4-(1H)-Imidazole derivatives and their medical uses

Abstract

The present invention discloses a class of 4-(1H)-imidazole derivatives represented by the following formula (I), their pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers, as well as pharmaceutical compositions containing them, and their use as α2-adrenergic receptor agonists, especially as α 2A -agonists and their methods of use. Compared with the prior art, the compounds of the present invention show more potent agonist activity and higher selectivity for α 2A -AR, superior to the positive drug dexmedetomidine; and at the same time have a potent in vivo sedative effect. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and more particularly, relates to a class of 4-(1H)-imidazole derivatives and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers thereof, as well as pharmaceutical compositions containing them, and their use as α2-adrenergic receptor agonists, especially as α 2A -agonists and methods of use thereof. Background Art

[0002] The α2-adrenergic receptor (α2-AR) is an important class of G protein-coupled receptors that mediate the central and peripheral physiological effects of the endogenous agonists catecholamines, epinephrine, and norepinephrine. Due to the diversity of its mediated biological functions, it is an attractive target for treating various diseases. α2-Adrenergic receptor drugs are clinically used to treat hypertension, glaucoma, attention deficit disorder, acute migraine, alcohol, nicotine, and opioid dependence and withdrawal, treatment of depression, schizophrenia, analgesia, sedation and hypnosis, and anesthesia maintenance, etc., as well as stimulant poisoning, sedative withdrawal, serotonin syndrome, anticholinergic poisoning, and cannabinoid poisoning. When administered as a pretreatment agent, α2-adrenergic receptor agonists can prevent the toxicity caused by organophosphorus, and can provide significant protection against acute and chronic toxicity after the irreversible inactivation of cholinesterase by soman.

[0003] The α2-adrenergic receptor is divided into α 2A α 2B and α 2C subtypes in mammals. In the central nervous system, the α 2A and α 2C subtypes are dominant, while the α 2B subtype rarely appears, only in the diencephalon. In the brain, 90% of the α2-adrenergic receptors are α 2A -adrenergic receptors and are highly expressed throughout, including the prefrontal cortex and locus coeruleus of the brain. Therefore, many physiological and pharmacological functions of clinical α2-adrenergic receptor agonists are achieved by activating the α 2A -adrenergic receptor. α 2A -AR agonists are known to mediate a variety of biological effects, including sedation, analgesia, anesthesia, anti-nociception, blood pressure lowering, etc.

[0004] Mario Giannella et al. (Gentili, F., Pigini, M., Piergentili, A., Giannella, M., 2007. Agonists and antagonists targeting the different alpha2 - adrenoceptor subtypes. Current topics in medicinal chemistry 7, 163 - 186.) reviewed the structures and pharmacological effects of agonists and antagonists for different alpha2 - AR receptor subtypes.

[0005] Duane D. Miller et al. (Zhang X, Yao XT, Dalton JT, Shams G, Lei L, Patil PN, et al. Medetomidine analogs as alpha 2 - adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine. Journal of medicinal chemistry 1996;39(15):3001 - 3013. doi:10.1021 / jm9506074.) prepared methylnaphthyl derivatives based on the structure of dexmedetomidine, which had similar potency and selectivity for alpha2 - AR and alpha1 - AR as medetomidine, but still had less in - vivo effect than dexmedetomidine.

[0006] A series of conformationally restricted analogs designed by Fu-Lian Hsu et al. (Zhang X, De Los Angeles JE, He MY, Dalton JT, Shams G, Lei L, et al. Medetomidine analogs as alpha 2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potential binding interactions with alpha2-adrenoceptors involving a "methyl pocket". Journal of medicinal chemistry 1997;40(19):3014-3024. doi:10.1021 / jm960642q.), such as 5-methyltetralin analogs and 4-methylindene analogs, showed a significant decrease in alpha2-AR selectivity.

[0007] Patent WO1997012874A1 discloses a series of imidazole compounds with alpha2-AR activity. Patent WO2007 / 085558A1 discloses a series of imidazole compounds with TAAR1 receptor activity for treating various central nervous system disorders such as schizophrenia and does not have alpha 2A -AR-mediated effects such as sedation, hypnosis, and anesthesia. WO2013150173A1 discloses a series of dihydroimidazole compounds with alpha2-AR agonist activity for use as sedatives or analgesics.

[0008] Ryan S. Renslow et al. (Schultz KJ, Colby SM, Lin VS, Wright AT, Renslow RS. Ligand-and Structure-Based Analysis of Deep Learning-Generated Potential alpha2a Adrenoceptor Agonists. Journal of chemical information and modeling 2021;61(1):481-492. doi:10.1021 / acs.jcim.0c01019.) applied de novo deep learning-based techniques to provide new ligands for alpha 2A -adrenergic receptor protein-ligand interactions and potential active compounds, but no activity data of the compounds were reported.

[0009] Dexmedetomidine (DEX) is a representative drug of α2 - adrenergic receptor agonists and is the S - isomer of medetomidine. It can produce synergistic sedation and anxiolytic effects. Compared with other sedative drugs, it can mediate natural sleep more effectively and is now used in the treatment of insomnia and sleep deprivation in intensive care. Compared with midazolam and propofol, it does not have an overly strong amnestic effect; compared with propofol and etomidate, it does not produce neuro - excitatory effects. At the same time, dexmedetomidine also has certain analgesic effects, relatively mild respiratory depression, and can reduce the dosage of opioid drugs, etc.

[0010] Dexmedetomidine

[0011] However, the main limitation in the use of existing α2 - adrenergic receptor agonists is the lack of subtype selectivity. Due to the common mechanism of signal transduction and the very high sequence homology (more than 80%) exhibited by α2 - ARs, information on subtype - selective compounds is still limited. The development of α 2A - adrenergic receptor subtype - selective drugs can lead to more selective potential therapeutic effects and fewer side effects. Summary of the Invention

[0012] In various embodiments, the present invention provides a class of 4 - (1H) - imidazole derivatives or pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, and tautomers thereof, as well as pharmaceutical compositions containing them, and their use as α2 - adrenergic receptor agonists, especially as α 2A - agonists and their methods of use. These compounds can be used for the prevention and / or treatment of diseases or disorders such as chronic insomnia, obstructive sleep apnea - hypopnea syndrome, mania, attention - deficit disorder, nicotine or alcohol or opioid withdrawal, premature ejaculation, glaucoma, hypertension, tachycardia, delirium, alcohol, nicotine, benzodiazepine, and opioid dependence and withdrawal, restless legs syndrome, muscle spasticity, hot flashes, depression, anxiety, post - traumatic stress disorder, pain, chronic pelvic pain syndrome, stimulant poisoning, sedative withdrawal, serotonin syndrome, anticholinergic poisoning, cannabinoid poisoning, organophosphate poisoning, breakthrough cancer pain, or diseases or conditions requiring sedative anesthesia or analgesia.

[0013] The compounds according to the present invention are selective α 2A - adrenergic receptor agonists that can cross the blood - brain barrier. They have higher α 2A - adrenergic receptor subtype selectivity and agonist activity relative to other α - adrenergic receptors, and have higher in - vivo sedative - hypnotic effects, more potent in - vivo action duration, and fewer side effects at the same time.

[0014] According to one aspect of the present invention, an object of the present invention is to provide a 4-(1H)-imidazole derivative represented by the following formula (I) or a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer, and tautomer thereof:

[0015]

[0016] wherein

[0017] represents a single bond or a double bond;

[0018] X1 is a linking bond, -CR6R7-, -NR8-, -S-, or -O-;

[0019] X2 is -CR9R 10 -, -NR 11 -, -S-, or -O-;

[0020] R1, R2, and R3 are each independently H, halogen, hydroxyl, amino, cyano, C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, C 1-15 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, C 6-14 aryl, a four- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;

[0021] R4 is H, halogen, hydroxyl, amino, cyano, C 1-15 alkyl, C 1-15 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, C 6-14 aryl;

[0022] R5 is H, halogen, hydroxyl, amino, cyano, C 1-15 alkyl, C 1-15 alkoxy;

[0023] R6, R7, R9, and R 10 are each independently H, halogen, hydroxyl, amino, cyano, C 1-15 alkyl, C 1-15 alkoxy;

[0024] R8 and R 11 are each independently H, C 1-15 alkyl;

[0025] X1 and X2 are not simultaneously -S- or -O-.

[0026] Preferably, X1 is a linking bond, -CR6R7-, -S-, or -O-, and X2 is -CR9R 10 -, -S-, or -O-.

[0027] More preferably, X1 is a linking bond, -CR6R7-, or -O-, and X2 is -CR9R 10 -, -S-, or -O-.

[0028] Preferably, R1, R2, and R3 are each independently H, halogen, hydroxyl, amino, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, C 6-10 aryl.

[0029] More preferably, R1, R2, and R3 are each independently H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy.

[0030] More preferably, R1, R2, and R3 are each independently H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl.

[0031] More preferably, R1, R2, and R3 are each independently H, halogen, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0032] Preferably, R4 is H, halogen, hydroxyl, amino, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 6-10 aryl.

[0033] More preferably, R4 is H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy.

[0034] More preferably, R4 is H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy.

[0035] More preferably, R4 is H, halogen, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.

[0036] Preferably, R5 is H, halogen, hydroxyl, amino, cyano, C 1-10 alkyl, C 1-10 alkoxy.

[0037] More preferably, R5 is H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy.

[0038] More preferably, R5 is H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy.

[0039] More preferably, R5 is H, halogen, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl.

[0040] More preferably, R5 is H.

[0041] Preferably, R6, R7, R9 and R 10 are each independently H, halogen, hydroxyl, amino, cyano, C 1-10 alkyl, C 1-10 alkoxy.

[0042] More preferably, R6, R7, R9 and R 10 are each independently H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy.

[0043] More preferably, R6, R7, R9 and R 10 are each independently H, halogen, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.

[0044] Preferably, R8 and R 11 are each independently H, C 1-10 alkyl.

[0045] More preferably, R8 and R 11 are each independently H, C 1-6 alkyl.

[0046] More preferably, R8 and R11 Each independently is H, methyl, ethyl, or propyl.

[0047] Preferably, R8 and R 11 Each independently is H.

[0048] Preferably, the 4-(1H)-imidazole derivative represented by the following formula (I) according to the present invention, or a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer, and tautomer thereof is selected from the following compounds:

[0049]

[0050]

[0051]

[0052] According to another aspect of the present invention, another object of the present invention is to provide a method for preparing a 4-(1H)-imidazole derivative represented by formula (I) or a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer, and tautomer thereof, and the method is carried out according to one of the following exemplary methods:

[0053] Method 1

[0054]

[0055]

[0056] Step c: Dissolve the 4-iodoimidazole derivative in dichloromethane or N,N-dimethylformamide, add triphenylmethyl chloride, then add triethylamine, and carry out the reaction at room temperature. After the reaction is completed, precipitate the solid by adding water, and obtain the crude product by suction filtration and drying, or obtain the crude product by extraction, drying, and evaporation. The crude product is obtained by column chromatography purification to obtain the target compound.

[0057] Step d: Dissolve the 4-iodo-1-(triphenylmethyl)-1H-imidazole derivative in dichloromethane, under ice bath conditions and argon protection, add ethylmagnesium bromide, and obtain the imidazole derivative Grignard reagent after reacting for 15 to 30 minutes.

[0058] Step e: React the imidazole derivative Grignard reagent obtained in step d with a commercially purchased or prepared raw material ketone in dichloromethane solvent under argon protection conditions to carry out the Grignard reaction to obtain a hydroxy compound.

[0059] Step f: The hydroxy compound obtained in step e undergoes hydroxy elimination under acidic conditions, such as acetic acid, and simultaneously removes the triphenylmethyl protecting group to obtain an olefin compound.

[0060] Step i: Introduce hydrogen gas into the olefin compound obtained in step f in an autoclave, and use palladium-carbon as a catalyst to carry out reduction under the conditions of 5 atmospheres and 50 °C to obtain the target alkane product.

[0061] Alternatively,

[0062] Step g: In an ice bath, trimethylsilyl iodide is in-situ generated from trimethylchlorosilane and sodium iodide under argon protection, and then the hydroxy compound obtained in step e is added to remove the hydroxyl group to obtain a crude alkane compound.

[0063] Step h: The alkane compound obtained in step g is deprotected with a trityl group under acidic conditions, such as acetic acid, to obtain the target alkane product.

[0064] Among them, the definitions of each substituent are the same as those in formula (I).

[0065] Method 2

[0066]

[0067]

[0068] Step a: A substituted phenol or substituted benzenethiol is dissolved in a sodium hydroxide solution, and an aqueous solution of 3-bromopropionate is added. Under the condition of heating and refluxing at 100 °C to 105 °C, a substituted 3-phenoxypropionic acid or 3-phenylthiopropionic acid is obtained.

[0069] Step b: The substituted 3-phenoxypropionic acid or 3-phenylthiopropionic acid undergoes a cyclization reaction through a Friedel-Crafts acylation reaction to obtain a chromanone or thiochromanone product (IV). The reaction conditions can be preparing an acyl chloride by adding the raw material acid to oxalyl chloride and carrying out Friedel-Crafts acylation with a Lewis acid such as aluminum chloride or tin chloride, or directly adding a dehydrating agent such as concentrated sulfuric acid or phosphorus pentoxide to the raw material acid for Friedel-Crafts acylation.

[0070] Step c: The 4-iodoimidazole derivative is dissolved in dichloromethane or N,N-dimethylformamide, trityl chloride is added, and then triethylamine is added. The reaction is carried out at room temperature. After the reaction is completed, a solid is precipitated by adding water, and the crude product is obtained by suction filtration and drying, or the crude product is obtained by extraction, drying, and evaporation. The crude product is obtained by column chromatography purification to obtain the target compound.

[0071] Step d: The 4-iodo-1-(trityl)-1H-imidazole derivative is dissolved in dichloromethane. Under ice bath conditions and argon protection, ethylmagnesium bromide is added, and an imidazole derivative Grignard reagent is obtained after reacting for 15 to 30 minutes.

[0072] Step e: The imidazole derivative Grignard reagent and the chromanone or thiochromanone product (IV) obtained in step b are subjected to a Grignard reaction in a dichloromethane solvent under argon protection conditions to obtain a hydroxy compound.

[0073] Step f: The hydroxy compound obtained in step e undergoes hydroxy elimination under acidic conditions, such as acetic acid, while removing the trityl protecting group to obtain an olefinic compound.

[0074] Step i: Hydrogen gas is introduced into the autoclave with the olefinic compound obtained in step f, and reduction is carried out under the conditions of 5 atmospheres and 50 °C using palladium on carbon as a catalyst to obtain the target alkane product.

[0075] Or,

[0076] Step g: Trimethylsilyl iodide is in-situ generated from trimethylchlorosilane and sodium iodide under argon protection in an ice bath, and then the hydroxy compound obtained in step e is added to obtain a crude alkane compound by removing the hydroxy group.

[0077] Step h: The alkane compound obtained in step g is de-tritylated under acidic conditions, such as acetic acid, to obtain the target alkane product.

[0078] Among them, the definitions of each substituent are the same as those in formula (Ⅰ).

[0079] According to another aspect of the present invention, the present invention provides the use of the 4-(1H)-imidazole derivative represented by formula (Ⅰ) or its pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer and tautomer as an α 2A -adrenergic receptor agonist.

[0080] According to another aspect of the present invention, the present invention provides the 4-(1H)-imidazole derivative represented by formula (Ⅰ) and the following specific compounds, or their pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers in the preparation of a drug for treating and / or preventing diseases or disorders related to α 2A -adrenergic receptor agonists

[0081]

[0082] According to the 4-(1H)-imidazole derivative represented by formula (Ⅰ) or its pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer and tautomer in the preparation of treating and / or preventing α 2AUse in a medicament for an α-adrenergic receptor agonist-related disease or disorder, wherein the disease or disorder is chronic insomnia, obstructive sleep hypopnea syndrome, mania, attention deficit disorder, nicotine or alcohol or opioid withdrawal, premature ejaculation, glaucoma, hypertension, tachycardia, delirium, alcohol, nicotine, benzodiazepine and opioid dependence and withdrawal, restless legs syndrome, muscle spasm state, hot flush, depression, anxiety, post-traumatic stress disorder, pain, chronic pelvic pain syndrome, stimulant intoxication, sedative withdrawal, serotonin syndrome, anticholinergic poisoning, cannabinoid poisoning, organophosphorus poisoning, breakthrough cancer pain or a disease or disorder requiring sedation anesthesia or analgesia.

[0083] According to another aspect of the present invention, the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of a 4-(1H)-imidazole derivative represented by formula (I) according to the present invention and the following specific compounds, or a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer and tautomer thereof as an active ingredient, and a pharmaceutically acceptable excipient,

[0084]

[0085] According to another aspect of the present invention, the present invention provides a method for treating an α 2A -adrenergic receptor agonist-related disease or disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a 4-(1H)-imidazole derivative represented by general formula (I) according to the present invention and the following specific compounds, or a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer and tautomer thereof, or the pharmaceutical composition according to the present invention,

[0086]

[0087] In the treatment method according to the present invention, the α 2A -adrenergic receptor agonist-related disease or disorder is chronic insomnia, obstructive sleep hypopnea syndrome, mania, attention deficit disorder, nicotine or alcohol or opioid withdrawal, premature ejaculation, glaucoma, hypertension, tachycardia, delirium, alcohol, nicotine, benzodiazepine and opioid dependence and withdrawal, restless legs syndrome, muscle spasm state, hot flush, depression, anxiety, post-traumatic stress disorder, pain, chronic pelvic pain syndrome, stimulant intoxication, sedative withdrawal, serotonin syndrome, anticholinergic poisoning, cannabinoid poisoning, organophosphorus poisoning, breakthrough cancer pain or a disease or disorder requiring sedation anesthesia or analgesia.

[0088] Beneficial effects

[0089] Compared with the prior art, the compounds of the present invention show more potent agonistic activity and higher selectivity for α 2A -AR than dexmedetomidine, a positive drug; and also have potent in vivo sedative effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0091] Figure 1 It is a bar graph of the in vivo sedative effect in mice according to Example 3 of the activity test. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0092] Hereinafter, the present invention will be described in detail. Before the description, it should be understood that the terms used in this specification and the appended claims should not be construed as limited to the general meaning and dictionary meaning, but should be interpreted based on the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that allows the inventor to appropriately define the terms for the best interpretation. Therefore, the description presented here is only a preferred example for illustrative purposes and is not intended to limit the scope of the present invention. Thus, it should be understood that other equivalent methods or improved methods can be obtained without departing from the spirit and scope of the present invention.

[0093] The following examples are merely listed as examples of the embodiments of the present invention and do not constitute any limitation to the present invention. Those skilled in the art can understand that modifications within the scope of the essence and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products.

[0094] In this text, terms such as "comprising", "including", "having", "containing", or any other similar terms are open-ended transitional phrases that are intended to cover non-exclusive inclusions. For example, a composition or article containing plural elements is not limited to only those elements listed herein, but may also include other elements not expressly listed but that are ordinarily inherent to the composition or article. In addition, unless expressly stated to the contrary, the term "or" means an inclusive "or" rather than an exclusive "or". For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), A and B are both true (or exist). Further, in this text, the interpretations of the terms "comprising", "including", "having", "containing" should be regarded as having specifically disclosed and simultaneously covered closed or semi-closed transitional phrases such as "consisting of" and "consisting essentially of".

[0095] In this text, all features or conditions defined in the form of numerical ranges or percentage ranges are only for brevity and convenience. Accordingly, the description of a numerical range or percentage range should be regarded as having covered and specifically disclosed all possible sub-ranges and individual values within the range, particularly integer values. For example, the description of the range "1 to 8" should be regarded as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be regarded as having specifically disclosed individual values within the range such as 1, 2, 3, 4, 5, 6, 7, 8. Unless otherwise specified, the foregoing method of interpretation applies to all content throughout this invention, regardless of the breadth of the range.

[0096] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that all ranges formed by any pair of the upper or preferred values of the range and the lower or preferred values of the range have been specifically disclosed herein, whether or not these ranges are separately disclosed. In addition, when a numerical range is mentioned in this text, unless otherwise stated, the range should include its endpoints and all integers and fractions within the range.

[0097] In this text, on the premise that the object of the invention can be achieved, a numerical value should be understood to have the precision of the significant digits of that numerical value. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0098] In this text, for cases where Markush groups or alternative terms are used to describe the features or examples of the present invention, those skilled in the art should understand that all sub-groups or any individual elements within the Markush group or list of alternatives can also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3", it also means that the claims that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, for cases where Markush groups or alternative terms are used to describe the features or examples of the present invention, those skilled in the art should understand that any combination of all sub-groups or individual elements within the Markush group or list of alternatives can also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3", and Y is described as "selected from the group consisting of Y1, Y2, and Y3", it means that the claims that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 have been fully described.

[0099] The following specific compounds have been disclosed in WO2007 / 085558A1, but all compounds in this document only target trace amine-associated receptors (TAAR), and there is no report on their activity against α2-adrenergic receptors and they cannot be used as α2-adrenergic receptor agonists.

[0100]

[0101]

[0102] Definitions

[0103] As used herein, the expression "compounds of the present invention" refers to 4-(1H)-imidazole derivatives of formula (I) or their pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, and tautomers.

[0104] The term "alkyl" refers to a group of straight-chain or branched-chain saturated hydrocarbon groups having 1 to 15 carbon atoms ("C 1-15 alkyl"). In some embodiments, alkyl has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, alkyl has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, alkyl has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, alkyl has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, alkyl has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, alkyl has 1 to 2 carbon atoms ("C 1-2"alkyl"). In some embodiments, the alkyl has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl has 2 to 6 carbon atoms ("C 2-6 alkyl"). C 1-6 Examples of alkyl include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl include n-heptyl (C7), etc.

[0105] "alkoxy" means a monovalent -O-alkyl, where the alkyl moiety has a specified number of carbon atoms. In the present disclosure, alkoxy generally contains 1 - 15 carbon atoms ("C1-15 alkoxy"), and examples include methoxy, ethoxy, isopropoxy, tert-butoxy, etc.

[0106] "alkenyl" refers to a group of a straight-chain or branched-chain hydrocarbon group having 2 to 15 carbon atoms, one or more carbon-carbon double bonds and no triple bonds ("C 2-15 alkenyl"). In some embodiments, the alkenyl has 2 to 7 carbon atoms ("C 2-7 alkenyl"). In some embodiments, the alkenyl has 2 to 6 carbon atoms ("C 2-6 alkenyl"). In some embodiments, the alkenyl has 2 to 5 carbon atoms ("C 2-5 alkenyl"). In some embodiments, the alkenyl has 2 to 4 carbon atoms ("C 2-4 alkenyl"). In some embodiments, the alkenyl has 2 to 3 carbon atoms ("C 2-3 alkenyl"). In some embodiments, the alkenyl has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2-4 Examples of alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. C 2-6 Examples of alkenyl include the aforementioned C 2-4 alkenyl and pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Further examples of alkenyl include heptenyl (C7), etc. In certain embodiments, in the alkenyl, the C═C double bond for which the stereochemistry is not specified can be an (E)- or (Z)-double bond.

[0107] "alkynyl" refers to a group of a straight-chain or branched-chain hydrocarbon group having 2 to 15 carbon atoms, one or more carbon-carbon triple bonds and optionally one or more double bonds ("C 2-15"alkynyl"). In some embodiments, the alkynyl has 2 to 7 carbon atoms ("C 2-7 alkynyl"). In some embodiments, the alkynyl has 2 to 6 carbon atoms ("C 2-6 alkynyl"). In some embodiments, the alkynyl has 2 to 5 carbon atoms ("C 2-5 alkynyl"). In some embodiments, the alkynyl has 2 to 4 carbon atoms ("C 2-4 alkynyl"). In some embodiments, the alkynyl has 2 to 3 carbon atoms ("C 2-3 alkynyl"). In some embodiments, the alkynyl has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C 2-4 Examples of alkynyl include but are not limited to ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. C 2-6 Examples of alkenyl include the above C 2-4 alkynyl as well as pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl, etc.

[0108] "Cycloalkyl" refers to a group of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl") and zero heteroatoms. Exemplary C 3-6 cycloalkyl include but are not limited to cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. As shown in the foregoing examples, in certain embodiments, the cycloalkyl is monocyclic ("monocyclic cycloalkyl") or contains a fused, bridged or spiro ring system, such as a bicyclic system ("bicyclic cycloalkyl") and can be saturated or can be partially unsaturated. "Cycloalkyl" also includes a ring system in which the cycloalkyl as defined above is fused to one or more aryl or heteroaryl groups at a carbon ring, and in this case, the carbon number continues to refer to the carbon number in the carbon ring system. Unless otherwise stated, each instance of the cycloalkyl group is independently optionally substituted, i.e., unsubstituted or substituted by one or more substituents.

[0109] "Heterocyclyl" refers to a group of a four- to eight-membered non-aromatic ring system having ring carbon atoms and one to three ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("four- to eight-membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as long as the valence allows. Heterocyclyl may be monocyclic ("monocyclic heterocyclyl group") or a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. The bicyclic heterocyclyl system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which the heterocycle as defined above is fused to one or more carbocyclic groups with the point of attachment on the carbocyclic group or the heterocycle, or a ring system in which the heterocycle as defined above is fused to one or more aryl or heteroaryl groups with the point of attachment on the heterocycle, and in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclic system.

[0110] "Aryl" refers to a group of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) ("C 6-14 aryl"). In some embodiments, aryl has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, aryl has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, aryl has 14 ring carbon atoms ("C 14 aryl"; e.g., anthryl). "Aryl" also includes a ring system in which the aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups with the group or the point of attachment on the aromatic ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system.

[0111] "Heteroaryl" refers to a group having a five- to eight-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic array) with ring carbon atoms and 1 to 4 ring heteroatoms provided in an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("five- to eight-membered heteroaryl"). In a heteroaryl containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, provided the valence allows. The bicyclic heteroaryl system can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups with the point of attachment on the heteroaryl ring, and in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups with the point of attachment on the aryl or heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system.

[0112] "Halogenated" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0113] The invention includes all possible geometric isomers of the compounds within its scope, such as Z and E isomers (cis and trans isomers), and all possible optical isomers of the compounds of the invention, such as diastereoisomers and enantiomers. Additionally, the invention includes individual isomers within its scope and any mixtures thereof, such as racemic mixtures. The individual isomers can be obtained using the corresponding isomeric forms of the starting materials, or they can be separated after the final compound preparation according to conventional separation methods. For the separation of optical isomers, such as enantiomers, from their mixtures, conventional resolution methods, such as fractional crystallization or preparative chiral chromatography, can be applied.

[0114] The compounds of the invention or their pharmaceutically acceptable salts can exist in the form of their hydrates, solvates, or prodrugs. Accordingly, hydrates, solvates, or prodrugs of the compounds of the invention or their pharmaceutically acceptable salts are also included within the scope of the invention.

[0115] As used herein, the term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0116] The term "pharmaceutically acceptable excipient" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and is non-toxic and has no side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, paste bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickening agents, transdermal promoters, etc. Their formulations are well-known to those skilled in the art of the cosmetics field or the topical drug field. For other information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the content of which is incorporated herein by reference.

[0117] The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered in the present invention with relatively non-toxic acids or bases. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt (i.e., a pharmaceutically acceptable salt) can be obtained by contacting the neutral form of such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Examples include inorganic acid salts and organic acid salts. The inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; the organic acids include, for example, benzoic acid, 2-hydroxyethanesulfonic acid, aminosulfonic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, fumaric acid, pantothenic acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheptonic acid, gluconic acid, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, pamoic acid, salicylic acid, suberic acid, phosphorous acid, etc.; acetic acid, edetic acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid and similar acids; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups and can thus be converted into either base or acid addition salts. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0118] Typical formulations are prepared by mixing a compound represented by formula (I) of the present invention with excipients, diluents or carriers. Suitable carriers, diluents or excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc.

[0119] The specific excipients, diluents or carriers used will depend on the mode of use and purpose of the compounds of the present invention. Generally, the solvent is selected based on a solvent that those skilled in the art consider to be safe and effective for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, light-blocking agents, glidants, processing aids, coloring agents, sweetening agents, flavoring agents, flavor enhancers or other known additives to make the drug in an acceptable form for manufacture or use.

[0120] When the compound of formula (I) described in the present invention is used in combination with at least one other drug, the two drugs or multiple drugs can be used separately or in combination, and are preferably administered in the form of a pharmaceutical composition. The compound of formula (I) or the pharmaceutical composition of the present invention can be administered to a subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal absorption, other local or systemic administration forms.

[0121] These pharmaceutical compositions may also contain one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, light-blocking agents, glidants, processing aids, coloring agents, sweetening agents, flavoring agents, flavor enhancers or other known additives to make the pharmaceutical composition in an acceptable form for manufacture or use.

[0122] The term "treatment" refers to reversing, alleviating, delaying the onset of or inhibiting the development of the diseases described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment can be administered in the absence of signs or symptoms of the disease. For example, treatment can be administered to a susceptible subject before the onset of symptoms (e.g., based on the history of symptoms and / or based on exposure to a pathogen) to delay or prevent the occurrence of the disease. For example, to delay or prevent recurrence, treatment can also be continued after the symptoms have subsided.

[0123] Appropriate starting materials can be used through a variety of synthetic routes similar to or in accordance with methods known in the literature, for example, by reacting chroman-4-one or thiochroman-4-one with 4-iodoimidazole or according to other known methods.

[0124] Examples

[0125] The reaction schemes below illustrate exemplary synthetic methods for preparing the compounds provided herein. Those skilled in the art will understand that suitable adjustments to the various reagents, protecting groups, reaction conditions, and reaction sequences can be used to prepare the compounds provided by the present invention.

[0126] Those skilled in the art will recognize that any starting materials or intermediates in the reactions described above, if desired, can be protected in a manner known in the art. Subsequently, any protected functional groups can be deprotected in a manner known in the art.

[0127] The synthetic routes described above are for illustrative purposes of the preparation of the compounds of formula (I), and the preparation is by no means limited thereto. That is, based on the general knowledge of those skilled in the art, there are other possible synthetic methods.

[0128] The present invention will be explained in more detail by the following examples. The examples are for illustrative purposes only and do not limit the scope of the invention defined in the claims.

[0129] The following general abbreviations were used: EA = ethyl acetate, DCM = dichloromethane, HCl = hydrochloric acid, MeOH = methanol, DMF = N,N-dimethylformamide, Et3N = triethylamine, THF = tetrahydrofuran, h = hour, RT = room temperature, etc. The structures of the products were confirmed by 1 1H-NMR and high-resolution mass spectrometry. 1 1H-NMR was measured using a Bruker 600 MHz spectrometer and the chemical shifts are quoted as the shift of the selected compound relative to tetramethylsilane as an internal standard in parts per million (ppm) downfield.

[0130] Preparation method of intermediate:

[0131] Preparation of 4(5)-iodo-1-(triphenylmethyl)-1H-imidazole:

[0132]

[0133] Add 4(5)-iodoimidazole (9699 mg, 50 mmol) to a 1 L round-bottom flask, dissolve it in 300 mL of DMF, slowly add triphenylmethyl chloride (16727 mg, 60 mmol) during stirring, add triethylamine (13.8 mL, 100 mmol), and a solid gradually precipitates during the reaction at room temperature. TLC detection shows no remaining starting material 4(5)-iodoimidazole. Add 500 mL of deionized water to the reaction, a large amount of white solid precipitates, filter by suction to obtain the filter residue, wash it 2 - 3 times with water, and evaporate to dryness to obtain the crude product. The crude product is purified by column chromatography, and the eluent ratio is gradient elution from PE:DCM = 1:1 to 1:5. Collect the required fractions, evaporate to dryness under reduced pressure to obtain 17.5 g of white solid, with a yield of 80.2%.

[0134] Preparation of 4(5)-Iodo-5(4)-methyl-1-(triphenylmethyl)-1H-imidazole:

[0135]

[0136] Add 4(5)-iodo-5(4)-methylimidazole (2080 mg, 10 mmol) to a 250 mL round-bottom flask, dissolve it in 90 mL of DCM, slowly add triphenylmethyl chloride (3345 mg, 12 mmol) during stirring, add triethylamine (2.77 mL, 20 mmol), and a solid gradually precipitates during the reaction at room temperature. TLC detection shows no remaining raw material 4(5)-iodo-5(4)-methylimidazole. Add 150 mL of deionized water to the reaction solution, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter to remove the desiccant, and evaporate the filtrate to dryness to obtain the crude product. The crude product is purified by column chromatography, and the eluent ratio is gradient elution from DCM:MeOH = 500:1 to 250:1. Collect the required fractions, evaporate to dryness under reduced pressure to obtain 3.8 g of white solid, with a yield of 84.7%.

[0137] Preparation method of intermediate substituted chroman-4-one:

[0138]

[0139] General synthetic method: Substituted phenol (1 mmol) was added to an aqueous solution of sodium hydroxide (1.05 mmol); an aqueous solution of sodium carbonate (0.5 mmol) was added to an aqueous solution of 3-bromopropionic acid (1 mmol) until no bubbles were generated, and then it was added to the solution of substituted phenol sodium salt. The mixture was heated to reflux. TLC detection showed that the raw materials were basically reacted completely. The pH was adjusted to 1 with concentrated hydrochloric acid, and suction filtration was carried out. The filter residue was dried to obtain the intermediate substituted 3-phenoxypropionic acid. The intermediate substituted 3-phenoxypropionic acid was dissolved in an appropriate amount of dichloromethane. Under argon protection, oxalyl chloride (2 mmol) was added, and the reaction was catalyzed by 1 drop of DMF. After the reaction was complete, it was evaporated to dryness under reduced pressure to obtain the acyl chloride intermediate. The acyl chloride was dissolved in an appropriate amount of dichloromethane. Under argon protection in an ice bath at 0 °C, aluminum chloride (3 mmol) was added in batches. After TLC detection showed that the reaction was complete, the reaction solution was slowly poured into dilute hydrochloric acid aqueous solution to quench. It was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined. The organic phase was adjusted to pH = 12 with sodium hydroxide solution and extracted with dichloromethane (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered to remove the desiccant, concentrated under reduced pressure, purified by column chromatography, eluted with PE:EA = 20:1, collected the required fractions, and concentrated under reduced pressure to obtain different substituted chroman-4-one products.

[0140] Example of synthesizing substituted chroman-4-one:

[0141] Synthesis of 8-bromochroman-4-one: Using 2-bromophenol as the raw material, it was synthesized according to the general synthetic method to obtain a colorless oil, with an overall yield of 45.1%.

[0142] Synthesis of 8-iodochroman-4-one: Using 2-iodophenol as the raw material, it was synthesized according to the general synthetic method to obtain a pale yellow solid, with an overall yield of 28.3%.

[0143] Synthesis of 6,8-dichlorochroman-4-one: Using 2,4-dichlorophenol as the raw material, it was synthesized according to the general synthetic method to obtain a colorless oil, with an overall yield of 11.2%.

[0144] Synthesis of 8-chloro-6-bromochroman-4-one: Using 2-chloro-4-bromophenol as the raw material, it was synthesized according to the general synthetic method to obtain a colorless oil, with an overall yield of 42.0%.

[0145] Synthesis of 6,8-dimethylchroman-4-one: Using 2,4-dimethylphenol as the raw material, it was synthesized according to the general synthetic method to obtain a pale yellow oil, with an overall yield of 14.0%.

[0146] Synthesis of 8-bromo-6-fluorochroman-4-one: Using 2-bromo-4-fluorophenol as the raw material, it was synthesized according to the general synthetic method to obtain an off-white solid, with an overall yield of 41.8%.

[0147] Synthesis of 8-bromo-7-methylchroman-4-one: Using 2-bromo-3-methylphenol as the raw material, it was synthesized according to the general synthetic method to obtain a yellow solid, with an overall yield of 38.1%.

[0148] Preparation method of intermediate substituted thiochroman-4-one:

[0149]

[0150] General synthetic method: Substituted benzenethiol (1 mmol) was added to an aqueous solution of sodium hydroxide (1.05 equivalents); an aqueous solution of potassium carbonate (0.5 mmol) was added to an aqueous solution of 3-bromopropionic acid (1 mmol). After no bubbles were generated, it was added to a solution of the substituted sodium phenylthiolate. The mixture was heated under reflux, and TLC was used to detect that the raw materials had basically reacted completely. The pH was adjusted to 1 with concentrated hydrochloric acid, and it was extracted with dichloromethane (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain the intermediate substituted 3-phenylthiopropionic acid. The intermediate substituted 3-phenylthiopropionic acid was added to 1 mL of concentrated sulfuric acid in batches. After the reaction until the raw materials had basically reacted completely, the reaction solution was carefully added dropwise to an ice sodium hydroxide solution with continuous stirring, and the pH was adjusted to 14. It was extracted with dichloromethane (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure and purified by column chromatography. It was eluted with PE:EA = 20:1, the required fractions were collected, and the filtrate was concentrated under reduced pressure to obtain different substituted thiochroman-4-one products.

[0151] Examples of the synthesis of substituted chroman-4-ones:

[0152] Synthesis of 8-chlorothiochroman-4-one: Using 2-chlorophenylthiol as the raw material, it was synthesized according to the general synthetic method to obtain a yellow solid with a total yield of 59.5%.

[0153] Synthesis of 8-bromothiochroman-4-one: Using 2-bromophenylthiol as the raw material, it was synthesized according to the general synthetic method to obtain a yellow solid with a total yield of 70.2%.

[0154] Synthesis of 8-(trifluoromethyl)thiochroman-4-one: Using o-(trifluoromethyl)phenylthiol as the raw material, it was synthesized according to the general synthetic method to obtain a pale yellow solid with a total yield of 65.7%.

[0155] Synthesis of 7,8-dichlorothiochroman-4-one: Using 2,3-dichlorophenylthiol as the raw material, it was synthesized according to the general synthetic method to obtain a white solid with a total yield of 82.7%.

[0156] Synthesis of 6,8-dichlorothiochroman-4-one: Using 2,4-dichlorophenylthiol as the raw material, it was synthesized according to the general synthetic method to obtain a pale yellow solid with a total yield of 99.4%.

[0157] Synthesis of 6,8-dimethylthiochroman-4-one: Using 2,4-dimethylphenylthiol as the raw material, it was synthesized according to the general synthetic method to obtain a yellow oil with a total yield of 84.4%.

[0158] Synthesis of 8-chloro-6-fluorothiochroman-4-one: Using 2-chloro-4-fluorophenylthiol as the raw material, it was synthesized according to the general synthetic method to obtain an off-white solid with a total yield of 95.3%.

[0159] Example 1: Synthesis of 4-(chroman-4-yl)-1H-imidazole (1)

[0160]

[0161] Synthesis method A: Hydrogenation reduction method

[0162] Step 1): Add 1571 mg of 4(5)-iodo-1-(triphenylmethyl)-1H-imidazole (3.6 mmol) to a dry three-necked flask, dissolve it in 15 mL of dichloromethane, protect it with argon, and under the condition of an ice bath at 0 °C, add 3.6 mL of 1 M ethylmagnesium bromide (3.6 mmol). After reacting for 0.5 h, add a dichloromethane solution of 445 mg of chroman-4-one (3 mmol) to the reaction. After reacting for 6 h, quench the reaction with saturated ammonium chloride solution, extract it with dichloromethane (30 mL × 3 times), dry it over anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, purify it by column chromatography, and elute it with a gradient of dichloromethane: methanol = 500:1 to 100:1. Collect the required fractions, and concentrate them under reduced pressure to obtain 1261 mg of white solid 4-(1-triphenylmethyl-1H-imidazol-4-yl)chroman-4-ol, with a yield of 91.8%.

[0163] Step 2): Add 19 mL of 90% aqueous acetic acid solution to 886 mg of 4-(1-triphenylmethyl-1H-imidazol-4-yl)chroman-4-ol (1.93 mmol), protect it with argon, and heat it at 80 °C for 4 h. After the reaction is completed, adjust the pH = 10 with sodium carbonate solution, extract it with dichloromethane (30 mL × 3 times), dry it over anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, purify it by column chromatography, and elute it with a gradient of dichloromethane: methanol = 1000:1 to 500:1 (1% ammonia water). Collect the required fractions, and concentrate them under reduced pressure to obtain 234 mg of white solid 4-(2H-chromen-4-yl)-1H-imidazole, with a yield of 61.2%.

[0164] Step 3): Add 198 mg of 4-(2H-chromen-4-yl)-1H-imidazole (1 mmol) to a reaction kettle, dissolve it in methanol, add 10% palladium on carbon, seal it, and introduce hydrogen gas. React at 5 atm and 50 °C for 7 h, filter to adsorb and remove the catalyst, concentrate the filtrate under reduced pressure, purify it by column chromatography, and elute it with a gradient of dichloromethane: methanol = 1000:1 to 500:1 (1% ammonia water). Collect the required fractions, and concentrate them under reduced pressure to obtain 137 mg of white solid 4-(chroman-4-yl)-1H-imidazole, with a yield of 68.4%.

[0165] Synthesis method B: Trimethylsilyl iodide reduction method

[0166] Step 1) Add 1745 mg of 4(5)-iodo-1-(triphenylmethyl)-1H-imidazole (4 mmol) into a dry three-necked flask, dissolve it with an appropriate amount of dichloromethane, protect it with argon, and under the condition of an ice bath at 0 °C, add ethylmagnesium bromide (4 mmol). After reacting for 0.5 h, add a dichloromethane solution of chroman-4-one (3.2 mmol) to the reaction. After reacting for 6 h, quench the reaction by adding saturated ammonium chloride solution, extract it with dichloromethane (30 mL × 3 times), dry it with anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, purify it by column chromatography, elute with a gradient of dichloromethane:methanol = 500:1 to 100:1, collect the required fractions, and concentrate under reduced pressure to obtain 1452 mg of white solid 4-(1-triphenylmethyl-1H-imidazol-4-yl)chroman-4-ol, with a yield of 98.95%.

[0167] Step 2) Add 1799 mg of sodium iodide (12 mmol) into a three-necked flask, dissolve it with 12 mL of acetonitrile, protect it with argon, and under the condition of an ice bath at 0 °C, add 1.5 mL of trimethylchlorosilane (12 mmol). React for 10 min, add 917 mg of 4-(1-triphenylmethyl-1H-imidazol-4-yl)chroman-4-ol (2 mmol) dissolved in dichloromethane, and react until the raw materials basically disappear. Add an appropriate amount of sodium hydroxide solution and sodium thiosulfate solution to the reaction, extract it with dichloromethane (30 mL × 3 times), dry it with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain the crude product. Add 10 mL of 90% acetic acid aqueous solution to the crude product (1 mmol), protect it with argon, heat it at 80 °C for 3 h. After the reaction is completed, adjust the pH = 12 with ice sodium carbonate solution, extract it with dichloromethane (30 mL × 3 times), dry it with anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, purify it by column chromatography, elute with a gradient of dichloromethane:methanol = 1000:1 to 500:1 (1% ammonia water), collect the required fractions, and concentrate under reduced pressure to obtain 175 mg of white solid 4-(chroman-4-yl)-1H-imidazole, with an overall yield of 43.69%. 1 H-NMR(600MHz,DMSO)δ11.86(s,1H),7.56(d,J=0.9Hz,1H),7.10–7.04(m,1H),7.00(d,J=7.5Hz,1H),6.81–6.72(m,2H),6.63(s,1H),4.14(ddd,J=11.1,7.3,3.2Hz,2H),4.11–4.05(m,1H),2.24–2.04(m,2H).HRMS(ESI):C 12 H 12 N2O[M+H] + 201.1024.

[0168] Example 2: Synthesis of 4-(6-methylchroman-4-yl)-1H-imidazole (2)

[0169]

[0170] Synthesis was carried out using a synthetic method B similar to that described in Example 1. Using 6-methylchroman-4-one instead of chroman-4-one as the raw material, a white solid was obtained with an overall yield of 43.9%. 1 H-NMR (600 MHz, MeOD) δ 7.61 (d, J = 1.1 Hz, 1H), 6.89 (dd, J = 8.3, 2.2 Hz, 1H), 6.77 (d, J = 1.7 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.58 (s, 1H), 4.23–3.97 (m, 3H), 2.19 (ddd, J = 5.3, 3.3, 1.8 Hz, 2H), 2.17 (d, J = 3.1 Hz, 3H). HRMS (ESI): C 13 H 14 N2O [M + H] + 215.1180.

[0171] Example 3: Synthesis of 4-(6-chromanyl)-1H-imidazole (3):

[0172]

[0173] Synthesis was carried out using a synthetic method B similar to that described in Example 1. Using 6-chromanyl-4-one instead of chroman-4-one as the raw material, a white solid was obtained with an overall yield of 34.7%. 1 H-NMR (600 MHz, MeOD) δ 7.64 (d, J = 1.2 Hz, 1H), 7.05 (ddd, J = 8.7, 2.6, 0.6 Hz, 1H), 6.92 (dd, J = 2.6, 0.7 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.71–6.66 (m, 1H), 4.23–4.10 (m, 3H), 2.27–2.13 (m, 2H). HRMS (ESI): C 12 H 11 ClN2O [M + H] + 235.0632

[0174] Example 4: Synthesis of 4-(7-bromochroman-4-yl)-1H-imidazole (4)

[0175]

[0176] Synthesis was carried out using synthetic method B similar to that described in Example 1. Using 7-bromochroman-4-one instead of chroman-4-one as the raw material, a white solid was obtained with an overall yield of 20.5%. 1 H-NMR(600MHz,MeOD)δ7.63(d,J=1.1Hz,1H),6.95(d,J=2.0Hz,1H),6.93(dd,J=8.2,2.0Hz,1H),6.88(dd,J=8.2,0.5Hz,1H),6.62(s,1H),4.27–4.08(m,3H),2.38–2.10(m,2H).HRMS(ESI):C 12 H 11 BrN2O[M+H] + 279.0128.

[0177] Example 5: Synthesis of 4-(8-chromanyl-4-yl)-1H-imidazole (5)

[0178]

[0179] Synthesis was carried out using synthetic method B similar to that described in Example 1. Using 8-chlorochroman-4-one instead of chroman-4-one as the raw material, a white solid was obtained with an overall yield of 33.3%. 1 H-NMR(600MHz,MeOD)δ7.62(d,J=1.2Hz,1H),7.19(ddd,J=7.9,1.5,0.5Hz,1H),6.94–6.90(m,1H),6.76(t,J=7.8Hz,1H),6.64–6.60(m,1H),4.33–4.26(m,1H),4.19(ddd,J=11.2,9.3,4.9Hz,2H),2.32–2.19(m,2H).HRMS(ESI):C 12 H 11 ClN2O[M+H] + 235.0634.

[0180] Example 6: Synthesis of 4-(6-bromochroman-4-yl)-1H-imidazole (6)

[0181]

[0182] Synthesis was carried out using synthetic method B similar to that described in Example 1. Using 6-bromochroman-4-one as the raw material, a white solid was obtained with an overall yield of 62.1%. 11H NMR (600 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.34–7.03 (m, 2H), 6.87–6.62 (m, 2H), 4.32–3.97 (m, 3H), 2.26–2.02 (m, 2H), HRMS (ESI): C 12 H 11 BrN2O [M+H] + 279.0128.

[0183] Example 7: Synthesis of 4-(7-Fluorochroman-4-yl)-1H-imidazole (7)

[0184]

[0185] Synthesis was carried out using synthetic method B described in Example 1. Using 7-fluorochroman-4-one as the raw material, a white solid was obtained with an overall yield of 63.1%. 1 1H-NMR (600 MHz, MeOD) δ 7.62 (d, J = 1.2 Hz, 1H), 6.95 (ddd, J = 8.4, 6.7, 0.5 Hz, 1H), 6.60–6.59 (m, 1H), 6.57–6.49 (m, 2H), 4.23–4.06 (m, 3H), 2.29–2.14 (m, 2H). HRMS (ESI): C 12 H 11 FN2O [M+H] + 219.0928

[0186] Example 8: Synthesis of 4-(8-Methylchroman-4-yl)-1H-imidazole (8)

[0187]

[0188] Synthesis was carried out using synthetic method A described in Example 1. Using 8-methylchroman-4-one instead of chroman-4-one as the raw material, a white solid was obtained with an overall yield of 48.7%. 1 1H-NMR (600 MHz, DMSO) δ 11.83 (s, 1H), 7.54 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.82 (d, J = 6.7 Hz, 1H), 6.67 (t, J = 7.5 Hz, 1H), 6.61 (s, 1H), 4.29–4.00 (m, 4H), 2.24–2.15 (m, 1H), 2.11 (s, 3H). HRMS (ESI): C 13 H 14 N2O [M+H] + 215.1180

[0189] Example 9: Synthesis of 4-(8-Fluorochroman-4-yl)-1H-imidazole (9)

[0190]

[0191] Synthesis was carried out using a synthetic method B similar to that described in Example 1. Using 8-fluorochroman-4-one as the raw material, a white solid was obtained with an overall yield of 59.1%. 1 H-NMR(600MHz,MeOD)δ7.63(d,J=1.1Hz,1H),6.94–6.89(m,1H),6.78–6.71(m,2H),6.62–6.61(m,1H),4.28–4.13(m,3H),2.32–2.17(m,2H).HRMS(ESI):C 12 H 11 FN2O[M+H] + 219.0931

[0192] Example 10: Synthesis of 4-(Isochroman-4-yl)-1H-imidazole (10)

[0193]

[0194] Synthesis was carried out using a synthetic method A similar to that described in Example 1. Using isochroman-4-one as the raw material, a white solid was obtained with an overall yield of 49.8%. 1 H-NMR(600MHz,DMSO-d6)δ11.90(s,1H),7.56(s,1H),7.20–7.10(m,2H),7.06(d,J=7.9Hz,2H),6.69(d,J=5.4Hz,1H),4.84–4.69(m,2H),4.09(t,J=5.8Hz,1H),4.04–3.95(m,2H).HRMS(ESI):C 12 H 12 N2O[M+H] + 201.1024.

[0195] Example 11: Synthesis of 4-(8-Bromochroman-4-yl)-1H-imidazole (11)

[0196]

[0197] Synthesis was carried out using a synthetic method B similar to that described in Example 1. Using 8-bromochroman-4-one as the raw material, an off-white solid was obtained with an overall yield of 44.9%. 1H-NMR (600 MHz, DMSO-d6) δ 11.88 (s, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.38 (dd, J = 7.8, 1.6 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.84–6.62 (m, 2H), 4.36–4.20 (m, 2H), 4.14 (t, J = 5.8 Hz, 1H), 2.28–2.04 (m, 2H). HRMS (ESI): C 12 H 11 BrN2O [M+H] + 279.0128

[0198] Example 12: Synthesis of 4-(8-iodochroman-4-yl)-1H-imidazole (12)

[0199]

[0200] Synthesis was carried out using synthetic method B described in Example 1. Using 8-iodochroman-4-one as the raw material, a pale yellow solid was obtained with an overall yield of 41.2%. 1 H-NMR (600 MHz, DMSO-d6) δ 11.87 (s, 1H), 7.93–7.19 (m, 2H), 7.14–6.93 (m, 1H), 6.81–6.66 (m, 1H), 6.65–6.57 (m, 1H), 4.35–4.02 (m, 3H), 2.28–2.03 (m, 2H). HRMS (ESI): C 12 H 11 IN2O [M+H] + 326.9990

[0201] Example 13: Synthesis of 4-(chromen-4-yl)-1H-imidazole (13)

[0202]

[0203] Synthesis method: Step 1) Add 2094 mg of 4(5)-iodo-1-(triphenylmethyl)-1H-imidazole (4.8 mmol) into a dry three-necked flask, dissolve it with 20 mL of dichloromethane, protect it with argon, and under the condition of an ice bath at 0 °C, add 4.8 mL of 1 M ethylmagnesium bromide (4.8 mmol). After reacting for 0.5 h, add a dichloromethane solution of 649 mg of chroman-4-one (4 mmol) to the reaction. After reacting for 7 h, quench the reaction with saturated ammonium chloride solution, extract it with dichloromethane (30 mL × 3 times), dry it with anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, purify it by column chromatography, elute with a gradient of dichloromethane: methanol = 500:1 to 100:1, collect the required fractions, and concentrate under reduced pressure to obtain 1801 mg of white solid 4-(1-triphenylmethyl-1H-imidazol-4-yl)chroman-4-ol with a yield of 95.3%.

[0204] Step 2) Add 15 mL of 90% aqueous acetic acid solution to 709 mg (1.5 mmol) of the intermediate alcohol, heat it at 80 °C for 4 h under argon protection. After the reaction is completed, adjust the pH to 10 with sodium carbonate solution, extract it with dichloromethane (30 mL × 3 times), dry it with anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, purify it by column chromatography, elute with a gradient of dichloromethane: methanol = 1000:1 to 500:1 (1% ammonia water), collect the required fractions, and concentrate under reduced pressure to obtain 56 mg of white solid 4-(2H-chromen-4-yl)-1H-imidazole with a yield of 17.6%. 1 1H-NMR (600 MHz, DMSO-d6) δ 12.24 (s, 1H), 7.73 (d, J = 0.9 Hz, 1H), 7.58 (s, 1H), 7.31–7.08 (m, 2H), 7.02–6.77 (m, 2H), 6.16 (s, 1H), 4.75 (d, J = 4.1 Hz, 2H). HRMS (ESI): C 12 H 10 N2O [M + H] + 199.0867.

[0205] Example 14:

[0206] Synthesis of 4-(6-methyl-2H-chromen-4-yl)-1H-imidazole (14)

[0207]

[0208] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 6-methylchroman-4-one as the raw material, an off-white solid was obtained with a yield of 46.2%. 1H-NMR (600 MHz, DMSO-d6) δ 12.46–12.05 (s, 1H), 7.73 (d, J = 1.1 Hz, 1H), 7.38 (s, 1H), 7.25 (s, 1H), 6.97 (dd, J = 8.2, 2.1 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.14 (t, J = 4.1 Hz, 1H), 4.69 (d, J = 4.1 Hz, 2H), 2.22 (s, 3H). HRMS (ESI): C 13 H 12 N2O[M + H] + 213.1023.

[0209] Example 15: Synthesis of 4-(6-chloro-2H-chromen-4-yl)-1H-imidazole (15)

[0210]

[0211] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 6-chlorochroman-4-one as the starting material, a pale yellow solid was obtained with a yield of 12.7%. 1 H-NMR (600 MHz, MeOD) δ 7.78 (d, J = 1.0 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.20 (d, J = 0.8 Hz, 1H), 7.13 (dd, J = 8.6, 2.6 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.11 (t, J = 4.1 Hz, 1H), 4.79 (d, J = 4.1 Hz, 2H). HRMS (ESI): C 12 H9ClN2O[M + H] + 233.0477

[0212] Example 16: Synthesis of 4-(7-bromo-2H-chromen-4-yl)-1H-imidazole (16)

[0213]

[0214] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 7-bromochroman-4-one as the starting material, an off-white solid was obtained with a yield of 58.5%. 1 H-NMR (600 MHz, MeOD) δ 7.74 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.18 (s, 1H), 7.07 (d, J = 1.9 Hz, 1H), 7.02 (d, J = 1.9 Hz, 1H), 6.09 (t, J = 4.0 Hz, 1H), 4.79 (d, J = 4.1 Hz, 2H). HRMS (ESI): C 12H9BrN2O[M+H] + 276.9971

[0215] Example 17: Synthesis of 4-(8-chloro-2H-chromen-4-yl)-1H-imidazole (17)

[0216]

[0217] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 8-chlorochroman-4-one as the raw material, a white solid was obtained with a yield of 52.1%. 1 H-NMR(600MHz,MeOD)δ7.74(d,J=1.1Hz,1H),7.29(dd,J=7.8,1.4Hz,1H),7.23(dd,J=8.0,1.5Hz,1H),7.18(d,J=0.8Hz,1H),6.88(t,J=7.9Hz,1H),6.13(t,J=4.1Hz,1H),4.86(d,J=4.1Hz,2H).HRMS(ESI):C 12 H9ClN2O[M+H] + 233.0476

[0218] Example 18: Synthesis of 4-(6-bromo-2H-chromen-4-yl)-1H-imidazole (18)

[0219]

[0220] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 6-bromochroman-4-one as the raw material, an off-white solid was obtained with a yield of 42.9%. 1 H-NMR(600MHz,MeOD)δ7.76(d,J=1.1Hz,1H),7.45(s,1H),7.26(dd,J=8.6,2.3Hz,1H),7.18(s,1H),6.78(d,J=8.6Hz,1H),6.10(t,J=4.0Hz,1H),4.79(d,J=4.1Hz,2H).HRMS(ESI):C 12 H9BrN2O[M+H] + 276.9971

[0221] Example 19: Synthesis of 4-(7-fluoro-2H-chromen-4-yl)-1H-imidazole (19)

[0222]

[0223] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 7-fluorochroman-4-one as the raw material, a white solid was obtained with a yield of 71.8%. 1 H-NMR(600MHz,MeOD)δ7.73(d,J=1.1Hz,1H),7.36(dd,J=8.4,6.7Hz,1H),7.17(s,1H),6.66–6.58(m,2H),6.02(t,J=4.1Hz,1H),4.79(d,J=4.1Hz,2H).HRMS(ESI):C 12 H9FN2O[M+H] + 217.0772

[0224] Example 20: Synthesis of 4-(8-methyl-2H-chromen-4-yl)-1H-imidazole (20)

[0225]

[0226] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 8-methylchroman-4-one as the raw material, a white solid was obtained with a yield of 54.2%. 1 H-NMR(600MHz,MeOD)δ7.72(d,J=1.0Hz,1H),7.17(d,J=7.3Hz,1H),7.12(s,1H),7.03(d,J=7.4Hz,1H),6.80(t,J=7.6Hz,1H),4.75(d,J=4.2Hz,2H),2.19(s,3H).HRMS(ESI):C 13 H 12 N2O[M+H] + 213.1022

[0227] Example 21: Synthesis of 4-(8-fluoro-2H-chromen-4-yl)-1H-imidazole (21)

[0228]

[0229] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 8-fluoromethylchroman-4-one as the raw material, a white solid was obtained with a yield of 57.8%. 1 H-NMR(600MHz,MeOD)δ7.74(d,J=1.0Hz,1H),7.22–7.13(m,2H),7.04–6.98(m,1H),6.87(td,J=8.0,5.0Hz,1H),6.15(t,J=4.1Hz,1H),4.82(d,J=4.1Hz,2H).HRMS(ESI):C 12H9FN2O[M+H] + 217.0772

[0230] Example 22: Synthesis of 4-(6-methoxy-2H-chromen-4-yl)-1H-imidazole (22)

[0231]

[0232] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 6-methoxyfluorochroman-4-one as the raw material, a light beige solid was obtained with a yield of 60.0%. 1 H-NMR(600MHz,DMSO)δ12.26(s,1H),7.74(s,1H),7.24(d,J=58.9Hz,2H),6.88–6.71(m,2H),6.20(t,J=4.0Hz,1H),4.68(d,J=4.2Hz,2H),3.69(s,3H).HRMS(ESI):C 13 H 12 N2O2[M+H] + 229.0972

[0233] Example 23: Synthesis of 4-(6,8-dichloro-2H-chromen-4-yl)-1H-imidazole (23)

[0234]

[0235] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 6,8-dichlorochroman-4-one as the raw material, a light beige solid was obtained with a yield of 21.7%. 1 H-NMR(600MHz,MeOD)δ7.77(d,J=1.1Hz,1H),7.28(q,J=2.5Hz,2H),7.22(d,J=1.0Hz,1H),6.16(t,J=4.0Hz,1H),4.90(d,J=4.0Hz,2H).HRMS(ESI):C 12 H8Cl2N2O[M+H] + 267.0087

[0236] Example 24: Synthesis of 4-(6-bromo-8-chloro-2H-chromen-4-yl)-1H-imidazole (24)

[0237]

[0238] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 6-bromo-8-chlorochroman-4-one as the raw material, a light yellow solid was obtained with a yield of 41.3%. 1H-NMR(600MHz, DMSO) δ 12.31 (s, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 1.0 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.37 (s, 1H), 6.23 (s, 1H), 4.94 (d, J = 4.0 Hz, 2H). HRMS(ESI): C 12 H8BrClN2O [M+H] + 312.9555

[0239] Example 25: Synthesis of 4-(6-bromo-2,2-dimethyl-2H-chromen-4-yl)-1H-imidazole (25)

[0240]

[0241] The synthesis was carried out using a synthetic method similar to that described in Example 13. Using 6-bromo-2,2-dimethylchroman-4-one as the raw material, a pale yellow solid was obtained with a yield of 20.0%. 1 H-NMR(600MHz, DMSO) δ 12.23 (s, 1H), 7.92 (s, 1H), 7.75 (d, J = 0.9 Hz, 1H), 7.31 (dd, J = 8.5, 2.3 Hz, 2H), 6.80 (d, J = 8.5 Hz, 1H), 6.02 (s, 1H), 1.41 (s, 6H). HRMS(ESI): C 14 H 13 BrN2O [M+H] + 305.0283

[0242] Example 26: Synthesis of 4-(8-bromo-2H-chromen-4-yl)-1H-imidazole (26)

[0243]

[0244] The synthesis was carried out using a synthetic method similar to that described in Example 13. Using 8-bromochroman-4-one as the raw material, an off-white solid was obtained with a yield of 43.3%. 1 H-NMR(600MHz, DMSO) δ 12.27 (s, 1H), 7.74 (s, 1H), 7.62 (d, J = 5.7 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 12.0 Hz, 1H), 6.89 (t, J = 7.9 Hz, 1H), 6.21 (t, J = 4.1 Hz, 1H), 4.88 (d, J = 4.1 Hz, 2H). HRMS(ESI): C 12 H9BrN2O [M+H] + 276.9971

[0245] Example 27: Synthesis of 4-(6,8-dimethyl-2H-chromen-4-yl)-1H-imidazole (27)

[0246]

[0247] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 6,8-dimethylchroman-4-one as the raw material, a yellow solid was obtained with a yield of 28.1%. The yield was 28.1%. 1 H-NMR (600 MHz, DMSO) δ 12.20 (s, 1H), 7.72 (s, 1H), 7.19 (d, J = 12.8 Hz, 2H), 6.87 (s, 1H), 6.13 (t, J = 4.1 Hz, 1H), 4.70 (d, J = 4.2 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H). HRMS (ESI): C 14 H 14 N2O [M + H] + 227.1179

[0248] Example 28: Synthesis of 4-(8-iodo-2H-chromen-4-yl)-1H-imidazole (28)

[0249]

[0250] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 8-iodochroman-4-one as the raw material, a yellow solid was obtained with a yield of 54.7%. 1 H-NMR (600 MHz, DMSO) δ 12.26 (s, 1H), 7.75 (d, J = 17.0 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.28 (t, J = 13.1 Hz, 1H), 7.22–6.65 (m, 2H), 6.16 (ddd, J = 19.6, 8.2, 4.0 Hz, 1H), 4.96–4.70 (m, 2H). HRMS (ESI): C 12 H9IN2O [M + H] + 324.9832

[0251] Example 29: Synthesis of 4-(8-bromo-6-fluoro-2H-chromen-4-yl)-1H-imidazole (29)

[0252]

[0253] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 8-bromo-6-fluorochroman-4-one as the raw material, a yellow solid was obtained with a yield of 30.1%. 1H-NMR (600 MHz, DMSO) δ 12.30 (s, 1H), 7.76 (s, 1H), 7.65–7.55 (m, 1H), 7.49–7.34 (m, 2H), 6.28 (s, 1H), 4.88 (d, J = 4.1 Hz, 2H). HRMS (ESI): C 12 H8BrFN2O [M+H] + 294.9877

[0254] Example 30: Synthesis of 4-(8-bromo-7-methyl-2H-chromen-4-yl)-1H-imidazole (30)

[0255]

[0256] The synthesis was carried out using a synthetic method similar to that described in Example 13. Using 8-bromo-7-methylchroman-4-one as the raw material, a pale yellow solid was obtained with a yield of 39.3%. 1 H-NMR (600 MHz, DMSO) δ 12.26 (s, 1H), 7.74 (s, 1H), 7.51 (s, 1H), 7.27 (s, 1H), 6.93 (d, J = 7.9 Hz, 1H), 6.16 (t, J = 4.0 Hz, 1H), 4.85 (d, J = 4.1 Hz, 2H), 2.34 (s, 3H). HRMS (ESI): C 13 H 11 BrN2O [M+H] + 291.0127

[0257] Example 31: Synthesis of 4-(8-chloro-2H-chromen-4-yl)-5-methyl-1H-imidazole (31)

[0258]

[0259] The synthesis was carried out using a synthetic method similar to that described in Example 13. Using 4(5)-iodo-5(4)-methyl-1-(triphenylmethyl)-1H-imidazole and 8-chlorochroman-4-one as the raw materials, an off-white solid was obtained with a yield of 35.4%. 1 H-NMR (600 MHz, DMSO) δ 12.01 (s, 1H), 7.58 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 7.9 Hz, 1H), 5.88 (s, 1H), 4.93 (d, J = 3.9 Hz, 2H), 2.15 (s, 3H). HRMS (ESI): C 13 H 11 ClN2O [M+H] + 247.0635

[0260] Example 32: Synthesis of 5-methyl-4-(8-methyl-2H-chromen-4-yl)-1H-imidazole (32)

[0261]

[0262] Synthesis was carried out using a synthetic method similar to that described in Example 13. Using 4(5)-iodo-5(4)-methyl-1-(triphenylmethyl)-1H-imidazole and 8-methylchroman-4-one as raw materials, a pale white solid was obtained with a yield of 35.4%. 1 1H-NMR (600 MHz, DMSO) δ 11.96 (s, 1H), 7.55 (s, 1H), 7.01 (d, J = 7.3 Hz, 2H), 6.75 (t, J = 7.5 Hz, 1H), 5.81 (s, 1H), 4.81 (d, J = 3.9 Hz, 2H), 2.14 (s, 3H), 2.12 (s, 3H). HRMS (ESI): C 14 1H 14 N2O [M + H] + 227.1176

[0263] Example 33: Synthesis of 4-(8-chloro-2H-thiochromen-4-yl)-1H-imidazole (33)

[0264]

[0265] Step 1): Add 4(5)-iodo-1-(triphenylmethyl)-1H-imidazole (1.25 mmol) to a dry three-necked flask, dissolve it in an appropriate amount of dichloromethane, protect it with argon, and add 1 M ethylmagnesium bromide (1.25 mmol) under an ice bath at 0 °C. After reacting for 1 h, add a dichloromethane solution of substituted 8-chlorothiochroman-4-one (1 mmol) to the reaction. After reacting for 6 h, quench the reaction with saturated ammonium chloride solution, extract it with dichloromethane (30 mL × 3 times), dry it over anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, purify it by column chromatography, elute it with a gradient of dichloromethane:methanol = 500:1 to 100:1, collect the required fractions, and concentrate it under reduced pressure to obtain the intermediate alcohol.

[0266] Step 2) Add 10 mL of 90% aqueous acetic acid solution to the intermediate alcohol (1 mmol), protect under argon, heat at 80 °C for 3 h. After the reaction is completed, adjust the pH to 10 with ice sodium carbonate solution, extract with dichloromethane (30 mL × 3 times), dry over anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, purify by column chromatography, elute with a gradient of dichloromethane:methanol = 1000:1 to 500:1 (1% ammonia water), collect the required fractions, and concentrate under reduced pressure to obtain the product 4-(8-chloro-2H-chromene-4-yl)-1H-imidazole, a pale yellow solid, with a yield of 44.7%. 1 H-NMR(600MHz,MeOD)δ7.70(d,J=1.0Hz,1H),7.25(ddd,J=16.2,7.9,1.1Hz,2H),7.12–7.02(m,2H),6.31(t,J=5.9Hz,1H),3.42(d,J=5.9Hz,2H).HRMS(ESI):C 12 H9ClN2S[M+H] + 249.0248

[0267] Example 34: Synthesis of 4-(8-bromo-2H-chromene-4-yl)-1H-imidazole (34)

[0268]

[0269] Synthesis was carried out using a synthetic method similar to that described in Example 33. Using 8-bromothiochroman-4-one as the raw material, a yellow solid was obtained with a yield of 61.6%. 1 H-NMR(600MHz,DMSO)δ12.17(s,1H),7.69(d,J=1.0Hz,1H),7.50(d,J=7.8Hz,2H),7.10(t,J=7.9Hz,2H),6.36(s,1H),3.48(d,J=5.8Hz,2H).HRMS(ESI):C 12 H9BrN2S[M+H] + 294.9722

[0270] Example 35: Synthesis of 4-(8-(trifluoromethyl)-2H-chromene-4-yl)-1H-imidazole (35)

[0271]

[0272] Synthesis was carried out using a synthetic method similar to that described in Example 33. Using 8-(trifluoromethyl)thiochroman-4-one as the raw material, a pale yellow solid was obtained with a yield of 50.1%. 1H-NMR (600 MHz, DMSO) δ 12.26 (s, 1H), 7.71 (dd, J = 12.7, 4.3 Hz, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.14 (s, 1H), 6.51 (t, J = 6.0 Hz, 1H), 3.43 (d, J = 6.0 Hz, 2H). HRMS (ESI): C 13 H9F3N2S [M+H] + 283.0439; found 283.0511

[0273] Example 36: Synthesis of 4-(7,8-dichloro-2H-chromene-4-yl)-1H-imidazole (36)

[0274]

[0275] Synthesis was carried out using a synthetic method similar to that described in Example 33. Using 7,8-dichlorothiochroman-4-one as the raw material, a white solid was obtained with a yield of 49.7%. 1 H-NMR (600 MHz, DMSO) δ 12.22 (s, 1H), 7.71 (s, 1H), 7.42 (q, J = 8.5 Hz, 2H), 7.14 (s, 1H), 6.38 (t, J = 5.9 Hz, 1H), 3.54 (d, J = 5.9 Hz, 2H). HRMS (ESI): C 12 H8Cl2N2S [M+H] + 282.9858

[0276] Example 37: Synthesis of 4-(6,8-dichloro-2H-chromene-4-yl)-1H-imidazole (37)

[0277]

[0278] Synthesis was carried out using a synthetic method similar to that described in Example 33. Using 6,8-dichlorothiochroman-4-one as the raw material, a pale yellow solid was obtained with a yield of 14.1%. 1 H-NMR (600 MHz, DMSO) δ 12.24 (s, 1H), 7.73 (d, J = 0.7 Hz, 1H), 7.60 (m, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 17.1 Hz, 1H), 6.40 (t, J = 5.9 Hz, 1H), 3.52 (d, J = 5.9 Hz, 2H). HRMS (ESI): C 12 H8Cl2N2S [M+H] + 282.9858

[0279] Example 38: Synthesis of 4-(6,8-dimethyl-2H-thiochromen-4-yl)-1H-imidazole (38)

[0280]

[0281] Synthesis was carried out using a synthetic method similar to that described in Example 33. Using 6,8-dimethylthiochroman-4-one as the raw material, a off-white solid was obtained with a yield of 73.5%. 1 H-NMR(600MHz,DMSO)δ12.17(s,1H),7.69(s,1H),7.08(s,1H),7.02(s,1H),6.96(s,1H),6.34(t,J=5.9Hz,1H),3.35(d,J=5.9Hz,2H),2.27(s,3H),2.20(s,3H).HRMS(ESI):C 14 H 14 N2S[M+H] + 243.0951

[0282] Example 39: Synthesis of 4-(8-chloro-6-fluoro-2H-thiochromen-4-yl)-1H-imidazole (39)

[0283]

[0284] Synthesis was carried out using a synthetic method similar to that described in Example 33. Using 8-chloro-6-fluorothiochroman-4-one as the raw material, a off-white solid was obtained with a yield of 50.2%. 1 H-NMR(600MHz,DMSO)δ12.29(s,1H),7.73(s,1H),7.43(d,J=8.1Hz,1H),7.30(dd,J=10.3,2.1Hz,1H),7.21(s,1H),6.45(t,J=5.9Hz,1H),3.50(d,J=5.9Hz,2H).HRMS(ESI):C 12 H8ClFN2S[M+H] + 267.0154

[0285] Example 40: Synthesis of 4-(benzofuran-3-yl)-1H-imidazole (40)

[0286]

[0287] Synthesis was carried out using a synthetic method similar to that described in Example 33. Using benzofuran-3(2H)-one as the raw material, a off-white solid was obtained with a yield of 29.1%. 1H-NMR (600 MHz, MeOD) δ 8.05 (s, 1H), 7.87 (dd, J = 7.1, 1.3 Hz, 1H), 7.80 (d, J = 0.9 Hz, 1H), 7.56–7.47 (m, 2H), 7.33 (dtd, J = 18.3, 7.3, 1.2 Hz, 2H). HRMS (ESI): C 11 H8N2O [M + H] + 185.0709

[0288] As mentioned above, the compounds represented by formula (I) exhibit interesting pharmacological properties, namely, they show agonist activity towards adrenergic α2 - adrenoceptors, especially α 2A - adrenoceptors, which is stronger than that of currently known α 2A - adrenoceptor agonists (such as medetomidine, dexmedetomidine), and have a potent sedative effect in vivo. The said activity was demonstrated by the pharmacological tests provided below.

[0289] The compounds and their pharmaceutically acceptable salts have valuable biological activities. Specifically, it has been verified that the compounds of the present invention have good affinity and agonist activity towards α2 - adrenoceptors (α2 - AR), especially α 2A - adrenoceptors.

[0290] The synthetic compounds were studied according to the experiments given below.

[0291] Example of activity test 1: In vitro activation activity test of α 2A - adrenoceptors

[0292] Using CHO - PKAcat - EGFP tool cells, when in the basal state, PKAcat fluorescent granules will aggregate; while when the AC - cAMP - PKA pathway is activated, PKAcat will be activated and dissociated, manifested as the dispersion of fluorescent granules. When α 2A - AR is activated, it can inhibit the AC - cAMP - PKA pathway and inhibit the process of fluorescent granule dispersion. By obtaining cell fluorescence images with an In Cell Analyzer 1000 and analyzing the degree of fluorescent granule dispersion, the activation degree of the drug on the receptor can be quantified, thereby analyzing the expression level of α 2A - AR and the action intensity of the drug (Yang Yi, Li Yulei, etc. Chinese Journal of Pharmacology and Toxicology [J]. 2016, 30(05): 576 - 81.). Using dexmedetomidine as a positive control drug, the in vitro agonist activity of the synthetic compounds on α 2A - adrenoceptors was tested according to the methods and experimental procedures reported in this literature.

[0293] The following general abbreviations are used: CHO = Chinese hamster ovary; PKAcat = catalytic subunit of protein kinase A; EGFP = enhanced green fluorescent protein; AC = adenylyl cyclase; cAMP = cyclic adenosine monophosphate.

[0294] Table 1 Compounds Agonize α 2A -AR's EC 50 Value

[0295]

[0296]

[0297] EC 50 : Median effective concentration; NA: Inactive

[0298] As shown in the results of Table 1, the compounds represented by formula (I) according to the present invention exhibit potent agonist activity against the α2-adrenergic receptor, especially α 2A -adrenergic receptor, and the agonist activities of Compounds 5, 8, 11, 12, 20, 26, 28, 29 against the α 2A -adrenergic receptor are significantly stronger than those of the positive drug. Therefore, it is proved that the compounds represented by formula (I) according to the present invention can be used as α2-AR agonists for the treatment of diseases or disorders related to α 2A -AR agonists.

[0299] Example 2 of Activity Test: Hypnotic Effect in Mice

[0300] Using medetomidine as the positive control drug, the compound was dissolved in 5% dimethyl sulfoxide, 5% Tween 80 was added, and then 90% normal saline was added. The mixture was uniformly mixed into a transparent liquid and administered by intraperitoneal injection (i.p.) at a dosage volume of 0.1 mL / 10 g. And the behavioral effects of different drugs on mice were observed within 10 hours. An appropriate amount of bedding was laid on the bottom of the breeding box, and the mice were placed separately in the mouse breeding box. The root of the mouse's tail was gently turned over by hand so that its four limbs were facing up and its back was facing down and placed horizontally. When the mouse maintained the dorsal recumbent position for more than 1 min, it was judged that the righting reflex disappeared. Thereafter, it was checked every 10 min until the mouse righted itself to the normal position, and it was judged that the righting reflex recovered. Immediately after that, the mouse was turned over to the dorsal recumbent position again. If the mouse righted itself to the normal position within 1 min, the time of the first righting was recorded as the time of righting reflex recovery, otherwise the time of the second righting was recorded as the recovery time.

[0301] During the experiment, the number of mice with disappearance of the righting reflex in each group, and the time of disappearance and recovery of the righting reflex were observed and recorded. The disappearance rate of the righting reflex (number of mice with disappearance of the righting reflex / number of samples), induction time (time from the end of drug administration to disappearance of the righting reflex), and immobilization time (time from disappearance of the righting reflex to recovery of the righting reflex) were calculated for each group.

[0302] Statistical processing of the data was completed using GraphPad Prism 8.0 software. P < 0.05 indicates statistical significance. The results of measurement data are expressed as mean ± standard error and represented. The chi-square test was used to compare the differences in the disappearance rate of the righting reflex induced by each compound and dexmedetomidine in mice. The Student’s t test was used to statistically analyze the differences in the latency and duration of the disappearance of the righting reflex among the treatment groups. The results are shown in Table 2 below, and the data on the righting reflex activity of some compounds are shown in the following table:

[0303] Table 2 Pharmacodynamic study of inducing hypnotic-like behavior in mice

[0304]

[0305] ED 50 : Median effective dose

[0306] The results showed that when the drug dose of 1 mg / kg of Compounds 5, 8, 11, and 12 of the drug dose examples, and 10 mg / kg of Compounds 17, 20, 26, 28, and 29 of the drug dose examples were administered, the disappearance rate of the righting reflex in normal mice was 100%, while the 2A -KO mice had no affected exercise amount and did not show sedative effects. This indicates that the disappearance of the righting reflex in mice is due to the compound acting on the 2A -adrenoceptor.

[0307] Activity test Example 3: Sedative effect in mice

[0308] Using the mouse spontaneous activity model, the sedative effect of the compound at a low dose was tested. Mice were placed in the experimental environment for feeding one week in advance, without restricting food and water. A pre-experiment was conducted one day in advance. The mice were placed in the spontaneous activity box for 40 minutes of exploratory activity. At this time, the activity amount was large to prevent the exploratory activity from affecting the formal experimental data. When conducting the formal experiment the next day, the same dose as the positive drug dexmedetomidine (0.1 mg / kg) was selected to compare the strength of the sedative effect. According to the grouping order, different dose drug groups, blank solvent group, and positive drug group were set. Different groups of drugs were administered at the same time point. After drug administration, they were simultaneously placed in the spontaneous activity box to eliminate the error caused by different drug administration time periods, and the movement distance of different groups of mice within 40 min was measured. The sedative effect of the mice was evaluated based on the movement distance of spontaneous activity.

[0309] The experimental results are as follows Figure 1 As shown in Table 3, which shows the spontaneous activity data of Example Compounds 5, 8, 11, and 12. The compounds 5, 8, 11, and 12 of the examples significantly inhibited spontaneous activity, showed potent sedative effects, had a shorter onset time (5 minutes), and a longer duration of action (more than 40 minutes).

[0310] Table 3

[0311]

[0312] Mean±SEM, n = 8.****P<0.0001, ***p<0.001, **P<0.01, *p<0.05, compared with the vehicle group.

[0313] Those skilled in the art will recognize that modifications can be made to the embodiments described in this application without departing from the spirit of the invention. Those skilled in the art should also understand that the present invention is not limited to the specific embodiments disclosed, but is also intended to cover modifications of the embodiments within the scope of the present invention. Therefore, the scope of protection of the present invention shall be determined by the scope of protection of the claims.

Claims

1. A 4-(1H)-imidazole derivative or a pharmaceutically acceptable salt thereof, characterized in that, The 4-(1H)-imidazole derivative is selected from the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. A pharmaceutical composition comprising a therapeutically effective amount of the 4-(1H)-imidazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.

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