KR20140063919A - Novel piperazine derivatives, pharmaceutically acceptable salts thereof or optical isomer thereof, preparation method thereof and pharmaceutical composition for prevention or treatment of the metabolic diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel piperazine derivative, to a pharmaceutically acceptable salt or an optical isomer thereof, to a method for preparing same, and to a pharmaceutical composition containing same as an active ingredient for preventing or treating metabolic diseases. The novel piperazine derivative and the pharmaceutically acceptable salt or the isomer thereof, according to the present invention, have excellent in vivo absorptivity and outstanding safety in the human body, since the present invention has a higher water solubility than those of compounds conventionally known as GPR119 activators and has low cytotoxicity. Moreover, since the present invention has the excellent effect of promoting cAMP by activating GPR119, thereby having the significantly outstanding effect of reducing blood glucose in a single dose, the present invention can be effectively used as a pharmaceutical composition for preventing or treating obesity, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin tolerance, hyperglycemia, hyperlipemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, or X syndrome which are treatable by activating GPR119.

Description

TECHNICAL FIELD The present invention relates to a novel piperazine derivative, a pharmaceutically acceptable salt or an optical isomer thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating metabolic diseases containing the same as an active ingredient. , preparation method thereof and pharmaceutical composition for prevention or treatment of the metabolic diseases containing the same as an active ingredient}

The present invention relates to a novel piperazine derivative, a pharmaceutically acceptable salt thereof or an optical isomer thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating metabolic diseases containing the same as an active ingredient.

Diabetes is a serious illness suffered by more than 100 million people worldwide and continues to threaten people's health. Diabetes can be classified into two clinical syndromes, type I and type II. Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is caused by autoimmune destruction of pancreatic beta-cells producing insulin and requires regular administration of exogenous insulin. Type II diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM), is characterized by a loss of ability to properly regulate blood glucose levels. Type II diabetes can be characterized by defects in insulin secretion or insulin resistance, that is, people with type 2 diabetes who have little or no insulin.

Diabetes, on the other hand, causes high levels of glucose to accumulate in the blood and urine, causing ebhls related to excessive urination, thirst, hunger, fat and protein metabolism. Such diabetes can cause life-threatening complications such as vision loss, kidney failure and heart disease, cause damage to the retina of the back of the eye, and increase the risk of cataracts and glaucoma. It also interferes with the ability to feel pain associated with nerve damage to the legs and feet, and can also cause serious infections.

Current treatments for diabetes include insulin, an insulin secretagogue, a glucose lowering effector, and an activator of peroxisome proliferator-activated receptor (PPAR). However, there are problems associated with currently available therapies, including hypoglycemia, weight gain, decreased responsiveness to treatment over time, gastrointestinal problems and edema. In order to introduce more effective new therapies into the market, studies are being conducted in various areas, and one specific target is GPR119. GPR119 is a G-protein coupled receptor (GPCR) that is predominantly expressed in the pancreas, small intestine, colon and adipose tissue. Recently, research has been published that the GPR119 expression profile has potential utility for the treatment of obesity and diabetes. Activation of GPR119 has been shown to stimulate cAMP to induce glucose-dependent GLP-1 and insulin secretion (Non-Patent Document 1). In addition, in addition to effects on plasma glucose levels, GPR119 activator has been shown to reduce acute food intake in rats after chronic administration and reduce body weight (Patent Documents 1 and 2 and Non-Patent Document 2).

The results of the research on the metabolic diseases of GPR119 have been continuously announced, and the development of GPR119 activator has been actively promoted.

First, interest in triple substituted heteroaryl derivatives has increased, and a therapeutic agent for metabolic diseases using triple substituted pyrimidine derivatives has been reported (Patent Document 3).

In addition, a therapeutic agent for diabetes using aryl, heteroaryl or heterocyclyl derivatives characterized by activating IC-GPCR2 or GPR119 as a therapeutic agent for type II diabetes associated with insulin resistance has been reported (Patent Documents 4 to 6 Document 6).

However, to date, the compounds having a piperazine skeleton and their use for the treatment of diabetes have not been known.

Accordingly, the present inventors have found that, when studying an activating agent for GPR119, the novel piperazine derivatives according to the present invention, their pharmaceutically acceptable salts or their isomers are excellent in solubility in water, Furthermore, activation of GPR119 was confirmed to promote cAMP, and the present invention was completed.

International Publication No. 2005/007647; International Publication No. 2005/007658; International Publication WO 2004/065380; International Publication No. 2008/083238; International Publication No. 2008/081206; International Publication No. 2008/081208.

T. Soga et al., Biochem. Biophy. Res. Commu. 326, (2005), 744-751; Overton, H.A. et al., Cell metabolism, 3, (2006), 167-175.

It is an object of the present invention to provide a novel piperazine derivative, a pharmaceutically acceptable salt thereof or an optical isomer thereof.

Another object of the present invention is to provide a novel piperazine derivative, a pharmaceutically acceptable salt thereof or a process for producing an optical isomer thereof.

Still another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of metabolic diseases containing a novel piperazine derivative, a pharmaceutically acceptable salt thereof or an optical isomer thereof as an active ingredient.

In order to achieve the above object,

The present invention provides a novel piperazine derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof or an optical isomer thereof.

[Chemical Formula 1]

(Wherein, A, B, R and n are as defined herein).

The present invention also provides a novel piperazine derivative represented by the general formula (1), a pharmaceutically acceptable salt thereof, or a process for producing an optical isomer thereof.

Further, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing the novel piperazine derivative represented by the above-mentioned formula (1), a pharmaceutically acceptable salt thereof or an optical isomer thereof as an active ingredient.

The novel piperazine derivatives, their pharmaceutically acceptable salts or isomers thereof according to the present invention are superior to conventional compounds known as GPR119 activators because of their high solubility in water and thus they are excellent in absorption ability and low cytotoxicity, This is quite good. Above all, the novel piperazine derivative of the present invention, its pharmaceutically acceptable salt or an isomer thereof according to the present invention is useful for the treatment of obesity, type I diabetes, And can be effectively used as a pharmaceutical composition for the prevention or treatment of type II diabetes, inadequate insulin resistance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X.

Hereinafter, the present invention will be described in detail.

The present invention provides a novel piperazine derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof or an optical isomer thereof.

In Formula 1,

A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;

R is -COOR '; Or unsubstituted or substituted heteroaryl;

B is an unsubstituted or substituted C ₁ -C ₅ straight or branched chain alkyl; Or an unsubstituted or substituted C ₁ -C ₅ linear or branched haloalkyl;

Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;

The substituted phenyl or substituted heteroaryl is -SOR ', - S (O) 2 R', -R'S (O) 2 R ", -NHS (O) 2 R ', -CN, halogen, C ₁ -C ₅ linear or branched haloalkyl, with an alkenyl group, -R ', = O, -COR ', -COOR ', -CONR'R ", -NR'R" , and N, O or S in the C ₁ -C ₅ Phenyl or substituted heteroaryl substituted with one or more substituents selected from the group consisting of 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms selected from the group consisting of:

Here, R ' Or R "are each independently hydrogen or C ₁ -C ₅ straight or branched chain alkyl unsubstituted or substituted with at least one hydroxy group; or R ' And R "together with the N to which they are attached may form a 5- or 6-membered heterocyclyl containing a heteroatom selected from the group consisting of N, O and S of 1 to 4;

n is an integer of 1 to 10;

In the compound of Formula 1 according to the present invention,

Preferably,

A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;

Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;

The substituted phenyl -S (O) ₂ R ', -R'S (O) ₂ R ", halogen, -R', -COOR ', -CONR'R" and N, O and S Phenyl which is substituted by at least one substituent selected from the group consisting of a 5-membered or 6-membered heteroaryl containing a hetero atom; Wherein R 'or R "are each independently hydrogen or C ₁ -C ₅ straight or branched chain alkyl unsubstituted or substituted with at least one hydroxy group, or R' And R "together with the N to which they are attached may form a 5- or 6-membered heterocyclyl containing a heteroatom selected from the group consisting of N, O and S of 1 to 4;

Said substituted heteroaryl is heteroaryl substituted with-R 'or -S (O) ₂ R'; Here, R 'is a straight or branched alkyl of C ₁ -C _5;

More preferably,

A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridines;

Wherein said substituted phenyl is selected from the group consisting of methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl, fluoro, chloro, bromo, methyl, ethyl, ethoxycarbonyl, hydroxyisopropylaminocarbonyl, dihydroxypropyl Phenyl substituted with one or more substituents selected from the group consisting of aminocarbonyl, dihydroxyisopropylaminocarbonyl, pyrrolidylcarbonyl and tetrazolyl; And

Wherein said substituted pyridine is pyridine substituted with at least one substituent selected from the group consisting of methyl, ethyl and methanesulfonyl.

In the compound of formula (I) according to the present invention,

Preferably,

R is -COOR '; Or unsubstituted or substituted heteroaryl;

Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;

Said substituted heteroaryl is heteroaryl substituted with C ₁ -C ₅ straight or branched chain alkyl;

More preferably,

Wherein R is t-butoxycarbonyl; Or an unsubstituted or substituted pyrimidine or oxadiazole;

Wherein said substituted pyrimidine or oxadiazole is heteroaryl substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and t-butyl.

In the compound of formula (I) according to the present invention,

Preferably,

Wherein B is an unsubstituted or substituted C ₁ -C ₅ straight or branched alkyl group;

More preferably,

B is methyl, ethyl or propyl.

Further, in the compound of Formula 1 according to the present invention,

More preferably,

A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;

Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;

The substituted phenyl -S (O) ₂ R ', -R'S (O) ₂ R ", halogen, -R', -COOR ', -CONR'R" and N, O and S Phenyl which is substituted by at least one substituent selected from the group consisting of a 5-membered or 6-membered heteroaryl containing a hetero atom; Wherein R 'or R "are each independently hydrogen or C ₁ -C ₅ straight or branched chain alkyl unsubstituted or substituted with at least one hydroxy group, or R' And R "together with the N to which they are attached may form a 5- or 6-membered heterocyclyl containing a heteroatom selected from the group consisting of N, O and S of 1 to 4;

Said substituted heteroaryl is heteroaryl substituted with-R 'or -S (O) ₂ R'; Here, R 'is a straight or branched alkyl of C ₁ -C _5;

R is -COOR '; Or unsubstituted or substituted heteroaryl;

Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;

Said substituted heteroaryl is heteroaryl substituted with C ₁ -C ₅ straight or branched chain alkyl;

B is an unsubstituted or substituted C ₁ -C ₅ straight or branched alkyl group; And

n is an integer from 1 to 5;

Even more preferably,

A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridines;

Wherein said substituted phenyl is selected from the group consisting of methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl, fluoro, chloro, bromo, methyl, ethyl, ethoxycarbonyl, hydroxyisopropylaminocarbonyl, dihydroxypropyl Phenyl substituted with one or more substituents selected from the group consisting of aminocarbonyl, dihydroxyisopropylaminocarbonyl, pyrrolidylcarbonyl and tetrazolyl;

Wherein said substituted pyridine is pyridine substituted with one or more substituents selected from the group consisting of methyl, ethyl and methanesulfonyl;

R is t-butoxycarbonyl; Or an unsubstituted or substituted pyrimidine or oxadiazole;

Wherein said substituted pyrimidine or oxadiazole is heteroaryl substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and t-butyl;

B is methyl, ethyl or propyl; And

n is an integer of 1 to 5;

In the compound of formula (I) according to the present invention,

Most preferably,

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Specific examples of the novel piperazine derivatives represented by the above formula (1) are shown below.

(1) t-Butyl-4- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalate;

(2) t-Butyl-4- (4- (2-fluoro-2 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazine-1 -carboxylate oxalate;

(3) 2- (4- (4- (4- (Methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate;

(4) 2- (4- (4- (3-Fluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;

(5) Synthesis of 2- (4- (4- (3-fluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin- salt;

(6) Synthesis of 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- -Yl) piperazine oxalate;

(7) t-Butyl 4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalate;

(8) Synthesis of 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- -Yl) piperazine hydrochloride;

(9) Synthesis of 1- (4- (2-fluoro-4- (1H-tetrazol-1-yl) phenoxy) Oxadiazol-5-yl) piperazine;

(10) Synthesis of 1- (4- (2-fluoro-4- (1H-tetrazol-1-yl) phenoxy) Oxadiazol-5-yl) piperazine oxalate;

(11) Synthesis of 1- (4- (2-fluoro-4- (methylsulfonyl) phenoxy) butan- -Yl) piperazine oxalate;

(12) Synthesis of 1- (4- (3-fluoro-4- (1H-tetrazol-1-yl) phenoxy) Oxadiazol-5-yl) piperazine oxalate;

(13) Synthesis of 1- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) -4- Oxalate;

(14) Synthesis of 1- (4- (4- (1H-tetrazol-1-yl) phenoxy) butan- -Yl) piperazine oxalate;

(15) 1- (4- (3,5-Difluoro-4- (1H-tetrazol-1-yl) phenoxy) butan- , 4-oxadiazol-5-yl) piperazine oxalate;

(16) Synthesis of 1- (4- (4-bromo-2,5-difluorophenoxy) butan-2-yl) -4- -Yl) piperazine oxalate;

(17) Synthesis of 1- (4- (3-chloro-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine oxalate;

(18) Synthesis of 1- (4- (3-methyl-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine oxalate;

(19) Synthesis of 1- (4- (5- (methylsulfonyl) pyridin-2-yloxy) butan- Yl) piperazine oxalate;

(20) Synthesis of 1- (4- (5- (methylsulfonyl) pyridin-2-yloxy) butan- Yl) piperazine hydrochloride;

(21) 1- (4- (6- (Methylsulfonyl) pyridin-3-yloxy) butan- ) Piperazine oxalate;

(22) Synthesis of 1- (4- (3-chloro-4 - ((methylsulfonyl) methyl) phenoxy) butan- -5-yl) piperazine oxalate;

(23) Synthesis of 1- (4- (3-chloro-4 - ((methylsulfonyl) methyl) phenoxy) butan- 5-yl) piperazine hydrochloride;

(24) Synthesis of 1- (4- (3-fluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan- Lt; / RTI > 5-yl) piperazine oxalate;

(25) Synthesis of 1- (4- (2-methyl-4 - ((methylsulfonyl) methyl) phenoxy) butan- -5-yl) piperazine oxalate;

(26) 2- (4- (4- (3-Fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate;

(27) Synthesis of 1 - ((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine oxalate;

(28) Synthesis of 1 - ((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine hydrochloride;

(29) 2- (4- (4- (3-Fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine hydrochloride;

(30) 2- (4- (4- (3-Chloro-4 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;

(31) Synthesis of 2- (4- (4- (3-chloro-4 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin- 1 -yl) -5-propylpyrimidine oxalate ;

(32) Synthesis of 2- (4- (4- (3-fluoro-4- (1- (methylsulfonyl) ethyl) phenoxy) butan-2-yl) piperazin- Methyl oxalate;

(33) Synthesis of 1- (4- (2,5-difluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan- -Oxadiazol-5-yl) piperazine oxalate;

(34) Synthesis of 1- (4- (2,5-difluoro-4- (methylsulfonyl) phenoxy) butan- Lt; / RTI > 5-yl) piperazine trifluoroacetate;

(35) Synthesis of 1- (4- (2,5-difluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine hydrochloride;

(36) Synthesis of 1- (4- (2,6-difluoro-4- (methylsulfonyl) phenoxy) butan- Lt; / RTI > 5-yl) piperazine oxalate;

(37) Synthesis of 1- (4- (2,6-difluoro-4- (methylsulfonyl) phenoxy) butan- Lt; / RTI > 5-yl) piperazine trifluoroacetate;

(38) Synthesis of 1- (4- (2,6-difluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine hydrochloride;

(39) 1- (4- (5-Methyl-6- (methylsulfonyl) pyridin-3- yloxy) butan- 5-yl) piperazine hydrochloride;

(40) 1- (4- (5-Methyl-6- (methylsulfonyl) pyridin-3- yloxy) butan- Lt; / RTI > 5-yl) piperazine oxalate;

(41) Synthesis of ethyl-4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate Oxalate;

(42) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluorobenzoate lithium salt ;

(43) ethyl-4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate oxalate;

(44) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate lithium salt;

(45) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin- 1 -yl) butoxy) -2-fluoro- 2-yl) benzamide oxalate;

(46) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin- 1 -yl) butoxy) -2-fluoro- 2-yl) benzamide hydrochloride;

(47) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro- -2-yl) benzamide oxalate;

(48) A mixture of 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro- -2-yl) benzamide hydrochloride;

(49) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro- Hydroxypropyl) benzamide oxalate;

(50) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin- 1 -yl) butoxy) -2-fluoro- Hydroxypropyl) benzamide hydrochloride;

(51) 4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- Dihydroxypropan-2-yl) benzamide oxalate;

(52) 4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- Dihydroxypropan-2-yl) benzamide hydrochloride;

(53) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -1-hydroxypropan-2-yl) benzamide oxalate;

(54) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -1-hydroxypropan-2-yl) benzamide hydrochloride;

(55) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide oxalate;

(56) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide hydrochloride;

(57) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide hydrochloride;

(58) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2- Pyrrolidin-1-yl) methanone hydrochloride;

(59) A mixture of ethyl 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorobenzoate oxalic acid salt;

(60) 4- (3- (4- (3-isopropyl-1, 2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorobenzoate lithium salt ;

(61) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N - -Hydroxypropan-2-yl) benzamide oxalate;

(62) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -N - -Hydroxypropan-2-yl) benzamide hydrochloride;

(63) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluoro- (S) -2,3-dihydroxypropyl) benzamide oxalate;

(64) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluoro- (S) -2,3-dihydroxypropyl) benzamide triflu or o acetic acid salt;

(65) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -N, N- - methylbenzamide oxalate;

(66) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -N, N- - methylbenzamide hydrochloride;

(67) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluorophenyl) Pyrrolidin-1-yl) methanone oxalate;

(68) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluorophenyl) Pyrrolidin-1-yl) methanone hydrochloride;

(69) A mixture of 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro- Dihydroxypropan-2-yl) benzamide oxalate;

(70) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro- Dihydroxypropan-2-yl) benzamide hydrochloride;

(71) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide oxalate;

(72) 1- (4- (5-Methyl-6- (methylsulfonyl) pyridin-3- yloxy) butan- Lt; / RTI > 5-yl) piperazine oxalate;

(73) A mixture of ethyl 4 - ((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) Rovenoate oxalate;

(74) 4 - ((R) -3- (4- (3-Isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro Benzoate lithium salt;

(75) 4 - ((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro -N - ((R) -2,3-dihydroxypropyl) benzamide oxalate;

(76) A mixture of ethyl 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) Robenzoate;

(77) 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro Benzoate lithium salt;

(78) 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1- yl) butoxy) -2-fluoro -N - ((R) -2,3-dihydroxypropyl) benzamide oxalate;

(79) t-Butyl-4- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate;

(80) t-Butyl-4- (4- (2-fluoro-2 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazine-1-carboxylate;

(81) 2- (4- (4- (4- (Methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;

(82) Synthesis of 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine;

(83) t-Butyl 4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate;

(84) Synthesis of 1- (4- (2-fluoro-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine;

(85) 1- (4- (3-Fluoro-4- (1H-tetrazol-1-yl) phenoxy) Oxadiazol-5-yl) piperazine;

(86) Synthesis of 1- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) -4- ;

(87) Synthesis of 1- (4- (4- (1H-tetrazol-1-yl) phenoxy) butan- Yl) piperazine;

(88) 1- (4- (3,5-Difluoro-4- (1H-tetrazol-1-yl) phenoxy) butan- , 4-oxadiazol-5-yl) piperazine;

(89) 1- (4- (4-Bromo-2,5-difluorophenoxy) butan-2-yl) -4- Yl) piperazine;

(90) Synthesis of 1- (4- (3-chloro-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine;

(91) 1- (4- (3-Methyl-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine;

(92) 1- (4- (5- (Methylsulfonyl) pyridin-2-yloxy) butan- Yl) piperazine;

(93) 1- (4- (6- (Methylsulfonyl) pyridin-3-yloxy) butan- ) Piperazine;

(94) Synthesis of 1- (4- (3-chloro-4 - ((methylsulfonyl) methyl) phenoxy) butan- 5-yl) piperazine;

(95) 1- (4- (3-Fluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan- 5-yl) piperazine;

(96) A mixture of 1- (4- (2-methyl-4 - ((methylsulfonyl) methyl) phenoxy) butan- 5-yl) piperazine;

(97) 2- (4- (4- (3-Fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate;

(98) Synthesis of 1 - ((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine;

(99) 2- (4- (4- (3-Fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;

(100) 2- (4- (4- (3-fluoro-4- (1- (methylsulfonyl) ethyl) phenoxy) butan-2-yl) piperazin- Midin;

(101) 1- (4- (2,5-Difluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan- -Oxadiazol-5-yl) piperazine;

(102) A mixture of 1- (4- (2,5-difluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine;

(103) 1- (4- (2,6-Difluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine;

(104) 1- (4- (5-Methyl-6- (methylsulfonyl) pyridin-3- yloxy) butan- 5-yl) piperazine;

(105) Ethyl-4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluorobenzoate ;

(106) 4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate;

(107) Ethyl-4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate;

(108) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate;

(109) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro- 2-yl) benzamide;

(110) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro- -2-yl) benzamide;

(S) -2,3-di (4-fluorophenyl) -1,3-di Hydroxypropyl) benzamide;

(112) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- 1,3-dihydroxypropan-2-yl) benzamide;

(113) 4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -1-hydroxypropan-2-yl) benzamide;

(114) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide;

(115) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorophenyl) Pyrrolidin-1-yl) methanone;

(116) Ethyl 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorobenzoate;

(117) 4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorobenzoate;

(118) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -N - -Hydroxypropan-2-yl) benzamide;

(119) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluoro- (S) -2,3-dihydroxypropyl) benzamide;

(120) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -N, N- - methylbenzamide;

(121) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluorophenyl) Pyrrolidin-1-yl) methanone;

(122) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluoro- 1,3-dihydroxypropan-2-yl) benzamide;

(123) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide;

(124) 1- (4- (5-methyl-6- (methylsulfonyl) pyridin-3- yloxy) butan- 5-yl) piperazine;

(125) ethyl 4 - ((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2- Robenzoate;

(126) 4 - ((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro Benzoates;

(127) 4 - ((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro -N - ((R) -2,3-dihydroxypropyl) benzamide;

(128) ethyl 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2- Robenzoate;

(129) 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro Benzoate; And

(130) 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro -N - ((R) -2,3-dihydroxypropyl) benzamide.

The piperazine derivatives of formula (I) or their pharmaceutically acceptable salts or isomers thereof according to the present invention are shown in Table 1 below.

Example constitutional formula Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 15

Example 16

Example 17

Example 18

Example 19

Example 20

Example 21

Example 22

Example 23

Example 24

Example 25

Example 26

Example 27

Example 28

Example 29

Example 30

Example 31

Example 32

Example 33

Example 34

Example 35

Example 36

Example 37

Example 38

Example 39

Example 40

Example 41

Example 42

Example 43

Example 44

Example 45

Example 46

Example 47

Example 48

Example 49

Example 50

Example 51

Example 52

Example 53

Example 54

Example 55

Example 56 Example 57

Example 58

Example 59

Example 60

Example 61

Example 62

Example 63

Example 64

Example 65

Example 66

Example 67

Example 68

Example 69

Example 70

Example 71

Example 72

Example 73

Example 74

Example 75

Example 76

Example 77

Example 78

The novel piperazine derivatives represented by formula (I) according to the present invention can be used in the form of pharmaceutically acceptable salts. Such salts are useful as acid addition salts formed by various pharmaceutically or physiologically acceptable organic acids or inorganic acids. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyric acid, succinic acid, succinic acid, succinic acid, succinic acid, succinic acid, succinic acid, succinic acid, succinic acid, Benzoic acid, chlorobenzoic acid, methylbenzoic acid, dinitrobenzoic acid, hydroxybenzoate, methoxybenzoic acid, phthalic acid, terephthalate, terephthalic acid, Benzenesulfonic acid, toluenesulfonic acid, chlorobenzenesulfonic acid, xylenesulfonic acid, phenylacetic acid, phenylpropionic acid, phenyl But are not limited to, thiourea, citrate, citrate, lactate, hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulphonate, naphthalene-2-sulphonate, mandelate or trifluro Acetic acid. ≪ / RTI > Of these, hydrochloric acid, oxalic acid or trifluoroacetic acid can be preferably used.

At this time, the acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a derivative of the formula (1) in an excess amount of an acid aqueous solution, and then mixing the salt with a water-miscible organic solvent such as methanol, ethanol, Followed by precipitation using nitrile. It may also be prepared by evaporating a solvent or excess acid in this mixture and then drying or by suction filtration of the precipitated salt.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce lithium, sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Also, as shown in the following Reaction Scheme 1,

A step of coupling a compound represented by formula (2) with a piperidine derivative represented by formula (3) to prepare a compound represented by formula (4) (step 1);

A step of reducing the compound of Formula 4 prepared in Step 1 to produce a compound of Formula 5 (Step 2); And

(3), which comprises reacting a compound represented by the formula (5) and a compound represented by the formula (6) to produce a compound represented by the formula (1a) Of the present invention.

[Reaction Scheme 1]

(Wherein A, B, and R are as defined in Formula 1, m is an integer of 0 to 3, and Formula 1a is a compound of Formula 1.)

Hereinafter, the above manufacturing method will be described in detail for each step.

First, step 1 according to the present invention is a step of coupling a compound represented by formula (2) with a piperidine derivative represented by formula (3) to produce a compound represented by formula (4).

More specifically, the step of dissolving the compound of the formula (2) and the piperazine of the formula (3) in methanol is followed by carrying out a reaction of adding an amine to the alkenyl group of the formula (2) by performing reflux stirring.

At this time, the usable solvent may be methanol, ethanol, dichloromethane (DCM) or toluene which does not adversely affect the reaction, and preferably methanol may be used.

The reaction temperature is not particularly limited, but can be used within the range of room temperature to the reflux temperature of the solvent.

Next, step 2 is a step of performing the reduction reaction of the compound of formula (4) prepared in step 1 to prepare a compound represented by formula (5).

More specifically, the step of reacting the compound of formula (4) prepared in step 1 with lithium aluminum hydride (LiAlH ₄ ) as a reducing agent to reduce the carboxylic acid of formula ( ₄ ) to alcohol.

At this time, usable solvents may be tetrahydrofuran (THF), diethyl ether, diphenyl ether or diisopropyl ether (DIPE) which do not adversely affect the reaction, preferably tetrahydrofuran (THF) .

Also, the reaction temperature may be in the range of -78 ° C to 5 ° C, preferably -10 ° C to 0 ° C.

Next, Step 3 is a step of coupling the compound of Formula 5 and the compound of Formula 6 prepared in Step 2 to prepare a compound represented by Formula 1a.

More specifically, the azocarboxylate reagent is slowly added dropwise to a solution obtained by mixing the compound of the formula (5), the compound of the formula (6) and triphenylphosphine to carry out a Mitsunobu reaction to prepare the compound of the formula .

At this time, the azo carboxylate compound that can be used may be diethyl azodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD), preferably diisopropyl azodicarboxylate A diisopropylazodicarboxylate (DIAD) may be used.

In addition, usable solvents may be tetrahydrofuran (THF), dichloromethane (DCM), toluene or acetonitrile which do not adversely affect the reaction, and preferably tetrahydrofuran (THF) may be used.

The method may further comprise the step of treating the compound of formula (Ia) prepared in step 3 according to the present invention with an organic acid or an inorganic acid to prepare an acid addition salt represented by the following formula (1A).

≪ EMI ID =

(Wherein A, B, R and n are as defined in the above formula (1), HA is an organic acid or an inorganic acid, and the compound of the formula (1A) is a compound of the formula (1).

At this time, oxalic acid, hydrochloric acid or trifluoroacetic acid may be used as the organic acid or inorganic acid usable.

In addition, as the usable solvent, methanol, ethanol, acetone, acetonitrile or ethyl acetate (EA) which does not adversely affect the reaction can be used, preferably ethyl acetate (EA) can be used.

Further, the present invention relates to a process for the preparation of

Reacting a compound represented by the formula (1b) with lithium hydroxide to prepare a lithium salt represented by the formula (1c) (step 1); And

(Step 2) of preparing a compound represented by the formula (1d) by carrying out an amidation reaction between the lithium salt of the formula (1c) and the compound represented by the formula (7) A process for the preparation of piperazine derivatives is provided.

[Reaction Scheme 2]

(Wherein B, R, R ', R "and n are as defined in the above formula (1), and the compounds of the formulas (1b) to (1d) are compounds of the formula (1)

Hereinafter, the above manufacturing method will be described in detail for each step.

First, step 1 is a step of reacting a compound represented by the formula (1b) with lithium hydroxide to prepare a lithium salt represented by the formula (1c).

More specifically, the compound of formula (1b) is dissolved in a mixed solution of tetrahydrofuran (THF) and distilled water, and then lithium hydroxide monohydrate is added to react and react. After the reaction, 1c. ≪ / RTI >

Next, the step 2 is a step of preparing the compound represented by the formula (1d) by carrying out amidation reaction between the lithium salt of the formula (1c) prepared in the step 1 and the compound represented by the formula (7).

More specifically, the lithium salt of formula (1c) prepared in step 1 and the amine compound of formula (7) are dissolved in an organic solvent, an amide reagent is added, and an amidation reaction is carried out at room temperature to obtain a compound of formula ≪ / RTI > compound.

Wherein the amide reagent is selected from the group consisting of benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate (Py-BOP), O-benzotriazole- N, N-tetramethyl-europium-hexafluoro-phosphate (HBTU), 2- (7-aza-lH-benzotriazol- 1-yl) -1,1,3,3-tetramethyluronium hexa (EDC) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), or a mixture of two or more compounds selected from the group consisting of fluorophosphate (HATU), 1-hydroxybenzotriazole (HOBt), dicyclohexylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) together with carbonyldiimidazole (CDI), preferably 1-ethyl-3- Can be used.

Further, as the usable organic solvent, it is possible to carry out the reaction using methanol, tetrahydrofuran (THF), dimethylformamide, dichloromethane or toluene which does not adversely affect the reaction, preferably dichloro Methane (DCM) can be used.

Also, as shown in the following Reaction Scheme 3,

Reacting a compound represented by the formula 8- (S) with t-butyldimethylsilyl chloride (TBSCl) to prepare a compound represented by the formula 9- (S) (step 1);

Reacting the compound of formula 9- (S) prepared in step 1 with methanesulfonyl chloride (MsCl) to prepare a compound represented by formula 10- (S) (step 2);

Reacting the compound of Formula 10- (S) prepared in Step 2 with a compound of Formula 3 to prepare a compound represented by Formula 11- (R) (Step 3);

(R) (step 4) by carrying out a deprotection reaction of the compound represented by the formula 11- (R) prepared in the above step 3 to prepare a compound represented by the formula 5- (R); And

(R) and a compound represented by the formula (6) to produce a compound represented by the formula 1 - (R) (step 5); There is provided a process for producing a novel piperazine derivative represented by the formula (1).

[Reaction Scheme 3]

TBS is a t-butyldimethylsilyl group, Ms is a methanesulfonyl group, and a compound of the formula 1 - (R) is a compound represented by the formula (1): wherein A, B and R are as defined in formula Lt; / RTI >

Hereinafter, the above manufacturing method will be described in detail for each step.

First, Step 1 is a step (Step 1) of reacting a compound represented by the formula 8- (S) with t-butyldimethylsilyl chloride (TBSCl) to prepare a compound represented by the formula 9- (S).

More specifically, it is a step of reacting a compound represented by the formula (8) having an S-configuration in the presence of a base with t-butyldimethylsilyl chloride (TBSCl) to protect the hydroxy group of the compound represented by the formula (8).

At this time, triethylamine (TEA), diethylamine (DEA), diisopropylethylamine (DIPEA), pyridine or imidazole can be used as the base which can be used for the reaction. Imidazole is preferably used.

In addition, organic solvents that can be used include organic solvents such as tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), dichloromethane (DCM), chlorobenzene, toluene or benzene And preferably dichloromethane (DCM) can be used.

Next, Step 2 is a step of reacting the compound of Formula 9- (S) prepared in Step 1 with methanesulfonyl chloride (MsCl) to prepare a compound represented by Formula 10- (S).

More specifically, the step of reacting the compound of formula (9) in which the stereostructure produced in step 1 is an S-form with methanesulfonyl chloride (MsCl) is a step of protecting the hydroxy group of formula (10) in which the stereostructure is S- .

The base used in the reaction may be triethylamine (TEA), diethylamine (DEA), diisopropylethylamine (DIPEA), pyridine or imidazole, preferably triethylamine (TEA) Can be used.

In addition, organic solvents that can be used include organic solvents such as tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), dichloromethane (DCM), chlorobenzene, toluene or benzene And preferably dichloromethane (DCM) can be used.

Next, Step 3 is a step of reacting the compound of Formula 10- (S) prepared in Step 2 with the compound of Formula 3 to prepare a compound represented by Formula 11- (R).

More specifically, the coupling reaction is carried out by reacting the compound of Formula 10 and the compound of Formula 3 in the presence of potassium carbonate (K ₂ CO ₃ ), wherein the stereostructure formed in Step 2 is S-form.

The organic solvent used may be tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO) or dichloromethane (DCM) Formamide (DMF) can be used.

The reaction temperature is not particularly limited, but can be used within the range of room temperature to the reflux temperature of the solvent.

Next, Step 4 is a step of performing the deprotection reaction of the compound represented by Formula 11- (R) prepared in Step 3 to prepare a compound represented by Formula 5- (R).

More specifically, the step of deprotecting the protected hydroxy group present at the end of the compound of formula (11) wherein the stereostructure produced in step 3 is R-form, using tetrabutylammonium fluoride (TBAF).

At this time, methanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO) or acetonitrile may be used as the organic solvent which can be used, and tetrahydrofuran (THF) .

The reaction temperature is not particularly limited, but can be used within a range of room temperature to reflux temperature of the solvent

Next, the step 5 is a step of performing a coupling reaction between the compound represented by the formula 5 (R) and the compound represented by the formula (6) prepared in the step 4 to prepare a compound represented by the formula 1- (R).

More specifically, the azocarboxylate reagent is slowly added dropwise to a solution obtained by mixing the compound of Formula 5, the compound of Formula 6, and triphenylphosphine, in which the stereostructure produced in Step 4 is in the R-form, to form a Mitsunobu reaction reaction to obtain a compound of formula (1) wherein the stereostructure is R-form.

At this time, the azo carboxylate compound that can be used may be diethyl azodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD), preferably diisopropyl azodicarboxylate A diisopropylazodicarboxylate (DIAD) may be used.

In addition, usable solvents may be tetrahydrofuran (THF), dichloromethane (DCM), toluene or acetonitrile which do not adversely affect the reaction, and preferably tetrahydrofuran (THF) may be used.

Further, the present invention relates to a process for preparing a compound represented by the formula

Reacting a compound represented by the formula 8- (R) with t-butyldimethylsilyl chloride (TBSCl) to prepare a compound represented by the formula 9- (R) (step 1);

Reacting a compound of the formula 9 - (R) prepared in the above step 1 with methanesulfonyl chloride (MsCl) to prepare a compound represented by the formula 10 - (R) (step 2);

Reacting the compound of Formula 10- (R) prepared in Step 2 with a compound of Formula 3 to prepare a compound represented by Formula 11- (S) (Step 3);

(Step 4) of preparing a compound represented by the formula 5- (S) by performing deprotection of the compound represented by the formula 11- (S) prepared in the step 3; And

(Step 5) of preparing a compound represented by the general formula 1- (S) by performing a coupling reaction between the compound represented by the formula 5 (S) and the compound represented by the formula 6 produced in the step 4 There is provided a process for producing a novel piperazine derivative represented by the formula (1).

[Reaction Scheme 4]

TBS is a t-butyldimethylsilyl group; Ms is a methanesulfonyl group; and a compound of the formula 1 - (S) is a compound represented by the formula (1): wherein A, B and R are as defined in the above formula Lt; / RTI >

The production method of Scheme 4 is a method for producing an S-isomer of a piperazine derivative according to the present invention. In the process of Scheme 3, instead of using the compound of Formula 8 in which the stereostructure is S-form, Was used instead of the compound of formula (8).

The present invention also provides a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a novel piperazine derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof or an optical isomer thereof as an active ingredient.

[Chemical Formula 1]

(In the above Reaction Scheme 1, A, B, R, and n are as defined in Formula 1.)

GPR119 is a G-protein coupled receptor (GPCR) that is predominantly expressed in the pancreas, small intestine, colon and adipose tissue. The GPR119 expression profile has potential utility for the treatment of various metabolic diseases including obesity and diabetes.

The novel piperazine derivative represented by the formula (1), a pharmaceutically acceptable salt thereof or an optical isomer thereof according to the present invention is excellent in the effect of activating the GPR119 receptor and thus is excellent in stimulating cAMP (Experimental Example 1 To Experimental Example 3). In addition, since the solubility in water is excellent, the water absorption rate is excellent, and cardiotoxicity and cytotoxicity are significantly lower than those of GPR119 activators known in the prior art, there is no side effect, and therefore the stability to human body is remarkably high (Experimental Examples 4 to 6 ).

Accordingly, the novel piperazine derivatives, their pharmaceutically acceptable salts or optical isomers thereof according to the present invention are excellent in the absorption rate in the body, have high stability to human body, and have an effect of activating GPR119, a receptor related to metabolic diseases It can be usefully used as a pharmaceutical composition for the prevention or treatment of metabolic diseases containing it as an active ingredient.

The metabolic diseases include, for example, obesity, type I diabetes, type II diabetes, inappropriate insulin resistance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X .

The compound of the present invention may be administered orally or parenterally in various dosage forms during clinical administration. In the case of formulation, the diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, .

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which may contain one or more excipients such as starch, calcium carbonate, Sucrose, lactose, gelatin or the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The effective dose of the compound of the present invention on the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally about 0.001-100 mg / kg / 0.0 > mg / kg / day. ≪ / RTI > It is generally from 0.07 to 7000 mg / day, preferably from 0.7 to 2500 mg / day, based on adult patients weighing 70 kg, and may be administered once a day It may be divided into several doses.

Hereinafter, the present invention will be described in detail with reference to Production Examples, Examples and Experimental Examples.

However, the following Production Examples, Examples and Experimental Examples are illustrative of the present invention, and the contents of the present invention are not limited thereto.

< Manufacturing example  1 > 2- Fluoro -4-( Methylsulfonyl ) Preparation of phenol

4-bromo-2-fluorophenol (8.8 g) and dimethylsulfate (DMSO, 100 mL) were added to a 250 mL flask under a nitrogen atmosphere and dissolved by stirring. Then sodium sulfinate (18.96 g) Copper (I) trifluoromethane sulfate benzene complex (2.33 g) and N, N-dimethylethylenediamine (0.82 g) were added dropwise and the mixture was refluxed for 12 hours or more. After completion of the reaction, 1N hydrochloric acid aqueous solution (100 mL) was added and extracted with ethyl acetate (EA, 100 mL), dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 7.64 (2H, m), 7.16 (1H, t), 3.07 (3H, s).

< Manufacturing example  2> 3- Fluoro -4-( Methylsulfonyl ) Preparation of phenol

3-fluoro-4-methylthiophenol (1.5 g) and tetrahydrofuran (tetrahydrofuran (THF), 80 mL) were added to a 250 mL flask under nitrogen atmosphere and dissolved by stirring. Oxone (12.3 g) dissolved in water (20 mL) was added dropwise thereto, followed by stirring at room temperature for 3 hours or longer. The solid was filtered off and the filtrate was extracted with ethyl acetate (EA, 100 mL) and washed with saturated aqueous sodium carbonate solution (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated, and then purified by silica column chromatography to obtain the target compound.

¹ H NMR (400 Hz, CDCl ₃ ):? 7.81 (1H, t), 6.75 (2H, m), 6.46 (1H, s), 3.23 (3H, s).

< Manufacturing example  3> 3- Fluoro -4-( Hydroxymethyl ) Preparation of phenol

2-fluoro-4-hydroxybenzoic acid (5 g) and tetrahydrofuran (THF, 100 mL) were added to a 250 mL flask under a nitrogen atmosphere and dissolved by stirring and then cooled to 0 占 폚. Then, lithium aluminum hydride (LAH, 2.43 g) was added, and the mixture was slowly stirred at room temperature and stirred for 3 hours or more. At the end of the reaction, lithium aluminum hydride (LAH) was removed using ethyl acetate (EA, 200 mL) and 10% sodium hydroxide aqueous solution (200 mL) and extracted with ethyl acetate (EA, 200 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, concentrated, and then solidified using ethyl acetate (EA) and diethyl ether to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 7.26 (1H, t), 6.62 (2H, m), 4.49 (1H, s), 4.68 (2H, d), 1.58 (3H, s).

< Manufacturing example  4> 3- Fluoro -4-( Methylthiomenyl ) Preparation of phenol

3-fluoro-4- (hydroxymethyl) phenyl propionate (1.8 g) and tetrahydrofuran (THF, 100 mL) were added to a 250 mL flask under nitrogen atmosphere and dissolved by stirring. Triphenylphosphine (PPh ₃ , 3.57 g) and N-bromosuccinimide (2.4 g) were added, and the mixture was slowly stirred at room temperature and stirred for 1 hour or more. Then, sodium thiomethoxide (1.9 g) was added, and the mixture was stirred at room temperature for 12 hours or longer. When the reaction was completed, 1N hydrochloric acid aqueous solution (100 mL) was added and extracted with ethyl acetate (EA, 100 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, concentrated, and then purified by silica column chromatography to obtain the target compound.

¹ H NMR (400 Hz, CDCl ₃ ):? 7.14 (1H, t), 6.58 (2H, m), 3.66 (2H, s), 2.05 (3H, s).

< Manufacturing example  5> 3- Fluoro -4-( Methylsulfonylmethyl ) Preparation of phenol

(Methylthiomethyl) phenol was used instead of 3-fluoro-4- (methylthio) phenol in the same manner as in Preparation Example 2, except that 3-fluoro-4- .

^{1 H NMR (400 Hz, CDCl} 3): δ 7.36 (1H, t), 6.68 (2H, t), 5.18 (1H, s), 4.25 (2H, s), 2.82 (3H, s).

< Manufacturing example  6> 3- methyl -4-( Methylsulfonyl ) Preparation of phenol

(Methylthio) -m-cresol was used instead of 3-fluoro-4- (methylthio) phenol, the objective compound was obtained.

¹ H NMR (400 Hz, CDCl ₃ ):? 7.94 (1H, d), 6.80 (2H, s), 5.47 (1H, s), 3.08 (3H, s), 2.67 (3H, s).

< Manufacturing example  7> 2,6- Difluoro -4-( Methylsulfonyl ) Preparation of phenol

Bromo-2-fluorophenol was used instead of 4-bromo-2-fluorophenol, the target compound was obtained by carrying out the same processes as in Preparation Example 1, except that 4-bromo-2,6-difluorophenol was used.

¹ H NMR (400 Hz, DMSO-d ₆ ):? 11.61 (1H, s), 7.64 (2H, d), 3.23 (3H, s).

< Manufacturing example  8> 3,5- Difluoro -4-( Methylsulfonyl ) Preparation of phenol

(Methylthio) phenol was used instead of 3-fluoro-4- (methylthio) phenol to obtain the target compound &Lt; / RTI &gt;

^{1 H NMR (400 Hz, CDCl} 3): δ 6.53 (2H, d), 3.28 (3H, s).

< Manufacturing example  9> 2- Fluoro -4-( Methylsulfonylmethyl ) Preparation of phenol

(Methylthiomethyl) phenol was used instead of 3-fluoro-4- (methylthio) phenol, the target compound was obtained by carrying out the same procedure as the preparation example 2 .

¹ H NMR (400 Hz, CDCl ₃ ):? 7.21 (1H, d), 7.07 (2H, m), 5.37 (1H, s), 4.18 (2H, s), 2.80

< Manufacturing example  10> 5- methyl -6- ( Methylsulfonyl ) Preparation of pyridin-3-ol

(Methylthio) pyridin-3-ol was used instead of 3-fluoro-4- (methylthio) phenol to obtain the target compound &Lt; / RTI &gt;

^{1 H NMR (400 Hz, CDCl} 3): δ 8.00 (1H, s), 7.10 (1H, s), 6.95 (1H, s), 3.38 (3H, s), 2.65 (3H, s)

< Manufacturing example  11> 3- Chloro -4-( Methylsulfonyl ) Preparation of phenol

(Methylthio) phenol was used instead of 3-fluoro-4- (methylthio) phenol in the same manner as in Preparation Example 2, except that 3-chloro-4-

¹ H NMR (400 Hz, CDCl ₃ ):? 8.01 (IH, d), 7.04 (IH, d), 6.89 (IH, d), 6.36 (IH, s), 3.26 (3H, s).

< Manufacturing example  12 > 6- ( Methylsulfonyl ) Preparation of pyridin-3-ol

2-Chloro-5-hydroxypyridine (2.55 g) and dimethyl sulfate (DMSO, 100 mL) were added to a 100 mL flask under nitrogen atmosphere and dissolved by stirring. Then sodium methanesulfinate (3.05 g), copper ) Trifluoromentansulfonate benzene complex (1.0 g) and N, N-dimethylethylenediamine (0.42 mL) were added, and the mixture was refluxed and stirred for 12 hours or more. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (EA, 100 mL), and washed with saturated sodium bicarbonate aqueous solution (100 mL) and brine (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to obtain the desired compound.

^{1 H NMR (400 Hz, DMSO} -d 6): δ 11.14 (1H, s), 8.26 (1H, d), 7.90 (1H, d), 7.38 (1H, d), 3.17 (3H, s)

< Manufacturing example  13> 3- Fluoro -4- (1- ( Methylsulfonyl ) Ethyl) phenol &lt; / RTI &gt;

The procedure of Preparation Example 2 was repeated except that 3-fluoro-4- (1- (methylthio) ethyl) phenol was used instead of 3-fluoro-4- (methylthio) To obtain the target compound.

¹ H NMR (400 Hz, CDCl ₃ ):? 7.38 (1H, t), 6.65 (2H, m), 4.60 (1H, q), 2.77 (3H, s), 1.77

< Manufacturing example  14> 2,5- Difluoro -4-( Methylsulfonylmethyl ) Preparation of phenol

The procedure of Preparation Example 2 was repeated except that 2,5-difluoro-4- (methylthiomethyl) phenol was used instead of 3-fluoro-4- (methylthio) Compound.

¹ H NMR (400 Hz, DMSO-d ₆ ):? 7.25 (1H, dd), 6.82 (1H, dd), 4.39 (2H, s), 2.96 (3H, s).

< Manufacturing example  15> 2- Fluoro -4- (1H- Tetrazole -1-yl) phenol &lt; / RTI &gt;

4-Amino-2-fluorophenol (4.8 g) and acetic acid (100 mL) were added to a 250 mL flask under a nitrogen atmosphere and stirred to dissolve. Sodium azide (3.3 g) and triethylorthoformate ) Was added and the mixture was stirred under reflux for 1.2 hours or more. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove acetic acid, and the residue was dissolved in ethyl acetate (EA, 100 mL), followed by washing with distilled water (100 mL) and saturated sodium bicarbonate solution (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated, and then solidified using ethyl acetate (EA) and hexane to obtain the desired compound.

¹ H NMR (400 Hz, DMSO-d ₆ ):? 10.68 (IH, s), 9.91 (IH, s), 7.81 (IH, d), 7.56 (IH, d), 7.17 (IH, t).

< Manufacturing example  16> 4- (1H- Tetrazole -1-yl) phenol &lt; / RTI &gt;

The objective compound was obtained by carrying out the same processes as in PREPARATION 15, except that 4-aminophenol was used instead of 4-amino-2-fluorophenol.

< Manufacturing example  17> 3- Fluoro -4- (1H- Tetrazole -1-yl) phenol &lt; / RTI &gt;

The target compound was obtained in the same manner as in PREPARATION 15, except that 4-amino-3-fluorophenol was used instead of 4-amino-2-fluorophenol.

¹ H NMR (400 Hz, CDCl ₃ ):? 10.75 (IH, s), 9.82 (IH, s), 7.63 (IH, t), 6.92 (IH, d), 6.82 (IH, d).

< Manufacturing example  18> 3,5, - Difluoro -4- (1H- Tetrazole -1-yl)

The target compound was obtained in the same manner as in PREPARATION 15, except that 4-amino-3,5-difluorophenol was used instead of 4-amino-2-fluorophenol.

^{1 H NMR (400 Hz, DMSO} -d 6): δ 9.91 (1H, s), 6.82 (2H, d).

< Manufacturing example  19> Ethyl 2- Fluoro -4- Hydroxybenzoate  Produce

2-Fluoro-4-hydroxybenzoic acid (100 g) and ethanol (320 mL) were added to a 250 mL flask under nitrogen atmosphere and dissolved by stirring. Sulfuric acid (34 mL) was slowly added dropwise and the mixture was refluxed for 12 hours or more. When the reaction was completed, distilled water (500 ml or more) was added and solidified to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 7.86 (1H, t), 7.01 (1H, br), 6.67 (2H, m), 4.38 (2H, q), 1.40 (3H, t).

< Manufacturing example  20> Ethyl 3- Fluoro -4- Hydroxybenzoate  Produce

Fluoro-4-hydroxybenzoic acid was used in place of 2-fluoro-4-hydroxybenzoic acid to obtain the target compound.

¹ H NMR (400 Hz, CDCl ₃ ):? 7.79 (2H, d), 7.05 (1H, t), 5.94 (1H, s), 4.37 (2H, q), 1.40 (3H, t).

< Manufacturing example  21> N, N- Diethyl -4- Hydroxy -3- Methylbenzamide  Produce

4- (t-butyldimethylsilyloxy) -N, N -diethyl-3-methylbenzamide (600 mg) and tetrahydrofuran (THF, 10 mL) were dissolved in a 100 mL flask under nitrogen atmosphere with stirring And a 1 M solution of tetrabutylammonium fluoride (THF solution) were slowly added dropwise thereto, followed by stirring at room temperature for 3 hours. When the reaction was completed, brine (10 ml) was added and extracted with ethyl acetate (EA). The ethyl acetate (EA) layer was dried over anhydrous magnesium sulfate, concentrated, and then solidified using ethyl acetate (EA) and hexane to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 7.13 (1H, s), 7.02 (1H, d), 6.73 (1H, s), 6.64 (1H, d), 3.43 (4H, br), 2.22 (3H , &lt; / RTI &gt; s), 1.19 (6H, br).

< Example  1 > t-Butyl-4- (4- (4- ( Methylsulfonyl ) Phenoxy ) Butan-2-yl) piperazin-l- Carboxylate  Preparation of oxalate

Step 1: tert-Butyl-4- (4- Methoxy -4- Oxobutane Yl) piperazin-l- Carboxylate  Produce

Methyl crotonate (3.3 g) and methanol (50 mL) were added to a 100 mL flask under a nitrogen atmosphere and stirred to dissolve. Then t-butyl-1-piperazinecarboxylate (5 g) was added dropwise Followed by reflux stirring for 24 hours or more. When the reaction was completed, the solvent was removed by concentration under reduced pressure and purified by silica column chromatography to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 3.69 (s, 3H), 3.40 (m, 4H), 3.20 (m, 1H), 2.57 (dd, 2H), 2.48 (. M 3H), 2.27 (dd , 2H), 1.47 (s, 9H), 1.06 (d, 3H).

Step 2: tert-Butyl-4- (4- Hydroxybutane Yl) piperazin-l- Carboxylate  Produce

Lithium aluminum hydride (LAH, 880 mg) was dissolved in tetrahydrofuran (THF, 50 mL) with stirring at 0 ° C and dissolved in tetrahydrofuran (THF, 50 mL) in a 100 mL flask under a nitrogen atmosphere. (2.7 g) was slowly added dropwise to the flask for 5 minutes. When the reaction was complete, 1 M sodium hydroxide (50 mL) was slowly added dropwise, extracted with ethyl acetate (40 mL), and washed with brine (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 3.83 (m, 2H), 3.47 (m, 4H), 2.96 (m, 1H), 2.72 (m, 2H), 2.44 (m, 2H), 1.91 (m , &Lt; / RTI &gt; 1H), 1.46 (s, 9H), 1.00 (d, 3H).

Step 3: t-Butyl-4- (4- (4- ( Methylsulfonyl ) Phenoxy ) Butan-2-yl) piperazin-l- Carboxylate  Preparation of oxalate

(PPh ₃ , 0.63 g), 4- (methylsulfonyl) phenol (0.35 g) and tetrahydrofuran (THF) were added to a 100 mL flask under nitrogen atmosphere, And dissolved by stirring. Diisopropyl azodicarboxylate (0.5 mL) was slowly added dropwise to the reaction at 0 ° C, and the mixture was stirred at room temperature for 12 hours or longer. When the reaction was completed, distilled water (20 mL) was slowly added to the reaction solution, extracted with ethyl acetate (EA, 60 mL), and washed with brine (40 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography. Ethyl acetate (EA, 10 mL) was added to the purified compound, which was dissolved by stirring. An equivalent amount of oxalic acid equivalent to that of the compound was added dropwise thereto, followed by reflux stirring for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.81 (2H, d), 7.08 (2H, d), 4.25 (2H, m), 4.14 (2H, m), 3.64 (1H, m), 3.41 ( 2H, d), 3.13 (3H, s), 3.12 (4H, m), 2.11 (2H, m), 1.51 (9H, s), 1.33 (3H, d).

< Example  2 > t-Butyl-4- (4- (2- Fluoro -2 - ((methylsulfonyl) methyl ) Phenoxy ) Butan-2-yl) piperazin-l- Carboxylate  Preparation of oxalate

The procedure of Example 1 was repeated except that 4- (methylsulfonyl) phenol was used instead of the compound prepared in Preparation Example 9 in Step 3 of Example 1 to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.30 (1H, t), 6.79 (2H, d), 4.47 (2H, s), 4.17 (2H, m), 4.04 (2H, m), 3.62 ( 1H, m), 3.40 (1H, d), 3.08 (4H, m), 2.98 (3H, s), 2.11 (2H, m), 1.43 (9H, s), 1.40

< Example  3 > 2- (4- (4- (4- ( Methylsulfonyl ) Phenoxy ) Butan-2-yl) piperazin-1-yl) -5- The Preparation of ropilpyrimidine oxalate salt

Step 1: 2-Piperazin-1-yl-5- Of propylpyrimidine  Produce

Butyl-1-piperazinecarboxylate (5 g) was poured into a 100 ml flask under a nitrogen atmosphere, 4N-hydrochloric acid (1,4-dioxane solution, 10 mL) was slowly added dropwise and stirred for 10 hours or longer. When stirring was complete, diethyl ether (20 mL) was added to the reaction and stirred for 30 min, then the resulting solid was filtered while washing with diethyl ether (50 mL). Thereafter, the filtered solid was dried and dissolved again by adding 10 mL of acetonitrile and distilled water, respectively. N, N-diisopropylethylamine (0.3 mL) and 2-chloro-5-propylpyrimidine (6.3 g) were added to the dissolved reaction product and the mixture was refluxed for 12 hours or more. When the reaction was completed, distilled water (15 mL) was added slowly, extracted with ethyl acetate (EA, 40 mL), and washed with brine (100 mL). The washed reaction product was dried with anhydrous magnesium sulfate, concentrated, and then purified by silica column chromatography to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 8.17 (2H, s), 3.21 (4H, m), 2.62 (4H, m), 2.43 (2H, t), 1.53 (2H, m), 1.18 (2H , t).

Step 2: methyl -3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) Butanoate  Produce

Methyl crotonate (3.3 g) and methanol (50 mL) were added to a 100 ml flask under a nitrogen atmosphere and the mixture was stirred to dissolve. Then, the compound (5 g) prepared in the above step 1 was added dropwise, Respectively. When the reaction was completed, the solvent was removed by concentration under reduced pressure and purified by silica column chromatography to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 8.16 (s, 2H), 3.77 (t, 4H), 3.69 (s, 3H), 3.24 (m, 1H), 2.59 (m, 5H), 2.40 (t , 2H), 2.31 (dd, 1H), 1.57 (m, 2H), 1.09 (d, 3H), 0.94 (t, 3H).

Step 3: 3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) butan-1-ol

Lithium aluminum hydride (LAH, 900 mg) was dissolved in tetrahydrofuran (THF, 50 mL) with stirring at 0 ° C and dissolved in tetrahydrofuran (THF, 50 mL) in a 100 ml flask under a nitrogen atmosphere. A solution of the prepared compound (2.7 g) was slowly added dropwise to the flask for 5 minutes. When the reaction was complete, 1 M sodium hydroxide (50 mL) was slowly added dropwise, extracted with ethyl acetate (40 mL), and washed with brine (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 8.16 (s, 2H), 3.84 (m, 6H), 3.00 (m, 1H), 2.84 (m, 2H), 2.54 (m, 2H), 2.41 (t 2H), 1.95 (m, 1H), 1.57 (m, 2H), 1.42 (dq, 1H), 1.01 (d, 3H), 0.94 (t, 3H).

Step 4: 3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) butyl Methanesulfonate Manufacturing

(2 g) prepared in Step 3 was dissolved in dichloromethane (DCM, 100 mL) and dissolved in triethylamine (TEA, 1.2 mL) to a 100 mL flask under a nitrogen atmosphere. (0.6 mL) was slowly added dropwise at 0 &lt; 0 &gt; C. After the addition was complete, it was stirred for 30 minutes, extracted with dichloromethane (DCM, 40 mL) and washed with brine (100 mL). The washed compound was dried over anhydrous magnesium sulfate and concentrated to obtain the target compound.

¹ H NMR (400 Hz, CDCl ₃ ):? 5.08 (m, 1H), 4.71 (m, 3H), 4.43 2H), 0.92 (t, 3H), 3.12 (t, 3H)

Step 5: 2- (4- (4- (4- ( Methylsulfonyl ) Phenoxy ) Butan-2-yl) piperazin-1-yl) -5- Propylpyrimidine  Oxalate of  Produce

(600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) were added to a 100 ml flask under a nitrogen atmosphere and the mixture was stirred to dissolve. Then, 4- (methylsulfonyl) Phenol (350 mg) was added, and the mixture was stirred at a temperature of 70 캜. After stirring was completed, the reaction mixture was cooled to room temperature, distilled water (20 mL) was slowly added thereto, and the mixture was extracted with ethyl acetate (EA, 60 mL). The extracted organic layer was washed with brine (40 mL), dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography. Ethyl acetate (EA, 10 mL) was then added and dissolved by stirring. Oxalic acid was added in the same volume of water and refluxed for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.21 (2H, s), 7.79 (2H, d), 7.07 (2H, d), 4.61 (2H, s), 4.18 (2H, m), 3.67 ( (1H, m), 3.45 (1H, m), 3.23 (4H, m), 3.12 (3H, s), 2.37 , d), 0.77 (3H, t).

< Example  4 > 2- (4- (4- (3- Fluoro -4-(( Methylsulfonyl ) methyl ) Phenoxy ) Butan-2-yl) piperazin-1-yl) -5- Of propylpyrimidine  Produce

The compound (600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) prepared in Step 4 of Example 3 were added to a 100 ml flask under nitrogen atmosphere and dissolved by stirring. The compound prepared in Example 5 (350 mg) was added, and the mixture was stirred at a temperature of 70 캜. After stirring was completed, the reaction mixture was cooled to room temperature, distilled water (20 mL) was slowly added thereto, and the mixture was extracted with ethyl acetate (EA, 60 mL). The extracted organic layer was washed with brine (40 mL), dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica column chromatography to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 8.17 (2H, s), 7.38 (1H, t), 6.74 (2H, dd), 4.25 (2H, s), 4.09 (2H, m), 3.78 (4H (2H, m), 2.91 (1H, q), 2.81 (3H, s), 2.68 m), 1.58 (2H, m), 1.05 (3H, d), 0.95 (3H, t).

< Example  5 > 2- (4- (4- (3- Fluoro -4-(( Methylsulfonyl ) methyl ) Phenoxy ) Butan-2-yl) piperazin-1-yl) -5- Propylpyrimidine  Preparation of oxalate

The procedure of Example 3 was repeated except that 4- (methylsulfonyl) phenol was used instead of the compound prepared in Preparation 5 in Step 5 of Example 3 to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.21 (2H, s), 7.30 (1H, t), 6.78 (2H, d), 4.62 (2H, m), 4.47 (2H, s), 4.18 ( (1H, m), 4.11 (1H, m), 3.64 (1H, m), 3.44 (2H, m), 3.22 m), 1.47 (2H, q), 1.33 (3H, d), 0.77 (3H, t).

< Example  6 > 1- (4- (3- Fluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

Step 1: t-Butyl-4- Cyanopiperazine -One- Carboxylate  Produce

Piperazine-1-carboxylic acid t-butyl ester (10 g), acetonitrile (50 mL) and distilled water (50 mL) were poured into a 250 ml flask under a nitrogen atmosphere and then cooled to 0 ° C and dissolved by stirring . Sodium bicarbonate (6 g) and cyanogen bromide (6.3 g) were slowly added to the flask. The mixture was then slowly cooled to 50 &lt; 0 &gt; C and stirred for 3 hours. After the reaction was completed, the pH was neutralized at 0 ° C using 1M hydrochloric acid, extracted with ethyl acetate (500 mL), and washed with brine (100 mL). Thereafter, the washed organic layer was dried over anhydrous magnesium sulfate to obtain the desired solid compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 3.54 (t, 4H), 3.21 (t, 4H), 1.48 (s, 9H).

Step 2: 3-Isopropyl-5- (piperazin-1-yl) -1,2,4- Oxadiazole  Produce

The compound (10 g) and ethyl acetate (EA, 30 mL) prepared in the above step 1 were added to a 100 ml flask under a nitrogen atmosphere and dissolved by stirring. N -Hydroxy-isobutylamidine (540 mg) was slowly added to the flask, stirred at room temperature for 1 hour, and then zinc chloride (Zinc chloride, 1M diethyl ether solution, 5 mL) was slowly added dropwise . When the addition was completed, stirring was continued for 3 hours, and the resulting solid was filtered, washed with ethyl acetate (EA, 100 mL) and dried. The dried solid was dissolved in ethanol (30 mL) and stirred. Then, 4- N hydrochloric acid (1.2 mL) was added dropwise and the mixture was stirred under reflux. After the reaction was completed, the reaction mixture was adjusted to pH 10 with 1M sodium hydroxide, extracted with ethyl acetate (EA, 100 mL), and the extracted organic layer was concentrated to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 3.59 (m, 4H), 2.94 (m, 4H), 1.30 (d, 6H).

Step 3: methyl -3- (4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazin-1-yl) butanoate &lt; / RTI &gt;

Methyl crotonate (3.3 g) and methanol (50 mL) were added to a 100 ml flask under nitrogen atmosphere and dissolved by stirring. Then, the compound (5 g) prepared in the above step 2 was added dropwise, Respectively. When the reaction was completed, the solvent was removed by concentration under reduced pressure and purified by silica column chromatography to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 3.66 (s, 3H), 3.55 (m, 4H), 3.21 (1H, q), 2.86 (1H, q), 2.58 (m, 5H), 1.25 (d , 6H), 1.04 (d, 3H).

Step 4: 3- (4- (3-Isopropyl-l, 2,4- Oxadiazole Yl) butan-1-ol &lt; / RTI &gt;

Lithium aluminum hydride (LAH, 900 mg) was dissolved in tetrahydrofuran (THF, 50 mL) at 0 ° C by dissolving in a 100 ml flask under a nitrogen atmosphere and then tetrahydrofuran (THF, 50 mL) (2.7 g) was slowly added dropwise to the flask for 5 minutes. When the reaction was complete, 1 M sodium hydroxide (50 mL) was slowly added dropwise, extracted with ethyl acetate (40 mL), and washed with brine (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 3.86 (m, 2H), 3.65 (m, 4H), 3.00 (m, 1H), 2.90 (m, 1H), 2.85 (m, 2H), 2.58 (m 2H), 1.92 (m, IH), 1.44 (m, IH), 1.31 (d, 6H), 1.03 (d, 3H).

Step 5: 3- (4- (3-Isopropyl-l, 2,4- Oxadiazole Yl) piperazin-1-yl) Butyl Preparation of Methane Sulfonate

(2 g) and dichloromethane (DCM, 100 mL) were added to a 100 ml flask under a nitrogen atmosphere and stirred to dissolve. Triethylamine (TEA, 1.2 mL) was added dropwise, (0.6 mL) was slowly added dropwise at 0 &lt; 0 &gt; C. When the addition is complete, it is stirred for 30 minutes and extracted with dichloromethane (DCM, 40 mL). The extracted organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate and concentrated to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 4.86 (q, 1H), 4.53 (q, 1H), 4.44 (m, 1H), 4.02 (m, 4H), 3.51 (m, 3H), 3.19 (m (D, IH), 2.72 (m, 2H), 2.54 (s, 3H), 2.45 (m,

Step 6: 1- (4- (3- Fluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; RTI ID = 0.0 &gt; of  Produce

(600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 ml) were added to a 100 ml flask under nitrogen atmosphere and dissolved by stirring. (350 mg) was added, and the mixture was stirred at a temperature of 70 캜. After the stirring was completed, the reaction mixture was cooled to room temperature, distilled water (20 ml) was slowly added thereto, and the mixture was extracted with ethyl acetate (EA, 60 ml). The extracted organic layer was washed with brine (40 ml), dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography. Ethyl acetate (EA, 10 mL) was then added and dissolved by stirring. Oxalic acid was added in the same volume of water and refluxed for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.76 (1H, t), 7.16 (1H, dd) 7.00 (1H, dd), 4.25 (2H, m), 4.21 (2H, m), 3.56 (4H (1H, m), 3.26 (3H, s), 3.04 (1H, q), 2.83 (3H, m), 2.68 d), 1.05 (3H, d).

< Example  7 > t-Butyl 4- (4- (3- Fluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) piperazin-l- Carboxylate  Preparation of oxalate

The procedure of Example 1 was repeated except that 4- (methylsulfonyl) phenol was used instead of the compound prepared in Preparation Example 2 in Step 3 of Example 1 to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.86 (1H, t), 6.82 (1H, dd) 6.76 (1H, dd), 4.19 (1H, m), 4.09 (1H, m), 3.39 (4H (1H, m), 3.20 (3H, s), 2.88 (1H, q), 2.56 (2H, m), 2.39 s), 1.02 (3 H, d).

< Example  8> 1- (4- (3- Fluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole 5-yl) piperazine hydrochloride

(600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF) were added to a 100 ml flask under a nitrogen atmosphere. , 30 ml) was added and dissolved by stirring. Then, the compound (350 mg) prepared in Preparation Example 2 was added, and the mixture was stirred at 70 ° C. After the reaction was completed, the reaction mixture was cooled to room temperature, distilled water (20 ml) was slowly added thereto, and extracted with ethyl acetate (EA, 60 ml). The extracted organic layer was washed with brine (40 mL), dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography. Then, the reaction mixture was dissolved in ethyl acetate (EA, 10 mL), and 4N hydrochloric acid (1,4-dioxane solution) equivalent to the equivalent amount was added dropwise and refluxed for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.74 (1H, t), 6.91 (2H, t) 4.71 (4H, s), 4.26 (1H, m), 4.16 (1H, m), 3.74 (1H (1H, m), 3.45 (4H, s), 3.26 (3H, s), 2.84 d).

< Example  9> 1- (4- (2- Fluoro -4- (1H- Tetrazole -1 day) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine &lt; / RTI &gt;

The compound (600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) prepared in Step 5 of Example 6 were dissolved in a 100 ml flask under nitrogen atmosphere and dissolved by stirring. The compound prepared in Example 15 (150 mg) was added and the temperature was kept at 70 DEG C with stirring. After stirring was completed, the reaction mixture was cooled to room temperature, distilled water (20 mL) was slowly added thereto, and the mixture was extracted with ethyl acetate (EA, 60 mL). The extracted organic layer was washed with brine (40 mL), dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica column chromatography to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 8.98 (1H, s), 7.52 (1H, dd) 7.46 (1H, d), 7.21 (1H, t), 4.27 (2H, m), 3.79 (4H, (1H, s), 3.26 (1H, s), 2.88 (4H, m), 2.63 (1H, m), 2.28 ).

< Example  10> 1- (4- (2- Fluoro -4- (1H- Tetrazole -1 day) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The compound (200 mg) prepared in Example 9 was dissolved in ethyl acetate (10 mL), and the same amount of oxalic acid was added dropwise thereto, followed by reflux stirring for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 9.48 (1H, s), 7.59 (1H, dd) 7.49 (1H, d), 7.23 (1H, t), 4.33 (2H, m), 4.25 (2H m), 3.77 (1H, m), 3.59 (4H, m), 3.35 (2H, m), 2.85 d), 1.16 (6H, d).

< Example  11 >. 1- (4- (2- Fluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that the compound prepared in Preparation Example 1 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.74 (1H, t), 6.91 (2H, t) 4.71 (4H, s), 4.26 (1H, m), 4.16 (1H, m), 3.74 (1H (1H, m), 3.45 (4H, s), 3.26 (3H, s), 2.84 d).

< Example  12> 1- (4- (3- Fluoro -4- (1H- Tetrazole -1 day) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The target compound was obtained in the same manner as in Example 6 except that the compound prepared in Preparation Example 17 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6.

^{1 H NMR (400 Hz, D} 2 O): δ 9.41 (1H, s), 7.61 (1H, t), 6.98 (1H, d) 6.91 (1H, d), 4.20 (2H, m), 4.10 (2H (1H, m), 3.72 (1H, m), 3.56 (4H, m), 3.33 d), 1.14 (6H, d).

< Example  13 > 1- (4- (4- ( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-1,2,4-ox buy 5-yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that 4- (methylsulfonyl) phenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.79 (2H, d), 7.07 (2H, d) 4.24 (4H, d), 4.01 (2H, d), 3.70 (1H, m), 3.52 (4H m), 3.32 (2H, m), 3.12 (3H, s), 2.81 (1H, m), 2.31 d).

< Example  14> 1- (4- (4- (1H- Tetrazole -1 day) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that the compound prepared in Preparation Example 16 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 9.46 (1H, s), 7.64 (2H, d), 7.10 (2H, d) 4.75 (2H, m), 4.27 (2H, d), 4.16 (1H (1H, m), 3.74 (1H, m), 3.54 (4H, m), 3.41 (2H, m), 2.86 d), 1.14 (6H, d).

< Example  15 >. 1- (4- (3,5- Difluoro -4- (1H- Tetrazole -1 day) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that the compound prepared in Preparation Example 18 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 9.38 (1H, s), 6.83 (2H, d) 4.23 (1H, m), 4.10 (1H, m), 3.72 (1H, m), 3.68 (4H m), 3.34 (2H, m), 2.80 (1H, m), 2.32 (1H, m), 2.04 (1H, m), 1.34 (3H, d), 1.13 (6H, d).

< Example  16 >. 1- (4- (4- Bromo -2,5- Difluorophenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that 4-bromo-2,5-difluorophenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6, Compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.36 (1H, dd), 6.98 (1H, dd) 4.27 (2H, m), 4.12 (2H, m), 3.72 (1H, m), 3.54 (4H m), 3.34 (2H, m), 2.82 (1H, m), 2.30 (1H, m), 2.03 (1H, m), 1.35 (3H, d), 1.13 (6H, d).

< Example  17> 1- (4- (3- Chloro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that the compound prepared in Preparation Example 11 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.89 (1H, d), 7.18 (1H, s) 6.99 (1H, d), 4.24 (2H, d), 4.14 (2H, m), 3.70 (1H m), 3.47 (4H, m), 3.36 (2H, m), 3.30 (3H, s), 2.82 d), 1.13 (6H, d).

< Example  18 >. 1- (4- (3- methyl -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that the compound prepared in Preparation Example 10 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.84 (1H, d), 6.95 (1H, t) 6.92 (1H, d), 4.24 (2H, d), 4.16 (2H, d), 3.74 (1H (1H, m), 3.53 (4H, m), 3.36 (2H, m), 3.19 (3H, s), 2.86 m), 1.38 (3H, d), 1.17 (6H, d).

< Example  19> 1- (4- (5- ( Methylsulfonyl ) Pyridin-2- Sake ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The compound (0.8 g) prepared in Step 5 of Example 6 and dimethylformamide (DMF, 30 mL) were added to a 100 mL flask under a nitrogen atmosphere and dissolved by stirring. The reaction was cooled to 0 &lt; 0 &gt; C and sodium hydride (NaH, 0.17 g) was added and stirred for 30 min. Then, 2-bromo-5- (methanesulfonyl) -pyridine (0.7 g) was added dropwise, the temperature was slowly kept at room temperature, and the mixture was stirred for 2 hours. When stirring was completed, the solution was cooled to 0 ° C, distilled water (20 mL) was slowly added thereto, and then extracted with ethyl acetate (EA, 60 mL). The extracted organic layer was washed with brine (40 mL), dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography. The purified compound was dissolved again in ethyl acetate (EA, 10 mL), and the same equivalent amount of oxalic acid was added dropwise, followed by reflux stirring for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.60 (1H, d), 8.13 (1H, d) 7.00 (1H, d), 4.53 (1H, m), 4.40 (1H, m), 4.19 (2H , 3.72 (1H, m), 3.49 (4H, m), 3.20 (3H, s), 2.82 d), 1.15 (6H, d).

< Example  20 > 1- (4- (5- ( Methylsulfonyl ) Pyridin-2- Sake ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole 5-yl) piperazine hydrochloride

The objective compound was obtained in the same manner as in Example 19, except that 4N-hydrochloric acid (1,4-dioxane solution) was used instead of oxalic acid in Example 19.

^{1 H NMR (400 Hz, D} 2 O): δ 8.60 (1H, d), 8.13 (1H, dd) 7.00 (1H, d), 4.50 (1H, m), 4.40 (1H, m), 4.24 (2H (d, 2H), 3.70 (1H, m), 3.70 (1H, m) m), 1.36 (3H, d), 1.14 (6H, d).

< Manufacturing example  21> 1- (4- (6- ( Methylsulfonyl ) Pyridin-3 - Sake ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that 6- (methylsulfonyl) pyridin-3-ol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound &Lt; / RTI &gt;

^{1 H NMR (400 Hz, D} 2 O): δ 8.33 (1H, d), 8.02 (1H, d) 7.55 (1H, dd), 4.25 (1H, m), 4.20 (1H, m), 3.75 (1H m), 3.47 (4H, m), 3.36 (2H, m), 3.19 (3H, s), 2.83 d), 1.15 (6H, d)

< Example  22 > 1- (4- (3- Chloro -4-(( Methylsulfonyl ) methyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that 3-chloro-4-methanesulfonylmethylphenol was used instead of the compound prepared in Preparation 2 in Step 6 of Example 6 to obtain the desired compound .

^{1 H NMR (400 Hz, D} 2 O): δ 7.35 (1H, d), 7.09 (1H, d) 6.90 (1H, dd), 4.61 (2H, s), 4.18 (1H, m), 4.10 (1H m), 3.70 (1H, m), 3.49 (4H, m), 3.23 (2H, m), 3.00 d), 1.13 (6H, d).

< Example  23> 1- (4- (3- Chloro -4-(( Methylsulfonyl ) methyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole 5-yl) piperazine hydrochloride

Except that 3-chloro-4-methanesulfonylmethylphenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6, and hydrochloric acid was used instead of oxalic acid. The procedure of Example 6 was repeated to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.35 (1H, d), 7.08 (1H, d) 6.83 (1H, dd), 4.60 (2H, s), 4.16 (1H, m), 4.04 (1H m), 3.68 (1H, m), 3.52 (4H, m), 3.26 (2H, m), 2.99 m), 1.33 (3H, d), 1.13 (6H, d).

< Example  24> 1- (4- (3- Fluoro -4-(( Methylsulfonyl ) methyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The target compound was obtained in the same manner as in Example 6 except that the compound prepared in Preparation Example 5 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6.

^{1 H NMR (400 Hz, D} 2 O): δ 7.30 (1H, t), 6.80 (2H, d) 4.47 (2H, s), 4.12 (1H, m), 4.04 (1H, m), 3.71 (1H m), 1.33 (1H, m), 3.33 (2H, m), 3.65 d), 1.13 (6H, d).

< Example  25 > 1- (4- (2- methyl -4-(( Methylsulfonyl ) methyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that 4-methanesulfonylmethyl-2-methylphenol was used instead of the compound prepared in Preparation 2 in Step 6 of Example 6 to obtain the desired compound .

^{1 H NMR (400 Hz, D} 2 O): δ 7.14 (2H, d), 6.90 (1H, d) 4.35 (2H, s), 4.14 (1H, m), 4.00 (1H, m), 3.68 (1H m), 3.63 (4H, m), 3.29 (2H, m), 2.89 (3H, s), 2.77 m), 1.32 (3H, d), 1.11 (6H, d).

< Example  26> 2- (4- (4- (3- Fluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) piperazin-1-yl) -5- Propylpyrimidine  Preparation of oxalate

The procedure of Example 3 was repeated except that 4- (methylsulfonyl) phenol was used instead of the compound prepared in Preparation Example 2 in Step 5 of Example 3 to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.19 (1H, s), 7.70 (1H, t), 6.87 (2H, m), 4.58 (2H, m), 4.25 (1H, m), 4.15 ( (1H, m), 3.67 (1H, m), 3.50 (4H, m), 3.22 (5H, m), 2.37 , q), 1.32 (3H, d), 0.76 (3H, t).

< Example  27> 1 - ((R) -4- (3-Fluoro-4- (methylsulfonyl) phenoxy) Work ) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

Step 1: (R) -4- (t- Butyl dimethylsilyloxy ) Butan-2-ol

(R) - (-) - 1,3-butanediol (5 g), imidazole (7.5 g) and dichloromethane (DCM, 200 mL) were added to a 500 mL flask under nitrogen atmosphere and dissolved by stirring Followed by dropwise addition of t-butyl dimethylsilyl chloride (9.16 g). Upon completion of the dropwise addition, the reaction mixture was stirred for 24 hours, extracted with dichloromethane (DCM, 100 mL), and washed with brine (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to obtain the desired compound.

¹ H NMR (400 Hz, CDCl ₃ ):? 4.04 (m, IH), 3.91 (m, IH), 3.83 (m, IH), 3.41 , 3H), 0.90 (s, 9H), 0.10 (s, 6H).

Step 2: (R) -4- (t- Butyl dimethylsilyloxy ) Butane-2- Yl methanesulfonate  Produce

(2 g) and dichloromethane (DCM, 100 mL) were poured into a 100 mL flask under nitrogen atmosphere and stirred and dissolved. Triethylamine (TEA, 1.2 mL) was added dropwise and methane Sulfonyl chloride (0.6 mL) was slowly added dropwise at 0 &lt; 0 &gt; C. The addition was complete and stirred for 30 min, extracted with dichloromethane (DCM, 40 mL) and washed with brine (100 mL). The washed reaction product was dried with anhydrous magnesium sulfate and concentrated to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 4.97 (m, 1H), 3.72 (m, 2H), 3.03 (s, 3H), 1.91 (m, 1H), 1.80 (m, 1H), 1.49 (d , 3H), 0.91 (s, 9H), 0.08 (s, 6H).

Step 3: (S) -3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) butan-1-ol &lt; / RTI &

The compound (1.4 g) prepared in the above Step 2 and dimethylformamide (DMF, 40 mL) were poured into a 100 mL flask under a nitrogen atmosphere and stirred to dissolve the compound. The compound prepared in Preparation 25 g) and potassium carbonate (1 g) were added and the mixture was stirred at 50 캜 for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, distilled water (30 mL) was slowly added thereto, and the mixture was extracted with ethyl acetate (EA, 100 mL). The extracted organic layer was washed three times with distilled water (20 mL), dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica column chromatography to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 3.70 (m, 2H), 3.61 (m, 4H), 2.87 (m, 2H), 2.65 (m, 2H), 2.53 (m, 2H), 1.77 (m (D, 3H), 1.98 (s, 9H), 0.07 (s, 6H).

Step 4: (S) -3- (4- (3-Isopropyl-l, 2,4- Oxadiazole Yl) piperazin-1-yl) butyl Methanesulfonate  Produce

The compound (2 g) and dichloromethane (DCM, 100 mL) prepared in Step 3 above were poured into a 100 mL flask under a nitrogen atmosphere and dissolved by stirring. Triethylamine (TEA, 1.2 mL) is then added dropwise and methanesulfonyl chloride (0.6 mL) is slowly added dropwise at 0 &lt; 0 &gt; C. When the addition was complete, it was stirred for 30 minutes, extracted with dichloromethane (DCM, 40 mL) and washed with brine (100 mL). The washed reaction product was dried with anhydrous magnesium sulfate and concentrated to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 5.05 (m, 1H), 4.81 (m, 1H), 4.55 (m, 1H), 4.24 (m, 3H), 3.96 (m, 2H), 3.71 (m 2H), 3.44 (m, IH), 3.24 (m, IH), 2.90 (m, IH) 6H).

Step 5: 1 - ((R) -4- (3- Fluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; RTI ID = 0.0 &gt; of  Produce

(600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) were added to a 100 mL flask under nitrogen atmosphere and dissolved by stirring. The compound (350 mg) was added and the mixture was stirred at a temperature of 70 캜. After stirring was completed, the reaction mixture was cooled to room temperature, distilled water (20 mL) was slowly added thereto, and the mixture was extracted with ethyl acetate (EA, 60 mL). The extracted organic layer was washed with brine (40 ml), dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography. Ethyl acetate (EA, 10 mL) was then added and dissolved by stirring. Oxalic acid was added in the same volume of water and refluxed for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.71 (1H, t), 6.89 (2H, m) 4.21 (2H, s), 4.13 (2H, m), 3.70 (1H, m), 3.51 (4H m), 3.35 (2H, m), 3.24 (3H, s), 2.82 (1H, m), 2.32 d).

< Example  28 > 1 - ((R) -4- (3- Fluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole 5-yl) piperazine hydrochloride

The procedure of Example 27 was repeated except that hydrochloric acid was used instead of oxalic acid in Step 5 of Example 27 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.71 (1H, t), 6.88 (2H, m), 4.15 (4H, m), 3.70 (1H, m), 3.56 (4H, m), 3.34 ( 2H), 3.24 (3H, s), 2.82 (1H, m), 2.30 (1H, m), 2.02 (1H, m), 1.33 (3H, d), 1.13 (6H, d).

< Example  29> 2- (4- (4- (3- Fluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) piperazin-1-yl) -5- Propylpyrimidine  Preparation of hydrochloride

The procedure of Example 3 was repeated except for using the compound prepared in Preparation Example 2 instead of 4- (methylsulfonyl) phenol in Step 5 of Example 3 and using hydrochloric acid instead of oxalic acid. The target compound was obtained.

^{1 H NMR (400 Hz, D} 2 O): δ 8.31 (2H, s), 7.71 (1H, t) 6.88 (2H, m), 4.61 (2H, m), 4.23 (1H, m), 4.12 (1H (2H, m), 3.72 (1H, m), 3.67 (2H, m), 3.40 m), 1.52 (2H, q), 1.34 (3H, d), 0.79 (3H, t).

< Example  30> 2- (4- (4- (3- Chloro -4-(( Methylsulfonyl ) methyl ) Phenoxy ) Butan-2-yl) piperazin-1-yl) -5- Of propylpyrimidine  Produce

The procedure of Example 4 was repeated except that 3-chloro-4-methanesulfonylmethyl-phenyl was used instead of the compound prepared in Preparation Example 5 in Example 4 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.17 (2H, s), 7.47 (1H, t), 7.02 (1H, d), 6.90 (1H, dd), 4.47 (2H, s), 4.14 ( (1H, m), 4.05 (1H, m), 3.80 (4H, m), 2.93 (1H, m), 2.80 , t), 2.03 (1H, m), 1.78 (1H, m), 1.57 (2H, q), 1.04 (3H, d), 0.95 (3H, t).

< Example  31> 2- (4- (4- (3- Chloro -4-(( Methylsulfonyl ) methyl ) Phenoxy ) Butan-2-yl) piperazin-1-yl) -5- Propylpyrimidine  Preparation of oxalate

The compound prepared in Example 30 was dissolved in ethyl acetate (EA, 10 mL), and the same equivalent amount of oxalic acid was added dropwise, followed by reflux stirring for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.19 (2H, s), 7.34 (1H, t) 7.06 (1H, d), 6.87 (1H, dd), 4.58 (4H, m), 4.16 (1H m), 4.06 (1H, m), 3.64 (1H, m), 3.50 (2H, s), 3.43 m), 1.98 (1H, m), 1.43 (2H, q), 1.32 (3H, d), 0.76 (3H, t).

< Example  32> 2- (4- (4- (3- Fluoro -4- (1- ( Methylsulfonyl )ethyl) Phenoxy ) Butan-2-yl) piperazin-1-yl) -5- Propylpyrimidine  Preparation of oxalate

The procedure of Example 3 was repeated except for using the compound prepared in Preparation Example 13 instead of using 4- (methylsulfonyl) phenol in Step 5 of Example 3 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.21 (2H, s), 7.36 (1H, t) 6.75 (2H, d), 4.80 (1H, s), 4.58 (2H, m), 4.18 (1H (2H, s), 4.08 (1H, s), 3.66 (2H, s), 3.53 (2H, s), 3.23 s), 2.00 (1H, s), 1.65 (3H, s), 1.46 (2H, s), 1.34 (3H, s), 0.77 (3H, s).

< Example  33> 1- (4- (2,5- Difluoro -4-(( Methylsulfonyl ) methyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that the compound prepared in Preparation Example 14 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.20 (1H, dd), 6.97 (1H, dd), 4.47 (2H, s), 4.25 (2H, m), 4.13 (2H, m), 3.74 ( (1H, m), 3.55 (4H, m), 3.33 (2H, m), 3.01 (3H, s), 2.82 , &lt; / RTI &gt; d), 1.14 (6H, d).

< Example  34> 1- (4- (2,5- Difluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine Trifluoroacetic acid  Manufacture of salt

Except that the compound prepared in Preparation Example 14 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 and triflu or o acetic acid was used instead of oxalic acid, 6, the target compound was obtained.

^{1 H NMR (400 Hz, D} 2 O): δ 7.57 (1H, dd), 7.09 (1H, dd), 4.30 (2H, m), 4.20 (2H, m), 3.73 (1H, m), 3.42 ( 4H, m), 3.25 (3H, s), 2.81 (1H, q), 2.35 (2H, m), 2.11 (2H, m), 1.35 (3H, d), 1.13 (6H, d).

< Example  35> 1- (4- (2,5- Difluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole 5-yl) piperazine hydrochloride

The same procedure as in Example 6 was repeated except that the compound prepared in Preparation Example 14 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 and hydrochloric acid was used instead of oxalic acid To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.58 (1H, dd), 7.11 (1H, dd), 4.31 (2H, m), 4.21 (2H, m), 3.72 (1H, m), 3.54 ( (2H, m), 1.35 (3H, d), 1.14 (2H, m), 3.31 , d).

< Example  36> 1- (4- (2,6- Difluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that the compound prepared in Preparation Example 7 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.57 (2H, d), 4.45 (1H, m), 4.35 (1H, m), 4.17 (2H, m), 3.76 (1H, m), 3.50 ( (2H, m), 1.36 (3H, d), 1.13 (6H, m), 3.33 , d).

< Example  37> 1- (4- (2,6- Difluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine Trifluoroacetic acid  Manufacture of salt

Except that in step 6 of Example 6, the compound prepared in Preparation Example 7 was used instead of the compound prepared in Preparation Example 2, and trifluoroacetic acid was used instead of oxalic acid, 6, the target compound was obtained.

^{1 H NMR (400 Hz, D} 2 O): δ 7.57 (2H, d), 4.46 (1H, m), 4.32 (1H, m), 4.17 (2H, m), 3.73 (1H, m), 3.42 ( (2H, m), 3.33 (2H, m), 3.16 (3H, s), 2.81 (1H, q), 2.32 , d).

< Example  38 > 1- (4- (2,6- Difluoro -4-( Methylsulfonyl ) Phenoxy ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole 5-yl) piperazine hydrochloride

In the same manner as in Example 6 except that the compound prepared in Preparation Example 7 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 and hydrochloric acid was used instead of oxalic acid To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.57 (2H, d), 4.48 (1H, m), 4.34 (1H, m), 4.30 (2H, m), 3.77 (1H, m), 3.54 ( (2H, m), 3.33 (2H, m), 3.16 (3H, s), 2.81 (1H, q), 2.33 , d).

< Example  39> 1- (4- (5- methyl -6- ( Methylsulfonyl ) Pyridine-3- Sake ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole 5-yl) piperazine hydrochloride

In the same manner as in Example 6 except that the compound prepared in Preparation Example 10 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 and hydrochloric acid was used instead of oxalic acid To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.07 (1H, d), 7.34 (1H, d), 4.28 (2H, m), 4.19 (2H, m), 3.71 (1H, m), 3.63 ( (1H, m), 3.35 (2H, m), 3.21 (3H, s), 2.79 , &lt; / RTI &gt; d), 1.13 (6H, d).

< Example  40> 1- (4- (5- methyl -6- ( Methylsulfonyl ) Pyridine-3- Sake ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that the compound prepared in Preparation Example 10 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.57 (2H, d), 4.45 (1H, m), 4.34 (1H, m), 4.17 (2H, m), 3.76 (1H, m), 3.50 ( (2H, m), 3.33 (2H, m), 3.17 (3H, s), 2.81 (1H, q), 2.32 , d).

< Example  41> Ethyl-4- (3- (4- (3-isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluorobenzoate  Preparation of oxalate

The procedure of Example 6 was repeated except that the compound prepared in Preparation Example 19 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.81 (1H, t), 6.75 (2H, m), 4.26 (2H, q), 4.22 (3H, m), 4.10 (1H, m), 3.70 ( (2H, m), 1.33 (3H, d), 1.23 (3H, m) , t), 1.12 (6H, d).

< Example  42> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluorobenzoate Lithium salt  Produce

The compound (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) prepared in Example 41 were dissolved in a 100 mL flask under nitrogen atmosphere and dissolved by stirring. Then, lithium hydroxide monohydrate (170 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. When the reaction was complete, the solvent was concentrated and then dissolved in dichloromethane (DCM, 50 mL) and the undissolved solid was filtered. The filtrate was concentrated, and solidified using diethyl ether and hexane to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.50 (1H, t), 6.68 (2H, m), 4.03 (2H, m), 3.50 (4H, t), 2.76 (2H, m), 2.60 ( 4H, q), 2.03 (1H, m), 1.79 (3H, s), 1.63 (1H, m), 1.11 (6H, d), 1.01 (3H, d).

< Example  43> Ethyl-4- (3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) Butoxy ) -2- Luoro benzoi Preparation of oxalate

The procedure of Example 3 was repeated except that 4- (methylsulfonyl) phenol was used instead of the compound prepared in Preparation 19 in Step 5 of Example 3 to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.20 (2H, s), 7.79 (1H, t), 6.73 (2H, m), 4.27 (2H, m), 4.22 (2H, t), 4.19 ( (1H, m), 4.08 (1H, m), 3.66 (1H, m), 3.52 (2H, m), 3.22 m), 1.50 (2H, m), 1.33 (3H, d), 1.25 (3H, t), 0.77 (3H, t).

< Example  4- (3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) Butoxy )-2- The Ruborobenzoate Lithium salt  Produce

The compound (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) prepared in Example 43 were dissolved in a 100 mL flask under a nitrogen atmosphere and dissolved by stirring. Then, lithium hydroxide monohydrate (170 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. When the reaction was complete, the solvent was concentrated and then dissolved in dichloromethane (DCM, 50 mL) and the undissolved solid was filtered. The filtrate was concentrated, and solidified using diethyl ether and hexane to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.06 (2H, s), 7.52 (1H, t), 6.63 (2H, m), 4.00 (2H, m), 3.53 (4H, t), 2.67 ( (1H, m), 2.51 (4H, m), 2.27 (2H, t), 1.96 (1H, m), 1.54 , t).

< Example  45> 4- (3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) Butoxy )-2- The (3, &lt; RTI ID = 0.0 &gt; Dihydroxypropane -2 days) Benzamide  Preparation of oxalate

(310 mg) and dichloromethane (DCM, 50 mL) were poured into a 100 mL flask under a nitrogen atmosphere and dissolved with stirring to obtain 1-ethyl-3- (3-dimethylaminopropyl ) Carbaldehyde hydrochloride (EDCI, 170 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 120 mg) were added and stirred for 30 minutes. Then, 2-amino-1,3-propanediol (100 mg) was added and stirred at room temperature for 5 hours. When the reaction was completed, distilled water (20 mL) was added slowly, extracted with ethyl acetate (EA, 60 mL) and washed with brine (40 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography. The purified compound was dissolved in ethyl acetate (EA, 10 mL) and stirred, followed by dropwise addition of the same equivalent amount of oxalic acid and reflux stirring for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.22 (2H, s), 7.60 (1H, t), 6.78 (2H, m), 4.59 (2H, m), 4.22 (1H, m), 4.11 ( (1H, m), 3.70 (5H, m), 3.60 (2H, m), 3.23 (4H, m), 2.42 , &lt; / RTI &gt; m), 1.33 (3H, d), 0.78 (3H, t).

< Example  46> 4- (3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) Butoxy )-2- The (3, &lt; RTI ID = 0.0 &gt; Dihydroxypropane -2 days) Benzamide  Preparation of hydrochloride

(310 mg) and dichloromethane (DCM, 50 mL) were charged into a 100 ml flask under a nitrogen atmosphere and dissolved by stirring to obtain 1-ethyl-3- (3-dimethylaminopropyl ) Carbaldehyde hydrochloride (EDCI, 170 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 120 mg) were added and stirred for 30 minutes. Then, 2-amino-1,3-propanediol (100 mg) was added and stirred at room temperature for 5 hours. When the reaction was completed, distilled water (20 mL) was added slowly, extracted with ethyl acetate (EA, 60 mL) and washed with brine (40 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography. The purified compound was dissolved in ethyl acetate (EA, 10 mL) and stirred, followed by the same equivalent of 4N-hydrochloric acid (1.4-dioxane solution) added dropwise and refluxed for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.22 (2H, s), 7.61 (1H, t), 6.78 (2H, m), 4.59 (2H, m), 4.22 (1H, m), 4.11 ( (1H, m), 3.71 (2H, m), 3.68 (3H, m), 3.60 (2H, m), 3.23 m), 1.49 (2H, m), 1.33 (3H, d), 0.78 (3H, t).

< Example  4- (3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) Butoxy )-2- The &Lt; RTI ID = 0.0 &gt; (S) -1- Hydroxypropane -2 days) Benzamide  Preparation of oxalate

Example 45 was repeated except that (R) - (-) - 2-amino-1-propanol was used instead of 2-amino-1,3-propanediol in the same manner as in Example 45, To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.33 (2H, s), 7.56 (1H, t), 6.79 (2H, m), 4.57 (2H, m), 4.21 (1H, m), 4.13 ( (2H, m), 3.71 (2H, m), 3.61 (3H, m), 3.52 m), 1.55 (2H, m), 1.36 (3H, d), 1.09 (3H, d), 0.78 (3H, t).

< Example  4- (3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) Butoxy )-2- The &Lt; RTI ID = 0.0 &gt; (S) -1- Hydroxypropane -2 days) Benzamide  Preparation of hydrochloride

Except that (R) - (-) - 2-amino-1-propanol was used instead of 2-amino-1,3-propanediol in Example 46, To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.33 (2H, s), 7.55 (1H, t), 6.79 (2H, m), 4.57 (2H, m), 4.19 (1H, m), 4.13 ( (2H, m), 3.71 (2H, m), 3.61 (3H, m), 3.47 m), 1.55 (2H, m), 1.36 (3H, d), 1.11 (3H, d), 0.78 (3H, t).

< Example  4- (3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) Butoxy )-2- The &Lt; RTI ID = 0.0 &gt; (S) -2,3- Dihydroxypropyl ) Benzamide  Preparation of oxalate

Example 45 was prepared in the same manner as in Example 45, except that (R) -3-amino-1,2-propanediol was used instead of 2-amino-1,3-propanediol in the above Example 45 To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.21 (2H, s), 7.58 (1H, t), 6.76 (2H, m), 4.56 (2H, m), 4.20 (1H, m), 4.10 ( (2H, m), 3.82 (1H, m), 3.65 (1H, m), 3.57 (5H, m), 3.23 m), 1.46 (2H, m), 1.33 (3H, d), 0.77 (3H, t).

< Example  50> 4- (3- (4- (5- Propylpyrimidine Yl) piperazin-1-yl) Butoxy )-2- The &Lt; RTI ID = 0.0 &gt; (S) -2,3- Dihydroxypropyl ) Benzamide  Preparation of hydrochloride

The procedure of Example 46 was repeated except that (R) -3-amino-1,2-propanediol was used instead of 2-amino-1,3-propanediol in Example 46, To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.35 (2H, s), 7.58 (1H, t), 6.77 (2H, m), 4.64 (2H, m), 4.20 (1H, m), 4.10 ( 2H), 3.82 (1H, m), 3.65 (1H, m), 3.57 (5H, m), 3.23 m), 1.46 (2H, m), 1.34 (3H, d), 0.77 (3H, t).

< Example  51> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluoro -N- (1, 3- Dihydroxypropane -2 days) Benzamide  Preparation of oxalate

(600 mg) and dichloromethane (DCM, 50 mL) were charged into a 100 mL flask under a nitrogen atmosphere and dissolved by stirring to obtain 1-ethyl-3- (3-dimethylaminopropyl ) Carbodiimide hydrochloride (EDCI, 420 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 290 mg) were added and stirred for 30 minutes. Then, 2-amino-1,3-propanediol (200 mg) was added and stirred at room temperature for 5 hours. When the reaction was completed, distilled water (20 mL) was added slowly, extracted with ethyl acetate (EA, 60 mL) and washed with brine (40 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography. The purified compound was dissolved in ethyl acetate (EA, 10 mL) and stirred, followed by dropwise addition of the same equivalent amount of oxalic acid and reflux stirring for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.58 (1H, t), 6.77 (2H, m), 4.56 (2H, m), 4.18 (2H, m), 4.03 (2H, m), 3.70 ( (2H, m), 3.66 (3H, m), 3.42 (2H, m), 2.81 (1H, m), 2.29 , d).

< Example  52> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluoro -N- (1, 3- Dihydroxypropane -2 days) Benzamide  Preparation of hydrochloride

(600 mg) and dichloromethane (DCM, 50 mL) were charged into a 100 mL flask under a nitrogen atmosphere and dissolved with stirring to obtain 1-ethyl-3- (3-dimethylaminopropyl ) Carbodiimide hydrochloride (EDCI, 420 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 290 mg) were added and stirred for 30 minutes. Then, 2-amino-1,3-propanediol (200 mg) was added and stirred at room temperature for 5 hours. After the reaction was completed, distilled water (20 mL) was added slowly, extracted with ethyl acetate (EA, 60 mL), and washed with brine (40 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography. The purified compound was dissolved in ethyl acetate (EA, 10 mL) with stirring, and the same equivalent amount of hydrochloric acid was added dropwise, followed by reflux stirring for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.60 (1H, m), 6.77 (2H, m), 4.21 (2H, m), 4.08 (2H, m), 3.79 (2H, m), 3.67 ( (2H, m), 3.53 (3H, m), 3.42 (2H, m), 2.81 (1H, m), 2.27 , d).

< Example  53> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluoro -N - ((R) -1- Hydroxypropane -2 days) Benzamide  Oxalate of  Produce

The procedure of Example 51 was repeated except that (R) - (-) - 2-amino-1-propanol was used instead of 2-amino-1,3-propanediol in Example 51 To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.55 (1H, m), 6.77 (2H, m), 4.21 (2H, m), 4.06 (2H, m), 3.72 (2H, m), 3.59 ( (1H, m), 3.43 (2H, m), 2.83 (1H, m), 2.31 (1H, m), 2.04

< Example  54> 4- (3- (4- (3-iso profile -1,2,4-oxadiazole-5- Work ) Piperazin-1-yl) Butoxy )-2- Fluoro -N - ((R) -1- Hydroxypropane -2 days) Benzamide  Hydrochloride of  Produce

The procedure of Example 52 was repeated except that (R) - (-) - 2-amino-1-propanol was used instead of 2-amino-1,3-propanediol in the above Example 52 To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.55 (1H, m), 6.77 (2H, m), 4.20 (2H, m), 4.06 (2H, m), 3.71 (2H, m), 3.50 ( (1H, m), 3.32 (2H, m), 2.81 (1H, m), 2.31 (1H, m), 2.04 (1H, m), 1.34

< Example  55> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluoro -N - ((R) -2,3- Dihydroxypropyl ) Benzamide  Preparation of oxalate

The procedure of Example 51 was repeated except that (R) -3-amino-1,2-propanediol was used instead of 2-amino-1,3-propanediol in the above Example 51 To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.58 (1H, t), 6.76 (2H, m), 4.21 (2H, m), 4.09 (2H, m), 3.82 (1H, m), 3.70 ( (2H, m), 3.52 (5H, m), 3.43 (2H, m), 2.81 (1H, m), 2.10 , m).

< Example  56> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluoro -N - ((R) -2,3- Dihydroxypropyl ) Benzamide  Hydrochloride of  Produce

The title compound was prepared in the same manner as in Example 52, except that (R) -3-amino-1,2-propanediol was used instead of 2-amino-1,3-propanediol in the above Example 52 To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.57 (1H, m), 6.76 (2H, m), 4.35 (1H, m), 4.20 (2H, m), 4.06 (2H, m), 3.82 ( (1H, m), 3.72 (2H, m), 3.59 (3H, m), 2.83 (1H, m), 2.31 , m).

< Example  57> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluoro -N - ((R) -2,3- Dihydroxypropyl ) Benzamide  Hydrochloride of  Produce

The procedure of Example 51 was repeated except for using pyrrolidine instead of 2-amino-1,3-propanediol in Example 51 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.29 (1H, m), 6.80 (2H, m), 4.22 (2H, m), 4.10 (2H, m), 3.73 (2H, m), 3.49 ( M), 1.81 (2H, m), 1.37 (2H, m), 3.28 , &lt; / RTI &gt; d), 1.16 (6H, m).

< Example  (4- (3- (4- (3-isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluorophenyl ) ( Pyrrolidine -1 day) Methanone  Preparation of hydrochloride

The target compound was obtained in the same manner as in Example 52, except that pyrrolidine was used instead of 2-amino-1,3-propanediol in Example 52.

^{1 H NMR (400 Hz, D} 2 O): δ 7.29 (1H, m), 6.80 (2H, m), 4.23 (2H, m), 4.11 (2H, m), 3.72 (1H, m), 3.48 ( (2H, m), 2.28 (2H, m), 2.82 (1H, m), 2.33 (1H, m), 2.06 , &lt; / RTI &gt; d), 1.11 (6H, m).

< Example  59> Ethyl 4- (3- (4- (3-isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy ) -3- Fluorobenzoate  Preparation of oxalate

The target compound was obtained in the same manner as in Example 6 except that the compound prepared in Preparation Example 20 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6.

^{1 H NMR (400 Hz, D} 2 O): δ 7.74 (1H, d), 7.69 (1H, dd), 7.11 (1H, t), 4.36 (2H, m), 4.31 (2H, m), 4.20 ( 2H, m), 3.76 (1 H, m). (2H, m), 2.38 (2H, m), 3.58 (4H, m), 3.34 (6H, d), 1.08 (3H, t).

< Example  60> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy ) -3- Fluorobenzoate Lithium salt  Produce

The compound (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) prepared in Example 59 were introduced into a 100 mL flask under a nitrogen atmosphere and dissolved by stirring. Then, lithium hydroxide monohydrate (170 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. When the reaction was complete, the solvent was concentrated and then dissolved in dichloromethane (DCM, 50 mL) and the undissolved solid was filtered. The filtrate was concentrated, and solidified using diethyl ether and hexane to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.51 (1H, t), 6.77 (2H, m), 3.99 (2H, m), 3.52 (4H, t), 2.76 (2H, m), 2.60 ( 4H, q), 2.07 (1H, m), 1.79 (3H, s), 1.53 (1H, m), 1.11 (6H, d), 1.01 (3H, d).

< Example  61> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy ) -N - ((R) -1- Hydroxypropane -2 days) Benzamide  Preparation of oxalate

(600 mg) and dichloromethane (DCM, 50 mL) were poured into a 100 mL flask under a nitrogen atmosphere and dissolved with stirring to obtain 1-ethyl-3- (3-dimethylaminopropyl ) Carbodiimide hydrochloride (EDCI, 420 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 290 mg) were added and stirred for 30 minutes. Then, (R) - (-) - 2-amino-1-propanol (200 mg) was added thereto and stirred at room temperature for 5 hours. When the reaction was completed, distilled water (20 mL) was added slowly, extracted with ethyl acetate (EA, 60 mL) and washed with brine (40 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography. The purified compound was dissolved in ethyl acetate (EA, 10 mL) and stirred, followed by dropwise addition of the same equivalent amount of oxalic acid and reflux stirring for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 7.54 (2H, m), 7.70 (1H, t), 6.20 (1H, d), 4.28 (2H, m), 4.14 (1H, m), 3.79 (1H m), 3.59 (5H, m), 3.79 (2H, m), 3.67 (1H, m), 3.58 m), 2.63 (1H, s), 2.52 (2H, m), 2.04 (1H, m), 1.85 (1H, m), 1.30 (9H,

< Example  62> 4- (3- (4- (3-iso profile -1,2,4-oxadiazole-5- Work ) Piperazin-1-yl) Butoxy ) -N - ((R) -1- Hydroxypropane -2 days) Benzamide  Preparation of hydrochloride

(600 mg) and dichloromethane (DCM, 50 mL) were poured into a 100 mL flask under a nitrogen atmosphere and dissolved with stirring to obtain 1-ethyl-3- (3-dimethylaminopropyl ) Carbodiimide hydrochloride (EDCI, 420 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 290 mg) were added and stirred for 30 minutes. Then, (R) - (-) - 2-amino-1-propanol (200 mg) was added thereto and stirred at room temperature for 5 hours. When the reaction was completed, distilled water (20 mL) was added slowly, extracted with ethyl acetate (EA, 60 mL) and washed with brine (40 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography. The purified compound was dissolved in ethyl acetate (EA, 10 mL) with stirring, and the same equivalent amount of hydrochloric acid was added dropwise, followed by reflux stirring for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.46 (2H, m), 7.09 (1H, t), 4.28 (2H, m), 4.16 (1H, m), 3.72 (1H, m), 3.54 ( 5H, m), 2.83 (1H, m), 2.29 (1H, m), 2.11 (1H, m), 1.34 (3H, d), 1.10 (9H, m).

< Example  63> 4- (3- (4- (3-iso profile -1,2,4-oxadiazole-5- Work ) Piperazin-l- Work ) Butoxy ) -3-fluoro-N - ((S) -2,3-dihydroxypropyl) benzamide oxalate

Example 61 was prepared in the same manner as in Example 61, except that (R) -3-amino-1,2-propanediol was used instead of (R) - (-) - 2- To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.49 (2H, m), 7.10 (1H, t), 4.29 (2H, m), 4.20 (2H, m), 3.83 (2H, m), 3.80 ( 1H, m), 3.70 (5H, m), 2.83 (1H, m), 2.31 (1H, m), 2.10 (1H, m), 1.33 (3H, d), 1.13 (6H, d).

< Example  64> 4- (3- (4- (3-iso profile -1,2,4-oxadiazole-5- Work ) Piperazin-1-yl) Butoxy ) -3- Fluoro -N - ((S) -2, 3- Dihydroxypropyl ) Benzamide  Preparation of trifluoroacetic acid salt

Example 62 was prepared in the same manner as in Example 62, except that (R) -3-amino-1,2-propanediol was used instead of (R) - (-) - 2- To give the title compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.50 (2H, m), 7.07 (1H, t), 4.29 (2H, m), 4.21 (2H, m), 3.83 (2H, m), 3.80 ( 1H, m), 3.65 (5H, m), 2.83 (1H, m), 2.31 (1H, m), 2.10 (1H, m), 1.35 (3H, d), 1.13 (6H, d).

< Example  65> 4- (3- (4- (3-iso profile -1,2,4-oxadiazole-5- Work ) Piperazin-1-yl) Butoxy ) -N, N- Diethyl -3- Methylbenzamide  Preparation of oxalate

The target compound was obtained in the same manner as in Example 6 except that the compound prepared in Preparation Example 21 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6.

^{1 H NMR (400 Hz, D} 2 O): δ 7.13 (2H, d), 6.91 (1H, d), 4.19 (2H, m), 4.08 (2H, m), 3.69 (2H, m), 3.43 ( (1H, m), 3.20 (2H, q), 2.82 (1H, m), 2.33 , t).

< Example  66> 4- (3- (4- (3-iso profile -1,2,4-oxadiazole-5- Work ) Piperazin-1-yl) Butoxy ) -N, N- Diethyl -3- Methylbenzamide  Preparation of hydrochloride

The target compound was obtained in the same manner as in Example 6 except that the compound prepared in Preparation Example 21 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6.

^{1 H NMR (400 Hz, D} 2 O): δ 7.13 (2H, d), 6.91 (1H, d), 4.19 (2H, m), 4.08 (2H, m), 3.69 (2H, m), 3.43 ( (1H, m), 3.20 (2H, q), 2.82 (1H, m), 2.33 , t).

< Example  (4- (3- (4- (3-isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy ) -3- Fluorophenyl ) ( Pyrrolidine -1 day) Methanone  Preparation of oxalate

The target compound was obtained in the same manner as in Example 61, except that pyrroline was used instead of (R) - (-) - 2-amino-1-propanol in Example 61.

^{1 H NMR (400 Hz, D} 2 O): δ 7.13 (2H, d), 6.91 (1H, d), 4.19 (2H, m), 4.08 (2H, m), 3.69 (2H, m), 3.43 ( (1H, m), 3.20 (2H, q), 2.82 (1H, m), 2.33 , t).

< Example  (4- (3- (4- (3-isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy ) -3- Fluorophenyl ) ( Pyrrolidine -1 day) Methanone  Preparation of hydrochloride

The target compound was obtained in the same manner as in Example 62, except that pyrroline was used instead of (R) - (-) - 2-amino-1-propanol in Example 62.

^{1 H NMR (400 Hz, D} 2 O): δ 7.22 (2H, t), 7.09 (1H, t), 4.30 (2H, m), 4.16 (2H, m), 3.70 (2H, m), 3.53 ( (2H, m), 1.75 (2H, m), 1.75 (2H, m), 3.42 (4H, t), 3.35 , &lt; / RTI &gt; m), 1.35 (3H, d), 1.12 (6H, d).

< Example  69> 4- (3- (4- (3-iso profile -1,2,4-oxadiazole-5- Work ) Piperazin-l- Work ) Butoxy ) -3-fluoro-N- (1,3-dihydroxypropan-2-yl) benzamide oxalate

Amino-1,3-propanediol was used in place of (R) - (-) - 2-amino-1-propanol in Example 61, To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.50 (2H, m), 7.10 (1H, t), 4.30 (1H, m), 4.20 (2H, m), 4.10 (2H, m), 3.74 ( 3H, m), 3.62 (2H, t), 3.43 (2H, t), 2.82 (1H, m), 2.30 , d).

< Example  70> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy ) -3- Fluoro -N- (1, 3- Dihydroxypropane -2 days) Benzamide  Hydrochloride of  Produce

The procedure of Example 62 was repeated except that 2-amino-1,3-propanediol was used instead of (R) - (-) - 2-amino- To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.51 (2H, m), 7.10 (1H, t), 4.30 (1H, m), 4.22 (2H, m), 4.09 (2H, m), 3.74 ( 3H, m), 3.62 (2H, t), 3.43 (2H, t), 2.82 (1H, m), 2.30 , d).

< Example  71> 4- (3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluoro -N - ((R) -2,3- Dihydroxypropyl ) Benzamide  Preparation of oxalate

Example 61 (a) was prepared in the same manner as in Example 61, except that (S) -3-amino-1,2-propanediol was used instead of (R) - To give the desired compound.

_{^{1 H NMR (400, D 2}} O): δ 7.59 (1H, t), 6.77 (2H, t), 4.20 (2H, m), 4.10 (2H, m), 3.83 (1H, m), 3.70 (2H (1H, m), 3.58 (2H, m), 3.46 (4H, m), 3.30 (4H, m), 2.81 d), 1.12 (6H, d).

< Example  72> 1- (4- (5- methyl -6- ( Methylsulfonyl ) Pyridine-3- Sake ) Butan-2-yl) -4- (3-isopropyl-l, 2,4- Oxadiazole Yl) piperazine oxalate &lt; / RTI &gt;

The procedure of Example 6 was repeated except that the compound prepared in Preparation Example 10 was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6 to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 8.07 (1H, s), 7.34 (1H, s), 4.28 (2H, m), 4.16 (2H, m), 3.71 (1H, m), 3.45 ( 3H, d), 1.12 (2H, m), 3.21 (3H, s), 2.81 (1H, m), 2.53 , d).

< Example  Ethyl 4 - ((R) -3- (4- (3-isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluorobenzoate  Preparation of oxalate

Step 1: (R) -4- (t- Butyl dimethylsilyloxy ) Butan-2-ol

(R) - (-) - 1,3-butanediol (5 g), imidazole (7.5 g) and dichloromethane (DCM, 200 mL) were added to a 500 mL flask under nitrogen atmosphere and dissolved by stirring Followed by dropwise addition of t-butyl dimethylsilyl chloride (9.16 g). Upon completion of the dropwise addition, the reaction mixture was stirred for 24 hours, extracted with dichloromethane (DCM, 100 mL), and washed with brine (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to obtain the desired compound.

¹ H NMR (400 Hz, CDCl ₃ ):? 4.04 (m, IH), 3.91 (m, IH), 3.83 (m, IH), 3.41 , 3H), 0.90 (s, 9H), 0.10 (s, 6H).

Step 2: (R) -4- (t- Butyl dimethylsilyloxy ) Butane-2- Yl methanesulfonate  Produce

(2 g) and dichloromethane (DCM, 100 mL) were poured into a 100 mL flask under nitrogen atmosphere and stirred and dissolved. Triethylamine (TEA, 1.2 mL) was added dropwise and methane Sulfonyl chloride (0.6 mL) was slowly added dropwise at 0 &lt; 0 &gt; C. The addition was complete and stirred for 30 min, extracted with dichloromethane (DCM, 40 mL) and washed with brine (100 mL). The washed reaction product was dried with anhydrous magnesium sulfate and concentrated to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 4.97 (m, 1H), 3.72 (m, 2H), 3.03 (s, 3H), 1.91 (m, 1H), 1.80 (m, 1H), 1.49 (d , 3H), 0.91 (s, 9H), 0.08 (s, 6H).

Step 3: (S) -3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) butan-1-ol &lt; / RTI &

The compound (1.4 g) prepared in the above Step 2 and dimethylformamide (DMF, 40 mL) were poured into a 100 mL flask under a nitrogen atmosphere and stirred to dissolve the compound. The compound prepared in Preparation 25 g) and potassium carbonate (1 g) were added and the mixture was stirred at 50 캜 for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, distilled water (30 mL) was slowly added thereto, and the mixture was extracted with ethyl acetate (EA, 100 mL). The extracted organic layer was washed three times with distilled water (20 mL), dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica column chromatography to obtain the desired compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 3.70 (m, 2H), 3.61 (m, 4H), 2.87 (m, 2H), 2.65 (m, 2H), 2.53 (m, 2H), 1.77 (m (D, 3H), 1.98 (s, 9H), 0.07 (s, 6H).

Step 4: (S) -3- (4- (3-Isopropyl-l, 2,4- Oxadiazole Yl) piperazin-1-yl) butyl Methanesulfonate  Produce

Compound (2 g) and dichloromethane (DCM, 100 mL) prepared in Step 3 above were poured into a 100 ml flask under a nitrogen atmosphere and dissolved by stirring. Triethylamine (TEA, 1.2 mL) is then added dropwise and methanesulfonyl chloride (0.6 mL) is slowly added dropwise at 0 &lt; 0 &gt; C. When the addition was complete, it was stirred for 30 minutes, extracted with dichloromethane (DCM, 40 ml) and washed with brine (100 mL). The washed reaction product was dried with anhydrous magnesium sulfate and concentrated to obtain the target compound.

^{1 H NMR (400 Hz, CDCl} 3): δ 5.05 (m, 1H), 4.81 (m, 1H), 4.55 (m, 1H), 4.24 (m, 3H), 3.96 (m, 2H), 3.71 (m 2H), 3.44 (m, IH), 3.24 (m, IH), 2.90 (m, IH) 6H).

Step 5: Preparation of ethyl 4 - ((R) -3- (4- (3-isopropyl- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluorobenzoate  Oxalate of  Produce

(600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) were added to a 100 mL flask under nitrogen atmosphere and dissolved by stirring. The compound (350 mg) was added and the mixture was stirred at a temperature of 70 캜. After the stirring was completed, the reaction mixture was cooled to room temperature, distilled water (20 ml) was slowly added thereto, and the mixture was extracted with ethyl acetate (EA, 60 ml). The extracted organic layer was washed with brine (40 mL), dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography. Ethyl acetate (EA, 10 mL) was then added and dissolved by stirring. Oxalic acid was added in the same volume of water and refluxed for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.84 (1H, t), 6.78 (2H, t), 4.26 (2H, q), 4.22 (2H, m), 4.11 (2H, m), 3.70 ( (1H, m), 3.48 (4H, m), 3.30 (2H, m), 2.84 (1H, m), 2.31 , t), 1.16 (6H, d).

< Example  74> 4 - ((R) -3- (4- (3-Isopropyl-1,2,4- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluorobenzoate Lithium salt  Produce

The compound (200 mg) prepared in Example 73, tetrahydrofuran (40 mL) and distilled water (20 mL) were poured into a 100 mL flask under a nitrogen atmosphere and dissolved by stirring. Then, lithium hydroxide monohydrate (170 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. When the reaction was complete, the solvent was concentrated and then dissolved in dichloromethane (DCM, 50 mL) and the undissolved solid was filtered. The filtrate was concentrated, and solidified using diethyl ether and hexane to obtain the target compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.50 (1H, t), 6.68 (2H, m), 4.03 (2H, m), 3.50 (4H, t), 2.76 (2H, m), 2.60 ( 4H, q), 2.03 (1H, m), 1.79 (3H, s), 1.63 (1H, m), 1.11 (6H, d), 1.01 (3H, d).

< Example  75> 4 - ((R) -3- (4- (3-Isopropyl- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluoro -N - ((R) -2,3- Dihydroxypropyl ) Benzamide  Preparation of oxalate

(600 mg) and dichloromethane (DCM, 50 mL) were poured into a 100 mL flask under a nitrogen atmosphere and dissolved with stirring to obtain 1-ethyl-3- (3-dimethylaminopropyl ) Carbodiimide hydrochloride (EDCI, 420 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 290 mg) were added and stirred for 30 minutes. Then, (R) -3-amino-1,2-propanol (200 mg) was added and stirred at room temperature for 5 hours. When the reaction was completed, distilled water (20 mL) was added slowly, extracted with ethyl acetate (EA, 60 mL) and washed with brine (40 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography. The purified compound was dissolved in ethyl acetate (EA, 10 mL) and stirred, followed by dropwise addition of the same equivalent amount of oxalic acid and reflux stirring for 30 minutes. When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.60 (1H, t), 6.87 (2H, t), 4.21 (2H, m), 4.11 (2H, m), 3.85 (1H, m), 3.70 ( (2H, m), 3.51 (8H, m), 3.33 (2H, m), 2.82 (1H, m), 2.32 , d).

< Example  76> ethyl 4 - ((S) -3- (4- (3-iso profile -1,2,4-oxadiazole-5- Work ) Piperazin-1-yl) Butoxy )-2- Fluorobenzoate  Produce

The procedure of Example 73 was repeated except that (S) - (+) - 1,3-butanediol was used instead of (R) - (-) - To give the desired compound.

^{1 H NMR (400 Hz, D} 2 O): δ 7.90 (1H, t), 6.67 (2H, dd), 4.37 (2H, q), 4.17 (2H, m), 4.09 (1H, m), 3.63 ( (2H, m), 2.90 (2H, m), 2.50 (2H, m), 1.99 , &lt; / RTI &gt; m), 1.28 (6H, d), 1.08 (3H, d).

< Example  77> 4 - ((S) -3- (4- (3-Isopropyl- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluorobenzoate Lithium salt  Produce

The target compound was obtained in the same manner as in Example 74, except that the compound prepared in Example 72 was used instead of the compound prepared in Example 73 in Example 74.

^{1 H NMR (400 Hz, D} 2 O): δ 7.50 (1H, t), 6.68 (2H, m), 4.03 (2H, m), 3.50 (4H, t), 2.76 (2H, m), 2.60 ( 4H, q), 2.03 (1H, m), 1.79 (3H, s), 1.63 (1H, m), 1.11 (6H, d), 1.01 (3H, d).

< Example  78> 4 - ((S) -3- (4- (3-Isopropyl- Oxadiazole Yl) piperazin-1-yl) Butoxy )-2- Fluoro -N - ((R) -2,3- Dihydroxypropyl ) Benzamide  Preparation of oxalate

The target compound was obtained in the same manner as in Example 75, except that the compound prepared in Example 77 was used instead of the compound prepared in Example 74 in Example 75.

^{1 H NMR (400 Hz, D} 2 O): δ 8.05 (1H, s), 7.08 (1H, m), 6.68 (2H, dd), 4.17 (2H, m), 4.10 (1H, m), 3.61 ( (2H, m), 2.50 (2H, m), 2.00 (1H, m), 1.81 , &lt; / RTI &gt; m), 1.29 (6H, d), 1.05 (3H, d).

< Experimental Example  1 > The compounds of the present invention cAMP  Activity evaluation

The following experiments were conducted to confirm cAMP activation of the novel piperazine derivatives according to the present invention.

First, HIT-T15 cells (Korean Cell Line Bank), a beta cell derived from a hamster containing GPR-119, was used to measure intracellular cAMP activation due to stimulation of GPR119. 60,000 HIT-T15 cells per well were plated in 96-well plates. The day after plating, the cells were treated with various concentrations of the compounds according to the invention and incubated for 1 hour at 37 ° C. At this time, the compound to be treated was treated with 6 concentrations in the range of 0.0032 to 10 μM. cAMP activity was measured using a cAMP dynamic kit from Cis Bio (Bedford, Mass.) according to the manufacturer's instructions. Cells were lysed and cAMP levels were measured by competitive immunoassay using D2-labeled cAMP and cryptate-labeled anti-cAMP antibodies. Fluorescence was read by a Flex Station (Molecular Devices). D2 and cryptate exhibited fluorescence resonance energy transfer (FRET) at very close proximity and were measured at a fluorescence ratio of 665 nm / 620 nm. Unlabeled cAMP in cell lysates compete with d2-labeled cAMP for cryptate-labeled antibodies. Since measured fluorescence resonance energy transfer (FRET) signal reduction is indicative of intracellular cAMP level, the activity of the compound was calculated as the degree of change in fluorescence resonance energy transfer (FRET) signal through the regulation of dimethyl sulfoxide (DMSO). The calculated EC ₅₀ value Table 2 shows the results.

Example EC ₅₀ Example EC ₅₀ Example EC ₅₀ Example EC ₅₀ One A 2 C 3 C 4 A 5 B 6 A 7 C 8 A 9 C 10 B 11 B 12 A 13 B 14 C 15 A 16 D 17 A 18 A 19 C 20 A 21 C 22 A 23 A 24 A 25 B 26 B 27 A 28 A 29 C 30 C 31 A 32 C 33 A 34 A 35 A 36 B 37 C 38 C 39 C 40 C 41 A 42 D 43 B 44 D 45 C 46 C 47 B 48 C 49 C 50 A 51 C 52 B 53 A 54 A 55 A 56 C 57 A 58 A 59 NT 60 NT 61 C 62 C 63 D 64 D 65 C 66 C 67 B 68 B 69 D 70 B 71 C 72 C 73 A 74 NT 75 A 76 C 77 NT 78 A A <1uM, 1uM <B <2uM, 2uM <C <5uM, D> 5uM
NT: Not Tested

As shown in Table 2, the compounds according to the present invention were found to activate cAMP. About 55% of the 74 compounds evaluated for cAMP activation were found to have an EC ₅₀ value of less than 2 μM, and in particular, Examples 1, 4, 6, 8, 12, 15, 17, 18, 20, 22-24, 27, 28, 31, 33-35, 41, 50, 53-55, 57, 58, 73 and 75 compounds are shown to have nanomolar unit EC ₅₀ value of less than or equal to 1 μM . From this, it can be seen that the piperazine derivative according to the present invention is excellent in the effect of activating cAMP by stimulating the GPR119 receptor.

Therefore, the novel piperazine derivatives according to the present invention are excellent in the effect of activating cAMP, and thus can be used for treating obesity, type I diabetes, type II diabetes, inappropriate insulin resistance, insulin resistance, hyperglycemia, hyperlipidemia, Hyperlipidemia, hypercholesterolemia, dyslipidemia, or syndrome X, which is useful as a pharmaceutical composition.

< Experimental Example  2> GPR119  Receptor overexpressed CHO - K1  In the cell cAMP  Activity evaluation

In order to confirm that the novel piperazine derivative according to the present invention activates GPR119 to promote cAMP, the following experiment was conducted.

10% of 100 μl CHO cells in 96-well plates FBS, 100 ug / ml penicillin (penicillin), and 2x10 ⁴ to RPMI (Wellgene) medium that contains the 100 ug / ml streptomycin (streptomycin); cells / well play . Then, a plasmid (Origene, RC216685) expressing human GPR119 and a plasmid (Genene, MR224908) expressing GPR119 in mouse were transfected into the CHO cell using FuGENE6 reagent (Promega, E2311) in the pCMV6-XL5 vector Lt; / RTI &gt; Forty-eight hours after transfection, cells were resuspended in HBSS (Hanks buffered salt solution, welgene, LB (Sigma, A7030) containing 5 mM HEPES (Gibco, 15630-106), 0.5 mM IBMX (Sigma, I5879) and 0.1% BSA 003-03) and cultured in a CO ₂ incubator for 10 minutes. Compounds according to the present invention were diluted to various concentrations (10, 2, 0.4, 0.08, 0.16, 0.0032 uM) in HBSS medium, treated with cells and cultured in a CO ₂ incubator at 37 ° C for 90 minutes. cAMP measurement was performed using the two step protocol of HTRF (Homogeneous Time-Resolved Fluorescence, CISBIO, 62AM4PEB) technique. The cells were mixed with cAMP-d2 and anti-cAMP cryptate conjugate and reacted at room temperature for 3 hours. Then, fluorescence (excitation wavelength: 337 nm, emissive) was measured using a flex station (Molecular Devices) Wavelength: 665 nm, 620 nm). The results were converted to EC ₅₀ (uM) values using the degree of activation (%) by treating the compound according to the present invention as a control group by calculating the value of δ F (%), Respectively.

Example Target cell EC ₅₀ (uM) Example 55 hGPR119 0.95 Example 75 hGPR119 0.7 Example 78 hGPR119 2.3 Example 55 mGPR119 1.5 Example 75 mGPR119 0.98 Example 78 mGPR119 3.2

As shown in Table 3, the piperazine derivatives according to the present invention were found to have an effect of activating cAMP in both human and mouse GPR119 overexpressed cell lines. In addition, the compound of Example 75 (R-form), which is the structural isomer of Example 55, was found to have an EC ₅₀ value in nanomole units, while the compound of Example 78 (S-form) Of EC ₅₀ values. From these results, it can be seen that the piperazine derivative according to the present invention has an excellent effect of promoting GPR119 in human and mouse, and the cAMP promoting effect is also excellent. In addition, S through the EC ₅₀ values of the compounds of the racemate (racemate) of Example 55, which are exemplary of the compounds and their structural isomers Example 75 (R- form) made according to the present invention and Example 78 (S- form) -Form isomer is more effective in activating cAMP than the structural isomer in the R-form.

Therefore, the novel piperazine derivatives according to the present invention are excellent in the effect of activating cAMP by promoting GPR119, and thus can be used for treating obesity, type I diabetes, type II diabetes, inadequate insulin resistance, insulin resistance, hyperglycemia, Hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, or syndromes of the X syndrome.

< Experimental Example  3> Oral sugar load test ( Oral Glucose Tolerance Test ; OGTT )

The following experiments were conducted to evaluate the in vivo efficacy of the novel piperazine derivatives according to the present invention.

First, oral C57BL / 6J mice were used for 8 to 10 weeks of age. After a period of at least 7 days of refinement, oral glucose tolerance test was performed using only healthy individuals. After fasting for 12-15 hours, 5 rats per group were randomly divided into groups, and the compounds prepared in Examples 33, 50, 55, 70 and 77 according to the present invention were administered respectively at a dose of 20 mg / kg. At this time, the excipient (0.5%, CarboxyMethyl Cellulase, CMC) was administered as a non-treated group, and the excipient and the compound administered in the above were orally administered at 10 ml / kg. As a positive control, Comparative Example 1 (B111, International Publication No. 2004065380), Comparative Example 2 (Compound of Example 52, International Publication No. 2008083238) and Comparative Example 3 (Example 3, International Publication No. 2008081206). Then, 30 minutes after administration, glucose (2 g / kg) was orally administered at a dose of 10 ml / kg. Blood glucose was measured using a Roche Diagnostic Co., and the measurement time was measured by puncturing the vein at -30, 0, 20, 40, 60 and 120 minutes based on the time of administration of glucose. The results are shown in Table 4 below.

Example % AUC Example 33 19.7 Example 50 22.8 Example 55 18.6 Example 70 17.4 Example 75 16.2

비교예 1

Comparative Example 1 16.5

Comparative Example 2 14.7

Comparative Example 3 13.6

As shown in Table 4, the compounds according to the present invention have an area under curve (AUC) lowering effect of about 16 to 23%. On the other hand, the compounds of Comparative Examples 1 to 3 conventionally known as activators of GPR119 showed an area under curve (AUC) strengthening effect of 16% or less as compared with the compounds of the present invention. From these results, it can be seen that the piperazine derivatives according to the present invention have a significantly lower area under curve (AUC) lowering effect than the compounds known as activators of conventional GPR119.

Therefore, the novel piperazine derivatives according to the present invention are excellent in the effect of activating cAMP by promoting GPR119, and thus can be used for treating obesity, type I diabetes, type II diabetes, inadequate insulin resistance, insulin resistance, hyperglycemia, Hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, or syndromes of the X syndrome.

< Experimental Example  4> Evaluation of solubility

In order to evaluate the degree of absorption of the piperazine derivatives according to the present invention, the following experiment was conducted to measure the solubility.

The piperazine derivative salt of Example 75 according to the present invention, the piperazine derivative of Example 75, the compound of Comparative Example 1 (B111, International Publication No. 2004065380) and the compound of Comparative Example 2 (the compound of Example 52, International Open Publication No. 2008083238) was dissolved in distilled water at a concentration of 2 mg / mL, transferred to a vial, decomposed for about 1 hour, and shaken at 300 rpm for about 24 hours. Thereafter, the solution is centrifuged at 2500C for 10 minutes at 10000 rpm, and the supernatant is filtered and transferred to a vial to prepare a test solution. The test solution was prepared at a concentration of 2.5 mM, diluted with methyl alcohol at a ratio of 1/10, and then diluted 1/2 times in order to prepare calibration solutions having different concentrations at five concentrations. The solubility was measured using high performance liquid chromatography (HPLC, wavelength: 210 nM, flow rate: 10 ml / min, mobile phase: distilled water / methyl alcohol = 30/70 → 40/60) as the calibration solution. Table 5 shows the results.

compound Solubility (uM) Example 75 > 25000 Example 75 (Free form) 5267 Comparative Example 1 0.48 Comparative Example 2 1.78

As shown in Table 5, the solubility of the piperazine derivative prepared in Example 75 according to the present invention was found to be 5267 uM, and the solubility of the pharmaceutically acceptable salt thereof in water was 25000 uM or more. On the other hand, in Comparative Example 1 and Comparative Example 2 which are conventionally known as GPR119 activators, the solubility in water was remarkably low. From the results, it can be seen that the piperazine derivatives according to the present invention have a solubility in water of at least 3,000 times or more as compared with the compounds known as GPR119 activators.

Accordingly, the novel piperazine derivatives according to the present invention have an excellent effect of promoting cAMP by activating GPR119, and are remarkably excellent in solubility in water as compared with the compounds known as GPR119 activators in the past, The present invention provides a method of treating obesity, type I diabetes, type II diabetes, inappropriate insulin resistance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X And can be usefully used as a pharmaceutical composition for prevention or treatment.

< Experimental Example  5> Cardiac toxicity  evaluation

In order to evaluate the cardiac toxicity of the novel piperazine derivatives according to the present invention, experiments were conducted as follows to confirm whether compounds inhibit the HERG channel, which is an important index of cardiac toxicity and arrhythmia.

Cell culture

First, HEK293 (human embryonic kidney 293) cells, in which expression of the HERG channel stably maintained, were used, and astemizole, a positive control substance, was used to confirm the inhibition of HERG channel.

Cells were cultured in a 37 ° C incubator containing 95% oxygen and 5% carbon dioxide, supplemented with 10% fetal bovine serum, 1 mM sodium pyruvate, 0.1 mM non-essential amino acid solution, 100 units / ml penicillin-streptomycin and cultured in a minimum essential medium (MEM) consisting of penicillin-streptomycin, 100 μg / ml streptomycin sulfate and 100 μg / ml zeocin. After 60-80% adherence, adherent cells were treated with medium containing 0.25% trypsin and 0.02% EDTA for 3 minutes, washed with fresh medium and dispensed into new plastic culture vessels. During electrophysiological recording, the cells were allowed to attach on a 5 mm diameter glass cover slide in a 24-well plate for 5-24 hours and then transferred to a recording chamber.

Whole cell patch clamp  (Whole-cell patch clamp) method

The total cell current can be measured using the convential patch-clamp technique or the Port-a-Patch (Nanion germany) semi-passive technique, which measures the microcurrent through the cell membrane. The composition of the extracellular perfusion solution and intracellular perfusion solution used in the above experiment is as follows. The extracellular perfusion solution was prepared with 136 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM glucose and 10 mM HEPES, and then with sodium hydroxide And titrated with an acidity of 7.4. Intracellular perfusion The pipette solution was composed of 130 mM potassium chloride (KCl), 1 mM magnesium chloride (MgCl ₂ ), 10 mM EGTA, 5 mM magnesium-ATP and 10 mM HEPES and then titrated with potassium hydroxide to an acidity of 7.2.

The patch pipette for the conventional patch-clamp technique was pulled with a PP-83 pipette puller (Narishige, Tokyo, Japan) and showed resistance of 2-4 MΩ in the external perfusion solution. The resulting ion current was recorded with EPC7 plus amplifiers (HEKA electronic, Germany). The pClamp computer program (Axon Instruments, USA) was used for voltage-clamp amplification control, data acquisition and analysis, and the solution was continuously perfused through the chamber into HEK 293 cells. Port-a-Patch (Nanion, Germany) The recording of the semi-automatic patch recording system follows the procedure recommended by Nanion and the amplifier is EPC10 (HEKA electronic, Germany).

Pulse protocols  (Pulse method)

The membrane potential -80 mV. It moved back to +20 mV for 4 seconds and returned to -80 mV after moving to -50 mV for 6 seconds. This process was repeated at 25 second intervals.

IC ₅₀  Evaluation analysis (50% The degree of inhibition  How to measure)

In order to obtain the concentration-response curve of the drug, the Hill equation was used for concentration-dependent inhibition.

I _drug : Peak tail current of the _drug

I _control : maximum tail current without drug

D: drug concentration

H: Heel coefficient

IC ₅₀ : degree of inhibition at the midpoint of maximum peak tail

 The results calculated by the Hill equation are shown in Table 6. &lt; tb &gt; &lt; TABLE &gt;

Example IC ₅₀ (uM) Example 55 124.11 Example 75 38.08 Comparative Example 2 5.5 Comparative Example 3 16.78

As shown in Table 6, the compounds of Example 55 and Example 75 according to the present invention exhibited an IC ₅₀ value of about 38 to 124 uM, whereas the compounds of Comparative Example 2 and Comparative Example 3 conventionally exhibited an IC ₅₀ value of about 17 uM Respectively. Compared with the compounds according to the present invention, compounds of the comparative examples known as GPR119 activators have a large effect of inhibiting the HERG channel, which is an important index of cardiac toxicity such as arrhythmia, It is found that cardiac toxicity such as arrhythmia is 2-20 times higher than GPR119 activator known.

Therefore, the novel piperazine derivatives according to the present invention have an excellent effect of promoting cAMP by activating GPR119, as well as being significantly less toxic to the heart than compounds known as GPR119 activators in the past, For the prophylaxis or treatment of obesity, type I diabetes, type II diabetes, inadequate endurance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X, And can be usefully used as a composition.

< Experimental Example  6> Mouse ( ICR ) Acute Toxicity Experiment

The following experiments were conducted to evaluate the cytotoxicity of the novel piperazine derivatives according to the present invention.

Five female ICR mice 7 weeks old were supplied to Nara Biotech and housed in a kennel and adapted to the environment with general solid feed and water. At the age of 8 weeks, the experiment was started. The ambient temperature is 23 ± 3 ℃, the humidity is 55 ± 15%, the illumination is 150-300 Lux, the ventilation frequency is 10-20 times / hour, the lighting time is 12 hours (light period: 8 o'clock off). Feeds were fed free from the Oriental Biotech (5L79 Lab Diet, Purina Mills, Richmond, IN, USA), which was sterilized by irradiation, and the water was fed to a UV sterilizer and microfilter And then freely consumed with a water bottle. Inspection of contaminants of water and feed was carried out according to the related SOP of KEMON. The compound of Example 55 was diluted in an excipient (0.5% CMC) at a concentration of 2000 mg / kg, and the test substance was intraperitoneally injected once a day in a mouse for 5 mice in a zonde, Two times a day, general condition of the animals, poisoning symptoms and the presence or absence of death were observed.

The results showed that the LD ₅₀ value of the tested ICR mouse females was over 2 g / kg. From this, it can be seen that the piperazine derivative according to the present invention has considerably low cytotoxicity.

Accordingly, the novel piperazine derivatives according to the present invention are excellent in the effect of activating GPR119 to promote cAMP, and also have low cytotoxicity and thus have high stability to the human body. Thus, the novel piperazine derivatives according to the present invention are useful for the treatment of obesity, , Hypertriglyceridemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, or syndrome X. The present invention also provides a pharmaceutical composition for preventing or treating diabetes mellitus, diabetes mellitus, insulin resistance, hyperglycemia, hyperlipidemia,

Meanwhile, the piperazine derivative of Formula 1 according to the present invention can be formulated into various forms according to the purpose. Hereinafter, some formulations containing the piperazine derivative represented by the formula (1) according to the present invention as an active ingredient are illustrated, but the present invention is not limited thereto.

< Formulation example  1> Preparation of pharmaceutical preparations

1-1. Sanje  Produce

500 mg of the compound of formula (1)

Lactose 100 mg

10 mg of talc

The above components are mixed and filled in airtight bags to prepare powders.

1-2. Manufacture of tablets

500 mg of the compound of formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.

1-3. Manufacture of capsules

500 mg of the compound of formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.

1-4. Injection preparation

500 mg of the compound of formula (1)

Sterile sterilized water for injection

pH adjuster

(2 ml) per ampoule in accordance with the usual injection method.

1-5. Liquid  Produce

100 mg of the compound of formula (1)

10 g per isomer

5 g mannitol

Purified water quantity

Each component was added to purified water in accordance with the usual liquid preparation method and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was adjusted to 100 ml with purified water, The liquid is prepared by sterilization.

Claims (20)

1. A novel piperazine derivative represented by the following formula (1), a pharmaceutically acceptable salt or an optical isomer thereof:
[Chemical Formula 1]

(In the formula 1,
A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
R is -COOR '; Or unsubstituted or substituted heteroaryl;
B is an unsubstituted or substituted C ₁ -C ₅ straight or branched chain alkyl; Or an unsubstituted or substituted C ₁ -C ₅ linear or branched haloalkyl;
Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;
The substituted phenyl or substituted heteroaryl is -SOR ', - S (O) 2 R', -R'S (O) 2 R ", -NHS (O) 2 R ', -CN, halogen, C ₁ -C ₅ linear or branched haloalkyl, with an alkenyl group, -R ', = O, -COR ', -COOR ', -CONR'R ", -NR'R" , and N, O or S in the C ₁ -C ₅ Phenyl or substituted heteroaryl substituted with one or more substituents selected from the group consisting of 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms selected from the group consisting of:
Here, R ' Or R "are each independently hydrogen or C ₁ -C ₅ straight or branched chain alkyl unsubstituted or substituted with at least one hydroxy group; or R ' And R "together with the N to which they are attached may form a 5- or 6-membered heterocyclyl containing a heteroatom selected from the group consisting of N, O and S of 1 to 4;
and n is an integer of 1 to 10).
The method according to claim 1,
A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;
The substituted phenyl -S (O) ₂ R ', -R'S (O) ₂ R ", halogen, -R', -COOR ', -CONR'R" and N, O and S Phenyl which is substituted by at least one substituent selected from the group consisting of a 5-membered or 6-membered heteroaryl containing a hetero atom; Wherein R 'or R "are each independently hydrogen or C ₁ -C ₅ straight or branched chain alkyl unsubstituted or substituted with at least one hydroxy group, or R' And R "together with the N to which they are attached may form a 5- or 6-membered heterocyclyl containing a heteroatom selected from the group consisting of N, O and S of 1 to 4;
Said substituted heteroaryl is heteroaryl substituted with-R 'or -S (O) ₂ R'; Here, R 'to novel piperazine derivatives, their pharmaceutically acceptable salts or their optical isomers, characterized in that a straight-chain or branched alkyl of C ₁ -C _5.
The method according to claim 1,
A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridines;
Wherein said substituted phenyl is selected from the group consisting of methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl, fluoro, chloro, bromo, methyl, ethyl, ethoxycarbonyl, hydroxyisopropylaminocarbonyl, dihydroxypropyl Phenyl substituted with one or more substituents selected from the group consisting of aminocarbonyl, dihydroxyisopropylaminocarbonyl, pyrrolidylcarbonyl and tetrazolyl; And
Wherein said substituted pyridine is pyridine substituted with at least one substituent selected from the group consisting of methyl, ethyl and methanesulfonyl, a pharmaceutically acceptable salt or an optical isomer thereof.
The method according to claim 1,
R is -COOR '; Or unsubstituted or substituted heteroaryl;
Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;
Wherein said substituted heteroaryl is heteroaryl substituted by C ₁ -C ₅ straight or branched chain alkyl; and pharmaceutically acceptable salts or optical isomers thereof.
The method according to claim 1,
Wherein R is t-butoxycarbonyl; Or an unsubstituted or substituted pyrimidine or oxadiazole;
Wherein said substituted pyrimidine or oxadiazole is heteroaryl substituted with at least one substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and t-butyl, A pharmaceutically acceptable salt or an optical isomer thereof.
The method according to claim 1,
Wherein B is an unsubstituted or substituted C ₁ -C ₅ linear or branched alkyl group, a pharmaceutically acceptable salt or an optical isomer thereof.
The method according to claim 1,
Wherein B is methyl, ethyl or propyl, or a pharmaceutically acceptable salt or an optical isomer thereof.
The method according to claim 1,
A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;
The substituted phenyl -S (O) ₂ R ', -R'S (O) ₂ R ", halogen, -R', -COOR ', -CONR'R" and N, O and S Phenyl which is substituted by at least one substituent selected from the group consisting of a 5-membered or 6-membered heteroaryl containing a hetero atom; Wherein R 'or R "are each independently hydrogen or C ₁ -C ₅ straight or branched chain alkyl unsubstituted or substituted with at least one hydroxy group, or R' And R "together with the N to which they are attached may form a 5- or 6-membered heterocyclyl containing a heteroatom selected from the group consisting of N, O and S of 1 to 4;
Said substituted heteroaryl is heteroaryl substituted with-R 'or -S (O) ₂ R'; Here, R 'is a straight or branched alkyl of C ₁ -C _5;
R is -COOR '; Or unsubstituted or substituted heteroaryl;
Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;
Said substituted heteroaryl is heteroaryl substituted with C ₁ -C ₅ straight or branched chain alkyl;
B is an unsubstituted or substituted C ₁ -C ₅ straight or branched alkyl group; And
and n is an integer of 1 to 5, a pharmaceutically acceptable salt or an optical isomer thereof.
The method according to claim 1,
A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridines;
Wherein said substituted phenyl is selected from the group consisting of methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl, fluoro, chloro, bromo, methyl, ethyl, ethoxycarbonyl, hydroxyisopropylaminocarbonyl, dihydroxypropyl Phenyl substituted with one or more substituents selected from the group consisting of aminocarbonyl, dihydroxyisopropylaminocarbonyl, pyrrolidylcarbonyl and tetrazolyl;
Wherein said substituted pyridine is pyridine substituted with one or more substituents selected from the group consisting of methyl, ethyl and methanesulfonyl;
R is t-butoxycarbonyl; Or an unsubstituted or substituted pyrimidine or oxadiazole;
Wherein said substituted pyrimidine or oxadiazole is heteroaryl substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and t-butyl;
B is methyl, ethyl or propyl; And
and n is an integer of 1 to 5, a pharmaceutically acceptable salt or an optical isomer thereof.
The method according to claim 1,
A is

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

ego;
R is

,

or

ego;
B is methyl; And
and n is an integer of 1 to 3, a pharmaceutically acceptable salt or an optical isomer thereof.
The method according to claim 1, wherein the piperazine derivative represented by Formula (1)
(1) t-Butyl-4- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalate;
(2) t-Butyl-4- (4- (2-fluoro-2 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalate;
(3) 2- (4- (4- (4- (Methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate;
(4) 2- (4- (4- (3-Fluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;
(5) Synthesis of 2- (4- (4- (3-fluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin- salt;
(6) Synthesis of 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- -Yl) piperazine oxalate;
(7) t-Butyl 4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalate;
(8) Synthesis of 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- -Yl) piperazine hydrochloride;
(9) Synthesis of 1- (4- (2-fluoro-4- (1H-tetrazol-1-yl) phenoxy) Oxadiazol-5-yl) piperazine;
(10) Synthesis of 1- (4- (2-fluoro-4- (1H-tetrazol-1-yl) phenoxy) Oxadiazol-5-yl) piperazine oxalate;
(11) Synthesis of 1- (4- (2-fluoro-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine oxalate;
(12) Synthesis of 1- (4- (3-fluoro-4- (1H-tetrazol-1-yl) phenoxy) Oxadiazol-5-yl) piperazine oxalate;
(13) Synthesis of 1- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) -4- Oxalate;
(14) Synthesis of 1- (4- (4- (1H-tetrazol-1-yl) phenoxy) butan- -Yl) piperazine oxalate;
(15) 1- (4- (3,5-Difluoro-4- (1H-tetrazol-1-yl) phenoxy) butan- , 4-oxadiazol-5-yl) piperazine oxalate;
(16) Synthesis of 1- (4- (4-bromo-2,5-difluorophenoxy) butan-2-yl) -4- -Yl) piperazine oxalate;
(17) Synthesis of 1- (4- (3-chloro-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine oxalate;
(18) Synthesis of 1- (4- (3-methyl-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine oxalate;
(19) Synthesis of 1- (4- (5- (methylsulfonyl) pyridin-2-yloxy) butan- Yl) piperazine oxalate;
(20) Synthesis of 1- (4- (5- (methylsulfonyl) pyridin-2-yloxy) butan- Yl) piperazine hydrochloride;
(21) 1- (4- (6- (Methylsulfonyl) pyridin-3-yloxy) butan- ) Piperazine oxalate;
(22) Synthesis of 1- (4- (3-chloro-4 - ((methylsulfonyl) methyl) phenoxy) butan- -5-yl) piperazine oxalate;
(23) Synthesis of 1- (4- (3-chloro-4 - ((methylsulfonyl) methyl) phenoxy) butan- 5-yl) piperazine hydrochloride;
(24) Synthesis of 1- (4- (3-fluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan- Lt; / RTI &gt; 5-yl) piperazine oxalate;
(25) Synthesis of 1- (4- (2-methyl-4 - ((methylsulfonyl) methyl) phenoxy) butan- -5-yl) piperazine oxalate;
(26) 2- (4- (4- (3-Fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate;
(27) Synthesis of 1 - ((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine oxalate;
(28) Synthesis of 1 - ((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine hydrochloride;
(29) 2- (4- (4- (3-Fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine hydrochloride;
(30) 2- (4- (4- (3-Chloro-4 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;
(31) Synthesis of 2- (4- (4- (3-chloro-4 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin- 1 -yl) -5-propylpyrimidine oxalate ;
(32) Synthesis of 2- (4- (4- (3-fluoro-4- (1- (methylsulfonyl) ethyl) phenoxy) butan-2-yl) piperazin- Methyl oxalate;
(33) Synthesis of 1- (4- (2,5-difluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan- -Oxadiazol-5-yl) piperazine oxalate;
(34) Synthesis of 1- (4- (2,5-difluoro-4- (methylsulfonyl) phenoxy) butan- Lt; / RTI &gt; 5-yl) piperazine trifluoroacetate;
(35) Synthesis of 1- (4- (2,5-difluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine hydrochloride;
(36) Synthesis of 1- (4- (2,6-difluoro-4- (methylsulfonyl) phenoxy) butan- Lt; / RTI &gt; 5-yl) piperazine oxalate;
(37) Synthesis of 1- (4- (2,6-difluoro-4- (methylsulfonyl) phenoxy) butan- Lt; / RTI &gt; 5-yl) piperazine trifluoroacetate;
(38) Synthesis of 1- (4- (2,6-difluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine hydrochloride;
(39) 1- (4- (5-Methyl-6- (methylsulfonyl) pyridin-3- yloxy) butan- 5-yl) piperazine hydrochloride;
(40) 1- (4- (5-Methyl-6- (methylsulfonyl) pyridin-3- yloxy) butan- Lt; / RTI &gt; 5-yl) piperazine oxalate;
(41) Synthesis of ethyl-4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate Oxalate;
(42) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluorobenzoate lithium salt ;
(43) ethyl-4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate oxalate;
(44) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate lithium salt;
(45) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin- 1 -yl) butoxy) -2-fluoro- 2-yl) benzamide oxalate;
(46) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin- 1 -yl) butoxy) -2-fluoro- 2-yl) benzamide hydrochloride;
(47) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro- -2-yl) benzamide oxalate;
(48) A mixture of 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro- -2-yl) benzamide hydrochloride;
(49) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro- Hydroxypropyl) benzamide oxalate;
(50) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin- 1 -yl) butoxy) -2-fluoro- Hydroxypropyl) benzamide hydrochloride;
(51) 4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- Dihydroxypropan-2-yl) benzamide oxalate;
(52) 4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- Dihydroxypropan-2-yl) benzamide hydrochloride;
(53) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -1-hydroxypropan-2-yl) benzamide oxalate;
(54) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -1-hydroxypropan-2-yl) benzamide hydrochloride;
(55) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide oxalate;
(56) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide hydrochloride;
(57) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide hydrochloride;
(58) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2- Pyrrolidin-1-yl) methanone hydrochloride;
(59) A mixture of ethyl 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorobenzoate oxalic acid salt;
(60) 4- (3- (4- (3-isopropyl-1, 2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorobenzoate lithium salt ;
(61) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N - -Hydroxypropan-2-yl) benzamide oxalate;
(62) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -N - -Hydroxypropan-2-yl) benzamide hydrochloride;
(63) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluoro- (S) -2,3-dihydroxypropyl) benzamide oxalate;
(64) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluoro- (S) -2,3-dihydroxypropyl) benzamide triflu or o acetic acid salt;
(65) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -N, N- - methylbenzamide oxalate;
(66) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -N, N- - methylbenzamide hydrochloride;
(67) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluorophenyl) Pyrrolidin-1-yl) methanone oxalate;
(68) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluorophenyl) Pyrrolidin-1-yl) methanone hydrochloride;
(69) A mixture of 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro- Dihydroxypropan-2-yl) benzamide oxalate;
(70) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro- Dihydroxypropan-2-yl) benzamide hydrochloride;
(71) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide oxalate;
(72) 1- (4- (5-Methyl-6- (methylsulfonyl) pyridin-3- yloxy) butan- Lt; / RTI &gt; 5-yl) piperazine oxalate;
(73) A mixture of ethyl 4 - ((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) Rovenoate oxalate;
(74) 4 - ((R) -3- (4- (3-Isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro Benzoate lithium salt;
(75) 4 - ((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro -N - ((R) -2,3-dihydroxypropyl) benzamide oxalate;
(76) A mixture of ethyl 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) Robenzoate;
(77) 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro Benzoate lithium salt;
(78) 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1- yl) butoxy) -2-fluoro -N - ((R) -2,3-dihydroxypropyl) benzamide oxalate;
(79) t-Butyl-4- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate;
(80) t-Butyl-4- (4- (2-fluoro-2 - ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazine-1-carboxylate;
(81) 2- (4- (4- (4- (Methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;
(82) Synthesis of 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine;
(83) t-Butyl 4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate;
(84) Synthesis of 1- (4- (2-fluoro-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine;
(85) 1- (4- (3-Fluoro-4- (1H-tetrazol-1-yl) phenoxy) Oxadiazol-5-yl) piperazine;
(86) Synthesis of 1- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) -4- ;
(87) Synthesis of 1- (4- (4- (1H-tetrazol-1-yl) phenoxy) butan- Yl) piperazine;
(88) 1- (4- (3,5-Difluoro-4- (1H-tetrazol-1-yl) phenoxy) butan- , 4-oxadiazol-5-yl) piperazine;
(89) 1- (4- (4-Bromo-2,5-difluorophenoxy) butan-2-yl) -4- Yl) piperazine;
(90) Synthesis of 1- (4- (3-chloro-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine;
(91) 1- (4- (3-Methyl-4- (methylsulfonyl) phenoxy) butan- Yl) piperazine;
(92) 1- (4- (5- (Methylsulfonyl) pyridin-2-yloxy) butan- Yl) piperazine;
(93) 1- (4- (6- (Methylsulfonyl) pyridin-3-yloxy) butan- ) Piperazine;
(94) Synthesis of 1- (4- (3-chloro-4 - ((methylsulfonyl) methyl) phenoxy) butan- 5-yl) piperazine;
(95) 1- (4- (3-Fluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan- 5-yl) piperazine;
(96) A mixture of 1- (4- (2-methyl-4 - ((methylsulfonyl) methyl) phenoxy) butan- 5-yl) piperazine;
(97) 2- (4- (4- (3-Fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate;
(98) Synthesis of 1 - ((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine;
(99) 2- (4- (4- (3-Fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;
(100) 2- (4- (4- (3-fluoro-4- (1- (methylsulfonyl) ethyl) phenoxy) butan-2-yl) piperazin- Midin;
(101) 1- (4- (2,5-Difluoro-4 - ((methylsulfonyl) methyl) phenoxy) butan- -Oxadiazol-5-yl) piperazine;
(102) A mixture of 1- (4- (2,5-difluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine;
(103) 1- (4- (2,6-Difluoro-4- (methylsulfonyl) phenoxy) butan- 5-yl) piperazine;
(104) 1- (4- (5-Methyl-6- (methylsulfonyl) pyridin-3- yloxy) butan- 5-yl) piperazine;
(105) Ethyl-4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluorobenzoate ;
(106) 4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate;
(107) Ethyl-4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate;
(108) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate;
(109) 4- (3- (4- (5-Propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro- 2-yl) benzamide;
(110) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro- -2-yl) benzamide;
(S) -2,3-di (4-fluorophenyl) -1,3-di Hydroxypropyl) benzamide;
(112) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- 1,3-dihydroxypropan-2-yl) benzamide;
(113) 4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -1-hydroxypropan-2-yl) benzamide;
(114) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide;
(115) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorophenyl) Pyrrolidin-1-yl) methanone;
(116) Ethyl 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorobenzoate;
(117) 4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorobenzoate;
(118) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -N - -Hydroxypropan-2-yl) benzamide;
(119) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluoro- (S) -2,3-dihydroxypropyl) benzamide;
(120) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -N, N- - methylbenzamide;
(121) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluorophenyl) Pyrrolidin-1-yl) methanone;
(122) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -3-fluoro- 1,3-dihydroxypropan-2-yl) benzamide;
(123) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2-fluoro- (R) -2,3-dihydroxypropyl) benzamide;
(124) 1- (4- (5-methyl-6- (methylsulfonyl) pyridin-3- yloxy) butan- 5-yl) piperazine;
(125) ethyl 4 - ((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2- Robenzoate;
(126) 4 - ((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro Benzoates;
(127) 4 - ((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro -N - ((R) -2,3-dihydroxypropyl) benzamide;
(128) ethyl 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1 -yl) butoxy) -2- Robenzoate;
(129) 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro Benzoate; And
(130) 4 - ((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5- yl) piperazin- 1 -yl) butoxy) -2-fluoro -N - ((R) -2,3-dihydroxypropyl) benzamide; or a pharmaceutically acceptable salt or an optical isomer thereof or a pharmaceutically acceptable salt or solvate thereof. .
As shown in Scheme 1 below,
A step of coupling a compound represented by formula (2) with a piperidine derivative represented by formula (3) to prepare a compound represented by formula (4) (step 1);
A step of reducing the compound of Formula 4 prepared in Step 1 to produce a compound of Formula 5 (Step 2); And
A process for producing a compound represented by the formula (1), comprising the steps of: (a) reacting a compound represented by the formula (5) with a compound represented by the formula Preparation of piperazine derivatives:
[Reaction Scheme 1]

Wherein A, B, and R are as defined in claim 1;
m is an integer from 0 to 3; And
(Ia) is a compound of the formula (I).
13. The method of claim 12,
The method for preparing a novel piperazine derivative according to claim 1, further comprising the step of treating the compound of formula (Ia) prepared in step 3 with an organic acid or an inorganic acid to prepare an acid addition salt represented by the following formula (1A)
&Lt; EMI ID =

Wherein A, B, R and n are the same as defined in claim 1;
HA is an organic or inorganic acid; And
Wherein the compound of formula (1A) is a compound of formula (1).
14. The method of claim 13,
The method of claim 1, wherein the organic acid or inorganic acid is oxalic acid, hydrochloric acid or trifluoroacetic acid.
As shown in Reaction Scheme 2 below,
Reacting a compound represented by the formula (1b) with lithium hydroxide to prepare a lithium salt represented by the formula (1c) (step 1); And
(1) of preparing a compound represented by the formula (1d) by carrying out an amidation reaction between the lithium salt of the formula (1c) and the compound represented by the formula (7) &Lt; RTI ID = 0.0 &gt;
[Reaction Scheme 2]

Wherein B, R, R ', R &quot; and n are as defined in claim 1; and
The compounds of formulas (Ib) to (Id) are compounds of formula (I).
As shown in Scheme 3 below,
Reacting a compound represented by the formula 8- (S) with t-butyldimethylsilyl chloride (TBSCl) to prepare a compound represented by the formula 9- (S) (step 1);
Reacting the compound of formula 9- (S) prepared in step 1 with methanesulfonyl chloride (MsCl) to prepare a compound represented by formula 10- (S) (step 2);
Reacting the compound of Formula 10- (S) prepared in Step 2 with a compound of Formula 3 to prepare a compound represented by Formula 11- (R) (Step 3);
(R) (step 4) by carrying out a deprotection reaction of the compound represented by the formula 11- (R) prepared in the above step 3 to prepare a compound represented by the formula 5- (R); And
(R) and a compound represented by the formula (6) to produce a compound represented by the formula 1 - (R) (step 5); A process for producing a novel piperazine derivative represented by the general formula (1)
[Reaction Scheme 3]

Wherein A, B and R are as defined in claim 1;
TBS is a t-butyldimethylsilyl group;
Ms is a methanesulfonyl group; And
The compound of formula 1- (R) is a compound of formula (I).
As shown in Scheme 4 below,
Reacting a compound represented by the formula 8- (R) with t-butyldimethylsilyl chloride (TBSCl) to prepare a compound represented by the formula 9- (R) (step 1);
Reacting a compound of the formula 9 - (R) prepared in the above step 1 with methanesulfonyl chloride (MsCl) to prepare a compound represented by the formula 10 - (R) (step 2);
Reacting the compound of Formula 10- (R) prepared in Step 2 with a compound of Formula 3 to prepare a compound represented by Formula 11- (S) (Step 3);
(Step 4) of preparing a compound represented by the formula 5- (S) by performing deprotection of the compound represented by the formula 11- (S) prepared in the step 3; And
(Step 5) of preparing a compound represented by the general formula 1- (S) by performing a coupling reaction between the compound represented by the formula 5 (S) and the compound represented by the formula 6 produced in the step 4 A process for producing a novel piperazine derivative represented by the general formula (1)
[Reaction Scheme 4]

(Wherein, A, B and R are as defined in claim 1;
TBS is a t-butyldimethylsilyl group;
Ms is a methanesulfonyl group; And
The compound of the formula 1- (S) is the compound of the formula (1).
A pharmaceutical composition for preventing or treating metabolic diseases, which comprises a novel piperazine derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof or an optical isomer thereof as an active ingredient.
[Chemical Formula 1]

(Wherein, A, B, R and n are as defined in claim 1).
19. The method of claim 18,
The pharmaceutical composition for preventing or treating metabolic diseases, wherein the piperazine derivative of Formula 1 activates GPR119 enzyme.
19. The method of claim 18,
Wherein the metabolic disease is selected from the group consisting of obesity, type I diabetes, type II diabetes, inappropriate insulin resistance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X Or a pharmaceutically acceptable salt thereof.