Imidazole derivative, intermediate, preparation method and application thereof

Abstract

The invention belongs to the field of medicines, particularly relates to imidazole derivatives or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds and application of the imidazole derivatives or the pharmaceutically acceptable salts and the pharmaceutical compositions in the field of medicines, and further relates to a method for preparing the compounds and intermediates.

Description

[0001] This application claims priority to Chinese patent application CN 202411679907.5, filed on November 22, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to a class of imidazole derivatives or pharmaceutically acceptable salts thereof, compositions comprising the compound and their applications in the pharmaceutical field, and also to methods for preparing the compound and intermediates. Background Technology

[0003] Adrenergic receptors are G-protein-coupled receptors, divided into adrenergic α receptors and β receptors. α receptors include α1 and α2 receptors, while β receptors include β1, β2, and β3 receptors. α2 receptors are widely distributed in the central and peripheral nervous systems and other organs and tissues (blood vessels, liver, kidneys, pancreas, platelets, etc.). 2A α 2B α 2C These are three subtypes of α2 receptors (Bylund et al., Mol. Pharmacol., 1992, 42, 1-5), and the α2 receptors in the brain... 2A Primarily concentrated in the pons and medulla oblongata, it participates in the transmission of sympathetic nerve signals from the central nervous system to the periphery. Stimulation of the presynaptic α... 2A It can regulate the release of adrenaline through negative feedback mechanisms; stimulation of postsynaptic α 2A It can cause hyperpolarization of nerve cell membranes.

[0004] The analgesic, anesthetic, and sedative effects of α2-adrenoceptor agonists are well-established (Pertovaara, A., Progress in Neurobiology, 40, 691 (1993)), and they have also been shown to induce potent hypnosis (Mika Scheinin, Debra A. Schwinn; The Locus Coeruleus Site of Hypnotic Actions of α2-Adrenoceptor Agonists. Anesthesiology, 1992; 76: 873–875). For example, in addition to its well-known sedative effects, systemic administration of clonidine has been shown to produce antinociceptive responses in a variety of species, including human patients. Intrathecal and epidural administration of clonidine has also proven effective in producing antinociceptive responses. Another α2-adrenoceptor agonist, dexmedetomidine, with better α2 / α1 selectivity and greater efficacy against α2 receptors than clonidine, has been widely used.

[0005] Dexmedetomidine is a highly selective α2-adrenergic receptor agonist. When acting on the central and peripheral nervous systems and other organs and tissues, it produces sedative, hypnotic, analgesic, anti-anxiety, and sympathetic nerve activity-inhibiting effects (Maud AS Weerinks et al. Clin Pharmacokinte, 2017, 56: 893-913). Due to its significant effects, it is now widely used in clinical practice. Although dexmedetomidine has good analgesic and sedative effects, can improve sleep quality, and treat chronic insomnia, its adverse drug reactions should also be taken seriously, especially hypotension and bradycardia, which are relatively common. Several cases of dexmedetomidine-related bradycardia progression have been reported clinically. In particular, high doses of dexmedetomidine can stimulate α2-adrenergic receptors on vascular smooth muscle. 2B Receptors cause vasoconstriction, leading to high blood pressure and a reflex decrease in heart rate.

[0006] Therefore, there is a need to find an α2-adrenergic receptor agonist with good cyclic stability, high potency, short duration of action, rapid onset of action in vivo, and few side effects, and to apply it to the preparation of drugs for sedation, and / or analgesia, and / or anesthetic effects, and / or anxiolytic, and / or inhibition of sympathetic nerve activity, and / or treatment of insomnia, and / or treatment of mental disorders. Summary of the Invention

[0007] International patent application PCT / CN2024 / 095046 also describes a class of imidazole derivatives, intermediates, preparation methods and applications, all of which are hereby incorporated herein by reference.

[0008] The present invention aims to provide an imidazole derivative or pharmaceutically acceptable salt having α2-adrenergic receptor agonist activity and pharmaceutical compositions thereof, said compounds and pharmaceutical compositions being used to prepare drugs related to α2-adrenergic receptor agonists, and further being used to prepare drugs that produce one or more effects such as sedation, analgesia, anesthesia, anxiolytic, or inhibition of sympathetic nerve activity in humans or animals, and / or for treating insomnia or mental disorders in humans or animals, and even further being used to prepare drugs that produce one or more effects such as sedation, analgesia, or anesthesia in humans or animals, and / or for treating insomnia in humans or animals.

[0009] On the one hand, the present invention provides compounds as shown in general formula I or II, their stereoisomers, or pharmaceutically acceptable salts thereof. Each of R1, R2, and R3 is independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, hydroxyl, nitro, cyano, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C2-C8 haloalkenyl, C2-C8 haloalkynyl, and C1-C8 haloalkylthio. R4 and R5 are each independently selected from H, halogen, hydroxyl, nitro, cyano, optionally substituted C1-C8 alkyl and optionally substituted C1-C8 alkoxy groups; the optional substituents are independently selected from halogen, hydroxyl, nitro and cyano groups; wherein R4 and R5 may be the same or different; Each R6 is independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, hydroxyl, nitro, cyano, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C2-C8 haloalkenyl, C2-C8 haloalkynyl and C1-C8 haloalkylthio; Q is selected from -CH2-, -O-, -NH-, and -S-; v is an integer selected from 1 to 5; n is an integer selected from 1 to 3; m is an integer selected from 1 to 4.

[0010] In one embodiment, the C1-C8 alkyl group is selected from C1-C5 alkyl and C1-C3 alkyl groups. Further, the C1-C5 alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. The C1-C3 alkyl group is selected from methyl, ethyl, propyl, and isopropyl. The propyl group includes, but is not limited to, n-propyl (n-Pr, -CH2CH2CH3) or isopropyl (i-Pr, -CH(CH3)2). The butyl group includes, but is not limited to, n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), or tert-butyl (t-Bu, -C(CH3)3). The pentyl group includes, but is not limited to, n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2) or 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3).

[0011] In one embodiment, the C1-C8 alkoxy group is selected from C1-C5 alkoxy and C1-C3 alkoxy groups. Further, the C1-C5 alkoxy group is selected from methoxy, ethoxy, propoxy, butoxy, and pentoxy groups. Even further, the C1-C3 alkoxy group is selected from methoxy, ethoxy, and propoxy groups.

[0012] In one embodiment, the C1-C8 alkylthio group is selected from C1-C5 alkylthio and C1-C3 alkylthio. Further, the C1-C5 alkylthio group is selected from methylthio, ethylthio, propylthio, butylthio, and pentylthio. Even further, the C1-C3 alkylthio group is selected from methylthio, ethylthio, and propylthio.

[0013] In one embodiment, the C1-C8 haloalkyl group is a C1-C5 haloalkyl group. Further, the C1-C8 haloalkyl group is a C1-C3 haloalkyl group.

[0014] In one embodiment, the C1-C8 haloalkoxy group is a C1-C5 haloalkoxy group. Further, the C1-C8 haloalkyl group is a C1-C3 haloalkoxy group.

[0015] In one embodiment, the C1-C8 haloalkylthio group is a C1-C5 haloalkylthio group. Further, the C1-C8 haloalkyl group is a C1-C3 haloalkylthio group.

[0016] In one embodiment, the C2-C8 alkenyl group is a C2-C4 alkenyl group. Further, the C2-C8 ynyl group is a C2-C4 ynyl group.

[0017] In one embodiment, the halogenated C2-C8 alkenyl group is a halogenated C2-C4 alkenyl group.

[0018] In one embodiment, the halogenated C2-C8 alkynyl group is a halogenated C2-C4 alkynyl group.

[0019] In one embodiment, the C1-C8 hydroxyalkyl group is a C1-C5 hydroxyalkyl group. Further, the C1-C5 hydroxyalkyl group is a C1-C3 hydroxyalkyl group.

[0020] In one embodiment, the C1-C8 hydroxyalkoxy group is a C1-C5 hydroxyalkoxy group. Further, the C1-C5 hydroxyalkoxy group is a C1-C3 hydroxyalkoxy group.

[0021] In one embodiment, the halogen is selected from fluorine, chlorine, bromine, and iodine. In a preferred embodiment, the halogen is selected from fluorine, chlorine, and bromine. In a more preferred embodiment, the halogen is selected from fluorine and chlorine.

[0022] In one embodiment, each R1 is independently selected from H, halogen, hydroxyl, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and C1-C8 haloalkoxy; preferably selected from H, halogen and C1-C8 alkyl; more preferably selected from H and methyl; and even more preferably H.

[0023] In one embodiment, each R2 is independently selected from H, halogen, hydroxyl, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and C1-C8 haloalkoxy; preferably selected from H, halogen and C1-C5 alkyl; more preferably selected from H, methyl, fluorine and chlorine; and even more preferably H.

[0024] In one embodiment, R3 is selected from H, halogen, hydroxyl, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and C1-C8 haloalkoxy; preferably selected from H and C1-C5 alkyl; more preferably selected from H and methyl; and even more preferably H.

[0025] In one embodiment, R4 and R5 are independently selected from H and optionally substituted C1-C5 alkyl groups, respectively, wherein the optional substituent is a hydroxyl group; and R4 and R5 may be the same or different.

[0026] In a preferred embodiment, R4 and R5 are independently selected from H, methyl, ethyl and hydroxymethyl, respectively; and R4 and R5 may be the same or different.

[0027] In a more preferred embodiment, R4 is methyl and R5 is H.

[0028] In one embodiment, each R6 is independently selected from H, halogen, hydroxyl, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and C1-C8 haloalkoxy; preferably selected from H, halogen, C1-C5 alkyl, more preferably selected from H, halogen and C1-C3 alkyl, and even more preferably selected from H, methyl and fluorine.

[0029] In one implementation, Q is selected from -CH2-, -O-, and -S-.

[0030] In one implementation, Q is selected from -CH2- and -S-.

[0031] In one implementation, v is selected from an integer from 1 to 3; preferably 1 or 2.

[0032] In one implementation, n is selected from 1 and 2; preferably 1.

[0033] In one implementation, m is selected from an integer from 1 to 3; preferably 1 or 2.

[0034] In a preferred embodiment, the compound or its stereoisomer represented by formula I or II is selected from Ia, Ib, II-a, II-b, or mixtures thereof: , , , Q, R1, R2, R3, R4, R5, R6, n, v, and m are defined as above, and R4 and R5 are not the same.

[0035] In a preferred embodiment, the compound or its stereoisomer represented by formula I or II is selected from III-a, III-b, IV-a, IV-b, or mixtures thereof: , , , Q is as defined above.

[0036] In a particularly specific embodiment, the compound represented by formula I or II, and its stereoisomers, are selected from the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0037] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula I or II as described above, its stereoisomers or pharmaceutically acceptable salts thereof, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combination thereof.

[0038] In some embodiments of the present invention, the above-described pharmaceutical composition can be formulated using one or more pharmaceutically acceptable carriers in a conventional manner. The carrier refers to a carrier conventional in the pharmaceutical field, such as diluents, excipients, binders, fillers, lubricants, etc. Additionally, other excipients such as flavoring agents and sweeteners may be added to the composition. For oral administration, it can be prepared into conventional solid dosage forms such as tablets, powders, lozenges, capsules, suspensions, syrups, etc.; for injection, it can be prepared into an injection solution.

[0039] On the other hand, the present invention provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament related to an α2-adrenergic receptor agonist.

[0040] In one embodiment, the application is to prepare a product that produces one or more effects such as sedation, analgesia, anesthetic, anxiolytic, or inhibition of sympathetic nerve activity in humans or animals, and / or to treat insomnia or mental disorders in humans or animals. More preferably, it is prepared to produce one or more effects such as sedation, analgesia, or anesthetic in humans or animals, and / or to treat insomnia or mental disorders in humans or animals. Even more preferably, it is prepared to produce one or more effects such as sedation, analgesia, or anesthetic in humans or animals, and / or to treat insomnia in humans or animals.

[0041] The present invention also relates to a method for treating diseases associated with mammalian α2-adrenergic receptor agonists, comprising administering to the mammal a therapeutically effective dose of any of the compounds shown above, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof, or pharmaceutical compositions thereof.

[0042] On the other hand, the present invention provides an intermediate compound or its stereoisomer with the following structure: , , or .

[0043] On the other hand, the present invention provides a method for preparing the aforementioned compound, comprising the following steps: starting from the aforementioned intermediate compound, subjecting it to a hydrogenation-reduction reaction in a solvent, followed by chiral resolution to obtain the corresponding compound represented by the aforementioned general formula I or II. In one embodiment, the method and conditions for the hydrogenation-reduction reaction can be conventional methods and conditions for such reactions in the art.

[0044] In one embodiment, the solvent may be a solvent conventional for such reactions in the art, such as methanol.

[0045] In one embodiment, the amount of solvent used may be the amount conventional for such reactions in the art; for example, the volume of the solvent may be 1 to 10 mL, preferably 5 mL.

[0046] In one embodiment, the temperature of the hydrogenation reduction can be a temperature conventional for such reactions in the art, such as room temperature.

[0047] In one embodiment, the hydrogenation reduction reaction further includes a catalyst, which may be a conventional catalyst for such reactions in the art, such as Pd / C.

[0048] In one embodiment, the deprotection reaction may further include the following post-processing steps: after hydrogenation reduction, the crude product is obtained by filtration and concentration, and the crude product is separated by column chromatography to obtain the aforementioned compound.

[0049] General terms and definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0050] The term “optional” or “optionally” means that the event or situation described below may, but not necessarily, occur, and the description includes both the cases in which the event or situation occurs and the cases in which it does not occur.

[0051] Generally, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced by a specific substituent. Unless otherwise indicated, a substituent may be substituted at any of the reasonable substituted positions in the group. When more than one position in a given structural formula can be substituted by one or more specific substituents selected from the group, the substituents may be substituted at the reasonable positions in the structural formula, either in the same or different ways.

[0052] Additionally, it should be noted that, unless otherwise explicitly stated, the description used in this invention as “each independently” should be interpreted broadly. It can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0053] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or range of groups. In particular, this invention includes every independent sub-combination of the members of these types and ranges. For example, the expression mn as used herein refers to the range from m to n, as well as the subrange consisting of the individual point values ​​therein, and the individual point values ​​themselves.

[0054] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, connected to the rest of the molecule by single bonds. Alkyl groups can have 1-8 carbon atoms, i.e., "C1-C8 alkyl", for example, C... 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C8 alkyl, C 1-8 Alkyl, C 3-8 Alkyl groups. They can have 1-5 carbon atoms, i.e., "C1-C5 alkyl"; or they can have 1-3 carbon atoms, i.e., "C1-C3 alkyl", for example, C 1-3 Alkyl, C 1-2Alkyl, C3 alkyl. The term "C1-C5 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -CH2CH2CH2CH3), and tert-butyl (t-Bu, -CH2CH(CH3)2). -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH 3) 4-Methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-Methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-Methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-Dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-Dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-Heptyl, n-Octyl, etc. For example, the expression "C1-C8" or "C1-8" covers a range of 1 to 8 carbon atoms, and should be understood to also cover any subrange and each point value within this range, such as C1-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, etc., and C1, C2, C3, C4, C5, C6, C7, C8, etc. Another example is the expression "C1-C5" or "C..." 1-5 "Covering a range of 1-5 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., and C1, C2, C3, C4, C5, etc. For example, expressing 'C2-C5' or 'C'..." 2-5"Covering a range of 2-5 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C2-C3, C2-C4, C3-C5, C4-C5, etc., and C2, C3, C4, C5, etc. Another example is expressing "C1-C8" or "C..." 1-8 "The term 'ternary' encompasses a range of 1 to 8 carbon atoms and should be understood to also include any subranges within this range, as well as each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, and C1, C2, C3, C4, C5, C6, C7, C8, etc. Similarly, the expression 'ternary to octernary' should be understood to encompass any subrange within this range, as well as each point value, such as ternary to pentaneous, ternary to hexane, ternary to heptaneous, ternary to octernary, quaternary to pentaneous, quaternary to hexane, quaternary to heptaneous, quaternary to octernary, pentaneous to heptaneous, pentaneous to octernary, heptaneous to heptaneous, heptaneous to octernary, etc., and tri-, quadri-, quinary-, quinary-, quinary-, quinary-, quinary-, and octernary-, etc. Other similar expressions in this text should also be understood in a similar manner."

[0055] The term “selected from…” means one or more elements from the groups listed below, selected independently, and may include combinations of two or more elements.

[0056] The term "halogen" or "halogenated" should be understood to mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine, chlorine or bromine atoms, more preferably fluorine or chlorine, and even more preferably fluorine atoms.

[0057] The term "hydroxyl group" refers to the -OH group.

[0058] The term "alkoxy group" refers to an alkyl group attached to the remainder of a molecule via an oxygen atom, wherein the alkyl group has the meaning as described in this invention. In one embodiment, the alkoxy group contains 1-8 carbon atoms. In another embodiment, the alkoxy group contains 1-5 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), etc.

[0059] The term "alkathio" refers to an alkyl group attached to the remainder of a molecule via a sulfur atom, wherein the alkyl group is as defined herein. In one embodiment, the alkathio group contains 1-8 carbon atoms. In another embodiment, the alkathio group contains 1-5 carbon atoms. In yet another embodiment, the alkathio group contains 1-3 carbon atoms. The alkathio group may optionally be substituted by one or more substituents described herein. Examples of alkathio groups include, but are not limited to, methylthio (-SCH3), ethylthio (-SCH2CH3), propylthio (-SCH2CH2CH3, -SCH(CH3)2), butylthio (-SCH2CH2CH2CH3, -SCH2CH(CH3)2, -SCH(CH3)CH2CH3, -SC(CH3)3), etc.

[0060] The terms "hydroxyalkyl" and "hydroxy-substituted alkyl" are used interchangeably, referring to an alkyl group in which one or more hydroxyl groups are substituted. Examples include, but are not limited to: hydroxymethyl (-CH2OH), hydroxyethyl (-CH2CH2OH, -CHOHCH3), hydroxypropyl (-CH2CH2CH2OH, -CH2CHOHCH3, -CHOHCH2CH3, -COHCH3CH3), and hydroxybutyl (-CH2CH2CH2CH2OH, -CH2CH2CHOHCH3, -CHOHCH2CH2CH3, -COHCH3CH2CH3), wherein the hydroxyl substitution can be monosubstituted or polysubstituted.

[0061] The terms “hydroxyalkoxy” and “hydroxy-substituted alkoxy” are used interchangeably and refer to an alkoxy group that is substituted by one or more hydroxyl groups.

[0062] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon containing carbon-carbon double bonds and having a chain-like structure. For example, vinyl (-CH=CH2). The "alkene" can have 2-8 carbon atoms, i.e., a "C2-C8" alkenyl group, such as C... 2-8 alkenyl, C 2-4 alkenyl, C 2-5 alkenyl, C3 alkenyl, C4 alkenyl, C6 alkenyl, C 2-6 alkenyl, C 3-8 alkenyl, C 3-6 Alkenyl groups, etc. They can also have 2-4 carbon atoms, i.e., "C2-C4 alkenyl groups", for example, C... 2-4 alkenyl, C 2-3 Alkenyl, C3 alkenyl, C4 alkenyl, etc. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), propenyl (-CH=CH-CH3), butenyl (-CH=CH-CH2-CH3, -CH2-CH=CH-CH3), pentenyl (-CH=CH-CH2-CH2-CH3, -CH2-CH2-CH=CH-CH3, -CH(CH3)-CH=CH-CH3), hexenyl, heptenyl, octenyl, etc.

[0063] The term "alkynyl" refers to a general term for hydrocarbons containing a carbon-carbon triple bond in their molecules; they are unsaturated aliphatic hydrocarbons. For example: ethynyl ( The "alkyne" may have 2-8 carbon atoms, i.e., a "C2-C8" ynyl group, for example, C 2-8 alkynyl group, C 2-4 alkynyl group, C 2-5 Alkynyl, C3 alkynyl, C4 alkynyl, C6 alkynyl, C 2-6 alkynyl group, C 3-8 alkynyl group, C 3-6 Alkyne groups, etc. They can also have 2-4 carbon atoms, i.e., "C2-C4 alkynyl groups", for example, C... 2-4 alkynyl group, C 2-3 Alkynyl, C3 alkynyl, C4 alkynyl, etc. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, penynyl, hexynyl, hepynyl, octyynyl, etc.

[0064] The term "hydrogen (H)" refers to a single hydrogen atom. Such a group of atoms can be attached to other groups, such as oxygen atoms, to form a hydroxyl group.

[0065] The terms "halogenated alkyl" and "halogen-substituted alkyl" are used interchangeably, referring to an alkyl group in which one or more halogens are substituted. Examples include, but are not limited to, halomethyl, haloethyl, halopropyl, halobutyl, and halopentyl, wherein the halogenation can be monohalogen-substituted, dihalogen-substituted, or trihalogen-substituted; when it is a trihalogen-substituted methyl group, trifluoromethyl is further preferred.

[0066] The terms "haloalkoxy" and "halogen-substituted alkoxy" are used interchangeably and refer to an alkoxy group that is substituted with one or more halogens. Examples include, but are not limited to, halomethoxy, haloethoxy, halopropoxy, halobutoxy, and halopentoxy, wherein the halogenation can be monohalogen substitution, dihalogen substitution, or trihalogen substitution.

[0067] The terms "haloalkylthio" and "halogen-substituted alkylthio" are used interchangeably and refer to an alkylthio group being substituted by one or more halogens. Examples include, but are not limited to, halomethylthio, haloethylthio, halopropylthio, halobutylthio, and halopentyl, wherein the halogenation can be monohalogen substitution, dihalogen substitution, or trihalogen substitution.

[0068] The terms "halogenated alkenyl" and "halogen-substituted alkenyl" are used interchangeably and refer to alkenyl groups that are substituted with one or more halogens. Examples include, but are not limited to, halogenated vinyl, halogenated propenyl, halogenated butenyl, and halogenated pentenyl, wherein the halogenation can be monohalogenated, dihalogenated, or trihalogenated.

[0069] The terms "halogenated alkyne" and "halogen-substituted alkyne" are used interchangeably and refer to the alkyne group being substituted by one or more halogens. Examples include, but are not limited to, halogenated ethynyl, halogenated propynyl, halogenated butynyl, and halogenated pentyyn, wherein the halogenation can be monohalogenated, dihalogenated, or trihalogenated.

[0070] The term "stereoisomer" refers to compounds that have the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, and hindered isomers, etc.

[0071] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0072] The term "pharmaceutically acceptable salt" refers to the organic or inorganic salt of the compounds of this invention.

[0073] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0074] The term "room temperature" refers to a temperature ranging from 0°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0075] For the purposes of this invention, "effective amount" refers to an amount sufficient to improve or prevent the symptoms or condition of the stated disease. Effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. Effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0076] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0077] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or stopping the symptom of a disease or symptom; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the treated symptom. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physiological symptoms of a disease, even though the disease has not yet been diagnosed.

[0078] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0079] Beneficial technical effects Compared with the prior art, the technical solution of the present invention has the following advantages: This invention relates to a class of novel structural compounds that exhibit good α2-adrenergic receptor agonist activity. These compounds can be used to prepare drugs related to α2-adrenergic receptor agonists, and further to prepare drugs that produce one or more sedative or analgesic effects in humans or animals, and / or to treat insomnia in humans or animals. These compounds have good pharmacodynamic activity and also exhibit good pharmacokinetic characteristics, good cyclic stability, high potency, short duration of action, rapid onset of action in vivo, and few side effects, showing good prospects for clinical application. Detailed Implementation

[0080] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims. Example The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available products. Unless otherwise specified, all proportions or percentages used herein are by weight. Synthesis Examples Example 1: Preparation of intermediates 4-[1-[(1aR,6aR)-1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl]vinyl]-1H-imidazolium and 4-[1-[(1aS,6aS)-1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl]vinyl]-1H-imidazolium 1.1 Preparation of 5-bromo-1H,1aH,6H,6aH-cyclopropyl[a]indene (intermediate Aa) Under a nitrogen atmosphere, TFA (8.77 g, 76.900 mmol, 5 equiv) was added dropwise to a DCM (30 mL) solution of diethylzinc (76.90 mL, 76.900 mmol, 5 equiv). The mixture was stirred for 20 minutes after the addition, followed by the addition of diiodomethane (20.60 g, 76.900 mmol, 5 equiv) at room temperature. 4-Bromo-3H-indene (3 g, 15.380 mmol, 1 equiv) was added to the mixture at room temperature. The mixture was stirred overnight at room temperature. The reaction was quenched with a saturated aqueous solution of ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (3 × 20 mL) at room temperature, and the organic layers were combined. The mixture was washed with saturated brine (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 5-bromo-1H,1aH,6H,6aH-cyclopropyl[a]indene (Aa) (1.65 g). (ES, m / z) = 208, 210.

[0081] 1.2 Preparation of 1-(1H,1aH,6H,6aH-cyclopropyl[a]indene-5-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (intermediate Ab) Under a nitrogen atmosphere, n-butyllithium (4.30 mL, 10.761 mmol, 1.5 equiv, 2.5 M in hexane) was added dropwise to a 20 mL solution of tetrahydrofuran containing Aa (1.5 g, 7.174 mmol, 1 equiv). After the addition was complete, the mixture was stirred for 1 hour. Then, a 5 mL solution of THF containing 1-[1-(triphenylmethyl)imidazol-4-yl]acetone (2.78 g, 7.891 mmol, 1.1 equiv) was added. The mixture was then slowly brought to room temperature and stirred overnight. The reaction was quenched at 0 °C with a saturated aqueous solution of ammonium chloride (50 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL), and the organic phases were combined. The mixture was washed with saturated brine (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 1-(1H,1aH,6H,6aH-cyclopropyl[a]indene-5-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (Ab) (1.8 g). (ES, m / z): [M+1]=483.

[0082] 1.3 Preparation of 4-[1-(1H,1aH,6H,6aH-cyclopropyl[a]indene-5-yl)vinyl]-1-(triphenylmethyl)imidazolium (intermediate Ac) Oxaloyl chloride monoethyl ester (1.27 g, 9.324 mmol, 3 equiv) was added dropwise to a stirred solution of Ab (1.5 g, 3.108 mmol, 1 equiv) and TEA (1.89 g, 18.648 mmol, 6 equiv) in DCM (20 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched at 0 °C with water / ice (10 mL), and the resulting mixture was extracted with EtOAc (3 × 20 mL) to synthesize the organic phase. The mixture was washed with saturated brine (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 4-[1-(1H,1aH,6H,6aH-cyclopropyl[a]indene-5-yl)vinyl]-1-(triphenylmethyl)imidazolium (Ac) (1.136 g). (ES, m / z): [M+1] = 465.

[0083] 1.4 Preparation of 4-[1-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl)vinyl]-1H-imidazolium (intermediate Ad) A solution of Ac (1.0 g, 2.15 mmol) in DCM (16 mL) and TFA (8 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to 4-[1-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl)vinyl]-1H-imidazole (Ad) (380 mg). (ES, m / z): [M+1] = 223.

[0084] 1.5 Preparation of intermediates A-1 and A-2 Ad (300 mg) was purified by chiral SFC under the following conditions (column: CHIRALPAK AD-H, 3.0). 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 2 mL / min, gradient: 15% mobile phase B isocratic elution; detector wavelength: 220 nm), to obtain intermediate A-1 (120 mg, retention time: 4.68 min) and intermediate A-2 (110 mg, retention time: 5.53 min).

[0085] Example 2: Synthesis of intermediates 4-[1-[(1aS,6bS)-1a,6b-dihydro-1H-benzo[b]cyclopropane[d]thiophene-3-yl]vinyl]-1H-imidazolium and 4-[1-[(1aR,6bR)-1a,6b-dihydro-1H-benzo[b]cyclopropane[d]thiophene-3-yl]vinyl]-1H-imidazolium 2.1 Preparation of 1-(2-bromo-6-formylphenoxy)-N,N-dimethylformylthioamide (intermediate Ba) Dimethylaminothiocarbamate chloride (9.84 g, 79.594 mmol, 2 equiv) was added dropwise to a stirred solution of 3-bromo-2-hydroxybenzaldehyde (8 g, 39.80 mmol, 1 equiv) and TEA (12.08 g, 119.39 mmol, 3 equiv) in 150 mL of THF under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched by adding water / ice (100 mL) at 0 °C, followed by extraction with EtOAc (3 × 500 mL) and drying over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 4 g of 1-(2-bromo-6-formylphenoxy)-N,N-dimethylformylthioamide (Ba). (ES, m / z): [M+1]=288, 290. 2.2 Preparation of 1-(2-bromo-6-formylphenylthio)-N,N-dimethylformamide (intermediate Bb) Ba (3.9 g, 13.534 mmol, 1 equiv) and diphenyl ether (20 mL) were added to a 50 mL two-necked round-bottom flask at room temperature. The resulting mixture was stirred at 200 °C for 30 min under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. The mixture was purified by silica gel column chromatography, eluting with PE / EA (4:1) to give 3 g of 1-(2-bromo-6-formylphenylthio)-N,N-dimethylformamide (Bb). (ES, m / z): [M+1] = 288, 290. 2.3 Preparation of 3-bromo-2-mercaptobenzaldehyde (intermediate Bc) At room temperature, sodium hydroxide (19.99 mL, 1 M) solution was added to a stirred methanol (25 mL) solution of Bb (3 g, 10.41 mmol, 1 equiv). After stirring at 60 °C for 2 hours, the reaction mixture was cooled to room temperature, and concentrated hydrochloric acid (15 mL) was added to the mixture. The resulting mixture was stirred at room temperature for another 30 minutes. The mixture was extracted with EA (3 × 100 mL), and the organic layers were combined. The mixture was washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (4:1) to give 1.5 g of 3-bromo-2-mercaptobenzaldehyde (Bc). (ES, m / z): [M⁻¹] = 215, 217. 2.4 Preparation of 3-bromo-2-[(2-bromoethyl)thio]benzaldehyde (intermediate Bd) Dibromoethane (1.95 g, 10.365 mmol, 1.5 equiv) was added to a mixture of Bc (1.5 g, 6.91 mmol, 1 equiv) and K2CO3 (1.91 g, 13.82 mmol, 2 equiv) in DMF (20 mL) under stirring at room temperature and a nitrogen atmosphere. The resulting mixture was stirred overnight at 70 °C. The reaction mixture was allowed to cool to room temperature, and then quenched by adding water / ice (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 × 100 mL), and the organic layers were combined. The mixture was washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was rapidly purified by reverse-phase chromatography to give 900 mg of 3-bromo-2-[(2-bromoethyl)thio]benzaldehyde (Bd). (ES, m / z): [M] = 321.8, 323.8, 325.8. 2.5 Preparation of 3-bromo-2-(vinylthio)benzaldehyde (intermediate Be) At room temperature, Bd (700 mg, 2.160 mmol, 1 equiv) and THF (20 mL) were added to a 50 mL round-bottom flask. Potassium tert-butoxy (363.6 mg, 3.240 mmol, 1.50 equiv) was added in portions to the above solution at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was rapidly purified by reverse-phase chromatography to give 444 mg of 3-bromo-2-(vinylthio)benzaldehyde (Be). (ES, m / z): M = 242, 244. 2.6 Preparation of N'-[(1Z)-[3-bromo-2-(vinylthio)phenyl]methylene]-4-methylbenzenesulfonylhydrazine (intermediate Bf) At room temperature, 4-toluenesulfonyl hydrazine (298.9 mg, 1.606 mmol, 1.09 equiv) was added fractionally to a stirred solution of Be (358 mg, 1.473 mmol, 1 equiv) in 20 mL of CH3OH. The resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was rapidly purified by reverse-phase to give 600 mg of N'-[(1Z)-[3-bromo-2-(vinylthioalkyl)phenyl]methylene]-4-methylbenzenesulfonyl hydrazine (Bf). (ES, m / z): [M+1] = 411, 413. 2.7 3-Bromo-1a,6b-dihydro-1 H Preparation of benzo[b]cyclopropyl[d]thiophene (intermediate Bg) At room temperature and under a nitrogen atmosphere, a rhodium(II) octanoate dimer (22.7 mg, 0.029 mmol, 0.02 equiv) was added to a stirred mixture of Bf (600 mg, 1.459 mmol, 1 equiv), lithium tert-butoxy (124.9 mL, 1.561 mmol, 1.07 equiv), and toluene (10 mL). The resulting mixture was stirred at 100 °C for 3 hours. The reaction mixture was allowed to cool to room temperature and then quenched with water (30 mL) at room temperature. The mixture was extracted with ethyl acetate (3 × 100 mL), and the organic layers were combined. The mixture was washed with brine (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 3-bromo-1a,6b-dihydro-1 H -Benzo[b]cyclopropyl[d]thiophene (Bg) 250 mg. (ES, m / z): M = 226, 228. 2.8 1-(1a,6b-dihydro-1) H -benzo[b]cyclopropyl[d]thiophene-3-yl)-1-(1-triphenylmethyl-1 H Preparation of 4-imidazolium-1-yl)ethanol (intermediate Bh) A solution of Bg (250 mg, 1.10 mmol, 1 equiv) in THF (10 mL) was reacted with n-butyllithium (0.48 mL, 1.211 mmol, 1.1 equiv, 2.5 M in-hexane) at -78 °C under nitrogen for 1 h. Then, 1-[1-(triphenylmethyl)imidazol-4-yl]acetone (465.5 mg, 1.321 mmol, 1 equiv) dissolved in THF (2 mL) was added dropwise to the system. The mixture was allowed to rise naturally to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride (aq). The resulting mixture was extracted with EtOAc (3 × 100 mL), and the organic phases were combined. The mixture was washed with water (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give 1-(1a,6b-dihydro-1 H -benzo[b]cyclopropyl[d]thiophene-3-yl)-1-(1-triphenylmethyl-1 H 4-Imidazol-4-yl)ethyl-1-ol (Bh) 40 mg, (ES, m / z): [M+1]=501.

[0086] 2.9 4-[1-(1a,6b-dihydro-1 H -benzo[b]cyclopropyl[d]thiophene-3-yl)vinyl]-1 H Preparation of β-imidazolium (intermediate Bi) At room temperature and under a nitrogen atmosphere, TFA (2.73 g, 23.947 mmol, 10 equiv) was added to a 20 mL solution of Bh (1.2 g, 2.397 mmol, 1 equiv) in THF. After 1 minute, triethylsilane (2.78 g, 23.97 mmol, 10 equiv) was added dropwise at room temperature. The resulting mixture was reacted overnight at 80 °C and cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN aqueous solution (10 mmol / L NH4HCO3) with a gradient of 0% to 50% over 10 minutes; detector wavelength: UV 220 nm. 4-[1-(1a,6b-dihydro-1-diethylsilane)] was obtained. H -benzo[b]cyclopropyl[d]thiophene-3-yl)vinyl]-1 H -Imidazole (Bi) 400 mg. (ES, m / z): [M+1]=241.

[0087] 2.10 Preparation of intermediates B-1 and B-2 Bi (400 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IG-3, 3.0). 25 cm, 5 μm, mobile phase: Hex (0.1% DEA): ethanol = 95:5; flow rate: 1.67 mL / min; gradient: isocratic elution; injection volume: 0.5 mL, yielding intermediate B-1 (177 mg, retention time: 3.36 min) and intermediate B-2 (156 mg, retention time: 4.04 min). (ES, m / z): [M+1] = 241.

[0088] Example 1: Preparation of 4-[(S)-1-[(1aR,6aR)-1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl]ethyl]-1H-imidazolium and 4-[(R)-1-[(1aR,6aR)-1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl]ethyl]-1H-imidazolium 1.1 At room temperature, Pd / C (4.79 mg, 10% w / t) was added fractionally to a methanol (5 mL) solution of 4-[1-[(1aR,6aR)-1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl]vinyl]-1H-imidazole (120 mg, 0.540 mmol), and the mixture was stirred for 20 min at room temperature under a hydrogen atmosphere. The resulting mixture was filtered through a diatomaceous earth filter, and the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep HPLC under the following conditions (column: (S,S)-Whelk-O1, 4.6). 50 mm, 3 μm; mobile phase A: hexane (10 mM NH3-MeOH), mobile phase B: ethanol; flow rate: 20 mL / min; wavelength: 220 / 234 nm, yielded 70 mg of 4-[1-[(1aR,6aR)-1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl]ethyl]-1H-imidazolium (1-a). (ES, m / z): [M+1] = 225. 1.2 1-a (70 mg) was purified by preparative chiral HPLC under the following conditions (column: (S,S)-Whelk-O1, 3). 25 cm, 5 μm; mobile phase A: hexane (10 mM NH3-MeOH)), mobile phase B: ethanol; gradient: 10%; isocratic elution with mobile phase B, flow rate: 40 mL / min, wavelength: UV 214 / 220 nm) to give compound 1 (18.3 mg, retention time: 9.5 min) and compound 2 (14.2 mg, retention time: 11.8 min).

[0089] Compound 1 (ES, m / z): [M+1] = 225. 1 H NMR (400 MHz, methanol-) d 4) δ 7.59 (d, J = 1.2 Hz, 1H), 7.16 (dd, J =7.4, 1.1 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.90 (dd, J = 7.6, 1.2 Hz, 1H), 6.76 (t, J = 1.1 Hz, 1H), 4.13 (q, J = 7.2 Hz, 1H), 3.13 – 2.93 (m, 2H), 2.41(dddd, J = 7.8, 6.1, 3.2, 1.6 Hz, 1H), 1.98 – 1.82 (m, 1H), 1.58 (d, J = 7.2Hz, 3H), 1.07 (td, J = 8.0, 4.1 Hz, 1H), -0.06 (s, 1H). Compound 2 (ES, m / z): [M+1] = 225. 1 H NMR (400 MHz, Methanol- d 4) δ 7.61 (d, J = 1.2 Hz, 1H), 7.18 (dd, J = 7.4, 1.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.94 (dd, J = 7.7, 1.2 Hz, 1H), 6.76 (d, J = 1.1 Hz, 1H), 4.15 (q, J= 7.2 Hz, 1H), 3.15 (dd, J = 16.9, 6.8Hz, 1H), 2.93 (dd, J = 16.9, 2.0 Hz, 1H), 2.41 (dddd, J = 7.8, 6.1, 3.2, 1.7Hz, 1H), 1.99 – 1.80 (m, 1H), 1.59 (d, J = 7.2 Hz, 3H), 1.10 (td, J = 7.9,4.1 Hz, 1H). 0.06 (s, 1H). Example 2: Preparation of 4-[(S)-1-[(1aS,6aS)-1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl]ethyl]-1H-imidazolium and 4-[(R)-1-[(1aS,6aS)-1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl]ethyl]-1H-imidazolium 2.1 At room temperature, Pd / C (26.33 mg, 10% w / t) was added in portions to a methanol (5 mL) solution of 4-[1-[(1aS,6aS)-1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl]vinyl]-1H-imidazole (110 mg, 0.495 mmol) and stirred for 20 min at room temperature under a hydrogen atmosphere. The resulting mixture was filtered through a diatomaceous earth filter, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase rapid chromatography under the following conditions: C18 silica gel column; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 10% to 50% over 10 min; detector wavelength UV 254 nm. 60 mg of 4-[1-[(1aS,6aS)-1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl]ethyl]-1H-imidazole (2-a) was obtained. (ES, m / z): [M+1]=225. 2.2 2-a was purified by preparative chiral HPLC under the following conditions (column: (S,S)-Whelk-O1, 3). 25 cm, 5 μm; mobile phase A: hexane (10 mM NH3-MeOH)), mobile phase B: ethanol; gradient: 10% mobile phase B isocratic elution, flow rate: 20 mL / min, wavelength: UV 220 / 234 nm), yielding compound 3 (28.9 mg, retention time: 15.5 min) and compound 4 (20.2 mg, retention time: 9 min).

[0090] Compound 3 (ES, m / z): [M+1]=225. 1 H NMR (400 MHz, Methanol- d 4) δ 7.60 (d, J J = 1.2 Hz, 1H), 7.16 (dd, J J = 7.4, 1.1 Hz, 1H), 7.12 – 7.00 (m, 1H), 6.90 (dd, J = 7.6, 1.1 Hz, 1H), 6.83– 6.62 (m, 1H), 4.22 – 3.96 (m, 1H), 3.13 – 2.93 (m, 2H), 2.40 (dddd, J J =7.8, 6.0, 3.2, 1.7 Hz, 1H), 1.89 (dtdd, J J = 7.7, 6.5, 4.1, 1.1 Hz, 1H), 1.58(d, J J = 7.2 Hz, 3H), 1.07 (td, J J = 7.9, 4.1 Hz, 1H). 0.00 (q, J J = 3.9 Hz,1H). Compound 4 (ES, m / z): [M+1]=22​​​​​​​​​​​​​​​​​​​​​​= 6.5, 1.9 Hz, 1H),1.96 – 1.82 (m, 1H), 1.59 (d, J = 7.2 Hz, 3H), 1.11 (tdd, J = 7.9, 4.1, 0.8Hz, 1H). 0.00 (q, J = 3.9 Hz, 1H). Example 3: Preparation of 4-[(R)-1-[(1a,6b-1aS,6bS)-1a,6b-dihydro-1H-benzo[b]cyclopropane[d]thiophene-3-yl]ethyl]-1H-imidazolium and 4-[(S)-1-[(1a,6b-1aS,6bS)-1a,6b-dihydro-1H-benzo[b]cyclopropane[d]thiophene-3-yl]ethyl]-1H-imidazolium 3.1 At room temperature, 4-[1-[(1aS,6bS)-1a,6b-dihydro-1H-benzo[b]cyclopropane[d]thiophene-3-yl]vinyl]-1H-imidazole (177 mg, 0.730 mmol), MeOH (5 mL), and Pd / C (85 mg, 0.080 mmol, 10% w / t) were added to a 25 mL round-bottom flask. The resulting mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The resulting mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN aqueous solution (10 mmol / L NH4HCO3) with a gradient of 0% to 40% over 10 min; detector: UV 220 nm. 117 mg of 4-[1-[(1aR,6bR)-1a,6b-dihydro-1H-benzo[b]cyclopropane[d]thiophene-3-yl]vinyl]-1H-imidazolium(3-a) was obtained. (ES, m / z): [M+1] = 243. 3.2 3-a was purified by preparative chiral HPLC under the following conditions: (Column: CHRAL ART Cellulose-SB, 3...) 25 cm, 5 μm; mobile phase A: MeOH, mobile phase B: hexane (0.1 % 2M NH3-MeOH), flow rate: 40 mL / min, elution with 10% mobile phase B isocratic, wavelength: UV 212 / 220 nm, to give compound 5 (45.2 mg, retention time: 7.2 min) and compound 6 (40.0 mg, retention time: 8.7 min).

[0091] Compound 5 (ES, m / z): [M+1] = 243.

[0092] 1 H NMR (400 MHz, Methanol- d 4) δ 7.55 (t, J J = 1.2 Hz, 1H), 7.19 (dd, J J = 7.4, 1.2 Hz, 1H), 6.95 (t, J J = 7.5 Hz, 1H), 6.86 – 6.76 (m, 2H), 3.91 (q, J J = 7.2 Hz, 1H), 3.06 (td, J J = 7.1, 4.0 Hz, 1H), 2.95 (ddd, J J = 8.9, 7.1, 4.3Hz, 1H), 1.54 (d, J J = 7.2 Hz, 3H), 1.31 (ddd, J J = 8.8, 7.2, 5.0 Hz, 1H), 0.25(dt, J J = 5.0, 4.2 Hz, 1H). Compound 6 (ES, m / z): [M+1] = 243.

[0093] 1 H NMR (400 MHz, Methanol- d 4) δ 7.55 (s, 1H), 7.20 (dd, J J = 7.4, 1.3Hz, 1H), 6.97 (t, J J = 7.5 Hz, 1H), 6.88 (dd, J J = 7.7, 1.2 Hz, 1H), 6.74 (s,1H), 3.91 (q, J J = 7.1 Hz, 1H), 3.04 (td,[[ID=4​​​​​​​​= 5.0, 4.2 Hz, 1H). Example 4: Preparation of 4-[(S)-1-[(1aR,6bR)-1a,6b-dihydro-1H-benzo[b]cyclopropane[d]thiophene-3-yl]ethyl]-1H-imidazolium and 4-[(R)-1-[(1aR,6bR)-1a,6b-dihydro-1H-benzo[b]cyclopropane[d]thiophene-3-yl]ethyl]-1H-imidazolium 4.1 At room temperature, 4-[1-[(1aR,6bR)-1a,6b-dihydro-1H-benzo[b]cyclopropane[d]thiophene-3-yl]vinyl]-1H-imidazole (156 mg, 0.644 mmol), MeOH (5 mL), and Pd / C (80 mg, 0.075 mmol, 10% w / t) were added to a 25 mL round-bottom flask. The resulting mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The resulting mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN aqueous solution (10 mmol / L NH4HCO3) with a gradient of 0% to 40% over 10 minutes; detector: UV 220 nm. 113 mg of 4-[1-[(1aR,6bR)-1a,6b-dihydro-1H-benzo[b]cyclopropane[d]thiophene-3-yl]ethyl]-1H-imidazolium (4-a) was obtained. (ES, m / z): [M+1] = 243. 4.2 4-a was purified by preparative chiral HPLC under the following conditions: (Column: CHRAL ART Cellulose-SB, 3...) 25 cm, 5 μm; mobile phase A: hexane (0.1 % 2M NH3-MeOH), mobile phase B: EtOH, flow rate: 40 mL / min, 10% mobile phase B isocratic elution, wavelength: UV 212 / 220 nm), yielding compound 7 (48.5 mg, retention time: 8 min) and compound 8 (42.6 mg, retention time: 9.7 min).

[0094] Compound 7 (ES, m / z): [M+1]=243.

[0095] 1 H NMR (400 MHz, Methanol- d 4) δ 7.55 (t, J = 2.5 Hz, 1H), 7.19 (dd,J = 7.5, 1.2 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.86 – 6.75 (m, 2H), 3.91 (q, J = 7.1 Hz, 1H), 3.06 (td, J = 7.1, 4.0 Hz, 1H), 2.95 (ddd, J = 8.8, 7.1, 4.3Hz, 1H), 1.54 (d, J = 7.1 Hz, 3H), 1.31 (ddd, J = 8.8, 7.2, 5.0 Hz, 1H), 0.25(q, J = 4.4 Hz, 1H). Compound 8 (ES, m / z): [M+1]=243.

[0096] 1 H NMR (400 MHz, Methanol- d 4) δ 7.55 (d, J = 1.4 Hz, 1H), 7.20 (dd, J = 7.4, 1.2 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.88 (dd, J = 7.8, 1.3 Hz, 1H), 6.74 (s, 1H), 3.91 (q, J = 7.1 Hz, 1H), 3.04 (td, J = 7.2, 4.1 Hz, 1H), 2.94(ddd, J = 8.8, 7.1, 4.3 Hz, 1H), 1.52 (d, J = 7.2 Hz, 3H), 1.31 (ddd, J =8.8, 7.2, 5.0 Hz, 1H), 0.25 (q, J = 4.4 Hz, 1H). Test Implementation Examples Test Example 1: In vitro affinity experiment 1. Experimental Methods 1.1 Preparation of buffer solution and test sample Standard buffer (for preparing α) 1Aα 2A α 2B α 2C (Receptor membrane): Weigh 146 mg of EDTA and add 50 mM Tris-HCl buffer to a total volume of 1000 mL. Adjust the pH to 7.7 to achieve a final concentration of 0.5 mM EDTA.

[0097] Test sample (compound): Calculate the theoretical sample weight based on the designed concentration and required volume. Generally, 5.0 × 10⁻⁶. -3 M is the initial dosage, dissolved in DMSO, and then sequentially diluted with DMSO to 5.0 × 10⁻⁶. -4 M~5.0×10 -9 M, dilute the diluted DMSO solution with buffer to the working concentration, 5.0 × 10⁻⁶. -5 M~5.0×10 -11 M, the final concentration of DMSO in the working solution is 1% (the final concentration of DMSO in the reaction system is 0.2%). The test sample should be stored at 4℃ after preparation and discarded after the test.

[0098] 1.2 Preparation of receptor membrane CHO-K1-α 1A ,CHO-K1-α 2A ,CHO-K1-α 2B ,CHO-K1-α 2C Cells were removed from the -80 ℃ freezer and thawed naturally. They were then centrifuged at 2000 g at 4 ℃ for 10 min, the supernatant was discarded, and the pellet was collected. Buffer was added to the pellet, and homogenization was performed for 20-30 s. The pellet was then centrifuged at 48000 g at 4 ℃ for 25 min, the supernatant was discarded, and the pellet was centrifuged again at 48000 g at 4 ℃ for 25 min. The supernatant was discarded, and the pellet was stored at -80 ℃.

[0099] 1.3 Receptor competition binding assay 1.3.1 Conditions for Radioactive Binding Tests Table 1. Conditions for Radioactive Binding Tests

[0100] Note: Prazosin; RX821002: 2-Methoxyidazoxan monohydrochloride.

[0101] 1.3.2 Receptor Binding Assay Procedure Step 1: Add 50 μL of solvent (1% DMSO) to the total binding tube (TB), and add 50 μL of non-specific binding solution (final concentration 1.0 × 10⁻⁶) to the non-specific binding tube (NB).-5 M), 50 μL of the test compound was added to each test compound tube (CB).

[0102] Step 2: Add 100 μL of buffer solution to each reaction tube.

[0103] Step 3: Prepare the membrane into a membrane suspension of the appropriate concentration using a buffer solution.

[0104] Step 4: Add 50 μL of the corresponding radioactive ligand to each reaction tube.

[0105] Step 5: Add 50 μL of membrane solution to each reaction tube.

[0106] Step 6: Incubate each reaction tube according to the incubation conditions. After the reaction is complete, the bound ligands are filtered under reduced pressure. The UniFilter GF / C plate is saturated with 0.5% PEI solution 1 h in advance, thoroughly washed with ice-cold Tris-HCl buffer, filtered, and then dried in a constant temperature drying oven for 30 min. The filter plate is then removed and MICROSCINT PS scintillation solution is added, 40 μL / well.

[0107] Step 7: Place the scintillation cup into the liquid scintillation counter for counting.

[0108] 1.4 Data Analysis Based on the effect values ​​at different concentration test points of the compound sample, the GraphPad Prism software was used to fit the curve of the compound sample's interaction with the receptor, and the Ki value was calculated.

[0109] Test Example 2: In Vitro Functional Experiment 2. Experimental Methods 2.1 Purpose Using the Cisbio HTRF cAMP-Gi and IP-One kit, adrenaline receptors (α-adrenergic receptors) were detected by microplate reader. 1A α 2A α 2B α 2C Changes in cAMP and IP1 concentrations in the signaling pathway were analyzed to calculate the EC50 of the compound. 50 The value is used to evaluate the agonistic effect of the compound on the adrenergic receptor.

[0110] 2.2 Experimental Materials: Cell line: 293-α 1A Stable cell line (Shanghai Shujing Biotechnology Co., Ltd.) 293-α 2A Stable cell line (Shanghai Shujing Biotechnology Co., Ltd.) CHO-α 2B / Gα15 stable cell line (Nanjing Genscript Biotech Co., Ltd.) CHO-α 2C / Gα15 stable cell line (Nanjing Genscript Biotech Co., Ltd.) Cell culture conditions: 293-α 1A (DMEM, 10 % FBS, 0.6 μg / mL puromycin) 293-α 2A (DMEM, 10 % FBS, 0.6 μg / mL puromycin) CHO-α 2B / Gα15 (F12, 10 % FBS, 200 μg / mL Zeocin, 100 μg / mL Hygromycin B) CHO-α 2C / Gα15 (F12, 10 % FBS, 400 μg / mL G418, 400 μg / mL Hygromycin B) Reagents and consumables: F12 (meilunbio, MA0229) DMEM (Gibco, 8121703) FBS (BOVOGEN, SFBS) Zeocin (invitrogen, R25001) Hygromycin B (invitrogen, 10687010) Puromycin (Solarbio, 119L042) PBS (meilunbio, MA0015) Pancreatic enzyme (Gibco, 25200-072) 96-cell plate (Cisbio, 66PL96025) cAMP-Gi kit (cisbio, 03E) IP-ONE Kit (cisbio, 16E) CO2 incubator (Thermo, 311) Centrifuge (Shanghai Anting, TGL-16C) Cell counter (Countstar, IC1000) Microplate reader (PerkinElmer, EnVision) 2.3 Experimental Procedure 2.3.1 Agonist Screening Method: cAMP Assay for (Adrenaline α) 2A (receptor) (1) Prepare the reaction buffer (1 x Stimulation buffer) required for the experiment: dilute the 5 x Stimulation buffer in the Cisbio cAMP-Gi kit with ddH2O at a ratio of 1:4 and set aside.

[0111] (2) Compound preparation: Dilute the compound with DMSO to a 5 mM stock solution, then dilute it 3.16 times to 10 gradients, and then dilute the prepared compound with Stimulation buffer to the corresponding concentration (2.5 x) for later use.

[0112] (3) Cell preparation: trypsin digestion of 293-α cells on culture dishes 2A Cells were washed with culture medium and collected into 5 mL centrifuge tubes. Centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. 3 mL of PBS was added, and the mixture was gently pipetted to mix. The cells were centrifuged again at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were resuspended in 1 x Stimulation buffer, counted using a Countstar cell counter, and the cell density was adjusted to 4 x 102. 5 Quantity / mL, for later use.

[0113] (4) Cell addition: Add the cell suspension to the experimental plate, 5 μL / well (i.e., about 2000 cells / well).

[0114] (5) Compound addition: Add the compound diluted with Stimulation buffer to the above experimental plate, 4 μL / well.

[0115] (6) Reaction incubation: After slow shaking, place the experimental plate at 37 °C for 20 minutes.

[0116] (7) Addition of the agonist Forskolin: Add 10 x adenylate cyclase agonist (final concentration 1 μM Forskolin) solution, 1 μL / well.

[0117] (8) Reaction incubation: After slow shaking, place the experimental plate at 37 °C for 45 minutes.

[0118] (9) Add detection reagents: Dilute cAMP-cryptate and Anti-cAMP-d2 1:20 with Lysis & detection buffer from the Cisbio cAMP-Gi detection kit, and add 5 μL of each diluted cAMP-cryptate and Anti-cAMP-d2 to the experimental plate. After shaking, let the experimental plate stand at room temperature for 60 minutes.

[0119] (10) Experimental readings: Read the plate on the Envision and detect the readings of the 665 nm and 615 nm channels. Calculate the ratio of the 665 nm / 615 nm readings.

[0120] 2.3.2 Agonist Screening Method: IP-One Assay (Adrenaline Alpha) 1A α 2B α 2C (receptor) (1) Prepare the reaction buffer (1 x Stimulation buffer) required for the experiment: dilute the 5 x Stimulation buffer in the Cisbio IP-One kit with ddH2O at a ratio of 1:4 and set aside.

[0121] (2) Compound preparation: Dilute the compound to a 5 mM stock solution with DMSO, then dilute it 3.16 times to 10 gradients, and then dilute the prepared compound to the corresponding concentration (2 x) with Stimulation buffer for later use.

[0122] (3) Cell preparation: trypsin digestion of 293-α cells on culture dishes 1A ,CHO-α 2B ,CHO-α 2C Cells were washed with culture medium and collected into 5 mL centrifuge tubes. Centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. 3 mL of PBS was added, and the mixture was gently pipetted to mix. The cells were centrifuged again at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were resuspended in 1 x Stimulation buffer, counted using a Countstar cell counter, and the cell density was adjusted to 1.7 x 10⁻⁶ cells / mL. 6 Quantity / mL, for later use.

[0123] (4) Cell addition: Add the cell suspension to the experimental plate at 7 μL / well (i.e., about 12,000 cells / well).

[0124] (5) Compound addition: Add the compound diluted with Stimulation buffer to the above experimental plate at a rate of 7 μL / well.

[0125] (6) Reaction incubation: After slow shaking, place the experimental plate at 37 °C for 60 minutes.

[0126] (7) Add detection reagents: Dilute IP1-cryptate and Anti-IP1-d2 at a ratio of 1:12 using Lysis & detection buffer from the Cisbio IP-One detection kit, and add 3 μL of the diluted cAMP-cryptate and Anti-cAMP-d2 to each well in the experimental plate. After shaking, let the experimental plate stand at room temperature for 60 minutes.

[0127] (8) Experimental readings: Read the plate on the Envision and detect the readings of the 665 nm and 615 nm channels. Calculate the ratio of the 665 nm / 615 nm readings.

[0128] 2.4 Data Analysis Based on the agonist effect values ​​at different concentration test points of the compound samples, data analysis and statistics were performed using the graphing software GraphPadPrism5 (log(agonist) vs. normalized response -- variable slope, n≥2), and EC was calculated. 50 .

[0129] 2.5 Experimental Results See Table 2 for details: Table 2 Results of in vitro affinity and functional experiments

[0130] “NA” indicates that it is not applicable.

[0131] As shown in the table above, the compounds in the embodiments of this application affect α. 2A It has good agonistic activity.

[0132] Test Example 3: Hypnotic Efficacy Experiment 3.1 Experimental Methods The ED of the rat righting reflex loss (LORR) induced by the compound of this invention was determined using a sequential method. 50(Median Effective Dose): Male SD rats, weighing 200-300 g, were given an initial dose via tail vein injection over 10 seconds after dissolving each compound in physiological saline. If the righting reflex disappeared after the initial dose, the next rat was given a lower dose (0.8 times the initial dose). If the righting reflex did not disappear after the initial dose, the next rat was given a higher dose (1.25 times the initial dose), and so on. The results were entered into AOT425 StatPgm software until the software could determine the ED. 50 The experiment is over. (Ed.) 50 Evaluate the hypnotic efficacy of the compounds of this invention, ED 50 The smaller the value, the stronger the effect.

[0133] Comparison of onset time and duration of action: Male SD rats, weighing 200-300 g, were injected via tail vein in a 10-second constant-rate bolus after each compound was dissolved in physiological saline. Each group consisted of 10 rats, and the injection dose was twice the ED. 50 (ED) 50 (50% of rats lost their righting reflex at the dose), and recorded the onset and duration of action.

[0134] The onset time refers to the time after injection when the rat is placed in a supine position, and the rat's righting reflex disappears when its forepaws cannot roll over to a prone position on their own, and the duration of this position is ≥10 seconds. This is used as an indicator of the compound's effectiveness. The duration of the righting reflex disappearance refers to the length of time the rat remains in this position. The drug effect is considered to have subsided once the righting reflex recovers on its own.

[0135] 3.2 Experimental Results The results are shown in Table 3 below: Table 3. Experimental results of the hypnotic effects of the compounds of this invention.

[0136] Experimental results show that the representative compounds of this invention can induce sleep in rats within 5 minutes, exhibiting a definite and reversible hypnotic effect, and thus possessing clinical value and significance.

[0137] Test Example 4: Spontaneous Activity Experiment 4.1. Experimental Methods Male SD rats, weighing 200-300 g, were randomly divided into groups of 8 rats each. Laboratory lighting was turned off, but warm-toned desk lamps were turned on. Reflection was observed using a camera to identify animal groups. Recording time was set to 35 minutes (recording the animal's movement distance over 30 minutes, from 5 to 35 minutes). The experiment began after background recording, with a maximum of 16 animals recorded simultaneously. Each compound was dissolved in physiological saline and administered to rats via a tail vein injection over 10 seconds. Animals were administered the compound sequentially according to their assigned numbers, then placed in a rat spontaneous activity box and recording began. After each group's recording, the activity distance (Dis) within 30 minutes in different dosage groups was analyzed using ANY-maze (spontaneous activity) software, comparing it to the inhibition rate (%) of the solvent control group's Dis. Inhibition rate % = (Dis... 化合物 -Dis 溶媒 ) / Dis 溶媒 100, the ED of spontaneous rat activity for each compound was calculated using GraphPad software. 50 .

[0138] 4.2 Experimental Results Table 4 Results of spontaneous activity experiments of the compounds of the present invention in rats

[0139] Experimental results show that the representative compound of this invention can significantly reduce the spontaneous activity distance of rats within 30 minutes after intravenous administration.

[0140] Test Example 5: Blood Pressure and Heart Rate Fluctuations After Drug Administration 5.1. Experimental Methods Male SD rats, weighing 250–300 g, were divided into groups of four. General anesthesia was maintained by isoflurane inhalation. Blood pressure and heart rate were monitored via femoral artery cannulation using a Powerlab data acquisition and analysis system. After 30 minutes of stabilization, the baseline mean arterial pressure (MAP0) and baseline heart rate (HR0) were measured. Rats were then injected intravenously via tail vein with saline solutions of the respective compounds (doses were the same as in test case 3, administered via a rapid 10-second bolus). Blood pressure and heart rate were continuously recorded for 90 minutes. The highest mean arterial pressure (MAP) within 90 minutes was calculated. max The difference between MAP0 and MAP0 + Minimum mean arterial pressure (MAP) min The difference between MAP0 and MAP0 - Minimum heart rate (HR) min The difference between HR0 and HR0 - Calculate the maximum rate of increase in mean arterial pressure (MAP). + / MAP0 100%, maximum decrease in mean arterial pressure = MAP - / MAP0 100% , Maximum Heart Rate Decrease = HR - / HR0 100%. See Table 5 below for details.

[0141] 5.2. Experimental Results Experimental results showed that no significant fluctuations in blood pressure and heart rate were observed in rats after intravenous injection of the representative compound of this invention, and the rats were able to recover to their pre-administration levels relatively quickly.

[0142] Table 5. Experimental results of blood pressure and heart rate fluctuations after administration of the compounds of the present invention.

[0143] Note: " / " indicates no relevant effect or not applicable.

[0144] Those skilled in the art will recognize that various modifications and variations can be made to this invention without departing from its spirit and scope. The specific embodiments described herein are provided by way of example only and are not intended to limit the scope in any way. The true scope and spirit of the invention are shown in the appended claims, and the description and embodiments are merely exemplary.

Claims

1. A compound represented by general formula I or II, its stereoisomer, or a pharmaceutically acceptable salt thereof, ， in, Each R1, R2, and R3 is independently selected from H, halogen, hydroxyl, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, and C1-C8 haloalkoxy. R4 and R5 are each independently selected from H, halogen, hydroxyl, nitro, cyano, optionally substituted C1-C8 alkyl and optionally substituted C1-C8 alkoxy groups; the optional substituents are independently selected from halogen, hydroxyl, nitro and cyano groups. Each R6 is independently selected from H, halogen, hydroxyl, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and C1-C8 haloalkoxy; Q is selected from -CH2-, -O-, -NH-, and -S-; v is an integer selected from 1 to 5; n is an integer selected from 1 to 3; m is an integer selected from 1 to 4.

2. The compound represented by general formula I or II according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, Selected from Ia, Ib, II-a, II-b or mixtures thereof: 、 、 、 Wherein, Q, R1, R2, R3, R4, R5, R6, n, v and m are as defined in claim 1, and R4 and R5 are not the same.

3. The compound of general formula I or II according to any one of claims 1-2, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from the following compounds: 、 、 、 、 , , and .

4. A pharmaceutical composition comprising a compound of formula I or II as claimed in any one of claims 1-3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable carrier or a combination thereof.

5. The use of a compound of formula I or II as described in any one of claims 1-3, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 4 in the preparation of a medicament related to an α2-adrenergic receptor agonist.

6. The application according to claim 5, wherein the drug associated with the α2-adrenergic receptor agonist is used to produce one or more effects of sedation, analgesia, anesthesia, anti-anxiety, or inhibition of sympathetic nerve activity in humans or animals, and / or to treat insomnia or mental disorders in humans or animals; more preferably, it is used to produce one or more effects of sedation, analgesia, or anesthesia in humans or animals, and / or to treat insomnia or mental disorders in humans or animals; even more preferably, it is used to produce one or more effects of sedation, analgesia, or anesthesia in humans or animals, and / or to treat insomnia in humans or animals.

7. Compounds with the following structures, their stereoisomers, or their salts: , , or .

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