KR101437890B1 - biphenyl amide derivatives acting on 5-HT7 receptor - Google Patents

Abstract

The biphenyl amide derivatives and their pharmaceutically acceptable salts according to the present invention are excellent neuroprotective agents acting on mitochondria and exhibit excellent activity and are useful for the treatment of depression, migraine, anxiety, inflammatory pain, neuropathic pain, , Sleep disorders and diseases related to smooth muscle, such as central nervous system disease, and is effective as a treatment.

Description

Biphenyl amide derivatives acting on the 5-HT7 receptor 5-HT7 receptor < RTI ID = 0.0 >

The present invention relates to a biphenylamide derivative which acts on a 5-HT ₇ receptor and exhibits a pharmacological activity against central nervous system diseases, a pharmaceutically acceptable salt thereof, a process for producing the compound, and a pharmaceutical composition containing the compound as an active ingredient .

Serotonin, a neurotransmitter, acts on 14 different serotonin receptors distributed in various organs, resulting in various physiological phenomena. Each receptor has a unique serotonin binding site, resulting in affinity for serotonin and a variety of physiological responses to its interaction with serotonin. The 5-HT ₇ receptors are the most recently cloned serotonin subtype receptors, and are particularly well distributed in the hypothalamus, thalamus, hippocampus, and cortex, and include body temperature regulation, circadian rhythm, learning and memory, It is known that it plays an important role such as hippocampal signal transduction. It is also known to be associated with neurological disorders such as depression, migraine, anxiety, pain, especially inflammatory pain and neuropathic pain.

Although a lot of efforts to develop, such as 5-HT ₇ receptor antagonists or agonists of the currently selected 5-HT ₇ receptor antagonists are known to be not much. Antagonists having sulfonamide as a basic skeleton have been reported in WO97 / 29097, WO03 / 048118, WO97 / 48648, WO97 / 48681 and WO97 / 49695, WO99 / 24022, WO00 / 00472 discloses 5- HT ₇ receptors have been reported.

Despite the above studies, it has been shown that selective 5-HT ₇ receptors have a good pharmacokinetic profile and are good at ADME (absorption, distribution, metabolism, and excretion) and are useful for the treatment of depression, migraine, anxiety, pain, especially inflammatory pain and neuropathic pain There is a continuing need to find 5-HT ₇ receptor modulators that are effective in neurological diseases, body temperature control, biorhythm, sleep, and smooth muscle-related diseases.

The first technical problem to be solved by the present invention is to provide a medicament which acts on the 5-HT ₇ receptor and which is useful as a medicament for depression, migraine, anxiety, inflammatory pain, neuropathic pain, thermoregulatory disorder, biorhythm control disorder, The present invention provides a biphenylamide derivative having pharmacological activity in a disease.

A second object of the present invention is to provide a process for preparing the biphenylamide derivative.

A third object of the present invention is to provide a pharmaceutical composition comprising the biphenylamide derivative and a pharmaceutically acceptable salt thereof as an active ingredient.

In order to solve the above-mentioned first problem, the present invention provides a biphenylamide derivative represented by the following formula 1:

≪ Formula 1 >

In Formula 1,

R ₁ and R ₂ May be the same or different from each other, and each independently may be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain having 1 to 6 carbon atoms, straight chain,

또는

이며,A is

or

Lt;

n is an integer of 1 to 4;

According to another aspect of the present invention, there is provided a method for preparing a biphenylamide derivative, which comprises the steps of: preparing a compound represented by Formula 1 by amide bonding of a compound represented by Formula 2 and a compound represented by Formula 3:

&Lt; Formula 2 > < EMI ID =

&Lt; Formula 1 >

In the above formula (1), (2) or (3)

R ₁ and R _{2, which} may be the same or different from each other, may each independently be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain of 1 to 6 carbon atoms, straight chain,

또는

이며,A is

or

Lt;

n is an integer of 1 to 4,

X in the formula 2 is COOH or NH ₂ , Y in the formula 3 is NH ₂ or COOH, and when X in the formula 2 is COOH, Y in the formula 3 is preferably NH ₂ , When X is NH ₂ , it is preferable that Y in the formula (3) is COOH.

According to an embodiment of the present invention, the compound of Formula 1 may be prepared by amide bonding of a biphenylamine derivative and an arylpiperazine alkylcarboxylic acid derivative using a reducing agent:

<Biphenylamine derivatives> <Arylpiperazine alkylcarboxylic acid derivatives>

In the formula of the biphenylamine derivative or the arylpiperazine alkylcarboxylic acid derivative,

R ₁ and R _{2, which} may be the same or different from each other, may each independently be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain of 1 to 6 carbon atoms, straight chain,

n is an integer of 1 to 4,

NaBH (OAc) ₃ to NaBH ₃ CN may be used as the reducing agent to be added in the amide bonding, but the present invention is not limited thereto.

According to one embodiment of the present invention, the biphenylamine derivative can be prepared by reducing a compound of the following formula:

&Lt; Formula 4 >

In Formula 4,

R ₁ May be hydrogen, halogen, nitro, alkyl groups and alkoxy groups including carbon chains of 1 to 6 carbon atoms, straight chain, branched and cyclic carbon atoms.

According to one embodiment of the present invention, the compound of Chemical Formula 4 may be prepared by Suzuki coupling reaction of a compound of Chemical Formula 5 with bromobenzenitrile:

&Lt; Formula 5 >

In Formula 5,

R ₁ May be hydrogen, halogen, nitro, alkyl groups and alkoxy groups including carbon chains of 1 to 6 carbon atoms, straight chain, branched and cyclic carbon atoms.

According to another embodiment of the present invention, the compound of Chemical Formula 1 may be prepared by amidating a biphenylcarboxylic acid derivative with an arylpiperazine alkylamine derivative.

&Lt; Biphenylcarboxylic acid derivative > < arylpiperazine alkylamine derivative >

In the formula of the biphenylcarboxylic acid derivative or arylpiperazine alkylamine derivative,

R ₁ and R _{2, which} may be the same or different from each other, may each independently be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain of 1 to 6 carbon atoms, straight chain,

n is an integer of 1 to 4;

According to another embodiment of the present invention, the biphenylcarboxylic acid derivative can be prepared by hydrolyzing a compound of the following formula (6): &lt; EMI ID =

(6)

In Formula 6,

R ₁ May be hydrogen, halogen, nitro, alkyl groups and alkoxy groups including carbon chains of 1 to 6 carbon atoms, straight chain, branched and cyclic carbon atoms.

According to another embodiment of the present invention, the compound of Chemical Formula 6 may be prepared by Suzuki coupling reaction of a compound of Chemical Formula 5 with ethyl bromophenylacetate:

&Lt; Formula 5 >

In Formula 5,

R ₁ May be hydrogen, halogen, nitro, alkyl groups and alkoxy groups including carbon chains of 1 to 6 carbon atoms, straight chain, branched and cyclic carbon atoms.

In order to accomplish the third technical object, the present invention provides a pharmaceutical composition comprising, as an active ingredient, the biphenyl compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

The biphenyl amide derivatives and their pharmaceutically acceptable salts according to the present invention are excellent neuroprotective agents acting on mitochondria and exhibit excellent activity and are useful for the treatment of depression, migraine, anxiety, inflammatory pain, neuropathic pain, , Sleep disorders, and smooth muscle-related diseases.

The present invention provides a biphenylamide derivative represented by the following general formula (1): &lt; EMI ID =

&Lt; Formula 1 >

The biphenyl amide derivatives of formula 1 according to the present invention act on 5-HT ₇ serotonin receptors and are useful for the treatment of depression, migraine, anxiety, inflammatory pain, neuropathic pain, body temperature control disorder, biorhythm control disorder, And the like.

In Formula 1,

R ₁ and R ₂ May be the same or different from each other, and each independently may be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain having 1 to 6 carbon atoms, straight chain,

또는

이며,A is

or

Lt;

n is an integer of 1 to 4,

The alkyl group may be any one or more selected from the group consisting of methyl, ethyl, normal propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl and phenyl Wherein the alkoxy group is an alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl and phenyl But is not limited to, an alkoxy group.

The biphenyl derivative according to the present invention is a biphenyl derivative,

N - ([1,1'-biphenyl] -2-ylmethyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) propanamide;

N - ([1,1'-biphenyl] -2-ylmethyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;

N - ([1,1'-biphenyl] -2-ylmethyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ([1,1'-biphenyl] -2-ylmethyl) -5- (4- (4-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ([1,1'-biphenyl] -2-ylmethyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ([1,1'-biphenyl] -2-ylmethyl) -6- (4- (4-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((2'-fluorobiphenyl-2-yl) methyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) propanamide;

N - ((2'-fluorobiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;

N - ((2'-fluorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((2'-fluorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((3'-fluorobiphenyl-2-yl) methyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) propanamide;

N - ((3'-fluorobiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;

N - ((3'-fluorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((3'-fluorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((4'-fluorobiphenyl-2-yl) methyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) propanamide;

N - ((4'-fluorobiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;

N - ((4'-fluorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((4'-fluorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((2'-chlorobiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;

N - ((2'-chlorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((2'-chlorobiphenyl-2-yl) methyl) -5- (4- (2-ethoxyphenyl) piperazin-1-yl) pentanamide;

N - ((2'-chlorobiphenyl-2-yl) methyl) -5- (4- (4-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((2'-chlorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((2'-chlorobiphenyl-2-yl) methyl) -6- (4- (2-ethoxyphenyl) piperazin-1-yl) hexanamide;

N - ((2'-chlorobiphenyl-2-yl) methyl) -6- (4- (4-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((3'-chlorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((3'-chlorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((4'-chlorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((4'-chlorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((2'-bromobiphenyl-2-yl) methyl) -5- (4- (4-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((2'-bromobiphenyl-2-yl) methyl) -6- (4- (4-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((2'-methoxybiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;

N - ((2'-methoxybiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((2'-methoxybiphenyl-2-yl) methyl) -5- (4- (2-ethoxyphenyl) piperazin-1-yl) pentanamide;

N - ((2'-methoxybiphenyl-2-yl) methyl) -5- (4- (4-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((2'-methoxybiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((2'-methoxybiphenyl-2-yl) methyl) -6- (4- (4-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((3'-methoxybiphenyl-2-yl) methyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) propanamide;

N - ((3'-methoxybiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;

N - ((3'-methoxybiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((3'-methoxybiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((4'-methoxybiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((4'-methoxybiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

N - ((2 ', 6'-dimethoxybiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((2 ', 6'-dimethoxybiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;

5- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((2'-methylbiphenyl-2-yl) methyl) pentanamide;

6- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((2'-methylbiphenyl-2-yl) methyl) hexanamide;

4- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((3'-methylbiphenyl-2-yl) methyl) butanamide;

5- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((3'-methylbiphenyl-2-yl) methyl) pentanamide;

6- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((3'-methylbiphenyl-2-yl) methyl) hexanamide;

5- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((4'-methylbiphenyl-2-yl) methyl) pentanamide;

6- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((4'-methylbiphenyl-2-yl) methyl) hexanamide;

N - ([1,1'-biphenyl] -3-ylmethyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

N - ((2'-methoxybiphenyl-3-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;

1-yl) butyl) acetamide &lt; / RTI &gt;(2-methoxy-;

Or a mixture of 2- (3'-methoxy- [1,1'-biphenyl] -2-yl) -N- (4- (4- (2-methoxyphenyl) piperazin- Acetamide;

But is not limited thereto.

The present invention also provides a process for preparing a biphenyl amide derivative comprising the step of preparing a compound of formula (1) by amide bonding of a compound of formula (2) and a compound of formula (3)

&Lt; Formula 2 > < EMI ID =

&Lt; Formula 1 >

In the above formula (1), (2) or (3)

R ₁ and R _{2, which} may be the same or different from each other, may each independently be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain of 1 to 6 carbon atoms, straight chain,

또는

이며,A is

or

Lt;

n is an integer of 1 to 4,

X in the formula 2 is COOH or NH ₂ , Y in the formula 3 is NH ₂ or COOH, and when X in the formula 2 is COOH, Y in the formula 3 is preferably NH ₂ , When X is NH ₂ , it is preferable that Y in the formula (3) is COOH.

The above reaction can be carried out by compounding the biphenylamine derivative and the arylpiperazine alkylcarboxylic acid derivative with an amide bond using a reducing agent.

<Biphenylamine derivatives> <Arylpiperazine alkylcarboxylic acid derivatives>

In the formula of the biphenylamine derivative or the arylpiperazine alkylcarboxylic acid derivative,

R ₁ and R _{2, which} may be the same or different from each other, may each independently be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain of 1 to 6 carbon atoms, straight chain,

n is an integer of 1 to 4,

NaBH (OAc) ₃ to NaBH ₃ CN may be used as the reducing agent to be added in the amide bond, but the reaction can be carried out by stirring at a temperature of 10 to 500 ° C. for 3 to 24 hours, And more preferably 4 to 8 hours at a temperature range of 20 to 30 占 폚. After completion of the reaction, the reaction mixture is extracted with an organic solvent, and concentrated under reduced pressure and dried to obtain the compound of Formula 1.

Preferably, the biphenylamine derivative can be prepared by reducing a compound of formula (4): &lt; EMI ID =

&Lt; Formula 4 >

In Formula 4,

R ₁ May be hydrogen, halogen, nitro, alkyl groups and alkoxy groups comprising carbon chains of 1 to 6 carbon atoms, straight chain, branched and cyclic carbon chains,

n is an integer of 1 to 4;

The compound of Formula 4 may be prepared by Suzuki coupling reaction of a compound of Formula 5 and bromobenzenitrile in an organic solvent.

&Lt; Formula 5 >

In Formula 5,

R ₁ May be hydrogen, halogen, nitro, alkyl groups and alkoxy groups comprising carbon chains of 1 to 6 carbon atoms, straight chain, branched and cyclic carbon chains,

n is an integer of 1 to 4,

For the Suzuki coupling reaction, a catalyst containing palladium such as Pd (PPH) ₄ may be used. The organic solvent may be selected from the group consisting of N, N-dimethylformamide, acetonitrile, and tetrahydrofuran, N, N-dimethylformamide is more preferable, but is not limited thereto. The reaction can be carried out by stirring at a temperature of 50 to 200 DEG C for 3 to 24 hours, more preferably 7 to 10 hours.

For reference, Scheme 1 below shows an exemplary schematic reaction diagram for preparing the compound of Formula 1 from the compound of Formula 5 and bromobenzenitrile.

<Reaction Scheme 1>

In the above Reaction Scheme 1,

R ₁ and R _{2, which} may be the same or different from each other, may each independently be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain of 1 to 6 carbon atoms, straight chain,

n is an integer of 1 to 4;

Meanwhile, the compound of Formula 1 of the present invention can be prepared by amidation reaction of a biphenylcarboxylic acid derivative and an arylpiperazine alkylamine derivative:

&Lt; Biphenylcarboxylic acid derivative > < arylpiperazine alkylamine derivative >

In the formula of the biphenylcarboxylic acid derivative or arylpiperazine alkylamine derivative,

R ₁ And R &lt; ₂ &gt; may be the same or different from each other, and each independently may be an alkyl group or an alkoxy group containing a hydrogen, halogen, nitro, a carbon chain having 1 to 6 carbon atoms, straight chain,

n is an integer of 1 to 4;

Preferably, the biphenylcarboxylic acid derivative can be prepared by hydrolysis of a compound of formula (6): &lt; EMI ID =

(6)

In Formula 6,

R ₁ May be hydrogen, halogen, nitro, alkyl groups and alkoxy groups comprising carbon chains of 1 to 6 carbon atoms, straight chain, branched and cyclic carbon chains,

n is an integer of 1 to 4;

The compound of formula (6) can also be prepared by Suzuki coupling reaction of the compound of formula (5) with ethyl bromophenylacetate:

&Lt; Formula 5 >

In Formula 5,

R ₁ May be hydrogen, halogen, nitro, alkyl groups and alkoxy groups comprising carbon chains of 1 to 6 carbon atoms, straight chain, branched and cyclic carbon chains,

n is an integer of 1 to 4;

For reference, Scheme 2 below shows an exemplary schematic reaction diagram for preparing the compound of Formula 1 from the compound of Formula 5 and bromophenylacetate.

<Reaction Scheme 2>

In the above Reaction Scheme 2,

R ₁ and R _{2, which} may be the same or different from each other, may each independently be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain of 1 to 6 carbon atoms, straight chain,

n is an integer of 1 to 4;

In order to achieve the third technical object of the present invention,

There is provided a pharmaceutical composition comprising, as an active ingredient, the biphenylamide compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention may be formulated into a biphenyl compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof by a formulation method including a carrier, an adjuvant or a diluent to prepare a form suitable for oral administration or parenteral administration . For oral administration, the preparation may be in the form of tablets, capsules, solutions, syrups, suspensions and the like. For parenteral administration, the preparation may be in the form of injections for intraperitoneal, subcutaneous, muscular and transdermal administration.

The pharmaceutical composition of the present invention is a modulator acting on a 5-HT ₇ serotonin receptor. The effective dose per day is 0.01 to 1000 mg / day on an adult basis. The administration dose varies depending on the age, body weight, sex, The condition and the degree of the disease. Depending on the judgment of the doctor or the pharmacist, it may be administered once or several times a day at a predetermined time interval.

The pharmaceutical composition of the present invention can be used for prevention and treatment of central nervous system diseases, and the central nervous system diseases include depression, migraine, anxiety, inflammatory pain, neuropathic pain, body temperature control disorder, biorhythm control disorder, A disease, or a disease.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to preferred embodiments for better understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto.

Example . Biphenyl Amide  Synthesis of derivatives

Example  1.1. Biphenyl -2- Carbonitrile

To the reaction vessel 2-iodo-benzonitrile (500 mg, 2.18 mmol), phenyl beam Nick Acid (320 mg, 2.62 mmol), Pd (PPh) 3 (25 mg, 0.022 mmol), Na 2 CO 3 (346 mg , 3.27 mmol) were dissolved in N, N-dimethylformamide (20 ml), and the mixture was heated to reflux at 160 ° C for 8 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, saturated NaHCO ₃ solution was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (hexane: diethyl ether = 8: 1) to obtain the desired compound (372 mg, 2.08 mmol, 95.2%).

(Dd, J = 7.7 Hz, J = 1.2 Hz, 1H), 7.64 (td, J = 7.7 Hz, J = 1.2 Hz, 1H), 7.58-7.42 )

Example  1.2. Biphenyl -2- Yl methane amide

Aluminum chloride (234 mg, 1.76 mmol) was dissolved in anhydrous THF (8 ml) and cooled to 0 占 폚. Then, 1.0 M lithium aluminum hydride solution (2.15 ml, 2.15 mmol) dissolved in anhydrous THF was added slowly and stirred for 20 minutes. After 20 minutes, 2-iodobenzonitrile (350 mg, 1.95 mmol) was slowly added and stirred at room temperature for 6 hours. After the reaction, methanol was added to the mixture to terminate the reaction, and the mixture was concentrated under reduced pressure. The concentrate was diluted with EtOAc, extracted with 1N HCl, and the aqueous layer was neutralized with 10 N NaOH. After re-extraction with dichloromethane, the solution was neutralized, and the organic layer was dried over anhydrous Na ₂ SO _4, and filtered. The filtrate was concentrated under reduced pressure to give the desired compound (256 mg, 1.40 mmol, 71.6%).

J = 7.5 Hz, 1 H), 7.41-7.42 (m, 2H), 7.37-7.32 (m, 3H), 7.30 (td, J = 7.5 Hz, J = (S, 2H), 1.34 (s, 2H), 2. &lt; RTI ID = 0.0 &

Example  2.1. N - ([1,1'- Biphenyl ]-2- Yl methyl ) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Propanamide  synthesis

The reaction vessel was charged with 3- (4- (2-methoxyphenyl) piperazin-1-yl) propanoic acid (80 mg, 0.30 mmol) and O-benzotriazol- (HBTU; 133 mg, 0.35 mmol) and triethylamine (TEA; 151 μl, 1.08 mmol) were dissolved in acetonitrile (5 ml), and the mixture was stirred for 20 minutes. After 20 minutes, biphenyl-2-ylmethanamine (50 mg, 0.27 mmol) was added and the mixture was stirred at room temperature for about 8 hours. After the completion of the reaction was confirmed by TLC, the concentrate obtained by distillation under reduced pressure was separated by column chromatography (MC: MeOH: H2O: NH3 = 80: 20: 1: 1) = 8: 1) to obtain 60 mg (0.14 mmol , 51.7%).

7.6 (td, J = 7.6 Hz, 1H), 7.92 (d, J = J = 1.5 Hz, 1H), 6.85 (dd, J = 7.8 Hz, J = 1.3 Hz, 1H), 6.82 (dd, J = 7.8 Hz, J = 3.6 Hz, 2H), 3.84 (s, 3H), 2.91 (brs, 4H) = 10.8 Hz, 2H)

Example  2.2. N - ([1,1'- Biphenyl ]-2- Yl methyl ) -4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Butanamide  synthesis

(83 mg, 0.30 mmol), HBTU (133 mg, 0.35 mmol) and TEA (151 [mu] L) in the same manner as in Example 2.1, , 1.08 mmol) and biphenyl-2-ylmethanamine (50 mg, 0.27 mmol) were used to obtain the desired compound (248 mg, 0.11 mmol, 40.1%).

J = 7.5Hz, 1H), 7.05 (m, 1H), 6.91 (t, J = 7.5Hz, 1H), 7.41-7.28 2H), 3.85 (s, 3H), 3.13 (brs, 8H), 2.98 (t, J = 5.6 Hz, 2H), 2.48 (t, J = 5.7 Hz, 2H), 1.89

Example  2.3. : N - ([1,1'- Biphenyl ]-2- Yl methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(88 mg, 0.30 mmol), HBTU (133 mg, 0.35 mmol) and TEA (151 [mu] l , 1.08 mmol) and biphenyl-2-ylmethanamine (50 mg, 0.27 mmol), 90 mg (0.20 mmol, 72.8%) of the title compound were obtained.

(M, 9H), 7.03 (td, J = 7.0 Hz, J = 2.0 Hz, 1H), 6.94-6.86 (m, 3H), 5.87 (brs, , 4.41 (d, J = 5.6 Hz, 2H), 3.86 (s, 3H), 3.12 (brs, 4H), 2.81 (brs, 4H), 2.62-2.59 (m, 2H), 2.21-2.18 ), 1.63 (m, 4H)

Example  2.4. N - ([1,1'- Biphenyl ]-2- Yl methyl ) -5- (4- (4- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(96 mg, 0.33 mmol), HBTU (133 mg, 0.35 mmol) and TEA (151 [mu] L , 1.08 mmol) and biphenyl-2-ylmethanamine (50 mg, 0.27 mmol), 74 mg (0.16 mmol, 59.9%) of the title compound were obtained.

(D, J = 5.4 Hz, 2H), 3.74 (s, 2H), 4.74 (s, J = 6.6 Hz 2H), 2.12 (t, J = 7.2 Hz 2H), 1.62-1.49 (m, 4H)

Example  2.5. N - ([1,1'- Biphenyl ]-2- Yl methyl ) -6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(100 mg, 0.33 mmol), HBTU (133 mg, 0.35 mmol) and TEA (151 [mu] L) in the same manner as in Example 2.1, , 1.08 mmol) and biphenyl-2-ylmethanamine (50 mg, 0.27 mmol), 45 mg (0.10 mmol, 35.3%) of the title compound were obtained.

(M, 3H), 5.65 (brt, J = 5.1 Hz, 1H), 4.43 (m, 2H) J = 5.4 Hz, 2H), 3.88 (s, 3H), 3.13 (brs, 4H), 2.74 2H), 1.52-1.66 (m, 4H), 1.38-1.33 (m, 2H)

Example  2.6. N - ([1,1'- Biphenyl ]-2- Yl methyl ) -6- (4- (4- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(100 mg, 0.33 mmol), HBTU (133 mg, 0.35 mmol) and TEA (151 [mu] L) in the same manner as in Example 2.1, , 1.08 mmol) and biphenyl-2-ylmethanamine (50 mg, 0.27 mmol), 56 mg (0.12 mmol, 44.0%) of the title compound were obtained.

(D, J = 5.4 Hz, 2H), 3.74 (s, 2H), 3.40 (s, 3H) J = 7.5 Hz 2H), 1.61-1.48 (m, 4H), 1.31 (brs, 4H) 1.26 (m, 2 H)

Example  2.7. N - ((2 ' - Fluorobiphenyl -2 days) methyl ) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Propanamide  synthesis

Propanoic acid (66 mg, 0.25 mmol), HATU (123.6 mg, 0.325 mmol), TEA (141 mg, 46.5 mg (0.10 mmol, 41.6%) of the title compound was obtained by using 2-fluorobiphenyl-2-yl) methanamine (50 mg, 0.25 mmol).

7.38 (d, J = 7.3 Hz, J = 1.3 Hz, 1H), 7.40-7.31 (m, 3H), 7.28-7.17 (m, 3H) J = 7.6 Hz, J = 1.5 Hz, 1H), 6.86 (dd, J = 2H), 3.85 (s, 3H), 2.92 (brs, 4H), 2.65 (d, J = 1.5 Hz, 1H) (m, 6 H), 2.40 (t, J = 6.2 Hz, 2 H)

Example  2.8. N - ((2 ' - Fluorobiphenyl -2 days) methyl ) -4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Butanamide  synthesis

(134 mg, 0.50 mmol), HATU (248 mg, 0.65 mmol), TEA (283 [mu] L (2-fluorobiphenyl-2-yl) methanamine (100 mg, 0.50 mmol), 51 mg (0.11 mmol, 22.1%) of the title compound was obtained.

J = 7.6 Hz, J = 1.5 Hz, 1 H), 7.41-7.33 (m, 3H), 7.28-7.10 (m, 4H), 7.01 (td, J = (M, 2H), 6.63 (brs, IH), 4.32 (brs, 2H), 6.92 (d, J = J = 6.6 Hz, 2H), 2.28 (t, J = 7.0 Hz 2H), 1.83 (brs, 4H) = 6.8 Hz, 2H)

Example  2.9. N - ((2 ' - Fluorobiphenyl -2 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(146.2 mg, 0.50 mmol), HATU (248 mg, 0.65 mmol), TEA (283 [mu] l , 2.00 mmol) and (2'-fluorobiphenyl-2-yl) methanamine (100 mg, 0.50 mmol) were used to yield 170 mg (0.36 mmol, 71.5%) of the desired compound.

7.46 (dd, J = 7.6 Hz, J = 1.5 Hz, 1 H), 7.42-7.33 (m, 3H), 7.26-7.12 (m, 4H), 7.06-7.02 3H), 2.88 (brs, 4H), 2.69 (brs, 2H) , 2.24 (t, J = 6.6 Hz, 2H), 1.67-1.65 (m, 4H)

Example  2.10. N - ((2 ' - Fluorobiphenyl -2 days) methyl ) -6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(128 mg, 0.42 mmol), HBTU (173 mg, 0.46 mmol) and TEA (197 [mu] L) in the same manner as in Example 2.1, , 1.40 mmol) and (2'-fluorobiphenyl-2-yl) methanamine (70 mg, 0.35 mmol) were used to yield the desired compound (90 mg, 0.18 mmol, 52.5%).

(M, 2H), 6.74 (m, 2H), 6.74 (d, J &lt; RTI ID = 0.0 & = 7.6 Hz, 1 H), 6.49 (brs, 1 H), 4.23 (br s, 2H), 3.80 (s, 3H), 3.22 (brs, 2H), 1.72 (brs, 2H), 1.55 (t, J = 7.0Hz, 2H), 1.35-1.33

Example  2.11. N - ((3 ' - Fluorobiphenyl -2 days) methyl ) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Propanamide  synthesis

Propanoic acid (133 mg, 0.50 mmol), HATU (248 mg, 0.65 mmol), TEA (283 mg, (4-fluorobiphenyl-2-yl) methanamine (100 mg, 0.50 mmol) was used to yield the desired compound (108 mg, 0.24 mmol, 48.3%).

J = 7.3 Hz, 1H), 7.39-7.29 (m, 3H), 7.24 (dd, J = 7.3 Hz, J = 1.5 Hz, 1H), 7.11-6.99 (m, 4H), 6.92 (td, J = 7.6 Hz, J = 1.5 Hz, 1H), 6.86 2H), 3.85 (s, 3H), 2.90 (brs, 4H), 2.68-2.63 (m, 1H), 6.81 (dd, J = 7.8 Hz, J = 1.5 Hz, , 6H), 2.42 (t, J = 6.2 Hz, 2H)

Example  2.12. N - ((3 ' - Fluorobiphenyl -2 days) methyl ) -4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Butanamide  synthesis

(134 mg, 0.50 mmol), HATU (248 mg, 0.65 mmol), TEA (283 [mu] L , 2.00 mmol) and (3'-fluorobiphenyl-2-yl) methanamine (100 mg, 0.50 mmol) were used to yield the desired compound (57 mg, 0.12 mmol, 24.7%).

(M, 3H), 7.23 (dd, J = 7.3 Hz, J = 1.8 Hz, 1H), 7.07-6.97 (m, 1H), 7.39-7. J = 1.5 Hz, 1H), 6.92 (dd, J = 7.8 Hz, J = 2H), 3.85 (s, 3H), 2.96 (brs, 4H), 2.65 (brs, 4H), 2.49 (t, J = 6.6 Hz, 2H), 2.30 (t, J = 6.4 Hz 2H), 1.83 (quintet, J = 6.8 Hz,

Example  2.13. N - ((3 ' - Fluorobiphenyl -2 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(88 mg, 0.30 mmol), HBTU (122 mg, 0.32 mmol) and TEA (140 [mu] l 27 mg (0.057 mmol, 22.7%) of the title compound was obtained by using (3'-fluorobiphenyl-2-yl) methanamine (50 mg, 0.25 mmol).

(D, J = 7.2 Hz, J = 1.5 Hz, IH), 7.08-6.85 (m, 7H), 6.29 (brs, IH) 2H), 3.32 (s, 3H), 3.18 (brs, 4H), 4.37 (d, J = 5.6 Hz, 2H) 1.74-1.62 (m, 4H)

Example  2.14. N - ((3 ' - Fluorobiphenyl -2 days) methyl ) -6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(92 mg, 0.30 mmol), HBTU (122 mg, 0.32 mmol) and TEA (140 [mu] l (3-fluorobiphenyl-2-yl) methanamine (50 mg, 0.25 mmol) was used to yield 39 mg (0.080 mmol, 31.9%) of the title compound.

(M, 3H), 5.81 (brs, IH), 7.29-7.21 (m, 2H), 3.87 (s, 3H), 3.16 (brs, 4H), 2.87 (brs, 4H), 2.63 (t, J = 7.9 Hz, 2H), 2.17 , J = 7.5 Hz, 2H), 1.68-1.58 (m, 4H), 1.41-1.31 (m, 2H)

Example  2.15. N - ((4 ' - Fluorobiphenyl -2 days) methyl ) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Propanamide  synthesis

(71 mg, 0.27 mmol), HBTU (124 mg, 0.325 mmol), TEA (141 mg, 0.25 mmol) 37 mg (0.083 mmol, 33.1%) of the title compound was obtained by using (4-fluorobiphenyl-2-yl) methanamine (50 mg, 0.25 mmol).

(M, 2H), 7.00 (dd, J = 7.5 (m, 2H), 7.37-7. J = 1.5 Hz, 1H), 6.81 (dd, J = 7.5 Hz, J = 1.5 Hz, 1H), 6.86 (dd, J = 7.9 Hz, 2H), 3.85 (s, 3H), 2.91 (brs, 4H), 2.68-2.64 (m, 6H), 2.41 (t, J = 6.0 Hz, 2H)

Example  2.16. N - ((4 ' - Fluorobiphenyl -2 days) methyl ) -4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Butanamide  synthesis

(134 mg, 0.50 mmol), HATU (248 mg, 0.65 mmol), TEA (283 [mu] L , 2.00 mmol) and (4'-fluorobiphenyl-2-yl) methanamine (100 mg, 0.50 mmol) were used to yield the title compound (58 mg, 0.13 mmol, 25.1%).

(M, 3H), 6.67 (br s, IH), 4.36 (d, J = 5.6 2H, J = 6.4 Hz, 2H), 1.83 (brs, 2H), 3.87 (s, 3H)

Example  2.17. N - ((4 ' - Fluorobiphenyl -2 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(79 mg, 0.27 mmol), HBTU (124 mg, 0.325 mmol) and TEA (140 [mu] l , 1.00 mmol) and (4'-fluorobiphenyl-2-yl) methanamine (50 mg, 0.25 mmol), 74 mg (0.16 mmol, 62.2%) of the title compound were obtained.

(M, 3H), 6.96-6.85 (m, 3H), 6.30 (brs, IH), 4.36 (d, J = 5.6 2H), 3.87 (s, 3H), 3.21 (brs, 4H), 3.08 (brs,

Example 2.18. Yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide

(83 mg, 0.27 mmol), HBTU (124 mg, 0.325 mmol) and TEA (140 [mu] l , 1.00 mmol) and (4'-fluorobiphenyl-2-yl) methanamine (50 mg, 0.25 mmol) to obtain 76 mg (0.16 mmol, 62.1%) of the desired compound.

1H NMR (400 MHz, CDCl3)? 7.44-7.24 (m, 6H), 7.16-7.11 (m, 2H), 7.06-7.00 2H), 3.89 (s, 3H), 3.15 (brs, 4H), 2.76 (brs, 4H), 2.51 (t, 2H), 1.69-1.56 (m, 4H), 1.40-1.33 (m, 2H), 2.17 (t, J = 7.6 Hz,

Example  2.19. N - ((2 ' - Chlorobiphenyl -2 days) methyl ) -4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Butanamide  synthesis

(70.3 mg, 0.25 mmol), HBTU (113.7 mg, 0.30 mmol), TEA (129 [mu] l , 0.92 mmol) and (2'-chlorobiphenyl-2-yl) methanamine (50 mg, 0.23 mmol) to obtain the desired compound (75 mg, 0.16 mmol, 69.6%).

(D, J = 7.2 Hz, 1H), 7.07-7.02 (m, 2H), 6.94-7.26 (m, 2H), 3.85 (s, 3H), 3.20 (brs, 8H), 3.05 (brt, J = 5.6 Hz, 2H), 2.50 (brs, 2H)

Example  2.20. N - ((2 ' - Chlorobiphenyl -2 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(73.1 mg, 0.25 mmol), HBTU (113.7 mg, 0.30 mmol) and TEA (129 [mu] l , 0.92 mmol) and (2'-chlorobiphenyl-2-yl) methanamine (50 mg, 0.23 mmol) were used to obtain the desired compound (87 mg, 0.18 mmol, 76.9%).

7.16 (d, J = 7.1 Hz, 1 H), 7.07 (m, 3H), 7.37-7.29 (m, 3H) J = 7.9 Hz, J = 1.9 Hz, 1H), 6.97-6.88 (m, 3H), 6.21 (brt, J = 5.6 Hz, 1H), 4.29-4.16 ), 3.23 (brs, 4H), 3.13 (brs, 4H), 2.93 (brs, 2H)

Example  2.21. N - ((2 ' - Chlorobiphenyl -2 days) methyl ) -5- (4- (2- Ethoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(169 mg, 0.55 mmol), HBTU (227 mg, 0.60 mmol), TEA (259 [mu] l , 1.84 mmol) and (2'-chlorobiphenyl-2-yl) methanamine (100 mg, 0.46 mmol) were used to yield 86 mg (0.17 mmol, 36.9%) of the desired compound.

1H), 4.69 (dd, J = 14.7Hz, J = 6.0Hz, 1H), 7.30-7.16 (m, J = 6.9 Hz, 2H), 3.09 (brs, 4H), 2.61 (brs, 4H), 2.39 (brt, J = 7.2 Hz, 2H), 2.14 (brt, J = 7.2 Hz, 2H), 1.65-1.51 (m, 4H), 1.45 (t, J = 6.9 Hz,

Example  2.22. N - ((2 ' - Chlorobiphenyl -2 days) methyl ) -5- (4- (4- Methoxyphenyl ) Pipera 1-yl) Pentanamide  synthesis

(80 mg, 0.28 mmol), HATU (114 mg, 0.30 mmol) and TEA (129 [mu] L) in the same manner as in the synthesis of Example 2.1 using 4- (4- methoxyphenyl) piperazin- , 0.92 mmol) and (2'-chlorobiphenyl-2-yl) methanamine (50 mg, 0.23 mmol) to obtain the title compound (88 mg, 0.18 mmol, 77.8%).

(D, J = 6.6 Hz, J = 2.1 Hz, 1H), 6.90-6.81 (m, 4H), 5.76 (brt, J = 5.1 Hz, 1H), 3.75 (s, 3H), 3.06 (brs, 1H), 4.31 (dd, J = 14.7 Hz, J = 6.0 Hz, 1H) (M, 4H), 2.56 (brs, 4H), 2.37 (t,

Example  2.23. N - ((2 ' - Chlorobiphenyl -2 days) methyl ) -6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(78 mg, 0.25 mmol), HBTU (113.7 mg, 0.30 mmol), TEA (129 [mu] L (50 mg, 0.23 mmol) and (2'-chlorobiphenyl-2-yl) methanamine (0.92 mmol, 59.3%).

(M, 6H), 7.23-7.20 (m, 1H), 7.16 (d, J = 6.8 Hz, 1H), 7.05 (td, J = 7.5 Hz, J = (D, J = 5.3 Hz, 2H), 3.86 (s, 3H), 3.22 (br s, J = 7.1 Hz, 2H), 1.77-1.67 (m, 2H), 1.65-1.51 (m, 2H), 3.13 (br s, ), 1.41-1.32 (m, 2H)

Example  2.24. N - ((2 ' - Chlorobiphenyl -2 days) methyl ) -6- (4- (2- Ethoxyphenyl ) Piperazin-1-yl) Hexane amyl  synthesis

(177 mg, 0.55 mmol), HBTU (227 mg, 0.60 mmol), TEA (259 [mu] l , 1.84 mmol) and (2'-chlorobiphenyl-2-yl) methanamine (100 mg, 0.46 mmol) to obtain 78 mg (0.15 mmol, 32.6%) of the desired compound.

1H), 4.32 (dd, J = 14.7 Hz, J = 6.0 Hz, IH), 7.99-7.16 (m, 8H), 6.99-6.83 (m, 4H) J = 6.9 Hz, 2H), 3.12 (brs, 4H), 2.64 (brs, 4H), 2.39 (brt, J = 2H), 2.11 (t, J = 7.5 Hz, 2H), 1.63-1.53 (m, 4H), 1.46 (t, J = 6.9 Hz, 3H), 1.36-1.27

Example  2.25. N - ((2 ' - Chlorobiphenyl -2 days) methyl ) -6- (4- (4- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(86 mg, 0.28 mmol), HATU (114 mg, 0.30 mmol) and TEA (129 [mu] l 78 mg (0.15 mmol, 67.0%) of the title compound was obtained by using the title compound (50 mg, 0.23 mmol) and (2'-chlorobiphenyl-2-yl) methanamine.

(D, J = 6.6 Hz, J = 1.8 Hz, 1H), 6.91-6.81 (m, 4H), 5.73 (brt, J = 4.8 Hz, 1H), 4.30 (dd, J = 15.0 Hz, J = 6.0 Hz, 1H), 4.16 (dd, J = 14.7 Hz, J = 5.1 Hz, 1H) J = 7.8 Hz 2H), 1.62-1.49 (m, 4H), 1.32-1.26 (m, 2H), 2.58 (br, )

Example  2.26. N - ((3 ' - Chlorobiphenyl -2 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(148 mg, 0.50 mmol), HBTU (228 mg, 0.60 mmol), TEA (259 [mu] l , 1.84 mmol) and (3'-chlorobiphenyl-2-yl) methanamine (100 mg, 0.46 mmol), 127 mg (0.26 mmol, 56.1%) of the desired compound was obtained.

(M, 2H), 7.05-6.87 (m, 4H), 5.80 (brs, IH), 4.42 (d, J = 5.7 (T, J = 7.5 Hz, 2H), 3.88 (s, 3H), 3.09 (brs, 1.70-1.58 (m, 4H)

Example  2.27. N - ((3 ' - Chlorobiphenyl -2 days) methyl ) -6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(78 mg, 0.25 mmol), HBTU (113.7 mg, 0.30 mmol), TEA (129 [mu] L , 0.92 mmol) and (3'-chlorobiphenyl-2-yl) methanamine (50 mg, 0.23 mmol), 37 mg (0.073 mmol, 31.8%) of the title compound were obtained.

(M, 8H), 7.04 (t, J = 6.4 Hz, 1H), 6.93-6.81 (m, 3H), 6.23 (brt, J = 5.3 Hz, 1H). 1H NMR (300 MHz, CDCl3)? 7.40-7.15 , 4.42 (d, J = 5.6 Hz, 2H), 3.85 (s, 3H), 3.19 (brs, 4H) J = 7.5 Hz, 2H), 1.73-1.56 (m, 4H), 1.39-1.31 (m, 2H)

Example  2.28. N - ((4 ' - Chlorobiphenyl -2 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(148 mg, 0.50 mmol), HBTU (228 mg, 0.60 mmol), TEA (259 [mu] l , 1.84 mmol) and (4'-chlorobiphenyl-2-yl) methanamine (100 mg, 0.46 mmol) to obtain the desired compound (170 mg, 0.35 mmol, 75.1%).

1H NMR (400 MHz, CDCl3)? 7.42-7.30 (m, 5H), 7.26-7.19 (m, 3H), 7.03-6.98 ), 4.40 (d, J = 5.6 Hz, 2H), 3.86 (s, 3H), 3.07 (brs, 4H) , J = 7.3 Hz, 2H), 1.64 - 1.55 (m, 4H)

Example  2.29. N - ((4 ' - Chlorobiphenyl -2 days) methyl ) -6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(78 mg, 0.25 mmol), HBTU (113.7 mg, 0.30 mmol), TEA (129 [mu] L (0.42 mmol, 51.5%) was obtained by using the title compound (50 mg, 0.23 mmol) and (4'-chlorobiphenyl-2-yl) methanamine.

(M, 2H), 7.05-6.87 (m, 4H), 5.60 (brs, IH), 4.41 (d, J = 5.6 J = 7.6 Hz, 2H), 3.88 (s, 3H), 3.34 (br s, 4H), 2.75 1.68-1.54 (m, 4H), 1.40-1.32 (m, 2H)

Example  2.30. N - ((2 ' - Bromobiphenyl -2 days) methyl ) -5- (4- (4- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(40 mg, 0.14 mmol), HBTU (54 mg, 0.143 mmol) and TEA (62 [mu] l , 0.44 mmol) and (2'-bromobiphenyl-2-yl) methanamine (30 mg, 0.11 mmol) were used to obtain 36 mg (0.067 mmol, 61.0%) of the title compound.

(M, 6H), 7.14 (dd, J = 6.9 Hz, J = 1.8 Hz, 1H), 6.90-6.81 (m, 1H), 7.43-7. (Dd, J = 14.7 Hz, J = 6.0 Hz, 1H), 4.17 (dd, J = 14.7 Hz, J = 5.1 Hz, 1H), 3.75 , 3.07 (brs, 4H), 2.57 (brs, 4H), 2.37 (t, J = 7.5 Hz, 2H)

Example  2.31. N - ((2 ' - Bromobiphenyl -2 days) methyl ) -6- (4- (4- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(56 mg, 0.18 mmol), HBTU (74 mg, 0.20 mmol) and TEA (84 [mu] L , 0.60 mmol) and (2'-bromobiphenyl-2-yl) methanamine (40 mg, 0.15 mmol) were used to yield the desired compound (29 mg, 0.053 mmol, 35.1%).

(M, 2H), 7.15 (dd, J = 8.3 Hz, 1H), 7.41-7.34 (m, 4H), 7.26-7.23 2H), 3.76 (s, 3H), 3.09 (br t, J = 4.8 (m, 2H) J = 7.6 Hz, 2H), 2.10 (t, J = 7.4 Hz, 2H), 1.62-1.50 (m, 4H) 1.32-1. 24 (m, 2H)

Example  2.32. N - ((2 ' - Methoxybiphenyl -2 days) methyl ) -4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Butanamide  synthesis

(72 mg, 0.26 mmol), HBTU (118 mg, 0.31 mmol) and TEA (135 [mu] L) in the same manner as in the synthesis of Example 2.1 using 4- (4- (2- methoxyphenyl) piperazin- , 0.96 mmol) and (2'-methoxybiphenyl-2-yl) methanamine (50 mg, 0.23 mmol) were used to yield the title compound (70 mg, 0.15 mmol, 64.3%).

(M, 4H), 7.21-7.18 (m, 1H), 7.12 (dd, J = 7.3 Hz, J = 1.8 Hz, 1H), 7.05-6.86 3H), 3.77 (s, 3H), 3.08 (brs, 4H), 2.80 (brs, 4H) ), 2.64 (brs, 2H), 2.29 (t, J = 6.8 Hz, 2H), 1.85 (quintet,

Example  2.33. N - ((2 ' - Methoxybiphenyl -2 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(76 mg, 0.26 mmol), HBTU (118 mg, 0.31 mmol) and TEA (135 [mu] L , 0.96 mmol) and (2'-methoxybiphenyl-2-yl) methanamine (50 mg, 0.23 mmol) were used to obtain the desired compound 110 mg (0.226 mmol, 98.1%).

(M, 4H), 7.21-7.18 (m, 1H), 7.14 (dd, J = 7.3 Hz, J = 1.8 Hz, 1H), 7.04-6.97 (M, 2H), 3.86 (s, 3H), 3.78 (s, 2H) J = 7.1 Hz, 2H), 1.67-1.53 (m, 4H), 2.51 (t, J = 7.1 Hz, 2H), 3.11 (brs,

Example  2.34. N - ((2 ' - Methoxybiphenyl -2 days) methyl ) -5- (4- (2- Ethoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(86 mg, 0.28 mmol), HBTU (113 mg, 0.30 mmol) and TEA (129 [mu] L , 0.92 mmol) and (2'-methoxybiphenyl-2-yl) methanamine (50 mg, 0.23 mmol), 81 mg (0.16 mmol, 70.2%) of the title compound was obtained.

J = 5.4 Hz, J = 1.5 Hz, 1H), 7.9 (dd, J = 6.6 Hz, ), 7.02-6.84 (m, 6H), 6.15 (brt, J = 5.4 Hz, IH), 4.31 (brs, 2H), 4.05 (q, J = 6.9 Hz, 2H) 2H), 1.65-1.61 (m, 4H), 1.44 (t, J = 6.9 Hz, 3H), 2.48 (brs,

Example  2.35. N - ((2 ' - Methoxybiphenyl -2 days) methyl ) -5- (4- (4- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(82 mg, 0.28 mmol), HATU (114 mg, 0.30 mmol) and TEA (131 [mu] L) in the same manner as in Example 2.1, , 0.93 mmol) and (2'-methoxybiphenyl-2-yl) methanamine (50 mg, 0.23 mmol) were used to yield 83 mg (0.17 mmol, 74.0%) of the title compound.

(M, 4H), 4.35 (dd, J), 7.20-7.30 (m, 2H), 7.02-6.95 3H), 3.75 (s, 3H), 3.05 (brs, 4H), 3.77 (s, 3H) J = 7.5 Hz, 2H), 1.64-1.47 (m, 4H), 2.56 (t, J = 7.5 Hz, 2H)

Example  2.36. N - ((2 ' - Methoxybiphenyl -2 days) methyl ) -6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(80 mg, 0.26 mmol), HBTU (118 mg, 0.31 mmol) and TEA (135 [mu] L) in the same manner as in the synthesis of Example 2.1, , 0.96 mmol) and (2'-methoxybiphenyl-2-yl) methanamine (50 mg, 0.23 mmol) to obtain the desired compound 110 mg (0.22 mmol, 95.3%).

(M, 2H), 4.36-4.14 (m, 2H), 7.14-6.87 (m, 7H) 2H), 2.16 (t, J = 7.2 Hz, 2H), 1.82 (s, 3H) -1.72 (m, 2H), 1.67-1.58 (m, 2H), 1.45-1.35 (m, 2H)

Example  2.37. N - ((2 ' - Methoxybiphenyl -2 days) methyl ) -6- (4- (4- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(86 mg, 0.28 mmol), HATU (114 mg, 0.30 mmol) and TEA (131 [mu] l , 0.93 mmol) and (2'-methoxybiphenyl-2-yl) methanamine (50 mg, 0.23 mmol) were used to obtain the title compound (40 mg, 0.080 mmol, 34.7%).

(M, 4H), 4.36 (dd, J &lt; RTI ID = 0.0 &gt; 3H), 3.75 (s, 3H), 3.08 (brs, 4H), 3.77 (s, 3H) 2H), 1.65-1.46 (m, 4H), 1.35-1.26 (m, 2H), 2.58 (t, J = 7.5 Hz, 2H)

Example  2.38. N - ((3 ' - Methoxybiphenyl -2 days) methyl ) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Propanamide  synthesis

Propanoic acid (136 mg, 0.52 mmol), HBTU (232 mg, 0.61 mmol), TEA (264 mg, (3-methoxybiphenyl-2-yl) methanamine (100 mg, 0.47 mmol) was used to yield the desired compound (66 mg, 0.14 mmol, 30.6%).

(M, 4H), 7.01 (td, J = 7.6 Hz, 1H), 7.47 (dd, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 2.90 (brs, 4H) , 2.64-2.67 (m, 6H), 2.41 (t, J = 5.8 Hz, 2H)

Example  2.39. N - ((3 ' - Methoxybiphenyl -2 days) methyl ) -4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Butanamide  synthesis

(145 mg, 0.52 mmol), HBTU (232 mg, 0.61 mmol) and TEA (264 [mu] l , 1.88 mmol) and (3'-methoxybiphenyl-2-yl) methanamine (100 mg, 0.47 mmol) were used to obtain the desired compound (75 mg, 0.16 mmol, 33.7%).

1H NMR (300 MHz, CDCl3)? 7.42-7.28 (m, 4H), 7.24-7.21 (m, IH), 7.09-7.04 2H), 2.50 (br s, 3H), 3.78 (s, 3H) , 2H), 1.91 (brs, 2H)

Example  2.40. N - ((3 ' - Methoxybiphenyl -2 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(145 mg, 0.52 mmol), HBTU (232 mg, 0.61 mmol) and TEA (264 [mu] l , 1.88 mmol) and (3'-methoxybiphenyl-2-yl) methanamine (100 mg, 0.47 mmol) were used to obtain the desired compound (90 mg, 0.18 mmol, 39.3%).

J = 7.6 Hz, J = 1.5 Hz, 1H), 7.39-7.31 (m, 3H), 7.27-7.25 (m, 1H), 7.07 (td, J = 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.96 (s, 3H), 3.22 (brs, 4H), 3.03 (brs, 4H), 2.84 (brs, 2H)

Example  2.41. N - ((3 ' - Methoxybiphenyl -2 days) methyl ) -6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(121 mg, 0.39 mmol), HBTU (163 mg, 0.43 mmol), TEA (186 [mu] l , 1.32 mmol) and (3'-methoxybiphenyl-2-yl) methanamine (70 mg, 0.33 mmol) were used to obtain the desired compound (92 mg, 0.18 mmol, 55.6%).

J = 7.0 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 6.89 - 6.77 (m, 6H) 3H), 3.15 (brs, 4H), 3.04 (br s, 3H), 6.29 (brt, J = 5.3 Hz, 2H), 1.69-1.52 (m, 4H), 1.36-1.28 (m, 2H), 2.15 (t, J =

Example  2.42. N - ((4 ' - Methoxybiphenyl -2 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(75 mg, 0.26 mmol), HBTU (114 mg, 0.30 mmol) and TEA (130 [mu] l , 0.92 mmol) and (4'-methoxybiphenyl-2-yl) methanamine (50 mg, 0.23 mmol), 103 mg (0.21 mmol, 91.8%) of the desired compound was obtained.

(M, 2H), 6.02 (brs, IH), 7.41-7.29 (m, 5H), 7.23-7. 2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.14 (brs, (br s, 2H), 1.66-1.65 (m, 4H)

Example  2.43: N - ((4 ' - Methoxybiphenyl -2 days) methyl ) -6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(80 mg, 0.26 mmol), HBTU (114 mg, 0.30 mmol) and TEA (130 [mu] l , 50 mg (0.23 mmol) of the title compound were obtained using the compound obtained in (2), 0.92 mmol) and (4'-methoxybiphenyl-2-yl) methanamine

(D, J = 7.5 Hz, 2H), 3.87 (s, 2H), 7.87 (T, J = 9.6 Hz, 2H), 1.71-1.56 (m, 4H), 3.85 (s, 3H) ), 1.38-1.27 (m, 2H)

Example  2.44. N - ((2 ', 6 ' - Dimethoxybiphenyl -2 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(66 mg, 0.23 mmol), HBTU (102 mg, 0.27 mmol), TEA (116 [mu] l , 0.82 mmol) and (2 ', 6'-dimethoxybiphenyl-2-yl) methanamine (50 mg, 0.21 mmol) were used to obtain 92 mg (0.18 mmol, 84.6%) of the title compound.

1H NMR (400 MHz, CDCl3)? 7.40-7.30 (m, 4H), 7.16-7.13 (m, IH), 7.08-7.03 2H), 3.86 (s, 3H), 3.71 (s, 6H), 3.24 (brs, 4H), 3.07 (brs, 4H), 2.87 (brs, 2H), 2.17 (brt, J = 6.3 Hz, 2H), 1.74-1.

Example  2.45. N - ((2 ', 6 ' - Dimethoxybiphenyl -2 days) methyl ) -6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Hexanamide  synthesis

(69 mg, 0.23 mmol), HBTU (102 mg, 0.27 mmol), TEA (116 [mu] l , 0.82 mmol) and (2 ', 6'-dimethoxybiphenyl-2-yl) methanamine (50 mg, 0.21 mmol) were used to obtain 84 mg (0.16 mmol, 75.2%) of the title compound.

1H NMR (400 MHz, CDCl3)? 7.33-7.23 (m, 4H), 7.09-7.06 (m, 1H), 6.99-6.94 ), 6.58 (s, IH), 5.82 (brt, J = 5.1 Hz, IH), 4.08 (d, J = 5.1 Hz, 2H), 3.79 (s, 2H), 1.65-1.57 (m, 2H), 1.55-1.48 (m, 2H), 1.31 (m, 2H) 1.24 (m, 2 H)

Example  2.46. 5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) -N - ((2 ' - Methyl biphenyl -2 days) methyl ) Pentanamide  synthesis

(54 mg, 0.18 mmol), HBTU (74 mg, 0.20 mmol) and TEA (85 [mu] L) in the same manner as the synthesis example 2.1, , 0.60 mmol) and (2'-methylbiphenyl-2-yl) methanamine (30 mg, 0.15 mmol) were used to yield the title compound 45 mg (0.095 mmol, 63.6%).

1H NMR (300 MHz, CDCl3)? 7.45-7.41 (m, 1H), 7.39-7.21 (m, 5H), 7.17-7.11 (m, 2H), 7.04-6.98 2H), 3.87 (s, 3H), 3.09 (brs, 4H), 6.87 (d, J = 7.5 Hz, 2H), 2.15 (t, J = 7.1 Hz, 2H), 2.08 (s, 3H), 1.69-1.48 (m, 4H)

Example  2.47. 6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) -N - ((2 ' - Methyl biphenyl -2 days) methyl ) Hexanamide  synthesis

(130 mg, 0.43 mmol), HBTU (173 mg, 0.46 mmol) and TEA (197 [mu] L) in the same manner as in Example 2.1, , 1.40 mmol) and (2'-methylbiphenyl-2-yl) methanamine (70 mg, 0.35 mmol) were used to obtain the desired compound 110 mg (0.23 mmol, 64.7%).

(M, 2H), 6.78 (d, J), 7.38-7.13 (m, = 7.3 Hz, 1H), 6.27 (brt, J = 5.8 Hz, 1H), 4.17-4.02 (m, 2H), 3.82 2H), 2.15 (brt, J = 7.3 Hz, 2H), 1.99 (s, 3H), 1.72-1.65 (m, 2H), 1.59-1.52

Example  2.48. 4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) -N - ((3 ' - Methyl biphenyl -2 days) methyl ) Butanamide  synthesis

(77.6 mg, 0.28 mmol), HBTU (124 mg, 0.33 mmol) and TEA (140 [mu] l (50 mg, 0.25 mmol) and (3'-methylbiphenyl-2-yl) methanamine (1.00 mmol).

(D, J = 7.5 Hz, 1H), 7.09-7.03 (m, 3H), 7.00-6.84 (m, 4H), 4.40 J = 5.6 Hz, 2H), 2.86 (s, 3H), 3.12 (brs, 4H), 3.01 (brs, 2H), 2.37 (s, 3H), 1.88 (brs, 2H)

Example  2.49. 5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) -N - ((3 ' - Methyl biphenyl -2 days) methyl ) Pentanamide  synthesis

(82 mg, 0.28 mmol), HBTU (124 mg, 0.33 mmol) and TEA (140 [mu] l (50 mg, 0.25 mmol), which was used in the next step without further purification, to obtain the target compound (106 mg, 0.22 mmol, 90.0%).

7.17 (d, J = 7.1 Hz, 1 H), 7.11-7.00 (m, 3H), 6.95-6.86 (m, 3H), 6.24 (m, 2H) 2H), 3.86 (s, 3H), 3.11 (brs, 4H), 2.79 (brs, 4H), 2.60 (brs, 2H) 2.34 (s, 3H), 2.21 (brs, 2H), 1.65-1.62 (m, 4H)

Example  2.50. 6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) -N - ((3 ' - Methyl biphenyl -2 days) methyl ) Hexanamide  synthesis

(131 mg, 0.43 mmol), HBTU (177 mg, 0.47 mmol) and TEA (197 [mu] L) in the same manner as in Example 2.1, , 1.40 mmol) and (3'-methylbiphenyl-2-yl) methanamine (70 mg, 0.35 mmol) were used to yield the title compound (80 mg, 0.16 mmol, 47.1%).

(M, 3H), 6.91-6.86 (m, 2H), 6.78 (d, J = 7.5 Hz, 1H), 6.30 (m, 2H), 7.38-7. J = 7.5 Hz, 2H), 2.35 (s, 3H), 3.32 (s, 3H) J = 7.2 Hz, 2H), 1.40-1.35 (m, 2H), 1.60 (brs,

Example  2.51. 5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) -N - ((4'- Methyl biphenyl -2 days) methyl ) Pentanamide  synthesis

(89 mg, 0.30 mmol), HBTU (128 mg, 0.34 mmol), TEA (142 [mu] l 55 mg (0.12 mmol, 46.6%) of the title compound was obtained by using (4'-methylbiphenyl-2-yl) methanamine (50 mg, 0.25 mmol).

(M, 3H), 7.22-7.15 (m, 5H), 7.06 (td, J = 7.5 Hz, J = 1.2 Hz, 1H), 6.94-6.82 3H), 3.86 (s, 3H), 3.16 (brs, 4H), 3.05 (brs, 4H), 2.87 (d, J = 5.7 Hz, 2H), 2.68 (s, 3H), 2.26 (t, J = 6.0 Hz, 2H), 1.68-1.65

Example  2.52. 6- (4- (2- Methoxyphenyl ) Piperazin-1-yl) -N - ((4'- Methyl biphenyl -2 days) methyl ) Hexanamide  synthesis

(92 mg, 0.30 mmol), HBTU (128 mg, 0.34 mmol), TEA (142 [mu] L , 50 mg (0.25 mmol) of (4'-methylbiphenyl-2-yl) methanamine was used to obtain 44 mg (0.090 mmol, 36.2%) of the title compound.

1H NMR (400 MHz, CDCl3)? 7.41-7.39 (m, IH), 7.36-7.29 (m, 2H), 7.28-7.18 2H), 6.87 (d, J = 7.6 Hz, IH), 5.54 (brs, IH), 4.42 (d, J = 5.6 Hz, 2H) (m, 2H), 1.37-1.29 (m, 2H), 2.40 (s, 3H) ), 1.37-1.29 (m, 2H)

Example  2.53. N - ([1,1'- Biphenyl ] -3- Yl methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(134 mg, 0.46 mmol), HBTU (187 mg, 0.50 mmol) and TEA (214 [mu] L , 1.52 mmol) and biphenyl-3-ylmethanamine (70 mg, 0.38 mmol) were used to obtain the desired compound (96 mg, 0.21 mmol, 55.2%).

J = 1.5 Hz, 1H), 6.89-6.77 (m, 3H), 6.55 (brt, J = 2H), 3.82 (s, 3H), 3.09 (brs, 4H), 2.85 (brs, 4H), 2.68 (t, J = 6.0 Hz, 2H) , 2.32 (t, J = 6.0 Hz, 2H), 1.65-1.62 (m, 4H)

Example  2.54. N - ((2 ' - Methoxybiphenyl -3 days) methyl ) -5- (4- (2- Methoxyphenyl ) Piperazin-1-yl) Pentanamide  synthesis

(82 mg, 0.28 mmol), HBTU (113 mg, 0.30 mmol) and TEA (130 [mu] l (50 mg, 0.23 mmol) and (2'-methoxybiphenyl-3-yl) methanamine (0.19 mmol, 59.7%).

J = 6.0 Hz, 1H), 4.45 (m, 2H), 7.38-7.23 (m, 4H), 7.04-6.81 d, J = 6.0 Hz, 2H ), 3.83 (s, 3H), 3.77 (s, 3H), 3.11 (brs, 4H), 2.84 (brs, 4H), 2.67 (t, J = 6.0 Hz, 2H), 2.31 (t, J = 6.0 Hz, 2H), 1.76-1.60 (m, 4H)

Example  3.1. 2- (2'- Methoxybiphenyl Yl) acetate

A reaction vessel ethyl-2- (2-bromophenyl) acetate (500 mg, 2.06 mmol), 2-methoxyphenyl beam Nick acid (376 mg, 2.47 mmol), Pd (PPh) 3 (24 mg, 0.021 mmol) and Na ₂ CO ₃ (328 mg, 3.09 mmol) were dissolved in N, N-dimethylformamide (20 ml) and the mixture was refluxed at 160 ° C for 8 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc, saturated NaHCO ₃ solution was added, and the aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (hexane: diethyl ether = 8: 1) to obtain 350 mg (1.29 mmol, 62.6%) of the title compound.

(Dd, J = 7.2 Hz, J = 5.7 Hz, 1H), 7.03 (td, J = 7.2 Hz, J = 0.9 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.75 (s, 3H), 3.51 (s, 2H), 1.19 (t, J = 6.9 Hz, 3 H)

Example  3.2. 2- (2'- Methoxybiphenyl -2 days) Acetate sheet  synthesis

To the reaction vessel was added 2- (2'-methoxybiphenyl-2-yl) acetate (350 mg, 1.29 mmol) and 1N KOH (2.6 ml, 2.60 mmol) and the mixture was treated with distilled water After melting, the mixture was heated to reflux at 75 ° C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethanol, diluted with distilled water (10 ml), and washed with diethyl ether. The aqueous layer was acidified with 3N HCl and extracted with dichloromethyl. The organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to obtain the desired compound (301 mg, 1.24 mmol, 96.3%).

1H NMR (300 MHz, CDCl3) δ 7.41-7.35 (m, 4H), 7.28-7.24 (m, 1H), 7.19 (dd, J = 7.2 Hz, J = 5.7 Hz, 1H), 7.03 (td, J = 7.2 Hz, J = 0.9 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 3.72 (s, 3H), 3.52 (d, J = 2.7 Hz, 2H)

Example 4.1. 2- (2'-methoxy- [1,1'-biphenyl] -2-yl) -N- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl) acetamide ;

Acetic acid (110 mg, 0.46 mmol) and EDCI (74 mg, 0.48 mmol), HOBT (65 mg, 0.48 mmol), NMM (53 mg, Mu] l, 0.48 mmol) was dissolved in dichloromethane (5 ml), followed by stirring for 2 hours. 1-amine (100 mg, 0.38 mmol) was added thereto at room temperature, and the mixture was stirred at room temperature for about 6 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, and then saturated NaHCO ₃ (MC: MeOH: H 2 O: NH 3 = 80: 20: 1: 1) = 8 (1: 1) was added to the reaction solution and the mixture was extracted with dichloromethane : 1) to obtain 87 mg (0.18 mmol, 47.0%) of the desired compound.

(Dd, J = 7.4 Hz, J = 1.7 Hz, 1 H), 7.21 (dd, J = 6.4 Hz, 3H), 3.42 (s, 3H), 3.42 (d, J = 7.7 Hz, 2H), 1.44-1.42 (m, 4H), 2.35 (m, 2H), 3.22 (br s, 2H)

Example  4.2. 2- (3'- Methoxy - [1,1'- Biphenyl] Yl) -N- (4- (4- (2- &lt; / RTI &gt; Methoxyphenyl ) Piperazin-1-yl) butyl) Acetamide ;

Acetic acid (77 mg, 0.32 mmol), EDCI (53 mg, 0.34 mmol) and HOBT (46 mg, 0.34 mmol) were obtained in the same manner as in Example 4.1 using 4- (3'-methoxybiphenyl) (70 mg, 0.27 mmol) was reacted with NMM (37 μL, 0.34 mmol) and 4- (4- (2- methoxyphenyl) piperazin-1-yl) butan- 0.10 mmol, 38.7%).

1H), 3.88 (s, 3H), 3.94 (s, 3H) 2H), 3.81 (s, 3H), 3.55 (s, 2H), 3.21 (brs, 2H), 3.08 (brs, (m, 4H)

Manufacturing example  One. Biphenyl Amide  Formulation of compounds

According to the following preparation examples, biphenylamide derivatives acting on the 5-HT ₇ receptor according to the present invention were formulated in various forms.

Manufacturing example  1.1. Direct pressurized purification

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Manufacturing example  1.2. Wet-type purification

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Manufacturing example  1.3. Powder and Capsule

After 5.0 mg of the active ingredient was sieved, the mixture was mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. 5 gelatin capsules.

Manufacturing example  1.4. Injection

Injections were prepared by adding 100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO _{4 12} H ₂ O and 2974 mg of distilled water.

Experimental Example . 5- HT7  Measurement of binding affinity for serotonin receptors

Human recombinant 5-HT ₇ receptor expressed in CHO cells was used as a receptor. To the container was added 50 mM Tris-HCl buffer (pH 7.4) containing 1 nM of [ ³ H] LSD, 15 μg / well of 5-HT ₇ receptor membrane, various concentrations of test drug, 10 mM MgCl ₂ and 0.1 mM EDTA Was added to make a final reaction volume of 0.25 ml, which was then incubated at 25 ° C for 90 minutes. After incubation, the reaction was terminated by rapid filtration through a Whatman GF / C glass fiber filter previously dipped in 0.3% polyethyleneimine using a Brandel harvester and washed with cold 50 mM Tris-HCl buffer. The filter was covered with Meltelex, sealed in a sample bag, dried in an oven and counted with a MicroBeta, Wallac. Nonspecific binding was measured in the presence of 0.5 uM Mianserin. The K _i value of the test drug was calculated by nonlinear regression method (GraphPad Prism Program, San Diego, USA) for the isotherm obtained by repeatedly testing the drug in 10-11 steps twice in two test tubes.

The results of% inhibition and binding affinity ( K _i ) of the novel compounds according to the present invention at a concentration of 10 mM for the 5-HT7 serotonin receptor are shown in Table 1 below.

Experimental compound % inhibition (10 [mu] M) K _i (nM) Example 2.1 59.7 537.0 Example 2.8 95.1 431.9 Example 2.9 86.2 192.0 Example 2.21 93.8 658.0 Example 2.22 84.0 367.3 Example 2.23 87.0 273.7 Example 2.24 93.8 255.5 Example 2.25 95.9 64.0 Example 2.36 91.3 79.0 Example 2.38 88.3 66.0 Example 2.47 95.4 15.0

Claims (13)

A biphenyl amide derivative represented by the following formula (1):
&Lt; Formula 1 >

In Formula 1,
R ₁ and R _{2, which} may be the same or different from each other, may each independently be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain of 1 to 6 carbon atoms, straight chain,
A is

or

Lt;
n is an integer of 1 to 4; The method according to claim 1, wherein the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl and phenyl A biphenyl amide derivative. The method according to claim 1, wherein the alkoxy group is an alkyl group selected from the group consisting of methyl, ethyl, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert- butyl group, cyclopentyl group, cyclohexyl group, Is an alkoxy group linked to oxygen. 2. The compound according to claim 1, wherein the biphenylamide derivative is
N - ([1,1'-biphenyl] -2-ylmethyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) propanamide;
N - ([1,1'-biphenyl] -2-ylmethyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;
N - ([1,1'-biphenyl] -2-ylmethyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ([1,1'-biphenyl] -2-ylmethyl) -5- (4- (4-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ([1,1'-biphenyl] -2-ylmethyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ([1,1'-biphenyl] -2-ylmethyl) -6- (4- (4-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((2'-fluorobiphenyl-2-yl) methyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) propanamide;
N - ((2'-fluorobiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;
N - ((2'-fluorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((2'-fluorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((3'-fluorobiphenyl-2-yl) methyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) propanamide;
N - ((3'-fluorobiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;
N - ((3'-fluorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((3'-fluorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((4'-fluorobiphenyl-2-yl) methyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) propanamide;
N - ((4'-fluorobiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;
N - ((4'-fluorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((4'-fluorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((2'-chlorobiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;
N - ((2'-chlorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((2'-chlorobiphenyl-2-yl) methyl) -5- (4- (2-ethoxyphenyl) piperazin-1-yl) pentanamide;
N - ((2'-chlorobiphenyl-2-yl) methyl) -5- (4- (4-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((2'-chlorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((2'-chlorobiphenyl-2-yl) methyl) -6- (4- (2-ethoxyphenyl) piperazin-1-yl) hexanamide;
N - ((2'-chlorobiphenyl-2-yl) methyl) -6- (4- (4-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((3'-chlorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((3'-chlorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((4'-chlorobiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((4'-chlorobiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((2'-bromobiphenyl-2-yl) methyl) -5- (4- (4-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((2'-bromobiphenyl-2-yl) methyl) -6- (4- (4-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((2'-methoxybiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;
N - ((2'-methoxybiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((2'-methoxybiphenyl-2-yl) methyl) -5- (4- (2-ethoxyphenyl) piperazin-1-yl) pentanamide;
N - ((2'-methoxybiphenyl-2-yl) methyl) -5- (4- (4-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((2'-methoxybiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((2'-methoxybiphenyl-2-yl) methyl) -6- (4- (4-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((3'-methoxybiphenyl-2-yl) methyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) propanamide;
N - ((3'-methoxybiphenyl-2-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butanamide;
N - ((3'-methoxybiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((3'-methoxybiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((4'-methoxybiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((4'-methoxybiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-yl) hexanamide;
N - ((2 ', 6'-dimethoxybiphenyl-2-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((2 ', 6'-dimethoxybiphenyl-2-yl) methyl) -6- (4- (2-methoxyphenyl) piperazin-1-ylhexanamide;
5- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((2'-methylbiphenyl-2-yl) methyl) pentanamide;
6- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((2'-methylbiphenyl-2-yl) methyl) hexanamide;
4- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((3'-methylbiphenyl-2-yl) methyl) butanamide;
5- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((3'-methylbiphenyl-2-yl) methyl) pentanamide;
6- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((3'-methylbiphenyl-2-yl) methyl) hexanamide;
5- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((4'-methylbiphenyl-2-yl) methyl) pentanamide;
6- (4- (2-methoxyphenyl) piperazin-1-yl) -N - ((4'-methylbiphenyl-2-yl) methyl) hexanamide;
N - ([1,1'-biphenyl] -3-ylmethyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
N - ((2'-methoxybiphenyl-3-yl) methyl) -5- (4- (2-methoxyphenyl) piperazin-1-yl) pentanamide;
1-yl) butyl) acetamide &lt; / RTI &gt;(2-methoxy-; or
1- (2-methoxyphenyl) piperazin-1-yl) butyl) acetamide &Lt; / RTI &gt; biphenyl amide derivative. A process for preparing a biphenyl amide derivative comprising the step of preparing a compound of formula (1) by amide bonding of a compound of the formula (2)
&Lt; Formula 2 >< EMI ID =

&Lt; Formula 1 &gt;

In the above formula (1), (2) or (3)
R ₁ and R _{2, which} may be the same or different from each other, may each independently be an alkyl group or an alkoxy group containing a hydrogen, a halogen, a carbon chain of 1 to 6 carbon atoms, straight chain,
A is

or

Lt;
n is an integer of 1 to 4,
Wherein X in the formula 2 is COOH or NH ₂ , Y in the formula 3 is NH ₂ or COOH, and when X in the formula 2 is COOH, Y in the formula 3 is NH ₂ and X in the formula 2 is NH ₂ , Y in the formula (3) is COOH. 6. The method of claim 5,
Wherein NaBH (OAc) ₃ to NaBH ₃ CN are added as a reducing agent in the amide coupling. 6. The method of claim 5,
Wherein the compound of formula (2) is prepared by reducing a compound of formula (4): < EMI ID =
&Lt; Formula 4 &gt;

In Formula 4,
R ₁ May be an alkyl group or an alkoxy group comprising a carbon chain of 1 to 6 carbon atoms, hydrogen, halogen, linear, branched and cyclic carbon atoms. [8] The method of claim 7, wherein the compound of formula (4) is prepared by Suzuki coupling of bromobenzenitrile with a compound of formula (5)
&Lt; Formula 5 >

In Formula 5,
R ₁ May be an alkyl group or an alkoxy group comprising a carbon chain of 1 to 6 carbon atoms, hydrogen, halogen, linear, branched and cyclic carbon atoms. 6. The method of claim 5,
Wherein the compound of formula (2) is prepared by hydrolyzing a compound of formula (6): < EMI ID =
(6)

In Formula 6,
R ₁ May be an alkyl group or an alkoxy group comprising a carbon chain of 1 to 6 carbon atoms, hydrogen, halogen, linear, branched and cyclic carbon atoms. 10. The method of claim 9,
Wherein the compound of formula (6) is prepared by reacting a compound of formula (5) with ethyl bromophenylacetate in a Suzuki coupling reaction.
&Lt; Formula 5 >

In Formula 5,
R ₁ May be an alkyl group or an alkoxy group comprising a carbon chain of 1 to 6 carbon atoms, hydrogen, halogen, linear, branched and cyclic carbon atoms. delete A pharmaceutical composition for the prevention and treatment of central nervous system diseases, which comprises, as an active ingredient, a biphenyl compound represented by the formula (1) or a pharmaceutically acceptable salt thereof:
&Lt; Formula 1 >

In Formula 1,
R ₁ and R _{2, which} may be the same or different from each other, may each independently be an alkyl group or an alkoxy group containing hydrogen, halogen, nitro, a carbon chain of 1 to 6 carbon atoms, straight chain,
A is

or

Lt;
n is an integer of 1 to 4; 13. The method of claim 12, wherein the central nervous system disease is one or more selected from the group consisting of depression, migraine, anxiety, inflammatory pain and neuropathic pain, body temperature control disorder, biorhythm control disorder, sleep disorder, &Lt; / RTI &gt;