WO2014077532A1 - Novel piperazine derivative, pharmaceutically acceptable salt or optical isomer thereof, method for preparing same, and pharmaceutical composition containing same as active ingredient for preventing or treating metabolic disorders - Google Patents

Novel piperazine derivative, pharmaceutically acceptable salt or optical isomer thereof, method for preparing same, and pharmaceutical composition containing same as active ingredient for preventing or treating metabolic disorders Download PDF

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WO2014077532A1
WO2014077532A1 PCT/KR2013/009857 KR2013009857W WO2014077532A1 WO 2014077532 A1 WO2014077532 A1 WO 2014077532A1 KR 2013009857 W KR2013009857 W KR 2013009857W WO 2014077532 A1 WO2014077532 A1 WO 2014077532A1
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isopropyl
piperazin
piperazine
butan
oxadiazol
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PCT/KR2013/009857
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French (fr)
Korean (ko)
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양진
김진웅
이한규
김재현
손창모
이규환
최형호
김대훈
최효선
이재걸
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현대약품 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel piperazine derivative, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating metabolic diseases containing the same as an active ingredient.
  • Type I diabetes also known as insulin dependent diabetes (IDDM)
  • IDDM insulin dependent diabetes
  • Type II diabetes also known as non-insulin dependent diabetes mellitus (NIDDM)
  • NIDDM non-insulin dependent diabetes mellitus
  • Type II diabetes can be characterized by a deficiency in insulin secretion or insulin resistance, ie, people with type II diabetes who have little insulin or are unable to use insulin effectively.
  • diabetes is high levels of glucose accumulate in the blood and urine within the bowl yeojeok, resulting in excessive urination, thirst, baegopum, fat and protein, and i rohyeon: Russia raises issues related ebhls and dysentery metabolism.
  • Such diabetes can cause life-threatening complications such as blindness, 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 cause serious infections.
  • current treatments for diabetes include insulin, insulin secretagogues, glucose lowering effectors, and activators of peroxysome proliferator-activated receptors (PPARs).
  • PPARs peroxysome proliferator-activated receptors
  • issues related to currently available therapies including hypoglycemia, weight gain, decreased responsiveness to treatment over time, and gastrointestinal edema, are aimed at areas aimed at bringing new, more effective therapies to market
  • GPR119 is a G-protein coupler receptor (GPCR) expressed in the pancreas, small intestine, colon and adipose tissue. Recently, GPR119 Studies have shown that the profile has potential utility for the treatment of obesity and diabetes. GPR119 activation has been demonstrated to stimulate cAMP to induce glucose-dependent GLP-1 and insulin secretion (Non-Patent Document 1). In addition to effects on plasma glucose levels, GPR119 activators have been demonstrated to cause acute food intake in rats after chronic administration and to reduce body weight (Patent Literatures 1 and 2 and Non-Patent Literature 2).
  • GPCR G-protein coupler receptor
  • Patent Documents 4 to 4 it has been reported for a diabetes treatment using aryl, heteroaryl or heterocyclyl derivatives, characterized in that activating IC-GPCR2 or GPR119 as a treatment for type II diabetes associated with insulin resistance (Patent Documents 4 to 4). Patent document 6).
  • Patent Document 1 International Publication No. 2005/007647;
  • Patent Document 2 International Publication No. 2005/007658
  • Patent Document 3 International Publication No. 2004/065380;
  • Patent Document 4 International Publication No. 2008/083238;
  • Patent Document 5 International Publication No. 2008/081206;
  • Patent Document 6 International Publication No. 2008/081208.
  • Non-Patent Document 1 T. Soga et al. , Biochem. B i ophy Res. Commu. 326, (2005), 744-751;
  • Non-Patent Document 2 0 Verton, H.A. et al Cell metabolism 3, (2006), 167-175.
  • An object of the present invention is to provide novel piperazine derivatives, pharmaceutically acceptable salts or optical isomers thereof.
  • the object of the invention is a novel piperazine derivative, To provide a pharmaceutically acceptable salt or a method for preparing the optical isomer thereof.
  • Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases, which contains a novel piperazine derivative, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.
  • the present invention provides a novel piperazine derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.
  • the present invention provides a novel piperazine derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.
  • the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, which comprises a novel piperazine derivative represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.
  • novel piperazine derivatives, pharmaceutically acceptable salts or isomers thereof according to the present invention have high solubility in water and are excellent in body absorption and low in cytotoxicity compared to the compounds known as GPR119 activators. This is pretty good. Above all, the effect of activating GPR119 to promote cAMP is remarkably excellent, so that the novel piperazine derivatives, pharmaceutically acceptable salts or isomers thereof according to the present invention can be treated by activating GPR119 to treat obesity, type I diabetes, It can be usefully used as a pharmaceutical composition for the prevention or treatment of type ⁇ diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X.
  • the present invention provides a novel piperazine derivative represented by the following Chemical Formula 1. It provides a pharmaceutically acceptable salt or optical isomer thereof. [Formula 1]
  • A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
  • R is — C00R '; Or unsubstituted or substituted heteroaryl;
  • B is unsubstituted or substituted straight or branched chain alkyl of dC 5 or unsubstituted or substituted d-Cs straight or branched haloalkyl;
  • heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S:
  • R 'or R' ' are each independently hydrogen; Or straight or branched chain alkyl of d-Cs unsubstituted or substituted with one or more hydroxy groups; Or R ′ and R ′ ′ are 1 to together with N to which they are attached
  • n is an integer from 1 to 10.
  • A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
  • heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S;
  • the substituted phenyl is selected from the group consisting of -S (0) 2 R ', -R'S (0) 2 R ", halogen, -R', -C00R ', -CONR'R", and N, 0 and S Phenyl substituted with one or more substituents selected from the group consisting of 5- or 6-membered heteroaryl containing 1 to 4 hetero atoms selected; Wherein R ′ or R ′′ are each independently hydrogen; or straight or branched chain alkyl of dC 5 unsubstituted or substituted with one or more hydroxy groups; or R ′ and R ′′ together with N to which they are attached 1-4 With N, 0 and S A five-member containing heteroatoms selected from the group consisting of
  • the substituted heteroaryl is heteroaryl substituted with —R ′ or —S (0) 2 R ′; Wherein R 'is straight or branched alkyl of dC 5 : more preferably,
  • A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridine;
  • the substituted phenyl is methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl, polouro, chloro, bromo, methyl, ethyl, ethoxycarbonyl, hydroxyisoisopropylaminocarbonyl, dihydroxy Propylaminocarbonyl ,
  • the substituted pyridine is pyridine substituted with one or more substituents selected from the group consisting of methyl, ethyl and methanesulfonyl.
  • substituents selected from the group consisting of methyl, ethyl and methanesulfonyl.
  • R is -C00R '; Or unsubstituted or substituted heteroaryl; Wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S;
  • the substituted heteroaryl is heteroaryl substituted with straight or branched chain alkyl of d-Cs;
  • R is t-butoxycarbonyl; Or unsubstituted or substituted pyrimidine or oxadiazole;
  • the 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.
  • substituents selected from the group consisting of methyl, ethyl, propyl isopropyl, butyl and t-butyl.
  • B is an unsubstituted or substituted d-Cs straight or branched alkyl group; More preferably,
  • B is methyl, ethyl or propyl. Furthermore, in the compound of Formula 1 according to the present invention, A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
  • heteroaryl is a 5 or 6 membered heteroaryl including 1 to 4 hetero atoms independently selected from the group consisting of N, 0 and S;
  • the substituted phenyl is -S (0) 2 R ', -R'S (0) 2 ", halogen, -R', -C00R '-CONR'R" and 1 selected from the group consisting of ⁇ , 0 and S Phenyl substituted with one or more substituents selected from the group consisting of 5- or 6-membered heteroaryl containing hetero atoms of 4 to 4;
  • the substituted heteroaryl is or heteroaryl substituted with —S (0) 2 R ′; Wherein R 'is straight or branched alkyl of;
  • R is — C00R '; 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, 0 and S;
  • the substituted heteroaryl is heteroaryl substituted with straight or branched chain alkyl of dC 5 ;
  • B is an unsubstituted or substituted d-Cs straight or branched alkyl group; n is an integer of 1 to 5;
  • A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridine;
  • the substituted phenyl is methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl fluoro, chloro, bromo, methyl, ethyl, ecoxycarbonyl, hydroxyisopropylaminocarbonyl, dihydroxypropylamino Carbonyl,
  • the substituted pyridine is pyridine substituted with one or more substituents selected from the group consisting of methyl, ethyl and methanesulfonyl;
  • R is t-subspecific carbonyl; Or unsubstituted or substituted pyrimidine or oxadiazole;
  • the 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 1-5.
  • n is an integer of 1-5.
  • n is an integer of 1-3.
  • Specific examples of the novel piperazine derivative represented by Chemical Formula 1 are as follows.
  • (21) 1 ′ (4- (6- (methylsulfonyl) pyridin 3-yloxy) butan-2-yl). 4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine oxalate; (22) l- (4- (3-chloro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazol -5-yl) piperazine oxalate;
  • (121) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorophenyl) ( Pyridin-1-yl) methanone;
  • the novel piperazine derivatives represented by Formula 1 according to the present invention can be used in the form of pharmaceutically acceptable salts.
  • acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphoric acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoate alkanedio Obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically toxic salts include sulfated, pyrosulfate 0 bisulfate, sulfite, bisulfite, nitrate phosphate 0 monohydrogen phosphate, dihydrogen phosphate 0 metaphosphate, pyrophosphate chloride, bro ⁇ oiodide, fluoride, acetate, propione ⁇ decanoate, caprylate, acrylate, pome ⁇ isobutyrate, caprate, tempanoate, propionic acid, oxalic acid malonic acid, succinic acid, suverate, Sebacate, fumarate, maleate butene-1,4-dioate, nucleic acid-1,6-dioic acid, benzoic acid, chlorobenzoic acid methylbenzoic acid, dinitrobenzoic acid, hydroxybenzoate, methoxybenzoic acid phthalic acid, terephthalate, Benzenesulfonic acid, toluenesul
  • hydrochloric acid, oxalic acid or trifluoroacetic acid can be preferably used.
  • the acid addition salt according to the present invention is dissolved in a conventional method, for example, an aqueous solution of an excess of acid, and the salt is dissolved in a water miscible organic solvent, such as methanol, ethanol, acetone or aceto. It can be prepared by precipitation using nitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, inexpensive compound salt filtering, and evaporation and drying of the filtrate.
  • the metal salt it is pharmaceutically suitable to produce lithium, sodium, potassium or calcium salts.
  • Corresponding silver salts are also obtained by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).
  • a suitable silver salt eg silver nitrate
  • Step 2 Preparing a compound represented by Chemical Formula 5 by performing a reaction of reducing the compound of Chemical Formula 4 prepared in Step 1 (Step 2); And coupling the compound represented by Chemical Formula 5 and the compound represented by Chemical Formula 6 prepared in Step 2 to prepare a compound represented by Chemical Formula la (Step 3).
  • Step 3 Provided are methods for preparing the derivatives.
  • step 1 is a step of preparing a compound represented by Chemical Formula 4 by coupling a compound represented by Chemical Formula 2 and a piperidine derivative represented by Chemical Formula 3 with a coupling reaction.
  • the compound of formula (2) and piperazine of formula (3) are dissolved in methane, and then subjected to a reflux stirring to perform a reaction of adding an amine to the alkenyl group of formula (2).
  • the solvent may be used methanol ethane, dichloromethane (DCM) or toluene which does not adversely affect the reaction, methane may be used.
  • step 2 is a step of preparing a compound represented by Formula 5 by performing a reduction reaction of the compound of Formula 4 prepared in Step 1.
  • the solvent may be used tetrahydrofuran (THF), diethyl ether, diphenyl ether or diisopropyl ether (DIPE) that does not adversely affect the reaction, preferably tetrahydrofuran (THF) Can be.
  • THF tetrahydrofuran
  • DIPE diisopropyl ether
  • step 3 is a step of preparing a compound represented by the formula la by coupling the compound represented by the formula (5) and the compound represented by the formula (6) prepared in step 2.
  • a compound of formula la is prepared by performing a Mitsunobu reaction by slowly adding dropwise addition of an azocarboxylate reagent to a solution containing a compound of formula 5, a compound of formula 6, and triphenylphosphine. Step.
  • the azocarboxylate compound that can be used is diethyl azodicarboxylate (DEAD) or
  • Di isopropyl azodi car boxy late may be used, and preferably diisoopropyl azodi car boxy late (DIAD) may be used.
  • the solvent which can be used can use tetrahydrofuran (THF), dichloromethane (DCM), toluene, or acetonitrile which does not adversely affect a reaction,
  • THF tetrahydrofuran
  • DCM dichloromethane
  • acetonitrile which does not adversely affect a reaction
  • tetrahydrofuran THF
  • the method may further include preparing an acid addition salt represented by Chemical Formula 1A by treating the compound with an organic acid or an inorganic acid.
  • the usable organic or inorganic acid may be used oxalic acid hydrochloric acid or trifluoroacetic acid.
  • the solvent which can be used methanol, ethane which does not adversely affect reaction, acetone, acetonitrile or ethyl acetate (EA) can be used, and ethyl acetate (EA) can be used preferably.
  • the present invention is as shown in the following reaction formula 2,
  • Lithium salt of Formula lc prepared in Step 1 and the formula (7) It provides a method for producing a novel piperazine derivative represented by the formula (1) comprising the step of preparing a compound represented by the formula (Id) by performing the compound amidation reaction.
  • Step 1 is a step of preparing a litop salt represented by Chemical Formula lc by reacting a compound represented by Chemical Formula lb and lithium hydroxide.
  • the compound of formula lb is dissolved in a mixed solution of tetrahydrofuran (THF) and distilled water, and then reacted with the addition of lithium hydroxide monohydrate. After the reaction, the undissolved compound is filtered
  • the step 2 is to prepare a compound represented by the formula (Id) by performing an amidation reaction between the lithium salt of the formula (lc) prepared in step 1 and the compound represented by the formula (7) to be.
  • the lithium salt of formula ( 1) prepared in step 1 and the amine compound of formula 7 are dissolved in an organic solvent, an amide reagent is added, and the amidation reaction is performed at room temperature. Step of preparing a compound of Id.
  • the amide reagent is benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium nucleofluorophosphate (Py-
  • BOP 0-benzotriazole- ⁇ , ⁇ , ⁇ , ⁇ -tetramethyl-uronium-nucleus-fluoro-phosphate
  • HBTU 2- (7-aza-in-benzotriazol-1-yl)- 1,1,3,3- Tetramethyluronium nucleus fluorophosphate
  • HOBt 1-hydroxybenzotriazole
  • DCC dicyclonucleosilcarbodiimide
  • EDC 1-ethyl— 3- (3-dimethylaminopropyl) carbodiimide
  • CDI carbonyldiimidazole
  • 1-ethyl-3- (3—dimethylaminopropyl) carbodiimide (EDC) and 1-hydroxybenzotriazole ( HOBt) can be used together.
  • the usable organic solvent may be reacted using methanol, tetrahydrodurofuran (THF), dimethylformamide, dichloromethane or tolueneol, which does not adversely affect the reaction.
  • Dichloromethane (DCM) can be used.
  • the present invention as shown in the following reaction formula 3,
  • Step 1 is a step of preparing a compound represented by Chemical Formula 9- (S) by reacting a compound represented by Chemical Formula 8- (S) with t-butyldimethylsilyl chloride (TBSC1) (Step 1).
  • the step of protecting the hydroxy group of the compound represented by the formula (8) by reacting t-butyldimethylsilyl chloride (TBSC1) with a compound of the formula (8) in the S- form in the presence of a base.
  • the base usable in the reaction may be triethylamine (TEA), diethylamine (DEA), diisopropylethylamine (DIPEA), pyridine or imidazole, and preferably imidazole may be used.
  • usable solvents include tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMS0), dichloromethane (DCM), chlorobenzene, toluene or benzene. May be used, preferably dichloromethane (DCM).
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • DMS0 dimethylsulfoxide
  • DCM dichloromethane
  • chlorobenzene toluene or benzene. May be used, preferably dichloromethane (DCM).
  • step 2 of the formula 9- (S) prepared in step 1 A compound and methanesulfonyl chloride (MsCl) are reacted to prepare a compound represented by Chemical Formula 10- (S).
  • the base usable in the reaction may be triethylamine (TEA), diethylamine (DEA), diisopropylethylamine (DIPEA), pyridine or imidazole, preferably triethylamine (TEA) Can be used.
  • TAA triethylamine
  • DEA diethylamine
  • DIPEA diisopropylethylamine
  • pyridine preferably triethylamine (TEA) Can be used.
  • Step 3 is a step of preparing a compound represented by Chemical Formula 11-0?) By reacting the compound represented by Chemical Formula 10- (S) and Chemical Formula 3 prepared in Step 2.
  • the usable organic solvent may use tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) or dichloromethane (DCM), preferably dimethyl Formamide (DMF) can be used.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • DMSO dimethyl sulfoxide
  • DCM dichloromethane
  • DMF dimethyl Formamide
  • step 4 is a step of preparing a compound represented by the formula (5-) by performing a deprotection reaction of the compound represented by the formula (ll- (R) prepared in step 3.
  • the protected hydroxy group present at the terminal of the compound of formula 11 in which the stereostructure prepared in step 3 is R-form is deprotected using tetrabutylammonium fluoride (TBAF).
  • TBAF tetrabutylammonium fluoride
  • the usable organic solvent may be methanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMS0) or acetonitrile, preferably tetrahydrofuran (THF) can be used.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • DMS0 dimethyl sulfoxide
  • acetonitrile preferably tetrahydrofuran (THF) can be used.
  • reaction is not particularly limited, but may be used within the range of room temperature to reflux temperature of the solvent. 7
  • step 5 is a step of preparing a compound represented by Formula 1- (R) by performing a coupling reaction of the compound represented by the formula 5-00 and the compound represented by the formula (6) prepared in step 4.
  • the azocarboxylate reagent is slowly added dropwise to the solution of the compound of Formula 5, the compound of Formula 6, and triphenylphosphine having the R-form conformation prepared in Step 4 to react Mitsunobu (Mitsi by performing an obu reaction) to prepare a compound of formula 1 having a R-form conformation.
  • the azocarboxylate compound that can be used is diethyl azodicarboxylate (DEAD) or
  • Diisopropyl azodi 7 carboxylate (di i sopropy 1 azodi carboxy 1 ate, DIAD) may be used, preferably di isoprop azodicarboxylate (di i sopropy 1 azodi car boxy late, DIAD) Can be used.
  • the usable solvent may be tetrahydrofuran (THF), dichloromethane (DCM), toluene or acetonitrile, which does not adversely affect the reaction, preferably tetrahydrofuran (THF) may be used.
  • THF tetrahydrofuran
  • the present invention is prepared by reacting the compound represented by the formula 8- (R) and t- butyl dimethylsilyl chloride (TBSC1) as shown in Scheme 4 to prepare a compound represented by the formula 9-(R) Step (step 1);
  • step 5 To prepare a compound represented by the formula 1- (S) by performing a coupling reaction between the compound represented by the formula (5-) and the compound represented by the formula (6) prepared in step 4 (step 5); Provided is a method for preparing a novel piperazine derivative represented by the formula (1).
  • the method of preparing Banung Formula 4 is a method for preparing S-isomers of the piperazine derivatives according to the present invention, and instead of using the compound of Formula 8 having a S-form conformation in the preparation method of Banung Formula 3. Except for using the compound of formula (8) in which the stereostructure is in the R- form was carried out in the same manner as the reaction conditions described in Scheme 3.
  • the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, which comprises a novel piperazine derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.
  • GPR119 is a common G-form found in the pancreas, small intestine, colon and adipose tissue With receptors bound to proteins (GPCR), the GPR119 expression profile has potential utility for the treatment of various metabolic diseases including obesity and diabetes.
  • GPCR receptors bound to proteins
  • novel piperazine derivatives represented by Formula 1 according to the present invention, pharmaceutically acceptable salts thereof, or optical isomers thereof have an excellent effect of activating the GPR119 receptor, thereby stimulating cAMP.
  • Experimental Example 3 the water solubility in water is excellent in the body absorption rate, the cardiac toxicity and cytotoxicity is significantly lower than the conventionally known GPRU9 activator, so there is no side effect, the stability to the human body is quite high (Experimental Examples 4 to 6 ). Therefore, the novel piperazine derivatives, pharmaceutically acceptable salts thereof or optical isomers thereof according to the present invention have excellent absorption in the body, high stability to the human body, and an effect of activating GPR119, a receptor associated with metabolic diseases.
  • the metabolic diseases include, for example, obesity, type I diabetes, type ⁇ diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, X syndrome Can be mentioned.
  • the compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, it is prepared using diluents or excipients such as filler extenders, binders, wetting agents, disintegrants, surfactants, etc., which are commonly used. do.
  • Solid preparations for oral administration include politics, patients, powders, granules, capsules, troches, and the like, which may comprise at least one excipient such as starch, calcium carbonate, water, or the like. Prepared with a mixture of sucrose or lactose (1 actose) or 3 ⁇ 4 latin. In addition to simple excipients, lubricating seeds such as magnesium styrate talc are also used.
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions or syrups.In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be used. Can be.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl acrylate and the like can be used.
  • a suppository base witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
  • the effective dosage of the compound of the present invention to the human body is generally about 0.001-100 mg / kg / day, preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, typically 0.0 7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals depending on the physician's or pharmacist's observations. It can also be administered in divided doses.
  • a target compound was obtained in the same manner as in Production Example 2, except that 4- (methylthio) -m-cresol was used instead of 3-fluoro-4— (methylthio) phenol.
  • a target compound was obtained in the same manner as in Preparation Example 1, except that 4-bromo-2,6-difluorophenol was used instead of 4-bromo-2-fluorophenol.
  • the target compound was prepared in the same manner as in Preparation Example 2, except that 3,5-difluoro-4— (methylthio) phenol was used instead of 3-fluoro-4- (methylthio) phenol. Got it.
  • a target compound was obtained in the same manner as in Preparation Example 15, except that 4-aminophenol was used instead of 4-amino-2-fluorophenol.
  • a target compound was obtained in the same manner as in Preparation Example 15, except that 4-amino-3-fluorophenol was used instead of 4-amino-2-fluorophenol.
  • a target compound was obtained in the same manner as in Preparation Example 15, except that 4-amino-3,5-difluorophenol was used instead of 4-amino-2-fluorophenol.
  • a target compound was obtained in the same manner as in Preparation Example 19, except that 3-fluoro-4-hydroxybenzoic acid was used instead of 2-fluoro-4-hydroxybenzoic acid.
  • Step 1 Preparation of t-butyl-4- (4-methoxy-4—oxobutan-2-yl) piperazine-1-carboxylate
  • Methyl crotonate (3.3 g) and methane (50 mL) were added and dissolved in a 100 mL flask under nitrogen atmosphere, and then t_butyl-1-piperazine carboxylate (5 g) was added dropwise. More than 24 hours The reflux was stirred. When the reaction was terminated, the solvent was removed by concentration under reduced pressure, and purified by silica column chromatography to obtain a wood compound.
  • Lithium aluminum hydride (LAH, 880 mg) was dissolved in tetrahydrofuran (THF, 50 mL) at 0 ° C. in a 100 mL flask under nitrogen atmosphere, and then the above step was added to tetrahydrofuran (THF, 50 mL).
  • THF tetrahydrofuran
  • the solution of compound (2.7 g) prepared in 1 was slowly added dropwise to the flask for 5 minutes.
  • 1M-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 target compound.
  • step 2 In a 100 mL flask under a nitrogen atmosphere, the compound (0.4 g), triphenylphosphine (PPh 3 , 0.63 g), 4- (methylsulfonyl) phenol (0.35 g) and tetrahydrofuran (THF) prepared in step 2 were prepared. Was added and stirred to dissolve. The reaction when slowly added dropwise in the reaction ⁇ diisopropylamino 0 1, crude dimethyl ⁇ 1 "Le butyl (di isopropyl azodi carboxyl ate, 0.5 mL) to 0 ° C and stirred at for 12 hours or more at room temperature.
  • triphenylphosphine PPh 3 , 0.63 g
  • 4- (methylsulfonyl) phenol (0.35 g)
  • THF tetrahydrofuran
  • Lithium aluminum hydride (LAH 900 mg) was dissolved in tetrahydrofuran (THF, 50 mL) at 0 ° C. in a 100 ml flask under nitrogen atmosphere, and then, in step 2 above, in tetrahydrofuran (THF, 50 mL).
  • a solution of the prepared compound (2.7 g) was slowly added dropwise to the flask for 5 minutes.
  • 1M-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 target compound.
  • step 3 the compound (2 g) ol dichloromethane (DCM, 100 mL) prepared in step 3 was stirred and dissolved, triethylamine (TEA, 1.2 mL) was added, Ponyl chloride (0.6 mL) was slowly added dropwise at 0 ° C. After the addition was completed, the mixture 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.
  • DCM dichloromethane
  • the target compound was obtained in the same manner as in Example 3, except that the compound prepared in Preparation Example 5 was used instead of 4- (methylsulfonyl) phenol in Step 5 of Example 3.
  • Step 1 Preparation of t-butyl-4-cyanopiperazine-1-carboxylate Piperazine-1-carboxylic acid t-butylester (10 g), acetonitrile (50 mL) and distilled water (50 mL) were injected, then cooled to 0 ° C. and stirred to dissolve. Sodium bicarbonate (6 g ) and cyanogenbromide (6.3 g) were slowly added to the flask. Then isothermally stirred to 50 ° C. and stirred for 3 hours. After the reaction was completed, the pH was neutralized at 1 ° C.
  • Methyl crotonate (3.3 g) and methanol (50 mL) were added and dissolved in a 100 ml flask under nitrogen atmosphere.
  • the compound (5 g) prepared in Step 2 was added dropwise and stirred under reflux for 24 hours. It was. When the reaction was terminated, the solvent was removed by concentration under reduced pressure, and purified by silica column chromatography to obtain the target compound.
  • Lithium aluminum hydride (LAH, 900 mg) was dissolved in tetrahydrofuran (THF, 50 mL) at 0 ° C. in a 100 ml pool flask under nitrogen atmosphere, and then dissolved in tetrahydrofuran (THF, 50 mL).
  • THF tetrahydrofuran
  • the solution of compound (2.7 g) prepared in step 3 was slowly added dropwise to the flask for 5 minutes.
  • 1M-Saturated 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 target compound.
  • Example 9 The compound (200 mg) prepared in Example 9 was dissolved in ethyl acetate (10 mL), and then the same equivalent number of oxalic acid was added dropwise and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
  • the target compound was obtained in the same manner as in Example 6, except that 4- (methylsulfonyl) phenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6.
  • 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 in ethyl acetate (EA, 10 mL) again and stirred under reflux for 30 minutes by adding the same equivalent number of oxalic acid dropwise. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
  • the target 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.
  • the target compound was prepared in the same manner as in Example 6, except that 3-chloro-4-methanesulfonylmethylphenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6.
  • H R R 400 Hz, D 2 0
  • 6 7.35 (lH, d), 7.09 (lH, d) 6.90 (lH, dd)
  • Example 6 The above procedure was performed in step 6 of Example 6, except that 3-chloro-4-methanesulfonylmethylphenol was used instead of the compound prepared in Preparation Example 2, and hydrochloric acid was used instead of oxalic acid.
  • the target compound was obtained in the same manner as in Example 6.
  • the target compound was prepared in the same manner as in Example 6, except that 4-methanesulfonylmethyl-2-methylphenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6. Got it.
  • the target compound was obtained in the same manner as in Example 3, except that the compound prepared in Preparation Example 2 was used instead of 4- (methylsulfonyl) phenol in Step 5 of Example 3.
  • the compound (1.4 g) prepared in step 2 and dimethylformamide (DMF, 40 mL) were injected and stirred to dissolve, followed by sequentially preparing the compound prepared in Preparation Example 25 (1.3 g) and potassium carbonate (1 g) were added and isothermalized to 5 C C and stirred for 24 h.
  • the temperature was cooled to room temperature, distilled water (30 mL) was added slowly, and 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, concentrated and purified by silica column chromatography to obtain the target compound.
  • Step 5 l-((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl—1,2,4-oxa Preparation of Diazol-5-yl) piperazine oxalate
  • the target compound was obtained in the same manner as in Example 27, except that hydrochloric acid was used instead of oxalic acid in Step 5 of Example 27.
  • Example 3 and Example 3 except that using the compound prepared in Preparation Example 2 instead of 4- (methylsulfonyl) phenol in Example 5, and using hydrochloric acid instead of oxalic acid
  • the target compound was obtained by the same method.
  • the target compound was obtained in the same manner as in Example 4, except that 3-chloro-4-methanesulfonylmethyl-phenyl was used instead of the compound prepared in Sezo Example 5 in Example 4.
  • Example 30 The compound prepared in Example 30 was dissolved in ethyl acetate (EA mL), and then the same equivalent number of oxalic acid was added dropwise and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
  • EA mL ethyl acetate
  • Example 6 except for using the compound prepared in Preparation Example 14 instead of using the compound prepared in Preparation Example 2 in Example 6, using trifluoroacetic acid instead of using oxalic acid
  • the target compound was obtained by the same method as the method of 6.
  • Example 6 except that the compound prepared in Preparation Example 14 is used instead of the compound prepared in Preparation Example 2, and hydrochloric acid is used instead of oxalic acid.
  • the target compound was obtained by the method.
  • Example 6 instead of using the compound prepared in Preparation Example 2 in the step 6 of Example 6 except for using trifluoroacetic acid instead of using oxalic acid
  • the target compound was obtained by the same method as the method of 6.
  • Example 6 in the same manner as in Example 6 except for using the compound prepared in Preparation Example 7 instead of using the compound prepared in Preparation Example 2, and instead of using the oxalic acid in step 6 of Example 6
  • the target compound was obtained by the method.
  • Example 6 except that the compound prepared in Preparation Example 10 is used instead of the compound prepared in Preparation Example 2, and hydrochloric acid is used instead of oxalic acid.
  • the target compound was obtained by the method.
  • Example 40 (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4- (3-isopropyl-1,2, 4- Preparation of oxadiazole-5-yl) piperazine oxalate
  • the target compound was obtained in the same manner as in Example 3, except that the compound prepared in Preparation Example 19 was used instead of 4- (methylsulfonyl) phenol in Step 5 of Example 3.
  • Example 44 Into a 100 ml flask under nitrogen atmosphere, the compound (310 mg) and dichloromethane (DCM, 50 mL) prepared in Example 44 were injected, stirred, and dissolved, and then 1-ethyl-3— (3-dimethylaminopropyl).
  • Carbodiimide hydrochloride (EDCI, 170 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 120 mg) ol were added and stirred for 30 minutes. Then 2-amino-1,3-propanediol (100 mg) ol was added and stirred at silver for 5 hours.
  • Example 45 In the same manner as in Example 45, except that (R)-(-)-2-amino-1-propanol was used instead of 2-amino-1,3-propanediol in Example 45. This was carried out to obtain the target compound.
  • Example 46 The same method as in Example 46, except that (R)-(-)-2-amino-1-propanol is used instead of 2-amino-1,3-propanediol in Example 46.
  • the title compound was obtained by the following procedure.
  • Example 45 The same procedure as in Example 45 was performed except that (R) -3 amino-1,2-propanedi was used instead of 2-amino-1,3-propanedi in Example 45. The compound was obtained.
  • Example 51 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro-N Preparation of-(l, 3-dihaadoxypropane-2-yl) benzamide oxalate
  • Example 42 Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Example 42 (600 mg) and dichloromethane (DCM, 50 mL) were added, stirred, and dissolved, and then 1-ethyl-3- (3-dimethylaminopropyl).
  • Example 42 Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Example 42 (600 mg) and dichloromethane (DCM, 50 mL) were added, stirred, and dissolved, and then 1-ethyl-3- (3-dimethylaminopropyl).
  • Example 51 The same method as in Example 51, except that (R) — ( ⁇ )-2-amino-1-propane is used instead of 2-amino-1,3—propanediol in Example 51.
  • the title compound was obtained by the following procedure.
  • Example 54 4- (3- (4- (3-isopropyl-1,2,4-oxadiazole-5) Preparation of 1) piperazin-1xyl) butoxy) -2-fluoro-N-((R) -1-hydroxypropan-2-yl) benzamide hydrochloride
  • Example 52 was carried out in the same manner as in Example 52, except for using (R)-(-)-2-amino-1-propanolol instead of using 2-amino-1,3-propanedi To obtain the target compound.
  • Example 55 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-yl-yl) particular) -2-fluoro-N Preparation of-((R) -2,3-dihydrotoxapropyl) benzamide oxalate
  • Example 51 was carried out in the same manner as in Example 51, except for using (R) -3 -amino-1,2-propanediol instead of 2-amino-1,3-propanedi The desired compound was obtained.
  • Example 52 The same procedure as in Example 52 was conducted except that 00-3-amino-1,2-propanediol was used instead of 2-amino-1, 3-propanediol in Example 52. The compound was obtained.
  • the target compound was obtained in the same manner as in Example 52, except for using pyrrolidine instead of using 2-amino-1,3-propanedi in Example 52.
  • Example 59 In a 100 mL flask under a nitrogen atmosphere, the compound (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) prepared in Example 59 were charged and dissolved by stirring. Lithium hydroxide monohydrate (170 mg) was then added to the reaction and stirred for 18 hours at phase silver. At the end of the reaction, the solvent was concentrated, dissolved in dichloromethane (DCM, 50 mL) and the insoluble solid was filtered off. The filtrate was concentrated and solidified using diethyl ether and nucleic acid to obtain the target compound.
  • DCM dichloromethane
  • Example 62 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N-((R) Preparation of -l-hydroxypropan-2-yl) benzamide hydrochloride
  • Example 60 Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Example 60 (600 mg) and dichloromethane (DCM, 50 mL) were dissolved by stirring, and dissolved in 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 and stirred at room temperature for 5 hours.
  • DCM dichloromethane
  • Example 61 above except for using (R) -3-amino-1,2-propanedi instead of using (R)-(-)-2-amino-1-propanol
  • the target compound was obtained by the same method.
  • Example 64 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -3-fluoro-N Preparation of-((S) -2,3-dihydroxypropyl) benzamide trifluoroacetate
  • Example 62 above except for using (R) -3-amino-1,2-propanediol instead of using (R)-(-)-2-amino— 1-propane
  • the target compound was obtained by the same method as the method of 62.
  • Example 61 Except for using (R)-(-)-2-amino-1-propane in Example 61 was carried out in the same manner as in Example 61 to obtain the target compound.
  • Example 62 Except for using (R)-(-)-2-amino-1-propanol in Example 62 was carried out in the same manner as in Example 62, except that pylinol was used to obtain the target compound.
  • Example 61 Except for using 2-amino-1,3-propanedi instead of using (R)-()-2-amino-1-propanol in Example 61, The target compound was obtained in the same manner as in Example 61.
  • H ⁇ R 400 Hz, D 2 0: ⁇ 7.50 (2H, m), 7.10 (1H, t), 4.30 (lH, m), 4.20 (2H, m), 4.10 (2H, m), 3.74 (3H, m), 3.62 (2H, t), 3.43 (2H, t), 2.82 (lH, m), 2.30 (lH, m), 2. ll (lH, m), 1.35 (3H, d), 1.10 (6 H, d).
  • Example 70 4- (3- (4- (3-isopropyl-l, 2,4-oxadiazol-5-yl) piperazin-l-yl) butoxy) -3-pullouro- Preparation of N- (l, 3-dihydroxypropane-2-yl) benzamide hydrochloride
  • Example 62 was carried out in the same manner as in Example 62, except that 2-amino-1,3-propanedi was used instead of (R)-(-)-2-amino-1-propanolol. To obtain the target compound.
  • Example 61 above except for using (S) -3-amino-1,2-propanedi instead of using (R)-(-)-2-amino-1-propane
  • the target compound was obtained by the same method as described above.
  • a target compound was obtained by the same method as described in 6, except that the compound prepared in Preparation Example 10 was used instead of the compound prepared in Preparation Example 2.
  • Step 2 Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Step 2 (1.4 g) and dimethylformamide (DMF, 40 mL) were injected and stirred to dissolve, followed by the compound prepared in Preparation Example 25 (1.3 g) and potassium carbonate (1 g) were added and isothermalized at 50 ° C. and stirred for 24 h.
  • the temperature was cooled to room temperature, distilled water (30 mL) was added slowly, and 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, concentrated and purified by silica column chromatography to obtain the target compound.
  • EA ethyl acetate
  • Step 5 ethyl 4- (00—3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin— 1-yl) butoxy) -2-fluorobenzo Preparation of ate oxalate
  • the compound (600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) prepared in step 4 were added thereto, stirred, and dissolved.
  • Compound (350 mg) prepared in 19 was added and silver was isothermally stirred to 70 ° C.
  • Distilled water (20 ml) was added slowly and extracted with ethyl acetate (EA, 60 mL).
  • Example 73 Into a 100 mL flask under a nitrogen atmosphere, the compound (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) prepared in Example 73 were injected and stirred to dissolve. Then, lithiumhydride-side monohydrate (170 mg) was added to the reaction product and stirred for 18 hours at phase silver. At the end of reaction, the solvent was concentrated and then dissolved in dichloromethane (DCM, 50 mL) and the insoluble solid was filtered off. The filtrate was concentrated and solidified with diethyl ether and nucleic acid to obtain the target compound.
  • DCM dichloromethane
  • Example 60 Prepared in Example 60 above in a 100 mL flask under nitrogen atmosphere Compound (600 mg) and dichloromethane (DCM, 50 mL) were injected and stirred to dissolve, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 420 mg) and 1 -Hydroxybenzotriazole monohydrate (KOBt, 290 mg) was added and stirred for 30 minutes. Then (R) -3-amino- 1,2-propane was added (200 mg) and stirred for 5 hours at phase silver.
  • DCM dichloromethane
  • Example 73 except that (S)-(+) -l, 3-butanediol was used instead of (R)-(-)-l, 3-butanedi in Example 73.
  • the target compound was obtained by the same method.
  • Example 74 was carried out 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, to obtain the target compound.
  • 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.
  • HIT-T15 cells Korea Cell Line Bank
  • beta cells derived from hamsters containing GPR-119 were used to accumulate intracellular cAMP activation due to stimulation of GPR119.
  • 60,000 HIT-T15 cells were plated per well in 96-well plates. The day after plating, cells were treated with various concentrations of the compounds according to the invention and incubated at 37 ° C. for 1 hour. At this time, the compound to be treated was treated at a concentration of 6 in the range of 0.0032 to 10 ⁇ .
  • cAMP activity was measured using the 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 Flex Station (Molecular Devices). D2 and cryptate showed fluorescence resonance energy transfer (FRET) when very close, and were measured at a fluorescence ratio of 665 nm / 620 nm. Unlabeled c P in cell lysate was cryptate labeled The antibody competed with D2 labeled cAMP.
  • FRET fluorescence resonance energy transfer
  • FRET Fluorescence Resonance Energy Transition
  • the activity of the compound was calculated to the extent of fluorescence resonance energy transfer (FRET) signal change through the amount of dimethyl sulfoxide (DMS0).
  • FRET fluorescence resonance energy transfer
  • the compounds according to the invention were shown to activate cAMP.
  • the 74 compounds evaluated for activating cAMP more than half of the compounds of about 55> were found to have EC 50 values of 2 ⁇ M or less, particularly in 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 have EC 50 values in nanomolar units of 1 ⁇ or less appear.
  • piperazine derivatives according to the present invention as a GPR119 receptor it can be seen that the effect of activating cAMP is excellent.
  • the L- piperazin derivative according to the present invention is excellent in activating cAMP and can be treated by activating J GPR119, obesity, type I diabetes mellitus, inadequate glucose tolerance, It can be usefully used as a pharmaceutical composition for the prevention or treatment of insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X.
  • Experimental Example 2 Evaluation of cAMP Activity in CH0-K1 Cells Overexpressing GPR119 Receptor
  • CH0 cells were plated in 96-well plates with RPMI (Wel lgene) medium containing 100 ⁇ L of 10% FBS, 100 ug / ml penicillin (penici 1 ⁇ ), and 100 ⁇ g / ml streptomycin. Plated at 4 cells / well. Then, the plasmid expressing human GPRU9 in pCMV6-XL5 vector (Origene, C216685) and the plasmid expressing GPR119 in mouse (Origene, MR224908) were transferred to the CH0 cells using FuGENE6 reagent (Promega, E2311). Transfection.
  • RPMI Wel lgene
  • HBSS Hanks buffered salt solut ion, welgene, LB containing 5 mM HEPES (Gibco, 15630-106), 0.5 mM IBMX (sigma, 15879) and 0.1% BSA (sigma, A7030). 003-03) was incubated in a C0 2 incubator for 10 minutes.
  • Compounds according to the invention in HBSS medium were diluted to various concentration ranges (10, 2, 0.4, 0.08, 0.16, 0.0032 ⁇ ), treated to cells and incubated in a 37 ° C., CO 2 incubator for 90 minutes.
  • Instant cAMP was measured using two step protoc in HTRF (Homogeneous Time-Resolved Fluorescence, CISBI0, 62AM4PEB) technique.
  • the cAMP-d2 and anti-cAMP cryptate conjugates were mixed in the cells and reacted in the silver for 3 hours, followed by fluorescence (f hiorescence, excitation wavelength: 337 nm) using flexation (Flexstat ion, Molecular Devices). , Emission wavelength: 665 nm, 620 nm).
  • the result was calculated as ⁇ F () value as the control group was not activated, converted to EC 50 (y M) value using the degree of activation (%) by treatment with the compoundol according to the present invention, 3 is shown.
  • the piperazine derivatives according to the present invention are used in both human and mouse GPR119 overexpressed cell lines. It has been shown to have an effect of activating cAMP.
  • the compound of Example 75 (R-form), which is the structural isomer of Example 55 was shown to have an EC 50 value with nanomolar units, whereas the compound (S-form) of Example 78 was from 2 y M to 4 It was found to have an EC 50 value of ⁇ ⁇ . From this, it can be seen that the piperazine derivatives according to the present invention have an excellent effect of promoting GPR119 in humans and mice, and thus the cAMP promoting effect is excellent.
  • Example 55 which is a racemate prepared according to the present invention, and the structural isomers thereof, through the EC 50 value of the compounds of Examples 75 (R-form) and Example 78 (S-form) It can be seen that the R-form structural isomer has a better effect of activating cAMP than the -form structural isomer. Therefore, the novel piperazine derivatives according to the present invention have an excellent effect of activating cAMP by promoting GPR119, and thus, obesity, type I diabetes, type II diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, It can be usefully used as a pharmaceutical composition for the prevention or treatment of hyperlipidemia, hyperlipidemia, hypercholesterolemia, dyslipidemia or syndrome X.
  • Experimental Example 3 Oral Glucose Tolerance Test Oral Glucose Tolerance Test;
  • glucose (2 g / kg) was orally administered at a dose of 10 mL / kg.
  • Blood glucose was measured using Accusek Active Co., Ltd. (Rosche diagnostic Co.) and measurement time was measured by puncture of the microvenous veins at -30, 0, 20, 40, 60 and 120 minutes based on the time of glucose administration. The results are shown in Table 4 below.
  • the compounds according to the present invention were found to have an AUC (area under curve) drop effect of about 16 to 23%.
  • the compounds of Comparative Examples 1 to 3, which are conventionally known as an activator of GPR119 were found to have an AUC (area under curve) strengthening effect of 16% or less compared to the compound according to the present invention. From this, it can be seen that the piperazine derivatives according to the present invention have considerably superior AUC (area under curve) lowering effects compared to the compounds known as activators of the conventional GPR119. Therefore, the novel piperazine derivatives according to the present invention have an excellent effect of activating cAMP by promoting GPR119.
  • obesity can be usefully used as a pharmaceutical composition for the prevention or treatment of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X.
  • Piperazine Derivative Salt of Example 75 was dissolved in distilled water at a concentration of 2 mg / mL, transferred to a vial, decomposed for about 1 hour, and then 300 for about 24 hours. Shake at rpm and mix. Thereafter, the solution is centrifuged at 10000 rpm at 25 ° C for 10 minutes, the supernatant is filtered and transferred to the vial to prepare a test solution.
  • a sample solution was prepared at a concentration of 2.5 mM, diluted in 1/10 times methyl alcohol, and then diluted 1/2 fold sequentially to prepare calibration solutions having five different concentrations.
  • the solubility of the piperazine derivative prepared in Example 75 according to the present invention was 5267 ⁇ , and the pharmaceutically acceptable salt thereof was more than 25000 ⁇ in water.
  • Comparative Examples 1 and 2 which are conventionally known as GPR119 activators, the solubility in water was markedly low. From this, it can be seen that the piperazine derivatives according to the present invention are remarkably superior in solubility in water to at least 3000 times compared to the compounds known in the art as GPR119 activators.
  • the novel piperazine derivatives according to the present invention not only have an excellent effect of activating GPR119 and promoting c P, but also have a superior solubility in water as compared to a compound known as a GPR119 activator.
  • Absorption, type I diabetes, type ⁇ diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, or X which can be treated by activating GPR119 due to its excellent absorption rate. It can be usefully used as a pharmaceutical composition for the prevention or treatment of syndrome.
  • HEK293 human embryonic kidney 293 cells in which the expression of the HERG channel was stably maintained, and the inhibition level of the HERG channel were confirmed by the positive control group, astemizole.
  • the method of measuring the total cell current includes a convexial patch-clamp technique or a port-a-patch (Nanion germany) semi-passive technique, which measures the microcurrent through the cell membrane.
  • the composition of the extracellular perfusion solution and the intracellular perfusion solution used in the experiment is as follows.
  • the extracellular perfusion solution was formulated with 136 mM sodium chloride (NaCl), 5.4 mM potassium chloride (KCl), 1.8 mM calcium chloride (CaCl 2 ), 1 mM magnesium chloride (MgCl 2 ), 10 mM glucose and 10 mM HEPES and then with sodium hydroxide. Titrated to pH 7.4.
  • the intracellular perfusion pipette solution was formulated with 130 mM potassium chloride (KCl), 1 mM magnesium chloride (MgCl 2 ), 10 mM EGTA, 5 mM magnesium-ATP and 10 mM HEPES, and titrated to pH 7.2 with potassium hydroxide.
  • Patch pipettes for conventional patch-clamp techniques were pulled with a PP-83 pipette puller (Nar ishige, Tokyo, Japan) and exhibited a resistance of 2-4 ⁇ to external perfusion solutions.
  • the resulting ion current was described in EPC7 plus am l f iers (HEKA electronic, Germany).
  • the pCl amp computer progr am (Axon Instruments, USA) was used for voltage one-clamp amplification control, data collection, and analysis.
  • the solution was continuously perfused through HEK 293 cells through the chamber.
  • Port-a-Patch (Nanion, Germany)
  • the recording of the semi-automatic patch recording system follows the procedure recommended by Nan ion and the amplifier is EPC10 (HEKA electronic, Germany).
  • the membrane potential was maintained at -80 mV. It moved to +20 mV for 4 seconds and back to -80 mV after moving to -50 mV for 6 seconds. This process was repeated every 25 seconds.
  • the compounds of the comparative example as GPR119 activators have a significant effect of inhibiting the HERG channel, which is important for cardiac toxicity such as arrhythmia, from which the compounds according to the present invention are known.
  • Rae jin can be an example, indicating that cardiac toxicity, such as arrhythmia, is 2-20 times or more lower than GPR119 activator. Therefore, the novel piperazine derivative according to the present invention activates GPR119, and not only has an excellent effect of promoting cAMP, but also significantly lowers cardiac toxicity compared to a compound known as a GPR119 activator.
  • compositions for the prevention or treatment of obesity, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X It can be usefully used as a red composition.
  • the setting is 23 ⁇ 3 ° C, humidity is 55 ⁇ 15%, illuminance is 150-300 Lux, ventilation rash
  • Feed is a laboratory animal feed pellets for sterilization by radiation received (5L79 Lab Diet, Purina Mills, Rich ⁇ mond, IN, USA) the Orient supplied from Bio-free, and to consume water is UV sterilizer, and microfiltration device to be water After sterilization, free sawing was ingested using a water bottle. Water and feed pollutants were inspected in accordance with the relevant SOP of CamOn Co., Ltd.
  • the compound of Example 55 was diluted in excipients (0.5% CMC) at a concentration of 2000 mg / kg, and the test substance was administered intragastricly once a day using a mouse zonde to 5 populations. Twice a day, the general condition, intoxication and death of the animals were observed. The results showed that the LD 50 value of the female ICR mice was more than 2 g / kg. From this, the piperazine derivatives according to the present invention can be seen that the cytotoxicity is very low.
  • the novel piperazine derivatives according to the present invention activate GPR119, and not only have an excellent effect of promoting cAMP, but also have low cytotoxicity and thus have high stability in the human body, obesity treatable by activating GPR119, type I diabetes mellitus. , ⁇ type diabetes mellitus, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, or X-syndrome can be usefully used as a pharmaceutical composition for the prevention or treatment of syndrome.
  • the piperazine derivative of Chemical Formula 1 according to the present invention may be formulated in various forms. The following illustrates a method in which the piperazine derivative represented by 1 according to the present invention is contained as an active phase, and the present invention is not limited thereto.
  • Talc 10 mg The above ingredients are combined and layered in an airtight cloth to prepare a powder.
  • Magnesium stearate 2 nig After mixing the above components and tableting according to the conventional manufacturing method of the tablet to prepare a tablet.
  • Magnesium stearate 2 mg A capsule is prepared by mixing the above ingredients and layering the gelatine capsules according to a conventional capsule preparation method.
  • pH adjuster amount Amount (2) per one ampoule is prepared according to the conventional method for preparing an injection. 1-5. Preparation of liquid
  • Appropriate amount of purified water Dissolve by adding each component to purified water according to the usual method of preparing a liquid solution, add a proper amount of lemon flavor, mix the above components, add purified water and adjust the total to 100 m by adding purified water to a brown bottle Layered and sterilized to prepare a liquid.
  • novel piperazine derivatives, pharmaceutically acceptable salts or isomers thereof according to the present invention have high solubility in water and are excellent in absorption in the body and low in cytotoxicity, as compared to the compounds known as GPR119 activators. This is pretty good. Above all, since the effect of activating GPR119 to promote cAMP is remarkably excellent, the novel piperazine derivatives, pharmaceutically acceptable salts thereof or isomers thereof according to the invention T / KR2013 / 009857

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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 disorders. 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

【명세서 】  【Specification 】
【발명의 명칭 】  【Name of Invention】
신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체， 이의 제조방법 및 이를 유호성분으로 함유하는 대사질환 예방 또는 치료용 약학적 조성물  Novel piperazine derivatives, pharmaceutically acceptable salts thereof, or optical isomers thereof, preparation methods thereof, and pharmaceutical compositions for the prevention or treatment of metabolic diseases containing the same
【기술분야 】 【Technical Fields】
본 발명은 신규한 피페라진 유도체 , 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체， 이의 제조방법 및 이를 유효성분으로 함유하는 대사질환 예방 또는 치료용 약학적 조성물에 관한 것이다.  The present invention relates to a novel piperazine derivative, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating metabolic diseases containing the same as an active ingredient.
【배경기술 】 Background technology
당뇨병은 전 세계적으로 1억 명이 넘는 사람들이 앓고 있는 심각한 질환으로, 사람의 건강을 계속적으로 위협하고 있다. 당뇨병은 I형 및 Π형 의 2개 임상 증후군으로 분류할 수 있다. 인슐린 의존성 당뇨병 (IDDM)으로도 공지된 I형 당뇨병은 인슐린을 생산하는 췌장 베타세포의 자가면역적인 파괴에 의해 비롯되며 외인성 인슬린의 정기적 투여를 필요로 한다. 비인슐린 의존성 당뇨병 (NIDDM)으로도 공지된 II형 당뇨병은 혈당 수치를 적절하게 조절되는 능력이 상실됨으로 나타난다. II형 당뇨병은 인슐린 분비에서의 결함 또는 인슐린 저항 (insulin resistance), 즉 인슐린이 거의 없거나 인슐린을 효과적으로 사용할 수 없는 II형 당뇨병을 앓는 사람들에 의해 특징이 될 수 있다.  Diabetes is a serious disease that affects more than 100 million people worldwide and continues to threaten human health. Diabetes can be classified into two clinical syndromes, type I and Π. Type I diabetes, also known as insulin dependent diabetes (IDDM), is caused by autoimmune destruction of insulin-producing pancreatic beta cells and requires regular administration of exogenous insulin. Type II diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM), appears to lack the ability to properly regulate blood glucose levels. Type II diabetes can be characterized by a deficiency in insulin secretion or insulin resistance, ie, people with type II diabetes who have little insulin or are unable to use insulin effectively.
데있 한편， 당뇨병은 높은 수치의 글루코스가 혈액 및 소변 주발여적내 .에 축적되고， 이로 인한 과도한 배뇨, 갈증， 배고품， 지방 및 단백 i로현및:러이질 대사와 관련 ebhls 문제를 일으킨다. 이러한 당뇨병은 삶을 위협하는 합병증, 예컨대 시력상실， 신장 부전 및 심장 질환을 일으킬 수 있으며， 안구 후면의 망막에 손상올 유발하는 원인되고， 백내장 및 녹내장의 위험성을 증가시킨다. 또한, 다리 및 발의 신경 손상과 관련하여 통증을 느끼는 능력을 방해하고， 심각한 감염의 원인이 되기도 한다. 종래， 당뇨병에 대한 현재의 치료에는 인슐린， 인슐린 분비촉진제， 글투코스 저하 이펙터 (effector) , 퍼옥시좀 증식자- 활성화된 수용체 (PPAR)의 활성화제 등이 있다 . 그러나, 저혈당， 체중 증가, 시간 경과에 따른 치료에 대한 반응성 감소， 위장관 문 부종을 포함하여， 현재 이용 가능한 치료법과 관련된 문제들이 이에 따른 더욱 효과적인 새로운 치료법을 시장에 도입하기 위해 영역을 목표로 연구가 이루어지고 있으며， 하나의 구체적인 Deit On the other hand, diabetes is high levels of glucose accumulate in the blood and urine within the bowl yeojeok, resulting in excessive urination, thirst, baegopum, fat and protein, and i rohyeon: Russia raises issues related ebhls and dysentery metabolism. Such diabetes can cause life-threatening complications such as blindness, 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 cause serious infections. Conventionally, current treatments for diabetes include insulin, insulin secretagogues, glucose lowering effectors, and activators of peroxysome proliferator-activated receptors (PPARs). However, issues related to currently available therapies, including hypoglycemia, weight gain, decreased responsiveness to treatment over time, and gastrointestinal edema, are aimed at areas aimed at bringing new, more effective therapies to market. Being done, one specific
GPR119이다 . GPR119는 췌장， 소장, 결장 및 지방 조직에서 발현되는 G-단백질 커풀링된 수용체 (GPCR)이다. 최근， GPR119 프로파일은 비만 및 당뇨병의 치료를 위한 잠재적 유용성을 가진다는 연구결과가 발표되고 있다 GPR119 활성화는 cAMP를 자극하여 글루코스 의존적인 GLP-1 및 인슬린 분비를 유도하는 것으로 입증되었다 (비특허문헌 1). 또한， 혈장 글루코스 수준에 대한 효과 이외에도， GPR119 활성화제는 만성투여 이후에 래트에서의 급성 음식 섭취의 감소를 일으키고， 체중을 감소시키는 것으로 입증되었다 (특허문헌 1 내지 2 및 비특허문헌 2) GPR119. GPR119 is a G-protein coupler receptor (GPCR) expressed in the pancreas, small intestine, colon and adipose tissue. Recently, GPR119 Studies have shown that the profile has potential utility for the treatment of obesity and diabetes. GPR119 activation has been demonstrated to stimulate cAMP to induce glucose-dependent GLP-1 and insulin secretion (Non-Patent Document 1). In addition to effects on plasma glucose levels, GPR119 activators have been demonstrated to cause acute food intake in rats after chronic administration and to reduce body weight (Patent Literatures 1 and 2 and Non-Patent Literature 2).
적 ¬.¬ Ever ¬.¬
다이 른의은  Silver of dyren
GPR119의 대사질환관련 연구결과들이 속속 발표됨에 따라 GPR119 활성화제의 개발도 더욱 활발히 진행되고 있다.  As the results of GPR119's metabolic diseases have been published one after another, the development of GPR119 activators has been progressing more actively.
먼저， 삼중치환된 해테로아릴 유도체에 대한 관심이 높아지면서 삼중치환된 피리미딘 유도체를 이용한 대사질환 치료제가 보고된 바 있다 (특허문헌 3).  First, as interest in triple-substituted heteroaryl derivatives increases, a metabolic disease therapeutic agent using triple-substituted pyrimidine derivatives has been reported (Patent Document 3).
또한， 인슐린 저항과 관련된 Π형 당뇨병에 대한 치료제로서 IC-GPCR2 또는 GPR119를 활성화하는 것을 특징으로 하는 아릴 , 헤테로아릴 또는 해테로사이클릴 유도체들을 이용한 당뇨병 치료제에 대하여 보고된 바 있다 (특허문헌 4 내지 특허문헌 6).  In addition, it has been reported for a diabetes treatment using aryl, heteroaryl or heterocyclyl derivatives, characterized in that activating IC-GPCR2 or GPR119 as a treatment for type II diabetes associated with insulin resistance (Patent Documents 4 to 4). Patent document 6).
그러나, 현재까지 피페라진 골격을 갖는 화합물 및 이의 당뇨병 치료 용도에 대해서는 알져진 바 없다 . 이에， 본 발명자들은 GPR119에 대한 활성화제를 연구하던 중， 본 발명에 따른 신규한 피페라진 유도체 , 이의 약학적으로 허용가능한 염 또는 이의 이성질체가 물에 대한 용해도가 우수하고 , 인체에 대한 안정성이 높을 만 아니라 GPR119를 활성화됨으로써 cAMP를 촉진시키는 것을 확인하고 본 발명을 완성하였다 선행기술문헌]  However, to date, there is no known compound having a piperazine skeleton and its use in the treatment of diabetes. Accordingly, the present inventors, while studying the activator for GPR119, the novel piperazine derivatives, pharmaceutically acceptable salts or isomers thereof according to the present invention has excellent solubility in water and high stability to the human body. As well as activating GPR119 confirmed to promote cAMP and completed the present invention]
특허문헌 1) 국제공개공보 제 2005/007647호；  Patent Document 1) International Publication No. 2005/007647;
특허문헌 2) 국제공개공보 제 2005/007658호；  Patent Document 2) International Publication No. 2005/007658;
(특허문헌 3) 국제공개공보 제 2004/065380호；  (Patent Document 3) International Publication No. 2004/065380;
특허문헌 4) 국제공개공보 제 2008/083238호；  Patent Document 4) International Publication No. 2008/083238;
특허문헌 5) 국제공개공보 제 2008/081206호；  Patent Document 5) International Publication No. 2008/081206;
특허문헌 6) 국제공개공보 제 2008/081208호 .  Patent Document 6) International Publication No. 2008/081208.
비특허문헌 1)T. Soga et al . , Biochem . B i ophy Res . Commu . 326, (2005)， 744-751；  Non-Patent Document 1) T. Soga et al. , Biochem. B i ophy Res. Commu. 326, (2005), 744-751;
(비특허문헌 2)0verton, H.A. et al Cell metabolism 3， (2006)， 167-175.  (Non-Patent Document 2) 0 Verton, H.A. et al Cell metabolism 3, (2006), 167-175.
【발명의 상세한 설명】 [Detailed Description of the Invention]
【기술적 과제】  [Technical problem]
발명의 목 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 광학이성질체를 제공하는데 있다.  An object of the present invention is to provide novel piperazine derivatives, pharmaceutically acceptable salts or optical isomers thereof.
발명의 목적은 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체의 제조방법올 제공하는데 있다. The object of the invention is a novel piperazine derivative, To provide a pharmaceutically acceptable salt or a method for preparing the optical isomer thereof.
본 발명의 또 다른 목적은 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체를 유효성분으로 함유하는 대사질환 예방 또는 치료용 약학적 조성물을 제공하는데 있다.  Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases, which contains a novel piperazine derivative, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.
【기술적 해결방법 】 【Technical Solution】
상기 목적을 달성하기 위하여，  In order to achieve the above object ，
본 발명은 하기 화학식 1로 표시되는 신규한 피페라진 유도체 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체를 제공한다.  The present invention provides a novel piperazine derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.
[화학식 1]
Figure imgf000004_0001
[Formula 1]
Figure imgf000004_0001
(상기 화학식 1에서， A, B, R 및 n은 본 명세서에서 정의한 바와 같다).  (In Formula 1, A, B, R and n are as defined herein).
또한， 본 발명은 상기 화학식 1로 표시되는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체의 제조방법을 제공한다.  In addition, the present invention provides a novel piperazine derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.
나아가， 본 발명은 상기 화학식 1로 표시되는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체를 유효성분으로 함유하는 대사질환 예방 또는 치료용 약학적 조성물을 제공한다.  Furthermore, the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, which comprises a novel piperazine derivative represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.
【유리한 효과】 Advantageous Effects
본 발명에 따른 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 이성질체는 종래에 GPR119 활성화제로 알려진 화합물들에 비하여 물에 대한 용해도가 높아 체내 흡수력이 우수하며， 세포독성이 낮아 인체에 안정성이 상당히 뛰어나다. 무엇보다， GPR119를 활성화하여 cAMP를 촉진시키는 효과가 현저히 우수하므로， 본 발명에 따른 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 이성질체는 GPR119를 활성화시킴으로써 치료가능한 비만, I 형 당뇨병 , Π형 당뇨병， 부적합한 내당력， 인슐린 내성， 고혈당증， 고지질혈증， 고중성지방혈증, 고콜레스테를혈증， 이상지질혈증 또는 X 증후군의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다.  The novel piperazine derivatives, pharmaceutically acceptable salts or isomers thereof according to the present invention have high solubility in water and are excellent in body absorption and low in cytotoxicity compared to the compounds known as GPR119 activators. This is pretty good. Above all, the effect of activating GPR119 to promote cAMP is remarkably excellent, so that the novel piperazine derivatives, pharmaceutically acceptable salts or isomers thereof according to the present invention can be treated by activating GPR119 to treat obesity, type I diabetes, It can be usefully used as a pharmaceutical composition for the prevention or treatment of type Π diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X.
【발명의 실시를 위한 최선의 형태】 [Best form for implementation of the invention]
이하， 본 발명을 상세히 설명한다ᅳ 본 발명은 하기 화학식 1로 표시되는 신규한 피페라진 유도체 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체를 제공한다. 【화학식 1】
Figure imgf000005_0001
Hereinafter, the present invention will be described in detail. The present invention provides a novel piperazine derivative represented by the following Chemical Formula 1. It provides a pharmaceutically acceptable salt or optical isomer thereof. [Formula 1]
Figure imgf000005_0001
상기 화학식 1에서  In Chemical Formula 1
Α는 비치환되거나 치환된 페닐 ; 또는 비치환되거나 치환된 헤테로아릴이고;  A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
R은 — C00R' ; 또는 비치환되거나 치환된 해테로아릴이고;  R is — C00R '; Or unsubstituted or substituted heteroaryl;
B는 비치환되거나 치환된 d-C5의 직쇄 또는 측쇄 알킬 또는 비치환되거나 치환된 d-Cs의 직쇄 또는 측쇄 할로알킬이고; B is unsubstituted or substituted straight or branched chain alkyl of dC 5 or unsubstituted or substituted d-Cs straight or branched haloalkyl;
상기 , 헤테로아릴은 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1 내지 4의 해테로 원자를 포함하는 5원 또는 6원의 헤테로아릴이고:  Wherein, heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S:
상기 치환된 페닐 또는 치환된 헤테로아릴은 SOR' , -S(0)2R' , -R'S(0)2 ", -NHS(0)2R' , -CN, 할로겐， d-Cs의 직쇄 또는 측쇄 할로알킬， d-C5의 알케닐기， -R' , =0, -COR' , -C00R' , -CONR'R" , - NR'R" 및 N, 0 및 S로 이루어진 군으로부터 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 해테로아릴로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 페닐 또는 치환된 해테로아릴이고; The substituted phenyl or substituted heteroaryl may be a straight chain of SOR ', -S (0) 2 R', -R'S (0) 2 ", -NHS (0) 2 R ', -CN, halogen, d-Cs or Branched haloalkyl, an alkenyl group of dC 5 , -R ', = 0, -COR', -C00R ', -CONR'R ", -NR'R" and 1 to 1 selected from the group consisting of N, 0 and S Phenyl or substituted heteroaryl substituted with one or more substituents selected from the group consisting of five or six membered heteroaryl containing a hetero atom of 4;
여여기기서서，， R' 또는 R' '는 각각 독립적으로 수소; 또는 비치환되거나 1 이상의 하이드록시기로 치환된 d-Cs의 직쇄 또는 측쇄 알킬이고; 또는 R' 및 R' '는 이들이 결합되어 있는 N과 함께 1 내지 Wherein R 'or R' 'are each independently hydrogen; Or straight or branched chain alkyl of d-Cs unsubstituted or substituted with one or more hydroxy groups; Or R ′ and R ′ ′ are 1 to together with N to which they are attached
4의 N, 0 및 S로 이루어진 군으로부터 선택되는 헤테로 원자를 포함하는 5원 또는 6원의 헤테로사이클릴을 형성할 수 있고; 및 To form a 5 or 6 membered heterocyclyl including a hetero atom selected from the group consisting of N, 0 and S of 4; And
n은 1 내지 10의 정수이다. 본 발명에 따른 상기 화학식 1의 화합물쎄 있어서，  n is an integer from 1 to 10. In the compound of Formula 1 according to the present invention,
바람직하게는,  Preferably,
상기 A는 비치환되거나 치환된 페닐 ; 또는 비치환되거나 치환된 헤테로아릴이고;  A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
여기서， 상기 해테로아릴은 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 해테로아릴이고;  Wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S;
상기 치환된 페닐은 -S(0)2R' , -R'S(0)2R" , 할로겐， -R' , -C00R ' , -CONR'R" 및， N, 0 및 S로 이투어진 군으로부터 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 헤테로아릴로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 페닐이고; 여기서， R'또는 R"는 각각 독립적으로 수소; 또는 비치환되거나 1 이상의 하이드록시기로 치환된 d-C5의 직쇄 또는 측쇄 알킬이고 ; 또는 R' 및 R"는 이들이 결합되어 있는 N과 함께 1 내지 4의 N, 0 및 S로 이루어진 군으로부터 선택되는 해테로 원자를 포함하는 5원 또The substituted phenyl is selected from the group consisting of -S (0) 2 R ', -R'S (0) 2 R ", halogen, -R', -C00R ', -CONR'R", and N, 0 and S Phenyl substituted with one or more substituents selected from the group consisting of 5- or 6-membered heteroaryl containing 1 to 4 hetero atoms selected; Wherein R ′ or R ″ are each independently hydrogen; or straight or branched chain alkyl of dC 5 unsubstituted or substituted with one or more hydroxy groups; or R ′ and R ″ together with N to which they are attached 1-4 With N, 0 and S A five-member containing heteroatoms selected from the group consisting of
6원의 해테로사이클릴을 형성할 수 있고; 및 Can form a six membered heterocyclyl; And
상기 치환된 헤테로아릴은 -R'또는 -S(0)2R'로 치환된 헤테로아릴이고; 여기서 , R'은 d-C5의 직쇄 또는 측쇄 알킬이고: 더욱 바람직하게는， The substituted heteroaryl is heteroaryl substituted with —R ′ or —S (0) 2 R ′; Wherein R 'is straight or branched alkyl of dC 5 : more preferably,
상기 A는 비치환되거나 치환된 페닐 ; 또는 비치환되거나 치환된 피리딘이고;  A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridine;
상기 치환된 페닐은 메탄설포닐， 메탄설포닐메틸， 1- 메탄설포닐에틸， 폴루오로， 클로로, 브로모， 메틸 , 에틸， 에록시카보닐 , 하이드특시이소프로필아미노카보닐 , 다이하이드록시프로필아미노카보닐，  The substituted phenyl is methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl, polouro, chloro, bromo, methyl, ethyl, ethoxycarbonyl, hydroxyisoisopropylaminocarbonyl, dihydroxy Propylaminocarbonyl ，
다이하이드특시이소프로필아미노카보닐， 피를리딜카보닐 및 테트라졸릴로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 페닐이고; 및 Phenyl substituted with one or more substituents selected from the group consisting of dihydrisoisopropylaminocarbonyl, pyridylcarbonyl and tetrazolyl; And
상기 치환된 피리딘은 메틸， 에틸 및 메탄설포닐로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 피리딘이다. 또한， 본 발명에 따른 상기 화학식 1의 화합물에 있어서， 바람직하게는  The substituted pyridine is pyridine substituted with one or more substituents selected from the group consisting of methyl, ethyl and methanesulfonyl. In addition, in the compound of Formula 1 according to the present invention, Preferably
상기 R은 -C00R' ; 또는 비치환되거나 치환된 해테로아릴이고; 여기서， 상기 헤테로아릴은 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1 내지 4의 해테로 원자를 포함하는 5원 또는 6원의 헤테로아릴이고;  R is -C00R '; Or unsubstituted or substituted heteroaryl; Wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S;
상기 치환된 해테로아릴은 d-Cs의 직쇄 또는 측쇄 알킬로 치환된 헤테로아릴이고;  The substituted heteroaryl is heteroaryl substituted with straight or branched chain alkyl of d-Cs;
더욱 바람직하게는,  More preferably,
상기 R은 t-부톡시카보닐 ; 또는 비치환되거나 치환된 피리미딘 또는 옥사다이아졸이고;  R is t-butoxycarbonyl; Or unsubstituted or substituted pyrimidine or oxadiazole;
상기 치환된 피리미딘 또는 옥사다이아졸은 메틸， 에틸 , 프로필 이소프로필 , 부틸 및 t—부틸로 이루어진 군으로부터 선택되는 1 종 이상의 치환기로 치환된 해테로아릴이다. 또한, 본 발명에 따른 상기 화학식 1의 화합물에 있어서， 바람직하게는,  The 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 addition, in the compound of Formula 1 according to the present invention, Preferably,
상기 B는 비치환되거나 치환된 d-Cs의 직쇄 또는 측쇄 알킬기이고; 더욱 바람직하게는，  B is an unsubstituted or substituted d-Cs straight or branched alkyl group; More preferably,
상기 B는 메틸 , 에틸 또는 프로필이다 나아가， 본 발명에 따른 상기 화학식 1의 화합물에 있어서 더욱 바람직하게는 상기 A는 비치환되거나 치환된 페닐 ; 또는 비치환되거나 치환된 헤테로아릴이고; B is methyl, ethyl or propyl. Furthermore, in the compound of Formula 1 according to the present invention, A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
여기서， 상기 헤테로아릴은 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 헤테로아릴이고;  Wherein said heteroaryl is a 5 or 6 membered heteroaryl including 1 to 4 hetero atoms independently selected from the group consisting of N, 0 and S;
상기 치환된 페닐은 -S(0)2R' , -R'S(0)2 " , 할로겐， -R' , -C00R' -CONR'R" 및 , Ν, 0 및 S로 이루어진 군으로부터 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 해테로아릴로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 페닐이고; 여기서， R'또는 R"는 각각 독립적으로 수소; 또는 비치환되거나 1 이상의 하이드톡시기로 치환된 d-Cs의 직쇄 또는 측쇄 알킬이고; 또는 R' 및 R"는 이들이 결합되어 있는 N과 함께 1 내지 4의 N, 0 및 S로 이루어진 군으로부터 선택되는 헤테로 원자를 포함하는 5원 또는 6원의 헤테로사이클릴을 형성할 수 있고; The substituted phenyl is -S (0) 2 R ', -R'S (0) 2 ", halogen, -R', -C00R '-CONR'R" and 1 selected from the group consisting of Ν, 0 and S Phenyl substituted with one or more substituents selected from the group consisting of 5- or 6-membered heteroaryl containing hetero atoms of 4 to 4; Wherein R 'or R "are each independently hydrogen; or straight or branched chain alkyl of d-Cs unsubstituted or substituted with one or more hydroxy groups; or R' and R " together with N to which they are attached To form a 5 or 6 membered heterocyclyl including a hetero atom selected from the group consisting of N, 0 and S of 4 to 4;
상기 치환된 헤테로아릴은 또는 -S(0)2R'로 치환된 헤테로아릴이고; 여기서， R'은 의 직쇄 또는 측쇄 알킬이고; The substituted heteroaryl is or heteroaryl substituted with —S (0) 2 R ′; Wherein R 'is straight or branched alkyl of;
상기 R은 — C00R' ; 또는 비치환되거나 치환된 헤테로아릴이고; 여기서 , 상기 헤테로아릴은 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 헤테로아릴이고;  R is — C00R '; 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, 0 and S;
상기 치환된 해테로아릴은 d-C5의 직쇄 또는 측쇄 알킬로 치환된 헤테로아릴이고; The substituted heteroaryl is heteroaryl substituted with straight or branched chain alkyl of dC 5 ;
B는 비치환되거나 치환된 d-Cs의 직쇄 또는 측쇄 알킬기이고; n은 1 내지 5의 정수이며 ;  B is an unsubstituted or substituted d-Cs straight or branched alkyl group; n is an integer of 1 to 5;
더욱 더 바람직하게는，  Even more preferably,
상기 A는 비치환되거나 치환된 페닐 ; 또는 비치환되거나 치환된 피리딘이고;  A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridine;
상기 치환된 페닐은 메탄설포닐， 메탄설포닐메틸， 1- 메탄설포닐에틸 플루오로, 클로로， 브로모， 메틸 , 에틸， 에특시카보닐， 하이드록시이소프로필아미노카보닐， 다이하이드록시프로필아미노카보닐 ,  The substituted phenyl is methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl fluoro, chloro, bromo, methyl, ethyl, ecoxycarbonyl, hydroxyisopropylaminocarbonyl, dihydroxypropylamino Carbonyl,
다이하이드록시이소프로필아미노카보닐， 피를리딜카보닐 및 테트라졸릴로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 페닐이고; Phenyl substituted with one or more substituents selected from the group consisting of dihydroxyisopropylaminocarbonyl, pyridylcarbonyl and tetrazolyl;
상기 치환된 피리딘은 메틸， 에틸 및 메탄설포닐로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 피리딘이고;  The substituted pyridine is pyridine substituted with one or more substituents selected from the group consisting of methyl, ethyl and methanesulfonyl;
R은 t-부특시카보닐 ; 또는 비치환되거나 치환된 피리미딘 또는 옥사다이아졸이고;  R is t-subspecific carbonyl; Or unsubstituted or substituted pyrimidine or oxadiazole;
상기 치환된 피리미딘 또는 옥사다이아졸은 메틸 , 에틸 , 프로필 , 이소프로필， 부틸 및 t-부틸로 이루어진 군으로부터 선택되는 1 종 이상의 치환기로 치환된 헤테로아릴이고;  The 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;
B는 메틸 , 에틸 또는 프로필이고; 및 n은 1 내지 5의 정수이다. 또한， 본 발명에 따른 상기 화학식 1의 화합물에 있어서 가장 바람직하게는， B is methyl, ethyl or propyl; And n is an integer of 1-5. In addition, most preferably in the compound of Formula 1 according to the present invention,
Figure imgf000008_0001
Figure imgf000008_0001
B는 메틸이고; 및  B is methyl; And
n은 1 내지 3의 정수이다. 상기 화학식 1로 표시되는 신규한 피페라진 유도체의 구체적인 실시예 화합물은 하기와 같다.  n is an integer of 1-3. Specific examples of the novel piperazine derivative represented by Chemical Formula 1 are as follows.
(1) t-부틸 -4— (4-(4- (메틸설포닐 )페녹시 )부탄 -2-일 )피페라진 -1- 카르복실레이트 옥살산염；  (1) t-butyl-4— (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalate;
(2) t-부틸— 4-(4-(2-플루오로 -2- ((메틸설포닐)메틸)페녹시 )부탄 -2-일 )피페라진 -1-카르복실레이트 옥살산염； (2) t-butyl- 4- (4- (2-fluoro-2- ((Methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalate;
(3) 2-(4-(4-(4— (메틸설포닐 )페녹시 )부탄 -2ᅳ일 )피페라진 -1-일 ) - 5-프로필피리미딘 옥살산염 ;  (3) 2- (4- (4- (4— (methylsulfonyl) phenoxy) butane-2xyl) piperazin-1-yl) -5-propylpyrimidine oxalate;
(4) 2-(4-(4-(3-플루오로 -4- ((메틸설포닐 )메틸)페녹시 )부탄 -2- 일)피페라진 -1ᅳ일 ) -5-프로필피리미딘 ;  (4) 2- (4- (4- (3-fluoro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1xyl) -5-propylpyrimidine;
(5) 2-(4-(4-(3-플루오로 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2- 일)피페라진 -1-일) -5-프로필피리미딘 옥살산염； (6) 1-(4-(3-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 ) -4-(3- 이소프로필 -1,2,4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (5) 2- (4- (4- (3-fluoro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalic acid Salt; (6) 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazol -5-yl) piperazine oxalate;
(7) t-부틸 4-(4-(3-풀루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일)피페라진 -1-카르복실레이트 옥살산염 ;  (7) t-butyl 4- (4- (3-pullouro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalate;
(8) 1-(4-(3-플투오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 ) -4-(3- 이소프로필 -1,2,4-옥사다이아졸—5-일 )피페라진 염산염 ;  (8) 1- (4- (3-Plutouro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole—5 -Yl) piperazine hydrochloride;
(9) 1-(4-(2-플루오로— 4-UH-테트라졸 -1-일)페녹시 )부탄 -2-일 ) - 4-(3-이소프로필 -1，2，4-옥사다이아졸 -5-일")피페라진 ; (9) 1- (4- (2-fluoro—4-UH-tetrazol-1-yl) phenoxy) butan-2-yl)-(4-isopropyl-1,2,4-oxa Diazol-5-yl " ) piperazine;
(10) 1-(4-(2-플루오로— 4-(1Η-테트라졸 -1-일)페녹시 )부탄 -2- 일 ) -4-(3—이소프로필 -1,2，4-옥사다이아졸 -5-일 )피페라진 옥살산염 ; (10) 1- (4- (2-fluoro— 4- (1Η-tetrazol-1-yl) phenoxy) butan-2-yl) -4- (3—isopropyl-1,2,4- Oxadiazole-5-yl) piperazine oxalate;
(11) 1-(4-(2-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 ) -4-(3- 이소프로필 -1，2，4-옥사다이아졸 -5-일)피페라진 옥살산염 ;  (11) 1- (4- (2-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine oxalate;
(12) 1-(4-(3-플루오로 -4-(1Η-테트라졸ᅳ1-일)페녹시 )부탄 -2- 일 )-4-(3-이소프로필 -1,2, 4-옥사다이아졸 -5-일)피페라진 옥살산염 ;  (12) 1- (4- (3-fluoro-4- (1Η-tetrazol-l-yl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2, 4- Oxadiazole-5-yl) piperazine oxalate;
(13) 1-(4-(4- (메틸설포닐)페녹시 )부탄 -2-일) -4-(3-이소프로필- (13) 1- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-
1,2, 4-옥사다이아졸 -5-일 )피페라진 옥살산염； 1,2,4-oxadiazol-5-yl) piperazine oxalate;
(14) 1-(4-(4-(1Η-테트라졸 -1-일)페녹시 )부탄 -2-일 )-4ᅳ(3- 이소프로필 -1,2 ,4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (14) 1- (4- (4- (1Η-tetrazol-1-yl) phenoxy) butan-2-yl) -4 ᅳ (3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine oxalate;
(15) 1-(4-(3， 5—다이플루오로 -4-(1Η-테트라졸 -1- 일 )페녹시 )부탄 -2-일 )-4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진 옥살산염；  (15) 1- (4- (3, 5—difluoro-4- (1Η-tetrazol-1-yl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2 , 4-oxadiazole-5 -yl) piperazine oxalate;
(16) 1 -(4-(4-브로모-2，5-다이플투오로페녹시 )부탄 -2-일 ) -4- ■(3- 이소프로필- 1, 2，4-옥사다이아졸 -5-일 )피페라진 옥살산염； (16) 1-(4- (4-Bromo-2,5-dipletofluorophenoxy) butan-2-yl) -4- ■ (3-isopropyl-1,2,4-oxadiazole- 5-yl) piperazine oxalate;
(17) 1-(4-(3-클로로 -4- (메틸설포닐 )페녹시 )부탄 -2-일) -4- •(3- 이소프로필- 1, 2, 4-옥사다이아졸 -5-일)피페라진 옥살산염 ; (17) 1- (4- (3-chloro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- • (3-isopropyl-1, 2, 4-oxadiazole-5 -Yl) piperazine oxalate;
(18) 1-(4-(3-메틸 -4- (메틸설포닐 )페녹시 )부탄 -2-일). -4- ■(3- 이소프로필- •1, 2,4-옥사다이아졸 -5-일 )피페라진 옥살산염 ; (18) 1- (4- (3-methyl-4- (methylsulfonyl) phenoxy) butan-2-yl). -4- ■ (3-isopropyl- • 1, 2,4-oxadiazol-5-yl) piperazine oxalate;
(19) 1-(4-(5- (메틸설포닐 )피리딘 -2-일옥시 )부탄 ·一 2-일)■ -4- ■(3— 이소프로필 - •1， 2,4-옥사다이아졸 -5-일 )피페라진 옥살산염 ; (19) 1- (4- (5- (methylsulfonyl) pyridin-2-yloxy) butane ·一2- il) ■ ■ -4- (3- isopropyl - • 1, 2,4- oxadiazol Sol-5-yl) piperazine oxalate;
(20) 1-(4-(5- (메틸설포닐 )피리딘 -2-일옥시 )부탄- -2-일 )- -4- ■(3- 이소프로필- .1， 2,4-옥사다이아졸 -5-일 )피페라진 염산염 ; (20) 1- (4- (5- (methylsulfonyl) pyridin-2-yloxy) butane-2-yl) - ■ -4- (3- isopropyl-0.1, 2, 4-oxadiazol Sol-5-yl) piperazine hydrochloride;
(21) 1ᅳ(4-(6- (메틸설포닐)피리딘 3-일옥시 )부탄- -2-일). -4- (3- 이소프로필 -1， 2， 4-옥사다이아졸 -5-일 )피페라진 옥살산염 ; (22) l-(4-(3-클로로 -4- ((메틸설포닐 )메틸)페녹시 )부탄 -2-일 ) - 4-(3-이소프로필 -1,2,4-옥사다이아졸 -5-일 )피페라진 옥살산염 ; (21) 1 ′ (4- (6- (methylsulfonyl) pyridin 3-yloxy) butan-2-yl). 4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine oxalate; (22) l- (4- (3-chloro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazol -5-yl) piperazine oxalate;
(23) 1-(4-(3-클로로 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2-일 ) - 4-(3-이소프로필 -1,2 ,4-옥사다이아졸 -5-일 )피페라진 염산염 ;  (23) 1- (4- (3-chloro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole -5-yl) piperazine hydrochloride;
(24) 1-(4-(3-폴루오로 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2- 일 ) -4ᅳ (3-이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (24) 1- (4- (3-polouro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4 ᅳ (3-isopropyl-1,2,4-oxa Diazol-5-yl) piperazine oxalate;
(25) 1-(4-(2-메틸 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2-일) -4- (3-이소프로필ᅳ 1,2,4-옥사다이아졸— 5-일 )피페라진 옥살산염 ;  (25) 1- (4- (2-methyl-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl ᅳ 1,2,4-oxadiazole —5-yl) piperazine oxalate;
(26) 2-(4-(4-(3ᅳ플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일)피페라진 -1-일) -5-프로필피리미딘 옥살산염 ;  (26) 2- (4- (4- (3'fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate;
(27) l-((R)-4-(3-플루오로— 4- (메틸설포닐 )페녹시 )부탄 -2-일 ) - 4-(3-이소프로필 -1,2 ,4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (27) l-((R) -4- (3-fluoro— 4- (methylsulfonyl) phenoxy) butan-2-yl)-4- (3-isopropyl-1,2,4-oxa Diazol-5-yl) piperazine oxalate;
(28) l-((R)-4-(3-플루오로 -4- (메틸설포닐)페녹시 )부탄 -2-일 ) - 4-(3—이소프로필 -1,2 ,4-옥사다이아졸 -5-일)피페라진 염산염 ;  (28) l-((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxa Diazol-5-yl) piperazine hydrochloride;
(29) 2-(4-(4-(3-플루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일)피페라진 -1-일) -5-프로필피리미딘 염산염 ;  (29) 2- (4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine hydrochloride;
(30) 2-(4-(4-(3-클로로 -4- ((메틸설포닐 )메틸)페녹시 )부탄 -2- 일 )피페라진 -1-일 ) -5-프로필피리미딘 ;  (30) 2- (4- (4- (3-chloro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;
(31) 2-(4-(4-(3-클로로 -4- ((메틸설.포닐)메틸)페녹시 )부탄 -2- 일)피페라진 -1-일) -5-프로필피리미딘 옥살산염 ;  (31) 2- (4- (4- (3-chloro-4-((methylsul.fonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalic acid Salt;
(32) 2-(4-(4-(3-플루오로 -4-(1- (메틸설포닐 )에틸)페녹시 )부탄- 2-일 )피페라진 -1-일 ) -5-프로필피리미딘 옥살산염 ;  (32) 2- (4- (4- (3-fluoro-4- (1- (methylsulfonyl) ethyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyri Midine oxalate;
(33) 1-(4-(2，5-다이플루오로 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2-일 )-4-(3-이소프로필— 1,2,4- 옥사다이아졸 -5-일)피페라진 옥살산염 ;  (33) 1- (4- (2,5-Difluoro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl— 1,2,4 Oxadiazole-5-yl) piperazine oxalate;
(34) 1-(4-(2，5-다이플루오로 -4- (메틸설포닐)페녹시 )부탄ᅳ 2- 일 )-4-(3-이소프로필-1，2，4-옥사다이아졸 -5-일 )피페라진  (34) 1- (4- (2,5-Difluoro-4- (methylsulfonyl) phenoxy) butanyl 2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine
트라이플루오로아세테이트산 염 ; Trifluoroacetate acid salts;
(35) 1-(4-(2，5-다이플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일 ) -4-(3-이소프로필 -1,2,4-옥사다이아졸 -5-일 )피페라진 염산염 ;  (35) 1- (4- (2,5-Difluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine hydrochloride;
(36) 1-(4-(2,6-다이플루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일 )-4-(3-이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (36) 1- (4- (2,6-difluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine oxalate;
(37) 1-(4-(2，6—다이플루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일 )-4— (3-이소프로필 -1,2,4-옥사다이아졸 -5-일)피페라진  (37) 1- (4- (2,6—difluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4— (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine
트라이플루오로아세테이트산 염 ; Trifluoroacetate acid salts;
(38) 1-(4-(2，6-다이폴루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일)— 4-(3-이소프로필 -1,2， 4-옥사다이아졸 -5-일)피페라진 염산염 :  (38) 1- (4- (2,6-difluorouro-4- (methylsulfonyl) phenoxy) butan-2-yl) — 4- (3-isopropyl-1,2, 4-oxadia Sol-5-yl) piperazine hydrochloride:
(39) 1-(4-(5-메틸 -6- (메틸설포닐 )피리딘 -3-일옥시 )부탄 -2-일 ) - 4-(3-이소프로필 -1,2,4-옥사다이아졸 -5-일)피페라진 염산염 ;  (39) 1- (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4 (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine hydrochloride;
(40) 1-(4-(5-메틸 -6- (메틸설포닐)피리딘 -3-일옥시)부탄 -2-일) - · (40) 1- (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl)-
4-(3-이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진 옥살산염 ; 4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine oxalate;
(41) 에틸 -4-(3-(4-(3-이소프로필 -1， 2，4-옥사다이아졸 -5- 일)피페라진 -1-일)부특시 )-2-폴루오로벤조에이트 옥살산염； (42) 4-(3-(4-(3—이소프로필ᅳ1， 2，4-옥사다이아졸 -5 일 )피페라진 -1-일 )부특시 )-2-풀루오로벤조에이트 리튬염 ; (41) Ethyl-4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) partial) -2-polorobenzo Eight oxalates; (42) 4- (3- (4- (3—isopropyl ᅳ 1,2,4-oxadiazol-5 day) piperazin-1-yl) particular))-2-fluorobenzoate lithium salt ;
(43) 에틸 -4-(3-(4— (5-프로필피리미딘 -2-일)피페라진- 일)부톡시 )-2—플투오로벤조에이트 옥살산염 ;  (43) ethyl-4- (3- (4— (5-propylpyrimidin-2-yl) piperazin-yl) butoxy) -2—flutobenzoate oxalate;
(44) 4-(3-(4-(5-프로필피리미딘 -2-일)피페라진 -1-일)부톡시 2-플루오로벤조에이트 리튬염 ;  (44) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy 2-fluorobenzoate lithium salt;
(45) 4-(3-(4-(5-프로필피리미딘 -2-일)피페라진 -1-일)부톡 2-풀루오로 -N-(l,3-다이하이드록시프로판 -2 -일)벤즈아마이드  (45) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy 2-pluoro-N- (l, 3-dihydroxypropane-2- Japanese benzamide
옥살산염； Oxalate;
(46) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1—일 )부톡시 2-플루오로 N-(l,3-다이하이드록시프로판 -2-일 )벤즈아마이드 염산염 ;  (46) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy 2-fluoro N- (l, 3-dihydroxypropan-2-yl ) Benzamide hydrochloride;
(47) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부특시 2-플루오로 N-((S)-1-하이드록시프로판 -2-일 )벤즈아마이드 옥살산염 ;  (47) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) particular 2-fluoro N-((S) -1-hydroxypropane-2- (1) benzamide oxalate;
(48) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진— 1-일 )부록시 2-플루오로 N-((S)-1-하이드록시프로판 -2-일 )벤즈아마이드 염산염； (49) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부톡시 2-풀루오로 N-((S)-2,3-다이하이드록시프로필)벤즈아마이드 옥살산염 (50) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부록시 2-플루오로 N-((S)-2,3-다이하이드록시프로필)벤즈아마이드 염산염 ;  (48) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin— 1-yl) butoxy 2-fluoro N-((S) -1-hydroxypropane-2- Yl) benzamide hydrochloride; (49) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy 2-fluuro N-((S) -2 , 3-dihydroxypropyl) benzamide oxalate (50) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy 2-fluoro N- ( (S) -2,3-dihydroxypropyl) benzamide hydrochloride;
(51) 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5 일 )피페라진 -1-일 )부톡시 )-2-플루오로— N— (1，3-다이하이드록시프로판- 2-일 )벤즈아마이드 옥살산염 ;  (51) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5 day) piperazin-1-yl) butoxy) -2-fluoro—N— (1 , 3-dihydroxypropane-2-yl) benzamide oxalate;
(52) 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5 일 )피페라진 -1-일 )부톡시 )-2-플루오로 -N-( 1,3-다이하이드록시프로판- 2-일 )벤즈아마이드 염산염 ;  (52) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5 day) piperazin-1-yl) butoxy) -2-fluoro-N- (1 , 3-dihydroxypropane-2-yl) benzamide hydrochloride;
(53) 4-(3— (4-(3-이소프로필 -1,2,4-옥사다이아졸 -5 일 )피페라진 -1-일 )부톡시 )-2-플루오로 -N-((R)-1-하이드록시프로판 -2- 일 )벤즈아마이드 옥살산염；  (53) 4- (3— (4- (3-isopropyl-1,2,4-oxadiazol-5 day) piperazin-1-yl) butoxy) -2-fluoro-N-(( R) -1-hydroxypropan-2-yl) benzamide oxalate;
(54) 4-(3-(4-(3-이소프로필-1，2,4-옥사다이아졸-5 일 )피페라진 -1-일 )부톡시 )-2-플루오로 -N-((R)-1-하이드특시프로판 -2- 일 )벤즈아마이드 염산염；  (54) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5 yl) piperazin-1-yl) butoxy) -2-fluoro-N-(( R) -1-Hydroxypropane-2-yl) benzamide hydrochloride;
(55) 4-(3-(4-(3-이소프로필 -1， 2，4-옥사다이아졸 -5 일 )피페라진 -1-일 )부톡시 )-2-플루오로— N-((R)-2,3- 다이하이드톡시프로필)벤즈아마이드 옥살산염 ;  (55) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5 day) piperazin-1-yl) butoxy) -2-fluoro—N-(( R) -2,3-dihydroxypropyl) benzamide oxalate;
(56) 4-(3-(4-(3-이소프로필-1,2,4-옥사다이아졸 -5 일 )피페라진 -1-일 )부톡시 )-2-플루오로 -N-((R)-2,3- 다이하이드특시프로필)벤즈아마이드 염산염 ;  (56) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5yl) piperazin-1-yl) butoxy) -2-fluoro-N-(( R) -2,3-dihydrospecificpropyl) benzamide hydrochloride;
(57) 4-(3-(4-(3-이소프로필 -1,2 ,4-옥사다이아졸 -5 일 )피페라진 -1-일 )부톡시 )-2-플루오로 -N-((R)-2,3- 다이하이드록시프로필)벤즈아마이드 염산염 ;  (57) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5yl) piperazin-1-yl) butoxy) -2-fluoro-N-(( R) -2,3-dihydroxypropyl) benzamide hydrochloride;
(58) (4-(3-(4-(3-이소프로필 -1， 2 ,4-옥사다이아졸 -5 일 )피페라진 -1-일 )부특시 )-2-플루오로페닐) (피를리딘 -1-일 )메타논  (58) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5 day) piperazin-1-yl) subspecial) -2-fluorophenyl) (blood Llidin-1-yl) methanone
< A  <A
ᄆ 나ᄋ · M n a ᄋ,
Γ ϋ ， (59) 에틸 4-(3-(4-(3_이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-플루오로벤조에이트 옥살산염 ; Γ ϋ, (59) 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-이소프로필 -1,2，4-옥사다이아졸 -5- 일)피페라진 -1-일)부톡시 )-3—플루오로벤조에이트 리튬염；  (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—이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일 )부특시 )-N-((R)-l-하이드록시프로판ᅳ2- 일 )벤즈아마이드 옥살산염；  (61) 4- (3- (4- (3—isopropyl-1,2,4-oxadiazol-5-yl) piperazin-l-yl) partial) -N-((R) -1 -Hydroxypropane # 2-yl) benzamide oxalate;
(62) 4-(3-(4-(3-이소프로필 -1,2 ,4-옥사다이 졸 -5- 일 )피페라진 -1-일 )부톡시 )-N-((R)-l-하이드록시프로판 -2- 일 )벤즈아마이드 염산염 ;  (62) 4- (3- (4- (3-isopropyl-1,2,4-oxadizol-5-yl) piperazin-1-yl) butoxy) -N-((R) -1 -Hydroxypropan-2-yl) benzamide hydrochloride;
(63) 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-플투오로 -N-((S)-2,3- 다이하이드톡시프로필)벤즈아마이드 옥살산염：  (63) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-flutouro-N- ( (S) -2,3-dihydroxypropyl) benzamide oxalate:
(64) 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-풀루오로 -N-((S)-2,3- 다이하이드록시프로필)벤즈아마이드 트라이플루오로아세트산염 ;  (64) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3- pullouro-N- ((S) -2,3-dihydroxypropyl) benzamide trifluoroacetic acid salt;
(65) 4-(3— (4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진 -1-일 )부특시 )-N,N-다이에틸 -3-메틸벤즈아마이드  (65) 4- (3— (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) partial) -N, N-diethyl-3 Methylbenzamide
옥살산염； Oxalate;
(66) 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일 )피페라진 -1-일 )부톡시 )-Nᅳ N-다이에틸 -3-메틸벤즈아마이드 염산염； (66) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N ᅳ N-diethyl-3 Methylbenzamide hydrochloride;
(67) (4ᅳ(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부록시 )-3-플루오로페닐) (피를리딘 -1—일 )메타논 옥살산염： (67) (4 '(3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorophenyl) ( Pyridin-1-yl) methanone oxalate ：
(68) (4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-플루오로페닐) (피를리딘 -1-일 )메타논 ᄆ ᄂ Γ σ ，  (68) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorophenyl) ( Pyridin-1-yl) methanone Kb Γ σ ，
(69) 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일 )피페라진 -1-일 )부특시 )-3-플루오로 -N-(l,3-다이하이드록시프로판- 2-일 )벤즈아마이드 옥살산염 ;  (69) 4- (3- (4- (3-isopropyl-l, 2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -3-fluoro-N- ( l, 3-dihydroxypropane-2-yl) benzamide oxalate;
(70) 4-(3-(4ᅳ(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-플루오로 N-(l,3-다이하이드록시프로판- 2-일)벤즈아마이드 염산염；  (70) 4- (3- (4 ᅳ (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro N- (l , 3-dihydroxypropane-2-yl) benzamide hydrochloride;
(71) 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진 -1-일)부톡시 )— 2-플루오로 -N-((R)-2,3- 다이하이드록시프로필)벤즈아마이드 옥살산염 ;  (71) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) — 2-fluoro-N- ( (R) -2,3-dihydroxypropyl) benzamide oxalate;
(72) 1-(4-(5-메틸 -6ᅳ (메틸설포닐 )피리딘 -3-일옥시 )부탄 -2-일 ) - 4-(3-이소프로필ᅳ1，2，4-옥사다이아졸— 5-일 )피페라진 옥살산염 ;  (72) 1- (4- (5-methyl-6 '(methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4- (3-isopropyl ᅳ 1,2,4-oxadia Sol—5-yl) piperazine oxalate;
(73) 에틸 4-((R)-3— (4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2-플루오로벤조에이트 옥살산염 ;  (73) Ethyl 4-((R) -3— (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluor Robenzoate oxalate;
(74) 4-((R)— 3-(4-(3-이소프로필 -1， 2， 4-옥사다이아졸 -5- 일)피페라진 -1ᅳ일)부톡시 )-2-플루오로벤조에이트 리튬염；  (74) 4-((R) — 3- (4- (3-isopropyl-1, 2, 4-oxadiazol-5-yl) piperazine-1xyl) butoxy) -2-fluorobenzo Eight lithium salts;
(75) 4-(0 -3-(4-(3-이소프로필-1,2,4-옥사다이아졸 -5— 일 )피페라진 -1ᅳ일 )부톡시 )-2-플루오로 -N-((R)— 2，3ᅳ (75) 4- (0-3- (4- (3-isopropyl-1,2,4-oxadiazole-5) 1) piperazin-1 phenylyl) butoxy) -2-fluoro-N-((R) — 2,3 ᅳ
다이하이드록시프로필 )벤즈아마이드 옥살산염 ; Dihydroxypropyl) benzamide oxalate;
(76) 에틸 4-((S)-3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진 -1-일 )부톡시 )—2-플루오로벤조에이트；  (76) ethyl 4-((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) —2-fluoro Robenzoate;
(77) 4-((S)-3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진 -1-일)부톡시 )-2—플루오로벤조에이트 리튬염；  (77) 4-((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2—fluoro Benzoate lithium salts;
(78) 4-((S)-3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진 -1-일)부톡시 )-2-풀루오로 -N-((R)-2,3- 다이하이드특시프로필)벤즈아마이드 옥살산염 ;  (78) 4-((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-pulluo Rho-N-((R) -2,3-dihydrospecificpropyl) benzamide oxalate;
(79) t-부틸 -4-(4-(4— (메틸설포닐)페녹시)부탄 -2-일)피페라진- (79) t-butyl-4- (4- (4— (methylsulfonyl) phenoxy) butan-2-yl) piperazine-
1ᅳ카르복실레이트; 1'carboxylate;
(80) t-부틸 -4-(4-(2-풀루오로 -2- ((메틸설포닐)메틸)페녹시)부탄 - 2 -일)피페라진 - 1 -카르복실레이트;  (80) t-butyl-4- (4- (2-pulluoro-2-((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazine-1-carboxylate;
(81) 2-(4-(4-(4- (메틸설포닐)페녹시 )부탄 -2-일)피페라진 -Il일 ) -5-프로필피리미딘 ; ' (81) 2- (4- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-Iyl) -5-propylpyrimidine; '
(82) 1-(4-(3-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 ) -4-(3- 이소프로필 -1,2,4-옥사다이아졸 -5-일 )피페라진；  (82) 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine;
(83) t-부틸 4-(4-(3—플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일)피페라진 -1-카르복실레이트;  (83) t-butyl 4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate;
(84) 1-(4-(2-플루오로 -4- (메틸설포닐)페녹시)부탄 -2-일) -4-(3- 이소프로필 -1,2 ,4-옥사다이아졸 -5-일 )피페라진 ;  (84) 1- (4- (2-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2, 4-oxadiazole-5 -Yl) piperazine;
(85) 1-(4-(3-플루오로 -4-(1Η-테트라졸 -1—일)페녹시 )부탄ᅳ 2- 일 )-4-(3-이소프로필-1,2，4-옥사다이아졸 -5-일 )피페라진 ;  (85) 1- (4- (3-fluoro-4- (1Η-tetrazol-1-yl) phenoxy) butanyl 2-yl) -4- (3-isopropyl-1,2,4- Oxadiazole-5-yl) piperazine;
(86) 1-(4-(4- (메틸설포닐 )페녹시 )부탄 -2-일 ) -4-(3-이소프로필- 1，2，4-옥사다이아졸ᅳ 5-일 )피페라진；  (86) 1- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazolyl 5-yl) piperazine ;
(87) 1-(4-(4-(1Η-테트라졸 -1-일 )페녹시 )부탄 -2—일 )-4-(3- 이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진；  (87) 1- (4- (4- (1Η-tetrazol-1-yl) phenoxy) butane-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine;
(88) 1-(4-(3，5-다이플루오로 -4-(1Η-테트라졸ᅳ1- 일 )페녹시)부탄 -2-일 )-4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진；  (88) 1- (4- (3,5-difluoro-4- (1Η-tetrazol ᅳ 1-yl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2 4-oxadiazol-5-yl) piperazine;
(89) 1 -(4-(4-브로모-2，5-다이풀루오로페녹시 )부탄 · -2- -일)ᅳ 4. -(3- 이소프로필 -1: ,2，4-옥사다이아졸 -5-일 )피페라진； (89) 1-(4- (4-Bromo-2,5-difluourophenoxy) butane-2--2-yl) ᅳ 4.-(3-isopropyl -1 :, 2,4- Oxadiazole-5-yl) piperazine;
(90) 1-( 4 - (3 -클로로 - 4- (메틸설포닐 )페녹시 )부탄- -2-일) -4- -(3- 이소프로필 -1, ,2,4-옥사다이아졸 -5-일 )피페라진；  (90) 1- (4- (3-chloro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4-(3-isopropyl-1,, 2,4-oxadiazole -5-yl) piperazine;
(91) 1-(4-(3-메틸 -4- (메틸설포닐)페녹시 )부탄' -2—일) -4- -(3- 이소프로필 -1， 2,4-옥사다이아졸 -5-일 )피페라진 ;  (91) 1- (4- (3-methyl-4- (methylsulfonyl) phenoxy) butane'-2—yl) -4-(3-isopropyl-1,2,4-oxadiazole- 5-yl) piperazine;
(92) 1-(4-(5- (메틸설포닐 )피리딘 2—일옥시 )부탄- -2-일) -4- -(3- 이소프로필 -1, 2, 4-옥사다이아졸— 5-일 )피페라진；  (92) 1- (4- (5- (methylsulfonyl) pyridin 2—yloxy) butan-2-yl) -4-(3-isopropyl-1, 2, 4-oxadiazole— 5 -Yl) piperazine;
(93) 1-(4-(6- (메틸설포닐)피리딘 3-일옥시 )부탄- -2-일 ) -4- -(3- 이소프로필 -1, 2，4-옥사다이아졸 -5-일)피페라진；  (93) 1- (4- (6- (methylsulfonyl) pyridin 3-yloxy) butan-2-yl) -4-(3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine;
(94) 1-(4-(3-클로로 -4- ((메틸설포닐)메틸)페녹시 )부탄- 2-'일) - -(3-이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진 ;  (94) 1- (4- (3-chloro-4-((methylsulfonyl) methyl) phenoxy) butan-2-'yl)-(3-isopropyl-1,2,4-oxadiazole -5-yl) piperazine;
(95) 1-(4-(3-플루오로 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2- 일 )-4ᅳ (3-이소프로필 -1，2，4-옥사다이아졸— 5-일)피페라진；(95) 1- (4- (3-fluoro-4-((methylsulfonyl) methyl) phenoxy) butane-2- Yl) -4 '(3-isopropyl-1,2,4-oxadiazole—5-day) piperazine;
(96) 1-(4-(2—메틸 -4- ((메틸설포닐 )메틸)페녹시 )부탄 -2-일 ) -4- (3-이소프로필 -1， 2 ,4-옥사다이아졸 -5-일 )피페라진 ; (96) 1- (4- (2—methyl-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole -5-yl) piperazine;
(97) 2-(4-(4-(3-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일)피페라진 -1-일) -5-프로필피리미딘 옥살산염 ;  (97) 2- (4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate;
(98) l-((R)-4-(3-플루오로 -4- (메틸설포닐 )페녹시 )부탄— 2-일 ) - 4-(3-이소프로필-1，2,4-옥사다이아졸 -5-일 )피페라진 ;  (98) l-((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butane- 2-yl)-4- (3-isopropyl-1,2,4-oxa Diazol-5-yl) piperazine;
(99) 2-(4-(4-(3ᅳ플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일 )피페라진 -1-일 )-5-프로필피리미딘；  (99) 2- (4- (4- (3'fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;
(100) 2-(4-(4-(3-플루오로 -4-(1- (100) 2- (4- (4- (3-fluoro-4- (1-)
(메틸설포닐)에틸)페녹시 )부탄 -2-일 )피페라진 -1-일 ) -5- 프로필피리미딘 ; (Methylsulfonyl) ethyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;
(101) 1-(4-(2，5-다이풀루오로 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2-일 )-4-(3-이소프로필 -1,2,4- 옥사다이아졸 -5-일 )피페라진 ;  (101) 1- (4- (2,5-Difluouro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2, 4-oxadiazol-5-yl) piperazine;
(102) 1-(4-(2，5-다이플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일 )-4-(3-이소프로필 -1,2,4-옥사다이아졸 -5-일)피페라진 ;  (102) 1- (4- (2,5-Difluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine;
(103) 1-(4-(2，6-다이플루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일 )-4-(3-이소프로필-1,2,4-옥사다이아졸 -5-일 )피페라진 ;  (103) 1- (4- (2,6-difluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine;
(104) 1-(4-(5-메틸 -6- (메틸설포닐)피리딘 -3-일옥시 )부탄 -2- 일 )-4-(3-이소프로필-1，2，4-옥사다이아졸 -5-일 )피페라진 ;  (104) 1- (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine;
(105) 에틸-4-(3-(4—(3-이소프로필-1，2,4-옥사다이아졸 -5- 일)피페라진 -1-일)부톡시 )-2ᅳ풀루오로벤조에이트;  (105) Ethyl-4- (3- (4— (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2 ᅳ fluorofluorobenzoate ;
(106) 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진 -1-일)부톡시 )-2-플루오로벤조에이트;  (106) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate;
(107) 에틸 -4-(3-(4-(5-프로필피리미딘 -2-일)피페라진 -1- 일 )부톡시 )-2-플루오로벤조에이트;  (107) ethyl -4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate;
(108) 4-(3-(4-(5-프로필피리미딘 -2-일)피페라진 -1-일 )부톡시 ) - 2-풀루오로벤조에이트；  (108) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-pululobenzoate;
(109) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부톡시 ) - (109) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy)-
2-플루오로 -N-(l,3-다이하이드록시프로판 -2-일 )벤즈아마이드; 2-fluoro-N- (l, 3-dihydroxypropan-2-yl) benzamide;
(110) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부록시 ) - 2-플루오로 -N-((S)-1-하이드톡시프로판—2-일 )벤즈아마이드;  (110) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy)-2-fluoro-N-((S) -1-hydroxypropane —2-yl) benzamide;
(111) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부톡시 ) - 2-플루오로 -N-((S)-2,3-다이하이드록시프로필 )벤즈아마이드;  (111) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy)-2-fluoro-N-((S) -2,3-di Hydroxypropyl) benzamide;
(112) 4-(3-(4-(3-이소프로필-1,2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2-풀루오로 -N-(l,3—다이하이드특시프로판- (112) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2- pullouro-N- (l, 3—dihydrate special propane-
2ᅳ일 )벤즈아마이드; 2 ᅳ yl) benzamide;
(113) 4-(3-(4-(3ᅳ이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-2-플루오로 -N-((R)-1-하이드록시프로판 -2- 일)벤즈아마이드；  (113) 4- (3- (4- (3 ᅳ isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) partial) -2-fluoro-N- ( (R) -1-hydroxypropan-2-yl) benzamide;
(114) 4—(3-(4-(3ᅳ이소프로필-1，2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2-풀루오로 -Nᅳ ((R)-2,3- 다이하이드록시프로필)벤즈아마이드; (114) 4— (3- (4- (3 ᅳ isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-pulluoro-N ᅳ ((R) -2,3- Dihydroxypropyl) benzamide;
(115) (4-(3-(4-(3-이소프로필 -1,2, 4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2—플루오로페닐) (피를리딘 -1-일 )메타논 ;  (115) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorophenyl) ( Pyridin-1-yl) methanone;
(116) 에틸 4ᅳ(3-(4-(3-이소프로필 -l，2,4-옥사다이아졸-5- 일)피페라진 -1-일 )부톡시 )—3-플루오로벤조에이트 ;  (116) ethyl 4 '(3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) —3-fluorobenzoate;
(117) 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일)피페라진 -1-일 )부톡시 )-3-플루오로벤조에이트;  (117) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorobenzoate;
(118) 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-N-((R)-l-하이드록시프로판 -2- 일)벤즈아마이드;  (118) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N-((R) -1 -Hydroxypropan-2-yl) benzamide;
(119) 4-(3-(4-(3-이소프로필 -l，2,4-옥사다이아졸-5- 일)피페라진-l-일)부톡시 )-3—풀루오로 -N-((S)-2,3- 다이하이드특시프로필)벤즈아마이드;  (119) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-l-yl) butoxy) -3—Pluoro-N- ((S) -2,3-dihydrospecificpropyl) benzamide;
(120) 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-N,N-다이에틸 -3-메틸벤즈아마이드 ;  (120) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N, N-diethyl-3 -Methyl benzamide;
(121) (4-(3-(4-(3-이소프로필 -1,2 ,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-플루오로페닐) (피를리딘 -1-일 )메타논 ;  (121) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorophenyl) ( Pyridin-1-yl) methanone;
(122) 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )— 3-플루오로 -N-(l,3-다이하이드록시프로판- 2-일 )벤즈아마이드;  (122) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) — 3-fluoro-N- ( 1,3-dihydroxypropane-2-yl) benzamide;
(123) 4-(3-(4-(3-이소프로필 -1,2 ,4—옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2-플루오로— N-( 00-2， 3- 다이하이드톡시프로필)벤즈아마이드;  (123) 4- (3- (4- (3-isopropyl-1,2,4—oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro—N- ( 00-2, 3-dihydroxypropyl) benzamide;
(124) 1-(4-(5-메틸 -6- (메틸설포닐)피리딘 -3-일옥시)부탄 -2- 일 )-4-(3-이소프로필 -1,2,4-옥사다이아졸 -5-일 )피페라진 ;  (124) 1- (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine;
(125) 에틸 4-((R)-3-(4-(3-이소프로필 -l，2,4-옥사다이아졸-5- 일)피페라진-l-일 )부톡시 )-2-플루오로벤조에이트；  (125) ethyl 4-((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-l-yl) butoxy) -2-fluoro Robenzoate;
(126) 4-((10-3-(4-(3-이소프로필-1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부록시 )-2-플루오로벤조에이；  (126) 4-((10-3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorobenzo a;
(127) 4-(00-3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2-플루오로 -N-((R)-2,3- 다이하이드록시프로필)벤즈아마이드;  (127) 4- (00-3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro-N -((R) -2,3-dihydroxypropyl) benzamide;
(128) 에틸 4-((S)-3-(4-(3-이소프로필 -1，2，4—옥사다이아졸ᅳ 5- 일 )피페라진 -1-일 )부톡시 )-2-플루오로벤조에이트；  (128) Ethyl 4-((S) -3- (4- (3-isopropyl-1,2,4—oxadiazol- 5-yl) piperazin-1-yl) butoxy) -2-fluoro Robenzoate;
(129) 4-((3)-3-(4-(3-이소프로필-1，2,4-옥사다이아졸 -5- 일 )피페라진 1-일 )부톡시 )-2-플루오로벤조에이트; 및 (129) 4-((3) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin 1-yl) butoxy) -2-fluorobenzo Eight; And
(130) 4-((3)-3-(4-(3-이소프로필-1,2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-2-플루오로 -N-((R)-2,3- 다이하이드록시프로필)벤즈아마이드. 본 발명에 따른 상기 화학식 1의 피페라진 유도체 또는 이의 약학적으로 허용가능한 염 또는 이의 이성질체의 구조식을 하기 표 나타내었다. 【표 1】
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
실시예 46 실시 예 47 실시예 48 실시예 49 실시예 50 실시 ^ 1 51 실시예 52 실시 예 53 실시 예 54 실시예 55 (130) 4-((3) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -2-fluoro -N-((R) -2,3-dihydroxypropyl) benzamide. The structural formulas of the piperazine derivatives of Formula 1 or their pharmaceutically acceptable salts or isomers thereof according to the present invention Indicated. Table 1
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Example 46 Example 47 Example 48 Example 49 Example 50 Example ^ 1 51 Example 52 Example 53 Example 54 Example 55
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
본 발명에 따른 화학식 1로 표시되는 신규한 피페라진 유도체 약학적으로 허용가능한 염의 형태로 사용할 수 있다. 상기 염으로는 약학적으로 또는 생리학적으로 허용되는 다양한 유기산 또는 무기산에 의해 형성된 산부가염이 유용하다. 산 부가염은 염산 질산， 인산， 황산， 브롬화수소산， 요드화수소산, 아질산 또는 +인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트， 페닐-치환된 알카노에이트， 하이드록시 알카노에이트 알칸디오에이트， 방향족 산류， 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이ᅳ , 피로설페 0 바이설페이트， 설파이트， 바이설파이트， 니트레이트 포스페 0 모노하이드로겐 포스페이트, 디하이드로겐 포스페 0 메타포스페이트， 피로포스페이트 클로라이드, 브로口 ]· o 아이오다이드， 플루오라이드， 아세테이트, 프로피오네 ο 데카노에이트， 카프릴레이트， 아크릴레이트, 포메 ο 이소부티레이트， 카프레이트， 템타노에이트， 프로피온산， 옥살산 말론산, 숙신산, 수베레이트， 세바케이트， 푸마레이트， 말리에이트 부틴 -1，4-디오에이트， 핵산 -1,6-디온산， 벤조산， 클로로벤조산 메틸벤조산， 디니트로 벤조산, 하이드톡시벤조에이트， 메톡시벤조산 프탈산， 테레프탈레이트， 벤젠설폰산， 를루엔설폰산 클로로벤젠설폰산， 크실렌설폰산， 페닐아세트산, 페닐프로피온산 페닐부티레이트， 시트레이트， 락테이트， 하이드록시부티레이트， 글리콜레이트, 말레이트， 타트레이트， 메탄설포네이트， 프로판설포네이트， 나프탈렌 -1-설포네이트， 나프탈렌 -2-설포네이트， 만델레이트 또는 트라이플루오로아세트산올 사용하여 제조할 수 있다. 이들 중에서 바람직하게는 염산， 옥살산 또는 트라이플루오로아세트산을 사용할 수 있다. 이때， 본 발명에 따른 상기 산 부가염은 통상의 방법 , 예를 들면 , 화학식 1의 유도체를 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매， 예를 들면 메탄올， 에탄올， 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다. The novel piperazine derivatives represented by Formula 1 according to the present invention can be used in the form of pharmaceutically acceptable salts. As the salts, acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful. Acid addition salts include inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphoric acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoate alkanedio Obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids. These pharmaceutically toxic salts include sulfated, pyrosulfate 0 bisulfate, sulfite, bisulfite, nitrate phosphate 0 monohydrogen phosphate, dihydrogen phosphate 0 metaphosphate, pyrophosphate chloride, bro口 oiodide, fluoride, acetate, propione ο decanoate, caprylate, acrylate, pome ο isobutyrate, caprate, tempanoate, propionic acid, oxalic acid malonic acid, succinic acid, suverate, Sebacate, fumarate, maleate butene-1,4-dioate, nucleic acid-1,6-dioic acid, benzoic acid, chlorobenzoic acid methylbenzoic acid, dinitrobenzoic acid, hydroxybenzoate, methoxybenzoic acid phthalic acid, terephthalate, Benzenesulfonic acid, toluenesulfonic acid chlorobenzenesulfonic acid, xylenesulfonic acid, phenylacetic acid, phenyl Propionic acid with Phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate or trifluoro It can be prepared using acetate. Among them, hydrochloric acid, oxalic acid or trifluoroacetic acid can be preferably used. At this time, the acid addition salt according to the present invention is dissolved in a conventional method, for example, an aqueous solution of an excess of acid, and the salt is dissolved in a water miscible organic solvent, such as methanol, ethanol, acetone or aceto. It can be prepared by precipitation using nitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
또한， 염기를 사용하여 약학적으로 허용 가능한 금속염올 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고， 비용해 화합물 염올 여과하고， 여액을 증발， 건조시켜 얻는다. 이때， 금속염으로는 리튬, 나트륨， 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다 . 또한， 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은 염 (예， 질산은)과 반웅시켜 얻는다. 또한, 본 발명은 하기 반웅식 1에 나타낸 바와 같이，  Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, inexpensive compound salt filtering, and evaporation and drying of the filtrate. In this case, as the metal salt, it is pharmaceutically suitable to produce lithium, sodium, potassium or calcium salts. Corresponding silver salts are also obtained by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg silver nitrate). In addition, the present invention, as shown in the following reaction formula 1,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 피페리딘 유도체를 커플링 반웅시켜 화학식 4로 표시되는 화합물올 제조하는 단계 (단계 1);  Coupling the compound represented by the formula (2) and the piperidine derivative represented by the formula (3) to prepare a compound represented by the formula (4) (step 1);
상기 단계 1에서 제조된 화학식 4의 화합물을 환원반웅을 수행하여 화학식 5로 표시되는 화합물을 제조하는 단계 (단계 2); 및 상기 단계 2에서 제조된 화학식 5의 화합물과 화학식 6으로 표시되는 화합물을 커플링 반응시켜 화학식 la로 표시되는 화합물을 제조하는 단계 (단계 3);를 포함하는 화학식 1로 표시되는 신규한 피페라진 유도체의 제조방법을 제공한다 .  Preparing a compound represented by Chemical Formula 5 by performing a reaction of reducing the compound of Chemical Formula 4 prepared in Step 1 (Step 2); And coupling the compound represented by Chemical Formula 5 and the compound represented by Chemical Formula 6 prepared in Step 2 to prepare a compound represented by Chemical Formula la (Step 3). Provided are methods for preparing the derivatives.
[반옹식 1] Rebellion 1
단계step
Figure imgf000026_0001
Figure imgf000026_0001
5 1a  5 1a
(상기 반응식 1에서， A, B, 및 R은 상기 화학식 1에서 정의한 바와 같고; m은 0 내지 3의 정수이고; 및 화학식 la는 화학식 1의 화합물이다.) 이하, 상기 제조방법을 각 단계별로 상세히 설명한다. 먼저， 본 발명에 따른 상기 단계 1은 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 피페리딘 유도체를 커풀링 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계이다.  (In Reaction Scheme 1, A, B, and R are as defined in Formula 1; m is an integer of 0 to 3; and Formula la is a compound of Formula 1.) It explains in detail. First, step 1 according to the present invention is a step of preparing a compound represented by Chemical Formula 4 by coupling a compound represented by Chemical Formula 2 and a piperidine derivative represented by Chemical Formula 3 with a coupling reaction.
더욱 상세하게는, 화학식 2의 화합물과 화학식 3의 피페라진을 메탄을에 용해시킨 다음， 환류교반을 수행함으로써 화학식 2의 알케닐기에 아민을 첨가하는 반응을 수행하는 단계이다.  More specifically, the compound of formula (2) and piperazine of formula (3) are dissolved in methane, and then subjected to a reflux stirring to perform a reaction of adding an amine to the alkenyl group of formula (2).
이때 , 사용가능한 용매는 반웅에 악영향을 미치지 않는 메탄올ᅵ 에탄을， 다이클로로메탄 (DCM) 또는 틀루엔을 이용할 수 있으며 , 바람직하게는 메탄을을 사용할 수 있다.  In this case, the solvent may be used methanol ethane, dichloromethane (DCM) or toluene which does not adversely affect the reaction, methane may be used.
또한, 반응은도는 특별히 제한되지는 않으나, 상온 내지 용매의 환류온도 범위 내에서 사용될 수 있다. 다음으로, 상기 단계 2는 단계 1에서 제조된 화학식 4의 화합물을 환원반응을 수행하여 화학식 5로 표시되는 화합물을 제조하는 단계이다.  In addition, the degree of the reaction is not particularly limited, but may be used within the range of room temperature to reflux temperature of the solvent. Next, step 2 is a step of preparing a compound represented by Formula 5 by performing a reduction reaction of the compound of Formula 4 prepared in Step 1.
더욱 상세하게는， 단계 1에서 제조된 화학식 4의 화합물와 환원제인 리튬알루미늄하이드라이드 (UA1H4)를 반응시켜 화학식 4의 카르복실산을 알콜로 환원하는 단계이다. More specifically, it is a step of reducing the carboxylic acid of Formula 4 to alcohol by reacting the compound of Formula 4 prepared in Step 1 with lithium aluminum hydride (UA1H 4 ) which is a reducing agent.
이때， 사용가능한 용매는 반응에 악영향올 미치지 않는 테트라하이드로퓨란 (THF) , 디에틸에테르, 디페닐에테르 또는 디이소프로필에테르 (DIPE)를 사용할 수 있고， 바람직하게는 테트라하이드로퓨란 (THF)을 사용할 수 있다.  At this time, the solvent may be used tetrahydrofuran (THF), diethyl ether, diphenyl ether or diisopropyl ether (DIPE) that does not adversely affect the reaction, preferably tetrahydrofuran (THF) Can be.
또한， 상기 반응은도는 ᅳ 78°C 내지 5°C 내에서 수행할 수 있고， 바람직하게는 — 10°C 내지 0°C에서 수행할 수 있다 . 다음으로， 상기 단계 3은 상기 단계 2에서 제조된 화학식 5의 화합물과 화학식 6으로 표시되는 화합물을 커플링 반응시켜 화학식 la로 표시되는 화합물을 제조하는 단계이다. In addition, the reaction can be carried out within ᅳ 78 ° C to 5 ° C, Preferably at 10 ° C. to 0 ° C. Next, step 3 is a step of preparing a compound represented by the formula la by coupling the compound represented by the formula (5) and the compound represented by the formula (6) prepared in step 2.
더욱 상세하게는， 화학식 5의 화합물， 화학식 6의 화합물 및 트라이페닐포스핀을 혼합한 용액에 아조카르복실레이트 시약을 천천히 적가하여 미츠노부 반응 (Mitsunobu reaction)을 수행함으로써 화학식 la의 화합물을 제조하는 단계이다.  More specifically, a compound of formula la is prepared by performing a Mitsunobu reaction by slowly adding dropwise addition of an azocarboxylate reagent to a solution containing a compound of formula 5, a compound of formula 6, and triphenylphosphine. Step.
이때， 사용가능한 아조카르복실레이트 화합물은 다이에틸아조다이카르복실레이트 (diethyl azodicarboxylate, DEAD) 또는  At this time, the azocarboxylate compound that can be used is diethyl azodicarboxylate (DEAD) or
다이이소프로필아조다이카르복실레이트 (di isopropyl azodi car boxy late, DIAD)를 사용할 수 있고 , 바람직하게는 다이이소프로필아조다이카르복실레이트 (di isopropyl azodi car boxy late, DIAD)를 사용할 수 있다. Di isopropyl azodi car boxy late (DIAD) may be used, and preferably diisoopropyl azodi car boxy late (DIAD) may be used.
또한， 사용가능한 용매는 반응에 악영향을 미치지 않는 테트라하이드로퓨란 (THF), 다이클로로메탄 (DCM), 를루엔 또는 아세토니트릴을 사용할 수 있고， 바람직하게는 테트라하이드로퓨란 (THF)을 사용할 수 있다. 본 발명에 따른 상기 단계 3에서 제조된 화학식 la의 .화합물에 유기산 또는 무기산을 처리하여 하기 화학식 1A로 표시되는 산 부가염을 제조하는 단계를 더 포함할 수 있다. In addition, the solvent which can be used can use tetrahydrofuran (THF), dichloromethane (DCM), toluene, or acetonitrile which does not adversely affect a reaction, Preferably tetrahydrofuran (THF) can be used. Of formula la prepared in step 3 according to the present invention . The method may further include preparing an acid addition salt represented by Chemical Formula 1A by treating the compound with an organic acid or an inorganic acid.
[화학식 1A]  [Formula 1A]
Figure imgf000027_0001
Figure imgf000027_0001
(상기 화학식 1A에서， A, B, R 및 n은 상기 화학식 1에서 정의한 바와 같고; HA는 유기산 또는 무기산이고; 및 상기 화학식 1A의 화합물은 화학식 1의 화합물이다.)  (In Formula 1A, A, B, R and n are as defined in Formula 1; HA is an organic acid or an inorganic acid; and the compound of Formula 1A is a compound of Formula 1.)
이때 , 사용가능한 유기산 또는 무기산은 옥살산 염산 또는 트라이플루오로아세트산올 사용할 수 있다.  At this time, the usable organic or inorganic acid may be used oxalic acid hydrochloric acid or trifluoroacetic acid.
또한， 사용가능한 용매는 반웅에 악영향을 미치지 않는 메탄올， 에탄을, 아세톤, 아세토니트릴 또는 에틸아세테이트 (EA)를 사용할 수 있고, 바람직하게는 에틸아세테이트 (EA)를 사용할 수 있다. 나아가， 본 발명은 하기 반웅식 2에 나타난 바와 같이，  In addition, as the solvent which can be used, methanol, ethane which does not adversely affect reaction, acetone, acetonitrile or ethyl acetate (EA) can be used, and ethyl acetate (EA) can be used preferably. Furthermore, the present invention is as shown in the following reaction formula 2,
화학식 lb로 표시되는 화합물과 리튬하이드록사이드를 반응시켜 화학식 lc로 표시되는 리튬염을 제조하는 단계 (단계 1); 및  Preparing a lithium salt represented by formula lc by reacting a compound represented by formula lb with lithium hydroxide (step 1); And
상기 단계 1에서 제조된 화학식 lc의 리튬염과 화학식 7로 표시되는 화합물올 아마이드화 반옹을 수행하여 화학식 Id로 표시되는 화합물을 제조하는 단계 (단계 2);를 포함하는 화학식 1로 표시되는 신규한 피페라진 유도체의 제조방법을 제공한다. Lithium salt of Formula lc prepared in Step 1 and the formula (7) It provides a method for producing a novel piperazine derivative represented by the formula (1) comprising the step of preparing a compound represented by the formula (Id) by performing the compound amidation reaction.
[반응식 2]  Scheme 2
내 R My R
—ᄌ， — ᄌ ，
Figure imgf000028_0001
Figure imgf000028_0001
(상기 반응식 2에서， B " 및 n은 상기 화학식 1에서 정의한 바와 갈고: 및 화학식
Figure imgf000028_0002
화학식 id의 화합물은 화학식 1의 화합물이다.) 상기 제조방법을 각 단계별로 상세히 설명한다. 먼저， 상기 단계 1은 화학식 lb로 표시되는 화합물과 리튬하이드록사이드를 반웅시켜 화학식 lc로 표시되는 리톱염을 제조하는 단계이다. (In Scheme 2, B "and n are as defined in Formula 1: wherein: and
Figure imgf000028_0002
The compound of formula id is a compound of formula 1. The preparation method is described in detail for each step. First, Step 1 is a step of preparing a litop salt represented by Chemical Formula lc by reacting a compound represented by Chemical Formula lb and lithium hydroxide.
더욱 상세하게는， 화학식 lb의 화합물을 테트라하이드로퓨란 (THF) 및 증류수를 흔합한 흔합용액에 용해시킨 다음， 리튬하이드록사이드 1수화물올 첨가하여 반웅시키고 반응 후， 비용해된 화합물을 여과하여 화학식 lc의 리톱염을 제조하는 단계이다 다음으로， 상기 단계 2는 단계 1에서 제조된 화학식 lc의 리튬염과 화학식 7로 표시되는 화합물을 아마이드화 반응을 수행하여 화학식 Id로 표시되는 화합물을 제조하는 단계이다.  More specifically, the compound of formula lb is dissolved in a mixed solution of tetrahydrofuran (THF) and distilled water, and then reacted with the addition of lithium hydroxide monohydrate. After the reaction, the undissolved compound is filtered Next, the step 2 is to prepare a compound represented by the formula (Id) by performing an amidation reaction between the lithium salt of the formula (lc) prepared in step 1 and the compound represented by the formula (7) to be.
더욱 상세하게는， 단계 1에서 제조된 화학식 1(:의 리튬염과 화학식 7의 아민 화합물을 유기용매에 용해시키고， 아마이드화제 (amide reagent)를 첨가한 다음， 상온에서 아마이드화 반응올 수행하여 화학식 Id의 화합물을 제조하는 단계이다. More specifically, the lithium salt of formula ( 1) prepared in step 1 and the amine compound of formula 7 are dissolved in an organic solvent, an amide reagent is added, and the amidation reaction is performed at room temperature. Step of preparing a compound of Id.
이때， 상기 아마이드화제 (amide reagent)는 벤조트리아졸 -1-일- 옥시 -트리스 (다이메틸아미노) -포스포니움 핵사플루오로포스페이트 (Py- In this case, the amide reagent is benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium nucleofluorophosphate (Py-
BOP), 0-벤조트리아졸 -Ν,Ν,Ν,Ν-테트라메틸-유로니움 -핵사플루오로- 포스페이트 (HBTU), 2-(7-아자—내-벤조트리아졸-1-일)-1,1，3,3- 테트라메틸유로니움핵사플루오로포스페이트 (HATU)， 1- 하이드록시벤조트리아졸 (HOBt) , 다이사이클로핵실카르보디이미드 (DCC) 1-에틸— 3-(3-다이메틸아미노프로필)카르보다이이미드 (EDC) 또는 카르보닐다이이미다졸 (CDI)을 사용할 수 있으며， 바람직하게는 1- 에틸 -3-(3—다이메틸아미노프로필)카르보다이이미드 (EDC) 및 1- 하이드록시벤조트리아졸 (HOBt)을 함께 사용할 수 있다. BOP), 0-benzotriazole-Ν, Ν, Ν, Ν-tetramethyl-uronium-nucleus-fluoro-phosphate (HBTU), 2- (7-aza-in-benzotriazol-1-yl)- 1,1，3,3- Tetramethyluronium nucleus fluorophosphate (HATU), 1-hydroxybenzotriazole (HOBt), dicyclonucleosilcarbodiimide (DCC) 1-ethyl— 3- (3-dimethylaminopropyl) carbodiimide (EDC) or carbonyldiimidazole (CDI) can be used, preferably 1-ethyl-3- (3—dimethylaminopropyl) carbodiimide (EDC) and 1-hydroxybenzotriazole ( HOBt) can be used together.
또한， 사용 가능한 유기용매로는 반응에 악영향을 미치지 않는 메탄올 ·, 테트라하이들로퓨란 (THF), 다이메틸포름아마이드， 다이클로로메탄 또는 를루엔올 이용하여 반웅을 수행할 수 있고， 바람직하게는 다이클로로메탄 (DCM)을 사용할 수 있다. 또한， 본 발명은 하기 반웅식 3에 나타난 바와 같이，  In addition, the usable organic solvent may be reacted using methanol, tetrahydrodurofuran (THF), dimethylformamide, dichloromethane or tolueneol, which does not adversely affect the reaction. Dichloromethane (DCM) can be used. In addition, the present invention, as shown in the following reaction formula 3,
화학식 8— (S)로 표시되는 화합물과 t- 부틸다이메틸실릴클로라이드 (TBSC1)를 반응시켜 화학식 9— (S)로 표시되는 화합물을 제조하는 단계 (단계 1);  Preparing a compound represented by Chemical Formula 9— (S) by reacting a compound represented by Chemical Formula 8— (S) with t-butyldimethylsilyl chloride (TBSC1) (step 1);
상기 단계 1에서 제조된 화학식 9-(S)의 화합물과 메탄설포닐클로라이드 (MsCl)를 반응시켜 화학식 10-(S)로 표시되는 화합물을 제조하는 단계 (단계 2);  Preparing a compound represented by Chemical Formula 10- (S) by reacting the compound of Chemical Formula 9- (S) prepared in Step 1 with methanesulfonyl chloride (MsCl) (Step 2);
상기 단계 2에서 제조된 화학식 10-(S)의 화합물과 화학식 3으로 표시되는 화합물을 반웅시켜 화학식 ll-(R)로 표시되는 화합물을 제조하는 단계 (단계 3);  Preparing a compound represented by Chemical Formula ll- (R) by reacting the compound represented by Chemical Formula 10- (S) and Chemical Formula 3 prepared in Step 2 (Step 3);
상기 단계 3에서 제조된 화학식 ll-(R)로 표시되는 화합물의 탈보호화 반웅을 수행하여 화학식 5— (R)로 표시되는 화합물을 제조하는 단계 (단계 4); 및  Preparing a compound represented by Chemical Formula 5— (R) by performing deprotection reaction of the compound represented by Chemical Formula ll- (R) prepared in Step 3 (Step 4); And
상기 단계 4에서 제조된 화학식 5-(R)의 화합물과 화학식 6으로 표시되는 화합물의 커플링 반응을 수행하여 화학식 1-(R)로 표시되는 화합물을 제조하는 단계 (단계 5);를 포함하는 화학식 1로 표시되는 신규한 피페라진 유도체의 제조방법을 제공한다.  Preparing a compound represented by Chemical Formula 1- (R) by performing a coupling reaction between the compound represented by Chemical Formula 5- (R) and the compound represented by Chemical Formula 6 prepared in Step 4; Provided is a method for preparing a novel piperazine derivative represented by the formula (1).
[반응식 3] Scheme 3
Figure imgf000030_0001
Figure imgf000030_0001
1-(R)  1- (R)
(상기 반웅식 3에서， A, B 및 R은 상기 화학식 1에서 정의한 바와 같고; TBS는 t-부틸다이메틸실릴기이고; Ms은 메탄설포닐기이고; 및 화학식 1-(R)의 화합물은 화학식 1의 화합물이다.) 이하， 상기 제조방법을 각 단계별로 상세히 설명한다. 먼저 , 상기 단계 1은 화학식 8-(S)로 표시되는 화합물과 t- 부틸다이메틸실릴클로라이드 (TBSC1)를 반응시켜 화학식 9-(S)로 표시되는 화합물을 제조하는 단계 (단계 1)이다.  (In Formula 3, A, B and R are as defined in Formula 1; TBS is a t-butyldimethylsilyl group; Ms is a methanesulfonyl group; and the compound of Formula 1- (R) is Compound 1). Hereinafter, the preparation method will be described in detail for each step. First, Step 1 is a step of preparing a compound represented by Chemical Formula 9- (S) by reacting a compound represented by Chemical Formula 8- (S) with t-butyldimethylsilyl chloride (TBSC1) (Step 1).
더욱 상세하게는, 염기 존재하에서 입체구조가 S-형태인 화학식 8의 화합물과 t-부틸다이메틸실릴클로라이드 (TBSC1)를 반응시켜 화학식 8로 표시되는 화합물의 하이드록시기를 보호화하는 단계이다. 이때， 반웅에 사용가능한 염기는 트리에틸아민 (TEA), 다이에틸아민 (DEA), 다이이소프로필에틸아민 (DIPEA), 피리딘 또는 이미다졸을 사용할 수 있으며， 바람직하게는 이미다졸을 사용할 수 있다.  More specifically, the step of protecting the hydroxy group of the compound represented by the formula (8) by reacting t-butyldimethylsilyl chloride (TBSC1) with a compound of the formula (8) in the S- form in the presence of a base. In this case, the base usable in the reaction may be triethylamine (TEA), diethylamine (DEA), diisopropylethylamine (DIPEA), pyridine or imidazole, and preferably imidazole may be used.
또한， 사용가능한 유가용매는 테트라히드로퓨란 (THF), 디메틸포름아미드 (DMF) , 디메틸아세트아미드 (DMA), 디메틸설폭사이드 (DMS0) , 다이클로로메탄 (DCM), 클로로벤젠 , 틀루엔 또는 벤젠을 사용할 수 있고， 바람직하게는 다이클로로메탄 (DCM)을 사용할 수 있다. 다음으로, 상기 단계 2는 단계 1에서 제조된 화학식 9-(S)의 화합물과 메탄설포닐클로라이드 (MsCl)를 반응시켜 화학식 10-(S)로 표시되는 화합물을 제조하는 단계이다. In addition, usable solvents include tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMS0), dichloromethane (DCM), chlorobenzene, toluene or benzene. May be used, preferably dichloromethane (DCM). Next, the step 2 of the formula 9- (S) prepared in step 1 A compound and methanesulfonyl chloride (MsCl) are reacted to prepare a compound represented by Chemical Formula 10- (S).
더욱 상세하게는， 단계 1에서 제조된 입체구조가 S-형태인 화학식 9의 화합물과 메탄설포닐클로라이드 (MsCI)를 반웅시켜 입체구조가 S-형태인 화학식 10의 하이드특시기를 보호화하는 단계이다.  More specifically, reacting the compound of Formula 9 having the S-form and the methanesulfonyl chloride (MsCI) prepared in Step 1 to protect the hydrogen-special group of Formula 10 having the S-form to be.
이때， 반응에 사용가능한 염기는 트리에틸아민 (TEA), 다이에틸아민 (DEA), 다이이소프로필에틸아민 (DIPEA), 피리딘 또는 이미다졸을 사용할 수 있으며 , 바람직하게는 트리에틸아민 (TEA)을 사용할 수 있다.  At this time, the base usable in the reaction may be triethylamine (TEA), diethylamine (DEA), diisopropylethylamine (DIPEA), pyridine or imidazole, preferably triethylamine (TEA) Can be used.
또한, 사용가능한 유기용매는 테트라히드로퓨란 (THF), 디메틸포름아미드 (DMF)， 디메틸아세트아미드 (DMA)， 디메틸설폭사이드 (DMS0), 다이클로로메탄 (DCM) , 클로로벤젠， 를루엔 또는 벤젠을 사용할 수 있고, 바람직하게는 다이클로로메탄 (DCM)을 사용할 수 있다. 다음으로 상기 단계 3은 단계 2에서 제조된 화학식 10-(S)의 화합물과 화학식 3으로 표시돠는 화합물올 반웅시켜 화학식 11-0?)로 표시되는 화합물을 제조하는 단계이다.  In addition, usable organic solvents include tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMS0), dichloromethane (DCM), chlorobenzene, toluene or benzene. Can be used, preferably dichloromethane (DCM). Next, Step 3 is a step of preparing a compound represented by Chemical Formula 11-0?) By reacting the compound represented by Chemical Formula 10- (S) and Chemical Formula 3 prepared in Step 2.
더욱 상세하게는, 단계 2에서 제조된 입체구조가 S-형태인 화학식 10의 화합물과 화학식 3으로 표시되는 화합물을 포타슘카보네이트 (K2C03) 존재하에서 반응시켜 커풀링 반응을 수행하는 단계이다 . More specifically, it is a step of carrying out a coupling reaction by reacting the compound represented by the formula (3) having the three-dimensional structure prepared in step 2 with the compound represented by the formula ( 3 ) in the presence of potassium carbonate (K 2 CO 3 ).
이때 , 사용가능한 유기용매는 테트라히드로퓨란 (THF), 디메틸포름아미드 (DMF) , 디메틸아세트아미드 (DMA), 디메틸설폭사이드 (DMSO) 또는 다이클로로메탄 (DCM)을 사용할 수 있고， 바람직하게는 디메틸포름아미드 (DMF)를 사용할 수 있다.  At this time, the usable organic solvent may use tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) or dichloromethane (DCM), preferably dimethyl Formamide (DMF) can be used.
또한, 반응은도는 특별히 제한되지는 않으나, 상은 내지 용매의 환류온도 범위 내에서 사용될 수 있다. 다음으로 상기 단계 4는 단계 3에서 제조된 화학식 ll-(R)로 표시되는 화합물의 탈보호화 반웅을 수행하여 화학식 5-(R)로 표시되는 화합물을 제조하는 단계이다.  In addition, the reaction is not particularly limited, but the phase may be used within the reflux temperature range of the solvent. Next, step 4 is a step of preparing a compound represented by the formula (5-) by performing a deprotection reaction of the compound represented by the formula (ll- (R) prepared in step 3.
더욱 상세하게는， 단계 3에서 제조된 입체구조가 R-형태인 화학식 11의 화합물의 말단에 존재하는 보호화된 하이드록시기를, 테트라부틸암모늄 플루오라이드 (TBAF)를 이용하여 탈보호화하는 단계이다. More specifically, the protected hydroxy group present at the terminal of the compound of formula 11 in which the stereostructure prepared in step 3 is R-form is deprotected using tetrabutylammonium fluoride (TBAF).
이때， 사용가능한 유기용매는 메탄올, 테트라히드로퓨란 (THF), 디메틸포름아미드 (DMF), 디메틸설폭사이드 (DMS0) 또는 아세토니트릴을 사용할 수 있고， 바람직하게는 테트라히드로퓨란 (THF)을 사용할 수 있다.  At this time, the usable organic solvent may be methanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMS0) or acetonitrile, preferably tetrahydrofuran (THF) can be used. .
또한， 반응은도는 특별히 제한되지는 않으나， 상온 내지 용매의 환류온도 범위 내에서 사용될 수 있다 7 In addition, the reaction is not particularly limited, but may be used within the range of room temperature to reflux temperature of the solvent. 7
31 다음으로， 상기 단계 5는 단계 4에서 제조된 화학식 5-00의 화합물과 화학식 6으로 표시되는 화합물의 커플링 반응을 수행하여 화학식 1-(R)로 표시되는 화합물을 제조하는 단계이다.  Next, step 5 is a step of preparing a compound represented by Formula 1- (R) by performing a coupling reaction of the compound represented by the formula 5-00 and the compound represented by the formula (6) prepared in step 4.
더욱 상세하게는， 단계 4에서 제조된 입체구조가 R-형태인 화학식 5의 화합물 , 화학식 6의 화합물 및 트라이페닐포스핀을 혼합한 용액에 아조카르복실레이트 시약을 천천히 적가하여 미츠노부 반응 (Mitsi obu reaction)을 수행함으로써 입체구조가 R-형태인 화학식 1의 화합물을 제조하는 단계이다.  In more detail, the azocarboxylate reagent is slowly added dropwise to the solution of the compound of Formula 5, the compound of Formula 6, and triphenylphosphine having the R-form conformation prepared in Step 4 to react Mitsunobu (Mitsi by performing an obu reaction) to prepare a compound of formula 1 having a R-form conformation.
이때， 사용가능한 아조카르복실레이트 화합물은 다이에틸아조다이카르복실레이트 (diethyl azodicarboxylate, DEAD) 또는  At this time, the azocarboxylate compound that can be used is diethyl azodicarboxylate (DEAD) or
다이이소프로필아조다이 7 르복실레이트 (di i sopropy 1 azodi carboxy 1 ate , DIAD)를 사용할 수 있고， 바람직하게는 다이이소프로필아조다이카르복실레이트 (di i sopropy 1 azodi car boxy late, DIAD)를 사용할 수 있다. Diisopropyl azodi 7 carboxylate (di i sopropy 1 azodi carboxy 1 ate, DIAD) may be used, preferably di isoprop azodicarboxylate (di i sopropy 1 azodi car boxy late, DIAD) Can be used.
또한， 사용가능한 용매는 반응에 악영향을 미치지 않는 테트라하이드로퓨란 (THF),, 다이클로로메탄 (DCM), 를루엔 또는 아세토니트릴을 사용할 수 있고, 바람직하게는 테트라하이드로퓨란 (THF)을 사용할 수 있다. 나아가， 본 발명은 하기 반응식 4에 나타난 바와 같이， 화학식 8-(R)로 표시되는 화합물과 t- 부틸다이메틸실릴클로라이드 (TBSC1)를 반응시켜 화학식 9 -(R)로 표시되는 화합물을 제조하는 단계 (단계 1);  In addition, the usable solvent may be tetrahydrofuran (THF), dichloromethane (DCM), toluene or acetonitrile, which does not adversely affect the reaction, preferably tetrahydrofuran (THF) may be used. . Furthermore, the present invention is prepared by reacting the compound represented by the formula 8- (R) and t- butyl dimethylsilyl chloride (TBSC1) as shown in Scheme 4 to prepare a compound represented by the formula 9-(R) Step (step 1);
상기 단계 1에서 제조된 화학식 9- (R)의 화합물과 메탄설포닐클로라이드 (MsCl)를 반옹시켜 화학식 10- (R)로 표시되는 화합물을 제조하는 단계 (단계 2);  Preparing a compound represented by Chemical Formula 10- (R) by reacting the compound of Chemical Formula 9- (R) prepared in Step 1 with methanesulfonylchloride (MsCl) (Step 2);
상기 단계 2에서 제조된 화학식 1()ᅳ (R)의 화합물과 화학식 Compound of Formula 1 () ᅳ (R) and formula prepared in step 2
3으로 표시되는 화합물을 반응시켜 화학식 ll-(S)로 표시되는 화합물을 제조하는 단계 (단계 3); Reacting the compound represented by 3 to prepare a compound represented by Chemical Formula ll- (S) (step 3);
상기 단계 3에서 제조된 화학식 ll-(S)로 표시되는 화합물의 탈보호화 반응을 수행하여 화학식 5-(S)로 표시되는 화합물을 제조하는 단계 (단계 4); 및  Preparing a compound represented by Chemical Formula 5- (S) by performing a deprotection reaction of the compound represented by Chemical Formula ll- (S) prepared in Step 3 (Step 4); And
상기 단계 4에서 제조된 화학식 5-(S)의 화합물과 화학식 6으로 표시되는 화합물의 커플링 반웅을 수행하여 화학식 1-(S)로 표시되는 화합물을 제조하는 단계 (단계 5);를 포함하는 화학식 1로 표시되는 신규한 피페라진 유도체의 제조방법을 제공한다.  To prepare a compound represented by the formula 1- (S) by performing a coupling reaction between the compound represented by the formula (5-) and the compound represented by the formula (6) prepared in step 4 (step 5); Provided is a method for preparing a novel piperazine derivative represented by the formula (1).
[반응식 4]
Figure imgf000033_0001
Scheme 4
Figure imgf000033_0001
1-(S)  1- (S)
(상기 반응식 4에서， A, B 및 R은 상기 화학식 1에서 정의한 바와 같고; TBS는 t—부틸다이메틸실릴기이고; Ms은 메탄설포닐기이고; 및 화학식 1-(S)의 화합물은 화학식 1의 화합물이다.) 상기 반웅식 4의 제조방법은 본 발명에 따른 피페라진 유도체의 S-이성질체 제조방법으로， 반웅식 3의 제조방법에서 입체구조가 S- 형태인 화학식 8의 화합물을 사용하는 대신에 입체구조가 R-형태인 화학식 8의 화합물을 사용한 것올 제외하고 상기 반응식 3에 기재된 반응 조건과 동일하게 수행하였다. 또한， 본 발명은 하기 화학식 1로 표시되는 신규한 피페라진 유도체 , 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체를 유효성분으로 함유하는 대사질환 예방 또는 치료용 약학적 조성물을 제공한다.  (In Scheme 4, A, B and R are as defined in Formula 1; TBS is a t-butyldimethylsilyl group; Ms is a methanesulfonyl group; and the compound of Formula 1- (S) is represented by Formula 1 The method of preparing Banung Formula 4 is a method for preparing S-isomers of the piperazine derivatives according to the present invention, and instead of using the compound of Formula 8 having a S-form conformation in the preparation method of Banung Formula 3. Except for using the compound of formula (8) in which the stereostructure is in the R- form was carried out in the same manner as the reaction conditions described in Scheme 3. In addition, the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, which comprises a novel piperazine derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.
[화학식 1]
Figure imgf000033_0002
[Formula 1]
Figure imgf000033_0002
(상기 반웅식 1에서 , A, B, R 및 n은 상기 화학식 1에서 정의한 바와 같다.)  (In Reaction Formula 1, A, B, R, and n are as defined in Formula 1.)
GPR119는 췌장， 소장， 결장 및 지방 조직에서 주로 발면되는 G- 단백질에 커폴링된 수용체 (GPCR)로， GPR119 발현 프로파일은 비만 및 당뇨병을 포함한 다양한 대사질환의 치료에 대하여 잠재적 유용성을 가진다. GPR119 is a common G-form found in the pancreas, small intestine, colon and adipose tissue With receptors bound to proteins (GPCR), the GPR119 expression profile has potential utility for the treatment of various metabolic diseases including obesity and diabetes.
본 발명에 따른 화학식 1로 표시되는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체는 GPR119 수용체를 활성화하는 효과가 뛰어나며， 이로 인하여 cAMP를 자극하는 효과가 우수하다 (실험예 1 내지 실험예 3) . 또한， 물에 대한 용해도가 우수하여 체내 흡수율이 뛰어나고， 심장독성 및 세포독성이 종래에 알려져 있는 GPRU9 활성화제들에 비하여 현저히 낮아 부작용이 없으므로 인체에 대한 안정도가 상당히 높다 (실험예 4 내지 실험예 6). 따라서， 본 발명에 따른 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체는 체내 흡수율이 우수하고, 인체에 대한 안정성이 높을 뿐만 아니라 대사질환과 관련된 수용체인 GPR119를 활성화하는 효과가 우수하므로， 이를 유효성분으로 함유하는 대사질환 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다. 이때 , 상기 대사질환은 예를 들면， 비만， I 형 당뇨병， Π형 당뇨병， 부적합한 내당력 , 인슐린 내성 , 고혈당증， 고지질혈증， 고증성지방혈증, 고콜레스테를혈증， 이상지질혈증， X 증후군 둥을 들 수 있다. 본 발명의 화합물은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있으며， 제제화할 경우에는 보통 사용하는 충진제 증량제 , 결합제 , 습윤제， 붕해제， 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.  The novel piperazine derivatives represented by Formula 1 according to the present invention, pharmaceutically acceptable salts thereof, or optical isomers thereof have an excellent effect of activating the GPR119 receptor, thereby stimulating cAMP. Experimental Example 3). In addition, the water solubility in water is excellent in the body absorption rate, the cardiac toxicity and cytotoxicity is significantly lower than the conventionally known GPRU9 activator, so there is no side effect, the stability to the human body is quite high (Experimental Examples 4 to 6 ). Therefore, the novel piperazine derivatives, pharmaceutically acceptable salts thereof or optical isomers thereof according to the present invention have excellent absorption in the body, high stability to the human body, and an effect of activating GPR119, a receptor associated with metabolic diseases. Since it is excellent, it can be usefully used as a pharmaceutical composition for preventing or treating metabolic diseases containing it as an active ingredient. At this time, the metabolic diseases include, for example, obesity, type I diabetes, type Π diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, X syndrome Can be mentioned. The compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, it is prepared using diluents or excipients such as filler extenders, binders, wetting agents, disintegrants, surfactants, etc., which are commonly used. do.
경구투여를 위한 고형 제제에는 정계， 환자， 산제， 과립제 , 캡슐제， 트로키제 등이 포함되며， 이러한 고형 제제는 하나 이상의 본 발명의 화합물에 적어도 하나 이상의 부형제 예를 들면， 전분， 탄산칼슘 , 수크로스 (sucrose) 또는 락토오스 ( 1 actose) 또는 ¾라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활쎄들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제， 내용 액제 , 유제 또는 시럽제 등이 해당되는데， 흔히 사용되는 단순 희석제인 물， 리퀴드 파라핀 이외에 여러 가지 부형제， 예를 들면 습윤제， 감미제， 방향제 , 보존제 등이 포함될 수 있다.  Solid preparations for oral administration include politics, patients, powders, granules, capsules, troches, and the like, which may comprise at least one excipient such as starch, calcium carbonate, water, or the like. Prepared with a mixture of sucrose or lactose (1 actose) or ¾ latin. In addition to simple excipients, lubricating seeds such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions or syrups.In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be used. Can be.
비경구 투여를 위한 제제에는 멸균된 수용액 , 비수성용제， 현탁용제， 유제， 동결건조제제 , 좌제 등이 포함된다. 비수성용제， 현탁 용제로는 프로필렌글리콜， 폴리에틸렌 글리콜， 올리브 오일과 같은 식물성 기름 , 에틸을레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트원 (tween) 61， 카카오지 , 라우린지， 글리세를， 젤라틴 등이 사용될 수 있다.  Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl acrylate and the like can be used. As a suppository base, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
또한, 본 발명의 화합물의 인체에 대한 효과적인 투여량은 환자의 나이 , 몸무게 , 성별， 투여형태， 건강상태 및 질환 정도에 따라 달라질 수 있으며 , 일반적으로 약 0.001-100 mg/kg/일이며， 바람직하게는 0.01-35 mg/kg/일이다. 몸무게가 70 kg인 성인 환자를 기준으로 할 때， 일반적으로 0.0그 7000 mg/일이며， 바람직하게는 0.7- 2500 mg/일이며 , 의사 또는 약사의 관단에 따라 일정시간 간격으로 1일 1회 내지 수희로 분할 투여할 수도 있다. In addition, the effective dosage of the compound of the present invention to the human body is Depending on the patient's age, weight, sex, dosage form, medical condition and the extent of the disease, it is generally about 0.001-100 mg / kg / day, preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, typically 0.0 7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals depending on the physician's or pharmacist's observations. It can also be administered in divided doses.
【발명의 실시를 위한 형태】 [Form for implementation of invention]
이하, 본 발명을 제조예， 실시예 및 실험예에 의하여 상세히 설명한다 .  Hereinafter, the present invention will be described in detail by production examples, examples and experimental examples.
단， 하기 제조예， 실시예 및 실험예는 본 발명을 예시하는 것일 뿐， 본 발명의 내용이 이에 한정되는 것은 아니다.  However, the following Preparation Examples, Examples and Experimental Examples are merely to illustrate the present invention, but the content of the present invention is not limited thereto.
：제조예 1> 2-플루오로 -4- (메틸설포닐)페놀의 제조
Figure imgf000035_0001
Preparation Example 1 Preparation of 2-Fluoro-4- (methylsulfonyl) phenol
Figure imgf000035_0001
질소 대기하의 250 mL 플라스크에 4-브로모 -2-플루오로페놀 (8.8 g)과 다이메틸설페이트 (DMS0, 100 mL)를 넣고 교반하여 용해시 ¾ 다음 소듐설피네이트 (sodium sulf inate, 18.96 g)， 구리 (I) 트라이폴투오로메탄설페이트벤젠 착물 (2.33 g) 및 Ν,Ν- 다이메틸에틸렌다이아민 (0.82 g)을 적가하고 12시간 이상 환류교반하였다. 반웅이 완료되면 1N 염산 수용액 (100 mL)을 첨가하고 에틸아세테이트 (EA, 100 mL)로 추출한 후 무수황산마그네슘으로 건조하고 농축 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물올 얻었다. 4-bromo-2-fluorophenol (8.8 g ) and dimethylsulfate (DMS0, 100 mL) were added to a 250 mL flask under nitrogen atmosphere and stirred to dissolve ¾ followed by sodium sulfinate (18.96 g). The copper (I) tripoltoromethanesulfate benzene complex (2.33 g) and Ν, Ν- dimethylethylenediamine (0.82 g) were added dropwise and stirred under reflux for at least 12 hours. Upon completion of reaction, 1N aqueous hydrochloric acid solution (100 mL) was added, extracted with ethyl acetate (EA, 100 mL), dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to obtain a target compound.
XH NMR (400 Hz, CDC13)： δ 7.64(2H, m), 7.16(1Η, t) , 3.07(311 s). X H NMR (400 Hz, CDC1 3 ): δ 7.64 (2H, m), 7.16 (1Η, t), 3.07 (311 s).
<제조예 2> 3-플루오로 -4- (메틸설포닐)페놀의 제조
Figure imgf000035_0002
Preparation Example 2 Preparation of 3-Fluoro-4- (methylsulfonyl) phenol
Figure imgf000035_0002
질소 대기하의 250 mL 플라스크에 3-플루오로 -4- 메틸티오페놀 (1.5 g)과 테트라하이드로퓨란 (테트라하이드로퓨란 (THF), 80 mL)을 넣고 교반하여 용해시킨 다음， 0 °C로 냉각시키고 증류수 (20 mL)에 용해시킨 옥손 (oxone, 12.3 g)을 적가한 후， 상온에서 3시간 이상 교반하였다. 고체를 여과한 후 여액을 에틸아세테이트 (EA， 100 mL)로 추출하고 포화 소듐카보네이트 수용액 (100 mL)으로 세척하였다. 세척된 유기층을 무수 황산마그네슘으로 건조하고 농축 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다. NMR (400 Hz, CDCls)： δ 7.8K1H, t) , 6.75(2H, m) , 6.46(1H s) , 3 23(3H, s) . In a 250 mL flask under nitrogen atmosphere, 3-fluoro-4-methylthiophenol (1.5 g) and tetrahydrofuran (tetrahydrofuran (THF), 80 mL) were added, stirred, dissolved, and cooled to 0 ° C. Oxone (oxone, 12.3 g) dissolved in distilled water (20 mL) was added dropwise, followed by stirring at room temperature for 3 hours or more. After the solid was filtered, 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 purified by silica column chromatography to obtain the target compound. NMR (400 Hz, CDCls): δ 7.8K1H, t), 6.75 (2H, m), 6.46 (1H s), 3 23 (3H, s).
<제조예 3> 3-플루오로 -4- (하이드톡시메틸)페놀의 제조
Figure imgf000036_0001
Preparation Example 3 Preparation of 3-Fluoro-4- (hydroxymethyl) phenol
Figure imgf000036_0001
질소 대기하의 250 mL 플라스크에 2-플루오로 4- 하이드록시벤조산 (5 g)과 테트라하이드로퓨란 (THF, 100 mL)을 넣고 교반하여 용해시킨 다음， 0 °C로 넁각하였다. 그 후， 리튬알루미늄하이드라이드 (LAH, 2.43 g)를 첨가하고 상온으로 천천히 등온하여 3시간 이상 교반하였다. 반응이 끝나면， 에틸아세테이트 (EA, 200 mL)와 10% 소듬하이드톡사이드 수용액 (200 mL)을 이용하여 리륨알루미늄하이드라이드 (LAH)를 제거하고 에틸아세테이트 (EA, 200 mL)로 추출하였다. 추출된 유기층을 무수 황산마그네슘으로 건조하고 농축한 후 에틸아세테이트 (EA)와 다이에틸에티르를 이용하여 고체화해서 목적화합물을 얻었다.  2-fluoro 4-hydroxybenzoic acid (5 g) and tetrahydrofuran (THF, 100 mL) were added to a 250 mL flask under a nitrogen atmosphere, stirred, and dissolved, followed by stirring at 0 ° C. Thereafter, lithium aluminum hydride (LAH, 2.43 g) was added thereto, and the mixture was slowly isothermalized to room temperature and stirred for 3 hours or more. After the reaction, lithium aluminum hydride (LAH) was removed using ethyl acetate (EA, 200 mL) and 10% sodium hydroxide solution (200 mL), and extracted with ethyl acetate (EA, 200 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and concentrated, and then solidified with ethyl acetate (EA) and diethyl ether to obtain a target compound.
:H NMR (400 Hz, CDCI3)： δ 7.26(1H, t) , 6.62(2Η, m) , 4.49(1Η s) , 4.68(2Η, d) , 1.58(3Η, s) . 제조예 4> 3-플루오로 -4- (메틸티오메닐)페놀의 제조
Figure imgf000036_0002
 : H NMR (400 Hz, CDCI3): δ 7.26 (1H, t), 6.62 (2Η, m), 4.49 (1Η s), 4.68 (2Η, d), 1.58 (3Η, s). Preparation Example 4 Preparation of 3-Fluoro-4- (methylthiomenyl) phenol
Figure imgf000036_0002
질소 대기하의 250 mL 플라스크에 3-플루오로 -4- (하이드톡시메틸)페닐프로피오네이트 ( 1.8 g)와 테트라하이드로퓨란 (THF, 100 mL)을 넣고 교반하여 용해시킨 다음， Into a 250 mL flask under a nitrogen atmosphere, 3-fluoro-4- (hydroxymethyl) phenylpropionate (1.8 g) and tetrahydrofuran (THF, 100 mL) were added, stirred, and dissolved.
0 °C으로 냉각하여 트라이페닐포스핀 (PPh3, 3.57 g) 및 N- 브로모숙신이미드 (2.4 g)를 첨가하고, 상온으로 천천히 둥온하여Cool to 0 ° C, add triphenylphosphine (PPh 3 , 3.57 g) and N-bromosuccinimide (2.4 g), slowly warm to room temperature
1시간 이상 교반하였다. 그 후， 소듐티오메특사이드 (1.9 g)를 첨가하고 상은에서 12시간 이상 교반하였다. 반응이 완료되면 1N 염산 수용액 (100 mL)을 첨가하고 에틸아세테이트 (EA, 100 mL)로 추출하였다 추출된 유기층을 무수 황산마그네슘으로 건조하고 농축한 다음， 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다. Stir at least 1 hour. Thereafter, sodium thiomethoxide (1.9 g) was added and the phases were stirred for 12 hours or more at silver. After the reaction was completed, 1N aqueous hydrochloric acid solution (100 mL) was added, followed by extraction with ethyl acetate (EA, 100 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to obtain the target compound. .
XH NMR (400 Hz, CDC13) : δ 7.14(1Η, t) , 6.58(2Η, m) , 3.66(2Η: s) , 2.05(3Η, s) . X H NMR (400 Hz, CDC1 3 ): δ 7.14 (1Η, t), 6.58 (2Η, m), 3.66 (2Η : s), 2.05 (3Η, s).
<제조예 5> 3-플루오로 -4- (메틸설포닐메틸)페놀의 제조
Figure imgf000036_0003
Preparation Example 5 Preparation of 3-Fluoro-4- (methylsulfonylmethyl) phenol
Figure imgf000036_0003
3-플루오로 -4- (메틸티오)페놀을 사용하는 대신에 3-폴루오로 -4- (메틸티오메틸)페놀올 사용하는 것을 제외하고 상기 제조예 2와 동일한 방법으로 수행하여 목적화합물을 얻었다. Instead of using 3-fluoro-4- (methylthio) phenol instead of using 3-polo-4- (methylthiomethyl) phenolol except that The target compound was obtained by the same method.
:H NM (400 Hz, CDC13) '· δ 7.36(1H, t) , 6.68(2Η
Figure imgf000037_0001
s) , 4.25(2Η, s) , 2.82(3Η, s). 제조예 6> 3-메틸 -4- (메틸설포닐)페놀의 제조
Figure imgf000037_0002
 : H NM (400 Hz, CDC1 3 ) ' δ 7.36 (1H, t), 6.68 (2Η
Figure imgf000037_0001
s), 4.25 (2Η, s), 2.82 (3Η, s). Preparation Example 6 Preparation of 3-methyl-4- (methylsulfonyl) phenol
Figure imgf000037_0002
3-플루오로 -4— (메틸티오)페놀을 사용하는 대신에 4- (메틸티오) - m-크레졸을 사용하는 것을 제외하고 상기 제조예 2와 동일한 방법으로 수행하여 목적화합물을 얻었다.  A target compound was obtained in the same manner as in Production Example 2, except that 4- (methylthio) -m-cresol was used instead of 3-fluoro-4— (methylthio) phenol.
:H NMR (400 Hz, CDC13)： δ 7.94(1H, d), 6.80(2Η, s) , 5.47(1Η s), 3.08C3H, s), 2.67(3Η, s) . 제조예 7> 2, 6-다이플루오로 -4- (메틸설포닐)페놀의 제조 : H NMR (400 Hz, CDC1 3 ): δ 7.94 (1H, d), 6.80 (2Η, s), 5.47 (1Η s), 3.08C3H, s), 2.67 (3Η, s). Preparation Example 7 Preparation of 2, 6-Difluoro-4- (methylsulfonyl) phenol
Figure imgf000037_0003
Figure imgf000037_0003
4-브로모 -2-플루오로페놀을 사용하는 대신에 4-브로모 -2， 6- 다이플루오로페놀을 사용하는 것을 제외하고 상기 제조예 1와 동일한 방법으로 수행하여 목적화합물을 얻었다.  A target compound was obtained in the same manner as in Preparation Example 1, except that 4-bromo-2,6-difluorophenol was used instead of 4-bromo-2-fluorophenol.
:Η 丽 R (400 Hz, DMS0-d6)： δ 11.6K1H, s) , 7.64(2Η, d), 3.23(3Η, s). : Η 丽 R (400 Hz, DMS0-d 6 ): δ 11.6K1H, s), 7.64 (2Η, d), 3.23 (3Η, s).
<제조예 8> 3, 5-다이플루오로 -4- (메틸설포닐)페놀의 제조
Figure imgf000037_0004
Preparation Example 8 Preparation of 3,5-difluoro-4- (methylsulfonyl) phenol
Figure imgf000037_0004
3-플루오로 -4- (메틸티오)페놀을 사용하는 대신에 3,5- 다이플루오로 -4— (메틸티오)페놀을 사용하는 것올 제외하고 상기 제조예 2와 동일한 방법으로 수행하여 목적화합물올 얻었다.  The target compound was prepared in the same manner as in Preparation Example 2, except that 3,5-difluoro-4— (methylthio) phenol was used instead of 3-fluoro-4- (methylthio) phenol. Got it.
XH NMR (400 Hz, CDCI3)： δ 6.53(2H, d), 3.28(3Η, s) . X H NMR (400 Hz, CDCI3): δ 6.53 (2H, d), 3.28 (3Η, s).
<제조예 9> 2-플루오로 -4- (메틸설포닐메틸)페놀의 제조
Figure imgf000037_0005
Preparation Example 9 Preparation of 2-Fluoro-4- (methylsulfonylmethyl) phenol
Figure imgf000037_0005
3-풀루오로— 4- (메틸티오)페놀을 사용하는 대신에 2-플루오로 -4- (메틸티오메틸)페놀을 사용하는 것을 제외하고 상기 제조예 2와 동일한 방법으로 수행하여 목적화합물을 얻었다. 3-Pluoro- 2-Fluoro-4- instead of 4- (methylthio) phenol A target compound was obtained in the same manner as in Preparation Example 2, except that (methylthiomethyl) phenol was used.
XH NMR (400 Hz, CDC13)： δ 7.21(1H, d)， 7.07(2H, m), 5.37(1H s), 4.18(2H, s), 2.80(3H, s) . X H NMR (400 Hz, CDC1 3 ): δ 7.21 (1H, d), 7.07 (2H, m), 5.37 (1H s), 4.18 (2H, s), 2.80 (3H, s).
<제조예 10> 5-메틸 -6- (메틸설포닐)피리딘 -3-올의 제조
Figure imgf000038_0001
Preparation Example 10 Preparation of 5-methyl-6- (methylsulfonyl) pyridin-3-ol
Figure imgf000038_0001
3-플루오로— 4- (메틸티오)페놀을 사용하는 대신에 5-메틸 -6- (메틸티오)피리딘 -3-을을 사용하는 것을 제외하고 상기 제조예 2와 동일한 방법으로 수행하여 목적화합물을 얻었다.  3-Fluoro— Subject to the same compound as in Preparation Example 2, except that 5-methyl-6- (methylthio) pyridine-3- was used instead of 4- (methylthio) phenol. Got.
:H NMR (400 Hz, CDCI3)： δ 8.00(1H, s) , 7.10(1Η, s) , 6.95(1Η: s), 3.38(3Η, s), 2.65(3Η, s) 3-클로로 -4- (메틸설포닐)페놀의 제조
Figure imgf000038_0002
 : H NMR (400 Hz, CDCI 3 ): δ 8.00 (1H, s), 7.10 (1Η, s), 6.95 (1Η : s), 3.38 (3Η, s), 2.65 (3Η, s) 3-chloro- Preparation of 4- (methylsulfonyl) phenol
Figure imgf000038_0002
3-플루오로— 4- (메틸티오)페놀을 사용하는 대신에 3-클로로 -4- (메틸티오)페놀을 사용하는 것을 제외하고 상기 제조예 2와 동일한 방법으로 수행하여 목적화합물을 얻었다.  3-fluoro-4- (methylthio) phenol Instead of using 3-chloro-4- (methylthio) phenol was used in the same manner as in Preparation Example 2 except that the target compound was obtained.
^ NMR (400 Hz, CDCls)'- δ 8.01(1H, d), 7.04(1H, d), 6.89(1H, d), 6.36(1H, s), 3.26(3H, s). ^ NMR (400 Hz, CDCls) ' -δ 8.01 (1H, d), 7.04 (1H, d), 6.89 (1H, d), 6.36 (1H, s), 3.26 (3H, s).
<제조예 12> 6- (메틸설포닐)피리딘 -3-을의 제조
Figure imgf000038_0003
Preparation Example 12 Preparation of 6- (methylsulfonyl) pyridine-3-
Figure imgf000038_0003
질소 대기하의 100 mL 플라스크에 2-클로로 -5- 하이드록시피리딘 (2.55 g)과 다이메틸설페이트 (DMS0, 100 mL)를 넣고 교반하여 용해시킨 다음， 소듬 메탄설피네이트 (3.05 g) , 구리 (I)트라이플루오로멘탄설포네이트벤젠 착물 (1.0 g) 및 Ν,Ν- 다이메틸에틸렌다이아민 (0.42 mL)을 첨가하여 12시간 이상 환류교반하였다. 반옹이 완결되면 에틸아세테이트 (EA, 100 mL)로 추출하고， 포화 소듐바이카보네이트 수용액 (100 mL)과 소금물 (100 mL)로 세척하였다. 세척된 유기층올 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다.  To a 100 mL flask under nitrogen atmosphere, 2-chloro-5-hydroxypyridine (2.55 g) and dimethyl sulfate (DMS0, 100 mL) were added and stirred, followed by dissolving methanesulfinate (3.05 g) and copper (I Trifluoromentanesulfonate benzene complex (1.0 g) and Ν, Ν- dimethylethylenediamine (0.42 mL) were added and the mixture was stirred under reflux for at least 12 hours. When reaction was complete, the mixture was extracted with ethyl acetate (EA, 100 mL) and washed with saturated aqueous sodium bicarbonate 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 target compound.
XH NMR (400 Hz, DMS0-d6): δ 11.14(1H, s), 8.26(1H, d) , 7.90(1H, d) , 7.38(1H, d)， 3.17(3H, s) X H NMR (400 Hz, DMS0-d 6 ): δ 11.14 (1H, s), 8.26 (1H, d), 7.90 (1 H, d), 7.38 (1 H, d), 3.17 (3 H, s)
<제조예 13> 3-플루오로 -4-(l- (메틸설포닐)에틸)페놀의 제조 Preparation Example 13 Preparation of 3-Fluoro-4- (l- (methylsulfonyl) ethyl) phenol
Figure imgf000039_0001
Figure imgf000039_0001
3-플루오로 -4— (메틸티오)페놀을 사용하는 대신에 3-플루오로 -4- (1- (메틸티오)에틸)페놀을 사용하는 것을 제외하고 상기 제조예 2와 동일한 방법으로 수행하여 목적화합물을 얻었다.  The same procedure as in Preparation Example 2 was conducted except that 3-fluoro-4- (1- (methylthio) ethyl) phenol was used instead of 3-fluoro-4— (methylthio) phenol. The desired compound was obtained.
lU NMR (400 Hz, CDC13) ·' δ 7.38(1H, t), 6.65(2Η, m) , 4.60(1Η q), 2.77C3H, s), 1.77(3Η, d) . l U NMR (400 Hz, CDC1 3 ) ' δ δ 7.38 (1H, t), 6.65 (2Η, m), 4.60 (1Η q), 2.77C3H, s), 1.77 (3Η, d).
<제조예 14> 2, 5-다이플루오로 -4- (메틸설포닐메틸)페놀의 제조
Figure imgf000039_0002
Preparation Example 14 Preparation of 2,5-difluoro-4- (methylsulfonylmethyl) phenol
Figure imgf000039_0002
3-플루오로 -4- (메틸티오)페놀을 사용하는 대신에 2,5- 다이플루오로 -4- (메틸티오메틸)페놀을 사용하는 것을 제외하고 상기 제조예 2와 동일한 방법으로 수행하여 목적화합물올 얻었다.  The procedure was carried out in the same manner as in Preparation Example 2, except that 2,5-difluoro-4- (methylthiomethyl) phenol was used instead of 3-fluoro-4- (methylthio) phenol. Compound all obtained.
:H NMR (400 Hz, DMSO-de): δ 7.25(1H, dd) , 6.82(1Η, dd) , 4.39(2Η, s), 2.96(3Η, s) . <제조예 15> 2-플루오로 -4-(1Η-테트라졸 -1-일)페놀의 제조 : H NMR (400 Hz, DMSO-de): δ 7.25 (1H, dd), 6.82 (1Η, dd), 4.39 (2Η, s), 2.96 (3Η, s). Preparation Example 15 Preparation of 2-Fluoro-4- (1Η-tetrazol-1-yl) phenol
Figure imgf000039_0003
Figure imgf000039_0003
질소 대기하의 250 mL 플라스크에 4-아미노 -2-플루오로페놀 (4.8 g)와 아세트산 (100 mL)을 넣고 교반하여 용해시킨 다음， 소듬아자이드 (3.3 g) 및 트라이에틸올쏘포르메이트 (7.58 g)을 첨가하여 1.2시간 이상 환류교반하였다. 반응이 완료되면 감압증류하여 아세트산을 제거하고 에틸아세테이트 (EA, 100 mL)에 용해시킨 후， 증류수 (100 mL)와 포화 소듐바이카보네이트 수용액 (100 mL)으로 세척하였다. 세척된 유기층을 무수 황산마그네슘으로 건조하고 농축한 후， 에틸아세테이트 (EA)와 핵산 (hexane)을 이용하여 고체화하여 목적화합물을 얻었다.  In a 250 mL flask under nitrogen atmosphere, 4-amino-2-fluorophenol (4.8 g) and acetic acid (100 mL) were added and dissolved by stirring, followed by dissolving azide (3.3 g) and triethylolsoformate (7.58 g ) Was added and stirred under reflux for 1.2 hours or more. After the reaction was completed, distilled under reduced pressure to remove acetic acid, dissolved in ethyl acetate (EA, 100 mL), and washed with distilled water (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate and concentrated, and then solidified using ethyl acetate (EA) and nucleic acid (hexane) to obtain a target compound.
:H NMR (400 Hz, DMS0-d6): δ 10.68(1H, s), 9.9K1H, s) , 7.8K1H, d) , 7.56(1H, d) , 7.17(1H, t) . : H NMR (400 Hz, DMS0-d 6 ): δ 10.68 (1H, s), 9.9K1H, s), 7.8K1H, d), 7.56 (1H, d), 7.17 (1H, t).
<제조예 16> 4-(1Η-테트라졸 -1-일)페놀의 제조
Figure imgf000040_0001
Preparation Example 16 Preparation of 4- (1Η-tetrazol-1-yl) phenol
Figure imgf000040_0001
4-아미노 -2-플루오로페놀을 사용하는 대신에 4-아미노페놀을 사용하는 것을 제외하고 상기 제조예 15와 동일한 방법으로 수행하여 목적화합물을 얻었다.  A target compound was obtained in the same manner as in Preparation Example 15, except that 4-aminophenol was used instead of 4-amino-2-fluorophenol.
<제조예 17> 3-플루오로 -4-(1Η-테트라졸 -1-일)페놀의 제조
Figure imgf000040_0002
Preparation 17 Preparation of 3-Fluoro-4- (1Η-tetrazol-1-yl) phenol
Figure imgf000040_0002
4-아미노 -2-플루오로페놀을 사용하는 대신에 4-아미노 -3- 플루오로페놀을 사용하는 것을 제외하고 상기 제조예 15와 동일한 방법으로 수행하여 목적화합물을 얻었다.  A target compound was obtained in the same manner as in Preparation Example 15, except that 4-amino-3-fluorophenol was used instead of 4-amino-2-fluorophenol.
:H 丽 R (400 Hz, CDC13)： δ 10.75(1H, s) , 9.82(1H, s) , 7.63(1H, t) , 6.92(1H, d) , 6.82(1H, d) . : H δ R (400 Hz, CDC1 3 ): δ 10.75 (1H, s), 9.82 (1H, s), 7.63 (1H, t), 6.92 (1H, d), 6.82 (1H, d).
<제조예 18> 3，5，-다이플루오로 -4-(lH-테트라졸 -1-일)의 제조
Figure imgf000040_0003
Preparation Example 18 Preparation of 3,5, -difluoro-4- (lH-tetrazol-1-yl)
Figure imgf000040_0003
4-아미노 -2-플루오로페놀을 사용하는 대신에 4-아미노 -3,5- 다이플루오로페놀을 사용하는 것을 제외하고 상기 제조예 15와 동일한 방법으로 수행하여 목적화합물을 얻었다.  A target compound was obtained in the same manner as in Preparation Example 15, except that 4-amino-3,5-difluorophenol was used instead of 4-amino-2-fluorophenol.
:H NMR (400 Hz, DMS0-d6)： δ 9.91(1H, s), 6.82(2Η, d) . 제조예 19> 에틸 2-플루오로 -4-하이드록시벤조에이트의 제조
Figure imgf000040_0004
 : H NMR (400 Hz, DMS0-d 6 ): δ 9.91 (1H, s), 6.82 (2Η, d). Preparation Example 19 Preparation of Ethyl 2-Fluoro-4-hydroxybenzoate
Figure imgf000040_0004
질소 대기하의 250 mL 플라스크에 2-플루오로 -4- 하이드록시벤조산 (100g)과 에탄올 (320 mL)을 넣고 교반하여 용해시키고 황산 (34ml)을 천천히 적가한 후 12시간 이상 환류교반한다 반응이 완료되면 증류수 (500ml 이상)를 첨가한 후 고체화하여 목적화합물을 얻었다.  2-fluoro-4-hydroxybenzoic acid (100 g) and ethanol (320 mL) were added to a 250 mL flask under a nitrogen atmosphere, stirred, and dissolved. The sulfuric acid (34 ml) was slowly added dropwise and stirred under reflux for 12 hours. When distilled water (500ml or more) was added to solidify the target compound.
'Η 匪 R (400 Hz, CDCI3)： δ 7.86(1H, t), 7.01(1H, br) , 6.67(2H, m) , 4.38(2H, q)， 1.40(3H, t) .  'Η 匪 R (400 Hz, CDCI3): δ 7.86 (1H, t), 7.01 (1H, br), 6.67 (2H, m), 4.38 (2H, q), 1.40 (3H, t).
<제조예 20> 에틸 3-플루오로 -4-하이드록시벤조에이트의 제조
Figure imgf000041_0001
Preparation Example 20 Preparation of Ethyl 3-fluoro-4-hydroxybenzoate
Figure imgf000041_0001
2-플루오로 -4-하이드록시벤조산을 사용하는 대신에 3-플루오로- 4-하이드록시벤조산올 사용하는 것올 제외하고 상기 제조예 19와 동일한 방법으로 수행하여 목적화합물을 얻었다.  A target compound was obtained in the same manner as in Preparation Example 19, except that 3-fluoro-4-hydroxybenzoic acid was used instead of 2-fluoro-4-hydroxybenzoic acid.
匪 R (400 Hz, CDCls): δ 7.79(2H, d), 7.05(1H, t) , 5.94(1H s), 4.37C2H, q) , 1.40(3H, t).  匪 R (400 Hz, CDCls): δ 7.79 (2H, d), 7.05 (1H, t), 5.94 (1H s), 4.37C2H, q), 1.40 (3H, t).
<제조예 21> N,N-다이에틸 -4-하이드록시 -3-메틸벤즈아마이드의 제조 Preparation Example 21 Preparation of N, N-diethyl-4-hydroxy-3-methylbenzamide
Figure imgf000041_0002
Figure imgf000041_0002
질소 대기하의 100 mL 플라스크에 4-(t-부틸다이메틸실릴옥시 ) - 씨다이에틸 -3-메틸벤즈아마이드 (600 mg)와 테트라하이드로퓨란 (THF, 10 mL)을 교반하여 용해시키고， 테트라부틸암모늄플루라이드 1M 용액 (THF 용액 )올 천천히 적가한 후 상온에서 3시간동안 교반하였다. 반응이 완료되면 소금물 (10 ml )을 가하고 에틸아세테이트 (EA)로 추출하였다. 에틸아세테이트 (EA)층을 무수 황산마그네슴으로 건조하고 농축한 후， 에틸아세테이트 (EA)와 핵산을 이용하여 고체화하여 목적화합물을 얻었다.  Dissolve by stirring 4- (t-butyldimethylsilyloxy) -cidiethyl-3-methylbenzamide (600 mg) and tetrahydrofuran (THF, 10 mL) in a 100 mL flask under nitrogen atmosphere. The fluoride 1M solution (THF solution) was slowly added dropwise and stirred 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 and concentrated, and then solidified using ethyl acetate (EA) and nucleic acid to obtain the target compound.
:H NMR (400 Hz, CDC13)： δ 7.13(1H, s), 7.02(1H, d), 6.73(1H s) , 6.64(1H, d) , 3.43(4H, br) , 2.22(3H, s) , 1.19(6H, br) . : H NMR (400 Hz, CDC1 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, s), 1.19 (6 H, br).
<실시예 1> t-부틸 -4-(4-(4- (메틸설포닐 )페녹시 )부탄 -2- 일 )피페라진 -1-카르복실레이트 옥살산 염의 제조 Example 1 Preparation of t-butyl-4- (4- (4- (4-methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalic acid salt
Figure imgf000041_0003
Figure imgf000041_0003
단계 1: t-부틸 -4-(4-메톡시 -4—옥소부탄 -2-일 )피페라진 -1- 카르복실레이트의 제조  Step 1: Preparation of t-butyl-4- (4-methoxy-4—oxobutan-2-yl) piperazine-1-carboxylate
질소 대기하의 100 mL 플라스크에 메틸크로포네이트 (methyl crotonate, 3.3 g)와 메탄을 (50 mL)을 넣고 교반하여 용해시킨 다음， t_부틸 -1-피페라진 카르복실레이트 (5 g)를 적가하고 24시간 이상 환류교반하였다. 반웅이 종결되면 용매를 감압농축하여 제거하고， 실리카 컬럼크로마토그래피로 정제하여 목작화합물을 얻었다. Methyl crotonate (3.3 g) and methane (50 mL) were added and dissolved in a 100 mL flask under nitrogen atmosphere, and then t_butyl-1-piperazine carboxylate (5 g) was added dropwise. More than 24 hours The reflux was stirred. When the reaction was terminated, the solvent was removed by concentration under reduced pressure, and purified by silica column chromatography to obtain a wood compound.
¾ NMR (400 Hz, CDCls)： 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). 단계 2: t-부틸 -4-(4-하이드톡시부탄 -2-일 )피페라진 -1- 카르복실레이트의 제조  ¾ NMR (400 Hz, CDCls): 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: Preparation of t-butyl-4- (4-hydroxybutan-2-yl) piperazine-1-carboxylate
질소 대기하의 100 mL 플라스크에 리튬알루미늄하이드라이드 (LAH, 880 mg)를 테트라하이드로퓨란 (THF， 50 mL)에 0°C에서 교반하여 용해시킨 다음， 테트라하이드로퓨란 (THF, 50 mL)에 상기 단계 1에서 제조된 화합물 (2.7 g)을 녹인 용액을 5분 동안 천천히 플라스크에 적가하였다. 반응이 종결되면 1M- 소듐하이드록사이드 (50 mL)을 천천히 적가하고 에틸아세테이트 (40 mL)로 추출한 다음， 소금물 (100 mL)로 세척하였다. 세척된 유기층을 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다 . Lithium aluminum hydride (LAH, 880 mg) was dissolved in tetrahydrofuran (THF, 50 mL) at 0 ° C. in a 100 mL flask under nitrogen atmosphere, and then the above step was added to tetrahydrofuran (THF, 50 mL). The solution of compound (2.7 g) prepared in 1 was slowly added dropwise to the flask for 5 minutes. After the reaction was completed, 1M-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 target compound.
XH NMR (400 Hz, CDC13): δ 3.83(m, 2H), 3.47(m, 4H), 2.96(m, 1H) , 2.72(m, 2H)， 2.44(m, 2H), 1.91(m, 1H) , 1.46(s, 9H), 1.00(d, 3H) . 단계 3: t-부틸 -4-(4-(4- (메틸설포닐)페녹시 )부탄 -2- 일 )피페라진 -1-카르복실레이트 옥살산 염의 제조 X H NMR (400 Hz, CDC1 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 , 1H), 1.46 (s, 9H), 1.00 (d, 3H). Step 3: t-butyl 4- (4- (4 (methylsulfonyl) phenoxy) butane-2-yl) manufactured piperazine-1-carboxylate oxalate
질소 대기하의 100 mL 플라스크에 상기 단계 2에서 제조된 화합물 (0.4 g), 트라이페닐포스핀 (PPh3, 0.63 g), 4- (메틸설포닐)페놀 (0.35 g) 및 테트라하이드로퓨란 (THF)을 넣고 교반하여 용해시켰다. 상기 반응물에 國다이이소프로필 01·조다이 ^1"르복실레이트 (di isopropyl azodi carboxyl ate , 0.5 mL)를 0°C에서 천천히 적가하고 12시간 이상 상온에서 교반하였다 . 반응이 종결되면 반응물에 증류수 (20 raL)를 천천히 가하고 에틸아세테이트 (EA, 60 ml)로 추출한 다음， 소금물 (40 ml)로 세척하였다. 세척된 유기층을 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 정제된 화합물에 에틸아세테이트 (EA, 10 mL)를 넣고 교반하여 용해시키고， 화합물과 같은 당량수의 옥살산을 적가한 후 30분간 환류교반하였다. 반응이 종결되면 온도를 상온으로 냉각시키고 고체를 여과하여 목적화합물올 얻었다. In a 100 mL flask under a nitrogen atmosphere, the compound (0.4 g), triphenylphosphine (PPh 3 , 0.63 g), 4- (methylsulfonyl) phenol (0.35 g) and tetrahydrofuran (THF) prepared in step 2 were prepared. Was added and stirred to dissolve. The reaction when slowly added dropwise in the reaction國diisopropylamino 0 1, crude dimethyl ^ 1 "Le butyl (di isopropyl azodi carboxyl ate, 0.5 mL) to 0 ° C and stirred at for 12 hours or more at room temperature. The reaction was terminated Distilled water (20 raL) was slowly added, 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, followed by stirring to dissolve it, and an equivalent amount of oxalic acid was added dropwise and stirred under reflux for 30 minutes.When the reaction was completed, the temperature was cooled to room temperature and the solid was filtered. The target compound was obtained.
LH NMR (400 Hz, D20)： 6 7.8K2H, 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. ll(2H,m) , 1.51(9H's), 1.33(3H,d) . L H NMR (400 Hz, D 2 0): 6 7.8K2H, 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.ll (2H, m), 1.51 (9H's), 1.33 (3H, d).
<실시예 2> t-부틸 -4-(4-(2-플루오로 -2-Example 2 t-butyl-4- (4- (2-fluoro-2-
((메틸설포닐)메틸)페녹시)부탄 -2-일)피페라진 -1-카르복실레이트 옥살산염의 제조 ((Methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazine-1-carboxylate Preparation of Oxalate
Figure imgf000043_0001
Figure imgf000043_0001
상기 실시예 1의 단계 3에서 4- (메틸설포닐 )페놀을 사용하는 대신에 제조예 9에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using 4- (methylsulfonyl) phenol in step 3 of Example 1 except that the compound prepared in Preparation Example 9 was carried out in the same manner as in Example 1 to obtain the target compound.
XH NMR (400 Hz, D20)： δ 7.30(1H, t), 6.79(2H,d), 4.47(2H, s), 4.17(2H,m), 4.04(211， m), 3.62 (lH,m) , 3.40(lH,d) , 3.08(4H,m) , 2.98(3H,s) , 2.11(2H,m), 1.43(9H,s), 1.40(3H,d) . <실시예 3> 2-(4-(4-(4- (메틸설포닐 )페녹시 )부탄 -2- 일)피페라진 -1-일) -5-프로필피리미딘 옥살산염의 제조 X H NMR (400 Hz, D 2 0): δ 7.30 (1H, t), 6.79 (2H, d), 4.47 (2H, s), 4.17 (2H, m), 4.04 (211, m), 3.62 ( lH, m), 3.40 (lH, d), 3.08 (4H, m), 2.98 (3H, s), 2.11 (2H, m), 1.43 (9H, s), 1.40 (3H, d). Example 3 Preparation of 2- (4- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5propylpyrimidine oxalate
Figure imgf000043_0002
Figure imgf000043_0002
단계 1: 2-피페라진 -1-일 -5-프로필피리미딘의 제조  Step 1: Preparation of 2-piperazin-1-yl-5-propylpyrimidine
질소 대기하의 100ml 플라스크에 t-부틸 -1-피페라진 카르복실레이트 (5 g)를 주입한 다음， 4N-염산 (1,4-다이옥산 용액， 10 mL)을 천천히 적가하고 10시간 이상 교반하였다. 교반이 종결되면 , 반웅물에 다이에틸에테르 (20 mL)를 첨가하고 30분 동안 교반한 후， 생성된 고체를 다이에틸에테르 (50 mL)로 세척하면서 여과하였다. 그 후, 여과된 고체를 건조시키고， 다시 아세토니트릴과 증류수를 각각 10 mL를 첨가하여 용해시켰다. 용해된 반응물에 Ν,Ν- 다이이소프로필에틸아민 (0.3 mL) 및 2-클로로 -5-프로필피리미딘 (6.3 g)을 첨가하여 12시간 이상 환류교반하였다. 반응이 종결되면 증류수 (15 mL)를 천천히 가하고, 에틸아세테이트 (EA, 40 mL)로 추출한 다음， 소금물 (100 ml)로 세척하였다. 세척된 반응물을 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적 화합물을 얻었다.  After t-butyl-1-piperazine carboxylate (5 g) was injected into a 100 ml flask under nitrogen atmosphere, 4N-hydrochloric acid (1,4-dioxane solution, 10 mL) was slowly added dropwise and stirred for 10 hours or longer. After stirring was completed, diethyl ether (20 mL) was added to the reaction solution and stirred for 30 minutes, and the resulting solid was filtered while washing with diethyl ether (50 mL). Thereafter, the filtered solid was dried, and 10 mL of acetonitrile and distilled water were further added to dissolve it. N, N- diisopropylethylamine (0.3 mL) and 2-chloro-5-propylpyrimidine (6.3 g) were added to the dissolved reaction and stirred at reflux for at least 12 hours. After 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 over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography to obtain the target compound.
XH NMR (400 Hz, CDC13): 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) .
Figure imgf000043_0003
질소 대기하의 100ml 폴라스크에 메틸크로포네이트 (methyl crotonate, 3.3 g)와 메탄올 (50 mL)을 넣고 교반하여 용해시킨 다음， 상기 단계 1에서 제조된 화합물 (5 g)을 적가하고 24시간 이상 환류교반하였다ᅳ 반응이 종결되면 용매를 감압농축하여 제거하고， 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다. X H NMR (400 Hz, CDC1 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).
Figure imgf000043_0003
Methyl crotonate (3.3 g) and methanol (50 mL) were added and dissolved in a 100 ml polar flask under a nitrogen atmosphere. The compound (5 g) prepared in Step 1 was added dropwise and refluxed for at least 24 hours. After stirring, the solvent was concentrated under reduced pressure to remove the reaction and purified by silica column chromatography to obtain the title compound.
lH MR (400 Hz, CDC13): S 8.16(s, 2H), 3.77(t , 4H) , 3.69(s, 3H) , 3.24(m, 1H)， 2.59(m, 5H) , 2.40(1;， 2H)， 2.31(dd, 1H) , 1.57(m, 2H) , 1.09(d, 3H) , 0.94(t , 3H) . 단계 3: 3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부탄 -1- 올의 제조 l MR (400 Hz, CDC1 3 ): S 8.16 (s, 2H), 3.77 (t, 4H), 3.69 (s, 3H), 3.24 (m, 1H), 2.59 (m, 5H), 2.40 (1; , 2H), 2.31 (dd, 1H), 1.57 (m, 2H), 1.09 (d, 3H), 0.94 (t, 3H). Step 3: Preparation of 3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butan-1-ol
질소 대기하의 lOOml 플라스크에 리튬알루미늄하이드라이드 (LAH 900 mg)를 테트라하이드로퓨란 (THF, 50 mL)에 0°C에서 교반하여 용해시킨 다음, 테트라하이드로퓨란 (THF, 50 mL)에 상기 단계 2에서 제조된 화합물 (2.7 g)을 녹인 용액을 5분 동안 천천히 플라스크에 적가하였다. 반응이 종결되면 1M-소듐하이드록사이드 (50 mL)을 천천히 적가하고 에틸아세테이트 (40 mL)로 추출한 다음， 소금물 (100 mL)로 세척하였다. 세척된 유기층을 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다. Lithium aluminum hydride (LAH 900 mg) was dissolved in tetrahydrofuran (THF, 50 mL) at 0 ° C. in a 100 ml flask under nitrogen atmosphere, and then, in step 2 above, in tetrahydrofuran (THF, 50 mL). A solution of the prepared compound (2.7 g) was slowly added dropwise to the flask for 5 minutes. After the reaction was completed, 1M-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 target compound.
:H NMR (400 Hz, CDCI3): δ 8.16(s, 2H) , 3.84(m, 6Η) , 3.00(m, 1Η) , 2.84(m, 2H) , 2.54(ra, 211) , 2.41(t , 2H) , 1.95(m, 1H) , 1.57(m, 2H), 1.42(dq, 1H) , l.OKd, 3H) , 0.94(t , 3H). 단계 4: 3-(4-(5-프로필피리미딘 -2-일)피페라진 -1-일)부틸 메탄설포네이트의 제조 : H NMR (400 Hz, CDCI 3 ): δ 8.16 (s, 2H), 3.84 (m, 6Η), 3.00 (m, 1Η), 2.84 (m, 2H), 2.54 (ra, 211), 2.41 (t , 2H), 1.95 (m, 1H), 1.57 (m, 2H), 1.42 (dq, 1H), l.OKd, 3H), 0.94 (t, 3H). Step 4: Preparation of 3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butyl methanesulfonate
질소 대기하의 100 mL 플라스크에 상기 단계 3에서 제조된 화합물 (2 g)올 다이클로로메탄 (DCM, 100 mL)에 교반하여 용해시키고， 트라이에틸아민 (TEA, 1.2 mL)을 첨가한 후， 메탄설포닐 클로라이드 (0.6 mL)를 0°C에서 천천히 적가하였다. 적가가 완료된 다음 30분 동안 교반하고 다이클로로메탄 (DCM, 40 mL)으로 추출한 후, 소금물 (brine, 100 mL)로 세척하였다. 세척된 화합물을 무수 황산마그네슘으로 건조하고 농축하여 목적화합물을 얻었다. In a 100 mL flask under nitrogen atmosphere, the compound (2 g) ol dichloromethane (DCM, 100 mL) prepared in step 3 was stirred and dissolved, triethylamine (TEA, 1.2 mL) was added, Ponyl chloride (0.6 mL) was slowly added dropwise at 0 ° C. After the addition was completed, the mixture 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.
XH NMR (400 Hz, CDCI3)： δ 5.08(m, 1H) , 4.71(m, 3H) , 4.43(m, 1H) , 4.14(dd, 1H), 3.86(dd, 1H), 3.42(m, 3H), 3.12(td, 1H) , 2.92(m, 1H), 2.74(s, 3H), 2.45(m, 5H) , 1.60(d, 3H), 1.53(m, 2H)， 0.92(t , 3H) 단계 5: 2-(4-(4-(4— (메틸설포닐 )페녹시 )부탄 -2-일 )피페라진 -1- 일) -5-프로필피리미딘 옥살산염의 제조 X H NMR (400 Hz, CDCI3): δ 5.08 (m, 1H), 4.71 (m, 3H), 4.43 (m, 1H), 4.14 (dd, 1H), 3.86 (dd, 1H), 3.42 (m, 3H), 3.12 (td, 1H), 2.92 (m, 1H), 2.74 (s, 3H), 2.45 (m, 5H), 1.60 (d, 3H), 1.53 (m, 2H), 0.92 (t, 3H ) Step 5: Preparation of 2- (4- (4- (4— (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate
질소 대기하의 100ml 플라스크에 상기 단계 4에서 제조된 화합물 (600 mg), 포타슴카보네이트 (360 mg) 및 다이메틸포름아마이드 (DMF, 30 mL)를 넣고 교반하여 용해시킨 다음 , 4ᅳ (메틸설포닐)페놀 (350 mg)을 첨가하고 온도를 70°C로 등온하여 교반하였다. 교반이 종결되면 상온으로 냉각시키고， 증류수 (20 mL)를 천천히 가한 후 에틸아세테이트 (EA, 60 mL)로 추출하였다. 추출된 유기층을 소금물 (40 mL)로 세척한 다음， 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 이후 에틸아세테이트 (EA, 10 mL)를 첨가하고 교반하여 용해시킨 뒤， 같은 당량수의 옥살산을 첨가하여 30분간 환류교반하였다 . 반응이 완료되면 은도를 상온으로 냉각시키고， 고체를 여과하여 목적화합물을 얻었다. In a 100 ml flask under nitrogen atmosphere, the compound (600 mg), formate carbonate (360 mg) and dimethylformamide (DMF, 30 mL) prepared in Step 4 were added thereto, stirred, and dissolved. 4 ᅳ (methylsulfonyl) phenol (350 mg) was added and the temperature was stirred to 70 ° C. After stirring was completed, the mixture was cooled to room temperature, distilled water (20 mL) was added slowly, 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. Thereafter, ethyl acetate (EA, 10 mL) was added, stirred and dissolved, and the same amount of oxalic acid was added thereto, followed by stirring under reflux for 30 minutes. When the reaction was completed, the silver was cooled to room temperature, and the solid was filtered to obtain the target compound.
:H NMR (400 Hz, D20): δ 8.21(2H,s) , 7.79(2Η, d), 7.07(2H,d) 4.6Κ2Η, s) , 4.18(2H,m) , 3.67(1H, m)， 3.45(lH,m) , 3.23(4H,m) , 3.12(3H,s), 2.37C2H, t) , 2.10(2H,m) , 1.48(2H,q) , 1.33(3H,d) 0.77(3H, t) . : H NMR (400 Hz, D 2 0): δ 8.21 (2H, s), 7.79 (2Η, d), 7.07 (2H, d) 4.6Κ2Η, s), 4.18 (2H, m), 3.67 (1H, m), 3.45 (lH, m), 3.23 (4H, m), 3.12 (3H, s), 2.37C2H, t), 2.10 (2H, m), 1.48 (2H, q), 1.33 (3H, d) 0.77 (3H, t).
<실시예 4> 2-(4-(4-(3-플루오로 -4-Example 4 2- (4- (4- (3-fluoro-4-)
((메틸설포닐 )메틸)페녹시 )부탄 -2-일 )피페라진 -1-일 ) -5- 프로필피리미딘의 제조 Preparation of ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine
Figure imgf000045_0001
Figure imgf000045_0001
질소 대기하의 100 ml 플라스크에 상기 실시예 3의 단계 4에서 제초된 화합물 (600 mg), 포타슘카보네이트 (360 mg) 및 다이메틸포름아마이드 (DMF, 30 mL)를 넣고 교반하여 용해시킨 다음， 상기 제조예 5에서 제조된 화합물 (350 mg)을 첨가하고 온도를 70°C로 등온하여 교반하였다. 교반이 종결되면 상온으로 냉각시키고, 증류수 (20 mL)를 천천히 가한 후 에틸아세테이트 (EA, 60 mL)로 추출하였다. 추출된 유기층을 소금물 (40 mU)로 세척한 다음, 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다. In a 100 ml flask under nitrogen atmosphere, the compound (600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) prepared in step 4 of Example 3 were added thereto, stirred, and dissolved. Compound (350 mg) prepared in Example 5 was added and the temperature was stirred to 70 ° C. After stirring was completed, the mixture was cooled to room temperature, distilled water (20 mL) was added slowly, and extracted with ethyl acetate (EA, 60 mL). The extracted organic layer was washed with brine (40 mU), dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography to obtain the target compound.
XH NMR (400 Hz, CDC13) '■ δ 8.17(2H,s)! 7.38(lH,t), 6.74(2H,dd) , 4.25(2H,s) , 4.09(2H,m), 3.78(4H, m) 2.91(lH,q)， 2.81(3H,s) , 2.68(2H,m) , 2.53(2H,m) , 2.43(2H,t), 2.04(lH,m)， 1.81(lH,m) , 1.58(2H,m) , 1.05(3H,d) 0.95(3H,t) . X H NMR (400 Hz, CDC1 3 ) ' ■ δ 8.17 (2H, s) ! 7.38 (lH, t), 6.74 (2H, dd), 4.25 (2H, s), 4.09 (2H, m), 3.78 (4H, m) 2.91 (lH, q), 2.81 (3H, s), 2.68 ( 2H, m), 2.53 (2H, m), 2.43 (2H, t), 2.04 (lH, m), 1.81 (lH, m), 1.58 (2H, m), 1.05 (3H, d) 0.95 (3H, t).
<실시예 5> 2-(4-(4-(3-플루오로 -4-Example 5 2- (4- (4- (3-fluoro-4-)
((메틸설포닐)메틸)페녹시 )부탄 -2-일 )피페라진 -1-일 ) -5- 프로필피리미딘 옥살산염의 제조 Preparation of ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate
Figure imgf000046_0001
Figure imgf000046_0001
상기 실시예 3의 단계 5에서 4- (메틸설포닐)페놀을 사용하는 대신에 제조예 5에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 3과 동일한 방법으로 수행하여 목적화합물을 얻었다.  The target compound was obtained in the same manner as in Example 3, except that the compound prepared in Preparation Example 5 was used instead of 4- (methylsulfonyl) phenol in Step 5 of Example 3.
1]\ 匪 R (400 Hz, D20)： δ 8.21(2H,s) , 7.30(lH,t), 6.78(2H,d) , 4.62(2H,m) , 4.47(2H,s), 4.18(lH,m) , 4. ll(lH,m) , 3.64(1H, m) , 3.44(2H,m) , 3.22(4H,m), 2.41(2H,t), 2.28(lH,m) , 2.01(lH,m), 1.47(2H,q) , 1.33(3H,d) , 0.77(3H,t) · 1 ] \ 匪 R (400 Hz, D 2 0): δ 8.21 (2H, s), 7.30 (lH, t), 6.78 (2H, d), 4.62 (2H, m), 4.47 (2H, s), 4.18 (lH, m), 4.ll (lH, m), 3.64 (1H, m), 3.44 (2H, m), 3.22 (4H, m), 2.41 (2H, t), 2.28 (lH, m) , 2.01 (lH, m), 1.47 (2H, q), 1.33 (3H, d), 0.77 (3H, t)
<실시예 6> l-(4-(3-플루오로 -4- (메틸설포닐)페녹시)부탄 -2- 일 ) -4-(3-이소프로필 -1,2,4-옥사다이아졸 -5-일 )피페라진 옥살산염의 제조 Example 6 l- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole Preparation of -5-yl) piperazine oxalate
Figure imgf000046_0002
Figure imgf000046_0002
단계 1: t-부틸 -4-시아노피페라진 -1-카르복실레이트의 제조 질소 대기하의 250 ml 풀라스크에 피페라진 -1-카르복실산 t- 부틸에스테르 (10 g), 아세토니트릴 (50 mL) 및 증류수 (50 mL)올 주입한 다음， 0°C로 냉각시키고 교반하여 용해시켰다. 소듐바이카보네이트 (6 g)와 시아노겐브로마이드 (6.3 g)를 천천히 플라스크에 첨가하였다. 이후 천천히 50°C까지 등온하고 3시간 동안 교반하였다. 반응이 종결되면 1M-염산을 사용하여 0°C에서 pH를 중성상태로 만든 뒤 에틸아세테이트 (500 mL)로 추출하고 소금물 (100 mL)로 세척하였다. 그 후, 세척된 유기층을 무수 황산마그네슘으로 건조하여 원하는 고체의 목적 화합물을 얻었다. Step 1: Preparation of t-butyl-4-cyanopiperazine-1-carboxylate Piperazine-1-carboxylic acid t-butylester (10 g), acetonitrile (50 mL) and distilled water (50 mL) were injected, then cooled to 0 ° C. and stirred to dissolve. Sodium bicarbonate (6 g ) and cyanogenbromide (6.3 g) were slowly added to the flask. Then isothermally stirred to 50 ° C. and stirred for 3 hours. After the reaction was completed, the pH was neutralized at 1 ° C. with 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 a target compound of the desired solid.
NMR (400 Hz, CDC13) ： δ 3.54(t, 4H) , 3.21(t , 4H) , 1.48(sNMR (400 Hz, CDC1 3 ): δ 3.54 (t, 4H), 3.21 (t, 4H), 1.48 (s
9Η) . 단계 2: 3-이소프로필— 5- (피페라진 -1-일 ) -1,2, 4-옥사다이아졸의 제조 9Η). Step 2: Preparation of 3-isopropyl—5- (piperazin-1-yl) -1,2, 4-oxadiazole
질소 대기하의 100 ml 플라스크에 상기 단계 1에서 제조된 화합물 (10 g) 및 에틸아세테이트 (EA, 30 mL)를 넣고 교반하여 용해시켰다. 상기 반웅물에 -하이드록시-이소부틸아미딘 (540 mg)을 천천히 플라스크에 첨가하고， 상온에서 1시간 동안 교반한 후 염화아연 (Zinc chloride, 1M 다이에틸에테르 용액， 5 mL)을 천천히 적가하였다. 적가가 종료되면 3시간 동안 교반하고， 생성되는 고체를 여과 후 에틸아세테이트 (EA, 100 mL)로 세척하고 건조하였다. 건조된 고체를 에탄을 (30 mL)에 용해시켜 교반한 다음 4- 염산 (1.2 mL)을 적가하고 환류교반하였다. 반웅이 종결되면 1M-소듐하이드록사이드로 H 10까지 올린 뒤 에틸아세테이트 (EA, 100 mL)로 추출하고， 추출된 유기층을 농축하여 원하는 목적화합물을 얻었다. In a 100 ml flask under a nitrogen atmosphere, compound (10 g) and ethyl acetate (EA, 30 mL) prepared in step 1 were added thereto, followed by stirring. Dissolved. -Hydroxy-isobutylamidine (540 mg) was slowly added to the reaction mixture, the mixture was stirred at room temperature for 1 hour, and zinc chloride (ZM chloride, 1M diethyl ether solution, 5 mL) was slowly added dropwise thereto. . After the dropwise addition was stirred for 3 hours, the resulting solid was filtered, washed with ethyl acetate (EA, 100 mL) and dried. The dried solid was dissolved in ethane (30 mL), stirred, and 4-hydrochloric acid (1.2 mL) was added dropwise and refluxed. When the reaction was terminated, the mixture was raised to H 10 with 1M sodium hydroxide, extracted with ethyl acetate (EA, 100 mL), and the extracted organic layer was concentrated to obtain a desired compound.
¾ 匪 R (400 Hz, CDC13)： δ 3.59(m, 4H), 2.94(m, 4H), 1.30(d( ¾ 匪 R (400 Hz, CDC1 3 ): δ 3.59 (m, 4H), 2.94 (m, 4H), 1.30 (d (
6H) . 단계 3: 메틸 -3— (4-(3-이소프로필 -1,2, 4—옥사다이아졸 -5- 일 )피페라진 -1-일 )부타노에이트의 제조 6H). Step 3: Preparation of Methyl-3— (4- (3-isopropyl-1,2, 4—oxadiazol-5-yl) piperazin-1-yl) butanoate
질소 대기하의 100ml 플라스크에 메틸크로포네이트 (methyl crotonate, 3.3 g)와 메탄올 (50 mL)올 넣고 교반하여 용해시킨 다음, 상기 단계 2에서 제조된 화합물 (5 g)을 적가하고 24시간 이상 환류교반하였다. 반웅이 종결되면 용매를 감압농축하여 제거하고， 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다.  Methyl crotonate (3.3 g) and methanol (50 mL) were added and dissolved in a 100 ml flask under nitrogen atmosphere. The compound (5 g) prepared in Step 2 was added dropwise and stirred under reflux for 24 hours. It was. When the reaction was terminated, the solvent was removed by concentration under reduced pressure, and purified by silica column chromatography to obtain the target compound.
XH NMR (400 Hz, CDC13): δ 3.66(s, 3Η) , 3.55(m, 4Η) , 3.21(1Η q), 2.86(1Η, q) , 2.58(m, 5Η) , 1.25(d, 6Η) , 1.04(d, 3Η) . 단계 4: 3-(4-(3—이소프로필 -l,2,4-옥사다이아졸-5-일)부탄-l- 올의 제조 XH NMR (400 Hz, CDC1 3 ): δ 3.66 (s, 3Η), 3.55 (m, 4Η), 3.21 (1Η q), 2.86 (1Η, q), 2.58 (m, 5Η), 1.25 (d, 6Η ), 1.04 (d, 3Η). Step 4: Preparation of 3- (4- (3—Isopropyl-l, 2,4-oxadiazol-5-yl) butan-l-ol
질소 대기하의 100 ml 풀라스크에 리튬알루미늄하이드라이드 (LAH, 900 mg)를 테트라하이드로퓨란 (THF， 50 mL)에 0°C에서 교반하여 용해시킨 다음， 테트라하이드로퓨란 (THF, 50 mL)에 상기 단계 3에서 제조된 화합물 (2.7 g)을 녹인 용액을 5분 동안 천천히 플라스크에 적가하였다. 반웅이 종결되면 1M- 소듬하이드록사이드 (50 mL)을 천천히 적가하고 에틸아세테이트 (40 mL)로 추출한 다음， 소금물 (100 mL)로 세척하였다. 세척된 유기층을 무수 황산마그네슴으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물올 얻었다. Lithium aluminum hydride (LAH, 900 mg) was dissolved in tetrahydrofuran (THF, 50 mL) at 0 ° C. in a 100 ml pool flask under nitrogen atmosphere, and then dissolved in tetrahydrofuran (THF, 50 mL). The solution of compound (2.7 g) prepared in step 3 was slowly added dropwise to the flask for 5 minutes. When the reaction was complete, 1M-Saturated 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 target compound.
¾ NMR (400 Hz, CDC13)： 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, 1H) , 1.44(m, 1H), 1.31(d, 6H) , 1.03(d, 3H) . 단계 5 3-(4-(3—이소프로필 -1,2, 4-옥사다이아졸 -5- 일)피페라진 - 1—일)부틸메탄설포네이트의 제조 ¾ NMR (400 Hz, CDC1 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, 1H), 1.44 (m, 1H), 1.31 (d, 6H), 1.03 (d, 3H). Step 5 Preparation of 3- (4- (3—isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butylmethanesulfonate
질소 대기하의 100 ml 플라스크에 상기 단계 4에서 제조된 화합물 (2 g) 및 다이클로로메탄 (DCM, 100 mL)을 넣어 교반하여 용해시킨 다음， 트라이에틸아민 (TEA, 1.2 mL)을 적가하고 메탄설포닐 클로라이드 (0.6 mL)를 0°C에서 천천히 적가하였다. 적가가 완료되면 30분 동안 교반하고， 다이클로로메탄 (DCM, 40 mL)으로 추출하였다. 추출된 유기층올 소금물 (100 mL)로 세척하고 무수 황산마그네슘으로 건조시킨 다음 농축하여 목적화합물을 얻었다. In a 100 ml flask under nitrogen atmosphere, the compound (2 g) prepared in step 4 and dichloromethane (DCM, 100 mL) were added thereto, stirred, and dissolved. Then, triethylamine (TEA, 1.2 mL) was added dropwise, Ponyl chloride (0.6 mL) was slowly added dropwise at 0 ° C. When the drop is completed Stir for 30 minutes and extract 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.
XH NM (400 Hz, CDC13)： δ 4.86(q, 1H) , 4.53(q, 1H)， 4.44(m, 1H) , 4.02(m, 4H) , 3.51(m, 3H) , 3.19(m, 1H) , 2.72(m, 2H) , 2.54(s, 3H) , 2.45(m, 1H)， 1.54(d, 3H), 1. ll(d, 6H) . 단계 6: l-(4-(3-풀루오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 ) -4- (3-이소프로필 -1,2,4-옥사다이아졸 -5-일)피페라진 옥살산염의 제조 X H NM (400 Hz, CDC1 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 , 1H), 2.72 (m, 2H), 2.54 (s, 3H), 2.45 (m, 1H), 1.54 (d, 3H), 1.ll (d, 6H). Step 6: l- (4- (3-Pluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole- Preparation of 5-yl) piperazine oxalate
질소 대기하의 100 ml 플라스크에 상기 단계 5에서 제조된 화합물 (600 mg), 포타슘카보네이트 (360 mg) 및 다이메틸포름아마이드 (DMF, 30 ml)를 넣고 교반하여 용해시킨 다음， 상기 제조예 2에서 제조된 화합물 (350 mg)을 첨가하고 은도를 70°C로 등온하여 교반하였다. 교반이 종결되면 상온으로 넁각시키고， 증류수 (20 ml)를 천천히 가한 후 에틸아세테이트 (EA, 60 ml)로 추출하였다. 추출된 유기층을 소금물 (40 ml)로 세척한 다음， 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 이후 에틸아세테이트 (EA, 10 mL)를 첨가하고 교반하여 용해시킨 뒤， 같은 당량수의 옥살산을 첨가하여 30분간 환류교반하였다. 반응이 완료되면 온도를 상온으로 냉각시키고， 고체를 여과하여 목적화합물을 얻었다.  In a 100 ml flask under a nitrogen atmosphere, the compound (600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 ml) prepared in Step 5 were added thereto, stirred to dissolve, and prepared in Preparation Example 2. Compound (350 mg) was added and silver was isothermally stirred to 70 ° C. When the stirring was terminated, the mixture was cooled to room temperature, distilled water (20 ml) was added slowly, 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. After ethyl acetate (EA, 10 mL) was added and stirred to dissolve, and the same equivalent number of oxalic acid was added and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
lU NMR (400 Hz, D20): δ 7.76(lH,t) , 7.16(lH,dd) 7.00(lH,dd)l U NMR (400 Hz, D 2 0): δ 7.76 (lH, t), 7.16 (lH, dd) 7.00 (lH, dd)
4.25(2H,m) , 4.21(2H,m) , . 3.56(4H,m), 3.26(3H,s) , 3.04(lH,q) ,4.25 (2H, m), 4.21 (2H, m),. 3.56 (4H, m), 3.26 (3H, s), 3.04 (lH, q),
2.83(3H,m) , 2.68(lH,m) , 2.05(lH,m) , 1.78(lH,m) , 1.19(6H,d) , 1.05(3H,d) . 2.83 (3H, m), 2.68 (lH, m), 2.05 (lH, m), 1.78 (lH, m), 1.19 (6H, d), 1.05 (3H, d).
<실시예 7> t-부틸 4-(4-(3-플루오로 -4-Example 7 t-butyl 4- (4- (3-fluoro-4-)
(메틸설포닐)페녹시)부탄 -2-일)피페라진 -1-카르복실레이트 옥살산염의 제조 Preparation of (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalate
Figure imgf000048_0001
Figure imgf000048_0001
상기 실시예 1의 단계 3에서 4- (메틸설포닐)페놀을 사용하는 대신에 제조예 2에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using 4- (methylsulfonyl) phenol in step 3 of Example 1 except that the compound prepared in Preparation Example 2 was carried out in the same manner as in Example 1 to obtain the target compound.
:H NMR (400 Hz, D20)： δ 7.86(lH,t) , 6.82(lH,dd) 6.76(lH,dd) 4.19(lH,m), 4.09(lH,m) , 3.39(4H,m), 3.20(3H,s), 2.88(lH,q) , 2.56(2H,m), 2.39(2H,m) , 2.00(lH,m) , 1.79(lH,m), 1.48(9H,s) , 1.02(3H,d) . <실시예 8> L_(4-(3-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일) -4-(3-이소프로필' ,2，4-옥사다이아졸 -5ᅳ일 )피페라진 염산염의 제조 : H NMR (400 Hz, D 2 0): δ 7.86 (lH, t), 6.82 (lH, dd) 6.76 (lH, dd) 4.19 (lH, m), 4.09 (lH, m), 3.39 (4H, m), 3.20 (3H, s), 2.88 (lH, q), 2.56 (2H, m), 2.39 (2H, m), 2.00 (lH, m), 1.79 (lH, m), 1.48 (9H, s ), 1.02 (3H, d). Example 8 L_ (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl ', 2,4-oxadiazole-5 Preparation of Single) piperazine Hydrochloride
Figure imgf000049_0001
Figure imgf000049_0001
질소 대기하의 100 ml 플라스크에 3-이소프로필 -5- (피페라진 -1- 일) -1,2,4-옥사다이아졸 (600 mg) , 포타슘카보네이트 (360 mg) 및 다이메틸포름아마이드 (DMF, 30 ml)를 넣고 교반하여 용해시킨 다음， 제조예 2에서 제조된 화합물 (350 mg)을 첨가하고 온도를 70°C로 등온하여 교반하였다. 반응이 종결되면 상온으로 냉각하고 증류수 (20 ml)를 천천히 가한 후， 에틸아세테이트 (EA, 60 mL)로 추출하였다. 추출된 유기층올 소금물 (40 mL)로 세척한 후 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 이후 에틸아세테이트 (EA, 10 mL)에 용해시킨 뒤， 같은 당량수의 4N 염산 (1,4-다이옥산 용액)을 적가하여 30분간 환류교반하였다. 반웅이 완료되면 온도를 상온으로 냉각시키고 고체를 여과하여 뜩적화합물을 얻었다.  In a 100 ml flask under nitrogen atmosphere, 3-isopropyl-5- (piperazin-1-yl) -1,2,4-oxadiazol (600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF , 30 ml) was added and stirred to dissolve. Then, the compound (350 mg) prepared in Preparation Example 2 was added, and the temperature was stirred by isothermal temperature at 70 ° C. After the reaction was completed, the mixture was cooled to room temperature, distilled water (20 ml) was added slowly, 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. Thereafter, the resultant was dissolved in ethyl acetate (EA, 10 mL), and stirred under reflux for 30 minutes by adding dropwise addition of 4N hydrochloric acid (1,4-dioxane solution) in the same amount. When the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain a bulk compound.
^ NMR (400 Hz, D20)： δ 7.74(lH,t) , 6.91(2H,t) 4.71(4H,s) , 4.26(lH,m) , 4.16(lH,m) , 3.74(lH,m) , 3.45(4H,s) , 3.26(3H,s) , 2.84(lH,m), 2.34(lH,m) , 2.06(lH,m) , 1.37(3H,d) , 1.17(6H,d) . ^ NMR (400 Hz, D 2 0): δ 7.74 (lH, t), 6.91 (2H, t) 4.71 (4H, s), 4.26 (lH, m), 4.16 (lH, m), 3.74 (lH, m), 3.45 (4H, s), 3.26 (3H, s), 2.84 (lH, m), 2.34 (lH, m), 2.06 (lH, m), 1.37 (3H, d), 1.17 (6H, d .
<실시예 9> l-(4-(2-플루오로 -4-(lH-테트라졸 -1ᅳ 일 )페녹시 )부탄-2-일 )-4-(3-이소프로필-1,2,4-옥사다이아졸 -5- 일 )피페라진의 제조 Example 9 l- (4- (2-fluoro-4- (lH-tetrazol-1xyl)) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2, Preparation of 4-oxadiazol-5-yl) piperazine
Figure imgf000049_0002
Figure imgf000049_0002
질소 대기하의 100 ml 플라스크에 상기 실시예 6의 단계 5에서 제조된 화합물 (600 mg), 포타슘카보네이트 (360 mg) 및 다이메틸포름아마이드 (DMF, 30 mL)를 넣고 교반하여 용해시킨 다음， 상기 제조예 15에서 제조된 화합물 (150 mg)을 첨가하고 온도를 70°C로 등온하여 교반하였다. 교반이 종결되면 상은으로 넁각시키고， 증류수 (20 mL)를 천천히 가한 후 에틸아세테이트 (EA, 60 mL)로 추출하였다. 추출된 유기층올 소금물 (40 mL)로 세척한 다음, 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다. In a 100 ml flask under a nitrogen atmosphere, the compound (600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) prepared in Step 5 of Example 6 were added thereto, stirred, and dissolved. Compound (150 mg) prepared in Example 15 was added and the temperature was stirred to 70 ° C. After stirring was completed, the mixture was angled with silver and distilled water (20 mL) was added slowly, followed by extraction 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. Purification gave the target compound.
:H NMR (400 Hz, CDC13): 8.98(lH,s) 7.52(lH,dd) 7.46(lH,d) , 7.21(lH,t) , 4.27(2H 3.79(4H,s) 3.26(lH,s) , 2.88(4H,m) , 2.63(lH,m) , 2.28(1H 1.95(lH,m) 1.31(6H,d) , 1.23(3H,d) . : H NMR (400 Hz, CDC1 3 ): 8.98 (lH, s) 7.52 (lH, dd) 7.46 (lH, d), 7.21 (lH, t), 4.27 (2H 3.79 (4H, s) 3.26 (lH, s), 2.88 (4H, m), 2.63 (lH, m), 2.28 (1H 1.95 (lH, m) 1.31 (6H, d), 1.23 (3H, d).
<실시예 10> l-(4-(2-플루오로 -4-(lH-테 Example 10 l- (4- (2-fluoro-4- (lH-te)
일 )페녹시 )부탄 -2-일 )-4-(3-이소프로필- ^2,4-옥사다이아졸 -5 Yl) phenoxy) butane-2-yl) - 4 - (3-isopropyl-2, 4-oxadiazol-5 ^
일)피페라진 옥살산염의 제조 (1) Preparation of piperazine oxalate
Figure imgf000050_0001
Figure imgf000050_0001
상기 실시예 9에서 제조된 화합물 (200 mg)을 에틸아세테이트 (10 mL)에 용해시킨 다음， 같은 당량수의 옥살산을 적가하고 30분간 환류교반하였다. 반응이 종결되면 온도를 상온으로 냉각시키고 고체를 여과하여 목적화합물을 얻었다.  The compound (200 mg) prepared in Example 9 was dissolved in ethyl acetate (10 mL), and then the same equivalent number of oxalic acid was added dropwise and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
XH NMR (400 Hz, D20)： δ 9.48(lH,s) , 7.59(lH,dd) 7.49(lH,d) ,XH NMR (400 Hz, D 2 0): δ 9.48 (lH, s), 7.59 (lH, dd) 7.49 (lH, d),
7.23(1H, t) , 4.33(2H,m) , 4.25(2H,m) , 3.77(lH,ra) , 3.59(4H,m) ,7.23 (1H, t), 4.33 (2H, m), 4.25 (2H, m), 3.77 (lH, ra), 3.59 (4H, m),
3.35(2H,m) , 2.85(lH,m) , 2.40(lH,m) , 2.15(lH,m), 1.40(3H,d) , 1.16(6H,d) . <실시예 11> l-(4-(2-플루오로 -4- (메틸설포닐)페녹시)부탄 -2- 일 ) -4-(3-이소프로필 -1,2, 4-옥사다이아졸 -5-일 )피페라진 옥살산염의 제조 3.35 (2H, m), 2.85 (lH, m), 2.40 (lH, m), 2.15 (lH, m), 1.40 (3H, d), 1.16 (6H, d). Example 11 l- (4- (2-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole Preparation of -5-yl) piperazine oxalate
Figure imgf000050_0002
Figure imgf000050_0002
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 상기 제조예 1에서 제조된 화합물올 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Instead of using the compound prepared in Preparation Example 2 in step 6 of Example 6 was carried out in the same manner as in Example 6 except for using the compound prepared in Preparation Example 1 to obtain the target compound.
lU NMR (400 Hz, D20)： δ 7.74(lH,t), 6.91(2H,t) 4.71(4H,s) , 4.26(lH,m) , 4.16(lH,m) , 3.74(lH,m), 3.45(4H,s), 3.26(3H,s), 2.84(lH,m) , 2.34(lH,m) , 2.06(lH,m) , 1.37(3H,d) , 1.17(6H,d) . <실시예 12> l-(4-(3-플루오로 -4-(1Η-테트라졸 -1- 일 )페녹시 )부탄-2-일 )-4-(3-이소프로필-1,2,4-옥사다이아졸 -5- 일 )피페라진 옥살산염의 제조 l U NMR (400 Hz, D 2 0): δ 7.74 (lH, t), 6.91 (2H, t) 4.71 (4H, s), 4.26 (lH, m), 4.16 (lH, m), 3.74 (lH, m), 3.45 (4H, s), 3.26 (3H, s), 2.84 (lH, m), 2.34 (lH, m), 2.06 (lH, m), 1.37 (3H, d), 1.17 (6H, d . Example 12 l- (4- (3-fluoro-4- (1Η-tetrazol-1-yl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2, Preparation of 4-oxadiazole-5-yl) piperazine oxalate
Figure imgf000051_0001
Figure imgf000051_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 상기 제조예 17에서 제조된 화합물을 사.용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using the compound prepared in Preparation Example 2 in step 6 of Example 6 was carried out in the same manner as in Example 6 except for using the compound prepared in Preparation Example 17 to obtain the target compound. .
丄 H NMR (400 Hz, D20) δ 9.41(1Η: s) 7.61(lH,t), 6.98(lH,d) 6.91(lH,d)， 4.20(2H,m)， 4.10(2H,m), 3.72(lH,m), 3.56(4H,m) , 3.33(2H,t) , 2.81(lH,q), 2.33(lH,m), 2.04(lH,m), 1.37(3H,d), 1.14(6H,d). N H NMR (400 Hz, D 2 0) δ 9.41 (1Η : s) 7.61 (lH, t), 6.98 (lH, d) 6.91 (lH, d), 4.20 (2H, m), 4.10 (2H, m ), 3.72 (lH, m), 3.56 (4H, m), 3.33 (2H, t), 2.81 (lH, q), 2.33 (lH, m), 2.04 (lH, m), 1.37 (3H, d) , 1.14 (6H, d).
<실시예 13> l-(4-(4- (메틸설포닐)페녹시)부탄 -2-일) -4-(3- 소프로필 -1,2, 4-옥사다이아졸 -5-일)피페라진 옥살산염의 제조 Example 13 l- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-sopropyl-1,2,4-oxadiazol-5-yl) Preparation of Piperazine Oxalate
Figure imgf000051_0002
Figure imgf000051_0002
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 4- (메틸설포닐)페놀을 사용하는 것올 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  The target compound was obtained in the same manner as in Example 6, except that 4- (methylsulfonyl) phenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6.
:H NMR (400 Hz, D20)： δ 7.79(2H,d) , 7.07(2H,d) 4.24(4H,d) , 4.01(2H,d) , 3.70(lH,m) , 3.52(4H,m) , 3.32(2H,m) , 3.12(3H,s) , 2.81(lH,m) , 2.31(lH,m) , 2.04(lH,m) , 1.34(3H,d), 1.13(6H,d) . : H NMR (400 Hz, D 2 0): δ 7.79 (2H, d), 7.07 (2H, d) 4.24 (4H, d), 4.01 (2H, d), 3.70 (lH, m), 3.52 (4H , m), 3.32 (2H, m), 3.12 (3H, s), 2.81 (lH, m), 2.31 (lH, m), 2.04 (lH, m), 1.34 (3H, d), 1.13 (6H, d).
<실시예 14> 1-(4-(4-(1Η-테트라졸 -1-일 )페녹시 )부탄 -2-일 )一 4- (3-이소프로필 -1,2, 4-옥사다이아졸 -5-일)피페라진 옥살산염의 제조 Example 14 1- (4- (4- (1Η-tetrazol-1-yl) phenoxy) butan-2-yl) 一 4- (3-isopropyl-1,2,4-oxadiazole Preparation of 5-5-yl) piperazine oxalate
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 상기 제조예 16에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다. Except for using the compound prepared in Preparation Example 2 in the step 6 of Example 6 was carried out in the same manner as in Example 6 to obtain the target compound.
XH NMR (400 Hz, D20)： δ 9.46(lH,s) , 7.64(2H,d) , 7.10(2H,d) 4.75(2H,m), 4.27(2H,d), 4.16(lH,m) , 3.74(lH,m) , 3.54(4H,m) , 3.41(2H,m) , 2.86(lH,m) , 2.33(lH,m) , 2.06(lH,m) , 1.36(3H,d) , 1.14(6H,d). X H NMR (400 Hz, D 2 0): δ 9.46 (lH, s), 7.64 (2H, d), 7.10 (2H, d) 4.75 (2H, m), 4.27 (2H, d), 4.16 (lH , m), 3.74 (lH, m), 3.54 (4H, m), 3.41 (2H, m), 2.86 (lH, m), 2.33 (lH, m), 2.06 (lH, m), 1.36 (3H, d), 1.14 (6H, d).
<실시예 15> 1-(4-(3，5-다이플루오로 -4-(lH-테트라졸 -1- 일 )페녹시 )부탄 -2-일 ) -4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진 옥살산염의 제조 Example 15 1- (4- (3,5-Difluoro-4- (lH-tetrazol-1-yl) phenoxy) butan-2-yl) -4- (3-isopropyl-1 , 2,4-Oxadiazol-5-yl) piperazine oxalate
Figure imgf000052_0001
Figure imgf000052_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 상기 제조예 18에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using the compound prepared in Preparation Example 2 in step 6 of Example 6 was carried out in the same manner as in Example 6 to obtain the target compound.
:H NMR (400 Hz, D20): δ 9.38(lH,s), 6.83(2H,d) 4.23(lH,m) , 4.10(lH,m), 3.72(lH,m), 3.68(4H,m) , 3.34(2H,m) , 2.80(lH,m) , 2.32(lH,m) , 2.04(lH,m) , 1.34(3H,d) , 1.13(6H,d) . : H NMR (400 Hz, D 2 0): δ 9.38 (lH, s), 6.83 (2H, d) 4.23 (lH, m), 4.10 (lH, m), 3.72 (lH, m), 3.68 (4H , m), 3.34 (2H, m), 2.80 (lH, m), 2.32 (lH, m), 2.04 (lH, m), 1.34 (3H, d), 1.13 (6H, d).
<실시예 16> l-(4-(4-브로모 -2,5-다이폴루오로페녹시)부탄-2- 일)-4-(3-이소프로필-l,2,4-옥사다이아졸 -5-일 )피페라진 옥살산염의 제조 13009857 Example 16 l- (4- (4-Bromo-2,5-dipolorophenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole Preparation of -5-yl) piperazine oxalate 13009857
52
Figure imgf000053_0001
52
Figure imgf000053_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 4—브로모 -2, 5-다이플루오로페놀올 사용하는 것올 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  In the same manner as in Example 6 except that instead of using the compound prepared in Preparation Example 2 in step 6 of Example 6 4—bromo-2, 5-difluorophenolol The compound was obtained.
LH NMR (400 Hz, D20)： δ 7.36(lH,dd), 6.98(lH,dd) 4.27(2H,m) 4.12(2H,m) , 3.72(lH,m) , 3.54(4H,m), 3.34(2H,m) , 2.82(lH,m) , 2.30(lH,m) , 2.03(lH,m), 1.35(3H,d) , 1.13(6H,d) . L H NMR (400 Hz, D 2 0): δ 7.36 (lH, dd), 6.98 (lH, dd) 4.27 (2H, m) 4.12 (2H, m), 3.72 (lH, m), 3.54 (4H, m), 3.34 (2H, m), 2.82 (lH, m), 2.30 (lH, m), 2.03 (lH, m), 1.35 (3H, d), 1.13 (6H, d).
<실시예 17> l-(4-(3-클로로 -4- (메틸설포닐)페녹시)부탄 -2-일) - 4-(3-이소프로필 -1，2,4-옥사다이아졸 -5-일)피페라진 옥살산염의 제조 Example 17 l- (4- (3-Chloro-4- (methylsulfonyl) phenoxy) butan-2-yl)-(4- (3-isopropyl-1,2,4-oxadiazole) Preparation of 5-yl) piperazine oxalate
Figure imgf000053_0002
Figure imgf000053_0002
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 상기 제조예 11에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using the compound prepared in Preparation Example 2 in step 6 of Example 6 was carried out in the same manner as in Example 6 to obtain the target compound.
¾ NMR (400 Hz, D20) δ 7.89(lH,d) , 7.18(lH,s) 6.99(lH,d) 4.24(2H,d) , 4.14(2H,m) , 3.70(lH,m) , 3.47(4H,m) , 3.36(2H,m) 3.30(3H,s) , 2.82(lH,m) , 2.31(lH,m) , 2.04(lH,m) , 1.34(3H,d) 1.13(6H,d) · ¾ NMR (400 Hz, D 2 0) δ 7.89 (lH, d), 7.18 (lH, s) 6.99 (lH, d) 4.24 (2H, d), 4.14 (2H, m), 3.70 (lH, m) , 3.47 (4H, m), 3.36 (2H, m) 3.30 (3H, s), 2.82 (lH, m), 2.31 (lH, m), 2.04 (lH, m), 1.34 (3H, d) 1.13 ( 6H, d)
<실시예 18> l-(4-(3-메틸 -4- (메틸설포닐 )페녹시 )부탄 -2-일 ) -4- (3-이소프로필 -1,2, 4-옥사다이아졸 -5-일 )피페라진 옥살산염의 제조 Example 18 l- (4- (3-methyl-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole- Preparation of 5-yl) piperazine oxalate
Figure imgf000053_0003
Figure imgf000053_0003
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 상기 제조예 10에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다. The compound prepared in Preparation Example 2 in Step 6 of Example 6 Except for using the compound prepared in Preparation Example 10 was carried out in the same manner as in Example 6 to obtain the target compound.
:H NMR (400 Hz, D20)： δ 7.84(lH,d), 6.95(lH,t) 6.92(lH,d) , 4.24(2H,d) , 4.16(2H,d)ᅳ 3.74(lH,m), 3.53(4H,m) , 3.36(2H,m) , 3.19(3H,s) , 2.86(lH,m) , 2.55(3H,s) , 2.34(lH,m) , 2.05(lH,m) , 1.38(3H,d) , 1.17(6H,d). : H NMR (400 Hz, D 2 0): δ 7.84 (lH, d), 6.95 (lH, t) 6.92 (lH, d), 4.24 (2H, d), 4.16 (2H, d) ᅳ 3.74 (lH , m), 3.53 (4H, m), 3.36 (2H, m), 3.19 (3H, s), 2.86 (lH, m), 2.55 (3H, s), 2.34 (lH, m), 2.05 (lH, m), 1.38 (3H, d), 1.17 (6H, d).
<실시예 19> l-(4-(5- (메틸설포닐 )피리딘 -2-일옥시)부탄 -2-일 ) - 4- (3-이소프로필 -1，2，4-옥사다이아졸 -5-일)피페라진 옥살산염의 제조 Example 19 l- (4- (5- (methylsulfonyl) pyridin-2-yloxy) butan-2-yl) -4- (3-isopropyl -1,2,4-oxadiazole- Preparation of 5-yl) piperazine oxalate
Figure imgf000054_0001
Figure imgf000054_0001
질소 대기하의 100 mL 플라스크에 상기 실시예 6의 단계 5에서 제조된 화합물 (0.8 g) 및 다이메틸포름아마ᄋ 드 (DMF, 30 mL)를 넣고 교반하여 용해시켰다. 상기 반응물을 0°C로 냉각시키고 소듐하이드라이드 (NaH, 0.17 g)를 첨가한 후 30분 동안 교반하였다. 그 후， 2-브로모 -5— (메탄설포닐) -피리딘 (0.7 g)을 적가한 후 천천히 온도를 상은으로 등온하여 2시간 동안 교반하였다. 교반이 완료되면 0°C로 냉각시키고 증류수 (20 mL)를 천천히 가한 다음， 에틸아세테이트 (EA, 60 mL)로 추출하였다. 추출된 유기층을 소금물 (40 mL)로 세척한 다음， 무수 황산마그네습으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 정제된 화합물은 다시 에틸아세테이트 (EA, 10 mL)에 용해시킨 후 같은 당량수의 옥살산을 적가하여 30분 동안 환류교반하였다. 반응이 완료되면 온도를 상온으로 냉각시키고 고체를 여과하여 목적화합물을 얻었다 . Compound (0.8 g) and dimethylformamide (DMF, 30 mL) prepared in Step 5 of Example 6 were added to a 100 mL flask under a nitrogen atmosphere, and dissolved by stirring. The reaction was cooled to 0 ° C and sodium hydride (NaH, 0.17 g) was added and stirred for 30 minutes. Thereafter, 2-bromo-5 (methanesulfonyl) -pyridine (0.7 g) was added dropwise, and the temperature was slowly isothermalized with phase silver and stirred for 2 hours. After stirring was complete, the mixture was cooled to 0 ° C., distilled water (20 mL) was added slowly, 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. The purified compound was dissolved in ethyl acetate (EA, 10 mL) again and stirred under reflux for 30 minutes by adding the same equivalent number of oxalic acid dropwise. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
XH NMR (400 Hz, D20)： δ 8.60(lH,d) , 8.13(lH,d) 7.00(lH,d) , 4.53(lH,m) , 4.40(lH,m) , 4.19(2H,s), 3.72(lH,m) , 3.49(4H,m) , 3.20(3H,s) , 2.82(lH,m) , 2.35(lH,m) , 2.04(lH,m) , 1.36(3H,d) , 1.15(6H,d) , <실시예 20> l-(4-(5- (메틸설포닐)피리딘 -2-일옥시)부탄 -2-일) - X H NMR (400 Hz, D 2 0): δ 8.60 (lH, d), 8.13 (lH, d) 7.00 (lH, d), 4.53 (lH, m), 4.40 (lH, m), 4.19 (2H , s), 3.72 (lH, m), 3.49 (4H, m), 3.20 (3H, s), 2.82 (lH, m), 2.35 (lH, m), 2.04 (lH, m), 1.36 (3H, d), 1.15 (6H, d), <Example 20> l- (4- (5- (methylsulfonyl) pyridin-2-yloxy) butan-2-yl)-
4-(3-이소프로필 -1,2, 4-옥사다이아졸 -5-일)피페라진 염산염의 제조 Preparation of 4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine hydrochloride
Figure imgf000054_0002
상기 실시예 19에서 옥살산을 사용하는 대신에 4N-염산 (1，4- 다이옥산 용액)을 사용하는 것을 제외하고 상기 실시예 19와 동일한 방법으로 수행하여 목적화합물을 얻었다.
Figure imgf000054_0002
The target 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.
:H NMR (400 Hz, D20)： δ 8.60(lH,d) , 8.13(lH,dd) 7.00(lH,d) , : H NMR (400 Hz, D 2 0): δ 8.60 (lH, d), 8.13 (lH, dd) 7.00 (lH, d),
4.50(lH,m), 4.40(lH,m) , 4.24(2H,d), 3.70(lH,m) , 3.55(4H,m) ,4.50 (lH, m), 4.40 (lH, m), 4.24 (2H, d), 3.70 (lH, m), 3.55 (4H, m),
3.33(2H, t) , 3.20(3H,s) , 2.83(lH,m) , 2.35(lH,m) , 2.06(lH,m) , 1.36(3H,d) , 1.14(6H,d) . 3.33 (2H, t), 3.20 (3H, s), 2.83 (lH, m), 2.35 (lH, m), 2.06 (lH, m), 1.36 (3H, d), 1.14 (6H, d).
<제조예 21> l-(4-(6- (메틸설포닐)피리딘 -3-일옥시)부탄 -2-일) - 4- (3-이소프로필 -1，2，4-옥사다이아졸 -5-일)피페라진 옥살산염의 제조 Preparation Example 21 l- (4- (6- (Methylsulfonyl) pyridin-3-yloxy) butan-2-yl)-(4- (3-isopropyl-1,2,4-oxadiazole) Preparation of 5-yl) piperazine oxalate
Figure imgf000055_0001
Figure imgf000055_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 6- (메틸설포닐)피리딘 -3-을을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using 6- (methylsulfonyl) pyridine-3- instead of using the compound prepared in Preparation Example 2 in step 6 of Example 6 in the same manner as in Example 6 to the target compound Got.
¾ NMR (400 Hz, D20) δ 8.33(lH,d) , 8.02(lH,d) 7.55(lH,dd) 4.25(lH,m)， 4.20(lH,m) , 3.75(lH,m) , 3.47(4H,ra) , 3.36(2H,m) 3.19(3H,s), 2.83(lH,m) , 2.37(lH,m) , 2.08(lH,m) , 1.36(3H,d) 1.15(6H,d) ¾ NMR (400 Hz, D 2 0) δ 8.33 (lH, d), 8.02 (lH, d) 7.55 (lH, dd) 4.25 (lH, m), 4.20 (lH, m), 3.75 (lH, m) , 3.47 (4H, ra), 3.36 (2H, m) 3.19 (3H, s), 2.83 (lH, m), 2.37 (lH, m), 2.08 (lH, m), 1.36 (3H, d) 1.15 ( 6H, d)
<실시예 22> 1-(4-(3-클로로 -4- ((메틸설포닐 )메틸)페녹시 )부탄-Example 22 1- (4- (3-Chloro-4-((methylsulfonyl) methyl) phenoxy) butane-
2-일) -4-(3-이소프로필-1,2,4-옥사다이아졸 -5-일 )피페라진 옥살산염의 제조 Preparation of 2-yl) -4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine oxalate
Figure imgf000055_0002
Figure imgf000055_0002
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 3-클로로 -4-메탄설포닐메틸페놀을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다. :H 丽 R (400 Hz, D20)： 6 7.35(lH,d) , 7.09(lH,d) 6.90(lH,dd)The target compound was prepared in the same manner as in Example 6, except that 3-chloro-4-methanesulfonylmethylphenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6. Got it. : H R R (400 Hz, D 2 0): 6 7.35 (lH, d), 7.09 (lH, d) 6.90 (lH, dd)
4.61(2H,s) , 4.18(lH,m) , 4.10(lH,m), 3.70(lH,m) , 3.49(4H,m) 3.23(2H,m) ' 3.00(3H,s) , 2.28(lH,m) , 2.00(lH,m) 1.33(3H,d) 1.13(6H,d). 4.61 (2H, s), 4.18 (lH, m), 4.10 (lH, m), 3.70 (lH, m), 3.49 (4H, m) 3.23 (2H, m) '3.00 (3H, s), 2.28 (lH, m), 2.00 (lH, m) 1.33 (3H, d) 1.13 (6H, d).
<실시예 23> l-(4-(3-클로로 -4- ((메틸설포닐)메틸)페녹시 )부탄- 2ᅳ일 ) _4-(3-이소프로필 -1,2, 4-옥사다이아졸 -5-일 )피페라진 염산염의 제조 Example 23 l- (4- (3-Chloro-4-((methylsulfonyl) methyl) phenoxy) butan-2-hexyl) _4- (3-isopropyl-1,2,4-oxadiazole Preparation of 5-5-yl) piperazine Hydrochloride
Figure imgf000056_0001
Figure imgf000056_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 3-클로로 -4-메탄설포닐메틸페놀을 사용하고， 옥살산을 사용하는 대신에 염산을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  The above procedure was performed in step 6 of Example 6, except that 3-chloro-4-methanesulfonylmethylphenol was used instead of the compound prepared in Preparation Example 2, and hydrochloric acid was used instead of oxalic acid. The target compound was obtained in the same manner as in Example 6.
lH NMR (400 Hz, D20) δ 7.35(lH,d) , 7.08(lH,d) 6.83(lH,dd) , 4.60(2H,s) , 4.16(lH,m) , 4.04(lH,m) , 3.68(lH,m) , 3.52(4H,m) , 3.26(2H,m) , 2.99(3H,s) , 2.79(lH,m) , 2.27(lH,m) , 2.00(lH,m) , 1.33(3H,d) , 1.13(6H,d) . l H NMR (400 Hz, D 2 0) δ 7.35 (lH, d), 7.08 (lH, d) 6.83 (lH, dd), 4.60 (2H, s), 4.16 (lH, m), 4.04 (lH, m ), 3.68 (lH, m), 3.52 (4H, m), 3.26 (2H, m), 2.99 (3H, s), 2.79 (lH, m), 2.27 (lH, m), 2.00 (lH, m) , 1.33 (3H, d), 1.13 (6H, d).
<실시예 24> l-(4-(3-플루오로ᅳ 4-Example 24 l- (4- (3-fluoro ᅳ 4-
((메 ¾설포닐 )메틸)페녹시 )부탄 -2-일 ) -4-(3-이소프로필 -1,2,4- 옥사다이아졸 -5-일)피페라진 옥살산염의 제조 Preparation of ((meth ¾sulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine oxalate
Figure imgf000056_0002
Figure imgf000056_0002
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 제조예 5에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using the compound prepared in Preparation Example 2 instead of the compound prepared in Preparation Example 2 in Example 6 was carried out in the same manner as in Example 6 to obtain the target compound.
XH NMR (400 Hz, D20)： δ 7.30(lH,t), 6.80(2H,d) 4.47(2H,s) , 4.12(lH,m) , 4.04(lH,m) , 3.71(lH,m), 3.65(4H,m) , 3.33(2H,m) , 2.98(3H,s) , 2.82(lH,m) , 2.27(lH,m) , 1.97(lH,m) , 1.33(3H;d) , 1.13(6H,d). X H NMR (400 Hz, D 2 0): δ 7.30 (lH, t), 6.80 (2H, d) 4.47 (2H, s), 4.12 (lH, m), 4.04 (lH, m), 3.71 (lH , m), 3.65 (4H, m), 3.33 (2H, m), 2.98 (3H, s), 2.82 (lH, m), 2.27 (lH, m), 1.97 (lH, m), 1.33 (3H ; d), 1.13 (6 H, d).
<실시예 25> l-(4-(2-메틸 -4- ((메틸설포닐)메틸)페녹시)부탄 -2- 일 )-4-(3-이소프로필ᅳ1,2,4-옥사다이아졸 -5-일 )피페라진 옥살산염의 제조 Example 25 l- (4- (2-methyl-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl ᅳ 1,2,4-oxa Preparation of Diazol-5-yl) piperazine oxalate
Figure imgf000057_0001
Figure imgf000057_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 4-메탄설포닐메틸 -2-메틸페놀을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  The target compound was prepared in the same manner as in Example 6, except that 4-methanesulfonylmethyl-2-methylphenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6. Got it.
:H NMR (400 Hz, D20)： δ 7.14(2H,d) , 6.90(lH,d) 4.35(2H,s) , 4.14(lH,m) , 4.00(lH,m), 3.68(lH,m), 3.63(4H,m) , 3.29(2H,m)， 2.89(3H,s) , 2.77(lH,m) , 2.28(lH,m) , 2.09(3H,s) , 1.99(lH,m)， 1.32(3H,d) , l.ll(6H,d) . : H NMR (400 Hz, D 2 0): δ 7.14 (2H, d), 6.90 (lH, d) 4.35 (2H, s), 4.14 (lH, m), 4.00 (lH, m), 3.68 (lH , m), 3.63 (4H, m), 3.29 (2H, m), 2.89 (3H, s), 2.77 (lH, m), 2.28 (lH, m), 2.09 (3H, s), 1.99 (lH, m), 1.32 (3H, d), l.ll (6H, d).
<실시예 26> 2-(4-(4-(3-플루오로 -4- (메틸설포닐)페녹시 )부탄- 2-일)피페라진 -1-일) -5-프로필피리미딘 옥살산염의 제조 Example 26 of 2- (4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5propylpyrimidine oxalate Produce
Figure imgf000057_0002
Figure imgf000057_0002
상기 실시예 3의 단계 5에서 4- (메틸설포닐 )페놀을 사용하는 대신에 제조예 2에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 3과 동일한 방법으로 수행하여 목적화합물을 얻었다.  The target compound was obtained in the same manner as in Example 3, except that the compound prepared in Preparation Example 2 was used instead of 4- (methylsulfonyl) phenol in Step 5 of Example 3.
lH NMR (400 Hz, D20): δ 8.19(lH,s), 7.70(lH,t) , 6.87(2H,m) , 4.58(2H,m) , 4.25(lH,m) , 4.15(lH,m) , 3.67(lH,m) , 3.50(4H,m) , 3.22(5H,m), 2.37(2H,t), 2.31(lH,m) , 2.04(lH,m), 1.47(2H,q) , 1.32(3H,d) , 0.76(3H,t) · l NMR (400 Hz, D 2 0): δ 8.19 (lH, s), 7.70 (lH, t), 6.87 (2H, m), 4.58 (2H, m), 4.25 (lH, m), 4.15 (lH , m), 3.67 (lH, m), 3.50 (4H, m), 3.22 (5H, m), 2.37 (2H, t), 2.31 (lH, m), 2.04 (lH, m), 1.47 (2H, q), 1.32 (3H, d), 0.76 (3H, t)
<실시예 27> l-((R)-4-(3-플루오로 -4- (메틸설포닐 )페녹시 )부탄- 2-일 )-4-(3-이소프로필-1,2，4-옥사다이아졸 -5-일 )피페라진 옥살산염의 제조 Example 27 l-((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4 Preparation of -oxadiazole-5-yl) piperazine oxalate
Figure imgf000057_0003
단계 1: (R)-4-(t-부틸다이메틸실릴옥시 )부탄 -2-을의 제조
Figure imgf000057_0003
Step 1: Preparation of (R) -4- (t-butyldimethylsilyloxy) butane-2-
질소 대기하의 500 mL 플라스크에 (R)-(-)-l,3-부탄다이을 (5 g)， 이미다졸 (7.5 g) 및 다이클로로메탄 (DCM, 200 mL)에 주입하고 교반하여 용해시킨 뒤 t—부틸다이메틸실릴 클로라이드 (9.16 g)를 적가하였다. 적가가 완료되면 24시간 동안 교반하고， 다이클로로메탄 (DCM, 100 mL)으로 추출한 다음， 소금물 (100 mL)로 세척하였다. 세척된 유기층을 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다.  Into a 500 mL flask under nitrogen atmosphere, (R)-(-)-l, 3-butanedi was injected into (5 g), imidazole (7.5 g) and dichloromethane (DCM, 200 mL), dissolved by stirring. t-butyldimethylsilyl chloride (9.16 g) was added dropwise. After the addition was completed, the mixture was stirred for 24 hours, extracted with dichloromethane (DCM, 100 mL), and then 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 target compound.
XH 讓 R (400 Hz, CDC13) ·· 5 4.04(m, 1H) , 3.91(m, 1H), 3.83(m, 1H) , 3.41(br , 1H), 1.67(m, 2H)， 1.21(d, 3H), 0.90(s, 9H), 0.10(s, 6H) . 단계 2： (R)-4-(t-부틸다이메틸실릴옥시 )부탄 -2- 일메탄설포네이트의 제조 X H 讓 R (400 Hz, CDC1 3 ) 5 4.04 (m, 1H), 3.91 (m, 1H), 3.83 (m, 1H), 3.41 (br, 1H), 1.67 (m, 2H), 1.21 (d, 3H), 0.90 (s, 9H), 0.10 (s, 6H). Step 2: Preparation of (R) -4- (t-butyldimethylsilyloxy) butane-2-ylmethanesulfonate
질소 대기하의 100 mL 플라스크에 상기 단계 1에서 제조된 화합물 (2 g) 및 다이클로로메탄 (DCM, 100 mL)을 주입하고 교반하여 용해시킨 다음， 트라이에틸아민 (TEA, 1.2 mL)을 적가하고 메탄설포닐 클로라이드 (0.6 mL)를 0°C에서 천천히 적가하였다. 적가가 완료되고 30분 동안 교반하고 다이클로로메탄 (DCM, 40 mL)으로 추출한 다음 소금물 (100 mL)로 세척하였다. 세척된 반응물을 무수 황산마그네슘으로 건조하고 농축하여 목적화합물을 얻었다. Into a 100 mL flask under nitrogen atmosphere, the compound (2 g) prepared in step 1 and dichloromethane (DCM, 100 mL) were added and stirred to dissolve, followed by dropwise addition of triethylamine (TEA, 1.2 mL) and methane. Sulfonyl chloride (0.6 mL) was slowly added dropwise at 0 ° C. After the addition was completed, the mixture was stirred for 30 minutes, extracted with dichloromethane (DCM, 40 mL), and washed with brine (100 mL). The washed reaction product was dried over anhydrous magnesium sulfate and concentrated to obtain the target compound.
:H NMR (400 Hz, CDC13)： 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) . 단계 3: (S)-3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부탄-l-올의 제조 : H NMR (400 Hz, CDC1 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: Preparation of (S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-l-yl) butan-1-ol
질소 대기하의 100 mL 플라스크에 상기 단계 2에서 제조된 화합물 (1.4 g) 및 다이메틸포름아마이드 (DMF, 40 mL)을 주입하고 교반하여 용해시킨 다음， 순차적으로 상기 제조예 25에서 제조된 화합물 (1.3 g) 및 포타슴카보네이트 (1 g)를 첨가하고 5C C로 등온하여 24시간 동안 교반하였다. 반웅이 종결되면 온도를 상온으로 냉각시키고 증류수 (30 mL)를 천천히 가한 후 에틸아세테이트 (EA, 100 mL)로 추출한하였다. 추출된 유기층을 증류수 (20 mL)로 3회 세척한 다음， 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다.  Into a 100 mL flask under nitrogen atmosphere, the compound (1.4 g) prepared in step 2 and dimethylformamide (DMF, 40 mL) were injected and stirred to dissolve, followed by sequentially preparing the compound prepared in Preparation Example 25 (1.3 g) and potassium carbonate (1 g) were added and isothermalized to 5 C C and stirred for 24 h. When the reaction was finished, the temperature was cooled to room temperature, distilled water (30 mL) was added slowly, and 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, concentrated and purified by silica column chromatography to obtain the target compound.
XH NMR (400 Hz, CDC13)： δ 3.70(m, 2Η)， 3.61(m, 4H) , 2.87(ra, 2Η) , 2.65(m, 2Η) , 2.53(m, 2Η)， 1.77(m, 1H) , 1.48(m, 1H) , 1.30(d, 3H) , 1.00(d, 3H) , 0.98(s, 9H) , 0.07(s, 6H) . 단계 4: (S)-3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부틸 메탄설포네이트의 제조 X H NMR (400 Hz, CDC1 3 ): δ 3.70 (m, 2Η), 3.61 (m, 4H), 2.87 (ra, 2Η), 2.65 (m, 2Η), 2.53 (m, 2Η) ， 1.77 (m , 1H), 1.48 (m, 1H), 1.30 (d, 3H), 1.00 (d, 3H), 0.98 (s, 9H), 0.07 (s, 6H). Step 4: Preparation of (S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-l-yl) butyl methanesulfonate
질소 대기하의 100 mL 플라스크에 상기 단계 3에서 제조된 화합물 (2 g) 및 다이클로로메탄 (DCM, 100 mL)을 주입하고 교반하여 용해시켰다. 그 후, 트라이에틸아민 (TEA, 1.2 mL)을 적가하고 메탄설포닐 클로라이드 (0.6 mL)를 0°C에서 천천히 적가한다. 적가가 완료되면 30분 동안 교반하고, 다이클로로메탄 (DCM, 40 mL)으 S 추출한 다음 소금물 (100 mL)로 세척하였다. 세척된 반응물올 무수 황산마그네슘으로 건조하고 농축한 후 목적화합물을 얻었다. Prepared in step 3 above in a 100 mL flask under nitrogen atmosphere Compound (2 g) and dichloromethane (DCM, 100 mL) were injected and stirred to dissolve. Then triethylamine (TEA, 1.2 mL) is added dropwise and methanesulfonyl chloride (0.6 mL) is slowly added dropwise at 0 ° C. After the addition was completed, the mixture was stirred for 30 minutes, extracted with dichloromethane (DCM, 40 mL), and washed with brine (100 mL). The washed reactant was dried over anhydrous magnesium sulfate and concentrated to obtain the target compound.
:H NMR (400 Hz, CDC13) ·' 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, 1H), 3.24(m, 1H), 2.90(m, 1H), 2.74(s, 3H), 2.58(m, 1H)， 1.65(d, 3H), 1.27(d, 6H) . 단계 5: l-((R)-4-(3-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일 )-4-(3-이소프로필—1,2,4-옥사다이아졸 -5-일 )피페라진 옥살산염의 제조 : H NMR (400 Hz, CDC1 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, 1H), 3.24 (m, 1H), 2.90 (m, 1H), 2.74 (s, 3H), 2.58 (m, 1H), 1.65 (d, 3H), 1.27 (d , 6H). Step 5: l-((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl—1,2,4-oxa Preparation of Diazol-5-yl) piperazine oxalate
질소 대기하의 100 mL 플라스크에 상기 단계 4에서 제조된 화합물 (600 mg) , 포타슘카보네이트 (360 mg) 및 다이메틸포름아마이드 (DMF, 30 mL)를 넣고 교반하여 용해시킨 다음， 제조예 2에서 제조된 화합물 (350 mg)을 첨가하고 은도를 70°C로 등은하여 교반하였다. 교반이 종결되면 상온으로 냉각시키고， 증류수 (20 mL)를 천천히 가한 후 에틸아세테이트 (EA, 60 mL)로 추출하였다. 추출된 유기층을 소금물 (40 ml)로 세척한 다음， 무수 황산마그네슴으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 이후 에틸아세테이트 (EA, 10 mL)를 첨가하고 교반하여 용해시킨 뒤， 같은 당량수의 옥살산을 첨가하여 30분간 환류교반하였다. 반응이 완료되면 은도를 상온으로 넁각시키고， 고체를 여과하여 목적화합물을 얻었다. In a 100 mL flask under a nitrogen atmosphere, the compound (600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) prepared in Step 4 were added thereto, stirred to dissolve, and prepared in Preparation Example 2. Compound (350 mg) was added and silver was stirred at 70 ° C. and the like. After stirring was completed, the mixture was cooled to room temperature, distilled water (20 mL) was added slowly, 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. After ethyl acetate (EA, 10 mL) was added and stirred to dissolve, and the same equivalent number of oxalic acid was added and stirred under reflux for 30 minutes. When the reaction was completed, silver was cooled to room temperature, and the solid was filtered to obtain the target compound.
XH NMR (400 Hz, D20): δ 7.71(lH,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(lH,ra) , 2.32(lH,m) , 2.02(lH,m) , 1.34(3H,d) , 1.13(6H,d) . X H NMR (400 Hz, D 2 0): δ 7.71 (lH, 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 (lH, ra), 2.32 (lH, m), 2.02 (lH, m), 1.34 (3H, d), 1.13 (6H, d).
<실시예 28> l-((R)-4-(3-플루오로 -4- (메틸설포닐)페녹시)부탄- 2-일 )-4-(3-이소프로필 -1，2,4-옥사다이아졸 -5-일 )피페라진 염산염의 제조 Example 28 l-((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4 Preparation of -oxadiazole-5-yl) piperazine Hydrochloride
Figure imgf000059_0001
Figure imgf000059_0001
상기 실시예 27의 단계 5에서 옥살산을 사용하는 대신에 염산을 사용하는 것을 제외하고 상기 실시예 27과 동일한 방법으로 수행하여 목적화합물을 얻었다.  The target compound was obtained in the same manner as in Example 27, except that hydrochloric acid was used instead of oxalic acid in Step 5 of Example 27.
l NMR (400 Hz, D20)： δ 7.71(lH,t), 6.88(2H,m) , 4.15(4H,ra) , 3.70(lH,m) , 3.56(4H,m) , 3.34(2H,ra) , 3.24(3H,s) , 2.82(lH,m) , 2.30(lH,m), 2.02(lH,m), 1.33(3H,d) , 1.13(6H,d). NMR (400 Hz, D 2 0): δ 7.71 (lH, t), 6.88 (2H, m), 4.15 (4H, ra), 3.70 (lH, m), 3.56 (4H, m), 3.34 (2H, ra), 3.24 (3H, s), 2.82 (lH, m), 2.30 (lH, m), 2.02 (lH, m), 1.33 (3H, d), 1.13 (6H, d).
<실시예 29> 2-(4-(4-(3-플루오로 -4- (메틸설포닐)페녹시 )부탄- 2-일)피페라진 -1-일) -5-프로필피리미딘 염산염의 제조 Example 29 of 2- (4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5propylpyrimidine hydrochloride Produce
Figure imgf000060_0001
Figure imgf000060_0001
상기 실시예 3의 단계 5에서 4- (메틸설포닐 )페놀을 사용하는 대신에 제조예 2에서 제조된 화합물을 사용하고， 옥살산을 사용하는 대신에 염산을 사용하는 것을 제외하고 상기 실시예 3과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Example 3 and Example 3 except that using the compound prepared in Preparation Example 2 instead of 4- (methylsulfonyl) phenol in Example 5, and using hydrochloric acid instead of oxalic acid The target compound was obtained by the same method.
XH 薩 R (400 Hz, D20): δ 8.31(2H,s) , 7.71(lH,t) 6.88(2H,m) , 4.61(2H,m), 4.23(lH(m), 4.12(lH,m) , 3.72(lH,m) , 3.67(2H,m) , 3.40(2H,m), 3.24(3H,s), 2.44(2H, t) , 2.31(lH,m) , 2.04(lH,m) , 1.52(2H,q) , 1.34(3H,d) , 0.79(3H, t) . X H 薩 R (400 Hz, D 2 0): δ 8.31 (2H, s), 7.71 (lH, t) 6.88 (2H, m), 4.61 (2H, m), 4.23 (lH ( m), 4.12 ( lH, m), 3.72 (lH, m), 3.67 (2H, m), 3.40 (2H, m), 3.24 (3H, s), 2.44 (2H, t), 2.31 (lH, m), 2.04 (lH , m), 1.52 (2H, q), 1.34 (3H, d), 0.79 (3H, t).
<실시예 30> 2-(4-(4-(3-클로로 -4-Example 30 2- (4- (4- (3-chloro-4-)
((메틸설포닐)메틸)페녹시 )부탄 -2-일 )피페라진 -1-일 ) -5- 프로필피리미딘의 제조 Preparation of ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine
Figure imgf000060_0002
Figure imgf000060_0002
상기 실시예 4에서 쎄조예 5에서 제조된 화합물을 사용하는 대신에 3-클로로 -4-메탄설포닐메틸-페닐을 사용하는 것을 제외하고 상기 실시예 4와 동일한 방법으로 수행하여 목적화합물을 얻었다.  The target compound was obtained in the same manner as in Example 4, except that 3-chloro-4-methanesulfonylmethyl-phenyl was used instead of the compound prepared in Sezo Example 5 in Example 4.
XH NMR (400 Hz, D20)： δ 8.17(2H,s) , 7.47(1H, t) , 7.02(lH,d) , 6.90(lH,dd) , 4.47(2H,s) , 4.14(lH,m) , 4.05(lH,m) , 3.80(4H,m) , 2.93(lH,m) , 2.80(3H,s), 2.67(2H,m) , 2.52(3H,m) , 2.241(2H, t) , 2.03(lH,m), 1.78(lH,m), 1.57(2H,q) , 1.04(3H,d) , 0.95(3H,t) . X H NMR (400 Hz, D 2 0): δ 8.17 (2H, s), 7.47 (1H, t), 7.02 (lH, d), 6.90 (lH, dd), 4.47 (2H, s), 4.14 ( lH, m), 4.05 (lH, m), 3.80 (4H, m), 2.93 (lH, m), 2.80 (3H, s), 2.67 (2H, m), 2.52 (3H, m), 2.241 (2H , t), 2.03 (lH, m), 1.78 (lH, m), 1.57 (2H, q), 1.04 (3H, d), 0.95 (3H, t).
〈실시예 31> 2-(4-(4-(3-클로로 -4-Example 31 2- (4- (4- (3-chloro-4-)
((메틸설포닐)메틸)페녹시 )부탄 -2-일 )피페라진 -1-일 ) -5- 프로필피리미딘 옥살산염의 제조 Preparation of ((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate
Figure imgf000061_0001
Figure imgf000061_0001
상기 실시예 30에서 제조된 화합물을 에틸아세테이트 (EA mL)에 용해시킨 다음, 같은 당량수의 옥살산을 적가하고 30분 환류교반하였다. 반응이 완료되면 온도를 상온으로 냉각시키고 고체를 여과하여 목적화합물을 얻었다.  The compound prepared in Example 30 was dissolved in ethyl acetate (EA mL), and then the same equivalent number of oxalic acid was added dropwise and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
¾ N R (400 Hz, D20): δ 8.19(2Η s), 7.34C1H, t) 7.06(lH,d) , 6.87(lH,dd) , 4.58(4H,m) , 4.16(lH,m) , 4.06(lH,m) , 3.64(lH,m)， 3.50(2H,s) , 3.43(4H,m) , 2.98(3H,s) , 2.37(2H,t) , 2.26(lH,m)，¾ NR (400 Hz, D 2 0): δ 8.19 (2Η s), 7.34C1H, t) 7.06 (lH, d), 6.87 (lH, dd), 4.58 (4H, m), 4.16 (lH, m) , 4.06 (lH, m), 3.64 (lH, m), 3.50 (2H, s), 3.43 (4H, m), 2.98 (3H, s), 2.37 (2H, t), 2.26 (lH, m) ，
98(lH,m) , 1.43(2H,q) , 1.32(3H,d) , 0.76(3H,t) 98 (lH, m), 1.43 (2H, q), 1.32 (3H, d), 0.76 (3H, t)
<실시예 32> 2-(4-(4-(3-플루오로 -4-(l-Example 32 2- (4- (4- (3-fluoro-4- (l-)
(메틸설포닐)에틸)페녹시)부탄 -2-일)피페라진 -1-일) -5-프로필피리미딘 옥살산염의 제조 Preparation of (methylsulfonyl) ethyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate
Figure imgf000061_0002
Figure imgf000061_0002
상기 실시예 3의 단계 5에서 4- (메틸설포닐 )페놀올 사용하는 대신에 제조예 13에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 3과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using the compound prepared in Preparation Example 13 instead of 4- (methylsulfonyl) phenolol in Step 5 of Example 3 was carried out in the same manner as in Example 3 to obtain the target compound.
aH NMR (400 Hz, D20)： δ 8.21(2H,s) , 7.36(lH,t) 6.75(2H,d) , 4.80(lH,s) , 4.58(2H,m) , 4.18(lH,s) , 4.08(lH,s) , 3.66(2H,s) , 3.53(2H,s) , 3.23(4H,m) , 2.91(3H,s) , 2.39(2H,s) , 2.29(lH,s) , 2.00(lH,s), 1.65(3H,s), 1.46(2H,s) , 1.34(3H, s) , 0.77(3H,s). aH NMR (400 Hz, D 2 0): δ 8.21 (2H, s), 7.36 (lH, t) 6.75 (2H, d), 4.80 (lH, s), 4.58 (2H, m), 4.18 (lH, s), 4.08 (lH, s), 3.66 (2H, s), 3.53 (2H, s), 3.23 (4H, m), 2.91 (3H, s), 2.39 (2H, s), 2.29 (lH, s ), 2.00 (lH, s), 1.65 (3H, s), 1.46 (2H, s), 1.34 (3H, s), 0.77 (3H, s).
<실시예 33> 1-(4-(2，5-다이폴루오로 -4-Example 33 1- (4- (2,5-Dipoleuro-4-)
((메틸설포닐 )메틸)페녹시 )부탄 -2-일 ) -4-(3-이소프로필 -1,2,4- 옥사다이아졸 -5-일 )피페라진 옥살산염의 제조 Preparation of ((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine oxalate
Figure imgf000062_0001
Figure imgf000062_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 제조예 14에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using the compound prepared in Preparation Example 2 in the step 6 of Example 6 was carried out in the same manner as in Example 6 to obtain the target compound.
lW 丽 R (400 Hz, D20)： δ 7.20(lH,dd) , 6.97(lH,dd) 4.47(2H,s) , 4.25(2H,m) , 4.13(2H,m) 3.74(lH,m) 3.55(4H,m) 3.33(2H,m) , 3.01(3H,s) , 2.82(lH,q) 2.32(2H,m) 2. ll(2H,m) 1.35(3H,d) , 1.14(6H,d) . lW R R (400 Hz, D 2 0): δ 7.20 (lH, dd), 6.97 (lH, dd) 4.47 (2H, s), 4.25 (2H, m), 4.13 (2H, m) 3.74 (lH, m) 3.55 (4H, m) 3.33 (2H, m), 3.01 (3H, s), 2.82 (lH, q) 2.32 (2H, m) 2.ll (2H, m) 1.35 (3H, d), 1.14 (6H, d).
<실시예 34> 1-(4-(2，5-다이플루오로 -4-Example 34 1- (4- (2,5-Difluoro-4-)
(메틸설포닐 )페녹시 )부탄-2-일 )-4-(3-이소프로필-1，2,4-옥사다이아졸- 5-일 )피페라진 트라이플루오로아세테이트산 염의 제조 Preparation of (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine trifluoroacetate acid salt
Figure imgf000062_0002
Figure imgf000062_0002
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 제조예 14에서 제조된 화합물을 사용하고， 옥살산을 사용하는 대신에 트라이플루오로아세트산을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Example 6 except for using the compound prepared in Preparation Example 14 instead of using the compound prepared in Preparation Example 2 in Example 6, using trifluoroacetic acid instead of using oxalic acid The target compound was obtained by the same method as the method of 6.
:H NMR (400 Hz, D20)： δ 7.57(lH,dd) , 7.09(lH,dd) , 4.30(2H,m) , 4.20(2H,m) , 3.73(lH,m) , 3.42(4H,m) , 3.25(3H,s) , 2.81(lH,q) , 2.35(2H,m), 2.11(2H,m) , 1.35(3H,d), 1.13(6H,d). : H NMR (400 Hz, D 2 0): δ 7.57 (lH, dd), 7.09 (lH, dd), 4.30 (2H, m), 4.20 (2H, m), 3.73 (lH, m), 3.42 ( 4H, m), 3.25 (3H, s), 2.81 (lH, q), 2.35 (2H, m), 2.11 (2H, m), 1.35 (3H, d), 1.13 (6H, d).
<실시예 35> l-(4-(2,5-다이플루오로 -4-Example 35 l- (4- (2,5-difluoro-4-)
(메틸설포닐 )폐녹시 )부탄 -2-일 ) -4-(3-이소프로필 -1,2,4-옥사다이아졸- 5一일 )피페라진 염산염의 제조 Preparation of (Methylsulfonyl) Punoxy) Butane-2-yl) -4- (3-isopropyl-1,2,4-oxadiazol-5yyl) piperazine hydrochloride
Figure imgf000062_0003
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 제조예 14에서 제조된 화합물을 사용하고， 옥살산을 사용하는 대신에 염산을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.
Figure imgf000062_0003
In Example 6, except that the compound prepared in Preparation Example 14 is used instead of the compound prepared in Preparation Example 2, and hydrochloric acid is used instead of oxalic acid. The target compound was obtained by the method.
lH NMR (400 Hz, D20)： δ 7.58(lH,dd) , 7. ll(lH,dd) , 4.31(2H,m) , 4.21(2H,m) , 3.72(lH,m) , 3.54(4H,m) , 3.31(2H,m) , 3.25(3H,s) , 2.82(lH,q) , 2.35(2H,m) , 2.14(2H,m) , 1.35(3H,d) , 1.14(6H,d) . l H NMR (400 Hz, D 2 0): δ 7.58 (lH, dd), 7.ll (lH, dd), 4.31 (2H, m), 4.21 (2H, m), 3.72 (lH, m), 3.54 (4H, m), 3.31 (2H, m), 3.25 (3H, s), 2.82 (lH, q), 2.35 (2H, m), 2.14 (2H, m), 1.35 (3H, d), 1.14 ( 6H, d).
<실시예 36> l-(4-(2,6-다이플루오로 -4-Example 36 l- (4- (2,6-difluoro-4-)
(메틸설포닐)페녹시 )부탄— 2-일) -4-(3-이소프로필 -1,2,4-옥사다이아졸- 5-일 )피페라진 옥살산염의 제조 Preparation of (methylsulfonyl) phenoxy) butane- 2-yl) -4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine oxalate
Figure imgf000063_0001
Figure imgf000063_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 제조예 7에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using the compound prepared in Preparation Example 2 instead of the compound prepared in Preparation Example 2 in Example 6 was carried out in the same manner as in Example 6 to obtain the target compound.
LH NMR (400 Hz, D20)： δ 7.57(2H,d) , 4.45(lH,m) , 4.35(lH,m) , 4.17(2H,m) , 3.76(lH,m) , 3.50(4H,m), 3.33(2H,m) , 3.16(3H,s) , 2.81(lH,q) , 2.32(2H,m) , 1.99(2H,m) , 1.36(3H,d) , 1.13(6H,d) . L H NMR (400 Hz, D 2 0): δ 7.57 (2H, d), 4.45 (lH, m), 4.35 (lH, m), 4.17 (2H, m), 3.76 (lH, m), 3.50 ( 4H, m), 3.33 (2H, m), 3.16 (3H, s), 2.81 (lH, q), 2.32 (2H, m), 1.99 (2H, m), 1.36 (3H, d), 1.13 (6H , d).
<실시예 37> 1-(4-(2，6-다이플루오로 -4-Example 37 1- (4- (2,6-Difluoro-4-)
(메틸설포닐 )페녹시 )부탄-2-일 )-4-(3-이소프로필-1,2，4-옥사다이아졸- 5-일)피페라진 트라이플루오로아세테이트산 염의 제조 Preparation of (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine trifluoroacetate acid salt
Figure imgf000063_0002
Figure imgf000063_0002
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 제조예 7에서 제조된 화합물을 사용하고， 옥살산을 사용하는 대신에 트라이플루오로아세트산을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Example 6 instead of using the compound prepared in Preparation Example 2 in the step 6 of Example 6 except for using trifluoroacetic acid instead of using oxalic acid Example The target compound was obtained by the same method as the method of 6.
:H NMR (400 Hz, D20)： δ 7.57(2H,d) , 4.46(lH,m) , 4.32(lH,m) , 4.17(2H,m) , 3.73(lH,m) , 3.42(4H,m) , 3.33(2H,m) , 3.16(3H,s), 2.81(lH,q) , 2.32(2H,m), 2.00(2H,m) , 1.36(3H,d), 1.13(6H,d) : H NMR (400 Hz, D 2 0): δ 7.57 (2H, d), 4.46 (lH, m), 4.32 (lH, m), 4.17 (2H, m), 3.73 (lH, m), 3.42 ( 4H, m), 3.33 (2H, m), 3.16 (3H, s), 2.81 (lH, q), 2.32 (2H, m), 2.00 (2H, m), 1.36 (3H, d), 1.13 (6H, d)
<실시예 38> 1-(4-(2,6-다이플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 ) -4-(3 -이소프로필 -1,2,4-옥사다이아졸- 5-일 )피페라진 염산염의 제조 Example 38 1- (4- (2,6-Difluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4- Preparation of oxadiazole-5-yl) piperazine hydrochloride
Figure imgf000064_0001
Figure imgf000064_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 제조예 7에서 제조된 화합물을 사용하고, 옥살산을 사용하는 대신에 염산을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Example 6 in the same manner as in Example 6 except for using the compound prepared in Preparation Example 7 instead of using the compound prepared in Preparation Example 2, and instead of using the oxalic acid in step 6 of Example 6 The target compound was obtained by the method.
lW NMR (400 Hz, D20)： δ 7.57(2H,d) , 4.48(lH,m) , 4.34(lH,m) , 4.30(2H,m) , 3.77(lH,m) , 3.54(4H,m) , 3.33(2H,m) , 3.16(3H,s) , 2.81(lH,q) , 2.33(2H,m) , 2.00(2H,rti)， 1.36(3H,d) , 1.13(611,(1). lW NMR (400 Hz, D 2 0): δ 7.57 (2H, d), 4.48 (lH, m), 4.34 (lH, m), 4.30 (2H, m), 3.77 (lH, m), 3.54 (4H , m), 3.33 (2H, m), 3.16 (3H, s), 2.81 (lH, q), 2.33 (2H, m), 2.00 (2H, rti), 1.36 (3H, d), 1.13 (611, (One).
<실시예 39> 1-(4-(5-메틸 -6- (메틸설포닐 )피리딘 -3- 일옥시 )부탄-2-일)-4-(3-이소프로필-1,2,4-옥사다이아졸 -5- 일 )피페라진 염산염의 제조 Example 39 1- (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4- (3-isopropyl-1,2,4- Preparation of oxadiazole-5-yl) piperazine hydrochloride
Figure imgf000064_0002
Figure imgf000064_0002
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 제조예 10에서 제조된 화합물올 사용하고， 옥살산을 사용하는 대신에 염산을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  In Example 6, except that the compound prepared in Preparation Example 10 is used instead of the compound prepared in Preparation Example 2, and hydrochloric acid is used instead of oxalic acid. The target compound was obtained by the method.
XH NMR (400 Hz, D20)： δ 8.07(lH,d) , 7.34(lH,d) 4.28(2H,m) 4.19(2H,m) , 3.71(lH,m) , 3.63(4H,m) , 3.35(2H,m) , 3.21(3H,s) 2.79(lH,q), 2.52(3H,s) , 2.35(lH,m) , 2.04(lH,m) , 1.33(3H,d) 1.13(6H,d) . X H NMR (400 Hz, D 2 0): δ 8.07 (lH, d), 7.34 (lH, d) 4.28 (2H, m) 4.19 (2H, m), 3.71 (lH, m), 3.63 (4H, m), 3.35 (2H, m), 3.21 (3H, s) 2.79 (lH, q), 2.52 (3H, s), 2.35 (lH, m), 2.04 (lH, m), 1.33 (3H, d) 1.13 (6 H, d).
<실시예 40> 1-(4-(5-메틸 -6- (메틸설포닐 )피리딘 -3- 일옥시 )부탄 -2-일 )-4-(3-이소프로필 -1,2, 4-옥사다이아졸 -5- 일)피페라진 옥살산염의 제조
Figure imgf000065_0001
Example 40 1- (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4- (3-isopropyl-1,2, 4- Preparation of oxadiazole-5-yl) piperazine oxalate
Figure imgf000065_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 제조예 10에서 제조된 화합물올 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using the compound prepared in Preparation Example 2 instead of the compound prepared in Preparation Example 2 in Example 6 was carried out in the same manner as in Example 6 to obtain the target compound.
:H NMR (400 Hz, D20)： δ 7.57(2H,d) , 4.45(lH,m) , 4.34(lH,m) , 4.17(2H,m) , 3.76(lH,m) , 3.50(4H,m) , 3.33(2H,m) , 3.17(3H,s) , 2.81(lH,q) , 2.32(2H,m), 2.00(2H,m) , 1.36(3H,d) , 1.13(6H,d) . : H NMR (400 Hz, D 2 0): δ 7.57 (2H, d), 4.45 (lH, m), 4.34 (lH, m), 4.17 (2H, m), 3.76 (lH, m), 3.50 ( 4H, m), 3.33 (2H, m), 3.17 (3H, s), 2.81 (lH, q), 2.32 (2H, m), 2.00 (2H, m), 1.36 (3H, d), 1.13 (6H , d).
<실시예 41> 에틸-4-(3-(4-(3-이소프로필-1,2，4-옥사다이아졸- 5-일 )피페라진 -1-일 )부톡시 )-2-플루오로벤조에이트 옥살산염의 제조 Example 41 Ethyl-4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro Preparation of Benzoate Oxalate
Figure imgf000065_0002
Figure imgf000065_0002
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 상기 제조예 19에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using the compound prepared in Preparation Example 2 in step 6 of Example 6 was carried out in the same manner as in Example 6 to obtain the target compound.
:H NMR (400 Hz, D20) δ 7.81(lH,t), 6.75(2H,m) 4.26(2H,q)， 4.22(3H,m) , 4. ΙΟ(ΙΗ,ηι) , 3.70(lH,m) , 3.53(4H,m) , 3.34(2H,m)， 2.80(lH,q) , 2.30(2H,m) , 2.00(2H,m) , 1.33(3H,d) , 1.23(3H,t), 1.12(6H,d). : H NMR (400 Hz, D 2 0) δ 7.81 (lH, t), 6.75 (2H, m) 4.26 (2H, q), 4.22 (3H, m), 4.ΙΟ (ΙΗ, ηι), 3.70 ( lH, m), 3.53 (4H, m), 3.34 (2H, m), 2.80 (lH, q), 2.30 (2H, m), 2.00 (2H, m), 1.33 (3H, d), 1.23 (3H , t), 1.12 (6H, d).
<실시예 42> 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부록시 )-2-플루오로벤조에이트 리튬염의 제조 Example 42 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate Preparation of Lithium Salt
Figure imgf000065_0003
Figure imgf000065_0003
질소 대기하의 100 mL 플라스크에 상기 실시예 41에서 제조된 화합물 (200 mg), 테트라하이드로퓨란 (40 mL) 및 증류수 (20 mL)를 P T/KR2013/009857 In a 100 mL flask under nitrogen atmosphere, the compound prepared in Example 41 (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) were added. PT / KR2013 / 009857
65 주입하고 교반하여 용해시켰다. 그 후， 상기 반응물에 리튬하이드톡사이드 1수화물 (170 mg)을 첨가하고 상온에서 18시간 동안 교반하였다. 반응이 종결되면 용매를 농축한 후 다이클로로메탄 (DCM, 50 mL)에 용해시키고 용해되지 않는 고체를 여과하였다. 여과된 여액을 농축하고， 다이에틸에테르 및 핵산을 이용하여 고체화하여 목적화합물을 얻었다. 65 injected and stirred to dissolve. Then, lithium hydroxide monohydrate (170 mg) was added to the reaction and stirred at room temperature for 18 hours. At the end of the reaction, the solvent was concentrated, dissolved in dichloromethane (DCM, 50 mL) and the insoluble solid was filtered off. The filtrate was concentrated and solidified using diethyl ether and nucleic acid to obtain the target compound.
i NM ((440000 HHzz,, D20) ： δ 7.50(lH,t) , 6.68(2H,m) , 4.03(2H,m) 3.50(4H,t) , 22..7766((22HH,m) , 2.60(4H,q) , 2.03(lH,m), 1.79(3H,s) ,i NM ((440000 HHzz ,, D 2 0): δ 7.50 (lH, t), 6.68 (2H, m), 4.03 (2H, m) 3.50 (4H, t), 22..7766 ((22HH, m ), 2.60 (4H, q), 2.03 (lH, m), 1.79 (3H, s),
1.63(lH,m) , l.ll(6H,d), 1.01(3H,d) 1.63 (lH, m), l.ll (6H, d), 1.01 (3H, d)
<실시예 43> 에틸 -4-(3-(4— (5-프로필피리미딘 -2-일 )피페라진 -l— 일)부톡시 )-2-플루오로벤조에이트 옥살산염의 제조 <Example 43> Ethyl-4- (3 - (4- (5-propyl-pyrimidin-2-yl) piperazin--l- yl) butoxy) -2-fluoro-benzoate oxalate prepared
Figure imgf000066_0001
Figure imgf000066_0001
상기 실시예 3의 단계 5에서 4- (메틸설포닐 )페놀을 사용하는 대신에 제조예 19에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 3과 동일한 방법으로 수행하여 목적화합물을 얻었다.  The target compound was obtained in the same manner as in Example 3, except that the compound prepared in Preparation Example 19 was used instead of 4- (methylsulfonyl) phenol in Step 5 of Example 3.
XH NMR (400 Hz, D20)： δ 8.20(2H,s) , 7.79(lH,t) ,않 6.73(2H,m) , X H NMR (400 Hz, D 2 0): δ 8.20 (2H, s), 7.79 (lH, t), not 6.73 (2H, m),
4.27(2H,m) 4.22(2H,t) , 4.19(lH,m) , 4.08(lH,m) 3는및.66(lH,m) 3.52(2H,m) 3.22(3H,m) , 2.38(2H, t) , 2.27(lH,m) 2.03(lH,m) 1.50(2H,m) .33(3H,d), 1 25(3H,t) , 0.77(3H, t) . 4.27 (2H, m) 4.22 (2H, t), 4.19 (lH, m), 4.08 (lH, m) 3 and .66 (lH, m) 3.52 (2H, m) 3.22 (3H, m), 2.38 (2H, t), 2.27 (lH, m) 2.03 (lH, m) 1.50 (2H, m) .33 (3H, d), 1 25 (3H, t), 0.77 (3H, t).
<실시예 44> 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1- 일)부톡시 )-2-플루오로벤조에이트 리튬염의 제조 Example 44 Preparation of 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate lithium salt
Figure imgf000066_0002
기 실入'예 43에서 제조된 화합물 (200 mg), 테트라하이드로퓨란 (40 mL) 및 증류수 (20 mL)를 주입하고 교반하여 용해시켰다. 그 후, 상기 반응물에 리튬하이드록사이드 1수화물 (170 mg)올 첨가하고 상온에서 18시간 동안 교반하였다. 반웅이 종결되면 용매를 농축한 후 다이클로로메탄 (DCM, 50 mL)에 용해시키고 용해되지 고체를 여과하였다. 여과된 여액을 농축하고， 다이에틸에테ᄅ 핵산을 이용하여 고체화하여 목적화합물을 얻었다. ¾ NMR (400 Hz, D20): δ 8.06(2H,s) , 7.52(lH,t), 6.63(2H,m) 4.00(2H,m) , 3.53(4H,t) , 2.67(lH,m) , 2.51(4H,m) , 2.27(2H,t) 1.96(lH,m) , 1.54(lH,m) , 1.38(2H,q) , 0.96(3H,d) , 0.73(3H,t) .
Figure imgf000066_0002
Group room入a "compound (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) prepared in Example 43 was placed, followed by stirring to dissolve. Then, lithium hydroxide monohydrate (170 mg) ol was added to the reaction and stirred at room temperature for 18 hours. Upon completion of reaction, the solvent was concentrated and then dissolved in dichloromethane (DCM, 50 mL) and the undissolved solid was filtered off. The filtrate was concentrated and solidified using diethyl ether nucleic acid to obtain the target compound. ¾ NMR (400 Hz, D 2 0): δ 8.06 (2H, s), 7.52 (lH, t), 6.63 (2H, m) 4.00 (2H, m), 3.53 (4H, t), 2.67 (lH, m), 2.51 (4H, m), 2.27 (2H, t) 1.96 (lH, m), 1.54 (lH, m), 1.38 (2H, q), 0.96 (3H, d), 0.73 (3H, t) .
<실시예 45> 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1- 일 )부특시 )-2-플루오로 -N-(l, 3-다이하이드록시프로판 -2- 일)벤즈아마이드 옥살산염의 제조 Example 45 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butespecial) -2-fluoro-N- (l, 3-dihydroxy Preparation of Propane-2-yl) benzamide oxalate
Figure imgf000067_0001
Figure imgf000067_0001
질소 대기하의 100 mL 플라스크에 상기 실시예 44에서 제조된 화합물 (310 mg) 및 다이클로로메탄 (DCM, 50 mL)을 주입하고 교반하여 용해시키고， 1-에틸 -3-(3-다이메틸아미노프로필 )카르보다이이미드 염산염 (EDCI， 170 mg) 및 1-하이드록시벤조트리아졸 1수화물 (KOBt, Into a 100 mL flask under nitrogen atmosphere, the compound (310 mg) and dichloromethane (DCM, 50 mL) prepared in Example 44 were injected and stirred to dissolve, 1-ethyl-3- (3-dimethylaminopropyl). Carbodiimide hydrochloride (EDCI, 170 mg) and 1-hydroxybenzotriazole monohydrate (KOBt,
120 mg)을 첨가하고 30분 동안 교반하였다. 그 후， 2-아미노 -1,3- 프로판다이올 (100 mg)을 첨가하고 상온에서 5시간 동안 교반하였다. 반응이 종결되면 증류수 (20 mL)를 천천히 가하고 에틸아세테이트 (EA, 60 mL)로 추출한 다음 소금물 (40 mL)로 세척하였다. 세척된 유기층을 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 정제된 화합물을 에틸아세테이트 (EA, 10 mL)를 가하고 교반하여 용해시킨 다음， 같은 당량수의 옥살산을 적가하고 30분 동안 환류교반하였다. 반응이 완료되면 온도를 상온으로 냉각시키고 고체를 여과하여 목적화합물을 얻었다. 120 mg) was added and stirred for 30 minutes. Then 2-amino-1,3-propanediol (100 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. Ethyl acetate (EA, 10 mL) was added to the purified compound, followed by stirring to dissolve it. Then, the same amount of oxalic acid was added dropwise and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
NMR (400 Hz, D20) δ 8.22(2H,s) , 7.60(lH,t) 6.78(2H,m) 4.59(2H,m) , 4.22(lH,m) , 4. ll(lH,m) , 3.70(5H,m) , 3.60(2H,m) 3.23(4H,m) , 2.42(2H,t) , 2.30(lH,m) , 2.06(lH,m) , 1.49(2H'm) 1.33(3H,d), 0.78(3H,t) . NMR (400 Hz, D 2 0) δ 8.22 (2H, s), 7.60 (lH, t) 6.78 (2H, m) 4.59 (2H, m), 4.22 (lH, m), 4. ll (lH, m ), 3.70 (5H, m), 3.60 (2H, m) 3.23 (4H, m), 2.42 (2H, t), 2.30 (lH, m), 2.06 (lH, m), 1.49 (2H'm) 1.33 (3H, d), 0.78 (3H, t).
<실시예 46> 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1- 일 )부톡시 )-2-플루오로 -N-(l, 3-다이하이드특시프로판 -2- 일 )벤즈아마이드 염산염의 제조 Example 46 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro-N- (l, 3-dihydric Preparation of Cipropan-2-yl) benzamide hydrochloride
Figure imgf000067_0002
질소 대기하의 100 ml 플라스크에 상기 실시예 44에서 제조된 화합물 (310 mg) 및 다이클로로메탄 (DCM, 50 mL)을 주입하고 교반하여 용해시키고， 1-에틸 -3— (3-다이메틸아미노프로필 )카르보다이이미드 염산염 (EDCI, 170 mg) 및 1-하이드록시벤조트리아졸 1수화물 (KOBt , 120 mg)올 첨가하고 30분 동안 교반하였다. 그 후, 2-아미노 -1,3- 프로판다이올 (100 mg)올 첨가하고 상은에서 5시간 동안 교반하였다. 반응이 종결되면 증류수 (20 mL)를 천천히 가하고 에틸아세테이트 (EA, 60 mL)로 추출한 다음 소금물 (40 mL)로 세척하였다. 세척된 유기층올 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 정제된 화합물을 에틸아세테이트 (EA, 10 mL)를 가하고 교반하여 용해시킨 다음， 같은 당량수의 4N_염산 (1 4_다이옥산 용액)을 적가하고 30분 동안 환류교반하였다ᅳ 반응이 완료되면 온도를 상온으로 냉각시키고 고체를 여과하여 목적화합물을 얻었다.
Figure imgf000067_0002
Into a 100 ml flask under nitrogen atmosphere, the compound (310 mg) and dichloromethane (DCM, 50 mL) prepared in Example 44 were injected, stirred, and dissolved, and then 1-ethyl-3— (3-dimethylaminopropyl). Carbodiimide hydrochloride (EDCI, 170 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 120 mg) ol were added and stirred for 30 minutes. Then 2-amino-1,3-propanediol (100 mg) ol was added and stirred at silver 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. Ethyl acetate (EA, 10 mL) was added to the purified compound, and then dissolved by stirring. Then, the same amount of 4N _ hydrochloric acid ( 1 4 _ dioxane solution) was added dropwise and stirred under reflux for 30 minutes. Cooled to room temperature and filtered to obtain the target compound.
XH NMR (400 Hz, D20)： δ 8.22(2H,s) , 7.61( 1H , t ) , 6.78(2H， m)，XH NMR (400 Hz, D 2 0): δ 8.22 (2H, s), 7.61 (1H, t), 6.78 (2H, m) ，
4.59(2H,m) , 4.22(lH,m) , 4. ll(lH,m) , 3.71(2H,m) , 3.68(3H,m) ,4.59 (2H, m), 4.22 (lH, m), 4.ll (lH, m), 3.71 (2H, m), 3.68 (3H, m),
3.60(2H,m) , 3.23(4H,m) , 2.42(2H, t) , 2.30(lH,m) , 2.06(lH,m) , 1.49(2H,m) , 1.33(3H,d) , 0.78(3H,t) . 3.60 (2H, m), 3.23 (4H, m), 2.42 (2H, t), 2.30 (lH, m), 2.06 (lH, m), 1.49 (2H, m), 1.33 (3H, d), 0.78 (3H, t).
<실시예 47> 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1- 일 )부톡시 )-2-플루오로 -N-((S)-1-하이드록시프로판 -2-일 )벤즈아마이드 옥살산염의 제조 Example 47 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro-N-((S) -1-hydro Preparation of Roxypropan-2-yl) benzamide oxalate
Figure imgf000068_0001
Figure imgf000068_0001
상기 실시예 45에서 2-아미노 -1,3-프로판다이올을 사용하는 대신에 (R)-(-)-2-아미노 -1-프로판올을 사용하는 것을 제외하고 상기 실시예 45와 동일한 방법으로 수행하여 목적화합물을 얻었다.  In the same manner as in Example 45, except that (R)-(-)-2-amino-1-propanol was used instead of 2-amino-1,3-propanediol in Example 45. This was carried out to obtain the target compound.
XH NMR (400 Hz, D20)： δ 8.33(2H,s) , 7.56(lH,t), 6.79(2H,m) , 4.57(2H,m) , 4.21(lH,m) , 4.13(2H,m) , 3.71(2H,m) , 3.61(3H,m) , 3.52(2H,m) , 3.27(2H,m) , 2.46(2H, t) , 2.32(lH,m) , 2.05(lH,m) , 1.55(2H,m) , 1.36(3H,d) , 1.09(3H,d) , 0.78(3H, t) . X H NMR (400 Hz, D 2 0): δ 8.33 (2H, s), 7.56 (lH, t), 6.79 (2H, m), 4.57 (2H, m), 4.21 (lH, m), 4.13 ( 2H, m), 3.71 (2H, m), 3.61 (3H, m), 3.52 (2H, m), 3.27 (2H, m), 2.46 (2H, t), 2.32 (lH, m), 2.05 (lH , m), 1.55 (2H, m), 1.36 (3H, d), 1.09 (3H, d), 0.78 (3H, t).
<실시예 48> 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1- 일 )부톡시 )-2-플루오로 -N-((S)-1-하이드록시프로판 -2-일 )벤즈아마이드 염산염의 제조
Figure imgf000069_0001
Example 48 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro-N-((S) -1-hydro Preparation of Roxypropan-2-yl) benzamide hydrochloride
Figure imgf000069_0001
상기 실시예 46에서 2-아미노 -1,3-프로판다이올을 사용하는 대신에 (R)-(-)-2—아미노 -1—프로판올을 사용하는 것을 제와하고 상기 실시예 46과 동일한 방법으로 수행하여 목적화합물을 얻었다 . The same method as in Example 46, except that (R)-(-)-2-amino-1-propanol is used instead of 2-amino-1,3-propanediol in Example 46. The title compound was obtained by the following procedure.
XH NMR (400 Hz, D20): δ 8.33(2H,s) , 7.55(lH,t), 6.79(2H,m) , 4.57(2H,m) , 4.19(lH,m) , 4.13(2H,m) , 3.71(2H,m) , 3.61(3H,m) , 3.47(2H,ra) , 3.27(2H,m) , 2.46(2H, t) , 2.32(lH,m) , 2.05(lH,m) , 1.55(2H,m) , 1.36(3H,d) , l.ll(3H,d) , 0.78(3H, t) . X H NMR (400 Hz, D 2 0): δ 8.33 (2H, s), 7.55 (lH, t), 6.79 (2H, m), 4.57 (2H, m), 4.19 (lH, m), 4.13 ( 2H, m), 3.71 (2H, m), 3.61 (3H, m), 3.47 (2H, ra), 3.27 (2H, m), 2.46 (2H, t), 2.32 (lH, m), 2.05 (lH , m), 1.55 (2H, m), 1.36 (3H, d), l.ll (3H, d), 0.78 (3H, t).
<실시예 49> 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1- 일 )부톡시 )-2-플루오로— N-((S)— 2,3- 다이하이드록시프로필)벤즈아마이드 옥살산염의 제조 Example 49 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro—N-((S) — 2,3 Preparation of dihydroxypropyl) benzamide oxalate
Figure imgf000069_0002
Figure imgf000069_0002
상기 실시예 45에서 2-아미노 -1,3-프로판다이을을 사용하는 대신에 (R)-3 아미노 -1,2-프로판다이을을 사용하는 것을 제외하고 상기 실시예 45와 동일한 방법으로 수행하여 목적화합물을 얻었다.  The same procedure as in Example 45 was performed except that (R) -3 amino-1,2-propanedi was used instead of 2-amino-1,3-propanedi in Example 45. The compound was obtained.
XH 匪 R (400 Hz, D20): δ 8.21(2H,s) , 7.58(lH,t), 6.76(2H,m) , 4.56(2H,m) , 4.20(lH,m) , 4.10(2H,m) , 3.82(lH,m) , 3.65(lH,m) , 3.57(5H,m) , 3.23(2H,m) , 2.38(2H,t) , 2.28(lH,m) , 1.96(lH,ra) , 1.46(2H,m) , 1.33(3H,d), 0.77(3H,t) . X H 匪 R (400 Hz, D 2 0): δ 8.21 (2H, s), 7.58 (lH, t), 6.76 (2H, m), 4.56 (2H, m), 4.20 (lH, m), 4.10 (2H, m), 3.82 (lH, m), 3.65 (lH, m), 3.57 (5H, m), 3.23 (2H, m), 2.38 (2H, t), 2.28 (lH, m), 1.96 ( lH, ra), 1.46 (2H, m), 1.33 (3H, d), 0.77 (3H, t).
<실시예 50> 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1- 일 )부톡시 )-2-플루오로 -N-((S)-2,3- 다이하이드록시프로필)벤즈아마이드 염산염의 제조 Example 50 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluoro-N-((S) -2,3 Preparation of dihydroxypropyl) benzamide hydrochloride
Figure imgf000069_0003
Figure imgf000069_0003
상기 실시예 46에서 2-아미노 -1,3-프로판다이올을 사용하는 대신에 (00-3-아미노— 1,2-프로판다이올을 사용하는 것을 제외하고 상기 실시예 46과 동일한 방법으로 수행하여 목적화합물을 얻었다.Except for using (00-3-amino— 1,2-propanediol instead of 2-amino-1,3-propanediol in Example 46 above The target compound was obtained in the same manner as in Example 46.
:H NMR (400 Hz, D20)： δ 8.35(2H,s) , 7.58(1H, t) , 6.77(2H,m) , 4.64(2H,m) , 4.20(lH,m) , 4.10(2H,m) , 3.82(lH,m) , 3.65(lH,m) , 3.57(5H,m) , 3.23(2H,m) , 2.38(2H, t), 2.28(lH,m) , 2.07(lH,m) , 1.46(2H,m) , 1.34(3H,d) , 0.77(3H,t) . : H NMR (400 Hz, D 2 0): δ 8.35 (2H, s), 7.58 (1H, t), 6.77 (2H, m), 4.64 (2H, m), 4.20 (lH, m), 4.10 ( 2H, m), 3.82 (lH, m), 3.65 (lH, m), 3.57 (5H, m), 3.23 (2H, m), 2.38 (2H, t), 2.28 (lH, m), 2.07 (lH , m), 1.46 (2H, m), 1.34 (3H, d), 0.77 (3H, t).
<실시예 51> 4-(3-(4-(3-이소프로필 -l，2,4-옥사다이아졸-5- 일)피페라진-l-일)부톡시 )-2-플루오로 -N-(l, 3-다이하아드톡시프로판- 2-일)벤즈아마이드 옥살산염의 제조 Example 51 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro-N Preparation of-(l, 3-dihaadoxypropane-2-yl) benzamide oxalate
Figure imgf000070_0001
Figure imgf000070_0001
질소 대기하의 100 mL 플라스크에 상기 실시예 42에서 제조된 화합물 (600 mg) 및 다이클로로메탄 (DCM, 50 mL)을 주입하고 교반하여 용해시키고, 1-에틸 -3-(3-다이메틸아미노프로필)카르보다이이미드 염산염 (EDCI , 420 mg) 및 1-하이드록시벤조트리아졸 1수화물 (KOBt , 290 mg)을 첨가하고 30분 홍안 교반하였다. 그 후， 2-아미노 -1,3- 프로판다이을 (200 mg)을 첨가하고 상온에서 5시간 동안 교반하였다. 반웅이 종결되면 증류수 (20 mL)를 천천히 가하고 에틸아세테이트 (EA, 60 mL)로 추출한 다음 소금물 (40 mL)로 세척하였다. 세척된 유기층올 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 정제된 화합물을 에틸아세테이트 (EA, 10 mL)를 가하고 교반하여 용해시킨 다음， 같은 당량수의 옥살산을 적가하고 30분 동안 환류교반하였다. 반응이 완료되면 온도를 상온으로 냉각시키고 고체를 여과하여 목적화합물을 얻었다.  Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Example 42 (600 mg) and dichloromethane (DCM, 50 mL) were added, stirred, and dissolved, and then 1-ethyl-3- (3-dimethylaminopropyl). Carbodiimide hydrochloride (EDCI, 420 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 290 mg) were added and stirred for 30 minutes in red eye. Then 2-amino-1,3-propanedi was added (200 mg) and stirred for 5 hours at room temperature. When the reaction was completed, distilled water (20 mL) was slowly added, 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, followed by stirring to dissolve it. Then, the same amount of oxalic acid was added dropwise and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
:H NMR (400 Hz, D20)： δ 7.58(lH,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(lH,m) , 2.29(lH,m) , 2.03(lH,m) , 1.33(3H,d) , 1.13(6H,d) . <실시예 52> 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )—2-플루오로 -N-(l, 3-다이하이드록시프로판- 2-일)벤즈아마이드 염산염의 제조 : H NMR (400 Hz, D 2 0): δ 7.58 (lH, 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 (lH, m), 2.29 (lH, m), 2.03 (lH, m), 1.33 (3H, d), 1.13 (6H , d). Example 52 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) —2-fluoro-N Preparation of-(l, 3-dihydroxypropane-2-yl) benzamide hydrochloride
Figure imgf000071_0001
Figure imgf000071_0001
질소 대기하의 100 mL 플라스크에 상기 실시예 42에서 제조된 화합물 (600 mg) 및 다이클로로메탄 (DCM, 50 mL)을 주입하고 교반하여 용해시키고, 1-에틸 -3-(3-다이메틸아미노프로필)카르보다이이미드 염산염 (EDCI, 420 mg) 및 1-하이드록시벤조트리아졸 1수화물 (KOBt, 290 mg)을 첨가하고 30분 동안 교반하였다. 그 후, 2-아미노 1,3- 프로판다이을 (200 mg)을 첨가하고 상온에서 5시간 동안 교반하였다. 반웅이 종결되면 증류수 (20 mL)를 천천히 가하고 에틸아세테이트 (EA, 60 mLl)로 추출한 다음 소금물 (40 ml)로 세척하였다. 세척된 유기층을 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 정제된 화합물을 에틸아세테이트 (EA, 10 mL)를 가하고 교반하여 용해시킨 다음， 같은 당량수의 염산을 적가하고 30분 동안 환류교반하였다. 반웅이 완료되면 온도를 상온으로 냉각시키고 고체를 여과하여 목적화합물을 얻었다.  Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Example 42 (600 mg) and dichloromethane (DCM, 50 mL) were added, stirred, and dissolved, and then 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-propanedi was added (200 mg) and stirred at room temperature for 5 hours. When the reaction was finished, distilled water (20 mL) was slowly added, 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, followed by stirring to dissolve it. Then, the same amount of hydrochloric acid was added dropwise and stirred under reflux for 30 minutes. When reaction was completed, the temperature was cooled to room temperature and the solid was filtered to obtain the target compound.
XH NMR (400 Hz, D20) ： δ 7.60(lH,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(lH,m) , 2.27(lH,m) , 2.00(lH,ra), 1.33(3H,d) , 1.13(6H,d). <실시예 53> 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이마졸-5- 일)피페라진-l-일)부톡시) -2-플루오로 -N- ( (R)-l-하이드록시프로판 -2- 일)벤즈아마이드 옥살산염의 제조 X H NMR (400 Hz, D 2 0): δ 7.60 (lH, 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 (lH, m), 2.27 (lH, m), 2.00 (lH, ra), 1.33 (3H, d), 1.13 (6H, d). Example 53 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-yl-butoxy) -2-fluoro-N Preparation of ((R) -l-hydroxypropan-2-yl) benzamide oxalate
Figure imgf000071_0002
Figure imgf000071_0002
상기 실시예 51에서 2-아미노 -1,3—프로판다이올을 사용하는 대신에 (R)— (-)-2-아미노 -1-프로판을을 사용하는 것을 제외하고 상기 실시예 51과 동일한 방법으로 수행하여 목적화합물을 얻었다 .  The same method as in Example 51, except that (R) — (−)-2-amino-1-propane is used instead of 2-amino-1,3—propanediol in Example 51. The title compound was obtained by the following procedure.
^ 匪 R (400 Hz, D20): δ 7.55(lH,m) , 6.77(2H,m) , 4.21(2H,m) , 4.06(2H,m) , 3.72(2H,m) , 3.59(5H,m) , 3.43(2H,m) , 2.83(lH,m) , 2.31(lH,m) , 2.04(lH,m), 1.34(3H,d), l.ll(9H,m) . ^ 匪 R (400 Hz, D 2 0): δ 7.55 (lH, m), 6.77 (2H, m), 4.21 (2H, m), 4.06 (2H, m), 3.72 (2H, m), 3.59 ( 5H, m), 3.43 (2H, m), 2.83 (lH, m), 2.31 (lH, m), 2.04 (lH, m), 1.34 (3H, d), l.ll (9H, m).
<실시예 54> 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1ᅳ일 )부톡시 )-2-플루오로 -N-((R)-1-하이드록시프로판 -2- 일 )벤즈아마이드 염산염의 제조 Example 54 4- (3- (4- (3-isopropyl-1,2,4-oxadiazole-5) Preparation of 1) piperazin-1xyl) butoxy) -2-fluoro-N-((R) -1-hydroxypropan-2-yl) benzamide hydrochloride
Figure imgf000072_0001
Figure imgf000072_0001
상기 실시예 52에서 2-아미노 -1，3-프로판다이을을 사용하는 대신에 (R)-(-)-2-아미노 -1-프로판올올 사용하는 것을 제외하고 상기 실시예 52와 동일한 방법으로 수행하여 목적화합물을 얻었다.  Example 52 was carried out in the same manner as in Example 52, except for using (R)-(-)-2-amino-1-propanolol instead of using 2-amino-1,3-propanedi To obtain the target compound.
XH NMR (400 Hz, D20)： δ 7.55(lH,m), 6.77(2H,m) , 4.20(2H,m) , 4.06(2H,m) , 3.71(2H,m) , 3.50(5H,m) , 3.32(2H,m) , 2.81(lH,m) , 2.31(lll,ni), 2.04(lH,m) , 1.34(3H,d) , 1.10(9H,m) . X H NMR (400 Hz, D 2 0): δ 7.55 (lH, m), 6.77 (2H, m), 4.20 (2H, m), 4.06 (2H, m), 3.71 (2H, m), 3.50 ( 5H, m), 3.32 (2H, m), 2.81 (lH, m), 2.31 (lll, ni), 2.04 (lH, m), 1.34 (3H, d), 1.10 (9H, m).
<실시예 55> 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부특시)-2-플루오로-N-((R)-2,3- 다이하이드톡사프로필)벤즈아마이드 옥살산염의 제조 Example 55 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-yl-yl) particular) -2-fluoro-N Preparation of-((R) -2,3-dihydrotoxapropyl) benzamide oxalate
Figure imgf000072_0002
Figure imgf000072_0002
상기 실시예 51에서 2-아미노 -1,3-프로판다이을을 사용하는 대신에 (R)-3ᅳ아미노 -1,2-프로판다이올을 사용하는 것을 제외하고 상기 실시예 51과 동일한 방법으로 수행하여 목적화합물올 얻었다.  Example 51 was carried out in the same manner as in Example 51, except for using (R) -3 -amino-1,2-propanediol instead of 2-amino-1,3-propanedi The desired compound was obtained.
¾ NMR (400 Hz, D20): δ 7.58(1H, t) , 6.76(2H,m) , 4.21(2H,m) , 4.09(2H,m) , 3.82(lH,m) , 3.70(2H,m) , 3.52(5H,ra) , 3.43(2H,m) , 2.81(lH,m) , 2.10(lH,m) , 2.00(lH,m) , 1.33(3H,d) , 1.12(6H,m) . ¾ NMR (400 Hz, D 2 0): δ 7.58 (1H, t), 6.76 (2H, m), 4.21 (2H, m), 4.09 (2H, m), 3.82 (lH, m), 3.70 (2H , m), 3.52 (5H, ra), 3.43 (2H, m), 2.81 (lH, m), 2.10 (lH, m), 2.00 (lH, m), 1.33 (3H, d), 1.12 (6H, m).
<실시예 56> 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-2-풀루오로 -N-((R)-2,3- 다이하이드록시프로필)벤즈아마이드 염산염의 제조 Example 56 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) partial) -2-pulolo Preparation of N-((R) -2,3-dihydroxypropyl) benzamide hydrochloride
Figure imgf000072_0003
Figure imgf000072_0003
상기 실시예 52에서 2-아미노 -1， 3—프로판다이을을 사용하는 대신에 00-3-아미노 -1,2-프로판다이올을 사용하는 것을 제외하고 상기 실시예 52와 동일한 방법으로 수행하여 목적화합물을 얻었다.  The same procedure as in Example 52 was conducted except that 00-3-amino-1,2-propanediol was used instead of 2-amino-1, 3-propanediol in Example 52. The compound was obtained.
¾ NMR (400 Hz, D20): δ 7.57(lH,m) , 6.76(2H， tn)， 4.35( 1H， m)， 4.20(2H,m) , 4.06(2H,m) , 3.82(lH,m) , 3.72(2H,m) , 3.59(3H,m): 2.83(lH,m), 2.31(lH,m), 2.02(lH,m), 1.34(3H,d) , l.ll(6H,m). ¾ NMR (400 Hz, D 2 0): δ 7.57 (lH, m), 6.76 (2H, tn), 4.35 (1H, m) ， 4.20 (2H, m), 4.06 (2H, m), 3.82 (lH, m), 3.72 (2H, m), 3.59 (3H, m) : 2.83 (lH, m), 2.31 (lH, m), 2.02 (lH, m), 1.34 (3H, d), l.ll (6H, m).
<실시예 57> 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부록시)-2-플루오로-N-((R)-2，3- 다이하이드록시프로필)벤즈아마이드 염산염의 제조 Example 57 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) buroxy) -2-fluoro-N Preparation of-((R) -2,3-dihydroxypropyl) benzamide hydrochloride
Figure imgf000073_0001
Figure imgf000073_0001
<실시예 58> (4- (3-(4-(3-이소프로필 -1,2, 4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 ) - 2-플루오로페닐) (피를리딘 -1-일 )메타논 염산염의 제조 Example 58 (4- (3- (4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) part-specific)-2-fluorophenyl Preparation of Pyridin-1-yl) methanone Hydrochloride
Figure imgf000073_0002
Figure imgf000073_0002
상기 실시예 52에서 2-아미노— 1,3-프로판다이을을 사용하는 대신에 피롤리딘을 사용하는 것을 제외하고 상기 실시예 52와 동일한 방법으로 수행하여 목적화합물을 얻었다.  The target compound was obtained in the same manner as in Example 52, except for using pyrrolidine instead of using 2-amino-1,3-propanedi in Example 52.
¾ NMR (400 Hz, D20)： δ 7.29(lH,m) , 6.80(2H,m) 4.23(2H,m)¾ NMR (400 Hz, D 2 0): δ 7.29 (lH, m), 6.80 (2H, m) 4.23 (2H, m)
4. ll(2H,m) , 3.72(lH,m) , 3.48(2H,m) , 2.28(2H,m) , 2.82(lH,m)4.ll (2H, m), 3.72 (lH, m), 3.48 (2H, m), 2.28 (2H, m), 2.82 (lH, m)
2.33(lH,m) , 2.06(lH,m) , 1.90(2H,m) , 1.78(2H,m) , 1.34(3H,d) 1. ll(6H,m) . 2.33 (lH, m), 2.06 (lH, m), 1.90 (2H, m), 1.78 (2H, m), 1.34 (3H, d) 1.ll (6H, m).
<실시예 59> 에틸 4-(3-(4-(3-이소프로필-1，2,4-옥사다이아졸- 5-일)피페라진 -1-일)부톡시 )-3-플루오로벤조에이트 옥살산염의 제조 Example 59 Ethyl 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorobenzo Preparation of Eight Oxalate
Figure imgf000074_0001
Figure imgf000074_0001
상기 실시예 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 상기 20에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예
Figure imgf000074_0002
심한 방법으로 수행하여 목적화합물을 얻었다. Example 6 in Example 6 except for using the compound prepared in Example 20 instead of using the compound prepared in Preparation Example 2
Figure imgf000074_0002
It was carried out in a severe manner to obtain the target compound.
XH 腿 (400 Hz, D20) ： δ 7.74(1Η d) , 7.69(lH,dd) 7. ll(lH,t) 4.36(2H,m)， 4.31(2H,m)， 4.20(2H,m) , 3.76(lH,m) , . 3.58(4H,m)， 3.34(2H,m)， 2.83(lH,m) , 2.36(lH,m) 2.13(lH,m)， 1.37(3H,d) , 1.28(3H,t) , 1.15(6H,d) , 1 08(3H,t) . X H 腿 (400 Hz, D 2 0): δ 7.74 (1Η d), 7.69 (lH, dd) 7.ll (lH, t) 4.36 (2H, m), 4.31 (2H, m), 4.20 (2H , m), 3.76 (lH, m),. 3.58 (4H, m), 3.34 (2H, m), 2.83 (lH, m), 2.36 (lH, m) 2.13 (lH, m), 1.37 (3H, d), 1.28 (3H, t), 1.15 ( 6H, d), 1 08 (3H, t).
<실시예 60> 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부특시)-3-플루오로벤조에이트 리튬염의 제조 Example 60 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-yl-yl) particular) -3-fluorobenzoate Preparation of Lithium Salt
Figure imgf000074_0003
Figure imgf000074_0003
질소 대기하의 100 mL 플라스크에 상기 실시예 59에서 제조된 화합물 (200 mg), 테트라하이드로퓨란 (40 mL) 및 증류수 (20 mL)를 주입하고 교반하여 용해시켰다. 그 후， 상기 반응물에 리튬하이드록사이드 1수화물 (170 mg)을 첨가하고 상은에서 18시간 동안 교반하였다. 반응이 종결되면 용매를 농축한 후 다이클로로메탄 (DCM, 50 mL)에 용해시키고 용해되지 않는 고체를 여과하였다. 여과된 여액을 농축하고， 다이에틸에테르 및 핵산을 이용하여 고체화하여 목적화합물을 얻었다.  In a 100 mL flask under a nitrogen atmosphere, the compound (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) prepared in Example 59 were charged and dissolved by stirring. Lithium hydroxide monohydrate (170 mg) was then added to the reaction and stirred for 18 hours at phase silver. At the end of the reaction, the solvent was concentrated, dissolved in dichloromethane (DCM, 50 mL) and the insoluble solid was filtered off. The filtrate was concentrated and solidified using diethyl ether and nucleic acid to obtain the target compound.
XH NMR (400 Hz, D20)： δ 7.5K1H, t) , 6.77(2H,m) , 3.99(2H,m) , 3.52(4H,t), 2.76(2H,m) , 2.60(4H,q) , 2.07(lH,m) , 1.79(3H,s) , 1.53(lH,m) , 1. ll(6H,d) , 1.01(3H,d) . X H NMR (400 Hz, D 2 0): δ 7.5K1H, t), 6.77 (2H, m), 3.99 (2H, m), 3.52 (4H, t), 2.76 (2H, m), 2.60 (4H , q), 2.07 (lH, m), 1.79 (3H, s), 1.53 (lH, m), 1.ll (6H, d), 1.01 (3H, d).
<실시예 61> 4-(3-(4-(3-이소프로필 -l，2,4-옥사다이아졸-5- 일)피페라진-l-일)부록시)-N-((R)-l-하이드록시프로판-2- 일)벤즈아마이드 옥살산염의 제조
Figure imgf000075_0001
Example 61 4- (3- (4- (3-isopropyl-l, 2,4-oxadiazol-5-yl) piperazin-l-yl) buroxy) -N-((R) Preparation of -l-hydroxypropan-2-yl) benzamide oxalate
Figure imgf000075_0001
질소 100 mL 풀라스크에 상기 실시예 60에서 제조된 화합물 (600
Figure imgf000075_0002
이클로로메탄 (DCM, 50 mL)을 주입하고 교반하여 용해시키고， 1-에틸 _3-(3ᅳ다이메틸아미노프로필 )카르보다이이미드 염산염 (EDCI 420 mg) 및 1-하이드록시벤조트리아졸 1수화물 (KOBt,Compound (600) prepared in Example 60 above in a 100 mL nitrogen flask.
Figure imgf000075_0002
Inject dichloromethane (DCM, 50 mL), dissolve by stirring, and dissolve 1-ethyl-3- (3'dimethylaminopropyl) carbodiimide hydrochloride (EDCI 420 mg) and 1-hydroxybenzotriazole 1 Luggage (KOBt,
290 mg)올 첨가하고 30분 동안 교반하였다. 그 후 , (R)-(-)-2-아미노-290 mg) was added and stirred for 30 minutes. After that, (R)-(-)-2-amino-
1-프로판을 (200 mg)을 첨가하고 상온에서 5시간 동안 교반하였다. 반응이 종결되면 증류수 (20 mL)를 천천히 가하고 에틸아세테이트 (EA,1-propane (200 mg) was added and stirred at room temperature for 5 hours. At the end of the reaction, distilled water (20 mL) was added slowly and ethyl acetate (EA,
60 mL)로 추출한 다음 소금물 (40 mL)로 세척하였다. 세척된 유기층을 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 정제된 화합물을 에틸아세테이트 (EA, 10 mL)를 가하고 교반하여 용해시킨 다음, 같은 당량수의 옥살산을 적가하고 30분 동안 환류교반하였다. 반응이 완료되면 온도를 상온으로 냉각시키고 고체를 여과하여 목적화합물을 얻었다. 60 mL) and then 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, the purified compound was dissolved by stirring, and the same equivalent number of oxalic acid was added dropwise and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
:H 丽 R (400 Hz, CDCls)： δ 7.54(2H,m) 7.70(lH,t), : H δ R (400 Hz, CDCls): δ 7.54 (2H, m) 7.70 (lH, t),
6.20(lH,d) , 4.28(2H,m) , 4.14(lH,m) , 3.79(lH,m) , 3.59(5H,m) ,6.20 (lH, d), 4.28 (2H, m), 4.14 (lH, m), 3.79 (lH, m), 3.59 (5H, m),
3.79(2H,m) , 3.67(lH,m) , 3.58(4H,m) , 2.96(2H,q) , 2.87(2H,q),3.79 (2H, m), 3.67 (lH, m), 3.58 (4H, m), 2.96 (2H, q), 2.87 (2H, q),
2.71(2H,m) , 2.63(lH,s) , 2.52(2H,m) , 2.04(lH,m), 1.85(lH,m) , 1.30(9H,m) , 1.10(3H,d). 2.71 (2H, m), 2.63 (lH, s), 2.52 (2H, m), 2.04 (lH, m), 1.85 (lH, m), 1.30 (9H, m), 1.10 (3H, d).
<실시예 62> 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부톡시 )-N-((R)-l-하이드록시프로판 -2- 일 )벤즈아마이드 염산염의 제조 Example 62 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N-((R) Preparation of -l-hydroxypropan-2-yl) benzamide hydrochloride
Figure imgf000075_0003
Figure imgf000075_0003
질소 대기하의 100 mL 플라스크에 상기 실시예 60에서 제조된 화합물 (600 mg) 및 다이클로로메탄 (DCM, 50 mL)을 주입하고 교반하여 용해시키고, 1-에틸 -3-(3-다이메틸아미노프로필)카르보다이이미드 염산염 (EDCI, 420 mg) 및 1-하이드록시벤조트리아졸 1수화물 (KOBt, 290 mg)을 첨가하고 30분 동안 교반하였다. 그 후， (R)-(-)— 2-아미노- 1-프로판올 (200 mg)을 첨가하고 상온에서 5시간 동안 교반하였다. 반응이 종결되면 증류수 (20 mL)를 천천히 가하고 에틸아세테이트 (EA, 60 mL)로 추출한 다음 소금물 (40 mL)로 세척하였다. 세척된 유기층을 무수 황산마그네슴으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 정제된 화합물을 에틸아세테이트 (EA, 10 mL)를 가하고 교반하여 용해시킨 다음， 같은 당량수의 염산을 적가하고 30분 동안 환류교반하였다. 반응이 완료되면 온도를 상은으로 냉각시키고 고체를 여과하여 목적화합물을 얻었다. Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Example 60 (600 mg) and dichloromethane (DCM, 50 mL) were dissolved by stirring, and dissolved in 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 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). Washed organic layer It was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography. Ethyl acetate (EA, 10 mL) was added to the purified compound, followed by stirring to dissolve it. Then, the same amount of hydrochloric acid was added dropwise and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to silver and the solid was filtered to obtain the target compound.
:H NMR (400 Hz, D20)： δ 7.46(2H,m) , 7.09(lH,t) , 4.28(2H,m) , 4.16(lH,ra), 3.72(lH,m) , 3.54(5H,m) , 2.83(lH,m) , 2.29(lH,m) , 2.11(lH,m), 1.34(3H,d), 1.10(9H,m) . : H NMR (400 Hz, D 2 0): δ 7.46 (2H, m), 7.09 (lH, t), 4.28 (2H, m), 4.16 (lH, ra), 3.72 (lH, m), 3.54 ( 5H, m), 2.83 (lH, m), 2.29 (lH, m), 2.11 (lH, m), 1.34 (3H, d), 1.10 (9H, m).
<실시예 63> 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부톡시)-3-플루오로-N-((S)-2,3- 다이하이드록시프로필)벤즈아마이드 옥살산염의 제조 Example 63 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro-N Preparation of-((S) -2,3-dihydroxypropyl) benzamide oxalate
Figure imgf000076_0001
Figure imgf000076_0001
상기 실시예 61에서 (R)-(-)-2-아미노 -1-프로판올을 사용하는 대신에 (R)-3-아미노 -1,2-프로판다이을을 사용하는 것을 제외하고 상기 실시예 61과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Example 61 above except for using (R) -3-amino-1,2-propanedi instead of using (R)-(-)-2-amino-1-propanol The target compound was obtained by the same method.
^ NMR (400 Hz, D20): δ 7.49(2Η,π , 7.10(lH,t), 4.29(2H,m) , 4.20(2H,m) , 3.83(2H,m) , 3.80(lH,m) , 3.70(5H,m), 2.83(lH,m) , 2.31(lH,m) , 2.10(lH,m), 1.33(3H,d) , 1.13(6H,d) . ^ NMR (400 Hz, D 2 0): δ 7.49 (2Η, π, 7.10 (lH, t), 4.29 (2H, m), 4.20 (2H, m), 3.83 (2H, m), 3.80 (lH, m), 3.70 (5H, m), 2.83 (lH, m), 2.31 (lH, m), 2.10 (lH, m), 1.33 (3H, d), 1.13 (6H, d).
<실시예 64> 4-(3-(4-(3-이소프로필 -1，2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-3-플루오로 -N-((S)-2,3- 다이하이드록시프로필)벤즈아마이드 트라이플루오로아세트산염의 제조 Example 64 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -3-fluoro-N Preparation of-((S) -2,3-dihydroxypropyl) benzamide trifluoroacetate
Figure imgf000076_0002
Figure imgf000076_0002
상기 실시예 62에서 (R)-(-)-2-아미노— 1-프로판을을 사용하는 대신에 (R)-3-아미노 -1,2-프로판다이올을 사용하는 것을 제외하고 상기 실시예 62와 동일한 방법으로 수행하여 목적화합물을 얻었다.  Example 62 above except for using (R) -3-amino-1,2-propanediol instead of using (R)-(-)-2-amino— 1-propane The target compound was obtained by the same method as the method of 62.
:H NMR (400 Hz, D20)： δ 7.50(2H,m) , 7.07(lH,t), 4.29(2H,m) , 4.21(2H,m) , 3.83(2H,m) , 3.80(lH,m) , 3.65(5H,m) , 2.83(lH,m) , 2.31(lH,m) , 2.10(lH,m) , 1.35(3H,d) , 1.13(6H,d) . <실시예 65> 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부톡시 )-N,N-다이에틸 -3-메틸벤즈아마이드 : H NMR (400 Hz, D 2 0): δ 7.50 (2H, m), 7.07 (lH, t), 4.29 (2H, m), 4.21 (2H, m), 3.83 (2H, m), 3.80 ( lH, m), 3.65 (5H, m), 2.83 (lH, m), 2.31 (lH, m), 2.10 (lH, m), 1.35 (3H, d), 1.13 (6H, d). Example 65 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N, N-diethyl -3-methylbenzamide
옥살산염의 제조 Preparation of Oxalate
Figure imgf000077_0001
Figure imgf000077_0001
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 상기 제조예 21에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다ᅳ  Except for using the compound prepared in Preparation Example 2 instead of the compound prepared in Preparation Example 2 in Example 6 was carried out in the same manner as in Example 6 to obtain the target compound.
:H NMR (400 Hz, D20)： δ 7.13(2H,d), 6.91(lH,d), 4.19(2H,m) , 4.08(2H,m) , 3.69(2H,m) , 3.43(5H,m) , 3.20(2H,q) , 2.82(lH,m) , 2.33(lH,m) , 2.02(lH,m) , 1.35(3H,d) , 1.10(6H,d) , 097(3H, t) . : H NMR (400 Hz, D 2 0): δ 7.13 (2H, d), 6.91 (lH, d), 4.19 (2H, m), 4.08 (2H, m), 3.69 (2H, m), 3.43 ( 5H, m), 3.20 (2H, q), 2.82 (lH, m), 2.33 (lH, m), 2.02 (lH, m), 1.35 (3H, d), 1.10 (6H, d), 097 (3H , t).
<실시예 66> 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부톡시)-N,N-다이쎄틸 -3-메틸벤즈아마이드 염산염의 제조 Example 66 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N, N-decetyl Preparation of 3-Methylbenzamide Hydrochloride
Figure imgf000077_0002
Figure imgf000077_0002
상기 실시예 6의 단계 6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 상기 제조예 21에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 수행하여 목적화합물을 얻었다ᅳ  Except for using the compound prepared in Preparation Example 2 instead of the compound prepared in Preparation Example 2 in Example 6 was carried out in the same manner as in Example 6 to obtain the target compound.
lH NMR (400 Hz, D20)： δ 7.13(2H,d) , 6.91(lH,d) , 4.19(2H,m) , 4.08(2H,m) , 3.69(2H,m) , 3.43(5H,m) , 3.20(2H,q) , 2.82(lH,m) , 2.33(lH,m) , 2.02(lH,m) , 1.35(3H,d) , 1.10(6H,d) , 097(3Η, t) . l NMR (400 Hz, D 2 0): δ 7.13 (2H, d), 6.91 (lH, d), 4.19 (2H, m), 4.08 (2H, m), 3.69 (2H, m), 3.43 (5H , m), 3.20 (2H, q), 2.82 (lH, m), 2.33 (lH, m), 2.02 (lH, m), 1.35 (3H, d), 1.10 (6H, d), 097 (3Η, t).
<실시예 67> (4-(3-(4-(3-이소프로필 -l,2，4-옥사다이아졸-5- 일)피페라진-l-일)부톡시)-3-플루오로페닐)(피를리딘-l-일)메타논 옥살산염의 제조 Example 67 (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorophenyl Preparation of (Pyridin-l-yl) methanone oxalate
Figure imgf000078_0001
Figure imgf000078_0001
상기 실시예 61에서 (R)-(-)-2-아미노 -1-프로판을을 사용하는 대신에 피를린을 사용하는 것을 제외하고 상기 실시예 61과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using (R)-(-)-2-amino-1-propane in Example 61 was carried out in the same manner as in Example 61 to obtain the target compound.
XH NMR (400 Hz, D20)： δ 7.13(2H,d), 6.91(lH,d), 4.19(2H,m), 4.08(2H,ra) , 3.69(2H,m) , 3.43(5H,m) , 3.20(2H,q) , 2.82(lH,m) , 2.33(lH,m), 2.02(lH,m), 1.34(3H,d), 1.10(6H,d) , 097(3H,t) . X H NMR (400 Hz, D 2 0): δ 7.13 (2H, d), 6.91 (lH, d), 4.19 (2H, m), 4.08 (2H, ra), 3.69 (2H, m), 3.43 ( 5H, m), 3.20 (2H, q), 2.82 (lH, m), 2.33 (lH, m), 2.02 (lH, m), 1.34 (3H, d), 1.10 (6H, d), 097 (3H , t).
<실시예 68> (4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부특시)-3-폴루오로페닐)(피를리딘-l-일)메타논 염산염의 제조 Example 68 (4- (3- (4- (3-isopropyl-l, 2,4-oxadiazol-5-yl) piperazin-yl-yl) partial) -3-polouro Phenyl) (pyridin-l-yl) methanone hydrochloride
Figure imgf000078_0002
Figure imgf000078_0002
상기 실시예 62에서 (R)-(-)-2-아미노 -1-프로판올을 사용하는 대신에 피를린올 사용하는 것을 제외하고 상기 실시예 62와 동일한 방법으로 수행하여 목적화합물을 얻었다.  Except for using (R)-(-)-2-amino-1-propanol in Example 62 was carried out in the same manner as in Example 62, except that pylinol was used to obtain the target compound.
LH NMR (400 Hz, D20): δ 7.22(2H,t), 7.09(lH,t), 4.30(2H,m) , L H NMR (400 Hz, D 2 0): δ 7.22 (2H, t), 7.09 (lH, t), 4.30 (2H, m),
4.16(2H,m), 3.70(2H,m) , 3.53(4H,m) , 3.42(4H,t) , 3.35(4H,t) ,4.16 (2H, m), 3.70 (2H, m), 3.53 (4H, m), 3.42 (4H, t), 3.35 (4H, t),
2.80(lH,m), 2.31(lH,m) , 2.07(lH,m) , 1.85(2H,m) , 1.75(2H,m) , 1.35(3H,d) , 1.12(6H,d). 2.80 (lH, m), 2.31 (lH, m), 2.07 (lH, m), 1.85 (2H, m), 1.75 (2H, m), 1.35 (3H, d), 1.12 (6H, d).
<실시예 69> 4-(3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부톡시)-3-플루오로-N-(l,3-다이하이드록시프로판- 2-일)벤즈아마이드 옥살산염의 제조 Example 69 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro-N Preparation of-(l, 3-dihydroxypropane-2-yl) benzamide oxalate
Figure imgf000078_0003
Figure imgf000078_0003
상기 실시예 61에서 (R)-( )-2-아미노 -1-프로판올을 사용하는 대신에 2-아미노 -1,3-프로판다이을을 사용하는 것을 제외하고 상기 실시예 61과 동일한 방법으로 수행하여 목적화합물을 얻었다. Except for using 2-amino-1,3-propanedi instead of using (R)-()-2-amino-1-propanol in Example 61, The target compound was obtained in the same manner as in Example 61.
:H 丽 R (400 Hz, D20): δ 7.50(2H,m) , 7.10(1H, t) , 4.30(lH,m) , 4.20(2H,m), 4.10(2H,m) , 3.74(3H,m) , 3.62(2H,t) , 3.43(2H,t), 2.82(lH,m) , 2.30( lH,m) , 2. ll(lH,m) , 1.35(3H,d) , 1.10(6H,d) . : H δ R (400 Hz, D 2 0): δ 7.50 (2H, m), 7.10 (1H, t), 4.30 (lH, m), 4.20 (2H, m), 4.10 (2H, m), 3.74 (3H, m), 3.62 (2H, t), 3.43 (2H, t), 2.82 (lH, m), 2.30 (lH, m), 2. ll (lH, m), 1.35 (3H, d), 1.10 (6 H, d).
<실시예 70> 4-(3-(4-(3-이소프로필 -l，2,4-옥사다이아졸-5- 일)피페라진-l-일)부톡시)-3-풀루오로-N-(l，3-다이하이드록시프로판- 2-일)벤즈아마이드 염산염의 제조 Example 70 4- (3- (4- (3-isopropyl-l, 2,4-oxadiazol-5-yl) piperazin-l-yl) butoxy) -3-pullouro- Preparation of N- (l, 3-dihydroxypropane-2-yl) benzamide hydrochloride
Figure imgf000079_0001
Figure imgf000079_0001
상기 실시예 62에서 (R)-(-)-2-아미노 -1-프로판올올 사용하는 대신에 2-아미노 -1，3-프로판다이을을 사용하는 것올 제외하고 상기 실시예 62와 동일한 방법으로 수행하여 목적화합물을 얻었다.  Example 62 was carried out in the same manner as in Example 62, except that 2-amino-1,3-propanedi was used instead of (R)-(-)-2-amino-1-propanolol. To obtain the target compound.
LH NMR (400 Hz, D20)： δ 7.51(2H,m) , 7.10(1H, t) , 4.30(lH,m) , 4.22(2H,m), 4.09(2H,m), 3.74(3H,m) , 3.62(2H,t) , 3.43(2H,t) , 2.82(lH,m) , 2.30(lH,m) , 2.11(lH,m), 1.35(3H,d), l.ll(6H(d). L H NMR (400 Hz, D 2 0): δ 7.51 (2H, m), 7.10 (1H, t), 4.30 (lH, m), 4.22 (2H, m), 4.09 (2H, m), 3.74 ( 3H, m), 3.62 (2H, t), 3.43 (2H, t), 2.82 (lH, m), 2.30 (lH, m), 2.11 (lH, m), 1.35 (3H, d), l.ll (6H ( d)).
<실시예 71> 4— (3-(4-(3-이소프로필 -l,2，4-옥사다이아졸-5- 일)피페라진 -1-일 )부톡시 )-2-플루오로 -N-((R)-2,3- 다이하이드록시프로필 )벤즈아마이드 옥살산염의 제조 Example 71 4— (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro-N Preparation of-((R) -2,3-dihydroxypropyl) benzamide oxalate
Figure imgf000079_0002
Figure imgf000079_0002
상기 실시예 61에서 (R)-(-)-2-아미노 -1-프로판을을 사용하는 대신에 (S)-3-아미노 -1,2-프로판다이을을 사용하는 것을 제외하고 상기 실시예 61과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Example 61 above except for using (S) -3-amino-1,2-propanedi instead of using (R)-(-)-2-amino-1-propane The target compound was obtained by the same method as described above.
¾ NMR (400， D20): δ 7.59(lH,t), 6.77(2H,t), 4.20(2H,m) 4.10(2H,m) , 3.83(lH,m) , 3.70(2H,m) , 3.58(2H,ra) , 3.46(4H,m) 3.30(4H,m), 2.81(lH,m) , 2.01(lH,m) , 1.95(lH,m) , 1.33(3H,d) 1.12(6H,d) . ¾ NMR (400, D 2 0): δ 7.59 (lH, t), 6.77 (2H, t), 4.20 (2H, m) 4.10 (2H, m), 3.83 (lH, m), 3.70 (2H, m ), 3.58 (2H, ra), 3.46 (4H, m) 3.30 (4H, m), 2.81 (lH, m), 2.01 (lH, m), 1.95 (lH, m), 1.33 (3H, d) 1.12 (6H, d).
<실시예 72> l-(4-(5-메틸 -6- (메틸설포닐)피리딘 -3- 일옥시 )부탄 -2-일) -4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일)피페라진 옥살산염의 제조 Example 72 l- (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4- (3-isopropyl-1,2,4- Preparation of oxadiazole-5-yl) piperazine oxalate
Figure imgf000080_0001
Figure imgf000080_0001
6에서 제조예 2에서 제조된 화합물을 사용하는 대신에 제조예 10에서 제조된 화합물을 사용하는 것을 제외하고 상기 동일한 방법으로 수행하여 목적화합물을 얻었다.  A target compound was obtained by the same method as described in 6, except that the compound prepared in Preparation Example 10 was used instead of the compound prepared in Preparation Example 2.
XH NMR (400 Hz, D20)： δ 8.07(lH,s) , 7.34(lH,s) , 4.28(2H,m) 4.16(2H,m) , 3.71(lH,m) , 3.45(8H,m) , 3.21(3H,s) , 2.81(lH,m) 2.53(3H,s), 2.33(lH,m) , 2.05(lH,m) , 1.33(3H,d) , 1.12(6H,d) . X H NMR (400 Hz, D 2 0): δ 8.07 (lH, s), 7.34 (lH, s), 4.28 (2H, m) 4.16 (2H, m), 3.71 (lH, m), 3.45 (8H , m), 3.21 (3H, s), 2.81 (lH, m) 2.53 (3H, s), 2.33 (lH, m), 2.05 (lH, m), 1.33 (3H, d), 1.12 (6H, d .
<실시예 73> 에틸 4-((R)-3-(4-(3-이소프로필 -1，2，4 옥사다이아졸 -5-일 )피페라진―；ᅡ -일 )부톡시 )-2-플루오로벤조에이트 옥살산염의 제조 Example 73 Ethyl 4-((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol- 5 -yl) piperazin-;-x-yl) butoxy) -2 Preparation of Fluorobenzoate Oxalate
Figure imgf000080_0002
Figure imgf000080_0002
단계 1: (R)— 4- -부틸다이메틸실릴옥시 )부탄 -2-올의 제조  Step 1: Preparation of (R) — 4--Butyldimethylsilyloxy) butan-2-ol
질소 대기하의 500 mL 플라스크에 (R)-(-)-l， 3-부탄다이을 (5 g) , 이미다졸 (7.5 g) 및 다이클로로메탄 (DCM, 200 raL)에 주입하고 교반하여 용해시킨 뒤 t-부틸다이메틸실릴 클로라이드 (9.16 g)를 적가하였다. 적가가 완료되면 24시간 동안 교반하고 다이클로로메탄 (DCM, 100 mL)으로 추출한 다음， 소금물 (100 mL)로 세척하였다 . 세척된 유기충을 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다.  Into a 500 mL flask under nitrogen atmosphere, (R)-(-)-l, 3-butanedi (5 g), imidazole (7.5 g) and dichloromethane (DCM, 200 raL) were dissolved and stirred to dissolve. t-butyldimethylsilyl chloride (9.16 g) was added dropwise. After the addition was completed, the mixture was stirred for 24 hours, extracted with dichloromethane (DCM, 100 mL), and then washed with brine (100 mL). The washed organic insects were dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography to obtain the target compound.
LH NMR (400 Hz, CDC13) ： δ 4.04(m, 1Η) , 3.91(m, 1H) , 3.83(m, 1H) , 3.41(br , 1H) , 1.67(m, 2H) , 1.21(d, 3H) , 0.90(s, 9H) , 0.10(s, 6H) . 단계 2： (R)-4-(t-부틸다이메틸실릴옥시 )부탄 -2- 일메탄설포네이트의 제조 L H NMR (400 Hz, CDC1 3 ): δ 4.04 (m, 1Η), 3.91 (m, 1H), 3.83 (m, 1H), 3.41 (br, 1H), 1.67 (m, 2H), 1.21 (d , 3H), 0.90 (s, 9H), 0.10 (s, 6H). Step 2: Preparation of (R) -4- (t-butyldimethylsilyloxy) butane-2-ylmethanesulfonate
질소 대기하의 100 mL 플라스크에 상기 단계 1에서 제조된 화합물 (2 g) 및 다이클로로메탄 (DCM, 100 mL)을 주입하고 교반하여 용해시킨 다음， 트라이에틸아민 (TEA, 1.2 mL)을 적가하고 메탄설포닐 클로라이드 (0.6 mL)를 0°C에서 천천히 적가하였다. 적가가 완료되고 30분 동안 교반하고 다이클로로메탄 (DCM, 40 mL)으로 추출한 다음 소금물 (100 mL)로 세척하였다. 세척된 반응물을 무수 황산마그네슘으로 건조하고 농축하여 목적화합물을 얻었다. Into a 100 mL flask under nitrogen atmosphere, the compound (2 g) prepared in step 1 and dichloromethane (DCM, 100 mL) were added and stirred to dissolve, followed by dropwise addition of triethylamine (TEA, 1.2 mL) and methane. Sulfonyl chloride (0.6 mL) was slowly added dropwise at 0 ° C. The enemy is finished Stir for 30 minutes, extract with dichloromethane (DCM, 40 mL) and wash with brine (100 mL). The washed reaction product was dried over anhydrous magnesium sulfate and concentrated to obtain the target compound.
XH NMR (400 Hz, CDC13)： 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) . 단계 3: (S)-3-(4-(3-이소프로필 -l,2.4-옥사다이아졸-5- 일)피페라진-l-일)부탄-l-올의 제조 X H NMR (400 Hz, CDC1 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: Preparation of (S) -3- (4- (3-isopropyl-l, 2.4-oxadiazol-5-yl) piperazin-l-yl) butan-l-ol
질소 대기하의 100 mL 플라스크에 상기 단계 2에서 제조된 화합물 (1.4 g) 및 다이메틸포름아마이드 (DMF, 40 mL)을 주입하고 교반하여 용해시킨 다음, 순차적으로 상기 제조예 25에서 제조된 화합물 (1.3 g) 및 포타슘카보네이트 (1 g)를 첨가하고 50°C로 등온하여 24시간 동안 교반하였다. 반웅이 종결되면 온도를 상온으로 냉각시키고 증류수 (30 mL)를 천천히 가한 후 에틸아세테이트 (EA, 100 mL)로 추출한하였다. 추출된 유기층을 증류수 (20 mL)로 3회 세척한 다음, 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하여 목적화합물을 얻었다. Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Step 2 (1.4 g) and dimethylformamide (DMF, 40 mL) were injected and stirred to dissolve, followed by the compound prepared in Preparation Example 25 (1.3 g) and potassium carbonate (1 g) were added and isothermalized at 50 ° C. and stirred for 24 h. When the reaction was finished, the temperature was cooled to room temperature, distilled water (30 mL) was added slowly, and 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, concentrated and purified by silica column chromatography to obtain the target compound.
LH NMR (400 Hz, CDC13)： δ 3.70(m, 2Η) , 3.61(m, 4Η) , 2.87(ra, 2Η) , 2.65(m, 2Η) , 2.53(m, 2Η) , 1.77(m, 1Η) , 1.48(m, 1H) , 1.30(d, 3H), l.OO d, 3H), 0.98(s, 9H) , 0.07(s, 6H) . 단계 4: (S)-3-(4-(3-이소프로필 -l,2，4-옥사다이아졸-5- 일)피페라진-l-일)부틸 메탄설포네이트의 제조 L H NMR (400 Hz, CDC1 3 ): δ 3.70 (m, 2Η), 3.61 (m, 4Η), 2.87 (ra, 2Η), 2.65 (m, 2Η), 2.53 (m, 2Η), 1.77 (m , 1Η), 1.48 (m, 1H), 1.30 (d, 3H), l.OO d, 3H), 0.98 (s, 9H), 0.07 (s, 6H). Step 4: Preparation of (S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butyl methanesulfonate
질소 대기하의 100 ml 플라스크에 상기 단계 3에서 제조된 화합물 (2 g) 및 다이클로로메탄 (DCM, 100 mL)을 주입하고 교반하여 용해시켰다. 그 후， 트라이에틸아민 (TEA, 1.2 mL)을 적가하고 메탄설포닐 클로라이드 (0.6 mL)를 0°C에서 천천히 적가한다. 적가가 완료되면 30분 동안 교반하고， 다이클로로메탄 (DCM, 40 ml)으로 추출한 다음 소금물 (100 mL)로 세척하였다. 세척된 반응물을 무수 황산마그네슘으로 건조하고 농축한 후 목적화합물을 얻었다. Into a 100 ml flask under nitrogen atmosphere, the compound (2 g) prepared in step 3 and dichloromethane (DCM, 100 mL) were injected and stirred to dissolve. Triethylamine (TEA, 1.2 mL) is then added dropwise and methanesulfonyl chloride (0.6 mL) is slowly added dropwise at 0 ° C. After the addition was completed, the mixture was stirred for 30 minutes, extracted with dichloromethane (DCM, 40 ml), and washed with brine (100 mL). The washed reaction product was dried over anhydrous magnesium sulfate and concentrated to obtain the target compound.
!H 廳 R (400 Hz, CDCI3): 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, 1H), 3.24(m, 1H) , 2.90(m, 1H) , 2.74(s, 3H) , 2.58(m, 1H) , 1.65(d, 3H) , 1.27(d, 6H) . 단계 5: 에틸 4-(00—3-(4-(3-이소프로필-1,2,4-옥사다이아졸- 5-일 )피페라진— 1-일 )부톡시 )-2-플루오로벤조에이트 옥살산염의 제조 질소 대기하의 100 mL 플라스크에 상기 단계 4에서 제조된 화합물 (600 mg) , 포타슘카보네이트 (360 mg) 및 다이메틸포름아마이드 (DMF, 30 mL)를 넣고 교반하여 용해시킨 다음 , 제조예 19에서 제조된 화합물 (350 mg)을 첨가하고 은도를 70°C로 등온하여 교반하였다. 교반이 종결되면 상온으로 냉각시키고， 증류수 (20 ml)를 천천히 가한 후 에틸아세테이트 (EA, 60 mL)로 추출하였다. 추출된 유기층올 소금물 (40 mL)로 세척한 다음, 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 이후 에틸아세테이트 (EA, 10 mL)를 첨가하고 교반하여 용해시킨 뒤， 같은 당량수의 옥살산을 첨가하여 30분간 환류교반하였다. 반응이 완료되면 은도를 상온으로 냉각시키고， 고체를 여과하여 목적화합물을 얻었다. ! H 廳 R (400 Hz, CDCI 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, 1H), 3.24 (m, 1H), 2.90 (m, 1H), 2.74 (s, 3H), 2.58 (m, 1H), 1.65 (d, 3H), 1.27 (d, 6H). Step 5: ethyl 4- (00—3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin— 1-yl) butoxy) -2-fluorobenzo Preparation of ate oxalate In a 100 mL flask under nitrogen atmosphere, the compound (600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) prepared in step 4 were added thereto, stirred, and dissolved. Compound (350 mg) prepared in 19 was added and silver was isothermally stirred to 70 ° C. When stirring is finished, cool to room temperature, Distilled water (20 ml) was added slowly 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. After ethyl acetate (EA, 10 mL) was added and stirred to dissolve, and the same equivalent number of oxalic acid was added and stirred under reflux for 30 minutes. When the reaction was completed, the silver was cooled to room temperature, and the solid was filtered to obtain the target compound.
XE NMR (400 Hz, D20): δ 7.84(lH,t), 6.78(2H,t), 4.26(2H,q) , X E NMR (400 Hz, D 2 0): δ 7.84 (lH, t), 6.78 (2H, t), 4.26 (2H, q),
4.22(2H,m) , 4.11(2H,m), 3.70(lH,m) , 3.48(4H,m), 3.30(2H,m) ,4.22 (2H, m), 4.11 (2H, m), 3.70 (lH, m), 3.48 (4H, m), 3.30 (2H, m),
2.84(lH,m), 2.31(lH,m) , 2.04(lH,m) , 1.35(3H,d) , 1.25(3H,t), 1.16(6H,d). 2.84 (lH, m), 2.31 (lH, m), 2.04 (lH, m), 1.35 (3H, d), 1.25 (3H, t), 1.16 (6H, d).
<실시예 74> 4-((R)-3-(4-(3-이소프로필-: ,2, 4-옥사다이아졸 -5- 일)피페라진 -l- 일 )부톡시 )-2-플루오로벤조에이트 리톱염의 제조 Example 74 4-((R) -3- (4- (3-isopropyl-:, 2,4-oxadiazol-5-yl) piperazin-l-yl) butoxy) -2- Preparation of Fluorobenzoate Litop Salt
Figure imgf000082_0001
Figure imgf000082_0001
질소 대기하의 100 mL 플라스크에 상기 실시예 73에서 제조된 화합물 (200 mg), 테트라하이드로퓨란 (40 mL) 및 증류수 (20 mL)를 주입하고 교반하여 용해시켰다. 그 후， 상기 반웅물에 리튬하이드- ·사이드 1수화물 (170 mg)을 첨가하고 상은에서 18시간 동안 교반하였다. 반웅이 종결되면 용매를 농축한 후 다이클로로메탄 (DCM, 50 mL)에 용해시키고 용해되지 않는 고체를 여과하였다. 여과된 여액을 농축하고 다이에틸에테르 및 핵산을 이용하여 고체화하여 목적화합물을 얻었다.  Into a 100 mL flask under a nitrogen atmosphere, the compound (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) prepared in Example 73 were injected and stirred to dissolve. Then, lithiumhydride-side monohydrate (170 mg) was added to the reaction product and stirred for 18 hours at phase silver. At the end of reaction, the solvent was concentrated and then dissolved in dichloromethane (DCM, 50 mL) and the insoluble solid was filtered off. The filtrate was concentrated and solidified with diethyl ether and nucleic acid to obtain the target compound.
:Η 丽 R (400 Hz， D20)： δ 7.50(lH,t) ， 6.68(2H,m) 4.03(2H,m) : Η 丽 R (400 Hz, D 2 0): δ 7.50 (lH, t), 6.68 (2H, m) 4.03 (2H, m)
3.50(4H, t) , 2.76(2H,m) , 2.60(4H,q) 2.03(lH,m), 1.79(3H,s) 1.63(lH,m) , l.ll(6H,d) , 1.01(3H,d) . 3.50 (4H, t), 2.76 (2H, m), 2.60 (4H, q) 2.03 (lH, m), 1.79 (3H, s) 1.63 (lH, m), l.ll (6H, d), 1.01 (3H, d).
<실시예 75> 4-((R)-3-(4-(3-이소프로필 -l,2,4-옥사다이아졸ᅳ5- 일)피페라진-l-일)부톡시 )-2-플루오로 -N-((R)-2,3- 다이하이드록시프로필)벤즈아마이드 옥살산염의 제조 Example 75 4-((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol ᅳ 5-yl) piperazin-1-yl) butoxy) -2- Preparation of Fluoro-N-((R) -2,3-dihydroxypropyl) benzamide oxalate
Figure imgf000082_0002
Figure imgf000082_0002
질소 대기하의 100 mL 플라스크에 상기 실시예 60에서 제조된 화합물 (600 mg) 및 다이클로로메탄 (DCM, 50 mL)을 주입하고 교반하여 용해시키고， 1-에틸 -3-(3-다이메틸아미노프로필 )카르보다이이미드 염산염 (EDCI, 420 mg) 및 1-하이드록시벤조트리아졸 1수화물 (KOBt, 290 mg)을 첨가하고 30분 동안 교반하였다. 그 후， (R)-3-아미노— 1,2- 프로판을 (200 mg)을 첨가하고 상은에서 5시간 동안 교반하였다. 반응이 종결되면 증류수 (20 mL)를 천천히 가하고 에틸아세테이트 (EA, 60 mL)로 추출한 다음 소금물 (40 mL)로 세척하였다. 세척된 유기층을 무수 황산마그네슘으로 건조하고 농축한 후 실리카 컬럼크로마토그래피로 정제하였다. 정제된 화합물을 에틸아세테이트 (EA, 10 mL)를 가하고 교반하여 용해시킨 다음， 갈은 당량수의 옥살산을 적가하고 30분 동안 환류교반하였다. 반응이 완료되면 온도를 상온으로 넁각시키고 고체를 여과하여 목적화합물을 얻었다. Prepared in Example 60 above in a 100 mL flask under nitrogen atmosphere Compound (600 mg) and dichloromethane (DCM, 50 mL) were injected and stirred to dissolve, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 420 mg) and 1 -Hydroxybenzotriazole monohydrate (KOBt, 290 mg) was added and stirred for 30 minutes. Then (R) -3-amino- 1,2-propane was added (200 mg) and stirred for 5 hours at phase silver. 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. Ethyl acetate (EA, 10 mL) was added to the purified compound, followed by stirring to dissolve it. Then, an equivalent amount of oxalic acid was added dropwise and stirred under reflux for 30 minutes. When the reaction was completed, the temperature was changed to room temperature and the solid was filtered to obtain the target compound.
JH NMR (400 Hz, D20): δ 7.60(lH,t) , 6.87(2H,t), 4.21(2H,m) , 4.11(2H,m) , 3.85(lH,m) , 3.70(2H,m) , 3.51(8H,m) , 3.33(2H,m), 2.82(lH,m) , 2.32(lH,m) , 2.05(lH,m) , 1.35(3H,d) , 1.14(6H,d) . J H NMR (400 Hz, D 2 0): δ 7.60 (lH, t), 6.87 (2H, t), 4.21 (2H, m), 4.11 (2H, m), 3.85 (lH, m), 3.70 ( 2H, m), 3.51 (8H, m), 3.33 (2H, m), 2.82 (lH, m), 2.32 (lH, m), 2.05 (lH, m), 1.35 (3H, d), 1.14 (6H , d).
<실시예 76> 에틸 4-((S)-3-(4-(3-이소프로필 -1,2,4- 옥사다이아졸 -5-일 )피페라진- -일)부톡시 )-2-플루오로벤조에이트의 제조 Example 76 Ethyl 4-((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin--yl) butoxy) -2- Preparation of Fluorobenzoate
Figure imgf000083_0001
Figure imgf000083_0001
상기 실시예 73에서 (R)-(-)-l,3-부탄다이을을 사용하는 대신에 (S)-( + )-l,3-부탄다이올을 사용하는 것을 제외하고 상기 실시예 73과 동일한 방법으로 수행하여 목적화합물을 얻었다.  Example 73 except that (S)-(+) -l, 3-butanediol was used instead of (R)-(-)-l, 3-butanedi in Example 73. The target compound was obtained by the same method.
:H NMR (400 Hz, D20)： δ 7.90(1Η, t) , 6.67(2H,dd) , 4.37(2H,q) 4.17(2H,m), 4.09(lH,m) , 3.63(4H,m) , 2.90(2H,m), 2.70(2H,m) , 2.52(2H,m), 1.99(lH,m) , 1.68(lH,m) , 1.40(3H,t), 2.05(lH,m) , 1.28(6H,d) , 1.08(3H,d) . : H NMR (400 Hz, D 2 0): δ 7.90 (1Η, t), 6.67 (2H, dd), 4.37 (2H, q) 4.17 (2H, m), 4.09 (lH, m), 3.63 (4H , m), 2.90 (2H, m), 2.70 (2H, m), 2.52 (2H, m), 1.99 (lH, m), 1.68 (lH, m), 1.40 (3H, t), 2.05 (lH, m), 1.28 (6H, d), 1.08 (3H, d).
<실시예 77> 4-((S)-3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진-l-일)부톡시)-2-풀루오로벤조에이트 리튬염의 제조 Example 77 4-((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2- Preparation of Pluorobenzoate Lithium Salt
Figure imgf000083_0002
상기 실시예 74에서 실시예 73에서 제조된 화합물을 사용하는 대신에 실시예 72에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 74와 동일한 방법으로 수행하여 목적화합물을 얻었다.
Figure imgf000083_0002
Example 74 was carried out 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, to obtain the target compound.
^ NMR (400 Hz, D20) ： δ 7.50(lH,t) , 6.68(2H,m) , 4.03(2H,m) 3.50C4H, t) , 2.76(2H,m) , 2.60(4H,q) , 2.03(lH,m) , 1.79(3H,s) , 1.63(lH.m) , l.ll(6H,d), 1.01(3H,d) . ^ NMR (400 Hz, D 2 0): δ 7.50 (lH, t), 6.68 (2H, m), 4.03 (2H, m) 3.50C4H, t), 2.76 (2H, m), 2.60 (4H, q ), 2.03 (lH, m), 1.79 (3H, s), 1.63 (lH.m), l.ll (6H, d), 1.01 (3H, d).
<실시예 78> 4-((S)-3-(4-(3-이소프로필 -l,2，4-옥사다이아졸-5- 일)피페라진-l-일)부톡시 )-2-플루오로 -N-((R)-2,3- 다이하이드톡시프로필)벤즈아마이드 옥살산염의 제조 Example 78 4-((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2- Preparation of Fluoro-N-((R) -2,3-dihydroxypropyl) benzamide oxalate
Figure imgf000084_0001
Figure imgf000084_0001
상기 실시예 75에서 실시예 74에서 제조된 화합물을 사용하는 대신에 실시예 77에서 제조된 화합물을 사용하는 것을 제외하고 상기 실시예 75와 동일한 방법으로 수행하여 목적화합물을 얻었다.  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.
:H NMR (400 Hz, D20)： δ 8.05(lH,s) , 7.08(lH,ra) , 6.68(2H,dd) 4.17(2H,m) , 4.10(lH,m) , 3.61(4H,m) , 3.04(lH,m) , 2.94(lH,m) , 2.88(2H,m) , 2.68(2H,m) , 2.55(2H,m) , 2.00(lH,m) , 1.81(lH,m) , 1.29(6H,d) , 1.05(3H,d) . : H NMR (400 Hz, D 2 0): δ 8.05 (lH, s), 7.08 (lH, ra), 6.68 (2H, dd) 4.17 (2H, m), 4.10 (lH, m), 3.61 (4H , m), 3.04 (lH, m), 2.94 (lH, m), 2.88 (2H, m), 2.68 (2H, m), 2.55 (2H, m), 2.00 (lH, m), 1.81 (lH, m), 1.29 (6H, d), 1.05 (3H, d).
<실험예 1> 본 발명에 따른 화합물의 cAMP 활성 평가 Experimental Example 1 Evaluation of cAMP Activity of Compounds According to the Present Invention
본 발명에 따른 신규한 피페라진 유도체들의 cAMP 활성화를 확인하기 위하여 하기와 같은 실험을 수행하였다. 먼저 GPR119의 자극으로 인한 세포 내 cAMP 활성화를 축정하기 위하여， GPR-119를 함유하고 있는 햄스터에서 유래된 베타세포인 HIT- T15 세포 (한국세포주은행)를 사용하였다. 96-웰 플레이트에 웰 당 60 ,000개의 HIT-T15 세포를 플레이팅하였다. 플레이팅한 다음날, 세포를 다양한 농도의 본 발명에 따른 화합물을 처리하고 1시간 동안 37°C에서 배양하였다. 이때， 처리되는 화합물은 0.0032 내지 10 μΜ 범위에서 6 농도로 처리하였다. cAMP 활성은 Cis Bio(Bedford, MA)로부터의 cAMP 다이나믹 키트를 사용하여 제조자의 지시에 따라 측정하였다. 세포를 용해하고 D2 표지된 cAMP 및 크립테이트 표지된 항 cAMP 항체를 사용하여 경쟁적 면역분석법에 의해 cAMP 수준을 측정하였다. 형광은 플렉스 스테이션 (Flex Station, Molecular Devices)으로 판독하였다. D2와 크립테이트는 매우 근접했을 때 형광공명에너지전이 (FRET)를 나타냈으며， 665 nm/620 nm의 형광비로 측정하였다. 세포 용해물 내의 미표지된 c P는 크립테이트 표지된 항체에 대하여 D2 표지된 cAMP와 경쟁하였다. In order to confirm cAMP activation of the novel piperazine derivatives according to the present invention, the following experiment was performed. First, HIT-T15 cells (Korea Cell Line Bank), which are beta cells derived from hamsters containing GPR-119, were used to accumulate intracellular cAMP activation due to stimulation of GPR119. 60,000 HIT-T15 cells were plated per well in 96-well plates. The day after plating, cells were treated with various concentrations of the compounds according to the invention and incubated at 37 ° C. for 1 hour. At this time, the compound to be treated was treated at a concentration of 6 in the range of 0.0032 to 10 μΜ. cAMP activity was measured using the 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 Flex Station (Molecular Devices). D2 and cryptate showed fluorescence resonance energy transfer (FRET) when very close, and were measured at a fluorescence ratio of 665 nm / 620 nm. Unlabeled c P in cell lysate was cryptate labeled The antibody competed with D2 labeled cAMP.
형광공명에너지전이 (FRET) 신호감소는 세포 내 cAMP Fluorescence Resonance Energy Transition (FRET) Signal Decrease in intracellular cAMP
나타내므로， 화합물의 활성을 다이메틸설폭사이드 (DMS0)의 양 통한 형광공명에너지전이 (FRET) 신호변화 정도로 계산하였다. As shown, the activity of the compound was calculated to the extent of fluorescence resonance energy transfer (FRET) signal change through the amount of dimethyl sulfoxide (DMS0).
EC50값올 표 2에 나타내었다. EC 50 values are shown in Table 2.
【표 2】  Table 2
수조측계 산준절정 된을된에
Figure imgf000085_0001
Countertop measurement
Figure imgf000085_0001
표 2에 나타낸 바와 같이 , 본 발명에 따론 화합물들은 cAMP를 활성화하는 것으로 나타났다 . cAMP를 활성화 I 평가한 74개의 화합물 중 절반이 넘는 약 55 >의 화합물들은 2 μ Μ 이하의 EC50값을 갖는 것으로 나타났으며， 특히 실시예 1， 4， 6， 8， 12, 15, 17, 18, 20, 22-24, 27, 28, 31 33-35, 41, 50, 53-55, 57， 58, 73 및 75의 화합물들은 1 μ Μ 이하의 나노몰 단위 EC50값을 가지는 것으로 나타났다. 이로부터 본 발명에 따른 피페라진 유도체는 GPR119 수용체 로써 , cAMP를 활성화하는 효과가 우수한 것을 알 수 있다. 따라서， 본 발명에 따른 L한 피페라진 유도체는 cAMP를 활성화시키는 효과가 우수하 J GPR119를 활성화시킴으로써 치료가능한 비만， I 형 당뇨병 형 당뇨병， 부적합한 내당력， 인슐린 내성， 고혈당증， 고지질혈증， 고중성지방혈증， 고콜레스테를혈증, 이상지질혈증 또는 X 증후군의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다. <실험예 2> GPR119 수용체를 과발현시킨 CH0-K1 세포에서의 cAMP 활성 평가 As shown in Table 2, the compounds according to the invention were shown to activate cAMP. Of the 74 compounds evaluated for activating cAMP, more than half of the compounds of about 55> were found to have EC 50 values of 2 μM or less, particularly in 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 have EC 50 values in nanomolar units of 1 μΜ or less appear. From this, piperazine derivatives according to the present invention as a GPR119 receptor, it can be seen that the effect of activating cAMP is excellent. Therefore, the L- piperazin derivative according to the present invention is excellent in activating cAMP and can be treated by activating J GPR119, obesity, type I diabetes mellitus, inadequate glucose tolerance, It can be usefully used as a pharmaceutical composition for the prevention or treatment of insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X. Experimental Example 2 Evaluation of cAMP Activity in CH0-K1 Cells Overexpressing GPR119 Receptor
본 발명에 따론 신규한 피페라진 유도체가 GPR119를 활성화하여 cAMP를 촉진시키는 것을 확인하기 위하여 하기와 같은 실험을 수행하였다.  In order to confirm that the novel piperazine derivative according to the present invention promotes cAMP by activating GPR119, the following experiment was performed.
CH0 세포를 96-웰 플레이트에 100 μ L의 10% FBS , 100 ug/ml 페니실린 (penici 1 Πη) 및 100 μ g/ml 스트랩토마이신 (streptomycin)을 포함하고 있는 RPMI (Wel lgene)배지로 2xl04 개의 세포 /웰로 플레이팅 하였다. 그런 다음, pCMV6-XL5 백터에 인간의 GPRU9를 발현하고 있는 플라스미드 (Origene, C216685) 및 마우스의 GPR119를 발현하고 있는 플라스미드 (Origene, MR224908)를 FuGENE6 시약 (Promega, E2311)을 사용하여 상기 CH0 세포에 형질감염시켰다. 형질감염시킨 지 48시간 후에 세포는 5 mM HEPES(Gibco, 15630-106) , 0.5 mM IBMX(sigma, 15879) 및 0.1% BSA(sigma, A7030)가 포함된 HBSS Hanks buffered salt solut ion, welgene, LB 003-03)로 배지를 바꿔주어 10분 동안 C02 배양기에서 배양하였다. HBSS 배지에 본 발명에 따른 화합물을 다양한 농도의 범위 (10, 2, 0.4， 0.08, 0.16, 0.0032 μ Μ)로 희석하여 세포에 처리하고 90분 동안 37°C， C02 배양기에서 배양하였다. cAMP 즉정은 HTRF( Homogeneous Time-Resolved Fluorescence, CISBI0 , 62AM4PEB)기법 중 Two step protoc 을 이용하여 측정되었다. 세포에 cAMP-d2 와 항 -cAMP 크립테이트 혼성 (cryptate conjugate)을 흔합하여 3시간 동안 상은에서 반웅시킨 후 플렉스테이션 (Flexstat ion, Molecular Devices)을 이용하여 형광값 ( f hiorescence , 여기파장: 337 nm, 방출파장: 665 nm , 620 nm)을 측정하였다. 그 결과는 δ F( ) 값을 산출하여 활성화되지 않은 군을 대조군으로 하여， 본 발명에 따른 화합물올 처리하여 활성화된 정도 (%)를 이용하여 EC50( y M)값으로 환산하였으며， 하기 표 3에 나타내었다. CH0 cells were plated in 96-well plates with RPMI (Wel lgene) medium containing 100 μL of 10% FBS, 100 ug / ml penicillin (penici 1 Πη), and 100 μg / ml streptomycin. Plated at 4 cells / well. Then, the plasmid expressing human GPRU9 in pCMV6-XL5 vector (Origene, C216685) and the plasmid expressing GPR119 in mouse (Origene, MR224908) were transferred to the CH0 cells using FuGENE6 reagent (Promega, E2311). Transfection. 48 hours after transfection, cells were HBSS Hanks buffered salt solut ion, welgene, LB containing 5 mM HEPES (Gibco, 15630-106), 0.5 mM IBMX (sigma, 15879) and 0.1% BSA (sigma, A7030). 003-03) was incubated in a C0 2 incubator for 10 minutes. Compounds according to the invention in HBSS medium were diluted to various concentration ranges (10, 2, 0.4, 0.08, 0.16, 0.0032 μΜ), treated to cells and incubated in a 37 ° C., CO 2 incubator for 90 minutes. Instant cAMP was measured using two step protoc in HTRF (Homogeneous Time-Resolved Fluorescence, CISBI0, 62AM4PEB) technique. The cAMP-d2 and anti-cAMP cryptate conjugates were mixed in the cells and reacted in the silver for 3 hours, followed by fluorescence (f hiorescence, excitation wavelength: 337 nm) using flexation (Flexstat ion, Molecular Devices). , Emission wavelength: 665 nm, 620 nm). The result was calculated as δ F () value as the control group was not activated, converted to EC 50 (y M) value using the degree of activation (%) by treatment with the compoundol according to the present invention, 3 is shown.
【표 3】  Table 3
Figure imgf000086_0001
Figure imgf000086_0001
상기 표 3에 나타낸 바와 같이， 본 발명에 따른 피페라진 유도체는 인간 및 마우스의 GPR119가 과발현된 세포주 모두에서 cAMP를 활성화시키는 효과가 있는 것으로 나타났다. 또한， 실시예 55의 구조이성질체인 실시예 75의 화합물 (R-형태)은 나노몰 단위와 EC50값을 갖는 것으로 나타난 반면에， 실시예 78의 화합물 (S-형태)은 2 y M 내지 4 μ Μ의 EC50값올 갖는 것으로 나타났다 . 이로부터， 본 발명에 따른 피페라진 유도체는 인간 및 마우스의 GPR119을 촉진시키는 효과가 우수한 것을 알 수 있으며， 이로 인한 cAMP 촉진 효과도 뛰어난 것을 알 수 있다. 또한， 본 발명에 따라 제조된 라세메이트 (racemate)인 실시예 55의 화합물과 이의 구조이성질체들인 실시예 75(R-형태) 및 실시예 78(S-형태)의 화합물들의 EC50값을 통하여 S-형태의 구조이성질체에 비하여 R-형태의 구조이성질체가 cAMP를 활성화시키는 효과가 더 우수한 것을 알 수 있다. 따라서， 본 발명에 따른 신규한 피페라진 유도체는 GPR119를 촉진시킴으로써 cAMP를 활성화시키는 효과가 우수하므로， GPR119를 활성화시킴으로써 치료가능한 비만， I 형 당뇨병 , Π형 당뇨병， 부적합한 내당력， 인슐린 내성， 고혈당증， 고지질혈증， 고증성지방혈증， 고콜레스테를혈증， 이상지질혈증 또는 X 증후군의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다. <실험예 3> 경구 당 부하 검사 (Oral Glucose Tolerance Test；As shown in Table 3, the piperazine derivatives according to the present invention are used in both human and mouse GPR119 overexpressed cell lines. It has been shown to have an effect of activating cAMP. In addition, the compound of Example 75 (R-form), which is the structural isomer of Example 55, was shown to have an EC 50 value with nanomolar units, whereas the compound (S-form) of Example 78 was from 2 y M to 4 It was found to have an EC 50 value of μ Μ. From this, it can be seen that the piperazine derivatives according to the present invention have an excellent effect of promoting GPR119 in humans and mice, and thus the cAMP promoting effect is excellent. In addition, the compound of Example 55, which is a racemate prepared according to the present invention, and the structural isomers thereof, through the EC 50 value of the compounds of Examples 75 (R-form) and Example 78 (S-form) It can be seen that the R-form structural isomer has a better effect of activating cAMP than the -form structural isomer. Therefore, the novel piperazine derivatives according to the present invention have an excellent effect of activating cAMP by promoting GPR119, and thus, obesity, type I diabetes, type II diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, It can be usefully used as a pharmaceutical composition for the prevention or treatment of hyperlipidemia, hyperlipidemia, hypercholesterolemia, dyslipidemia or syndrome X. Experimental Example 3 Oral Glucose Tolerance Test (Oral Glucose Tolerance Test;
OGTT) OGTT)
본 발명에 따른 신규한 피페라진 유도체들의 생체 내의 유효효과를 평가하기 위하여 하기와 같은 실험을 수행하였다. 먼저， 8 내지 10 주령의 수컷 C57BL/6J 쥐를 이용하여 최소 In order to evaluate the effective effect of the novel piperazine derivatives according to the present invention in vivo, the following experiment was performed. First, a minimum of 8 to 10 weeks old male C57BL / 6J rats was used.
7일간의 순화기간을 가진 후에 건강한 개체만을 이용하여 경구 당 부하 검사를 수행하였다. 12-15시간 동안 절식시킨 후에 각 군당 5마리씩 무작위로 군 분리하고， 본 발명에 따른 실시예 33， 50， 55, 70 및 실시예 77에서 제조된 화합물을 각각 20 mg/kg 용량으로 투여하였다. 이때， 무처리군으로 부형제 (0.5¾>， CarboxyMethyl Celluluse, CMC)를 투여하였으며 , 부형제와 상기에서 투여된 화합물은 10 mL/kg으로 경구 투여하였다. 또한， 양성 대조군으로 종래에 GPR119 활성화제로 공지된 비교예 KB111, 국제공개공보 제 2004065380호)， 비교예 2(실시예 52의 화합물， 국채공개공보 제 2008083238호) 및 비교예 3(실시예 3， 국제공개공보 제 2008081206호)으로 사용하였다. 그런 다음， 투여하고 30분 후에 글루코스 (2 g/kg)를 10 mL/kg의 용량으로 경구 투여하였다. 혈당은 아큐책 액티브 (Rosche diagnostic Co.)를 이용하여 측정하였으며， 측정시간은 글루코스를 투여한 시간을 기준으로 -30， 0， 20， 40, 60 및 120분에 미정맥을 천자하여 측정하였다. 그 결과를 하기 표 4에 나타내었다 . After 7 days of acclimation, the oral glucose tolerance test was performed using only healthy subjects. After fasting for 12-15 hours, five mice per group were randomly grouped, and the compounds prepared in Examples 33, 50, 55, 70 and 77 according to the present invention were administered at 20 mg / kg doses, respectively. At this time, an excipient (0.5¾>, CarboxyMethyl Celluluse, CMC) was administered as an untreated group, and the excipient and the compound administered above were orally administered at 10 mL / kg. In addition, Comparative Example KB111, International Publication No. 2004065380, Comparative Example 2 (Compound No. 52, National Treasure 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 Accusek Active Co., Ltd. (Rosche diagnostic Co.) and measurement time was measured by puncture of the microvenous veins at -30, 0, 20, 40, 60 and 120 minutes based on the time of glucose administration. The results are shown in Table 4 below.
【표 4】
Figure imgf000087_0001
Figure imgf000088_0001
Table 4
Figure imgf000087_0001
Figure imgf000088_0001
표 4에 나타낸 바와 같이， 본 발명에 따른 화합물들은 약 16 내지 23%의 AUC(area under curve) 강하효과가 있는 것으로 나타났다. 반면 , 종래에 GPR119의 활성화제로 알려져 있는 비교예 1 내지 비교예 3의 화합물은 본 발명에 따른 화합물에 비하여 AUC(area under curve) 강화효과가 16% 이하인 것으로 나타났다. 이로부터 , 본 발명에 따른 피페라진 유도체들은 종래의 GPR119의 활성화제로 알려져 있는 화합물들에 비하여 AUC(area under curve) 강하효과가 상당히 우수하다는 것을 알 수 있다. 따라서， 본 발명에 따른 신규한 피페라진 유도체는 GPR119를 촉진시킴으로써 cAMP를 활성화시키는 효과가 우수하므로 , GPR119를 활성화시킴으로써 치료가능한 비만， I 형 당뇨병， Π형 당뇨병， 부적합한 내당력 , 인슐린 내성， 고혈당증， 고지질혈증, 고중성지방혈증， 고콜레스테를혈증， 이상지질혈증 또는 X 증후군의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다.  As shown in Table 4, the compounds according to the present invention were found to have an AUC (area under curve) drop effect of about 16 to 23%. On the other hand, the compounds of Comparative Examples 1 to 3, which are conventionally known as an activator of GPR119, were found to have an AUC (area under curve) strengthening effect of 16% or less compared to the compound according to the present invention. From this, it can be seen that the piperazine derivatives according to the present invention have considerably superior AUC (area under curve) lowering effects compared to the compounds known as activators of the conventional GPR119. Therefore, the novel piperazine derivatives according to the present invention have an excellent effect of activating cAMP by promoting GPR119. Thus, obesity, type I diabetes, type Π diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, It can be usefully used as a pharmaceutical composition for the prevention or treatment of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X.
<실험예 4> 용해도 평가 Experimental Example 4 Solubility Evaluation
본 발명에 따른 피페라진 유도체의 체내 흡수도를 평가하기 위하여 용해도를 측정하는 하기와 같은 실험을 수행하였다. 본 발명에 따른 실시예 75의 피페라진 유도체염， 실시예 75의 피페라진 유도체 , 비교예 1의 화합물 (Bill, 국제공개공보 제 2004065380호) 및 비교예 2의 화합물 (실시예 52의 화합물， 국제공개공보 제 2008083238호)을 증류수에 2 mg/mL 농도로 용해하여 약병에 옮기고， 약 1시간 동안 분해한 후， 약 24시간 동안 300 rpm으로 흔들어 섞었다. 그 후， 용해액을 10분 동안 25°C에서 10000 rpm으로 원심분리하고 상층액을 여과하여 약병에 옮겨 검사액을 제조한다. 2.5 mM의 농도로 검체액올 조제하고， 1/10배로 메틸알코올에 희석한 다음 순차적으로 1/2배씩 희석하여 5개의 농도가 다른 검량액을 제조하여 검량선을 확립하였다. 상기 검량액으로 고성능 액체크로마토그래피 (HPLC, 파장: 210 nM, 유속: 10 ml/min, 이동상 : 증류수 /메틸알코올 =30/70→40/60)를 이용하여 용해도를 측정하였으며， 그 결과를 하기 표 5에 나타내었다. In order to evaluate the absorbency of the piperazine derivatives according to the present invention, solubility was measured. Piperazine Derivative Salt of Example 75, Piperazine Derivative of Example 75, Compound of Comparative Example 1 (Bill, WO 2004065380) and Compound of Comparative Example 2 (Compound of Example 52, International 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 then 300 for about 24 hours. Shake at rpm and mix. Thereafter, the solution is centrifuged at 10000 rpm at 25 ° C for 10 minutes, the supernatant is filtered and transferred to the vial to prepare a test solution. A sample solution was prepared at a concentration of 2.5 mM, diluted in 1/10 times methyl alcohol, and then diluted 1/2 fold sequentially to prepare calibration solutions having five different 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), and the results were as follows. Table 5 shows.
【표 5]  [Table 5]
Figure imgf000089_0001
Figure imgf000089_0001
표 5에 나타낸 바와 같이 , 본 발명에 따른 실시예 75에서 제조된 피페라진 유도체의 용해도는 5267 μΜ로 나타났으며， 이의 약학적으로 허용가능한 염은 물에 대한 용해도가 25000 μ Μ 이상으로 나타났다. 반면， 종래에 GPR119 활성화제로 알려져 있는 비교예 1 및 비교예 2의 경우, 물에 대한 용해도가 현저히 낮은 것으로 나타났다. 이로부터 본 발명에 따른 피페라진 유도체는 종래에 GPR119 활성화제로 알려져 있는 화합물에 비하여 물에 대한 용해도가 최소 3000배 이상으로 현저히 우수한 것을 알 수 있다 . 따라서， 본 발명에 따른 신규한 피페라진 유도체는 GPR119를 활성화하여， c P를 촉진시키는 효과가 우수할 뿐만 아니라 종래에 GPR119 활성화제로 알려져 있는 화합물에 비하여 물에 대한 용해도가 현저히 우수하며， 이로 인한 체내 흡수율이 상당히 우수하므로， GPR119를 활성화시킴으로써 치료가능한 비만， I 형 당뇨병， Π형 당뇨병， 부적합한 내당력 , 인슐린 내성， 고혈당증， 고지질혈증， 고중성지방혈증， 고콜레스테를혈증, 이상지질혈증 또는 X 증후군의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다.  As shown in Table 5, the solubility of the piperazine derivative prepared in Example 75 according to the present invention was 5267 μΜ, and the pharmaceutically acceptable salt thereof was more than 25000 μΜ in water. On the other hand, in Comparative Examples 1 and 2, which are conventionally known as GPR119 activators, the solubility in water was markedly low. From this, it can be seen that the piperazine derivatives according to the present invention are remarkably superior in solubility in water to at least 3000 times compared to the compounds known in the art as GPR119 activators. Therefore, the novel piperazine derivatives according to the present invention not only have an excellent effect of activating GPR119 and promoting c P, but also have a superior solubility in water as compared to a compound known as a GPR119 activator. Absorption, type I diabetes, type Π diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, or X, which can be treated by activating GPR119 due to its excellent absorption rate. It can be usefully used as a pharmaceutical composition for the prevention or treatment of syndrome.
<실험예 5> 심장독성 평가 Experimental Example 5 Cardiotoxicity Evaluation
본 발명에 따른 신규한 피페라진 유도체의 심장 독성을 평가하기 위하여 심장 독성과 부정맥의 중요한 지표인 HERG채널을 화합물이 억제 여부를 확인하는 하기와 같은 실험을 수행하였다. 세포배양  In order to evaluate the cardiac toxicity of the novel piperazine derivatives according to the present invention, the following experiment was performed to determine whether the compound inhibits the HERG channel, which is an important indicator of cardiac toxicity and arrhythmia. Cell culture
먼저， HERG 채널의 발현이 안정적으로 유지되는 HEK293(human embryonic kidney 293) 세포를 이용하고 양성 대조물질인 아스테미졸 (astemizole)로 HERG채널의 억제 정도를 확인하였다.  First, HEK293 (human embryonic kidney 293) cells in which the expression of the HERG channel was stably maintained, and the inhibition level of the HERG channel were confirmed by the positive control group, astemizole.
세포는 95% 산소와 5¾> 이산화탄소가 함유한 37° C 배양기 내에서 배양하였으며 , 이는 10% fetal bovine serum, 1 mM 소듐피루베이트， 0.1 mM 비- 필수 아미노산 용액 , 100 units/ml 페니실린-스트렙토마이신 (penici 11 in-streptomycin)， 100 μ g/ml 스트렙토마이신 설페이트 (streptomycin sulfate) 및 100 μ g/ml 제오신 ( zeoc i n)으로 조성된 최소필수배지 (minimum essential medium , MEM)로 배양하였다. 60-8M 정도 부착되면 부착된 세포를 3분 동안 0.25% 트립신 (trypsin) 및 0.02% EDTA가 함유된 배지로 처리하고 , 신선한 배지로 세척한 다음 새로운 플라스틱 배양 용기에 분주하였다. 전기생리학적 기록을 하는 동안 세포는 24-웰 플레이트의 5 mm 지름 유리 커버 슬라이드 위에 5-24시간 부착시킨 후 기록 챔버에 옮겼다. Cells were incubated at 37 ° C with 95% oxygen and 5¾> carbon dioxide Cultured in 10% fetal bovine serum, 1 mM sodium pyruvate, 0.1 mM non-essential amino acid solution, 100 units / ml penicillin-streptomycin, 100 μg / ml streptomycin sulfate cultured with minimal essential medium (MEM) composed of streptomycin sulfate and 100 μg / ml zeocin. Once attached about 60-8M attached cells were treated with medium containing 0.25% trypsin and 0.02% EDTA for 3 minutes, washed with fresh medium and then dispensed into fresh plastic culture containers. During electrophysiological recording, cells were attached for 5 to 24 hours on a 5 mm diameter glass cover slide on a 24-well plate and then transferred to the recording chamber.
Whole eel 1 patch clamp (전체 -세포 패치 클램프)방법 Whole eel 1 patch clamp method
전체세포 전류를 측정하는 방법은 convent ial patch-clamp 기술 또는 Port-a-Patch (Nanion germany) 반수동 기술이 있으며 이는 세포막을 통한 미세전류를 측정방법이다. 상기 실험에서 사용한 세포 외부 관류용액과 세포 내부 관류용액의 조성은 하기와 같다. 세포 외부 관류 용액은 136 mM 염화나트륨 (NaCl), 5.4 mM 염화칼륨 (KCl), 1.8 mM 염화칼슘 (CaCl2), 1 mM 염화마그네슘 (MgCl2)， 10 mM 글루코스 및 10 mM HEPES로 조성한 다음， 수산화나트륨으로 산도 7.4로 적정하였다. 세포 내부 관류 파이펫 용액은 130 mM 염화칼륨 (KCl), 1 mM 염화마그네슘 (MgCl2)， 10 mM EGTA, 5 mM 마그네슘 -ATP 및 10 mM HEPES로 조성한 다음 , 수산화칼륨으로 산도 7.2로 적정했다. The method of measuring the total cell current includes a convexial patch-clamp technique or a port-a-patch (Nanion germany) semi-passive technique, which measures the microcurrent through the cell membrane. The composition of the extracellular perfusion solution and the intracellular perfusion solution used in the experiment is as follows. The extracellular perfusion solution was formulated with 136 mM sodium chloride (NaCl), 5.4 mM potassium chloride (KCl), 1.8 mM calcium chloride (CaCl 2 ), 1 mM magnesium chloride (MgCl 2 ), 10 mM glucose and 10 mM HEPES and then with sodium hydroxide. Titrated to pH 7.4. The intracellular perfusion pipette solution was formulated with 130 mM potassium chloride (KCl), 1 mM magnesium chloride (MgCl 2 ), 10 mM EGTA, 5 mM magnesium-ATP and 10 mM HEPES, and titrated to pH 7.2 with potassium hydroxide.
conventional patch— clamp technique을 위한 패치 파이펫은 PP— 83 pipette puller (Nar ishige, Tokyo, Japan)로 당겼으며 외부 관류용액에 2-4 ΜΩ의 저항을 보였다. 이때 생기는 이온 전류는 EPC7 plus am l i f iers(HEKA electronic, Germany)로 기톡이 되었다. The pCl amp computer progr am(Axon Instruments, USA)는 전압一클램프 증폭 조절, 데이터 수집 , 분석에 이용하였고 용액은 챔버를 통해 HEK 293 cell에 계속적으로 관류시켰다. Port-a-Patch (Nanion, Germany) 반자동 패치 기록시스템의 기록은 Nan ion에 의해 추천된 과정에 따르며 증폭기는 EPC10 (HEKA electronic, Germany)이다.  Patch pipettes for conventional patch-clamp techniques were pulled with a PP-83 pipette puller (Nar ishige, Tokyo, Japan) and exhibited a resistance of 2-4 ΜΩ to external perfusion solutions. The resulting ion current was described in EPC7 plus am l f iers (HEKA electronic, Germany). The pCl amp computer progr am (Axon Instruments, USA) was used for voltage one-clamp amplification control, data collection, and analysis. The solution was continuously perfused through HEK 293 cells through the chamber. Port-a-Patch (Nanion, Germany) The recording of the semi-automatic patch recording system follows the procedure recommended by Nan ion and the amplifier is EPC10 (HEKA electronic, Germany).
Pulse protocols (필스 방법 ) Pulse protocols
막 전위는 -80 mV로 유지되었다. 이는 4초 동안 +20 mV로 이동하고 6초 동안 -50 mV로 이동된 후에 -80 mV로 되돌아왔다 . 이 과정이 25초 간격으로 반복되었다 .  The membrane potential was maintained at -80 mV. It moved to +20 mV for 4 seconds and back to -80 mV after moving to -50 mV for 6 seconds. This process was repeated every 25 seconds.
ICso 평가 분석 (50% 억제정도를 측정하는 방법 ) 약물의 농도 -반응 곡선을 얻기 위해서는 농도-의존적인 억제는 힐 방정식 (Hill equation)을 사용하였다. ICso Evaluation Analysis (Method for Measuring 50% Inhibition) To obtain the concentration-response curve of the drug, the concentration-dependent inhibition was used by the Hill equation.
【수학식 1】
Figure imgf000091_0001
[Equation 1]
Figure imgf000091_0001
drug ' 정점 꼬리 전류  drug '' vertex tail current
대물농수약  Agricultural pesticide
-^control · 없이 최대 꼬리 전류  -^ control, without maximum tail current
의물도  Water
D: 약물  D: medication
H: 힐 계  H: Hill system
IC50: 최 점 꼬리의 중간농도에서 억제되는 정도 상기 힐 방정식 (Hi 11 equation)에 의해 계산된 결과를 하기 나타내었다. IC 50 : Inhibition at Intermediate Concentration of Peak Tail The results calculated by the Hill 11 equation are shown below.
【표 6】  Table 6
Figure imgf000091_0002
Figure imgf000091_0002
표 6에 나타낸 바와 같이， 본 발명에 따른 실시예 55 및 실 75의 화합물은 IC50값이 약 38 내지 124 μ M로 나타난 반면에， 종 비교예 2 및 비교예 3의 화합물들은 약 17 y M 이하로 나타났다 . As shown in Table 6, compounds of Examples 55 and 75 according to the present invention showed IC 50 values of about 38 to 124 μM, while compounds of Species Comparative 2 and 3 were about 17 y M It appeared as below.
본 발명에 따른 화합물에 비하여 종래에 GPR119 활성화제로 알 비교예의 화합물들이 부정맥 등의 심장 독성의 중요한 지 HERG채널을 억제하는 효과가 크다는 것을 알 수 있는 것으로， 이로부터 본 발명에 따른 화합물들은 종래 알려져 있는 GPR119 활성화제에 비해 2-20배 이상 부정맥 등의 심장 독성이 낮은 것을표시이려래알 진는예에인 수 있다. 따라서， 본 발명에 따른 신규한 피페라진 유도체는 GPR119를 활성화하여， cAMP를 촉진시키는 효과가 우수할 뿐만 아니라 종래에 GPR119 활성화제로 알려져 있는 화합물에 비하여 심장 독성이 상당히 낮아 그에 따른 부작용이 적으므로， GPR119를 활성화시킴으로써 치료가능한 비만， I 형 당뇨병， Π형 당뇨병 , 부적합한 내당력， 인슐린 내성 , 고혈당증, 고지질혈증， 고중성지방혈증， 고콜레스테를혈증， 이상지질혈증 또는 X 증후군의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다. Compared with the compound according to the present invention, it can be seen that the compounds of the comparative example as GPR119 activators have a significant effect of inhibiting the HERG channel, which is important for cardiac toxicity such as arrhythmia, from which the compounds according to the present invention are known. Rae jin can be an example, indicating that cardiac toxicity, such as arrhythmia, is 2-20 times or more lower than GPR119 activator. Therefore, the novel piperazine derivative according to the present invention activates GPR119, and not only has an excellent effect of promoting cAMP, but also significantly lowers cardiac toxicity compared to a compound known as a GPR119 activator. Pharmaceuticals for the prevention or treatment of obesity, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X It can be usefully used as a red composition.
<실험예 6> 마우스 (ICR) 급성 독성 실험 Experimental Example 6 Mouse (ICR) Acute Toxicity Experiment
본 발명에 따른 신규한 피페라진 유도체의 세포독성을 평가하기 위하여 하기와 같은 실험을 수행하였다. 생후 7주령된 ICR 마우스 암컷 5마리를 나라 바이오텍에 목상아 ¾ In order to evaluate the cytotoxicity of the novel piperazine derivatives according to the present invention, the following experiment was performed. Five female ICR mouse of 7 weeks old to Nara Biotech Ivory ¾
니기몇적  Few
공급다에받화제아 사육장에 수용하며 일반 고형사료와 물을 주면서 환경에 적응을 시켰다. 8주령이 되었올 때 실험을 시작하였다. 환경조건은 따학제 It was accommodated in the feeder and fed to the environment by feeding general solid feed and water. The experiment began when it was eight weeks of age. Environmental conditions
설정은도는 23 士 3°C , 습도는 55 士 15%, 조도는 150-300 Lux, 환기 라시화 The setting is 23 士 3 ° C, humidity is 55 士 15%, illuminance is 150-300 Lux, ventilation rash
횟수는 10-20 회 /시간， 조명시간은 12시간 (명암주기 : 아침 8시 점등- 오후 8시. 소등)으로 일정하게 유지하였다. 사료는 방사선조사로 멸균한 실험동물용 고형사료 (5L79 Lab Diet , Purina Mills, Rich¬ mond, IN, USA)를 오리엔트 바이오로부터 공급받아 자유롭게 섭취하도록 하고, 물은 상수도수를 자외선 살균기 및 미세여과장치로 소독한 후， 물병을 이용하여 자유톱게 섭취하도록 하였다. 물과 사료의 오염물질에 대한 검사는 (주)캠온의 관련 SOP에 따라 실시하였다. 실시예 55의 화합물을 2000 mg/kg의 농도로 부형제 (0.5% CMC)에 희석하여 개체수 5 마리에 마우스용 존대 (zonde)를 이용해서 시험물질을 하루에 한번 , 위 내 투여하고 시험기간 중에 1일 2회씩 동물의 일반상태， 중독증상 및 사망 유무에 대해서 관찰하였다ᅳ 그 결과는 실험된 ICR 마우스ᅳ 암컷의 LD50값은 2 g/kg 이상으로 확인되었다. 이로부터， 본 발명에 따른 피페라진 유도체는 세포독성이 상당히 낮은 것을 알 수 있다. 따라서， 본 발명에 따른 신규한 피페라진 유도체는 GPR119를 활성화하여， cAMP를 촉진시키는 효과가 우수할 뿐만 아니라 세포독성이 낮아 인체에 안정도가 상당히 높음으로， GPR119를 활성화시킴으로써 치료가능한 비만， I 형 당뇨병， Π형 당뇨병， 부적합한 내당력， 인슐린 내성， 고혈당증， 고지질혈증， 고증성지방혈증， 고콜레스테를혈증， 이상지질혈증 또는 X 증후군의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다. 한편 본 발명에 따른 상기 화학식 1의 피페라진 유도체는 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 1로 표시되는 피페라진 유도체를 활성상분으로 함유시킨 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 The number of times was 10-20 times / hour, and the lighting time was kept constant at 12 hours (contrast cycle: 8 am on 8 pm, 8 pm off). Feed is a laboratory animal feed pellets for sterilization by radiation received (5L79 Lab Diet, Purina Mills, Rich ¬ mond, IN, USA) the Orient supplied from Bio-free, and to consume water is UV sterilizer, and microfiltration device to be water After sterilization, free sawing was ingested using a water bottle. Water and feed pollutants were inspected in accordance with the relevant SOP of CamOn Co., Ltd. The compound of Example 55 was diluted in excipients (0.5% CMC) at a concentration of 2000 mg / kg, and the test substance was administered intragastricly once a day using a mouse zonde to 5 populations. Twice a day, the general condition, intoxication and death of the animals were observed. The results showed that the LD 50 value of the female ICR mice was more than 2 g / kg. From this, the piperazine derivatives according to the present invention can be seen that the cytotoxicity is very low. Therefore, the novel piperazine derivatives according to the present invention activate GPR119, and not only have an excellent effect of promoting cAMP, but also have low cytotoxicity and thus have high stability in the human body, obesity treatable by activating GPR119, type I diabetes mellitus. , Π type diabetes mellitus, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, or X-syndrome can be usefully used as a pharmaceutical composition for the prevention or treatment of syndrome. Meanwhile, the piperazine derivative of Chemical Formula 1 according to the present invention may be formulated in various forms. The following illustrates a method in which the piperazine derivative represented by 1 according to the present invention is contained as an active phase, and the present invention is not limited thereto.
<제제예 1> 약학적 제제의 제조 Preparation Example 1 Preparation of Pharmaceutical Formulation
1-1. 산제의 제조  1-1. Manufacture of powder
화학식 1의 화합물 500 mg  500 mg of compound of Formula 1
유당 100 mg  Lactose 100 mg
탈크 10 mg 상기의 성분들을 흔합하고 기밀포에 층진하여 산제를 제조한다  Talc 10 mg The above ingredients are combined and layered in an airtight cloth to prepare a powder.
1-2. 정제의 제조 1-2. Manufacture of tablets
화학식 1의 화합물 500 mg 옥수수전분 100 nig 유당 100 nig 500 mg of compound of Formula 1 Corn starch 100 nig lactose 100 nig
스테아린산 마그네슘 2 nig 상기의 성분들을 흔합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.  Magnesium stearate 2 nig After mixing the above components and tableting according to the conventional manufacturing method of the tablet to prepare a tablet.
1-3. 캅샐제의 제조 1-3. Production of capsule
화학식 1의 화합물 500 nig  500 nig of compound of Formula 1
옥수수전분 100 mg  Corn starch 100 mg
유당 100 nig  Lactose 100 nig
스테아린산 마그네슘 2 mg 통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 층전하여 캡슐제를 제조한다 .  Magnesium stearate 2 mg A capsule is prepared by mixing the above ingredients and layering the gelatine capsules according to a conventional capsule preparation method.
1-4. 주사제의 제조 1-4. Preparation of Injectables
화학식 1의 화합물  Compound of Formula 1
주사용 멸균 증류수 ^적적  Sterile Distilled Water for Injection ^
pH 조절제 ^량량 통상의 주사제의 제조방법에 따라 1 앰플당 (2 ) 상기의 성분 함량으로 제조한다 . 1-5. 액제의 제조  pH adjuster amount Amount (2) per one ampoule is prepared according to the conventional method for preparing an injection. 1-5. Preparation of liquid
화학식 1의 화합물 100 mg  100 mg of compound of Formula 1
이성화당 10 g  10 g of isomerized sugar
만니를 5 g  5 g of Manni
정제수 적량 통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 m 로 조절한 후 갈색 병에 층진하여 멸균시켜 액체를 제조한다.  Appropriate amount of purified water Dissolve by adding each component to purified water according to the usual method of preparing a liquid solution, add a proper amount of lemon flavor, mix the above components, add purified water and adjust the total to 100 m by adding purified water to a brown bottle Layered and sterilized to prepare a liquid.
【산업상 이용가능성 】 【Industrial Availability】
본 발명에 따른 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 이성질체는 종래에 GPR119 활성화제로 알려진 화합물들에 비하여 물에 대한 용해도가 높아 체내 흡수력이 우수하며， 세포독성이 낮아 인체에 안정성이 상당히 뛰어나다 . 무엇보다， GPR119를 활성화하여 cAMP를 촉진시키는 효과가 현저히 우수하므로， 본 발명에 따른 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 이성질체는 GPR119를 T/KR2013/009857 The novel piperazine derivatives, pharmaceutically acceptable salts or isomers thereof according to the present invention have high solubility in water and are excellent in absorption in the body and low in cytotoxicity, as compared to the compounds known as GPR119 activators. This is pretty good. Above all, since the effect of activating GPR119 to promote cAMP is remarkably excellent, the novel piperazine derivatives, pharmaceutically acceptable salts thereof or isomers thereof according to the invention T / KR2013 / 009857
93 활성화시킴으로써 치료가능한 비만， I 형 당뇨병， π형 당뇨병 부적합한 내당력 ' 인슐린 내성， 고혈당증' 고지질혈증' 고중성지방혈증, 고콜레스테를혈증， 이상지질혈증 또는 X 증후군의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다.  93 Pharmacology for the prevention or treatment of obesity, type I diabetes mellitus, π diabetes inadequate glucose tolerance 'insulin resistance, hyperglycemia' hyperlipidemia 'hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X It can be usefully used as a composition.

Claims

【청구의 범위】 【청구항 1】 하기 화학식 표시되는 신규한 피페라진 유도체， 이의 약학적으로 허용가 또는 이의 광학이성질체： Claims [Claim 1] A novel piperazine derivative represented by the following formula, a pharmaceutically acceptable value thereof or an optical isomer thereof:
[화학식 1]
Figure imgf000095_0001
[Formula 1]
Figure imgf000095_0001
(상기 화학식 1에서  (In Chemical Formula 1)
A는 비치환되거나 치환된 페닐 ; 또는 비치환되거나 치환된 헤테로아릴이고;  A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
R은 -C00R' ; 또는 비치환되거나 치환된 헤테로아릴이고;  R is -C00R '; Or unsubstituted or substituted heteroaryl;
B는 비치환되거나 치환된 d-C5의 직쇄 또는 측쇄 알킬 또는 비치환되거나 치환된 의 직쇄 또는 측쇄 할로알킬이고 ; B is unsubstituted or substituted straight or branched chain alkyl of dC 5 or unsubstituted or substituted straight or branched chain haloalkyl;
상기， 해테로아릴은 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 헤테로아릴이고;  The heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S;
상기 치환된 페닐 또는 치환된 헤테로아릴은 -S0R' , -S(0)2 ' , -R'S(0)2 " , -NHS(0)2R' , -CN, 할로겐， d-C5의 직쇄 또는 측쇄 할로알킬， Ci-C5의 알케닐기 , -R' , =0， -COR' , -C00R' , -CONR'R" , - NR'R" 및 ^ 0 및 S로 이루어진 군으로부터 선택되는 1 내지 4의 해테로 원자를 포함하는 5원 또는 6원의 헤테로아릴로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 페닐 또는 치환된 해테로아릴이고; The substituted phenyl or substituted heteroaryl is -S0R ', -S (0) 2 ', -R'S (0) 2 ", -NHS (0) 2 R ', -CN, halogen, straight or branched chain of dC 5 Haloalkyl, Ci-C 5 alkenyl group, -R ', = 0, -COR', -C00R ', -CONR'R ", -NR'R" and 1 to 0 selected from the group consisting of S Phenyl substituted with one or more substituents selected from the group consisting of five or six membered heteroaryl containing a hetero atom of 4 or substituted heteroaryl;
여기서 , R' 또는 R"는 각각 독립적으로 수소; 자또측내 비치환되거나 1 이상의 하이드록시기로 치환된 d-Cs의 직쇄 또는 를는지쇄 알킬이고; 또는 R' 및 R"는 이들이 결합되어 있는 N과 함께 1  Wherein R 'or R "are each independently hydrogen; a straight or branched chain alkyl of d-Cs unsubstituted or substituted with one or more hydroxy groups in the vineyard; or R' and R" are N and Together 1
4의 N, 0 및 S로 이루어진 군으로부터 선택되는 헤테로 원 포함하는 5원 또는 6원의 헤테로사이클릴을 형성할 수 있고; 및 To form a 5 or 6 membered heterocyclyl including a hetero member selected from the group consisting of N, 0 and S of 4; And
n은 1 내지 10의 정수이다)  n is an integer from 1 to 10)
【청구항 2】 [Claim 2]
제 1항에 있어서，  The method of claim 1,
상기 A는 비치환되거나 치환된 페닐 ; 또는 비치환되거나 치환된 헤테로아릴이고;  A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
여기서， 상기 헤테로아릴은 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 헤테로아릴이고;  Wherein said heteroaryl is a 5 or 6 membered heteroaryl including 1 to 4 hetero atoms independently selected from the group consisting of N, 0 and S;
상기 치환된 페닐은 -S(0)2R' , -R'S(0)2R" , 할로겐， -R' , -C00R ' , -CONR'R" 및， N, 0 및 S로 이루어진 군으로부터 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 헤테로아릴로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 페닐이고; 여기서 , R'또는 R' '는 각각 독립적으로 수소; 또는 비치환되거나 1 이상의 하이드록시기로 치환된 (：广(：5의 직쇄 또는 측쇄 알킬이고; 또는 R' 및 R"는 이들이 결합되어 있는 N과 함께 1 내지 4의 N, 0 및 S로 이루어진 군으로부터 선택되는 헤테로 원자를 포함하는 5원 또는 6원의 헤테로사이클릴을 형성할 수 있고; 및 The substituted phenyl is selected from the group consisting of -S (0) 2 R ', -R'S (0) 2 R ", halogen, -R', -C00R ', -CONR'R" and, N, 0 and S Phenyl substituted with one or more substituents selected from the group consisting of five or six membered heteroaryl containing 1 to 4 hetero atoms; here , R 'or R''are each independently hydrogen; Or unsubstituted or substituted with one or more hydroxy groups (： is a straight or branched chain alkyl of 5 ; or R ′ and R ″ are groups of 1 to 4 N, 0 and S together with N to which they are attached) To form a 5 or 6 membered heterocyclyl including a hetero atom selected from; and
상기 치환된 헤테로아릴은 -R'또는 -S(0)2R'로 치환된 헤테로아릴이고; 여기서， R'은 d-C5의 직쇄 또는 측쇄 알킬인 것을 특징으로 하는 신규한 피페라진 유도체 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체 The substituted heteroaryl is heteroaryl substituted with —R ′ or —S (0) 2 R ′; Wherein R ′ is a novel piperazine derivative, pharmaceutically acceptable salt or optical isomer thereof, characterized in that it is a straight or branched chain alkyl of dC 5
【청구항 3】 [Claim 3]
제 1항에 있어서，  The method of claim 1,
상기 A는 비치환되거나 치환된 페닐 ; 또는 비치환되거나 치환된 피리딘이고;  A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridine;
상기 치환된 페닐은 메탄설포닐 , 메탄설포닐메틸， 1- 메탄설포닐에틸 , 플루오로， 클로로， 브로모， 메틸， 에틸， 에톡시카보닐， 하이드록시이소프로필아미노카보닐， 다이하이드톡시프로필아미노카보닐，  The substituted phenyl is methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl, fluoro, chloro, bromo, methyl, ethyl, ethoxycarbonyl, hydroxyisopropylaminocarbonyl, dihydroxypropyl Aminocarbonyl ，
다이하이드톡시이소프로필아미노카보닐， 피롤리딜카보닐 및 테트라졸릴로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 페닐이고; 및 Phenyl substituted with one or more substituents selected from the group consisting of dihydroxyisopropylaminocarbonyl, pyrrolidylcarbonyl and tetrazolyl; And
상기 치환된 피리딘은 메틸 , 에틸 및 메탄설포닐로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 피리딘인 것을 특징으로 하는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체ᅳ  The substituted pyridine is a novel piperazine derivative, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, which is a pyridine substituted with at least one substituent selected from the group consisting of methyl, ethyl and methanesulfonyl.
【청구항 4】 [Claim 4]
제 1항에 있어서，  The method of claim 1,
상기 R은 -C00R '； 또는 비치환돠거나 치환된 해테로아릴이고; 여기서， 상기 헤테로아릴은 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 헤테로아릴이고;  R is -C00R '; or unsubstituted or substituted heteroaryl; Wherein said heteroaryl is a 5 or 6 membered heteroaryl including 1 to 4 hetero atoms independently selected from the group consisting of N, 0 and S;
상기 치환된 헤테로아릴은 (：广 의 직쇄 또는 측쇄 알킬로 치환된 헤테로아릴인 것을 특징으로 하는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체 .  The substituted heteroaryl is a novel piperazine derivative, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein the heteroaryl is heteroaryl substituted with straight or branched chain alkyl.
【청구항 5】 [Claim 5]
제 1항에 있어서，  The method of claim 1,
상기 R은 t-부특시카보닐 ; 또는 비치환되거나 치환된 피리미딘 또는 옥사다이아졸이고;  R is t-subspecific carbonyl; Or unsubstituted or substituted pyrimidine or oxadiazole;
상기 치환된 피리미딘 또는 옥사다이아졸은 메틸， 에틸 , 프로필 이소프로필 , 부틸 및 t-부틸로 이루어진 군으로부터 선택되는 1 종 이상의 치환기로 치환된 해테로아릴인 것을 특징으로 하는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체 . The substituted pyrimidine or oxadiazole may be heteroaryl substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl isopropyl, butyl and t-butyl. Piperazine derivatives, pharmaceutically acceptable salts thereof, or optical isomers thereof.
【청구항 6】 [Claim 6]
제 1항에 있어서，  The method of claim 1,
상기 B는 비치환되거나 치환된 d-Cs의 직쇄 또는 측쇄 알킬기인 것을 특징으로 하는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체 .  B is a novel piperazine derivative, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, which is a straight or branched chain alkyl group of an unsubstituted or substituted d-Cs.
【청구항 7】 [Claim 7]
제 1항에 있어서，  The method of claim 1,
상기 B는 메틸， 에틸 또는 프로필인 것을 특징으로 하는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체 .  Wherein B is methyl, ethyl or propyl novel piperazine derivatives, pharmaceutically acceptable salts thereof or optical isomers thereof.
【청구항 8】 [Claim 8]
제 1항에 있어서 ,  The method of claim 1,
상기 A는 비치환되거나 치환된 페닐; 또는 비치환되거나 치환된 해테로아릴이고;  A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
여기서， 상기 헤테로아릴은 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 헤테로아릴이고;  Wherein said heteroaryl is a 5 or 6 membered heteroaryl including 1 to 4 hetero atoms independently selected from the group consisting of N, 0 and S;
상기 치환된 페닐을 -S(0)2R' , -R*S(0)2 " , 할로겐， -R' , -C00R' -CONR'R" 및， N, 0 및 S로 이루어진 군으로부터 선택되는 1 내지 4의 해테로 원자를 포함하는 5원 또는 6원의 헤테로아릴로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 페닐이고; 여기서， R'또는 R"는 각각 독립적으로 수소; 또는 비치환되거나 1 이상의 하이드록시기로 치환된 d-Cs의 직쇄 또는 측쇄 알킬이고; 또는 R' 및 R"는 이들이 결합되어 있는 N과 함께 1 내지 4의 N, 0 및 S로 이루어진 군으로부터 선택되는 헤테로 원자를 포함하는 5원 또는 6원의 헤테로사이클릴을 형성할 수 있고; The substituted phenyl is selected from the group consisting of -S (0) 2 R ', -R * S (0) 2 ", halogen, -R', -C00R '-CONR'R" and, N, 0 and S Phenyl substituted with one or more substituents selected from the group consisting of 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms; Wherein R 'or R "are each independently hydrogen; or straight or branched chain alkyl of d-Cs unsubstituted or substituted with one or more hydroxy groups; or R' and R " are 1 to 1 with N to which they are attached To form a 5 or 6 membered heterocyclyl including a hetero atom selected from the group consisting of N, 0 and S of 4;
상기 치환된 헤테로아릴은 -R' 또는 -S(0)2R'로 치환된 헤테로아릴이고; 여기서， R'은 d-Cs의 직쇄 또는 측쇄 알킬이고; The substituted heteroaryl is heteroaryl substituted with -R 'or -S (0) 2 R'; Wherein R 'is a straight or branched chain alkyl of d-Cs;
R은 -C00R' ; 또는 비치환되거나 치환된 헤테로아릴이고;  R is -C00R '; Or unsubstituted or substituted heteroaryl;
여기서， 상기 헤테로아릴은 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1 내지 4의 헤테로 원자를 포함하는 5원 또는 6원의 헤테로아릴이고;  Wherein said heteroaryl is a 5 or 6 membered heteroaryl including 1 to 4 hetero atoms independently selected from the group consisting of N, 0 and S;
상기 치환된 헤테로아릴은 d-Cs의 직쇄 또는 측쇄 알킬로 치환된 헤테로아릴이고;  The substituted heteroaryl is heteroaryl substituted with d-Cs straight or branched alkyl;
B는 비치환되거나 치환된 d-C5의 직쇄 또는 측쇄 알킬기이고; n은 1 내지 5의 정수인 것올 특징으로 하는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체 . B is an unsubstituted or substituted dC 5 straight or branched alkyl group; Novel piperazine derivatives, pharmaceutically acceptable salts thereof, or optical isomers thereof, wherein n is an integer from 1 to 5.
【청구항 9】 [Claim 9]
제 1항에 있어서，  The method of claim 1,
상기 A는 비치환되거나 치환된 페닐 ; 또는 비치환되거나 치환된 피리딘이고;  A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridine;
상기 치환된 페닐은 메탄설포닐， 메탄설포닐메틸， 1- 메탄설포닐에틸， 플루오로， 클로로， 브로모, 메틸， 에틸 , 에톡시카보닐， 하이드록시이소프로필아미노카보닐， 다이하이드특시프로필아미노카보닐，  The substituted phenyl is methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl, fluoro, chloro, bromo, methyl, ethyl, ethoxycarbonyl, hydroxyisopropylaminocarbonyl, dihydric Propylaminocarbonyl ，
다이하이드록시이소프로필아미노카보닐， 피를리딜카보닐 및 테트라졸릴로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 페닐이고; Phenyl substituted with one or more substituents selected from the group consisting of dihydroxyisopropylaminocarbonyl, pyridylcarbonyl and tetrazolyl;
상기 치환된 피리딘은 메틸， 에틸 및 메탄설포닐로 이루어진 군으로부터 선택되는 1 이상의 치환기로 치환된 피리딘이고;  The substituted pyridine is pyridine substituted with one or more substituents selected from the group consisting of methyl, ethyl and methanesulfonyl;
R은 t-부톡시카보닐 ; 또는 비치환되거나 치환된 피리미딘 또는 옥사다이아졸이고;  R is t-butoxycarbonyl; Or unsubstituted or substituted pyrimidine or oxadiazole;
상기 치환된 피리미딘 또는 옥사다이아졸은 메틸， 에틸， 프로필 이소프로필， 부틸 및 t-부틸로 이루어진 군으로부터 선택되는 1 종 이상의 치환기로 치환된 헤테로아릴이고;  The 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;
B는 메틸， 에틸 또는 프로필이고; 및  B is methyl, ethyl or propyl; And
n은 1 내지 5의 정수인 것을 특징으로 하는 신규한 피페라진 유도체 , 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체 .  n novel piperazine derivatives, pharmaceutically acceptable salts thereof or optical isomers thereof, wherein n is an integer from 1 to 5.
【청구항 10】 [Claim 10]
제 1항에 있어서  The method of claim 1
Figure imgf000098_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000099_0001
B는 메틸이고; 및  B is methyl; And
n은 1 내지 3의 정수인 것올 특징으로 하는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체 .  Novel piperazine derivatives, pharmaceutically acceptable salts thereof, or optical isomers thereof, wherein n is an integer from 1 to 3.
【청구항 11】 [Claim 11]
제 1항에 있어서， 상기 화학식 1로 표시되는 피페라진 유도체는: According to claim 1, wherein the piperazine derivative represented by Formula 1 is:
(1) t-부틸 -4-(4-(4- (메틸설포닐)페녹시 )부탄 -2-일)피페라진 -1- 카르복실레이트 옥살산염； (1) t-butyl-4- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-carboxylate oxalate;
(2) t-부틸ᅩ 4-(4— (2-플루오로 -2- ((메틸설포닐)메틸)페녹시 )부탄— 2-일 )피페라진 -1—카르복실레이트 옥살산염 ; (2) t-butyl ᅩ 4- (4— (2-fluoro-2-((methylsulfonyl) methyl) phenoxy) butane- 2-yl) piperazine-1-carboxylate oxalate;
(3) 2-(4-(4-(4- (메틸설포닐 )페녹시 )부탄 -2-일 )피페라진— 1-일 ) - 5-프로필피리미딘 옥살산염；  (3) 2- (4- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin— 1-yl) -5-propylpyrimidine oxalate;
(4) 2-(4-(4-(3-플루오로 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2- 일 )피페라진 -1-일 )-5-프로필피리미딘 ;  (4) 2- (4- (4- (3-fluoro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;
(5) 2-(4-(4-(3-플루오로 -4- ((메틸설포닐 )메틸)페녹시 )부탄 -2- 일)피페라진 -1-일) -5-프로필피리미딘 옥살산염；  (5) 2- (4- (4- (3-fluoro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalic acid salt;
(6) 1-(4-(3-플루오로 -4- (메틸설포닐)페녹시 )부탄 -2-일) -4-(3- 이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (6) 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine oxalate;
(7) t—부틸 4-(4— (3-폴루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일)피페라진 -1-카르복실레이트 옥살산염 :  (7) t-Butyl 4- (4— (3-polouro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate oxalate:
(8) 1-(4-(3-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 )-4-(3- 이소프로필 -1，2，4-옥사다이아졸 -5-일)피페라진 염산염 ;  (8) 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine hydrochloride;
(9) 1-(4-(2-플루오로 -4-UH-테트라졸 -1-일 )페녹시 )부탄 -2-일 ) - 4-(3—이소프로필-1，2，4-옥사다이아졸 -5-일 )피페라진 ;  (9) 1- (4- (2-fluoro-4-UH-tetrazol-1-yl) phenoxy) butan-2-yl)-4- (3-isopropyl-1,2,4-oxa Diazol-5-yl) piperazine;
(10) 1-(4— (2-풀루오로 -4-UH-테트라졸 -1-일)페녹시 )부탄 -2- 일 )-4-(3—이소프로필-1，2，4-옥사다이아졸 -5-일 )피페라진 옥살산염 ; (11) l-(4-(2-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 ) -4-(3- 이소프로필-， 2，4—옥사다이아졸 -5-일 )피페라진 옥살산염 ; (10) 1- (4— (2-Pluoro-4-UH-tetrazol-1-yl) phenoxy) butan-2-yl) -4- (3—isopropyl-1,2,4- Oxadiazole-5-yl) piperazine oxalate; (11) l- (4- (2-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-, 2,4-oxadiazole-5- (I) piperazine oxalate;
(12) 1-(4-(3-플루오로 -4-(1Η-테트라졸 1-일)페녹시 )부탄 -2- 일 )-4-(3-이소프로필-1,2，4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (12) 1- (4- (3-fluoro-4- (1Η-tetrazol 1-yl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxa Diazol-5-yl) piperazine oxalate;
(13) 1-(4— (4- (메틸설포닐)페녹시 )부탄 -2-일) -4-(3-이소프로필- (13) 1- (4— (4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-
1，2，4-옥사다이아졸 -5-일 )피페라진 옥살산염； 1,2,4-oxadiazol-5-yl) piperazine oxalate;
(14) 1-(4-(4-(1Η—테트라졸 -1-일)페녹시 )부탄 -2-일) -4-(3- 이소프로필 -1,2 ,4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (14) 1- (4- (4- (1Η-tetrazol-1-yl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine oxalate;
(15) 1-(4-(3， 5-다이플루오로 -4-UH-테트라졸 -1- 일)페녹시 )부탄 -2-일) -4— (3-이소프로필 -1,2, 4-옥사다이아졸 -5- 일)피페라진 옥살산염；  (15) 1- (4- (3,5-Difluoro-4-UH-tetrazol-1-yl) phenoxy) butan-2-yl) -4— (3-isopropyl-1,2, 4-oxadiazol-5-yl) piperazine oxalate;
(16) 1-(4— (4—브로모 -2,5-다이플루오로페녹시 )부탄 -2-일 )-4-(3- 이소프로필 -1,2, 4-옥사다이아졸 -5-일)피페라진 옥살산염 ;  (16) 1- (4— (4—bromo-2,5-difluorophenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine oxalate;
(17) 1— (4-(3-클로로 -4- (메틸설포닐)페녹시 )부탄 -2-일) _4-(3- 이소프로필 -1,2，4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (17) 1— (4- (3-chloro-4- (methylsulfonyl) phenoxy) butan-2-yl) _4- (3-isopropyl-1,2,4-oxadiazol-5-yl ) Piperazine oxalate;
(18) 1-(4-(3-메틸 -4- (메틸설포닐 )페녹시 )부탄 -2-일 )-4— (3- 이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (18) 1- (4- (3-methyl-4- (methylsulfonyl) phenoxy) butan-2-yl) -4— (3-isopropyl-1,2,4-oxadiazole-5- (I) piperazine oxalate;
(19) 1-(4-(5- (메틸설포닐)피리딘 -2-일옥시 )부탄— 2-일) -4-(3- 이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (19) 1- (4- (5- (methylsulfonyl) pyridin-2-yloxy) butane- 2-yl) -4- (3-isopropyl-1,2,4-oxadiazole-5- (I) piperazine oxalate;
(20) 1-(4-(5- (메틸설포닐)피리딘 -2-일옥시 )부탄 -2-일) -4-(3- 이소프로필 -1,2, 4-옥사다이아졸 -5-일)피페라진 염산염 ;  (20) 1- (4- (5- (methylsulfonyl) pyridin-2-yloxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole-5- (1) piperazine hydrochloride;
(21) 1-(4-(6- (메틸설포닐 )피리딘 3-일옥시 )부탄 -2-일 )-4-(3- 이소프로필 -1,2, 4-옥사다이아졸 -5-일)피페라진 옥살산염 ;  (21) 1- (4- (6- (methylsulfonyl) pyridin 3-yloxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazol-5-yl ) Piperazine oxalate;
(22) 1-(4-(3-클로로 4- ((메틸설포닐)메틸)페녹시 )부탄 -2-일) - 4-(3—이소프로필 -1,2,4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (22) 1- (4- (3-Chloro 4- ((methylsulfonyl) methyl) phenoxy) butan-2-yl)-4- (3-isopropyl-1,2,4-oxadiazole- 5-yl) piperazine oxalate;
(23) 1— (4-(3-클로로 -4- ((메틸설포닐 )메틸)페녹시 )부탄 -2-일 ) - 4-(3-이소프로필 -1， 2 ,4-옥사다이아졸 -5-일)피페라진 염산염 ;  (23) 1— (4- (3-chloro-4- ((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1, 2,4-oxadiazole -5-yl) piperazine hydrochloride;
(24) 1-(4-(3-플루오로 -4- ((메틸설포닐 )메틸)페녹시 )부탄 -2- 일 ) -4-(3-이소프로필 -1,2， 4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (24) 1- (4- (3-fluoro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine oxalate;
(25) 1-(4-(2-메틸 -4- ((메틸설포닐 )메틸)페녹시 )부탄 -2-일 ) -4- (25) 1- (4- (2-methyl-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4-
(3-이소프로필 -1，2，4-옥사다이아졸 -5-일)피페라진 옥살산염 ; (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine oxalate;
(26) 2— (4-(4— (3-플루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일)피페라진 -1-일)— 5-프로필피리미딘 옥살산염；  (26) 2— (4- (4— (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) — 5-propylpyrimidine oxalate;
(27) l-((R)-4-(3-플루오로 -4- (메틸설포닐)페녹시 )부탄 -2-일) - 4-(3-이소프로필 -1,2,4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (27) l-((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxa Diazol-5-yl) piperazine oxalate;
(28) l-((R)-4-(3-풀루오로 -4- (메틸설포닐 )페녹시 )부탄 -2—일 ) - 4-(3-이소프로필 -1,2 ,4-옥사다이아졸 -5-일 )피페라진 염산염 ;  (28) 1-((R) -4- (3-Pluoro-4- (methylsulfonyl) phenoxy) butane-2-yl) -4- (3-isopropyl-1,2,4- Oxadiazole-5-yl) piperazine hydrochloride;
(29) 2-(4— (4-(3-플루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일 )피페라진 -1-일 ) -5—프로필피리미딘 염산염 ;  (29) 2- (4— (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine hydrochloride;
(30) 2-(4-(4-(3-클로로 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2- 일 )피페라진 -1-일 )-5—프로필피리미딘 ;  (30) 2- (4- (4- (3-chloro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5—propylpyrimidine;
(31) 2-(4-(4-(3-클로로 -4- ((메틸설포닐 )메틸)페녹시 )부탄 -2- 일 )피페라진 -1-일 )-5-프로필피리미딘 옥살산염； (31) 2- (4- (4- (3-chloro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate ;
(32) 2-(4-(4— (3-플루오로 -4-(l- (메틸설포닐)에틸)페녹시 )부탄- 2-일 )피페라진 -1-일 ) -5-프로필피리미딘 옥살산염； (32) 2- (4- (4— (3-fluoro-4- (l- (methylsulfonyl) ethyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyri Midine oxalate;
(33) 1-(4-(2，5—다이플루오로 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2-일 )-4-(3-이소프로필 -1，2，4- 옥사다이아졸 -5—일)피페라진 옥살산염 ;  (33) 1- (4- (2,5—difluoro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4 Oxadiazole-5-yl) piperazine oxalate;
(34) 1-(4-(2，5-다이플루오로 -4— (메틸설포닐)페녹시 )부탄 -2— 일 )-4-(3-이소프로필 -1,2,4-옥사다이아졸 -5—일 )피페라진  (34) 1- (4- (2,5-Difluoro-4— (methylsulfonyl) phenoxy) butane-2—yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine
트라이플루오로아세테이트산 염 ; Trifluoroacetate acid salts;
(35) 1-(4-(2，5-다이플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일 ) -4-(3—이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진 염산염 ;  (35) 1- (4- (2,5-Difluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine hydrochloride;
(36) 1-(4-(2,6-다이플루오로 -4— (메틸설포닐 )페녹시 )부탄 -2- 일 )-4-(3-이소프로필-1,2，4—옥사다이아졸— 5-일 )피페라진 옥살산염 ;  (36) 1- (4- (2,6-difluoro-4— (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4—oxadia Sol—5-yl) piperazine oxalate;
(37) 1— (4-(2,6-다이플루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일 )-4-(3-이소프로필 -1，2，4-옥사다이아졸 -5-일)피페라진  (37) 1— (4- (2,6-difluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine
트라이플루오로아세테이트산 염 ; Trifluoroacetate acid salts;
(38) 1-(4-(2，6-다이폴루오로 4- (메틸설포닐)페녹시 )부탄 -2- 일 )-4-(3-이소프로필-1，2，4-옥사다이아졸 -5-일 )피페라진 염산염 ;  (38) 1- (4- (2,6-dipolouro 4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole -5-yl) piperazine hydrochloride;
(39) 1-(4-(5-메틸 -6- (메틸설포닐 )피리딘 -3-일옥시 )부탄 -2-일 ) - 4-(3-이소프로필 -1,2,4-옥사다이아졸 -5-일)피페라진 염산염；  (39) 1- (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4 (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine hydrochloride;
(40) 1-(4-(5-메틸 -6- (메틸설포닐 )피리딘 3—일옥시 )부탄 -2-일 ) - (40) 1- (4- (5-methyl-6- (methylsulfonyl) pyridin 3-yloxy) butan-2-yl)-
4-(3-이소프로필— 1,2， 4-옥사다이아졸 -5-일 )피페라진 옥살산염 ; 4- (3-isopropyl— 1,2, 4-oxadiazol-5-yl) piperazine oxalate;
(41) 에틸— 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )—2-플루오로벤조에이트 옥살산염 ;  (41) ethyl— 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) —2-fluorobenzoate Oxalate;
(42) 4— (3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진— 1-일 )부톡시 ) 2-플루오로벤조에이트 리튬염 ;  (42) 4— (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1-yl) butoxy) 2-fluorobenzoate lithium salt;
(43) 에틸 -4-(3-(4-(5-프로필피리미딘 -2—일)피페라진 -1- 일)부톡시 )-2-플루오로벤조에이트 옥살산염 ;  (43) ethyl-4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate oxalate;
(44) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부록시 ) - 2-플루오로벤조에이트 리튬염 ;  (44) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate lithium salt;
(45) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부록시 ) - (45) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) buroxy)-
2-플루오로 -N-(l,3-다이하이드록시프로판 -2—일 )벤즈아마이드 2-fluoro-N- (l, 3-dihydroxypropane-2-yl) benzamide
옥살산염 ; Oxalate;
(46) 4— (3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부특시 ) - 2-플루오로 -N-( 1,3-다이하이드톡시프로판 -2-일)벤즈아마이드 염산염 ;  (46) 4— (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) subspecific) -2-fluoro-N- (1,3-dihydroxypropane- 2-yl) benzamide hydrochloride;
(47) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부톡시 ) - (47) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy)-
2-플루오로 -N-((S)-1-하이드록시프로판 -2-일 )벤즈아마이드 옥살산염 ; 2-fluoro-N-((S) -1-hydroxypropan-2-yl) benzamide oxalate;
(48) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부록시 ) - 2-플루오로 -N-((S)— 1-하이드록시프로판 -2-일)벤즈아마이드 염산염 ;  (48) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy)-2-fluoro-N-((S) — 1-hydroxypropane 2-yl) benzamide hydrochloride;
(49) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1—일 )부록시 ) - 2-폴루오로 -N-((S)_2,3-다이하이드록시프로필)벤즈아마이드 옥살산염 ;  (49) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) buroxy) -2-polouro-N-((S) _2,3-di Hydroxypropyl) benzamide oxalate;
(50) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부톡시 ) - 2-플루오로 -N-((S)-2,3-다이하이드록시프로필)벤즈아마이드 염산염 ;  (50) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy)-2-fluoro-N-((S) -2,3-di Hydroxypropyl) benzamide hydrochloride;
(51) 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부록시 )-2-플루오로 -N-( 1,3—다이하이드록시프로판— 2-일)벤즈아마이드 옥살산염 ; (51) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5- 1) piperazin-1-yl) buroxy) -2-fluoro-N- (1,3—dihydroxypropane—2-yl) benzamide oxalate;
(52) 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5— 일 )피페라진 -1-일 )부록시 )-2-플루오로 -N-( 1,3-다이하이드록시프로판- 2-일)벤즈아마이드 염산염 ;  (52) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) buroxy) -2-fluoro-N- ( 1,3-dihydroxypropane-2-yl) benzamide hydrochloride;
(53) 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-2-플루오로 -N-((R)-1-하이드록시프로판 -2- 일)벤즈아마이드 옥살산염 ;  (53) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -2-fluoro-N- ( (R) -1-hydroxypropan-2-yl) benzamide oxalate;
(54) 4-(3-(4-(3-이소프로필-1 2 4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-2-플루오로 -N-((R)— 1-하이드록시프로판 -2- 일 )벤즈아마이드 염산염 ;  (54) 4- (3- (4- (3-isopropyl-1 2 4-oxadiazol-5-yl) piperazin-1-yl) particular) -2-fluoro-N-((R )-1-hydroxypropan-2-yl) benzamide hydrochloride;
(55) 4-(3-(4-(3-이소프로필 -1 2 4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2-플루오로 -N-( 00-2 3- 다이하이드록시프로필)벤즈아마이드 옥살산염 ;  (55) 4- (3- (4- (3-isopropyl-1 2 4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro-N- (00- 2 3-dihydroxypropyl) benzamide oxalate;
(56) 4-(3-(4-(3-이소프로필 -l 2,4-옥사다이아졸-5- 일)피페라진 -1-일 )부톡시 )-2-플루오로 -N-((R)-2,3- 다이하이드록시프로필)벤즈아마이드 염산염 ;  (56) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro-N-(( R) -2,3-dihydroxypropyl) benzamide hydrochloride;
(57) 4-(3-(4-(3-이소프로필 -1 2 4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2-플루오로 -N-((R)-2,3- 다이하이드특시프로필 )벤즈아마이드 염산염 ;  (57) 4- (3- (4- (3-isopropyl-1 2 4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro-N-((R ) -2,3-dihydric propyl) benzamide hydrochloride;
(58) (4-(3-(4-(3-이소프로필 -1,2 ,4-옥사다이아졸 -5- 일)피페라진— 1-일)부특시 )-2-플루오로페닐) (피를리딘— 1-일)메타논  (58) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin- 1-yl) particular) -2-fluorophenyl) ( Pirridin— 1-day) Methanone
(59) 에틸 4-(3-(4-(3-이소프로필 -1 2 4-옥사다이아졸 -5- 일 )피페라진— 1-일 )부톡시 )-3-플루오로벤조에이트 옥살산염 ; (59) ethyl 4- (3- (4- (3-isopropyl-1 12 4-oxadiazol-5-yl) piperazin- 1-yl) butoxy) -3-fluorobenzoate oxalate;
(60) 4-(3-(4-(3—이소프로필 -1,2 4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-플루오로벤조에이트 리튬염；  (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-이소프로필 -1 2 4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-N-((R)-l-하이드록시프로판 -2- 일)벤즈아마이드 옥살산염 ;  (61) 4- (3- (4- (3-isopropyl-1 2 4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N-((R) -l-hydr Roxypropan-2-yl) benzamide oxalate;
(62) 4-(3-(4-(3-이소프로필 -1 2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-N-((R)-l-하이드록시프로판 -2- 일 )벤즈아마이드 염산염 ;  (62) 4- (3- (4- (3-isopropyl-1 2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N-((R) -l- Hydroxypropan-2-yl) benzamide hydrochloride;
(63) 4-(3-(4-(3-이소프로필 -1,2 4-옥사다이아졸 -5- 일)피페라진 -1-일)부톡시 )-3-플루오로 -N-((S)-2,3- 다이하이드톡시프로필)벤즈아마이드 옥살산염 ;  (63) 4- (3- (4- (3-isopropyl-1,2 4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro-N-(( S) -2,3-dihydroxypropyl) benzamide oxalate;
(64) 4-(3-(4— (3-이소프로필 -1 2 ,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3—플루오로 -N-((S)-2,3—  (64) 4- (3- (4— (3-isopropyl-1 2, 4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro-N-(( S) -2,3—
다이하이드록시프로필)벤즈아마이드 트라이플루오로아세트산염 ; Dihydroxypropyl) benzamide trifluoroacetic acid salt;
(65) 4-(3-(4-(3-이소프로필 -l 2,4-옥사다이아졸-5- 일 )피페라진— 1-일 )부톡시 )-N,N-다이에틸 -3-메틸벤즈아마이드  (65) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin— 1-yl) butoxy) -N, N-diethyl-3- Methylbenzamide
옥살산염； Oxalate;
(66) 4— (3-(4-(3-이소프로필 -1,2, 4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-N,N-다이에틸 -3—메틸벤즈아마이드 염산염；(66) 4— (3- (4- (3-isopropyl-1,2, 4-oxadiazole-5- 1) piperazin-1-yl) butoxy) -N, N-diethyl-3—methylbenzamide hydrochloride;
(67) (4-(3-(4-(3-이소프로필— 1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-플루오로페닐) (피를리딘 -1-일 )메타논 (67) (4- (3- (4- (3-isopropyl— 1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorophenyl) ( Pyridin-1-yl) methanone
Λ}- Λΐ- .  Λ}-Λΐ-.
(68) (4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-플루오로페닐) (피를리딘 -1-일 )메타논 o 사 ο ·  (68) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorophenyl) ( Pyridin-1-yl) methanone o sao ο ·
(69) 4-(3-(4— (3-이소프로필 -1，2，4—옥사다이아졸 -5- 일 )피페라진 -1-일 )부록시 )-3-폴루오로 -N-( 1,3-다이하이드록시프로판- 22--일일 ))벤멘즈즈아아마이드 옥살산염 ;  (69) 4- (3- (4— (3-isopropyl-1,2,4—oxadiazol-5-yl) piperazin-1-yl) buroxy) -3-polouro-N- (1,3-dihydroxypropane-22-yl)) bemenzamide oxalate;
(70) 4-(3-(4-(3-이소프로필 -1,2 ,4-옥사다이아졸 -5- 일 )피페라진 1-일 )부톡시 )-3-플루오로 -N-(l,3-다이하이드록시프로판- 2-일 )벤즈아마이드 염산염；  (70) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin 1-yl) butoxy) -3-fluoro-N- (l , 3-dihydroxypropane-2-yl) benzamide hydrochloride;
(71) 4-(3— (4-(3-이소프로필 -1,2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부록시 )-2-플루오로 -N-((R)-2,3- 다이하이드톡시프로필)벤즈아마이드 옥살산염 ;  (71) 4- (3— (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) buroxy) -2-fluoro-N- ( (R) -2,3-dihydroxypropyl) benzamide oxalate;
(72) 1-(4-(5-메틸 -6— (메틸설포닐 )피리딘 -3-일옥시 )부탄 -2—일 ) - 4-(3-이소프로필— 1，2,4-옥사다이아졸 -5-일 )피페라진 옥살산염 ;  (72) 1- (4- (5-methyl-6-6 (methylsulfonyl) pyridin-3-yloxy) butan-2-yl)-4- (3-isopropyl— 1,2,4-oxadia Sol-5-yl) piperazine oxalate;
(73) 에틸 4-((R)-3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-2-플루오로벤조에이트 옥살산염 ;  (73) ethyl 4-((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -2-fluor Robenzoate oxalate;
(74) 4-((R)-3-(4-(3-이소프로필 -1， 2 , 4-옥사다이아졸 -5- 일)피페라진 -1-일)부특시 )-2-플루오로벤조에이트 리튬염 ;  (74) 4-((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -2-fluoro Benzoate lithium salts;
(75) 4-((10-3-(4-(3-이소프로필-1,2，4-옥사다이아졸 _5- 일 )피페라진 -1—일 )부특시 )-2-플루오로 N_((R)-2,3- 다이하이드톡시프로필)벤즈아마이드 옥살산염 ;  (75) 4-((10-3- (4- (3-isopropyl-1,2,4-oxadiazol _5-yl) piperazin-1-yl) partial) -2-fluoro N_ ( (R) -2,3-dihydroxypropyl) benzamide oxalate;
(76) 에틸 4-((S)-3-(4-(3-이소프로필 -l,2,4-옥사다이아졸-5- 일)피페라진 -1-일 )부톡시 )-2-플루오로벤조에이트;  (76) ethyl 4-((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluor Robenzoate;
(77) 4-((S)-3-(4-(3-이소프로필 -1，2，4—옥사다이아졸 -5- 일)피페라진 -1-일)부톡시 )-2-플루오로벤조에이트 리튬염 ;  (77) 4-((S) -3- (4- (3-isopropyl-1,2,4—oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro Benzoate lithium salts;
(78) 4-((S)_3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-2-플루오로 -N-((R)— 2,3- 다이하이드록시프로필)벤즈아마이드 옥살산염 ;  (78) 4-((S) _3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -2-fluoro- N-((R) — 2,3-dihydroxypropyl) benzamide oxalate;
(79) t-부틸 -4-(4-(4- (메틸설포닐)페녹시 )부탄 -2-일)피페라진- 1-카르복실레이트；  (79) t-butyl-4- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate;
(80) t-부틸 -4-(4-(2-플루오로 -2- (80) t-butyl-4- (4- (2-fluoro-2-
((메틸설포닐)메틸)페녹시 )부탄 -2-일 )피페라진 1-카르복실레이트； ((Methylsulfonyl) methyl) phenoxy) butan-2-yl) piperazine 1-carboxylate;
(81) 2-(4-(4-(4- (메틸설포닐)페녹시 )부탄 -2-일)피페라진 -1- 일 ) -5-프로필피리미딘；  (81) 2- (4- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;
(82) 1-(4-(3-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 )-4-(3- 이소프로필 -1， 2, 4-옥사다이아졸 -5-일)피페라진 ;  (82) 1- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1, 2, 4-oxadiazole-5 -Yl) piperazine;
(83) t_부틸 4-(4-(3-플루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일)피페라진 -1-카르복실레이트;  (83) t_butyl 4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazine-1-carboxylate;
(84) 1-(4-(2-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 )-4-(3- 이소프로필 -1,2 ,4-옥사다이아졸 -5-일 )피페라진 ; (84) 1- (4- (2-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3- Isopropyl-1,2,4-oxadiazol-5-yl) piperazine;
(85) 1-(4-(3-플루오로 -4-(1Η-테트라졸 -1—일)페녹시 )부탄 -2- 일 )-4-(3-이소프로필-1,2，4-옥사다이아졸 -5-일 )피페라진 ;  (85) 1- (4- (3-fluoro-4- (1Η-tetrazol-1-yl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4- Oxadiazole-5-yl) piperazine;
(86) 1-(4-(4- (메틸설포닐)페녹시 )부탄 -2-일 )-4-(3-이소프로필- 1，2，4ᅳ옥사다이아졸 -5-일 )피페라진 ;  (86) 1- (4- (4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4oxoxadiazol-5-yl) piperazine ;
(87) ΐ-(4-(4-(1Η—테트라졸 -1-일 )페녹시 )부탄 -2-일 )-4-(3- 이소프로필 -1,2, 4-옥사다이아졸 -5-일 )피페라진 ;  (87) ΐ- (4- (4- (1Η—tetrazol-1-yl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine;
(88) 1— (4-(3， 5-다이플루오로 -4- 1H-테트라졸 -1- 일 )페녹시 )부탄 -2-일 )-4-(3-이소프로필-1,2，4-옥사다이아졸 -5- 일 )피페라진 ，  (88) 1— (4- (3, 5-difluoro-4- 1H-tetrazol-1-yl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2, 4-oxadiazole-5-yl) piperazine ，
(89) 1 -(4-(4-브로모-2，5-다이플루오로페녹시 )부탄 -2-일) -4- -(3- 이소프로필- 1, 2，4-옥사다이아졸 -5-일 )피페라진 ;  (89) 1- (4- (4-Bromo-2,5-difluorophenoxy) butan-2-yl) -4-(3-isopropyl-1,2,4-oxadiazole- 5-yl) piperazine;
(90) 1-(4-(3—클로로 -4- (메틸설포닐 )페녹시 )부탄 -2-일) —4. -(3- 이소프로필- 1, 2，4-옥사다이아졸 -5-일 )피페라진；  (90) 1- (4- (3—chloro-4- (methylsulfonyl) phenoxy) butan-2-yl) —4. -(3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine;
(91) 1-(4-(3-메틸 -4- (메틸설포닐)페녹시)부탄 -2-일) -4- -(3- 이소프로필- 1, 2,4-옥사다이아졸 -5-일 )피페라진；  (91) 1- (4- (3-methyl-4- (methylsulfonyl) phenoxy) butan-2-yl) -4-(3-isopropyl-1,2,4-oxadiazole-5 -Yl) piperazine;
(92) 1-(4— (5- (메틸설포닐)피리던 -2-일옥시 )부탄 -2-일 ) -4- -(3- 이소프로필- 1, 2，4-옥사다이아졸 -5-일 )피페라진；  (92) 1- (4— (5- (methylsulfonyl) pyridin-2-yloxy) butan-2-yl) -4-(3-isopropyl-1,2,4-oxadiazole- 5-yl) piperazine;
(93) 1-(4-(6- (메틸설포닐 )피리딘 3-일옥시 )부탄 -2-일) -4· -(3- 이소프로필 - 1， 2,4-옥사다이아졸 -5-일 )피페라진；  (93) 1- (4- (6- (methylsulfonyl) pyridin 3-yloxy) butan-2-yl) -4 .- (3-isopropyl-1,2,4-oxadiazole-5- (I) piperazine;
(94) 1-(4— (3-클로로 -4- ((메틸설포닐 )메틸)페녹시 )부탄- 2-'일) - (94) 1- (4— (3-chloro-4-((methylsulfonyl) methyl) phenoxy) butan-2-2-'yl)-
4-(3-이소프로필 -1,2,4-옥사다이아졸— 5-일 )피페라진 ; 4- (3-isopropyl-1,2,4-oxadiazol—5-yl) piperazine;
(95) 1— (4-(3-플투오로 -4- ((메틸설포닐 )메틸)페녹시 )부탄 -2- 일 )-4-(3-이소프로필 -1,2,4-옥사다이아졸 -5-일 )피페라진；  (95) 1— (4- (3-Plutouro-4- ((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine;
(96) 1-(4-(2-메틸 -4- ((메틸설포닐 )메틸 )페녹시 )부탄 -2-일 )-4- (96) 1- (4- (2-methyl-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4-
(3-이소프로필 -1，2，4-옥사다이아졸 -5-일)피페라진 ; (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine;
(97) 2-(4-(4-(3-플루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일)피페라진 -1-일) -5-프로필피리미딘 옥살산염 ;  (97) 2- (4- (4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine oxalate;
(98) l-((R)-4-(3-플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2-일 ) - 4-(3-이소프로필 -1，2，4-옥사다이아졸— 5-일 )피페라진 ;  (98) l-((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxa Diazol—5-yl) piperazine;
(99) 2-(4-(4-(3-풀루오로 -4- (메틸설포닐)페녹시 )부탄 -2- 일 )피페라진 -1-일 )-5-프로필피리미딘；  (99) 2- (4- (4- (3-pulluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine;
(100) 2-(4-(4-(3-플루오로 -4-U- (메틸설포닐)에틸)페녹시 )부탄 -2-일 )피페라진 -1-일 ) -5- 프로필피리미딘 ;  (100) 2- (4- (4- (3-fluoro-4-U- (methylsulfonyl) ethyl) phenoxy) butan-2-yl) piperazin-1-yl) -5-propylpyrimidine ;
(101) 1-(4-(2,5_다이플루오로 -4- ((메틸설포닐)메틸)페녹시 )부탄 -2-일 )-4-(3-이소프로필— 1，2，4— 옥사다이아졸 -5-일 )피페라진 ;  (101) 1- (4- (2,5_difluoro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl— 1,2,4 —Oxadiazol-5-yl) piperazine;
(102) 1-(4-(2,5—다이플루오로 -4- (메틸설포닐 )페녹시 )부탄 -2- 일 )-4-(3-이소프로필-1，2,4-옥사다이아졸 -5-일 )피페라진 ;  (102) 1- (4- (2,5—difluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine;
(103) 1— (4-(2,6-다이플루오로— 4- (메틸설포닐 )페녹시 )부탄 -2- 일 )-4-(3-이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진 ;  (103) 1— (4- (2,6-difluoro— 4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadia Sol-5-yl) piperazine;
(104) 1— (4-(5-메틸 -6- (메틸설포닐 )피리딘 -3-일옥시 )부탄 -2- 일 )-4-(3—이소프로필 -1,2,4-옥사다이아졸 -5-일 )피페라진 ; (104) 1— (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butane-2- Yl) -4- (3—isopropyl-1,2,4-oxadiazol-5-yl) piperazine;
(105) 에틸 -4-(3-(4-(3-이소프로필 -1， 2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부록시 )-2-플루오로벤조에이트;  (105) ethyl-4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate ;
(106) 4-(3— (4-(3—이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2-폴루오로벤조에이트；  (106) 4- (3— (4- (3—isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-polorobenzoate;
(107) 에틸 -4-(3-(4-(5-프로필피리미딘 -2-일)피페라진 -1- 일 )부톡시 )-2-플루오로벤조에이트;  (107) ethyl -4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy) -2-fluorobenzoate;
(108) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부톡시 ) - 2-플루오로벤조에이트；  (108) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy)-2-fluorobenzoate;
(109) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부특시 ) - (109) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) partial)-
2-플루오로— N-( 1,3-다이하이드톡시프로판 -2-일 )벤즈아마이드; 2-fluoro—N- (1,3-dihydroxypropan-2-yl) benzamide;
(110) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부톡시 ) - 2-플루오로 -N-((S)-1-하이드록시프로판 -2-일 )벤즈아마이드；  (110) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy)-2-fluoro-N-((S) -1-hydroxypropane 2-yl) benzamide;
(111) 4-(3-(4-(5-프로필피리미딘 -2-일 )피페라진 -1-일 )부톡시；卜 2-풀루오로 -N-((S)-2,3-다이하이드록시프로필)벤즈아마이드:  (111) 4- (3- (4- (5-propylpyrimidin-2-yl) piperazin-1-yl) butoxy; 卜 2-Pluoro-N-((S) -2,3- Dihydroxypropyl) benzamide:
(112) 4— (3-(4— (3-이소프로필— 1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-2-플루오로 -N-( 1,3-다이하이드록시프로판- 2-일)벤즈아마이드;  (112) 4— (3- (4— (3-isopropyl— 1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -2-fluoro-N- ( 1,3-dihydroxypropane-2-yl) benzamide;
(113) 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2—플루오로 -N-((R)-1-하이드록시프로판 -2- 일)벤즈아마이드; ' (113) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2—fluoro-N- ( (R) -1-hydroxypropan-2-yl) benzamide; '
(114) 4-(3-(4— (3-이소프로필 -l，2,4-옥사다이아졸-5- 일)피페라진—l-일)부록시 )-2-플루오로 -N-( 00-2， 3- 다이하이드톡시프로필)벤즈아마이드;  (114) 4- (3- (4— (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-l-yl) buroxy) -2-fluoro-N- ( 00-2, 3-dihydroxypropyl) benzamide;
(115) (4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부록시 )-2-플루오로페닐) (피를리딘 -1-일 )메타논 ;  (115) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluorophenyl) ( Pyridin-1-yl) methanone;
(116) 에틸 4-(3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진— 1-일 )부톡시 )-3-플루 ί로벤조에이트 ;  (116) ethyl 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin— 1-yl) butoxy) -3-flulobenzoate ;
(117) 4-(3-(4-(3-이소프로필 -1,2 ,4—옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )—3-플루오로벤조에이트;  (117) 4- (3- (4- (3-isopropyl-1,2,4—oxadiazol-5-yl) piperazin-1-yl) subspecial) —3-fluorobenzoate;
(118) 4-(3-(4-(3—이소프로필 -1,2,4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-N-((R)-l-하이드록시프로판 -2- 일 )벤즈아마이드;  (118) 4- (3- (4- (3—isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N-((R) -1 -Hydroxypropan-2-yl) benzamide;
(119) 4-(3-(4-(3-이소프로필 -1,2 ,4—옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-플루오로 -N-((S)-2,3—  (119) 4- (3- (4- (3-isopropyl-1,2,4—oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro-N- ( (S) -2,3—
다이하이드록시프로필)벤즈아마이드; Dihydroxypropyl) benzamide;
(120) 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진 -1-일 )부톡시 )-N,N-다이에틸 -3-메틸벤즈아마이드；  (120) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N, N-diethyl-3 -Methyl benzamide;
(121) (4-(3-(4-(3-이소프로필— 1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-3-플루오로페닐) (피를리딘 -1-일 )메타논 ;  (121) (4- (3- (4- (3-isopropyl— 1,2,4-oxadiazol-5-yl) piperazin-1-yl) subspecial) -3-fluorophenyl) ( Pyridin-1-yl) methanone;
(122) 4-(3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-3-플루오로 -N— (1，3-다이하이드록시프로판- (122) 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluoro-N— ( 1,3-dihydroxypropane-
2一일 )벤즈아마이드; 2 1 day) benzamide;
(123) 4— (3-(4— (3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-2-플루오로 -N-( (R)-2,3- 다이하이드록시프로필)벤즈아마이드; (123) 4— (3- (4— (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -2-fluoro-N- ( (R) -2,3-dihydroxypropyl) benzamide;
(124) 1-(4-(5-메틸 -6- (메틸설포닐)피리딘 -3-일옥시 )부탄 -2- 일 )-4-(3—이소프로필 -1，2，4-옥사다이아졸 -5-일 )피페라진 ;  (124) 1- (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4- (3—isopropyl-1,2,4-oxadia Sol-5-yl) piperazine;
(125) 에틸 4-((R)-3-(4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진 -1-일)부톡시 )-2-플루오로벤조에이트;  (125) ethyl 4-((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluor Robenzoate;
(126) 4-((R)-3-(4-(3-이소프로필 -1,2ᅳ 4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부톡시 )-2-플루오로벤조에이；  (126) 4-((R) -3- (4- (3-isopropyl-1,2'4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro Benzoa;
(127) 4-((R)-3-(4-(3-이소프로필 -1,2,4-옥사다이아졸 -5- 일)피페라진 -1-일 )부록시 )-2-플루오로 -N-( 00-2,3- 다이하이드록시프로필)벤즈아마이드;  (127) 4-((R) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro -N- (00-2,3-dihydroxypropyl) benzamide;
(128) 에틸 4-((S)-3-(4-(3-이소프로필 -1，2，4—옥사다이아졸 -5- 일)피페라진 -1-일 )부톡시 )-2-플루오로벤조에이트;  (128) ethyl 4-((S) -3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro Robenzoate;
(129) 4-((S)-3— (4-(3-이소프로필 -1，2，4-옥사다이아졸 -5- 일)피페라진 -1-일)부톡시 )-2-풀루오로벤조에이트; 및  (129) 4-((S) -3— (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-pulluo Robenzoate; And
(130) 4-((S)-3— (4— (3-이소프로필 -1，2，4-옥사다이아졸 -5- 일 )피페라진 -1-일 )부특시 )-2-플루오로 -N-((R)-2,3- 다이하이드록시프로필 )벤즈아마이드；으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체 .  (130) 4-((S) -3— (4— (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -2-fluoro -N-((R) -2,3-dihydroxypropyl) benzamide; novel piperazine derivatives, pharmaceutically acceptable salts thereof or optical isomers thereof, characterized in that any one selected from the group consisting of: .
【청구항 12】 [Claim 12]
하기 반응식 1에 나타낸 바와 같이，  As shown in Scheme 1 below,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 피페리딘 유도체를 커플링 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계 (단계 1);  Preparing a compound represented by Chemical Formula 4 by coupling a compound represented by Chemical Formula 2 with a piperidine derivative represented by Chemical Formula 3 (step 1);
상기 단계 1에서 제조된 화학식 4의 화합물을 환원반응을 수행하여 화학식 5로 표시되는 화합물을 제조하는 단계 (단계 2); 및 상가 단계 2에서 제조된 화학식 5의 화합물과 화학식 6으로 표시되는 화합물을 커플링 반응시켜 화학식 la로 표시되는 화합물을 제조하는 단계 (단계 3);를 포함하는 계 1항의 화학식 1로 표시되는 신규한 피페라진 유도체의 제조방법 :  Preparing a compound represented by Chemical Formula 5 by performing a reduction reaction on the compound of Chemical Formula 4 prepared in Step 1 (Step 2); And coupling the compound represented by Chemical Formula 5 and the compound represented by Chemical Formula 6 prepared in step 2 to prepare a compound represented by Chemical Formula la (step 3). Process for the preparation of one piperazine derivative:
[반응식 1] Scheme 1
단계
Figure imgf000107_0001
step
Figure imgf000107_0001
Figure imgf000107_0002
Figure imgf000107_0002
같고;
Figure imgf000107_0003
Equal to;
Figure imgf000107_0003
【청구항 13】 [Claim 13]
제 12항에 있어서，  The method of claim 12,
상기 단계 3에서 제조된 화학식 la의 화합물에 유기산 또는 무기산을 처리하여 하기 화학식 1A로 표시되는 산 부가염을 제조하는 단계를 더 포함하는 것을 특징으로 하는 제 1항의 신규한 피페라진 유도체의 제조방법：  A process for preparing the novel piperazine derivative of claim 1, further comprising the step of preparing an acid addition salt represented by the following Formula 1A by treating the compound of Formula la prepared in Step 3 with an organic acid or an inorganic acid:
[화학식 1A]  [Formula 1A]
Figure imgf000107_0004
Figure imgf000107_0004
(상기 화학식 1A에서 , A, B, R 및 n은 제 1항에서 정의한 같고;  (In Formula 1A, A, B, R and n are the same as defined in claim 1;
HA는 유기산 또는 무기산이고; 및  HA is an organic or inorganic acid; And
상기 화학식 1A의 화합물은 화학식 1의 화합물이다) . 【청구항 14】  The compound of Formula 1A is a compound of Formula 1). [Claim 14]
제 13항에 있어서，  The method of claim 13,
상기 유기산 또는 무기산은 옥살산, 염산 또는 트라이플루오로아세트산인 것을 특징으로 하는 제 1항의 화학식 1로 표시되는 신규한 피페라진 유도체의 제조방법 .  The organic or inorganic acid is oxalic acid, hydrochloric acid or trifluoroacetic acid, characterized in that the novel piperazine derivative represented by the formula (1) characterized in that.
【청구항 15】 [Claim 15]
하기 반응식 2에 나타난 바와 같이， 화학식 lb로 표시되는 화합물과 리튬하이드톡사 o' 반응시켜 화학식 lc로 표시되는 리튬염을 제조하는 단계 (단계 1); As shown in Scheme 2 below, Preparing a lithium salt represented by Chemical Formula lc by reacting a compound represented by Chemical Formula lb with lithium hydroxa o ' (step 1);
상기 단계 1에서 제조된 화학식 lc의 리튬염과 화학식 7로 표시되는 화합물을 아마이드화 반웅을 수행하여 화학식 Id로 표시되는 화합물을 제조하는 단계 (단계 2);를 포함하는 제 1항의 화학식 1로 표시되는 신규한 피페라진 유도체의 제조방법 :  A method of preparing a compound represented by Chemical Formula Id by performing amidation reaction of the lithium salt of Chemical Formula lc prepared in Step 1 and the compound represented by Chemical Formula 7 (Step 2); Process for the preparation of novel piperazine derivatives:
[반응식 2]  Scheme 2
Figure imgf000108_0001
Figure imgf000108_0001
(상기 반웅식 2에서， B, R, R' . R" 및 n은 제 1항에서 정의한 바와 같고; 및  (In Reaction Formula 2, B, R, R'.R "and n are as defined in claim 1; and
화학식 lb 내지 화학식 Id의 화합물은 화학식 1의 화합물이다).  Compound of Formula lb to Formula Id is a compound of Formula 1).
【청구항 16】 [Claim 16]
하기 반응식 3에 나타난 바와 같이 ,  As shown in Scheme 3,
화학식 8-(S)로 표시되는 화합물과 t- 부틸다이메틸실릴클로라이드 (TBSC1)를 반응시켜 화학식 9-(S)로 표시되는 화합물올 제조하는 단계 (단계 1);  Preparing a compound represented by Chemical Formula 9- (S) by reacting a compound represented by Chemical Formula 8- (S) with t-butyldimethylsilyl chloride (TBSC1) (step 1);
상기 단계 1에서 제조된 화학식 9-(S)의 화합물과 메탄설포닐클로라이드 (MsCl)를 반응시켜 화학식 10-(S)로 표시되는 화합물을 제조하는 단계 (단계 2);  Preparing a compound represented by Chemical Formula 10- (S) by reacting the compound of Chemical Formula 9- (S) prepared in Step 1 with methanesulfonyl chloride (MsCl) (Step 2);
상기 단계 2에서 제조된 화학식 10-(S)의 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 ll-(R)로 표시되는 화합물을 제조하는 단계 (단계 3);  Reacting the compound represented by Chemical Formula 10- (S) prepared in Step 2 with the compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula ll- (R) (step 3);
상기 단계 3에서 제조된 화학식 ll-(R)로 표시되는 화합물의 탈보호화 반응을 수행하여 화학식 5-(R)로 표시되는 화합물을 제조하는 단계 (단계 4); 및  Preparing a compound represented by Chemical Formula 5- (R) by performing a deprotection reaction of the compound represented by Chemical Formula ll- (R) prepared in Step 3 (Step 4); And
상기 단계 4에서 제조된 화학식 5-(R)의 화합물과 화학식 6으로 표시되는 화합물의 커플링 반웅을 수행하여 화학식 ι-αυ로 표시되는 화합물을 제조하는 단계 (단계 5);를 포함하는 제 1항의 화학식 1로 표시되는 신규한 피페라진 유도체의 제조방법 :  A step of preparing a compound represented by the chemical formula ι-αυ by performing coupling reaction between the compound represented by the chemical formula 5- (R) prepared in step 4 and the compound represented by the chemical formula 6 (step 5); Method for preparing a novel piperazine derivative represented by the formula (1):
[반응식 3]
Figure imgf000109_0001
Scheme 3
Figure imgf000109_0001
(상기 반응식 3에서 , A, B 및 R은 제 1항에서 정의한 바와 같고 TBS는 t-부틸다이메틸실릴기이고;  (In Scheme 3, A, B and R are as defined in claim 1 and TBS is a t-butyldimethylsilyl group;
Ms은 메탄설포닐기이고; 및  Ms is a methanesulfonyl group; And
화학식 1-00의 화합물은 화학식 1의 화합물이다).  Compound of Formula 1-00 is a compound of Formula 1).
【청구항 17】 [Claim 17]
하기 반응식 4에 나타난 바와 같이，  As shown in Scheme 4 below,
화학식 8-(R)로 표시되는 화합물과 t- 부틸다이메틸실릴클로라이드 (TBSC1)를 반웅시켜 화학식 9-(R)로 표시되는 화합물을 제조하는 단계 (단계 1);  Preparing a compound represented by Chemical Formula 9- (R) by reacting the compound represented by Chemical Formula 8- (R) with t-butyldimethylsilyl chloride (TBSC1) (Step 1);
상기 단계 1에서 제조된 화학식 9- 00의 화합물과 메탄설포닐클로라이드 (MsCl)를 반응시켜 화학식 10- (R)로 표시되는 화합물을 제조하는 단계 (단계 2);  Preparing a compound represented by Chemical Formula 10- (R) by reacting a compound of Chemical Formula 9-00 prepared in Step 1 with methanesulfonyl chloride (MsCl) (Step 2);
상기 단계 2에서 제조된 화학식 1()-(R)의 화합물과 화학식 Compounds of formula 1 ()-(R) and formula prepared in step 2
3으로 표시되는 화합물을 반응시켜 화학식 ll-(S)로 표시되는 화합물을 제조하는 단계 (단계 3); Reacting the compound represented by 3 to prepare a compound represented by Chemical Formula ll- (S) (step 3);
상기 단계 3에서 제조된 화학식 ll-(S)로 표시되는 화합물의 탈보호화 반응을 수행하여 화학식 5-(S)로 표시되는 화합물을 제조하는 단계 (단계 4); 및  Preparing a compound represented by Chemical Formula 5- (S) by performing a deprotection reaction of the compound represented by Chemical Formula ll- (S) prepared in Step 3 (Step 4); And
상기 단계 4에서 제조된 화학식 5-(S)의 화합물과 화학식 6으로 표시되는 화합물의 커플링 반응을 수행하여 화학식 1-(S)로 표시되는 화합물을 제조하는 단계 (단계 5);를 포함하는 제 1항의 화학식 1로 표시되는 신규한 피페라진 유도체의 제조방법 :  Preparing a compound represented by Chemical Formula 1- (S) by performing a coupling reaction between the compound represented by Chemical Formula 5- (S) and the compound represented by Chemical Formula 6 prepared in step 4; Method for preparing a novel piperazine derivative represented by Formula 1 of claim 1:
[반응식 4]
Figure imgf000110_0001
Scheme 4
Figure imgf000110_0001
(상기 반응식 4에서 , A, B 및 ！^은 제 1항에서 정의한 바와 같고; TBS는 t-부틸다이메틸실릴기이고; (In Reaction Scheme 4, A, B and! ^ Are as defined in claim 1; TBS is a t-butyldimethylsilyl group;
Ms은 메탄설포닐기이고 ; 및  Ms is a methanesulfonyl group; And
화학식 1-(S)의 화합물은 화학식 1의 화합물이다).  Compound of formula 1- (S) is a compound of formula 1).
【청구항 18】 [Claim 18]
하기 화학식 1로 표시되는 신규한 피페라진 유도체， 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체를 유효성분으로 함유하는 대사질환 예방 또는 치료용 약학적 조성물.  A pharmaceutical composition for preventing or treating metabolic diseases comprising a novel piperazine derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.
[화학식 1]
Figure imgf000110_0002
[Formula 1]
Figure imgf000110_0002
(상기 반응식 1에서 , A, B, R 및 n은 제 1항에서 정의한 바와 같다).  (In Scheme 1, A, B, R and n are as defined in claim 1).
【청구항 19】 [Claim 19]
제 18항에 있어서，  The method of claim 18,
상기 화학식 1의 피페라진 유도체는 GPR119 효소를 활성화시키는 것을 특징으로 하는 대사질환 예방 또는 치료용 약학적 조성물.  Piperazine derivative of Formula 1 is a pharmaceutical composition for preventing or treating metabolic diseases, characterized in that to activate the GPR119 enzyme.
【청구항 20】 [Claim 20]
제 18항에 있어서 상기 대사질환은 비만， I 형 당뇨병， Π형 당뇨병， 부적합한 내당력 , 인슐린 내성， 고혈당증， 고지질혈증, 고중성지방혈증， 고콜레스테롤혈증， 이상지질혈증 및 X 증후군으로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 대사질환 예방 또는 치료용 약학적 조성물. The method of claim 18 The metabolic disease is any one selected from the group consisting of obesity, type I diabetes, type Π diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and X syndrome Pharmaceutical composition for preventing or treating metabolic diseases, characterized in that the.
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