KR20120018236A - Substituted pyridinyl derivatives and methods for manufacturing the same - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing substituted pyrimidinyl derivatives for treating metabolic disorders is provided to activate GPR119 and to treat metabolic syndrome and obesity. CONSTITUTION: A substituted pyrimidinyl derivative is denoted by chemical formula 1. In chemical formula 1, Z_1 and Z_3 are N; Z_2 and Z_4 are CH; and L_1 is O. A pharmaceutical composition for treating metabolic disorders contains the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The metabolic disorders include type I diabetes, type II diabetes, insulin resistance, hyperlipidemis, hypercholesterolemia, and dyslipidemia.

Description

Substituted pyridinyl derivatives and methods for manufacturing the same

The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for treating metabolic related disorders including the same.

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 type II diabetes. Type I diabetes, also known as insulin dependent diabetes (IDDM), is caused by the 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 by insulin resistance, ie, people with type II diabetes who have little insulin or are unable to use insulin effectively.

In diabetics, glucose levels accumulate in the blood and urine, which causes problems with excessive urination, thirst, hunger, fat and protein metabolism. Such diabetes can lead to 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. Diabetes is also associated with nerve damage to the legs and feet, which interferes with the ability to feel pain and causes serious infections.

Current treatments for diabetes include insulin, insulin secretagogues, glucose lowering effectors, activators of peroxysome proliferator-activated receptors (PPARs), and the like. However, there are problems associated with currently available therapies, including hypoglycemia, weight gain, decreased responsiveness to treatment over time, gastrointestinal problems and edema.

In order to introduce new more effective therapies to the market, research is being conducted in various areas, and one specific target is GPR119. GPR119 is a G-protein coupled receptor (GPCR) expressed primarily in the pancreas, small intestine, colon and adipose tissue. The GPR119 expression profile shows its potential utility as a target for the treatment of obesity and diabetes. GPR119 activation has been demonstrated to stimulate cAMP to induce 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 cause acute food intake reduction and weight loss in rats after chronic administration (Overton, HA 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 patent applications WO 05/007647 and WO 05/007658).

Activators for GPR119 can be used for the treatment of diabetes and related diseases, microvascular complications associated with diabetes, macrovascular complications associated with diabetes, cardiovascular abnormalities, metabolic syndrome and its component diseases, obesity and other diseases.

The present invention provides a novel compound or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for treating metabolic related disorders including the same.

The present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

X ₁ and X ₂ are, each independently, (C _{1 -6)} alkyl, (C _{1 -6)} substituted with one or more substituents independently selected from the group consisting of alkoxy and carboxy, or which may be unsubstituted (C _{1 - 3} ) alkylene;

Y ₁ is CR ₁ R ₂ or NR _2, wherein R ₁ is selected from H, (C _{1 -6)} alkyl, (C _{1 -6)} alkoxy, halo and hydroxyl indeed the group consisting of;

R ₂ is H, (C _{1 -6)} acyl, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _{2 6)} alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 - 6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino, aryl, arylcarbonyl, aryloxy, di - (C _{1 -6)} - alkylamino, carboxylic night yimido yl, (C _{1 -6)} alkoxycarbonyl, C ₃ -7- cycloalkoxy-carbonyl, carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio carboxamido, guanidine, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl , (C _{1 -6)} Oh haloalkylthio, heteroaryl, heterocycloalkyl - (C _{1 -3)} - alkylene, heteroaryl is selected from carbonyl, heteroaryloxy, heterocyclic carboxamide, hydroxyl, amino and hydroxyl group consisting of nitro; Wherein R ₂ are each (C _{1 -6)} acyl, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _1-6) alkyl carboxamides, (C _{2 6)} alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 - 6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino, aryl, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} -alkyl carboxamide, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio carboxamido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, heterocyclic, heteroaryl, hydroxyl, hydroxyl-amino And independent from the group consisting of nitro By substituted by one or more substituents selected or may be unsubstituted, wherein the (C _{1 -6)} alkyl is more (C _{1 -6)} acyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl amino, (C _{1 -6)} alkyl carboxamides, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _1-6) alkylsulfonyl, (C _{1 -6)} alkyl thio, (C _{1 -6)} alkyl, urea, amino, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6} ) cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl, sulfonamide, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen , (C _{1 -6)} independent of the haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, heterocyclic, hydroxyl, hydroxyl amino, and the group consisting of nitro May be substituted with one or more substituents selected from;

Y ₂ is N, C or CR _3, where R ₃ is H or (C _{1 -6)} alkyl;

은 Y₂가 N 또는 CR₃인 경우에 단일 결합이거나, 또는 Y₂가 C인 경우에 이중 결합이고;

Is a single bond when Y ₂ is N or CR ₃ , or a double bond when Y ₂ is C;

R ₄ is (C _{1 -6)} alkyl, (C _{1 -6)} alkoxy, carboxy, cyano, and each optionally substituted from the group consisting of halogen with one or more substituents independently selected (C _3-, which may be unsubstituted ₆ ) cycloalkylene or (C _{1 -3} ) alkylene group;

n is 0 or 1;

L ₁ is NR ₅ or O, wherein R ₅ is H, (C _{1 -6)} acyl, (C _{1 -6)} alkyl, (C _{2 -6)} alkenyl, (C _{2 -6)} alkynyl, ( C _{3 -7)} cycloalkyl or (C _{3 -7)} - cycloalkyl, - (C _{1 -3)} - alkylene and wherein the (C _{1 -6)} alkyl (C _{1 -6)} acyl, (C _{1 - 6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamide, (C _{2 -6)} alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _1-6) alkylthio carboxamide, (C _1-6) alkyl, thioureido rail, (C _1-6) alkyl, urea, amino, di - (C _1-6) - alkylamino, (C _{1 -6} ) alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide,

Di - (C _{1 -6)} - alkylthio carboxamido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, hydroxyl, hydroxyl, amino and nitro substituted with one or more substituents independently selected from the group consisting of or may be unsubstituted;

Z ₁ is N or CH;

Z ₂ is N or CR ₆ ;

Z ₃ is N or CR ₇ ;

Z ₄ is N or CR ₈ ;

R ₆ , R ₇ And R ₈ is H, (C _{1 -6)} acyl, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _1-6) alkylamino, (C _1-6) alkyl carboxamides, (C _{2 6)} alkynyl, (C _1-6) alkyl-sulfonamide, (C _1-6) alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino , di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio carboxamido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} halo each independently selected from alkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, hydroxyl, hydroxyl amino, and the group consisting of nitro It is selected, where the (C _{2 -6)} Al Carbonyl, (C _{1 -6)} alkyl, (C _2-6) alkynyl and (C _{3 -6)} cycloalkyl (C _{1 -6)} acyl, (C _{1 -6)} acyloxy, (C _{2 -6} ) alkenyl, (C _1-6) alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _{2 -6)} alkynyl, ( C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy , cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _1-6) - alkyl thio carboxamido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _1-6) from haloalkylthio, hydroxyl, hydroxyl amino, and the group consisting of nitro Each optionally substituted with one or more substituents selected neutral or may be unsubstituted;

P ₁ is substituted or unsubstituted heteroaryl, characterized in that the carbon constituting the ring is substituted with one or more atoms selected from the group consisting of N, O and S;

Wherein said substituted heteroaryl (C _{1 -6)} acyl, (C _{1 -6)} acyl sulfonamide, (C _{1 -6)} acyloxy, (C _2-6) alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _{2 -6)} alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 6)} alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _1-6) alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail ( C _{1 -6)} alkyl, urea, amino, aryl, arylcarbonyl, arylsulfonyl, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano furnace, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkyl thiocarboxylic carboxamide amido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 - 6} ) haloalkylthio, heteroaryl, heteroarylcarbonyl, Heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino and nitro may be substituted with one or more substituents, wherein the substituents of two adjacent carbons excluding the bonding carbon of heteroaryl are 5 to 6 may form an unsaturated ring of the circle, where the unsaturated ring (C _{1 -6)} acyl, (C _{1 -6)} acyl sulfonamide, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _1-6) alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _{2 -6)} alkynyl, (C _{1 -6} ) alkyl sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 - 6)} alkyl-thioureido rail, (C _{1 -6)} alkyl, urea, amino, aryl, arylcarbonyl, arylsulfonyl, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl , carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkenyl , Di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio carboxamido, (C _{1 -6)} haloalkoxy, (C _1-6) haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, heteroaryl, heterocycloalkyl May be substituted with one or more substituents selected from the group consisting of arylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino and nitro;

P ₂ is H or (C _{1 -6)} alkyl.

The present invention also provides a compound or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula 1 is Z ₁ and Z ₃ is N, Z ₂ and Z ₄ is CH, L ₁ is O. .

The present invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 is a compound of Formula 2.

[Formula 2]

In Chemical Formula 2,

R` is H, (C <sub>1 -6)</sub> acyl, (C <sub>1 -6)</sub> acyloxy, (C <sub>2 -6)</sub> alkenyl, (C <sub>1 -6)</sub> alkoxy, (C <sub>1 -6)</sub> alkyl, (C <sub>1 -6)</sub> alkylamino, (C <sub>1 -6)</sub> alkyl carboxamides, (C <sub>2 6)</sub> alkynyl, (C <sub>1 -6)</sub> alkyl, sulfonamide, (C <sub>1 -6)</sub> alkylsulfinyl, (C <sub>1 - 6)</sub> alkylsulfonyl, (C <sub>1 -6)</sub> alkylthio, (C <sub>1 -6)</sub> alkylthio carboxamide, (C <sub>1 -6)</sub> alkyl thioureido rail, (C <sub>1 -6)</sub> alkyl, urea, amino, aryl, arylcarbonyl, aryloxy, di - (C <sub>1 -6)</sub> - alkylamino, carboxylic night yimido yl, (C <sub>1 -6)</sub> alkoxycarbonyl, (C <sub>3 -7)</sub> - cycloalkyl alkoxycarbonyl, carboxamide, amide, carboxy, cyano, (C <sub>3 -6)</sub> cycloalkyl, di - (C <sub>1 -6)</sub> - alkyl carboxamides, di - (C <sub>1 -6)</sub> - alkyl sulfonamide, di - (C <sub>1 -6</sub> ) -alkylthio carboxamido, guanidine, (C <sub>1 -6)</sub> haloalkoxy, (C <sub>1 -6)</sub> haloalkyl, halogen, (C <sub>1 -6)</sub> haloalkylsulfinyl, (C <sub>1 -6)</sub> haloalkyl sulfonyl, (C <sub>1 -6)</sub> Oh haloalkylthio, heteroaryl, heterocycloalkyl Reels - (C <sub>1 -3)</sub> - alkylene, heteroaryl-carbonyl, heteroaryloxy, heterocyclic carboxamide, is selected from hydroxyl, hydroxyl, amino and nitro group consisting of; Wherein R` are each (C _{1 -6)} acyl, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _{2 6)} alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 - 6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino, aryl, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} -alkyl carboxamide, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio carboxamido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, heterocyclic, heteroaryl, hydroxyl, hydroxyl-amino And independent from the group consisting of nitro By substituted by one or more substituents selected or may be unsubstituted, wherein the (C _{1 -6)} alkyl is more (C _{1 -6)} acyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl amino, (C _{1 -6)} alkyl carboxamides, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _1-6) alkylsulfonyl, (C _{1 -6)} alkyl thio, (C _{1 -6)} alkyl, urea, amino, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6} ) cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl, sulfonamide, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen , (C _{1 -6)} independent of the haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, heterocyclic, hydroxyl, hydroxyl amino, and the group consisting of nitro May be substituted with one or more substituents selected from;

R`` is substituted or unsubstituted phenyl;

The substituted phenyl (C _{1 -6)} acyl, (C _{1 -6)} acyl sulfonamide, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, ( C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _2-6) alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 - 6)} alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _1-6) alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino, aryl, arylcarbonyl, arylsulfonyl, di - (C _1-6) - alkylamino, (C _1-6) alkoxycarbonyl, carboxamide, carboxy, cyano, , (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio-carboxamide amido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6} ) Haloalkylthio, heteroaryl, heteroarylcarbonyl, hetero It may be substituted with one or more substituents selected from the group consisting of arylsulfonyl, heterocyclic, hydroxyl, hydroxylamino and nitro.

The present invention also provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 is any one selected from the group consisting of the following compounds:

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxymethyl] -piperidine-1-carboxylic acid tert-butyl ester;

4- [5-Methyl-6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-{(4-phenyl-imidazol-1-yl) -6- [1- (5-ethyl-pyrimidin-2-yl) piperidin-4-yloxy]}-pyrimidine;

4- {6- [4- (4-Bromo-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester;

4- {6- [4- (4-Chloro-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester;

4-{[4- (4-Chloro-phenyl-imidazol-1-yl)]-6- [1- (5-ethyl-pyrimidin-2-yl) piperidin-4-yloxy]}- Pyrimidine;

4-{[4- (4-Bromo-phenyl-imidazol-1-yl)]-6- [1- (5-ethyl-pyrimidin-2-yl) piperidin-4-yloxy]} -Pyrimidine;

4- {2- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -ethyl} -piperidine-1-carboxylic acid tert-butyl ester;

4- {6- [4- (4-Fluoro-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester;

4- {6- [4- (3-Methylsulfanyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester;

4- {6- [4- (4-Methanesulfonyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester;

4- {6- [4- (3-Bromo-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester;

4- {6- [4- (2-Methylsulfanyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester;

4- {6- [4- (3-Fluoro-4-methylsulfanyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert Butyl ester;

4- {6- [4- (3-Fluoro-4-methanesulfinyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert Butyl ester;

4- {6- [4- (3-Fluoro-4-methanesulfonyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert Butyl ester;

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester;

4- {6- [4- (4-Bromo-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester;

4- {6- [4- (4-Chloro-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester;

4- {6- [4- (3,4-Dichloro-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester;

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butylamide;

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid ethylamide;

4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine;

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid (2,4-difluoro-phenyl) -amide;

3,4-Difluoro-phenyl)-{4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidin-1-yl} -methanone ;

 (4-methylsulfanyl-phenyl)-{4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidin-1-yl} -methanone;

2-methyl-1- {4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidin-1-yl} -propan-1-one;

4- (1-Methanesulfonyl-piperidin-4-yloxy) -6- (4-phenyl-imidazol-1-yl) -pyrimidine;

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carbonitrile;

3- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl- 5'-carbonitrile;

2- {4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidin-1-yl} -benzoxazole;

5- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -dihydro-pyrimidine-1,3-dicarboxylic acid di-tert-butyl ester;

4- [6- (5-Fluoro-indol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4- [6- (5-Cyano-indol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4- (6-benzimidazol-1-yl-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester;

4- (6-Indol-1-yl-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester;

4- (6-indazol-1-yl-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester;

1- {6- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -pyrimidin-4-yl} -1H-indol-5-carbonitrile;

4- [6- (5-Bromo-indol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

1- {6- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -pyrimidin-4-yl} -5-methoxy-1H-indole;

1- [6- (1-tert-Butoxycarbonyl-piperidin-4-yloxy) -pyrimidin-4-yl] -1H-indole-5-carboxylic acid methyl ester;

1- [6- (1-Carboxylic acid isopropyl ester; -piperidin-4-yloxy) -pyrimidin-4-yl] -1H-indole-5-carbonitrile;

1- {6- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -pyrimidin-4-yl} -1H-indol-4-carbonitrile; And

1- {6- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -pyrimidin-4-yl} -5-nitro-1H-indole.

Wherein the compound of formula 1 is preferably any one selected from the group consisting of:

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-{(4-phenyl-imidazol-1-yl) -6- [1- (5-ethyl-pyrimidin-2-yl) piperidin-4-yloxy]}-pyrimidine;

4- {6- [4- (4-Bromo-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester;

4- {6- [4- (4-Chloro-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester;

4- {6- [4- (4-Methanesulfonyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester; And

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester.

The present invention also provides a pharmaceutical composition for treating metabolic related disorders, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

Wherein the metabolic related disorders include, for example, obesity, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, X syndrome, and the like. do.

를 반응시켜 화학식 1의 화합물을 제조하는 방법을 제공한다.
Furthermore, the present invention relates to P ₁ -H

It provides a method for preparing a compound of formula (1) by reacting.

와

를 반응시켜 화학식 1의 화합물을 제조하는 방법을 제공한다.
In addition, the present invention

Wow

It provides a method for preparing a compound of formula (1) by reacting.

In the production method of the present invention, A is halogen and X ₁ , X ₂ , Y ₁ , Y ₂ , L ₁ , R ₄ , n, Z ₁ , Z ₂ , Z ₃ , Z ₄ , P ₁ and P ₂ Is as defined above.

Hereinafter, the present invention will be described in detail by the following Preparation Examples and Examples. However, the following Preparation Examples and Examples are merely to illustrate the present invention, but the content of the present invention is not limited thereto.

All reagents were purchased from Sigma Aldrich, Fluka and TCI, and ¹ H NMR Spectra was recorded using a Bruker Biospin AVANCE II 400 instrument using tetramethylsilane as an internal standard. It was.

Preparation Example 1

Synthesis of 4- [5-methyl- (6-chloro-pyrimidin-4-yloxy)]-piperidine-1-carboxylic acid tert -butyl ester

500 mg of 4,6-dichloro-5-methyl pyrimidine and 50 ml of THF were added and dissolved in a 100 ml flask under air. Add 1000mg of Nyl) -4-hydroxypiperidine. The reaction mixture is slowly heated to reflux for at least 4 hours. After completion of the reaction, 300 ml of ethyl acetate was added to the reaction mixture, followed by extraction. The organic layer was extracted, washed with 100 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.39 (1H, s), 5.37-5.33 (1H, m), 3.77-3.74 (2H, m), 3.44-3.37 (2H, m), 2.05 (3H, s) , 2.05-1.97 (2H, m), 1.81-1.75 (2H, m), 1.56 (9H, s)

Production Example 2

Synthesis of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester

In the same manner as in Preparation Example 1, using 4,6-dichloro pyrimidine in place of 1- (tert-butoxycarbonyl) -4-hydroxypiperidine and 4,6-dichloro-5-methyl pyrimidine The desired compound was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): 8.51 (1H, s), 6.71 (1H, s), 5.29-5.23 (1H, m), 3.73-3.70 (2H, m), 3.27-3.21 (2H, m) , 1.98-1.93 (2H, m), 1.72-1.64 (2H, m), 1.45 (9H, s)

Production Example 3

Synthesis of 1- (5-ehtyl-2-pyrimidineyl) -4-hydroxypiperidine

Into a 500 mL flask under nitrogen atmosphere, 9.6 g of 4-hydroxypiperidine and 250 mL of acetonitrile / distilled water 2/1 were added thereto, stirred, and dissolved. 19.5 mL of diisopropylethylamine and 11.2 g of 2-chloro-5-ethylpyrimidine were dissolved. After heating, reflux at least 2.5 days. Lower the temperature to room temperature, dissolve in 200 mL of 1N HCl aqueous solution and wash with 200 mL of ethyl acetate. The aqueous layer was adjusted to pH 7 with 1N NaOH aqueous solution and extracted with 200 mL of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and dried under reduced pressure to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.18 (2H, s), 4.43-4.38 (2H, m), 3.94 (1H, m), 3.30-3.23 (2H, m), 2.49-2.44 (2H, q) , 1.98-1.95 (2H, m), 1.59-1.51 (2H, m), 1.19 (3H, t)

Preparation Example 4

Synthesis of 4-chloro-6- (4-phenyl-imidazol-1-yl) -pyrimidine

The target compound was obtained in the same manner as in Preparation Example 1, using 4-phenyl-imidazole instead of 4-phenyl-imidazole and 1- (tert-butoxycarbonyl) -4-hydroxypiperidine.

¹ H NMR (400 MHz, CDCl ₃ ): 8.90 (1H, d), 8.52 (1H, d), 7.92 (1H, d), 7.86 (2H, d), 7.45 (2H, t), 7.42 (1H, s ), 7.37 (2H, t)

Preparation Example 5

Synthesis of 4-chloro-6- [1- (5-ethyl-pyrimidin-2-yl) -piperidinyl-oxy] -pyrimidine

1- (5-ethyl-pyrimidin-2-yl) -piperidine-4- in place of 4,6-dichloro pyrimidine and 1- (tert-butoxycarbonyl) -4-hydroxypiperidine Using the ol, to obtain the target compound in the same manner as in Preparation Example 1.

¹ H NMR (400 MHz, CDCl ₃ ): 8.17 (2H, s), 7.40 (1H, s), 5.29-5.23 (1H, m), 3.73-3.70 (2H, m), 3.27-3.21 (2H, m) , 2.44-2.40 (2H, q), 1.98-1.93 (2H, m), 1.72-1.64 (2H, m), 1.21 (3H, t)

Preparation Example 6

4- (3-methylthiolphenyl)- Synthesis of 1 H -imidazole

In a 100 ml flask under air, 1 g of 4-bromo- 1H -imidazole was dissolved in 30 ml of n-propanol and 5 ml of water, followed by 256 mg of 3-methylthiophenyl boronic acid, 1.25 g of triphenylphosphine, 1 g of potassium carbonate, and palladium (? ) 75 mg of acetate are added sequentially and the reaction mixture is heated slowly to reflux for at least 24 hours. After completion of the reaction, 500 ml of ethyl acetate was added to the reaction mixture, followed by extraction with 1N-HCl. The aqueous layer was taken, basified with 50% aqueous sodium hydroxide solution, extracted with 500 ml of ethyl acetate, the organic layer was taken, and washed with 100 ml of saturated sodium bicarbonate solution. Then, dried over anhydrous magnesium sulfate and dried under reduced pressure to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 7.55 (1H, s), 7.27 (1H, s), 7.49 (1H, d), 7.38 (1H, s), 7.35 (1H, t), 7.19 (1H, d ), 2.5 7 (3H, s)

Preparation Example 7

4- (4-methanesulfonylphenyl)- Synthesis of 1 H -imidazole

The target compound was obtained in the same manner as in Preparation Example 6, using 4-methanesulfonylphenyl boronic acid instead of 4-bromo-1 H -imidazole and 4- (3-methylthiophenyl) boronic acid.

¹ H NMR (400 MHz, CDCl ₃ ): 8.50 (1H, s), 8.12 (1H, s), 8.09 (2H, d), 7.99 (2H, d), 3.15 (3H, s),

Preparation Example 8

4- (2-methylthiophenyl)- Synthesis of 1 H -imidazole

The target compound was obtained in the same manner as in Preparation Example 5, using 2-methylthiophenyl boronic acid instead of 4-bromo-1 H -imidazole and 4- (3-methylthiophenyl) boronic acid.

¹ H NMR (400 MHz, CDCl ₃ ): 7.76 (1H, s), 7.64 (1H, d), 7.49 (1H, s), 7.36-7.20 (3H, m)

Preparation Example 9

4- (3,4-difluorophenyl)- Synthesis of 1 H -imidazole

The target compound was prepared in the same manner as in Preparation Example 5, using 3,4-difluorophenyl boronic acid instead of 4-bromo-1 H -imidazole and 4- (3-methylthiophenyl) boronic acid. Got it.

¹ H NMR (400 MHz, CDCl ₃ ): 7.90 (1H, s), 7.62 (1H, dd), 7.58 (1H, dd), 7.30 (1H, t), 7.28 (1H, s)

Preparation Example 10

Synthesis of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester

After dissolving 5 g of 4-hydroxypiperidine in 200 ml of acetonitrile and 100 ml of water in a 500 ml flask under air, 8.3 g of potassium carbonate was added at 0 ° C, and 45 ml of isopropyl chloroformate (1.0 M in toluene) was slowly added dropwise. After stirring at room temperature for 24 hours or more, 300 ml of ethyl acetate was added to the reaction mixture, followed by extraction. The organic layer was taken, washed twice with 100 ml of 1N-HCl aqueous solution, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain a target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 4.92 (1H, q), 3.88-3.84 (3H, m), 3.12-3.07 (2H, m), 1.89-1.85 (2H, m), 1.73 (1H, s) , 1.51-1.45 (2H, m), 1.24 (6H, d)

Preparation Example 11

Synthesis of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid isopropyl ester

The target compound was obtained in the same manner as in Preparation Example 1, using Preparation Example 10 instead of 4,6-dichloro pyrimidine and 1- (tert-butoxycarbonyl) -4-hydroxypiperidine.

¹ H NMR (400 MHz, CDCl ₃ ): 8.38 (1H, s), 7.34 (1H, s), 5.34 (1H, m), 4.93 (1H, m), 3.77-3.74 (2H, m), 3.44-3.37 (2H, m), 2.05-1.99 (2H, m), 1.81-1.74 (2H, m), 1.26 (6H, d)

Example 1

Synthesis of 4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

In a 100 ml flask under air, 400 mg of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 50 ml of THF were added thereto, stirred, and dissolved. Add 750 mg of butoxide and stir for 30 minutes, then add 4-phenyl-imidazole 300 mg. The reaction mixture is slowly heated to reflux for at least 2 hours. After completion of the reaction, 300 ml of ethyl acetate was added to the reaction mixture, followed by extraction. The organic layer was extracted, washed with 100 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.66 (1H, s), 8.48 (1H, s), 7.91 (1H, s), 7.88 (2H, d), 7.45 (2H, t),

7.33 (1H, t), 6.73 (1H, s), 5.40 (1H, m), 3.84-3.80 (2H, m), 3.36-3.30 (2H, m), 2.06-2.03 (2H, m), 1.83- 1.78 (2H, m), 1.62 (9H, s)

Example 2

Synthesis of 4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxymethyl] -piperidine-1-carboxylic acid tert-butyl ester

In the same manner as in Example 1 using 4-chloro-6- (4-phenyl-imidazol-1-yl) -pyrimidine and tert -butyl 4- (hydroxymethyl) -1-piperidinecarboxylate The desired compound was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): 8.54 (1H, s), 8.45 (1H, s), 7.90 (1H, s), 7.88 (2H, d), 7.44 (2H, t),

7.33 (1H, t), 6.45 (1H, s), 3.77 (4H, s), 3.60 (4H, s), 1.51 (9H, s)

Example 3

Synthesis of 4- [5-methyl-6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

4- [5-Methyl- (6-chloro-pyrimidin-4-yloxy)]-piperidine-1-carboxylic acid tert -butyl ester and 4-phenyl-imidazole as in Example 1 The target compound was obtained by the method.

¹ H NMR (400 MHz, CDCl ₃ ): 8.58 (1H, s), 8.11 (1H, s), 7.88 (2H, d), 7.76 (1H, d), 7.42 (2H, t),

7.33 (1H, t), 5.45 (1H, m), 3.78-3.77 (2H, m), 3.43-3.37 (2H, m), 2.34 (3H, s), 2.07-2.00 (2H, m), 1.87- 1.80 (2H, m), 1.55 (9H, s)

Example 4

Synthesis of 4-{(4-phenyl-imidazol-1-yl) -6- [1- (5-ethyl-pyrimidin-2-yl) piperidin-4-yloxy]}-pyrimidine

Example 1 using 4-chloro-6- (4-phenyl-imidazol-1-yl) -pyrimidine and 1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-ol In the same manner as in the title compound was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): 8.69 (1H, s), 8.48 (1H, s), 7.91 (1H, s), 7.88 (2H, d), 7.44 (2H, t),

7.31 (1H, t), 6.73 (1H, s), 5.50 (1H, m), 4.34-4.28 (2H, m), 3.66-3.59 (2H, m), 2.51 (2H, q), 2.16-2.12 ( 2H, m), 1.90-1.82 (2H, m), 1.24 (3H, t)

Example 5

Synthesis of 4- {6- [4- (4-Bromo-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester

4- (4-Bromophenyl) imidazole in place of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4-phenyl-imidazole To obtain the target compound in the same manner as in Example 1

¹ H NMR (400 MHz, CDCl ₃ ): 8.66 (1H, s), 8.45 (1H, s), 7.91 (1H, s), 7.74 (2H, d), 7.56 (2H, d),

6.72 (1H, s), 5.40 (1H, m), 3.83-3.80 (2H, m), 3.36-3.30 (2H, m), 2.06-2.03 (2H, m), 1.82-1.78 (2H, m), 1.50 (9H, s)

Example 6

Synthesis of 4- {6- [4- (4-chloro-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester

4- (4-chlorophenyl) imidazole in place of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4-phenyl-imidazole In the same manner as in Example 1 to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.46 (1H, s), 7.90 (1H, s), 7.80 (2H, d), 7.41 (2H, d),

6.72 (1H, s), 5.40 (1H, m), 3.84-3.80 (2H, m), 3.36-3.29 (2H, m), 2.06-2.03 (2H, m), 1.82-1.78 (2H, m), 1.48 (9H, s)

Example 7

4-{[4- (4-Chloro-phenyl-imidazol-1-yl)]-6- [1- (5-ethyl-pyrimidin-2-yl) piperidin-4-yloxy]}- Synthesis of pyrimidine

4-Chloro-6- [1- (5-ethyl-pyrimidin-2-yl) -piperidinyl-oxy] -pyrimidine and 4- (4-chlorophenyl) imidazole as in Example 1 The target compound was obtained by the method.

¹ H NMR (400 MHz, CDCl ₃ ): 8.69 (1H, s), 8.46 (1H, s), 7.91 (1H, s), 7.80 (2H, d), 7.41 (2H, d),

6.73 (1H, s), 5.50 (1H, m), 3.34-3.28 (2H, m), 3.66-3.59 (2H, m), 2.51 (2H, q), 2.14-2.11 (2H, m), 1.89- 1.83 (2H, m), 1.23 (3H, t)

Example 8

4-{[4- (4-Bromo-phenyl-imidazol-1-yl)]-6- [1- (5-ethyl-pyrimidin-2-yl) piperidin-4-yloxy]} Synthesis of -pyrimidine

Example 1 using 4-chloro-6- [1- (5-ethyl-pyrimidin-2-yl) -piperidinyl-oxy] -pyrimidine and 4- (4-bromophenyl) imidazole In the same manner to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.68 (1H, s), 8.46 (1H, s), 7.92 (1H, s), 7.73 (2H, d), 7.56 (2H, d),

6.73 (1H, s), 5.50 (1H, m), 4.37-4.25 (2H, m), 3.66-3.59 (2H, m), 2.51 (2H, q), 2.18-2.10 (2H, m), 1.89- 1.81 (2H, m), 1.23 (3H, t)

Example 9

Synthesis of 4- {2- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -ethyl} -piperidine-1-carboxylic acid tert-butyl ester

4-chloro-6- (4-phenyl-imidazol-1-yl) -pyrimidine and tert-butyl 4- (hydroxymethyl) -1-piperidinecarboxylate in place of tert-butyl 4- (hydroxy Using oxyethyl) -1-piperidine carboxylate to obtain the target compound in the same manner as in Example 2

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.47 (1H, s), 7.92 (1H, s), 7.88 (2H, d), 7.44 (2H, t),

7.31 (1H, t), 6.72 (1H, s), 4.51 (2H, t), 4.13 (2H, s), 2.76-2.70 (2H, m), 1.81-1.62 (5H, m), 1.50 (9H, s), 1.26-1.18 (2H, m)

Example 10

Synthesis of 4- {6- [4- (4-fluoro-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester

4- (4-fluorophenyl) imidazole in place of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4-phenyl-imidazole To obtain the target compound in the same manner as in Example 1

¹ H NMR (400 MHz, CDCl ₃ ): 8.66 (1H, s), 8.45 (1H, s), 7.85 (1H, s), 7.83 (2H, t), 7.13 (2H, t),

6.73 (1H, s), 5.40 (1H, m), 3.84-3.80 (2H, m), 3.35-3.29 (2H, m), 2.06-2.03 (2H, m), 1.81-1.77 (2H, m), 1.50 (9H, s),

Example 11

Synthesis of 4- {6- [4- (3-methylsulfanyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester

4- (6-Chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4- (3-methylthiophenyl)-in place of 4-phenyl-imidazole Using 1 H -imidazole, the target compound was obtained in the same manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.47 (1H, s), 7.92 (1H, d), 7.79 (1H, t), 7.62 (2H, dd), 7.33 (1H, t ), 7.22 (1H, dd), 6.73 (2H, d), 5.40 (1H, m), 3.84-3.80 (2H, m), 3.36-3.30 (2H, m), 2.06-2.02 (2H, m), 1.81-1.77 (2H, m), 1.50 (9H, s),

Example 12

Synthesis of 4- {6- [4- (4-methanesulfonyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester

4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4- (4-methanesulfonylphenyl)-in place of 4-phenyl-imidazole Using 1 H -imidazole, the target compound was obtained in the same manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ): 8.69 (1H, s), 8.48 (1H, s), 8.09 (1H, s), 8.05 (2H, d), 8.01 (2H, d), 6.77 (1H, d ), 5.41 (1H, m), 3.84-3.81 (2H, m), 3.36-3.30 (2H, m), 3.11 (3H, s), 2.06-2.02 (2H, m), 1.83-1.77 (2H, m ), 1.52 (9H, s),

Example 13

Synthesis of 4- {6- [4- (3-Bromo-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester

4- (3-Bromophenyl) imidazole in place of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4-phenyl-imidazole Using the same method as in Example 1 to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.46 (1H, s), 8.03 (1H, t), 7.93 (1H, d), 7.77 (1H, dd), 7.45 (1H, dd ), 7.28 (1H, m), 6.73 (1H, d), 5.41 (1H, m), 3.83-3.80 (2H, m), 3.36-3.30 (2H, m), 3.11 (3H, s), 2.06- 2.02 (2H, m), 1.83-1.77 (2H, m), 1.52 (9H, s),

Example 14

Synthesis of 4- {6- [4- (2-methylsulfanyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester

4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4- (4-methanesulfonylphenyl)-in place of 4-phenyl-imidazole Using 1 H -imidazole, the target compound was obtained in the same manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.53 (1H, s), 8.16 (1H, s), 7.98 (1H, d), 7.29 (2H, m), 7.42 (1H, m ), 6.73 (1H, s), 5.40 (1H, m), 3.90-3.82 (2H, m), 3.36-3.30 (2H, m), 2.54 (3H, s), 2.08-2.02 (2H, m), 1.81-1.75 (2H, m), 1.52 (9H, s),

Example 15

4- {6- [4- (3-Fluoro-4-methylsulfanyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert Synthesis of -butyl Ester

4- (2-methylthiophenyl)-in place of 4-phenyl-imidazole 1H- imidazole was used to obtain the target compound in the same manner as in Example 1, and then 100 mg of the compound was dissolved in 50 ml of DMF without any separation. After completion of the reaction, 300 ml of ethyl acetate was added to the reaction mixture, followed by extraction. The organic layer was extracted, washed with 100 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.66 (1H, s), 8.45 (1H, s), 7.90 (1H, s), 7.60 (1H, d), 7.56 (1H, d), 7.30 (1H, t ), 6.72 (1H, s), 5.41 (1H, m), 3.83-3.81 (2H, m), 3.36-3.29 (2H, m), 2.52 (3H, s), 2.06-2.02 (2H, m), 1.81-1.76 (2H, m), 1.50 (9H, s),

Example 16

4- {6- [4- (3-Fluoro-4-methanesulfinyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert Synthesis of -butyl Ester

In a 50 ml flask under air, 4- {6- [4- (3-fluoro-4-methylsulfanyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1 - insert the carboxylic Acid tert- butyl ester 130mg of Oxone ^® at 0 ℃ was dissolved in 15ml THF and water 5ml (Oxone ^®) 165mg is stirred for 24 hours at room temperature. After completion of the reaction, 300 ml of ethyl acetate was added to the reaction mixture, followed by extraction. The organic layer was extracted, washed with 100 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.68 (1H, s), 8.52 (1H, s), 8.04 (1H, s), 7.90 (1H, d), 7.86 (1H, d), 7.71 (1H, d ), 6.77 (1H, s), 5.41 (1H, m), 3.84-3.81 (2H, m), 3.36-3.29 (2H, m), 2.88 (3H, s), 2.06-2.02 (2H, m), 1.81-1.76 (2H, m), 1.50 (9H, s),

Example 17

4- {6- [4- (3-Fluoro-4-methanesulfonyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert Synthesis of -butyl Ester

In a 50 ml flask under air, 4- {6- [4- (3-fluoro-4-methylsulfanyl-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1 -130 mg of carboxylic acid tert-butyl ester is dissolved in 15 ml of THF and 5 ml of water. Then, 600 mg of oxone ^® (Oxone ^® ) is added at 0 ° C. and stirred at room temperature for at least 24 hours. After completion of the reaction, 300 ml of ethyl acetate was added to the reaction mixture, followed by extraction. The organic layer was extracted, washed with 100 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.68 (1H, s), 8.46 (1H, s), 8.10 (1H, s), 8.00 (1H, t), 7.80 (1H, d), 7.76 (1H, s ), 6.77 (1H, s), 5.41 (1H, m), 3.84-3.80 (2H, m), 3.50-3.32 (2H, m), 3.27 (3H, s), 2.06-2.02 (2H, m), 1.83-1.76 (2H, m), 1.50 (9H, s),

Example 18

Synthesis of 4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid isopropyl ester

4- (6- on behalf of 4-phenyl-imidazole and 4- [5-methyl- (6-chloro-pyrimidin-4-yloxy)]-piperidine-1-carboxylic acid tert -butyl ester The target compound was obtained in the same manner as in Example 1 using chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid isopropyl ester.

¹ H NMR (400 MHz, CDCl ₃ ): 8.66 (1H, s), 8.47 (1H, d), 7.90 (1H, s), 7.87 (2H, d), 7.44 (2H, t), 7.33 (1H, t ), 6.73 (1H, s), 5.41 (1H, m), 4.96 (1H, m), 3.78-3.73 (2H, m), 3.42-3.34 (2H, m), 2.06-2.02 (2H, m), 1.81-1.76 (2H, m), 1.28 (6H, d),

Example 19

Synthesis of 4- {6- [4- (4-Bromo-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester

4- (4-bromophenyl) imidazole in place of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid isopropyl ester and 4-phenyl-imidazole To obtain the target compound in the same manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.45 (1H, d), 7.91 (1H, s), 7.73 (2H, d), 7.55 (2H, d), 6.72 (1H, d ), 5.41 (1H, m), 4.96 (1H, m), 3.87-3.83 (2H, m), 3.42-3.34 (2H, m), 2.06-2.02 (2H, m), 1.81-1.76 (2H, m ), 1.27 (6H, d),

Example 20

Synthesis of 4- {6- [4- (4-chloro-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid isopropyl ester

4- (4-chlorophenyl) imidazole in place of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid isopropyl ester and 4-phenyl-imidazole To obtain the target compound in the same manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ): 8.66 (1H, s), 8.45 (1H, d), 7.90 (1H, s), 7.79 (2H, d), 7.40 (2H, d), 6.72 (1H, d ), 5.41 (1H, m), 4.96 (1H, m), 3.87-3.83 (2H, m), 3.40-3.34 (2H, m), 2.06-2.02 (2H, m), 1.81-1.76 (2H, m ), 1.27 (6H, d),

Example 21

Synthesis of 4- {6- [4- (3,4-Dichloro-phenyl) -imidazol-1-yl] -pyrimidin-4-yloxy} -piperidine-1-carboxylic acid tert-butyl ester

4- (6-Chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4- (3,4-dichlorophenyl) amine on behalf of 4-phenyl-imidazole Using the doazole to obtain the target compound in the same manner as in Example 1

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.45 (1H, d), 7.99 (1H, d), 7.93 (2H, d), 7.68 (1H, d), 7.50 (1H, d ), 6.73 (1H, s), 5.41 (1H, m), 3.83-3.80 (2H, m), 3.36-3.30 (2H, m), 2.06-2.02 (2H, m), 1.83-1.76 (2H, m ), 1.50 (9H, s),

Example 22

Synthesis of 4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butylamide

In a 100 ml flask under air, 500 mg of 4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine, 20 ml of acetonitrile, and 10 ml of water were added, stirred, and dissolved. Add 580 mg of potassium carbonate at 0 ° C and slowly add dropwise 0.15 ml of tert -butyl isocyanate. After stirring at room temperature for 24 hours or more, 300 ml of ethyl acetate was added to the reaction mixture, followed by extraction. The organic layer was extracted, washed twice with 100 ml of 1N-HCl aqueous solution, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain the target compound.

¹ H NMR (400 MHz, DMSO- d ₆ ): 8.77 (1H, s), 8.72 (1H, d), 8.54 (1H, d), 7.88 (2H, d), 7.42 (3H, m), 7.27 (1H , t), 5.88 (1H, s), 5.30 (1H, m), 3.73-3.69 (2H, m), 3.1 _1-3 .00 (2H, m), 1.99-1.97 (2H, m), 1.63- 1.54 (2H, m), 1.57 (9H, s),

Example 23

Synthesis of 4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid ethylamide

In the same manner as in Example 22 using ethyl isocyanate instead of 4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine and tert -butyl isocyanate The desired compound was obtained.

¹ H NMR (400 MHz, DMSO- d ₆ ): 8.79 (1H, s), 8.72 (1H, d), 8.54 (1H, d), 7.88 (2H, d), 7.42 (3H, m), 7.27 (1H , t), 5.88 (1H, s), 5.30 (1H, m), 3.73-3.69 (2H, m), 3.24 (2H, q), 3.1 _1-3 .00 (2H, m), 1.99-1.97 ( 2H, m), 1.63-1.54 (2H, m), 1.37 (3H, t)

Example 24

Synthesis of 4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine

1 g of 4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester and 50 ml of dioxane in a 100 ml flask under atmosphere And 10 ml of methanol were added and stirred to dissolve, and 15 ml of 4N-HCl in dioxane was slowly added dropwise. After stirring for 5 hours at room temperature and dried under reduced pressure to obtain the target compound.

¹ H NMR (400 MHz, DMSO- d ₆ ): 9.14 (2H, s), 8.82 (1H, s), 8.70 (1H, s), 7.92 (2H, d), 7.54 (1H, s), 7.44 (2H , t), 7.33 (1H, t), 5.42 (1H, m), 3.39-3.37 (2H, m), 3.16-3.14 (2H, m), 2.23-2.20 (2H, m), 2.02-1.92 (2H , m),

Example 25

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid (2,4-difluoro-phenyl) -amide synthesis

4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine and tert -butyl isocyanate in place of 2,4-difluoro isocyanate In the same manner as in Example 22, the target compound was obtained.

¹ H NMR (400 MHz, DMSO- d ₆ ): 8.77 (1H, s), 8.72 (1H, d), 8.54 (1H, d), 8.04 (1H, s), 7.88 (2H, d), 7.42-7.31 (4H, m), 7.27 (2H, m), 5.88 (1H, s), 5.30 (1H, m), 3.73-3.69 (2H, m), 3.1 _1-3 .00 (2H, m), 1.99- 1.97 (2H, m), 1.63-1.54 (2H, m),

Example 26

Of 3,4-difluoro-phenyl)-{4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidin-1-yl} -methanone synthesis

150 mg of 4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine and 50 ml of dichloromethane were added to a 100 ml flask under air, stirred, and dissolved at 0 ° C. 80 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 154 mg of dimethylamino pyridine and 100 mg of 3,4-difluorobenzoic acid were added dropwise sequentially. After stirring at room temperature for 2 hours or more, 50 ml of dichloromethane was added to the reaction mixture, followed by extraction. The organic layer was taken, washed with 20 ml of 1N-HCl aqueous solution, washed with 20 ml of 1N-NaOH aqueous solution, dried over anhydrous magnesium sulfate, and dried under reduced pressure. Got it.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.48 (1H, d), 7.91 (1H, d), 7.88 (2H, d), 7.44 (2H, t), 7.35-7.18 (4H , m), 6.74 (1H, s), 5.52 (1H, m), 4.15-3.47 (4H, m), 2.19-2.06 (2H, m), 1.97-1.76 (2H, m), 1.59 (9H, s ),

Example 27

Synthesis of (4-methylsulfanyl-phenyl)-{4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidin-1-yl} -methanone

4- (methylthio) benzo on behalf of 4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine and 3,4-difluorobenzoic acid The target compound was obtained in the same manner as in Example 26 using Ix Acid.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.48 (1H, d), 7.91 (1H, d), 7.88 (2H, d), 7.46-7.24 (10H, m), 6.45 (1H , s), 5.51 (1H, m), 4.20-3.67 (4H, m), 2.53 (3H, s), 2.19-2.06 (2H, m), 1.97-1.76 (2H, m), 1.60 (9H, s ),

Example 28

Synthesis of 2-methyl-1- {4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidin-1-yl} -propan-1-one

Using isobutyric acid instead of 4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine and 3,4-difluorobenzoic acid The target compound was obtained in the same manner as in Example 26.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.48 (1H, d), 7.91 (1H, d), 7.86 (2H, d), 7.46 (2H, t), 7.33 (1H, t ), 6.73 (1H, s), 5.47 (1H, m), 4.06 (1H, m), 3.81 (1H, m), 3.5 _1-3 .48 (1H, m), 2.90 (1H, m), 2.09 -2.01 (2H, m), 1.97-1.76 (2H, m), 1.17 (6H, d),

Example 29

Synthesis of 4- (1-methanesulfonyl-piperidin-4-yloxy) -6- (4-phenyl-imidazol-1-yl) -pyrimidine

150 mg of 4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine and 50 ml of THF were added to a 100 ml flask under air, stirred, and dissolved. Add 0.18 ml of amine and add methanesulfonyl chloride. After stirring at room temperature for 2 hours or more, 300 ml of ethyl acetate was added to the reaction mixture, followed by extraction. The organic layer was extracted, washed twice with 100 ml of 1N-HCl aqueous solution, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.48 (1H, d), 7.91 (1H, d), 7.86 (2H, d), 7.46 (2H, t), 7.32 (1H, t ), 6.75 (1H, s), 5.44 (1H, m), 3.54-3.48 (2H, m), 3.37-3.31 (2H, m), 2.86 (1H, s), 2.20-2.14 (2H, m), 2.06-2.01 (2H, m)

Example 30

Synthesis of 4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carbonitrile

4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine and tert -butyl isocyanate in place of cyanogenbromide The target compound was obtained in the same manner as in Example 22.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.48 (1H, d), 7.91 (1H, d), 7.88 (2H, d), 7.43 (2H, t), 7.32 (1H, t ), 6.75 (1H, s), 5.42 (1H, m), 3.56-3.50 (2H, m), 3.32-3.28 (2H, m), 2.20-2.14 (2H, m), 2.04-1.98 (2H, m )

Example 31

Synthesis of 3- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

In the same manner as in Example 1 using 4-chloro-6- (4-phenyl-imidazol-1-yl) -pyrimidine and 1- (tert-butoxycarbonyl) -3-hydroxypiperidine The desired compound was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): 8.67 (1H, s), 8.47 (1H, d), 7.90 (1H, d), 7.88 (2H, d), 7.44 (2H, t), 7.31 (1H, t ), 6.71 (1H, s), 5.23 (1H, m), 3.8 _1-3 .30 (4H, m), 2.10-1.87 (4H, m), 1.45-1.40 (9H, bs)

Example 32

4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl- Synthesis of 5'-carbonitrile

4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine The target compound was obtained in the same manner as in Example 22 using 2-chloro-5-cyano pyridine in place of tert -butyl isocyanate.

¹ H NMR (400 MHz, DMSO- d ₆ ): 8.78 (2H, s), 8.55 (1H, s), 8.51 (1H, s), 7.87 (3H, d), 7.43 (3H, m), 7.29 (1H , t), 7.03 (1H, d), 5.46 (1H, m), 4.14-4.10 (2H, m), 3.60-3.55 (2H, m), 2.17-1.10 (2H, m), 1.77-1.72 (2H , m),

Example 33

Synthesis of 2- {4- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -piperidin-1-yl} -benzoxazole

4- (4-phenyl-imidazol-1-yl) -6- (piperidin-4-yloxy) -pyrimidine The target compound was obtained in the same manner as in Example 22 using 2-chlorobenzoxazole in place of tert -butyl isocyanate.

¹ H NMR (400 MHz, CDCl ₃ ): 9.24 (1H, s), 8.73 (1H, s), 8.08 (1H, s), 7.95 (2H, d), 7.58 (1H, d), 7.47 (2H, t ), 7.39-7.29 (3H, m), 7.20-7.17 (2H, m), 5.60 (1H, m), 4.20-4.15 (2H, m), 4.02-3.98 (2H, m), 2.29-1.19 (2H , m), 2.13-2.08 (2H, m),

Example 34

Synthesis of 5- [6- (4-phenyl-imidazol-1-yl) -pyrimidin-4-yloxy] -dihydro-pyrimidine-1,3-dicarboxylic acid di-tert-butyl ester

4-chloro-6- (4-phenyl-imidazol-1-yl) -pyrimidine and 4-hydroxy-dihydro-pyrimidine-1,3-dicarboxylic acid di-tert-butyl ester The target compound was obtained in the same manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ): 8.68 (1H, s), 8.45 (1H, s), 7.87-7.66 (3H, m), 7.35 (2H, m), 7.33 (1H, t), 6.68 (3H , m), 5.73 (1H, m), 5.41-5.22 (2H, m), 4.07-4.32 (2H, m), 4.16-3.97 (2H, m), 3.65-3.45 (2H, m), 1.53-1.37 (9H, m)

Example 35

Synthesis of 4- [6- (5-fluoro-indol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

Example 1 using 5-fluoroindole in place of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4-phenyl-imidazole In the same manner as in the title compound was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): 8.70 (1H, s), 8.45 (1H, q), 7.75 (1H, d), 7.30 (1H, d), 7.08 (1H, m), 6.75 (1H, s ), 6.71 (1H, d), 5.39 (1H, m), 3.87-3.83 (2H, m), 3.34-3.30 (2H, m), 2.10-2.01 (2H, m), 1.84-1.80 (2H, m ), 1.49 (9H, s)

Example 36

Synthesis of 4- [6- (5-cyano-indol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

Example 1 using 5-cyanoindole in place of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4-phenyl-imidazole In the same manner as in the title compound was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): 8.74 (1H, s), 8.61 (1H, d), 8.00 (1H, d), 7.80 (1H, d), 7.58 (1H, d), 6.83 (1H, d ), 6.78 (1H, s), 5.41 (1H, m), 3.85-3.83 (2H, m), 3.34-3.32 (2H, m), 2.10-2.01 (2H, m), 1.79-1.76 (2H, m ), 1.45 (9H, s)

Example 37

Synthesis of 4- (6-benzimidazol-1-yl-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester

4- (6-Chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and benzimidazole in place of 4-phenyl-imidazole as in Example 1 The target compound was obtained by the method.

¹ H NMR (400 MHz, CDCl ₃ ): 8.76 (1H, s), 8.72 (1H, s), 8.16 (1H, dd), 7.90 (1H, dd), 7.43 (2H, m), 6.96 (1H, s ), 5.42 (1H, m), 3.87-3.85 (2H, m), 3.36-3.32 (2H, m), 2.12-2.10 (2H, m), 1.86-1.80 (2H, m), 1.61 (9H, s )

Example 38

Synthesis of 4- (6-indol-1-yl-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester

In the same manner as in Example 1 using indole instead of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4-phenyl-imidazole The desired compound was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): 8.70 (1H, s), 8.42 (1H, d), 7.36 (1H, d), 7.24 (1H, d), 6.80 (1H, s), 6.75 (1H, d ), 5.39 (1H, m), 3.85-3.82 (2H, m), 3.34-3.30 (2H, m), 2.07-2.03 (2H, m), 1.80-1.76 (2H, m), 1.49 (9H, s )

Example 39

Synthesis of 4- (6-indazol-1-yl-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester

Example 1 using 1H -indazole in place of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4-phenyl-imidazole In the same manner to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.89 (1H, d), 8.71 (1H, s), 8.24 (1H, s), 7.78 (1H, d), 7.58 (1H, t), 7.35 (2H, m ), 5.40 (1H, m), 3.84-3.81 (2H, m), 3.38-3.36 (2H, m), 2.05-2.01 (2H, m), 1.84-1.80 (2H, m), 1.51 (9H, s )

Example 40

Synthesis of 1- {6- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -pyrimidin-4-yl} -1H-indole-5-carbonitrile

4-chloro-6- [1- (5-ethyl-pyrimidin-2-yl) -piperidinyl-oxy] -pyrimidine and 4-phenyl-imidazole were carried out using 5-cyanoindole. The target compound was obtained in the same manner as in Example 1.

¹ H NMR (400 MHz, DMSO- d ₆ ): 8.84 (1H, s), 8.81 (1H, s), 8.37 (1H, d), 8.27 (2H, s), 8.20 (1H, s), 7.70 (1H , d), 7.37 (1H, s), 6.99 (1H, d), 5.48 (1H, m), 4.30-4.26 (2H, m), 3.5 _1-3 .32 (2H, m), 2.43 (2H, q), 2.11-2.09 (2H, m), 1.71-1.64 (2H, m), 1.14 (3H, t)

Example 41

Synthesis of 4- [6- (5-Bromo-indol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

Example 1 using 5-bromoindole instead of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid tert -butyl ester and 4-phenyl-imidazole In the same manner as in the title compound was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): 8.70 (1H, d), 8.38 (1H, d), 7.78 (1H, d), 7.72 (1H, d), 7.42 (1H, dd), 6.75 (1H, s ), 6.65 (1H, s), 5.39 (1H, m), 3.84-3.81 (2H, m), 3.35-3.28 (2H, m), 2.07-2.03 (2H, m), 1.84-1.80 (2H, m ), 1.58 (9H, s)

Example 42

Synthesis of 1- {6- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -pyrimidin-4-yl} -5-methoxy-1H-indole

4-chloro-6- [1- (5-ethyl-pyrimidin-2-yl) -piperidinyl-oxy] -pyrimidine and 4-phenyl-imidazole in place of 5-methoxy indole The target compound was obtained in the same manner as in Example 1.

¹ H NMR (400 MHz, DMSO- d ₆ ): 8.76 (1H, d), 8.58 (1H, d), 8.27 (2H, s), 8.15 (1H, d), 7.22 (1H, d), 7.15 (1H , d), 6.91 (1H, dd), 6.75 (1H, s), 5.42 (1H, m), 4.30-4.25 (2H, m), 3.80 (3H, s), 3.55-3.44 (2H, m), 2.45 (2H, q), 2.11-2.07 (2H, m), 1.70-1.63 (2H, m), 1.42 (3H, t)

Example 43

Synthesis of 1- [6- (1-tert-butoxycarbonyl-piperidin-4-yloxy) -pyrimidin-4-yl] -1H-indole-5-carboxylic acid methyl ester

4-chloro-6- [1- (5-ethyl-pyrimidin-2-yl) -piperidinyl-oxy] -pyrimidine and 4-phenyl-imidazole in place of 5-methoxy indole The target compound was obtained in the same manner as in Example 1.

H NMR (400 MHz, CDCl ₃ ): 8.73 (1H, d), 8.48 (1H, d), 8.39 (1H, d), 8.05 (1H, d), 7.80 (1H, d), 6.84 (1H, d) , 6.81 (1H, s), 5.40 (1H, m), 3.96 (3H, s), 3.90-3.80 (2H, m), 3.36-3.29 (2H, m), 2.07-2.03 (2H, m), 1.82 -1.80 (2H, m), 1.50 (9H, s)

Example 44

Synthesis of 1- [6- (1-carboxylic acid isopropyl ester-piperidin-4-yloxy) -pyrimidin-4-yl] -1H-indole-5-carbonitrile

Example 1 using 5-cyanoindole in place of 4- (6-chloro-pyrimidin-4-yloxy) -piperidine-1-carboxylic acid isopropyl ester and 4-phenyl-imidazole In the same manner to obtain the target compound.

¹ H NMR (400 MHz, CDCl ₃ ): 8.70 (1H, d), 8.38 (1H, d), 7.78 (1H, d), 7.72 (1H, d), 7.42 (1H, dd), 6.75 (1H, s ), 6.65 (1H, s), 5.39 (1H, m), 4.96 (1H, m), 3.84-3.81 (2H, m), 3.35-3.28 (2H, m), 2.07-2.03 (2H, m), 1.84-1.80 (2H, m), 1.26 (6H, d)

Example 45

Synthesis of 1- {6- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -pyrimidin-4-yl} -1H-indole-4-carbonitrile

4-chloro-6- [1- (5-ethyl-pyrimidin-2-yl) -piperidinyl-oxy] -pyrimidine and 4-phenyl-imidazole in place of 4-cyanoindole The target compound was obtained in the same manner as in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ): 8.78 (2H, d), 8.22 (2H, d), 7.87 (1H, t), 7.61 (1H, d), 7.42 (1H, t), 6.98 (1H, s ), 6.79 (1H, s), 5.51 (1H, m), 4.35-4.32 (2H, m), 3.64-3.59 (2H, m), 2.51 (2H, q), 2.14-2.09 (2H, m), 1.90-1.82 (2H, m), 1.22 (3H, t)

Example 46

Synthesis of 1- {6- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -pyrimidin-4-yl} -5-nitro-1H-indole

Example using 5-nitro indole in place of 4-chloro-6- [1- (5-ethyl-pyrimidin-2-yl) -piperidinyl-oxy] -pyrimidine and 4-phenyl-imidazole The target compound was obtained in the same manner as in 1.

¹ H NMR (400 MHz, CDCl ₃ ): 8.76 (2H, d), 8.63 (1H, s), 8.60 (1H, dd), 8.25 (1H, dd), 7.85 (1H, d), 6.93 (1H, d ), 6.80 (1H, s), 5.43 (1H, m), 3.86-3.83 (2H, m), 3.49-3.29 (2H, m), 2.07-2.05 (2H, m), 1.83-1.79 (2H, m ), 1.57 (9H, s)

The structural formulas of the compounds of Examples 1-46 are shown in Table 1 below.

[Table 1]

Example 47. Determination of Compound Activity on cAMP Stimulation

Hamster-derived beta cells, HIT-T15 cells (Korea Cell Line Bank), were used to measure intracellular cAMP activity in response to GPR119 agonists. HIT-T15 cells were plated at 60,000 numbers per well in 96 well plates. The day after plating the cells were incubated at 37 ° C. with various concentrations of GPR119 agonist for 1 hour. Compounds were treated at 6 concentrations ranging from 0.0032 to 10 micromolar. 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 with a Flex Station from Molecular Devices. D2 and cryptate undergo fluorescence resonance energy transfer (FRET) when in close proximity and are measured as fluorescence ratio (665/620 nm). Unlabeled cAMP in cell lysates competed with D2 labeled cAMP for cryptate labeled antibodies. The resulting FRET signal reduction corresponds to intracellular cAMP levels. Compound activity was calculated to the extent of FRET signal change from DMSO regulation. The results are shown in Table 2 below.

Example EC50 (nM) One 160 2 310 5 90 6 240 7 220 15 380 18 300 40 92

Example 48. Oral Glucose Tolerance Test (OGTT)

After 8 to 10 weeks old male C57 / 6J rats were allowed to undergo at least 7 days of acclimatization, followed by OGTT test using only healthy subjects. After fasting for 12 to 15 hours, 10 animals per group were separated based on fasting blood glucose, and then vehicle (80% PEG, 10% tween 80, 10% ethanol) or 5 kinds of test substances (Examples 1, 10, 12, and 16). , 17) were administered at 20 mg / kg doses, respectively. Vehicle and test substance were administered orally at 10 ml / kg. Thirty minutes after vehicle or test substance administration, glucose (3g / kg) was orally administered at a dose of 10 ml / kg. Blood glucose was measured using Accusture 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 of glucose administration. As a result, five test materials (Examples 1, 10, 12, 16, and 17) showed 20-50% lower AUC (area under curve) drop effect than the vehicle.

Claims (9)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof.
[Formula 1]

In Chemical Formula 1,
X ₁ and X ₂ are, each independently, (C _{1 -6)} alkyl, (C _{1 -6)} substituted with one or more substituents independently selected from the group consisting of alkoxy and carboxy, or which may be unsubstituted (C _{1 - 3} ) alkylene;
Y ₁ is CR ₁ R ₂ or NR _2, wherein R ₁ is selected from H, (C _{1 -6)} alkyl, (C _{1 -6)} alkoxy, halo and hydroxyl indeed the group consisting of;
R ₂ is H, (C _{1 -6)} acyl, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _{2 6)} alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 - 6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino, aryl, arylcarbonyl, aryloxy, di - (C _{1 -6)} - alkylamino, carboxylic night yimido yl, (C _{1 -6)} alkoxycarbonyl, C ₃ -7- cycloalkoxy-carbonyl, carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio carboxamido, guanidine, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl , (C _{1 -6)} Oh haloalkylthio, heteroaryl, heterocycloalkyl - (C _{1 -3)} - alkylene, heteroaryl is selected from carbonyl, heteroaryloxy, heterocyclic carboxamide, hydroxyl, amino and hydroxyl group consisting of nitro; Wherein R ₂ are each (C _{1 -6)} acyl, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _1-6) alkyl carboxamides, (C _{2 6)} alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 - 6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino, aryl, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} -alkyl carboxamide, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio carboxamido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, heterocyclic, heteroaryl, hydroxyl, hydroxyl-amino And independent from the group consisting of nitro By substituted by one or more substituents selected or may be unsubstituted, wherein the (C _{1 -6)} alkyl is more (C _{1 -6)} acyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl amino, (C _{1 -6)} alkyl carboxamides, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _1-6) alkylsulfonyl, (C _{1 -6)} alkyl thio, (C _{1 -6)} alkyl, urea, amino, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6} ) cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl, sulfonamide, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen , (C _{1 -6)} independent of the haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, heterocyclic, hydroxyl, hydroxyl amino, and the group consisting of nitro May be substituted with one or more substituents selected from;
Y ₂ is N, C or CR _3, where R ₃ is H or (C _{1 -6)} alkyl;

Is a single bond when Y ₂ is N or CR ₃ , or a double bond when Y ₂ is C;
R ₄ is (C _{1 -6)} alkyl, (C _{1 -6)} alkoxy, carboxy, cyano, and each optionally substituted from the group consisting of halogen with one or more substituents independently selected (C _3-, which may be unsubstituted ₆ ) cycloalkylene or (C _{1 -3} ) alkylene group;
n is 0 or 1;
L ₁ is NR ₅ or O, wherein R ₅ is H, (C _{1 -6)} acyl, (C _{1 -6)} alkyl, (C _{2 -6)} alkenyl, (C _{2 -6)} alkynyl, ( C _{3 -7)} cycloalkyl or (C _{3 -7)} - cycloalkyl, - (C _{1 -3)} - alkylene and wherein the (C _{1 -6)} alkyl (C _{1 -6)} acyl, (C _{1 - 6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamide, (C _{2 -6)} alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _1-6) alkylthio carboxamide, (C _1-6) alkyl, thioureido rail, (C _1-6) alkyl, urea, amino, di - (C _1-6) - alkylamino, (C _{1 -6} ) alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide,
Di - (C _{1 -6)} - alkylthio carboxamido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, hydroxyl, hydroxyl, amino and nitro substituted with one or more substituents independently selected from the group consisting of or may be unsubstituted;

Z ₁ is N or CH;
Z ₂ is N or CR ₆ ;
Z ₃ is N or CR ₇ ;
Z ₄ is N or CR ₈ ;

R ₆ , R ₇ And R ₈ is H, (C _{1 -6)} acyl, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _1-6) alkylamino, (C _1-6) alkyl carboxamides, (C _{2 6)} alkynyl, (C _1-6) alkyl-sulfonamide, (C _1-6) alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino , di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio carboxamido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} halo each independently selected from alkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, hydroxyl, hydroxyl amino, and the group consisting of nitro It is selected, where the (C _{2 -6)} Al Carbonyl, (C _{1 -6)} alkyl, (C _2-6) alkynyl and (C _{3 -6)} cycloalkyl (C _{1 -6)} acyl, (C _{1 -6)} acyloxy, (C _{2 -6} ) alkenyl, (C _1-6) alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _{2 -6)} alkynyl, ( C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy , cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _1-6) - alkyl thio carboxamido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _1-6) from haloalkylthio, hydroxyl, hydroxyl amino, and the group consisting of nitro Each optionally substituted with one or more substituents selected neutral or may be unsubstituted;

P ₁ is substituted or unsubstituted heteroaryl, characterized in that the carbon constituting the ring is substituted with one or more atoms selected from the group consisting of N, O and S;
Wherein said substituted heteroaryl (C _{1 -6)} acyl, (C _{1 -6)} acyl sulfonamide, (C _{1 -6)} acyloxy, (C _2-6) alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _{2 -6)} alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 6)} alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _1-6) alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail ( C _{1 -6)} alkyl, urea, amino, aryl, arylcarbonyl, arylsulfonyl, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano furnace, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkyl thiocarboxylic carboxamide amido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 - 6} ) haloalkylthio, heteroaryl, heteroarylcarbonyl, Heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino and nitro may be substituted with one or more substituents, wherein the substituents of two adjacent carbons excluding the bonding carbon of heteroaryl are 5 to 6 may form an unsaturated ring of the circle, where the unsaturated ring (C _{1 -6)} acyl, (C _{1 -6)} acyl sulfonamide, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _1-6) alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _{2 -6)} alkynyl, (C _{1 -6} ) alkyl sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 - 6)} alkyl-thioureido rail, (C _{1 -6)} alkyl, urea, amino, aryl, arylcarbonyl, arylsulfonyl, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl , carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkenyl , Di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio carboxamido, (C _{1 -6)} haloalkoxy, (C _1-6) haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, heteroaryl, heterocycloalkyl May be substituted with one or more substituents selected from the group consisting of arylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino and nitro;

P ₂ is H or (C _{1 -6)} alkyl.
The method of claim 1,
Z ₁ and Z ₃ are N, Z ₂ and Z ₄ is CH, L ₁ is O, a compound or a pharmaceutically acceptable salt thereof.

The method of claim 1,
The compound of formula 1 is a compound or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (2).
(2)

In Chemical Formula 2,
R` is H, (C <sub>1 -6)</sub> acyl, (C <sub>1 -6)</sub> acyloxy, (C <sub>2 -6)</sub> alkenyl, (C <sub>1 -6)</sub> alkoxy, (C <sub>1 -6)</sub> alkyl, (C <sub>1 -6)</sub> alkylamino, (C <sub>1 -6)</sub> alkyl carboxamides, (C <sub>2 6)</sub> alkynyl, (C <sub>1 -6)</sub> alkyl, sulfonamide, (C <sub>1 -6)</sub> alkylsulfinyl, (C <sub>1 - 6)</sub> alkylsulfonyl, (C <sub>1 -6)</sub> alkylthio, (C <sub>1 -6)</sub> alkylthio carboxamide, (C <sub>1 -6)</sub> alkyl thioureido rail, (C <sub>1 -6)</sub> alkyl, urea, amino, aryl, arylcarbonyl, aryloxy, di - (C <sub>1 -6)</sub> - alkylamino, carboxylic night yimido yl, (C <sub>1 -6)</sub> alkoxycarbonyl, (C <sub>3 -7)</sub> - cycloalkyl alkoxycarbonyl, carboxamide, amide, carboxy, cyano, (C <sub>3 -6)</sub> cycloalkyl, di - (C <sub>1 -6)</sub> - alkyl carboxamides, di - (C <sub>1 -6)</sub> - alkyl sulfonamide, di - (C <sub>1 -6</sub> ) -alkylthio carboxamido, guanidine, (C <sub>1 -6)</sub> haloalkoxy, (C <sub>1 -6)</sub> haloalkyl, halogen, (C <sub>1 -6)</sub> haloalkylsulfinyl, (C <sub>1 -6)</sub> haloalkyl sulfonyl, (C <sub>1 -6)</sub> Oh haloalkylthio, heteroaryl, heterocycloalkyl Reels - (C <sub>1 -3)</sub> - alkylene, heteroaryl-carbonyl, heteroaryloxy, heterocyclic carboxamide, is selected from hydroxyl, hydroxyl, amino and nitro group consisting of; Wherein R` are each (C _{1 -6)} acyl, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _{2 6)} alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _{1 - 6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino, aryl, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} -alkyl carboxamide, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio carboxamido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, heterocyclic, heteroaryl, hydroxyl, hydroxyl-amino And independent from the group consisting of nitro By substituted by one or more substituents selected or may be unsubstituted, wherein the (C _{1 -6)} alkyl is more (C _{1 -6)} acyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkyl amino, (C _{1 -6)} alkyl carboxamides, (C _{1 -6)} alkyl, sulfonamide, (C _{1 -6)} alkylsulfinyl, (C _1-6) alkylsulfonyl, (C _{1 -6)} alkyl thio, (C _{1 -6)} alkyl, urea, amino, di - (C _{1 -6)} - alkylamino, (C _{1 -6)} alkoxycarbonyl, carboxamide, carboxy, cyano, (C _{3 -6} ) cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl, sulfonamide, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen , (C _{1 -6)} independent of the haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6)} haloalkylthio, heterocyclic, hydroxyl, hydroxyl amino, and the group consisting of nitro May be substituted with one or more substituents selected from;

R`` is substituted or unsubstituted phenyl;
The substituted phenyl (C _{1 -6)} acyl, (C _{1 -6)} acyl sulfonamide, (C _{1 -6)} acyloxy, (C _{2 -6)} alkenyl, (C _{1 -6)} alkoxy, ( C _{1 -6)} alkyl, (C _{1 -6)} alkylamino, (C _{1 -6)} alkyl carboxamides, (C _2-6) alkynyl, (C _{1 -6)} alkyl, sulfonamide, (C _{1 - 6)} alkylsulfinyl, (C _{1 -6)} alkylsulfonyl, (C _{1 -6)} alkylthio, (C _{1 -6)} alkylthio carboxamide, (C _{1 -6)} alkyl thioureido rail, (C _{1 -6)} alkyl, urea, amino, aryl, arylcarbonyl, arylsulfonyl, di - (C _1-6) - alkylamino, (C _1-6) alkoxycarbonyl, carboxamide, carboxy, cyano, , (C _{3 -6)} cycloalkyl, di - (C _{1 -6)} - alkyl carboxamides, di - (C _{1 -6)} - alkyl sulfonamide, di - (C _{1 -6)} - alkylthio-carboxamide amido, (C _{1 -6)} haloalkoxy, (C _{1 -6)} haloalkyl, halogen, (C _{1 -6)} haloalkylsulfinyl, (C _{1 -6)} haloalkylsulfonyl, (C _{1 -6} ) Haloalkylthio, heteroaryl, heteroarylcarbonyl, hete Aryl which may be substituted with alkylsulfonyl, heterocyclic, hydroxyl, hydroxyl, amino and nitro one or more substituents selected from the group consisting of a.
The method of claim 1,
Compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound of Formula 1 is any one selected from the group consisting of:

The method of claim 1,
The compound of formula 1 is a compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that any one selected from the group consisting of:

A pharmaceutical composition for treating metabolic related disorders, comprising the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 6,
The metabolic disorder is any one selected from the group consisting of obesity, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and X syndrome A pharmaceutical composition for treating metabolic related disorders.
A method of preparing the compound of claim 1 by reacting P ₁ -H with a compound of Formula 3
(3)

In the above formulas,
A is halogen,
X ₁ , X ₂ , Y ₁ , Y ₂ , L ₁ , R ₄ , n, Z ₁ , Z ₂ , Z ₃ , Z ₄ , P ₁ and P ₂ are as defined in claim 1.

A method of preparing the compound of claim 1 by reacting a compound of Formula 4:

[Chemical Formula 4]

In the formula, A is halogen,
X ₁ , X ₂ , Y ₁ , Y ₂ , L ₁ , R ₄ , n, Z ₁ , Z ₂ , Z ₃ , Z ₄ , P ₁ and P ₂ are as defined in claim 1.