Biphenyl pyrrolidine and biphenyl dihydroimidazole derivatives for inhibiting 5-HT7 serotonin receptor activity and pharmaceutical compositions containing the same as an active ingredient

Abstract

The present invention relates to a compound for inhibiting 5-HT7 serotonin receptor activity represented by structural formula 1 or 2, or a pharmaceutically acceptable salt thereof.

Description

Detailed Description of the Invention

[0001] 〔Technical Field〕 The present invention relates to biphenyl pyrrolidine and biphenyl dihydroimidazole derivatives for inhibiting 5-HT 7 serotonin receptor activity, and pharmaceutical compositions containing the same as an active ingredient. More specifically, in the beta-arrestin (β-arrestin) signaling pathway, 5-HT 7 biphenyl pyrrolidine and biphenyl dihydroimidazole derivatives that can act as antagonists of serotonin receptors and inhibit activity, and pharmaceutical compositions containing the same as an active ingredient.

[0002] 〔Background Art〕 Serotonin, a neurotransmitter, acts on 14 different serotonin receptors that are variously distributed in each organ, causing various physiological phenomena. Each receptor induces various physiological reactions by interacting with serotonin. Among these, the 5-HT 7 receptor is a recently discovered serotonin subtype receptor, and is particularly abundantly distributed in the hypothalamus, thalamus, hippocampus, cortex, etc., and is known to perform important functions such as body temperature regulation, biological rhythm, learning and memory, sleep, and hippocampal signal transmission. It is also known to be associated with diseases such as depression, migraine, anxiety, developmental disorders, and neurological diseases such as inflammatory pain and neuropathic pain.

[0003] As research on GPCR progresses, it is known that in addition to the signal system by G-protein activity, there is also a signal system by beta-arrestin (β-arrestin) activity, and the activity of both signal systems can be regulated by the structure of the GPCR ligand, and various ligands have been developed. 5-HT 7The receptor is one of the GPCRs (G-protein coupled receptors), where the G-protein signaling system and the beta-arrestin signaling system exist, and an assay system capable of confirming their activities has also been developed (Journal of Medicinal Chemistry, 2018, 61, 7218). According to this, 5-HT 7 SB-269970, which is well-known as a 5-HT

[0004] receptor antagonist, is known to act as an antagonist for both the activity against the G-protein signaling system and the activity against beta-arrestin.

[0005] [Prior Art Documents] [Patent Documents] [Patent Document 1] Korean Registered Patent No. 10-1779991 [Summary of the Invention] [Problems to be Solved by the Invention] An object of the present invention is to provide a biphenylpyrrolidine / dihydroimidazole derivative or a pharmaceutically acceptable salt thereof that can suppress the activity of the 5-HT 7 serotonin receptor by acting as an antagonist of the beta-arrestin pathway against the 5-HT 7 serotonin receptor.

[0006] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating central nervous system diseases including sleep disorders, depression, migraine, anxiety, pain, inflammatory pain, neuropathic pain, thermoregulatory disorders, biological rhythm regulatory disorders, developmental disorders including autism spectrum disorder, and smooth muscle disorders, which contains the biphenylpyrrolidine / dihydroimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0007] [Means for Solving the Problems] According to one aspect of the present invention, 5-HT represented by the following Structural Formula 1 or 2 7Provided is a compound for inhibiting serotonin receptor activity or a pharmaceutically acceptable salt thereof.

[0008]

Chemical formula

[0009] In structural formula 1 or 2, R 1 ~R 8 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0010] Preferably, the compound represented by the above structural formula 1 or 2 may be one represented by the following structural formula 3 or 4.

[0011]

Chemical formula

[0012] In structural formula 3 or 4, R 9 ~R 16 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0013] Preferably, R 9 ~R 16 are the same as or different from each other, and each independently may be a hydrogen atom, a chloro group, a C1-C4 alkyl group, or a C1-C4 alkoxy group.

[0014] The compound represented by the above structural formula 1 or 2 may be any one selected from the following Compounds 1 to 44.

[0015]

Chemical formula

[0016] The pharmaceutically acceptable salt may be a salt formed using any one inorganic acid or organic acid selected from hydrochloric acid, bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, and methanesulfonic acid.

[0017] According to another aspect of the present invention, a method for producing a compound for inhibiting 5-HT serotonin receptor activity, which includes reacting a compound represented by the following structural formula A with pyrrolidine or ethylenediamine, is provided. 7

[0018] [Chemical formula]

[0019] In structural formula 1 or 2, R 1 ~R 8 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group. In structural formula B, R 17 ~R 20 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0020] Preferably, the compound represented by the structural formula 1 or 2 is represented by the following structural formula 3 or 4. The compound represented by the structural formula A may be the one represented by the following structural formula B.

[0021] ​ [Chemical formula]

[0022] In Structural Formula 3 or 4, R 9 ~R 16 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group. In Structural Formula B, R 21 ~R 24 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0023] The compound represented by the above Structural Formula B may be produced by subjecting the compound represented by the following Structural Formula C and the compound represented by the following Structural Formula D to a Suzuki reaction.

[0024] [Chemical formula]

[0025] In Structural Formula C or D, X 1 is a bromo group or an iodo group. R 25 and R 26 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0026] Preferably, R 25 is a hydrogen atom, and X 1 may be a bromo group.

[0027] Also preferably, R 26 is a chloro group, and X 1 may be an iodo group.

[0028] According to still another aspect of the present invention, a pharmaceutical composition for preventing or treating central nervous system diseases, comprising as an active ingredient a compound represented by the following structural formula 1 or 2 or a pharmaceutically acceptable salt thereof;

[0029] [Chemical formula]

[0030] In structural formula 1 or 2, R 1 ~R 8 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0031] Most preferably, the compound represented by the structural formula 1 or 2 may be any one selected from the following compounds 1 to 44.

[0032] [Chemical formula] JPEG0007692481000011.jpg209169JPEG0007692481000012.jpg100169

[0033] The central nervous system disease may be any one disease selected from sleep disorder, depression, migraine, anxiety, pain, inflammatory pain, neuropathic pain, thermoregulatory disorder, biological rhythm regulatory disorder, autism spectrum disorder, and smooth muscle disorder.

[0034] [Effect of the invention] The biphenylpyrrolidine / dihydroimidazole derivative of the present invention and a pharmaceutically acceptable salt thereof exhibit excellent binding affinity and excellent antagonistic activity against the 5-HT 7 serotonin receptor, and thus can suppress the activity of the 5-HT 7 serotonin receptor. Therefore, a pharmaceutical composition containing this as an active ingredient is a 5-HT7 5-HT by antagonistic activity 7 Brain diseases including central nervous system diseases that require suppression of serotonin receptor activity, specifically, depression, migraine, anxiety, pain, inflammatory pain, neuropathic pain, thermoregulatory disorders, biological rhythm regulatory disorders, sleep disorders, developmental disorders including autism spectrum disorder, and smooth muscle-related diseases, etc., have a preventive or therapeutic effect.

[0035] [Brief Description of the Drawings] [Figure 1] It is the experimental result for the Tango assays of Test Example 2.

[0036] [Figure 2] It is the result of measuring the pA 2 value using a Schild plot for the Tango assay of Test Example 2.

[0037] [Modes for Carrying Out the Invention] The present invention can be subjected to various conversions and can have various embodiments. Specific embodiments are illustrated and described in detail in the detailed description. However, this is not intended to limit the present invention to specific embodiments, and it should be understood to include all conversions, equivalents, or alternatives included in the spirit and technical scope of the present invention. When explaining the present invention, if it is determined that a specific description of related known technologies may obscure the gist of the present invention, the detailed description thereof will be omitted.

[0038] The term "substituted" means that at least one hydrogen atom is deuterium, a C1-C30 alkyl group, a C3-C30 cycloalkyl group, a C2-C30 heterocycloalkyl group, a C1-C30 halogenated alkyl group, a C6-C30 aryl group, a C1-C30 heteroaryl group, a C1-C30 alkoxy group, a C3-C30 cycloalkoxy group, a C1-C30 heterocycloalkoxy group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a C6-C30 aryloxy group, a C1-C30 heteroaryloxy group, a silyloxy group (-OSiH 3 ), -OSiR 1 H 2 (R1 is a C1-C30 alkyl group or a C6-C30 aryl group), -OSiR 1 R 2 H (R 1 and R 2 are each independently a C1-C30 alkyl group or a C6-C30 aryl group), -OSiR 1 R 2 R 3 , (R 1 , R 2 , and R 3 are each independently a C1-C30 alkyl group or a C6-C30 aryl group), a C1-C30 acyl group, a C2-C30 acyloxy group, a C2-C30 heteroaryloxy group, a C1-C30 sulfonyl group, a C1-C30 alkylthiol group, a C3-C30 cycloalkylthiol group, a C1-C30 heterocycloalkylthiol group, a C6-C30 arylthiol group, a C1-C30 heteroarylthiol group, a C1-C30 phosphoric acid amide group, a silyl group (SiR 1 R 2 R 3 )(R 1 , R 2 , and R 3 are each independently a hydrogen atom, a C1-C30 alkyl group or a C6-C30 aryl group), an amine group (-NRR') (wherein R and R' are each independently a substituent selected from the group consisting of a hydrogen atom, a C1-C30 alkyl group, and a C6-C30 aryl group).), a carboxyl group, a halogen group, a cyano group, a nitro group, an azo group, and a hydroxy group, which means that it is substituted with a substituent selected from the group consisting of these groups.

[0039] Also, among the above substituents, two adjacent substituents may combine to form a saturated or unsaturated ring.

[0040] In addition, the range of the number of carbon atoms of the alkyl group or aryl group in the "substituted or unsubstituted C1-C30 alkyl group" or "substituted or unsubstituted C6-C30 aryl group" means the total number of carbon atoms constituting the alkyl part or aryl part when regarded as unsubstituted without considering the substituted part of the substituent. For example, a phenyl group substituted with a butyl group at the para position corresponds to an aryl group having 6 carbon atoms substituted with a butyl group having 4 carbon atoms.

[0041] In this specification, "hydrogen" means deuterium, dihydrogen, or tritium unless otherwise defined.

[0045] A The alkyl group may be branched, or linear in the form of and may be.

[0046] The alkyl group may be a C1-C30 alkyl group. More specifically, it may be a C1-C20 alkyl group, a C1-C10 alkyl group, or a C1-C6 alkyl group.

[0047] For example, a C1-C4 alkyl group has 1 to 4 carbon atoms in the alkyl chain, that is, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0048] Specific examples include the alkyl group being a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, a hexyl group What does it mean.

[0049] On the one hand, in this specification, the term "comprising as an active ingredient" means containing an amount sufficient to achieve the efficacy or activity of the 2,6-diarylbenzoxazole derivative or a pharmaceutically acceptable salt thereof. As an example, the 2,6-diarylbenzoxazole derivative or a pharmaceutically acceptable salt thereof may be used at a concentration of 10 to 1500 μg / μl, preferably 100 to 1000 μg / ml. However, the scope of the present invention is not limited thereto, and those skilled in the art can select and implement the upper limit of the amount of the 2,6-diarylbenzoxazole derivative contained in the pharmaceutical composition of the present invention within an appropriate range.

[0050] Hereinafter, the compound for inhibiting 5-HT 7 receptor activity of the present invention or a pharmaceutically acceptable salt thereof will be described.

[0051] The 5-HT 7 compound for inhibiting serotonin receptor activity of the present invention is represented by the following Structural Formula 1 or 2.

[0052]

Chemical formula

[0053] In Structural Formula 1 or 2, R 1 ~R 8 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0054] Preferably, the compound represented by Structural Formula 1 or 2 may be the one represented by the following Structural Formula 3 or 4.

[0055]

Chemical formula

[0056] In Structural Formula 3 or 4, R 9 ~R 16They are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0057] Preferably, R 9 ~R 16 may be the same as or different from each other, and each independently may be a hydrogen atom, a chloro group, a C1-C4 alkyl group, or a C1-C4 alkoxy group.

[0058] Most preferably, the compound represented by the structural formula 1 or 2 may be any one selected from the following Compounds 1 to 44.

[0059]

Chemical formula

[0060] The pharmaceutically acceptable salt may be a salt formed using any one inorganic acid or organic acid selected from hydrochloric acid, bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, p-toluenesulfonic acid, and methanesulfonic acid.

[0061] Hereinafter, a method for producing a compound for inhibiting 5-HT 7 serotonin receptor activity or a pharmaceutically acceptable salt thereof will be described.

[0062] The method for producing a compound for inhibiting 5-HT 7 serotonin receptor activity or a pharmaceutically acceptable salt thereof represented by the following structural formula 1 or 2 of the present invention may include a step of reacting a compound represented by the following structural formula A with pyrrolidine or ethylenediamine.

[0063]

Chemical formula

[0064] In Structural Formula 1 or 2, R 1 ~R 8 are the same as or different from each other and are each independently a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, In Structural Formula B, R 17 ~R 20 are the same as or different from each other and are each independently a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0065] Preferably, the compound represented by the above Structural Formula 1 or 2 may be represented by the following Structural Formula 3 or 4, and the compound represented by the above Structural Formula A may be represented by the following Structural Formula B.

[0066]

Chemical formula

[0067] In Structural Formula 3 or 4, R 9 ~R 16 are the same as or different from each other and are each independently a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, In Structural Formula B, R 21 ~R 24 are the same as or different from each other and are each independently a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0068] The compound represented by the above Structural Formula B may be produced by subjecting the compound represented by the following Structural Formula C and the compound represented by the following Structural Formula D to a Suzuki reaction.

[0069]

Chem.

[0070] In the structural formula C or D, X 1 is a bromo group or an iodo group, R 25 and R 26 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0071] Preferably, R 25 is a hydrogen atom, and X 1 may be a bromo group.

[0072] Also preferably, R 26 is a chloro group, and X 1 may be an iodo group.

[0073] The present invention provides a pharmaceutical composition for preventing or treating central nervous system diseases, containing as an active ingredient a compound represented by the following structural formula 1 or 2 or a pharmaceutically acceptable salt thereof.

[0074]

Chem.

[0075] In the structural formula 1 or 2, R 1 ~R 8 are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

[0076] The description of the compound represented by the above structural formula 1 or 2 is as described above, and the specific content is referred to that part.

[0077] The central nervous system disease may be any one disease selected from sleep disorder, depression, migraine, anxiety, pain, inflammatory pain, neuropathic pain, thermoregulatory disorder, biological rhythm regulatory disorder, autism spectrum disorder, and smooth muscle disorder.

[0078] In addition to the active ingredient, the pharmaceutical composition of the present invention may be manufactured using pharmaceutically compatible and physiologically acceptable adjuvants. As the adjuvants, excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, lubricating agents, flavoring agents, etc. can be used.

[0079] For administration, the pharmaceutical composition may further contain one or more pharmaceutically acceptable carriers in addition to the active ingredient described above, and can be suitably formulated as a pharmaceutical composition.

[0080] The dosage form of the pharmaceutical composition may be granules, powders, tablets, coated tablets, capsules, suppositories, liquids, syrups, juices, suspensions, emulsions, drip agents, injectable liquids, etc. For example, for formulation into the form of tablets or capsules, the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Also, if desired or necessary, appropriate binders, lubricants, disintegrants, and coloring agents may also be included in the mixture. Appropriate binders include, but are not limited to, starches, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starches, methylcellulose, agar, bentonite, xanthan gum, etc.

[0081] In the composition formulated as a liquid solution, acceptable pharmaceutical carriers are those that are sterile and biocompatible, such as saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components can be mixed and used. If necessary, other common additives such as antioxidants, buffers, bacteriostatic agents, etc. can be added. Further, diluents, dispersants, surfactants, binders, and lubricants can be added to formulate into dosage forms for injection such as aqueous solutions, suspensions, emulsions, pills, capsules, granules, or tablets.

[0082] The pharmaceutical composition of the present invention can be administered orally or parenterally. In the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc., and preferably, it is oral administration.

[0083] The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, administration method, patient's age, weight, gender, pathological condition, diet, administration time, administration route, excretion rate, and reactivity. A skilled ordinary physician can easily determine and prescribe a dosage effective for the desired treatment or prevention. According to a preferred embodiment of the present invention, the daily dosage of the pharmaceutical composition of the present invention is 0.001 - 10 g / kg.

[0084] The pharmaceutical composition of the present invention may be manufactured in the form of a unit dosage or filled into a multi-dose container by formulating using a pharmaceutically acceptable carrier and / or excipient. At this time, the dosage form may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granule, tablet, or capsule, and may further contain a dispersant or stabilizer.

[0085] Further, the present invention provides the use of the compound represented by the structural formula 1 or 2 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating central nervous system diseases.

[0086] The present invention also relates to a method for treating central nervous system diseases, which comprises administering to a mammal a compound represented by the structural formula 1 or 2 or a pharmaceutically acceptable salt thereof.

[0087] 〔Example〕 <Example 1. Preparation of Compound 1> (Step 1: Preparation of [1,1'-biphenyl]-3-carbaldehyde) 3-Bromobenzaldehyde (1.0 mmol), phenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol) were dissolved in tetrahydrofuran (10 ml), and then heated to reflux at 70 °C for 24 hours. After the temperature was lowered to room temperature, distilled water was added to the reaction mixture, and the organic layer obtained by extraction with dichloromethane was dried over anhydrous magnesium sulfate and then filtered. The concentrated solution obtained by concentrating the filtrate under reduced pressure was separated by column chromatography (hexane:ethyl acetate = 20:1) to obtain a compound (91% yield).

[0088]

Chemical formula

[0089] 1 H NMR (400 MHz, CDCl 3 ) δ 10.12 (s, 1H), 8.13 (t, J = 1.8 Hz, 1H), 7.89 (dd, J = 7.7, 1.8 Hz, 2H), 7.68 - 7.61 (m, 3H), 7.54 - 7.48 (m, 2H), 7.46 - 7.41 (m, 1H) 13 C NMR (100 MHz, CDCl 3 ) δ 192.35, 142.19, 139.72, 136.95, 133.08, 129.52, 129.03, 128.65, 128.22, 128.04, 127.17 (Step 2: Production of (1-(1,1'-Biphenyl-3-ylmethyl)pyrrolidine)) Into a reaction vessel, [1,1'-Biphenyl]-3-carbaldehyde (1.0 mmol) and pyrrolidine (2.0 mmol) produced in Step 1 were added and dissolved in methanol, then acetic acid (1.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (3.0 mmol) was added to the reaction mixture and stirred for 24 hours. A saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer obtained by extraction with dichloromethane was dried over anhydrous magnesium sulfate and then filtered. The concentrated solution obtained by concentrating the filtrate under reduced pressure was separated by column chromatography (hexane:ethyl acetate = 3:1) to obtain Compound 1 (36% yield).

[0090]

Chemical formula

[0091] 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 - 7.61 (m, 2H), 7.61 - 7.58 (m, 1H), 7.53 - 7.49 (m, 1H), 7.49 - 7.39 (m, 3H), 7.39 - 7.32 (m, 2H), 3.72 (s, 2H), 2.61 - 2.51 (m, 4H), 1.85 - 1.79 (m, 4H) 13 C NMR (100MHz, CDCl 3 ) δ 141.50, 140.80, 136.50, 128.99, 128.78, 128.47, 128.43, 127.42, 127.20, 126.65, 59.54, 53.30, 23.28 <Example 2: Production of 1-((2'-Chloro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthesis method of Example 1, 3-Bromobenzaldehyde (1.0 mmol), 2-Chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 )2 (0.1 mmol) and Na 2 CO 3 Using the compound 2'-chloro-[1,1'-biphenyl]-3-carbaldehyde (85% yield) obtained with (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol), compound 2 (86% yield) was obtained.

[0092] [Chemical formula]

[0093] 1 H NMR (400 MHz, CDCl3) δ 7.42 - 7.31 (m, 2H), 7.34 - 7.27 (m, 2H), 7.30 - 7.23 (m, 2H), 7.21(dd, J = 7.1, 1.9 Hz, 2H), 3.62 (s, 2H), 2.52 - 2.46 (m, 4H), 1.77 - 1.69 (m, 4H) 13 C NMR (100 MHz, CDCl3) δ 140.59, 139.32, 139.17, 132.55, 131.45, 130.00, 129.91, 128.45, 128.20, 127.98, 127.94, 126.76, 60.63, 54.19, 23.50 <Example 3: Preparation of 1-((3'-chloro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthesis method of Example 1, 3-bromobenzaldehyde (1.0 mmol), 3-chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3Compound 3'-chloro-[1,1'-biphenyl]-3-carbaldehyde (86% yield) obtained using [[ID=]] (4.0 mmol) was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain Compound 3 (85% yield).

[0094] [Chemical formula]

[0095] 1 H NMR (400 MHz, CDCl3) δ 7.63 (t, J = 1.9 Hz, 1H), 7.57 (t, J = 1.8 Hz, 1H), 7.51 (dt, J = 7.5, 1.6 Hz, 1H), 7.48 (dt, J = 7.5, 1.7 Hz, 1H), 7.44 - 7.35 (m, 3H), 7.35 - 7.31 (m, 1H), 3.71 (s, 2H), 2.60 - 2.54 (m, 4H), 1.87 - 1.80 (m, 4H) 13 C NMR (100MHz, CDCl3) δ 143.11, 140.19, 139.77, 134.60, 129.93, 128.80, 128.48, 127.60, 127.35, 127.21, 125.69, 125.39, 60.74, 54.26, 23.51 <Example 4: Preparation of 1-((4'-chloro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthetic method of Example 1, 3-bromobenzaldehyde (1.0 mmol), 4-chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3Compound 4'-chloro-[1,1'-biphenyl]-3-carbaldehyde (78% yield) obtained using [[ID=]] (4.0 mmol) was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain Compound 4 (77% yield).

[0096]

Chem.

[0097] 1 H NMR (400 MHz, CDCl3) δ 7.59 - 7.53 (m, 3H), 7.47 (dt, J = 7.6, 1.7 Hz, 1H), 7.45 - 7.39 (m, 3H), 7.36 (dt, J = 7.4, 1.7 Hz, 1H), 3.71 (s, 2H), 2.62 - 2.53 (m, 4H), 1.87 - 1.79 (m, 4H) 13 C NMR (100MHz, CDCl3) δ 140.12, 139.95, 139.69, 133.30, 128.84, 128.78, 128.47, 128.20, 127.49, 125.57, 60.74, 54.25, 23.50 <Example 5: Preparation of 1-((2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthetic method of Example 1, 3-bromobenzaldehyde (1.0 mmol), 2-methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), Compound 2'-methyl-[1,1'-biphenyl]-3-carbaldehyde (93% yield) was obtained. This was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain Compound 5 (68% yield).

[0098] [Chemical formula]

[0099] 1 H NMR (400 MHz, CDCl3) δ 7.43 - 7.32 (m, 2H), 7.36 - 7.25 (m, 4H), 7.29 - 7.21 (m, 2H), 3.70 (s, 2H), 2.62 - 2.50 (m, 4H), 2.31 (s, 3H), 1.89 - 1.75 (m, 4H) 13 C NMR (100MHz, CDCl3) δ 141.98, 141.84, 139.17, 135.35, 130.26, 129.83, 129.77, 127.96, 127.73, 127.40, 127.18, 125.70, 60.72, 54.19, 23.49, 20.53 <Example 6: Preparation of 1 - ((3’ - methyl - [1,1’ - biphenyl] - 3 - yl)methyl)pyrrolidine> Using the synthesis method of Example 1, 3 - bromobenzaldehyde (1.0 mmol), 3 - methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 3’ - methyl - [1,1’ - biphenyl] - 3 - carbaldehyde (95% yield) obtained was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain compound 6 (83% yield).

[0100] [Chemical formula]

[0101] 11H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 1.9 Hz, 1H), 7.54 - 7.49 (dt, J = 7.5, 1.7 Hz, 1H), 7.47 - 7.39 (m, 3H), 7.38 - 7.33 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 3.74 (s, 2H), 2.64 - 2.67 (m, 4H), 2.45 (s, 3H), 1.89 - 1.80 (m, 4H) 13 13C NMR (100MHz, CDCl3) δ 141.32, 141.19, 138.28, 128.65, 128.62, 128.03, 127.98, 127.91, 127.81, 125.86, 124.35, 60.72, 54.16, 23.46, 21.56 <Example 7: Preparation of 1 - ((4'-methyl - [1,1'-biphenyl] - 3 - yl)methyl)pyrrolidine> Using the synthetic method of Example 1, 3 - bromobenzaldehyde (1.0 mmol), 4 - methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 4'-methyl - [1,1'-biphenyl] - 3 - carbaldehyde (96% yield) obtained was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain Compound 7 (52% yield).

[0102]

Chemical Structure

[0103] 11H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 1.8 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.50 (dt, J = 7.6, 1.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.34 (dt, J = 7.6, 1.6 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 3.73 (s, 2H), 2.63 - 2.56 (m, 4H), 2.43 (s, 3H), 1.89 - 1.79 (m, 4H) 13 13C NMR (100MHz, CDCl3) δ 141.11, 139.67, 138.36, 136.95, 129.42, 128.63, 127.65, 127.56, 127.07, 125.59, 60.76, 54.18, 23.50, 21.11 <Example 8: Preparation of 1-((2'-Methoxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Compound 2'-Methoxy-[1,1'-biphenyl]-3-carbaldehyde (92% yield) obtained using 3-bromobenzaldehyde (1.0 mmol), 2-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 2 3 CO

[0104]

Chemical formula

[0105] 11H NMR (400 MHz, CDCl3) δ 7.52 (t, J = 1.8 Hz, 1H), 7.49 - 7.44 (dt, J = 7.3, 1.7 Hz, 1H), 7.42 - 7.31 (m, 4H), 7.08 - 7.02 (td, J = 7.5, 1.1 Hz, 1H), 7.02 - 6.98 (dd, J = 8.2, 1.1 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 2H), 2.71 - 2.55 (m, 4H), 1.90 - 1.80 (m, 4H) 13 13C NMR (100MHz, CDCl3) δ 156.49, 138.46, 138.25, 130.96, 130.67, 130.24, 128.59, 128.30, 127.93, 127.68, 120.82, 111.24, 60.56, 55.58, 54.02, 23.46 <Example 9: Preparation of 1-((3'-methoxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Compound 3'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (96% yield) obtained using 3-bromobenzaldehyde (1.0 mmol), 3-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 2 3 CO

[0106]

Chemical formula

[0107] 11H NMR (400 MHz, CDCl3) δ 7.48 (t, J = 1.7 Hz, 1H), 7.42 - 7.37 (dt, J = 7.5, 1.7 Hz, 1H), 7.33 - 7.22 (m, 3H), 7.14 - 7.09 (dt, J = 7.7, 1.3 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.84 - 6.78 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 3.78 (s, 3H), 3.61 (s, 2H), 2.48 (m, 4H), 1.76 - 1.68 (m, 4H) 13 13C NMR (100MHz, CDCl3) δ 159.93, 142.79, 141.06, 139.74, 129.69, 128.66, 128.09, 127.78, 125.84, 119.80, 112.99, 112.65, 60.74, 55.35, 54.21, 23.50 <Example 10: Preparation of 1-((4'-methoxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthetic method of Example 1, 3-bromobenzaldehyde (1.0 mmol), 4-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 4'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (91% yield) was obtained. Then, using pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol), compound 10 (95% yield) was obtained.

[0108] [Chemical formula]

[0109] 11H NMR (400 MHz, CDCl3) δ 7.61 - 7.55 (m, 3H), 7.50 - 7.45 (m, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.03 - 6.98 (m, 2H), 3.88 (s, 3H), 3.72 (s, 2H), 2.63 - 2.56 (m, 4H), 1.88 - 1.80 (m, 4H) 13 13C NMR (100MHz, CDCl3) δ 159.13, 140.78, 139.64, 133.77, 128.65, 128.24, 127.35, 127.32, 125.37, 114.15, 60.80, 55.36, 54.22, 23.50 <Example 11: Preparation of 1-((2’,6’-dimethoxy-[1,1’-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthetic method of Example 1, 3-bromobenzaldehyde (1.0 mmol), 2,6-dimethoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 2’,6’-dimethoxy-[1,1’-biphenyl]-3-carbaldehyde (89% yield) was obtained. Then, using pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol), compound 11 (66% yield) was obtained.

[0110]

Chemical Structure

[0111] 11H NMR (400 MHz, CDCl3) δ 7.38 - 7.33 (m, 1H), 7.31 - 7.27 (m, 2H), 7.27 - 7.22 (m, 2H), 6.64 (d, J = 8.4 Hz, 2H), 3.71 (s, 6H), 3.70 (s, 2H), 2.61 - 2.56 (m, 4H), 1.82 - 1.77 (m, 4H) 13 13C NMR (100MHz, CDCl3) δ 157.70, 137.63, 133.93, 131.80, 129.61, 128.59, 127.60, 127.55, 119.59, 104.31, 60.49, 55.93, 53.88, 23.47 <Example 12: Preparation of 1-((6-chloro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> (Step 1: Preparation of 4-chloro-3-iodobenzaldehyde) Iodine (0.44 mmol) and sodium iodate (0.22 mmol) were placed in a reaction vessel and dissolved in sulfuric acid (10 ml), and then stirred for 30 minutes. 4-Chlorobenzaldehyde was added to the reaction mixture and stirred at room temperature for 2 hours. The temperature was lowered to 0 °C, distilled water was added to the reaction mixture, and the resulting solid was filtered. The filtered solid was placed in a sodium thiosulfate solution and extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was separated by column chromatography (hexane:ethyl acetate = 10:1) to obtain the compound (73% yield).

[0112]

Chemical formula

[0113] 1 1H NMR (400 MHz, CDCl 3 ) δ 9.85 (s, 1H), 8.28 (d, J = 1.9 Hz, 1H), 7.73 (dd, J = 8.2, 1.9 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H) 13 C NMR (100 MHz, CDCl 3 ) δ 189.41, 145.07, 141.38, 135.70, 130.01, 129.96, 98.84 (Step 2: Preparation of 6-chloro-[1,1'-biphenyl]-3-carbaldehyde) 4-Chloro-3-iodobenzaldehyde (1.0 mmol), phenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol) were dissolved in tetrahydrofuran (10 ml), and then heated to reflux at 70 °C for 24 hours. After the temperature was lowered to room temperature, distilled water was added to the reaction mixture, and the organic layer obtained by extraction with dichloromethane was dried over anhydrous magnesium sulfate and then filtered. The concentrated solution obtained by concentrating the filtrate under reduced pressure was separated by column chromatography (hexane:ethyl acetate = 20:1) to obtain the compound (96% yield).

[0114]

Chemical formula

[0115] 1 H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 7.88 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.55 - 7.43 (m, 5H) 13 C NMR (100MHz, CDCl3) δ 190.96, 141.56, 139.21, 138.09, 135.02, 132.62, 130.90, 129.33, 129.05, 128.32, 128.27. (Step 3: Preparation of 1-((6-chloro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine) 6-Chloro-[1,1'-biphenyl]-3-carbaldehyde (1.0 mmol) and pyrrolidine (2.0 mmol) were placed in a reaction vessel, dissolved in methanol, then acetic acid (1.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (3.0 mmol) was added to the reaction mixture, and the mixture was stirred for 24 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the organic layer obtained by extraction with dichloromethane was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution obtained was separated by column chromatography (hexane:ethyl acetate = 3:1) to obtain compound 12 (44% yield).

[0116] [Chemical formula]

[0117] 1 H NMR (400 MHz, CDCl3) δ 7.51 - 7.38 (m, 6H), 7.35 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 8.0, 2.4 Hz, 1H), 3.65 (s, 2H), 2.60 - 2.51 (m, 4H), 1.86 - 1.78 (m, 4H) 13 C NMR (100MHz, CDCl3) δ 140.19, 139.48, 138.37, 131.75, 130.78, 129.73, 129.52, 128.96, 127.99, 127.54, 59.93, 54.19, 23.50 <Example 13: Preparation of 1-((2',6-dichloro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> In the synthesis method of Example 12, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3Compound 13 (58% yield) was obtained using 2’,6-dichloro-[1,1’-biphenyl]-3-carbaldehyde (87% yield) obtained using [[ID=]] (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol).

[0118] [Chemical formula]

[0119] 1 H NMR (400 MHz, CDCl3) δ 7.49 - 7.45 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.34 - 7.27 (m, 4H), 7.25 (d, J = 2.1 Hz, 1H), 3.62 (s, 2H), 2.55 - 2.49 (m, 4H), 1.79 (m, 4H) 13 C NMR (100MHz, CDCl3) δ 138.43, 138.09, 138.01, 133.55, 131.73, 131.52, 131.29, 129.64, 129.41, 129.18, 129.15, 126.44, 59.85, 54.14, 23.51 <Example 14: Preparation of 1-((3’,6-dichloro-[1,1’-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthetic method of Example 12, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 Compound 14 (60% yield) was obtained using 3’,6-dichloro-[1,1’-biphenyl]-3-carbaldehyde (85% yield) obtained using (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol).

[0120]

Chem.

[0121] 1 1H NMR (400 MHz, CDCl3) δ 7.45 - 7.42 (m, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.36 - 7.31 (m, 3H), 7.30 - 7.25 (m, 2H), 3.61 (s, 2H), 2.55 - 2.47 (m, 4H), 1.83 - 1.75 (m, 4H) 13 13C NMR (100MHz, CDCl3) δ 141.16, 138.82, 138.64, 133.86, 131.49, 130.64, 129.82, 129.59, 129.42, 129.22, 127.81, 127.66, 59.88, 54.21, 23.51 <Example 15: Preparation of 1 - ((4’,6 - dichloro - [1,1’ - biphenyl] - 3 - yl)methyl)pyrrolidine> Using the synthetic method of Example 12, 4 - chloro - 3 - iodobenzaldehyde (1.0 mmol), 4 - chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 4’,6 - dichloro - [1,1’ - biphenyl] - 3 - carbaldehyde (77% yield) obtained was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain compound 15 (42% yield).

[0122]

Chem.

[0123] 11H NMR (400 MHz, CDCl3) δ 7.41 - 7.37 (m, 5H), 7.29 - 7.24 (m, 2H), 3.61 (s, 2H), 2.55 - 2.48 (m, 4H), 1.82 - 1.75 (m, 4H) 13 13C NMR (100MHz, CDCl3) δ 139.00, 138.62, 137.84, 133.64, 131.49, 130.88, 130.67, 129.82, 129.26, 128.22, 59.89, 54.21, 23.51 <Example 16: Preparation of 1-((6-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthetic method of Example 12, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 6-chloro-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde (97% yield) obtained was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain Compound 16 (62% yield).

[0124]

Chemical formula

[0125] 1 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.2 Hz, 1H), 7.37 - 7.29 (m, 1H), 7.33 - 7.22 (m, 3H), 7.23 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 7.4, 1.4 Hz, 1H), 3.65 (s, 2H), 2.60 - 2.50 (m, 4H), 2.15 (s, 3H), 1.82 (m, 4H) 13 13C NMR (100 MHz, CDCl3) δ 140.27, 139.44, 137.99, 136.24, 131.71, 131.40, 129.76, 129.45, 129.15, 129.04, 127.85, 125.46, 59.88, 54.13, 23.49, 19.84 <Example 17: Preparation of 1-((6-chloro-3'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthetic method of Example 12, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 6-chloro-3'-methyl-[1,1'-biphenyl]-3-carbaldehyde (97% yield) thus obtained was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain Compound 17 (60% yield).

[0126]

Chemical Structure

[0127] 1 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.1 Hz, 1H), 7.24 - 7.15 (m, 5H), 7.11 (d, J = 7.2 Hz, 1H), 3.54 (s, 2H), 2.44 (m, 4H), 2.33 (s, 3H), 1.76 - 1.68 (m, 4H) 1313C NMR (100 MHz, CDCl3) δ 140.32, 139.41, 138.20, 137.61, 131.75, 130.79, 130.17, 129.68, 128.88, 128.29, 127.85, 126.60, 59.93, 54.17, 23.49, 21.49 <Example 18: Preparation of 1-((6-chloro-4'-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthetic method of Example 12, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 6-chloro-4'-methyl-[1,1'-biphenyl]-3-carbaldehyde (64% yield) obtained was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain the compound (68% yield).

[0128] [Chemical formula]

[0129] 1 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 7.33 (d, J = 2.1 Hz, 1H), 7.29 - 7.25 (m, 3H), 3.65 (s, 2H), 2.55 (m, 4H), 2.44 (s, 3H), 1.87 - 1.76 (m, 4H) 13 13C NMR (100 MHz, CDCl3) δ 140.15, 138.20, 137.31, 136.57, 131.78, 130.85, 129.71, 129.38, 128.78, 128.72, 59.90, 54.15, 23.49, 21.27 <Example 19: Preparation of 1-((6-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthetic method of Example 12, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 6-chloro-2'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (55% yield) obtained was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain Compound 19 (72% yield).

[0130]

Chemical Structure

[0131] 1 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.33 (m, 2H), 7.28 - 7.22 (m, 2H), 7.22 - 7.17 (dd, J = 7.5, 1.8 Hz, 1H), 7.03 - 6.98 (td, J = 7.5, 1.1 Hz, 1H), 6.98 - 6.94 (dd, J = 7.2, 1.2 Hz, 1H), 3.77 (s, 3H), 3.61 (s, 2H), 2.56 - 2.46 (m, 4H), 1.83 - 1.74 (m, 4H) 13 13C NMR (100 MHz, CDCl3) δ 156.80, 137.78, 137.40, 132.23, 132.09, 131.10, 129.30, 129.07, 128.97, 128.67, 120.32, 111.01, 59.94, 55.64, 54.16, 23.51 <Example 20: Preparation of 1-((6-chloro-3'-methoxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthesis method of Example 12, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 6-chloro-3'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (45% yield) was obtained. Then, using pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol), compound 20 was obtained (86% yield).

[0132]

Chemical Structure

[0133] 1 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.1 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.33 - 7.29 (dd, J = 8.2, 2.2 Hz, 1H), 7.10 - 7.06 (dt, J = 7.6, 1.2 Hz, 1H), 7.05 (t, J = 2.1 Hz, 1H), 6.99 - 6.93 (dd, J = 8.2, 2.2 Hz, 1H), 3.87 (s, 3H), 3.66 (s, 2H), 2.56 (m, 4H), 1.83 (m, 4H) 13 13C NMR (100 MHz, CDCl3) δ 159.20, 140.80, 140.07, 138.19, 131.69, 130.80, 129.77, 129.05, 129.02, 121.99, 115.24, 113.15, 59.87, 55.33, 54.18, 23.51 <Example 21: Preparation of 1-((6-chloro-4'-methoxy-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine> Using the synthesis method of Example 12, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 6-chloro-4'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (55% yield) was obtained. Using pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol), compound 21 was obtained (84% yield).

[0134]

Chemical formula

[0135] 1 H NMR (400 MHz, CDCl3) δ 7.45 - 7.39 (m, 3H), 7.33 (d, J = 2.2 Hz, 1H), 7.28 - 7.24 (dd, J = 8.1, 2.2 Hz, 1H), 7.01 - 6.97 (m, 2H), 3.88 (s, 3H), 3.64 (s, 2H), 2.59 - 2.52 (m, 4H), 1.85 - 1.79 (m, 4H) 13 C NMR (100 MHz, CDCl3) δ 159.08, 139.81, 138.18, 131.86, 131.77, 130.92, 130.68, 129.73, 128.65, 113.43, 59.92, 55.30, 54.17, 23.49 <Example 22: Preparation of 1-((6-chloro-2,6'-dimethoxy-[1,1'-biphenyl]-3-ylmethyl)pyrrolidine> Using the synthesis method of Example 12, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2,6-dimethoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3Compound 6-chloro-2’,6’-dimethoxy-[1,1’-biphenyl]-3-carbaldehyde (92% yield) obtained using (4.0 mmol) was reacted with pyrrolidine (2.0 mmol), acetic acid (1.0 mmol), and sodium triacetoxyborohydride (3.0 mmol) to obtain compound 22 (70% yield).

[0136]

Chem.

[0137] 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.1 Hz, 1H), 7.31 (t, J = 8.3 Hz, 1H), 7.24 (dd, J = 8.2, 2.1 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 6.64 (d, J = 8.4 Hz, 2H), 3.72 (s, 6H), 3.62 (s, 2H), 2.56 - 2.50 (m, 4H), 1.81 - 1.75 (m, 4H) 13 C NMR (100 MHz, CDCl3) δ 157.85, 137.14, 133.43, 133.02, 133.00, 129.39, 128.93, 128.89, 117.17, 104.11, 59.88, 55.99, 53.98, 23.49 <Example 23: Preparation of 2-([1,1’-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> (Step 1: Preparation of [1,1’-biphenyl]-3-carbaldehyde) In a reaction vessel, 3-bromobenzaldehyde (1.0 mmol), phenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3(4.0 mmol) was dissolved in tetrahydrofuran (10 ml), and then heated under reflux at 70 °C for 24 hours. After the temperature was lowered to room temperature, distilled water was added to the reaction mixture, and the organic layer obtained by extraction with dichloromethane was dried over anhydrous magnesium sulfate and then filtered. The concentrated solution obtained by concentrating the filtrate under reduced pressure was separated by column chromatography (hexane:ethyl acetate = 20:1) to obtain the target compound (91% yield).

[0138] [Chemical formula]

[0139] 1 H NMR (400 MHz, CDCl 3 ) δ 10.12 (s, 1H), 8.13 (t, J = 1.8 Hz, 1H), 7.89 (dd, J = 7.7, 1.8 Hz, 2H), 7.68 - 7.61 (m, 3H), 7.54 - 7.48 (m, 2H), 7.46 - 7.41 (m, 1H) 13 C NMR (100 MHz, CDCl 3 ) δ 192.35, 142.19, 139.72, 136.95, 133.08, 129.52, 129.03, 128.65, 128.22, 128.04, 127.17 (Step 2: Preparation of 2-([1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole) Into the reaction vessel, [1,1'-biphenyl]-3-carbaldehyde (1.0 mmol) and ethylenediamine (1.2 mmol) prepared in Step 1 were placed and dissolved in dichloromethane, and then stirred at 0 °C for 1 hour. After adding N-bromosuccinimide (1.2 mmol) to the reaction mixture under the same temperature condition, it was stirred for 24 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the organic layer obtained by extraction with dichloromethane was dried over anhydrous magnesium sulfate and then filtered. The concentrated solution obtained by concentrating the filtrate under reduced pressure was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 23 (53% yield).

[0140]

Chem.

[0141] 1 1H NMR (400 MHz, DMSO-d6) δ 8.12 (t, J = 1.8 Hz, 1H), 7.87 - 7.82 (dt, J = 7.7, 1.4 Hz, 1H), 7.78 - 7.74 (dt, J = 7.8, 1.5 Hz, 1H), 7.74 - 7.69 (m, 2H), 7.56 - 7.46 (m, 3H), 7.44 - 7.36 (m, 1H), 3.64 (s, 4H) 13 13C NMR (100 MHz, DMSO-d6) δ 163.99, 140.54, 140.16, 131.73, 129.46, 129.33, 128.86, 128.17, 127.22, 126.64, 125.81, 50.12 <Example 24: Preparation of 2-(2'-chloro-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 23, 3-bromobenzaldehyde (1.0 mmol), 2-chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 2'-chloro-[1,1'-biphenyl]-3-carbaldehyde (85% yield) obtained was reacted with ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol) to obtain Compound 24 (90% yield).

[0142]

Chem.

[0143] 11H NMR (400 MHz, DMSO-d6) δ 7.91 - 7.86 (m, 2H), 7.61 - 7.57 (m, 1H), 7.57 - 7.52 (m, 2H), 7.47 - 7.42 (m, 3H), 3.64 (s, 4H) 13 13C NMR (100 MHz, DMSO-d6) δ 163.88, 139.75, 139.14, 131.97, 131.78, 131.68, 130.62, 130.33, 129.93, 128.68, 128.46, 128.05, 126.99, 49.81 <Example 25: Preparation of 2-(3'-chloro-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 23, 3'-chloro-[1,1'-biphenyl]-3-carbaldehyde (86% yield) obtained with 3-bromobenzaldehyde (1.0 mmol), 3-chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), and compound 25 (65% yield) was obtained using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

[0144]

Chemical Structure

[0145] 11H NMR (400 MHz, DMSO-d6) δ 8.17 (t, J = 1.8 Hz, 1H), 7.95 - 7.90 (m, 1H), 7.84 (dt, J = 8.0, 1.4 Hz, 1H), 7.81 (t, J = 1.9 Hz, 1H), 7.71 (dt, J = 7.6, 1.4 Hz, 1H), 7.54 (dt, J = 16.0, 7.8 Hz, 2H), 7.46 (dt, J = 8.2, 1.4 Hz, 1H), 3.71 (s, 4H) 13 13C NMR (100 MHz, DMSO-d6) δ 164.03, 142.03, 139.07, 134.32, 131.30, 130.42, 129.63, 129.62, 128.11, 127.50, 126.97, 126.15, 125.94, 49.24 <Example 26: Preparation of 2-(4'-chloro-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 23, 3-bromobenzaldehyde (1.0 mmol), 4-chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 4'-chloro-[1,1'-biphenyl]-3-carbaldehyde (78% yield) was obtained. Then, using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol), the compound (58% yield) was obtained.

[0146]

Chemical Structure

[0147] 11H NMR (400 MHz, DMSO-d6) δ 8.11 (t, J = 1.8 Hz, 1H), 7.88 - 7.84 (dt, J = 7.7, 1.4 Hz, 1H), 7.79 - 7.73 (m, 3H), 7.58 - 7.51 (m, 3H), 3.65 (s, 4H) 13 13C NMR (100 MHz, DMSO-d6) δ 163.89, 139.19, 138.91, 133.10, 131.62, 129.47, 129.43, 128.98, 128.88, 127.00, 125.74, 50.01 <Example 27: Preparation of 2-(2'-methyl-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 23, 3-bromobenzaldehyde (1.0 mmol), 2-methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 2'-methyl-[1,1'-biphenyl]-3-carbaldehyde (93% yield) was obtained, and then using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol), compound 27 (27% yield) was obtained.

[0148]

Chemical formula

[0149] 1 1H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.84 (dt, J = 7.7, 1.6 Hz, 1H), 7.82 - 7.79 (t, J = 1.7 Hz, 1H), 7.54 - 7.47 (t, J = 7.6 Hz, 1H), 7.47 - 7.42 (dt, J = 7.6, 1.5 Hz, 1H), 7.33 - 7.21 (m, 4H), 3.64 (s, 4H), 2.23 (s, 3H) 13 C NMR (100 MHz, DMSO-d6) δ 164.04, 141.69, 141.20, 135.19, 131.42, 130.83, 130.54, 129.97, 128.66, 128.14, 128.03, 126.46, 126.26, 49.77, 20.58 <Example 28: Preparation of 2-(3'-methyl-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 23, 3-bromobenzaldehyde (1.0 mmol), 3-methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 3'-methyl-[1,1'-biphenyl]-3-carbaldehyde (95% yield) thus obtained was reacted with ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol) to obtain Compound 28 (54% yield).

[0150]

Chemical Structure

[0151] 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (t, J = 1.8 Hz, 1H), 7.85 - 7.81 (dt, J = 7.8, 1.4 Hz, 1H), 7.77 - 7.72 (dt, J = 7.9, 1.4 Hz, 1H), 7.55 - 7.47 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 3.64 (s, 4H), 2.40 (s, 3H) 1313C NMR (100 MHz, DMSO-d6) δ 163.99, 140.62, 140.11, 138.62, 131.68, 129.35, 129.27, 128.83, 128.80, 127.85, 126.54, 125.77, 124.33, 50.21, 21.58 <Example 29: Preparation of 2-(4'-methyl-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 23, 3-bromobenzaldehyde (1.0 mmol), 4-methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 4'-methyl-[1,1'-biphenyl]-3-carbaldehyde (96% yield) obtained was reacted with ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol) to obtain Compound 29 (47% yield).

[0152] [Chemical formula]

[0153] 1 1H NMR (400 MHz, DMSO-d6) δ 8.12 - 8.09 (t, J = 1.8 Hz, 1H), 7.84 - 7.79 (dt, J = 7.8, 1.4 Hz, 1H), 7.78 - 7.73 (dt, J = 8.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.33 - 7.28 (m, 2H), 3.66 (s, 4H), 2.36 (s, 3H) 1313C NMR (100 MHz, DMSO-d6) δ 164.11, 140.47, 137.57, 137.14, 131.12, 130.06, 129.35, 128.85, 127.03, 126.40, 125.60, 49.75, 21.15 <Example 30: Preparation of 2-(2'-Methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 23, 3-bromobenzaldehyde (1.0 mmol), 2-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 2'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (92% yield) was obtained, and then using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol), compound 30 (82% yield) was obtained.

[0154] [Chemical formula]

[0155] 1 1H NMR (400 MHz, DMSO-d6) δ 7.91 (t, J = 1.8 Hz, 1H), 7.80 - 7.76 (dt, J = 7.7, 1.4 Hz, 1H), 7.59 - 7.54 (dt, J = 7.7, 1.4 Hz, 1H), 7.48 - 7.42 (t, J = 7.7 Hz, 1H), 7.41 - 7.35 (ddd, J = 8.2, 7.3, 1.8 Hz, 1H), 7.34 -7.30 (dd, J = 7.5, 1.8 Hz, 1H), 7.16 - 7.11 (dd, J = 8.3, 1.1 Hz, 1H), 7.08 - 7.03 (td, J = 7.4, 1.1 Hz, 1H), 3.77 (s, 3H), 3.62 (s, 4H) 1313C NMR (100 MHz, DMSO-d6) δ 164.14, 156.58, 138.57, 131.56, 130.93, 130.90, 129.80, 129.60, 128.43, 128.29, 126.05, 121.25, 112.21, 55.99, 50.05 <Example 31: Preparation of 2-(3'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 23, 3-bromobenzaldehyde (1.0 mmol), 3-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 3'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (96% yield) was obtained. Then, using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol), compound 31 (73% yield) was obtained.

[0156]

Chemical Structure

[0157] 1 1H NMR (400 MHz, DMSO-d6) δ 8.08 (t, J = 1.7 Hz, 1H), 7.88 - 7.82 (dt, J = 7.7, 1.3 Hz, 1H), 7.79 - 7.74 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.31 - 7.25 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.25 - 7.23 (m, 1H), 7.00 - 6.95 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 3.84 (s, 3H), 3.64 (s, 4H) 1313C NMR (100 MHz, DMSO-d6) δ 163.94, 160.27, 141.66, 140.42, 131.67, 130.53, 129.28, 128.98, 126.79, 125.83, 119.55, 113.73, 112.75, 55.64, 50.07 <Example 32: Preparation of 2-(4'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 23, 3-bromobenzaldehyde (1.0 mmol), 4-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 4'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (91% yield) was obtained. Then, using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol), compound 32 (60% yield) was obtained.

[0158]

Chemical Structure

[0159] 1 1H NMR (400 MHz, DMSO-d6) δ 8.07 (t, J = 1.8 Hz, 1H), 7.82 - 7.77 (dt, J = 7.7, 1.4 Hz, 1H), 7.74 - 7.69 (dt, J = 7.9, 1.4 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.48 (t, J = 7.7 Hz, 1H), 7.08 - 7.02 (m, 2H), 3.81 (s, 3H), 3.64 (s, 4H) 13 13C NMR (100 MHz, DMSO-d6) δ 164.08, 159.56, 140.17, 132.46, 131.64, 129.24, 128.33, 128.30, 125.93, 125.27, 114.88, 55.65, 50.06 <Example 33: Preparation of 2-(2’,6’-Dimethoxy-[1,1’-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 23, 3-bromobenzaldehyde (1.0 mmol), 2,6-dimethoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 2’,6’-dimethoxy-[1,1’-biphenyl]-3-carbaldehyde (89% yield) was obtained, and then using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol), compound 33 (55% yield) was obtained.

[0160]

Chemical Structure

[0161] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 - 7.74 (dt, J = 7.8, 1.5 Hz, 1H), 7.68 (t, J = 1.7 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.36 - 7.28 (m, 2H), 6.76 (d, J = 8.4 Hz, 2H), 3.66 (s, 6H), 3.62 (s, 4H) 13 C NMR (100 MHz, DMSO-d6) δ 164.31, 157.61, 134.76, 133.36, 130.02, 129.98, 129.70, 128.00, 125.87, 118.56, 104.81, 56.16, 49.71 <Example 34: Preparation of 2-(6-Chloro-[1,1’-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> (Step 1: Preparation of 4-Chloro-3-iodobenzaldehyde) The target compound was synthesized in the same method as in Step 1 of Example 12.

[0162] (Step 2: Production of 6-chloro-[1,1'-biphenyl]-3-carbaldehyde) The target compound was synthesized in the same manner as in Step 2 of Example 12.

[0163] (Step 3: Production of 2-(6-chloro-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole) 6-Chloro-[1,1'-biphenyl]-3-carbaldehyde (1.0 mmol) and ethylenediamine (1.2 mmol) were placed in a reaction vessel, dissolved in dichloromethane, and stirred at 0 °C for 1 hour. After adding N-bromosuccinimide (1.2 mmol) to the reaction mixture under the same temperature conditions, the mixture was stirred for 24 hours. A saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer obtained by extraction with dichloromethane was dried over anhydrous magnesium sulfate and then filtered. The concentrated solution obtained by concentrating the filtrate under reduced pressure was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 34 (34% yield).

[0164] [Chemical formula]

[0165] 1 H NMR (400 MHz, DMSO-d6) δ 7.88 - 7.84 (m, 2H), 7.67 - 7.63 (m, 1H), 7.53 - 7.43 (m, 5H), 3.64 (s, 4H) 13 C NMR (100 MHz, DMSO-d6) δ 163.01, 140.09, 138.73, 133.68, 130.49, 130.33, 129.87, 129.69, 128.77, 128.47, 128.17, 49.92 <Example 35: Production of 2-(2',6-dichloro-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole>[[]] ​Using the synthetic method of Example 34, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 2’,6-dichloro-[1,1’-biphenyl]-3-carbaldehyde (87% yield) was obtained. Using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol), compound 35 (50% yield) was obtained.

[0166]

Chemical formula

[0167] 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (dd, J = 8.4, 2.2 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.51 - 7.44 (m, 2H), 7.41 - 7.36 (m, 1H), 3.63 (s, 4H) 13 C NMR (100 MHz, DMSO-d6) δ 162.84, 138.08, 137.74, 134.85, 132.82, 131.73, 130.60, 130.26, 129.78, 129.76, 129.61, 128.92, 127.78, 49.93 <Example 36: Preparation of 2-(3’,6-dichloro-[1,1’-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 34, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-chlorophenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3Compound 36 (49% yield) was obtained using compound 3’,6-dichloro-[1,1’-biphenyl]-3-carbaldehyde (85% yield) obtained using [[ID=]] (4.0 mmol), ethylenediamine (1.2 mmol), and N-bromosuccinimide (1.2 mmol).

[0168] [Chemical formula]

[0169] 1 H NMR (400 MHz, DMSO-d6) δ 7.93 - 7.89 (m, 2H), 7.73 - 7.68 (m, 1H), 7.58 - 7.51 (m, 3H), 7.49 - 7.44 (m, 1H), 3.70 (s, 4H) 13 C NMR (100 MHz, DMSO-d6) δ 163.10, 140.49, 138.74, 134.29, 133.46, 130.69, 130.68, 130.61, 129.45, 128.87, 128.68, 128.58, 128.57, 49.13 [Example 37: Preparation of 2-(4’,6-dichloro-[1,1’-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole] Using the synthesis method of Example 34, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-chlorophenylboronic acid (1.2 mmol), PdCl 2 [(PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), compound 4’,6-dichloro-[1,1’-biphenyl]-3-carbaldehyde (77% yield) obtained was used with ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol) to obtain compound 37 (43% yield).

[0170] [Chemical formula]

[0171] 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.86 (m, 2H), 7.67 - 7.64 (m, 1H), 7.58 - 7.54 (m, 2H), 7.52 - 7.48 (m, 2H), 3.64 (s, 4H) 13 C NMR (100 MHz, DMSO-d6) δ 162.96, 138.84, 137.46, 133.71, 133.44, 131.59, 130.42, 129.82, 128.81, 128.52, 49.83 <Example 38: Preparation of 2-(6-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> The compound 6-chloro-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde (97% yield) obtained using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol) in the synthesis method of Example 34, and compound 38 (57% yield) was obtained using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

[0172]

Chemical formula

[0173] 11H NMR (400 MHz, DMSO-d6) δ 7.89 (dd, J = 8.4, 2.2 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.36 - 7.32 (m, 2H), 7.32 - 7.26 (m, 1H), 7.17 - 7.12 (m, 1H), 3.65 (s, 4H), 2.06 (s, 3H) 13 13C NMR (100 MHz, DMSO-d6) δ 163.07, 140.29, 138.76, 135.93, 134.95, 130.34, 130.21, 129.82, 129.64, 129.10, 128.71, 128.39, 126.28, 49.59, 19.84 <Example 39: Preparation of 2-(6-chloro-3'-methyl-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Compound 6-chloro-3'-methyl-[1,1'-biphenyl]-3-carbaldehyde (76% yield) obtained using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol) in the synthesis method of Example 34 was reacted with ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol) to obtain Compound 39 (47% yield).

[0174]

Chemical Structure

[0175] 11H NMR (400 MHz, DMSO-d6) δ 7.87 - 7.81 (m, 2H), 7.66 - 7.61 (m, 1H), 7.38 (td, J = 7.3, 1.1 Hz, 1H), 7.29 - 7.22 (m, 3H), 3.65 (s, 4H), 2.38 (s, 3H) 13 13C NMR (100 MHz, DMSO-d6) δ 163.08, 140.24, 138.66, 138.02, 133.82, 130.51, 130.33, 130.21, 129.56, 129.08, 128.62, 128.11, 126.80, 49.75, 21.46 <Example 40: Preparation of 2-(6-chloro-4'-methyl-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 34, 6-chloro-4'-methyl-[1,1'-biphenyl]-3-carbaldehyde (64% yield) obtained using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-methylphenylboronic acid (1.2 mmol), PdCl 2 (PPh 3 ) 2 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), and compound 40 (76% yield) was obtained using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

[0176]

Chemical Structure

[0177] 1 1H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.82(m, 2H), 7.67 - 7.61 (m, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 3.66 (s, 4H), 2.37 (s, 3H) 1313C NMR (100 MHz, DMSO-d6) δ 163.17, 140.11, 137.87, 135.75, 134.03, 130.57, 130.37, 129.57, 129.32, 128.04, 49.58, 21.26 <Example 41: Preparation of 2-(6-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 34, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 6-chloro-2'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (55% yield) was obtained, and then using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol), compound 41 (96% yield) was obtained.

[0178]

Chemical Structure

[0179] 1 1H NMR (400 MHz, DMSO-d6) δ 7.85 - 7.81 (dd, J = 8.3, 2.2 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.43 (ddd, J = 8.2, 7.4, 1.8 Hz, 1H), 7.20 - 7.16 (dd, J = 7.4, 1.8 Hz, 1H), 7.15 - 7.11 (dd, J = 8.4, 1.0 Hz, 1H), 7.07 - 7.02 (td, J = 7.4, 1.0 Hz, 1H), 3.73 (s, 3H), 3.62 (s, 4H) 1313C NMR (100 MHz, DMSO-d6) δ 163.09, 156.78, 137.79, 135.38, 130.96, 130.81, 130.30, 129.51, 129.45, 128.02, 127.78, 120.80, 111.83, 55.88, 49.96 <Example 42: Preparation of 2-(6-chloro-3'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 34, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 6-chloro-3'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (45% yield) was obtained, and then using ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol), compound 42 (37% yield) was obtained.

[0180]

Chemical Structure

[0181] 1 1H NMR (400 MHz, DMSO-d6) δ 7.88 - 7.83 (m, 2H), 7.65 - 7.59 (m, 1H), 7.44 - 7.37 (m, 1H), 7.05 - 6.99 (m, 3H), 3.81 (s, 3H), 3.62 (s, 4H) 13 13C NMR (100 MHz, DMSO-d6) δ 162.95, 159.50, 140.09, 139.92, 133.51, 130.35, 130.28, 130.13, 129.85, 128.17, 121.99, 115.35, 113.96, 55.65, 50.11 <Example 43: Preparation of 2-(6-chloro-4'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 34, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-methoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO 3 (4.0 mmol), the compound 6-chloro-4'-methoxy-[1,1'-biphenyl]-3-carbaldehyde (55% yield) obtained was reacted with ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol) to obtain compound 43 (72% yield).

[0182]

Chemical formula

[0183] 1 H NMR (400 MHz, DMSO-d6) δ 7.87 - 7.79 (m, 2H), 7.63 (d, J = 8.3 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.08 - 7.02 (m, 2H), 3.82 (s, 3H), 3.65 (s, 4H) 13 C NMR (100 MHz, DMSO-d6) δ 163.16, 159.51, 139.81, 133.99, 130.98, 130.85, 130.54, 130.37, 129.44, 127.80, 114.20, 55.68, 49.66 <Example 44: Preparation of 2-(6-chloro-2',6'-dimethoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole> Using the synthetic method of Example 34, 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2,6-dimethoxyphenylboronic acid (1.2 mmol), Pd(PPh 3 ) 4 (0.1 mmol) and Na 2 CO3 Compound 6-chloro-2’,6’-dimethoxy-[1,1’-biphenyl]-3-carbaldehyde (92% yield) obtained using (4.0 mmol) was reacted with ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol) to obtain Compound 44 (67% yield).

[0184] 1 H NMR (400 MHz, DMSO-d6) δ 7.99 - 7.94 (dd, J = 8.4, 2.4 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.43 (t, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H), 3.98 (s, 4H), 3.69 (s, 6H) 13 C NMR (100 MHz, DMSO-d6) δ 164.29, 157.57, 140.66, 135.57, 132.84, 131.09, 130.55, 129.11, 121.70, 114.77, 104.69, 56.30, 45.21 [Production Example] The biphenylpyrrolidine / dihydroimidazole derivative synthesized in the above Example was formulated in various forms.

[0185] [Production Example 1: Pressurized Tablets] 5.0 mg of the active ingredient synthesized in the Example was sieved, and then mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate, and then compressed into tablets.

[0186] [Production Example 2: Wet Granulation Tablets] 5.0 mg of the active ingredient synthesized in the Example was sieved, and then mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water, an appropriate amount of this solution was added, and then atomized. After drying, the fine particles were sieved, and then mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The fine particles were compressed into tablets.

[0187] <Production Example 3: Powder and Capsule>[[]] After sieving 5.0 mg of the active ingredient synthesized in the example, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg of magnesium stearate, and then filled into hard No. 5 gelatin capsules.

[0188] <Production Example 4: Injection>[[]] 100 mg of the compound of the example was contained as the active ingredient, and 180 mg of mannitol, Na 2 HPO 4 ·12H 2 O 26 mg and 2974 mg of distilled water were contained to produce an injection.

[0189] 〔Test Example〕 Test Example 1: 5-HT 7 Measurement of Serotonin Receptor Activity Inhibition Rate a) cAMP assays For the cAMP assay based on luminescence, HEK293 cells were cultured in a 150 mm container. Before transfection, the culture medium was changed from DMEM containing 10% FBS, 100 U / mL penicillin, and 100 μg / ml streptomycin to DMEM containing 10% dialyzed FBS, 100 U / mL penicillin, and 100 μg / ml streptomycin. After 4 hours, human 5-HT 7 ​​Transfection was performed with 10 μg of R plasmid and 10 μg of GloSensor-22F plasmid (Promega). The transfected cells were prepared in 384-well flat-bottom white clear-bottom plates (Greiner) (15,000 cells / well, 20 μg / well). After removing the culture medium 6 hours later, 20 μg of 3% Glosensor cAMP reagent containing luciferin in 1X HBSS, 1M HEPES, pH 7.4 buffer was taken for each cell. In addition, the compounds according to the examples of the present invention were prepared at different concentrations in an assay buffer containing 0.1% bovine serum albumin. After 30 minutes, 10 μg of the novel compound solution was taken for each cell. The luminescence level was measured using a Tecan microplate reader Spark, and the IC 50 value was obtained using the Prism 8.0 program (GraphPad Software).

[0190] Table 1 below shows the results of the 5-HT 7 serotonin receptor activity inhibition rate (%) of Examples 1 to 22 which are biphenylpyrrolidine derivatives, and Table 2 shows the 5-HT 7 serotonin receptor activity inhibition rate (%) of Examples 23 to 44 which are biphenyldihydroimidazole derivatives.

[0191] In addition, Table 3 below shows the measurement results of the IC 50 value of the examples which are biphenylpyrrolidine derivatives, and Table 4 shows the measurement results of the IC 50 value of the examples which are biphenyldihydroimidazole derivatives.

[0192]

Table 1

[0193]

Table 2

[0194]

Table 3

[0195]

Table 4

[0196] b) Tango assay To examine the activity in the beta-arrestin signaling system, a Tango assay was performed using the HTLA cell line. The culture medium used was DMEM containing 10% FBS, 100 U / μg penicillin and 100 μg / ml streptomycin, 2 μg / ml puromycin, and 100 μg / ml hygromycin B. Before transfection, it was changed to DMEM containing 10% dialyzed FBS, 100 U / mL penicillin and 100 μg / ml streptomycin. After 4 hours, 5-HT 7 R-TCS-tTA construct (5-HT 7 R Tango DNA) 20 μg was used for transfection. The transfected cells were prepared in a 384-well flat-bottom white clear-bottom plate (Greiner) using DMEM containing 1% dialyzed FBS, 100 U / μg penicillin and 100 μg / ml streptomycin (15,000 cells / well, 20 μg / well). After 6 hours, 10 μg each of the freshly prepared compound solutions at different concentrations in the same culture medium were taken. After 22 hours of culture, the culture medium was removed, and then 20 μL each of BrightGlo reagent (Promega) diluted in 1X HBSS, 1 M HEPES, pH 7.4 buffer was taken. The luminescence level was measured using a Tecan microplate reader Spark, and graphs and IC 50 values were obtained using the Prism 8.0 program (GraphPad Software).

[0197] Table 5 below shows the results of the 5-HT 7 serotonin receptor activity inhibition rate (%) for Examples 1 to 22 which are biphenylpyrrolidine derivatives, and Table 6 shows the 5-HT 7 serotonin receptor activity inhibition rate (%) for Examples 23 to 44 which are biphenyldihydroimidazole derivatives.

[0198] Also, Table 7 below shows the measurement results of the IC 50 values for Example 1 which is a biphenylpyrrolidine derivative and the Examples which are biphenyldihydroimidazole derivatives.

[0199] [Table 5]

[0200] [Table 6]

[0201] [Table 7]

[0202] Test Example 2: Schild plot experiment for the Tango assay To examine the activity of the β-arrestin mediated signaling pathway for a specific compound, a Schild plot experiment for the Tango assay was conducted. The culture and the culture medium were changed as in b) of Test Example 1, and cells were prepared for transfection and plating. After 6 hours, 10 μg of serotonin solution prepared at different concentrations in the same culture medium, and 10 μg each at different concentrations where the final concentration of the specific compound was 5 μM, 10 μM, and 30 μM were taken. After culturing for 22 hours, the degree of luminescence was measured using a Tecan microplate reader Spark, and a graph and EC 50The value was obtained, and Excel was utilized to obtain the pA 2 value. For Compound 23 and Compound 30 according to the examples of the present invention, the pA 2 value was measured using a Schild plot for the Tango assay, and the results were tabulated in Figure 1, Figure 2, and Table 8 below.

[0203]

Table 8

[0204] Accordingly, the biphenylpyrrolidine / dihydroimidazole derivatives according to the present invention exhibit antagonistic activity against 5-HT 7 receptors, and as a result of the Schild plot, it was understood that they are competitive inhibitors in terms of mechanism.

[0205] Despite the differences in the structure and physical properties of the substituents due to the type of substituents, the reaction principles and conditions of the above examples may also be applicable to the compounds according to the present invention containing substituents not included in the above examples. Therefore, it is obvious that a person skilled in the art can easily manufacture and confirm compounds containing substituents not included in the above examples based on the disclosure content of the above examples and common knowledge in the industry.

Brief Description of the Drawings

[0206]

Figure 1

Figure 2

Claims

1. A compound for inhibiting 5-HT serotonin receptor activity or a pharmaceutically acceptable salt thereof, which is represented by the following structural formula 3 or 4; ７ ​ 【Chemical 1】 represented by Structural Formula 3 or 4, (i) R ９ and R １３ are the same as or different from each other, and each independently is a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, R １０ to R １２ and R １４ to R １６ are the same as or different from each other and are each independently a hydrogen atom, a halogen group, an unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, or (ii) R ９ and R １０ are hydrogen atoms, and R １１ and R １２ are the same as or different from each other and are each independently a halogen group, a C1-C10 alkyl group, or a C2-C10 alkoxy group.

2. (i) R ９ and R １３ are the same as or different from each other, and each independently is a chloro group, a C1-C4 alkyl group, or a C1-C4 alkoxy group, R １０ to R １２ and R １４ to R １６ are the same as or different from each other, and each independently is a hydrogen atom, a chloro group, a C1-C4 alkyl group, or a C1-C4 alkoxy group, or, (ii) R ９ and R １０ are hydrogen atoms, and R １１ and R １２ are the same as or different from each other and are each independently a chloro group, a C1-C4 alkyl group, or a C2-C4 alkoxy group, and the 5-HT ７ compound for inhibiting 5-hydroxytryptamine receptor activity or a pharmaceutically acceptable salt thereof.

3. A compound for inhibiting 5-HT serotonin receptor activity, which is any one selected from the following compounds 2 to 22, 24 to 28, and 32 to 44, or a pharmaceutically acceptable salt thereof. ７ ​ 【Chemical 2】 【Chem.】 【Chem.】

4. The pharmaceutically acceptable salt is a salt formed by using any one inorganic acid or organic acid selected from hydrochloric acid, bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, p-toluenesulfonic acid, and methanesulfonic acid, and is characterized in that it is a 5-HT according to claim 1 or 3 ７ Compound for inhibiting 5-hydroxytryptamine receptor activity or a pharmaceutically acceptable salt thereof.

5. A method for producing a compound for inhibiting 5-HT ７ serotonin receptor activity, comprising reacting a compound represented by the following structural formula B with pyrrolidine; ７ ​ [Chemical 3] represented by Structural Formula 3, R ９ is a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, R １０ to R １２ are the same as or different from each other and are each independently a hydrogen atom, a halogen group, an unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, represented by Structural Formula B, R ２１ is a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, R ２２ ~R ２４ are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, an unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, or, represented by Structural Formula 3, R ９ and R １０ are hydrogen atoms, and R １１ and R １２ are the same as or different from each other and are each independently a halogen group, a C1-C10 alkyl group, or a C2-C10 alkoxy group, represented by Structural Formula B, R ２１ and R ２２ is a hydrogen atom, and R ２３ and R ２４ are the same as or different from each other and are each independently a halogen group, a C1-C10 alkyl group, or a C2-C10 alkoxy group.

6. A method for producing a compound for inhibiting 5-HT7 serotonin receptor activity, represented by the following Structural Formula 4, comprising reacting a compound represented by the following Structural Formula B with ethylenediamine; 【Chemical 4】 represented by Structural Formula 4, R １３ is a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, R １４ to R １６ are the same as or different from each other and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, represented by Structural Formula B, R ２１ is a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, R ２２ to R ２４ are the same as or different from each other, and each independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

7. The compound represented by the structural formula B is produced by subjecting the compound represented by the following structural formula C and the compound represented by the following structural formula D to a Suzuki reaction, and is the 5-HT according to claim 5 ７ Process for producing a compound for inhibiting serotonin receptor activity; [Chemical Formula 5] represented by Structural Formula C or D, X １ is a bromo group or an iodo group, R ２５ is a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, R ２６ is a hydrogen atom, a halogen group, an unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, or represented by Structural Formula C or D, X １ is a bromo group or an iodo group, R ２５ is a hydrogen atom, and R ２６ is a halogen group, a C1-C10 alkyl group, or a C2-C10 alkoxy group.

8. The method for producing a compound for inhibiting 5-HT7 serotonin receptor activity according to Claim 6, wherein the compound represented by the Structural Formula B is produced by subjecting a compound represented by the following Structural Formula C and a compound represented by the following Structural Formula D to a Suzuki reaction; 【Chemical Formula 6】 represented by Structural Formula C or D, X １ is a bromo group or an iodo group, R ２５ is a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, R ２６ is a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

9. R ２５ is a hydrogen atom, and X １ is a bromo group, and a method for producing a 5-HT ７ serotonin receptor activity inhibitory compound or a pharmaceutically acceptable salt thereof.

10. R ２６ is a chloro group, and X １ is an iodo group, and a method for producing a 5-HT ７ serotonin receptor activity inhibitory compound or a pharmaceutically acceptable salt thereof according to claim 7 or 8.

11. A pharmaceutical composition for preventing or treating central nervous system diseases, comprising a compound represented by the following Structural Formula 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient; 【Chemical Formula 7】 represented by Structural Formula 1 or 2, R １ to R ８ are the same as or different from each other and are each independently a hydrogen atom, a halogen group, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group.

12. The pharmaceutical composition for preventing or treating central nervous system diseases according to Claim 11, wherein the compound represented by the Structural Formula 1 or 2 is any one selected from the following Compounds 1 to 44. [Chemical Formula 8] 【Chem.】 [Chemical]

13. The pharmaceutical composition for preventing or treating central nervous system diseases according to Claim 11, wherein the central nervous system disease is any one selected from sleep disorder, depression, migraine, anxiety, pain, inflammatory pain, neuropathic pain, thermoregulatory disorder, biological rhythm regulatory disorder, autism spectrum disorder, and smooth muscle disorder.

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