BIPHENYL PYRROLIDINE AND BIPHENYL DIHYDROIMIDAZOLE DERIVATIVES FOR INHIBITING ACTIVITY OF 5-HT7 SEROTONIN RECEPTOR, AND PHARMACEUTICAL COMPOSITION COMPRISING SAME AS ACTIVE INGREDIENT

Abstract

The present disclosure relates to a compound represented by Structural Formula 1 or 2 or a pharmaceutically acceptable salt thereof, for inhibiting the activity of the 5-HT.sub.7 serotonin receptor.

Claims

1. A compound for inhibiting the activity of the 5-HT.sub.7 serotonin receptor, which is represented by Structural Formula 1 or 2, or a pharmaceutically acceptable salt thereof: ##STR00078## wherein each of R.sup.1 to R.sup.8, which are identical to or different from each other, is independently a hydrogen atom, a halogen group, a substituted or unsubstituted C.sub.1-C.sub.10 alkyl group or a substituted or unsubstituted C.sub.1-C.sub.10 alkoxy group.

2. The compound for inhibiting the activity of the 5-HT.sub.7 serotonin receptor or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by Structural Formula 1 or 2 is represented by Structural Formula 3 or 4: ##STR00079## wherein each of R.sup.9 to R.sup.16, which are identical to or different from each other, is independently is a hydrogen atom, a halogen group, a substituted or unsubstituted C.sub.1-C.sub.10 alkyl group or a substituted or unsubstituted C.sub.1-C.sub.10 alkoxy group.

3. The compound for inhibiting the activity of the 5-HT.sub.7 serotonin receptor or a pharmaceutically acceptable salt thereof according to claim 2, wherein each of R.sup.9 to R.sup.16, which are identical to or different from each other, is independently a hydrogen atom, a chloro group, a C.sub.1-C.sub.4 alkyl group or a C.sub.1-C.sub.4 alkoxy group.

4. The compound for inhibiting the activity of the 5-HT.sub.7 serotonin receptor or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by Structural Formula 1 or 2 is any one selected from the following compounds 1-44: ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085##

5. The compound for inhibiting the activity of the 5-HT.sub.7 serotonin receptor or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a salt formed using any 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.

6-13. (canceled)

Description

BRIEF DESCRIPTION OF DRAWINGS

[0041] FIGS. 1A and 1B show results of Tango assay in Test Example 2.

[0042] FIG. 2 shows a result of measuring the pA.sub.2 value using a Schild plot for Tango assay in Test Example 2.

BEST MODE

[0043] The present disclosure may be changed variously and may have various exemplary embodiments. Hereinafter, the specific exemplary embodiments of the present disclosure will be described in detail. However, the present disclosure is not limited to specific exemplary embodiments but encompasses all changes, equivalents and substitutes included within the technical idea and scope of the present disclosure. When describing the present disclosure, detailed description of well-known matters may be omitted to avoid unnecessarily obscuring the present disclosure.

[0044] The term “substituted” means that at least one hydrogen atom is substituted with a substituent selected from a group consisting of deuterium, a C.sub.1-C.sub.30 alkyl group, a C.sub.3-C.sub.30 cycloalkyl group, a C.sub.2-C.sub.30 heterocycloalkyl group, a C.sub.1-C.sub.30 haloalkyl group, a C.sub.6-C.sub.30 aryl group, a C.sub.1-C.sub.30 heteroaryl group, a C.sub.1-C.sub.30 alkoxy group, a C.sub.3-C.sub.30 cycloalkoxy group, a C.sub.1-C.sub.30 heterocycloalkoxy group, a C.sub.2-C.sub.30 alkenyl group, a C.sub.2-C.sub.30 alkynyl group, a C.sub.6-C.sub.30 aryloxy group, a C.sub.1-C.sub.30 heteroaryloxy group, a silyloxy group (—OSiH.sub.3), —OSiR.sup.1H.sub.2 (R.sup.1 is a C.sub.1-C.sub.30 alkyl group or a C.sub.6-C.sub.30 aryl group), —OSiR.sup.1R.sup.2H (each of R.sup.1 and R.sup.2 is independently a C.sub.1-C.sub.30 alkyl group or a C.sub.6-C.sub.30 aryl group), —OSiR.sup.1R.sup.2R.sup.3 (each of R.sup.1, R.sup.2 and R.sup.3 is independently a C.sub.1-C.sub.30 alkyl group or a C.sub.6-C.sub.30 aryl group), a C.sub.1-C.sub.30 acyl group, a C.sub.2-C.sub.30 acyloxy group, a C.sub.2-C.sub.30 heteroaryloxy group, a C.sub.1-C.sub.30 sulfonyl group, a C.sub.1-C.sub.30 alkylthio group, a C.sub.3-C.sub.30 cycloalkylthio group, a C.sub.1-C.sub.30 heterocycloalkylthio group, a C.sub.6-C.sub.30 arylthio group, a C.sub.1-C.sub.30 heteroarylthio group, a C.sub.1-C.sub.30 phosphoramide group, a silyl group (SiR.sup.1R.sup.2R.sup.3) (each of R.sup.1, R.sup.2 and R.sup.3 is independently a hydrogen atom, a C.sub.1-C.sub.30 alkyl group or a C.sub.6-C.sub.30 aryl group), an amine group (—NRR′) (each of R and R′ is independently a substituent selected from a group consisting of a hydrogen atom, a C.sub.1-C.sub.30 alkyl group and a C.sub.6-C.sub.30 aryl group), a carboxyl group, a halogen group, a cyano group, a nitro group, an azo group and a hydroxyl group.

[0045] In addition, two neighboring substituents may be fused to form a saturated or unsaturated ring.

[0046] The number of carbons in the alkyl group or the aryl group of “substituted or unsubstituted C.sub.1-C.sub.30 alkyl group”, “substituted or unsubstituted C.sub.6-C.sub.30 aryl group”, etc. means the number of the carbons constituting the alkyl or aryl moiety without considering the substituent. For example, a phenyl group in which a butyl group is substituted at the para-position is a C.sub.6 aryl group substituted with a C.sub.4 butyl group.

[0047] In the present specification, “hydrogen” refers to hydrogen, deuterium or tritium unless defined otherwise.

[0048] In the present specification, the term “alkyl group” refers to an aliphatic hydrocarbon group unless defined otherwise.

[0049] The alkyl group may be a “saturated alkyl group” containing no double or triple bond.

[0050] The alkyl group may also be an “unsaturated alkyl group” containing at least one double or triple bond.

[0051] The alkyl group may be branched, straight or cyclic whether it is saturated or unsaturated.

[0052] The alkyl group may be a C.sub.1-C.sub.30 alkyl group. More specifically, it may be a C.sub.1-C.sub.20 alkyl group, a C.sub.1-C.sub.10 alkyl group or a C.sub.1-C.sub.6 alkyl group.

[0053] For example, a C.sub.1-C.sub.4 alkyl group has 1-4 carbon atoms in the alkyl chain. That is to say, the C.sub.1-C.sub.4 alkyl group may be selected from a group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

[0054] As specific examples, the alkyl group may be 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, an ethenyl group, a propenyl group, a butenyl group, a cyclopropyl group, a cyclobutyl group, a cyclopenyl group, a cyclohexyl group, etc.

[0055] In the present specification, the expression ‘containing as an active ingredient’ means that the 2,6-diarylenebenzoxazole derivative or a pharmaceutically acceptable salt thereof is contained in an amount sufficient to achieve the desired efficacy or activity. For example, the 2,6-diarylenebenzoxazole derivative or a pharmaceutically acceptable salt thereof may be used at a concentration of 10-1500 μg/mL, specifically 100-1000 μg/mL. However, the scope of the present disclosure is not limited thereto and the upper limit of the amount of the 2,6-diarylenebenzoxazole derivative contained in the pharmaceutical composition of the present disclosure may be selected adequately by those skilled in the art.

[0056] Hereinafter, the compound for inhibiting the activity of the 5-HT7 serotonin receptor or a pharmaceutically acceptable salt thereof of the present disclosure will be described in detail.

[0057] The compound for inhibiting the activity of the 5-HT.sub.7 serotonin receptor of the present disclosure is represented by Structural Formula 1 or 2.

##STR00019##

[0058] In Structural Formula 1 or 2,

[0059] each of R.sup.1 to R.sup.8, which are identical to or different from each other, is independently a hydrogen atom, a halogen group, a substituted or unsubstituted C.sub.1-C.sub.10 alkyl group or a substituted or unsubstituted C.sub.1-C.sub.10 alkoxy group.

[0060] Specifically, the compound represented by Structural Formula 1 or 2 may be represented by Structural Formula 3 or 4.

##STR00020##

[0061] In Structural Formula 3 or 4,

[0062] each of R.sup.9 to R.sup.16, which are identical to or different from each other, is independently a hydrogen atom, a halogen group, a substituted or unsubstituted C.sub.1-C.sub.10 alkyl group or a substituted or unsubstituted C.sub.1-C.sub.10 alkoxy group.

[0063] Specifically, each of R.sup.9 to R.sup.16, which are identical to or different from each other, may independently be a hydrogen atom, a chloro group, a C.sub.1-C.sub.4 alkyl group or a C.sub.1-C.sub.4 alkoxy group.

[0064] Most specifically, the compound represented by Structural Formula 1 or 2 may be any one selected from the following compounds 1-44.

##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026##

[0065] The pharmaceutically acceptable salt may be a salt formed using any 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.

[0066] Hereinafter, a method for preparing the compound for inhibiting the activity of the 5-HT.sub.7 serotonin receptor or a pharmaceutically acceptable salt thereof according to the present disclosure will be described.

[0067] The method for preparing the compound for inhibiting the activity of the 5-HT.sub.7 serotonin receptor or a pharmaceutically acceptable salt thereof according to the present disclosure may include a step of reacting a compound represented by Structural Formula A with pyrrolidine or ethylenediamine.

##STR00027##

[0068] In Structural Formula 1 or 2,

[0069] each of R.sup.1 to R.sup.8, which are identical to or different from each other, is independently a hydrogen atom, a halogen group, a substituted or unsubstituted C.sub.1-C.sub.10 alkyl group or a substituted or unsubstituted C.sub.1-C.sub.10 alkoxy group, and,

[0070] in Structural Formula B,

[0071] each of R.sup.17 to R.sup.20, which are identical to or different from each other, is independently a hydrogen atom, a halogen group, a substituted or unsubstituted C.sub.1-C.sub.10 alkyl group or a substituted or unsubstituted C.sub.1-C.sub.10 alkoxy group.

[0072] Specifically, the compound represented by Structural Formula 1 or 2 may be represented by Structural Formula 3 or 4, and the compound represented by Structural Formula A may be represented by Structural Formula B.

##STR00028##

[0073] In Structural Formula 3 or 4,

[0074] each of R.sup.9 to R.sup.16, which are identical to or different from each other, is independently a hydrogen atom, a halogen group, a substituted or unsubstituted C.sub.1-C.sub.10 alkyl group or a substituted or unsubstituted C.sub.1-C.sub.10 alkoxy group, and,

[0075] in Structural Formula A,

[0076] each of R.sup.21 to R.sup.24, which are identical to or different from each other, is independently a hydrogen atom, a halogen group, a substituted or unsubstituted C.sub.1-C.sub.10 alkyl group or a substituted or unsubstituted C.sub.1-C.sub.10 alkoxy group.

[0077] The compound represented by Structural Formula B may be prepared by the Suzuki reaction of a compound represented by Structural Formula C with a compound represented by Structural Formula D.

##STR00029##

[0078] In Structural Formula C or D,

[0079] X.sub.1 is a bromo group or an iodo group, and

[0080] each of R.sup.25 and R.sup.26, which are identical to or different from each other, is independently a hydrogen atom, a halogen group, a substituted or unsubstituted C.sub.1-C.sub.10 alkyl group or a substituted or unsubstituted C.sub.1-C.sub.10 alkoxy group.

[0081] Specifically, R.sup.25 may be a hydrogen atom and X.sub.1 may be a bromo group.

[0082] Also, specifically, R.sup.26 may be a chloro group and X.sub.1 may be an iodo group.

[0083] The present disclosure provides a pharmaceutical composition for preventing or treating a central nervous system disease, which contains a compound represented by Structural Formula 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

##STR00030##

[0084] In Structural Formula 1 or 2,

[0085] each of R.sup.1 to R.sup.8, which are identical to or different from each other, is independently a hydrogen atom, a halogen group, a substituted or unsubstituted C.sub.1-C.sub.10 alkyl group or a substituted or unsubstituted C.sub.1-C.sub.10 alkoxy group.

[0086] The description about the compound represented by Structural Formula 1 or 2 will be omitted because it was described in detail above.

[0087] The central nervous system disease may be any disease selected from sleep disorder, depression, migraine, anxiety, pain, inflammatory pain, neuropathic pain, thermoregulation disorder, biorhythm disorder, autism spectrum disorder and smooth muscle disorder.

[0088] The pharmaceutical composition of the present disclosure may be prepared using a pharmaceutically acceptable and physiologically allowed adjuvant in addition to the active ingredient. The adjuvant may be an excipient, a disintegrant, a sweetener, a binder, a coating agent, a swelling agent, a lubricant, a glidant, a flavorant, etc.

[0089] The pharmaceutical composition may be prepared into a formulation using one or more pharmaceutically acceptable carrier in addition to the active ingredient described above.

[0090] The pharmaceutical composition may be prepared into a formulation such as a granule, a powder, a tablet, a coated tablet, a capsule, a suppository, a liquid, a syrup, a juice, a suspension, an emulsion, a medicinal drop, an injectable liquid, etc. For example, for formulation into a tablet or a capsule, the active ingredient may be bound to an oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Also, if desired or necessary, a suitable binder, lubricant, disintegrant or coloring agent may be added. The suitable binder includes but is not limited to starch, gelatin, natural sugar such as glucose or β-lactose, corn sweetener, natural or synthetic gum such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. The disintegrant includes but is not limited to starch, methyl cellulose, agar, bentonite, xanthan gum, etc.

[0091] For a composition formulated into a liquid solution, one or more of saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol and ethanol may be added as an acceptable pharmaceutical carrier suitable for sterilization and biological use and, if necessary, another common additive such as an antioxidant, a buffer, a bacteriostat, etc. may be added. In addition, an injectable formulation such as an aqueous solution, a suspension, an emulsion, etc., a pill, a capsule, a granule or a tablet may be formulated by additionally adding a diluent, a dispersant, a surfactant, a binder or a lubricant.

[0092] The pharmaceutical composition of the present disclosure may be administered orally or parenterally. The parenteral administration may be accomplished by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal injection, etc. Specifically, it may be administered orally.

[0093] The adequate administration dosage of the pharmaceutical composition of the present disclosure varies depending on various factors such as formulation method, administration method, the age, body weight, sex, pathological condition and diet of a patient, administration time, administration route, excretion rate and response sensitivity. An ordinarily skilled physician can easily determine and prescribe an administration dosage effective for the desired treatment or prevention. According to a specific exemplary embodiment of the present disclosure, a daily administration dosage of the pharmaceutical composition of the present disclosure is 0.001-10 g/kg.

[0094] The pharmaceutical composition of the present disclosure may be prepared into a single-dose or multiple-dose formulation using a pharmaceutically acceptable carrier and/or excipient. The formulation may be in the form of a solution in an oily or aqueous medium, a suspension, an emulsion, an extract, a powder, a granule, a tablet or a capsule, and may further contain a dispersant or a stabilizer.

[0095] In addition, the present disclosure provides a use of the compound represented by Structural Formula 1 or 2 or a pharmaceutically acceptable salt thereof for preparation of a drug for treating a central nervous system disease.

[0096] In addition, the present disclosure relates to a method for treating a central nervous system disease, which includes administering the compound represented by Structural Formula 1 or 2 or a pharmaceutically acceptable salt thereof to a mammal.

EXAMPLES

Example 1. Preparation of Compound 1

Step 1: Preparation of [1,1′-biphenyl]-3-carbaldehyde

[0097] After dissolving 3-bromobenzaldehyde (1.0 mmol), phenylboronic acid (1.2 mmol), PdCl.sub.2 (PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol) in tetrahydrofuran (10 mL) in a reaction vessel, the reaction mixture was refluxed for 24 hours while heating at 70° C. After cooling to room temperature and adding distilled water, the reaction mixture was extracted with dichloromethane. The obtained organic layer was dried with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the obtained concentrate was separated by column chromatography (hexane:ethyl acetate=20:1) to obtain the target compound (yield: 91%).

##STR00031##

[0098] .sup.1H NMR (400 MHz, CDCl.sub.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).

[0099] .sup.13C NMR (100 MHz, CDCl.sub.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 1-([1,1′-biphenyl]-3-ylmethyl)pyrrolidine

[0100] After adding the [1,1′-biphenyl]-3-carbaldehyde prepared in the step 1 (1.0 mmol) and pyrrolidine (2.0 mmol) in a reaction vessel and then dissolving with methanol, acetic acid (1.0 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. After adding sodium triacetoxyborohydride (3.0 mmol), the reaction mixture was stirred for 24 hours. After adding a saturated sodium bicarbonate solution to the reaction mixture and extracting with dichloromethane, the obtained organic layer was dried with anhydrous magnesium sulfate and then filtered. After concentrating the filtrate under reduced pressure, the obtained concentrate was separated by column chromatography (hexane:ethyl acetate=3:1) to obtain compound 1 (yield: 36%).

##STR00032##

[0101] 1 H NMR (400 MHz, CDCl.sub.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).

[0102] .sup.13C NMR (100 MHz, CDCl.sub.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: Preparation of 1-((2′-chloro-[1,1′-biphenyl]-3-yl)methyl)pyyrolidine

[0103] Compound 2 (yield: 86%) was obtained using the compound 2′-chloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 85%) prepared in the same manner as in Example 1 using 3-bromobenzaldehyde (1.0 mmol), 2-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00033##

[0104] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0105] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0106] Compound 3 (yield: 85%) was obtained using the compound 3′-chloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 86%) prepared in the same manner as in Example 1 using 3-bromobenzaldehyde (1.0 mmol), 3-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00034##

[0107] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0108] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0109] Compound 4 (yield: 77%) was obtained using the compound 4′-chloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 78%) prepared in the same manner as in Example 1 using 3-bromobenzaldehyde (1.0 mmol), 4-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00035##

[0110] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0111] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0112] Compound 5 (yield: 68%) was obtained using the compound 2′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 93%) prepared in the same manner as in Example 1 using 3-bromobenzaldehyde (1.0 mmol), 2-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00036##

[0113] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0114] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0115] Compound 6 (yield: 83%) was obtained using the compound 3′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 95%) prepared in the same manner as in Example 1 using 3-bromobenzaldehyde (1.0 mmol), 3-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00037##

[0116] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0117] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0118] Compound 7 (yield: 52%) was obtained using the compound 4′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 96%) prepared in the same manner as in Example 1 using 3-bromobenzaldehyde (1.0 mmol), 4-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00038##

[0119] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0120] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 141.11, 139.67, 138.36, 136.95, 129.42, 128.63, 15 127.65, 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

[0121] Compound 8 (yield: 90%) was obtained using the compound 2′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 92%) prepared in the same manner as in Example 1 using 3-bromobenzaldehyde (1.0 mmol), 2-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00039##

[0122] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0123] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0124] Compound 9 (yield: 78%) was obtained using the compound 3′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 96%) prepared in the same manner as in Example 1 using 3-bromobenzaldehyde (1.0 mmol), 3-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00040##

[0125] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0126] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0127] Compound 10 (yield: 95%) was obtained using the compound 4′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 91%) prepared in the same manner as in Example 1 using 3-bromobenzaldehyde (1.0 mmol), 4-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00041##

[0128] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0129] .sup.13C NMR (100 MHz, CDCl.sub.3) 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 Compound 11 (yield: 66%) was obtained using the compound 2′,6′-dimethoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 89%) prepared in the same manner as in Example 1 using 3-bromobenzaldehyde (1.0 mmol), 2,6-dimethoxyphenylboronic acid (1.2 mmol), Pd(PPh.SUB.3.).SUB.4 .(0.1 mmol) and Na.SUB.2.CO.SUB.3 .(4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

[0130] ##STR00042##

[0131] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0132] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0133] After dissolving iodine (0.44 mmol) and sodium iodate (0.22 mmol) in sulfuric acid (10 mL) in a reaction vessel, the reaction mixture was stirred for 30 minutes. After adding 4-chlorobenzaldehyde, the reaction mixture was stirred at room temperature for 2 hours. After cooling to 0° C. and adding distilled water to the reaction mixture, the produced solid was filtered. The filtered solid was added to a sodium thiosulfate solution and extracted with dichloromethane. The obtained organic layer was dried with anhydrous magnesium sulfate and then filtered. After concentrating the filtrate under reduced pressure, the obtained concentrate was separated by column chromatography (hexane:ethyl acetate=10:1) to obtain the target compound (yield: 73%).

##STR00043##

[0134] .sup.1H NMR (400 MHz, CDCl.sub.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).

[0135] .sup.13C NMR (100 MHz, CDCl.sub.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

[0136] After dissolving 4-chloro-3-iodobenzaldehyde (1.0 mmol), phenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol) in tetrahydrofuran (10 mL) in a reaction vessel, the reaction mixture was refluxed by heating at 70° C. for 24 hours. After cooling to room temperature and adding distilled water, the reaction mixture was extracted with dichloromethane. The obtained organic layer was dried with anhydrous magnesium sulfate and then filtered. After concentrating the filtrate under reduced pressure, the obtained concentrate was separated by column chromatography (hexane:ethyl acetate=20:1) to obtain the target compound (yield: 96%).

##STR00044##

[0137] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0138] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0139] After dissolving 6-chloro-[1,1′-biphenyl]-3-carbaldehyde (1.0 mmol) and pyrrolidine (2.0 mmol) in methanol in a reaction vessel, acetic acid (1.0 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. After adding sodium triacetoxyborohydride (3.0 mmol), the reaction mixture was stirred for 24 hours. After adding a saturated sodium bicarbonate solution, the reaction mixture was extracted with dichloromethane. The obtained organic layer was dried with anhydrous magnesium sulfate and then filtered. After concentrating the filtrate under reduced pressure, the obtained concentrate was separated by column chromatography (hexane:ethyl acetate=3:1) to obtain compound 12 (yield: 44%).

##STR00045##

[0140] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0141] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0142] Compound 13 (yield: 58%) was obtained using the compound 2′,6-dichloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 87%) prepared in the same manner as in Example 12 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00046##

[0143] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0144] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0145] Compound 14 (yield: 60%) was obtained using the compound 3′,6-dichloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 85%) prepared in the same manner as in Example 12 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00047##

[0146] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0147] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0148] Compound 15 (yield: 42%) was obtained using the compound 4′,6-dichloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 77%) prepared in the same manner as in Example 12 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00048##

[0149] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0150] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0151] Compound 16 (yield: 62%) was obtained using the compound 6-chloro-2′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 97%) prepared in the same manner as in Example 12 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00049##

[0152] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0153] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0154] Compound 17 (yield: 60%) was obtained using the compound 6-chloro-3′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 97%) prepared in the same manner as in Example 12 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00050##

[0155] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0156] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0157] Compound 18 (yield: 68%) was obtained using the compound 6-chloro-4′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 64%) prepared in the same manner as in Example 12 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00051##

[0158] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0159] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0160] Compound 19 (yield: 72%) was obtained using the compound 6-chloro-2′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 55%) prepared in the same manner as in Example 12 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4(0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00052##

[0161] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0162] .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

[0163] Example 20: Preparation of 1-((6-chloro-3′methoxy-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine

[0164] Compound 20 (yield: 86%) was obtained using the compound 6-chloro-3′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 45%) prepared in the same manner as in Example 12 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4(0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00053##

[0165] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0166] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0167] Compound 21 (yield: 84%) was obtained using the compound 6-chloro-4′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 55%) prepared in the same manner as in Example 12 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4(0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00054##

[0168] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0169] .sup.13C NMR (100 MHz, CDCl.sub.3) 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-yl)methyl)pyrrolidine

[0170] Compound 22 (yield: 70%) was obtained using the compound 6-chloro-2′,6′-dimethoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 92%) prepared in the same manner as in Example 12 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2,6-dimethoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), pyrrolidine (2.0 mmol), acetic acid (1.0 mmol) and sodium triacetoxyborohydride (3.0 mmol).

##STR00055##

[0171] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0172] .sup.13C NMR (100 MHz, CDCl.sub.3) 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

[0173] After dissolving 3-bromobenzaldehyde (1.0 mmol), phenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol) in tetrahydrofuran (10 mL) in a reaction vessel, the reaction mixture was refluxed by heating at 70° C. for 24 hours. After cooling to room temperature and adding distilled water, the reaction mixture was extracted with dichloromethane. The obtained organic layer was dried with anhydrous magnesium sulfate and then filtered. After concentrating the filtrate under reduced pressure, the obtained concentrate was separated by column chromatography (hexane:ethyl acetate=20:1) to obtain the target compound (yield: 91%).

##STR00056##

[0174] .sup.1H NMR (400 MHz, CDCl.sub.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).

[0175] .sup.13C NMR (100 MHz, CDCl.sub.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

[0176] After dissolving the [1,1′-biphenyl]-3-carbaldehyde prepared in the step 1 (1.0 mmol) and ethylenediamine (1.2 mmol) in dichloromethane in a reaction vessel, the reaction mixture was stirred at 0 ° C. for 1 hour. After adding N-bromosuccinimide (1.2 mmol) at the same temperature, the reaction mixture was stirred for 24 hours. After adding a saturated sodium bicarbonate solution, the reaction mixture was extracted with dichloromethane. The obtained organic layer was dried with anhydrous magnesium sulfate and then filtered. After concentrating the filtrate under reduced pressure, the obtained concentrate was separated by column chromatography (dichloromethane:methanol=20:1) to obtain compound 23 (yield: 53%).

##STR00057##

[0177] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0178] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0179] Compound 24 (yield: 90%) was obtained using the compound 2′-chloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 85%) prepared in the same manner as in Example 23 using 3-bromobenzaldehyde (1.0 mmol), 2-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00058##

[0180] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0181] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0182] Compound 25 (yield: 65%) was obtained using the compound 3′-chloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 86%) prepared in the same manner as in Example 23 using 3-bromobenzaldehyde (1.0 mmol), 3-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00059##

[0183] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0184] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0185] Compound 26 (yield: 58%) was obtained using the compound 4′-chloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 78%) prepared in the same manner as in Example 23 using 3-bromobenzaldehyde (1.0 mmol), 4-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00060##

[0186] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0187] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0188] Compound 27 (yield: 27%) was obtained using the compound 2′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 93%) prepared in the same manner as in Example 23 using 3-bromobenzaldehyde (1.0 mmol), 2-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00061##

[0189] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0190] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0191] Compound 28 (yield: 54%) was obtained using the compound 3′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 95%) prepared in the same manner as in Example 23 using 3-bromobenzaldehyde (1.0 mmol), 3-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00062##

[0192] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ≢7 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).

[0193] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0194] Compound 29 (yield: 47%) was obtained using the compound 4′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 96%) prepared in the same manner as in Example 23 using 3-bromobenzaldehyde (1.0 mmol), 4-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00063##

[0195] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0196] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0197] Compound 30 (yield: 82%) was obtained using the compound 2′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 92%) prepared in the same manner as in Example 23 using 3-bromobenzaldehyde (1.0 mmol), 2-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00064##

[0198] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0199] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0200] Compound 31 (yield: 73%) was obtained using the compound 3′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 96%) prepared in the same manner as in Example 23 using 3-bromobenzaldehyde (1.0 mmol), 3-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3(4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00065##

[0201] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0202] .sup.13H NMR (100 MHz, DMSO-d.sub.6) 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

[0203] Compound 32 (yield: 60%) was obtained using the compound 4′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 91%) prepared in the same manner as in Example 23 using 3-bromobenzaldehyde (1.0 mmol), 4-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00066##

[0204] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0205] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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-v1)-4 1 5-dihydro-1H-imidazole

[0206] Compound 33 (yield: 55%) was obtained using the compound 2′,6′-dimethoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 89%) prepared in the same manner as in Example 23 using 3-bromobenzaldehyde (1.0 mmol), 2,6-dimethoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00067##

[0207] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0208] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0209] The target compound was synthesized in the same manner as in the step 1 of Example 12.

Step 2: Preparation of 6-chloro-[1,1′-biphenyl]-3-carbaldehyde

[0210] The target compound was synthesized in the same manner as in the step 2 of Example 12.

Step 3: Preparation of 2-(6-chloro-[1,1′-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole

[0211] After dissolving 6-chloro-[1,1′-biphenyl]-3-carbaldehyde (1.0 mmol) and ethylenediamine (1.2 mmol) in dichloromethane in a reaction vessel, the reaction mixture was stirred at 0° C. for 1 hour. After adding N-bromosuccinimide (1.2 mmol) at the same temperature, the reaction mixture was stirred for 24 hours. After adding a saturated sodium bicarbonate solution, the reaction mixture was extracted with dichloromethane. The obtained organic layer was dried with anhydrous magnesium sulfate and then filtered. After concentrating the filtrate under reduced pressure, the obtained concentrate was separated by column chromatography (dichloromethane:methanol=20:1) to obtain compound 34 (yield: 34%).

##STR00068##

[0212] 1 H NMR (400 MHz, DMSO-d.sub.6) δ 7.88-7.84; (m, 2H), 7.67-7.63; (m, 1H), 7.53-7.43; (m, 5H), 3.64; (s, 4H).

[0213] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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: Preparation of 2-(2′,6-dichloro-[1,1′-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole

[0214] Compound 35 (yield: 50%) was obtained using the compound 2′,6-dichloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 87%) prepared in the same manner as in Example 34 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00069##

[0215] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0216] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0217] Compound 36 (yield: 49%) was obtained using the compound 3′,6-dichloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 85%) prepared in the same manner as in Example 34 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00070##

[0218] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0219] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0220] Compound 37 (yield: 43%) was obtained using the compound 4′,6-dichloro-[1,1′-biphenyl]-3-carbaldehyde (yield: 77%) prepared in the same manner as in Example 34 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-chlorophenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00071##

[0221] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0222] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0223] Compound 38 (yield: 57%) was obtained using the compound 6-chloro-2′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 97%) prepared in the same manner as in Example 34 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00072##

[0224] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0225] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0226] Compound 39 (yield: 47%) was obtained using the compound 6-chloro-3′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 76%) prepared in the same manner as in Example 34 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00073##

[0227] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0228] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0229] Compound 40 (yield: 76%) was obtained using the compound 6-chloro-4′-methyl-[1,1′-biphenyl]-3-carbaldehyde (yield: 64%) prepared in the same manner as in Example 34 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-methylphenylboronic acid (1.2 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00074##

[0230] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0231] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0232] Compound 41 (yield: 96%) was obtained using the compound 6-chloro-2′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 55%) prepared in the same manner as in Example 34 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00075##

[0233] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0234] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0235] Compound 42 (yield: 37%) was obtained using the compound 6-chloro-3′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 45%) prepared in the same manner as in Example 34 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 3-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00076##

[0236] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0237] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0238] Compound 43 (yield: 72%) was obtained using the compound 6-chloro-4′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 55%) prepared in the same manner as in Example 34 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 4-methoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

##STR00077##

[0239] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0240] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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

[0241] Compound 44 (yield: 67%) was obtained using the compound 6-chloro-2′,6′-dimethoxy-[1,1′-biphenyl]-3-carbaldehyde (yield: 92%) prepared in the same manner as in Example 34 using 4-chloro-3-iodobenzaldehyde (1.0 mmol), 2,6-dimethoxyphenylboronic acid (1.2 mmol), Pd(PPh.sub.3).sub.4 (0.1 mmol) and Na.sub.2CO.sub.3 (4.0 mmol), ethylenediamine (1.2 mmol) and N-bromosuccinimide (1.2 mmol).

[0242] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

[0243] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 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.

Preparation Examples

[0244] The biphenylpyrrolidine/dihydroimidazole derivatives synthesized in the examples were prepared into various formulations.

Preparation Example 1: Pressed Tablet

[0245] 5.0 mg of the active ingredient synthesized in each of the examples was sieved, mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate, and then prepared into a tablet by pressing.

Preparation Example 2: Wet Granulation Tablet

[0246] 5.0 mg of the active ingredient synthesized in each of the examples was sieved, and then mixed with 16.0 mg of lactose and 4.0 mg of starch. Fine granules were prepared by dissolving 0.3 mg of polysorbate 80 in pure water and adding an adequate amount of the solution. After drying, the fine granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. A tablet was prepared by compressing the fine granules.

Preparation Example 3: Powder and Capsule

[0247] 5.0 mg of the active ingredient synthesized in each of the examples was sieved, mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate and then filled in a hard No. 5 gelatin capsule.

Preparation Example 4: Injection

[0248] An injection was prepared using 100 mg of the compound synthesized in each of the examples as an active ingredient, 180 mg of mannitol, 26 mg of Na.sub.2HPO.sub.4.Math.12H.sub.2O and 2974 mg of distilled water.

Test Examples

Test Example 1: Measurement of Inhibition of Activity of 5-HT.SUB.7 .Serotonin Receptor

a) cAMP Assay

[0249] For luminescence-based cAMP assay, HEK293 cells were cultured on a 150-mm dish. Prior to transfection, the culture medium was replaced 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. 4 hours later, transfection was conducted using 10 μg of a human 5-HT.sub.7R plasmid and 10 μg of a GloSensor-22F plasmid (Promega). The transfected cells were prepared on a white, flat, clear-bottom, 384-well plate (Greiner) (15,000 cells/well, 20 μL/well). 6 hours later, after removing the culture medium, the cells were treated with 20 μL of a 3% Glosensor cAMP reagent containing luciferin in a 1×HBSS, 1 M HEPES, pH 7.4 buffer. In addition, the compound of each of the examples was prepared at different concentrations in an assay buffer containing 0.1% bovine serum albumin. 30 minutes later, 10 μL of the compound solution was treated to the cells. After measuring luminescence using a Tecan microplate reader (Spark), IC.sub.50 value was obtained using the Prism 8.0 program (GraphPad Software).

[0250] Table 1 shows the inhibition of the activity of the 5-HT.sub.7 serotonin receptor (%) by the biphenylpyrrolidine derivatives of Examples 1-22, and Table 2 shows the inhibition of the activity of the 5-HT.sub.7 serotonin receptor (%) by the biphenyldihydroimidazole derivatives of Examples 23-44.

[0251] In addition, Table 3 shows the IC.sub.50 values of the biphenylpyrrolidine derivatives of the examples, and Table 4 shows the IC.sub.50 values of the biphenyldihydroimidazole derivatives of the examples.

TABLE-US-00001 TABLE 1 % Inhibition Compounds (10 μM) Compound 1 42.1 Compound 2 62.6 Compound 3 85.9 Compound 4 38.1 Compound 5 49.5 Compound 6 38.9 Compound 7 32.5 Compound 8 57.1 Compound 9 67.2 Compound 10 37.9 Compound 11 32.8 Compound 12 80.8 Compound 13 90.7 Compound 14 51.1 Compound 15 63.8 Compound 16 73.3 Compound 17 51.8 Compound 18 73.4 Compound 19 51.8 Compound 20 70.1 Compound 21 44.7 Compound 22 42.7

TABLE-US-00002 TABLE 2 % Inhibition Compounds (10 μM) Compound 23 83.3 Compound 24 47.6 Compound 25 50.9 Compound 26 43.0 Compound 27 55.3 Compound 28 44.6 Compound 29 35.2 Compound 30 94.1 Compound 31 72.5 Compound 32 40.8 Compound 33 32.8 Compound 34 48.4 Compound 35 53.8 Compound 36 52.4 Compound 37 43.3 Compound 38 51.4 Compound 39 48.1 Compound 40 48.9 Compound 41 44.3 Compound 42 49.8 Compound 43 36.8 Compound 44 48.4

TABLE-US-00003 TABLE 3 IC.sub.50 Compounds (μM) Compound 2 9.51 Compound 3 4.88 Compound 9 6.44 Compound 12 4.89 Compound 13 3.20 Compound 15 7.15 Compound 16 6.42 Compound 18 8.20 Compound 20 7.48

TABLE-US-00004 TABLE 4 IC.sub.50 Compounds (μM) Compound 23 5.10 Compound 30 2.58 Compound 31 5.77

b) Tango Assay

[0252] Tango assay was conducted using HTLA cells in order to investigate the activity of the β-arrestin signaling system. Prior to transfection, the culture medium was replaced from DMEM containing 10% FBS, 100 U/mL penicillin, 100 μg/mL streptomycin, 2 μg/mL puromycin and 100 μg/mL hygromycin B to DMEM containing 10% dialyzed FBS, 100 U/mL penicillin and 100 μg/mL streptomycin. 4 hours later, transfection was conducted using 20 μg of a 5-HT.sub.7R-TCS-tTA construct (5-HT.sub.7R Tango DNA). The transfected cells were prepared on a white, flat, clear-bottom, 384-well plate (Greiner) (15,000 cells/well, 20 μL/well) using DMEM containing 10% dialyzed FBS, 100 U/mL penicillin and 100 μg/mL streptomycin. 6 hours later, after removing the culture medium, the cells were treated with 10 μL of the compound solution. After culturing for 22 hours and removing the culture medium, the cells were treated with 20 μL of a BrightGlo reagent (Promega) diluted in a 1×HBSS, 1 M HEPES, pH 7.4 buffer. After measuring luminescence using a Tecan microplate reader (Spark), IC.sub.50 value was obtained using the Prism 8.0 program (GraphPad Software).

[0253] Table 5 shows the inhibition of the activity of the 5-HT.sub.7 serotonin receptor (%) by the biphenylpyrrolidine derivatives of Examples 1-22, and Table 6 shows the inhibition of the activity of the 5-HT.sub.7 serotonin receptor (%) by the biphenyldihydroimidazole derivatives of Examples 23-44.

[0254] In addition, Table 7 shows the 1050 values of the biphenylpyrrolidine derivative of Example 1 and the biphenyldihydroimidazole derivatives of the examples.

TABLE-US-00005 TABLE 5 % Inhibition Compounds (10 μM) Compound 1 17.5 Compound 2 29.9 Compound 3 33.2 Compound 4 14.1 Compound 5 25.0 Compound 6 22.0 Compound 7 20.6 Compound 8 18.0 Compound 9 16.7 Compound 10 23.1 Compound 11 5.1 Compound 12 26.1 Compound 13 50.5 Compound 14 27.9 Compound 15 34.3 Compound 16 30.9 Compound 17 11.4 Compound 18 21.5 Compound 19 19.7 Compound 20 26.0 Compound 21 18.6 Compound 22 3.3

TABLE-US-00006 TABLE 6 % Inhibition Compounds (10 μM) Compound 23 44.2 Compound 24 36.0 Compound 25 43.6 Compound 26 23.1 Compound 27 23.0 Compound 28 28.8 Compound 29 17.2 Compound 30 40.6 Compound 31 27.8 Compound 32 11.9 Compound 33 14.0 Compound 34 31.6 Compound 35 42.0 Compound 36 44.8 Compound 37 39.6 Compound 38 31.7 Compound 39 27.0 Compound 40 31.3 Compound 41 27.7 Compound 42 23.4 Compound 43 21.5 Compound 44 9.8

TABLE-US-00007 TABLE 7 IC.sub.50 Compounds (μM) Compound 1 22.9 Compound 23 47.9 Compound 25 10.5 Compound 30 39.8 Compound 35 20.4 Compound 36 10.0

Test Example 2: Schild Plot for Tango Assay

[0255] Schild plots were constructed for the Tango assay in order to investigate the effect of the compounds on the activity of the β-arrestin signaling pathway. After culturing cells and replacing the culture medium as described in b) of Test Example 1, the cells were transfected and prepared on a plate. 6 hours later, the cells were treated with 10 μL of the solution of serotonin or the compounds at final concentrations of 5 μM, 10 μM and 30 μM. After culturing for 22 hours, luminescence was measured using a Tecan microplate reader (Spark) and the Schild plot and the EC.sub.50 value were obtained using the Prism 8.0 program (GraphPad Software). In addition, the pA.sub.2 value was obtained using the Excel software. The Schild plots and pA.sub.2 values of compound 23 and compound 30 according to the present disclosure are summarized in FIGS. 1A-1B, FIG. 2 and Table 8.

TABLE-US-00008 TABLE 8 Compounds pA.sub.2 Example 23 5.24 Example 30 5.90

[0256] It can be seen that the biphenylpyrrolidine/dihydroimidazole derivatives according to the present disclosure show antagonistic activity for the 5-HT.sub.7 receptor. The Schild plots show that they are competitive inhibitors.

[0257] Despite the difference in the structures and physical properties of the substituents, the principles and conditions of the reactions of the examples described above apply to the compounds according to the present disclosure having substituents not described in the examples. Accordingly, it is obvious that those skilled in the art can prepare and investigate the compounds having substituents not described in the examples without special difficulty based on the foregoing disclosure and the common sense in the art.