Substituted imidazole derivatives, intermediates, manufacturing methods, and applications thereof

Abstract

The present invention belongs to the pharmaceutical field and specifically relates to compounds represented by the following general formula I, or pharmaceutically acceptable salts, stereoisomers, tautomers, and compositions containing said compounds, intermediates thereof, methods for producing them, and applications in the pharmaceutical field. JPEG2026523174000101.jpg2143

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 202310724980.9, filed on 19 June 2023, entitled "Substitutable Imidazole Derivatives, Intermediates, Methods for Manufacturing the Same and Applications thereof," and Chinese Patent Application No. 202410149322.6, filed on 2 February 2024, whose entire contents are incorporated herein by reference. The present invention belongs to the pharmaceutical field and specifically relates to substituted imidazole derivatives or pharmaceutically acceptable salts thereof, stereoisomers, tautomers, and compositions containing such compounds, intermediates thereof, methods for production, and applications in the pharmaceutical field. [Background technology]

[0002] Adrenergic receptors are G protein-bound receptors and are divided into adrenergic α receptors and β receptors. α receptors include α1 and α2 receptors, while β receptors include β1, β2, and β3 receptors. α2 receptors are widely distributed in the central and peripheral nervous systems and other organ tissues (blood vessels, liver, kidneys, pancreas, platelets, etc.). α2A, α2B, and α2C are three isoforms of the α2 receptor (Bylund et al., Mol. Pharmacol., 1992, 42, 1-5). In the brain, α2A is mainly concentrated in the pons and medulla oblongata and is involved in the transmission of sympathetic nerve signals from the central to the periphery. Stimulating presynaptic α2A can regulate adrenaline release through a negative feedback mechanism, while stimulating postsynaptic α2A can cause hyperpolarization of the nerve cell membrane.

[0003] The analgesic, anesthetic, and sedative effects of α2 receptor agonists have already been well-established (Pertovaara, A., Progress in Neurobiology, 40, 691 (1993)). For example, in addition to its well-known sedative effect, systematic administration of clonidine has been shown to induce antinociceptivity in various species, including human patients. Intradural and epidural administration of clonidine has also been shown to effectively induce antinociceptivity. Another α2 receptor agonist, medetomidine, has better α2 / α1 selectivity and is more effective against the α2 receptor than clonidine, and is already widely used.

[0004] Dexmedetomidine is a highly selective α2 adrenergic receptor agonist that can produce sedative, analgesic, anxiolytic, and sympathetic activity-suppressing effects when acting on the central and peripheral nervous systems and other organs and tissues (Maud ASWeerinks, et al. Clin Pharmacokinte, 2017, 56:893-913). Due to its remarkable effects, it is now widely used clinically. While dexmedetomidine exhibits good analgesic and sedative effects, adverse drug reactions should also be considered, particularly hypotension and bradycardia, which are relatively common. Currently, many cases of progressive dexmedetomidine-associated bradycardia have been reported clinically. In particular, high doses of dexmedetomidine can stimulate α2B receptors on vascular smooth muscle, causing vasoconstriction, hypertension, and a decrease in reflex heart rate.

[0005] Therefore, there is a need to find an α2 adrenergic receptor agonist that exhibits excellent circulatory stability, high potency, short maintenance time, rapid in vivo effects, and few side effects, and to apply it to the manufacture of drugs that produce sedative and / or analgesic and / or anesthetic effects, and / or anxiolytic and / or suppress sympathetic nerve activity, and / or treat insomnia and / or mental disorders. [Overview of the Initiative]

[0006] The following is merely illustrative of some aspects of the present invention, and therefore the present invention is not limited thereto.

[0007] The present invention aims to provide substituted imidazole derivatives or pharmaceutically acceptable salts, stereoisomers, tautomers, and pharmaceutical compositions thereof having α2-adrenergic receptor agonist activity. The above compounds and pharmaceutical compositions can be used in the manufacture of drugs related to α2-adrenergic receptor agonists, and can be used in the manufacture of drugs for sedation, and / or analgesia, and / or anesthetic effects, and / or anxiolytic effects, and / or inhibition of sympathetic nerve activity, and / or treatment of insomnia and / or treatment of mental disorders in humans or animals.

[0008] According to one embodiment, the present invention provides a compound represented by the following general formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer,

[0009] [ka]

[0010] Of these, X is selected from CH and N, and is preferably CH. n is an integer selected from 1 to 3, preferably 1. m is an integer selected from 1 to 8, preferably an integer selected from 1 to 3. Each R1 is independently selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the optionally substituted substituents are independently selected from halogen and hydroxyl groups. R2 is selected from H, a cyano group, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkene group, and an optionally substituted C2-C8 alkyne group, and the optionally substituted substituents are independently selected from halogens and hydroxyl groups. R3 is selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the above optionally substituted substituents are independently selected from halogen and hydroxyl groups. Ring A is selected from a 3-8 membered heterocyclyl group containing 1-3 heteroatoms independently selected from C3-C8 cycloalkyl groups, C3-C8 cycloalkenyl groups, oxygen, nitrogen, and sulfur, and a 5-8 membered heteroaryl group containing 1-3 heteroatoms independently selected from oxygen and sulfur, preferably selected from a 3-8 membered heterocyclyl group containing 1 heteroatom selected from C3-C8 cycloalkyl groups, oxygen, nitrogen, and sulfur, and a 5-8 membered heteroaryl group containing 1 heteroatom selected from oxygen and sulfur. Each R 10 Each of these is independently selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the above optionally substituted substituents are independently selected from halogen, C1-C8 alkyl group, and hydroxyl group. R 11The substituent is selected from H, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkene group, and an optionally substituted C2-C8 alkyne group, preferably H and an optionally substituted C1-C5 alkyl group, and more preferably H, wherein the optionally substituted substituent is selected from a hydroxyl group and a halogen. Furthermore, the compound of formula I is not 5-(2,3-dihydro-benzofuran-7-ylmethyl)-1-imidazole, 8-((1H-imidazole-5-yl)methyl)-1,2,3,4-tetrahydroquinoline, 5-(benzofuran-7-ylmethyl)-1H-imidazole, or 5-((5-bromobenzofuran-7-yl)methyl)-1H-imidazole.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and further comprising optionally pharmaceutically acceptable excipients, carriers, adjuvants, solvents, or combinations thereof.

[0012] In another aspect, the present invention provides applications of the compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof in the manufacture of drugs related to α2 adrenergic receptor agonists, preferably in the manufacture of drugs for sedation, and / or analgesia, and / or anesthetic effects, and / or anxiolytic effects, and / or inhibition of sympathetic nerve activity, and / or treatment of insomnia and / or treatment of mental disorders in humans or animals, and more preferably in the manufacture of drugs for sedation, and / or analgesia, and / or anesthetic effects, and / or treatment of insomnia and / or treatment of mental disorders in humans or animals.

[0013] In another embodiment, the present invention provides compounds represented by formula IA, formula I-A', formula IB, formula I-B', formula IC, formula ID, or formula I-D', or salts thereof.

[0014] [ka]

[0015] In Formula I-A, n, ring A, R1, R3, m, R 10 are as described above, In Formula I-A', n, ring A, R1, R3, m, R 10 are as described above, In Formula I-B, n, ring A, R1, R3, m, R 10 are as described above, R8 is selected from C1-C5 alkyl groups, preferably selected from a methyl group, an ethyl group, and a propyl group, and more preferably is a methyl group, In Formula I-B', n, ring A, R1, R3, m, R 10 are as described above, In Formula I-C, n, ring A, R1, R2, R3, m, R 10 are as described above, In Formula I-D, n, ring A, R1, R2, R3, m, R 10 are as described above, R9 is selected from hydroxy protecting groups, preferably selected from silyl ether hydroxy protecting groups, and more preferably is selected from a trimethylsilyl group, a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, and a triisopropylsilyl group, and even more preferably is selected from a tert-butyldimethylsilyl group, In Formula I-D', n, ring A, R1, R2, R3, m, R 10 are as described above, R7 in Formula I-A, Formula I-B, Formula I-B', Formula I-C, Formula I-D, or Formula I-D' is selected from amino protecting groups, and preferably is a trityl group.

[0016] In another aspect, the present invention provides a method for producing a compound represented by formula I, comprising the steps of: obtaining intermediate IA from intermediate IB-1 by a dehydration reaction; obtaining intermediate IC by a hydrogenation-reduction reaction; removing the amino protecting group from intermediate IC to obtain a compound represented by formula I-1; or obtaining intermediate I-A' by removing the amino protecting group and water from intermediate IB-1 in one step; then obtaining a compound represented by formula I-1 by a hydrogenation-reduction reaction; or obtaining a compound represented by formula I-2 from intermediate I-B' by removing the amino protecting group in one step and simultaneously performing a reduction reaction; or obtaining intermediate I-D' by removing the hydroxy protecting group from intermediate ID; removing the amino protecting group from intermediate I-D' and dehydrating it to obtain a compound represented by formula I.

[0017] [ka]

[0018] Among them, n, ring A, R1, R2, R3, m, R 10 As stated above, R7 is selected from amino protecting groups, preferably a trityl group. R9 is selected from hydroxy protecting groups, preferably from silyl ether hydroxy protecting groups, more preferably from trimethylsilyl group, tert-butyldiphenylsilyl group, tert-butyldimethylsilyl group, and triisopropylsilyl group, and even more preferably from tert-butyldimethylsilyl group. [Modes for carrying out the invention]

[0019] Unless otherwise specified or unless clearly contradicted by the context, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. In the event of any contradiction, the definitions provided herein shall prevail. Where trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, previously published patent applications, and publications incorporated herein by reference are incorporated herein by reference.

[0020] General terms and definitions The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur.

[0021] The term "optionally substituted" is used interchangeably with the terms "substituted or unsubstituted," i.e., the structure or group is either unsubstituted or substituted with one or more substituents described in the present invention, the substitution occurring at a reasonable position where any valence on the given structure or group is acceptable.

[0022] Unless otherwise specified herein, the linking points of substituents may originate from any suitable position on the substituent, as used herein. If the bonding of a substituent indicates that it penetrates a bond linking two atoms in a ring, such substituent may be bonded to any one of the ring-constituting atoms in the substituteable ring.

[0023] Generally, the term "substitution" means that one or more hydrogen atoms in a given structure or group are replaced by specific substituents. Unless otherwise specified in other embodiments, a single substituent may be substituted at each reasonable substitutable position of the group. When one or more positions in a given structural formula are selectively substituted with one or more specific substituents, the substituents may be homologous or heterologous at each reasonable position in the structural formula.

[0024] Furthermore, it should be explained that, unless otherwise specified, the phrase "each independently" as used in this invention should be understood in a broad sense, meaning that specific options represented by the same symbol within different bases do not influence each other, or that specific options represented by the same symbol within the same base do not influence each other.

[0025] Where lower and upper limits of a numerical range are disclosed, any numerical value and any range included within that range are also specifically disclosed. In particular, each possible range of values ​​disclosed herein should be understood to represent numerical values ​​and ranges that fall within a relatively broad range. Where any variable (e.g., R) and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear one or more times in the composition or structure of a compound, the definition in each case is independent for each occurrence. For example, where a group is substituted with 0, 1, 2, or 3 R substituents, the group may be optionally substituted with up to 3 R substituents, and each choice of R substituent in each case is independent of the others. That is, each R substituent may be the same or different.

[0026] In each part of this specification, substituents of the compounds disclosed herein are disclosed according to the type or range of the group. In particular, it should be noted that the present invention includes each independent secondary combination of each member of these types and ranges of groups. For example, the expression m~n as used herein refers to the range from m to n, and the subranges consisting of each point value within that range, as well as each point value.

[0027] The term "alkyl group" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms that is linked to the rest of the molecule by a single bond. An alkyl group may have 1 to 8 carbon atoms, i.e., a "C1-C8 alkyl group," for example, C 1-5 Alkyl alkyl group, C 1-3 Alkyl alkyl group, C 1-2 Alkyl alkyl groups, C3 alkyl groups, C4 alkyl groups, C8 alkyl groups, C1-8 Alkyl alkyl group, C 3-8 It is an alkyl group. It may have 1 to 5 carbon atoms, i.e., a "C1-C5 alkyl group", and may have 1 to 3 carbon atoms, i.e., a "C1-C3 alkyl group", for example, C 1-3 Alkyl alkyl group, C 1-2Alkyl groups, C3 alkyl groups. The term "C1-C5 alkyl groups" specifically refers to methyl groups, ethyl groups, C3 alkyl groups, C4 alkyl groups, and C5 alkyl groups, which are disclosed independently. Examples of alkyl groups include methyl group (Me, -CH3), ethyl group (Et, -CH2CH3), propyl group (e.g., n-propyl group (n-Pr, -CH2CH2CH3), isopropyl group (i-Pr, -CH(CH3)2)), butyl group (e.g., n-butyl group (n-Bu, -CH2CH2CH2CH3), isobutyl group (i-Bu, -CH2CH(CH3)2), sec-butyl group (s-Bu, -CH(CH3)CH2CH3), tert-butyl t-Bu, -C(CH3)3, pentyl group (e.g., n-pentyl group (-CH2CH2CH2CH2CH3), 2-pentyl group (-CH(CH3)CH2CH2CH3), 3-pentyl group (-CH(CH2CH3)2), 2-methyl-2-butyl group (-C(CH3)2CH2CH3), 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), 2-methyl -1-butyl group (-CH2CH(CH3)CH2CH3), hexyl group (e.g., n-hexyl group (-CH2CH2CH2CH2CH2CH3), 2-hexyl group (-CH(CH3)CH2CH2CH2CH3), 3-hexyl group (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl group (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl group (-CH(CH3)CH(CH3)CH2CH3), This includes, but is not limited to, 4-methyl-2-pentyl group (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl group (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl group (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl group (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl group (-CH(CH3)C(CH3)3), heptyl group, octyl group, etc.For example, the expression "C1-C8" or "C1-8" should be understood to encompass the range of 1 to 8 carbon atoms, and any sub-ranges within that range, as well as each point value, such as C1-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, etc., and also C1, C2, C3, C4, C5, C6, C7, C8, etc. Also, for example, "C1-C5" or "C... 1-5 The expression "C2-C5" should be understood to encompass the range of 1 to 5 carbon atoms, and any sub-ranges within that range, as well as each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., and also C1, C2, C3, C4, C5, etc. Also, for example, "C2-C5" or "C 2-5 The expression "C1-C8" should be understood to encompass a range of 2 to 5 carbon atoms, and also include any sub-ranges within that range, as well as each point value, such as C2-C5, C3-C4, C2-C3, C2-C4, C3-C5, C4-C5, and C2, C3, C4, C5, etc. Also, for example, "C1-C8" or "C 1-8 The expression "1 to 8 carbon atoms" should be understood to encompass the range of 1 to 8 carbon atoms, and also any sub-ranges and point values ​​within that range, 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. Similarly, the expression "3 to 8 members" should be understood to encompass any sub-ranges and point values ​​within that range, such as 3 to 5 members, 3 to 6 members, 3 to 7 members, 3 to 8 members, 4 to 5 members, 4 to 6 members, 4 to 7 members, 4 to 8 members, 5 to 7 members, 5 to 8 members, 6 to 7 members, 6 to 8 members, etc., as well as 3, 4, 5, 6, 7, 8 members, etc. Other similar expressions in this specification should be understood in a similar manner.

[0028] The term "one or more (species)" or similar expression "at least one (species)" may mean, for example, one, two, three, four, five, six, seven, eight, nine, ten (species) or more (species).

[0029] The term "selected from..." refers to one or more elements listed thereafter that are independently selectable and may include combinations of two or more elements.

[0030] The term "inclusion" is a non-limiting expression, meaning it includes the content specified in this invention but does not exclude other embodiments.

[0031] When it is stated that each carbon atom in the group may be optionally substituted with a heteroatom, the condition is that the valence of all atoms in the group does not exceed the normal valence in the current case, and that a stable compound is formed.

[0032] When it is stated that a group is substituted with a substituent, the conditions are that the substitution does not exceed the normal valence of all atoms in the group in their current state, and a stable compound is formed; otherwise, the substituent does not exist.

[0033] If "ring A" is defined, it does not include the double bond portion on the benzene ring with which it is condensed.

[0034] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from one or more of oxygen, sulfur, and nitrogen. The term "heteroaryl group" may be used interchangeably with the terms "heteroaryl ring" or "heteroaromatic compound." Examples of heteroaryl groups include 5-14 membered heteroaryl groups, 5-8 membered heteroaryl groups, 5-10 membered monocyclic or polycyclic heteroaryl groups, and 5-6 membered monocyclic heteroaryl groups. A "5-8 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from oxygen and sulfur" refers to a heteroaromatic system of 5 to 8 ring atoms containing 1 to 3 heteroatoms selected from oxygen and sulfur. A "5-8 membered heteroaryl group containing 1 heteroatom selected from oxygen and sulfur" refers to a heteroaromatic system of 5 to 8 ring atoms containing 1 heteroatom selected from oxygen or sulfur. The heteroaryl group described above may be monocyclic or bicyclic and may be optionally substituted with one or more substituents described in the present invention.

[0035] Specific examples of the term "5- to 6-membered heteroaryl group containing one oxygen atom" include, but are not limited to, furan groups and pyranyl groups. The heteroaryl group containing one oxygen atom may be optionally substituted with one or more substituents described in the present invention.

[0036] Specific examples of the term "5-6 membered heteroaryl group containing one sulfur atom" include, but are not limited to, thienyl and thiopyranyl groups. The heteroaryl group containing one sulfur atom may be optionally substituted with one or more substituents described in the present invention.

[0037] The term “heterocyclic” may be used interchangeably with “heterocyclyl group” and refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system containing 3 to 14 ring atoms, or 3 to 8 ring atoms, or 4 to 6 ring atoms, where one or more atoms in the ring are independently substituted with heteroatoms, the heteroatoms having the meanings described in this invention, and the ring may be fully saturated or contain one or more degrees of unsaturation. Unless otherwise specified, the -CH2- group on the heterocyclyl group may be optionally substituted with -C(=O)-. The sulfur atom of the ring may be optionally oxidized to an S-oxide. The nitrogen atom of the ring may be optionally oxidized to an N-acid compound. Examples of heterocyclyl groups include 3 to 14-membered heterocyclyl groups, 3 to 8-membered heterocyclyl groups, 4 to 6-membered heterocyclyl groups, and 5 to 10-membered monocyclic or bicyclic heterocyclyl groups. A "3- to 8-membered heterocyclyl group containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur" refers to a heterocyclyl system having 3 to 8 ring atoms containing 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur. A "3- to 8-membered heterocyclyl group containing 1 heteroatom selected from oxygen, nitrogen, and sulfur" refers to a heterocyclyl system having 3 to 8 ring atoms containing 1 heteroatom selected from oxygen, sulfur, and nitrogen. The above heterocyclyl groups may be monocyclic or bicyclic ring systems and may be optionally substituted with one or more substituents described in the present invention.

[0038] Specific examples of the term "4-6 membered heterocyclyl group containing one nitrogen atom" include, but are not limited to, azetidinyl, tetrahydropyrrolyl, hexahydropyridyl, dihydropyrrolyl, and tetrahydropyridyl groups. The heterocyclyl group containing one nitrogen atom may be optionally substituted with one or more substituents described in the present invention. The phrase "the heterocyclyl group may be substituted with substituents" means that all substituted positions in the "4-6 membered heterocyclyl group containing one nitrogen atom" may be substituted with substituents.

[0039] Specific examples of the term "4- to 6-membered heterocyclyl group containing one sulfur atom" include, but are not limited to, thiethanyl groups, tetrahydrothienyl groups, dihydrothienyl groups, tetrahydrothiopyranyl groups, dihydrothiopyranyl groups, 2H-thiopyranyl groups, and 4H-thiopyranyl groups. The heterocyclyl group containing one sulfur atom may be optionally substituted with one or more substituents described in the present invention.

[0040] Specific examples of the term "4- to 6-membered heterocyclyl group containing one oxygen atom" include, but are not limited to, oxetanyl, tetrahydrofuran, dihydrofuran, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, and 4H-pyranyl groups. The heterocyclyl group containing one oxygen atom may be optionally substituted with one or more substituents described in the present invention.

[0041] The term "alkene group" refers to a general term for hydrocarbon compounds that contain a carbon-carbon double bond in their molecule, and are unsaturated aliphatic hydrocarbons. For example, a vinyl group (-CH=CH2). The above "olefin" may have 2 to 8 carbon atoms, i.e., a "C2-C8" alkenyl group, for example, C 2-8 Alkenyl group, C 2-4 Alkenyl group, C 2-5 Alkenyl group, C3 alkenyl group, C4 alkenyl group, C6 alkenyl group, C 2-6 Alkenyl group, C 3-8 Alkenyl group, C 3-6 Examples include alkenyl groups. They may have 2 to 5 carbon atoms, i.e., "C2-C5 alkenyl groups," for example, C 2-4 Alkenyl group, C 2-3Examples of alkenyl groups include C3 alkenyl groups and C4 alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl groups (-CH=CH2), propenyl groups (-CH=CH-CH3), butenyl groups (-CH=CH-CH2-CH3, -CH2-CH=CH-CH3), pentenyl groups (-CH=CH-CH2-CH2-CH3, -CH2-CH2-CH=CH-CH3, -CH(CH3)-CH=CH-CH3), hexenyl groups, heptenyl groups, and octenyl groups.

[0042] The term "alkyne group" refers to a general term for hydrocarbon compounds that contain a carbon-carbon triple bond in their molecule, and are unsaturated aliphatic hydrocarbons. For example, the ethynyl group. JPEG2026523174000005.jpg1032 The above "alkynyl group" may have 2 to 8 carbon atoms, that is, it is a "C2-C8" alkynyl group, for example, C 2-8 Alkynyl group, C 2-4 Alkynyl group, C 2-5 Alkynyl group, C3 alkynyl group, C4 alkynyl group, C6 alkynyl group, C 2-6 Alkynyl group, C 3-8 Alkynyl group, C 3-6 Examples include alkynyl groups. They may have 2 to 4 carbon atoms, i.e., "C2-C4 alkynyl groups," for example, C 2-4 Alkynyl group, C 2-3 Examples include alkynyl groups, C3 alkynyl groups, and C4 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and octinyl groups.

[0043] The term "hydrogen (H)" refers to a single hydrogen atom, and such a group of atoms can be linked to other groups, such as an oxygen atom, to form a hydroxyl group.

[0044] The terms "halogen" or "halogenated" should be understood to represent fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), preferably the "halogen" or "halogenated" is selected from fluorine, chlorine, and bromine atoms, more preferably selected from fluorine and chlorine, and even more preferably the "halogen" or "halogenated" is fluorine.

[0045] The term "alkoxy group" refers to an alkyl group linked to the rest of a molecule by an oxygen atom, where the alkyl group has the meaning described in this invention. In one embodiment, the alkoxy group contains 1 to 8 carbon atoms. In another embodiment, the alkoxy group contains 1 to 5 carbon atoms, and in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy groups (MeO, -OCH3), ethoxy groups (EtO, -OCH2CH3), 1-propoxy groups (n-PrO, n-propoxy group, -OCH2CH2CH3), 2-propoxy groups (i-PrO, i-propoxy group, -OCH(CH3)2), 1-butoxy groups (n-BuO, n-butoxy group, -OCH2CH2CH2CH3), 2-methyl-l-propoxy groups (i-BuO, i-butoxy group, -OCH2CH(CH3)2), 2-butoxy groups (s-BuO, s-butoxy group, -OCH(CH3)CH2CH3), and 2-methyl-2-propoxy groups (t-BuO, t-butoxy group, -OC(CH3)3).

[0046] The term "alkylthio group" refers to a group in which an alkyl group is linked to the rest of the molecule by a sulfur atom, where the alkyl group has the meaning described in this invention. In one embodiment, the alkylthio group contains 1 to 8 carbon atoms. In another embodiment, the alkylthio group contains 1 to 5 carbon atoms. In yet another embodiment, the alkylthio group contains 1 to 3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described in this invention. Examples of alkylthio groups include, but are not limited to, methylthio group (-SCH3), ethylthio group (-SCH2CH3), propylthio group (-SCH2CH2CH3, -SCH(CH3)2), butylthio group (-SCH2CH2CH2CH3, -SCH2CH(CH3)2, -SCH(CH3)CH2CH3, -SC(CH3)3), etc.

[0047] The term "cycloalkyl group" broadly includes cyclic hydrocarbon groups or cyclic alkenyl groups consisting of carbon atoms and hydrogen atoms, preferably containing one or two rings. The cycloalkyl group may have a monocyclic, fused polycyclic, crosslinked cyclic, or spirocyclic structure. A cycloalkyl group may have 3 to 8 carbon atoms, i.e., a "C3-C8 cycloalkyl group," or 3 to 6 carbon atoms, i.e., a "C3-C6 cycloalkyl group," such as a C6 cycloalkyl group, C5 cycloalkyl group, C4 cycloalkyl group, or C3 cycloalkyl group. Examples of cycloalkyl groups include C3-C8 cycloalkyl groups and C3-C6 cycloalkyl groups, specifically including cyclopropyl group, cyclopropenyl group, cyclobutenyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopentenyl group, cyclopentadiene group, cyclohexenyl group, cyclohexadienyl group, etc. The term also includes cases where the C atom is substituted with oxo (=O). A typical cycloalkyl group refers to a saturated cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms. The term "cycloalkenyl group" typically refers to an alicyclic hydrocarbon containing a carbon-carbon double bond in a molecule, consisting of carbon atoms and hydrogen atoms. A cycloalkenyl group may have 3 to 8 carbon atoms, i.e., a "C3-C8 cycloalkenyl group," or 3 to 6 carbon atoms, i.e., a "C3-C6 cycloalkenyl group," such as a C6 cycloalkenyl group, C5 cycloalkenyl group, C4 cycloalkenyl group, or C3 cycloalkenyl group. Examples of cycloalkenyl groups include C3-C8 and C3-C6 cycloalkenyl groups, specifically including cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl groups. The term also includes cases where the carbon atom is substituted with oxo (=O).

[0048] The term "hydroxyl group" refers to the -OH group.

[0049] Examples of the term "amino protecting group" include, but are not limited to, trityl group, benzyloxycarbonyl group, tert-butoxycarbonyl group, fluorenylmethoxycarbonyl group, allyloxycarbonyl group, p-methoxybenzyl group, and benzyl group.

[0050] The term "hydroxy protecting group" preferably refers to a silyl ether hydroxy protecting group, and the examples include, but are not limited to, trimethylsilyl group (TMS), tert-butyldiphenylsilyl group (TBDPS), tert-butyldimethylsilyl group (TBS / TBDMS), and triisopropylsilyl group (TIPS).

[0051] The term "stereoisomer" refers to a compound that has the same chemical structure but in which atoms or groups are arranged in different spatial configurations. Stereoiomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and atrop isomers.

[0052] for example

[0053] [ka]

[0054] [ka]

[0055] That is the case.

[0056] The term "tautomer" refers to structural isomers with different energies that can be interconverted over a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomerism can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversions that occur via protricsis, such as keto-enol isomerization and imine-enamine isomerization.

[0057] The term "pharmaceutically acceptable salt" refers to an organic or inorganic salt of the compound of the present invention.

[0058] The term "pharmaceutically acceptable carrier" refers to a substance that does not have an apparent irritant effect on an organism and does not impair the biological activity and performance of the active compound. "pharmaceutically acceptable carriers" include, but are not limited to, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0059] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that those skilled in the art may better understand the technical concept, principle, and practical applications of the invention, thereby enabling them to modify and implement the invention in many forms to best suit the requirements of their particular use.

[0060] Compound of formula I The present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, stereoisomer, or tautomer.

[0061] [ka]

[0062] Of these, X is selected from CH and N, and is preferably CH. n is an integer selected from 1 to 3, preferably 1. m is an integer selected from 1 to 8, preferably an integer selected from 1 to 3. Each R1 is independently selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the optionally substituted substituents are independently selected from halogen and hydroxyl groups. R2 is selected from H, a cyano group, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkene group, and an optionally substituted C2-C8 alkyne group, and the optionally substituted substituents are independently selected from halogens and hydroxyl groups. R3 is selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the above optionally substituted substituents are independently selected from halogen and hydroxyl groups. Ring A is selected from a 3-8 membered heterocyclyl group containing 1-3 heteroatoms independently selected from C3-C8 cycloalkyl groups, C3-C8 cycloalkenyl groups, oxygen, nitrogen, and sulfur, and a 5-8 membered heteroaryl group containing 1-3 heteroatoms independently selected from oxygen and sulfur, preferably selected from a 3-8 membered heterocyclyl group containing 1 heteroatom selected from C3-C8 cycloalkyl groups, oxygen, nitrogen, and sulfur, and a 5-8 membered heteroaryl group containing 1 heteroatom selected from oxygen and sulfur. Each R 10Each of these is independently selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the above optionally substituted substituents are independently selected from halogen, C1-C8 alkyl group, and hydroxyl group. R 11 The substituent is selected from H, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkene group, and an optionally substituted C2-C8 alkyne group, preferably H and an optionally substituted C1-C5 alkyl group, and more preferably H, wherein the optionally substituted substituent is selected from a hydroxyl group and a halogen. Furthermore, the compound of formula I is not 5-(2,3-dihydro-benzofuran-7-ylmethyl)-1-imidazole, 8-((1H-imidazole-5-yl)methyl)-1,2,3,4-tetrahydroquinoline, 5-(benzofuran-7-ylmethyl)-1H-imidazole, or 5-((5-bromobenzofuran-7-yl)methyl)-1H-imidazole.

[0063] In one embodiment, a 3- to 8-membered heterocyclyl group containing one heteroatom selected from oxygen, nitrogen, and sulfur is a 3- to 8-membered heterocyclyl group containing one sulfur atom, a 3- to 8-membered heterocyclyl group containing one oxygen atom, or a 3- to 8-membered heterocyclyl group containing one nitrogen atom.

[0064] In one embodiment, the 3-8 membered heterocyclyl group containing one sulfur atom is a 4-6 membered heterocyclyl group containing one sulfur atom. In one preferred embodiment, the 3-8 membered heterocyclyl group containing one sulfur atom and / or the 4-6 membered heterocyclyl group containing one sulfur atom are selected from a thiethanyl group, a tetrahydrothienyl group, a dihydrothienyl group, a tetrahydrothiopyranyl group, and a dihydrothiopyranyl group.

[0065] In one embodiment, the 3- to 8-membered heterocyclyl group containing one oxygen atom is a 4- to 6-membered heterocyclyl group containing one oxygen atom. In one preferred embodiment, the 3- to 8-membered heterocyclyl group containing one oxygen atom and / or the 4- to 6-membered heterocyclyl group containing one oxygen atom are selected from an oxetanyl group, a tetrahydrofuran group, a dihydrofuran group, a tetrahydropyranyl group, and a dihydropyranyl group.

[0066] In one embodiment, the 3-8 membered heterocyclyl group containing one nitrogen atom is a 4-6 membered heterocyclyl group containing one nitrogen atom. In one preferred embodiment, the 3-8 membered heterocyclyl group containing one nitrogen atom and / or the 4-6 membered heterocyclyl group containing one nitrogen atom are selected from an azetidinyl group, a tetrahydropyrrolyl group, a dihydropyrrolyl group, a hexahydropyridyl group, a tetrahydropyridyl group, and a dihydropyridyl group.

[0067] In one embodiment, the 5-8 membered heteroaryl group containing one heteroatom selected from oxygen and sulfur is a 5-8 membered heteroaryl group containing one oxygen atom or a 5-8 membered heteroaryl group containing one sulfur atom.

[0068] 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 one preferred embodiment, the 5-8 membered heteroaryl group containing one oxygen atom and / or the 5-6 membered heteroaryl group containing one oxygen atom is selected from a furan group and a pyranyl group.

[0069] 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 one preferred embodiment, the 5-8 membered heteroaryl group containing one sulfur atom and / or the 5-6 membered heteroaryl group containing one sulfur atom is selected from a thienyl group and a thiopyranyl group.

[0070] In one embodiment, the C1-C8 alkyl group is selected from C1-C5 alkyl groups and C1-C3 alkyl groups. In a more specific embodiment, the C1-C8 alkyl group, C1-C5 alkyl group and C1-C3 alkyl group are each independently selected from a methyl group, an ethyl group, a propyl group, a butyl group, or a pentyl group. In a more specific embodiment, the C1-C8 alkyl group, C1-C5 alkyl group and C1-C3 alkyl group are each independently selected from a methyl group, an ethyl group, and a propyl group.

[0071] In one embodiment, the propyl group includes, but is not limited to, an n-propyl group (n-Pr, -CH2CH2CH3) or an isopropyl group (i-Pr, -CH(CH3)2). The butyl group includes, but is not limited to, an n-butyl group (n-Bu, -CH2CH2CH2CH3), an isobutyl group (i-Bu, -CH2CH(CH3)2), a sec-butyl group (s-Bu, -CH(CH3)CH2CH3), or a tert-butyl group (t-Bu, -C(CH3)3). The above pentyl groups include, but are not limited to, n-pentyl groups (-CH2CH2CH2CH2CH3), 2-pentyl groups (-CH(CH3)CH2CH2CH3), 3-pentyl groups (-CH(CH2CH3)2), 2-methyl-2-butyl groups (-C(CH3)2CH2CH3), 3-methyl-2-butyl groups (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl groups (-CH2CH2CH(CH3)2), or 2-methyl-1-butyl groups (-CH2CH(CH3)CH2CH3).

[0072] In one embodiment, the C1-C8 alkoxy group is selected from the C1-C5 alkoxy group and the C1-C3 alkoxy group. In a more specific embodiment, the C1-C8 alkoxy group, the C1-C5 alkoxy group and the C1-C3 alkoxy group are each independently selected from the methoxy group, the ethoxy group, the propoxy group, the butoxy group, and the pentoxy group. In a more specific embodiment, the C1-C8 alkoxy group, the C1-C5 alkoxy group and the C1-C3 alkoxy group are each independently selected from the methoxy group, the ethoxy group, and the propoxy group.

[0073] In one embodiment, the C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group. In one preferred embodiment, the C3-C8 cycloalkyl group and the C3-C6 cycloalkyl group are selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclopentadiene group, a cyclohexenyl group, or a cyclohexadienyl group. In one more preferred embodiment, the C3-C8 cycloalkyl group and the C3-C6 cycloalkyl group are selected from a cyclopropyl group, a cyclobutenyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopentenyl group, or a cyclohexenyl group.

[0074] In one embodiment, the C3-C8 cycloalkenyl group is a C3-C6 cycloalkenyl group. In one preferred embodiment, the C3-C8 cycloalkenyl group and the C3-C6 cycloalkenyl group are selected from a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, and a cyclohexadienyl group. In one more preferred embodiment, the C3-C8 cycloalkenyl group and the C3-C6 cycloalkenyl group are selected from a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.

[0075] In one embodiment, the C atom in the above C3-C8 cycloalkyl and / or C3-C6 cycloalkyl is substituted with oxo (=O).

[0076] In one embodiment, the C atom in the C3-C8 cycloalkenyl group and / or C3-C6 cycloalkenyl group is 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.

[0077] In one embodiment, the C1-C8 alkylthio group is selected from the C1-C5 alkylthio group and the C1-C3 alkylthio group. In a more specific embodiment, the C1-C8 alkylthio group, the C1-C5 alkylthio group and the C1-C3 alkylthio group are each independently selected from the methylthio group, the ethylthio group, the propylthio group, the butylthio group, or the pentylthio group. In a more specific embodiment, the C1-C8 alkylthio group, the C1-C5 alkylthio group and the C1-C3 alkylthio group are each independently selected from the methylthio group, the ethylthio group, or the propylthio group.

[0078] In one embodiment, the C2-C8 alkene group is selected from the C2-C4 alkene group.

[0079] In one embodiment, the C2-C8 alkyne group is selected from the C2-C4 alkyne group.

[0080] In one embodiment, ring A is selected from a 4-6 membered heterocyclyl group containing one heteroatom selected from a C3-C8 cycloalkyl group, a C3-C8 cycloalkenyl group, oxygen, nitrogen, and sulfur, and a 5-6 membered heteroaryl group containing one heteroatom selected from oxygen and sulfur, preferably an azetidinyl group, an oxetanyl group, a thietanyl group, a thienyl group, a furan group, a thiopyranyl group, a pyranyl group, a tetrahydropyrrolyl group, a hexahydropyridyl group, a dihydropyrrolyl group, a tetrahydropyridyl group, a tetrahydrothienyl group, a dihydropyridyl group, a dihydrothienyl group, a tetrahydrothiopyranyl group, a dihydrofuran group, a dihydrofuran group, a tetrahydropyranyl group, a dihydropyranyl group The group is selected from cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclobutenyl group, cyclopentenyl group, cyclopentadiene group, cyclohexenyl group and cyclohexadienyl group, and more preferably from tetrahydropyrrolyl group, hexahydropyridyl group, dihydropyrrolyl group, tetrahydropyridyl group, thienyl group, furan group, thiopyranyl group, pyranyl group, dihydropyridyl group, tetrahydrothiopyranyl group, dihydrothiopyranyl group, tetrahydrothienyl group, dihydrothienyl group, tetrahydrofuran group, dihydrofuran group, cyclobutyl group, cyclobutenyl group, cyclopentyl group, cyclohexyl group, cyclopentenyl group, cyclohexenyl group and cyclopentadiene group.

[0081] In one embodiment, R1 is selected from H, halogen, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, hydroxyl group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C6 cycloalkyl group, preferably from H, halogen, optionally substituted C1-C5 alkyl group, optionally substituted C1-C5 alkoxy group, hydroxyl group, optionally substituted C1-C5 alkylthio group, and optionally substituted C3-C6 cycloalkyl group, more preferably from H, halogen, optionally substituted C1-C5 alkyl group, and hydroxyl group, even more preferably from H, halogen, and optionally substituted C1-C5 alkyl group, and even more preferably from H or -F, where the optionally substituted substituent is selected from a hydroxyl group and a halogen, preferably from F.

[0082] In one embodiment, R1 is selected from H and halogen.

[0083] In one embodiment, R1 is H.

[0084] In one embodiment, R1 is a halogen (for example, fluorine).

[0085] In one embodiment, R3 is selected from H, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 alkoxy group, a hydroxyl group, an optionally substituted C1-C8 alkylthio group, and an optionally substituted C3-C6 cycloalkyl group, preferably from H, a halogen, an optionally substituted C1-C5 alkyl group, an optionally substituted C1-C5 alkoxy group, a hydroxyl group, and an optionally substituted C3-C6 cycloalkyl group, more preferably from H, a halogen, and an optionally substituted C1-C5 alkyl group, and even more preferably from H, and the optionally substituted substituent is selected from a hydroxyl group and a halogen, preferably from F.

[0086] In one embodiment, R3 is H.

[0087] In one embodiment, each R 10 Each of these is independently selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy group, hydroxyl group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C6 cycloalkyl group, preferably selected from H, halogen, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy group, hydroxyl group, optionally substituted C1-C5 alkylthio group, and optionally substituted C3-C6 cycloalkyl group, more preferably selected from H, halogen, and optionally substituted C1-C5 alkyl group, and the optional substituent is independently selected from halogen, C1-C8 alkyl and hydroxyl group, preferably selected from halogen, C1-C5 alkyl and hydroxyl group, more preferably halogen, and even more preferably F. In one embodiment, R2 is selected from H and optionally substituted C1-C8 alkyl groups, preferably from H and optionally substituted C1-C5 alkyl groups, and the optionally substituted substituent is independently selected from halogens and hydroxyl groups.

[0088] In one embodiment, R2 is selected from an optionally substituted C1-C5 alkyl group, and the optionally substituted substituent is independently selected from halogens and hydroxyl groups. In one preferred embodiment, R2 is selected from a C1-C5 alkyl group.

[0089] In one embodiment, the compound represented by formula I is formula I-a' or formula I-b',

[0090] [ka]

[0091] As shown.

[0092] In one embodiment, ring A is selected from a 5-6 membered heterocyclyl group containing one oxygen atom and a 5-6 membered heteroaryl group containing one oxygen atom, preferably,

[0093] [ka]

[0094] Selected from, more preferably,

[0095] [ka]

[0096] R2 is selected from a C1-C8 alkyl group that is optionally substituted, and the optional substituent is independently selected from a halogen and a hydroxyl group.

[0097] In one embodiment, ring A is

[0098] [ka]

[0099] Selected from.

[0100] In one embodiment, ring A is selected from a 4-6 membered heterocyclyl group containing one sulfur atom and a 5-6 membered heteroaryl group containing one sulfur atom, preferably,

[0101] [ka]

[0102] Selected from, more preferably,

[0103] [ka]

[0104] Selected from.

[0105] In one embodiment, ring A is

[0106] [ka]

[0107] Selected from.

[0108] In one embodiment, ring A is

[0109] [ka]

[0110] Selected from.

[0111] In one embodiment, ring A is selected from a 4- to 6-membered heterocyclyl group containing one nitrogen atom, preferably,

[0112] [ka]

[0113] Selected from.

[0114] In one embodiment, ring A is selected from a 4- to 6-membered heterocyclyl group containing one nitrogen atom, preferably,

[0115] [ka]

[0116] R2 is selected from a C1-C8 alkyl group which is optionally substituted, and the optional substituent is independently selected from halogens and hydroxyl groups.

[0117] In one embodiment, ring A is

[0118] [ka]

[0119] That is the case.

[0120] In one embodiment, ring A is selected from a C3-C8 cycloalkyl group, preferably,

[0121] [ka]

[0122] Selected from, more preferably,

[0123] [ka]

[0124] Selected from, and more preferably,

[0125] [ka]

[0126] That is the case.

[0127] In one specific embodiment, the compound represented by formula I is as shown in formula II:

[0128] [ka]

[0129] Of these, R2 is selected from an optionally substituted C1-C8 alkyl group, and the optional substituent is independently selected from halogens and hydroxyl groups. n, R1, and R3 are as described above. R4, R5, and R6 are each independently selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the optional substituents are independently selected from halogen, C1-C8 alkyl group, and hydroxyl group.

[0130] In one embodiment, R4, R5, and R6 are each independently selected from H, a halogen, and an optionally substituted C1-C8 alkyl group, and the optionally substituted group is independently selected from a halogen and a hydroxyl group.

[0131] In one specific embodiment, the compound represented by formula I is as shown in formula III:

[0132] [ka]

[0133] Of these, R2 is selected from an optionally substituted C1-C8 alkyl group, and the above optionally substituted substituents are independently selected from halogens, C1-C8 alkoxy groups, and hydroxyl groups. n, R1, and R3 are as described above. R4, R5, and R6 are each independently selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the optional substituents are independently selected from halogen, C1-C8 alkyl group, and hydroxyl group.

[0134] In one embodiment, R4, R5, and R6 are each independently selected from H, a halogen, and an optionally substituted C1-C8 alkyl group, and the optionally substituted group is independently selected from a halogen and a hydroxyl group.

[0135] In one specific embodiment, the compound represented by formula I is as shown in formula IV:

[0136] [ka]

[0137] Of these, n, R1, R2, and R3 are as described above. R4, R5, and R6 are each independently selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the optional substituents are independently selected from halogen, C1-C8 alkyl group, and hydroxyl group.

[0138] In one embodiment, R4, R5, and R6 are each independently selected from H, a halogen, and an optionally substituted C1-C8 alkyl group, and the optionally substituted group is independently selected from a halogen and a hydroxyl group.

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

[0140] [ka]

[0141] Of these, n, R1, R2, and R3 are as described above. R4, R5, and R6 are each independently selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the optional substituents are independently selected from halogen, C1-C8 alkyl group, and hydroxyl group.

[0142] In one embodiment, R4, R5, and R6 are each independently selected from H, a halogen, and an optionally substituted C1-C8 alkyl group, and the optionally substituted group is independently selected from a halogen and a hydroxyl group.

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

[0144] [ka]

[0145] Of these, n, R1, R2, and R3 are as described above. R4, R5, and R6 are each independently selected from H, halogen, hydroxyl group, nitro group, cyano group, optionally substituted C1-C8 alkyl group, optionally substituted C1-C8 alkoxy group, optionally substituted C2-C8 alkene group, optionally substituted C2-C8 alkyne group, optionally substituted C2-C8 alkyne group, optionally substituted C1-C8 alkylthio group, and optionally substituted C3-C8 cycloalkyl group, and the optional substituents are independently selected from halogen, C1-C8 alkyl group, and hydroxyl group.

[0146] In one embodiment, R4, R5, and R6 are each independently selected from H, a halogen, and an optionally substituted C1-C8 alkyl group, and the optionally substituted group is independently selected from a halogen and a hydroxyl group.

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

[0148] [ka]

[0149] [ka]

[0150] [ka]

[0151] intermediate The present invention provides compounds represented by formula IA, formula I-A', formula IB, formula I-B', formula IC, formula ID, or formula I-D', or salts thereof.

[0152] [ka]

[0153] In formula IA, n, ring A, R1, R3, m, R 10 As stated above, In equation I-A', n, ring A, R1, R3, m, R 10 As stated above, In formula IB, n, ring A, R1, R3, m, R 10 As stated above, R8 is selected from C1-C5 alkyl groups, preferably from methyl, ethyl, and propyl groups, and more preferably from methyl groups. In equation I-B', n, ring A, R1, R3, m, R 10 As stated above, In formula IC, n, ring A, R1, R2, R3, m, R 10 As stated above, In formula ID, n, ring A, R1, R2, R3, m, R 10 As stated above, R9 is selected from hydroxy protecting groups, preferably from silyl ether hydroxy protecting groups, more preferably from trimethylsilyl group, tert-butyldiphenylsilyl group, tert-butyldimethylsilyl group, and triisopropylsilyl group, and even more preferably from tert-butyldimethylsilyl group. In formula I-D', n, ring A, R1, R2, R3, m, R 10 As stated above, In formulas IA, IB, I-B', IC, ID, or I-D', R7 is selected from amino protecting groups, and is preferably a trityl group.

[0154] Manufacturing method The present invention provides a method for producing a compound represented by formula I, comprising the steps of: obtaining intermediate IA from intermediate IB-1 by a dehydration reaction, then obtaining intermediate IC by a hydrogenation-reduction reaction, and removing the amino protecting group from intermediate IC to obtain the compound represented by formula I-1; or obtaining intermediate I-A' by removing the amino protecting group and water from intermediate IB-1 in one step, and then obtaining the compound represented by formula I-1 by a hydrogenation-reduction reaction; or obtaining a compound represented by formula I-2 from intermediate I-B' by removing the amino protecting group in one step and simultaneously performing a reduction reaction; or obtaining intermediate I-D' by removing the hydroxy protecting group from intermediate ID, and then removing the amino protecting group from intermediate I-D' and dehydrating it to obtain the compound represented by formula I.

[0155] [ka]

[0156] Among them, n, ring A, R1, R2, R3, m, R 10 As stated above, R7 is selected from amino protecting groups, preferably a trityl group. R9 is selected from hydroxy protecting groups, preferably from silyl ether hydroxy protecting groups, more preferably from trimethylsilyl group, tert-butyldiphenylsilyl group, tert-butyldimethylsilyl group, and triisopropylsilyl group, and even more preferably from tert-butyldimethylsilyl group.

[0157] Beneficial technical effects of the present invention Compared to the prior art, the proposed technology of the present invention has the following advantages.

[0158] The present invention relates to a novel structural compound, which exhibits good α2-adrenergic receptor agonist activity and can be used in the manufacture of drugs related to α2-adrenergic receptor agonists, and can be used in the manufacture of drugs for sedation and / or analgesia and / or anesthetic effects, and / or anxiolytic and / or suppression of sympathetic nerve activity and / or treatment of insomnia and / or treatment of mental disorders in humans or animals, and can be used in the manufacture of drugs for sedation and / or analgesia and / or anesthetic effects and / or treatment of insomnia and / or treatment of mental disorders in humans or animals, and the compound has relatively good pharmacokinetic activity, and at the same time exhibits good pharmacokinetic properties, has excellent circulatory stability, high potency, short maintenance time, can exert a rapid effect in vivo, and has few side effects, and has a relatively good prospect for clinical application.

[0159] Examples The following describes embodiments of the present invention in detail. The embodiments described below are illustrative and are used only to interpret the present invention and should not be understood as limiting the present invention. Unless otherwise specified, all proportions, percentages, etc., referred to herein are by weight.

[0160] Synthesis Examples

[0161] [ka]

[0162] Synthesis flow 1 of some examples The brominated aromatic cyclide underwent lithium-halogen exchange with butyllithium, followed by nucleophilic attack on 1-trityl-4-acetylimidazole to obtain intermediate Ia. Ia was dehydrated with ethyl chloroglyoxylate / triethylamine to obtain intermediate Ib. Ib was hydrogenated and reduced with Pd / C to obtain intermediate Ic. Ic was then protected with trifluoroacetic acid to obtain the compound shown in formula I-1.

[0163] [ka]

[0164] Synthesis flow 2 of some examples The brominated aromatic cyclide underwent lithium-halogen exchange with butyllithium, then underwent nucleophilic attack on 1-trityl-4-acetylimidazole to obtain intermediate Ia. Ia was then subjected to trifluoroacetic acid / triethylsilyl to remove the trityl group and water in a single step to obtain intermediate Id. Id was then hydrogenated and reduced with Pd / C to obtain the compound shown in formula I-1.

[0165] [ka]

[0166] Synthesis flow 3 of some examples The brominated aromatic cyclide underwent lithium-halogen exchange with butyllithium, and then underwent nucleophilic attack on 1-trityl-4-formylimidazole to obtain intermediate Ie. Ie was then reduced by trifluoroacetic acid / triethylsilyl, removing the trityl group in a single step to obtain the compound shown in formula I-2.

[0167] [ka]

[0168] Synthesis flow 4 of some embodiments The brominated aromatic cyclide underwent lithium-halogen exchange with butyllithium, followed by nucleophilic attack on 1-trityl-4-acetylimidazole to obtain intermediate If. If was dehydrated with ethyl chloroglyoxylate / triethylamine to obtain intermediate Ig. Ig was hydrogenated and reduced with Pd / C to obtain intermediate Ih. Ih had its protecting group removed with TBAF to obtain intermediate Ii. Ii had its protecting group removed and was dehydrated with p-toluenesulfonic acid to obtain the compound shown in formula I-3.

[0169] [ka]

[0170] Synthesis Flow 5 of Some Examples Brominated aromatic cyclides and tripenzyl(1-ethoxyvinyl) stannane undergo a coupling reaction catalyzed by tetrakistriphenylphosphine palladium to obtain intermediate Ij. Ij is hydrolyzed with hydrochloric acid to obtain intermediate Ik. Ik and 4-iodo-1-(triphenylmethyl)imidazole undergo a nucleophilic reaction with i-PrMgBr to obtain intermediate Ia. Ia is dehydrated with ethyl chloroglyoxylate / triethylamine to obtain intermediate Ib. Ib is hydrogenated and reduced with Pd / C to obtain intermediate Ic. Ic is protected by trifluoroacetic acid to obtain the compound shown in formula I-1.

[0171] [ka]

[0172] Synthesis flow 6 of some examples Brominated aromatic cyclides and tripenzyl(1-ethoxyvinyl) stannane undergo a coupling reaction catalyzed by tetrakistriphenylphosphine palladium to obtain intermediate Ij. Ij is hydrolyzed with hydrochloric acid to obtain intermediate Ik. Ik and 4-iodo-1-(triphenylmethyl)imidazole undergo a nucleophilic reaction with i-PrMgBr to obtain intermediate Ia. Ia is dehydrated with trifluoroacetic acid / triethylsilane to obtain intermediate Ib. Ib is hydrogenated and reduced with Pd / C to obtain intermediate Ic. Ic is protected by trifluoroacetic acid to obtain the compound shown in formula I-1.

[0173] Example 1: Preparation of 4-[1-(thiochroman-8-yl)methyl]-1H-imidazole

[0174] [ka]

[0175] 1.1 At 0°C and under a nitrogen gas atmosphere, a stirring mixture of 2-bromobenzenethiol (3.0 g, 15.867 mmol, 1 equivalent) and NaOH (634.6 mg, 15.867 mmol, 1 equivalent) in H2O (30 mL) was added dropwise to a solution of 3-bromopropionic acid (2.43 g, 15.86 mmol, 1 equivalent) and Na2CO3 (1.68 g, 15.867 mmol, 1 equivalent) in H2O (30 mL). The resulting mixture was stirred further at 100°C for 2 hours. After cooling the resulting mixture to room temperature, it was acidified to pH=1 with 2 N HCl(aq). The resulting mixture was extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with NaCl(aq) (3 × 200 mL). It was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 3-(2-bromophenylthio)propionic acid (4.02 g, crude product) was obtained. (ES, m / z): [M+1] = 260.95, 262.95.

[0176] 1.2 At room temperature, 3-(2-bromophenylthio)propionic acid (4.02 g, 15.39 mmol, 1 equivalent) and H2SO4 (40.20 mL, 754.20 mmol, 48.99 equivalents) were added to a 250 mL round-bottom flask. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction was quenched by adding water / ice (150 mL) at 0°C, and the aqueous layer was extracted with ELISA (2 × 300 mL). The organic layer was washed with 100 mL of sodium bicarbonate (aq) and saline solution (2 × 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 and eluted with PE / EA (4:1) to obtain 8-bromo-2,3-dihydro-1-benzothiopyran-4-one (2.63 g). (ES,m / z): [M+1]= 242.94,244.94. 1.3 8-Bromo-2,3-dihydro-1-benzothiopyran-4-one (2.63 g, 10.82 mmol, 1 equivalent) and triethylsilane (24 mL) were dissolved in DCM (53 mL) and treated under a nitrogen atmosphere for 1 minute. BF3Et2O (24 mL, 189.39 mmol, 17.51 ​​equivalents) was added dropwise at 0°C. The reaction mixture was then allowed to rise naturally to room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by adding water (100 mL) at 0°C. The resulting mixture was extracted with CH2Cl2 (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 and eluted with PE / EA (8:1) to obtain 8-bromo-3,4-dihydro-2H-1-benzothiopyran (2.04 g). (ES, m / z): [M+1] = 228.96, 230.96. 1. A solution of 8-bromo-3,4-dihydro-2H-1-benzothiopyran (500 mg, 2.18 mmol, 1 equivalent) in THF (10 mL) was reacted with n-butyllithium (1.05 mL, 2.618 mmol, 1.2 equivalents, 2.5 M in n-hexane) in nitrogen gas at -78 °C for 1 hour. Then, 1-trityl-1H-imidazole-4-carboxaldehyde (769.0 mg, 2.182 mmol, 1 equivalent) was dissolved in THF (2 mL) and added dropwise to the system. The temperature was allowed to rise naturally to room temperature and stirred overnight. Saturated ammonium chloride (aq) was added to quench the reaction. The resulting mixture was extracted with EtOAc (2 × 70 mL), and the organic phases were combined. It was washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1), and thiochroman-8-yl(1-trityl-1H-imidazol-4-yl)methanol (300 mg) was obtained, (ES, m / z): [M+1]=489.65.

[0177] 1.5 Under a nitrogen gas atmosphere, at room temperature, TFA (665.0 mg, 5.830 mmol, 10 equivalents) was added dropwise to a solution of thiochroman-8-yl(1-trityl-1H-imidazol-4-yl)methanol (285 mg, 0.583 mmol, 1 equivalent) and triethylsilane (339.1 mg, 2.915 mmol, 5 equivalents) in DCM (6 mL). The resulting mixture was stirred at room temperature for an additional 3 hours. This reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (285 mg) was separated by preparative HPLC to obtain 4-[1-(thiochroman-8-yl)methyl]-1H-imidazole (32.6 mg). (ES, m / z): [M+1]=231.**** 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 1.1 Hz, 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). Example 2 Production of 4-(1-[Thiochroman-8-yl)ethyl]-1H-imidazole

[0178]

Chemical formula

[0179] 2.1 The compound was produced according to the method of Example 1, but 1-trityl-1H-imidazole-4-formaldehyde was replaced with 1-[1-(trityl)imidazol-4-yl]ethanone (commercially available), and 1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (160 mg) was obtained. (ES, m / z): [M+1]=503.68.

[0180] 2.2 Under room temperature and nitrogen gas atmosphere, TFA (0.3 mL, 1.930 mmol, 10 equivalents) was added to a DCM (2 mL) solution of 1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (97 mg, 0.193 mmol, 1 equivalent). After 1 minute, triethylsilane (0.54 mL, 0.965 mmol, 5 equivalents) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for an additional 4 hours. It was concentrated under reduced pressure. 4-[1-(3,)-dihydro-2H-1-benzothiopyran-8-yl)vinyl]-1H-imidazole (250 mg, crude product) was obtained. (ES, m / z): [M+1]=243.34.

[0181] 2.3 At room temperature, 250 mg (1.032 mmol, 1 equivalent) of 4-[1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)vinyl]-1H-imidazole was added to a 6 mL solution of MeOH with 100 mg (10% w / t) of Pd / C. The mixture was hydrogenated under a hydrogen pressure of 10 atm for 4 hours, filtered through a diatomaceous earth pad, and concentrated under reduced pressure. Purified by preparative HPLC, 23.9 mg of 4-[1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)ethyl]-1H-imidazole was obtained. (ES, m / z): [M+1] = 245.20. 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 10.5 Hz, 1H), 6.98 - 6.62 (m, 4H), 4.32 (dq, J = 29.2, 6.9 Hz, 1H), 3.09 - 2.95 (m, 2H), 2.78 (q, J = 6.0 Hz, 2H), 2.04 - 1.92 (m, 2H), 1.45 (dd, J = 16.1, 7.1 Hz, 3H). Example 3: Preparation of 4-(1-(bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)ethyl)-1H-imidazole

[0182] [ka]

[0183] 3.1 Under a nitrogen atmosphere at -78°C, n-butyllithium (1.3 mL, 3.17 mmol, 1.5 equivalents, 2.5 M in hexane) was added dropwise to a stirred mixture of 2,5-dibromovicyclo[4.2.0]octa-1(6),2,4-triene (550 mg, 2.11 mmol, 1 equivalent) in THF (1 mL). After the addition was complete, the mixture was stirred for 0.5 hours. At -78°C, a solution of 1-[1-(triphenylmethyl)imidazole-4-yl]etanone (743 mg, 2.11 mmol, 1 equivalent) in THF (2 mL) was added dropwise to the mixture over 3 minutes. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was quenched at room temperature with saturated ammonium chloride aqueous solution (30 mL). The resulting mixture was extracted with ethyl acetate (3 × 20 mL) and the organic phases were combined. The mixture was washed with saturated saline (1 × 20 mL) and dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (4:1) to obtain 1-(5-bromovicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-1-(1-trityl-1H-imidazole-4-yl)ethane-1-ol (216 mg). (ES, m / z):[M+1]=535,537.

[0184] 3.2 At room temperature and under a nitrogen atmosphere, 1-(5-bromovicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-1-(1-trityl-1H-imidazole-4-yl)ethane-1-ol (216 mg, 0.403 mmol, 1 equivalent) was mixed in 5 mL of DCM, to which TFA (5 mL) and triethoxysilane (5 mL) were added dropwise. The resulting mixture was stirred at 40°C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. 4-(1-(bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)ethyl)-1H-imidazole (230 mg, crude product) was obtained. The resulting crude mixture was used directly in the next step without further purification. (ES, m / z): [M+1]=275, 277.

[0185] 3.3 At room temperature and under a hydrogen atmosphere, 4-(1-(bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)ethyl)-1H-imidazole (216 mg, 0.779 mmol, 1 equivalent) was added to a MeOH (5 mL) stirred solution with Pd / C (44 mg, 10% w / t). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with methanol (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain 4-(1-(bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)ethyl)-1H-imidazole (31.8 mg). (ES, m / z): [M+1] = 199. 1 H NMR (400 MHz, Chloroform-d) δ 7.52 (s, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.98 - 6.50 (m, 3H), 4.01 (q, J = 7.1 Hz,1H), 3.06 - 2.83 (m, 4H), 1.57 (d, J = 6.8 Hz, 3H). Example 4: Preparation of 4-(1-(5,6,7,8-tetrahydronaphthalene-1-yl)ethyl)-1H-imidazole

[0186] [ka]

[0187] The compound was prepared according to the method of Example 3, but 2,5-dibromovicyclo[4.2.0]octa-1(6),2,4-triene was substituted with 5-bromo-1,2,3,4-tetrahydronaphthalene (commercially available) to obtain 4-(1-(5,6,7,8-tetrahydronaphthalene-1-yl)ethyl)-1H-imidazole, with (ES,m / z):[M+1]=227.15. 1H NMR (400 MHz, Chloroform-d) δ 7.66 (s, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.95 (s, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.73 (s, 1H), 4.33 (q, J = 7.2, 6.8 Hz, 1H), 2.81 -2.61 (m, 4H), 1.85 - 1.68 (m, 4H), 1.55 (d, J = 6.8 Hz, 3H). Example 5: Preparation of 4-[1-(1,3-dihydroisobenzofuran-4-yl)ethyl]-1H-imidazole

[0188] [ka]

[0189] The compound was prepared according to the method of Example 3, but 2,5-dibromovicyclo[4.2.0]octa-1(6),2,4-triene was substituted with 4-bromo-1,3-dihydroisobenzofuran (commercially available) to obtain 4-[1-(1,3-dihydroisobenzofuran-4-yl)ethyl]-1H-imidazole, (ES,m / z):[M+1]=215. 1 H NMR (400 MHz, Methanol-d4) δ 7.56 (d, J = 1.2 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.5 Hz, 2H), 6.79 (t, J = 1.1 Hz, 1H), 4.91 (dt, J = 60.3, 2.1 Hz, 4H), 4.05 (q, J = 7.2 Hz, 1H), 1.56 (d, J = 7.2 Hz, 3H). At the same time, its stereoisomer

[0190] [ka]

[0191] It was separated.

[0192] Example 6 Preparation of 4-(1-(2-Methyl-2,3-dihydro-1H-inden-4-yl)ethyl)-1H-imidazole

[0193]

Chemical formula

[0194] 6.1 Under 0 °C and a nitrogen gas atmosphere, trifluoroacetic acid (TFA) (8.77 g, 76.900 mmol, 5 equivalents) was added dropwise to a DCM (30 mL) solution of diethylzinc (76.90 mL, 76.900 mmol, 5 equivalents). After the addition was complete, the mixture was stirred for 20 minutes, and then, at room temperature, iodomethane (20.60 g, 76.900 mmol, 5 equivalents) was added over 20 minutes. At room temperature, 4-bromo-3H-indene (3 g, 15.380 mmol, 1 equivalent) was added to the above mixture. The mixture was further stirred overnight at room temperature. The reaction was quenched with a saturated aqueous ammonium chloride solution (50 mL). At room temperature, the mixture was extracted with ethyl acetate (3 × 20 mL), and the organic layers were combined. The combined organic layers were washed with saturated brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1), to obtain 5-bromo-1H,1aH,6H,6aH-cycloprop[a]indene (1.65 g). (ES, m / z): [M] = 208, 210.

[0195] 6.2 At -78°C under a nitrogen atmosphere, n-butyllithium (4.30 mL, 10.761 mmol, 1.5 equivalents, 2.5 M in hexane) was added dropwise to a solution of 5-bromo-1H,1aH,6H,6aH-cycloprop[a]indene (1.5 g, 7.174 mmol, 1 equivalent) in tetrahydrofuran (20 mL). After the addition was complete, the mixture was stirred for 1 hour. Next, a solution of 1-[1-(triphenylmethyl)imidazole-4-yl]ethanone (2.78 g, 7.891 mmol, 1.1 equivalents) in THF (5 mL) was added. After the addition was complete, the temperature was gradually raised to room temperature and the mixture was stirred overnight. The reaction was quenched at 0°C with saturated ammonium chloride aqueous solution (50 mL). The resulting mixture was extracted with RINKAN (3 × 20 mL) and the organic phases were combined. The mixture was washed with saturated brine (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain 1-(1H,1aH,6H,6aH-cycloprop[a]inden-5-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (1.8 g). (ES, m / z):[M+1]=483.

[0196] The compound was prepared according to the method of Example 2, but 1-(3,4-dihydro-2H-1-benzothiopyran-8-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol was substituted with 1-(1H,1aH,6H,6aH-cycloprop[a]inden-5-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (homemade) to obtain 4-(1-(2-methyl-2,3-dihydro-1H-inden-4-yl)ethyl)-1H-imidazole, (ES,m / z):[M+1]=227. 1H NMR (400 MHz, Methanol-d4) δ 8.27 (dd, J = 2.6, 1.4 Hz, 1H), 7.16 - 6.89 (m, 3H), 6.77 (ddt, J = 11.2, 6.5, 3.0 Hz, 1H), 4.16 (q, J = 7.1 Hz, 1H), 3.04 - 2.78 (m, 2H), 2.53 - 2.04 (m, 3H), 1.49 (dd, J = 7.2, 4.1 Hz, 3H), 1.02 (d, J = 6.1 Hz, 3H). Example 7: Preparation of 4-[1-(1-methyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole

[0197] [ka]

[0198] 7.1 At 0°C and under a nitrogen atmosphere, methylmagnesium bromide (1.90 mL, 5.7 mmol, 1.2 equivalents, 3 M in THF) was added dropwise to a stirred solution of 4-bromo-2,3-dihydroinden-1-one (1 g, 4.738 mmol, 1 equivalent) in THF (25 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. Saturated ammonium chloride (10 mL) was added to quench the reaction. The resulting mixture was extracted with SiO2 (3 × 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 and eluted with PE / EA (4:1) to obtain 4-bromo-1-methyl-2,3-dihydroinden-1-ol (0.97 g) as a colorless oil. (ES, m / z): [M] = 226, 228. 7.2 At room temperature, 4-bromo-1-methyl-2,3-dihydroinden-1-ol (400 mg, 1.761 mmol, 1 equivalent), toluene (8 mL), and p-toluenesulfonic acid (30.33 mg, 0.176 mmol, 0.10 equivalents) were added to a 20 mL sealed tube. The resulting mixture was stirred at 110°C for 3 hours. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain 4-bromo-1-methyl-3H-inden (300 mg) as a colorless oil. (ES, m / z): [M] = 208, 210. 7.3 At -78°C under a nitrogen atmosphere, n-butyllithium (1.00 mL, 2.5 mmol, 1.5 equivalents, 2.5 M in hexane) was added dropwise to a solution of 4-bromo-1-methyl-3H-indene (350 mg, 1.674 mmol, 1 equivalent) in THF (10 mL) and stirred for 1 hour after the addition was complete. Then 1-[1-(triphenylmethyl)imidazole-4-yl]ethanone (707.9 mg, 2.009 mmol, 1.2 equivalents) was added and, after the addition was complete, the temperature was raised to room temperature and stirred overnight. The mixture was quenched at room temperature with saturated ammonium chloride aqueous solution (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL), the organic phases were combined, washed with saline solution (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 and eluted with PE / EA (1:1) to obtain 1-(1-methyl-3H-inden-4-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (700 mg). (ES, m / z):[M+1]=483.

[0199] 7.4 At room temperature under a nitrogen atmosphere, 1-(1-methyl-3H-inden-4-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (600 mg, 1.243 mmol, 1 equivalent) was dissolved in DCM (8 mL), to which TEA (1.01 g, 9.944 mmol, 8 equivalents) was added, and the mixture was stirred for 2 minutes. The temperature was then lowered to 0°C, and ethyl chloroglyoxylate (339.5 mg, 2.486 mmol, 2 equivalents) was added. The resulting mixture was stirred overnight at room temperature, and the mixture was concentrated under reduced pressure. The residue was prepared by preparative column chromatography to obtain 4-[1-(1-methyl-3H-inden-4-yl)vinyl]-1-(triphenylmethyl)imidazole (120 mg). (ES, m / z): [M+1] = 465.

[0200] 7.5 At room temperature, 4-[1-(1-methyl-3H-inden-4-yl)vinyl]-1-(triphenylmethyl)imidazole (60 mg, 0.129 mmol, 1 equivalent), MeOH (2 mL), and Pd / C (30 mg, 10% w / t) were added to a 20 mL round-bottom flask. The resulting mixture was stirred under a hydrogen atmosphere for 3 hours. The resulting mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure. 4-[1-(1-methyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1-(triphenylmethyl)imidazole (20 mg, crude product) was obtained. (ES, m / z): [M+1] = 469.

[0201] 7.6 At room temperature, 4-[1-(1-methyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1-(triphenylmethyl)imidazole (60 mg, 0.128 mmol, 1 equivalent) and DCM (3 mL) / TFA (1 mL) were added to a 20 mL round-bottom flask. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography. 4-[1-(1-methyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (5.1 mg) was obtained. (ES, m / z):[M+1]=227. 1H NMR (400 MHz, Methanol-d4) δ 7.53 (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). Example 8: Preparation of 4-[1-(1H-inden-4-yl)ethyl]-1H-imidazole

[0202] [ka]

[0203] 8.1 At 0°C, 11 g, 52.118 mmol, 1 equivalent of 7-bromo-2,3-dihydroinden-1-one was added in 100 mL of THF and 50 mL of methanol, to which NaBH4 (10.75 g, 284.280 mmol, 6 equivalents) was added in several portions. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with ice water (100 mL) at room temperature, the resulting mixture was extracted with ethyl acetate (3 × 100 mL), the organic phases were combined, washed with saline solution (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 and eluted with PE / EA (1:1) to obtain 7-bromo-2,3-dihydro-1H-inden-1-ol (9.8 g) as a colorless liquid. (ES, m / z) = 212, 214.

[0204] 8.2 At room temperature under a nitrogen atmosphere, imidazole (4.10 g, 60.260 mmol, 1.2 equivalents) and 7-bromo-2,3-dihydro-1H-inden-1-ol (10.7 g, 50.217 mmol, 1 equivalent) were dissolved in THF (100 mL), and then tert-butyldimethylchlorosilane (15.14 g, 100.434 mmol, 2 equivalents) was added in several portions at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched at room temperature by adding water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL) and the organic phases were combined. The organic layer was 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 silica gel column chromatography and eluted with PE / EA (10:1) to obtain pale yellow oily [(7-bromo-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (15.2 g).

[0205] 8.3 At -78°C, under a nitrogen gas atmosphere, n-butyllithium (11.00 mL, 27.45 mmol, 1.5 equivalents, 2.5 M in hexane) was added dropwise to a solution of [(7-bromo-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (6 g, 18.330 mmol, 1 equivalent) in THF (100 mL). After the addition was complete, the mixture was stirred for 1 hour. Then, 1-[1-(triphenylmethyl)imidazole-4-yl]ethanone (9.69 g, 27.495 mmol, 1.2 equivalents) was added. After the addition was complete, the temperature was raised to room temperature and the mixture was stirred overnight. The mixture was quenched at room temperature with saturated ammonium chloride aqueous solution (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 150 mL), the organic phases were combined, washed with saline solution (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 and eluted with PE / EA (1:1) to obtain 1-[3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl]-1-(1-trityl-1H-imidazole-4-yl)ethanol (10.2 g). (ES, m / z):[M+1]=601.

[0206] 8.4 At room temperature and under a nitrogen gas atmosphere, 1-[3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl]-1-(1-trityl-1H-imidazole-4-yl)ethanol (6 g, 9.985 mmol, 1 equivalent) was added to a 70 mL solution of DCM, TEA (4.04 g, 39.940 mmol, 4 equivalents) was added, and the mixture was stirred for 2 minutes. The temperature was then lowered to 0°C, and then ethyl chloroglyoxylate (2.73 g, 19.970 mmol, 2 equivalents) was added. The resulting mixture was stirred overnight at room temperature, and the mixture was quenched by adding it to water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 150 mL), the organic phases were combined, washed with saline solution (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 and eluted with PE / EA (5:1) to obtain the yellow solid 4-(1-{3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl}vinyl)-1-(triphenylmethyl)imidazole (4.0 g), with (ES, m / z): [M+1] = 583.

[0207] 8.5 At room temperature, 4-(1-{3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl}vinyl)-1-(triphenylmethyl)imidazole (4 g, 6.863 mmol, 1 equivalent), MeOH (30 mL), and Pd / C (0.15 g, 10% w / t) were added to a 100 mL round-bottom flask. The resulting mixture was stirred under a hydrogen atmosphere for 3 hours. The resulting mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with methanol (3 × 50 mL). The filtrate was concentrated under reduced pressure. 4-(1-{3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-inden-4-yl}ethyl)-1-(triphenylmethyl)imidazole (2.1 g) was obtained. (ES, m / z): [M+1] = 585.

[0208] 8.6 At room temperature and under a nitrogen atmosphere, TBAF (39.46 mL, 39.460 mmol, 5 equivalents) was added 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 equivalent) in tetrahydrofuran (40 mL). The resulting mixture was stirred overnight at room temperature and under a nitrogen atmosphere. The reaction was quenched at room temperature by adding water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 80 mL) and the organic phases were combined. The organic layer was 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 flash chromatography to obtain 7-{1-[1-(triphenylmethyl)imidazole-4-yl]ethyl}-2,3-dihydro-1H-inden-1-ol (1.8 g) as a grayish-white solid. (ES, m / z):[M+1]=471.

[0209] 8.7 At room temperature and under a nitrogen atmosphere, TsOH (0.10 g, 0.595 mmol, 0.2 equivalents) was added to a solution of 7-{1-[1-(triphenylmethyl)imidazole-4-yl]ethyl}-2,3-dihydro-1H-inden-1-ol (1.4 g, 2.975 mmol, 1 equivalent) in ACN (20 mL) with TsOH (0.10 g, 0.595 mmol, 0.2 equivalents). Under a nitrogen atmosphere, the resulting mixture was stirred overnight at 70°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain 4-[1-(1H-inden-4-yl)ethyl]-1H-imidazole (389 mg). (ES, m / z):[M+1]=211. 1H NMR (400 MHz, Methanol-d4) δ 8.35 - 7.87 (m, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.29 - 7.18 (m, 1H), 7.12 (t, J = 7.4 Hz, 1H), 6.98 (dt, J = 13.5, 7.5 Hz, 2H), 6.56 (ddd, J = 9.3, 5.8, 3.6 Hz, 1H), 4.63 -4.27 (m, 1H), 3.39 (s, 2H), 1.64 (d, J = 6.3 Hz, 3H). At the same time, its stereoisomer

[0210] [ka]

[0211] It was separated.

[0212] Example 9: Preparation of 4-[1-(1,3-dihydrobenzo[c]thiophen-4-yl)ethyl]-1H-imidazole

[0213] [ka]

[0214] 9.1 At room temperature and under a nitrogen atmosphere, 3-bromo-1,2-xylene (2.0 g, 10.807 mmol, 1 equivalent) and AIBN (0.41 g, 2.486 mmol, 0.23 equivalents) were stirred in CCl4 (30 mL), to which NBS (3.85 g, 21.614 mmol, 2 equivalents) was added in several batches. The resulting mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched at 0°C with water / ice (100 mL). The resulting mixture was extracted with dichloromethane (3 × 100 mL), and the organic layers were combined. The mixture was washed with water (1 × 100 mL) and dried over anhydrous Na₂SO₄. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (12:1) to obtain 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. 9.2 Sodium sulfide (182.0 mg, 2.333 mmol, 1 equivalent) was dissolved in H2O (2.4 mL) and stirred at 80°C for 20 minutes under a nitrogen atmosphere. Then, a solution of 1-bromo-2,3-bis(bromomethyl)benzene (800 mg, 2.333 mmol, 1 equivalent) in ethanol (8.4 mL) was added dropwise at 80°C. The resulting mixture was stirred overnight at 80°C under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched at room temperature by adding water (30 mL). The resulting mixture was extracted with ethyl acetate (3 × 20 mL) and the organic layers were combined. The mixture was washed with water (1 × 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 and eluted with PE / EA (12:1) to obtain 4-bromo-1,3-dihydro-2-benzo[c]thiophene (220 mg) as a colorless oil. (ES, m / z):[M]=214,216. The compound was prepared according to the method of Example 3, but 2,5-dibromovicyclo[4.2.0]octa-1(6),2,4-triene was substituted with 4-bromo-1,3-dihydro-2-benzo[c]thiophene to obtain 4-[1-(1,3-dihydrobenzo[c]thiophen-4-yl)ethyl]-1H-imidazole. (ES,m / z):[M+1]=231. 1 H NMR (400 MHz, Chloroform-d) δ7.46 (s, 1H), 7.05 (dt, J = 15.8, 7.5 Hz, 2H), 6.87 (d, J = 7.3 Hz, 1H), 6.65 (s, 1H), 4.50 - 3.74 (m, 5H), 1.50 (d, J = 7.1 Hz, 3H). Example 10: Preparation of 4-[1-(2,3-dihydrobenzofuran-7-yl)ethyl]-1H-imidazole

[0215] [ka]

[0216] The compound was prepared according to the method of Example 1, but 8-bromo-3,4-dihydro-2H-1-benzothiopyran was substituted with 7-bromo-2,3-dihydrobenzofuran and 1-trityl-1H-imidazole-4-formaldehyde was substituted with 1-[1-(trityl)imidazole-4-yl]ethanone to obtain 4-[1-(2,3-dihydrobenzofuran-7-yl)ethyl]-1H-imidazole. (ES,m / z):[M+1]=215. 1 H NMR (400 MHz, Methanol-d4) δ 7.55 (d, J = 1.2 Hz, 1H), 7.03 (dd, J = 7.2, 1.4 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.78 - 6.69 (m, 2H), 4.52 (t, J = 8.7 Hz, 2H), 4.28 (q, J = 7.2 Hz, 1H), 3.17 (t, J = 8.7 Hz, 2H), 1.54 (d, J = 7.1 Hz, 3H). At the same time, its stereoisomer

[0217] [ka]

[0218] It was separated.

[0219] Example 11: 4-[1-(6-fluoro-1H-inden-4-yl)ethyl]-1H-imidazole

[0220] [ka]

[0221] 11.1 A mixed solution of 7-bromo-5-fluoro-2,3-dihydroinden-1-one (5 g, 21.829 mmol) dissolved in THF (40 mL) and MeOH (20 mL) was treated with NaBH4 (3.30 g, 87.316 mmol) at 0°C under a nitrogen gas atmosphere. The resulting mixture was stirred overnight under a nitrogen gas atmosphere at room temperature. The reaction was quenched at room temperature by adding water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with water (1 × 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 and eluted with PE / EA (5:1) to obtain yellow oily 7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-ol (4.6 g). (ES, m / z): [M-18+1]=213,215.

[0222] 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 50 mL solution of DCM and stirred. Then, tert-butyldimethylchlorosilane (3.91 g, 25.967 mmol) was added in several portions. The resulting mixture was stirred overnight under a nitrogen atmosphere and at room temperature. Subsequently, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (12:1) to obtain a colorless oily [(7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (7 g).

[0223] 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 60 mL THF solution, and n-butyllithium (9.38 mL, 23.456 mmol, 2.5 M in n-hexane) was added at -78°C. The mixture was reacted for 40 minutes, and then 1-[1-(triphenylmethyl)imidazole-4-yl]ethanone (5.51 g, 15.637 mmol) in a 20 mL THF solution was added dropwise at -78°C. The resulting mixture was stirred overnight under a nitrogen atmosphere and at room temperature. The reaction was quenched at room temperature by adding a saturated NH4Cl aqueous solution (200 mL). The resulting mixture was extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with water (1 × 200 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain yellow oily 1-[3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (5.2 g). (ES, m / z): [M+1]=619.

[0224] 11.4 At room temperature and under a nitrogen gas atmosphere, 1-[3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (5 g, 8.079 mmol) was added to DCM (50 mL) solution, and triethylamine (6.54 g, 64.632 mmol) was added and reacted for 1 minute. Then, at 0°C, ethyl chloroglyoxylate (4.41 g, 32.316 mmol) was added dropwise. The resulting mixture was stirred overnight under a nitrogen gas atmosphere and at room temperature, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain yellow oily 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]vinyl]-1-(triphenylmethyl)imidazole (3.8 g). (ES, m / z): [M+1]=601.

[0225] 11.5 At room temperature, 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 solution of MeOH (10 mL). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 40 minutes. The resulting reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain yellow oily 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]ethyl]-1-(triphenylmethyl)imidazole (900 mg). (ES, m / z): [M+1]=603.

[0226] 11.6 At room temperature, 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). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched at room temperature by adding water (100 mL). The resulting mixture was extracted with siRNA (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 silica gel column chromatography and eluted with PE / EA (5:1) to obtain colorless oily 5-fluoro-7-[1-[1-(triphenylmethyl)imidazole-4-yl]ethyl]-2,3-dihydro-1H-inden-1-ol (2.1 g). (ES, m / z): [M+1]=489.

[0227] 11.7 At room temperature, p-toluenesulfonic acid (888.1 mg, 5.158 mmol) was added to a solution of 5-fluoro-7-[1-[1-(triphenylmethyl)imidazole-4-yl]ethyl]-2,3-dihydro-1H-inden-1-ol (4.2 g, 8.596 mmol) in acetonitrile (80 mL). The resulting mixture was stirred at 70°C under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column C18 silica gel, mobile phase MeCN-water (0.1% NH3H2O ​​+ 10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes, detector UV 220 nm. 4-[1-(6-fluoro-1H-inden-4-yl)ethyl]-1H-imidazole (1.9 g) was obtained. (ES, m / z): [M+1]=229. 1H NMR (400 MHz, Methanol-d4) δ 7.57 (d, J = 1.2 Hz, 1H), 7.05 (dd, J = 8.6, 2.3 Hz, 1H), 6.97 (dt, J = 4.5, 2.0 Hz, 1H), 6.80 (d, J = 1.1 Hz, 1H), 6.75 (dd, J = 10.9, 2.4 Hz, 1H), 6.52 (dt, J = 5.8, 2.1 Hz, 1H), 4.44 (q, J = 7.2 Hz, 1H), 3.38 (d, J = 2.2 Hz, 2H), 1.60 (d, J = 7.2 Hz, 3H). 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 obtain 4-[(1R)-1-(6-fluoro-1H-inden-4-yl)ethyl]-1H-imidazolium (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).

[0228] 4-[(1R)-1-(6-fluoro-1H-inden-4-yl)ethyl]-1H-imidazole(11-a) (ES, m / z): [M+1]=229, 1 H NMR (400 MHz, Methanol-d4) δ 7.57 (d, J= 1.4 Hz, 1H), 7.06 (dd, J = 8.6, 2.5 Hz, 1H), 7.00 - 6.93 (m, 1H), 6.81 (s, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.52 (dt, J = 6.2, 2.2 Hz, 1H), 4.44 (q, J = 7.2 Hz, 1H), 3.38 (d, J = 2.5 Hz, 2H), 1.60 (d, J = 7.2 Hz, 3H). 4-[(1S)-1-(6-fluoro-1H-inden-4-yl)ethyl]-1H-imidazole(11-b) (ES, m / z): [M+1]=229, 1 H NMR (400 MHz, Methanol-d4) δ7.74 - 7.50 (m, 1H), 7.09 - 7.03 (m, 1H), 7.00 - 6.93 (m, 1H), 6.81 (d, J= 1.1 Hz, 1H), 6.75 (dd, J = 10.9, 2.4 Hz, 1H), 6.52 (ddt, J = 5.6, 4.0, 2.0 Hz, 1H), 4.44 (q, J = 7.2 Hz, 1H), 3.38 (q, J = 2.2 Hz, 2H), 1.60 (dd, J = 7.2, 1.3 Hz, 3H). Example 12: Preparation of 4-[1-(6-fluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole

[0229] [ka]

[0230] 12.1 At room temperature and 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 filtrate was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN-water (0.1% NH3H2O ​​+ 10 mmol / L NH4HCO3), gradient from 10% to 30% over 10 minutes, detector: UV 254 nm. 4-[1-(6-fluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (34.1 mg) was obtained. (ES, m / z):[M+1]=231. 1H NMR (400 MHz, Methanol-d4) δ 7.57 (s, 1H), 6.80 - 6.72 (m, 2H), 6.60 (d, J = 10.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 1H), 2.92 - 2.81 (m, 3H), 2.81 (s, 1H), 2.12 - 1.99 (m, 2H), 1.53 (dd, J = 7.1, 2.1 Hz, 3H). Example 13: Preparation of 4-[1-(1-benzofuran-4-yl)ethyl]-1H-imidazole

[0231] [ka]

[0232] 13.1 Under a nitrogen atmosphere, n-butyllithium (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 equivalent) in THF (4 mL), and the mixture was reacted at -78°C for 45 minutes. Then, at -78°C, a solution of 1-[1-(triphenylmethyl)imidazole-4-yl]ethanone (322.0 mg, 0.913 mmol, 1.2 equivalents) in tetrahydrofuran (6 mL) was added dropwise. The resulting mixture was stirred at room temperature for a further 5 hours. The reaction was quenched at room temperature by adding saturated NH4Cl (aqueous solution) (10 mL). The resulting mixture was extracted with siRNA (2 × 30 mL). The combined organic layers were washed with water (3 × 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 under 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. Pale yellow oily 1-(1-benzofuran-4-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (340 mg) was obtained. (ES, m / z): [M+1] = 471.

[0233] 13.2 At room temperature and under a nitrogen gas atmosphere, triethylsilane (840.1 mg, 7.230 mmol) was added to a solution of 1-(1-benzofuran-4-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (340 mg, 0.723 mmol) in DCM (8 mL) and reacted for 1 minute. Then, trifluoroacetic acid (823.8 mg, 7.230 mmol) was added dropwise at room temperature. The resulting mixture was stirred for a further 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under 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. A yellow oily substance, 4-[1-(1-benzofuran-4-yl)vinyl]-1H-imidazole (120 mg), was obtained. (ES,m / z):[M+1]=211.

[0234] 13.3 At room temperature and under a nitrogen atmosphere, 10% Pd / C (10 mg) was added to a 2 mL round-bottom flask containing 4-[1-(1-benzofuran-4-yl)vinyl]-1H-imidazole (50 mg, 0.238 mmol) in MeOH (2 mL). At room temperature, the mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon for 2 hours. Diatomaceous earth was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel mobile phase, MeCN-water (10 mmol / L NH4HCO3), 10% to 30% gradient 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. 1H NMR (400 MHz, Methanol-d4) δ 7.66 (d, J = 2.1 Hz, 1H), 7.56 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.28 - 7.15 (m, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.85 - 6.70 (m, 2H), 4.45 (q, J = 7.1 Hz, 1H), 1.68 (dd, J = 7.3, 1.8 Hz, 3H). Example 14: Preparation of 4-[1-(2H-chroman-8-yl)ethyl]-1H-imidazole

[0235] [ka]

[0236] 14.1 At 0°C and under a nitrogen atmosphere, NaBH4 (666.4 mg, 17.616 mmol) was added in several batches to a stirred mixture of 8-bromo-2,3-dihydro-1-benzopyran-4-one (2 g, 8.808 mmol) in MeOH (14 mL) and THF (7 mL). The resulting mixture was stirred under a nitrogen atmosphere and at room temperature for 2 hours. The reaction was quenched at 0°C by adding saturated NH4Cl aqueous solution (20 mL). The resulting mixture was extracted with siRNA (3 × 100 mL). The combined organic layers were 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 and eluted with PE / EA (5:1) to obtain yellow oily 8-bromo-3,4-dihydro-2H-1-benzopyran-4-ol (1.8 g). (ES, m / z):[M-18]=211,213.

[0237] 14.2 At 0°C and under a nitrogen atmosphere, tert-butyldimethylchlorosilane (1.7 g, 11.132 mmol) was added to a stirred mixture of 8-bromo-3,4-dihydro-2H-1-benzopyran-4-ol (1.7 g, 7.421 mmol) and imidazole (0.6 g, 8.905 mmol) in DMF (40 mL). The resulting mixture was stirred under a nitrogen atmosphere and at room temperature for 4 hours. The mixture was quenched with water (20 mL) and extracted with SiO2 (3 × 50 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 silica gel column chromatography and eluted with PE / EA (7:1) to obtain a yellow oily [(8-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)oxy](tert-butyl)dimethylsilane (2.2 g).

[0238] 14.3 Under a nitrogen atmosphere, a solution of [(8-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)oxy](tert-butyl)dimethylsilane (2.1 g, 6.116 mmol) in THF (40 mL) was treated with n-butyllithium (3.6 mL, 9.174 mmol, 2.5 M in n-hexane) at -78°C for 40 minutes, and then a solution of 1-[1-(triphenylmethyl)imidazole-4-yl]ethanone (2.4 g, 6.728 mmol) in tetrahydrofuran (10 mL) was added dropwise at -78°C. The resulting mixture was stirred overnight under a nitrogen atmosphere and at room temperature. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with CH2Cl2 (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 flash chromatography under 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. Yellow oily 1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-benzopyran-8-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (1.2 g) was obtained. (ES, m / z): [M+1] = 617.

[0239] 14.4 At room temperature and under a nitrogen gas atmosphere, ethyl chloroglyoxylate (730.3 mg, 5.349 mmol) was added dropwise, to a stirred mixture of 1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-benzopyran-8-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (1.1 g, 1.783 mmol) and triethylamine (1.4 mL, 10.698 mmol) in DCM (22 mL). The resulting mixture was stirred under a nitrogen gas atmosphere and at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (12:1) to obtain 750 mg of yellow oily 4-[1-[4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-benzopyran-8-yl]-vinyl]-1-(triphenylmethyl)imidazole. (ES,m / z):[M+1]=599.

[0240] 14.5 At room temperature, 10% Pd / C (177.7 mg) was added to a stirred solution of 4-[1-[4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-benzopyran-8-yl]-vinyl]-1-(triphenylmethyl)imidazole (500 mg, 0.835 mmol) in THF (10 mL). The resulting mixture was stirred for 30 min under a hydrogen atmosphere at room temperature. The resulting mixture was filtered, and the filter cake was washed with THF (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN-water (0.1% NH3H2O), gradient from 10% to 50% over 10 minutes, detector: UV 254 nm. A yellow, oily 4-[1-[4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-benzopyran-8-yl]-ethyl]-1-(triphenylmethyl)imidazole (420 mg) was obtained. (ES, m / z):[M+1] = 601.

[0241] 14.6 At room temperature and under a nitrogen atmosphere, tetrabutylammonium fluoride (2.0 mL, 1.998 mmol, 1 M in THF) was added dropwise to a stirred mixture of 4-[1-[4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-benzopyran-8-yl]-ethyl]-1-(triphenylmethyl)imidazole (400 mg, 0.666 mmol) in THF (8 mL). The resulting mixture was stirred under a nitrogen atmosphere and at room temperature for 2 hours. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (100 mL) at room temperature. The resulting mixture was extracted with siRNA (3 × 200 mL). The combined organic layers were 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 reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile in water (0.1% NH3H2O), gradient from 10% to 50% over 10 minutes, detector: UV 254 nm. The yellow oily substance 8-[1-[1-(triphenylmethyl)imidazole-4-yl]ethyl]-3,4-dihydro-2H-1-benzopyran-4-ol (180 mg) was obtained. (ES, m / z): [M+1] = 487.

[0242] 14.7 At room temperature and under a nitrogen atmosphere, p-toluenesulfonic acid (113.2 mg, 0.656 mmol) was added in several portions to a stirred mixture of 8-[1-[1-(triphenylmethyl)imidazole-4-yl]ethyl]-3,4-dihydro-2H-1-benzopyran-4-ol (80 mg, 0.164 mmol) in acetonitrile (2 mL). The resulting mixture was stirred at 70°C and under a 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 C18 column 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3H2O), mobile phase B: methanol, flow rate: 60 mL / min, gradient: 20% B to 38% B over 10 minutes, wavelength: 254 nm / 220 nm, room temperature, 1 (min): 11.82 / 15.28) to obtain 4-[1-(2H-chroman-8-yl)ethyl]-1H-imidazole (14.3 mg). (ES, m / z): [M+1] = 227. 1 H NMR (400 MHz, Methanol-d4) δ 7.54 (d, J= 1.2 Hz, 1H), 6.87 -6.79 (m, 2H), 6.79 - 6.71 (m, 2H), 6.44 (dq, J = 9.8, 1.7 Hz, 1H), 5.82 (dtd, J = 9.5, 3.6, 1.8 Hz, 1H), 4.77 (dt, J = 3.5, 1.6 Hz, 2H), 4.44 (q, J = 7.1 Hz, 1H), 1.51 (d, J = 7.2 Hz, 3H). Example 15: Preparation of 4-[1-(2,2-difluoro-1,3-dihydroinden-4-yl)ethyl]-1H-imidazole

[0243] [ka]

[0244] 15.1 Diethylaminosulfur trifluoride (421.8 mg, 11.372 mmol) was added to a solution of 4-bromo-1,3-dihydroinden-2-one (600 mg, 2.843 mmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature. The reaction was quenched by adding ice water (10 mL) at 0°C. The resulting mixture was extracted with siRNA (3 × 10 mL). The combined organic layers were washed with water (1 × 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 under 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. A light brown, oily substance, 4-bromo-2,2-difluoro-1,3-dihydroindene (400 mg), was obtained.

[0245] 15.2 At room temperature and under a nitrogen atmosphere, 4-bromo-2,2-difluoro-1,3-dihydroindene (350 mg, 1.502 mmol) was dissolved in toluene (4 mL), to which tripenzyl(1-ethoxyvinyl) stannan (834.8 mg, 1.802 mmol) was added and reacted for 1 minute. Then, at room temperature, Pd(PPh3)4 (173.5 mg, 0.150 mmol) was added in several portions. The resulting mixture was stirred overnight at 110°C under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. A brownish oily 4-(1-ethoxyvinyl)-2,2-difluoro-1,3-dihydroindene (340 mg, crude product) was obtained. (ES, m / z): [M+1] = 225.

[0246] 15.3 At room temperature and under a nitrogen atmosphere, 4-(1-ethoxyvinyl)-2,2-difluoro-1,3-dihydroindene (350 mg, 1.561 mmol) was added to a toluene (5 mL) solution with H₂O (1 mL) and reacted for 1 minute. Then, at room temperature, 4 M hydrogen chloride solution (5 mL) was added dropwise. The resulting mixture was stirred under a nitrogen atmosphere and at room temperature for 2 hours. The reaction was quenched by adding water (20 mL) at room temperature. The resulting mixture was extracted with ELISA (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 and eluted with PE / EA (5:1) to obtain pale yellow oily 1-(2,2-difluoro-1,3-dihydroindene-4-yl)ethanone (280 mg). (ES,m / z): [M+1]=197.

[0247] 15.4 At 0°C and under a nitrogen atmosphere, i-PrMgBr (1.83 mL, 4.584 mmol, 1 M in THF) was added to a solution of 4-iodo-1-(triphenylmethyl)imidazole (1 g, 2.292 mmol) in THF (10 mL) and reacted for 30 minutes. Then, at 0°C, a solution of 1-(2,2-difluoro-1,3-dihydroinden-4-yl)ethanone (0.30 g, 1.528 mmol) in THF (2 mL) was added in several batches. The resulting mixture was stirred under a nitrogen atmosphere and at room temperature for 4 hours. The reaction was quenched at room temperature by adding saturated NH4Cl (aqueous solution) (10 mL). The resulting mixture was extracted with SiO4 (3 × 10 mL). The combined organic layers were washed with water (1 × 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 and eluted with PE / EA (1:1) to obtain yellow oily 1-(2,2-difluoro-1,3-dihydroinden-4-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (260 mg). (ES, m / z): [M+1]=507.

[0248] 15.5 At room temperature and under a nitrogen gas atmosphere, trifluoroacetic acid (1.03 g, 9.080 mmol) was added to a solution of 1-(2,2-difluoro-1,3-dihydroinden-4-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (230 mg, 0.454 mmol) in DCM (2 mL) and reacted for 1 minute. Then, triethylsilane (1.05 g, 9.080 mmol) was added dropwise at room temperature. The resulting mixture was stirred overnight under a nitrogen gas atmosphere and at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under 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. A colorless oily substance, 4-[1-(2,2-difluoro-1,3-dihydroinden-4-yl)vinyl]-1H-imidazole (30 mg), was obtained. (ES, m / z): [M+1]=247.

[0249] 15.6 At room temperature, Pd / C (3.9 mg, 10% w / t) was added to a solution of 4-[1-(2,2-difluoro-1,3-dihydroinden-4-yl)vinyl]-1H-imidazole (30 mg, 0.122 mmol) in tetrahydrofuran (3 mL). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 30 minutes. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with THF (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN-water (0.1% NH3H2O), gradient from 10% to 50% over 10 minutes, detector: UV 220 nm. 4-[1-(2,2-difluoro-1,3-dihydroinden-4-yl)ethyl]-1H-imidazole (12 mg) was obtained. (ES, m / z): [M+1]=249. 1H NMR (400 MHz, Methanol-d4) δ 7.56 (d, J = 1.2 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.07 (dd, J = 12.7, 7.6 Hz, 2H), 6.76 (d, J = 1.3 Hz, 1H), 4.11 (q, J = 7.2 Hz, 1H), 3.43 - 3.31 (m, 4H), 1.56 (d, J = 7.2 Hz, 3H). Example 16: Preparation of 4-[1-(2-fluoro-1-benzofuran-7-yl)ethyl]-1H-imidazole

[0250] [ka]

[0251] At 16.1°C, bromomethyl methyl ether (3.7 g, 29.847 mmol) was added dropwise to a stirred solution of 3-bromo-2-hydroxybenzaldehyde (2 g, 9.949 mmol) and DIEA (3.9 g, 29.847 mmol) in DCM. The resulting mixture was stirred overnight at room temperature. The mixture was quenched with H2O (20 mL) and extracted with DCM (3 × 100 mL). The combined organic layer was washed with H2O (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 and eluted with PE / EA (5:1) to obtain yellow oily 3-bromo-2-(methoxymethoxy)benzaldehyde (2.3 g). (ES, m / z): [M+1] = 245, 247.

[0252] 16.2 3-Bromo-2-(methoxymethoxy)benzaldehyde (1.5 g, 6.121 mmol) and 2,2-difluoro-2-(triphenylphosphonio)ethyl acetate (4.3 g, 12.242 mmol) were added to NMP (30 mL), and the resulting mixture was stirred at 80°C for 2 hours under N2 protection. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was 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 silica gel column chromatography and eluted with PE / EA (3:1) to obtain colorless oily 1-bromo-3-(2,2-difluorovinyl)-2-(methoxymethoxy)benzene (1.3 g).

[0253] 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 hour. The resulting mixture was diluted with water (10 mL) and concentrated under vacuum. The residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water, gradient from 10% to 60%, 10 minutes, detector: ultraviolet 254 nm. Colorless oily 2-bromo-6-(2,2-difluorovinyl)phenol (900 mg) was obtained. (ES, m / z): [M+1] = 234, 236.

[0254] 16.4 2-Bromo-6-(2,2-difluorovinyl)phenol (700 mg, 2.98 mmol) and DBU (544.1 mg, 3.574 mmol) were added to DMF (6 mL), and the resulting mixture was stirred overnight at 100°C. The mixture was also irradiated with microwaves at 100°C for 20 min. After the resulting mixture was cooled to room temperature, it was diluted with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were 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 reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water, 10% to 50% gradient, 10 min, detector: ultraviolet 254 nm. Yellow oily 7-bromo-2-fluoro-1-benzofuran (170 mg) was obtained.

[0255] 16.5 7-Bromo-2-fluoro-1-benzofuran (117 mg, 0.544 mmol, 1 equivalent), tributyl(1-ethoxyethylene)tin (235.8 mg, 0.653 mmol, 1.2 equivalents), and Pd(PPh3)4 (62.88 mg, 0.054 mmol, 0.1 equivalent) were added to toluene (3 mL). The resulting mixture was stirred overnight at 110°C under the protection of N2. 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.

[0256] 16.6 7-(1-ethoxyvinyl)-2-fluoro-1-benzofuran (120 mg, 0.582 mmol) was added to a mixture of hydrochloric acid (0.2 mL) / toluene (2.4 mL) and stirred at room temperature for 2 hours. The resulting mixture was extracted with siRNA (3 × 50 mL). The combined organic layer was washed with H₂O (0.2 mL) (3 × 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 and eluted with PE / EA (5:1) to obtain yellow oily 1-(2-fluoro-1-benzofuran-7-yl)ethanone (88 mg). (ES, m / z): [M+1] = 179.

[0257] 16.7 4-Iodo-1-(trityl)imidazole (281.6 mg, 0.645 mmol) and bromo(isopropyl)magnesium (0.645 mL, 0.645 mmol, 1 M in THF) were added to DCM (0.8 mL), and the resulting mixture was stirred at 0°C for 20 min under N2 protection. Then, 1-(2-fluoro-1-benzofuran-7-yl)etanone (115 mg, 0.645 mmol) was added dropwise. The resulting mixture was stirred overnight at 0°C under a nitrogen atmosphere. The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with saline (1 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was 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%, 10 min, detector: UV 254 nm. Yellow, oily 1-(2-fluoro-1-benzofuran-7-yl)-1-[1-(trityl)imidazole-4-yl]ethanol (64 mg) was obtained. (ES, m / z): [M+1] = 489.

[0258] 16.8 1-(2-fluoro-1-benzofuran-7-yl)-1-[1-(trityl)imidazole-4-yl]ethanol (63 mg, 0.129 mmol, 1 equivalent) and triethanolamine (78.2 mg, 0.774 mmol, 6 equivalents) were added to DCM (2 mL), followed by the dropwise addition of ethyl acetoethyl (52.8 mg, 0.387 mmol, 3 equivalents) at 0°C. The resulting mixture was stirred overnight at room temperature under N2 protection. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 8:1) to obtain colorless oily 4-[1-(2-fluoro-1-benzofuran-7-yl)vinyl]-1-(trityl)imidazole (35 mg). (ES, m / z): [M+1] = 471.

[0259] 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), and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The resulting mixture was filtered, and the filtrate was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The crude product (40 mg) was purified by preparative high-performance liquid chromatography under the following conditions: (Column: XBridge Prep OBD C18 column 30 × 150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3H2O); Mobile phase B: MeOH; Flow rate: 60 mL / min; Gradient: 40% B ~ 58% B; 10 min; Wavelength: 254 nm / 220 nm; Room temperature; 1 (min): 12.33; 4-[1-(2-fluoro-1-benzofuran-7-yl)ethyl]-1H-imidazole (5 mg) was obtained. (ES, m / z): [M+1] = 231. 1 H NMR (400 MHz, Methanol-d4) δ 7.58 (s, 1H), 7.35 (dd, J = 7.7, 1.2 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.03 (dd, J = 7.7, 1.3 Hz, 1H), 6.85 (s, 1H), 6.00 (d, J = 6.4 Hz, 1H), 4.57 (q, J = 7.2 Hz, 1H), 1.68 (d, J = 7.3 Hz, 3H). Example 17: Preparation of 4-[1-(1,1-dimethyl-1H-inden-4-yl)ethyl]-1H-imidazole

[0260] [ka]

[0261] 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), and the resulting mixture was stirred at -40°C for 20 min under N2 protection, followed by dropwise addition of a DCM (10 mL) solution of 4-bromo-1-indanone (3 g, 14.214 mmol). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was quenched with saturated NH4Cl aqueous solution. Extraction was performed with siRNA (3 × 200 mL). The combined organic layers were washed with saline (2 × 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 and eluted with PE to obtain colorless oily 4-bromo-1,1-dimethyl-2,3-dihydro-1H-indene (2.4 g).

[0262] 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), and the resulting mixture was stirred at 60°C for 3 hours under N2 protection. After cooling the resulting mixture to room temperature, it was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN-water (0.1% FA), gradient from 10% to 50%, 20 minutes, detector: ultraviolet 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.

[0263] 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 hours. Then, it was quenched with water. After concentration under reduced pressure, the residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN-water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector: ultraviolet 254 nm. Yellow oily 7-bromo-3,3-dimethyl-1,2-dihydroinden-1-ol (210 mg) was obtained. (ES, m / z): [M+1] = 223, 225.

[0264] 17.4 Under a nitrogen gas atmosphere, 7-bromo-3,3-dimethyl-1,2-dihydroinden-1-ol (110 mg, 0.456 mmol, 1 equivalent) and imidazole (62.1 mg, 0.912 mmol, 2 equivalents) were added to DCM (2 mL), and the resulting mixture was stirred at room temperature, followed by the addition of tert-butyldimethylchlorosilane (82.5 mg, 0.547 mmol, 1.2 equivalents). The resulting mixture was stirred at room temperature for 2 hours. Then, it was quenched with water and extracted with siRNA (3 × 50 mL). The combined organic layers were washed with saline solution (1 × 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 and eluted with PE / EA (5:1) to obtain a yellowish oily [(7-bromo-3,3-dimethyl-1,2-dihydroinden-1-yl)oxy](tert-butyl)dimethylsilane (150 mg).

[0265] Under a nitrogen gas atmosphere, n-butyllithium (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-dihydroinden-1-yl)oxy](tert-butyl)dimethylsilane (190 mg, 0.535 mmol) in THF (4 mL), stirred at -78°C for 2 hours, and then a solution of 1-[1-(trityl)imidazole-4-yl]etanone (188.4 mg, 0.535 mmol) in THF (4 mL) was added dropwise. The resulting mixture was stirred overnight at room temperature. The resulting mixture was quenched with saturated NH4Cl aqueous 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 under 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. Yellow oily 1-(3-((tert-butyldimethylsiloxy)-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)-1-(1-trityl-1H-imidazole-4-yl)ethanol (80 mg) was obtained. (ES, m / z): [M+1] = 629.

[0266] At 17.6°C, ethyl chloroformate (104.5 mg, 0.765 mmol) was added dropwise to a 1.5 mL solution of (3Z)-3-amino-2-(3-[(tert-butyldimethylsilyl)oxy]-1,1-dimethyl-2,3-dihydroinden-4-yl-4-[(trityl)amino]buta-3-en-2-ol) and triethylamine (154.9 mg, 1.530 mmol) in DCM. The resulting mixture was stirred at room temperature for 2 hours. It was 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 NH4HCO3), gradient from 10% to 55% over 10 minutes, detector: UV 254 nm. A colorless oily 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-1,1-dimethyl-2,3-dihydroinden-4-yl]vinyl]-1-(trityl)imidazole (80 mg) was obtained. (ES, m / z): [M+1] = 611.5.

[0267] 17.7 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-1,1-dimethyl-2,3-dihydroinden-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 under a hydrogen atmosphere at room temperature for 30 minutes. The resulting mixture was filtered through diatomaceous earth, and the filtrate was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-1,1-dimethyl-2,3-dihydroinden-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.

[0268] 17.8 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-1,1-dimethyl-2,3-dihydroinden-4yl]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. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 40% over 10 minutes, detector: ultraviolet light at 254 nm. As a result, 7-[1-(1H-imidazole-4-yl)ethyl]-3,3-dimethyl-1,2-dihydroinden-1-ol (18 mg) was obtained as a colorless oil. (ES,m / z): [M+1]= 257.

[0269] 17.9 7-[1-(1H-imidazole-4-yl)ethyl]-3,3-dimethyl-1,2-dihydroinden-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. Quenched with water at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes, detector: ultraviolet 254 nm. 4-[1-(1,1-dimethyl-1H-inden-4-yl)ethyl]-1H-imidazole (3.4 mg) was obtained. (ES, m / z): [M+1] = 239. 1H NMR (400 MHz, Methanol-d4) δ 7.63 (s, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.75 (d, J = 5.6 Hz, 1H), 6.36 (d, J = 5.6 Hz, 1H), 4.40 (q, J = 7.2 Hz, 1H), 1.61 (d, J = 7.2 Hz, 3H), 1.28 (d, J = 4.1 Hz, 6H). Example 18: Production of 7-[1-(1H-imidazole-4-yl)ethyl]-2,3-dihydro-1H-indole

[0270] [ka]

[0271] 18.1 Under a nitrogen atmosphere, n-butyllithium (0.2 mL, 0.503 mmol, 2.5 M in hexane) was added dropwise to a solution of 7-bromo-2,3-dihydroindole-1-formate tert-butyl (100 mg, 0.335 mmol) in THF (1 mL), and the mixture was stirred at -78°C for 1 hour. Then, 1-[1-(trityl)imidazole-4-yl]etanone (118.2 mg, 0.335 mmol) was added dropwise. The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with toluene (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was 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 NH4HCO3), gradient from 10% to 60% over 10 minutes, detector: UV 254 nm. 1-(indolin-7-yl)-1-(1-trityl-1H-imidazole-4-yl)ethane-1-ol (60 mg) was obtained as a yellow oily substance. (ES, m / z): [M+1] = 454.

[0272] 18.2 1-(indolin-7-yl)-1-(1-trityl-1H-imidazole-4-yl)ethane-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 hours. It was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN-water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector: ultraviolet 254 nm. 7-[1-(1H-imidazole-4-yl)vinyl]-2,3-dihydro-1H-indole (80 mg) was obtained as a yellow oily substance. (ES, m / z): [M+1] = 212.

[0273] 18.3 7-[1-(1H-imidazole-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), and the resulting mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The resulting mixture was filtered through diatomaceous earth, and the filtrate was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product (60 mg) was purified by preparative high-performance liquid chromatography under the following conditions: (Column: XBridge Prep OBD C18 column 30 × 150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3H2O); Mobile phase B: MEOH; Flow rate: 60 mL / min; Gradient: 40% B ~ 58% B; 10 min: Wavelength: 254 nm / 220 nm; Room temperature; 1 (min): 12.33). 7-[1-(1H-imidazole-4-yl)ethyl]-2,3-dihydro-1H-indole (15.9 mg) was obtained. (ES, m / z): [M+1] = 214. 1H NMR (400 MHz, Methanol-d4) δ 7.55 (d, J = 1.2 Hz, 1H), 6.96 (dt, J = 7.3, 1.2 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.76 (t, J = 1.1 Hz, 1H), 6.66 (t, J = 7.5 Hz, 1H), 4.08 (q, J = 7.2 Hz, 1H), 3.44 (t, J = 8.2 Hz, 2H), 2.98 (t, J = 8.3 Hz, 2H), 1.56 (d, J = 7.2 Hz, 3H). Example 19: Production of 4-[1-(1H-imidazole-4-yl)ethyl]-2,3-dihydro-1H-indole

[0274] [ka]

[0275] 19.1 Under a nitrogen atmosphere, n-butyllithium (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), and the mixture was stirred at -78°C for 40 min. Then, 1-[1-(trityl)imidazole-4-yl]etanone (811.0 mg, 2.301 mmol) was added dropwise. The resulting mixture was stirred overnight at room temperature. Saturated aqueous NH4Cl (20 mL) was added, and the reaction was quenched at room temperature. The resulting mixture was extracted with ELISA (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 and eluted with PE / EA (1:1) to obtain 4-(1-hydroxy-1-(1-trityl-1H-imidazole-4-yl)ethyl)indoline-1-carboxylate tert-butyl (500 mg) as a brown oily substance. (ES, m / z): [M+1] = 572.

[0276] 19.2 Under a nitrogen gas atmosphere, ethyl chloroglyoxylate (286.6 mg, 2.100 mmol) was added dropwise to a solution of 4-(1-hydroxy-1-(1-trityl-1H-imidazole-4-yl)ethyl)indoline-1-carboxylate tert-butyl (400 mg, 0.700 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 1 minute. Then, triethylamine (424.8 mg, 4.200 mmol) was added dropwise at 0°C. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. Elution with PE / EA (5:1) yielded 4-(1-(1-trityl-1H-imidazole-4-yl)vinyl)indoline-1-carboxylate tert-butyl (320 mg) as a yellow oil. (ES, m / z): [M+1] = 554.

[0277] 19.3 4-(1-(1-trityl-1H-imidazole-4-yl)vinyl)indoline-1-carboxylate tert-butyl (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 diatomaceous earth, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. 4-[1-[1-(trityl)imidazole-4-yl]ethyl]-2,3-dihydroindole-1-formate tert-butyl (150 mg, crude product) was obtained as a yellow solid. (ES, m / z): [M+1] = 556.

[0278] 19.4 4-[1-[1-(trityl)imidazole-4-yl]ethyl]-2,3-dihydroindole-1-tert-butyl formate (100 mg, 0.180 mmol) was dissolved in TFA (1 mL) and DCM (4 mL). 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 reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN-water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes, detector: ultraviolet 220 nm. 4-[1-(1H-imidazole-4-yl)ethyl]-2,3-dihydro-1H-indole (15.2 mg) was obtained. (ES, m / z): [M+1] = 214. 1 H NMR (400 MHz, Methanol-d4) δ 7.53 (s, 1H), 6.93 (t, J = 7.7 Hz, 1H), 6.72 (s, 1H), 6.54 (t, J = 7.1 Hz, 2H), 4.10 (q, J = 7.2 Hz, 1H), 3.42 (t, J = 8.3 Hz, 2H), 2.90 (ddq, J = 23.8, 15.8, 8.3 Hz, 2H), 1.54 (d, J = 7.2 Hz, 3H). Example 20: Preparation of N-(2,3-dihydro-1H-inden-4-yl)-1H-imidazole-4-amine

[0279] [ka]

[0280] 20.1 Under a nitrogen gas 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 overnight at 90°C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN-water (0.1% FA), gradient from 40% to 100%, for 10 minutes, detector: ultraviolet 254 nm. N-(2,3-dihydro-1H-inden-4-yl)-1-(trityl)imidazole-4-amine (70 mg) was obtained as a yellow solid. (ES, m / z): [M+1] = 442.

[0281] 20.2 Trifluoroacetic acid (6 mL) was added dropwise to a solution of N-(2,3-dihydro-1H-inden-4-yl)-1-(trityl)imidazole-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 preparative high-performance liquid chromatography 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 ~ 44% B, 10 min, Wavelength: 254 nm / 220 nm, Room temperature 1 (min): 4.7), to obtain N-(2,3-dihydro-1H-inden-4-yl)-1H-imidazole-4-amine (7.4 mg). (ES, m / z): [M+1] = 200. 1H NMR (400 MHz, Methanol-d4) δ 8.25 (s, 1H), 7.79 (s, 1H), 6.96 (t, J = 7.7 Hz, 1H), 6.70 (d, J = 7.3 Hz, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.80 (t, J = 7.3 Hz, 2H), 2.09 (p, J = 7.5 Hz, 2H). Example 21: Preparation of 7-(1-(1H-imidazole-4-yl)ethyl)-1-methylindoline

[0282] [ka]

[0283] 21.1 A solution of 7-[1-(1H-imidazole-4-yl)ethyl]-2,3-dihydro-1H-indole (500 mg, 2.344 mmol) in MeOH (10 mL) was mixed with formaldehyde (0.86 mL, 23.440 mmol) and AcOH (14.08 mg, 0.234 mmol), and the mixture was stirred for 30 minutes at 0°C under a nitrogen atmosphere. Then NaBH3CN (486.14 mg, 7.735 mmol) was added and stirring was continued for 1 hour. The resulting mixture was concentrated under reduced pressure and then purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: water-methanol (0.1% NH3H2O), gradient from 10% to 50% over 10 minutes, detector: UV 254 nm. 7-(1-(1H-imidazole-4-yl)ethyl)-1-methylindoline (57 mg) was obtained. (ES,m / z): [M+1] = 228. 1H NMR (400 MHz, Methanol-d4) δ 7.56 (d, J = 1.2 Hz, 1H), 6.97 (dq, J = 7.3, 1.2 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H), 6.66 (t, J = 1.1 Hz, 1H), 4.47 (q, J = 7.1 Hz, 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 = 7.1 Hz, 3H). Example 22: Preparation of 4-[1-(6-chloro-1H-inden-4-yl)ethyl]-1H-imidazole

[0284] [ka]

[0285] At 22.1°C, 7-bromo-5-chloro-2,3-dihydroinden-1-one (500 mg, 2.037 mmol) was added to a stirred solution of anhydrous THF (10 mL) / MeOH (5 mL) with NaBH4 (462.3 mg, 12.222 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, 5 mL of water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate (100 mL). The organic phases were combined and washed with saline solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain 7-bromo-5-chloro-2,3-dihydro-1H-inden-1-ol (400 mg) as a colorless oil. (ES, m / z): [M-18] = 231.

[0286] 22.2 7-Bromo-5-chloro-2,3-dihydro-1H-inden-1-ol (450 mg, 1.818 mmol), tert-butyldimethylchlorosilane (328.8 mg, 2.182 mmol), and imidazole (247.5 mg, 3.636 mmol) were dissolved in DCM (9 mL) and reacted with stirring at room temperature for 2 hours. After the reaction was complete, the resulting mixture was quenched with water and extracted with siRNA (3 × 100 mL). The organic layer was synthesized, washed with saline solution (1 × 100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE to obtain the white solid [(7-bromo-5-chloro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (500 mg).

[0287] At 22.3°C, under a nitrogen atmosphere, n-butyllithium (0.73 mL, 1.838 mmol, 2.5 M in n-hexane) was added 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) and stirred for 1 hour. Then, 1-[1-(triphenylmethyl)imidazole-4-yl]ethanone (431.56 mg, 1.225 mmol) was added in several portions. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. At room temperature, the reaction was quenched with saturated NH4Cl (aqueous solution), extracted with RINKAN (3 × 100 mL), washed with brine (1 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained product was purified by reverse-phase flash chromatography (under 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) to obtain 1-[3-[(tert-butyldimethylsilyl)oxy]-6-chloro-2,3-dihydro-1H-inden-4-yl]-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (350 mg) as a yellow oily substance. (ES, m / z): [M+1] = 635.

[0288] 22.4 1-[3-[(tert-butyldimethylsilyl)oxy]-6-chloro-2,3-dihydro-1H-inden-4-yl-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (486 mg, 0.765 mmol), TEA (464.5 mg, 4.590 mmol), and ethyl chloroglyoxylate (313.3 mg, 2.295 mmol) were dissolved in DCM (10 mL) and stirred at 0°C under a nitrogen atmosphere for 2 hours. The reaction was quenched at 0°C by adding water, and then extracted with CH2Cl2 (3 × 50 mL). The organic phase was washed with saline solution (1 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by reverse-phase flash chromatography under 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 oily substance. (ES, m / z): [M+1] = 617.

[0289] 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) (14694-95-2) (104.6 mg, 0.113 mmol) were dissolved in MeOH (6 mL) and stirred overnight at 50°C under a hydrogen atmosphere. 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 and eluted with PE / EA (5:1) to obtain 4-[1-[3-[(tert-butyldimethylsilyl)oxy]-6-chloro-2,3-dihydro-1H-inden-4-yl]ethyl]-1-(triphenylmethyl)imidazole (277 mg) as a yellow oily substance. (ES,m / z):[M+1]=619.

[0290] 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 under 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-imidazole-4-yl)ethyl]-2,3-dihydro-1H-inden-1-ol (277 mg) was obtained as a yellow oily substance. (ES,m / z):[M+1]=505.

[0291] 22.7 5-chloro-7-[1-(1-triphenylmethyl-1H-imidazole-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 gas atmosphere for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under 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 (400 MHz, Methanol-d4) δ 7.58 (d, J= 1.2 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.82 (s, 1H), 6.57 (dt, J = 5.7, 2.0 Hz, 1H), 4.43 (q, J = 7.2 Hz, 1H), 3.40 (d, J = 2.2 Hz, 2H), 1.61 (d, J = 7.2 Hz, 3H). Example 23: Preparation of 4-[(2H-chroman-8-yl)methyl]-1H-imidazole

[0292] [ka]

[0293] 23.1 At room temperature, 8-bromo-2,3-dihydro-1-benzopyran-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) were added to a 40 mL sealed tube. The resulting mixture was stirred overnight at 60°C under nitrogen gas protection. The mixture was cooled to room temperature. The resulting mixture was extracted with siRNA (3 × 100 mL). The combined organic layers were washed with saline solution (3 × 100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain the white solid 8-bromo-2,3-dihydrospiro[1-benzopyran-4,2'-[1,3]dioxolane] (270 mg). (ES,m / z): [M+1]=271,273.

[0294] 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), and n-butyllithium (2.43 mL, 6.086 mmol, 1.1 eq, 2.5 M in n-hexane) was added and the reaction was carried out for 1 hour at -78°C under a nitrogen atmosphere. Then, a solution of 1-(triphenylmethyl)imidazole-4-carbaldehyde (2.06 g, 6.086 mmol) in tetrahydrofuran (10 mL) was added dropwise at -78°C. The resulting mixture was stirred overnight at room temperature under nitrogen gas conditions. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (2 mL), and the resulting mixture was extracted with ethyl acetate (3 × 200 mL). The organic phases were combined and washed with saline solution (3 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: aqueous acetonitrile (10 mmol / L NH4HCO3), gradient of 50% to 70% over 10 minutes, detector: UV 220 nm. 2,3-dihydrospiro[1-benzopyran-4,2'-[1,3]dioxolan]-8-yl[1-(triphenylmethyl)imidazole-4-yl]methanol (1.3 g) was obtained as a white solid. (ES, m / z): [M+1] = 531.

[0295] 23.3 At room temperature, 2,3-dihydrospiro[1-benzopyran-4,2'-[1,3]dioxolan]-8-yl[1-(triphenylmethyl)imidazole-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) were added to a 20 mL sealed tube. The resulting mixture was stirred overnight at 70°C under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile aqueous solution (10 mmol / L NH4HCO3), 10% to 20% gradient over 10 minutes, detector: UV 220 nm. 8-(1H-imidazole-4-ylmethyl)-2,3-dihydro-1-benzopyran-4-one (30 mg) was obtained. (ES,m / z): [M+1]=229.

[0296] At 23.4°C, NaBH4 (124.30 mg, 3.286 mmol) was added dropwise to a stirred solution of 8-(1H-imidazole-4-ylmethyl)-2,3-dihydro-1-benzopyran-4-one (375 mg, 1.643 mmol) in THF (5 mL) and MeOH (5 mL). The resulting product was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched at room temperature with water / ice (2 mL). The resulting product was concentrated under reduced pressure and purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, liquid phase: acetonitrile aqueous solution (10 mmol / L NH4HCO3), gradient from 0% to 10% over 10 minutes, detector: ultraviolet 220 nm. 8-(1H-imidazole-4-ylmethyl)-3,4-dihydro-2H-1-benzopyran-4-ol (355 mg) was obtained. (ES,m / z): [M-1]=229.

[0297] 23.5 At room temperature, 8-(1H-imidazole-4-ylmethyl)-3,4-dihydro-2H-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) were added to a 20 mL sealed tube and stirred overnight at 75°C under a nitrogen atmosphere. The obtained product was concentrated under reduced pressure to obtain the crude product (60 mg), which was then purified by preparative HPLC under the following conditions: (Column: XBridge Prep Phenyl OBD column 19 × 250 mm, 5 μm, Mobile phase A: Water (0.1% FA), Mobile phase B: MeCN, Flow rate: 60 mL / min, Gradient: 6% B to 21% B in 10 minutes, Wavelength: 254 nm / 220 nm, Room temperature, 1 (min): 5.3), yielding 4-[(2H-chroman-8-yl)methyl]-1H-imidazolium formate (22.7 mg). (ES, m / z): [M+1] = 213. 1 H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.19 (s, 1H), 6.97 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 7.3 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 9.8 Hz, 1H), 5.81 (dt, J = 9.9, 3.6 Hz, 1H), 4.87 - 4.69 (m, 2H), 3.90 (s, 2H). Example 24: Preparation of 4-[1-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)ethyl]-1H-imidazole

[0298] [ka]

[0299] 24.1 Under nitrogen gas protection, 2,6-dibromo-4-fluorophenol (2 g, 7.410 mmol) was dissolved in DMF (30 mL), K2CO3 (2.1 g, 14.820 mmol) was added, and the mixture was stirred for 15 minutes. Then, dibromoethane (2.1 g, 11.115 mmol) was added dropwise. The resulting mixture was stirred overnight at room temperature. After dilution with water (100 mL), it was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined and washed with water (1 × 100 mL), and dried over anhydrous Na2SO4. 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 of 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 oily substance.

[0300] At 24.2°C -78°C, under a nitrogen atmosphere, 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 for 1 hour. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched at room temperature with saturated NH4Cl (aqueous solution) and extracted with CH2Cl2 (3 × 100 mL). The organic phases were combined and washed with water (1 × 100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography under 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 oily substance.

[0301] 24.3 At -78°C, under a nitrogen atmosphere, 7-bromo-5-fluoro-2,3-dihydro-1-benzofuran (155 mg, 0.714 mmol) was added to a solution of THF (3 mL) to which n-butyllithium (0.4 mL, 1.071 mmol, 2.5 M in n-hexane) was added and the mixture was stirred for 30 minutes. Then, at -78°C, 1-[1-(triphenylmethyl)imidazole-4-yl]etanone (251.7 mg, 0.714 mmol) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched by adding saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The organic layers were washed with water (1 × 100 mL), dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and then purified by reverse-phase flash chromatography under 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-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (100 mg) was obtained as a white solid. (ES, m / z): [M+1] = 491.

[0302] 24.4 1-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)-1-[1-(triphenylmethyl)imidazole-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 a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under vacuum and purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, liquid phase, MeCN-water (10 mmol / L NH4HCO3), gradient of 10% to 30% over 10 minutes, detector: UV 254 nm. 4-[1-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)vinyl]-1Himidazole (42 mg) was obtained. (ES, m / z):[m+1]=231.

[0303] 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 diatomaceous earth pad, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain the 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 over 10 minutes, wavelength: 254 nm / 200 nm, room temperature, 1 (min): 10.63), to obtain 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 (400 MHz, Methanol-d4) δ 7.56 (d, J = 1.2 Hz, 1H), 6.83 - 6.74 (m, 2H), 6.51 (dd, J = 10.3, 2.7 Hz, 1H), 4.55 (td, J = 8.8, 1.6 Hz, 2H), 4.26 (q, J = 7.2 Hz, 1H), 3.27 - 3.12 (m, 2H), 1.52 (d, J = 7.2 Hz, 3H). Example 25: Preparation of 4-[1-(1-benzofuran-7-yl)ethyl]-1H-imidazole

[0304] [ka]

[0305] 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-butyllithium (1.52 mL, 3.807 mmol, 2.5 M in n-hexane) was added to the mixture over 1 minute. The resulting mixture was stirred further at -78°C for 1 hour. At -78°C, 1-[1-(triphenylmethyl)imidazole-4-yl]etanone (983.8 mg) was added dropwise to the mixture over 2 minutes. The resulting mixture was stirred overnight at room temperature. At room temperature, the reaction was quenched by adding NH4Cl (aqueous solution) (10 mL). The resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic phase was washed with water (1 × 50 mL), dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and then purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile aqueous solution (10 mmol / L NH₄HCO₃), gradient of 70% to 75% over 20 min, detector: UV 254 nm, yielding 1-(1-benzofuran-7-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (400 mg). (ES, m / z): [M] = 470. 1 H NMR (400 MHz, Chloroform-d) δ 7.54 (dd, J = 7.6, 1.2 Hz, 1H), 7.48 (td, J= 3.4, 1.2 Hz, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.34 - 7.30 (m, 9H), 7.22 (t, J = 7.7 Hz, 1H), 7.14 - 7.09 (m, 6H), 6.85 (d, J = 1.4 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 5.29 (s, 1H), 2.01 (s, 3H). 25.2 At room temperature, triethylsilane (2 mL) was added to a solution of 1-(1-benzofuran-7-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (400 mg, 0.893 mmol) and TFA (2 mL) in DCM (8 mL), and the mixture was stirred overnight. The resulting mixture was concentrated under reduced pressure. 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 of 20% to 25% over 20 minutes, detector: UV 254 nm, yielding 4-[1-(1-benzofuran-7-yl)vinyl]-1Himidazole (130 mg). (ES, m / z): [2M+1] = 421.

[0306] 25.3 In a pressure tank, 15 mg of Pd / C (10% w / t) was added to a solution of 4-[1-(1-benzofuran-7-yl)vinyl]-1H-imidazole (120 mg, 0.571 mmol) in MeOH (3 mL). The mixture was hydrogenated at room temperature under a hydrogen pressure of 30 psi for 1 hour. After monitoring the completion of the reaction by LC-MS, the resulting product was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the crude product (120 mg). 4-[1-(1-benzofuran-7-yl)ethyl]-1H-imidazole (20.7 mg) was obtained 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 within 10 min; wavelength: 254 nm / 220 nm; room temperature; 1 (min): 10.63 / 11.72). (ES, m / z): [M+1] = 213. 1H NMR (400 MHz, Methanol-d4) δ 7.71 (t, J = 2.5 Hz, 1H), 7.56 (d, J = 1.3 Hz, 1H), 7.44 (dt, J = 7.7, 1.6 Hz, 1H), 7.13 (td, J = 7.6, 1.8 Hz, 1H), 7.03 (dd, J = 7.5, 1.2 Hz, 1H), 6.85 - 6.77 (m, 2H), 4.67 (q, J = 7.2 Hz, 1H), 1.69 (dd, J = 7.3, 1.6 Hz, 3H). Example 26: Preparation of 4-[1-(6-fluoro-3H-inden-4-yl)ethyl]-1H-imidazole

[0307] [ka]

[0308] 26.1 A mixed solution of 4-bromo-6-fluoro-2,3-dihydroinden-1-one (1 g, 4.366 mmol, 1 equivalent) in THF (10 mL) and MeOH (5 mL) was treated with NaBH4 (0.66 g, 17.464 mmol, 4 equivalents) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched at room temperature by adding water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with water (1 × 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 and eluted with PE / EA (5:1) to obtain colorless oily 4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-ol (950 mg). (ES,m / z):[M]=230,232.

[0309] 26.2 At room temperature and under a nitrogen atmosphere, tert-butyldimethylchlorosilane (704.5 mg, 4.674 mmol) was added 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). 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 and eluted with PE / EA (12:1) to obtain colorless oily [(4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (1.1 g).

[0310] 26.3 At -78°C and under a nitrogen atmosphere, 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 mixed with n-butyllithium (2.08 mL, 5.213 mmol, 2.5 M in n-hexane) and reacted for 40 minutes. Then, at -78°C, a solution of 1-[1-(triphenylmethyl)imidazole-4-yl]ethanone (1.35 g, 3.823 mmol) in THF (5 mL) was added dropwise, and the mixture was stirred overnight under a nitrogen atmosphere and at room temperature. At room temperature, the reaction was quenched by adding saturated aqueous NH4Cl (50 mL). The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with water (1 × 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 and eluted with PE / EA (1:1) to obtain 1-[1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (1.4 g) as a white solid. (ES, m / z): [M+1]=619.

[0311] 26.4 At room temperature and under a nitrogen gas atmosphere, a solution of 1-[1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]-1-[1-(triphenylmethyl)imidazole-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, and then ethyl chloroglyoxylate (0.99 g, 7.7272 mmol) was added dropwise at 0°C. The resulting mixture was stirred overnight at room temperature under a nitrogen gas atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain yellow oily 4-[1-[1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]vinyl]-1-(triphenylmethyl)imidazole (1.1 g). (ES, m / z): [M+1]=601.

[0312] 26.5 At room temperature, 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, 2.496 mmol) in MeOH (15 mL) was treated with Pd / C (0.13 g, 10% w / t). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 50 minutes. The resulting mixture was filtered through diatomaceous earth, and the filtrate was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain the white solid 4-[1-[1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl]ethyl]-1-(triphenylmethyl)imidazole (1.2 g). (ES, m / z): [M+1]=603.

[0313] 26.6 At room temperature, 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). The resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature. At room temperature, the reaction was quenched by adding water (20 mL). The resulting mixture was extracted with siRNA (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 and eluted with PE / EA (5:1) to obtain 6-fluoro-4-[1-[1-(triphenylmethyl)imidazole-4-yl]ethyl]-2,3-dihydro-1H-inden-1-ol (443 mg) as a white solid. (ES, m / z): [M+1]=489.

[0314] 26.7 At room temperature, a solution of 6-fluoro-4-[1-[1-(triphenylmethyl)imidazole-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). The resulting mixture was stirred at 70°C under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile in water (0.1% NH3H2O ​​+ 10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes, detector: UV 220 nm. 4-[1-(6-fluoro-3H-inden-4-yl)]ethyl]-1H-imidazole (16 mg) was obtained. (ES, m / z): [M+1]=229. 1H NMR (400 MHz, Methanol-d4) δ 7.57 (d, J = 1.2 Hz, 1H), 6.95 (dd, J = 8.7, 2.4 Hz, 1H), 6.87 - 6.82 (m, 2H), 6.70 (dd, J = 10.9, 2.4 Hz, 1H), 6.64 (dt, J = 5.6, 2.1 Hz, 1H), 4.46 - 4.19 (m, 1H), 3.36 (dq, J = 23.3, 1.8 Hz, 1H), 3.26 (dq, J = 23.2, 1.8 Hz, 1H), 1.61 (d, J = 7.2Hz, 3H). Example 27: Preparation of 4-[1-(benzothiophen-7-yl)ethyl]-1H-imidazole

[0315] [ka]

[0316] At 27.1°C, a mixture of 2-bromothiophenol (1.7 g, 8.991 mmol) and NaOH (359.6 mg, 8.991 mmol) in water (10 mL) was mixed with 2-bromoacetic acid (1.2 g, 8.991 mmol) and an aqueous solution of Na2CO3 (952.9 mg, 8.991 mmol) (40 mL) was added dropwise. The resulting mixture was stirred at 100°C for 1.5 hours. The mixture was acidified with HCl (aq.) until pH=1. The resulting mixture was extracted with SiO2 (2 × 50 mL), and the combined organic layer was washed with H2O (3 × 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 pale yellow solid. The crude product was used directly in the next step without further purification. (ES, m / z): [M-1] = 245, 247 27.2 Under a nitrogen gas 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 in DCM (30 mL) and stirred at 0°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL). At 0°C, AlCl3 (4.2 g, 31.564 mmol) was slowly added to the mixture (over 5 minutes or more). The mixture was then transferred to room temperature and stirred overnight. At 0°C, HCl (aq.) (0.5 mL) was added to quench the reaction. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL), and the combined organic layer was washed with H2O (1 × 50 mL) to obtain 7-bromo-2H-1-benzothiophen-3-one (375.0 mg), which was a pink solid. (ES, m / z): [M-1] = 227, 229. 27.3 Under a nitrogen gas atmosphere, 7-bromo-2H-1-benzothiophen-3-one (375.0 mg, 1.637 mmol), Et3SiH (3.8 mL), and BF3Et2O (3.8 mL) were added to a solution in DCM (9 mL) and stirred overnight at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with CH2Cl2 (3 × 100 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 and eluted with PE / EA (3:1) to obtain colorless oily 7-bromobenzothiophene (230.0 mg). (ES, m / z): M = 212, 214. Under a nitrogen gas atmosphere at 27.4°C -78°C, n-butyllithium (0.6 mL, 1.603 mmol, 2.5 M in n-hexane) was added dropwise to a solution of 7-bromobenzothiophene (230.0 mg, 1.069 mmol) in THF (5 mL), and the mixture was stirred for 1 hour. Then, 1-[1-(trityl)imidazole-4-yl]etanone (376.8 mg, 1.069 mmol) was added dropwise to the mixture, and the mixture was transferred to room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl, and the resulting mixture was extracted with siRNA (3 × 50 mL). The combined organic layers were washed with H2O (3 × 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 and eluted with PE / EA (3:1) to obtain 210 mg of yellow oily 1-(1-benzothiophen-7-yl)-1-[1-(trityl)imidazole-4-yl]ethanol. (ES, m / z): [M+1] = 488. 27.5 Under a nitrogen gas atmosphere, 1-(1-benzothiophen-7-yl)-1-[1-(trityl)imidazole-4-yl]ethanol (210 mg, 0.432 mmol, 1 equivalent), TFA (492.05 mg, 4.320 mmol), and Et3SiH (250.89 mg, 2.160 mmol) were added to a solution in DCM (4 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water (0.1% FA), gradient from 10% to 40%, 10 min, detector: UV 254 nm. Yellow, oily 4-[1-(1-benzothiophen-7-yl)vinyl]-1H-imidazole (50 mg) was obtained. (ES, m / z): [M+1] = 227. 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 overnight at room temperature. The resulting mixture was filtered through a Celite pad, and the filtrate was washed with MeOH (3 × 10 mL). 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 (0.1% FA), 10% to 30% gradient, 10 min, detector: UV 254 nm. Colorless oily 4-[1-(benzothiophen-7-yl)ethyl]-1H-imidazole (15.9 mg) was obtained. (ES, m / z): [M+1] = 229. 1 H NMR (400 MHz, Methanol-d4) δ 8.84 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.49 (s, 1H), 7.38 - 7.25 (m, 2H), 7.23 (s, 1H), 4.69 (q, J = 7.1 Hz, 1H), 1.82 (d, J = 7.1 Hz, 3H). Example 28: Preparation of 4-[1-(1-ethyl-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole

[0317] [ka]

[0318] 28.1 Under a nitrogen gas atmosphere, 4-bromo-2,3-dihydroinden-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 hours. The mixture was quenched with ice water at 0°C. The resulting mixture was extracted with RINKAN (3 × 100 mL), and the combined organic layer was washed with saline solution (3 × 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 and eluted with PE / EA (12:1) to obtain yellow oily 4-bromo-1-methylene-2,3-dihydroinden (3.8 g). (ES, m / z): [M] = 208. 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 the mixture was stirred for 20 minutes. Then, diiodomethane (5.25 g, 19.610 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 20 minutes. Finally, at 0°C, a solution of 4-bromo-1-methylene-2,3-dihydroindene (820 mg, 3.922 mmol) in DCM (10 mL) was added dropwise to the above mixture and the mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated NH4Cl (30 mL), the resulting mixture was extracted with ELISA (2 × 70 mL), the combined organic layers were washed with saline (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 and eluted with PE / EA (4:1) to obtain colorless oily 4'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (250 mg). (ES, m / z):[M]=222. Under a nitrogen gas atmosphere at 28.3°C -78°C, 4'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (250 mg, 1.121 mmol) was added to THF (5 mL) and n-butyllithium (0.67 mL, 1.681 mmol) was added dropwise. After stirring for 1 hour, 1-[1-(trityl)imidazole-4-yl]etanone (473.9 mg, 1.345 mmol) was added dropwise to the mixture and the mixture was transferred to room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl (15 mL), and the resulting mixture was extracted with ELISA (2 × 50 mL). The combined organic layers were washed with saline (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water (10 mmol / L NH4HCO3), gradient from 30% to 80%, 10 min, detector: UV 220 nm. 1-(2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-yl)-1-[1-(trityl)imidazole-4-yl]ethanol (300 mg) was obtained as a pale yellow solid. (ES, m / z): [M+1] = 497. 28.4 Under a nitrogen gas atmosphere, 1-(2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-yl)-1-[1-(trityl)imidazole-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 DCM (3 mL) solution and stirred overnight at room temperature. The mixture 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), 40%-70% gradient, 10 min, detector: UV 220 nm. 4-[1-(1-ethyl-2,3-dihydro-1H-inden-4-yl)vinyl]-1H-imidazole (80 mg) was obtained as an off-white solid. (ES,m / z):[M+1]=239. 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 hours. The resulting mixture was filtered through a Celite pad, and the filtrate was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, liquid phase: acetonitrile-water (10 mmol / L NH4HCO3), 30% to 70% gradient, 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 (400 MHz, Methanol-d4) δ 7.56 (s, 1H), 7.12 - 6.98 (m, 2H), 6.90 (dd, J = 11.5, 7.4 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 4.18 (d, J = 7.3 Hz, 1H), 3.09 - 2.81 (m, 2H), 2.74 (tt, J = 15.7, 8.1 Hz, 1H), 2.26 (dq, J = 8.2, 4.1 Hz, 1H), 1.87 (ddd, J = 12.4, 7.4, 4.8 Hz, 1H), 1.66 (s, 1H), 1.55 (td, J = 5.7, 3.0 Hz, 3H), 1.41 (q, J = 12.3, 9.5 Hz, 1H), 0.98 (td, J = 7.4, 3.7 Hz, 3H). Example 29: Preparation of 4-[(3-ethyl-2,3-dihydro-1H-inden-4-yl)methyl]-1H-imidazole

[0319] [ka]

[0320] 29.1 Under a nitrogen atmosphere at 0°C, t-BuOK (5.21 mL, 1 M in THF) was added dropwise to a solution of 7-bromo-2,3-dihydroinden-1-one (1 g, 4.738 mmol) and methyltriphenylphosphonium bromide (5.92 g, 16.583 mmol) in THF (5 mL). The mixture was transferred to room temperature and stirred for 3 hours. The reaction was quenched by adding ice water at 0°C. The resulting mixture was extracted with siRNA (3 × 10 mL), and the combined organic layers were washed with saline (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 and eluted with PE / EA (10:1) to obtain yellow oily 7-bromo-1-methylene-2,3-dihydroinden (657 mg). (ES, m / z): [M] = 208, 210. 29.2 Under a nitrogen gas atmosphere 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 minutes. Then, diiodomethane (1280.9 mg, 4.785 mmol) was added dropwise at room temperature and stirred for 20 minutes. Finally, at room temperature, a solution of 7-bromo-1-methylene-2,3-dihydroindene (500 mg, 2.563 mmol) in DCM (10 mL) was added dropwise to the above mixture and stirred overnight at room temperature. The reaction was quenched by adding saturated NH4Cl (50 mL), the resulting mixture was extracted with siRNA (1 × 50 mL), the combined organic layers were washed with saline (1 × 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 and eluted with PE / EA (5:1) to obtain pale yellow oily 7'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (170 mg). (ES, m / z): [M] = 222, 224. Under a nitrogen gas atmosphere at -78°C, n-butyllithium (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), and the mixture was stirred for 1 hour. Then, 1-[1-(trityl)imidazole-4-yl]etanone (682.5 mg, 2.017 mmol) was added dropwise to the mixture, and the mixture was transferred to room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl (20 mL), and the resulting mixture was extracted with siRNA (3 × 20 mL). The combined organic layers were washed with saline (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 and eluted with PE / EA (1:1) to obtain 2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7'-yl[1-(trityl)imidazole-4-yl]methanol (450 mg) as an off-white solid. (ES,m / z): [M+1]=483. 29.4 Under a nitrogen gas atmosphere, 2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7'-yl[1-(trityl)imidazole-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 in DCM (5 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue (160 mg) was purified by preparative high-performance liquid chromatography 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 ~ 41% B; 10 min; Wavelength: 254 nm / 220 nm; Room temperature; 1 (min): 10.23 / 12.13; Colorless oily 4-[(3-ethyl-2,3-dihydro-1H-inden-4-yl)methyl]-1H-imidazole (21.7 mg) was obtained. (ES, m / z): [M+1] = 227. 1H NMR (400 MHz, Methanol-d4) δ 7.55 (d, J = 1.2 Hz, 1H), 7.03 (d, J = 4.6 Hz, 2H), 6.91 (q, J = 4.1 Hz, 1H), 6.59 (s, 1H), 4.07 - 3.79 (m, 2H), 3.11 (dddd, J = 9.6, 8.0, 3.4, 1.5 Hz, 1H), 2.97 (ddd, J = 15.8, 10.5, 7.9 Hz, 1H), 2.75 (ddd, J = 15.9, 8.9, 1.8 Hz, 1H), 2.16 - 1.83 (m, 2H), 1.56 (dqd, J = 14.8, 7.5, 3.2 Hz, 1H), 1.44 - 1.20 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H). Example 30: Preparation of 4-[1-(2,3-dihydrobenzofuran-4-yl)ethyl]-1H-imidazole

[0321] [ka]

[0322] Under a nitrogen gas atmosphere at -78°C, n-butyllithium (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), and the mixture was stirred for 1 hour. Then, 1-[1-(trityl)imidazole-4-yl]etanone (584.31 mg, 1.658 mmol) was added dropwise to the mixture, and the mixture was transferred to room temperature and stirred overnight. Saturated NH4Cl (20 mL) was added to quench the reaction, and the resulting mixture was extracted with siRNA (3 × 20 mL). The combined organic layers were washed with saline (1 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water (10 mmol / L NH4HCO3), 50%-55% gradient, 10 min, detector: UV 254 nm. 1-(2,3-dihydro-1-benzofuran-4-yl)-1-[1-(trityl)imidazole-4-yl]ethanol (430 mg) was obtained as a yellow solid. (ES, m / z): [M+1] = 473. 30.2 Under a nitrogen gas atmosphere, 1-(2,3-dihydro-1-benzofuran-4-yl)-1-[1-(trityl)imidazole-4-yl]ethanol (430 mg, 0.910 mmol), TFA (1 mL), and Et3SiH (1 mL) were added to a solution in DCM (8 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water (0.1% NH3, H2O), 20%-25% gradient, 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. 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 hours. The resulting mixture was filtered through a Celite pad, and the filtrate was washed with MeOH (1 × 10 mL). 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 (0.1% NH3H2O), 20%-25% gradient, 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 (400 MHz, Methanol-d4) δ 7.55 (d, J = 1.2 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.76 (d, J = 1.1 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.56 (d, J = 7.9 Hz, 1H), 4.48 (t, J = 8.7 Hz, 2H), 4.10 (q, J = 7.2 Hz, 1H), 3.21 - 2.93 (m, 2H), 1.56 (d, J = 7.2 Hz, 3H). Example 31: Preparation of 4-[1-(2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole

[0323] [ka]

[0324] 31.1 Under a nitrogen gas atmosphere at -78°C, n-butyllithium (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), and after stirring for 1 hour, 1-[1-(trityl)imidazole-4-yl]etanone (590.15 mg, 1.674 mmol) was added dropwise to the mixture, and the mixture was transferred to room temperature and stirred overnight. Saturated NH4Cl (20 mL) was added to quench the reaction, and the resulting mixture was extracted with siRNA (3 × 20 mL). The combined organic layers were washed with saline (1 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water (10 mmol / L NH4HCO3), 70%-75% gradient, 10 min, detector: UV 254 nm. 1-(2,3-dihydro-1H-inden-4-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (530 mg) was obtained as a yellow solid. (ES, m / z): [M+1]=471. 31.2 Under a nitrogen gas atmosphere, 1-(2,3-dihydro-1H-inden-4-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (530 mg, 1.126 mmol), TFA (2 mL), and Et3SiH (2 mL) were added to a solution in DCM (6 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water (0.1% FA), 20%-25% gradient, 15 min, detector: UV 200 nm. A colorless oily 4-[1-(2,3-dihydro-1H-inden-4-yl)vinyl]-1H-imidazole (170 mg) was obtained. (ES, m / z): [M+1]=211. 31.3 Under a hydrogen atmosphere, 4-[1-(2,3-dihydro-1H-inden-4-yl)vinyl]-1H-imidazole (180 mg, 0.856 mmol) and 10% Pd / C (72.88 mg, 50% w / t) were added to MeOH solution (5 mL) and stirred at room temperature for 3 hours. The resulting mixture was filtered through a Celite pad, and the filtrate was washed with MeOH (3 × 10 mL). 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 (0.1% FA), 20%-25% gradient, 10 min, detector: UV 254 nm. Yellow oily 4-[1-(2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole (97.2 mg) was obtained. (ES, m / z): [M+1] = 213. 1 H NMR (400 MHz, Methanol-d4) δ 8.47 (d, J = 1.4 Hz, 1H), 7.20 (d, J = 1.3 Hz, 1H), 7.16 - 7.00 (m, 2H), 6.87 (dd, J = 6.3, 2.4 Hz, 1H), 4.30 (q, J = 7.2 Hz, 1H), 2.87 (dq, J = 19.2, 7.9 Hz, 4H), 2.06 (p, J = 7.4 Hz, 2H), 1.61 (d, J = 7.2 Hz, 3H). 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 obtain (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).

[0325] (R)-4-[1-(2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole(31-a) (ES, m / z): [M+1]=213. 1 H NMR (400 MHz, Chloroform-d) δ 7.43 - 7.38 (m, 1H), 7.12 - 7.02 (m, 2H), 6.91 - 6.84 (m, 1H), 6.72 (s, 1H), 4.17 (q, J = 7.1 Hz, 1H), 2.97 - 2.69 (m, 4H), 2.10 - 1.89 (m, 2H), 1.57 (d, J = 7.2 Hz, 3H). (S)-4-[1-(2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole(31-b) (ES, m / z): [M+1]=213. 1 H NMR (400 MHz, Chloroform-d) δ 9.41 (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 = 7.1 Hz, 1H), 2.95 - 2.68 (m, 4H), 2.08 - 1.86 (m, 2H), 1.56 (d, J = 7.2 Hz, 3H). Example 32: Preparation of 4-[1-(2-methyl-2,3-dihydrobenzofuran-7-yl)ethyl]-1H-imidazole

[0326] [ka]

[0327] 32.1 In an 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 hour. Then, within 1 minute, allyl bromide (2.31 g, 19.074 mmol) was added to the mixture in several portions. The resulting mixture was stirred overnight at room temperature. Water (20 mL) was added to quench the reaction, and the mixture was extracted with SiO2 (3 × 50 mL). The combined organic layer was washed with water (1 × 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 and eluted with PE / EA (5:1) to obtain colorless oily 1-bromo-2-(prop-2-ene-1-oxy)benzene (2 g). (ES, m / z): [M] = 212, 214. 32.2 In an air atmosphere, 1-bromo-2-(prop-2-en-1-oxy)benzene (1 g, 4.693 mmol) and diethylaluminum chloride (0.85 g, 7.039 mmol) were added to a mixture of hexane (14 mL) and stirred at room temperature for 2 hours. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ELISA (3 × 50 mL). The combined organic layer was washed with water (1 × 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 and eluted with PE / EA (5:1) to obtain 2-bromo-6-(prop-2-en-1-yl)phenol (800 mg) as a yellow solid. (ES, m / z): [M] = 212, 214. 32.3 Under a nitrogen gas 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 hours. After the mixture was cooled to room temperature, it was diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (1 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water (0.1% NH₃, H₂O), 45%-50% gradient, 10 min, detector: UV 254 nm. A colorless oily solution of 7-bromo-2-methyl-2,3-dihydro-1-benzofuran (100 mg) was obtained. (ES, m / z): [M] = 212, 214. Under a nitrogen gas atmosphere at 32.4°C -78°C, n-butyllithium (0.28 mL, 0.704 mmol, 2.5 M in n-hexane) was added dropwise to 7-bromo-2-methyl-2,3-dihydro-1-benzofuran (100 mg, 0.469 mmol) in THF (4 mL) solution, and the mixture was stirred for 1 hour. Then, 1-[1-(trityl)imidazole-4-yl]etanone (181.95 mg, 0.516 mmol) was added dropwise to the mixture, and the mixture was transferred to room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl (20 mL), and the resulting mixture was extracted with siRNA (3 × 20 mL). The combined organic layers were washed with saline (1 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water (10 mmol / L NH4HCO3), 50%-55% gradient, 10 min, detector: UV 254 nm. 1-(2-methyl-2,3-dihydro-1-benzofuran-7-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (80 mg) was obtained as a yellow solid. (ES, m / z): [M+1] = 487. 32.5 Under a nitrogen gas atmosphere, 1-(2-methyl-2,3-dihydro-1-benzofuran-7-yl)-1-[1-(trityl)imidazole-4-yl]ethanol (80 mg, 0.164 mmol), TFA (1 mL), and Et3SiH (1 mL) were added to a solution in DCM (2 mL) and stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, mobile phase: acetonitrile-water (0.1% FA), 20%-25% gradient, 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. 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 hours. The resulting mixture was filtered through a Celite pad, and the filtrate cake was washed with MeOH (1 × 10 mL). 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 (0.1% NH3H2O), 20%-25% gradient, 10 min, detector: UV 254 nm. A colorless oily 4-[1-(2-methyl-2,3-dihydrobenzofuran-7-yl)ethyl]-1H-imidazole (14.4 mg) was obtained. (ES, m / z): [M+1] = 229. 1 H NMR (400 MHz, Chloroform-d) δ 7.75 (s, 1H), 7.04 - 6.97 (m, 1H), 6.90 - 6.83 (m, 1H), 6.81 (s, 1H), 6.74 (t, J = 7.4 Hz, 1H), 4.97 - 4.81 (m, 1H), 4.29 (p, J = 7.0 Hz, 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). Example 33: Preparation of 4-[1-(2H-thiochroman-8-yl)ethyl]-1H-imidazole

[0328] [ka]

[0329] 33.1 In an air atmosphere, 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 hours. Water was added to quench the reaction, and the resulting mixture was extracted with SiO4 (3 × 100 mL). The combined organic layer was washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain colorless oily 8-bromo-3,4-dihydro-2H-1-thiochroman-4-ol (1.9 g). (ES, m / z): [M-18] = 227, 229. 33.2 In a room temperature air atmosphere, tert-butyldimethylchlorosilane (1.3 g, 8.812 mmol) was added in several portions 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). The resulting mixture was stirred overnight. Water (10 mL) was added to quench the reaction, and the resulting mixture was extracted with phenylethylamine (3 × 100 mL). The combined organic layer was washed with water (3 × 100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain a colorless oily [(8-bromo-3,4-dihydro-2H-1-thiochroman-4-yl)oxy](tert-butyl)dimethylsilane (2.2 g).

[0330] Under a nitrogen gas atmosphere at -78°C, n-butyllithium (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), and the mixture was stirred for 1 hour. Then, a solution of 1-[1-(trityl)imidazole-4-yl]etanone (2.8 g, 7.791 mmol) in THF (10 mL) was added dropwise to the mixture, and the mixture was transferred to room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl, and the resulting mixture was extracted with SiO4 (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. A colorless oily solution, 1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-thiochroman-8-yl)-1-[1-(trityl)imidazole-4-yl]ethanol (3.6 g), was obtained. (ES, m / z):[M+1]=634. 33.4 In an air atmosphere at 0°C, 1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-thiochroman-8-yl)-1-[1-(trityl)imidazole-4-yl]ethanol (4.6 g, 7.481 mmol) and TEA (4.54 g, 44.886 mmol) were added to a solution in DCM (400 mL), and ethyl chlorooxoethyl (3.06 g, 22.443 mmol) was added dropwise. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-TLC (PE / EA 8:1) to obtain yellow oily 4-(1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-thiochroman-8-yl)vinyl)-1-(trityl)imidazole (3.5 g). (ES, m / z): [M+1] = 615. 33.5 Under a hydrogen atmosphere, 4-(1-(4-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-1-thiochroman-8-yl)vinyl)-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 hours. The resulting mixture was filtered through a Celite pad, and the filtrate 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: column: C18 silica gel, liquid phase: acetonitrile-water (0.1% NH3H2O ​​+ 10 mmol / L NH4HCO3), gradient from 10% to 40%, 10 min, detector: UV 254 nm. A colorless, oily solution of 4-(1-(4-((tert-butyldimethylsilyl)oxy)thiochroman-8-yl)ethyl)-1-trityl-1H-imidazole (220 mg) was obtained. (ES, m / z):[M+1]=617. 33.6 Under a nitrogen gas atmosphere, 4-(1-(4-((tert-butyldimethylsilyl)oxy)thiochroman-8-yl)ethyl)-1-trityl-1H-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 hour. The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, liquid phase: acetonitrile-water (10 mmol / L NH4HCO3), gradient from 10% to 50%, 10 min, detector: UV 254 nm. A yellow, oily solution of 8-(1-[1-(triphenylmethyl)imidazole-4-yl]ethyl-3,4-dihydro-2H-1-benzothiopyran-4-ol (160 mg) was obtained. (ES,m / z):[M+1]=504. 33.7 Under a nitrogen gas atmosphere, 8-(1-[1-(triphenylmethyl)imidazole-4-yl]ethyl-3,4-dihydro-2H-1-benzothiopyran-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 hours. The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography under the following conditions: column: C18 silica gel, liquid phase: acetonitrile-water (10 mmol / L NH4HCO3), 10% to 50% gradient, 10 min, detector: UV 254 nm. 4-[1-(2H-thiochroman-8-yl)ethyl]-1H-imidazolium formate (3.5 mg) was obtained. (ES, m / z): [M+1] = 243. 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.72 (d, J = 10.2 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.79 (s, 1H), 6.48 (d, J = 10.1 Hz, 1H), 5.94 (dt, J = 10.0, 5.0 Hz, 1H), 4.55 (q, J = 7.0 Hz, 1H), 3.44 - 3.28 (m, 2H), 1.58 (d, J = 7.1 Hz, 3H). Example 34: Preparation of 4-[1-(5-fluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-1H-imidazole

[0331] [ka]

[0332] 34.1 At room temperature, triethylsilane (888.4 mg, 7.640 mmol) was added to a solution of 7-bromo-6-fluoro-2,3-dihydroinden-1-one (700 mg, 3.056 mmol) in trifluoroacetic acid (3 mL). At room temperature, the resulting mixture was stirred overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain colorless oily 4-bromo-5-fluoro-2,3-dihydro-1H-inden (320 mg). (ES, m / z): [M] = 214, 216. 34.2 At -78°C and under a nitrogen atmosphere, n-butyllithium (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). After reacting at -78°C for 40 minutes, a solution of 1-[1-(triphenylmethyl)imidazole-4-yl]etanone (622.7 mg, 1.767 mmol) in tetrahydrofuran (4 mL) was added dropwise. After the addition was complete, the temperature was raised to room temperature and the mixture was stirred overnight. At room temperature, the reaction was quenched by adding saturated aqueous NH4Cl (20 mL). Extraction was performed with ethyl acetate (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 and eluted with PE / EA (5:1) to obtain 1-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (350 mg) as a white solid. (ES, m / z): [M+1] = 489. 34.3 At room temperature and under a nitrogen gas atmosphere, 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)imidazole-4-yl]ethanol (300 mg, 0.614 mmol) in dichloromethane (5 mL). After reacting for 1 minute, triethylsilane (1.427 g, 12.280 mmol) was added dropwise. The resulting mixture was stirred overnight. The resulting mixture was concentrated and dried, and the residue was purified by reverse-phase flash chromatography under 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. A colorless oily substance, 4-[1-(5-fluoro-2,3-dihydro-1H-inden-4-yl)vinyl]-1H-imidazole (60 mg), was obtained. (ES, m / z): [M+1] = 229. 34.4 At room temperature, 10% Pd / C (20 mg) was added to a methanol (5 mL) solution of 4-[1-(5-fluoro-2,3-dihydro-1H-inden-4-yl)vinyl]-1H-imidazole (60 mg, 0.263 mmol). The reaction mixture was stirred in a hydrogen atmosphere at room temperature for 40 minutes, then filtered through a diatomaceous earth pad, 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 under the following conditions: column: C18 silica gel, mobile phase: aqueous acetonitrile (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. 1H NMR (400 MHz, Methanol-d4) δ 7.54 (s, 1H), 7.02 (dd, J = 8.2, 4.8 Hz, 1H), 6.86 - 6.72 (m, 2H), 4.38 (q, J = 7.3 Hz, 1H), 2.84 (dt, J = 26.1, 7.6 Hz, 3H), 2.53 (dt, J = 15.6, 7.4 Hz, 1H), 2.12 - 1.84 (m, 2H), 1.61 (d, J = 7.3 Hz, 3H). Example 37: Preparation of 7-[1-(1H-imidazole-4-yl)ethyl]-5-fluoro-2,3-dihydro-1H-inden-1-ol

[0333] [ka]

[0334] 37.1 At room temperature, Pd / C (10%, 20 mg) was added to a solution of 5-fluoro-7-{1-[1-(triphenylmethyl)imidazole-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 and eluted with PE / EA (1:1) to obtain 7-[1-(1H-imidazole-4-yl)ethyl]-5-fluoro-2,3-dihydro-1H-inden-1-ol (26.6 mg). (ES, m / z): [M+1]=247.1. 1H NMR (400 MHz, DMSO-d6) δ 11.78 (d, J = 22.4 Hz, 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, 8.0 Hz, 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, 7.2 Hz, 3H). Example 38: Preparation of 7-[1-(1H-imidazole-4-yl)ethyl]-5-fluoro-2,3-dihydro-1H-inden-1-one

[0335] [ka]

[0336] At 38.1°C and under a nitrogen atmosphere, NaBH4 (33.05 g, 873.18 mmol) was added in several portions to a mixed solution of 7-bromo-5-fluoro-2,3-dihydroinden-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 × 1000 mL). The combined organic layers were washed with saline solution and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. A yellowish oily 7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-ol (53.60 g) was obtained. (ES, m / z): [M] = 213. 38.2 At room temperature, tert-butyldimethylchlorosilane (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 in an air atmosphere for 1 hour. The resulting mixture was extracted with RINKAN (2 × 1000 mL). The combined organic layer was washed with saline solution and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded a yellowish oily [(7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (62 g). (ES, m / z): [M]=345. At 38.3°C and under a nitrogen atmosphere, n-butyllithium (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, a solution of 1-[1-(triphenylmethyl)imidazole-4-yl]ethanone (63.36 g, 179.75 mmol, 1.00 equivalent) in tetrahydrofuran (200 mL) was added dropwise. The temperature was raised to 25°C and stirred overnight under a nitrogen atmosphere. At 25°C, the reaction was quenched with saturated aqueous NH4Cl (1000 mL). Extraction was performed with dichloromethane (3 × 1000 mL). The combined organic layers were washed with saline solution and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain yellow oily 1-{3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl}-1-[1-(triphenylmethyl)imidazole-4-yl]ethanol (68.00 g). (ES, m / z): [M+1] = 619. At 38.4°C and 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)imidazole-4-yl]ethanol (68 g, 109.82 mmol) and triethylamine (88.91 g, 878.98 mmol) in dichloromethane (800 mL). The mixture was heated to room temperature and stirred for 1 hour. Extraction was performed with dichloromethane (3 × 1000 mL). The combined organic layers were washed with saline solution and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain the yellow solid 4-(1-{3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-4-yl}vinyl)-1-(triphenylmethyl)imidazole (62.00 g). (ES, m / z): [M+1] = 601. 38.5 At room temperature, TBAF (97.65 g, 309.50 mmol, 3 equivalents) 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 equivalent) in THF (800 mL). After stirring for 2 hours, the mixture was extracted with dichloromethane (2 × 1000 mL). The combined organic layers were washed with saline solution and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. A yellow solid, 5-fluoro-7-{1-[1-(triphenylmethyl)imidazole-4-yl]vinyl}-2,3-dihydro-1H-inden-1-ol (65.00 g), was obtained. (ES, m / z): [M+1] = 487. 38.6 Under a nitrogen gas atmosphere, Pd / C (10%, 13.00 g) was added to a solution of 5-fluoro-7-{1-[1-(triphenylmethyl)imidazole-4-yl]vinyl}-2,3-dihydro-1H-inden-1-ol (65.00 g, 133.58 mmol) in THF (1000 mL). The mixture was hydrogenated overnight at room temperature under a hydrogen atmosphere. 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 and eluted with PE / EA (1:1) to obtain the grayish-white solid 5-fluoro-7-{1-[1-(triphenylmethyl)imidazole-4-yl]ethyl}-2,3-dihydro-1H-inden-1-ol (46.00 g). (ES, m / z): [M+1] = 489. 38.7 At room temperature and under a nitrogen atmosphere, pyridinium chlorochromate (PCC) (30.43 g, 141.22 mmol) was added to a solution of 5-fluoro-7-{1-[1-(triphenylmethyl)imidazole-4-yl]ethyl}-2,3-dihydro-1H-inden-1-ol (46.00 g, 94.14 mmol) in DCM (600 mL). After the reaction was complete, the reaction mixture was extracted with dichloromethane (2 × 1000 mL). The combined organic layers were washed with saline solution and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. A yellowish oily 5-fluoro-7-{1-[1-(triphenylmethyl)imidazole-4-yl]ethyl}-2,3-dihydroinden-1-one (52.00 g) was obtained. (ES, m / z): [M+1] = 487. 38.8 Under room temperature and air atmosphere, a hydrochloric acid solution of dioxane was added to a solution of 5-fluoro-7-{1-[1-(triphenylmethyl)imidazole-4-yl]ethyl}-2,3-dihydroinden-1-one (52.00 g, 106.7 mmol) in THF (300 mL). After reacting at room temperature for 2 hours, the residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: aqueous acetonitrile solution, gradient of 10% to 50% over 40 minutes, detector: UV 254 nm. 7-[1-(1H-imidazole-4-yl)ethyl]-5-fluoro-2,3-dihydro-1H-inden-1-one (10.00 g) was obtained. (ES, m / z): [M+1] = 245. 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 7.54 (d, J = 10.6 Hz, 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). 38.9 7-[1-(1H-imidazole-4-yl)ethyl]-5-fluoro-2,3-dihydro-1H-inden-1-one (60 mg) was purified by Prep Chiral SFC under the following conditions (column: CHIRALPAK IG, 3 × 25 cm, 5 μm, mobile phase A: CO2, mobile phase B: MEOH (0.1% 2 M NH3-MEOH)): (R)-7-(1-(1H-imidazole-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-imidazole-4-yl)ethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one (38-b, 13.7 mg). A dose of mg (with a retention time of 0.87 min) was obtained.

[0337] (R)-7-(1-(1H-imidazole-4-yl)ethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one(38-a) (ES, m / z): [M+1] = 245. 1 H NMR (400 MHz, Methanol-d4) δ 7.82 (d, J = 1.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.02 (t, J = 1.2 Hz, 1H), 6.81 (dd, J = 10.4, 2.4 Hz, 1H), 5.48 (q, J = 7.2 Hz, 1H), 3.21 - 3.11 (m, 2H), 2.77 - 2.70 (m, 2H), 1.58 (d, J = 7.2 Hz, 3H). (S)-7-(1-(1H-Imidazol-4-yl)ethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one (38-b) (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 example Test Example Ⅰ, In vitro affinity 1. Experimental method 1.1 Preparation of buffer and test sample Standard buffer (α 1A α 2A α 2B α 2C for preparing receptor membrane): Weighed 146 mg of EDTA, added 50 mM Tris-HCl buffer to make the total volume 1000 mL, and adjusted the pH to 7.7. The final concentration was 0.5 mM of EDTA.[[ID=2\6]]

[0338] Test sample (compound): The theoretical charge amount was calculated according to the designed concentration and desired volume. Generally, 5.0×10 -3M was dissolved in DMSO as the initial preparation dosage, and then sequentially diluted to 5.0×10 -4 M to 5.0×10 -9 M with DMSO. The diluted DMSO solution was further diluted to 5.0×10 -5 M to 5.0×10 -11 M with Buffer, and the final concentration of DMSO in the working solution was 1% (the final concentration of DMSO in the reaction system was 0.2%). After the preparation of the test samples, they were stored at 4°C and discarded after the test.

[0339] 1.2 Preparation of receptor membrane CHO-K1-α 1A 、CHO-K1-α 2A 、CHO-K1-α 2B 、CHO-K1-α 2C cells were taken out from the -80°C refrigerator and thawed naturally, centrifuged at 2000 g for 10 min at 4°C, the supernatant was discarded, and the precipitate was collected. Buffer was added to the precipitate, homogenized for 20 - 30 s, then centrifuged at 48000 g for 25 min at 4°C, the supernatant was discarded, buffer was added again, homogenized for 20 - 30 s, centrifuged at 48000 g for 25 min at 4°C, the supernatant was discarded, and the precipitate was collected and stored at -80°C.

[0340] 1.3 Receptor competition binding experiment 1.3.1 Radioactive binding experiment conditions

[0341]

Table 1

[0342] 1.3.2 Steps of receptor binding experiment The first step: 50 μL of vehicle (1% DMSO) was added to the total binding tube (TB), 50 μL of non-standard (final concentration 1.0×10 -5 M) was added to the non-specific binding tube (NB), and 50 μL of the test compound was added to each test compound tube (CB).

[0343] The second step: 100 μL of buffer was added to each reaction tube respectively.

[0344] Step 3: The fabricated membranes were prepared for use by preparing membrane suspensions of the corresponding concentrations using buffer solutions.

[0345] Step 4: 50 μL of the corresponding radioactive ligand was added to each reaction tube.

[0346] Step 5: 50 μL of membrane suspension was added to each reaction tube.

[0347] Step 6: Each reaction tube was incubated under incubation conditions. After the reaction was complete, the bound ligand was rapidly filtered under reduced pressure. The UniFilter GF / C plate was saturated with 0.5% PEI solution 1 hour prior to the reaction, thoroughly washed with ice-cooled Tris-HCl buffer, filtered by suction, and then dried in a constant temperature drying chamber for 30 minutes. The filtered plate was removed and MICROSCINT PS scintillation solution was added at a rate of 40 μL / well.

[0348] Step 7: The scintillation cup was placed in a liquid scintillation counter and counted.

[0349] 1.4 Data Analysis Based on the effect values ​​at test points of different concentrations of the compound sample, the action curve of the compound sample on the receptor was fitted using GraphPad Prism software, and the Ki value was calculated.

[0350] 1.5 Experimental Results Examples include compounds 1, 3, 4, and 8 of the present invention and α 2A The receptor affinity corresponds to that of dexmedetomidine hydrochloride, and compounds 2, 10 and α 2A The receptor affinity is superior to that of dexmedetomidine hydrochloride, and the affinity α of compound 3 is superior. 1A / 2A This corresponds to dexmedetomidine hydrochloride, and the affinity α of compounds 4, 8, and 10 1A / 2A It was superior to dexmedetomidine hydrochloride. Details are shown in Table 2.

[0351] Test Example 2, In Vitro Function 2. Experimental Method 2.1 Objective: To use the Cisbio HTRF cAMP-Gi and IP-One reagent kit to analyze adrenergic receptors (α) using a microplate reader. 1A , α 2A , α 2B , α 2C )Detect changes in cAMP and IP1 concentrations in the signaling pathway and the EC of compounds 50 The values ​​were calculated to evaluate the agonist effect of dexmedetomidine hydrochloride compounds on adrenaline receptors.

[0352] 2.2 Materials for the experiment: Cell line:293-α 1A Stably transformed cell line (Shanghai Cardinal Biotechnology Co., Ltd.) 293-α 2A Stably transformed cell line (Shanghai Cardinal Biotechnology Co., Ltd.) CHO-α 2B / Gα15 stably transformed cell line (Nanjing Jinsurui Biological Technology Co., Ltd.) CHO-α 2C / Gα15 stably transformed cell line (Nanjing Jinsurui Biological Technology Co., Ltd.) Cell culture conditions: 293-α 1A (DMEM, 10% FBS, 0.6 μg / mL puromycin) 293-α 2A (DMEM, 10% FBS, 0.6 μg / mL puromycin) CHO-α 2B / Gα15(F12, 10% FBS, 200 μg / mL Zeocin, 100 μg / mL Hygromycin B) CHO-α 2C / Gα15 (F12, 10% FBS, 400 μg / mL G418, 400 μg / mL Hygromycin B) Reagents and consumables: F12(meilunbio, MA0229) DMEM (Gibco, 8121703) FBS (BOVOGEN, SFBS) Zeocin (invitrogen, R25001) Hygromycin B (invitrogen, 10687010) Puromycin (Solarbio, 119L042) PBS (meilunbio, MA0015) Pancreatin (Gibco, 25200-072) 96-cell plate (cisbio, 66PL96025) cAMP-Gi kit (cisbio, 03E) IP-ONE Kit (Cisbio, 16E) CO2 incubator (Thermo, 311) Centrifugal separator (Shanghai Anting, TGL-16C) Site meter (Countstar, IC1000) Microplate readers (PerkinElmer, EnVision) 2.3 Experimental Procedure 2.3.1 Detection of agonists using the cAMP method (adrenaline α 2A Receptors) (1) Preparation of reaction buffer (1×Stimulation buffer) required for the experiment: The 5×Stimulation buffer and ddH2O in the Cisbio cAMP-Gi kit were diluted in a 1:4 ratio and prepared for use.

[0353] (2) Preparation of the compound: The compound was diluted with DMSO to a 5 mM stock solution, then diluted 3.16 times in 10 gradients, and the prepared compound was then diluted with Stimulation buffer to the corresponding concentration (2.5 ×) to prepare for use.

[0354] (3) Cell preparation: 293-α on a culture dish 2AThe cells were trypsin-treated, eluted in culture medium, and collected in a 5 mL centrifuge tube. Centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. 3 mL of PBS was added and mixed uniformly by light pipetting. Centrifuged again at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were resuspended in 1 × Stimulation buffer and counted using a Countstar cytometer to obtain a cell density of 4 × 10⁶. 5 The amount was adjusted to 1 / mL and prepared for use.

[0355] (4) Addition of cells: The cell suspension was added to the experimental plate at a rate of 5 μL / well (i.e., approximately 2000 cells / well).

[0356] (5) Addition of compound: The compound diluted in Stimulation buffer was added to the experimental plate described above at a rate of 4 μL / well.

[0357] (6) Incubation of the reaction: After gently shaking, the experimental plate was incubated at 37°C for 20 minutes.

[0358] (7) Addition of the agonist Forskolin: A 10× adenylyl cyclase agonist (Forskolin with a final concentration of 1 μM) solution was added at a rate of 1 μL / well.

[0359] (8) Incubation of the reaction: After gently shaking, the experimental plate was incubated at 37°C for 45 minutes.

[0360] (9) Addition of detection reagents: cAMP-cryptate and Anti-cAMP-d2 were diluted 1:20 times with Lysis & detection buffer from the Cisbio cAMP-Gi detection kit, and 5 μL / well of the diluted cAMP-cryptate and Anti-cAMP-d2 were added to the experimental plate. After shaking, the experimental plate was left to stand at room temperature for 60 minutes.

[0361] (10) Reading experimental values: The plate was read on Envision, the readings for the 665 nm and 615 nm channels were detected, and the ratio of the 665 nm / 615 nm readings was calculated.

[0362] 2.3.2 Agonist Screening Mode Detection by IP-One Method (Adrenaline α 1A , α 2B , α 2C Receptors) (1) Preparation of reaction buffer (1×Stimulation buffer) required for the experiment: The 5×Stimulation buffer and ddH2O from the Cisbio IP-One reagent kit were diluted in a 1:4 ratio and prepared for use.

[0363] (2) Preparation of the compound: The compound was diluted with DMSO to a 5 mM stock solution, then diluted 3.16 times in 10 gradients, and the prepared compound was then diluted with Stimulation buffer to the corresponding concentration (2×) for use.

[0364] (3) Cell preparation: 293-α on a culture dish 1A , CHO-α 2B , CHO-α 2C The cells were trypsin-treated, eluted in culture medium, and collected in a 5 mL centrifuge tube. Centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. 3 mL of PBS was added and mixed uniformly by light pipetting. Centrifuged again at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were resuspended in 1 × Stimulation buffer and counted using a Countstar cytometer to obtain a cell density of 1.7 × 10⁶. 6 The amount was adjusted to 1 / mL and prepared for use.

[0365] (4) Addition of cells: The cell suspension was added to the experimental plate at a rate of 7 μL / well (i.e., approximately 12,000 cells / well).

[0366] (5) Addition of compound: The compound diluted in Stimulation buffer was added to the experimental plate described above at a rate of 7 μL / well.

[0367] (6) Incubation of the reaction: After gently shaking, the experimental plate was incubated at 37°C for 60 minutes.

[0368] (7) Addition of detection reagents: IP1-cryptate and Anti-IP1-d2 were diluted 1:12 times with the Lysis & detection buffer in the Cisbio IP-One detection kit, and 3 μL / well of the diluted IP1-cryptate and Anti-IP1-d2 were added to the experimental plate. After shaking, the experimental plate was left to stand at room temperature for 60 minutes.

[0369] (8) Reading experimental values: The plate was read on Envision, the readings for the 665 nm and 615 nm channels were detected, and the ratio of the 665 nm / 615 nm readings was calculated.

[0370] 2.4 Data Analysis Based on the agonist effect values ​​at different concentration test points of the compound sample, data analysis and statistics were performed using the graphing software GraphPad Prism5 (log(agonist) vs. normalized response -- Variable slope, n≧2), and EC 50 I calculated it.

[0371] 2.5 Experimental Results As an example, the α of compounds 1, 3, 4, 10, 11-b, and 31-b of the present invention. 2A The agonist activity against the receptor is equivalent to that of dexmedetomidine hydrochloride, and the α of compounds 2 and 8 2A The agonist activity against the receptor is superior to that of dexmedetomidine hydrochloride, and the agonist activity of compounds 2, 4, 10, 11-b, 17, and 31-b is α 1A / 2A This corresponds to dexmedetomidine hydrochloride, and the agonist activity of compounds 3 and 8 is α 1A / 2A It was superior to dexmedetomidine hydrochloride. Details are shown in Table 2.

[0372] [Table 2-1]

[0373] [Table 2-2]

[0374] Test Example 3: Hypnotic Efficacy 3.1 Experimental Method The compound of the present invention reduces the loss of the righting reflex (LORR) in rats. 50 The half-effective dose (MLD) was measured sequentially: Male SD rats, 200-300 g body weight, were used. Each compound was dissolved in saline solution, and the initial dose was administered via isokinetic bolus injection into the tail vein for 10 seconds (one dose administered to one rat). If the righting reflex disappeared after the initial dose, the next rat was given a lower dose (0.8 times the initial dose). If the righting reflex did not disappear after the initial dose, the next rat was given a higher dose (1.25 times the initial dose), and so on. The results were entered into the AOT425 Statpm software, and the software was updated to ED. 50 The experiment was continued until the desired result was obtained, and then terminated. The hypnotic effect of the compound of the present invention was obtained in ED. 50 Evaluated by ED 50 The smaller the value, the stronger the medicinal effect.

[0375] Comparison of onset and maintenance time: Male SD rats, body weight 200-300 g, each compound was dissolved in physiological saline and injected as an isokinetic bolus via tail vein for 10 seconds. There were 10 rats per group, and the injection dose was twice that of the ED. 50 (ED 50 The dose used was the dose at which the righting reflex disappeared in 50% of rats, and the onset time and maintenance time of the effect were recorded.

[0376] The onset time is determined by placing the rat in a supine position after injection. The rat's forelimbs are unable to reverse to a prone position on their own, and the duration of this absence is ≥ 10 seconds. This serves as an effective indicator of the compound's effectiveness. The duration of absence of the righting reflex in the rat is defined as the period during which the rat maintains this state. The drug effect is considered to have subsided after the rat's righting reflex recovers on its own.

[0377] 3.2 Experimental Results The results are shown in Table 3:

[0378] [Table 3]

[0379] As can be seen from the experimental results, the onset time of the hypnotic effect 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 reliable and reversible hypnotic effect. The onset time of the hypnotic effect of compound 11-b and the maintenance time of compounds 5, 8, 10, 11-b, 12-b, 17, 31-b, and 38-b are all significantly lower than that of dexmedetomidine hydrochloride, expanding the range of applications for these compounds.

[0380] 4. Changes in blood pressure and heart rate after administration. 4.1 Experimental Method Male SD rats, weighing 250-300 g, were used in groups of four. General anesthesia was maintained by inhaling isoflurane, and a cannula was inserted into the femoral artery. Blood pressure and heart rate were monitored using a Powerlab data acquisition and analysis system. Mean arterial pressure (MAP0) and heart rate (HR0) were measured 30 minutes after baseline stabilization. Saline solutions of each compound were injected into the tail vein (the dosage of each compound was the same as in Experiment 3, administered intravenously for 10 seconds and then rapidly as a bolus injection). Blood pressure and heart rate were recorded for 90 minutes. The mean arterial pressure peak (MAP0) within the 90-minute period was recorded. max ) and the difference between MAP0 and MAP + , mean arterial pressure quotient (MAP) min ) and the difference between MAP0 and MAP- , lowest heart rate (HR) min ) and the difference between HR0 - The following was calculated: Maximum rate of increase in mean arterial pressure = MAP + / MAP0 × 100%, maximum rate of decrease in mean arterial pressure = MAP - / MAP0 × 100%, maximum heart rate reduction rate = HR - The calculation was performed using / HR0 × 100%. Details are shown in Table 4.

[0381] 4.2 Experimental Results After injecting rats with physiological saline, no significant changes in blood pressure or heart rate were observed (the range of change was less than 10%). After administering dexmedetomidine hydrochloride to the animals, MAP showed a bidirectional change, initially increasing and then decreasing, and both MAP and HR continued to decrease for 90 minutes.

[0382] The maximum increase in MAP for compounds 5, 10, 11-b, and 31-b was lower than that of dexmedetomidine hydrochloride. Compounds 5, 8, 10, 11-b, and 31-b did not show a significant decrease in MAP exceeding 10%. The maximum decrease in HR for compounds 5, 8, 10, 11-b, and 31-b was lower than that of dexmedetomidine hydrochloride in all cases, and recovery was faster.

[0383] [Table 4]

Claims

1. A compound represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, 【Chemistry 1】 Of these, X is selected from CH and N, and is preferably CH. n is an integer selected from 1 to 3, preferably 1. m is an integer selected from 1 to 8, preferably an integer selected from 1 to 3. Each R 1 is independently selected from H, halogen, hydroxy group, nitro group, cyano group, optionally substituted C 1 -C 8 alkyl group, optionally substituted C 1 -C 8 alkoxy group, optionally substituted C 2 -C 8 alkene group, optionally substituted C 2 -C 8 alkyne group, optionally substituted C 1 -C 8 alkylthio group and optionally substituted C 3 -C 8 cycloalkyl group, and the optional substituents are independently selected from halogen and hydroxy group, R 2 This consists of H, a cyano group, and a C that is optionally substituted. 1 -C 8 Alkyl alkyl group, optionally substituted C 2 -C 8 Alkene groups and optionally substituted C 2 -C 8 The alkyne group is selected, and the optional substituent is independently selected from halogens and hydroxyl groups. R 3 C is optionally substituted with H, halogen, hydroxyl group, nitro group, cyano group, or 1 -C 8 Alkyl alkyl group, optionally substituted C 1 -C 8 Alkoxy groups, optionally substituted C 2 -C 8 Alkene group, optionally substituted C 2 -C 8 Alkyne group, optionally substituted with C 1 -C 8 Alkylthio groups and optionally substituted C 3 -C 8 Selected from cycloalkyl groups, the optional substituents are independently selected from halogens and hydroxyl groups. Ring A is C 3 -C 8 Cycloalkyl groups, C 3 -C 8 A 3-8 membered heterocyclyl group containing 1-3 heteroatoms independently selected from a cycloalkenyl group, oxygen, nitrogen, and sulfur, and a 5-8 membered heteroaryl group containing 1-3 heteroatoms independently selected from oxygen and sulfur, preferably C 3 -C 8 Selected from 3- to 8-membered heterocyclyl groups containing one heteroatom selected from cycloalkyl groups, oxygen, nitrogen, and sulfur, and 5- to 8-membered heteroaryl groups containing one heteroatom selected from oxygen and sulfur, Each R 10 Each of these is independently H, halogen, hydroxyl group, nitro group, cyano group, or optionally substituted C. 1 -C 8 Alkyl alkyl group, optionally substituted C 1 -C 8 Alkoxy groups, optionally substituted C 2 -C 8 Alkene group, optionally substituted C 2 -C 8 Alkyne group, optionally substituted with C 1 -C 8 Alkylthio groups and optionally substituted C 3 -C 8 Selected from cycloalkyl groups, the optional substituents are independently halogens, C 1 -C 8 Selected from alkyl groups and hydroxyl groups, R 11 H is replaced by C, which can be optionally substituted. 1 -C 8 Alkyl alkyl group, optionally substituted C 2 -C 8 Alkene groups and optionally substituted C 2 -C 8 Selected from alkyne groups, preferably H and optionally substituted C 1 -C 5 Selected from alkyl groups, more preferably H, and the optional substituent is selected from hydroxyl groups and halogens. Furthermore, the compound of formula I is not 5-(2,3-dihydro-benzofuran-7-ylmethyl)-1-imidazole, 8-((1H-imidazole-5-yl)methyl)-1,2,3,4-tetrahydroquinoline, 5-(benzofuran-7-ylmethyl)-1H-imidazole, or 5-((5-bromobenzofuran-7-yl)methyl)-1H-imidazole. The compound represented by formula I, or its pharmaceutically acceptable salts, stereoisomers, and tautomers.

2. below, (1) Ring A is C 3 -C 8 Cycloalkyl groups, C 3 -C 8 Selected from a cycloalkenyl group, a 4-6 membered heterocyclyl 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 an azetidinyl group, oxetanyl group, thietanyl group, thienyl group, furan group, thiopyranyl group, pyranyl group, tetrahydropyrrolyl group, hexahydropyridyl group, dihydropyrrolyl group, tetrahydropyridyl group, tetrahydrothienyl group, dihydropyridyl group, dihydrothienyl group, tetrahydrothiopyranyl group, dihydrothiopyranyl group, tetrahydrofuran group, dihydrofuran group, tetrahydropyranyl group, dihydropyranyl group, cyclopropyl group, cyclobutyl Selected from a cyclopentyl group, cyclopentyl group, cyclohexyl group, cyclobutenyl group, cyclopentenyl group, cyclopentadiene group, cyclohexenyl group and cyclohexadienyl group, more preferably selected from a tetrahydropyrrolyl group, hexahydropyridyl group, dihydropyrrolyl group, tetrahydropyridyl group, thienyl group, furan group, thiopyranyl group, pyranyl group, dihydropyridyl group, tetrahydrothiopyranyl group, dihydrothiopyranyl group, tetrahydrothienyl group, dihydrothienyl group, tetrahydrofuran group, dihydrofuran group, cyclobutyl group, cyclobutenyl group, cyclopentyl group, cyclohexyl group, cyclopentenyl group, cyclopentadiene group and cyclohexenyl group, (2) R 1 H, halogen, and C which can be optionally substituted. 1 -C 8 Alkyl alkyl group, optionally substituted C 1 -C 8 Alkoxy groups, hydroxyl groups, and optionally substituted C 1 -C 8 Alkylthio groups and optionally substituted C 3 -C 6 Selected from cycloalkyl groups, preferably H, halogen, or optionally substituted C 1 -C 5 Alkyl alkyl group, optionally substituted C 1 -C 5 Alkoxy groups, hydroxyl groups, and optionally substituted C 1 -C 5 Alkylthio groups and optionally substituted C 3 -C 6 Selected from cycloalkyl groups, more preferably H, halogen, or optionally substituted C 1 -C 5 Selected from alkyl groups and hydroxyl groups, more preferably H, -F, -Cl, and optionally substituted C 1 -C 5 The alkyl group is selected from alkyl groups, more preferably H or -F, and the optional substituent is selected from hydroxyl groups and halogens, preferably F. (3)R 3 is H, halogen, optionally substituted C 1 -C 8 alkyl group, optionally substituted C 1 -C 8 alkoxy group, hydroxy group, optionally substituted C 1 -C 8 alkylthio group and optionally substituted C 3 -C 6 cycloalkyl group, preferably selected from H, halogen, optionally substituted C 1 -C 5 alkyl group, optionally substituted C 1 -C 5 alkoxy group, hydroxy group and optionally substituted C 3 -C 6 cycloalkyl group, more preferably selected from H, halogen and optionally substituted C<00,000104>-C 5 alkyl group, even more preferably H, and the optional substituent is selected from hydroxy group, halogen, preferably F (4) Each R 10 These are H, halogen, and C, which can be optionally substituted, and are independent of each other. 1 -C 8 Alkyl alkyl group, optionally substituted C 1 -C 8 Alkoxy groups, hydroxyl groups, and optionally substituted C 1 -C 8 Alkylthio groups and optionally substituted C 3 -C 6 Selected from cycloalkyl groups, preferably H, halogen, or optionally substituted C 1 -C 5 Alkyl alkyl group, optionally substituted C 1 -C 5 Alkoxy groups, hydroxyl groups, and optionally substituted C 1 -C 5 Alkylthio groups and optionally substituted C 3 -C 6 Selected from cycloalkyl groups, more preferably H, halogens, and optionally substituted C 1 -C 5 Selected from alkyl groups, the optional substituents are independently halogens, C 1 -C 8 Selected from alkyl groups and hydroxyl groups, preferably halogens and C 1 -C 5 Selected from alkyl groups and hydroxyl groups, more preferably halogens, and even more preferably fluorine. (5) R 2 H and C which can be optionally substituted. 1 -C 8 Selected from alkyl groups, preferably H and optionally substituted C 1 -C 5 A C selected from alkyl groups, and more preferably optionally substituted. 1 -C 5 The characteristic is that it satisfies one or more of the following conditions: it is selected from alkyl groups, and the optional substituent is independently selected from halogens and hydroxyl groups. The compound represented by formula I as described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

3. The compound represented by formula I is formula I-a' or formula I-b', 【Chemistry 2】 The following characteristics are shown: A compound represented by formula I as described in any one of claims 1 to 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

4. Ring A is selected from a 4-6 membered heterocyclyl group containing one oxygen atom, or a 5-6 membered heteroaryl group containing one oxygen atom, preferably, 【Transformation 3】 Selected from, more preferably, 【Chemistry 4】 Selected from, R 2 C is optionally substituted. 1 -C 8 The alkyl group is selected, and the substituent is independently selected from halogens and hydroxyl groups, characterized in that A compound represented by formula I as described in any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

5. Ring A is selected from a 4-6 membered heterocyclyl group containing one sulfur atom, or a 5-6 membered heteroaryl group containing one sulfur atom, preferably, 【Transformation 5】 Selected from, more preferably, 【Transformation 6】 Characterized by being selected from, A compound represented by formula I as described in any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

6. Ring A is selected from a 4- to 6-membered heterocyclyl group containing one nitrogen atom, preferably 【Transformation 7】 【Transformation 8】 Selected from, R 2 C is optionally substituted. 1 -C 8 The alkyl group is selected from alkyl groups, and the substituent is independently selected from halogens and hydroxyl groups, characterized in that A compound represented by formula I as described in any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

7. Ring A is C 3 -C 8 Selected from cycloalkyl groups, preferably, 【Chemistry 9】 Selected from, more preferably, 【Chemistry 10】 Selected from, and more preferably, 【Chemistry 11】 Characterized by being, A compound represented by formula I as described in any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

8. The compound represented by formula I is a compound represented by formula II or formula III. 【Chemistry 12】 As shown, Eventually, R 2 C is optionally substituted. 1 -C 8 Selected from alkyl groups, the optional substituents are independently selected from halogens and hydroxyl groups. n, R 1 , R 3 The definition of the corresponding base is the same as in claims 1 to 4, R 4 , R 5 , R 6 Each of these can be independently replaced by H, halogen, hydroxyl group, nitro group, cyano group, or optionally substituted C. 1 -C 8 Alkyl alkyl group, optionally substituted C 1 -C 8 Alkoxy groups, optionally substituted C 2 -C 8 Alkene group, optionally substituted C 2 -C 8 Alkyne group, optionally substituted with C 1 -C 8 Alkylthio groups and optionally substituted C 3 -C 8 Selected from cycloalkyl groups, the optional substituents are independently halogens, C 1 -C 8 Characterized by being selected from alkyl groups and hydroxyl groups, A compound represented by formula I as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

9. The compound represented by formula I is a compound represented by formula V or formula VI. 【Chemistry 13】 As shown, Among them, n, R 1 , R 2 , R 3 This is the same as the definition of the corresponding base in claims 1 to 3 and 7, R 4 , R 5 , R 6 Each of these can be independently replaced by H, halogen, hydroxyl group, nitro group, cyano group, or optionally substituted C. 1 -C 8 Alkyl alkyl group, optionally substituted C 1 -C 8 Alkoxy groups, optionally substituted C 2 -C 8 Alkene group, optionally substituted C 2 -C 8 Alkyne group, optionally substituted with C 1 -C 8 Alkylthio groups and optionally substituted C 3 -C 8 Selected from cycloalkyl groups, the optional substituents are independently halogens, C 1 -C 8 Characterized by being selected from alkyl groups and hydroxyl groups, A compound represented by formula I according to any one of claims 1 to 3 and 7, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

10. The compounds shown below, 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 Characterized by being selected from, A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

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

12. An application of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a drug related to an α2 adrenergic receptor agonist, preferably in the manufacture of a drug for sedation, and / or analgesia, and / or anesthetic effects, and / or anxiolytic effects, and / or inhibition of sympathetic nerve activity, and / or treatment of insomnia, and / or treatment of mental disorders in humans or animals, more preferably in the manufacture of a drug for 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 represented by formula IA, formula I-A', formula IB, formula I-B', formula IC, formula ID, or formula I-D', or a salt thereof, 【Chemistry 17】 Eventually, In formula IA, n, ring A, R 1 , R 3 , m, R 10 This is the same as the definition of the corresponding base in claims 1 to 10, In equation I-A', n, ring A, R 1 , R 3 , m, R 10 This is the same as the definition of the corresponding base in claims 1 to 10, In formula IB, n, ring A, R 1 , R 3 , m, R 10 This is the same as the definition of the corresponding base in claims 1 to 9, R 8 is C 1 -C 5 Selected from alkyl groups, preferably selected from methyl, ethyl, and propyl groups, and more preferably a methyl group. In equation I-B', n, ring A, R 1 , R 3 , m, R 10 This is the same as the definition of the corresponding base in claims 1 to 9, In formula IC, n, ring A, R 1 , R 2 , R 3 , m, R 10 This is the same as the definition of the corresponding base in claims 1 to 9, In formula ID, n, ring A, R 1 , R 2 , R 3 , m, R 10 This is the same as the definition of the corresponding base in claims 1 to 9, R 9 The hydroxy protecting group is selected from hydroxy protecting groups, preferably from silyl ether hydroxy protecting groups, more preferably from trimethylsilyl group, tert-butyldiphenylsilyl group, tert-butyldimethylsilyl group, and triisopropylsilyl group, and even more preferably from tert-butyldimethylsilyl group. In formula I-D', n, ring A, R 1 , R 2 , R 3 , m, R 10 This is the same as the definition of the corresponding base in claims 1 to 10, R in formulas IA, IB, I-B', IC, ID, or I-D' 7 This is selected from amino protecting groups, preferably a trityl group. Compounds represented by formula IA, formula I-A', formula IB, formula I-B', formula IC, formula ID, or formula I-D', or salts thereof.

14. A method for producing the compound according to any one of claims 1 to 10, comprising the steps of: obtaining intermediate IA from intermediate IB-1 by a dehydration reaction, then obtaining intermediate IC by a hydrogenation-reduction reaction, and removing the amino protecting group from intermediate IC to obtain the compound represented by formula I-1; or obtaining intermediate I-A' by removing the amino protecting group and water from intermediate IB-1 in one step, then obtaining the compound represented by formula I-1 by a hydrogenation-reduction reaction; or obtaining the compound represented by formula I-2 from intermediate I-B' by removing the amino protecting group in one step and simultaneously by a reduction reaction; or obtaining intermediate I-D' by removing the hydroxy protecting group from intermediate ID, and removing the amino protecting group from intermediate I-D' and dehydrating it to obtain the compound represented by formula I; [Chemistry 18] Among them, n, ring A, R 1 , R 2 , R 3 , m, R 10 This is the same as the definition of the corresponding base in claims 1 to 10, R 7 This is selected from amino protecting groups, preferably a trityl group. R 9 The hydroxy protecting group is selected from hydroxy protecting groups, preferably from silyl ether hydroxy protecting groups, more preferably from trimethylsilyl group, tert-butyldiphenylsilyl group, tert-butyldimethylsilyl group, and triisopropylsilyl group, and even more preferably from tert-butyldimethylsilyl group. Manufacturing method.

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