WO2013105753A1

WO2013105753A1 - Substituted piperidine derivatives and methods for preparing the same

Info

Publication number: WO2013105753A1
Application number: PCT/KR2013/000009
Authority: WO
Inventors: Jin Yang; Jinwoong Kim; Hankyu LEE; Jaehyun Kim; Changmo SON; Kyuhwan Lee; Hyungho Choi; Daehoon Kim; Hyosun CHOI; Jaekeol Rhee
Original assignee: Hyundai Pharm Co., Ltd.
Priority date: 2012-01-13
Filing date: 2013-01-03
Publication date: 2013-07-18
Also published as: KR20130083592A

Abstract

The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition for treating metabolism-related disorder containing the same. Specifically, the present invention relates to a compound of the formula 1, which can activate GPR119 to treat metabolism-related disorders, including diabetes and related diseases, diabetes-related microvascular complications, diabetes-related macrovascular complications, cardiovascular abnormalities, metabolic syndrome and its constituent diseases, and obesity.

Description

SUBSTITUTED PIPERIDINE DERIVATIVES AND METHODS FOR PREPARING THE SAME

The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition for treating metabolism-related disorder containing the same.

Diabetes is a serious disease affecting more than 100 million people worldwide and is an ever-increasing threat to human health. Diabetes can be divided into two clinical syndromes, type I diabetes and type II diabetes. Type I diabetes, also known as insulin-dependent mellitus (IDDM), is caused by the autoimmune destruction of the insulin producing pancreatic β-cells and necessitates regular administration of exogenous insulin. Type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM), manifests with an inability to adequately regulate blood-glucose levels. Type II diabetes may be characterized by a defect in insulin secretion or by insulin resistance, namely those that suffer from Type II diabetes have too little insulin or cannot use insulin effectively.

In diabetics, glucose levels build up in the blood and urine causing excessive urination, thirst, hunger, and problems with fat and protein metabolism. Diabetes mellitus may cause life-threatening complications, including blindness, kidney failure, and heart disease. Diabetes is also a leading cause of damage to the retina at the back of the eye and increases risk of cataracts and glaucoma. In addition, diabetes is associated with nerve damage in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections.

Current therapies for diabetes mellitus include insulin, insulin secretagogues, glucose-lowering effectors, activators of the peroxisome proliferator-activated receptor (PPAR), and so on. However, there are deficiencies associated with currently available treatments, including hypoglycemic episodes, weight gain, loss in responsiveness to therapy over time, gastrointestinal problems, and edema.

There are several areas at which research is being targeted in order to bring new, more effective, therapies to the marketplace. One particular target is GPR119. GPR119 is a G-protein-coupled receptor that is expressed mainly in the pancreas, the small intestines, the colon, and adipose tissue. The expression profile of GPR119 indicates its potential utility as a target for the treatment of obesity and diabetes. Activation of GPR119 has been demonstrated to stimulate intracellular cAMP and lead to glucose-dependent GLP-1 and insulin secretion (T. Soga et al., Biochemical and Biophysical Research Communication 326 (2005) 744-751). In addition to effects on plasma glucose levels, GPR119 activators have also been demonstrated to produce reductions in acute food intake and to reduce body weight in rats following chronic administration (Overton, H.A. et al., "Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agent" Cell metabolism, 3:167-175 (2006), and PCT Publication Nos. WO 05/007647 and WO 05/007658).

An activator of GPR119 may be used for treatment of diabetes, diabetes-related diseases, diabetes-related microvascular complications, diabetes-related macrovascular complications, cardiovascular abnormalities, metabolic syndrome and its constituent diseases, obesity, and other diseases.

The present invention provides a novel compound or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition for treating metabolism-related disorder containing the same.

The present invention provides a compound of the following formula 1 or a pharmaceutically acceptable salt thereof:

[Formula 1]

wherein

A is selected from among a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heterocyclic group;

n is an integer ranging from 1 to 3;

m is an integer ranging from 0 to 3;

R₁ is selected from among -COOR₃, or a substituted or unsubstituted heterocyclic group;

R₂ and R₃ are each independently a straight- or branched- chain, substituted or unsubstituted C_1-5 alkyl group;

wherein the heterocyclic group represents a 5- or 6-membered heterocyclic ring containing 4 or less heteroatoms selected from the group consisting of O, N and S;

wherein the substituted phenyl group, the substituted heterocyclic group and the substituted C_1-5 alkyl group represent that one or more carbon atoms constituting the phenyl group, the heterocyclic group or the C_1-5 alkyl group are each independently substituted with one or more substituents selected from the group consisting of -SOR', -S(O)₂R', -NHS(O)₂R', -CN, halogen, methyl halide, C_2-5 alkenyl, -R', =O, -COR', -COOR', -CONR'R", and -NR'R", wherein R' and R" are each independently represent H or straight- or branched-chain C_1-5 alkyl, or may be linked together with 4 or less heteroatoms selected from the group consisting of O, N and S to form a 5- or 6-membered heterocyclic ring; and the substituents may be further substituted with one or more substituents selected from the group consisting of -SOR', -S(O)₂R', -NHS(O)₂R', -CN, halogen, a substituted heterocyclic group, methyl halide, -R', =O, -COR', -COOR', -CONR'R", and -NR'R" as defined above.

In the present invention, the compound of formula 1 may be either any one selected from the group consisting of compounds represented by the following formulas or a pharmaceutically acceptable salt thereof:

In the present invention, the compound of formula 1 is preferably any one selected from the group consisting of compounds represented by the following formulas:

The present invention also provides a pharmaceutical composition for treatment of metabolism-related disorder, which contains the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, examples of the metabolism-related disorder include obesity, type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and X syndrome.

Hereinafter, the present invention will be described in detail with reference to preparation examples and examples. It is to be understood, however, that these preparation examples and examples are for illustrative purposes and are not intended to limit the scope of the present invention.

All reagents used in these preparation examples and examples were purchased from Sigma Aldrich, Fluka, and TCI, and 1H NMR spectra were recorded on a Bruker Biospin AVANCE II 400 spectrometer using tetramethyl silane as an internal standard.

Intermediate 1

Synthesis of tert-butyl 4-((2-hydroxyethyl)(methyl)amino)piperidine-1-carboxylate

10.0 g of 1-(tert-butoxycarbonyl)-4-piperidon and 5.3 mL of 2-(methylamino)ethanol were dissolved in 100 mL of THF solution with stirring in a 250-mL flask under a nitrogen flask. 3.2 mL of acetic acid was added dropwise to the solution at 0 ℃, and the mixture was stirred at room temperature for 1 hour or more. Next, 16 g of sodium triacetoxyborohydride was added to the reaction solution which was then stirred at room temperature for 12 hours or more. After completion of the reaction, 50 mL of distilled water was added dropwise to the reaction solution, followed by addition of 100 mL of EA. The water layer was adjusted to a basic pH using sodium bicarbonate, after which it was extracted with 100 mL of EA, dried with anhydrous magnesium and concentrated, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 4.20 (2H, s), 3.57 (2H, t), 2.66 (2H, t), 2.60 (2H, t), 2.56 (2H, m), 2.27 (3H, s), 1.73 (2H,d), 1.47 (9H, s), 1.41 (2H, m).

Intermediate 2

Synthesis of tert-butyl 4-(methyl(2-(methylsulfonyloxy)ethyl)amino)piperidine-1-carboxylate

1.75 g of tert-butyl-4-((2-hydroxyethyl)(methyl)amino)piperidine-1-carboxylate was dissolved in 50 mL of chloroform with stirring in a 100-mL flask under a nitrogen atmosphere. 1.9 mL of triethylamine was added dropwise to the solution at 0 ℃, and the mixture was stirred for 30 minutes. After completion of the stirring, 0.6 mL of methanesulfonyl chloride was added dropwise to the reaction mixture which was then stirred at room temperature for 3 hours or more. After completion of the reaction, the reaction solution was washed with 50 mL of distilled water, dried with anhydrous magnesium sulfate, dried, concentrated, and then purified by silica column chromatography, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 4.15 (2H, s), 3.54 (2H, t), 2.79 (2H, t), 2.70 (2H, m), 2.56 (2H, m), 2.34 (3H, s), 1.74 (2H,d), 1.49 (9H, s), 1.40 (2H, m).

Intermediate 3

Synthesis of 1-(3-isopropyl-1,2,4-oxadiazole-5-yl)piperidin-4-one

25 g of 1-(tert-butoxycarbonyl)-4-piperidone was dissolved in 100 mL of MC with stirring in a 250-mL flask under a nitrogen atmosphere. 160 mL of 4M HCl in dioxane was added slowly dropwise to the solution, and the mixture was stirred for 3 hours or more. After completion of the reaction, the produced solid was filtered and washed with 100 mL of EA. The produced solid was dissolved in 100 mL of a 1:1 solution of acetonitrile and distilled water with stirring, and 35.5 g of sodium bicarbonate and 15 g of cyanogen bromide were added to the solution which was then heated under reflux for 12 hours or more. After completion of the reaction, 100 mL of distilled water was added slowly to the reaction solution which was then extracted three times with 100 mL of MC, dried with anhydrous magnesium sulfate and concentrated. The residue was dissolved in 100 mL of EA with stirring, and 7.43 g of N-hydroxyisobutyramidine was added to the solution. Then, 69 mL of 1M solution of zinc chloride in diethyl ether was added slowly dropwise to the solution which was then stirred for 12 hours. After completion of the reaction, the produced solid was filtered and washed with 50 mL of diethyl ether. The produced solid was dissolved in 100 mL of ethanol with stirring, and 60 mL of 4N HCl aqueous solution was added dropwise thereto. Then, the solution was heated under reflux for 4 hours or more. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove ethanol, after which it was adjusted to a basic pH using sodium bicarbonate and extracted twice with 100 mL of EA. The extracted solution was dried with anhydrous magnesium sulfate and concentrated, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 3.95 (4H, m), 2.93 (1H, m), 2.60 (4H, m), 1.31 (6H, d).

Intermediate 4

Synthesis of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethanol

The title compound was obtained in the same manner as intermediate 1, except that 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-one was used instead of 1-(tert-butoxycarbonyl)-4-piperidone.

¹H NMR (400, CDCl₃) : 4.25 (2H, d), 3.59 (2H, t), 3.06 (2H, t), 2.90 (1H, m), 2.65 (3H, m), 2.29 (3H, s), 1.85 (2H,d), 1.63 (2H, m), 1.31 (6H, d).

Intermediate 5

Synthesis of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate

The title compound was obtained in the same manner as intermediate 2, except that 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethanol was used instead of tert-butyl-4-(methyl(2-(methylsulfonyloxy)ethyl)amino)piperidine-1-carboxylate.

¹H NMR (400, CDCl₃) : 4.21 (2H, d), 3.55 (2H, t), 3.04 (2H, t), 2.90 (1H, m), 2.81 (2H, t), 2.65 (1H, m), 2.31 (3H, s), 1.86 (2H,d), 1.61 (2H, m), 1.30 (6H, d).

Intermediate 6

Synthesis of 1-(5-ethylpyrimidin-2-yl)piperidin-4-one

25 g of 1-(tert-butoxycarbonyl)-4-piperidone was dissolved in 100 mL of MC with stirring in a 250 mL flask under a nitrogen atmosphere, and 160 mL of 4M HCl in dioxane was added slowly dropwise to the solution which was then stirred for 3 hours or more. After completion of the reaction, the produced solid was filtered and washed with 100 mL of EA. The produced solid was dissolved in 100 mL of a 1:1 solution of acetonitrile and distilled water with stirring, and 35.5 g of sodium bicarbonate and 20 g of 2-chloro-ethylpyrimidine were added to the solution which was then heated under reflux for 12 hours. After completion of the reaction, 100 mL of distilled water was added slowly to the reaction solution which was then extracted three times with 100 mL of MC, dried with anhydrous magnesium sulfate and concentrated.

¹H NMR (400, CDCl₃) : 4.21 (2H, d), 3.55 (2H, t), 3.04 (2H, t), 2.90 (1H, m), 2.81 (2H, t), 2.65 (1H, m), 2.31 (3H, s), 1.86 (2H,d), 1.61(2H, m), 1.30(6H, d).

Intermediate 7

Synthesis of 2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethanol

The title compound was obtained in the same manner as intermediate 1, except that 1-(5-ethylpyrimidin-2-yl)piperidin-4-one was used instead of 1-(tert-butoxycarbonyl)-4-piperidone.

¹H NMR (400, CDCl₃) : 8.17 (2H, s), 4.80 (2H, d), 3.57 (2H, t), 2.82 (2H, m), 2.69 (2H, m), 2.48 (2H, q), 2.27 (3H, s), 1.82 (2H, d), 1.53 (2H, m), 1.19 (3H, t).

Intermediate 8

Synthesis of 2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate

The title compound was obtained in the same manner as intermediate 2, except that 2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethanol was used instead of tert-butyl-4-(methyl(2-(methylsulfonyloxy)ethyl)amino)piperidine-1-carboxylate.

¹H NMR (400, CDCl₃) : 8.18 (2H, s), 4.79 (2H, d), 3.55 (2H, t), 2.83 (4H, m), 2.69 (1H, m), 2.48 (2H, q), 2.36 (3H, s), 1.84 (2H, d), 1.47 (2H, m), 1.20 (3H, t).

Intermediate 9

Synthesis of 2-(ethyl(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)amino)ethanol

The title compound was obtained in the same manner as intermediate 1, except that 2-(ethylamino)ethanol was used instead of 2-(methylamino)ethanol and 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-one was used instead of tert-butyl-4-((2-hydroxyethyl)(methyl)amino)piperidine-1-carboxylate.

¹H NMR (400, CDCl₃) : 4.22 (2H, m), 3.52 (2H, t), 3.04 (2H, t), 2.92 (1H, m), 2.80 (1H, m), 2.52 (2H, t), 2.58 (2H, q), 1.80 (2H, d), 1.57 (2H, m), 1.29 (6H, d), 1.08 (3H. t).

Intermediate 10

Synthesis of 2-(ethyl(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)amino)ethyl methanesulfonate

The title compound was obtained in the same manner as intermediate 2, except that 2-(ethyl(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)amino)ethanol was used instead of tert-butyl-4-(methyl(2-(methylsufonyloxy)ethyl)amino)piperidine-1-carboxylate.

¹H NMR (400, CDCl₃) : 4.23 (2H, d), 3.44 (2H, t), 3.06 (2H, t), 2.89 (1H, m), 2.81 (2H, t), 2.73 (1H, m), 2.62 (2H, q), 1.85 (2H, d), 1.60 (2H, m), 1.30 (6H, d), 1.07 (3H, t).

Intermediate 11

Synthesis of 2-fluoro-4-(methylsufonyl)phenol

8.8 g of 4-bromo-2-fluorophenol was dissolved in 100 mL of DMSO with stirring in a 250- mL flask under a nitrogen atmosphere. 18.96 g of sodium sulfinate, 2.33 g of kappa (I) trifluoromethanesulfate benzene complex and 0.82 g of dimethylethylenediamine were added dropwise to the solution which was then heated under reflux for 12 hours or more. After completion of the reaction, 100 mL of 1N HCl aqueous solution was added to the reaction solution which was then extracted with 100 mL of EA, after which it was dried with anhydrous magnesium sulfate, concentrated, and then purified by silica column chromatography, thereby obtaining the title compound.

Intermediate 12

Synthesis of (2-fluoro-4-nitrophenyl)(methyl)sulfone

17 g of 3,4-difluoronitrobenzene was dissolved in 100 mL of THF with stirring in a 250 mL flask under a nitrogen atmosphere. 11.2 g of sodium thiomethoxide and 10 mL of DMF were added slowly dropwise to the solution which was then stirred at room temperature for 4 hours or more. After completion of the reaction, 500 mL of distilled water was added to the reaction solution to form a solid. The solid was filtered and washed with 100 mL of distilled water and 100 mL of hexane, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 8.06 (1H, d), 7.92 (2H, d), 7.31 (1H, d), 2.58 (3H, s).

Intermediate 13

Synthesis of 3-fluoro-4-(methylthio)benzeneamine

21.2 g of intermediate 12 was dissolved in 600 mL of a 5:1 solution of acetic acid and distilled water with stirring in a 1,000 mL flask under a nitrogen atmosphere. 32 g of iron was added slowly dropwise to the solution which was then stirred at room temperature for 3 hours or more. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove acetic acid and dissolved in 500 mL of EA, followed by filtration through celite. The filtrate was washed twice with 1 L of saturated NaHCO₃ aqueous solution and washed with 1 L of brine. The washed filtrate was dried with anhydrous magnesium sulfate, concentrated and then purified by silica column chromatography, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.21 (1H, t), 6.53 (2H, m), 3.81 (2H, s), 2.39 (3H, s).

Intermediate 14

Synthesis of 3-fluoro-4-(methylthio)phenol

13.3 g of intermediate 13 was dissolved in 650 mL of distilled water and 20 mL of THF with stirring in a 1,000 mL flask under a nitrogen atmosphere, and 35 mL of sulfuric acid was added dropwise to the solution. 9.7 g of sodium nitrite in 15 mL of distilled water was added dropwise to the solution at 0 ℃, and the mixture was stirred at 0 ℃ for 3 hours or more. A solution of 145 g of kappa (II) nitrate and 18.5 g of kappa (I) oxide in 500 mL of distilled water was added dropwise to the reaction solution which was then stirred at room temperature for 30 minutes or more. After completion of the reaction, the reaction solution was extracted twice with 200 mL of EA. The EA layer was washed with 100 mL of brine, dried with anhydrous magnesium sulfate, dried, concentrated and then purified by silica column chromatography, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.26 (1H, m), 6.62 (2H, m), 5.22 (1H, s), 2.42 (3H, s).

Intermediate 15

Synthesis of 3-fluoro-4-(methylsulfonyl)phenol

1.5 g of intermediate 14 was dissolved in 80 mL of THF with stirring in a 250 mL flask under a nitrogen atmosphere, and a solution of 12.3 g of oxone in 20 mL of distilled water was added thereto at 0 ℃. The mixture was stirred at room temperature for 3 hours or more. The solid was filtered, and the filtrate was extracted with 100 mL of EA and washed with 100 mL of saturated NaHCO₃ aqueous solution, after which it was dried with anhydrous magnesium sulfate, concentrated and then purified by silica column chromatography, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.81 (1H, t), 6.75 (2H, m), 6.46 (1H, s), 3.23 (3H, s).

Intermediate 16

Synthesis of 3-fluoro-4-(hydroxymethyl)phenol

5 g of 2-fluoro-4-hydroxybenzoic acid was dissolved in 100 mL of THF with stirring in a 250 mL flask under a nitrogen atmosphere. 2.43 g of LAH was added dropwise to the solution at 0 ℃, and the mixture was stirred at room temperature for 3 hours or more. The reaction material was washed with 200 mL of EA and 200 mL of 10% NaOH aqueous solution to remove LAH and extracted with 200 mL of EA. The extract was dried with anhydrous magnesium sulfate, concentrated and then crystallized using EA and diethyl ether, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.26 (1H, t), 6.62 (2H, m), 4.49 (1H, s), 4.68 (2H, d), 1.58 (3H, s).

Intermediate 17

Synthesis of 3-fluoro-4-(methylthiomethyl)phenol

1.8 g of 3-fluoro-4-(hydroxymethyl)phenyl was dissolved in 100 mL of THF with stirring in a 250 mL flask under a nitrogen atmosphere. 3.57 g of triphenylphosphine and 2.4 g of N-bromosuccinimide were added dropwise to the solution at 0 ℃, and the mixture was stirred at room temperature for 1 hour or more. After completion of the reaction, 1.9 g of sodium thiomethoxide was added dropwise to the reaction solution which was then stirred at room temperature for 12 hours or more. After completion of the reaction, 100 mL of 1N HCl aqueous solution was added to the reaction solution which was then extracted with 100 mL of EA. The extract was dried with anhydrous magnesium sulfate, concentrated and then purified by silica column chromatography, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.14 (1H, t), 6.58 (2H, m), 3.66 (2H, s), 2.05 (3H, s).

Intermediate 18

Synthesis of 3-fluoro-4-(methylsulfonylmethyl)phenol

The title compound was obtained in the same manner as intermediate 15, except that 3-fluoro-4-(methylthiomethyl)phenol was used instead of 3-fluoro-4-(methylthio)phenol.

¹H NMR (400, CDCl₃) : 7.36 (1H, t), 6.68 (2H, t), 5.18 (1H, s), 4.25 (2H, s), 2.82 (3H, s).

Intermediate 19

Synthesis of 3-methyl-4-(methylsulfonyl)phenol

The title compound was obtained in the same manner as intermediate 15, except that 4-(methylthio)-m-cresol was used instead of 3-fluoro-4-(methylthio)phenol.

¹H NMR (400, CDCl₃) : 7.94 (1H, d), 6.80 (2H, s), 5.47 (1H, s), 3.08 (3H, s), 2.67 (3H, s).

Intermediate 20

Synthesis of (Z)-5-(4-hydrozybenzylidene)thiazolidin-2,4-dione

17 g of 4-hydroxybenzaldehyde and 11.5 g of 2,4-thiazolidinedione were dissolved in 100 mL of toluene with stirring in a 250 mL flask under a nitrogen atmosphere. 2.4 mL of piperidine and 2.5 g of benzoic acid were added dropwise to the solution which was then heated under reflux for 4 hours. After completion of the reaction, the temperature was lowered to room temperature, and 24 mL of methanol was added dropwise to the reaction solution which was then stirred at room temperature for 0.5 hours. The produced solid was filtered and washed with 50 mL of methanol, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.74 (1H, s), 7.45 (2H, d), 6.92 (2H, d), 3.32 (1H, s).

Intermediate 21

Synthesis of 5-(4-hydroxybenzyl)thiazolidin-2,4-dione

6 g of intermediate 20 was dissolved in 100 mL of acetic acid with stirring in a 250 mL flask under a nitrogen atmosphere. 6.3 g of ammonium formate and 6 g of platinum/activated carbon were added dropwise to the solution which was then heated under reflux for 9 hours or more. After completion of the reaction, the temperature was lowered to room temperature, and the solid was filtered. The filtrate was distilled under reduced pressure to remove acetic acid and extract with 100 mL of EA, after which it was washed with 100 mL of distilled water and 100 mL of brine. The EA layer was dried with anhydrous magnesium sulfate, concentrated and then crystallized using EA and diethyl ether, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 12.00 (1H, s), 9.34 (1H, s), 7.02 (2H, d), 6.67 (2H, d), 4.82 (2H, q), 3.24 (1H, q), 2.98 (1H, q).

Intermediate 22

Synthesis of 2,6-difluoro-4-(methylsufonyl)phenol

The title compound was obtained in the same manner as intermediate 11, except that 4-bromo-2,6-difluorophenol was used instead of 4-bromo-2-fluorophenol.

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

Intermediate 23

Synthesis of 5-(2-fluoro-4-hydroxybenzyl)thiazolidin-2,4-dione

The title compound was obtained in the same manner as intermediate 20 and intermediate 21, except that 3-fluoro-4-hydroxybenzaldehyde was used instead of 4-hydroxybenzaldehyde.

¹H NMR (400, CDCl₃) : 12.08 (1H, s), 9.88 (1H, s), 7.07 (1H, t), 6.55 (2H, m), 4.79 (1H, q), 3.31 (1H, q), 3.01 (1H, q).

Intermediate 24

Synthesis of (2,6-difluoro-4-nitrophenyl)(methyl)sulfone

The title compound was obtained in the same manner as intermediate 12, except that 2,3,4-trifluoronitrobenzene was used instead of 3,4-difluoronitrobenzene.

¹H NMR (400, CDCl₃) : 7.80 (2H, d), 2.63 (3H, s).

Intermediate 25

Synthesis of 3,5-difluoro-4-(methylthio)benzenamine

The title compound was obtained in the same manner as intermediate 13, except that (2,6-difluoro-4-nitrophenyl)(methyl)sulfone was used instead of (2-fluoro-4-nitrophenyl)(methyl)sulfone.

¹H NMR (400, CDCl₃) : 6.24 (2H, d), 3.96 (2H, s), 2.34 (3H, s).

Intermediate 26

Synthesis of 3,5-dlfluoro-4-(methylthio)phenol

The title compound was obtained in the same manner as intermediate 14, except that 3,5-difluoro-4-(methylthio)benzenamine was used instead of 3-fluoro-4-(methylthio)benzenamine.

¹H NMR (400, CDCl₃) : 6.46 (2H, d), 5.47 (1H, s), 2.38 (3H, s).

Intermediate 27

Synthesis of 3,5-dlfluoro-4-(methylsulfonyl)phenol

The title compound was obtained in the same manner as intermediate 15, except that 3,5-difluoro-4-(methylthio)phenol was used instead of 3-fluoro-4-(methylthio)phenol.

¹H NMR (400, CDCl₃) : 6.53 (2H, d), 3.28 (3H, s).

Intermediate 28

Synthesis of N-(2-fluoro-4-hydroxyphenyl)methanesulfonamide

500 mg of 4-amino-3-fluorophenol was dissolved in 40 mL with stirring in a 100 mL flask under a nitrogen atmosphere. 0.33 mL of methanesulfonyl chloride was added dropwise to the solution at 0 ℃, and the mixture was stirred for 48 hours or more. After completion of the reaction, pyridine was removed by distillation under reduced pressure. The residue was extracted with 50 mL of EA and washed with 50 mL of distilled water and 100 mL of brine. The EA layer was dried with anhydrous magnesium sulfate, concentrated and then crystallized using EA and hexane, thereby obtaining the title compound.

¹H NMR (400, DMSO) : 9.99 (1H, s), 9.14 (1H, s), 7.14 (1H, t), 6.61 (2H, m), 2.91 (3H, s).

Intermediate 29

Synthesis of 2-fluoro-4-(hydroxymethyl)phenyl propionate

3.3 g of 2-fluoro-4-(hydroxyphenyl)phenol was dissolved in 100 mL of EA with stirring in a 250 mL flask under a nitrogen atmosphere. 3.1 mL of triethylamine and 2.1 g of propionyl chloride were added dropwise to the solution which was then stirred for 4 hours or more. After completion of the reaction, the reaction solution was washed with 50 mL of distilled water and 100 mL of brine. The EA layer was dried with anhydrous magnesium sulfate, concentrated and then purified by silica column chromatography, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.20 (1H, d), 7.12 (2H, m), 4.69 (2H, d), 2.65 (2H, q), 1.30 (3H, t).

Intermediate 30

Synthesis of 2-fluoro-4-(methylthiomethyl)phenol

The title compound was obtained in the same manner as intermediate 17, except that 2-fluoro-4-(hydroxymethyl)phenyl propionate was used instead of 3-fluoro-4-(hydroxymethyl)phenol.

¹H NMR (400, CDCl₃) : 7.07 (1H, d), 6.96 (2H, m), 5.09 (1H, s), 3.62 (2H, s), 2.01 (3H, s).

Intermediate 31

Synthesis of 2-fluoro-4-(methylsulfonylmethyl)phenol

The title compound was obtained in the same manner as intermediate 15, except that 2-fluoro-4-(methylthiomethyl)phenol was used instead of 3-flioro-4-(methylthio)phenol.

¹H NMR (400, CDCl₃) : 7.21 (1H, d), 7.07 (2H, m), 5.37 (1H, s), 4.18 (2H, s), 2.80 (3H, s).

Intermediate 32

Synthesis of 1-(methylsulfonyl)piperazine

15 g of piperazine was dissolved in 400 mL of MC with stirring in a 1,000 mL flask under a nitrogen atmosphere. A solution of 50 mL of MC in methanesulfonyl chloride was added dropwise to the solution at -14 ℃, and the mixture was stirred at room temperature for 12 hours or more. After completion of the reaction, the reaction solution was filtered to remove the solid, after which it was concentrated and then purified by silica column chromatography, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 3.21 (4H, t), 2.98 (4H, t), 2.79 (3H, s), 1.63 (1H, s).

Intermediate 33

Synthesis of 2-fluoro-4-(1H-tetrazol-1-yl)phenol

4.8 g of 4-amino-2-fluorophenol was dissolved in 100 mL of acetic acid with stirring in a 250 mL flask under a nitrogen atmosphere. 3.3 g of sodium azide and 7.58 g of triethyl orthofomate were added dropwise to the solution which was then heated under reflux for 1.2 hours or more. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove acetic acid, after which it was dissolved in 100 mL of EA and washed with 100 mL of distilled water and 100 mL of saturated NaHCO₃ aqueous solution. The EA layer was dried with anhydrous magnesium sulfate, concentrated and then crystallized using EA and hexane, thereby obtaining the title compound.

¹H NMR (400, DMSO) : 10.68 (1H, s), 9.91 (1H, s), 7.81 (1H, d), 7.56 (1H, d), 7.17 (1H, t).

Intermediate 34

Synthesis of 3-fluoro-4-(1H-tetrazol-1-yl)phenol

The title compound was obtained in the same manner as intermediate 33, except that 4-amino-3-fluorophenol was used instead of 4-amino-2-fluorophenol.

¹H NMR (400, CDCl₃) : 10.75 (1H, s), 9.82 (1H, s), 7.63 (1H, t), 6.92 (1H, d), 6.82 (1H, d).

Intermediate 35

Synthesis of (S)-tert-butyl-3-(4-hydroxyphenyl)-1-oxo-1-(pyrrolidin-1-yl)propan-2-ylcarbamate

13.56 g of N-Boc-tyrosine was dissolved in 100 mL of THF with stirring in a 250 mL flask under a nitrogen atmosphere. 12 g of EDCI, 7.18 g of HOBt , 19 mL of DIPEA and 4.9 mL of pyrolidine were added dropwise to the solution which was then stirred for 24 hours or more. After completion of the reaction, the reaction mixture was dissolved in 100 mL of EA and washed with 100 mL of distilled water. The EA layer was dried with anhydrous magnesium sulfate, concentrated and then purified silica column chromatography, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.06 (2H, d), 6.74 (2H, d), 6.40 (1H, s), 5.43 (1H, d), 4.57 (1H, q), 3.47 (2H, m), 3.33 (2H, m), 2.91 (2H, m), 2.72 (1H, m), 1.78 (2H, m), 1.64 (2H, m), 1.44 (9H, s).

Intermediate 36

Synthesis of 3-methyl-2-(methylthio)-5-nitropyridine

The title compound was obtained in the same manner as intermediate 12, except that 6-chloro-2-methyl-3-nitropyridine was used instead of 3,4-difluoronitrobenzene.

¹H NMR (400, CDCl₃) : 9.15 (1H, s), 8.09 (1H, s), 2.68 (3H, s), 2.38 (3H, s).

Intermediate 37

Synthesis of 5-methyl-6-(methylthio)pyridin-3-amine

The title compound was obtained in the same manner as intermediate 13, except that 3-methyl-2-(methylthio)-5-nitropyridine was used instead of (2-fluoro-4-nitrophenyl)(methyl)sulfone.

¹H NMR (400, CDCl₃) : 7.90 (1H, d), 6.79 (1H, d), 3.49 (2H, s), 2.55 (3H, s), 2.09 (3H, s).

Intermediate 38

Synthesis of 5-methyl-6-(methylthio)pyridin-3-ol

The title compound was obtained in the same manner as intermediate 14, except that 5-methyl-6-(methylthio)puyridin-3-amine was used instead of 3-fluoro-4-(methylthio)benzenamine.

¹H NMR (400, CDCl₃) : 8.00 (1H, s), 6.92 (1H, s), 5.83 (1H, s), 2.59 (3H, s), 2.22 (3H, s).

Intermediate 39

Synthesis of 5-methyl-6-(methylsufonyl)pyridin-3-ol

The title compound was obtained in the same manner as intermediate 15, except that 5-methyl-6-(methylthio)pyridin-3-ol was used instead of 3-fluoro-4-(methylthio)phenol.

¹H NMR (400, CDCl₃) : 8.00 (1H, s), 7.10 (1H, s), 6.95 (1H, s), 3.38 (3H, s), 2.65 (3H, s).

Intermediate 40

Synthesis of 3-chloro-4-(methylsulfonyl)phenol

The title compound was obtained in the same manner as intermediate 14, except that 3-chloro-4-(methylsulfonyl)aniline was used instead of 3-fluoro-4-(methylthio)benzenamine.

¹H NMR (400, CDCl₃) : 8.01 (1H, d), 7.04 (1H, d), 6.89 (1H, d), 6.36 (1H, s), 3.26 (3H, s).

Intermediate 41

Synthesis of 6-(methylsulfonyl)pyridin-3-ol

2.55 g of 2-chloro-5-hydroxypyridine was dissolved in 100 mL of DMSO in a 100 mL flask under a nitrogen atmosphere. 3.05 g of sodium methanesulfinate. 1.0 g of kappa (I) trifluoromethanesulfonate benzene complex and 0.42 mL of DMEDA were added to the solution which was then heated under reflux for 12 hours or more. After completion of the reaction, the reaction solution was extracted with 100 mL of EA and washed with 100 mL of saturated NaHCO₃ aqueous solution and 100 mL of brine. The EA layer was dried with anhydrous magnesium sulfate, concentrated and then purified by silica column chromatography, thereby obtaining the title compound.

¹H NMR (400, DMSO) : 11.14 (1H, s), 8.26 (1H, d), 7.90 (1H, d), 7.38 (1H, d), 3.17 (3H, s).

Intermediate 42

Synthesis of 3-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)propan-1-ol

The title compound was obtained in the same manner as intermediate 1, except that 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-one and 3-(methylamino)-1-propanol were used instead of 1-(tert-butoxycarbonyl)-4-piperidone and 2-(methylamino)ethanol.

¹H NMR (400, CDCl₃) : 4.23 (2H, m), 3.83 (2H, t), 3.06 (2H, m), 2.90 (1H, m), 2.75 (2H, m), 2.71 (1H, m), 2.32 (3H,s), 1.85 (2H, d), 1.73 (2H, m), 1.61 (2H, m), 1.30 (6H,d).

Example 1

Synthesis of tert-butyl 4-((2-(2-fluoro-4-(methylsulfonyl)phenoxy)ethyl)(methyl)amino)piperidine-1-carboxylate

426 mg of tert-butyl 4-(methyl(2-(methylsulfonyloxy)ethyl)amino)piperidine-1-carboxylate was dissolved in 50 mL of DMF with stirring in a 100 mL flask under a nitrogen atmosphere. 240 mg of 2-fluoro-4-(methylsulfonyl)phenol and 50 mg of sodium hydride were added to the solution which was then heated under reflux for 3 hours or more. After completion of the reaction, the reaction was extracted with 100 mL of EA and washed with 100 mL of distilled water and 100 mL of brine. The EA layer was dried with anhydrous magnesium sulfate, concentrated and then crystallized using EA and hexane, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.71 (1H, d), 7.66 (1H, d), 7.11 (1H, t), 4.18 (4H, m), 3.06 (3H, s), 2.97 (2H, m), 2.71 (2H, m), 2.61 (1H, m), 2.41 (3H, s), 1.79 (2H, d), 1.48 (9H, s), 1.43 (2H, m).

Example 2

Synthesis of tert-butyl 4-((2-(4-cyano-3-fluorophenoxy)ethyl)(methyl)amino)piperidine-1-carboxylate

The title compound was obtained in the same manner as Example 1, except that 2-fluoro-4-hydroxybenzonitrile was used instead of 2-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.52 (1H, t), 6.78 (1H, d), 6.72 (1H, d), 4.16 (2H, s), 4.07 (2H, t), 2.87 (2H, m), 2.70 (2H, m), 2.58 (2H, m), 2.39 (3H, s), 1.76 (2H, d), 1.47 (9H, s), 1.38 (2H, m).

Example 3

Synthesis of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methyl-N-(2-(4-(methylsulfonyl)phenoxy)ethyl)piperidine-4-amine

The title compound was obtained in the same manner as Example 1, except that 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 4-methylsulfonylphenol were used instead of tert-butyl 4-(methyl(2-(methylsulfonyloxy)ethyl)amino)piperidine-1-carboxylate and 2-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.88 (2H, d), 7.03 (2H, d), 4.23 (2H, d), 4.12 (2H, t), 3.10 (2H, d), 3.05 (3H, s), 2.90 (3H, m), 2.69 (1H, m), 2.42 (3H, s), 1.90 (2H, d), 1.65 (2H, m), 1.30 (6H, d).

Example 4

Synthesis of N-(2-(3-fluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

892 mg of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethyl methane sulfonate was dissolved in 50 mL of acetone with stirring in a 100 mL flask under a nitrogen atmosphere. 540 mg of 3-fluoro-4-(methylsulfonyl)phenol and 535 mg of potassium carbonate were added dropwise to the solution which was then heated under reflux for 3 hours or more. After completion of the reaction, the reaction solution was extracted with 100 mL of EA and washed with 100 mL of distilled water. The EA layer was extracted twice with 50 mL of 1N HCl aqueous solution, and the aqueous layer was adjusted to a basic pH using NaHCO₃, followed by extraction with 100 mL of EA. The EA layer was dried with anhydrous magnesium sulfate and concentrated, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.88 (2H, d), 7.03 (2H, d), 4.43 (2H, d), 4.31 (2H, t), 3.46 (2H, d), 3.26 (3H, s), 2.90 (3H, m), 2.69 (1H, m), 2.42 (3H, s), 1.90 (2H, d), 1.65 (2H, m) 1.30 (6H, d).

Example 5

Synthesis of N-(2-(3-fluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine trifluoroacetate

500 mg of N-(2-(3-fluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidin-4-amine was dissolved in 10 mL of EA under a nitrogen atmosphere. 0.18 mL of trifluoroacetic acid was added dropwise to the solution which was then heated under reflux for 30 minutes. After completion of the reaction, the temperature was lowered to room temperature, and the solid was filtered, thereby obtaining the title compound.

¹H NMR (400, D₂O) : 7.88 (2H, d), 7.03 (2H, d), 4.23 (2H, d), 4.12 (2H, t), 3.10 (2H, d), 3.05 (3H, s), 2.90 (3H, m), 2.69 (1H, m), 2.42 (3H, s), 1.90 (2H, d), 1.65 (2H, m) 1.30 (6H, d).

Example 6

Synthesis of tert-butyl 4-((2-(3-fluoro-4-(methylsulfonyl)phenoxy)ethyl)(methyl)amino)piperidine-1-carboxylate

The title compound was obtained in the same manner as Example 4, except that tert-butyl 4-(methyl(2-(methylsulfonyloxy)ethyl)amino)piperidine-1-carboxylate was used instead of 2-((1-(3-isopropyl-1,2,4-oxadizol-5-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate.

¹H NMR (400, CDCl₃) : 7.75 (1H, t), 6.91 (2H, t), 4.76 (2H, s), 4.68 (2H, t), 4.34 (2H, d), 3.78 (1H, m), 3.51 (2H, m), 3.22 (3H, s), 2.81 (3H, s), 2.73 (2H, m), 1.98 (2H, s) 1.58 (2H, m), 1.33 (9H, s).

Example 7

Synthesis of tert-butyl 4-((2-(3-fluoro-4-(methylsufonyl)phenoxy)ethyl)(methyl)amino)piperidine-1-carboxylate L-tartrate

The title compound was obtained in the same manner as Example 5, except that tartaric acid was used instead of trifluoroacetic acid.

¹H NMR (400, D₂O) : 7.75 (1H, t), 6.91 (2H, t), 4.54 (2H, s), 4.40 (2H, t), 4.14 (2H, d), 3.69 (1H, m), 3.51 (2H, m), 3.22 (3H, s), 2.81 (3H, s), 2.73 (2H, m), 1.98 (2H, s) 1.58 (2H, m), 1.33 (9H, s).

Example 8

Synthesis of 1-(5-ethylpyrimidin-2-yl)-N-(2-(3-fluoro-4-(methylsulfonyl)phenoxy)ethyl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate was used instead of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate.

¹H NMR (400, CDCl₃) : 8.20 (2H, s), 7.73 (1H, t), 6.90 (2H, t), 4.82 (2H, d), 4.58 (2H, t), 4.45 (2H, s), 3.51 (2H, m), 3.47 (1H, m), 3.23 (3H, s), 2.94 (2H, t), 2.81 (3H, s), 2.40 (2H, t) 2.07 (2H, d), 1.64 (2H, m), 1.04 (3H, t).

Example 9

Synthesis of 1-(5-ethyllpyrimidin-2-yl)-N-(2-(3-fluoro-4-(methylsulfonyl)phenoxy)ethyl)-N-methylpiperidine-4-amine L-tartrate

¹H NMR (400, D₂O) : 8.20 (2H, s), 7.73 (1H, t), 6.90 (2H, t), 4.57 (2H, d), 4.40 (2H, t), 4.33 (2H, s), 3.64 (2H, m), 3.47 (1H, m), 3.23 (3H, s), 2.94 (2H, t), 2.81 (3H, s), 2.40 (2H, t) 2.07 (2H, d), 1.64 (2H, m), 1.04 (3H, t).

Example 10

Synthesis of 1-(5-ethylpyrimidin-2-yl)-N-(2-(3-fluoro-4-(methylsulfonylmethyl)phenoxy)ethyl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, 2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 3-fluoro-4-(methylsulfonylmethyl)phenol were used instead of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 8.19 (2H, s), 7.38 (1H, t), 6.77 (1H, d), 6.69 (1H, d), 4.50 (2H, d), 4.41 (2H, s), 3.85 (2H, t), 2.90 (4H, m), 2.80 (3H, s), 2.71 (2H, m), 2.49 (2H, q), 2.41 (3H, s) 1.90 (2H, d), 1.48 (2H, m), 1.20 (3H, t).

Example 11

Synthesis of 1-(5-ethylpyrimidin-2-yl)-N-(2-(3-fluoro-4-(methylsulfonylmethyl)phenoxy)ethyl)-N-methylpiperidine-4-amine malonate

The title compound was obtained in the same manner as Example 5, except that malonic acid was used instead of trifluoroacetic acid.

¹H NMR (400, D₂O) : 8.12 (2H, s), 7.29 (1H, t), 6.79 (2H, d), 4.49 (2H, d), 4.45 (2H, s), 4.29 (2H, t), 3.60 (1H, m), 3.08 (2H, m), 2.96 (3H, s), 2.86 (2H, t), 2.79 (3H, s), 2.37 (2H, q) 2.03 (2H, d), 1.61 (2H, m), 1.03 (3H, t).

Example 12

Synthesis of 1-(5-ethylpyrimidin-2-yl)-N-methyl-N-(2-(3-methyl-4-(methylsulfonyl)phenoxy)ethyl)piperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 3-methyl-4-(methanesulfonyl)phenol were used instead of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, D₂O) : 8.18 (2H, s), 7.80 (1H, d), 6.92 (2H, m), 4.75 (2H, d), 4.65 (2H, t), 3.88 (2H, t), 3.46 (1H, s), 3.14 (3H, s), 2.96 (2H, t), 2.82 (3H, s), 2.50 (3H, s), 2.40 (2H, q) 2.07 (2H, d), 1.66 (2H, m), 1.05 (3H, t).

Example 13

Synthesis of 1-(5-ethylpyrimidin-2-yl)-N-methyl-N-(2-(3-methyl-4-(methylsulfonyl)phenoxy)ethyl)piperidine-4-amine oxalate

The title compound was obtained in the same manner as Example 5, except that oxalic acid was used instead of trifluoroacetic acid.

¹H NMR (400, D₂O) : 8.18 (2H, s), 7.80 (1H, d), 6.92 (2H, m), 4.50 (2H, d), 4.37 (2H, t), 3.73 (2H, t), 3.76 (1H, s), 3.14 (3H, s), 2.96 (2H, t), 2.82 (3H, s), 2.50 (3H, s), 2.40 (2H, q) 2.07 (2H, d), 1.66 (2H, m), 1.05 (3H, t).

Example 14

Synthesis of N-(2-(3-fluoro-4-(methylsulfonylmethyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 3-fluoro-4-(methylsulfonylmethyl)phenol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.30 (1H, t), 6.80 (2H, m), 4.65 (2H, s), 4.53 (2H, t), 4.21 (2H, d), 3.45 (2H, s), 3.41 (1H, m), 3.45 (2H, s), 3.11 (2H, t), 2.96 (3H, s), 2.82 (3H, s), 2.74 (1H, m) 2.09 (2H, d), 1.76 (2H, m), 1.11 (6H, d).

Example 15

Synthesis of N-(2-(3-fluoro-4-(methylsulfonylmethyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amone oxalate

¹H NMR (400, D₂O) : 7.30 (1H, t), 6.80 (2H, m), 4.45 (2H, s), 4.31 (2H, t), 4.09 (2H, d), 3.67 (2H, s), 3.57 (1H, m), 3.45 (2H, s), 3.11 (2H, t), 2.96 (3H, s), 2.82 (3H, s), 2.74 (1H, m) 2.09 (2H, d), 1.76 (2H, m), 1.11 (6H, d).

Example 16

Synthesis of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methyl-N-(2-(3-methyl-4-(methylsulfonyl)phenoxy)ethyl)piperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 3-methyl-4-(methylsulfonyl)phenol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.78 (1H, d), 6.90 (2H, m), 4.76 (2H, t), 4.35 (2H, d), 3.84 (1H, m), 3.60 (2H, s), 3.12 (5H, t), 2.83 (3H, s), 2.72 (1H, m), 2.46 (3H, s) 2.10 (2H, d), 1.77 (2H, m), 1.11 (6H, d).

Example 17

Synthesis of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methyl-N-(2-(3-methyl-4-(methylsulfonyl)phenoxy)ethyl)piperidine-4-amine oxalate

¹H NMR (400, D₂O) : 7.78 (1H, d), 6.90 (2H, m), 4.36 (2H, t), 4.09 (2H, d), 3.63 (1H, m), 3.46 (2H, s), 3.12 (5H, t), 2.83 (3H, s), 2.72 (1H, m), 2.46 (3H, s) 2.10 (2H, d), 1.77 (2H, m), 1.11 (6H, d).

Example 18

Synthesis of 1-((3-isopropyl-1,2,4-oxadiazol-5-yl)methyl)-N-methyl-N-(2-(3-methyl-4-(methylsulfonyl)phenoxy)ethyl)piperidine-4-amine

300 mg of tert-butyl 4-(methyl(2-(methylsulfonyloxy)ethyl)amino)piperidine-1-carboxylate was dissolved in 50 mL of acetone with stirring in a 100 mL flask under a nitrogen atmosphere. 199 mg of 3-methyl-4-(methylsulfonyl)phenol and 32 mg of sodium hydride were added dropwise to the solution which was then heated under reflux. After completion of the reaction, the reaction solution was extracted with 100 mL of EA and washed with 100 mL of distilled water. The EA layer was dried with anhydrous magnesium sulfate, concentrated, and then dissolved in 10 mL of EA 10 mL with stirring. 0.18 mL of trifluoroacetic acid was added dropwise to the solution which was then heated under reflux for 30 minutes. After completion of the reaction, the temperature was lowered to room temperature, and the solid was filtered. The residue was dissolved in 20 mL of DMF with stirring, and 90 mg of (3-isopropyl-1,2,4-oxadiazol-5-yl)methyl bromide and 227 mg of cesium carbonate were added dropwise to the solution which was then heated under reflux for 3 hours or more. After completion of the reaction, the reaction solution was extracted with 100 mL of EA and washed with 100 mL of distilled water. The EA layer was extracted twice with 50 mL of 1N HCl aqueous solution, and the aqueous layer was adjusted to a basic pH using NaHCO₃, followed by extraction with 100 mL of EA. The EA layer was dried with anhydrous magnesium sulfate and concentrated, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.79 (1H, d), 6.90 (2H, d), 4.52 (2H, s), 4.33 (2H, s), 3.14 (5H, t), 3.00 (3H, s), 2.94 (3H, m), 2.87 (3H, s) 2.49 (3H, s), 2.31 (2H, d), 2.00 (2H, m), 1.18 (6H, d).

Example 19

Synthesis of 1-((3-isopropyl-1,2,4-oxadiazol-5-yl)methyl)-N-methyl-N-(2-(3-methyl-4-(methylsulfonyl)phenoxy)ethyl)piperidine-4-amine oxalate

¹H NMR (400, D₂O) : 7.79 (1H, d), 6.90 (2H, d), 4.49 (2H, s), 4.37 (2H, s), 3.64 (5H, t), 3.13 (3H, s), 3.04 (3H, m), 2.87 (3H, s) 2.49 (3H, s), 2.31 (2H, d), 2.00 (2H, m), 1.18 (6H, d).

Example 20

Synthesis of 4-(2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzoic acid

The title compound was obtained in the same manner as Example 4, except that 2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 4-hydroxybenzoic acid were used instead of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 8.13 (2H, s), 7.80 (2H, d), 6.81 (2H, d), 4.67 (2H, t), 4.60 (2H, d), 3.84 (1H, m), 3.51 (2H, s), 2.87 (2H, t), 2.81 (3H, s), 2.36 (2H, q), 2.03 (2H, d), 1.60 (2H, m), 1.02 (3H, t).

Example 21

Synthesis of 4-(2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzoic acid oxalate

The title compound was obtained in the same manner as Example 5, except that oxalic acid was used instead of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethyl trifluoroacetic acid.

¹H NMR (400, D₂O) : 8.13 (2H, s), 7.80 (2H, d), 6.81 (2H, d), 4.53 (2H, t), 4.45 (2H, d), 3.64 (1H, m), 3.51 (2H, s), 2.87 (2H, t), 2.81 (3H, s), 2.36 (2H, q), 2.03 (2H, d), 1.60 (2H, m), 1.02 (3H, t).

Example 22

Synthesis of 4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzaldehyde

The title compound was obtained in the same manner as Example 4, except that 4-hydroxybenzaldehyde was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 9.90 (1H, s), 7.85 (2H, d), 7.02 (2H, d), 4.62 (2H, dt), 4.48 (2H, t), 3.29 (2H, m), 2.95 (4H, m), 2.71 (1H, m), 2.42 (3H, s), 1.90 (2H, d), 1.62 (2H, m), 1.30 (6H, d).

Example 23

Synthesis of 5-(4-(2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione

The title compound was obtained in the same manner as Example 4, except that 2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 5-(4-hydroxybenzyl)thiazolidine-2,4-dione were used instead of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 8.16 (2H, s), 7.05 (2H, d), 6.68 (2H, d), 4.87 (2H, d), 3.64 (2H, t), 3.53 (1H, m), 3.14 (2H, m), 2.89 (2H, t), 2.82 (2H, s), 2.64 (3H, s), 2.38 (2H, q), 1.87 (2H, d), 1.52 (2H, m), 1.01 (3H, t).

Example 24

Synthesis of 5-(4-(2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione oxalate

¹H NMR (400, D₂O) : 8.16 (2H, s), 7.05 (2H, d), 6.68 (2H, d), 4.47 (2H, d), 3.74 (2H, t), 3.53 (1H, m), 3.14 (2H, m), 2.89 (2H, t), 2.82 (2H, s), 2.64 (3H, s), 2.38 (2H, q), 1.87 (2H, d), 1.52 (2H, m), 1.01 (3H, t).

Example 25

(Z)-5-(4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzylidene)thiazolidine-2,4-dione

The title compound was obtained in the same manner as Example 4, except that (Z)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione was used instead of 3-fluoro-4-(methylsulfonyl)phenol and trifluoroacetic acid.

¹H NMR (400, CDCl₃) : 7.47 (1H, s), 7.33 (2H, d), 6.92 (2H, d), 4.26 (2H, d), 4.16 (2H, t), 3.10 (2H, t), 2.95 (2H, t), 2.92 (1H, m), 2.82 (1H, m), 2.50 (3H, s), 2.03 (2H, d), 1.66 (2H, m), 1.31 (6H, d).

Example 26

Synthesis of 4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzoic acid

The title compound was obtained in the same manner as Example 4, except that 4-hydroxybenzoic acid was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.83 (2H, d), 6.84 (2H, d), 4.84 (2H, t), 4.30 (2H, d), 3.83 (3H, m), 3.39 (2H, t), 2.85 (3H, s), 2.74 (1H, m), 2.08 (2H, d), 1.74 (2H, m), 1.10 (6H, d).

Example 27

Synthesis of 4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzoic acid oxalate

The title compound was obtained in the same manner as Example 4, except that oxalic acid was used instead of trifluoroacetic acid.

¹H NMR (400, D₃O) : 7.83 (2H, d), 6.84 (2H, d), 4.55 (2H, t), 4.08 (2H, d), 3.63 (3H, m), 3.09 (2H, t), 2.85 (3H, s), 2.74 (1H, m), 2.08 (2H, d), 1.74 (2H, m), 1.10 (6H, d).

Example 28

Synthesis of 5-(4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione

The title compound was obtained in the same manner as Example 4, except that 5-(4-hydroxybenzyl)thiazolidine-2,4-dione was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.05 (2H, d), 6.68 (2H, d), 4.56 (2H, d), 3.94 (2H, t), 3.62 (1H, m), 3.36 (2H, d), 3.08 (2H, m), 2.77 (3H, m), 2.66 (3H, s), 1.61 (2H, m), 1.09 (3H, t).

Example 29

Synthesis of 5-(4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione oxalate

¹H NMR (400, D₃O) : 7.05 (2H, d), 6.68 (2H, d), 4.06 (2H, d), 3.74 (2H, t), 3.53 (1H, m), 3.16 (2H, d), 3.08 (2H, m), 2.77 (3H, m), 2.66 (3H, s), 1.61 (2H, m), 1.09 (3H, t).

Example 30

Synthesis of N-(2-(2,6-difluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 2,6-difluoro-4-(methylsulfonyl)phenol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.56 (2H, d), 4.55 (2H, s), 3.86 (2H, d), 3.75 (2H, m), 3.54 (1H, m), 3.12 (5H, t), 2.85 (3H, s), 2.73 (1H, m), 2.08 (2H, d), 1.78 (2H, m), 1.07 (6H, d).

Example 31

Synthesis of N-(2-(2,6-difluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine oxalate

¹H NMR (400, D₃O) : 7.56 (2H, d), 4.55 (2H, s), 3.86 (2H, d), 3.65 (2H, m), 3.46 (1H, m), 3.12 (5H, t), 2.85 (3H, s), 2.73 (1H, m), 2.08 (2H, d), 1.78 (2H, m), 1.07 (6H, d).

Example 32

Synthesis of 5-(2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidine-2,4-dinoe

The title compound was obtained in the same manner as Example 4, except that 5-(2-fluoro-4-hydroxybenzyl)thiazolidine-2,4-dione was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.07 (1H, t), 6.52 (2H, m), 4.08 (2H, d), 3.84 (2H, t), 3.66 (1H, t), 3.45 (2H, m), 3.37 (2H, m), 3.10 (2H, m), 2.79 (1H, m), 2.71 (3H, s), 1.97 (2H, t), 1.67 (2H, m), 1.11 (6H, d).

Example 33

Synthesis of 5-(2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidine-2,4-dion oxalate

¹H NMR (400, D₃O) : 7.07 (1H, t), 6.52 (2H, m), 4.08 (2H, d), 3.84 (2H, t), 3.57 (1H, t), 3.21 (2H, m), 3.17 (2H, m), 3.10 (2H, m), 2.79 (1H, m), 2.71 (3H, s), 1.97 (2H, t), 1.67 (2H, m), 1.11 (6H, d).

Example 34

Synthesis of 4-(2-((1-(5-ethylpyrimidin-4-yl)(methyl)amino)ethoxy)-2-fluorobenzoic acid

The title compound was obtained in the same manner as Example 4, except that 2-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 2-fluoro-4-hydroxybenzoic acid were used instead of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 8.18 (2H, s), 7.60 (1H, t), 6.43 (1H, d), 6.36 (1H, d), 4.80 (2H, d), 3.43 (2H, t), 2.93 (2H, t), 2.85 (3H, m), 2.48 (2H, q), 2.43 (3H, s), 1.93 (2H, d), 1.56 (2H, m), 1.18 (3H, t).

Example 35

Synthesis of N-(2-(3,5-difluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 3,5-difluoro-4-(methylsulfonyl)phenol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 6.74 (2H, d), 4.65 (2H, t), 4.49 (2H, d), 3.84 (3H, m), 3.21 (3H, s), 3.13 (2H, t), 2.84 (3H, s), 2.78 (1H, m), 2.13 (2H, d), 1.79 (2H, m), 1.12 (6H, d).

Example 36

Synthesis of N-(2-(3,5-difluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine oxalate

¹H NMR (400, D₃O) : 6.74 (2H, d), 4.40 (2H, t), 4.19 (2H, d), 3.64 (3H, m), 3.30 (3H, s), 3.13 (2H, t), 2.84 (3H, s), 2.78 (1H, m), 2.13 (2H, d), 1.79 (2H, m), 1.12 (6H, d).

Example 37

Synthesis of N-(2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)phenyl)methanesulfonamide

The title compound was obtained in the same manner as Example 4, except that N-(2-fluoro-4-hydroxyphenyl)methanesulfonamide was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.28 (1H, t), 4.49 (2H, d), 4.31 (4H, t), 3.84 (3H, m), 3.40 (3H, s), 3.13 (2H, t), 2.84 (3H, s), 2.78 (1H, m), 2.13 (2H, d), 1.79 (2H, m), 1.12 (6H, d).

Example 38

Synthesis of N-(2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)phenyl)methanesulfonamide oxalate.

¹H NMR (400, D₃O) : 7.28 (1H, t), 4.03 (4H, t), 4.19 (2H, d), 3.64 (3H, m), 3.30 (3H, s), 3.13 (2H, t), 2.84 (3H, s), 2.78 (1H, m), 2.13 (2H, d), 1.79 (2H, m), 1.12 (6H, d).

Example 39

Synthesis of 2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzoate

The title compound was obtained in the same manner as Example 4, except that 2-fluoro-4-hydroxybenzoic acid was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.79 (1H, s), 6.33 (2H, d), 4.13 (2H, d), 3.87 (2H, s), 3.00 (2H, t), 2.89 (1H, m), 2.77 (2H, s), 2.60 (1H, s), 2.30 (3H, s), 1.80 (2H, d), 1.52 (2H, s), 1.28 (6H, d).

Example 40

Synthesis of lithium 2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzoate

The title compound was obtained in the same manner as Example 5, except that lithium hydroxide was used instead of trifluoroacetic acid.

¹H NMR (400, D₂O) : 7.79 (1H, s), 6.33 (2H, d), 4.13 (2H, d), 3.87 (2H, s), 3.00 (2H, t), 2.89 (1H, m), 2.77 (2H, s), 2.60 (1H, s), 2.30 (3H, s), 1.80 (2H, d), 1.52 (2H, s), 1.28 (6H, d).

Example 41

Synthesis of N-(2-(2-fluoro-4-(methylsulfonylmethyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 2-fluoro-4-(methylsulfonylmethyl)phenol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.21 (1H, d), 7.14 (2H, m), 4.72 (4H, s), 4.52 (2H, d), 3.75 (3H, m), 3.24 (2H, t), 2.96 (3H, s), 2.88 (3H, s), 2.79 (1H, m), 2.14 (2H, d), 1.82 (2H, m), 1.14 (6H, d).

Example 42

Synthesis of N-(2-(2-fluoro-4-(methylsulfonylmethyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine oxalate

¹H NMR (400, D₂O) : 7.21 (1H, d), 7.14 (2H, m), 4.42 (4H, s), 4.12 (2H, d), 3.66 (3H, m), 3.15 (2H, t), 2.96 (3H, s), 2.88 (3H, s), 2.79 (1H, m), 2.14 (2H, d), 1.82 (2H, m), 1.14 (6H, d).

Example 43

Synthesis of (2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)phenyl)(pyrolidin-1-yl)methanone

300 mg of lithium 2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)benzoate was dissolved in 50 mL of MC with stirring in a 100 mL flask under a nitrogen atmosphere. 118 mg of HOBt was added dropwise to the solution which was then stirred at room temperature for 30 minutes. 167 mg of EDCI and 0.12 mL of pyrolidine were added dropwise to the reaction solution which was then stirred at room temperature for 4 hours or more. After completion of the reaction, the reaction solution was washed with 50 mL of distilled water, dried with anhydrous magnesium sulfate and concentrated, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.28 (1H, t), 6.80 (2H, m), 4.65 (2H, t), 4.51 (2H, d), 3.78 (2H, s), 3.65 (2H, t), 3.33 (2H, t), 3.25 (2H, t), 3.12 (2H, t), 2.84 (3H, s), 2.78 (1H, m), 2.11 (2H, d), 1.87 (4H, m), 1.76 (2H, m), 1.12 (6H, d).

Example 44

Synthesis of (2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)phenyl)(pyrolidin-1-yl)methanone oxalate

¹H NMR (400, D₂O) : 7.28 (1H, t), 6.80 (2H, m), 4.34 (2H, t), 4.11 (2H, d), 3.68 (2H, s), 3.59 (2H, t), 3.44 (2H, t), 3.25 (2H, t), 3.12 (2H, t), 2.84 (3H, s), 2.78 (1H, m), 2.11 (2H, d), 1.87 (4H, m), 1.76 (2H, m), 1.12 (6H, d).

Example 45

Synthesis of N-(2-(2-fluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 2-fluoro-4-(methylsulfonyl)phenol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.69 (2H, d), 7.26 (1H, t), 4.76 (2H, t), 4.52 (2H, d), 3.81 (3H, m), 3.25 (3H, t), 2.85 (3H, s), 2.76 (1H, m), 2.14 (2H, d), 1.80 (2H, d), 1.13 (6H, d).

Example 46

Synthesis of N-(2-(2-fluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine oxalate

¹H NMR (400, D₂O) : 7.69 (2H, d), 7.26 (1H, t), 4.50 (2H, t), 4.12 (2H, d), 3.65 (3H, m), 3.15 (3H, t), 2.85 (3H, s), 2.76 (1H, m), 2.14 (2H, d), 1.80 (2H, d), 1.13 (6H, d).

Example 47

Synthesis of N-(2-(2-fluoro-4-(1H-tetrazol-1-yl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 2-fluoro-4-(1H-tetrazol-1-yl)phenol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 9.46 (1H, s), 7.56 (1H, d), 7.46 (1H, d), 7.21 (1H, t), 4.68 (2H, t), 4.38 (2H, d), 3.67 (3H, m), 3.25 (2H, t), 2.87 (3H, s), 2.75 (1H, m), 2.12 (2H, d), 1.78 (2H, m), 1.11 (6H, d).

Example 48

Synthesis of N-(2-(2-fluoro-4-(1H-tetrazol-1-yl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine oxalate

¹H NMR (400, D₂O) : 9.46 (1H, s), 7.56 (1H, d), 7.46 (1H, d), 7.21 (1H, t), 4.43 (2H, t), 4.10 (2H, d), 3.67 (3H, m), 3.14 (2H, t), 2.87 (3H, s), 2.75 (1H, m), 2.12 (2H, d), 1.78 (2H, m), 1.11 (6H, d).

Example 49

Synthesis of (2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)phenyl)(4-(methylsulfonyl)piperazin-1-yl)methanone

The title compound was obtained in the same manner as Example 26, except that 1-(methylsulfonyl)piperazine was used instead of pyrolidine.

¹H NMR (400, CDCl₃) : 7.27 (2H, t), 6.81 (2H, t), 4.64 (2H, t), 4.42 (2H, d), 3.98 (2H, d), 3.60 (2H, m), 3.41 (4H, d), 3.27 (2H, d), 3.16 (4H, d), 2.89 (3H, s), 2.83 (3H, s), 2.75 (1H, m), 2.10 (2H, d), 1.80 (2H, m), 1.11 (6H, d).

Example 50

Synthesis of (2-fluoro-4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)phenyl)(4-(methylsulfonyl)piperazin-1-yl)methanone oxalate

¹H NMR (400, D₂O) : 7.27(2H, t), 6.81 (2H, t), 4.34 (2H, t), 4.11 (2H, d), 3.75 (2H, d), 3.63 (2H, m), 3.43 (4H, d), 3.27 (2H, d), 3.16 (4H, d), 2.89 (3H, s), 2.83 (3H, s), 2.75 (1H, m), 2.10 (2H, d), 1.80 (2H, m), 1.11 (6H, d).

Example 51

Synthesis of N-(2-(3-fluoro-4-(1H-tetrazol-1-yl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 3-fluoro-4-(1H-tetrazol-1-yl)phenol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 9.39 (1H, s), 7.62 (1H, t), 6.97 (1H, d), 6.91 (1H, d), 4.89 (2H, t), 4.56 (2H, d), 3.41 (3H, m), 3.33 (2H, t), 2.84 (3H, s), 2.74 (1H, m), 2.10 (2H, d), 1.75 (2H, m), 1.10 (6H, d).

Example 52

Synthesis of N-(2-(3-fluoro-4-(1H-tetrazol-1-yl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine oxalate

¹H NMR (400, D₂O) : 9.39 (1H, s), 7.62 (1H, t), 6.97 (1H, d), 6.91 (1H, d), 4.49 (2H, t), 4.13 (2H, d), 3.61 (3H, m), 3.13 (2H, t), 2.84 (3H, s), 2.74 (1H, m), 2.10 (2H, d), 1.75 (2H, m), 1.10 (6H, d).

Example 53

Synthesis of N-ethyl-N-(2-(2-fluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine-4-amine

The title compound was obtained in the same manner as Example 4, 2-(ethyl(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)amino)ethyl methanesulfonate and 2-fluoro-4-(methylsulfonyl)phenol were used instead of 2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethyl methanesulfonate and 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.68 (2H, d), 7.23 (1H, t), 4.82 (2H, t), 4.35 (2H, d), 3.84 (3H, m), 3.67 (2H, t), 3.14 (5H, t), 2.78 (1H, m), 2.10 (2H, d), 1.76 (2H, m), 1.24 (3H, t), 1.12 (6H, d).

Example 54

Synthesis of N-ethyl-N-(2-(2-fluoro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine-4-amine trifluoroacetate

The title compound was obtained in the same manner as Example 5.

¹H NMR (400, D₂O) : 7.68 (2H, d), 7.23 (1H, t), 4.42 (2H, t), 4.09 (2H, d), 3.57 (3H, m), 3.17 (2H, t), 3.14 (5H, t), 2.78 (1H, m), 2.10 (2H, d), 1.76 (2H, m), 1.24 (3H, t), 1.12(6H, d).

Example 55

Synthesis of N-(2-(2-fluoropyridin-4-yloxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 2-fluoro-4-hydroxypyridine was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.95 (1H, d), 6.87 (1H, d), 6.61 (1H, s), 4.84 (2H, t), 4.36 (2H, d), 3.74 (3H, m), 3.31 (2H, t), 2.85 (3H, s), 2.79 (1H, m), 2.06 (2H, s), 1.81 (2H, m), 1.14 (6H, d).

Example 56

Synthesis of N-(2-(2-fluoropyridin-4-yloxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine hydrochloride

The title compound was obtained in the same manner as Example 5, except that hydrochloric acid was used instead of trifluoroacetic acid.

¹H NMR (400, D₂O) : 7.95 (1H, d), 6.87 (1H, d), 6.61 (1H, s), 4.87 (2H, t), 4.51 (2H, d), 3.84 (3H, m), 3.23 (2H, t), 2.85 (3H, s), 2.79 (1H, m), 2.06 (2H, s), 1.81 (2H, m), 1.14 (6H, d).

Example 57

Synthesis of N-(2-(4-bromo-2,5-difluorophenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 4-bromo-2,5-difluorophenol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.40 (1H, q), 7.02 (1H, t), 4.68 (2H, s), 4.32 (2H, d), 3.78 (3H, m), 3.24 (2H, t), 2.87 (3H, s), 2.79 (1H, m), 2.05 (2H, s), 1.80 (2H, m), 1.14 (6H, d).

Example 58

Synthesis of N-(2-(4-bromo-2,5-difluorophenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine hydrochloride

¹H NMR (400, D₂O) : 7.40 (1H, q), 7.02 (1H, t), 4.38 (2H, s), 4.12 (2H, d), 3.63 (3H, m), 3.16 (2H, t), 2.87 (3H, s), 2.79 (1H, m), 2.05 (2H, s), 1.80 (2H, m), 1.14 (6H, d).

Example 59

Synthesis of (S)-2-amino-3-(4-(2-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(methyl)amino)ethoxy)phenyl)-1-(pyrolidin-1-yl)propan-1-one

The title compound was obtained in the same manner as Example 4, except that (S)-tert-butyl 3-(4-hydroxyphenyl)-1-oxo-1-(pyrolidin-1-yl)propan-2-ylcarbamate was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.15 (2H, s), 6.92 (2H, m), 4.17 (2H, d), 3.98 (4H, m), 3.42 (3H, s), 3.24 (5H, m), 2.80 (2H, m), 2.33 (2H, d), 1.87 (2H, s), 1.68 (2H, s), 1.50 (2H, s), 1.13 (6H, d).

Example 60

Synthesis of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methyl-N-(2-(5-methyl-6-(methylsulfonyl)pyridin-3-yloxy)ethyl)piperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 5-methyl-6-(methylsulfonyl)pyridin-3-ol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 8.12 (1H, s), 7.40 (1H, s), 4.64 (2H, t), 4.33 (2H, d), 3.76 (3H, m), 3.54 (3H, s), 3.23 (2H, t), 2.86 (3H, s), 2.77 (1H, m), 2.54 (3H, s), 2.13 (2H, d), 1.82 (2H, m), 1.12 (6H, d).

Example 61

Synthesis of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methyl-N-(2-(5-methyl-6-(methylsulfonyl)pyridin-3-yloxy)ethyl)piperidine-4-amine hydrochloride

¹H NMR (400, D₂O) : 8.12 (1H, s), 7.40 (1H, s), 4.45 (2H, t), 4.15 (2H, d), 3.67 (3H, m), 3.44 (3H, s), 3.23 (2H, t), 2.86 (3H, s), 2.77 (1H, m), 2.54 (3H, s), 2.13 (2H, d), 1.82 (2H, m), 1.12 (6H, d).

Example 62

Synthesis of N-(2-(3-chloro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 3-chloro-4-(methylsulfonyl)phenol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 7.94 (1H, d), 7.23 (1H, d), 7.04 (1H, d), 4.67 (2H, t), 4.54 (2H, d), 3.84 (3H, m), 3.51 (3H, s), 3.16 (2H, t), 2.82 (3H, s), 2.78 (1H, m), 2.14 (2H, s), 1.81 (2H, m), 1.13 (6H, d).

Example 63

Synthesis of N-(2-(3-chloro-4-(methylsulfonyl)phenoxy)ethyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine hydrochloride

¹H NMR (400, D₂O) : 7.94 (1H, d), 7.23 (1H, d), 7.04 (1H, d), 4.43 (2H, t), 4.12 (2H, d), 3.64 (3H, m), 3.31 (3H, s), 3.16 (2H, t), 2.82 (3H, s), 2.78 (1H, m), 2.14 (2H, s), 1.81 (2H, m), 1.13 (6H, d).

Example 64

Synthesis of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methyl-N-(2-(6-(methylsulfonyl)pyridin-3-yloxy)ethyl)piperidine-4-amine

The title compound was obtained in the same manner as Example 4, except that 6-(methylsulfonyl)pyridin-3-ol was used instead of 3-fluoro-4-(methylsulfonyl)phenol.

¹H NMR (400, CDCl₃) : 8.35 (1H, d), 8.03 (1H, d), 7.58 (1H, d), 4.82 (2H, t), 4.54 (2H, d), 3.87 (3H, m), 3.61 (5H, m), 2.86 (3H, s), 2.77 (1H, m), 2.14 (2H, s), 1.80 (2H, m), 1.12 (6H, d).

Example 65

Synthesis of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methyl-N-(2-(6-(methylsulfonyl)pyridin-3-yloxy)ethyl)piperidine-4-amine hydrochloride

¹H NMR (400, D₂O) : 8.35 (1H, d), 8.03 (1H, d), 7.58 (1H, d), 4.50 (2H, t), 4.12 (2H, d), 3.63 (3H, m), 3.71 (5H, m), 2.86 (3H, s), 2.77 (1H, m), 2.14 (2H, s), 1.80 (2H, m), 1.12 (6H, d).

Example 66

Synthesis of N-(3-(3-fluoro-4-(methylsulfonyl)phenoxy)propyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

481 mg of 3-fluoro-4-(methylsulfonyl)phenol and 714 mg of HD-G-1043 were dissolved in 50 mL of MC with stirring in a 100 mL flask under a nitrogen atmosphere, and 996 mg of triphenylphosphine was added slowly dropwise thereto. 0.76 mL of isopropyl azodicarboxylate was added slowly dropwise to the solution at 0 ℃, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was washed with 50 mL of distilled water, and the organic layer was extracted twice with 50 mL of 1N-HCl aqueous solution. The water layer was washed with 50 mL of EA 50, after which it was adjusted to a basic pH using sodium bicarbonate and was extracted twice with 50 mL of EA. The organic layer was dried with anhydrous magnesium sulfate and concentrated, thereby obtaining the title compound.

¹H NMR (400, CDCl₃) : 7.71 (1H, t), 6.89 (2H, t), 4.54 (4H, m), 3.97 (1H, m), 3.64 (1H, m), 3.27 (1H, m), 3.23 (3H, s), 3.11 (2H, t), 2.82 (3H, s), 2.76 (1H, m), 2.20 (2H, m), 2.07 (2H, d), 1.76 (2H, m), 1.12 (6H, d).

Example 67

N-(3-(3-fluoro-4-(methylsulfonyl)phenoxy)propyl)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-methylpiperidine-4-amine

The title compound was obtained in the same manner as Example 5, except that phosphoric acid was used instead of trifluoroacetic acid.

¹H NMR (400, D₂O) : 7.71 (1H, t), 6.89 (2H, t), 4.10 (4H, m), 3.61 (1H, m), 3.40 (1H, m), 3.27 (1H, m), 3.23 (3H, s), 3.11 (2H, t), 2.82 (3H, s), 2.76 (1H, m), 2.20 (2H, m), 2.07 (2H, d), 1.76 (2H, m), 1.12 (6H, d).

[Table 1]

Example 68: Determination of activities of compounds for cAMP stimulation

To measure intracellular cAMP activity in response to a GPR119 agonist, the hamster beta-cell line HIT-T15 (Korean Cell Line Bank) was used. HIT-T15 cells were plated on a 96-well plate at a density of 60,000 cells per well. On the day after plating, the cells were incubated with various concentrations of a GPR119 agonist at 37 ℃ for 1 hour. The compound was used at a concentration ranging from 0.0032 μM to 10 μM. cAMP activity was measured using a cAMP dynamic kit (Cis Bio, Bedford, MA) according to the manufacturer’s instruction. The cells were lysed, and the level of cAMP in the cells was measured by a competitive immunoassay using D2-labeled cAMP and cryptate-labeled anti-cAMP antibody. The fluorescence of the cells was measured using the Flex Station (Molecular Devices). When D2 and cryptate are in close proximity to each other, they undergo fluorescence resonance energy transfer (FRET), which is measured as a fluorescence ratio (665 nm/620 nm). Unlabeled cAMP in the cell lysate competed with the D2-labeled cAMP for the cryptate-labeled antibody. The resulting decrease in FRET signal corresponds to the intracellular cAMP level. The activity of the compound was expressed as the change in FRET signal from DMSO control. As a result, the compounds generally had an EC₅₀ of less than 10 μM.

Example 69: Oral Glucose Tolerance Test (OGTT)

8-10-week old male C57BL/6J mice were acclimated for at least 7 days, and then only healthy mice were selected and used in an OGTT test. The mice were fasted for 12-15 hours, and then divided into groups (n=8) according to fasting glucose levels. Then, each of a vehicle (0.5 % carboxymethyl cellulose (CMC)) or test materials (Examples 5, 11 and 15) was administered orally to the mice at a dose of 20 mg/kg. Each of the vehicle and the test materials was administered orally at 10 ml/kg.

At 30 minutes after administration of the vehicle or the test material, glucose (2 g/kg) was orally administered at a dose of 10 ml/kg. Blood glucose levels were measured using Accu-Check active (Roche Diagnostic GmbH) by tail vein puncture at 30 minutes before glucose administration and 0, 20, 40, 60 and 120 minutes after glucose administration. The test results are shown in Table 2 below. As can be seen in Table 2, the three test materials showed decreases in AUC (area under curve) of about 23.3-38.8%.

Table 2

Example	%AUC
Example 5	23.3%
Example 11	26.8%
Example 15	38.8%

As described above, the compounds of the present invention are useful for the treatment of metabolism-related disorders, including diabetes and related diseases, diabetes-related microvascular complications, diabetes-related microvascular complications, cardiovascular abnormalities, metabolic syndrome and its constituent diseases, and obesity.

While the present invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the present invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the present invention not be limited to the particular embodiments disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

A compound of the following formula 1 or a pharmaceutically acceptable salt thereof:

[Formula 1]

wherein

A is selected from among a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heterocyclic group;

n is an integer ranging from 1 to 3;

m is an integer ranging from 0 to 3;

R₁ is selected from among -COOR₃, or a substituted or unsubstituted heterocyclic group;

R₂ and R₃ are each independently a straight- or branched- chain, substituted or unsubstituted C_1-5 alkyl group;

wherein the heterocyclic group represents a 5- or 6-membered heterocyclic ring containing 4 or less heteroatoms selected from the group consisting of O, N and S;

wherein the substituted phenyl group, the substituted heterocyclic group and the substituted C_1-5 alkyl group represent that one or more carbon atoms constituting the phenyl group, the heterocyclic group or the C_1-5 alkyl group are each independently substituted with one or more substituents selected from the group consisting of -SOR', -S(O)₂R', -NHS(O)₂R', -CN, halogen, methyl halide, C_2-5 alkenyl, -R', =O, -COR', -COOR', -CONR'R", and -NR'R", wherein R' and R" are each independently represent H or straight- or branched-chain C_1-5 alkyl, or may be linked together with 4 or less heteroatoms selected from the group consisting of O, N and S to form a 5- or 6-membered heterocyclic ring; and the substituents may be further substituted with one or more substituents selected from the group consisting of -SOR', -S(O)₂R', -NHS(O)₂R', -CN, halogen, a substituted heterocyclic group, methyl halide, -R', =O, -COR', -COOR', -CONR'R", and -NR'R" as defined above.
The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound of formula 1 is any one selected from the group consisting of compounds represented by the following formulas:
The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound of formula 1 is any one selected from the group consisting of compounds represented by the following formulas:
A pharmaceutical composition for treatment of metabolism-related disorder, which contains the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
The pharmaceutical composition of claim 4, wherein the metabolism-related disorder is any one selected from the group consisting of obesity, type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and X syndrome.