Substituted imidazole derivative, intermediate, preparation method therefor and use thereof

Abstract

The present invention relates to the field of medicines, and particularly relates to a compound represented by general formula (I) or a pharmaceutically acceptable salt, a stereoisomer, a tautomer and a composition containing the compound, an intermediate thereof, a preparation method therefor and a use thereof in the field of medicines.

Description

A substituted imidazole derivative, intermediate, preparation method and application thereof

[0001] This application claims priority to Chinese patent application No. 202310724980.9 filed on June 19, 2023, entitled “A substituted imidazole derivative, an intermediate, a preparation method and its application” and Chinese patent application No. 202410149322.6 filed on February 2, 2024, entitled “A substituted imidazole derivative, an intermediate, a preparation method and its application”, the entire contents of which are incorporated herein. Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to a substituted imidazole derivative or a pharmaceutically acceptable salt, stereoisomer, tautomer and a composition containing the compound, an intermediate thereof, a preparation method and application in the field of medicine. Background Art

[0003] Adrenergic receptors are G-protein-coupled receptors, divided into α- and β-adrenergic receptors. Alpha 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.). α2A, α2B, and α2C are the three subtypes of α2 receptors (Bylund et al., Mol. Pharmacol., 1992, 42, 1-5). α2A in the brain is primarily concentrated in the pons and medulla oblongata, participating in the transmission of sympathetic nerve signals from the central nervous system to the periphery. Stimulation of presynaptic α2A can regulate the release of epinephrine through a negative feedback mechanism; stimulation of postsynaptic α2A can cause hyperpolarization of the nerve cell membrane.

[0004] The effects of α2 receptor agonists on analgesia, anesthesia, and sedation are well documented (Pertovaara, A., Progress in Neurobiology, 40, 691 (1993)). For example, in addition to its well-known sedative effects, systemic administration of clonidine has been shown to produce antinociception in various species, including human patients. Intrathecal and epidural administration of clonidine has also been shown to be effective in producing antinociception. Another α2 receptor agonist, medetomidine, has better α2 / α1 selectivity and is more effective at α2 receptors than clonidine and has been widely used.

[0005] Dexmedetomidine is a highly selective α2-adrenergic receptor agonist that produces sedative, analgesic, anxiolytic, and sympathetic nervous system inhibitory effects on the central and peripheral nervous systems and other organs and tissues (Maud AS Weerinks, et al. Clin Pharmacol, 2017, 56:893-913). Due to its significant efficacy, it is currently widely used in clinical practice. While dexmedetomidine has excellent analgesic and sedative effects, its adverse drug reactions should also be taken seriously, particularly hypotension and bradycardia, which are common. Numerous case reports of dexmedetomidine-associated bradycardia progression have been reported. In particular, high doses of dexmedetomidine can stimulate α2B receptors on vascular smooth muscle, causing vasoconstriction and resulting in hypertension and a reflex decrease in heart rate.

[0006] Therefore, it is necessary to find an α2 adrenergic receptor agonist with good circulation stability, high potency, short duration, rapid onset of action in the body and few side effects, and to use it in the preparation of drugs with sedative, and / or analgesic, and / or anesthetic effects, and / or anti-anxiety, and / or sympathetic nerve activity inhibition, and / or treatment of insomnia, and / or treatment of mental disorders.

[0007] Summary of the Invention

[0008] The following merely illustrates some aspects of the present invention, and the present invention is not limited thereto.

[0009] The present invention aims to provide a substituted imidazole derivative or a pharmaceutically acceptable salt, stereoisomer, tautomer and pharmaceutical composition thereof having α2 adrenergic receptor agonist activity. The compound and pharmaceutical composition can be used to prepare drugs related to α2 adrenergic receptor agonists, and can further be used to prepare drugs that produce sedative, and / or analgesic, and / or anesthetic effects, and / or anti-anxiety, and / or sympathetic nerve activity inhibition, and / or treatment of insomnia, and / or treatment of mental disorders in humans or animals. They can further be used to prepare drugs that produce sedative, and / or analgesic, and / or anesthetic effects, and / or treatment of insomnia, and / or treatment of mental disorders in humans or animals.

[0010] In one aspect, the present invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, or tautomer represented by the following general formula I:

[0011] wherein X is selected from CH and N, preferably CH;

[0012] n is an integer selected from 1-3, preferably 1;

[0013] m is an integer selected from 1-8, preferably an integer selected from 1-3;

[0014] each R1 is independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl, the optional substituents being independently selected from halogen and hydroxy;

[0015] R2 is selected from H, cyano, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl, the optional substituents being independently selected from halogen and hydroxy;

[0016] R3 is selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl, the optional substituents being independently selected from halogen and hydroxy;

[0017] Ring A is selected from C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from oxygen and sulfur, preferably selected from C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen and sulfur, and 5-8 membered heteroaryl containing 1 heteroatom selected from oxygen and sulfur;

[0018] Each R 10 are independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl; the optional substituents are independently selected from halogen, C1-C8 alkyl and hydroxy;

[0019] R 11 is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl, preferably selected from H and optionally substituted C1-C5 alkyl, further preferably H; the optional substituent is selected from hydroxyl and halogen;

[0020] and the compound of formula I is not: 5-(2,3-dihydro-benzofuran-7-ylmethyl)-1-imidazole, 8-((1H-imidazol-5-yl)methyl)-1,2,3,4-tetrahydroquinoline, 5-(benzofuran-7-ylmethyl)-1H-imidazole, or 5-((5-bromobenzofuran-7-yl)methyl)-1H-imidazole.

[0021] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by Formula I as described above or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or a combination thereof.

[0022] On the other hand, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, or a pharmaceutical composition thereof for use in preparing drugs related to α2 adrenergic receptor agonists, preferably for use in preparing drugs that produce sedative, and / or analgesic, and / or anesthetic effects, and / or anti-anxiety, and / or sympathetic nerve activity inhibition, and / or treatment of insomnia, and / or treatment of mental disorders in humans or animals, and further preferably for use in preparing drugs that produce sedative, and / or analgesic, and / or anesthetic effects, and / or treatment of insomnia, and / or treatment of mental disorders in humans or animals.

[0023] In another aspect, the present invention provides a compound or a salt thereof as shown in Formula IA, Formula IA', Formula IB, Formula IB', Formula IC, Formula ID or Formula ID',

[0024] In Formula IA, n, Ring A, R1, R3, m, R 10 As mentioned above;

[0025] In formula I-A', n, ring A, R1, R3, m, R 10 As mentioned above;

[0026] In Formula IB, n, Ring A, R1, R3, m, R 10 As mentioned above;

[0027] R8 is selected from C1-C5 alkyl, preferably methyl, ethyl, propyl, more preferably methyl;

[0028] In formula I-B', n, ring A, R1, R3, m, R 10 As mentioned above;

[0029] In formula IC, n, ring A, R1, R2, R3, m, R 10 As mentioned above;

[0030] In Formula ID, n, Ring A, R1, R2, R3, m, R10 As mentioned above;

[0031] R9 is selected from a hydroxyl protecting group, preferably selected from a silyl ether hydroxyl protecting group, further preferably selected from a trimethylsilyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, a triisopropylsilyl group, and further preferably selected from a tert-butyldimethylsilyl group;

[0032] In formula I-D', n, ring A, R1, R2, R3, m, R 10 As mentioned above;

[0033] R7 in Formula IA, Formula IB, Formula I-B', Formula IC, Formula ID, or Formula I-D' is selected from an amino protecting group, preferably a trityl group.

[0034] In another aspect, the present invention provides a method for preparing a compound of formula I, comprising the following steps: dehydrating intermediate I-B-1 to obtain intermediate IA, followed by hydrogenation reduction to obtain intermediate IC, removing the amino protecting group from intermediate IC to obtain the compound of formula I-1, or removing the amino protecting group and water from intermediate I-B-1 in one step to obtain intermediate I-A', then subjecting the compound of formula I-1 to hydrogenation reduction, or removing the amino protecting group from intermediate I-B' in one step, and simultaneously subjecting the compound of formula I-2 to reduction, or removing the hydroxyl protecting group from intermediate I-D to obtain intermediate I-D', removing the amino protecting group from intermediate I-D' and dehydrating it to obtain the compound of formula I;

[0035] Among them, n, ring A, R1, R2, R3, m, R 10 As mentioned above;

[0036] R7 is selected from an amino protecting group, preferably a trityl group;

[0037] R9 is selected from hydroxyl protecting groups, preferably selected from silyl ether hydroxyl protecting groups, further preferably selected from trimethylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and further preferably selected from tert-butyldimethylsilyl. DETAILED DESCRIPTION

[0038] Unless otherwise indicated or there is an obvious conflict in the context, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commercial product or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0039] General Terms and Definitions

[0040] The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0041] The term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted", i.e., the structure or group is unsubstituted or substituted with one or more substituents described herein, wherein the substitution occurs at any reasonable position on the given structure or group as allowed by valence.

[0042] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent. When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring atom in the substitutable ring.

[0043] In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a specified substituent. Unless otherwise indicated, a substituent may be substituted at every possible position in the group. When more than one position in a given structure can be substituted with one or more of the specified substituents, the substituents may be the same or different at every possible position in the structure.

[0044] In addition, it should be noted that, unless otherwise expressly stated, the description method used in the present invention of "respectively and independently" should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0045] When the lower limit and upper limit of a numerical range are disclosed, any numerical value and any included range falling within the scope are specifically disclosed. In particular, each range of values ​​disclosed herein is understood to represent each numerical value and range encompassed within a wider range. When any variable (such as R), and a variable (such as R1, R2, R3, R4, R5, R6, R7, etc.) with a mark occurs more than once in the composition or structure of a compound, its definition in each case is independent at each occurrence. For example, if a group is substituted with 0, 1, 2 or 3 R substituents, the group can optionally be substituted with three R substituents at most, and the options for each R substituent in each case are independent of each other. That is, each R substituent can be identical or different.

[0046] Throughout this specification, substituents of the compounds disclosed herein are disclosed in terms of group classes or ranges. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group classes and ranges. For example, the expression mn as used herein refers to the range from m to n, as well as the subranges consisting of the individual values ​​therein, and the individual values.

[0047] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. "Alkyl" can have 1 to 8 carbon atoms, i.e., "C1-C8 alkyl", for example, C 1-5 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C8 alkyl, C 1-8 Alkyl, C 3-8 Alkyl groups can have 1-5 carbon atoms, i.e., "C1-C5 alkyl groups"; they can also have 1-3 carbon atoms, i.e., "C1-C3 alkyl groups", for example, C 1-3 Alkyl, C 1-2Alkyl, C3 alkyl. The term "C1-C5 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl disclosed independently. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), propyl (e.g., n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2)), butyl (e.g., n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl ( t-Bu, -C(CH3)3)), pentyl (e.g., 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)), hexyl (e.g., 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 )CH2CH3), 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)), heptyl, octyl, etc. For example, the expression "C1-C8" or "C 1-8 " covers the range of 1-8 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C1-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, etc. For another example, the expression "C1-C5" or "C 1-5" covers the range of 1-5 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., as well as C1, C2, C3, C4, C5, etc. For another example, the expression "C2-C5" or "C 2-5 " covers the range of 2-5 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C2-C3, C2-C4, C3-C5, C4-C5, etc., as well as C2, C3, C4, C5, etc. For another example, the expression "C1-C8" or "C 1-8 " covers the range of 1-8 carbon atoms, and should be understood to also cover any subranges therein, as well as each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, etc. For another example, the expression "ternary to octal" should be understood to cover any subranges therein and each point value, such as ternary to pentyl, ternary to hexayl, ternary to heptyl, ternary to octal, quaternary to pentyl, quaternary to hexayl, quaternary to heptyl, quaternary to octal, quinary to quinary, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, etc., as well as 3, 4, 5, 6, 7, 8, etc. Other similar expressions herein should also be understood in a similar manner.

[0048] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0049] The term "selected from..." means one or more elements from the group listed thereafter, selected independently, and may include combinations of two or more elements.

[0050] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0051] When it is stated that each carbon atom in a group may be optionally replaced by a heteroatom, the normal valencies of all atoms in the group in the present circumstances are not exceeded and a stable compound is formed.

[0052] When a group is described as being substituted with a substituent, the substituent is not present provided that the normal valences of all atoms in the group under the circumstances are not exceeded and a stable compound is formed.

[0053] When defining "Ring A", it does not include the double bond portion of the benzene ring to which it is fused.

[0054] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from one or more of oxygen, sulfur, and nitrogen. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." Examples of heteroaryl groups include 5-14 membered heteroaryl, 5-8 membered heteroaryl, 5-10 membered monocyclic or polycyclic heteroaryl, and 5-6 membered monocyclic heteroaryl. "5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from oxygen and sulfur" refers to a heteroaromatic system containing 5 to 8 ring atoms containing 1-3 heteroatoms selected from oxygen and sulfur. "5-8 membered heteroaryl containing 1 heteroatom selected from oxygen and sulfur" refers to a heteroaromatic system containing 5 to 8 ring atoms containing 1 heteroatom selected from oxygen or sulfur. The heteroaryl group can be a monocyclic or bicyclic ring system and is optionally substituted with one or more substituents described herein.

[0055] Specific examples of the term "5-6 membered heteroaryl containing one oxygen atom" include, but are not limited to, furyl and pyranyl. The heteroaryl group containing one oxygen atom may be optionally substituted with one or more substituents described herein.

[0056] Specific examples of the term "5-6 membered heteroaryl containing one sulfur atom" include, but are not limited to, thienyl and thiopyranyl. The heteroaryl group containing one sulfur atom may be optionally substituted with one or more substituents described herein.

[0057] The terms "heterocycle" and "heterocyclyl" are used interchangeably to refer to a monovalent or multivalent monocyclic, bicyclic, or tricyclic ring system containing 3-14 ring atoms, or 3-8 ring atoms, or 4-6 ring atoms, wherein one or more ring atoms are independently replaced by a heteroatom, wherein the heteroatom has the meaning as described herein, and the ring may be fully saturated or contain one or more degrees of unsaturation. Unless otherwise specified, a -CH2- group in a heterocyclyl group may optionally be replaced by -C(=O)-. A sulfur atom of the ring may optionally be oxidized to an S-oxide. A nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclyl groups include 3-14 membered heterocyclyl, 3-8 membered heterocyclyl, 4-6 membered heterocyclyl, and 5-10 membered monocyclic or bicyclic heterocyclyl. "3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur" refers to a heterocyclic ring system having 3 to 8 ring atoms containing 1-3 heteroatoms selected from oxygen, nitrogen and sulfur. "3-8 membered heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen and sulfur" refers to a heterocyclic ring system having 3 to 8 ring atoms containing 1 heteroatom selected from oxygen, nitrogen and sulfur. The heterocyclyl group can be a monocyclic or bicyclic ring system and is optionally substituted with one or more substituents described herein.

[0058] Specific examples of the term "a 4-6 membered heterocyclic group containing one nitrogen atom" include, but are not limited to, azetidinyl, tetrahydropyrrolyl, hexahydropyridinyl, dihydropyrrolyl, and tetrahydropyridinyl. The heterocyclic group containing one nitrogen atom may be optionally substituted with one or more substituents described herein. The term "the heterocyclic group may be substituted with a substituent" means that all substitutable positions on the "a 4-6 membered heterocyclic group containing one nitrogen atom" may be substituted with a substituent.

[0059] Specific examples of the term "4-6 membered heterocyclyl containing one sulfur atom" include, but are not limited to, thietanyl, tetrahydrothienyl, dihydrothienyl, tetrahydrothiopyranyl, dihydrothiopyranyl, 2H-thiopyranyl, and 4H-thiopyranyl. The heterocyclyl group containing one sulfur atom may be optionally substituted with one or more substituents described herein.

[0060] Specific examples of the term "4-6 membered heterocyclyl containing one oxygen atom" include, but are not limited to, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, and 4H-pyranyl. The heterocyclyl group containing one oxygen atom may be optionally substituted with one or more substituents described herein.

[0061] The term "alkenyl" refers to a general term for hydrocarbons containing a carbon-carbon double bond in the molecule, which is an unsaturated aliphatic hydrocarbon. For example: vinyl (-CH=CH2). The "alkene" can have 2-8 carbon atoms, i.e. "C2-C8" alkenyl, for example 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, etc. It can also have 2-5 carbon atoms, i.e. "C2-C4 alkenyl", such as C 2-4 Alkenyl, C 2-3 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, and the like.

[0062] The term "alkyne" is a general term for hydrocarbons containing a carbon-carbon triple bond in the molecule, which is an unsaturated aliphatic hydrocarbon. For example: ethynyl (-C≡CH). The "alkyne" can have 2-8 carbon atoms, i.e. "C2-C8" alkynyl, for example C2-8 Alkynyl, C 2-4 Alkynyl, C 2-5 Alkynyl, C3 alkynyl, C4 alkynyl, C6 alkynyl, C 2-6 Alkynyl, C 3-8 Alkynyl, C 3-6 Alkynyl, etc. It can also have 2-4 carbon atoms, i.e. "C2-C4 alkynyl", such as C 2-4 Alkynyl, C 2-3 Alkynyl, C3 alkynyl, C4 alkynyl, etc. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, etc.

[0063] The term "hydrogen (H)" refers to a single hydrogen atom, which may be linked to other groups, such as oxygen atoms, to form a hydroxyl group.

[0064] The term "halogen" or "halo" is understood to mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably selected from fluorine, chlorine, bromine atoms, more preferably selected from fluorine, chlorine, and even more preferably fluorine.

[0065] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein alkyl has the meaning as described herein. In one embodiment, the alkoxy group contains 1-8 carbon atoms. In one embodiment, the alkoxy group contains 1-5 carbon atoms; in another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein. 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-1-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), and the like.

[0066] The term "alkylthio" refers to an alkyl group attached to the rest of the molecule through a sulfur atom, wherein the alkyl group is as defined herein. In one embodiment, the alkylthio group contains 1-8 carbon atoms. In one embodiment, the alkylthio group contains 1-5 carbon atoms. In another embodiment, the alkylthio group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents as described herein. Examples of alkylthio 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), and the like.

[0067] The term "cycloalkyl" broadly includes cyclic hydrocarbon groups or cyclic alkenyl groups composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl group can be a monocyclic, fused polycyclic, bridged ring or spirocyclic structure. The cycloalkyl group can have 3-8 carbon atoms, i.e., "C3-C8 cycloalkyl", or can have 3-6 carbon atoms, i.e., "C3-C6 cycloalkyl", such as C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, C3 cycloalkyl. Examples of cycloalkyl groups include C3-C8 cycloalkyl and C3-C6 cycloalkyl, specifically including: cyclopropyl, cyclopropenyl, cyclobutenyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc. The term also covers cases where the C atoms can be substituted by oxo (=O). Typical cycloalkyl groups refer to cyclic saturated hydrocarbon groups composed of carbon atoms and hydrogen atoms. In addition, the term "cycloalkenyl" typically refers to an alicyclic hydrocarbon containing a carbon-carbon double bond in a molecule consisting of carbon atoms and hydrogen atoms. The cycloalkenyl group may have 3-8 carbon atoms, i.e., a "C3-C8 cycloalkenyl group," or may have 3-6 carbon atoms, i.e., a "C3-C6 cycloalkenyl group," such as a C6 cycloalkenyl group, a C5 cycloalkenyl group, a C4 cycloalkenyl group, or a C3 cycloalkenyl group. Examples of cycloalkenyl groups include C3-C8 cycloalkenyl groups and C3-C6 cycloalkenyl groups, specifically including cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, and the like. The term also encompasses situations in which a C atom may be substituted with an oxo (=O) group.

[0068] The term "hydroxy" refers to an -OH group.

[0069] Examples of the term "amino protecting group" include, but are not limited to, trityl, benzyloxycarbonyl, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, p-methoxybenzyl, and benzyl.

[0070] The term "hydroxy protecting group" is preferably a silyl ether hydroxy protecting group, examples of which include, but are not limited to, trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), and triisopropylsilyl (TIPS).

[0071] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0072] like The stereoisomers of The stereoisomers of The stereoisomers of

[0073] The term "tautomer" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization.

[0074] The term "pharmaceutically acceptable salt" refers to an organic salt or an inorganic salt of a compound of the present invention.

[0075] The term "pharmaceutically acceptable carrier" refers to substances that are non-irritating to organisms 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, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0076] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses.

[0077] Compounds of formula I

[0078] The present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0079] wherein X is selected from CH and N, preferably CH;

[0080] n is an integer selected from 1-3, preferably 1;

[0081] m is an integer selected from 1-8, preferably an integer selected from 1-3;

[0082] each R1 is independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl, the optional substituents being independently selected from halogen and hydroxy;

[0083] R2 is selected from H, cyano, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl, the optional substituents being independently selected from halogen and hydroxy;

[0084] R3 is selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl, the optional substituents being independently selected from halogen and hydroxy;

[0085] Ring A is selected from C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from oxygen and sulfur, preferably selected from C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen and sulfur, and 5-8 membered heteroaryl containing 1 heteroatom selected from oxygen and sulfur;

[0086] Each R 10 are independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl; the optional substituents are independently selected from halogen, C1-C8 alkyl and hydroxy;

[0087] R 11is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl, preferably selected from H and optionally substituted C1-C5 alkyl, further preferably H; the optional substituent is selected from hydroxyl and halogen;

[0088] And the compound of formula I is not: 5-(2,3-dihydro-benzofuran-7-ylmethyl)-1-imidazole, 8-((1H-imidazol-5-yl)methyl)-1,2,3,4-tetrahydroquinoline, or 5-(benzofuran-7-ylmethyl)-1H-imidazole, 5-((5-bromobenzofuran-7-yl)methyl)-1H-imidazole.

[0089] In one embodiment, the 3-8 membered heterocyclic group containing one heteroatom selected from oxygen, nitrogen and sulfur is a 3-8 membered heterocyclic group containing one sulfur atom, a 3-8 membered heterocyclic group containing one oxygen atom or a 3-8 membered heterocyclic group containing one nitrogen atom.

[0090] In one embodiment, the 3-8 membered heterocyclic group containing one sulfur atom is a 4-6 membered heterocyclic group containing one sulfur atom. In a preferred embodiment, the 3-8 membered heterocyclic group containing one sulfur atom and / or the 4-6 membered heterocyclic group containing one sulfur atom are selected from thietanyl, tetrahydrothienyl, dihydrothienyl, tetrahydrothiopyranyl and dihydrothiopyranyl.

[0091] In one embodiment, the 3-8 membered heterocyclic group containing one oxygen atom is a 4-6 membered heterocyclic group containing one oxygen atom. In a preferred embodiment, the 3-8 membered heterocyclic group containing one oxygen atom and / or the 4-6 membered heterocyclic group containing one oxygen atom are selected from oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl and dihydropyranyl.

[0092] In one embodiment, the 3-8 membered heterocyclic group containing one nitrogen atom is a 4-6 membered heterocyclic group containing one nitrogen atom. In a preferred embodiment, the 3-8 membered heterocyclic group containing one nitrogen atom and / or the 4-6 membered heterocyclic group containing one nitrogen atom are selected from azetidinyl, tetrahydropyrrolyl, dihydropyrrolyl, hexahydropyridinyl, tetrahydropyridinyl and dihydropyridinyl.

[0093] In one embodiment, the 5- to 8-membered heteroaryl group containing one heteroatom selected from oxygen and sulfur is a 5- to 8-membered heteroaryl group containing one oxygen atom or a 5- to 8-membered heteroaryl group containing one sulfur atom.

[0094] In one embodiment, the 5-8 membered heteroaryl group containing one oxygen atom is a 5-6 membered heteroaryl group containing one oxygen atom. In a preferred embodiment, the 5-8 membered heteroaryl group containing one oxygen atom and / or the 5-6 membered heteroaryl group containing one oxygen atom are selected from furyl and pyranyl.

[0095] In one embodiment, the 5-8 membered heteroaryl group containing one sulfur atom is a 5-6 membered heteroaryl group containing one sulfur atom. In a preferred embodiment, the 5-8 membered heteroaryl group containing one sulfur atom and / or the 5-6 membered heteroaryl group containing one sulfur atom are selected from thienyl and thiopyranyl.

[0096] In one embodiment, C1-C8 alkyl is selected from C1-C5 alkyl and C1-C3 alkyl. In a specific embodiment, C1-C8 alkyl, C1-C5 alkyl and C1-C3 alkyl are independently selected from methyl, ethyl, propyl, butyl or pentyl. In a more specific embodiment, C1-C8 alkyl, C1-C5 alkyl and C1-C3 alkyl are independently selected from methyl, ethyl and propyl.

[0097] In one embodiment, 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).

[0098] In one embodiment, C1-C8 alkoxy is selected from C1-C5 alkoxy and C1-C3 alkoxy. In a specific embodiment, C1-C8 alkoxy, C1-C5 alkoxy and C1-C3 alkoxy are independently selected from methoxy, ethoxy, propoxy, butoxy and pentoxy. In a more specific embodiment, C1-C8 alkoxy, C1-C5 alkoxy and C1-C3 alkoxy are independently selected from methoxy, ethoxy and propoxy.

[0099] In one embodiment, the C3-C8 cycloalkyl is a C3-C6 cycloalkyl. In a preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. In a more preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl are selected from cyclopropyl, cyclobutenyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl.

[0100] In one embodiment, the C3-C8 cycloalkenyl group is a C3-C6 cycloalkenyl group. In a preferred embodiment, the C3-C8 cycloalkenyl group and the C3-C6 cycloalkenyl group are selected from cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohexadienyl. In a more preferred embodiment, the C3-C8 cycloalkenyl group and the C3-C6 cycloalkenyl group are selected from cyclobutenyl, cyclopentenyl and cyclohexenyl.

[0101] In one embodiment, the C atoms in the C3-C8 cycloalkyl group and / or the C3-C6 cycloalkyl group are substituted with oxo (=O).

[0102] In one embodiment, the C atoms in the C3-C8 cycloalkenyl and / or C3-C6 cycloalkenyl are substituted with oxo (=O). 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. In a particularly preferred embodiment, the halogen is fluorine.

[0103] In one embodiment, the C1-C8 alkylthio group is selected from a C1-C5 alkylthio group and a C1-C3 alkylthio group. In a specific embodiment, the C1-C8 alkylthio group, the C1-C5 alkylthio group, and the C1-C3 alkylthio group are independently selected from a methylthio group, an ethylthio group, a propylthio group, a butylthio group, or a pentylthio group. In a more specific embodiment, the C1-C8 alkylthio group, the C1-C5 alkylthio group, and the C1-C3 alkylthio group are independently selected from a methylthio group, an ethylthio group, or a propylthio group.

[0104] In one embodiment, the C2-C8 alkenyl group is selected from C2-C4 alkenyl groups.

[0105] In one embodiment, the C2-C8 alkynyl group is selected from C2-C4 alkynyl groups.

[0106] In one embodiment, ring A is selected from C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-6 membered heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen and sulfur, and 5-6 membered heteroaryl containing 1 heteroatom selected from oxygen and sulfur; preferably selected from azetidinyl, oxetanyl, thietanyl, thienyl, furanyl, thiopyranyl, pyranyl, tetrahydropyrrolyl, hexahydropyridinyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydrothiophenyl, dihydropyridinyl, dihydrothiophenyl, tetrahydrothiopyranyl, dihydrothiopyranyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl; further preferably selected from tetrahydropyrrolyl, hexahydropyridinyl, dihydropyrrolyl, tetrahydropyridinyl, thienyl, furanyl, thiopyranyl, pyranyl, dihydropyridinyl, tetrahydrothiopyranyl, dihydrothiopyranyl, tetrahydrothiophenyl, dihydrothienyl, tetrahydrofuranyl, dihydrofuranyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and cyclopentadienyl.

[0107] In one embodiment, R1 is selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, hydroxy, optionally substituted C1-C8 alkylthio and optionally substituted C3-C6 cycloalkyl, preferably selected from H, halogen, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, hydroxy, optionally substituted C1-C5 alkylthio and optionally substituted C3-C6 cycloalkyl, further preferably selected from H, halogen, optionally substituted C1-C5 alkyl and hydroxy, further preferably selected from H, halogen, and optionally substituted C1-C5 alkyl, further preferably H or -F; the optional substituent is selected from hydroxy and halogen, preferably F.

[0108] In one embodiment, R1 is selected from H and halogen.

[0109] In one embodiment, R1 is H.

[0110] In one embodiment, R1 is halogen (eg, fluorine).

[0111] In one embodiment, R3 is selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, hydroxy, optionally substituted C1-C8 alkylthio and optionally substituted C3-C6 cycloalkyl, preferably selected from H, halogen, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, hydroxy and optionally substituted C3-C6 cycloalkyl, further preferably selected from H, halogen and optionally substituted C1-C5 alkyl, further preferably H; the optional substituent is selected from hydroxy and halogen, preferably F.

[0112] In one embodiment, R3 is H.

[0113] In one embodiment, each R 10 R2 is independently selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, hydroxy, optionally substituted C1-C8 alkylthio and optionally substituted C3-C6 cycloalkyl, preferably selected from H, halogen, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, hydroxy, optionally substituted C1-C5 alkylthio and optionally substituted C3-C6 cycloalkyl, further preferably selected from H, halogen and optionally substituted C1-C5 alkyl; the optional substituent is independently selected from halogen, C1-C8 alkyl and hydroxy, preferably selected from halogen, C1-C5 alkyl and hydroxy, further preferably halogen, and even more preferably F. In one embodiment, R2 is selected from H and optionally substituted C1-C8 alkyl, preferably selected from H and optionally substituted C1-C5 alkyl; the optional substituent is independently selected from halogen and hydroxy.

[0114] In one embodiment, R2 is selected from optionally substituted C1-C5 alkyl; said optional substituents are independently selected from halogen and hydroxy. In a preferred embodiment, R2 is selected from C1-C5 alkyl.

[0115] In one embodiment, the compound represented by Formula I is represented by Formula I-a' or Formula I-b':

[0116] In one embodiment, ring A is selected from a 5-6 membered heterocyclic group containing one oxygen atom, a 5-6 membered heteroaryl group containing one oxygen atom, and is preferably selected from More preferably, R2 is selected from optionally substituted C1-C8 alkyl; the optional substituents are independently selected from halogen and hydroxy.

[0117] In one embodiment, Ring A is selected from

[0118] In one embodiment, ring A is selected from a 4-6 membered heterocyclic group containing one sulfur atom, a 5-6 membered heteroaryl group containing one sulfur atom, and is preferably selected from More preferably,

[0119] In one embodiment, Ring A is selected from

[0120] In one embodiment, Ring A is selected from

[0121] In one embodiment, ring A is selected from a 4-6 membered heterocyclic group containing one nitrogen atom, preferably selected from

[0122] In one embodiment, ring A is selected from a 4-6 membered heterocyclic group containing one nitrogen atom, preferably selected from and R2 is selected from optionally substituted C1-C8 alkyl; said optional substituents are independently selected from halogen and hydroxy.

[0123] In one embodiment, Ring A is

[0124] In one embodiment, ring A is selected from C3-C8 cycloalkyl, preferably selected from More preferably, More preferably

[0125] In a specific embodiment, the compound represented by formula I is represented by formula II:

[0126] wherein R2 is selected from optionally substituted C1-C8 alkyl, the optional substituents being independently selected from halogen and hydroxyl;

[0127] n, R1, and R3 are as described above;

[0128] R4, R5, and R6 are each independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio, and optionally substituted C3-C8 cycloalkyl; and the optional substituents are independently selected from halogen, C1-C8 alkyl, and hydroxy.

[0129] In one embodiment, R4, R5, and R6 are each independently selected from H, halogen, and optionally substituted C1-C8 alkyl; and the optional substituents are independently selected from halogen and hydroxy.

[0130] In a specific embodiment, the compound represented by formula I is represented by formula III:

[0131] wherein R2 is selected from optionally substituted C1-C8 alkyl, wherein the optional substituents are independently selected from halogen, C1-C8 alkoxy, and hydroxy;

[0132] n, R1, and R3 are as described above;

[0133] R4, R5, and R6 are each independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio, and optionally substituted C3-C8 cycloalkyl; and the optional substituents are independently selected from halogen, C1-C8 alkyl, and hydroxy.

[0134] In one embodiment, R4, R5, and R6 are each independently selected from H, halogen, and optionally substituted C1-C8 alkyl; and the optional substituents are independently selected from halogen and hydroxy.

[0135] In a specific embodiment, the compound represented by formula I is represented by formula IV:

[0136] wherein n, R1, R2, and R3 are as described above;

[0137] R4, R5, and R6 are each independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio, and optionally substituted C3-C8 cycloalkyl; and the optional substituents are independently selected from halogen, C1-C8 alkyl, and hydroxy.

[0138] In one embodiment, R4, R5, and R6 are each independently selected from H, halogen, and optionally substituted C1-C8 alkyl; and the optional substituents are independently selected from halogen and hydroxy.

[0139] In a specific embodiment, the compound represented by formula I is represented by formula V:

[0140] wherein n, R1, R2, and R3 are as described above;

[0141] R4, R5, and R6 are each independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio, and optionally substituted C3-C8 cycloalkyl; and the optional substituents are independently selected from halogen, C1-C8 alkyl, and hydroxy.

[0142] In one embodiment, R4, R5, and R6 are each independently selected from H, halogen, and optionally substituted C1-C8 alkyl; and the optional substituents are independently selected from halogen and hydroxy.

[0143] In a specific embodiment, the compound represented by formula I is represented by formula VI:

[0144] wherein n, R1, R2, and R3 are as described above;

[0145] R4, R5, and R6 are each independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio, and optionally substituted C3-C8 cycloalkyl; and the optional substituents are independently selected from halogen, C1-C8 alkyl, and hydroxy.

[0146] In one embodiment, R4, R5, and R6 are each independently selected from H, halogen, and optionally substituted C1-C8 alkyl; and the optional substituents are independently selected from halogen and hydroxy.

[0147] In a specific embodiment, the compound of formula I is selected from any one of the following compounds:

[0148] intermediates

[0149] The present invention provides a compound or a salt thereof as shown in Formula IA, Formula IA', Formula IB, Formula IB', Formula IC, Formula ID or Formula ID',

[0150] In Formula IA, n, Ring A, R1, R3, m, R 10 As mentioned above;

[0151] In formula I-A', n, ring A, R1, R3, m, R 10 As mentioned above;

[0152] In Formula IB, n, Ring A, R1, R3, m, R 10 As mentioned above;

[0153] R8 is selected from C1-C5 alkyl, preferably methyl, ethyl, propyl, more preferably methyl;

[0154] In formula I-B', n, ring A, R1, R3, m, R 10 As mentioned above;

[0155] In formula IC, n, ring A, R1, R2, R3, m, R 10 As mentioned above;

[0156] In Formula ID, n, Ring A, R1, R2, R3, m, R10 As mentioned above;

[0157] R9 is selected from a hydroxyl protecting group, preferably selected from a silyl ether hydroxyl protecting group, further preferably selected from a trimethylsilyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, a triisopropylsilyl group, and further preferably selected from a tert-butyldimethylsilyl group;

[0158] In formula I-D', n, ring A, R1, R2, R3, m, R 10 As mentioned above;

[0159] R7 in (Formula IA, Formula IB, Formula I-B', Formula IC, Formula ID, or Formula I-D') is selected from an amino protecting group, preferably a trityl group.

[0160] Preparation method

[0161] The present invention provides a method for preparing a compound represented by formula I, comprising the following steps: performing a dehydration reaction on an intermediate I-B-1 to obtain an intermediate IA, followed by a hydrogenation reduction reaction to obtain an intermediate IC, removing the amino protecting group from the intermediate IC to obtain the compound represented by formula I-1, or removing the amino protecting group and water from the intermediate I-B-1 in one step to obtain an intermediate I-A', then performing a hydrogenation reduction reaction to obtain the compound represented by formula I-1, or removing the amino protecting group from the intermediate I-B' in one step and simultaneously performing a reduction reaction to obtain the compound represented by formula I-2, or removing the hydroxyl protecting group from the intermediate I-D to obtain an intermediate I-D', removing the amino protecting group from the intermediate I-D' and dehydrating it to obtain the compound represented by formula I;

[0162] Among them, n, ring A, R1, R2, R3, m, R 10 As mentioned above;

[0163] R7 is selected from an amino protecting group, preferably a trityl group;

[0164] R9 is selected from hydroxyl protecting groups, preferably selected from silyl ether hydroxyl protecting groups, further preferably selected from trimethylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and further preferably selected from tert-butyldimethylsilyl.

[0165] Beneficial technical effects of the present invention

[0166] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0167] The present invention relates to a class of novel structural compounds, which exhibit good α2 adrenergic receptor agonist activity and can be used to prepare drugs related to α2 adrenergic receptor agonists. They can further be used to prepare drugs that produce sedation, and / or analgesia, and / or anesthetic effects, and / or anti-anxiety, and / or inhibition of sympathetic nerve activity, and / or treatment of insomnia, and / or treatment of mental disorders in humans or animals. They can further be used to prepare drugs that produce sedation, and / or analgesia, and / or anesthetic effects, and / or treatment of insomnia, and / or treatment of mental disorders in humans or animals. These compounds have good pharmacodynamic activity and also exhibit good pharmacokinetic properties, good circulation stability, high potency, short maintenance time, rapid onset of action in the body, and few side effects, and have good clinical application prospects.

[0168] Example

[0169] The following embodiments of the present invention are described in detail. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Unless otherwise specified, the ratios, percentages, etc. referred to herein are all by weight.

[0170] Synthesis Example

[0171] [Corrected 01.07.2024 according to Rule 91] Synthesis Scheme 1 of Some Examples

[0172] The brominated aromatic ring compound undergoes lithium-halogen exchange under the action of butyl lithium, and then nucleophilically attacks 1-trityl-4-acetylimidazole to obtain intermediate Ⅰ-a. Ⅰ-a is dehydrated under the action of monoethyl oxalyl chloride / triethylamine to obtain intermediate Ⅰ-b. Ⅰ-b is hydrogenated and reduced under the action of Pd / C to obtain intermediate Ⅰ-c. Ⅰ-c is deprotected under the action of trifluoroacetic acid to obtain the compound shown in formula Ⅰ-1.

[0173] [Corrected 01.07.2024 according to Rule 91] Synthesis Scheme 2 of Some Examples

[0174] The brominated aromatic ring compound undergoes lithium-halogen exchange under the action of butyl lithium, and then nucleophilically attacks 1-trityl-4-acetylimidazole to obtain intermediate Ⅰ-a. Under the action of trifluoroacetic acid / triethylsilyl hydride, Ⅰ-a removes the trityl group and water in one step to obtain intermediate Ⅰ-d. Ⅰ-d is hydrogenated and reduced under the action of Pd / C to obtain the compound shown in formula Ⅰ-1.

[0175] [Corrected 01.07.2024 according to Rule 91] Synthesis Scheme 3 of Some Examples

[0176] The brominated aromatic ring compound undergoes lithium-halide exchange under the action of butyl lithium, and then nucleophilically attacks 1-trityl-4-formyl imidazole to obtain intermediate Ⅰ-e. Ⅰ-e is further subjected to one-step removal of the trityl group and reduction under the action of trifluoroacetic acid / triethylsilyl hydride to obtain the compound shown in formula Ⅰ-2.

[0177] [Corrected 01.07.2024 according to Rule 91] Synthesis Scheme 4 of Some Examples

[0178] The brominated aromatic ring compound undergoes lithium-halogen exchange under the action of butyl lithium, and then nucleophilically attacks 1-trityl-4-acetylimidazole to obtain intermediate Ⅰ-f. Ⅰ-f is dehydrated under the action of monoethyl oxalyl chloride / triethylamine to obtain intermediate Ⅰ-g. Ⅰ-g is hydrogenated and reduced under the action of Pd / C to obtain intermediate Ⅰ-h. Ⅰ-h is deprotected under the action of TBAF to obtain intermediate Ⅰ-i. Ⅰ-i is deprotected and dehydrated under the action of p-toluenesulfonic acid to obtain the compound shown in formula Ⅰ-3.

[0179] [Corrected 01.07.2024 according to Rule 91] Synthesis Scheme 5 of Some Examples

[0180] The brominated aromatic ring compound is coupled with tribenzyl(1-ethoxyvinyl)stannane under the catalysis of tetrakistriphenylphosphine palladium to obtain intermediate Ij, Ij is hydrolyzed under the action of hydrochloric acid to obtain intermediate Ik, I-k undergoes a nucleophilic reaction with 4-iodo-1-(triphenylmethyl)imidazole under the action of i-PrMgBr to obtain intermediate Ia, Ia is dehydrated under the action of monoethyl oxalyl chloride / triethylamine to obtain intermediate I-b, I-b is hydrogenated and reduced under the action of Pd / C to obtain intermediate I-c, and I-c is deprotected under the action of trifluoroacetic acid to obtain the compound shown in formula I-1.

[0181] [Corrected 01.07.2024 according to Rule 91] Synthesis Scheme 6 of Some Examples

[0182] The brominated aromatic ring compound is coupled with tribenzyl(1-ethoxyvinyl)stannane under the catalysis of tetrakistriphenylphosphine palladium to obtain intermediate Ij, Ij is hydrolyzed under the action of hydrochloric acid to obtain intermediate Ik, I-k undergoes a nucleophilic reaction with 4-iodo-1-(triphenylmethyl)imidazole under the action of i-PrMgBr to obtain intermediate Ia, Ia is dehydrated under the action of trifluoroacetic acid / triethylsilane to obtain intermediate I-b, I-b is hydrogenated and reduced under the action of Pd / C to obtain intermediate I-c, and I-c is deprotected under the action of trifluoroacetic acid to obtain the compound shown in formula I-1.

[0183] Example 1 Preparation of 4-(1-[thiochroman-8-yl)methyl]-1H-imidazole

[0184] 1.1 To a stirred mixture of 2-bromobenzenethiol (3.0 g, 15.867 mmol, 1 equiv) and NaOH (634.6 mg, 15.867 mmol, 1 equiv) in H2O (30 mL) was added dropwise a solution of 3-bromopropionic acid (2.43 g, 15.86 mmol, 1 equiv) and Na2CO3 (1.68 g, 15.867 mmol, 1 equiv) in H2O (30 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for an additional 2 h. The resulting mixture was cooled to room temperature and then acidified to pH = 1 with 2N HCl(aq). The resulting mixture was extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with NaCl(aq) (3 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to yield 3-(2-bromophenylthio)propanoic acid (4.02 g, crude). (ES,m / z):[M+1]=260.95,262.95.

[0185] 1.2 To a 250 mL round-bottom flask at room temperature were added 3-(2-bromophenylthio)propanoic acid (4.02 g, 15.39 mmol, 1 equiv) and H2SO4 (40.20 mL, 754.20 mmol, 48.99 equiv). The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction was quenched by the addition of water / ice (150 mL) at 0°C, and the aqueous layer was extracted with EtOAc (2 x 300 mL). The organic layer was washed with 100 mL of sodium bicarbonate (aq) and brine (2 x 400 mL). It was 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 8-bromo-2,3-dihydro-1-benzothiopyran-4-one (2.63 g). (ES,m / z):[M+1]=242.94, 244.94.

[0186] 1.3 8-Bromo-2,3-dihydro-1-benzothiopyran-4-one (2.63 g, 10.82 mmol, 1 equiv) and triethylsilane (24 mL) were dissolved in DCM (53 mL) and treated under a nitrogen atmosphere for 1 minute. BF₃·Et₂O (24 mL, 189.39 mmol, 17.51 ​​equiv) was then added dropwise at 0°C. The reaction mixture was then allowed to warm to room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (100 mL) at 0°C. The resulting mixture was extracted with CHCl₂ (2 x 200 mL), and the organic phases were combined. The mixture was washed with water (3 x 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (8:1) as the eluent to afford 8-bromo-3,4-dihydro-2H-1-benzothiopyran (2.04 g). (ES,m / z):[M+1]=228.96, 230.96.

[0187] 1.4 A solution of 8-bromo-3,4-dihydro-2H-1-benzothiopyran (500 mg, 2.18 mmol, 1 equiv) in THF (10 mL) was reacted with n-butyllithium (1.05 mL, 2.618 mmol, 1.2 equiv, 2.5 M in n-hexane) at -78°C under nitrogen for 1 hour. 1-Trityl-1H-imidazole-4-carbaldehyde (769.0 mg, 2.182 mmol, 1 equiv) was dissolved in THF (2 mL) and added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of saturated ammonium chloride (aq). The resulting mixture was extracted with EtOAc (2 × 70 mL), and the organic phases were combined, 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 thiochroman-8-yl(1-trityl-1H-imidazol-4-yl)methanol (300 mg), (ES, m / z): [M+1]=489.65.

[0188] 1.5 To a solution of thiochroman-8-yl(1-trityl-1H-imidazol-4-yl)methanol (285 mg, 0.583 mmol, 1 equiv) and triethylsilane (339.1 mg, 2.915 mmol, 5 equiv) in DCM (6 mL) was added dropwise TFA (665.0 mg, 5.830 mmol, 10 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (285 mg) was purified by preparative HPLC to yield 4-(1-[thiochroman-8-yl)methyl]-1H-imidazole (32.6 mg). (ES, m / z): [M+1] = 231.00. 1 H NMR(400MHz,DMSO-d6)δ7.52(d,J=1.1Hz,1H),6.99–6.78(m,3H),6.69(s, 1H),3.60(s,2H),3.14–2.89(m,2H),2.85–2.66(m,2H),2.12–1.87(m,2H).

[0189] Example 2 Preparation of 4-(1-[thiochroman-8-yl)ethyl]-1H-imidazole

[0190] 2.1 The compound was prepared according to the method of Example 1, except that 1-[1-(trityl)imidazol-4-yl]ethanone (commercially available) was used instead of 1-trityl-1H-imidazole-4-carbaldehyde to obtain 1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (160 mg). (ES, m / z): [M+1] = 503.68.

[0191] 2.2 At room temperature under nitrogen, to a solution of 1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (97 mg, 0.193 mmol, 1 equiv) in DCM (2 mL) was added TFA (0.3 mL, 1.930 mmol, 10 equiv). After 1 minute, triethylsilane (0.54 mL, 0.965 mmol, 5 equiv) was added dropwise at room temperature. The resulting mixture was stirred for an additional 4 hours at room temperature. The mixture was concentrated under reduced pressure to yield 4-[1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)vinyl]-1H-imidazole (250 mg, crude). (ES, m / z): [M+1] = 243.34.

[0192] 2.3 To a solution of 4-[1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)vinyl]-1H-imidazole (250 mg, 1.032 mmol, 1 equiv) in MeOH (6 mL) was added Pd / C (100 mg, 10% w / t) at room temperature. The mixture was hydrogenated under 10 atm of hydrogen pressure for 4 hours, filtered through a pad of Celite, and concentrated under reduced pressure. Purification by preparative HPLC gave 4-[1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)ethyl]-1H-imidazole (23.9 mg). (ES, m / z): [M+1] = 245.20. 1 H NMR(400MHz,DMSO-d6)δ7.49(d,J=10.5Hz,1H),6.98–6.62(m,4H),4.32(dq,J=29.2,6.9Hz,1 H),3.09–2.95(m,2H),2.78(q,J=6.0Hz,2H),2.04–1.92(m,2H),1.45(dd,J=16.1,7.1Hz,3H).

[0193] Example 3 Preparation of 4-[1-(Benzocyclobutene-2-yl)ethyl]-1H-imidazole

[0194] 3.1 To a stirred mixture of 2,5-dibromobenzocyclobutene (550 mg, 2.11 mmol, 1 equiv) and THF (1 mL) was added dropwise n-butyllithium (1.3 mL, 3.17 mmol, 1.5 equiv, 2.5 Min hexane) at -78°C under a nitrogen atmosphere. After the addition, the mixture was stirred for 0.5 h. A solution of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (743 mg, 2.11 mmol, 1 equiv) in THF (2 mL) was added dropwise over 3 min at -78°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The mixture was quenched with saturated aqueous ammonium chloride (30 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 20 mL), and the organic phases were combined, washed with saturated brine (1 x 20 mL), and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give 1-(5-bromobenzocyclobuten-2-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (216 mg). (ES, m / z): [M+1]=535,537.

[0195] 3.2 To a stirred solution of 1-(5-bromobenzocyclobuten-2-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (216 mg, 0.403 mmol, 1 equiv) in DCM (5 mL) was added dropwise TFA (5 mL) and triethoxysilane (5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 40° C. under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure to afford 4-[1-(5-bromobenzocyclobuten-2-yl)vinyl]-1H-imidazole (230 mg, crude). The crude mixture was used in the next step without further purification. (ES, m / z): [M+1] = 275, 277.

[0196] 3.3 To a stirred solution of 4-[1-(5-bromobenzocyclobuten-2-yl)vinyl]-1H-imidazole (216 mg, 0.779 mmol, 1 equiv) in MeOH (5 mL) at room temperature was added Pd / C (44 mg, 10% w / t) under a hydrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a hydrogen atmosphere. The resulting mixture was filtered through a pad of Celite, and the filter cake was washed with methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 4-[1-(benzocyclobuten-2-yl)ethyl]-1H-imidazole (31.8 mg). (ES, m / z): [M+1] = 199. 1 H NMR (400MHz, Chloroform-d) δ7.52(s,1H),7.08(t,J=7.5Hz,1H),6.98–6.50(m,3H),4.01(q,J=7.1Hz,1H),3.06–2.83(m,4H),1.57(d,J=6.8Hz,3H).

[0197] Example 4 Preparation of 4-(1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)-1H-imidazole

[0198] The compound was prepared according to the method of Example 3, except that 5-bromo-1,2,3,4-tetrahydronaphthalene (commercially available) was used instead of 2,5-dibromobenzocyclobutene to obtain 4-(1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)-1H-imidazole, (ES, m / z): [M+1] = 227.15. 1H NMR(400MHz,Chloroform-d)δ7.66(s,1H),7.03(t,J=7.5Hz,1H),6.95(s,1H),6.88(d,J=7.5Hz,1H), 6.73(s,1H),4.33(q,J=7.2,6.8Hz,1H),2.81–2.61(m,4H),1.85–1.68(m,4H),1.55(d,J=6.8Hz,3H).

[0199] Example 5 Preparation of 4-[1-(1,3-dihydroisobenzofuran-4-yl)ethyl]-1H-imidazole

[0200] The compound was prepared according to the method of Example 3, except that 4-bromo-1,3-dihydroisobenzofuran (commercially available) was used instead of 2,5-dibromobenzocyclobutene to obtain 4-[1-(1,3-dihydroisobenzofuran-4-yl)ethyl]-1H-imidazole, (ES, m / z): [M+1]=215. 1 H NMR(400MHz, Methanol-d4)δ7.56(d,J=1.2Hz,1H),7.23(t,J=7.5Hz,1H),7.11(d,J=7.5Hz,2H), 6.79(t,J=1.1Hz,1H), 4.91(dt,J=60.3,2.1Hz,4H), 4.05(q,J=7.2Hz,1H), 1.56(d,J=7.2Hz,3H).

[0201] At the same time, its stereoisomers were separated

[0202] Example 6 Preparation of 4-(1-(2-methyl-2,3-dihydro-1H-inden-4-yl)ethyl)-1H-imidazole

[0203] 6.1 To a solution of diethylzinc (76.90 mL, 76.900 mmol, 5 equiv) in DCM (30 mL) at 0°C under nitrogen was added TFA (8.77 g, 76.900 mmol, 5 equiv) dropwise. The mixture was stirred for 20 minutes, followed by the addition of diiodomethane (20.60 g, 76.900 mmol, 5 equiv) at room temperature over 20 minutes. To this mixture was added 4-bromo-3H-indene (3 g, 15.380 mmol, 1 equiv) at room temperature. The mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (3 x 20 mL) at room temperature, and the organic layers were combined. The mixture was washed with saturated brine (3 x 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 (1.65 g). (ES, m / z): [M]=208,210.

[0204] 6.2 To a solution of 5-bromo-1H,1aH,6H,6aH-cyclopropyl[a]indene (1.5 g, 7.174 mmol, 1 equiv) in tetrahydrofuran (20 mL) was added dropwise n-butyllithium (4.30 mL, 10.761 mmol, 1.5 equiv, 2.5 M in hexane) at -78°C under a nitrogen atmosphere. After the addition was complete, the mixture was stirred for 1 hour. Then, a solution of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (2.78 g, 7.891 mmol, 1.1 equiv) in THF (5 mL) was added. After the addition was complete, the mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 20 mL), and the organic phases were combined, washed with saturated brine (3 x 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 using PE / EA (5:1) as the eluent to give 1-(1H,1aH,6H,6aH-cyclopropyl[a]inden-5-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (1.8 g). (ES, m / z): [M+1] = 483.

[0205] The compound was prepared according to the method of Example 2, except that 1-(1H,1aH,6H,6aH-cyclopropyl[a]inden-5-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (prepared in-house) was used instead of 1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol to give 4-(1-(2-methyl-2,3-dihydro-1H-inden-4-yl)ethyl)-1H-imidazole, (ES, m / z): [M+1]=227. 1 H NMR(400MHz, Methanol-d4)δ8.27(dd,J=2.6,1.4Hz,1H),7.16–6.89(m,3H),6.77(ddt,J=11.2,6.5,3.0Hz,1H), 4.16(q,J=7.1Hz,1H),3.04–2.78(m,2H),2.53–2.04(m,3H),1.49(dd,J=7.2,4.1Hz,3H),1.02(d,J=6.1Hz,3H).

[0206] Example 7 Preparation of 4-[1-(1-methyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole

[0207] 7.1 To a stirred solution of 4-bromo-2,3-dihydroindan-1-one (1 g, 4.738 mmol, 1 equiv) in THF (25 mL) at 0°C under a nitrogen atmosphere was added methylmagnesium bromide (1.90 mL, 170 mmol, 1.2 equiv, 3 M in THF) dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched by the addition of saturated ammonium chloride (10 mL). The resulting mixture was extracted with EtOAc (3 x 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 4-bromo-1-methyl-2,3-dihydroindan-1-ol (0.97 g) as a colorless oil. (ES, m / z): [M] = 226, 228.

[0208] 7.2 To a 20 mL sealed tube was added 4-bromo-1-methyl-2,3-dihydroindan-1-ol (400 mg, 1.761 mmol, 1 equiv), toluene (8 mL), and p-toluenesulfonic acid (30.33 mg, 0.176 mmol, 0.10 equiv) at room temperature. The resulting mixture was stirred at 110°C for 3 hours. The resulting mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (5:1) as the eluent to afford 4-bromo-1-methyl-3H-indene (300 mg) as a colorless oil. (ES, m / z): [M] = 208, 210.

[0209] 7.3 To a solution of 4-bromo-1-methyl-3H-indene (350 mg, 1.674 mmol, 1 equiv) in THF (10 mL) was added dropwise n-butyllithium (1.00 mL, 2.5 mmol, 1.5 equiv, 2.5 M in hexane) at -78°C under a nitrogen atmosphere. The mixture was stirred for 1 hour, followed by the addition of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (707.9 mg, 2.009 mmol, 1.2 equiv). The mixture was warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride (10 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (1 x 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-(1-methyl-3H-inden-4-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (700 mg). (ES, m / z): [M+1]=483.

[0210] 7.4 To a solution of 1-(1-methyl-3H-inden-4-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (600 mg, 1.243 mmol, 1 equiv) in DCM (8 mL) at room temperature under a nitrogen atmosphere was added TEA (1.01 g, 9.944 mmol, 8 equiv). The mixture was stirred for 2 minutes, cooled to 0°C, and then ethyl oxalyl chloride (339.5 mg, 2.486 mmol, 2 equiv) was added. The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative column chromatography to afford 4-[1-(1-methyl-3H-inden-4-yl)vinyl]-1-(triphenylmethyl)imidazole (120 mg). (ES, m / z): [M+1] = 465.

[0211] 7.5 To a 20 mL round-bottom flask was added 4-[1-(1-methyl-3H-inden-4-yl)vinyl]-1-(triphenylmethyl)imidazole (60 mg, 0.129 mmol, 1 equiv), MeOH (2 mL), and Pd / C (30 mg, 10% w / t) at room temperature. The resulting mixture was stirred under a hydrogen atmosphere for 3 hours. The resulting mixture was filtered through a pad of Celite, and the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford 4-[1-(1-methyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1-(triphenylmethyl)imidazole (20 mg, crude). (ES, m / z): [M+1] = 469.

[0212] 7.6 To a 20 mL round-bottom flask was added 4-[1-(1-methyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1-(triphenylmethyl)imidazole (60 mg, 0.128 mmol, 1 equiv) and DCM (3 mL) / TFA (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to yield 4-[1-(1-methyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (5.1 mg). (ES, m / z): [M+1] = 227. 1 H NMR(400MHz,Methanol-d4)δ7.53(s,1H),7.17–6.84(m,3H),6.70(s,1H),4.30–4 .07(m,1H),2.98–2.64(m,2H),2.29(s,1H),1.57–1.47(m,3H),1.34–1.21(m,5H).

[0213] Example 8 Preparation of 4-[1-(1H-inden-4-yl)ethyl]-1H-imidazole

[0214] 8.1 To a solution of 7-bromo-2,3-dihydroindan-1-one (11 g, 52.118 mmol, 1 equiv) in THF (100 mL) and methanol (50 mL) was added portionwise NaBH₄ (10.75 g, 284.280 mmol, 6 equiv) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with ice-cold water (100 mL) at room temperature and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (1 x 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 using PE / EA (1:1) as the eluent to afford 7-bromo-2,3-dihydro-1H-indan-1-ol (9.8 g) as a colorless liquid. (ES, m / z) = 212, 214.

[0215] 8.2 At room temperature under a nitrogen atmosphere, imidazole (4.10 g, 60.260 mmol, 1.2 equiv) and 7-bromo-2,3-dihydro-1H-inden-1-ol (10.7 g, 50.217 mmol, 1 equiv) were dissolved in THF (100 mL), followed by the addition of tert-butyldimethylsilyl chloride (15.14 g, 100.434 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL), and the organic phases were combined. The organic layer was washed with water (1 x 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give [(7-bromo-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (15.2 g) as a pale yellow oil.

[0216] 8.3 To a solution of [(7-bromo-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (6 g, 18.330 mmol, 1 equiv) in THF (100 mL) was added dropwise n-butyllithium (11.00 mL, 27.45 mmol, 1.5 equiv, 2.5 M in hexane) at -78°C under a nitrogen atmosphere. The mixture was stirred for 1 hour, followed by the addition of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (9.69 g, 27.495 mmol, 1.2 equiv). The mixture was warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride (200 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic phases were washed with brine (1 x 200 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-[3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl]-1-(1-trityl-1H-imidazol-4-yl)ethanol (10.2 g). (ES, m / z): [M+1]=601.

[0217] 8.4 To a solution of 1-[3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl]-1-(1-trityl-1H-imidazol-4-yl)ethanol (6 g, 9.985 mmol, 1 equiv) in DCM (70 mL) at room temperature under a nitrogen atmosphere was added TEA (4.04 g, 39.940 mmol, 4 equiv). The mixture was stirred for 2 minutes, cooled to 0°C, and then ethyl oxalyl chloride (2.73 g, 19.970 mmol, 2 equiv) was added. The resulting mixture was stirred at room temperature overnight and quenched by addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were washed with brine (1 × 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-{3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl}vinyl)-1-(triphenylmethyl)imidazole (4.0 g) as a yellow solid (ES, m / z): [M+1]=583.

[0218] 8.5 To a 100 mL round-bottom flask was added 4-(1-{3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl}vinyl)-1-(triphenylmethyl)imidazole (4 g, 6.863 mmol, 1 equiv), MeOH (30 mL), and Pd / C (0.15 g, 10% w / t) at room temperature. The resulting mixture was stirred under a hydrogen atmosphere for 3 hours. The resulting mixture was filtered through a pad of Celite, and the filter cake was washed with methanol (3×50 mL). The filtrate was concentrated under reduced pressure to yield 4-(1-{3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl}ethyl)-1-(triphenylmethyl)imidazole (2.1 g). (ES, m / z): [M+1] = 585.

[0219] 8.6 To a solution of 4-(1-{3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl}ethyl)-1-(triphenylmethyl)imidazole (4.6 g, 7.892 mmol, 1 equiv) in tetrahydrofuran (40 mL) was added TBAF (39.46 mL, 39.460 mmol, 5 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 80 mL), and the organic phases were combined. The organic layer was washed with water (1 x 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 7-{1-[1-(triphenylmethyl)imidazol-4-yl]ethyl}-2,3-dihydro-1H-inden-1-ol (1.8 g) as an off-white solid. (ES, m / z): [M+1] = 471.

[0220] 8.7 TsOH (0.10 g, 0.595 mmol, 0.2 equiv) was added to a solution of 7-{1-[1-(triphenylmethyl)imidazol-4-yl]ethyl}-2,3-dihydro-1H-inden-1-ol (1.4 g, 2.975 mmol, 1 equiv) in ACN (20 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70° C. overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 4-[1-(1H-inden-4-yl)ethyl]-1H-imidazole (389 mg). (ES, m / z): [M+1] = 211. 1H NMR (400MHz, Methanol-d4) δ8.35–7.87(m,1H),7.35(d,J=7.3Hz,1H),7.29–7.18(m,1H),7.12(t,J=7.4Hz,1H),6.9 8(dt,J=13.5,7.5Hz,2H),6.56(ddd,J=9.3,5.8,3.6Hz,1H),4.63–4.27(m,1H),3.39(s,2H),1.64(d,J=6.3Hz,3H).

[0221] At the same time, its stereoisomers were separated

[0222] Example 9 Preparation of 4-[1-(1,3-dihydrobenzo[c]thiophen-4-yl)ethyl]-1H-imidazole

[0223] 9.1 To a stirred solution of 3-bromo-1,2-dimethylbenzene (2.0 g, 10.807 mmol, 1 equiv) and AIBN (0.41 g, 2.486 mmol, 0.23 equiv) in CCl₄ (30 mL) was added portionwise NBS (3.85 g, 21.614 mmol, 2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with water / ice (100 mL) at 0°C. The resulting mixture was extracted with dichloromethane (3 x 100 mL), and the organic layers were combined, washed with water (1 x 100 mL), and dried over anhydrous Na₂SO₄. Filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (12:1) as eluent to give 1-bromo-2,3-bis(bromomethyl)benzene (1.7 g) as a colorless oil. (ES, m / z): [m / z] = 339.8, 341.8, 343.8, 345.8.

[0224] 9.2 Sodium sulfide (182.0 mg, 2.333 mmol, 1 equiv) was dissolved in H2O (2.4 mL) and stirred at 80°C for 20 minutes under a nitrogen atmosphere. A solution of 1-bromo-2,3-bis(bromomethyl)benzene (800 mg, 2.333 mmol, 1 equiv) in ethanol (8.4 mL) was then added dropwise at 80°C under a nitrogen atmosphere. The resulting mixture was stirred at 80°C overnight under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 20 mL), and the organic layers were combined. The mixture was washed with water (1 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (12:1) as the eluent to afford 4-bromo-1,3-dihydro-2-benzo[c]thiophene (220 mg) as a colorless oil. (ES, m / z): [M] = 214, 216.

[0225] The compound was prepared according to the method of Example 3, except that 4-bromo-1,3-dihydro-2-benzo[c]thiophene was used instead of 2,5-dibromobenzocyclobutene to give 4-[1-(1,3-dihydrobenzo[c]thiophen-4-yl)ethyl]-1H-imidazole. (ES, m / z): [M+1] = 231. 1 H NMR (400MHz, Chloroform-d) δ7.46(s,1H),7.05(dt,J=15.8,7.5Hz,2H),6.87(d,J=7.3Hz,1H),6.65(s,1H),4.50–3.74(m,5H),1.50(d,J=7.1Hz,3H).

[0226] Example 10 Preparation of 4-[1-(2,3-dihydrobenzofuran-7-yl)ethyl]-1H-imidazole

[0227] The compound was prepared according to the method of Example 1, except that 7-bromo-2,3-dihydrobenzofuran was used instead of 8-bromo-3,4-dihydro-2H-1-benzothiopyran, and 1-[1-(trityl)imidazol-4-yl]ethanone was used instead of 1-trityl-1H-imidazole-4-carbaldehyde to give 4-[1-(2,3-dihydrobenzofuran-7-yl)ethyl]-1H-imidazole. (ES, m / z): [M+1] = 215. 1H NMR (400MHz, Methanol-d4) δ7.55(d,J=1.2Hz,1H),7.03(dd,J=7.2,1.4Hz,1H),6.82(d,J=7.7Hz,1H),6.7 8–6.69(m,2H),4.52(t,J=8.7Hz,2H),4.28(q,J=7.2Hz,1H),3.17(t,J=8.7Hz,2H),1.54(d,J=7.1Hz,3H).

[0228] At the same time, its stereoisomers were separated

[0229] Example 11 4-[1-(6-Fluoro-1H-inden-4-yl)ethyl]-1H-imidazole

[0230] 11.1 To a mixture of 7-bromo-5-fluoro-2,3-dihydroindan-1-one (5 g, 21.829 mmol) in THF (40 mL) and MeOH (20 mL) at 0°C under a nitrogen atmosphere was added NaBH4 (3.30 g, 87.316 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with water (1 x 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 (5:1) to afford 7-bromo-5-fluoro-2,3-dihydro-1H-indan-1-ol (4.6 g) as a yellow oil. (ES,m / z):[M-18+1]=213,215.

[0231] 11.2 At room temperature and under a nitrogen atmosphere, 7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-ol (5 g, 21.639 mmol) and imidazole (2.95 g, 43.278 mmol) were added to a DCM (50 mL) solution and stirred. Tert-butyldimethylsilyl chloride (3.91 g, 25.967 mmol) was then added portionwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. It was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (12:1) as the eluent to afford [(7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (7 g) as a colorless oil.

[0232] 11.3 Under a nitrogen atmosphere, [(7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (5.4 g, 15.637 mmol) was added to a solution of THF (60 mL). n-BuLi (9.38 mL, 23.456 mmol, 2.5 M in n-hexane) was added at -78°C. The mixture was allowed to react for 40 minutes, followed by the dropwise addition of a solution of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (5.51 g, 15.637 mmol) in THF (20 mL) at -78°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched by the addition of saturated aqueous NH4Cl (200 mL) at room temperature. The resulting mixture was extracted with CHCl (3 × 200 mL). The combined organic layers were washed with water (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (1:1) as eluent to give 1-[3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (5.2 g) as a yellow oil. (ES, m / z): [M+1] = 619.

[0233] 11.4 At room temperature under a nitrogen atmosphere, 1-[3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (5 g, 8.079 mmol) was added to a DCM (50 mL) solution, followed by the addition of triethylamine (6.54 g, 64.632 mmol) and the reaction was continued for 1 minute. Then, ethyl oxalyl chloride (4.41 g, 32.316 mmol) was added dropwise at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]vinyl]-1-(triphenylmethyl)imidazole (3.8 g) as a yellow oil. (ES, m / z): [M+1]=601.

[0234] 11.5 10% Pd / C (0.04 g) and 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]vinyl]-1-(triphenylmethyl)imidazole (1 g, 1.664 mmol) were added to a MeOH (10 mL) solution at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 40 minutes. The resulting reaction mixture was filtered through Celite, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (5:1) as the eluent to afford 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]ethyl]-1-(triphenylmethyl)imidazole (900 mg) as a yellow oil. (ES, m / z): [M+1] = 603.

[0235] 11.6 Tetrabutylammonium fluoride (18.41 mL, 18.411 mmol, 1 M in THF) was added to a solution of 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]ethyl]-1-(triphenylmethyl)imidazole (3.7 g, 6.137 mmol) in THF (60 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (1 x 100 mL) and dried over anhydrous NaSO. 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-fluoro-7-[1-[1-(triphenylmethyl)imidazol-4-yl]ethyl]-2,3-dihydro-1H-inden-1-ol (2.1 g) as a colorless oil. (ES, m / z): [M+1]=489.

[0236] 11.7 p-Toluenesulfonic acid (888.1 mg, 5.158 mmol) was added to a solution of 5-fluoro-7-[1-[1-(triphenylmethyl)imidazol-4-yl]ethyl]-2,3-dihydro-1H-inden-1-ol (4.2 g, 8.596 mmol) in acetonitrile (80 mL) at room temperature. The resulting mixture was stirred at 70°C under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (0.1% NH3.H2O + 10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. This afforded 4-[1-(6-fluoro-1H-inden-4-yl)ethyl]-1H-imidazole (1.9 g). (ES, m / z): [M+1] = 229. 1 H NMR (400MHz, Methanol-d4) δ7.57(d,J=1.2Hz,1H),7.05(dd,J=8.6,2.3Hz,1H),6.97(dt,J=4.5,2.0Hz,1H),6.80(d,J=1.1Hz,1H ), 6.75 (dd, J = 10.9, 2.4Hz, 1H), 6.52 (dt, J = 5.8, 2.1Hz, 1H), 4.44 (q, J = 7.2Hz, 1H), 3.38 (d, J = 2.2Hz, 2H), 1.60 (d, J = 7.2Hz, 3H).

[0237] 11.8 4-[1-(6-Fluoro-1H-inden-4-yl)ethyl]-1H-imidazole (500 mg) was purified by chiral HPLC under the following conditions (Column: (S,S)-Whelk-O1, 4.6*50 mm, 3 μm; Gradient: isocratic % B) to give 4[(1R)-1-(6-fluoro-1-inden-4-ylethyl]-1H-imidazole (11-a, 271 mg) (retention time 3.29 min) and 4-[(1S)-1-(6-fluoro-1H-inden-4-yl)ethyl]-1H-imidazole (11-b, 274 mg) (retention time 4.22 min).

[0238] 4-[(1R)-1-(6-fluoro-1H-inden-4-yl)ethyl]-1H-imidazole (11-a) (ES, m / z): [M+1]=229, 1HNMR(400MHz,Methanol-d4)δ7.57(d,J=1.4Hz,1H),7.06(dd,J=8.6,2.5Hz,1H),7.00–6.93(m,1H),6.81(s,1H),6. 76(d,J=2.4Hz,1H), 6.52(dt,J=6.2,2.2Hz,1H), 4.44(q,J=7.2Hz,1H), 3.38(d,J=2.5Hz,2H), 1.60(d,J=7.2Hz,3H).

[0239] 4-[(1S)-1-(6-fluoro-1H-inden-4-yl)ethyl]-1H-imidazole (11-b) (ES, m / z): [M+1]=229, 1 HNMR(400MHz, Methanol-d4)δ7.74–7.50(m,1H),7.09–7.03(m,1H),7.00–6.93(m,1H),6.81(d,J=1.1Hz,1H),6.75(dd,J=10 .9,2.4Hz,1H),6.52(ddt,J=5.6,4.0,2.0Hz,1H),4.44(q,J=7.2Hz,1H),3.38(q,J=2.2Hz,2H),1.60(dd,J=7.2,1.3Hz,3H).

[0240] Example 12 Preparation of 4-[1-(6-fluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole

[0241] 12.1 At room temperature under a hydrogen atmosphere, 4-[1-(6-fluoro-1H-inden-4-yl)ethyl]-1H-imidazole (50 mg, 0.219 mmol) and 10% Pd / C (10 mg) were added to MeOH (1 mL), and the mixture was stirred under a hydrogen atmosphere for 1 hour. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (0.1% NH3.H2O + 10 mmol / L NH4HCO3), gradient from 10% to 30% over 10 minutes; detector, UV 254 nm. This afforded 4-[1-(6-fluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (34.1 mg). (ES, m / z): [M+1] = 231. 1H NMR (400MHz, Methanol-d4) δ7.57 (s, 1H), 6.80–6.72 (m, 2H), 6.60 (d, J = 10.4Hz, 1H), 4.17 (q, J=7.2Hz,1H),2.92–2.81(m,3H),2.81(s,1H),2.12–1.99(m,2H),1.53(dd,J=7.1,2.1Hz,3H).

[0242] Example 13 Preparation of 4-[1-(1-benzofuran-4-yl)ethyl]-1H-imidazole

[0243] 13.1 Under a nitrogen atmosphere, n-BuLi (0.46 mL, 1.141 mmol, 2.5 M in n-hexane) was added to a solution of 4-bromo-1-benzofuran (150 mg, 0.761 mmol, 1 equiv) in THF (4 mL). The mixture was reacted at -78°C for 45 minutes, followed by the dropwise addition of a solution of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (322.0 mg, 0.913 mmol, 1.2 equiv) in tetrahydrofuran (6 mL) at -78°C. The resulting mixture was stirred at room temperature for an additional 5 hours. The reaction was quenched by the addition of saturated NH4Cl (aqueous) (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 30% to 70% over 10 minutes; detector, UV 220 nm. 1-(1-benzofuran-4-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (340 mg) was obtained as a pale yellow oil. (ES, m / z): [M+1] = 471.

[0244] 13.2 To a solution of 1-(1-benzofuran-4-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (340 mg, 0.723 mmol) in DCM (8 mL) was added triethylsilane (840.1 mg, 7.230 mmol) at room temperature under nitrogen atmosphere for 1 minute, followed by the dropwise addition of trifluoroacetic acid (823.8 mg, 7.230 mmol) at room temperature. The resulting mixture was stirred for an additional 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. 4-[1-(1-benzofuran-4-yl)vinyl]-1H-imidazole (120 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 211.

[0245] 13.3 At room temperature and under nitrogen, 10% Pd / C (10 mg) was added to a solution of 4-[1-(1-benzofuran-4-yl)vinyl]-1H-imidazole (50 mg, 0.238 mmol) in MeOH (2 mL) in a 25 mL round-bottom flask. The mixture was hydrogenated using a hydrogen balloon under a hydrogen atmosphere for 2 hours at room temperature, filtered through Celite, and the filtrate concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 30% over 10 minutes; detector, UV 220 nm. 4-[1-(1-benzofuran-4-yl)ethyl]-1H-imidazole (13.6 mg) was obtained. (ES, m / z): [M+1] = 213. 1 H NMR (400MHz, Methanol-d4) δ7.66(d,J=2.1Hz,1H),7.56(s,1H),7.34(d,J=8.2Hz,1H),7.28–7.15( m,1H),7.04(d,J=7.4Hz,1H),6.85–6.70(m,2H),4.45(q,J=7.1Hz,1H),1.68(dd,J=7.3,1.8Hz,3H).

[0246] Example 14 Preparation of 4-[1-(2H-chroman-8-yl)ethyl]-1H-imidazole

[0247] 14.1 To a stirred solution of 8-bromo-2,3-dihydro-1-chromen-4-one (2 g, 8.808 mmol) in MeOH (14 mL) and THF (7 mL) at 0°C under a nitrogen atmosphere was added NaBH4 (666.4 mg, 17.616 mmol) in portions. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl solution (20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 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 8-bromo-3,4-dihydro-2H-1-chromen-4-ol (1.8 g) as a yellow oil. (ES, m / z): [M-18] = 211, 213.

[0248] 14.2 To a stirred mixture of 8-bromo-3,4-dihydro-2H-1-chromen-4-ol (1.7 g, 7.421 mmol) and imidazole (0.6 g, 8.905 mmol) in DMF (40 mL) was added tert-butyldimethylsilyl chloride (1.7 g, 11.132 mmol) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with water (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE / EA (7:1) to give [(8-bromo-3,4-dihydro-2H-1-chromen-4-yl)oxy](tert-butyl)dimethylsilane (2.2 g) as a yellow oil.

[0249] 14.3 Under nitrogen, a solution of [(8-bromo-3,4-dihydro-2H-1-chromen-4-yl)oxy](tert-butyl)dimethylsilane (2.1 g, 6.116 mmol) in THF (40 mL) was treated with n-BuLi (3.6 mL, 9.174 mmol, 2.5 M in n-hexane) at -78°C for 40 minutes, followed by the dropwise addition of a solution of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (2.4 g, 6.728 mmol) in tetrahydrofuran (10 mL) at -78°C. The resulting mixture was stirred overnight at room temperature under nitrogen. The reaction was quenched with saturated NH4Cl (aq) at room temperature. The resulting mixture was extracted with CHCl (3 x 100 mL). The combined organic layers were washed with water (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 70% over 10 minutes; detector, UV 254 nm. 1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-chromen-8-yl-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (1.2 g) was obtained as a yellow oil. (ES, m / z): [M+1] = 617.

[0250] 14.4 To a stirred mixture of 1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-chromen-8-yl-1-[(triphenylmethyl)imidazol-4-yl]ethanol (1.1 g, 1.783 mmol) and triethylamine (1.4 mL, 10.698 mmol) in DCM (22 mL) was added ethyl oxalyl chloride (730.3 mg, 5.349 mmol) dropwise at room temperature under nitrogen atmosphere. 1). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (12:1) to give 4-[1-[4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-chromen-8-yl]-vinyl]-1-(triphenylmethyl)imidazole (750 mg) as a yellow oil. (ES, m / z): [M+1] = 599.

[0251] 14.5 To a stirred solution of 4-[1-[4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-chromen-8-yl]-vinyl]-1-(triphenylmethyl)imidazole (500 mg, 0.835 mmol) in THF (10 mL) at room temperature was added 10% Pd / C (177.7 mg). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 30 min. The resulting mixture was filtered, and the filter cake was washed with THF (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel mobile phase, MeCN-water (0.1% NH3.H2O), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. 4-[1-[4-[(tert-Butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-chromen-8-yl]-ethyl]-1-(triphenylmethyl)imidazole (420 mg) was obtained as a yellow oil. (ES, m / z): [M+1]=601.

[0252] 14.6 To a stirred mixture of 4-[1-[4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-chromen-8-yl]-ethyl]-1-(triphenylmethyl)imidazole (400 mg, 0.666 mmol) in THF (8 mL) was added tetrabutylammonium fluoride (2.0 mL, 1.998 mmol, 1 M in THF) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction was quenched by the addition of saturated NH4Cl (aqueous solution) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel mobile phase, acetonitrile in water (0.1% NH₃·H₂O), gradient from 10% to 50% over 10 minutes; detector, UV at 254 nm. 8-[1-[1-(triphenylmethyl)imidazol-4-yl]ethyl]-3,4-dihydro-2H-1-chromen-4-ol (180 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 487.

[0253] 14.7 To a stirred mixture of 8-(-[1-[1-(triphenylmethyl)imidazol-4-yl]ethyl]-3,4-dihydro-2H-1-chromen-4-ol (80 mg, 0.164 mmol) in acetonitrile (2 mL) was added p-toluenesulfonic acid (113.2 mg, 0.656 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70° C. under nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under vacuum. The crude product (50 mg) was purified by preparative HPLC (column: XBridge Prep OBD A C18 column (30 × 150 mm, 5 μm); mobile phase A: water (10 mmol / L NH₄HCO₃ + 0.1% NH₃·H₂O), mobile phase B: methanol; flow rate: 60 mL / min; gradient: 20% B to 38% B over 10 minutes; wavelength: 254 nm / 220 nm; RT (min): 11.82 / 15.28) was used to obtain 4-[1-(2H-chroman-8-yl)ethyl]-1H-imidazole (14.3 mg). (ES, m / z): [M+1] = 227. 1 H NMR(400MHz, Methanol-d4)δ7.54(d,J=1.2Hz,1H),6.87–6.79(m,2H),6.79–6.71(m,2H),6.44(dq,J=9.8,1.7Hz, 1H), 5.82 (dtd, J=9.5, 3.6, 1.8Hz, 1H), 4.77 (dt, J=3.5, 1.6Hz, 2H), 4.44 (q, J=7.1Hz, 1H), 1.51 (d, J=7.2Hz, 3H).

[0254] Example 15 Preparation of 4-[1-(2,2-difluoro-1,3-dihydroindan-4-yl)ethyl]-1H-imidazole

[0255] 15.1 Diethylaminosulfur trifluoride (421.8 mg, 11.372 mmol) was added to a solution of 4-bromo-1,3-dihydroindan-2-one (600 mg, 2.843 mmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature overnight. The reaction was quenched by the addition of ice water (10 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (1 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (0.1% TFA), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. 4-Bromo-2,2-difluoro-1,3-dihydroindene (400 mg) was obtained as a light brown oil.

[0256] 15.2 To a solution of 4-bromo-2,2-difluoro-1,3-dihydroindene (350 mg, 1.502 mmol) in toluene (4 mL) was added tribenzyl(1-ethoxyvinyl)stannane (834.8 mg, 1.802 mmol) at room temperature under a nitrogen atmosphere. The reaction was allowed to proceed for 1 minute, followed by the addition of Pd(PPh3)4 (173.5 mg, 0.150 mmol) in portions at room temperature. The resulting mixture was stirred at 110°C under a nitrogen atmosphere overnight. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. 4-(1-ethoxyvinyl)-2,2-difluoro-1,3-dihydroindene (340 mg, crude) was obtained as a brown oil. (ES, m / z): [M+1] = 225.

[0257] 15.3 To a solution of 4-(1-ethoxyvinyl)-2,2-difluoro-1,3-dihydroindene (350 mg, 1.561 mmol) in toluene (5 mL) was added H₂O (1 mL) at room temperature under a nitrogen atmosphere for 1 minute, followed by the dropwise addition of 4 M hydrogen chloride solution (5 mL) at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (1 x 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 afford 1-(2,2-difluoro-1,3-dihydroindene-4-yl)ethanone (280 mg) as a light yellow oil. (ES, m / z): [M+1] = 197.

[0258] 15.4 To a solution of 4-iodo-1-(triphenylmethyl)imidazole (1 g, 2.292 mmol) in THF (10 mL) at 0°C under a nitrogen atmosphere was added i-PrMgBr (1.83 mL, 4.584 mmol, 1 M in THF). The mixture was allowed to react for 30 minutes, followed by the addition of a solution of 1-(2,2-difluoro-1,3-dihydroindan-4-yl)ethanone (0.30 g, 1.528 mmol) in THF (2 mL) in portions at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was quenched by the addition of saturated NH4Cl (aqueous solution) (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (1 x 10 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-(2,2-difluoro-1,3-dihydroindan-4-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (260 mg) as a yellow oil. (ES, m / z): [M+1] = 507.

[0259] 15.5 A solution of 1-(2,2-difluoro-1,3-dihydroindan-4-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (230 mg, 0.454 mmol) in DCM (2 mL) was added to trifluoroacetic acid (1.03 g, 9.080 mmol) at room temperature under a nitrogen atmosphere for 1 minute, followed by the dropwise addition of triethylsilane (1.05 g, 9.080 mmol) at room temperature. The resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. 4-[1-(2,2-difluoro-1,3-dihydroindan-4-yl)vinyl]-1H-imidazole (30 mg) was obtained as a colorless oil. (ES, m / z): [M+1]=247.

[0260] 15.6 Pd / C (3.9 mg, 10% w / t) was added to a solution of 4-[1-(2,2-difluoro-1,3-dihydroindan-4-yl)vinyl]-1H-imidazole (30 mg, 0.122 mmol) in tetrahydrofuran (3 mL) at room temperature. The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 30 minutes. The resulting mixture was filtered through celite, and the filter cake was washed with THF (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel mobile phase, MeCN-water (0.1% NH3.H2O), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. This afforded 4-[1-(2,2-difluoro-1,3-dihydroindan-4-yl)ethyl]-1H-imidazole (12 mg). (ES, m / z): [M+1] = 249. 1 H NMR (400MHz, Methanol-d4) δ7.56(d,J=1.2Hz,1H),7.18(t,J=7.6Hz,1H),7.07(dd,J=12.7,7.6 Hz,2H),6.76(d,J=1.3Hz,1H),4.11(q,J=7.2Hz,1H),3.43–3.31(m,4H),1.56(d,J=7.2Hz,3H).

[0261] Example 16 Preparation of 4-[1-(2-fluoro-1-benzofuran-7-yl)ethyl]-1H-imidazole

[0262] 16.1 To a stirred solution of 3-bromo-2-hydroxybenzaldehyde (2 g, 9.949 mmol) and DIEA (3.9 g, 29.847 mmol) in DCM at 0°C was added bromomethyl methyl ether (3.7 g, 29.847 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The resulting mixture was quenched with H2O (20 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with H2O (1 x 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 3-bromo-2-(methoxymethoxy)benzaldehyde (2.3 g) as a yellow oil. (ES, m / z): [M+1] = 245, 247.

[0263] 16.2 3-Bromo-2-(methoxymethoxy)benzaldehyde (1.5 g, 6.121 mmol) and ethyl 2,2-difluoro-2-(triphenylphosphono)acetate (4.3 g, 12.242 mmol) were added to NMP (30 mL), and the resulting mixture was stirred at 80°C for 2 h under N₂ protection. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (1 x 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 using PE / EA (3:1) as the eluent to afford 1-bromo-3-(2,2-difluorovinyl)-2-(methoxymethoxy)benzene (1.3 g) as a colorless oil.

[0264] 16.3 1-Bromo-3-(2,2-difluorovinyl)-2-(methoxymethoxy)benzene (2 g, 7.166 mmol) and HCl (261.2 g, 7.166 mmol) were added to MeOH (40 mL), and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (10 mL) and concentrated under vacuum. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water, 10%-60% gradient over 10 minutes; detector, UV 254 nm. 2-Bromo-6-(2,2-difluorovinyl)phenol (900 mg) was obtained as a colorless oil. (ES, m / z): [M+1] = 234,236.

[0265] 16.4 2-Bromo-6-(2,2-difluorovinyl)phenol (700 mg, 978 mmol) and DBU (544.1 mg, 3.574 mmol) were added to DMF (6 mL), and the resulting mixture was stirred at 100°C overnight. The mixture was then irradiated with microwaves at 100°C for 20 min. The resulting mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water, 10%-50% gradient over 10 minutes; detection, UV 254 nm. 7-Bromo-2-fluoro-1-benzofuran (170 mg) was obtained as a yellow oil.

[0266] 16.5 7-Bromo-2-fluoro-1-benzofuran (117 mg, 0.544 mmol, 1 equiv), tributyl(1-ethoxyethylene)tin (235.8 mg, 0.653 mmol, 1.2 equiv), and Pd(PPh3)4 (62.88 mg, 0.54 mmol, 1 equiv) were added to toluene (3 mL). The resulting mixture was stirred at 110°C overnight under N2 protection. The resulting mixture was cooled to room temperature. The resulting mixture was used directly in the next step without further purification. (ES, m / z): [M+1] = 207.

[0267] 16.6 7-(1-Ethoxyvinyl)-2-fluoro-1-benzofuran (120 mg, 582 mmol) was added to a mixture of hydrochloric acid (0.2 mL) and toluene (2.4 mL) and stirred at room temperature for 2 h. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with H₂O (0.2 mL) (3 x 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 using PE / EA (5:1) as the eluent to afford 1-(2-fluoro-1-benzofuran-7-yl)ethanone (88 mg) as a yellow oil. (ES, m / z): [M+1] = 179.

[0268] 16.7 4-iodo-1-(trityl)imidazole (281.6 mg, 645 mmol) and bromo(isopropyl)magnesium (0.645 mL, 0.645 mmol, 1M in THF) were added to DCM (0.8 mL), and the resulting mixture was stirred at 0°C for 20 min under N2 protection. 1-(2-fluoro-1-benzofuran-7-yl)ethanone (115 mg, 0.645 mmol) was then added dropwise. The resulting mixture was stirred at 0°C overnight under a nitrogen atmosphere. The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH4HCO3), gradient 10%-50% over 10 min; detector, UV 254 nm. 1-(2-fluoro-1-benzofuran-7-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (64 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 489.

[0269] 16.8 1-(2-Fluoro-1-benzofuran-7-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (63 mg, 0.129 mmol, 1 equiv) and triethanolamine (78.2 mg, 0.774 mmol, 6 equiv) were added to DCM (2 mL), followed by the dropwise addition of ethyl acetoacetate (52.8 mg, 0.387 mmol, 3 equiv) at 0°C. The resulting mixture was stirred at room temperature overnight under N2 protection. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 8:1) to afford 4-[1-(2-fluoro-1-benzofuran-7-yl)vinyl]-1-(trityl)imidazole (35 mg) as a colorless oil. (ES, m / z): [M+1] = 471.

[0270] 16.9 4-[1-(2-Fluoro-1-benzofuran-7-yl)vinyl]-1-(trityl)imidazole (40 mg, 0.175 mmol) and Pd / C (3.7 mg, 10% w / t) were added to MeOH (4 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (1 mL) (3 x 5 mL). The filtrate was concentrated under reduced pressure. The crude product (40 mg) was purified by pre-HPLC using the following conditions (Column: XBridge Prep OBD C18 column 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: MeOH; Flow rate: 60 mL / min; Gradient: 40% B to 58% B, 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 12.33 to give 4-[1-(2-fluoro-1-benzofuran-7-yl)ethyl]-1H-imidazole (5 mg). (ES, m / z): [M+1] = 231. 1 H NMR (400MHz, Methanol-d4) δ7.58(s,1H),7.35(dd,J=7.7,1.2Hz,1H),7.16(t,J=7.7Hz,1H),7.03(dd ,J=7.7,1.3Hz,1H),6.85(s,1H),6.00(d,J=6.4Hz,1H),4.57(q,J=7.2Hz,1H),1.68(d,J=7.3Hz,3H).

[0271] Example 17 Preparation of 4-[1-(1,1-dimethyl-1H-inden-4-yl)ethyl]-1H-imidazole

[0272] 17.1 TiCl4 (29.9 mL, 29.849 mmol) and dimethylzinc (42.6 mL, 42.642 mmol, 1 M in hexane) were added to DCM (10 mL). The resulting mixture was stirred at -40°C for 20 min under N2 protection, followed by the dropwise addition of a solution of 4-bromo-1-indanone (3 g, 14.214 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 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 to afford 4-bromo-1,1-dimethyl-2,3-dihydro-1H-indene (2.4 g) as a colorless oil.

[0273] 17.2 4-Bromo-1,1-dimethyl-2,3-dihydro-1H-indene (2.3 g, 10.216 mmol) and chromium trioxide (6.1 g, 61.296 mmol) were added to acetic acid (10 mL). The resulting mixture was stirred at 60°C for 3 h under N2 protection. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (0.1% FA), 10%-50% gradient over 20 minutes; detector, UV 254 nm. 7-Bromo-3,3-dimethyl-2H-indene-1-one (716 mg) was obtained as a brown solid. (ES, m / z): [M+1] = 239, 241.

[0274] 17.3 7-Bromo-3,3-dimethyl-2H-inden-1-one (716 mg, 2.994 mmol) and NaBH4 (679.6 mg, 17.964 mmol) were added to MeOH (3 mL) / THF (6 mL), and the resulting mixture was stirred at 0°C for 2 h. The mixture was then quenched with water. After concentration under reduced pressure, the residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (0.1% FA), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. 7-Bromo-3,3-dimethyl-1,2-dihydroindan-1-ol (210 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 223, 225.

[0275] 17.4 Under a nitrogen atmosphere, 7-bromo-3,3-dimethyl-1,2-dihydroindan-1-ol (110 mg, 0.456 mmol, 1 equiv) and imidazole (62.1 mg, 0.912 mmol, 2 equiv) were added to DCM (2 mL). The resulting mixture was stirred at room temperature, followed by the addition of tert-butyldimethylsilyl chloride (82.5 mg, 0.547 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 2 h. It was then quenched with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous NaSO. 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 [(7-bromo-3,3-dimethyl-1,2-dihydroindan-1-yl)oxy](tert-butyl)dimethylsilane (150 mg) as a yellow oil.

[0276] 17.5 Under nitrogen atmosphere, n-BuLi (0.4 mL, 0.802 mmol, 2.5 M in hexane) was added dropwise to a solution of [(7-bromo-3,3-dimethyl-1,2-dihydroindan-1-yl)oxy](tert-butyl)dimethylsilane (190 mg, 0.535 mmol) in THF (4 mL). The mixture was stirred at -78 ° C for 2 hours, followed by the dropwise addition of a solution of 1-[1-(trityl)imidazol-4-yl]ethanone (188.4 mg, 0.535 mmol) in THF (4 mL). The resulting mixture was stirred at room temperature overnight. The resulting mixture was quenched with saturated aqueous NH4Cl solution and extracted with DCM (3×100 mL). The combined organic layers were washed with water (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 70% over 10 minutes; detection, UV 254 nm. 1-(3-((tert-butyldimethylsilyloxy)-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)-1-(1-trityl-1H-imidazol-4-yl)ethanol (80 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 629.

[0277] 17.6 Ethyl chloroformate (104.5 mg, 0.765 mmol) was added dropwise to a solution of (3Z)-3-amino-2-(3-[(tert-butyldimethylsilyl)oxy]-1,1-dimethyl-2,3-dihydroindan-4-yl-4-[(trityl)amino]but-3-en-2-ol (158 mg, 0.255 mmol) and triethylamine (154.9 mg, 1.530 mmol) in DCM (1.5 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L The reaction mixture was stirred at 4°C for 10 minutes (10% to 55% gradient over 10 minutes); detection: UV 254 nm. 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-1,1-dimethyl-2,3-dihydroindan-4-yl]vinyl]-1-(trityl)imidazole (80 mg) was obtained as a colorless oil. (ES, m / z): [M+1] = 611.5.

[0278] 17.7 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-1,1-dimethyl-2,3-dihydroindan-4-yl]vinyl]-1-(trityl)imidazole (80 mg, 0.131 mmol) and Pd / C (2.79 mg, 10% w / t) were added to MeOH (2 mL), and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. The resulting mixture was filtered through Celite, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to give 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-1,1-dimethyl-2,3-dihydroindan-4-yl]ethyl]-1-(trityl)imidazole. The crude product was used directly in the next step without further purification. (ES, m / z): [M+1] = 613.

[0279] 17.8 4-[1-[3-[(tert-Butyldimethylsilyl)oxy]-1,1-dimethyl-2,3-dihydroindan-4-yl]ethyl]-1-(trityl)imidazole (45 mg, 0.073 mmol) and TBAF (57.6 mg, 0.219 mmol) were added to THF (1 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with water at room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 40% over 10 minutes; detection, UV 254 nm. The result was 7-[1-(1H-imidazol-4-yl)ethyl]-3,3-dimethyl-1,2-dihydroindan-1-ol (18 mg) as a colorless oil. (ES, m / z): [M+1] = 257.

[0280] 17.9 7-[1-(1H-imidazol-4-yl)ethyl]-3,3-dimethyl-1,2-dihydroindan-1-ol (18 mg, 0.070 mmol) and p-toluenesulfonic acid (2.4 mg, 0.014 mmol) were added to MeCN (0.4 mL), and the resulting mixture was stirred at 70°C for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and quenched with water at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. 4-[1-(1,1-dimethyl-1H-indan-4-yl)ethyl]-1H-imidazole (3.4 mg) was obtained. (ES, m / z): [M+1] = 239. 1 H NMR (400MHz, Methanol-d4) δ7.63(s,1H),7.18(d,J=7.4Hz,1H),7.10(t,J=7.5Hz,1H),6.96(d,J=7.6Hz,1H),6.80(s, 1H), 6.75 (d, J = 5.6Hz, 1H), 6.36 (d, J = 5.6Hz, 1H), 4.40 (q, J = 7.2Hz, 1H), 1.61 (d, J = 7.2Hz, 3H), 1.28 (d, J = 4.1Hz, 6H).

[0281] Example 18 Preparation of 7-[1-(1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-indole

[0282] 18.1 Under nitrogen atmosphere, n-BuLi (0.2 mL, 0.503 mmol, 2.5 M in hexane) was added dropwise to a solution of tert-butyl 7-bromo-2,3-dihydroindole-1-carboxylate (100 mg, 0.335 mmol) in THF (1 mL). The mixture was stirred at -78 ° C for 1 hour, followed by the dropwise addition of 1-[1-(trityl)imidazol-4-yl]ethanone (118.2 mg, 0.335 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 60% over 10 minutes; detection, UV 254 nm. 1-(indol-7-yl)-1-(1-triyl-1H-imidazol-4-yl)ethan-1-ol (60 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 454.

[0283] 18.2 1-(Indol-7-yl)-1-(1-triyl-1H-imidazol-4-yl)ethan-1-ol (400 mg, 0.700 mmol), TFA (800.1 mg, 6.999 mmol), and Et3SiH (813.54 mg, 7.000 mmol) were added to DCM (8 mL). The resulting mixture was stirred at room temperature for 2 h. After concentration under reduced pressure, the residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (0.1% FA), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. 7-[1-(1H-imidazol-4-yl)vinyl]-2,3-dihydro-1H-indole (80 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 212.

[0284] 18.3 7-[1-(1H-imidazol-4-yl)vinyl]-2,3-dihydro-1H-indole (75 mg, 0.355 mmol) and Pd / C (7.56 mg, 0.071 mmol, 10% w / t) were added to MeOH (1.5 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 h. The resulting mixture was filtered through Celite, and the filter cake was washed with MeOH (1.5 mL) (3 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product (60 mg) was purified by pre-HPLC using the following conditions (column: XBridge Prep OBD C18 Column 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: MEOH; flow rate: 60 mL / min; gradient: 40% B to 58% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.33) to yield 7-[1-(1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-indole (15.9 mg). (ES, m / z): [M+1] = 214. 1 H NMR (400MHz, Methanol-d4) δ7.55(d,J=1.2Hz,1H),6.96(dt,J=7.3,1.2Hz,1H),6.82(d,J=7.7Hz,1H),6.76(t,J=1.1Hz ,1H),6.66(t,J=7.5Hz,1H),4.08(q,J=7.2Hz,1H),3.44(t,J=8.2Hz,2H),2.98(t,J=8.3Hz,2H),1.56(d,J=7.2Hz,3H).

[0285] Example 19 Preparation of 4-[1-(1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-indole

[0286] 19.1 Under a nitrogen atmosphere, n-BuLi (221.1 mg, 3.452 mmol, 2.5 M in n-hexane) was added dropwise to a solution of tert-butyl 4-bromo-2,3-dihydroindole-1-carboxylate (500 mg, 2.301 mmol) in THF (1 mL), stirred at -78 ° C for 40 min, and then 1-[1-(trityl)imidazol-4-yl]ethanone (811.0 mg, 2.301 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. Saturated aqueous NH4Cl solution (20 mL) was added and the reaction was quenched at room temperature. The resulting mixture was extracted with EtOAc (3x20 mL). The combined organic layer was washed with water (1x20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (1:1) as the eluent to give tert-butyl 4-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)ethyl]indole-1-carboxylate (500 mg) as a brown oil. (ES, m / z): [M+1] = 572.

[0287] 19.2 Under a nitrogen atmosphere, ethyl oxalyl chloride (286.6 mg, 2.100 mmol) was added dropwise to a solution of tert-butyl 4-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)ethyl]indole-1-carboxylate (400 mg, 0.700 mmol) in DCM (10 mL) and stirred at room temperature for 1 minute. Triethylamine (424.8 mg, 4.200 mmol) was then added dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using PE / EA (5:1) as the eluent to afford tert-butyl 4-[1-(1-trityl-1H-imidazol-4-yl)vinyl]indole-1-carboxylate (320 mg) as a yellow oil. (ES, m / z): [M+1] = 554.

[0288] 19.3 Tert-butyl 4-[1-(1-trityl-1H-imidazol-4-yl)vinyl]indole-1-carboxylate (200 mg, 0.361 mmol) and 10% Pd / C (11.53 mg) were added to MeOH (5 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 40 minutes. The resulting mixture was filtered through celite, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. Tert-butyl 4-[1-[1-(trityl)imidazol-4-yl]ethyl]-2,3-dihydroindole-1-carboxylate (150 mg, crude) was obtained as a yellow solid. (ES, m / z): [M+1] = 556.

[0289] 19.4 Tert-butyl 4-[1-[1-(trityl)imidazol-4-yl]ethyl]-2,3-dihydroindole-1-carboxylate (100 mg, 0.180 mmol) was dissolved in TFA (1 mL) and DCM (4 mL). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. 4-[1-(1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-indole (15.2 mg) was obtained. (ES, m / z): [M+1] = 214. 1 H NMR (400MHz, Methanol-d4) δ7.53(s,1H),6.93(t,J=7.7Hz,1H),6.72(s,1H),6.54(t,J=7.1Hz,2H),4. 10(q,J=7.2Hz,1H),3.42(t,J=8.3Hz,2H),2.90(ddq,J=23.8,15.8,8.3Hz,2H),1.54(d,J=7.2Hz,3H).

[0290] Example 20 Preparation of N-(2,3-dihydro-1H-inden-4-yl)-1H-imidazol-4-amine

[0291] 20.1 Under a nitrogen atmosphere, 4-iodo-1-(trityl)imidazole (200 mg, 0.458 mmol), 2,3-dihydro-1H-inden-4-amine (73.27 mg, 0.550 mmol), X-phos (21.85 mg, 0.046 mmol), sodium tert-butoxide (88.11 mg, 0.916 mmol), and Xphos Pd G3 (38.80 mg, 0.046 mmol) were added to toluene (5 mL). The resulting mixture was stirred at 90°C overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (0.1% FA), gradient 40%-100% over 10 minutes; detection, UV 254 nm. N-(2,3-Dihydro-1H-inden-4-yl)-1-(trityl)imidazol-4-amine (70 mg) was obtained as a yellow solid. (ES, m / z): [M+1]=442.

[0292] 20.2 Trifluoroacetic acid (6 mL) was added dropwise to a solution of N-(2,3-dihydro-1H-inden-4-yl)-1-(trityl)imidazol-4-amine (70 mg, 0.159 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by pre-HPLC under the following conditions (column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 29% B to 44% B over 10 min; wavelength: 254 nm / 220 nm; RT (min): 4.7) to afford N-(2,3-dihydro-1H-inden-4-yl)-1H-imidazol-4-amine (7.4 mg). (ES, m / z): [M+1] = 200. 1 H NMR (400MHz, Methanol-d4) δ8.25 (s, 1H), 7.79 (s, 1H), 6.96 (t, J = 7.7Hz, 1H), 6.70 ( d,J=7.3Hz,2H),2.89(t,J=7.5Hz,2H),2.80(t,J=7.3Hz,2H),2.09(p,J=7.5Hz,2H).

[0293] Example 21 Preparation of 7-[1-(1H-imidazol-4-yl)ethyl]-1-methylindole

[0294] 21.1 To a solution of 7-[1-(1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-indole (500 mg, 2.344 mmol) in MeOH (10 mL) was added formaldehyde (0.86 mL, 23.440 mmol) and AcOH (14.08 mg, 0.234 mmol). The mixture was stirred at 0°C under a nitrogen atmosphere for 30 minutes, followed by the addition of NaBH3CN (486.14 mg, 7.735 mmol) and continued stirring for 1 hour. The resulting mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water-methanol (0.1% NH3.H2O), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. 7-[1-(1H-imidazol-4-yl)ethyl]-1-methylindole (57 mg) was obtained. (ES, m / z): [M+1] = 228. 1H NMR (400MHz, Methanol-d4) δ7.56(d,J=1.2Hz,1H),6.97(dq,J=7.3,1.2Hz,1H),6.89(d,J=7.7Hz,1H),6.76(t,J=7.5Hz,1H),6.66( t,J=1.1Hz,1H),4.47(q,J=7.1Hz,1H),3.42–3.33(m,1H),3.29–3.20(m,1H),3.02–2.87(m,2H),2.84(s,3H),1.56(d,J=7.1Hz,3H).

[0295] Example 22 Preparation of 4-[1-(6-chloro-1H-inden-4-yl)ethyl]-1H-imidazole

[0296] 22.1 To a stirred solution of 7-bromo-5-chloro-2,3-dihydroindene-1-one (500 mg, 2.037 mmol) in anhydrous THF (10 mL) / MeOH (5 mL) was added NaBH4 (462.3 mg, 12.222 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, 5 mL of water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 7-bromo-5-chloro-2,3-dihydro-1H-indene-1-ol (400 mg) as a colorless oil. (ES, m / z): [M-18] = 231.

[0297] 22.2 7-Bromo-5-chloro-2,3-dihydro-1H-inden-1-ol (450 mg, 1.818 mmol), tert-butyldimethylsilyl chloride (328.8 mg, 2.182 mmol), and imidazole (247.5 mg, 3.636 mmol) were dissolved in DCM (9 mL) and stirred at room temperature for 2 hours. After completion of the reaction, the resulting mixture was quenched with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE to obtain [(7-bromo-5-chloro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (500 mg) as a white solid.

[0298] 22.3 To a solution of [(7-bromo-5-chloro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (443 mg, 1.225 mmol) in THF (10 mL) was added n-BuLi (0.73 mL, 1.838 mmol, 2.5 M in n-hexane) at -78°C under a nitrogen atmosphere. The mixture was stirred for 1 h, followed by the addition of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (431.56 mg, 1.225 mmol) in portions. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched with saturated NH4Cl (aq.) at room temperature, extracted with EtOAc (3 x 100 mL), washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting product was purified by reverse-phase flash chromatography (conditions as follows: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm) to afford 1-[3-[(tert-butyldimethylsilyl)oxy]-6-chloro-2,3-dihydro-1H-inden-4-yl-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (350 mg) as a yellow oil. (ES, m / z): [M+1] = 635.

[0299] 22.4 1-[3-[(tert-Butyldimethylsilyl)oxy]-6-chloro-2,3-dihydro-1H-inden-4-yl-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (486 mg, 0.765 mmol), TEA (464.5 mg, 4.590 mmol), and ethyl oxalyl chloride (313.3 mg, 2.295 mmol) were dissolved in DCM (10 mL) and stirred at 0°C under nitrogen for 2 hours. The reaction was quenched by addition of water at 0°C and extracted with CH2Cl2 (3 x 50 mL). The organic phase was washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-6-chloro-2,3-dihydro-1H-inden-4-yl]vinyl]-1-(triphenylmethyl)imidazole (350 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 617.

[0300] 22.5 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-6-chloro-2,3-dihydro-1H-inden-4-yl]vinyl]-1-(triphenylmethyl)imidazole (349 mg, 0.565 mmol) and tris(triphenylphosphine)rhodium(I) chloride (14694-95-2) (104.6 mg, 0.113 mmol) were dissolved in MeOH (6 mL) and stirred at 50° C. under a hydrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with MeOH (2×10 mL). The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (5:1) as the eluent to give 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-6-chloro-2,3-dihydro-1H-inden-4-yl]ethyl]-1-(triphenylmethyl)imidazole (277 mg) as a yellow oil. (ES, m / z): [M+1] = 619.

[0301] 22.6 4-[1-[3-[(tert-Butyldimethylsilyl)oxy]-6-chloro-2,3-dihydro-1H-inden-4-yl]ethyl]-1-(triphenylmethyl)imidazole (340 mg, 0.549 mmol) and TBAF (430.6 mg, 1.647 mmol) were dissolved in THF (6 mL) and stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. 5-Chloro-7-[1-(1-triphenylmethyl-1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-inden-1-ol (277 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 505.

[0302] 22.7 5-Chloro-7-[1-(1-triphenylmethyl-1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-inden-1-ol (200 mg, 0.396 mmol) and p-toluenesulfonic acid (136.38 mg, 0.792 mmol) were dissolved in MeCN (4 mL) and stirred at 70°C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. 4-[1-(6-chloro-1H-inden-4-yl)ethyl]-1H-imidazole (58 mg) was obtained. (ES, m / z): [M+1] = 245. 1H NMR(400MHz, Methanol-d4)δ7.58(d,J=1.2Hz,1H),7.31(d,J=1.8Hz,1H),7.03–6.95(m,2H),6.82(s, 1H), 6.57 (dt, J = 5.7, 2.0Hz, 1H), 4.43 (q, J = 7.2Hz, 1H), 3.40 (d, J = 2.2Hz, 2H), 1.61 (d, J = 7.2Hz, 3H).

[0303] Example 23 Preparation of 4-[(2H-chroman-8-yl)methyl]-1H-imidazole

[0304] 23.1 To a 40 mL sealed tube was added 8-bromo-2,3-dihydro-1-chromen-4-one (300 mg, 1.321 mmol), toluene (10 mL), ethylene glycol (0.5 mL), trimethyl orthoformate (1 mL), and p-toluenesulfonic acid (22.75 mg, 0.132 mmol) at room temperature. The resulting mixture was stirred at 60°C under nitrogen overnight. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 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 8-bromo-2,3-dihydrospiro[1-chromen-4,2'-[1,3]dioxolane] (270 mg) as a white solid. (ES, m / z): [M+1] = 271, 273.

[0305] 23.2 8-Bromo-2,3-dihydrospiro[1-benzopyran-4,2'-[1,3]dioxolane] (1.5 g, 5.533 mmol) was dissolved in THF (40 mL). n-Butyl lithium (2.43 mL, 6.086 mmol, 1.1 eq, 2.5 M in n-hexane) was added under nitrogen at -78°C for 1 h. A solution of 1-(triphenylmethyl)imidazole-4-carbaldehyde (2.06 g, 6.086 mol) in tetrahydrofuran (10 mL) was then added dropwise at -78°C. The resulting mixture was stirred at room temperature overnight under nitrogen. The reaction was quenched by the addition of saturated aqueous NH4Cl (2 mL), and the resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine (3 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH₄HCO₃), gradient from 50% to 70% over 10 minutes; detector, UV 220 nm. 2,3-Dihydrospiro[1-chromene-4,2'-[1,3]dioxolane]-8-yl[1-(triphenylmethyl)imidazol-4-yl]methanol (1.3 g) was obtained as a white solid. (ES, m / z): [M+1] = 531.

[0306] 23.3 To a 20 mL sealed tube was added 2,3-dihydrospiro[1-chromene-4,2'-[1,3]dioxolane]-8-yl[1-(triphenylmethyl)imidazol-4-yl]methanol (200 mg, 0.377 mmol), THF (5.00 mL), triethylsilane (438.27 mg, 3.770 mmol), and trifluoroacetic acid (429.77 mg, 37.70 mmol) at room temperature. The resulting mixture was stirred at 70°C under a nitrogen atmosphere overnight. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH4HCO3), gradient from 10% to 20% over 10 minutes; detector, UV 220 nm. 8-(1H-imidazol-4-methylene)-2,3-dihydro-1-chromen-4-one (30 mg) was obtained. (ES, m / z): [M+1]=229.

[0307] 23.4 To a stirred solution of 8-(1H-imidazole-4-methylene)-2,3-dihydro-1-chromen-4-one (375 mg, 1.643 mmol) in THF (5 mL) and MeOH (5 mL) at 0°C was added NaBH4 (124.30 mg, 3.286 mmol) dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched with water / ice (2 mL) at room temperature. The resulting mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water solution (10 mmol / L NH4HCO3), gradient from 0% to 10% over 10 minutes; detector, UV 220 nm. This afforded 8-(1H-imidazole-4-methylene)-3,4-dihydro-1-chromen-4-ol (355 mg). (ES, m / z): [M-1] = 229.

[0308] 23.5 To a 20 mL sealed tube were added 8-(imidazole-4-methylene)-3,4-dihydro-1-benzopyran-4-ol (200 mg, 0.869 mmol), THF (10 mL), triethylsilane (1009.95 mg, 8.690 mmol) and TFA (990.35 mg, 8.690 mmol) at room temperature and stirred at 75 ° C under nitrogen atmosphere overnight. The resulting product was concentrated under reduced pressure to give a crude product (60 mg), which was then purified by preparative HPLC using the following conditions: (column: XBridge Prep Phenyl OBD column 19*250 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 6% B to 21% B over 10 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 5.3) to afford 4-[(2H-chroman-8-yl)methyl]-1H-imidazolecarboxylate (22.7 mg). (ES, m / z): [M+1] = 213. 1 H NMR (400MHz, Methanol-d4) δ8.49(s,1H),8.19(s,1H),6.97(d,J=8.5Hz,2H),6.88(d,J=7.3Hz,1H),6. 79(t,J=7.5Hz,1H),6.43(d,J=9.8Hz,1H),5.81(dt,J=9.9,3.6Hz,1H),4.87–4.69(m,2H),3.90(s,2H).

[0309] Example 24 Preparation of 4-[1-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)ethyl]-1H-imidazole

[0310] 24.1 Under nitrogen, 2,6-dibromo-4-fluorophenol (2 g, 7.410 mmol) was dissolved in DMF (30 mL). KCO (2.1 g, 14.820 mmol) was added and stirred for 15 minutes. Dibromoethane (2.1 g, 11.115 mmol) was then added dropwise. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with water (1 x 100 mL) and dried over anhydrous NaSO. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% FA), gradient from 40% to 50% over 20 minutes; detector, UV 254 nm. 1,3-dibromo-2-(2-bromoethoxy)-5-fluorobenzene (1.5 g) was obtained as a colorless oil.

[0311] 24.2 A solution of 1,3-dibromo-2-(2-bromoethoxy)-5-fluorobenzene (2 g, 5.307 mmol) and n-butyllithium (2.1 mL, 5.360 mmol, 2.5 M in n-hexane) in THF (40 mL) was stirred at -78°C under a nitrogen atmosphere for 1 h. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched with saturated NH4Cl (aq) at room temperature and extracted with C2Cl2 (3 x 100 mL). The combined organic phases were washed with water (1 x 100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% TFA), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. 7-Bromo-5-fluoro-2,3-dihydro-1-benzofuran (300 mg) was obtained as a brown oil.

[0312] 24.3 To a solution of 7-bromo-5-fluoro-2,3-dihydro-1-benzofuran (155 mg, 0.714 mmol) in THF (3 mL) was added n-BuLi (0.4 mL, 1.071 mmol, 2.5 M in n-hexane) at -78°C under a nitrogen atmosphere. The mixture was stirred for 30 minutes, followed by the addition of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (251.7 mg, 0.714 mmol) at -78°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched by the addition of saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with CHCl (3 x 100 mL). The combined organic layers were washed with water (1 x 100 mL), dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NHHCO), gradient from 10% to 70% over 10 minutes; detector, UV 254 nm. 1-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (100 mg) was obtained as a white solid. (ES, m / z): [M+1] = 491.

[0313] 24.4 1-(5-Fluoro-2,3-dihydro-1-benzofuran-7-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (100 mg, 0.204 mmol), Et3SiH (0.23 g, 1.978 mmol), and TFA (0.23 g, 2.040 mmol) were added to DCM (2 mL) and stirred at room temperature under nitrogen for 2 hours. The resulting mixture was concentrated in vacuo and purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 30% over 10 minutes; detector, UV 254 nm. This afforded 4-[1-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)vinyl]-1H-imidazole (42 mg). (ES, m / z): [m+1] = 231.

[0314] 24.5 4-[1-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)vinyl]-1H imidazole (48 mg, 0.208 mmol) and 10% Pd / C (20 mg) were added to MeOH and stirred at room temperature under a hydrogen atmosphere for 1 hour. The resulting mixture was filtered through a pad of celite, and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure to give a crude product (40 mg), which was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 27% B to 47% B in 10 minutes; wavelength: 254 nm / 200 nm; RT1 (min): 10.63) to give 4-[1-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)ethyl]-1H-imidazole (13.5 mg). (ES, m / z): [M+1] = 233. 1 H NMR(400MHz, Methanol-d4)δ7.56(d,J=1.2Hz,1H),6.83–6.74(m,2H),6.51(dd,J=10.3,2.7Hz,1 H),4.55(td,J=8.8,1.6Hz,2H),4.26(q,J=7.2Hz,1H),3.27–3.12(m,2H),1.52(d,J=7.2Hz,3H).

[0315] Example 25 Preparation of 4-[1-(1-benzofuran-7-yl)ethyl]-1H-imidazole

[0316] 25.1 At -78 ° C, under a nitrogen atmosphere, 7-bromo-1-benzofuran (500 mg, 2.538 mmol) was dissolved in THF (14 mL) and stirred for 2 minutes. Then, n-BuLi (1.52 mL, 3.807 mmol, 2.5 M in n-hexane) was added to the above mixture for 1 minute. The resulting mixture was stirred at -78 ° C for another hour. At -78 ° C, 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (983.8 mg) was added dropwise to the above mixture over 2 minutes. The resulting mixture was stirred at room temperature overnight. At room temperature, NH4Cl (aqueous solution) (10 mL) was added to quench the reaction. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic phases were washed with water (1×50 mL), dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH₄HCO₃), gradient 70%-75% over 20 min; detector, UV 254 nm, to obtain 1-(1-benzofuran-7-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (400 mg). (ES, m / z): [M] = 470. 1 H NMR(400MHz,Chloroform-d)δ7.54(dd,J=7.6,1.2Hz,1H),7.48(td,J=3.4,1.2Hz,2H),7.38(d,J=2.4Hz,1H),7.34–7.30 (m,9H),7.22(t,J=7.7Hz,1H),7.14–7.09(m,6H),6.85(d,J=1.4Hz,1H),6.73(d,J=2.2Hz,1H),5.29(s,1H),2.01(s,3H).

[0317] 25.2 To a solution of 1-(1-benzofuran-7-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (400 mg, 0.893 mmol) and TFA (2 mL) in DCM (8 mL) was added triethylsilane (2 mL) at room temperature and stirred overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% FA), gradient from 20% to 25% over 20 minutes; detector, UV 254 nm, to afford 4-[1-(1-benzofuran-7-yl)vinyl]-1H-imidazole (130 mg). (ES, m / z): [2M+1] = 421.

[0318] 25.3 To a solution of 4-[1-(1-benzofuran-7-yl)vinyl]-1H-imidazole (120 mg, 0.571 mmol) in MeOH (3 mL) was added Pd / C (15 mg, 10% w / t) in a pressure vessel. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for 1 hour. After completion of the reaction, as monitored by LCMS, the product was filtered through celite and concentrated under reduced pressure to afford the crude product (120 mg). The product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 19% B to 37% B in 10 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 10.63 / 11.72) to give 4-[1-(1-benzofuran-7-yl)ethyl]-1H-imidazole (20.7 mg). (ES, m / z): [M+1] = 213. 1 H NMR (400MHz, Methanol-d4) δ7.71(t,J=2.5Hz,1H),7.56(d,J=1.3Hz,1H),7.44(dt,J=7.7,1.6Hz,1H),7.13(td,J= 7.6,1.8Hz,1H),7.03(dd,J=7.5,1.2Hz,1H),6.85–6.77(m,2H),4.67(q,J=7.2Hz,1H),1.69(dd,J=7.3,1.6Hz,3H).

[0319] Example 26 Preparation of 4-[1-(6-fluoro-3H-inden-4-yl)ethyl]-1H-imidazole

[0320] 26.1 A mixed solution of 4-bromo-6-fluoro-2,3-dihydroindan-1-one (1 g, 4.366 mmol, 1 equiv) in THF (10 mL) and MeOH (5 mL) was treated with NaBH4 (0.66 g, 17.464 mmol, 4 equiv) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with CHCl2 (3 x 50 mL). The combined organic layers were washed with water (1 x 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 (5:1) to give 4-bromo-6-fluoro-2,3-dihydro-1H-indan-1-ol (950 mg) as a colorless oil. (ES, m / z): [M] = 230, 232.

[0321] 26.2 To a stirred solution of 4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-ol (900 mg, 3.895 mmol) and imidazole (530.3 mg, 7.790 mmol) in DCM (20 mL) was added tert-butyldimethylsilyl chloride (704.5 mg, 4.674 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (12:1) to give [(4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (1.1 g) as a colorless oil.

[0322] 26.3 To a solution of [(4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (1.2 g, 3.475 mmol) in THF (10 mL) was added n-BuLi (2.08 mL, 5.213 mmol, 2.5 M in n-hexane) at -78°C under a nitrogen atmosphere. The mixture was allowed to react for 40 minutes. Then, a solution of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (1.35 g, 3.823 mmol) in THF (5 mL) was added dropwise at -78°C and stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched by the addition of saturated aqueous NH4Cl (50 mL) at room temperature. The resulting mixture was extracted with CHCl (3 x 50 mL). The combined organic layers were washed with water (1 x 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 (1:1) to give 1-[1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (1.4 g) as a white solid. (ES, m / z): [M+1]=619.

[0323] 26.4 At room temperature and under a nitrogen atmosphere, a solution of 1-[1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (1.5 g, 2.424 mmol) in DCM (20 mL) was treated with triethylamine (1.47 g, 14.544 mmol) for 1 minute, followed by the dropwise addition of ethyl oxalyl chloride (0.99 g, 7.7.272 mmol) at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 4-[1-[1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]vinyl]-1-(triphenylmethyl)imidazole (1.1 g) as a yellow oil. (ES, m / z): [M+1]=601.

[0324] 26.5 A solution of 4-[1-[1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]vinyl]-1-(triphenylmethyl)imidazole (1.5 g, 2496 mmol) in MeOH (15 mL) was treated with Pd / C (0.13 g, 10% w / t) at room temperature. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 50 minutes. The resulting mixture was filtered through celite, and the filter cake was washed with MeOH (3 x 10 mL). 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-[1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]ethyl]-1-(triphenylmethyl)imidazole (1.2 g) as a white solid. (ES, m / z): [M+1] = 603.

[0325] 26.6 A solution of 4-[1-[1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]ethyl]-1-(triphenylmethyl)imidazole (1 g, 1.659 mmol) in THF (10 mL) was treated with tetrabutylammonium fluoride (5.0 mL, 4.977 mmol, 1 M in THF) at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature overnight. Water (20 mL) was added to quench the reaction at room temperature. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (1×20 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 6-fluoro-4-[1-[1-(triphenylmethyl)imidazol-4-yl]ethyl]-2,3-dihydro-1H-inden-1-ol (443 mg) as a white solid. (ES, m / z): [M+1]=489.

[0326] A solution of 6-fluoro-4-[1-[1-(triphenylmethyl)imidazol-4-yl]ethyl]-2,3-dihydro-1H-inden-1-ol (150 mg, 0.307 mmol) in acetonitrile (5 mL) was treated with p-toluenesulfonic acid (52.7 mg, 0.307 mmol) at room temperature. The resulting mixture was stirred at 70°C under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% NH3.H2O + 10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. This afforded 4-[1-(6-fluoro-3H-inden-4-yl)ethyl]-1H-imidazole (16 mg). (ES, m / z): [M+1] = 229. 1 H NMR(400MHz, Methanol-d4)δ7.57(d,J=1.2Hz,1H),6.95(dd,J=8.7,2.4Hz,1H),6.87–6.82(m,2H),6.70(dd,J=10.9,2.4Hz,1H), 6.64(dt,J=5.6,2.1Hz,1H),4.46–4.19(m,1H),3.36(dq,J=23.3,1.8Hz,1H),3.26(dq,J=23.2,1.8Hz,1H),1.61(d,J=7.2Hz,3H).

[0327] Example 27 Preparation of 4-[1-(Benzothiophene-7-yl)ethyl]-1H-imidazole

[0328] 27.1 To a mixture of 2-bromothiophenol (1.7 g, 8.991 mmol) and NaOH (359.6 mg, 8.991 mmol) in water (10 mL) at 0°C were added dropwise 2-bromoacetic acid (1.2 g, 8.991 mmol) and an aqueous solution of Na2CO3 (952.9 mg, 8.991 mmol) (40 mL). The resulting mixture was stirred at 100°C for 1.5 h. The mixture was acidified to pH = 1 with HCl (aq.). The resulting mixture was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with H2O (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. [(2-bromophenyl)thio]acetic acid (1.9 g) was obtained as a light yellow solid. The crude product was used directly in the next step without further purification. (ES, m / z): [M-1] = 245, 247

[0329] 27.2 Under a nitrogen atmosphere, [(2-bromophenyl)thio]acetic acid (1.9 g, 7.689 mmol) and SOCl2 (1.8 g, 15.378 mmol) were added to a solution of DCM (30 mL) and stirred at 0°C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL). AlCl3 (4.2 g, 31.564 mmol) was slowly added to the above mixture at 0°C (over 5 min). The mixture was then transferred to room temperature and stirred overnight. HCl (aq.) (0.5 mL) was added at 0°C to quench the reaction. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL), and the combined organic layers were washed with H2O (1 x 50 mL) to yield 7-bromo-2H-1-benzothiophene-3-one (375.0 mg) as a pink solid. (ES, m / z): [M-1] = 227, 229.

[0330] 27.3 Under a nitrogen atmosphere, 7-bromo-2H-1-benzothiophene-3-one (375.0 mg, 1.637 mmol), Et3SiH (3.8 mL), and BF3.Et2O (3.8 mL) were added to a solution of DCM (9 mL) and stirred at room temperature overnight. The resulting mixture was diluted with water (10 mL) and extracted with CH2Cl2 (3 x 100 mL). Drying was performed over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (3:1) as the eluent to afford 7-bromo-2,3-dihydro-1-benzothiophene (230.0 mg) as a colorless oil. (ES, m / z): M = 212, 214.

[0331] 27.4 Under a nitrogen atmosphere at -78°C, n-BuLi (0.6 mL, 1.603 mmol, 2.5 M in n-hexane) was added dropwise to a solution of 7-bromo-2,3-dihydro-1-benzothiophene (230.0 mg, 1.069 mmol) in THF (5 mL). After stirring for 1 h, 1-[1-(trityl)imidazol-4-yl]ethanone (376.8 mg, 1.069 mmol) was added dropwise to the mixture, which was then stirred at room temperature overnight. The reaction was quenched by the addition of saturated NH4Cl, and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with H2O (3 x 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 using PE / EA (3:1) as the eluent to give 1-(1-benzothiophen-7-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (210 mg) as a yellow oil. (ES, m / z): [M+1] = 488.

[0332] 27.5 Under a nitrogen atmosphere, 1-(1-benzothiophen-7-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (210 mg, 0.432 mmol, 1 equiv), TFA (492.05 mg, 4.320 mmol), and Et3SiH (250.89 mg, 2.160 mmol) were added to a solution of DCM (4 mL) and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% FA), gradient from 10% to 40% over 10 min; detector, UV 254 nm. 4-[1-(1-benzothiophen-7-yl)vinyl]-1H-imidazole (50 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 227.

[0333] 27.6 Under a hydrogen atmosphere, 4-[1-(1-benzothiophen-7-yl)vinyl]-1H-imidazole (50 mg, 0.221 mmol) and 10% Pd / C (20 mg) were added to a solution of MeOH (1 mL) and stirred at room temperature overnight. The resulting mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% FA), gradient from 10% to 30% over 10 min; detector, UV 254 nm. 4-[1-(Benzothiophen-7-yl)ethyl]-1H-imidazole (15.9 mg) was obtained as a colorless oil. (ES, m / z): [M+1] = 229. 1H NMR (400MHz, Methanol-d4) δ8.84(s,1H),7.79(d,J=7.8Hz,1H),7.74(d,J=7.7Hz,1H),7 .49(s,1H),7.38–7.25(m,2H),7.23(s,1H),4.69(q,J=7.1Hz,1H),1.82(d,J=7.1Hz,3H).

[0334] Example 28 Preparation of 4-[1-(1-ethyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole

[0335] 28.1 Under a nitrogen atmosphere, 4-bromo-2,3-dihydroindan-1-one (4 g, 18.952 mmol) and methyltriphenylphosphonium bromide (13.54 g, 37.904 mmol) were added to a solution of THF (80 mL) and stirred at 20°C for 5 h. The mixture was quenched by the addition of ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL), and the combined organic layers were washed with brine (3 x 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 using PE / EA (12:1) as the eluent to afford 4-bromo-1-methylene-2,3-dihydroindan (3.8 g) as a yellow oil. (ES, m / z): [M] = 208.

[0336] 28.2 Under a nitrogen atmosphere at 0°C, TFA (1.46 mL, 19.610 mmol) was added to a solution of diethylzinc (19.61 mL, 19.610 mmol) in DCM (20 mL) and stirred for 20 min. Diiodomethane (5.25 g, 19.610 mmol) was then added dropwise at 0°C. The resulting mixture was stirred at 0°C for 20 min. Finally, a solution of 4-bromo-1-methylene-2,3-dihydroindene (820 mg, 3.922 mmol) in DCM (10 mL) was added dropwise to the mixture at 0°C and stirred overnight at room temperature. The reaction was quenched by the addition of saturated NH4Cl (30 mL), and the resulting mixture was extracted with EtOAc (2 x 70 mL). The combined organic layers were washed with brine (3 x 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 using PE / EA (4:1) as eluent to give 4'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (250 mg) as a colorless oil. (ES, m / z): [M] = 222.

[0337] 28.3 Under a nitrogen atmosphere at -78°C, n-BuLi (0.67 mL, 1.681 mmol) was added dropwise to a solution of 4'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (250 mg, 1.121 mmol) in THF (5 mL). After stirring for 1 h, 1-[1-(trityl)imidazol-4-yl]ethanone (473.9 mg, 1.345 mmol) was added dropwise to the mixture, which was then stirred at room temperature overnight. The reaction was quenched by the addition of saturated NH4Cl (15 mL), and the resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH4HCO3), gradient from 30% to 80% over 10 min; detector, UV 220 nm. 1-(2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (300 mg) was obtained as a pale yellow solid. (ES, m / z): [M+1] = 497.

[0338] 28.4 Under a nitrogen atmosphere, 1-(2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (100 mg, 0.201 mmol), TFA (688.8 mg, 6.030 mmol), and Et3SiH (702.4 mg, 6.030 mmol) were added to a solution of DCM (3 mL) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH4HCO3), 40% to 70% gradient over 10 min; detector, UV 220 nm. 4-[1-(1-ethyl-2,3-dihydro-1H-indene-4-yl)vinyl]-1H-imidazole (80 mg) was obtained as an off-white solid. (ES, m / z): [M+1] = 239.

[0339] 28.5 Under a hydrogen atmosphere, 4-[1-(1-ethyl-2,3-dihydro-1H-inden-4-yl)vinyl]-1H-imidazole (70 mg, 0.294 mmol) and 10% Pd / C (8 mg, 10% w / t) were added to a solution of MeOH (2 mL) and stirred at room temperature for 3 h. The resulting mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH4HCO3), gradient from 30% to 70% over 10 min; detector, UV 220 nm. 4-[1-(1-ethyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (40.7 mg) was obtained. (ES, m / z): [M+1] = 241. 1 H NMR(400MHz,Methanol-d4)δ7.56(s,1H),7.12–6.98(m,2H),6.90(dd,J=11.5,7.4Hz,1 H),6.72(d,J=7.8Hz,1H),4.18(d,J=7.3Hz,1H),3.09–2.81(m,2H),2.74(tt,J=15.7,8 .1Hz,1H),2.26(dq,J=8.2,4.1Hz,1H),1.87(ddd,J=12.4,7.4,4.8Hz,1H),1.66(s,1H) ,1.55(td,J=5.7,3.0Hz,3H),1.41(q,J=12.3,9.5Hz,1H),0.98(td,J=7.4,3.7Hz,3H).

[0340] Example 29 Preparation of 4-[(3-ethyl-2,3-dihydro-1H-inden-4-yl)methyl]-1H-imidazole

[0341] 29.1 Under a nitrogen atmosphere at 0°C, to a solution of 7-bromo-2,3-dihydroindan-1-one (1 g, 4.738 mmol) and methyltriphenylphosphine bromide (5.92 g, 16.583 mmol) in THF (5 mL) was added dropwise t-BuOK (5.21 mL, 1 M in THF). The mixture was transferred to room temperature and stirred for 3 h. The reaction was quenched by the addition of ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 10 mL), and the combined organic layers were washed with brine (1 x 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 (10:1) to afford 7-bromo-1-methylene-2,3-dihydroindan (657 mg) as a yellow oil. (ES, m / z): [M] = 208, 210.

[0342] 29.2 Under nitrogen at 0°C, TFA (545.34 mg, 4.785 mmol) was added to a solution of diethylzinc (4.78 mL, 4.785 mmol) in DCM (10 mL) and stirred for 20 min. Diiodomethane (1280.9 mg, 4.785 mmol) was then added dropwise at room temperature and stirred for 20 min. Finally, a solution of 7-bromo-1-methylene-2,3-dihydroindene (500 mg, 2.563 mmol) in DCM (10 mL) was added dropwise to the mixture and stirred overnight at room temperature. The reaction was quenched by the addition of saturated NH4Cl (50 mL), and the resulting mixture was extracted with EtOAc (1 x 50 mL). The combined organic layers were washed with brine (1 x 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 using PE / EA (5:1) as the eluent to give 7'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (170 mg) as a pale yellow oil. (ES, m / z): [M] = 222,224.

[0343] 29.3 Under a nitrogen atmosphere at -78°C, n-BuLi (1.21 mL, 3.026 mmol, 2.5 M in n-hexane) was added dropwise to a solution of 7'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (450 mg, 2.017 mmol) in THF (10 mL). After stirring for 1 h, 1-[1-(trityl)imidazol-4-yl]ethanone (682.5 mg, 2.017 mmol) was added dropwise to the mixture, which was then stirred at room temperature overnight. The reaction was quenched by the addition of saturated NH4Cl (20 mL), and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 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 using PE / EA (1:1) as the eluent to afford 2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7'-yl[1-(trityl)imidazol-4-yl]methanol (450 mg) as an off-white solid. (ES, m / z): [M+1] = 483.

[0344] 29.4 Under nitrogen atmosphere, 2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7'-yl[1-(trityl)imidazol-4-yl]methanol (150 mg, 0.311 mmol), TFA (567.01 mg, 4.980 mmol) and Et3SiH (578.2 mg, 4.980 mmol) were added to a solution of DCM (5 mL) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue (160 mg) was purified by pre-HPLC under the following conditions: (column: XBridge Shield RP18 OBD column 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 41% B, 10 min; wavelength: 254 nm / 220 m; RT1 (min): 10.23 / 12.13) to give 4-[(3-ethyl-2,3-dihydro-1H-inden-4-yl)methyl]-1H-imidazole (21.7 mg) as a colorless oil. (ES, m / z): [M+1] = 227. 1 H NMR (400MHz, Methanol-d4) δ7.55(d,J=1.2Hz,1H),7.03(d,J=4.6Hz,2H),6.91(q,J= 4.1Hz,1H),6.59(s,1H),4.07–3.79(m,2H),3.11(dddd,J=9.6,8.0,3.4,1.5Hz,1H), 2.97(ddd,J=15.8,10.5,7.9Hz,1H),2.75(ddd,J=15.9,8.9,1.8Hz,1H),2.16–1.83( m,2H),1.56(dqd,J=14.8,7.5,3.2Hz,1H),1.44–1.20(m,1H),0.92(t,J=7.4Hz,3H).

[0345] Example 30 Preparation of 4-[1-(2,3-dihydrobenzofuran-4-yl)ethyl]-1H-imidazole

[0346] 30.1 Under a nitrogen atmosphere at -78°C, n-BuLi (0.90 mL, 2.260 mmol, 2.5 M in n-hexane) was added dropwise to a solution of 4-bromo-2,3-dihydro-1-benzofuran (300 mg, 1.507 mmol) in THF (10 mL). After stirring for 1 h, 1-[1-(trityl)imidazol-4-yl]ethanone (584.31 mg, 1.658 mmol) was added dropwise to the mixture, which was then stirred at room temperature overnight. The reaction was quenched by the addition of saturated NH4Cl (20 mL), and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH4HCO3), gradient from 50% to 55% over 10 min; detector, UV 254 nm. 1-(2,3-dihydro-1-benzofuran-4-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (430 mg) was obtained as a yellow solid. (ES, m / z): [M+1] = 473.

[0347] 30.2 Under a nitrogen atmosphere, 1-(2,3-dihydro-1-benzofuran-4-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (430 mg, 0.910 mmol), TFA (1 mL), and Et3SiH (1 mL) were added to a solution of DCM (8 mL) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% NH3.H2O), 20% to 25% gradient over 15 min; detector, UV 200 nm. 4-[1-(2,3-dihydro-1-benzofuran-4-yl)vinyl]-1H-imidazole (170 mg) was obtained as a white solid. (ES, m / z): [M+1] = 213.

[0348] 30.3 Under a hydrogen atmosphere, 4-[1-(2,3-dihydro-1-benzofuran-4-yl)vinyl]-1H-imidazole (180 mg, 0.848 mmol) and 10% Pd / C (72.20 mg) were added to a solution of THF (4 mL) and stirred at room temperature for 3 h. The resulting mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (1 x 10 mL). The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% NH3.H2O), gradient from 20% to 25% over 10 min; detector, UV 254 nm. 4-[1-(2,3-dihydro-1-benzofuran-4-yl)ethyl]-1H-imidazole (129.1 mg) was obtained. (ES, m / z): [M+1] = 215. 1 H NMR (400MHz, Methanol-d4) δ7.55(d,J=1.2Hz,1H),7.01(t,J=7.8Hz,1H),6.76(d,J=1.1Hz,1H),6.65(d,J=7.8Hz, 1H), 6.56 (d, J = 7.9Hz, 1H), 4.48 (t, J = 8.7Hz, 2H), 4.10 (q, J = 7.2Hz, 1H), 3.21–2.93 (m, 2H), 1.56 (d, J = 7.2Hz, 3H).

[0349] Example 31 Preparation of 4-[1-(2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole

[0350] 31.1 Under a nitrogen atmosphere at -78°C, n-BuLi (0.60 mL, 10.761 mmol, 2.5 M in n-hexane) was added dropwise to a solution of 4-bromo-2,3-dihydro-1H-indene (300 mg, 1.522 mmol) in THF (8 mL). After stirring for 1 h, 1-[1-(trityl)imidazol-4-yl]ethanone (590.15 mg, 1.674 mmol) was added dropwise to the mixture, which was then stirred at room temperature overnight. The reaction was quenched by the addition of saturated NH4Cl (20 mL), and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH4HCO3), gradient from 70% to 75% over 10 min; detector, UV 254 nm. 1-(2,3-dihydro-1H-inden-5-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (530 mg) was obtained as a yellow solid. (ES, m / z): [M+1] = 471.

[0351] 31.2 Under a nitrogen atmosphere, 1-(2,3-dihydro-1H-inden-5-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (530 mg, 1.126 mmol), TFA (2 mL), and Et3SiH (2 mL) were added to a solution of DCM (6 mL) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% FA), gradient from 20% to 25% over 15 min; detector, UV 200 nm. 4-[1-(2,3-dihydro-1H-inden-5-yl)vinyl]-1H-imidazole (170 mg) was obtained as a colorless oil. (ES, m / z): [M+1] = 211.

[0352] 31.3 Under a hydrogen atmosphere, 4-[1-(2,3-dihydro-1H-inden-5-yl)vinyl]-1H-imidazole (180 mg, 0.856 mmol) and 10% Pd / C (72.88 mg, 50% w / t) were added to a solution of MeOH (5 mL) and stirred at room temperature for 3 h. The resulting mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% FA), gradient from 20% to 25% over 10 min; detector, UV 254 nm. 4-[1-(2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (97.2 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 213. 1 H NMR(400MHz, Methanol-d4)δ8.47(d,J=1.4Hz,1H),7.20(d,J=1.3Hz,1H),7.16–7.00(m,2H),6.87(dd,J=6.3, 2.4Hz, 1H), 4.30 (q, J = 7.2Hz, 1H), 2.87 (dq, J = 19.2, 7.9Hz, 4H), 2.06 (p, J = 7.4Hz, 2H), 1.61 (d, J = 7.2Hz, 3H).

[0353] 4-(1-(2,3-dihydro-1H-inden-4-yl)ethyl)-1H-imidazole (400 mg) was purified by chiral HPLC under the following conditions (column: (S,S)-WELK-O1, 2*25 cm, 5 μm; mobile phase A: Hex (10 mM NH3-MeOH), mobile phase B: EtOH) to give (R)-4-[1-(2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (31-a) (103.4 mg) (retention time 1.14 min) and (S)-4-[1-(2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (31-b) (89 mg) (retention time 1.64 min).

[0354] (R)-4-[1-(2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (31-a) (ES, m / z): [M+1] = 213.

[0355] 1H NMR(400MHz,Chloroform-d)δ7.43–7.38(m,1H),7.12–7.02(m,2H),6.91–6.84(m,1H),6.72 (s,1H),4.17(q,J=7.1Hz,1H),2.97–2.69(m,4H),2.10–1.89(m,2H),1.57(d,J=7.2Hz,3H).

[0356] (S)-4-[1-(2,3-Dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (31-b) (ES, m / z): [M+1] = 213.

[0357] 1 H NMR(400MHz,Chloroform-d)δ9.41(s,1H),7.41(s,1H),7.10–7.00(m,2H),6.88–6.82(m,1H),6 .69(s,1H),4.16(q,J=7.1Hz,1H),2.95–2.68(m,4H),2.08–1.86(m,2H),1.56(d,J=7.2Hz,3H).

[0358] Example 32 Preparation of 4-[1-(2-methyl-2,3-dihydrobenzofuran-7-yl)ethyl]-1H-imidazole

[0359] 32.1 Under air atmosphere, 2-bromophenol (2.2 g, 12.716 mmol) and K2CO3 (3.51 g, 25.432 mmol) were added to a solution of acetone (22 mL) and stirred at room temperature for 1 h. Allyl bromide (2.31 g, 19.074 mmol) was then added portionwise to the mixture over 1 min. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (1 x 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 using PE / EA (5:1) as the eluent to afford 1-bromo-2-(prop-2-en-1-oxy)benzene (2 g) as a colorless oil. (ES, m / z): [M] = 212, 214.

[0360] 32.2 Under air, a mixture of 1-bromo-2-(prop-2-en-1-yl)benzene (1 g, 4.693 mmol) and diethylaluminum chloride (0.85 g, 7.039 mmol) was added to hexane (14 mL) and stirred at room temperature for 2 h. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (1 x 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 using PE / EA (5:1) as the eluent to afford 2-bromo-6-(prop-2-en-1-yl)phenol (800 mg) as a yellow solid. (ES, m / z): [M] = 212, 214.

[0361] 32.3 Under a nitrogen atmosphere, 2-bromo-6-(prop-2-en-1-yl)phenol (350 mg, 1.643 mmol) and silver trifluoromethanesulfonate (84.41 mg, 0.329 mmol) were added to a solution of dichloroethane (8 mL) and stirred at 90°C for 2 h. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (1 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% NH3.H2O), gradient from 45% to 50% over 10 min; detector, UV 254 nm. 7-bromo-2-methyl-2,3-dihydro-1-benzofuran (100 mg) was obtained as a colorless oil. (ES, m / z): [M] = 212, 214.

[0362] 32.4 Under a nitrogen atmosphere at -78°C, n-BuLi (0.28 mL, 0.704 mmol, 2.5 M in n-hexane) was added dropwise to a solution of 7-bromo-2-methyl-2,3-dihydro-1-benzofuran (100 mg, 0.469 mmol) in THF (4 mL). After stirring for 1 h, 1-[1-(trityl)imidazol-4-yl]ethanone (181.95 mg, 0.516 mmol) was added dropwise to the mixture, which was then stirred at room temperature overnight. The reaction was quenched by the addition of saturated NH4Cl (20 mL), and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH4HCO3), gradient from 50% to 55% over 10 min; detector, UV 254 nm. 1-(2-methyl-2,3-dihydro-1-benzofuran-7-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (80 mg) was obtained as a yellow solid. (ES, m / z): [M+1] = 487.

[0363] 32.5 Under a nitrogen atmosphere, 1-(2-methyl-2,3-dihydro-1-benzofuran-7-yl)-1-[1-(trityl)imidazol-4-yl]ethanol (80 mg, 0.164 mmol), TFA (1 mL), and Et3SiH (1 mL) were added to a solution of DCM (2 mL) and stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% FA), gradient from 20% to 25% over 15 min; detector, UV 200 nm. 4-[1-(2-methyl-2,3-dihydro-1-benzofuran-7-yl)vinyl]-1H-imidazole (20 mg) was obtained as a yellow solid. (ES, m / z): [M+1] = 227.

[0364] 32.6 Under a hydrogen atmosphere, a solution of 4-[1-(2-methyl-2,3-dihydro-1-benzofuran-7-yl)vinyl]-1H-imidazole (20 mg, 0.088 mmol) and 10% Pd / C (7.52 mg) in MeOH (2 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (1 x 10 mL). The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (0.1% NH3.H2O), gradient from 20% to 25% over 10 min; detector, UV 254 nm. 4-[1-(2-methyl-2,3-dihydrobenzofuran-7-yl)ethyl]-1H-imidazole (14.4 mg) was obtained as a colorless oil. (ES, m / z): [M+1] = 229. 1 H NMR(400MHz,Chloroform-d)δ7.75(s,1H),7.04–6.97(m,1H),6.90–6.83(m,1H),6.81(s,1H),6.74(t,J=7.4Hz,1H), 4.97–4.81(m,1H),4.29(p,J=7.0Hz,1H),3.34–3.22(m,1H),2.83–2.73(m,1H),1.63–1.56(m,3H),1.45–1.38(m,3H).

[0365] Example 33 Preparation of 4-[1-(2H-thiochroman-8-yl)ethyl]-1H-imidazole

[0366] 33.1 Under air, 8-bromo-2,3-dihydro-1-thiochroman-4-one (2 g, 8.226 mmol) and NaBH4 (1.8 g, 49.356 mmol) were added to a solution of THF (30 mL) and stirred at room temperature for 2 h. The reaction was quenched by adding water, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 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 using PE / EA (1:1) as the eluent to afford 8-bromo-3,4-dihydro-2H-1-thiochroman-4-ol (1.9 g) as a colorless oil. (ES, m / z): [M-18] = 227.229.

[0367] 33.2 To a mixture of 8-bromo-3,4-dihydro-2H-1-thiochroman-4-ol (1.8 g, 7.343 mmol) and imidazole (1.0 g, 14.686 mmol) in DCM (40 mL) was added portionwise tert-butyldimethylsilyl chloride (1.3 g, 8.812 mmol) at room temperature under air. The resulting mixture was stirred overnight. Water (10 mL) was added to quench the reaction, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 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 [(8-bromo-3,4-dihydro-2H-1-thiochroman-4-yl)oxy](tert-butyl)dimethylsilane (2.2 g) as a colorless oil.

[0368] 33.3 Under a nitrogen atmosphere at -78°C, n-BuLi (0.7 g, 11.687 mmol, 2.5 M in n-hexane) was added dropwise to a solution of [(8-bromo-3,4-dihydro-2H-1-thiochroman-4-yl)oxy](tert-butyl)dimethylsilane (2.8 g, 7.791 mmol) in THF (40 mL). After stirring for 1 h, a solution of 1-[1-(trityl)imidazol-4-yl]ethanone (2.8 g, 7.791 mmol) in THF (10 mL) was added dropwise to the mixture, which was then stirred at room temperature overnight. The reaction was quenched by the addition of saturated NH4Cl, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-thiochroman-8-yl-1-[1-(trityl)imidazol-4-yl]ethanol (3.6 g) was obtained as a colorless oil. (ES, m / z): [M+1]=634.

[0369] 33.4 Under air atmosphere at 0°C, a solution of 1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-thiochroman-8-yl-1-[1-(trityl)imidazol-4-yl]ethanol (4.6 g, 7.481 mmol) and TEA (4.54 g, 44.886 mmol) was added in DCM (400 mL), and ethyl oxalyl chloride (3.06 g, 22.443 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-TLC (PE / EA 8:1) to give 4-(1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-thiochroman-8-ylvinyl)-1-(trityl)imidazole (3.5 g) as a yellow oil. (ES, m / z): [M+1]=615.

[0370] 33.5 Under a hydrogen atmosphere, 4-(1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-thiochroman-8-ylvinyl)-1-(trityl)imidazole (1.5 g, 2.439 mmol) and 10% Pd / C (52 mg) were added to a solution of MeOH (30 mL) and stirred at room temperature for 2 h. The resulting mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (3×5 mL). The filtrate was concentrated under reduced pressure and purified by reverse phase chromatography under the following conditions: chromatographic column, C18 silica gel; mobile phase, acetonitrile-water (0.1% NH 3 .H 2 O + 10 mmol / L NH 4 HCO 3 ), 10% to 40% gradient, 10 min; detector, UV 254 nm. 4-(1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-thiochroman-8-ethyl)-1-(trityl)imidazole (220 mg) was obtained as a colorless oil. (ES, m / z): [M+1] = 617.

[0371] 33.6 Under a nitrogen atmosphere, 4-(1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-thiochroman-8-ethyl)-1-(trityl)imidazole (212 mg, 0.344 mmol) and TBAF (269.5 mg, 1.032 mmol) were added to a solution of THF (4 mL) and stirred at room temperature for 1 h. The filtrate was concentrated under reduced pressure and purified by reverse phase chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 min; detector, UV 254 nm. 8-(1-[1-(trityl)imidazol-4-yl]ethyl-3,4-dihydro-2H-1-thiochroman-4-ol (160 mg) was obtained as a yellow oil. (ES, m / z): [M+1] = 504.

[0372] 33.7 Under a nitrogen atmosphere, 8-(1-[1-(trityl)imidazol-4-yl]ethyl-3,4-dihydro-2H-1-thiochroman-4-ol (100 mg, 0.199 mmol) and TsOH (7.4 mg, 0.043 mmol) were added to a solution of acetonitrile (2 mL) and stirred at 70°C for 2 h. The filtrate was concentrated under reduced pressure and purified by reverse phase chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile-water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 min; detector, UV 254 nm. 4-[1-(2H-thiochroman-8-yl)ethyl]-1H-imidazolecarboxylate (3.5 mg) was obtained. (ES, m / z): [M+1] = 243. 1 H NMR(400MHz,Chloroform-d)δ8.43(s,1H),7.72(d,J=10.2Hz,1H),7.01(t,J=7.5Hz,1H),6.98–6.89(m,2H),6.79(s,1H ),6.48(d,J=10.1Hz,1H),5.94(dt,J=10.0,5.0Hz,1H),4.55(q,J=7.0Hz,1H),3.44–3.28(m,2H),1.58(d,J=7.1Hz,3H).

[0373] Example 34 Preparation of 4-[1-(5-fluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole

[0374] 34.1 Triethylsilane (888.4 mg, 7.640 mmol) was added to a solution of 7-bromo-6-fluoro-2,3-dihydroindene-1-one (700 mg, 3.056 mmol) in trifluoroacetic acid (3 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 4-bromo-5-fluoro-2,3-dihydro-1H-indene (320 mg) as a colorless oil. (ES, m / z): [M] = 214, 216.

[0375] 34.2 At -78°C under a nitrogen atmosphere, n-BuLi (1.06 mL, 2.651 mmol, 2.5 M in n-hexane) was added dropwise to a solution of 4-bromo-5-fluoro-2,3-dihydro-1H-indene (380 mg, 1.767 mmol) in tetrahydrofuran (6 mL). The mixture was allowed to react at -78°C for 40 minutes, followed by the dropwise addition of a solution of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (622.7 mg, 1.767 mmol) in tetrahydrofuran (4 mL). After the addition was complete, the mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous NH4Cl (20 mL) at room temperature. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (1 x 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 using PE / EA (5:1) as the eluent to give 1-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (350 mg) as a white solid. (ES, m / z): [M+1] = 489.

[0376] 34.3 Trifluoroacetic acid (1.4 g, 12.280 mmol) was added to a solution of 1-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (300 mg, 0.614 mmol) in dichloromethane (5 mL) at room temperature under a nitrogen atmosphere. After a 1-min reaction, triethylsilane (1.427 g, 12.280 mmol) was added dropwise. The resulting mixture was stirred overnight. The resulting mixture was spin-dried to dryness, and the residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. 4-[1-(5-fluoro-2,3-dihydro-1H-inden-4-yl)vinyl]-1H-imidazole (60 mg) was obtained as a colorless oil. (ES, m / z): [M+1] = 229.

[0377] 34.4 At room temperature, 10% Pd / C (20 mg) was added to a solution of 4-[1-(5-fluoro-2,3-dihydro-1H-inden-4-yl)vinyl]-1H-imidazole (60 mg, 0.263 mmol) in methanol (5 mL). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 40 minutes, then filtered through a pad of Celite, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. 4-[1-(5-fluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (32 mg) was obtained. (ES, m / z): [M+1] = 231. 1 H NMR(400MHz, Methanol-d4)δ7.54(s,1H),7.02(dd,J=8.2,4.8Hz,1H),6.86–6.72(m,2H),4.38(q,J=7.3Hz ,1H),2.84(dt,J=26.1,7.6Hz,3H),2.53(dt,J=15.6,7.4Hz,1H),2.12–1.84(m,2H),1.61(d,J=7.3Hz,3H).

[0378] Example 37 Preparation of 7-[1-(1H-imidazol-4-yl)ethyl]-5-fluoro-2,3-dihydro-1H-inden-1-ol

[0379] 37.1 At room temperature, Pd / C (10%, 20 mg) was added to a solution of 5-fluoro-7-{1-[1-(triphenylmethyl)imidazol-4-yl]vinyl}-2,3-dihydro-1H-inden-1-ol (100 mg, 0.20 mmol) in THF (1 mL). The reaction mixture was replaced with a hydrogen atmosphere and hydrogenated overnight at room temperature. The resulting mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give 7-[1-(1H-imidazol-4-yl)ethyl]-5-fluoro-2,3-dihydro-1H-inden-1-ol (26.6 mg). (ES, m / z): [M+1] = 247.1. 1H NMR(400MHz, DMSO-d6)δ11.78(d,J=22.4Hz,1H),7.57–7.41(m,1H),6.93–6.61(m,3H),5.33–5.08(m,2H),4.68–4.37(m, 1H),3.03(dt,J=16.0,8.0Hz,1H),2.77–2.64(m,1H),2.36–2.16(m,1H),1.99–1.84(m,1H),1.52(dd,J=8.4,7.2Hz,3H).

[0380] Example 38 Preparation of 7-[1-(1H-imidazol-4-yl)ethyl]-5-fluoro-2,3-dihydro-1H-inden-1-one

[0381] 38.1 At 0°C under a nitrogen atmosphere, NaBH4 (33.05 g, 873.18 mmol) was added portionwise to a mixed solution of 7-bromo-5-fluoro-2,3-dihydro-1H-indene-1-one (50.00 g, 218.25 mmol) in THF (500 mL) and MeOH (250 mL). The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 1 hour. The resulting mixture was extracted with dichloromethane (2 x 1000 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 7-bromo-5-fluoro-2,3-dihydro-1H-indene-1-ol (53.60 g) was obtained as a yellow oil. (ES, m / z): [M] = 213.

[0382] 38.2 At room temperature, tert-butyldimethylsilyl chloride (42.56 g, 282.47 mmol) was added to a mixture of 7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-ol (53.60 g, 231.95 mmol) and imidazole (31.58 g, 463.90 mmol) in dichloromethane (800 mL). The resulting mixture was stirred at room temperature under air atmosphere for 1 hour. The resulting mixture was extracted with EtOAc (2 x 1000 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave [(7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (62 g) as a yellow oil. (ES, m / z): [M] = 345.

[0383] 38.3 At -78°C under a nitrogen atmosphere, n-BuLi (108 mL, 269.67 mmol, 2.5 M in n-hexane) was added dropwise to a solution of [(7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (62.00 g, 179.74 mmol) in THF (600 mL). After 40 minutes, 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (63.36 g, 179.75 mmol, 1.00 equiv) in tetrahydrofuran (200 mL) was added dropwise. The mixture was warmed to 25°C and stirred under a nitrogen atmosphere overnight. The reaction was quenched with saturated aqueous NH4Cl (1000 mL) at 25°C. The mixture was extracted with dichloromethane (3 x 1000 mL). The combined organic layers were washed with brine 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-{3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl}-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (68.00 g) as a yellow oil. (ES, m / z): [M+1] = 619.

[0384] 38.4 At 0°C under a nitrogen atmosphere, ethyl chloroglyoxylate (60.01 g, 439.45 mmol) was added to a solution of 1-{3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl}-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (68 g, 109.82 mmol) and triethylamine (88.91 g, 878.98 mmol) in dichloromethane (800 mL). The mixture was warmed to room temperature and stirred for 1 hour. The mixture was extracted with dichloromethane (3 x 1000 mL). The combined organic layers were washed with brine 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-{3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl}vinyl)-1-(triphenylmethyl)imidazole (62.00 g) as a yellow solid. (ES, m / z): [M+1] = 601.

[0385] 38.5 TBAF (97.65 g, 309.50 mmol, 3 equiv) was added to a solution of 4-(1-{3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl}vinyl)-1-(triphenylmethyl)imidazole (62 g, 103.16 mmol, 1 equiv) in THF (800 mL) at room temperature. After stirring for 2 hours, the mixture was extracted with dichloromethane (2 x 1000 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 5-Fluoro-7-{1-[1-(triphenylmethyl)imidazol-4-yl]vinyl}-2,3-dihydro-1H-inden-1-ol (65.00 g) was obtained as a yellow solid. (ES, m / z): [M+1] = 487.

[0386] 38.6 Under a nitrogen atmosphere, Pd / C (10%, 13.00 g) was added to a solution of 5-fluoro-7-{1-[1-(triphenylmethyl)imidazol-4-yl]ethenyl}-2,3-dihydro-1H-inden-1-ol (65.00 g, 133.58 mmol) in THF (1000 mL). The mixture was hydrogenated under a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 5-fluoro-7-{1-[1-(triphenylmethyl)imidazol-4-yl]ethenyl}-2,3-dihydro-1H-inden-1-ol (46.00 g) as an off-white solid. (ES, m / z): [M+1] = 489.

[0387] 38.7 At room temperature under nitrogen atmosphere, pyridinium chlorochromate (PCC) (30.43 g, 141.22 mmol) was added to a solution of 5-fluoro-7-{1-[1-(triphenylmethyl)imidazol-4-yl]ethyl}-2,3-dihydro-1H-indene-1-ol (46.00 g, 94.14 mmol) in DCM (600 mL). After completion of the reaction, the reaction solution was extracted with dichloromethane (2 x 1000 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 5-fluoro-7-{1-[1-(triphenylmethyl)imidazol-4-yl]ethyl}-2,3-dihydroindene-1-one (52.00 g) was obtained as a yellow oil. (ES, m / z): [M+1] = 487.

[0388] 38.8 At room temperature under air, a solution of hydrochloric acid in dioxane was added to a solution of 5-fluoro-7-{1-[1-(triphenylmethyl)imidazol-4-yl]ethyl}-2,3-dihydroindan-1-one (52.00 g, 106.7 mmol) in THF (300 mL). After reacting for 2 hours at room temperature, the residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, gradient from 10% to 50% over 40 minutes; detector, UV 254 nm. 7-[1-(1H-imidazol-4-yl)ethyl]-5-fluoro-2,3-dihydro-1H-indan-1-one (10.00 g) was obtained. (ES, m / z): [M+1] = 245. 1 H NMR(400MHz, DMSO-d6)δ11.83(s,1H),7.54(d,J=10.6Hz,1H),7.28–7.12(m,1H),6.97–6 .68(m,2H),5.48–5.24(m,1H),3.10–3.03(m,2H),2.71–2.64(m,2H),1.51–1.41(m,3H).

[0389] 38.9 7-[1-(1H-imidazol-4-yl)ethyl]-5-fluoro-2,3-dihydro-1H-inden-1-one (60 mg) was purified by Prep Chiralal SFC under the following conditions (column: CHIRALPAK IG, 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MEOH (0.1% 2M NH3-MEOH) to give (R)-7-(1-(1H-imidazol-4-yl)ethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one (38-a, 22.2 mg) (retention time 0.96 min) and (S)-7-(1-(1H-imidazol-4-yl)ethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one (38-b, 13.7 mg) (retention time 0.87 min).

[0390] (R)-7-(1-(1H-imidazol-4-yl)ethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one (38-a)

[0391] (ES, m / z): [M+1] = 245. 1H NMR (400MHz, Methanol-d4) δ7.82(d,J=1.2Hz,1H),7.11(d,J=8.4Hz,1H),7.02(t,J=1.2Hz,1H),6.81(dd ,J=10.4,2.4Hz,1H),5.48(q,J=7.2Hz,1H),3.21–3.11(m,2H),2.77–2.70(m,2H),1.58(d,J=7.2Hz,3H).

[0392] (S)-7-(1-(1H-imidazol-4-yl)ethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one (38-b)

[0393] (ES, m / z): [M+1] = 245. 1 H NMR (400 MHz, Methanol-d4) δ 8.05 (d, J = 1.2 Hz, 1H), 7.17–7.09 (m, 2H), 6.84 (dd, J = 10.4, 2.4 Hz, 1H), 5.51 (q, J = 7.2 Hz, 1H), 3.16 (t, J = 6.0 Hz, 2H), 2.78–2.68 (m, 2H), 1.60 (d, J = 7.2 Hz, 3H). Biological test examples

[0394] Test Example 1: In vitro affinity

[0395] 1. Experimental Methods

[0396] 1.1 Preparation of buffer and test sample

[0397] Standard buffer (for preparation of α 1A , α 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, adjusting the pH to 7.7. The final concentration is 0.5 mM EDTA.

[0398] Test sample (compound): Calculate the theoretical sample weight according to the designed concentration and required volume. Generally 5.0×10 -3 M is the initial preparation dose, which is dissolved in DMSO and then diluted with DMSO to 5.0×10 -4 M~5.0×10 - 9 M, dilute the diluted DMSO solution with Buffer to a working concentration of 5.0×10 -5 M~5.0×10 -11M, 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 samples were stored at 4°C after preparation and discarded after the test.

[0399] 1.2 Preparation of receptor membrane

[0400] CHO-K1-α 1A ,CHO-K1-α 2A ,CHO-K1-α 2B ,CHO-K1-α 2C After removing cells from a -80°C freezer, thaw naturally and centrifuge at 2000g, 4°C for 10 min. Discard the supernatant and collect the pellet. Add buffer to the pellet and homogenize for 20-30 s. Centrifuge at 48,000g, 4°C for 25 min. Discard the supernatant. Add buffer again and homogenize for 20-30 s. Centrifuge at 48,000g, 4°C for 25 min. Discard the supernatant and collect the pellet. Store at -80°C.

[0401] 1.3 Receptor competition binding assay

[0402] 1.3.1 Radioactive binding experimental conditions

[0403] Table 1 Radioactive binding experimental conditions Note: Prazosin: Prazosin; RX821002: 2-Methoxyidazoxan monohydrochloride.

[0404] 1.3.2 Receptor Binding Experiment Procedure

[0405] Step 1: Add 50 μL of solvent (1% DMSO) to the total binding tube (TB) and 50 μL of non-specific binding (final concentration 1.0×10 -5 M), and 50 μL of the test compound was added to each test compound tube (CB).

[0406] Step 2: Add 100 μL of buffer to each reaction tube.

[0407] Step 3: Use the prepared membrane buffer to make a membrane suspension of corresponding concentration for later use.

[0408] Step 4: Add 50 μL of the corresponding radioligand to each reaction tube.

[0409] Step 5: Add 50 μL of membrane solution to each reaction tube.

[0410] Step 6: Incubate each reaction tube according to the incubation conditions. After the reaction is complete, the bound ligand is filtered by vacuum rapid filtration. UniFilter GF / C plates are saturated with 0.5% PEI solution 1 hour in advance, washed thoroughly with ice-cold Tris-HCl buffer, filtered, and dried in a constant temperature drying oven for 30 minutes. Remove the filter plate and add MICROSCINT PS scintillation fluid (40 μL / well).

[0411] Step 7: Place the scintillation cup into the liquid scintillation counter for counting.

[0412] 1.4 Data Analysis

[0413] According to the effect values ​​of the compound samples at different concentration test points, GraphPad Prism software was used to fit the compound sample-receptor action curve and calculate the Ki value.

[0414] 1.5 Experimental Results

[0415] For example, compounds 1, 3, 4, 8 and α 2A The receptor affinity of compounds 2 and 10 is comparable to that of dexmedetomidine hydrochloride. 2A The affinity of compound 3 for the receptor is better than that of dexmedetomidine hydrochloride; the affinity of compound 3 is α 1A / 2A The affinity of compounds 4, 8, and 10 is comparable to that of dexmedetomidine hydrochloride. 1A / 2A It is superior to dexmedetomidine hydrochloride. See Table 2 for details.

[0416] Test Example 2: In vitro function

[0417] 2 Experimental methods

[0418] 2.1 Objective: To detect adrenergic receptors (α 1A , α 2A , α 2B , α 2C ) signaling pathway, and calculate the EC of the compound. 50 The values ​​were used to evaluate the agonist effects of the dexmedetomidine hydrochloride series of compounds on adrenaline receptors.

[0419] 2.2 Experimental Materials

[0420] Cell line: 293-α 1A Stable cell line (Shanghai Shujing Biotechnology Co., Ltd.)

[0421] 293-α 2A Stable cell line (Shanghai Shujing Biotechnology Co., Ltd.)

[0422] CHO-α 2B / Gα15 stably transfected cell line (Nanjing GenScript Biotechnology Co., Ltd.)

[0423] CHO-α 2C / Gα15 stably transfected cell line (Nanjing GenScript Biotechnology Co., Ltd.)

[0424] Cell culture conditions:

[0425] 293-α 1A (DMEM, 10% FBS, 0.6μg / mL puromycin)

[0426] 293-α 2A (DMEM, 10% FBS, 0.6μg / mL puromycin)

[0427] CHO-α 2B / Gα15 (F12, 10% FBS, 200 μg / mL Zeocin, 100 μg / mL Hygromycin B)

[0428] CHO-α 2C / Gα15 (F12, 10% FBS, 400 μg / mL G418, 400 μg / mL Hygromycin B)

[0429] Reagents and consumables:

[0430] F12 (meilunbio, MA0229)

[0431] DMEM (Gibco, 8121703)

[0432] FBS (BOVOGEN, SFBS)

[0433] Zeocin (Invitrogen, R25001)

[0434] Hygromycin B (invitrogen, 10687010)

[0435] Puromycin (Solarbio, 119L042)

[0436] PBS (meilunbio, MA0015)

[0437] Pancreatin (Gibco, 25200-072)

[0438] 96-cell plate (cisbio, 66PL96025)

[0439] cAMP-Gi kit (cisbio, 03E)

[0440] IP-ONE Kit (cisbio, 16E)

[0441] CO2 incubator (Thermo, 311)

[0442] Centrifuge (Shanghai Anting, TGL-16C)

[0443] Cell counter (Countstar, IC1000)

[0444] Microplate reader (PerkinElmer, EnVision)

[0445] 2.3 Experimental steps

[0446] 2.3.1 Agonist screening mode cAMP assay (epinephrine α 2A receptors)

[0447] (1) Prepare the reaction buffer (1x Stimulation buffer) required for the experiment: dilute the 5x Stimulation buffer in the Cisbio cAMP-Gi kit with ddH2O in a ratio of 1:4 and set aside.

[0448] (2) Compound preparation: Dilute the compound to a 5 mM stock solution with DMSO, then dilute it 3.16-fold to form 10 gradients, and then dilute the prepared compound to the corresponding concentration (2.5x) with stimulation buffer for later use.

[0449] (3) Cell preparation: Trypsin digestion of 293-α on culture dishes 2A Cells were washed with culture medium and collected into a 5 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes and discard the supernatant. Add 3 mL of PBS and mix thoroughly by gently pipetting. Centrifuge again at 1000 rpm for 5 minutes and discard the supernatant. Resuspend the cells in 1x Stimulation buffer and count using a Countstar cell counter. Adjust the cell density to 4 x 10 5 / mL, for future use.

[0450] (4) Cell addition: Add the cell suspension to the experimental plate, 5 μL / well (i.e., approximately 2000 cells / well).

[0451] (5) Compound addition: Add the compound diluted with Stimulation buffer to the above experimental plate, 4 μL / well.

[0452] (6) Reaction incubation: After slow shaking, incubate the experimental plate at 37°C for 20 minutes.

[0453] (7) Addition of agonist Forskolin: Add 10x adenylate cyclase agonist (final concentration 1 μM Forskolin) solution, 1 μL / well.

[0454] (8) Reaction incubation: After slow shaking, incubate the experimental plate at 37°C for 45 minutes.

[0455] (9) Add detection reagents: Dilute cAMP-cryptate and Anti-cAMP-d2 at a 1:20 ratio using the Lysis & Detection Buffer in the Cisbio cAMP-Gi Assay Kit. Add 5 μL of each diluted cAMP-cryptate and Anti-cAMP-d2 to the assay plate. After shaking, incubate the plate at room temperature for 60 minutes.

[0456] (10) Experimental reading: Read the plate on Envision, detect the readings of the 665nm and 615nm channels, and calculate the ratio of 665nm / 615nm readings.

[0457] 2.3.2 Agonist Screening Mode IP-One Assay (epinephrine α 1A , α 2B , α 2C receptors)

[0458] (1) Prepare the reaction buffer (1x Stimulation buffer) required for the experiment: dilute the 5x Stimulation buffer in the Cisbio IP-One kit with ddH2O in a ratio of 1:4 and set aside.

[0459] (2) Compound preparation: Dilute the compound to a 5 mM stock solution with DMSO, then dilute it 3.16-fold to form 10 gradients, and then dilute the prepared compound to the corresponding concentration (2x) with stimulation buffer for later use.

[0460] (3) Cell preparation: Trypsin digestion of 293-α on culture dishes 1A ,CHO-α 2B ,CHO-α 2C Cells were washed with culture medium and collected into a 5 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes and discard the supernatant. Add 3 mL of PBS and mix thoroughly by gently pipetting. Centrifuge again at 1000 rpm for 5 minutes and discard the supernatant. Resuspend the cells in 1x Stimulation buffer and count using a Countstar cell counter to adjust the cell density to 1.7 x 10 6 / mL, for future use.

[0461] (4) Cell addition: Add the cell suspension to the experimental plate, 7 μL / well (i.e., approximately 12,000 cells / well).

[0462] (5) Compound addition: Add the compound diluted with Stimulation buffer to the above experimental plate, 7 μL / well.

[0463] (6) Reaction incubation: After slow shaking, the experimental plate was incubated at 37°C for 60 minutes.

[0464] (7) Add detection reagents: Dilute IP1-cryptate and Anti-IP1-d2 at a 1:12 ratio using the Lysis & Detection Buffer in the Cisbio IP-One Detection Kit. Add 3 μL of each diluted cAMP-cryptate and Anti-cAMP-d2 to the assay plate. After shaking, incubate the plate at room temperature for 60 minutes.

[0465] (8) Experimental reading: Read the plate on Envision, detect the readings of the 665nm and 615nm channels, and calculate the ratio of 665nm / 615nm readings.

[0466] 2.4 Data Analysis

[0467] According to the agonist effect values ​​of the compound samples at different concentrations, the data were analyzed and statistically analyzed using the graphing software GraphPad Prism5 (log(agonist) vs. normalized response--Variable slope, n≥2), and the EC was calculated. 50 .

[0468] 2.5 Experimental Results

[0469] For example, compounds 1, 3, 4, 10, 11-b, and 31-b of the present invention are effective for α 2A The agonist activity of compounds 2 and 8 on α 2A The agonist activity of the receptor is better than that of dexmedetomidine hydrochloride; the agonist activity of compounds 2, 4, 10, 11-b, 17, and 31-b is α 1A / 2A The agonist activity of compounds 3 and 8 is comparable to that of dexmedetomidine hydrochloride. 1A / 2A It is superior to dexmedetomidine hydrochloride. See Table 2 for details.

[0470] Table 2 In vitro affinity and functional data Note:" a " indicates superiority to dexmedetomidine hydrochloride," b"" indicates equivalent to dexmedetomidine hydrochloride, and "N / A" indicates not applicable.

[0471] Test Example 3: Hypnotic Effect

[0472] Experimental methods

[0473] The ED of the compounds of the present invention in rats with loss of righting reflex (LORR) was determined by sequential method. 50 (50% effective dose): Male SD rats, weighing 200-300 g, were given an initial dose of each compound dissolved in physiological saline via the tail vein at a constant rate of 10 seconds (one rat was given each dose). If the rat's righting reflex disappeared after the initial dose, the next rat was given a lower dose (0.8 times the initial dose). If the rat's 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 the AOT425 Statpm software until the software could produce the ED value. 50 , the experiment ends. 50 Evaluation of the hypnotic efficacy of the compounds of the present invention, ED 50 The smaller the value, the stronger the drug effect.

[0474] Comparison of onset time and duration of effect: Male SD rats weighing 200-300 g were given a dose of 2 times the ED after each compound was dissolved in physiological saline and injected into the tail vein at a constant speed of 10 seconds. There were 10 rats in each group. 50 (ED 50 : the dose that causes loss of righting reflex in 50% of rats), and record the onset time and maintenance time.

[0475] The onset time refers to the time after the injection when the rat is placed in the supine position. The rat's front paw cannot turn over to the prone position on its own and the time is maintained for ≥10 seconds, which is considered to be the standard of the rat's righting reflex disappearance. It is used as an indicator of the compound's effectiveness. The maintenance time refers to the duration of the rat's righting reflex disappearance. The drug effect is considered to have subsided after the rat's righting reflex recovers on its own.

[0476] 3.2 Experimental Results

[0477] The results are shown in Table 3:

[0478] Table 3 Hypnotic efficacy data Note: Compared with dexmedetomidine hydrochloride, ** p<0.01.

[0479] The experimental results show that the hypnotic onset time of compounds 5, 8, 10, 12-b, 17, 31-b, and 38-b of the present invention is equivalent to or slightly longer than that of dexmedetomidine hydrochloride, but all can induce sleep in rats within 5 minutes, and have a definite and reversible hypnotic effect; the hypnotic onset time of compound 11-b and the maintenance time of 5, 8, 10, 11-b, 12-b, 17, 31-b, and 38-b are all significantly lower than those of dexmedetomidine hydrochloride, expanding other application scenarios of the compounds.

[0480] 4. Fluctuations in blood pressure and heart rate after administration

[0481] 4.1 Experimental methods

[0482] Male SD rats, weighing 250-300 g, 4 rats per group, were placed under general anesthesia with isoflurane inhalation, cannulated through the femoral artery, and monitored for blood pressure and heart rate using a Powerlab data acquisition and analysis system. 30 minutes after the baseline values ​​stabilized, the baseline mean arterial pressure (MAP0) and baseline heart rate (HR0) were measured. The rats were injected with physiological saline solutions of each compound via the tail vein (the dosage of each compound was the same as in Test Example 3, with a rapid intravenous injection of 10 seconds), and blood pressure and heart rate were continuously recorded for 90 minutes. The maximum mean arterial pressure (MAP0) within 90 minutes was calculated. max ) and MAP0 + , mean arterial pressure nadir (MAP min ) and MAP0 - , Heart rate minimum (HR min ) and HR0 - Calculate the maximum rate of increase in mean arterial pressure = MAP + / MAP0*100%, maximum reduction rate of mean arterial pressure = MAP - / MAP0*100%, maximum heart rate reduction rate = HR - / HR0*100%. See Table 4 for details.

[0483] 4.2 Experimental Results

[0484] After injection of normal saline, rats showed no significant fluctuation in blood pressure and heart rate (the fluctuation amplitude was less than 10%). After administration of dexmedetomidine hydrochloride, MAP of the animals showed a bidirectional change of first increasing and then decreasing, and MAP and HR continued to decrease for 90 minutes.

[0485] The maximum increase rate of MAP of compounds 5, 10, 11-b, and 31-b was lower than that of dexmedetomidine hydrochloride. The MAP of compounds 5, 8, 10, 11-b, and 31-b did not show a significant decrease of more than 10%. The maximum decrease rate of HR of compounds 5, 8, 10, 11-b, and 31-b was lower than that of dexmedetomidine hydrochloride and recovered faster.

[0486] Table 4 Fluctuations of blood pressure and heart rate after administration Note: “ / ” indicates no relevant effect or not applicable; compared with dexmedetomidine hydrochloride, * p<0.05.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in, X is selected from CH and N, preferably CH; n is an integer selected from 1-3, preferably 1; m is an integer selected from 1-8, preferably an integer selected from 1-3; Each R1 is independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl, and the optional substituents are independently selected from halogen and hydroxy; R2 is selected from H, cyano, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl, the optional substituents being independently selected from halogen and hydroxy; R3 is selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl, the optional substituents being independently selected from halogen and hydroxy; Ring A is selected from C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from oxygen and sulfur, preferably selected from C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen and sulfur, and 5-8 membered heteroaryl containing 1 heteroatom selected from oxygen and sulfur; Each R 10 are independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl; the optional substituents are independently selected from halogen, C1-C8 alkyl and hydroxy; R 11 is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl, preferably selected from H and optionally substituted C1-C5 alkyl, further preferably H; the optional substituent is selected from hydroxyl and halogen; And the compound of formula I is not: 5-(2,3-dihydro-benzofuran-7-ylmethyl)-1-imidazole, 8-((1H-imidazol-5-yl)methyl)-1,2,3,4-tetrahydroquinoline, 5-(benzofuran-7-ylmethyl)-1H-imidazole, or 5-((5-bromobenzofuran-7-yl)methyl)-1H-imidazole.

2. The compound of formula I as claimed in claim 1 or its pharmaceutically acceptable salt, stereoisomer, or tautomer, characterized in that: One or more of the following conditions are met: (1) Ring A is selected from C3-C8 cycloalkyl, C3-C8 cycloalkenyl, a 4-6 membered heterocyclic group containing one heteroatom selected from oxygen, nitrogen and sulfur, and a 5-6 membered heteroaryl group containing one heteroatom selected from oxygen and sulfur; preferably selected from azetidinyl, oxetanyl, thietanyl, thienyl, furanyl, thiopyranyl, pyranyl, tetrahydropyrrolyl, hexahydropyridinyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydrothiophenyl, dihydropyridinyl, dihydrothiophenyl, tetrahydrothiopyranyl, dihydrothiopyranyl, tetrahydrofuranyl, dihydrofuranyl , tetrahydropyranyl, dihydropyranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl; further preferably selected from tetrahydropyrrolyl, hexahydropyridyl, dihydropyrrolyl, tetrahydropyridyl, thienyl, furanyl, thiopyranyl, pyranyl, dihydropyridyl, tetrahydrothiopyranyl, dihydrothiopyranyl, tetrahydrothiophenyl, dihydrothiophenyl, tetrahydrofuranyl, dihydrofuranyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl; (2) R1 is selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, hydroxy, optionally substituted C1-C8 alkylthio and optionally substituted C3-C6 cycloalkyl, preferably selected from H, halogen, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, hydroxy, optionally substituted C1-C5 alkylthio and optionally substituted C3-C6 cycloalkyl, further preferably selected from H, halogen, optionally substituted C1-C5 alkyl and hydroxy, further preferably selected from H, -F, -Cl and optionally substituted C1-C5 alkyl, further preferably H or -F; the optional substituent is selected from hydroxy and halogen, preferably F; (3) R3 is selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, hydroxy, optionally substituted C1-C8 alkylthio and optionally substituted C3-C6 cycloalkyl, preferably selected from H, halogen, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, hydroxy and optionally substituted C3-C6 cycloalkyl, further preferably selected from H, halogen and optionally substituted C1-C5 alkyl, further preferably H; the optional substituent is selected from hydroxy, halogen, preferably F; (4) Each R 10 are independently selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, hydroxy, optionally substituted C1-C8 alkylthio and optionally substituted C3-C6 cycloalkyl, preferably selected from H, halogen, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, hydroxy, optionally substituted C1-C5 alkylthio and optionally substituted C3-C6 cycloalkyl, further preferably selected from H, halogen and optionally substituted C1-C5 alkyl; the optional substituent is independently selected from halogen, C1-C8 alkyl and hydroxy, preferably selected from halogen, C1-C5 alkyl and hydroxy, further preferably halogen, and further preferably F; (5) R2 is selected from H and optionally substituted C1-C8 alkyl, preferably selected from H and optionally substituted C1-C5 alkyl, further preferably selected from optionally substituted C1-C5 alkyl; the optional substituents are independently selected from halogen and hydroxyl.

3. The compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof according to any one of claims 1 or 2, characterized in that: The compound represented by formula I is represented by formula I-a' or formula I-b':

4. The compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof according to any one of claims 1 to 3, characterized in that: Ring A is selected from a 4-6 membered heterocyclic group containing one oxygen atom, a 5-6 membered heteroaryl group containing one oxygen atom, and is preferably selected from More preferably selected from R2 is selected from optionally substituted C1-C8 alkyl; the substituents are independently selected from halogen and hydroxy.

5. The compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof according to any one of claims 1 to 3, characterized in that: Ring A is selected from a 4-6 membered heterocyclic group containing one sulfur atom, a 5-6 membered heteroaryl group containing one sulfur atom, and is preferably selected from More preferably selected from 6. The compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof according to any one of claims 1 to 3, characterized in that: Ring A is selected from a 4-6 membered heterocyclic group containing one nitrogen atom, preferably selected from R2 is selected from optionally substituted C1-C8 alkyl; said substituents are independently selected from halogen and hydroxy.

7. The compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof according to any one of claims 1 to 3, characterized in that: Ring A is selected from C3-C8 cycloalkyl, preferably selected from More preferably selected from More preferably 8. The compound of formula I according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound shown in formula I is shown in formula II or formula III: wherein R2 is selected from optionally substituted C1-C8 alkyl, the optional substituents being independently selected from halogen and hydroxyl; n, R1, R3 are the same as the definitions of the corresponding groups in claims 1-4; R4, R5, R6 are independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl; the optional substituents are independently selected from halogen, C1-C8 alkyl and hydroxy.

9. The compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof according to any one of claims 1 to 3 or 7, characterized in that: The compound represented by formula I is represented by formula V or formula VI: Wherein, n, R1, R2, and R3 are the same as the definitions of the corresponding groups in claims 1 to 3 or 7; R4, R5, R6 are independently selected from H, halogen, hydroxy, nitro, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylthio and optionally substituted C3-C8 cycloalkyl; the optional substituents are independently selected from halogen, C1-C8 alkyl and hydroxy.

10. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: Selected from the following compounds:

11. A pharmaceutical composition, characterized in that Containing the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, and a pharmaceutically acceptable carrier.

12. Use of the compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt, stereoisomer, tautomer, or the pharmaceutical composition according to claim 11 in the preparation of drugs related to α2 adrenergic receptor agonists, preferably in the preparation of drugs that produce sedation, and / or analgesia, and / or anesthetic effects, and / or anti-anxiety, and / or inhibition of sympathetic nerve activity, and / or treatment of insomnia, and / or treatment of mental disorders in humans or animals, and further preferably in the preparation of drugs that produce sedation, and / or analgesia, and / or anesthetic effects, and / or treatment of insomnia, and / or treatment of mental disorders in humans or animals.

13. A compound of formula IA, formula IA', formula IB, formula IB', formula IC, formula ID or formula ID', or a salt thereof, in, In Formula IA, n, Ring A, R1, R3, m, R 10 Same as the definitions of the corresponding groups in claims 1-10; In Formula I-A', n, Ring A, R1, R3, m, R 10 Same as the definitions of the corresponding groups in claims 1-10; In Formula IB, n, Ring A, R1, R3, m, R 10 Same as the definitions of the corresponding groups in claims 1-9; R8 is selected from C1-C5 alkyl, preferably methyl, ethyl, propyl, and more preferably methyl; In Formula I-B', n, Ring A, R1, R3, m, R 10 Same as the definitions of the corresponding groups in claims 1-9; In Formula IC, n, Ring A, R1, R2, R3, m, R 10 Same as the definitions of the corresponding groups in claims 1-9; In Formula ID, n, Ring A, R1, R2, R3, m, R 10 Same as the definitions of the corresponding groups in claims 1-9; R9 is selected from hydroxyl protecting groups, preferably selected from silyl ether hydroxyl protecting groups, further preferably selected from trimethylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and further preferably selected from tert-butyldimethylsilyl; In Formula I-D', n, Ring A, R1, R2, R3, m, R 10 Same as the definitions of the corresponding groups in claims 1-10; R7 in Formula IA, Formula IB, Formula I-B', Formula IC, Formula ID, or Formula ID' is selected from an amino protecting group, preferably a trityl group.

14. A method for preparing the compound according to any one of claims 1 to 10, characterized in that: The method comprises the following steps: intermediate IA is obtained by dehydration reaction of intermediate Ⅰ-B-1, and then intermediate IC is obtained by hydrogenation reduction reaction, intermediate IC is deprotected by amino protecting group to obtain compound shown in formula Ⅰ-1; or intermediate Ⅰ-B-1 is deprotected by amino protecting group and water in one step to obtain intermediate IA', and then hydrogenation reduction reaction is performed to obtain compound shown in formula Ⅰ-1; or intermediate Ⅰ-B' is deprotected by amino protecting group in one step and simultaneously reduced by reduction reaction to obtain compound shown in formula Ⅰ-2; or intermediate Ⅰ-D is deprotected by hydroxy protecting group to obtain intermediate Ⅰ-D', intermediate Ⅰ-D' is deprotected by amino protecting group and dehydrated to obtain compound shown in formula Ⅰ; Among them, n, ring A, R1, R2, R3, m, R 10 Same as the definitions of the corresponding groups in claims 1-10; R7 is selected from an amino protecting group, preferably a trityl group; R9 is selected from hydroxyl protecting groups, preferably selected from silyl ether hydroxyl protecting groups, further preferably selected from trimethylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and further preferably selected from tert-butyldimethylsilyl.

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