KR20060053788A - 1-[(2-alkoxy-6-substituted-quinoxalin-3-yl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives - Google Patents

Abstract

The present invention provides a novel 1-[(2-alkoxy-6-substituted-quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivative and a medicament having excellent anticancer activity Scientifically acceptable salts thereof, methods for preparing the compounds, and the use of the compounds as anticancer agents.

In Formula 1, X and Y are each N, or CR ⁶ ; R ¹ is a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group, or a halogen atom, and R ² is a C ₁ -C ₆ alkyl group; ^{R 3, R 4, R 5} , and R ⁶ are each a hydrogen atom, alkyl of C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ of the Carbonyl group, halogen atom, cyano group, or nitro group.

Quinoxaline, Piperazine, Urea, Regioselective, Anticancer

Description

1-[(2-alkoxy-6-substituted-quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivative {1-[(2-Alkoxy-6-substituted-quinoxalin-3- yl) aminocarbonyl] -4- (hetero) arylpiperazine Derivatives}

The present invention provides novel 1-[(2-alkoxy-6-substituted-quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivatives with excellent anticancer activity and pharmaceutically acceptable salts thereof. The present invention relates to a method for producing the compound, and to the use of the compound as an anticancer agent.

Current anticancer drugs are not complete in terms of efficacy and toxicity. For that reason, it is necessary to overcome the problems of existing anticancer drugs and to develop anticancer drugs having excellent activity.

Regarding the development of a new anticancer agent that can overcome the problems with existing anticancer agents, US Patent Application Publication No. 2003/0092910 discloses a piperazine derivative represented by the following structural formula.

In addition, U.S. Patent Application Publication No. 2003/0092910 discloses 1-[(2-alkoxyquinoxalin-3-yl) aminocarbonyl] -4- by substituents R _a and R _b are bonded to each other to form a C4 unsaturated junction ring. It is also known to synthesize arylpiperazine derivatives. However, these compounds are only known compounds in which the C-5, C-6, C-7, and C-8 positions of the quinoxaline ring are all substituted with hydrogen atoms.

That is, US Patent Application Publication No. 2003/0092910 discloses 1-[(2-alkoxyquinoxalin-3-yl) aminocarbonyl] -4-arylpiperazine derivatives in which the C-6 position is substituted with another substituent instead of a hydrogen atom. Substituted compounds are not considered at all, and there is no fact that the anticancer activity was synthesized.

The present invention was developed in view of the excellent anticancer activity and low toxicity of 1-[(2-alkoxyquinoxalin-3-yl) aminocarbonyl] -4-arylpiperazine derivatives. New 1-[(2-alkoxy-6-substituted), wherein a substituent other than a hydrogen atom is introduced at the C-6 position of the quinoxaline ring of the alkoxyquinoxalin-3-yl) aminocarbonyl] -4-arylpiperazin derivative The present invention was completed by synthesizing quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivatives and confirming the anticancer activity of this novel compound.

It is therefore an object of the present invention to provide novel 1-[(2-alkoxy-6-substituted-quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivatives.

Another object of the present invention is to provide a method for preparing a novel 1-[(2-alkoxy-6-substituted-quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivative. .

In addition, the present invention provides a novel 1-[(2-alkoxy-6-substituted-quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivative exhibiting excellent anticancer effects, Another purpose is to provide use as an anticancer agent.

The present invention has a novel anti-cancer effect represented by the following formula (1) It is characterized by a 1-[(2-alkoxy-6-substituted-quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivative.

[Formula 1]

In Formula 1, X and Y are each N, or CR ⁶ ; R ¹ is a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group, or a halogen atom, and R ² is a C ₁ -C ₆ alkyl group; Of ^{R 3, R 4, R 5} , and R ⁶ are each hydrogen atom, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl group, a haloalkyl group of _{C 1 -C 6, C 1 -C} 6 of An alkylcarbonyl group, a halogen atom, a cyano group, or a nitro group.

'Halogen atom' in the present invention means fluorine, chlorine, bromine or iodine atom.

The term "alkoxy group" in the present invention means a C ₁ -C ₆ alkoxy group including a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t -butoxy group.

The term 'alkyl group' in the present invention includes methyl, ethyl, propyl, isopropyl, n -butyl, isobutyl, t -butyl group, n -pentyl, isopentyl, n -hexyl, isohexyl and cyclohexyl groups It means a C ₁ -C ₆ alkyl group.

In the present invention, the "haloalkyl group" means a C ₁ -C ₆ alkyl group substituted with a halogen atom such as F and Cl, such as a trifluoromethyl group.

In the present invention, the term "alkylcarbonyl group" means a group in which a carbonyl group is ketoneized by an alkyl group, such as methylcarbonyl group or ethylcarbonyl group.

In the compound represented by Formula 1 according to the present invention, particularly preferably X and Y are each N, CH, CF, C-Cl, C-CN, C-CH ₃ , or C-OCH ₃ , R ¹ is a fluorine atom, a chloro atom, a methyl group, or a methoxy group, R ² is a methyl group, R ³ , R ⁴ , And R ⁵ is a hydrogen atom, a chloro atom, a nitro group, a methyl group, a trifluoromethyl group, a methoxy group, or an acetoxy group, and R ⁶ is a hydrogen atom, a fluorine atom, a chloro atom, a cyan group, a methyl group, or a methoxy group In the case of phosphorus compounds.

On the other hand, the present invention includes a method for producing a compound represented by the formula (1). The preparation method according to the invention comprises a two step preparation process as shown in Scheme 1:

Next, the 6-substituted-2-alkoxy-3-aminoquinoxaline represented by Chemical Formula 2 and the carbonyl group donating reagent represented by LC (= O) -L 'are reacted in an organic solvent in the presence of a base, First step reaction to prepare the compound,

The second step of preparing a compound represented by the following formula 1 by reacting the compound represented by the formula (3) prepared in the organic solvent in the presence of a compound represented by the following formula (4) and a base.

In Scheme 1, X, Y, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are each as defined above, and L and L 'are imidazole, chlorine atom, ethoxy group, phenoxy group, 4-nitrophenoxy group.

In the two-step preparation reaction according to Scheme 1, the following reaction may be continuously performed without separating and purifying the compound represented by Formula 3 synthesized as an intermediate.

Referring to the production method of the present invention according to Scheme 1 in more detail as follows.

Carbonyl donor reagents used in the first reaction may include 1,1-carbonyldiimidazole, phosgene, carbonyldiphenoxide, phenylchloroformate, 4-nitrophenylchloroformate, ethylchloroformate, and the like. have. The carbonyl donor reagent may be used in an amount of 1.0 to 1.5 equivalents based on the compound represented by Formula 2, and preferably 1.0 to 1.1 equivalents. This reaction is preferably using a conventional organic solvent such as tetrahydrofuran (THF), dichloromethane, acetonitrile, dimethylformamide and the like. It is also preferable that the reaction is carried out in the presence of a conventional inorganic or organic base. Common inorganic or organic bases used in this reaction are sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, 1,8- Diazabai Cyclo [5.4.0] -Undetsu-7-en (hereinafter referred to as "DBU"). The reaction is reacted at a boiling point temperature of 0 ° C. to the solvent, preferably at room temperature to 100 ° C. for 5 to 48 hours, preferably 10 to 24 hours.

The second reaction is carried out for 5 hours to 48 hours at 50 ℃ to 100 ℃ in a conventional organic solvent. The compound represented by Chemical Formula 4 uses 1.0 to 1.5 equivalents. In addition, this reaction is preferably carried out in the presence of a conventional organic or inorganic base, for example, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, Triethylamine, pyridine, DBU and the like.

In addition, the 6-substituted-2-alkoxy-3-aminoquinoxaline derivative represented by Formula 2 used as a starting material in the preparation method according to the present invention is a novel compound, prepared by an alkoxylation reaction according to the following Scheme 2. Can be.

In Reaction Scheme 2, R ¹ and R ² are as defined in Formula 1, respectively.

The compound represented by the formula (5) is J. Med. Chem. 1995, 38 , 3720-3740, Bull. Chem. Soc. Jpn . It may be prepared and used by the method described in 1998, 71 , 1125-1135 and the like or a similar method.

The alkoxylation reaction according to Scheme 2 may be prepared by reacting with sodium alkoxide in an organic solvent such as THF. Sodium alkoxide is preferably used in an amount of 1.0 to 10.0 equivalents based on the amount of the compound represented by Formula 5, preferably 1.0 to 1.1 equivalents.

In addition, in order to confirm the production of the target compound represented by Chemical Formula 1 according to the present invention, a multi-column chromatography apparatus (Quad ³⁺ ; manufactured by Biotage, USA) and a high-speed liquid with an automatic sample injection device in the final step after the reaction After purification by chromatography equipment, the structure was analyzed by NMR and Mass spectra.

On the other hand, the compound represented by the formula (1) according to the present invention is excellent in the activity of inhibiting the growth of cancer cells can be usefully used for cancer drug development.

Accordingly, the present invention relates to 1-[(2-alkoxy-6-substituted-quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivatives or pharmaceutically acceptable salts thereof. It contains a pharmaceutical composition effective in preventing and treating various cancers caused by abnormal growth of cells.

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, gustyic 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 or parenteral administration such as tablets, capsules, troches, solutions, suspensions, and the like, and may be used for the prevention and treatment of various types of tumors.

Excipients that may be used in the pharmaceutical compositions of the present invention 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, arginine acid, 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 5000 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 as described above will be described in more detail based on the following Examples and Experimental Examples, but the present invention is not limited thereto.

Example 1) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4-phenylpiperazine

a) 3-amino-6-fluoro-2-methoxyquinoxaline

3-amino-2-chloro-6-fluoroquinoxaline (550 mg, 2.78 mmol) was dissolved in tetrahydrofuran (40 mL) and then stirred with 25 wt% sodium methoxide / methanol solution (6.01 g, 27.8 mmol) Was added at room temperature. After stirring at the same temperature for 60 minutes, the reaction was concentrated under reduced pressure, water was added, and extracted with dichloromethane. The dichloromethane layer was washed several times with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with a hexane and ethyl acetate mixed solvent (2: 1) afforded the above compound (491 mg, 91%).

b) ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate

3-amino-6-fluoro-2-methoxyquinoxaline (580 mg, 3.00 mmol) and ethylchloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 mL) at room temperature, followed by stirring with pyridine (285). mg, 3.60 mmol) was added. After stirring for 10 hours at the same temperature, the residue was concentrated under reduced pressure and the residue was chromatographed on a silica gel column. Elution with a hexane and ethyl acetate mixed solvent (3: 1) afforded the above compound (740 mg, 93%).

c) 1-[(6-fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4-phenylpiperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate (27 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) at room temperature were added with tetrahydrofuran (2 mL). ) And DBU (23 mg, 0.15 mmol) was added. The mixture was stirred at 70 ° C. for 7 hours and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with a hexane and ethyl acetate mixed solvent (2: 1) afforded the above compound (34 mg, 88%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.29 (s, 4H), 3.77 (s, 3H), 4.14 (s, 4H), 6.89-6.97 (m, 4H), 7.24-7.56 (m, 5H), 7.62-7.71 (m, 1 H).

Example 2) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (84%). Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.15 (s, 4H), 3.79-3.87 (m, 6H), 4.11 (s, 4H), 6.86-7.02 (m, 4H), 7.18-7.22 (m, 1H ), 7.39-7.50 (m, 1 H), 7.65-7.72 (m, 1 H).

Example 3) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-methoxyphenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (87%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.28 (s, 4H), 3.80 (s, 6H), 4.13 (s, 4H), 6.45-6.58 (m, 3H), 7.01 (s, 1H), 7.17- 7.23 (m, 2 H), 7.37-7.70 (m, 2 H).

Example 4) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-methoxyphenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (4-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (80%). Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.18 (s, 4H), 3.79 (s, 6H), 4.08-4.15 (m, 4H), 6.85-6.98 (m, 4H), 7.22-7.76 (m, 4H ).

Example 5) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3,4,5-trimethoxyphenyl) piperazine

The compound was reacted with ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3,4,5-trimethoxyphenyl) piperazine in the same manner as in Example 1. (76%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.22 (s, 4H), 3.79-3.85 (m, 12H), 4.13 (s, 4H), 6.19 (s, 2H), 7.20-7.34 (m, 1H), 7.35-7.36 (m, 1 H), 7.44 (s, 1 H), 7.67-7.70 (m, 1 H).

Example 6) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-methylphenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-methylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (73%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.35 (s, 3H), 2.98-3.03 (m, 4H), 3.73-3.78 (m, 3H), 4.10-4.14 (m, 4H), 7.02-7.17 (m , 2H), 7.19-7.29 (m, 2H), 7.36 (s, 1H), 7.48-7.60 (m, 1H), 7.67-7.74 (m, 1H).

Example 7) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-methylphenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3-methylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (90%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.33 (s, 3H), 3.26-3.30 (m, 4H), 3.74-3.78 (m, 3H), 4.13 (s, 4H), 6.75-6.78 (m, 3H ), 7.14-7.28 (m, 2H), 7.36 (s, 1H), 7.44-7.51 (dd, J = 9.8 and 2.4 Hz, 1H), 7.67-7.74 (m, 1H).

Example 8) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2,6-dimethylphenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2,6-dimethylphenyl) piperazine were reacted in the same manner as in Example 1 to give the above compound (65%). Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.26 (s, 3H), 3.20 (s, 4H), 3.71 (s, 3H), 4.12-4.18 (m, 4H), 6.99-7.01 (m, 3H), 7.26-7.32 (m, 2 H), 7.53-7.81 (m, 2 H).

Example 9) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (79%). Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.29 (s, 6H), 3.27 (s, 4H), 3.88 (s, 3H), 4.14 (s, 4H), 6.59 (s, 3H), 7.01-7.10 ( s, 1H), 7.24-7.36 (m, 2H), 7.47-7.71 (m, 2H).

Example 10) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-trifluorotoryl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3-trifluorotortolyl) piperazine were reacted in the same manner as in Example 1 to give the above compound (80%). Got.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.34 (s, 4H), 3.79 (s, 3H), 4.10 (s, 4H), 7.07-7.24 (m, 3H), 7.35-7.43 (m, 3H), 7.71 (m, 1 H).

Example 11) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-fluorophenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-fluorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (91%). .

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.18 (s, 4H), 3.78 (s, 3H), 4.13 (s, 4H), 6.93-7.10 (m, 5H), 7.20-7.34 (m, 1H), 7.46-7.60 (m, 1 H), 7.67-7.74 (m, 1 H).

Example 12) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-fluorophenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3-fluorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (85%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.19 (s, 4H), 3.77 (s, 3H), 4.13 (s, 4H), 6.88-7.02 (m, 4H), 7.23-7.27 (m, 1H), 7.45-7.71 (m, 3 H).

Example 13) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-chlorophenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (87%). .

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.14 (s, 4H), 3.79 (s, 3H), 4.13 (s, 4H), 6.97-7.05 (m, 2H), 7.22-7.28 (m, 2H), 7.33-7.40 (m, 2H), 7.46-7.51 (d, J = 10.2 Hz, 1H), 7.66-7.73 (m, 1H).

Example 14) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-chlorophenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (70%). .

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.30 (s, 4H), 3.76 (s, 3H), 4.13 (s, 4H), 6.77-6.91 (m, 3H), 7.15-7.33 (m, 3H), 7.44-7.58 (d, J = 10.0 Hz, 1H), 7.58-7.75 (m, 1H).

Example 15) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-chlorophenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (4-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (95%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.25 (s, 4H), 3.78 (s, 3H), 4.13 (s, 4H), 6.86 (d, J = 8.4 Hz, 2H), 7.22-7.26 (m, 3H), 7.44 (m, 1 H), 7.70 (m, 1 H).

Example 16) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-cyanophenyl) piperazine

The compound (85%) was reacted with ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-cyanophenyl) piperazine in the same manner as in Example 1. Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.31 (s, 4H), 3.73-3.85 (m, 3H), 4.06-4.16 (m, 4H), 7.03-7.11 (m, 3H), 7.20-7.34 (m , 1H), 7.50-7.62 (m, 3H), 7.67-7.74 (m, 1H).

Example 17) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-acetylphenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (4-acetylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (90%). .

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.54 (s, 3H), 3.42-3.48 (m, 4H), 3.79 (s, 3H), 4.14 (s, 4H), 6.89 (d, J = 9.0 Hz, 2H), 7.10-7.50 (m, 3H), 7.69-7.80 (m, 1H), 7.91 (d, J = 7.8 Hz, 2H).

Example 18) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-nitrophenyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (4-nitrophenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (86%). Got it.

¹ H NMR (200 MHz, DMSO- d ₆ ) δ 3.18 (s, 4H), 3.62 (s, 3H), 3.99-4.01 (m, 4H), 7.01-7.18 (m, 4H), 7.53-7.57 (m , 1H), 7.70-7.78 (m, 1 H), 8.06-8.11 (m, 2H).

Example 19) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-pyridyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-pyridyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (79%). .

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.71 (s, 7H), 4.11 (s, 4H), 6.66 (d, J = 9.0 Hz, 2H), 7.10 (m, 1H), 7.22-7.25 (m, 1H), 7.38-7.54 (m, 3H), 7.65-7.68 (m, 1H), 8.19 (d, J = 3.8 Hz, 1H).

Example 20) 1-[(6-Fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-pyrimidyl) piperazine

Ethyl N- (6-fluoro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-pyrimidyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (71%). .

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.68 (s, 4H), 3.96 (s, 3H), 4.12 (s, 4H), 6.23 (t, J = 4.4 Hz, 1H), 7.02 (s, 1H) , 6.89-7.00 (m, 1H), 7.36-7.43 (m, 1H), 7.67 (m, 1H), 8.32 (d, J = 4.4 Hz, 2H).

Example 21) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4-phenylpiperazin

a) 3-amino-6-chloro-2-methoxyquinoxaline

3-amino-2,6-dichloroquinoxaline (1.30 g, 6.07 mmol) was dissolved in tetrahydrofuran (60 mL), followed by stirring with a 25 wt% methanol solution of sodium methoxide (13.1 g, 60.7 mmol). It was added at room temperature. After stirring for 90 minutes at the same temperature, the reaction was concentrated under reduced pressure, water was added, and extracted with dichloromethane. The dichloromethane layer was washed several times with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with a hexane and ethyl acetate mixed solvent (2: 1) gave the above compound (1.22 g, 96%).

b) ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate

3-amino-6-chloro-2-methoxyquinoxaline (629 mg, 3.00 mmol) and ethylchloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 mL) at room temperature, followed by stirring with pyridine (285). mg, 3.60 mmol) was added. After stirring for 10 hours at the same temperature, the residue was concentrated under reduced pressure and the residue was chromatographed on a silica gel column. Elution with a mixed solvent of hexane and ethyl acetate (3: 1) afforded the above compound (803 mg, 95%).

c) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4-phenylpiperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate (28 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) at room temperature were added with tetrahydrofuran (2 mL). ) And DBU (23 mg, 0.15 mmol) was added. The mixture was stirred at 70 ° C. for 7 hours and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with a hexane and ethyl acetate mixed solvent (2: 1) afforded the above compound (36 mg, 91%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.22-3.30 (m, 4H), 3.75-3.78 (m, 3H), 4.08-4.13 (m, 4H), 6.89-6.96 (m, 3H), 7.19-7.44 (m, 5 H), 7.64-7.80 (m, 1 H).

Example 22) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (77%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.10-3.17 (m, 4H), 3.80-3.89 (m, 6H), 4.08-4.15 (m, 4H), 6.88-7.07 (m, 4H), 7.20-7.32 (m, 1 H), 7.41-7.44 (m, 1 H), 7.50-7.68 (m, 1 H), 7.82 (s, 1 H).

Example 23) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-methoxyphenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (70%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.22-3.30 (m, 4H), 3.76-3.80 (m, 6H), 4.08-4.14 (m, 4H), 6.46-6.57 (m, 3H), 7.20 (t , J = 8.1 Hz, 1H), 7.34-7.44 (m, 1H), 7.50-7.67 (m, 1H), 7.80 (s, 1H).

Example 24) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-methoxyphenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (4-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (81%). Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.16 (s, 4H), 3.78 (s, 3H), 4.16 (s, 4H), 6.88-6.93 (m, 4H), 7.27-7.80 (m, 4H).

Example 25) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3,4,5-trimethoxyphenyl) piperazine

The compound was reacted with ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3,4,5-trimethoxyphenyl) piperazine in the same manner as in Example 1. (84%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.17-3.25 (m, 4H), 3.81-3.86 (m, 12H), 4.09-4.16 (m, 4H), 6.21 (s, 2H), 7.21-7.30 (m , 1H), 7.33-7.54 (m, 1H), 7.58-7.69 (m, 1H), 7.81 (s, 1H).

Example 26) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-methylphenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-methylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (80%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.35 (s, 3H), 2.95-3.02 (m, 4H), 3.74-3.77 (m, 3H), 4.08-4.14 (m, 4H), 7.01-7.57 (m , 7H), 7.64-7.85 (m, 1H).

Example 27) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-methylphenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3-methylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (90%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.20-3.30 (m, 4H), 3.74-3.77 (m, 3H), 4.11-4.14 (m, 4H), 6.74-6.77 (m, 3H), 7.16-7.25 (m, 4 H), 7.64-7. 81 (m, 1 H).

Example 28) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2,6-dimethylphenyl) piperazine

The compound (67%) was reacted with ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2,6-dimethylphenyl) piperazine in the same manner as in Example 1. Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.33-2.40 (m, 6H), 3.14-3.22 (m, 4H), 3.69-3.76 (m, 3H), 4.06-4.18 (m, 4H), 6.97-7.04 (m, 3 H), 7.20-7.85 (m, 4 H).

Example 29) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the compound (79 %) Was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.29 (s, 6H), 3.19-3.29 (m, 4H), 3.73-3.89 (m, 3H), 4.11-4.14 (m, 4H), 6.58 (s, 3H ), 7.19-7.25 (m, 1 H), 7.36-7.64 (m, 2 H), 7.67-7.81 (m, 1 H).

Example 30) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-trifluorotoryl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3-trifluorotoryl) piperazine were reacted in the same manner as in Example 1 to give the compound (84%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.27-3.37 (m, 4H), 3.76-3.80 (m, 3H), 4.12-4.14 (m, 4H), 7.08-7.26 (m, 4H), 7.36-7.45 (m, 3 H), 7.64-7.80 (m, 1 H).

Example 31) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-fluorophenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-fluorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (80%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.12-3.21 (m, 4H), 3.77-3.84 (m, 3H), 4.11-4.15 (m, 4H), 6.95-7.10 (m, 4H), 7.20-7.45 (m, 3 H), 7.65-7.82 (m, 1 H).

Example 32) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-fluorophenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3-fluorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (77%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.13-3.20 (m, 4H), 3.77 (s, 3H), 4.14 (s, 4H), 6.88-7.02 (m, 4H), 7.20-7.24 (m, 1H ), 7.36-7.44 (m, 1 H), 7.50-7.67 (m, 1 H), 7.80 (s, 1 H).

Example 33) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-chlorophenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (76%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.08-3.17 (m, 4H), 3.78-3.86 (m, 3H), 4.09-4.15 (m, 4H), 7.00-7.07 (m, 2H), 7.20-7.45 (m, 5 H), 7.65-7.84 (m, 1 H).

Example 34) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-chlorophenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (3-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (85%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.22-3.32 (m, 4H), 3.73-3.77 (m, 3H), 4.11-4.14 (m, 4H), 6.78-6.90 (m, 3H), 7.19-7.44 (m, 4 H), 7.64-7.80 (m, 1 H).

Example 35) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-cloyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (4-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (96%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.18-3.26 (m, 4H), 3.76 (s, 3H), 4.11-4.14 (m, 4H), 6.84-6.87 (d, J = 8.7 Hz, 2H), 7.22-7.34 (m, 3H), 7.41-7.53 (m, 1H), 7.65-7.66 (m, 1H), 7.79 (s, 1H).

Example 36) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-cyanophenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-cyanophenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (91%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.25-3.32 (m, 4H), 3.84 (s, 3H), 4.08-4.15 (m, 4H), 7.06-7.08 (m, 2H), 7.21 (m, 1H ), 7.41-7.67 (m, 4H), 7.82 (s, 1H).

Example 37) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-acetylphenyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (4-acetylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (85%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.54 (s, 3H), 3.50 (s, 4H), 3.80 (s, 3H), 4.14 (s, 4H), 6.89 (d, J = 7.7 Hz, 2H) , 7.44 (s, 1H), 7.66 (s, 1H), 7.79 (s, 1H), 7.79 (s, 1H), 7.91 (d, J = 7.7 Hz, 2H).

Example 38) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-nitrophenyl) piperazine

The compound (82%) was reacted with ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (4-nitrophenyl) piperazine in the same manner as in Example 1. Got it.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.62-3.66 (m, 8H), 4.06 (s, 3H), 7.07 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.76-7.80 (m, 2H), 8.11 (d, J = 9.0 Hz, 2H), 9.46 (s, 1H).

Example 39) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-pyridyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-pyridyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (70%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.63-3.73 (m, 7H), 4.08-4.15 (m, 4H), 6.68 (d, J = 8.7 Hz, 2H), 7.20-7.31 (m, 1H), 7.42-7.53 (m, 2H), 7.65-7.80 (m, 2H), 8.21 (d, J = 3.6 Hz, 1H).

Example 40) 1-[(6-chloro-2-methoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-pyrimidyl) piperazine

Ethyl N- (6-chloro-2-methoxyquinoxalin-3-yl) carbamate and 1- (2-pyrimidyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (90%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.71 (s, 4H), 3.99 (s, 3H), 4.15 (s, 4H), 6.55 (s, 1H), 7.27-7.43 (m, 2H), 7.66 ( s, 1H), 7.80 (s, 1H), 8.35 (s, 2H).

Example 41) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4-phenylpiperazine

a) 3-amino-2-methoxy-6-methylquinoxaline

3-amino-2-chloro-6-methylquinoxaline (550 mg, 2.84 mmol) was dissolved in tetrahydrofuran (30 mL), followed by stirring with a 25 wt% methanol solution of sodium methoxide (6.14 g, 28.4 mmol) Was added at room temperature. After stirring at the same temperature for 60 minutes, the reaction was concentrated under reduced pressure, water was added, and extracted with methyl chloride. The methylene chloride layer was washed several times with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with a hexane and ethyl acetate mixed solvent (2: 1) gave the above compound (467 mg, 87%).

b) ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate

3-amino-2-methoxy-6-methylquinoxaline (568 mg, 3.00 mmol) and ethylchloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 mL) at room temperature, followed by stirring with pyridine (285). mg, 3.60 mmol) was added. After stirring for 10 hours at the same temperature, the residue was concentrated under reduced pressure and the residue was chromatographed on a silica gel column. Elution with a mixture of hexane and ethyl acetate (3: 1) gave the above compound (768 mg, 98%).

c) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4-phenylpiperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate (26 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) at room temperature were added with tetrahydrofuran (2 mL). ) And DBU (23 mg, 0.15 mmol) was added. The mixture was stirred at 70 ° C. for 7 hours and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with a mixed solvent of hexane and ethyl acetate (2: 1) afforded the above compound (34 mg, 90%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.42-2.48 (m, 3H), 3.22-3.30 (m, 4H), 3.77 (s, 3H), 4.12 (s, 4H), 6.90-7.12 (m, 4H ), 7.25-7.32 (m, 3H), 7.48-7.65 (m, 2H).

Example 42) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine

The compound (66%) was reacted with ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (2-methoxyphenyl) piperazine in the same manner as in Example 1. Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.42-2.49 (m, 3H), 3.10-3.16 (m, 4H), 3.80-3.89 (m, 6H), 4.08-4.17 (m, 4H), 6.88-7.11 (m, 5H), 7.26-7.32 (m, 1H), 7.48-7.64 (m, 2H).

Example 43) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (3-methoxyphenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (3-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (73%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.43-2.48 (m, 3H), 3.23-3.30 (m, 4H), 3.76-3.87 (m, 3H), 4.04-4.13 (m, 4H), 6.45-6.50 (m, 2H), 6.57 (d, J = 8.4 Hz, 1H), 7.01-7.12 (m, 1H), 7.17-7.33 (m, 3H), 7.48-7.65 (m, 2H).

Example 44) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (4-methoxyphenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (4-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (80%). Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.48 (s, 3H), 3.16-3.14 (m, 4H), 3.78-3.82 (m, 6H), 4.13 (s, 4H), 6.84-7.02 (m, 4H ), 7.14-7.33 (m, 3 H), 7.53-7.64 (m, 1 H).

Example 45) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (3,4,5-trimethoxyphenyl) piperazine

The compound was reacted with ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (3,4,5-trimethoxyphenyl) piperazine in the same manner as in Example 1. (94%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.44-2.49 (m, 3H), 3.18-3.25 (m, 4H), 3.80-3.86 (m, 12H), 4.04-4.13 (m, 4H), 6.20 (s , 2H), 7.02-7.20 (m, 1 H), 7.31-7.40 (m, 1 H), 7.46-7.63 (m, 2H).

Example 46) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (2-methylphenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (2-methylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (95%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.32-2.56 (m, 6H), 2.88-3.00 (m, 4H), 3.77 (s, 3H), 4.08-4.13 (m, 4H), 7.02-7.04 (m , 3H), 7.19-7.39 (m, 3H), 7.51-7.65 (m, 2H).

Example 47) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (3-methylphenyl) piperazine

The compound (90%) was obtained by reacting ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (3-methylphenyl) piperazine in the same manner as in Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.33-2.46 (m, 6H), 3.14-3.37 (m, 4H), 3.73-3.87 (m, 3H), 4.05-4.18 (m, 4H), 6.72-6.78 (m, 3H), 7.00-7.20 (m, 2H), 7.30-7.38 (m, 1H), 7.49-7.62 (m, 2H).

Example 48) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (2,6-dimethylphenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (2,6-dimethylphenyl) piperazine were reacted in the same manner as in Example 1 to give the above compound (88%). Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.04-2.58 (m, 9H), 3.14-3.20 (m, 4H), 3.71-3.76 (m, 3H), 4.07-4.14 (m, 4H), 7.00-7.15 (m, 4 H), 7.25-7.76 (m, 3 H).

Example 49) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine were reacted in the same manner as in Example 1 to give the above compound (87%). Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.29 (s, 6H), 2.42-2.48 (m, 3H), 3.20-3.28 (m, 4H), 3.75-3.80 (m, 3H), 4.10-4.13 (m , 4H), 6.59 (s, 3H), 7.00-7.12 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.48-7.65 (m, 2H).

Example 50) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (3-trifluorotoryl) piperazine

The compound (82%) was reacted with ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (3-trifluorotoryl) piperazine in the same manner as in Example 1. Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.46-2.49 (m, 3H), 3.18-3.31 (m, 4H), 3.73-3.80 (m, 3H), 4.10-4.19 (m, 4H), 7.10-7.20 (m, 4H), 7.34-7.39 (m, 2H), 7.56-7.65 (m, 2H).

Example 51) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (2-fluorophenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (2-fluorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (79%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.42-2.49 (m, 3H), 3.12-3.19 (m, 4H), 3.79 (s, 3H), 4.11-4.13 (m, 4H), 6.97-7.12 (m , 5H), 7.26-7.33 (m, 1 H), 7.48-7.63 (m, 2H).

Example 52) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (3-fluorophenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (3-fluorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (70%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.43-2.49 (m, 3H), 3.13-3.21 (m, 4H), 3.77 (s, 3H), 4.11-4.13 (m, 4H), 6.88-6.99 ( m, 4H), 7.13 (m, 1H), 7.25 (m, 1H), 7.48-7.65 (m, 2H).

Example 53) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (2-chlorophenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (2-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (66%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.43-2.49 (m, 3H), 3.10-3.15 (m, 4H), 3.81 (s, 3H), 3.08-4.12 (m, 4H), 7.00-7.12 (m , 3H), 7.24-7.40 (m, 3H), 7.49-7.65 (m, 2H).

Example 54) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (3-chlorophenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (3-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (72%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.45 (s, 3H), 3.26 (s, 4H), 3.77 (s, 3H), 4.08-4.18 (m, 4H), 6.78-6.90 (m, 3H), 7.15-7.38 (m, 3H), 7.56-7.64 (m, 2H).

Example 55) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (4-chlorophenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (4-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (78%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.44-2.47 (m, 3H), 3.19-3.26 (m, 4H), 3.78 (s, 3H), 4.12 (s, 4H), 6.87 (d, J = 8.9 Hz, 2H), 7.01-7.11 (m, 1H), 7.22-7.26 (m, 3H), 7.52-7.61 (m, 2H).

Example 56) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (2-cyanophenyl) piperazine

The compound (91%) was reacted with ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (2-cyanophenyl) piperazine in the same manner as in Example 1. Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.46 (s, 3H), 3.28 (s, 4H), 3.86 (s, 3H), 4.08-4.19 (m, 4H), 7.01-7.08 (m, 3H), 7.17-7.37 (m, 1 H), 7.49-7.61 (m, 4 H).

Example 57) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (4-acetylphenyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (4-acetylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (87%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.45-2.53 (m, 6H), 3.47 (s, 4H), 3.81 (s, 3H), 3.87-4.13 (m, 4H), 6.88 (d, J = 8.7 Hz, 2H), 7.22-7.36 (m, 2H), 7.56-7.76 (m, 2H), 7.90 (d, J = 8.7 Hz, 2H).

Example 58) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (4-nitrofenyl) piperazine

Ethyl N- (2-methoxy-methylquinoxalin-3-yl) carbamate and 1- (4-nitrophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (86%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.46 (s, 3H), 3.52-3.58 (m, 4H), 3.82 (s, 3H), 4.09-4.13 (m, 4H), 6.85 (d, J = 9.2 Hz, 2H), 7.03-7.15 (m, 1H), 7.41 (m, 1H), 7.52-7.58 (m, 2H), 8.16 (d, J = 9.2 Hz, 2H).

Example 59) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (2-pyridyl) piperazine

Ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (2-pyridyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (83%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.43-2.47 (m, 3H), 3.63-3.73 (m, 7H), 4.13 (s, 4H), 6.67 (d, J = 8.4 Hz, 2H), 7.01- 7.12 (m, 1 H), 7.30-7.33 (m, 1 H), 7.48-7.62 (m, 3 H), 8.21 (dd, J = 4.8 and 1.5 Hz, 1 H).

Example 60) 1-[(2-methoxy-6-methylquinoxalin-3-yl) aminocarbonyl] -4- (2-pyrimidyl) piperazine

The compound (93%) was reacted with ethyl N- (2-methoxy-6-methylquinoxalin-3-yl) carbamate and 1- (2-pyrimidyl) piperazine in the same manner as in Example 1. Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.47 (s, 4H), 3.71 (s, 3H), 3.91-3.99 (m, 4H), 4.13 (s, 3H), 6.53 (s, 1H), 7.01- 7.13 (m, 1 H), 7.27-7.30 (m, 1 H), 7.52-7.61 (m, 2H), 8.33 (d, J = 4.8 Hz, 2H).

Example 61) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4-phenylpiperazine

a) 3-amino-2,6-dimethoxyquinoxaline

3-amino-2-chloro-6-methoxyquinoxaline (1.50 g, 7.16 mmol) was dissolved in tetrahydrofuran (60 mL), followed by stirring with a 25 wt% methanol solution of sodium methoxide (15.5 g, 71.6 mmol). ) Was added at room temperature. After stirring at the same temperature for 21 hours, the reaction mixture was concentrated under reduced pressure, water was added, and extracted with methyl chloride. The methylene chloride layer was washed several times with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with a hexane and ethyl acetate mixed solvent (2: 1) afforded the above compound (1.18 g, 80%).

b) ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate

3-amino-2,6-dimethoxyquinoxaline (616 mg, 3.00 mmol) and ethylchloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 mL) at room temperature, followed by stirring with pyridine (285 mg). , 3.60 mmol) was added. After stirring for 10 hours at the same temperature, the residue was concentrated under reduced pressure and the residue was chromatographed on a silica gel column. Elution with a hexane and ethyl acetate mixed solvent (3: 1) afforded the above compound (799 mg, 96%).

c) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4-phenylpiperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate (28 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) at room temperature are added to tetrahydrofuran (2 mL). After dissolving in DBU (23 mg, 0.15 mmol) was added. The mixture was stirred at 70 ° C. for 7 hours and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with a mixed solvent of hexane and ethyl acetate (2: 1) afforded the above compound (36 mg, 92%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.27 (s, 4H), 3.73-3.86 (m, 6H), 4.08-4.11 (m, 4H), 6.88-7.03 (m, 4H), 7.15 (s, 1H ), 7.26-7.33 (m, 3 H), 7.57-7.62 (m, 1 H).

Example 62) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (2-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (84%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.15 (s, 4H), 3.83-3.89 (m, 9H), 4.12-4.17 (m, 4H), 6.88-6.95 (m, 3H), 7.02-7.05 (m , 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.31 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H).

Example 63) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-methoxyphenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (3-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (80%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.28 (s, 4H), 3.80-3.87 (m, 9H), 4.11 (s, 4H), 6.45-6.49 (m, 2H), 6.56 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 7.04-7.36 (m, 3H), 7.53-7.62 (m, 1H).

Example 64) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-methoxyphenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (4-methoxyphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (81%). .

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.16 (s, 4H), 3.78-3.88 (m, 9H), 4.12-4.17 (m, 4H), 6.84-6.97 (m, 4H), 7.16-7.32 (m , 3H), 7.62-7.66 (m, 1H).

Example 65) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (3,4,5-trimethoxyphenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (3,4,5-trimethoxyphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the compound ( 97%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.55-3.87 (m, 10H), 4.12 (s, 4H), 6.67 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H) , 7.25 (s, 1H), 7.34 (s, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 8.21 (d, J = 3.6 Hz, 1H) .

Example 66) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-methylphenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (2-methylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (90%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.35 (s, 3H), 2.95-3.02 (m, 4H), 3.75-3.90 (m, 6H), 4.09-4.13 (m, 4H), 6.99-7.31 (m , 7H), 7.50-7.66 (m, 1H).

Example 67) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-methylphenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (3-methylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the compound (95%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.33 (s, 3H), 3.26 (s, 4H), 3.72-3.89 (m, 6H), 4.09-4.18 (m, 4H), 6.72-6.78 (m, 4H ), 7.03-7.37 (m, 3H), 7.57-7.65 (m, 1H).

Example 68) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (2,6-dimethylphenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (2,6-dimethylphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (87%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.33-2.36 (m, 6H), 3.14-3.22 (m, 4H), 3.70-3.90 (m, 6H), 4.09-4.15 (m, 4H), 6.67-7.32 (m, 6 H), 7.50-7.65 (m, 1 H).

Example 69) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine were reacted in the same manner as in Example 1 to give the compound (65%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.28 (s, 6H), 3.26 (s, 4H), 3.76-3.87 (m, 6H), 4.11 (s, 4H), 6.59 (s, 2H), 6.90 ( m, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.32 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H).

Example 70) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-trifluorotoryl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (3-trifluorotoryl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (77%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.33 (s, 4H), 3.74-3.90 (m, 6H), 4.09-4.19 (m, 4H), 6.92 (s, 1H), 7.02-7.19 (m, 5H ), 7.38 (t, J = 7.5 Hz, 1H), 7.59-7.66 (m, 1H).

Example 71) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-fluorophenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (2-fluorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the compound (72%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.18 (s, 4H), 3.73-3.88 (m, 6H), 4.11-4.15 (m, 4H), 6.88-7.15 (m, 5H), 7.33 (s, 1H ), 7.51 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H).

Example 72) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-fluorophenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (3-fluorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (90%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.17 (s, 4H), 3.78-3.89 (m, 6H), 4.11-4.15 (m, 4H), 6.88-7.02 (m, 4H), 7.14-7.36 (m , 3H), 7.58-7. 62 (m, 1H).

Example 73) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-chlorophenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (2-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the compound (89%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.09-3.16 (m, 4H), 3.79-3.90 (m, 6H), 4.10-4.16 (m, 4H), 7.00-7.30 (m, 7H), 7.38-7.66 (m, 1 H).

Example 74) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (3-chlorophenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (3-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the compound (85%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.21-3.32 (m, 4H), 3.75-3.88 (m, 6H), 4.10-4.13 (m, 4H), 6.80-6.90 (m, 4H), 7.14-7.29 (m, 3 H), 7.63-7.66 (m, 1 H).

Example 75) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-chlorophenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (4-chlorophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the compound (86%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.25 (s, 4H), 3.77 (s, 3H), 3.87 (s, 3H), 4.09-4.12 (m, 4H), 6.86-7.00 (m, 3H), 7.12-7.24 (m, 3H), 7.55-7.65 (m, 2H).

Example 76) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-cyanophenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (2-cyanophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (94%). .

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.30 (s, 4H), 3.88-3.90 (m, 6H), 4.07-4.20 (m, 4H), 6.94-7.07 (m, 3H), 7.27-7.34 (m , 2H), 7.53-7.63 (m, 3H).

Example 77) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-acetylphenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (4-acetylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (87%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.54-2.58 (m, 3H), 3.49-3.67 (m, 4H), 3.87-3.96 (m, 6H), 4.12-4.16 (m, 4H), 6.87-7.03 (m, 2H), 7.19-7.31 (m, 3H), 7.62-7.66 (m, 1H), 7.89-7.97 (m, 2H).

Example 78) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (4-nitrophenyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (4-nitrophenyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (81%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.57 (s, 4H), 3.75-3.87 (m, 6H), 4.09-4.16 (m, 4H), 6.84 (d, J = 9.3 Hz, 2H), 6.91- 7.27 (m, 3H), 7.56-7.63 (m, 1H), 8.16 (d, J = 9.3 Hz, 2H).

Example 79) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-pyridyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (2-pyridyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (84%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.87 (s, 3H), 3.73-3.88 (m, 6H), 4.11-4.15 (m, 4H), 6.88-7.15 (m, 5H), 7.33 (s, 1H ), 7.51 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H).

Example 80) 1-[(2,6-dimethoxyquinoxalin-3-yl) aminocarbonyl] -4- (2-pyrimidyl) piperazine

Ethyl N- (2,6-dimethoxyquinoxalin-3-yl) carbamate and 1- (2-pyrimidyl) piperazine were reacted in the same manner as in Example 1 to obtain the above compound (80%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.72 (s, 3H), 3.87-3.96 (m, 7H), 4.12-4.15 (m, 4H), 6.54 (t, J = 4.8 Hz, 1H), 6.92 ( s, 1H), 7.04-7.36 (m, 3H), 7.62 (m, 1H), 8.34 (d, J = 4.8 Hz, 2H).

The structures of the compounds synthesized in the above examples are shown in Table 1 below.

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation 1) Tablet (Direct Press)

After sifting 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

Formulation 2) 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 and 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 3) Powders and Capsules

5.0 mg of the active ingredient was sieved, followed by mixing 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.

Formulation 4) Injection

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.

In addition, the anticancer pharmacological activity of various cancer cell lines of the novel compounds represented by Formula 1 according to the present invention was tested by the method of the following experimental example, the results are shown in Table 2 below.

Experimental Example) Growth Inhibition Experiment of Cancer Cell Line

a) culture of cancer cell lines

Cancer cell lines used in this experiment were obtained from: PANC-1 (pancreas), MDA-MB-231 (breast), PC3 (proatate), HepG2 (liver), Caki-1 (kidney), and OVCAR (ovary). ), MCF-7 (breast, hormoan-dependent), and HT-29 (colon) were obtained from the American Type Culture Collection (ATCC) (Manassas, VA), MKN45 (stomach) from DSMZ (Germany) and UMRC2 (kidney) was obtained from the United States National Cancer Institute (Bethesda, MD), and A549 (lung), Huvec, HT29, and SK-OV-3 were from the Korean Cell Line Bank of Seoul National University Cancer Institute. Secured.

MDA-MB-231, UMRC2, PANC-1, Caki-1, and HEK293 cell lines each contain 10% fetal bovine serum (FBS) and 10 mM HEPES, 100 U / mL penicillin, 100 μg / mL streptomycin (Dulbecco's modified Eagle's medium; Invitogen, Carlsbad, Calif.), A549, MKN45, HepG2, HT29, PC-3, OVCAR3, and MCF7 were cultured in RPMI medium, and HUVEC was M199 and bFGF 3mg / ml, Heparn 100mg / ml Incubated in 20% FBS. All cell lines were incubated in an incubator maintained at 37 ° C., 5% CO ₂ .

b) cell growth inhibition experiment

Inhibitory effect on the cell growth of the compounds according to the present invention used cell lines derived from various tissues of human. Efficacy of cell growth inhibition of various compounds was performed using the SRB (Sulforhodamine B) method (Skehan et al., J. National Cancer Institute, 82: 1107-1112 (1990)). As follows.

Each cell line was aliquoted into 96-well plates at a concentration of 2-3 ³ 10 ³ cells / well and treated with the search compound the next day. The experiment for each search compound was performed in three iterations. After 96 hours of incubation in the wells containing the respective search compounds and cell lines, the cells were fixed with 10% trichloroacetic acid (TCA), left at 4 ° C. for 1 hour, and washed three times with distilled water. Each cell was then stained with 0.4% SRB (Sulforhodamine B) dissolved in 1% acetic acid for 30 minutes, washed four times with 1% acetic acid and dried in air. After shaking for 5 minutes in 10 mM Tris buffer, the value was measured at 530 nm using a Benchmark Plus Microplate reader (Bio-Rad Laboratories, Hercules, CA).

To convert from OD ₅₃₀ values to viable cells per well, OD ₅₃₀ values were substituted into the cell number curves for the standard OD ₅₃₀ -versus-each cell line. % Survival rate was calculated by the following equation.

IC ₅₀ values were then calculated by nonlinear regression analysis.

Table 2 below shows IC ₅₀ values measured by selecting some representative compounds among the compounds synthesized in the above Examples.

As confirmed through the above experiments, the novel compounds according to the present invention show excellent anticancer effects, and thus are useful for developing new anticancer agents.

Claims (10)

1-[(2-alkoxy-6-substituted-quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [Formula 1]

In Formula 1, X and Y are each N, or CR ⁶ ; R ¹ is a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group, or a halogen atom, and R ² is a C ₁ -C ₆ alkyl group; ^{R 3, R 4, R 5} , and R ⁶ are each a hydrogen atom, alkyl of C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ of the Carbonyl group, halogen atom, cyano group, or nitro group. The compound of claim 1, wherein X and Y are each N, CH, CF, C-Cl, C-CN, C-CH ₃ , or C-OCH ₃ . The compound of claim 1, wherein R ¹ is a fluorine atom, a chloro atom, a methyl group, or a methoxy group. The compound of claim 1, wherein R ² is a methyl group. The method according to claim 1, wherein R ³ , R ⁴ , And R ⁵ is a hydrogen atom, a chloro atom, a nitro group, a methyl group, a trifluoromethyl group, a methoxy group, or an acetoxy group, respectively. The compound of claim 1, wherein R ⁶ is a hydrogen atom, a fluorine atom, a chloro atom, a cyan group, a methyl group, or a methoxy group. Preparing a compound represented by the following Chemical Formula 3 by reacting 6-substituted-3-amino-2-alkoxyquinoxaline represented by the following Chemical Formula 2 with a carbonyl group donating reagent represented by L-C (= O) -L '; The process of preparing the compound represented by the following formula 1 by reacting the compound represented by the formula (3) and the 1- (hetero) aryl piperazine derivative represented by the following formula (4) Manufacturing method characterized in that it comprises:

[Formula 1]

In the above formula, X, Y, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as defined in claim 1, respectively, and L and L 'are imidazole, chlorine atom, ethoxy group, phenoxy, respectively. Season, 4-nitrophenoxy. According to claim 7, 6-substituted-2-alkoxy-3-aminoquinoxaline represented by the formula (2) is The preparation method characterized by the reaction of the compound represented by Formula 5 with sodium alkoxide represented by NaOR ²

In Formula 5, R ¹ and R ² are as defined in claim 1, respectively. 6-substituted-2-alkoxy-3-aminoquinoxaline represented by the following formula (2): [Formula 2]

In Formula 2, R ¹ and R ² are as defined in claim 1, respectively. Containing 1-[(2-alkoxy-6-substituted-quinoxalin-3-yl) aminocarbonyl] -4- (hetero) arylpiperazine derivative represented by the following formula (1), or a pharmaceutically acceptable salt thereof Anticancer agent characterized in that: [Formula 1]

In Formula 1, X, Y, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as defined in Claim 1, respectively.