed by concentration. Another reaction vessel was charged with 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), and the mixture was stirred for 20 minutes. The DCM solution of the acyl chloride was added under an ice bath, and the reaction was continued under an ice bath for 30 minutes and then at room temperature overnight. The mixture was extracted with dichloromethane. The organic phase was dried and concentrated, and compound 26-a (about 1.17 g) was obtained by column chromatography. 1 H NMR (400 MHz, CDCl3) δ 6.46 (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).

[0258] Step 2:

[0259] 26-a (1.17 g, 3.84 mmol, 1.0 eq) was placed in a reaction flask. The flask was purged 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 the reaction was carried out for 20 min. The reaction mixture was allowed to warm to room temperature naturally and reacted for 2 h. The reaction was monitored by TLC. The reaction solution was slowly added dropwise to ice water for quenching, extracted with DCM, dried and concentrated, and compound 26-b was obtained by column chromatography. 1 H NMR (400 MHz, DMSO) δ 9.33 (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).

[0260] Step 3:

[0261] Compound 26-b (150 mg, 0.54 mmol, 1.0 eq) was placed in a reaction flask. After replacing the atmosphere with N₂ three times, 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 then a DCM solution containing (+)-limonene (97 mg, 0.73 mmol, 1.35 eq) was slowly added. The reaction was monitored by TLC, quenched with saturated brine, extracted, dried, concentrated, and purified by column chromatography to obtain the title compound 26. ESI-MS m / z 410.6 (M-H) - , 412.4 (M+H) + .

[0262] The compounds in Examples 18 - 53 are shown in the following table. These compounds can be prepared by using the same method as in the above examples, except using the starting materials and intermediates corresponding to the final products.

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269] In vivo pharmacodynamic experiment

[0270] 1) Hot Plate Test:

[0271] The test drug was mixed with 5% DMSO and then added to HS 15 and further mixed. Then 90% normal saline was added to prepare a solution with an appropriate concentration. The solution was prepared freshly before use. Female ICR mice, weighing 18 - 22 g.

[0272] One day before the experiment, the mice were screened on a hot plate for 45 s at a temperature of 55 °C. Mice with similar thermal pain latency were selected, and those that were too sensitive or too insensitive to pain were excluded.

[0273] ​For the formal experiment, before drug administration, the thermal pain latency was measured. The measurement time was 90 s, and the hot plate temperature was 55 °C. The thermal pain latency was recorded. The animals were randomly grouped 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 formulation or each test drug. 60 minutes after drug administration, the hot plate test was conducted. The test time was 90 s, and the temperature was 55 °C. The time when the standard animal licked its hind paw or jumped was recorded as the thermal pain latency. The thermal pain latency before drug administration and after drug administration of each group of mice, as well as the MPE percentage, were statistically analyzed. The MPE percentage was calculated using the following formula: [(T1 - T0) / T0] * 100, where the latencies before and after drug injection were T0 and T1 respectively, and the results were expressed as mean ± SD. The thermal pain latency and MPE percentage of mice before and after drug administration in each group were compared respectively, and the results were statistically analyzed using one-way ANOVA.

[0274] 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.

[0275]

[0276] 2) Forced Swim Test:

[0277] The test drug was mixed with 5% DMSO and then added to HS 15 and mixed well, and then 90% normal saline was added to prepare a solution with an appropriate concentration, which was prepared and used immediately. Male ICR mice, about 32 g. The animals were randomly grouped 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 formulation or each test drug. The water level in the forced swimming device was 45 cm, and the water temperature was 25 °C. Before the experiment, the mice were placed in the experimental room to adapt to the environment for 1 h. At the start of the experiment, the mice were placed in the device for 6 min, and the whole process was recorded with a camera. Only the immobile time of the mice in the last 4 min was counted when analyzing the data.

[0278] The drug groups (compounds of Example 1 and Example 4) both 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.

[0279]

[0280] 3) Stress-induced hyperthermia reaction experiment

[0281] The test drug was mixed with 10% DMSO and then added to Mix well with HS 15, then add 80% normal saline to prepare a solution with an appropriate concentration. Use it immediately after preparation. Male ICR mice, about 35 g. Randomly divide the animals into a blank control group and each test drug group, with 8 animals in each group. The mice in each group were subcutaneously injected with the vehicle formulation or each test drug. Stress-induced hyperthermia (SIH) is a transient increase in core body temperature in response to stress, a phenomenon present in all mammals. The stress can be physical or emotional, or both, causing a rapid increase in body temperature (peaking 10 to 15 minutes later). Depending on the intensity and duration of the stress, the temperature returns to the basal level within 60 - 120 minutes. When mice are pre-treated with anxiolytic drugs (such as benzodiazepines or 5-HT 1A receptor agonists), the SIH response is reduced, making it a relatively simple procedure for screening anxiolytic drugs. This protocol describes a procedure for quantifying SIH in singly housed mice (n = 1 / cage) using rectal temperature measurement as the 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. Statistically analyze the T1 value, T2 value, and ΔT value (Reference: Current Protocols in Pharmacology 5.16.1 - 5.16.12, June 2009).

[0282] The drug groups showed significant antidepressant-like effects at doses of 3 - 30 mg / kg, while CBD showed significant anxiolytic-like effects at a dose of 100 mpk.

[0283]

[0284]

[0285] 4) Marble burying test

[0286] Mix the test drug well with 5% DMSO and then add Mix well with HS 15, then add 90% normal saline to prepare a solution with an appropriate concentration. Use it immediately after preparation. Male ICR mice, about 32 g. Randomly divide the animals into a blank control group and each test drug group, with 8 - 10 animals in each group. The mice in each group were intraperitoneally injected with the vehicle formulation or each test drug.

[0287] Prepare a rat cage (6 cm x 48 cm x 20 cm), fresh bedding, glass beads of different colors (diameter 15 mm, about 5.2 g, cleaned and dried after each use); animals should be housed in a room with a 12-hour light-dark cycle, and all mice have free access to food and water. Add 5 cm thick fresh bedding to the rat cage and spread the bedding flat. Place 20 glass beads in the cage (arranged in 4 rows * 5 columns). 15 minutes after administration, place the mice in the corner as far away from the glass beads as possible, cover the cage lid, and carefully return the mice after 30 minutes; count the number of glass beads buried in the test cage.

[0288] In the dose range of 3 - 30 mg / kg, the compound of the present invention significantly reduces the number of buried beads compared with the blank control group, showing a significant antidepressant-like effect, while CBD shows a significant antidepressant-like effect only at a dose of 30 - 60 mg / kg in this experiment.

[0289]

[0290] 5) Elevated plus-maze test

[0291] The test drug is mixed with 5% DMSO and then added to HS15 and mixed well, and then 90% normal saline is added to prepare a solution with an appropriate concentration, which is prepared and used immediately. Male ICR mice, about 32 g. The animals are randomly grouped into a blank control group and each test drug group, with 8 - 10 animals in each group. Each group of mice is intraperitoneally injected with the vehicle formulation or each test drug.

[0292] Elevated plus-maze (EPM) experimental device: made of medical organic board, consisting of two opposite open arms (open arm, length × width are 30 cm × 5 cm respectively), two opposite enclosed arms (enclosed arm, length × width × height are 30 cm × 5 cm × 15 cm respectively) and a central platform (centre platform, 5 cm × 5 cm) connecting the four arms to form a cross shape, 40 cm above the ground. The mouse elevated plus-maze video acquisition system is purchased from Shanghai Yishu Information Technology Co., Ltd. 30 minutes after intraperitoneal administration, use the Yishu elevated plus-maze video acquisition system to record the animal activity trajectory within 5 minutes, and then use the Yishu video analysis system to record and count the number of times the mice enter the open arm and the cumulative residence time in the open arm within 5 minutes.

[0293] In the dose range of 3 - 30 mg / kg, the compound of the present invention significantly increases the residence time in the open arm compared with the blank control group, showing a significant anxiolytic-like effect, while CBD shows a significant effect only at a dose above 30 mg / kg in this experiment.

[0294]

[0295] 6) Pharmacokinetic experiment

[0296] The compounds prepared in Example 1 and the compound prepared in Example 9 were subjected to a pharmacokinetic experiment in mice (ICR mice, administered by gavage, dose 25 mg / kg, n = 3). Blood sampling points: 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h. The results are shown in the following table.

[0297]

[0298] The experimental results showed that when R2 in the general formula (I) is a substituted C3-C 10 cycloalkyl (for example, the compound prepared in Example 9), the compound has a higher blood drug concentration.

[0299] In vitro experiment

[0300] 1) Solubility determination

[0301] The solubility was tested by quantitative analysis using the external standard method of high performance liquid chromatography.

[0302] Chromatographic conditions:

[0303] Mobile phase A: 10 mM KH2PO4, pH 2.0

[0304] Mobile phase B: Acetonitrile

[0305] Chromatographic column: ZORBAX Bonus-RP Rapid Resolution 150×4.6 mm, 3.5 μm LC-SH-510

[0306] Wavelength: 220 nm

[0307] Column temperature: 30 °C

[0308] Flow rate: 1 ml / min

[0309] Injection volume: 10 μl

[0310] Diluent: Acetonitrile

[0311] Solution preparation: Test solution: Weigh 1 mg of the test sample and place it in a 1 ml centrifuge tube. Add 10 mM KH2PO4 solution (pH 6.8, 1 ml), place it on a shaker and shake at 25 °C for 30 min. Take out and centrifuge in a centrifuge for 1.5 min, then take the supernatant for injection. Reference solution: Weigh about 1 mg of the reference substance and place it in a 1 ml centrifuge tube. Dissolve it with 1 ml of acetonitrile, shake well. Take 1 ml of the resulting solution and place it in a 5 ml volumetric flask, dilute to the mark with acetonitrile and shake well. The solubility results are shown in the following table:

[0312]

[0313]

[0314] Compared with CBD, the solubility of the compounds of the examples is significantly improved, which is beneficial to drug absorption.

[0315] All documents mentioned in the present invention are cited herein by reference as if each individual document was specifically and individually cited herein. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A compound or its enantiomer, diastereomer, racemate, and its pharmaceutically acceptable inorganic or organic salt, characterized in that, The compound is represented by Formula I: In the formula, R0 is R1 is selected from the group consisting of carbamoyl and carbamoyl substituted by C1-C4 alkyl; R2 is selected from the group consisting of: substituted C3-C 10 cycloalkyl; wherein said substitution means having 1 substituent selected from the group consisting of: C1-C6 alkyl; R3 is H; Indicates a double bond.

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

3. The compound according to claim 1, wherein R2 is a substituted cyclopropyl, and the substituent of the substitution is C1-C6 alkyl.

4. A compound, characterized in that, The compound is selected from the following compounds:

5. A compound, characterized in that, The compound is the following compound:

6. A compound, characterized in that, The compound is selected from the group consisting of:

7. A method for preparing a compound of formula I-2, characterized in that, Comprising the steps of: providing a compound of formula (III) and NH(R4)2 to obtain the compound through ammonolysis reaction, and the steps are as shown in Reaction Scheme 2: Reaction Scheme 2; In Formula I-2, R2 and R0 are as defined in claim 1; R4 are each independently H or C1-C4 alkyl.

8. Use of a compound as claimed in claim 1, or an enantiomer, diastereomer, racemate thereof, and pharmaceutically acceptable inorganic or organic salts thereof, characterized in that, The compound is used for preparing a pharmaceutical composition or preparation for treating, alleviating, and / or preventing central nervous system diseases; The central nervous system diseases are selected from the group consisting of depression, anxiety disorder, and pain.

9. The use according to claim 8, wherein, The depression is selected from the group consisting of endogenous depression, major depressive disorder, and treatment-resistant depression.

10. The use according to claim 8, characterized in that, The preparation is an oral preparation or a non-oral preparation.

11. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains: (1) The compound of formula I according to claim 1 as an active ingredient; (2) Optionally, an antidepressant; (3) A pharmaceutically acceptable carrier or excipient.

12. Use of a compound as claimed in claim 4, 5 or 6, characterized in that, The compound is used for preparing a pharmaceutical composition or preparation for treating, alleviating, and / or preventing central nervous system diseases; The central nervous system diseases are selected from the group consisting of depression, anxiety disorder, and pain.

13. The use according to claim 12, characterized in that, The depression is selected from the group consisting of endogenous depression, major depressive disorder, and treatment-resistant depression.

14. The use according to claim 12, wherein The preparation is an oral preparation or a non-oral preparation.

15. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains: (1) The compound according to claim 4, 5, or 6 as an active ingredient; (2) Optionally, an antidepressant; (3) A pharmaceutically acceptable carrier or excipient.

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