KR101140133B1 - 1-6,7-difluoro-3-methoxyquinoxalin-2-yl-3-[1-heteroarylmethylpiperidin-4-yl] urea derivatives and pharmaceutically acceptable salt thereof, process for preparation and use thereof - Google Patents

Abstract

[상기에서, R¹ 및 R²는 발명의 상세한 설명에서 정의한 바와 같다.]The present invention provides 1- (6,7-difluoro-3-methoxyquinoxaline-) represented by the following Chemical Formula 1 having an excellent melanin-concentrating hormone 1 receptor (hereinafter referred to as “MCH1R”) inhibitory activity. 2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative or pharmaceutically acceptable salt thereof, preparation method thereof and treatment and prevention of obesity disease containing the same as an active ingredient It relates to a pharmaceutical composition for. In addition, the present invention is 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl represented by the following formula (1) The present invention relates to an inhibitor composition of melanin enriched hormone receptor (MCH1R) containing a urea derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
[Formula 1]

[Wherein R ¹ and R ² are as defined in the detailed description of the invention]

Description

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative, preparation method thereof and use thereof { 1- (6,7-DIFLUORO-3-METHOXYQUINOXALIN-2-YL) -3- [1- (HETEROARYLMETHYL) PIPERIDIN-4-YL] UREA DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, PROCESS FOR PREPARATION AND USE THEREOF}

The present invention provides 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) pi with MCH1R (melanin-concentrating hormone 1-receptor) inhibitory activity. Ferridin-4-yl] urea derivative or pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition for the treatment and prevention of obesity disease containing the same as an active ingredient and inhibitor composition of melanin enriched hormone receptor (MCH1R) It is about.

Obesity refers to a condition in which adipose tissue is excessively accumulated in the body, and as a cause of complications such as diabetes, heart disease, high blood pressure, and stroke, attention and research on obesity treatments have been focused.

Representative methods for treating obesity include non-drug therapies such as diet, exercise therapy, behavioral correction and surgery, and are classified into drug treatments except for the non-drug therapy.

In addition, the obesity treatment method that can be approached by drug treatment has emerged as an obesity treatment agent divided into appetite suppressant, food absorption inhibitor, energy metabolic accelerator and the like depending on the mechanism of action of the drug.

As a representative obesity treatment drug approved by the US Food and Drug Administration (FDA), drugs that are recognized in Korea as specialty medicines for obesity treatment include sibutramine (sibutramine) and orlistat.

Sibutramine inhibits the reuptake of serotonin, and the appetite suppression effect increases satiety even with a small amount of meal.Olistat inhibits the absorption of pancreatic lipase enzymes that break down fat, thereby preventing fat absorption.

However, currently known drug treatment for obesity is being used as an auxiliary means of non-drug therapy, such as diet, exercise therapy, behavioral correction, and surgery, and does not suggest a fundamental treatment.

Most drugs used to treat obesity have a noticeable effect in the beginning, but gradually decrease over time and disappear after 6 to 8 months. Is reproduced.

In addition, the biggest problem of obesity treatment drugs used in the past, although there was some effect on weight loss and weight maintenance, most of the market was stopped due to side effects during taking. Problems with these side effects are still present with sibutramine and olistat, which are currently recognized as obesity drugs.

Therefore, in recent years, in order to develop a new obesity treatment agent that is guaranteed both efficacy and safety, efforts have been made to identify new hormones and peptides related to weight control and to develop obesity treatments using their mechanism of action.

In this context, MCH1R is a promising target for the development of obesity treatments and has been the subject of intense research and development by major pharmaceutical companies. Melanin-concentrating hormone (MCH) is one of many neuropeptides that are involved in weight control and is a kind of anorexogenic neuropeptide that is primarily expressed in the hypothalamus. )to be. Since 1999, orphan G protein-coupled receptors (SLC-1) have been shown to be a receptor for MCH, oral G-protein coupled receptors (SLC-1) have been actively studied. It has been genetically and physiologically identified in animal model experiments that MCH1R plays an important role in weight control. As a result, efforts have been made to discover organic small molecule MCH1R inhibitors to explore the possibility of developing obesity drugs by controlling food intake by successful MCH antagonism. In the early 2000s, Lundbeck's arylpiperidine-based SNAP-7941 compound and Takeda's tetrahydronaphthalene-based T-226296 compound were reported to have weight loss effects in obese animal model experiments as organic small molecule MCH1R antagonists. In addition, Amgen's indole-based polycyclic compound, AMG-076, GSK's cynopyrimidinone-based GW-856464 compound, and Neurogen's piperazine-based NGD-4715 compound have been evaluated through Phase I clinical trials. and it is, in particular Neurogen Corporation NGD-4715 compound has been reported to have a special side effects clinical phase I evaluation results observed [Drug Discovery Today 2007 , 12 , 972-979; Current Medicinal Chemistry 2008 , 15 , 1025-1043; Current Topics in Medicinal Chemistry 2009 , 9 , 504-538.

Accordingly, the present inventors have made efforts to develop an anti-obesity agent that ensures efficacy and safety, and has a novel 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3 having MCH1R inhibitory activity. Pharmaceutical composition and melanin for the preparation and treatment of-[1- (heteroarylmethyl) piperidin-4-yl] urea derivatives and pharmaceutically acceptable salts thereof, and containing them as active ingredients The present invention was completed by providing an inhibitor composition of concentrated hormone receptor (MCH1R).

An object of the present invention is 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] having MCH1R inhibitory activity. To provide urea derivatives and pharmaceutically acceptable salts thereof.

Another object of the present invention is the 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative It is to provide a manufacturing method.

Another object of the present invention is the 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative Or to provide a pharmaceutical composition for the treatment and prevention of obesity diseases containing a pharmaceutically acceptable salt thereof as an active ingredient and inhibitor composition of melanin enriched hormone receptor (MCH1R).

The present invention is a novel compound having excellent MCH1R inhibitory activity, wherein 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroaryl) represented by the following general formula (1): Methyl) piperidin-4-yl] urea derivatives or pharmaceutically acceptable salts thereof, methods for preparing the same, and pharmaceutical compositions for the treatment and prevention of obesity diseases containing the same as an active ingredient.

In addition, the present invention is 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl represented by the following formula (1) The present invention relates to an inhibitor composition of melanin enriched hormone receptor (MCH1R) containing a urea derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

[In Formula 1, R ¹ is hydrogen or halogen; R ² is (C 3 -C 20) heteroaryl comprising one or more hetero atoms selected from N, O and S, wherein the heteroaryl of R ² is (C 1 -C 20) alkyl, halo (C 1 -C 20) alkyl, halogen Selected from (C1-C20) alkoxy, (C6-C20) aryloxy, (C1-C20) alkylcarbonyl, (C6-C20) arylcarbonyl, (C6-C20) aryl and halo (C6-C20) aryl May be further substituted with one or more substituents.

In Formula 1, R ¹ is hydrogen or fluorine; R ² is heteroaryl selected from the following structures;

R ^a , R ^b and R ^c are each independently hydrogen, (C1-C20) alkyl, halo (C1-C20) alkyl, halogen, (C1-C20) alkoxy, (C6-C20) aryloxy, (C1-C20 ) Alkylcarbonyl, (C6-C20) arylcarbonyl, (C6-C20) aryl and halo (C6-C20) aryl; m is an integer from 1 to 4, n is an integer from 1 to 3, l is an integer of 1 or 2.

R ² is more preferably a heteroaryl selected from the following structures.

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative of the formula 1 of the present invention The above solvates, hydrates and pharmaceutically acceptable salts are also within the scope of the present invention as they can be used in the form of solvates, hydrates and pharmaceutically acceptable salts to enhance in vivo absorption or increase solubility. .

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative of formula 1 according to the present invention Scheme 1 is illustrated as a preparation method of, and the following preparation method does not limit the preparation of the compound of formula 1 according to the present invention. Modifications of the following preparation method will be apparent to those skilled in the art, and unless otherwise stated. The definition of the substituent of the following scheme is the same as the definition in the formula (1).

Preparation for preparing 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative of the present invention The method was carried out with ethyl N- (6,7-difluoro-3-methoxyquinoxalin-2-yl) carbamate compound ( 2 ) and 4-aminopyri having a protecting group at position 1, as shown in Scheme 1 below. Condensation reaction of the ferridine compound ( 3 ) to 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- (1-protected-piperidin-4-yl) urea compound ( 4 ) preparing a first step; Deprotection reaction of the prepared urea compound ( 4 ) to give a 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3-piperidin-4-yl urea compound ( 5 Manufacturing a second step; And 1- (6,7-difluoro-3-methoxyquinoxaline-) represented by Chemical Formula 1 according to the present invention through a reduction alkylation reaction of the prepared urea compound ( 5 ) and heteroaryl aldehyde compound ( 6 ). 2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea compound.

Scheme 1

[In the above scheme, R ¹ and R ² are the same as defined in the formula (1).]

In detail step by step in the preparation method, the ethyl N- (6,7-difluoro-3-methoxyquinoxalin-3-yl) carbamate compound ( 2 used as starting material in the first step of the preparation method ) Can be prepared from a technique known by the applicant (International Patent No. 2006054830). Further, when R ¹ is a hydrogen atom, ethyl N- (6,7-difluoro-3-methoxyquinoxalin-3-yl) is disclosed by a technique known by the present applicant (Korean Patent Publication No. 2009090791). 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) through the condensation reaction of a carbamate compound ( 2 ) with a 4-aminopiperidine compound ( 3 ) having a protecting group at position 1 3- (1-protected-piperidin-4-yl) urea compound ( 4 ) may be prepared. At this time, in the manufacturing process of the prepared urea compound ( 4 ), it contains t -butoxycarbonyl (hereinafter referred to as 'Boc') as a protecting group for the 4-aminopiperidine compound ( 3 ) having a protecting group at position 1 Conventional amino group protecting group can be used.

Further, with respect to the ethyl N- (6,7-difluoro-3-methoxyquinoxalin-3-yl) carbamate compound ( 2 ), the 4-aminopiperidine compound having a protecting group at the 1 position ( 3) It is preferred to use 1.0 to 1.5 molar equivalents, and more preferably 1.0 molar equivalents. At this time, in the reaction, triethylamine, diisopropylethylamine (hereinafter referred to as 'DIEA'), pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 1,8-diazabicyclo [5.4.0] -Reaction can be carried out using a conventional organic base such as Undeth-7-en (hereinafter referred to as 'DBU') or without using an organic base, and tetrahydrofuran (hereinafter referred to as 'THF'), It is carried out using a conventional organic solvent or a mixture of conventional organic solvents such as methanol, ethanol, dichloromethane, acetonitrile and dimethylformamide (hereinafter referred to as 'DMF'). The reaction temperature has a good boiling point range from room temperature to a solvent, and more preferably maintains the boiling point of the solvent. The reaction time is 1 to 24 hours, preferably 1 to 8 hours.

The second step of the present invention is carried out through the deprotection reaction of the urea compound ( 4 ) prepared by the technique known by the present applicant when R ¹ is a hydrogen atom 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3-piperidin-4-yl urea compound ( 5 ) was prepared. The solvent used in the second step is a conventional organic solvent, for example, dichloromethane (hereinafter referred to as 'DCM') using a conventional organic acid, for example trifluoroacetic acid (hereinafter referred to as 'TFA') and the like Perform on At this time, the reaction temperature is preferably in the range of 0 ℃ to room temperature, preferably room temperature. The reaction time is 1 to 24 hours, preferably 1 to 5 hours.

The third step of the present invention is the 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3-piperidin-4-yl urea compound ( 5 ) and heteroaryl aldehyde prepared above Through reduction alkylation of compound ( 6 ), 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) pi Ferridin-4-yl] to obtain a urea compound. The third step is a conventional organic solvent, for example dichloroethane (hereinafter referred to as 'DCE'), in the presence of a reducing agent such as sodium triacetoxyborohydride (hereinafter referred to as 'NaBH (OAc) ₃ '), It is carried out using dichloromethane, acetonitrile, dimethylformamide and the like. For the compound represented by Formula 5, it is preferable to use 1.0 to 3.0 molar equivalents, more preferably 1.0 to 2.0 molar equivalents. In addition, it is preferable to use 1.0 to 1.5 molar equivalents, and more preferably 1.0 to 1.1 molar equivalents, for the compound represented by the formula (6). At this time, the reaction temperature is good in the boiling point range of 0 ℃ to the solvent, more preferably it is good to maintain the room temperature. The reaction time is 1 to 24 hours, preferably 1 to 8 hours.

In accordance with the preparation method of the present invention, in order to confirm the production of the compound represented by the formula (1), after the final reaction was separated and purified by a multi-column chromatography equipment (Quad3 +; Biotage, Inc. of the United States), structure by NMR and Mass spectrum Was analyzed.

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] represented by Chemical Formula 1 according to the present invention Since urea derivatives have excellent MCH1R inhibitory activity, they can be usefully used for the treatment and prevention of obesity-related diseases caused by MCH activity. Thus, 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative or pharmaceutical agent of Formula 1 It is possible to provide a pharmaceutical composition effective in the treatment and prevention of obesity in which adipose tissue is excessively accumulated in the body by containing the salt which is scientifically acceptable as an active ingredient.

Pharmaceutically acceptable salts in the present invention may be prepared by conventional methods in the art, for example, with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like. Salts, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin Salts with organic acids such as), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methanesulfonic acid, ethanesulfonic acid And salts with sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, metal salts by reaction with alkali metals such as sodium and potassium, salts with ammonium ions and the like.

In addition, the pharmaceutical composition of the present invention is a conventional formulation in the pharmaceutical field by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient to the compound represented by the formula (1) or pharmaceutically acceptable salts thereof For example, it may be prepared by oral administration or preparations for parenteral administration such as tablets, capsules, troches, solutions, suspensions, and the like, and may be used for the treatment of obesity.

Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, alginate, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

In addition, the dosage of the compound represented by Formula 1 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, based on an adult patient with a weight of 70 kg In general, 0.01 mg to 5,000 mg per day, and may be dividedly administered once to several times a day at regular intervals according to the judgment of a doctor or pharmacist.

The present invention provides 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative as a novel compound. And MCH1R inhibitory activity. In addition, the animal experiment using the compound exhibits excellent MCH1R inhibitory activity and can be used without side effects as a prophylactic and therapeutic agent for obesity diseases.

Hereinafter, the present invention will be described in detail with reference to examples. The following examples are merely illustrative of the present invention, but the scope of the present invention is not limited to the following examples.

[ Example  1] 1- (6,7- Difluorine -3- Methoxyquinoxaline -2-yl) -3- [1- (1 H -Indol-3-yl) piperidin-4-yl] Urea  Produce

(a) step: 1- [1- (4- t -Butoxycarbonyl) piperidin-4-yl] -3- (6,7-difluoro-3-methoxyquinoxalin-2-yl) Urea  Produce

Ethyl (6,7-difluoro-3-methoxyquinoxalin-2-yl) carbamate (570 mg, 2.02 mmol) and 4-amino-1-Boc-piperidine (484 mg, 2.42 mmol) were room temperature Was dissolved in 30 mL of THF, DBU (459 mg, 3.02 mmol) was added thereto, and the resulting mixture was stirred at 60 ° C. for 16 hours. After completion of the reaction, the residue was evaporated under reduced pressure to remove the solvent, and then the residue was purified by silica gel column chromatography ( n -hexane: EA, 2: 1 v / v) to obtain the target compound (781 mg, 89%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.49 (s, 9H), 1.52-1.57 (m, 2H), 2.04-2.07 (m, 2H), 3.05-3.10 (m, 2H), 3.97-4.04 (m , 3H), 4.14 (s, 3H), 7.41 (dd, J = 10.6 and 8.0 Hz, 1H), 7.52 (dd, J = 10.7 and 8.1 Hz, 1H), 9.32 (d, J = 7.4 Hz, 1H) ; MS (ESI) m / z 438 ([M + H] ⁺ ).

(b) step: preparation of 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3-piperidin-4-yl urea

1- [1- (4- t -butoxycarbonyl) piperidin-4-yl] -3- (6,7-difluoro-3-methoxyquinoxalin-2-yl) urea (678 mg, 1.55 mmol) was dissolved in DCM (2 mL) at room temperature and treated with 10 mL of 50% TFA / DCM solution and stirred for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was neutralized by treatment with saturated aqueous sodium bicarbonate solution. The neutralized mixture was extracted with DCM, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give the target compound (478 mg, 92%).

¹ H NMR (500 MHz, CDCl ₃ + MeOD) δ 1.58-1.64 (m, 2H), 2.05-2.08 (m, 2H), 2.76-2.81 (m, 2H), 3.13-3.16 (m, 2H), 3.90 (m, 1 H), 4.09 (s, 3 H), 7.42-7.50 (m, 2 H); MS (ESI) m / z 338 ([M + H] ⁺ ).

(c) step: 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3-piperidin-4-yl urea (30 mg, 0.089 mmol) and 1 H -indole-3-car at room temperature Boxaldehyde (26 mg, 0.18 mmol) was added to DCE / THF (3/1, 2.8 mL) and then treated with NaBH (OAc) ₃ (38 mg, 0.18 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (23 mg, 56%).

Example 2 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1-methyl-1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 1-methyl-1 H -indole-3-carboxaldehyde (28 mg, 0.18 mmol) were added to 2 ml of DCE at room temperature followed by NaBH (OAc) ₃ (57 mg, 0.27 mmol) and stirred at the same temperature for 15 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 25: 1 v / v) to obtain the target compound (25 mg, 59%).

Example 3 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (2-methyl-1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 2-methyl-1 H -indole-3-carboxaldehyde (28 mg, 0.18 mmol) were added to 2 mL of DCE at room temperature followed by NaBH (OAc) ₃ (57 mg, 0.27 mmol) and stirred at the same temperature for 17 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 25: 1 v / v) to obtain the target compound (7 mg, 17%).

Example 4 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (7-methyl-1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 7-methyl-1 H -indole-3-carboxaldehyde (28 mg, 0.18 mmol) were added to 2 mL of DCE at room temperature followed by NaBH (OAc) ₃ (57 mg, 0.27 mmol) and stirred at the same temperature for 17 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 25: 1 v / v) to obtain the target compound (27 mg, 62%).

[ Example  5] 1- (6,7- Difluorine -3- Methoxyquinoxaline -2-yl) -3- [1- (5-fluor-1) H -Indol-3-yl) piperidin-4-yl] Urea  Produce

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 5-fluor-1 H -indole-3-carboxaldehyde (29 mg, 0.18 mmol) were added to 2 mL of DCE at room temperature followed by NaBH (OAc). ₃ (57 mg, 0.27 mmol) and stirred at the same temperature for 15 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 25: 1 v / v) to obtain the target compound (5 mg, 11%).

Example 6 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (5-methoxy-1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 5-methoxy-1 H -indole-3-carboxaldehyde (31 mg, 0.18 mmol) were added to 2 ml of DCE at room temperature followed by NaBH (OAc ) ₃ (57 mg, 0.27 mmol) and stirred at the same temperature for 15 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 25: 1 v / v) to obtain the target compound (23 mg, 51%).

Example 7 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (6-fluor-1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 6-fluor-1 H -indole-3-carboxaldehyde (11 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. ) Was treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (12 mg, 56%).

Example 8 1- [1- (5-chloro-1 H Preparation of Indo-3-yl) piperidin-4-yl] -3- (6,7-difluoro-3-methoxyquinoxalin-2-yl) urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 5-chloro-1 H -indole-3-carboxaldehyde (32 mg, 0.18 mmol) were added to DCE (2 mL) at room temperature followed by NaBH ( OAc) ₃ (57 mg, 0.27 mmol) and stirred at the same temperature for 15 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 25: 1 v / v) to obtain the target compound (17 mg, 38%).

[ Example  9] 1- [1- (1-acetyl-1 H -Indol-3-yl) piperidin-4-yl] -3- (6,7- Difluorine -3- Methoxyquinoxaline -2 days) Urea  Produce

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 1-acetyl-1 H -indole-3-carboxaldehyde (13 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. ) Was treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (15 mg, 65%).

Example 10 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (5-methyl-1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 5-methyl-1 H -indole-3-carboxaldehyde (28 mg, 0.18 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. ) Was treated with NaBH (OAc) ₃ (38 mg, 0.18 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (36 mg, 85%).

Example 11 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1 H -Indol-6-yl) piperidin-4-yl] preparation of urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 1 H -indole-6-carboxaldehyde (10 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. Treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (13 mg, 62%).

Example 12 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1 H -Indol-5-yl) piperidin-4-yl] preparation of urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 1 H -indole-6-carboxaldehyde (10 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. Treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (13 mg, 63%).

Example 13 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1 H -Indol-2-yl) piperidin-4-yl] Preparation of Urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 1 H -indole-2-carboxaldehyde (28 mg, 0.18 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature Treated with NaBH (OAc) ₃ (38 mg, 0.18 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (24 mg, 58%).

Example 14 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1-methyl-1 H -Indol-2-yl) piperidin-4-yl] Preparation of Urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 1-methyl-1 H -indole-2-carboxaldehyde (28 mg, 0.18 mmol) were added to DCE (2 mL) at room temperature followed by NaBH ( OAc) ₃ (57 mg, 0.27 mmol) and stirred at the same temperature for 15 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 25: 1 v / v) to obtain the target compound (19 mg, 45%).

Example 15 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1 H -Pyrrolo [2,3- b ] Pyridin-3-yl) piperidin-4-yl] Urea Preparation

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 1 H -pyrrolo [2,3- b ] pyridine-3-carboxaldehyde (9.8 mg, 0.067 mmol) were added to DCE / THF (3 / 1, 2.8 mL) and then treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (19 mg, 91%).

Example 16 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1 H -Indazol-5-yl) piperidin-4-yl] preparation of urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 1 H -indazol-5-carboxaldehyde (9.8 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. Then treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (11 mg, 51%).

Example 17 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1 H -Indazol-6-yl) piperidin-4-yl] preparation of urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 1 H -indazol-6-carboxaldehyde (9.8 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. Then treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (17 mg, 80%).

Example 18 of 1- [1- (benzofuran-2-yl) piperidin-4-yl] -3- (6,7-difluoro-3-methoxyquinoxalin-2-yl) urea Produce

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (15 mg, 0.045 mmol) and benzofuran-2-carboxaldehyde (9.8 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature followed by NaBH ( OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (9.8 mg, 47%).

Example 19 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1 H -Pyrrole-2-yl) piperidin-4-yl] Preparation of Urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 1 H -pyrrole-2-carboxaldehyde (17 mg, 0.18 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. Treated with NaBH (OAc) ₃ (38 mg, 0.18 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (6.9 mg, 19%).

Example 20 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1-methyl-1 H -Pyrrole-2-yl) piperidin-4-yl] Preparation of Urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 1-methyl-1 H -pyrrole-2-carboxaldehyde (18 mg, 0.12 mmol) were charged with DCE / THF (3/1, 2.8 mL) at room temperature. ) Was treated with NaBH (OAc) ₃ (57 mg, 0.27 mmol) and stirred at the same temperature for 17 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 25: 1 v / v) to obtain the target compound (6.5 mg, 17%).

Example 21 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (3,5-dimethyl-1 H -Pyrrole-2-yl) piperidin-4-yl] Preparation of Urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (30 mg, 0.089 mmol) and 3,5-dimethyl-1 H -pyrrole-2-carboxaldehyde (22 mg, 0.18 mmol) were added to DCE (2 mL) at room temperature. Then treated with NaBH (OAc) ₃ (57 mg, 0.27 mmol) and stirred at the same temperature for 15 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 25: 1 v / v) to obtain the target compound (8.3 mg, 21%).

Example 22 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (5-methylfuran-2-yl) piperidin-4-yl] Manufacture of urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 5-methylfuran-2-carboxaldehyde (7.4 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. Treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (12 mg, 61%).

Example 23 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (2,3-dimethylfuran-5-yl) piperidine-4 -Sun] Manufacture of Urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 2,3-dimethylfuran-5-carboxaldehyde (8.3 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. And then treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (7.4 mg, 37%).

Example 24 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1-methyl-1H-imidazol-2-yl) piperidine- 4-day] preparation of urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (40 mg, 0.12 mmol) and 1-methyl-1 H -imidazole-2-carboxaldehyde (17 mg, 0.15 mmol) were added to DCE / THF (3/1, 2.8 at room temperature). ML) and then treated with NaBH (OAc) ₃ (38 mg, 0.18 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 3: 1 v / v) to obtain the target compound (28 mg, 54%).

Example 25 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1-methyl-1 H -Imidazol-5-yl) piperidin-4-yl] preparation of urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (40 mg, 0.12 mmol) and 1-methyl-1 H -imidazole-5-carboxaldehyde (17 mg, 0.15 mmol) were added at room temperature with DCE / THF (3/1, 2.8 ML) and then treated with NaBH (OAc) ₃ (38 mg, 0.18 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 3: 1 v / v) to obtain the target compound (11 mg, 21%).

Example 26 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (4-methyl-1 H -Imidazol-5-yl) piperidin-4-yl] preparation of urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (40 mg, 0.12 mmol) and 4-methyl-1 H -imidazole-5-carboxaldehyde (17 mg, 0.15 mmol) were added at room temperature with DCE / THF (3/1, 2.8 ML) and then treated with NaBH (OAc) ₃ (38 mg, 0.18 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 3: 1 v / v) to obtain the target compound (30 mg, 58%).

Example 27 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (1-methyl-1 H -Pyrazol-5-yl) piperidin-4-yl] urea preparation

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (40 mg, 0.12 mmol) and 1-methyl-1 H -pyrazole-5-carboxaldehyde (17 mg, 0.15 mmol) were added at room temperature with DCE / THF (3/1, 2.8 ML) and then treated with NaBH (OAc) ₃ (38 mg, 0.18 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 3: 1 v / v) to obtain the target compound (34 mg, 66%).

Example 28 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (3-methyl-1-phenyl-1 H -Pyrazol-4-yl) piperidin-4-yl] preparation of urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 3-methyl-1-phenyl-1 H -pyrazole-4-carboxaldehyde (12 mg, 0.067 mmol) were added at room temperature with DCE / THF (3 / 1, 2.8 mL) and then treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (19 mg, 85%).

Example 29 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- {1- [3- (4-fluorophenyl) -1 H -Pyrazol-4-yl] piperidin-4-yl} urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 3- (4-fluorophenyl) -1 H -pyrazole-4-carboxaldehyde (13 mg, 0.067 mmol) were treated with DCE / THF ( 3/1, 2.8 mL) and then treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (15 mg, 63%).

Example 30 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (5-methylisoxazol-3-yl) piperidine-4- Manufacture of Urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 5-methylisoxazole-3-carboxaldehyde (7.4 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. The solution was then treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (8.1 mg, 42%).

Example 31 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (thiazol-2-yl) piperidin-4-yl] of urea Produce

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (15 mg, 0.045 mmol) and thiazole-2-carboxaldehyde (7.6 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature followed by NaBH ( OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (14 mg, 70%).

Example 32 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (4-methylthiazol-2-yl) piperidin-4-yl Manufacture of Urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 4-methylthiazole-2-carboxaldehyde (8.5 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. Then treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (17 mg, 82%).

Example 33 1- (6,7-Difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (2,4-dimethylthiazol-5-yl) piperidine- 4-day] preparation of urea

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- obtained through Example 1 (a)-(b), in the same manner as in Example 1 (c) Piperidin-4-yl urea (15 mg, 0.045 mmol) and 2,4-dimethylthiazole-5-carboxaldehyde (9.4 mg, 0.067 mmol) were added to DCE / THF (3/1, 2.8 mL) at room temperature. ) Was treated with NaBH (OAc) ₃ (19 mg, 0.089 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol 10: 1 v / v) to obtain the target compound (9 mg, 43%).

[ Example  34] 1- [1- (1 H -Indol-3-yl) piperidin-4-yl] -3- (3- Methoxy -5,6,7- Trifluoroquinoxaline -2 days) Urea  Produce

(a) step: 1- [1- (4- t -Butoxycarbonyl) piperidin-4-yl] -3- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) urea

Ethyl (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) carbamate (730 mg, 2.41 mmol) and 4-amino-1-Boc-piperidine (582 mg, 2.91 mmol) Was dissolved in 70 mL of THF at room temperature, followed by addition of DBU (553 mg, 3.64 mmol) and stirring at 60 ° C. for 8 hours. After completion of the reaction, the residue was evaporated under reduced pressure to remove the solvent, and then the residue was purified by silica gel column chromatography ( n -hexane: EA, 2: 1 v / v) to obtain the target compound (812 mg, 74%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.48 (s, 9H), 1.53-1.55 (m, 2H), 2.04-2.07 (m, 2H), 3.04-3.09 (m, 2H), 3.97-4.04 (m , 3H), 4.20 (s, 3H), 7.22-7.26 (m, 1H), 7.71 (s, 1H, NH), 9.21 (d, J = 7.5 Hz, 1H, NH) MS (ESI) m / z 456 ([M + H] ⁺ ).

(b) Step: Preparation of 1- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) -3-piperidin-4-yl urea

1- [1- (4- t -butoxycarbonyl) piperidin-4-yl] -3- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) urea (810 mg, 1.78 mmol) was dissolved in DCM (20 ml) at room temperature and treated with 10 ml of 50% TFA / DCM solution and stirred for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was neutralized by treatment with saturated aqueous sodium bicarbonate solution. The neutralized mixture was extracted with DCM, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give the target compound (630 mg, 99%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.52-1.60 (m, 2H), 2.05-2.10 (m, 2H), 2.76-2.82 (m, 2H), 3.10-3.14 (m, 2H), 3.90 (m , 1H), 4.20 (s, 3H), 7.21-7.24 (m, 1H), 7.70 (s, 1H, NH), 9.22 (d, J = 6.7 Hz, 1H) MS (ESI) m / z 356 ([ M + H] ⁺ ).

(c) step: 1- [1- (1 H Preparation of Indo-3-yl) piperidin-4-yl] -3- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) urea

1- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) -3-piperidin-4-yl urea (23 mg, 0.067 mmol) and 1 H -indole-3 at room temperature Carboxaldehyde (14 mg, 0.097 mmol) was added to DCE / THF (3/1, 2 mL) and then treated with NaBH (OAc) ₃ (27 mg, 0.13 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 50: 1 v / v) to obtain the target compound (36 mg, 77%).

Example 35 1- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) -3- [1- (1-methyl-1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Examples 34 (a)-(b)-, in the same manner as in Example 34 (c). 3-piperidin-4-yl urea (23 mg, 0.067 mmol) and 1-methyl-1 H -indole-3-carboxaldehyde (16 mg, 0.097 mmol) were added at room temperature with DCE / THF (3/1, 2 mL) and then treated with NaBH (OAc) ₃ (27 mg, 0.13 mmol) and stirred at the same temperature for 12 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 30: 1 v / v) to obtain the target compound (27 mg, 82%).

Example 36 1- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) -3- [1- (2-methyl-1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Examples 34 (a)-(b)-, in the same manner as in Example 34 (c). 3-piperidin-4-yl urea (23 mg, 0.067 mmol) and 2-methyl-1 H -indole-3-carboxaldehyde (16 mg, 0.097 mmol) were added at room temperature with DCE / THF (3/1, 2 mL) and then treated with NaBH (OAc) ₃ (27 mg, 0.13 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 30: 1 v / v) to obtain the target compound (22 mg, 68%).

Example 37 1- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) -3- [1- (7-methyl-1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Examples 34 (a)-(b)-, in the same manner as in Example 34 (c). 3-piperidin-4-yl urea (23 mg, 0.067 mmol) and 7-methyl-1 H -indole-3-carboxaldehyde (16 mg, 0.097 mmol) were added at room temperature with DCE / THF (3/1, 2 mL) and then treated with NaBH (OAc) ₃ (27 mg, 0.13 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 30: 1 v / v) to obtain the target compound (30 mg, 92%).

[ Example  38] 1- [1- (5-Fluoro-1) H -Indol-3-yl) piperidin-4-yl] -3- (3- Methoxy -5,6,7-t Lyfluoroquine Noxolin-2-yl) Urea  Produce

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Examples 34 (a)-(b)-, in the same manner as in Example 34 (c). 3-piperidin-4-yl urea (23 mg, 0.067 mmol) and 5-fluor-1 H -indole-3-carboxaldehyde (16 mg, 0.097 mmol) were added at room temperature with DCE / THF (3/1, 2 mL) and then treated with NaBH (OAc) ₃ (27 mg, 0.13 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 30: 1 v / v) to obtain the target compound (26 mg, 81%).

Example 39 1- [1- (5-methoxy-1 H Preparation of Indo-3-yl) piperidin-4-yl] -3- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) urea

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Example 34 (a)-(b), in the same manner as in Example 34 (c) 3-piperidin-4-yl urea (23 mg, 0.067 mmol) and 5-methoxy-1 H -indole-3-carboxaldehyde (17 mg, 0.097 mmol) were added at room temperature with DCE / THF (3/1 , 2 mL) and treated with NaBH (OAc) ₃ (27 mg, 0.13 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 30: 1 v / v) to obtain the target compound (27 mg, 80%).

Example 40 1- [1- (5-chloro-1 H Preparation of Indo-3-yl) piperidin-4-yl] -3- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) urea

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Example 34 (a)-(b), in the same manner as in Example 34 (c) 3-piperidin-4-yl urea (23 mg, 0.067 mmol) and 5-chloro-1 H -indole-3-carboxaldehyde (17 mg, 0.097 mmol) were added at room temperature with DCE / THF (3/1, 2 mL) and then treated with NaBH (OAc) ₃ (27 mg, 0.13 mmol) and stirred at the same temperature for 12 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 30: 1 v / v) to obtain the target compound (25 mg, 74%).

Example 41 1- [1- (1-acetyl-1 H Preparation of Indo-3-yl) piperidin-4-yl] -3- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) urea

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Examples 34 (a)-(b)-, in the same manner as in Example 34 (c). 3-piperidin-4-yl urea (23 mg, 0.067 mmol) and 1-acetyl-1 H -indole-3-carboxaldehyde (18 mg, 0.097 mmol) were added at room temperature with DCE / THF (3/1, 2 mL) and then treated with NaBH (OAc) ₃ (27 mg, 0.13 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol, 10: 1 v / v) to obtain the target compound (19 mg, 53%).

Example 42 1- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) -3- [1- (5-methyl-1 H -Indol-3-yl) piperidin-4-yl] Urea Preparation

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Examples 34 (a)-(b)-, in the same manner as in Example 34 (c). 3-piperidin-4-yl urea (21 mg, 0.058 mmol) and 5-methyl-1 H -indole-3-carboxaldehyde (14 mg, 0.088 mmol) were added at room temperature with DCE / THF (3/1, 2 mL) and then treated with NaBH (OAc) ₃ (25 mg, 0.12 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 30: 1 v / v) to obtain the target compound (27 mg, 93%).

Example 43 1- [1- (1 H Preparation of Indo-2-yl) piperidin-4-yl] -3- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) urea

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Example 34 (a)-(b), in the same manner as in Example 34 (c) 3-piperidin-4-yl urea (23 mg, 0.067 mmol) and 1 H -indole-2-carboxaldehyde (14 mg, 0.097 mmol) were added to DCE / THF (3/1, 2 mL) at room temperature. The solution was then treated with NaBH (OAc) ₃ (27 mg, 0.13 mmol) and stirred at the same temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 50: 1 v / v) to obtain the target compound (31 mg, 97%).

[ Example  44] 1- (3- Methoxy -5,6,7- Trifluoroquinoxaline -2-yl) -3- [1- (1 H -Pyrrole-2-yl) piperidin-4-yl] Urea  Produce

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Examples 34 (a)-(b)-, in the same manner as in Example 34 (c). 3-piperidin-4-yl urea (33 mg, 0.093 mmol) and 1 H -pyrrole-2-carboxaldehyde (18 mg, 0.19 mmol) were added to DCE / THF (3/1, 2 mL) at room temperature. The solution was then treated with NaBH (OAc) ₃ (19 mg, 0.19 mmol) and stirred at the same temperature for 12 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol, 10: 1 v / v) to obtain the target compound (26 mg, 65%).

Example 45 1- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) -3- [1- (1-methyl-1 H -Pyrrole-2-yl) piperidin-4-yl] Preparation of Urea

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Example 34 (a)-(b), in the same manner as in Example 34 (c) 3-piperidin-4-yl urea (23 mg, 0.067 mmol) and 1-methyl-1 H -pyrrole-2-carboxaldehyde (11 mg, 0.097 mmol) were added at room temperature with DCE / THF (3/1, 2 mL) and then treated with NaBH (OAc) ₃ (27 mg, 0.13 mmol) and stirred at the same temperature for 12 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol, 40: 1 v / v) to obtain the target compound (5.8 mg, 20%).

Example 46 1- [1- (3,5-Dimethyl-1 H Preparation of Pyrrole-2-yl) piperidin-4-yl] -3- (3-methoxy-5,6,7-trifluoroquinoxalin-2-yl) urea

1- (3-methoxy-5,6,7-difluoroquinoxalin-2-yl)-obtained through Example 34 (a)-(b), in the same manner as in Example 34 (c) 3-piperidin-4-yl urea (33 mg, 0.093 mmol) and 3,5-dimethyl-1 H -pyrrole-2-carboxaldehyde (23 mg, 0.19 mmol) were added to DCE / THF (3 / 1, 2 mL) and then treated with NaBH (OAc) ₃ (39 mg, 0.19 mmol) and stirred at the same temperature for 12 hours. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with DCM. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA: methanol, 10: 1 v / v) to obtain the target compound (25 mg, 58%).

In order to confirm the structure of the compounds prepared in Examples 1 to 46, after the final reaction was separated and purified by a multi-column chromatography equipment (Quad3 +; Biotage, USA), ¹ H NMR (Bruker Avance 500 MHz) and Mass spectrum The structure is analyzed and described in Table 1 below.

[Table 1]

Experimental Example 1 Pharmacological Activity Confirmation Experiment (MCH Binding Inhibitory Activity)

The buffer solution is prepared by two kinds of washing solution (25 mM HEPES pH 7.4, 5 mM MgCl ₂ , 1 mM CaCl ₂ ) and experimental solution (adding 0.5% BSA to the washing solution), and MCH1R (Melanin Concentration Hormone receptor). subtype-1; Europium-labeled MCH (Eu-MCH), PerkinElmer, Turku, Finland) and 1 mM melanin-rich hormone (MCH) labeled with Euroscreen, Gosselies, Belgium) and 1 μM of europium (Eu) , # 070-47, Phoenix, Belmont CA, USA) was prepared at 4 ° C. 1 μM Eu-MCH and 1 mM MCH were diluted to 8 nM (final reaction concentration: 2 nM) and 2 μM (final reaction concentration: 0.5 μM), respectively. The buffer solution used in all dilutions and preparations was the experimental solution, and the washing solution was used only to wash the plate at the end.

First, homogenize by diluting MCH1R (200 assays / vial) in 1 ml of experimental solution, and then using an 8-channel pipette on a filter paper-attached microplate (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA). (multi 8-channel, Eppendorf, Hamburg, Germany) was used to dispense the reaction to 100 μl total volume per well. At this time, 25 μl of Eu-MCH, 50 μl of receptor and 25 μl of MCH were used as a non-specific binding control. 25 μl of 10% DMSO experimental solution and 25 μl of Eu-MCH 25 were used as the total binding control. Μl and 50 μl of receptor were used. As the experimental group, 25 µl of the compound prepared in Example, 25 µl of Eu-MCH and 50 µl of receptor were used. Each test compound, Eu-MCH and MCH, accounted for 25% of the total volume during the reaction, was prepared at a concentration of 4 times immediately before addition. Then, shake gently for 15 seconds and reacted at room temperature for 90 minutes. At the end of the reaction, the plate was washed by applying pressure to a partially prepared washer (microplate washer, EMBLA, Molecular Devices). 300 μl / well of the wash solution was filtered three times to remove Eu-MCH that remained without reaction. Wipe off the water on the bottom, and dissociate solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland) to 150μl per well was added. After being left at room temperature for 2-4 hours, the time-resolved fluorescence (TRF) value was measured using a multi-function fluorimeter (multilabel counter, Victor2, PerkinElmer, Turku, Finland) (emission wavelength: 615nm, excitation) Wavelength: 340 nm), and the differential fluorescence inhibition rate was calculated according to the following equation, and the result was expressed as an IC ₅₀ value, which is the concentration of a test substance which inhibited the MCH receptor by 50% in vitro .

[Equation 1]

Some of the MCH binding inhibitory activity results are shown in Table 2 below.

TABLE 2

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative prepared in the examples of the present invention Has a different skeleton from the existing compounds, and MCH binding inhibition activity is confirmed by MCH binding inhibition experiment, it can be used as an effective pharmaceutical composition as a therapeutic agent for obesity in which adipose tissue is excessively accumulated in the body. I could see that.

The following formulation is a 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative according to the present invention. It is merely illustrative of the preparation containing the active ingredient, but is not limited thereto.

Preparation Example 1 Preparation of Tablet (Direct Press Method)

As an active ingredient, 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidine-4- represented by the formula (1) of the present invention After sieving 5.0 mg of urea derivative, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized into tablets.

Preparation Example 2 Preparation of Tablet (Wet Granulation)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water, then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

< Formulation example  3> Preparation of Powders and Capsules

After sifting 5.0 mg of active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

<Example 4> Injection preparation

Injectables were prepared by containing 100 mg of the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ 12H ₂ O and 2974 mg of distilled water.

Claims (7)

1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative or drug represented by Formula 1 below Scholarly acceptable his salts.
[Formula 1]

[In Formula 1, R ¹ is hydrogen or halogen; R ² is heteroaryl selected from the following structures;

R ^a , R ^b and R ^c are each independently hydrogen, (C1-C20) alkyl, halo (C1-C20) alkyl, halogen, (C1-C20) alkoxy, (C6-C20) aryloxy, (C1-C20 ) Alkylcarbonyl, (C6-C20) arylcarbonyl, (C6-C20) aryl or halo (C6-C20) aryl; m is an integer of 1 to 4, n is an integer of 1 to 3, l is an integer of 1 or 2.] The method of claim 1,
R ¹ is hydrogen or fluorine, characterized in that 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidine-4- General] Urea derivatives or pharmaceutically acceptable salts thereof. The method of claim 1,
R ² is 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperi, characterized in that heteroaryl is selected from the following structures: Din-4-yl] urea derivative or a pharmaceutically acceptable salt thereof.

1- (6,7-difluoro-3-methoxyquinoxaline-2 represented by Formula 1 of claim 1 through a reduction alkylation reaction of a compound represented by Formula 5 and a heteroaryl aldehyde compound represented by Formula 6 -Yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea compound.
[Chemical Formula 5]

[Formula 6]

[In Formulas 5 and 6, R ¹ and R ² are the same as defined in Formula 1 of claim 1.] delete 1- (6,7-difluoro-3-methoxyquinoxalin-2-yl) -3- [1- (heteroarylmethyl) piperidin-4-yl] urea derivative represented by formula 1 of claim 1 Or a pharmaceutical composition for the treatment and prevention of obesity diseases, characterized in that it contains a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 6,
The obesity disease is a pharmaceutical composition for the treatment and prevention of obesity, characterized in that caused by melanin-concentrating hormone activity.