KR100204318B1 - Novel piperazine derivatives and their preparation method - Google Patents

Abstract

The present invention provides a compound represented by the following general structural formula (I) having excellent anticancer activity and low toxicity, a pharmaceutically acceptable acid addition salt, a preparation method thereof, and a pharmaceutical preparation containing the same.

Wherein R ₁ and R ₂ each represent a hydrogen atom, a substituted or unsubstituted C ₁ -C ₈ alkyl group, a C ₈ -C ₈ substituted or unsubstituted 3-6 membered cyclic alkyl group, a substituted or unsubstituted C ₂ -C ₈ unsaturated alkyl group, ketone group, substituted or unsubstituted aryl group, substituted or unsubstituted arylhydroxy group, substituted or unsubstituted amine group, C ₁ -C ₄ lower ester group, C ₁ -C ₄ lower Together with the thioester group, thiol group, substituted or unsubstituted carboxyl group, epoxy group, or R ₁ and R ₂ form an unsaturated or saturated ring having 3 to 4 carbon atoms, and R ₃ , R ₄ , R ₅ , R ₆ and R ₇ is a halogen atom, and are each a hydrogen atom a hydroxyl group, a nitro group, a lower alkyl group, a substituted or unsubstituted unsaturated alkyl group of C ₃ -C ₈ ester groups of a lower _{C 1 -C 4, C 1 -C} 4, C 3 -C ₈ substituted or unsubstituted 3-6 membered cycloalkyl group, C ₁ -C ₄ lower alkoxy group, C ₁ -C ₄ lower thioalkoxy group, substituted Or an unsubstituted aryl group, a substituted or unsubstituted aryl lower alkoxy group, a substituted or unsubstituted lower alkylamino group, or a lower alkyl substituted or unsubstituted carbamate group, or in R ₃ , R ₄ , R ₅ , R ₆ and R ₇ Two adjacent groups are bonded to each other to form a phenylene ring or a naphthylene ring, X is an oxygen atom, a sulfur atom, a substituted or unsubstituted imine group, Y is an oxygen atom or NH, and Z is a hydrogen atom, a hydroxyl group, C Lower alkoxy group of ₁ -C ₈ , lower thioalkoxy group of C ₁ -C ₄ , substituted or unsubstituted aryloxy group, lower alkylamine group of C ₁ -C ₄ , and may contain 1 to 5 nitrogen atoms It is a substituted or unsubstituted cyclic amine group.

Description

Novel piperazine derivatives and preparation method thereof

The present invention relates to a novel piperazine derivative represented by the following general structural formula (I) and a preparation method thereof.

[Formula 1]

Wherein R ₁ and R ₂ each represent a hydrogen atom, a substituted or unsubstituted C ₁ -C ₈ alkyl group, a C ₃ -C ₈ substituted or unsubstituted 3-6 membered cyclic alkyl group, a substituted or unsubstituted C ₂ -C ₈ unsaturated alkyl group, ketone group, substituted or unsubstituted aryl group, substituted or unsubstituted arylhydroxy group, substituted or unsubstituted amine group, C ₁ -C ₄ lower ester group, C ₁ -C ₄ lower Together with the thioester group, thiol group, substituted or unsubstituted carboxyl group, epoxy group, or R ₁ and R ₂ form an unsaturated or saturated ring having 3 to 4 carbon atoms, and R ₃ , R ₄ , R ₅ , R ₆ and R ₇ is a halogen atom, and are each a hydrogen atom a hydroxyl group, a nitro group, a lower alkyl group, a substituted or unsubstituted unsaturated alkyl group of C ₃ -C ₈ ester groups of a lower _{C 1 -C 4, C 1 -C} 4, C 3 -C ₈ substituted or unsubstituted cycloalkyl group of 3-6 won, lower alkylthio of C ₁ -C ₄ lower alkoxy group, a C ₁ -C ₄ alkoxy group, Chi Or unsubstituted aryl group, a substituted or unsubstituted aryl lower alkoxy group, a substituted or unsubstituted lower alkyl group, or lower alkyl substituted or unsubstituted carbamate group is or _{R 3, R 4, R 5} , R 6 and R ₇ of the Two adjacent groups are bonded to each other to form a phenylene ring or a naphthylene ring, X is an oxygen atom, a sulfur atom, a substituted or unsubstituted imine group, Y is an oxygen atom or NH, and Z is a hydrogen atom, a hydroxyl group, C A lower alkoxy group of ₁ -C ₈ , a lower thioalkoxy group of C ₁ -C ₄ , a substituted or unsubstituted aryloxy group, a lower alkylamine group of C ₁ -C ₄ , and up to 1 to 5 nitrogen atoms Substituted or unsubstituted cyclic amine group.

Alkyl groups of C ₁ -C ₈ are linear or branched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, 2-methylpentyl, etc. It means an alkyl group.

Lower alkyl groups of C ₁ -C ₄ are sensitive to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl groups.

C ₁ -C ₈ substituted or unsubstituted 3-6 membered cycloalkyl group is a substituted or unsubstituted cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted cyclopropyl, substituted cyclopentyl, substituted cyclohexyl, or the like. it means.

The lower ester group of C ₁ -C ₄ means a group in which the carboxyl group is esterified by a lower alkyl group.

Lower alkoxy of C ₁ -C ₄ refers to a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy group.

The lower thioalkoxy group of C ₁ -C ₄ refers to methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, t-butylthio group.

The lower alkylamine group of C ₁ -C ₄ refers to a methylamine group, an ethylamine group, a propylamine group, or a butylamine group.

An aryloxy group means a phenoxy group, a substituted phenoxy group, a naphthyloxy group, or a substituted naphthyloxy group.

The cyclic amine group which may contain 1 to 5 nitrogen atoms is pyrrolidinyl group, pyrrolinyl group, imidazolyl group, imidazolyldinyl group, pyrazole group, pyrazolinyl group, pyrazolinyl group, triazolyl group, A tetrazolyl group, a piperazinyl group, etc. are meant.

The present inventors have long studied the compound which has anticancer activity. As a result, the present inventors have found the surprising fact that the compound of the general formula (I), and acid addition salts thereof have excellent anticancer effects and have extremely low toxicity, thus completing the present invention.

It is therefore an object of the present invention to provide compounds of general formula (I) and acid addition salts thereof having excellent anticancer effects and low toxicity.

Another object of the present invention is to provide a compound of the general formula (I) and a process for preparing acid addition salts thereof.

The compounds of the present invention can be used for the prevention and treatment of various types of tumors by preparing pharmaceutical preparations according to the methods of preparing pharmaceutical preparations commonly used in combination with pharmaceutically acceptable excipients and the like.

Therefore, another object of the present invention is to provide a pharmaceutical formulation containing the compound of general formula (I) as an active ingredient.

Acids capable of reacting with compound (I) of the present invention to form acid addition salts are pharmaceutically acceptable inorganic or organic acids, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; Organic acids such as formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid and the like; Amino acids such as serine, cysterin, cystine, asparagine, glutamine, lysine, arginine, pyrosine, proline and the like; Sulfonic acids such as metalsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like can be used.

Excipients that can be used as excipients in the preparation of pharmaceutical preparations containing the compound of formula (I) as an active ingredient in the present invention include sweeteners, binders, solubilizers, dissolution aids, humectants, emulsifiers, isotonic agents, adsorbents, boric Release, antioxidants, preservatives, glidants, fillers, fragrances and the like can be used, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, traga Tant rubber, methyl cellulose, sodium carboxymethyl cellulose, agar, alginate, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanilla flavor have.

The normal dose of the compound of the general formula (I) of the present invention may vary depending on the age, sex, degree of disease, etc. of the patient, but may be administered once to several times daily from 1 mg to 5000 mg.

Compounds of the general formula (I) of the present invention may be prepared by the following scheme (I).

[Scheme I]

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , X, Y, Z are as described above, and Lie is a leaving group such as a hydrogen atom.

Compound of general formula (a) is reacted in a conventional organic solvent in the presence of a -C (= X) -donating reagent to effectively obtain a compound of general formula (b). Subsequently, the compound of general formula (I) is prepared by reaction with general compound (c).

Examples of the -C (= X) -group donor reagent include 1,1-carbonyldiimidazole, 1,1-carbonylthiodiimidazole, phosgene, thiophosgen, carbonyldiphenoxide, phenylchloroformate and the like. use. This reaction is preferably using a conventional organic solvent, for example tetrahydrofuran, dichloromethane, chloroform, acetonitrile, dimethylformamide and the like.

It is also preferable that the reaction is carried out in the presence of a binding reagent. As a binding reagent that can be used for this reaction, a conventional inorganic or organic base is used.

Common inorganic or organic bases of this reaction include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, DBU, and the like. It is preferred that the amount used thereof is used from 1 equivalent to 5 equivalents.

The reaction is carried out at a boiling point temperature of 3 ° C. to a solvent, preferably 50 ° C. to 100 ° C. for 5 to 48 hours, preferably 10-24 hours.

The amount of -C (= X) -donating reagent used is 1-1.5 equivalents, preferably 1-1.1 equivalents.

In the case of the reaction in which the acidic substances are by-produced during the reaction, it is preferable to add a basic substance to remove these substances from the reaction system and then react. Such basic substances include alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, potassium bicarbonate, and the like. , Oxides, carbonates or bicarbonates; And in the presence of a base of an organic amine family.

Compounds of the general formula (a) are known compounds, J. Med. Chem., 1992. 35, 3784, 3792, etc. or may be prepared and used in a similar manner.

EXAMPLE

The following compounds were prepared according to the method described above.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , X, Y, Z are as described above.

Example 1

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (2-methylthiophenyl) piperazine

a) phenyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) carbamate

3-amino-5,6-dimethyl-2-methoxypyridine (1.52 grams, 0.01 mol) and phenylchloroformate (1.56 grams, 0.01 mol) were dissolved in dichloromethane and stirred at room temperature for 2 hours. After concentration under reduced pressure to remove the solvent, the residue was purified by column chromatography (ethyl acetate: hexane = 1: 6) to obtain the compound.

Yield: 92%

H NMR (CDClI 3) δ: 2.18 (3H, s), 2.36 (3H, s), 4.00 (3H, s), 7.31 (5H, m), 8.07 (1H, s)

b) 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (2-meththiophenyl) piperazine

Phenyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) carbamate (136 mg, 0.5 mmol) and 1- (2-methylthiophenyl) piperazine (104 mg, 0.5 mmol) It was dissolved in anhydrous tetrahydrofuran and DBU (76 mg, 0.5 mmol) was added, followed by stirring at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and then separated and purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.

Yield: 59%

Melting Point: 167-169 ℃

H NMR (CDCl) δ: 2.21 (3H, s), 2.43 (6H, s), 3.06 (4H, t) 3.68 (4H, t), 4.09 (3H, s), 6.89 (1H, s), 7.06 ( 1H, m), 7.14 (3H, s), 8.26 (1H, s)

Example 2

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] 4- (2-isopropenylphenyl) piperazine

The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) carbamate and 1- (2-isopropenylphenyl) piperazine in the same manner as in Example 1. .

Yield: 62%

Melting Point: 139-140 ℃

H NMR (CDCl) δ: 2.20 (3H, s), 2.21 (6H, s), 3.10 (4H, t) 3.64 (4H, t), 3.84 (3H, s), 5.07 (1H, s), 5.13 ( 1H, s), 6.64 (1H, s), 6.98 (1H, s), 7.04 (3H, dd), 7.18 (1H, d), 7.91 (1H, s)

Example 3

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] 4- (2,3,5,6-tetramethylphenyl) piperazine

Phenyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) carbamate and 1- (2,3,5,6-tetramethylphenyl) piperazine were reacted in the same manner as in Example 1 The compound was obtained.

Yield: 71%

Melting Point: 190-192 ℃

H NMR (CDCl) δ: 2.21 (15H, s), 2.42 (3H, s), 3.17 (4H, t) 3.61 (4H, t), 4.08 (3H, s), 6.84 (1H, s), 6.89 ( 1H, s), 8.26 (1H, s)

Example 4

1-[(5-ethyl-6-methyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (2-methylthiophenyl) piperazine

The compound was obtained by reacting phenyl N- (5-ethyl-6-methyl-2-methoxypyridin-3-yl) carbamate and 1- (2-methylthiophenyl) piperazine in the same manner as in Example 1. .

Yield: 56%

Melting Point: 160-161 ℃

H NMR (CDCl) δ: 1.19 (3H, t), 2.43 (3H, s), 2.50 (3H, s) 2.58 (2H, q), 3.07 (4H, t), 3.69 (4H, t), 4.15 ( 3H, s), 6.93 (1H, s), 7.06 (1H, m), 7.14 (3H, m), 8.35 (1H, s)

Mass (EI) m / z: 400.1925 (MH, CHNO2 calculated: 400.1932)

Example 5

1-[(5-ethyl-6-methyl-2-methoxypyridin-3-yl) aminocarbonyl] 4- (2-isopropenylphenyl) piperazine

The compound was reacted with phenyl N- (5-ethyl-6-methyl-2-methoxypyridin-3-yl) carbamate and 1- (2-isopropenylphenyl) piperazine in the same manner as in Example 1. Got it.

Yield: 51%

Melting Point: 185-187 ℃

H NMR (CDCl) δ: 1.18 (3H, t), 2.21 (3H, s), 2.42 (3H, s) 2.56 (2H, q), 3.08 (4H, t), 3.62 (4H, t), 4.03 ( 3H, s), 5.08 (1H, s), 5.13 (1H, s), 6.90 (1H, s), 7.02 (3H, m) 7.18 (1H, d), 8.25 (1H, s)

Example 6

1-[(5-ethyl-2-methyl-6-methoxypyridin-3-yl) aminocarbonyl] 4- (2,3,5,6-tetramethylphenyl) piperazine

Phenyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) carbamate and 1- (2,3,5,6-terramethylphenyl) piperazine in the same manner as in Example 1 Reaction to obtain the compound.

Yield: 69%

Melting Point: 176-177 ℃

H NMR (CDCl) δ: 1.19 (3H, t), 2.21 (12H, s), 2.44 (3H, s) 2.56 (2H, q), 3.17 (4H, t), 3.62 (4H, t), 4.06 ( 3H, s), 6.84 (1H, s), 6.92 (1H, s), 8.30 (1H, s)

Example 7

1-[(5-ethyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3-thiophenyl) piperazine

The compound was obtained by reacting phenyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) carbamate and 1- (3-thiophenyl) piperazine in the same manner as in Example 1.

Yield: 63%

Melting Point: 108-110 ℃

H NMR (CDCl) δ: 1.17 (3H, t), 2.37 (3H, s), 2.49 (2H, q), 3.28 (4H, t), 3.60 (4H, t), 3.98 (3H, s), 6.87 (4H, m), 6.98 (1H, s), 8.18 (1H, s)

Example 8

1-[(2-methoxy-6-methyl-2-propylpyridin-3-yl) aminocarbonyl] 4- (3,5-isopropenylphenyl) piperazine

Phenyl N- (2-methoxy-6-methyl-5-propylpyridin-3-yl) carbamate and 1- (3,5-dimethoxyphenyl) piperazine were reacted in the same manner as in Example 1 The compound was obtained.

Yield: 67%

Melting Point: 82-84 ℃

H NMR (CDCl) δ: 0.94 (3H, t), 1.58 (2H, m), 2.37 (3H, s), 2.49 (H, q), 3.25 (4H, t), 3.66 (4H, t), 3.78 (6H, s), 3.99 (3H, s), 6.07 (3H, m), 6.88 (1H, s), 8.16 (1H, s)

Mass (EI) m / z: 428.2447 (MH, calculated from CHNO: 428.2423)

Example 9

1-[(2-methoxy-6-methyl-5-propylpyridin-3-yl) aminocarbonyl] 4- (3,5-dimethylphenyl) piperazine

The compound was reacted with phenyl N- (2-methoxy-6-methyl-5-propylpyridin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 1. Got it.

Yield: 64%

Melting Point: 145-146 ℃

H NMR (CDCl) δ: 0.94 (3H, t), 1.59 (2H, m), 2.29 (6H, s), 2.41 (3H, s), 2.49 (2H, q), 3.24 (4H, t), 3.67 (4H, t), 3.98 (3H, s), 6.59 (3H, m), 6.89 (1H, s), 8.17 (1H, s)

Mass (EI) m / z: 428.2385 (MH, CHNO4 calculated: 428.2423)

Example 10

1-[(2-methoxy-6-methyl-5-propylpyridin-3-yl) aminocarbonyl] 4- (3,5-difluorophenyl) piperazine

Phenyl N- (2-methoxy-6-methyl-5-propylpyridin-3-yl) carbamate and 1- (3,5-difluorophenyl) piperazine were reacted in the same manner as in Example 1 The compound was obtained.

Yield: 57%

Melting Point: 121-123 ℃

H NMR (CDCl) δ: 0.95 (3H, t), 1.59 (2H, m), 2.38 (3H, s), 2.50 (2H, q), 3.29 (3H, t) 3.66 (3H, t), 4.00 ( 3H, s), 6.28 (1H, m) 6.36 (2H, d), 6.87 (1H, s), 8.17 (1H, s)

Example 11

1-[(2-methoxy-6-methyl-5-propylpyridin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine

The compound was obtained by reacting phenyl N- (2-methoxy-6-methyl-5-propylpyridin-3-yl) carbamate and 1- (2-methoxyphenyl) piperazine in the same manner as in Example 1. .

Yield: 71%

Melting Point: 109-110 ℃

H NMR (CDCl) CDCl 3) δ: 0.95 (3H, t), 1.59 (2H, m), 2.37 (3H, s), 2.49 (2H, q), 3.12 (4H, t), 3.70 (4H, t) , 3.89 (3H, s), 3.97 (3H, s), 6.91 (4H, m), 6.95 (1H, s), 8.19 (1H, s)

Example 12

1-[(6-methyl-2-methoxy-5-methylpyridin-3-yl) aminocarbonyl] 4- (3,5-dimethoxyphenyl) piperazine

Phenyl N- (6-ethyl-2-methoxy-5-methylpyridin-3-yl) carbamate and 1- (3,5-dimethoxyphenyl) piperazine were reacted in the same manner as in Example 1 The compound was obtained.

Yield: 65%

Melting Point: 115-116 ℃

H NMR (CDCl) δ: 1.21 (3H, t), 2.21 (3H, s), 2.65 (2H, q), 3.27 (4H, t), 3.64 (4H, t), 3.79 (6H, s), 3.98 (3H, s), 6.09 (3H, m), 6.86 (1H, s), 8.12 (1H, s)

Mass (EI) m / z: 414.2240 (MH, CHNO4 calculated: 414.2267)

Example 13

1-[(6-ethyl-2-methoxy-5-methylpyridin-3-yl) aminocarbonyl] 4- (3,5-dimethylphenyl) piperazine

The compound was reacted with phenyl N- (2-ethyl-2-methoxy-5-methylpyridin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 1. Got it.

Yield: 61%

Melting Point: 135-136 ℃

H NMR (CDCl) δ: 1.22 (3H, t), 2.21 (3H, s), 2.29 (6H, s), 2.65 (2H, q), 3.24 (4H, t), 3.66 (4H, t), 3.98 (3H, s), 6.59 (3H, m) 6.87 (1H, s), 8.12 (1H, s)

Mass (EI) m / z: 382.2376 (MH calculated based on CHNO2: 382.2368)

Example 14

1-[(6-ethyl-2-methoxy-5-methylpyridin-3-yl) aminocarbonyl] 4- (2-hydroxyphenyl) piperazine

The compound was obtained by reacting phenyl N- (6-ethyl-2-methoxy-5-methylpyridin-3-yl) carbamate and 1- (3-hydroxyphenyl) piperazine in the same manner as in Example 1. .

Yield: 56%

Melting Point: 168-170 ℃

H NMR (CDCl) δ: 1.21 (3H, t), 2.20 (2H, s), 2.63 (2H, t), 3.28 (4H, t), 3.68 (4H, t), 3.98 (3H, s), 6.41 (1H, d), 6.55 (1H, d), 6.84 (1H, m), 6.87 (1H, s), 7.13 (1H, t), 8.10 (1H, s)

Mass (EI) m / z: 370.1992 (MH, CHNO3 calculated: 370.2004)

Example 15

1-[(2-methoxy-6-methyl-5-propylpyridin-3-yl) aminocarbonyl] 4- (3,5-dimethoxyphenyl) piperazine

Phenyl N- (2-methoxy-5-methyl-6-propylpyridin-3-yl) carbamate and 1- (3,5-dimethoxyphenyl) piperazine were reacted in the same manner as in Example 1 The compound was obtained.

Yield: 57%

Melting Point: 121-122 ℃

H NMR (CDCl) δ: 0.96 (3H, t), 1.67 (2H, m), 2.21 (3H, s), 2.58 (2H, t), 3.26 (4H, t), 3.68 (4H, t), 3.79 (6H, s), 3.97 (3H, s), 6.14 (3H, m), 6.89 (1H, s), 8.11 (1H, s)

Mass (EI) m / z: 428.2423 (MH, CHNO4 calculated: 428.2423)

Example 16

1-[(2-methoxy-5-methyl-2-methoxypyridin-3-yl) aminocarbonyl] 4- (3,5-dimethylphenyl) piperazine

The compound was reacted with phenyl N- (2-methoxy-5-methyl-6-propylpyridin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 1. Got it.

Yield: 54%

Melting Point: 138-139 ℃

H NMR (CDCl) δ: 0.96 (3H, t), 1.72 (2H, m), 2.21 (6H, s), 2.30 (3H, s), 2.59 (2H, t), 3.28 (4H, t), 3.76 (4H, t), 3.97 (3H, s), 6.70 (3H, m) 6.87 (1H, s), 8.11 (1H, s)

Mass (EI) m / z: 396.2432 (MH, CHNO2 calculated: 396.2525)

Example 17

1- [N- (2-methoxy-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) aminocarbonyl] 4- (3,5-dimethylphenyl) piperazine

The compound was obtained by reacting phenyl N- (2-methoxy-5-methyl-6-propylpyridin-3-yl) carbamate and 1- (3-hydroxyphenyl) piperazine in the same manner as in Example 1. .

Yield: 52%

Melting Point: 153-155 ℃

H NMR (CDCl) δ: 0.95 (3H, t), 1.69 (2H, m), 2.19 (6H, s), 2.59 (2H, t), 3.22 (4H, t), 3.68 (4H, t), 3.97 (3H, s), 6.42 (1H, d), 6.52 (1H, d), 6.87 (1H, s), 7.12 (1H, t), 8.09 (1H, s)

Mass (EI) m / z: 384.2153 (MH, CHNO3 calculated: 384.2161)

Example 18

1- [N- (2-methoxy-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) aminocarbonyl] 4- (3,5-dimethoxyphenyl) piperazine

Example of Phenyl N- (2-methoxy-6,7-dihydro-5H-cyclopenta [b] methylpyridin-3-yl) carbamate and 1- (3,5-dimethoxyphenyl) piperazine It reacted by the same method as 1, and the said compound was obtained.

Yield: 59%

Melting Point: 143-144 ℃

H NMR (CDCl) δ: 2.10 (2H, m), 2.87 (4H, m), 3.12 (4H, t), 3.70 (4H, t), 3.78 (6H, s) 4.00 (3H, s), 6.08 ( 3H, m), 6.90 (1H, s), 8.24 (1H, s)

Example 19

1- [N- (2-methoxy-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) aminocarbonyl] 4- (3,5-dimethylphenyl) piperazine

Phenyl N- (2-methoxy-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine are the same as in Example 1 Reaction was carried out to obtain the compound.

Yield: 55%

Melting Point: 183-185 ℃

H NMR (CDCl) δ: 2.08 (2H, m), 2.28 (6H, s), 2.87 (4H, m), 3.22 (4H, t), 3.67 (4H, t) 4.00 (3H, s), 6.57 ( 3H, m), 6.89 (1H, s), 8.24 (1H, s)

Example 20

1-[(2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl) aminocarbonyl] 4- (3,5-dimethoxyphenyl) piperazine

Phenyl N- (2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl) carbamate and 1- (3,5-dimethoxyphenyl) piperazine in the same manner as in Example 1 Reaction to obtain the compound.

Yield: 54%

Melting Point: 161-163 ℃

1 H NMR (CDCl) δ: 1.75 (2H, m), 1.84 (2H, m), 2.67 (2H, t), 2.73 (2H, t), 3.27 (4H, t) 3.71 (4H, t), 3.79 ( 6H, s), 3.97 (3H, s), 6.10 (3H, m) 6.90 (1H, s), 8.07 (1H, s)

Example 21

1-[(2-methoxy-5,6,7,8 ′; trihydroquinolin-3-yl) aminocarbonyl] 4- (3,5-dimethylphenyl) piperazine

Phenyl N- (2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine were reacted in the same manner as in Example 1 The compound was obtained.

Yield: 51%

Melting Point: 143-144 ℃

H NMR (CDCl) δ: 1.75 (2H, m), 1.84 (2H, m), 2.30 (6H, s), 2.68 (3H, t), 2.72 (2H, t), 3.26 (4H, t), 3.67 (4H, t), 3.97 (3H, s), 6.61 (3H, m), 6.91 (1H, s), 8.07 (1H, s)

Example 22

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] 4- (3,5-dimethylphenyl) piperazine

Phenyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) thiocarbamate (200 mg, 0.7 mmol) and 1- (3,5-dimethylphenyl) piperazine (154 mg, 0.7 mmol ) Was dissolved in anhydrous tetrahydrofuran and DBU (106 mg) was added, followed by stirring at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove the solvent, and then purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.

Yield: 50%

Melting Point: 192-193 ℃

H NMR (CDCl) δ: 2.21 (3H, s), 2.29 (6H, s), 2.36 (3H, s), 3.33 (4H, t), 3.96 (3H, s), 4.09 (4H, t), 6.57 (3H, m), 7.33 (1H, s), 8.11 (1H, s)

Mass (EI) m / z: 384.1992 (MH, CHNOS calculated: 384.1983)

Example 23

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] 4- (3,5-difluorophenyl) piperazine

Phenyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) thiocarbamate and 1- (3,5-difluorophenyl) piperazine were reacted in the same manner as in Example 22 to The compound was obtained.

Yield: 47%

Melting Point: 60-62 ℃

H NMR (CDCl) δ: 2.21 (3H, s), 2.36 (3H, s), 3.39 (4H, t), 3.96 (3H, s), 4.10 (3H, t), 6.29 (3H, m), 7.33 (1H, s), 8.14 (1H, s)

Example 24

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] 4- (3,5-hydroxyphenyl) piperazine

The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) thiocarbamate and 1- (3-hydroxyphenyl) piperazine in the same manner as in Example 22. .

Yield: 43%

Melting Point: 185-186 ℃

H NMR (CDCl) δ: 2.14 (3H, s), 2.36 (3H, s), 3.25 (4H, t), 3.89 (3H, s), 4.09 (4H, t) 6.30 (1H, d), 6.36 ( 2H, m), 7.03 (1H, t), 7.48 (1H, s) 8.56 (1H, s)

Example 25

1-[(2-methoxy-6-methyl-5-propylpyridin-3-yl) aminocarbonyl] 4- (3,5-dimethoxyphenyl) piperazine

Phenyl N- (2-methoxy-6-methyl-5-propylpyridin-3-yl) thiocarbamate and 1- (3,5-dimethoxyphenyl) piperazine were reacted in the same manner as in Example 22. The compound was obtained.

Yield: 55%

Melting Point: 143-144 ℃

H NMR (CDCl) δ: 0.93 (3H, t), 1.66 (2H, m), 2.17 (3H, s), 2.65 (2H, t), 3.38 (4H, t), 3.79 (6H, s), 3.98 (3H, s), 4.15 (4H, t), 6.11 (3H, m) 7.43 (1H, s), 8.25 (1H, s)

Example 26

1-[(2-methoxy-5-methyl-6-propylpyridin-3-yl) aminocarbonyl] 4- (3,5-dimethoxyphenyl) piperazine

Phenyl N- (2-methoxy-5-methyl-6-propylpyridin-3-yl) thiocarbamate and 1- (3,5-dimethoxyphenyl) piperazine were reacted in the same manner as in Example 22. The compound was obtained.

Yield: 52%

Melting Point: 183-184 ℃

H NMR (CDCl) δ: 0.98 (3H, t), 1.72 (2H, m), 2.17 (3H, s), 2.62 (2H, t), 3.39 (4H, t), 3.79 (6H, s), 3.96 (3H, s), 4.19 (4H, t) 6.15 (3H, m), 7.42 (1H, s), 8.08 (1H, s)

Mass (EI) m / z: 444.2171 (MH, calculated from CHNOS: 444.2195

Example 27

1-[(2-methoxy-5-methyl-6-propylpyridin-3-yl) aminocarbonyl] 4- (3,5-dimethylphenyl) piperazine

The compound was reacted with phenyl N- (2-methoxy-5-methyl-6-propylpyridin-3-yl) thiocarbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 22. Got.

Yield: 49%

Melting Point: 195-197 ℃

H NMR (CDCl) δ: 0.98 (3H, t), 1.73 (2H, m), 2.18 (6H, s), 2.34 (3H, s), 2.62 (2H, t), 3.47 (4H, t), 3.96 (3H, s), 4.01 (4H, t), 6.59 (3H, m), 7.02 (1H, s), 7.99 (1H, s)

Mass (EI) m / z: 412.2296 (MH, CHNOS calculated: 412.2296)

Example 28

1-[(2-methoxy-5-methyl-6-propylpyridin-3-yl) aminocarbonyl] 4- (3-hydroxyphenyl) piperazine

The compound was reacted with phenyl N- (2-methoxy-5-methyl-6-propylpyridin-3-yl) thiocarbamate and 1- (3-hydroxyphenyl) piperazine in the same manner as in Example 22. Got it.

Yield: 48%

Melting Point: 160-162 ℃

H NMR (CDCl) δ: 0.98 (3H, t), 1.72 (2H, m), 2.22 (3H, s), 2.61 (3H, t), 3.31 (4H, t) 3.95 (3H, s), 4.10 ( 4H, t), 6.45 (3H, m), 7.12 (1H, t) 7.41 (1H, s), 8.08 (1H, s)

Mass (EI) m / z: 400.1969 (MH, CHNOS calculated: 400.1932)

Example 29

1- [N- (2-methoxy-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) aminocarbonyl] 4- (3,5-dimethoxyphenyl) piperazine

Example of Phenyl N- (2-methoxy-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) thiocarbamate and 1- (3,5-dimethoxyphenyl) piperazine The compound was reacted in the same manner as in 22.

Yield: 55%

Melting Point: 169-170 ℃

1 H NMR (CDCl) δ: 2.10 (2H, m), 2.89 (4H, m), 3.30 (4H, t), 3.77 (6H, s), 3.98 (3H, s), 4.20 (4H, t), 6.05 (3H, m), 7.37 (1H, s), 8.25 (1H, s)

Example 30

1- [N- (2-methoxy-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) aminocarbonyl] 4- (3,5-dimethylphenyl) piperazine

Phenyl N- (2-methoxy-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) thiocarbamate and 1- (3,5-dimethylphenyl) piperazine Reaction was carried out in the same manner to obtain the compound.

Yield: 52%

Melting Point: 159-161 ℃

1 H NMR (CDCl) δ: 2.09 (2H, m), 2.28 (6H, s), 2.87 (4H, m), 3.67 (4H, t), 4.00 (3H, s), 4.21 (4H, t), 6.57 (3H, m), 6.93 (1H, s), 8.24 (1H, s)

Example 31

1-[(2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

Phenyl N- (2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl) thiocarbamate and 1- (3,5-dimethoxyphenyl) piperazine in the same manner as in Example 22 Reaction to obtain the compound.

Yield: 56%

Melting Point: 160-161 ℃

1 H NMR (CDCl) δ: 1.77 (2H, m), 1.83 (2H, m), 2.70 (2H, t), 2.76 (2H, t), 3.38 (4H, t) 3.79 (6H, s), 3.96 ( 3H, s), 4.16 (4H, t), 6.12 (3H, m), 7.45 (1H, s), 8.03 (1H, s)

Example 32

1-[(2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl) aminocarbonyl] 4- (3,5-dimethylphenyl) piperazine

Reaction of phenyl N- (2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl) thiocarbamate with 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 22 To obtain the compound.

Yield: 54%

Melting Point: 200-201 ℃

1 H NMR (CDCl) δ: 1.77 (2H, m), 1.84 (2H, m), 2.34 (6H, s), 2.71 (3H, t), 2.75 (3H, t), 3.47 (4H, t), 3.97 (3H, s), 4.42 (4H, t) 6.35 (3H, m), 6.91 (1H, s), 7.91 (1H, s)

Example 33

1-[(5,6-dimethyl-2-methylaminopyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

The compound was reacted with phenyl N- (5,6-dimethyl-2-methylaminopyridin-3-yl) carbamate and 1- (3,5-dimethoxyphenyl) piperazine in the same manner as in Example 1. Got.

Yield: 53%

Melting Point: 150-151 ℃

H NMR (CDCl) δ: 2.29 (3H, s), 2.48 (3H, s), 3.29 (4H, t), 3.45 (3H, s), 3.77 (6H, s), 3.79 (4H, t), 6.10 (3H, m), 7.40 (1H, s)

Example 34

1-[(5,6-dimethyl-2-methylaminopyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methylaminopyridin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 1. .

Yield: 52%

Melting Point: 160-162 ℃

H NMR (CDCl) δ: 2.30 (9H, s), 2.48 (3H, s), 3.31 (4H, t), 3.46 (3H, s), 3.78 (4H, t), 6.60 (3H, m), 7.41 (1H, s)

Example 35

1-[(5-ethyl-6-methyl-6-ethylaminopyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

The compound was reacted with phenyl N- (5-ethyl-6-methyl-2-methylaminopyridin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 1. Got it.

Yield: 56%

Melting Point: 143-145 ℃

H NMR (CDCl) δ: 1.22 (3H, t), 2.28 (6H, s), 2.52 (3H, s), 2.72 (2H, q), 3.29 (4H, t), 3.45 (3H, s), 3.78 (4H, t), 6.59 (3H, m), 7.41 (1H, s)

Example 36

1-[(2-methylamino-6,7-dihydro-5H-cyclopenta [b] -pyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

Example 1 with phenyl N- (2-methylamino-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) carbamate and 1- (3,5-dimethoxyphenyl) piperazine Reaction was carried out in the same manner as to obtain the compound.

Yield: 49%

Melting Point: 148-150 ℃

H NMR (CDCl) δ: 2.09 (2H, m), 2.95 (4H, m), 3.30 (4H, t), 3.47 (3H, s), 3.77 (4H, t) 3.80 (6H, s), 6.10 ( 3H, m), 7.49 (1H, s)

Example 37

1-[(2-methylamino-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

Phenyl N- (2-methylamino-6,7-dihydro-5H-cyclopenta [b] pyridin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine are the same as in Example 1 Reaction was carried out to obtain the compound.

Yield: 48%

Melting Point: 185-187 ℃

H NMR (CDCl) δ: 2.14 (2H, m), 2.29 (6H, s), 2.95 (4H, m), 3.32 (4H, t), 3.47 (3H, s) 3.79 (4H, t), 6.59 ( 3H, m), 7.48 (1H, s)

Example 38

1-{[5,6-dimethyl-2- (4'-t-butoxycarbonylpiperazinyl) pyridin-3-yl] aminocarbonyl} -4- (3,5-dimethoxyphenyl) Piperazine

Phenyl N- [5,6-dimethyl-2- (4'-t-butoxycarbonylpiperazinyl) pyridin-3-yl] carbamate and 1- (3,5-dimethoxyphenyl) piperazine Was reacted in the same manner as in Example 1 to obtain the compound.

Yield: 58%

Melting Point: 74-75 ℃

H NMR (CDCl) δ: 1.46 (9H, s), 2.20 (3H, s), 2.21 (3H, s), 2.90 (4H, t), 3.20 (4H, t) 3.55 (4H, t), 3.65 ( 4H, t), 3.98 (3H, s), 6.02 (3H, m), 8.20 (1H, s)

Example 39

1-{[(5,6-dimethyl-2- (4'-t-butoxycarbonylpiperazinyl) pyridin-3-yl] aminocarbonyl} -4- (3,5-dimethylphenyl) pipe Razin

Example of Phenyl N- [5,6-dimethyl-2 (4′-t-butoxycarbonylpiperazinyl) pyridin-3-yl] carbamate and 1- (3,5-dimethylphenyl) piperazine It reacted by the same method as 1, and the said compound was obtained.

Yield: 56%

Melting Point: 155-156 ℃

H NMR (CDCl) δ: 1.48 (9H, s), 2.22 (3H, s), 2.29 (6H, s), 2.35 (3H, s), 2.95 (4H, t), 3.25 (4H, t), 3.25 (4H, t), 3.57 (4H, t), 3.67 (4H, t), 6.59 (3H, m), 8.21 (1H, s)

Example 40

1-{[5-ethyl-6-methyl-2- (4'-t-butoxycarbonylpiperazinyl) pyridin-3-yl] aminocarbonyl] -4- (3,5-dimethylphenyl) pipe Razin

Phenyl N- [5-ethyl-6-methyl-2- (4'-t-butoxycarbonylpiperazinyl) pyridin-3-yl] carbamate and 1- (3,5-dimethoxyphenyl) pipe Razine was reacted in the same manner as in Example 1 to obtain the compound.

Yield: 52%

Melting Point: 119-120 ℃

H NMR (CDCl) δ: 1.25 (3H, t), 1.48 (9H, s), 2.38 (3H, s), 2.51 (2H, q), 2.96 (4H, t), 3.27 (4H, t), 3.58 (8H, m), 3.78 (6H, s), 6.08 (3H, m), 8.24 (1H, s)

Example 41

1-{[5-ethyl-6-methyl-2- (4'-t-butoxycarbonylpiperazinyl) pyridin-3-yl] aminocarbonyl] -4- (3,5-dimethylphenyl) pipe Razin

Phenyl N- [5-ethyl-6-methyl-2- (4′-t-butoxycarbonylpiperazinyl) pyridin-3-yl] carbamate and 1- (3,5-dimethylphenyl) piperazine The compound was obtained by reacting in the same manner as in Example 1.

Yield: 50%

Melting Point: 126-128 ℃

H NMR (CDCl) δ: 1.20 (3H, t), 1.49 (9H, s), 2.29 (6H, s), 2.39 (3H, s), 2.52 (2H, q), 2.98 (4H, t), 3.23 (4H, t), 3.59 (8H, m), 6.59 (3H, m), 7.58 (1H, s), 8.26 (1H, s)

Example 42

1-[(5,6-dimethyl-2-piperazinylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

1-{[5,6-dimethyl-2- (4'-t-butoxycarbonylpiperazinyl) pyridin-3-yl] aminocarbonyl} -4- (3,5-dimethoxyphenyl After dissolving piperazine (0.218 grams, 0.4 mmol) in dichloromethane: nitromethane = 2: 1 (10 milliliters), anisole (0.26 grams, 2.4 mmol) and aluminum chloride (0.3 grams, 2.4 mmol) were slowly added. After the addition, the mixture was stirred at room temperature for 20 minutes. Distilled water (50 milliliters) is added, basified with saturated sodium bicarbonate and extracted with dichloromethane. Concentrated under reduced pressure to remove the solvent, and purified by column chromatography (methanol: dichloromethane = 8: 1) to obtain the compound.

Yield: 89%

Melting Point: Oil Phase

H NMR (CDCl) δ: 2.21 (3H, s), 2.35 (3H, s), 3.02 (4H, t), 3.34 (4H, t), 3.59 (4H, t) 3.62 (4H, t), 3.78 ( 6H, s), 6.08 (3H, m), 8.18 (1H, s)

Example 43

1-[(5,6-dimethyl-2-piperazinylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

1-{[5,6-dimethyl-2- (4'-t-butoxycarbonylpiperazinyl) pyridin-3-yl] aminocarbonyl} -4- (3,5-dimethylphenyl) pipe The compound was obtained by reacting in the same manner as in Razin Example 42.

Yield: 85%

Melting Point: 103-105 ℃

H NMR (CDCl) δ: 2.16 (3H, s), 2.24 (6H, s), 2.40 (3H, s), 3.30 (4H, t), 3.44 (4H, t), 3.50 (4H, t), 3.81 (4H, t), 6.95 (3H, m), 7.72 (1H, s)

Example 44

1-[(5-ethyl-6-methyl-2-piperazinylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

1-{[5-ethyl-6-dimethyl-2- (4'-t-butoxycarbonylpiperazinyl) pyridin-3-yl] aminocarbonyl} -4- (3,5-dime The oxyphenyl) piperazine was reacted in the same manner as in Example 42 to obtain the compound.

Yield: 88%

Melting Point: 68-70 ℃

H NMR (CDCl) δ: 1.20 (3H, t), 2.40 (3H, s), 2.52 (2H, q), 2.75 (4H, t), 3.32 (4H, t), 3.70 (8H, m), 3.78 (6H, s), 6.09 (3H, m), 7.68 (1H, s), 8.23 (1H, s)

Example 45

1-[(5-ethyl-6-methyl-2-piperazinylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

1, {[5-ethyl-6-methyl-2- (4'-t-butoxycarbonylpiperazinyl) pyridin-3-yl] aminocarbonyl} -4- (3,5-dimethoxy Phenyl) piperazine

The compound was obtained in the same manner as in Example 42 to obtain the compound.

Yield: 85%

Melting Point: 100-102 ℃

H NMR (CDCl) δ: 1.20 (3H, t), 2.28 (6H, s), 2.39 (3H, s), 2.65 (2H, q), 2.76 (4H, t), 3.00 (4H, t), 3.23 (4H, t), 3.70 (4H, t), 6.58 (3H, m), 7.66 (1H, s), 8.24 (1H, s)

Example 46

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

Phenyl N- [5-acetyl-2-methoxy-6-methylpyridin-3-yl] carbamate (200 mg, 0.67 mmol) and 1- (3,5-dimethoxyphenyl) piperazine (150 mg, 0.67 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), DBU (100 mg, 0.67 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and then purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.

Yield: 83%

Melting Point: 149-151 ℃

H NMR (CDCl) δ: 2.57 (3H, s), 2.65 (3H, s), 3.28 (4H, t, J = 4.65Hz), 3.70 (4H, t, J = 4.65Hz) 3.79 (6H, s) , 4.06 (3H, s), 6.09 (1H, s), 6.14 (2H, d), 6.94 (1H, s), 8.87 (1H, s)

Example 47

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

The compound was reacted with phenyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 46. Got it.

Yield: 82%

Melting Point: 66-69 ℃

H NMR (CDCl) δ: 2.31 (6H, s), 2.57 (3H, s), 2.65 (3H, s), 3.08 (4H, t), 3.30 (4H, t), 4.10 (3H, s), 6.71 (2H, d), 6.94 (1H, s), 8.89 (1H, s)

Example 48

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-difluorophenyl) piperazine

Phenyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-yl] carbamate and 1- (3,5-difluorophenyl) piperazine were reacted in the same manner as in Example 46 to The compound was obtained.

Yield: 77%

Melting Point: 180-181 ℃

H NMR (CDCl) δ: 2.57 (3H, s), 2.65 (3H, s), 3.33 (4H, t, J = 5.0Hz), 3.74 (4H, t, J = 5.0Hz), 4.07 (3H, s ), 6.37 (1H, s), 6.46 (2H, d), 6.93 (1H, s), 8.85 (1H, s)

Example 49

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dichlorophenyl) piperazine

The compound was reacted with N- [5-acetyl-2-methoxy-6-methylpyridin-3-yl] carbamate and 1- (3,5-dichlorophenyl) piperazine in the same manner as in Example 46. Got it.

Yield: 81%

Melting Point: Oil Phase

H NMR (CDCl) δ: 2.57 (3H, s), 2.65 (3H, s), 3.34 (4H, t), 3.78 (4H, t), 4.04 (3H, s) 6.93 (3H, m), 8.80 ( 1H, s)

Example 50

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

The compound was reacted with phenyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) carbamate and 1- (2,3-dimethylphenyl) piperazine in the same manner as in Example 46. Got it.

Yield: 81%

Melting Point: 173-174 ℃

H NMR (CDCl) δ: 2.29 (6H, s), 2.58 (3H, s), 2.65 (3H, s), 2.98 (4H, t), 3.70 (4H, t), 4.06 (3H, s), 6.91 (1H, d), 6.97 (1H, s), 7.10 (1H, t), 8.89 (1H, s)

Example 51

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine

Phenyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-yl] carbamate and 1- (2-methoxyphenyl) piperazine were reacted in the same manner as in Example 46 to obtain the compound. .

Yield: 79%

Melting Point: 153-154 ℃

H NMR (CDCl) δ: 2.58 (3H, s), 2.65 (3H, s), 3.15 (4H, t), 3.73 (4H, t), 3.90 (3H, s), 4.06 (3H, s), 6.91 (1H, d), 6.96 (1H, d), 6.97 (1H, s), 7.10 (1H, t), 8.89 (1H, s)

Example 52

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3-hydroxyphenyl) piperazine

The compound was obtained by reacting phenyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-ylcarbamate and 1- (3-hydroxyphenyl) piperazine in the same manner as in Example 46.

Yield: 76%

Melting Point: Oil Phase

H NMR (CDCl) δ: 2.60 (3H, s), 2.72 (3H, s), 3.34 (4H, t), 3.79 (4H, t), 3.98 (3H, s), 6.45 (3H, m), 6.98 (1H, m), 8.97 (1H, s)

Example 53

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

Phenyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-ylthiocarbamate and 1- (3,5-dimethoxyphenyl) piperazine were reacted in the same manner as in Example 22, The compound was obtained.

Yield: 77%

Melting Point: 167-169 ℃

H NMR (CDCl) δ: 2.58 (3H, s), 2.68 (3H, s), 3.47 (4H, t), 3.81 (6H, s), 4.05 (3H, s), 4.36 (4H, t), 6.42 (3H, m), 7.49 (1H, s), 9.05 (1H, s)

Example 54

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

The compound was reacted with phenyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-ylthiocarbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 22. Got it.

Yield: 75%

Melting Point: 176-177 ℃

H NMR (CDCl) δ: 2.34 (6H, s), 2.58 (3H, s), 2.68 (3H, s), 3.48 (4H, t), 4.06 (3H, s), 4.43 (4H, t), 7.05 (3H, m), 7.52 (1H, s), 9.04 (1H, s)

Example 55

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3-hydroxyphenyl) piperazine

Phenyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-ylthiocarbamate and 1- (3-hydroxyphenyl) piperazine were reacted in the same manner as in Example 22 to obtain the compound. .

Yield: 71%

Melting Point: 114-115 ℃

H NMR (CDCl) δ: 2.56 (3H, s), 2.75 (3H, s), 3.68 (4H, t), 4.05 (3H, s), 4.45 (4H, t), 7.30 (4H, m), 9.03 (1H, s)

Mass (EI) m / z: 458.2527 (MH, CHNOS calculated: 458.1987)

Example 56

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (100 mg, 0.23 mmol) Dissolved in ethanol (15 milliliters), sodium borohydride (8.66 milligrams) was added and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove ethanol, and then separated and purified by column chromatography (ethyl acetate: hexane = 2: 1) at room temperature to obtain the compound.

Yield: 97%

Melting Point: 124-126 ℃

H NMR (CDCl) δ: 1.48 (3H, d), 2.42 (3H, s), 3.27 (4H, t), 3.69 (4H, t), 3.79 (6H, s) 3.99 (3H, s), 5.03 ( 1H, q), 6.09 (1H, s), 6.15 (2H, d), 6.90 (1H.s), 8.46 (1H, s)

Mass (EI) m / z: 430.2265 (MH-calculated CHNO: 430.2216)

Example 57

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-dimethylphenyl) piperazine

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl} aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 56 to The compound was obtained.

Yield: 95%

Melting Point: 153-154 ℃

H NMR (CDCl) δ: 1.48 (3H, d), 2.30 (6H, s), 2.42 (3H, s), 3.26 (4H, t), 3.68 (4H, t), 3.99 (3H, s), 5.05 (1H, q), 6.71 (2H, d), 6.96 (1H, s), 8.46) (1H, s)

Mass (EI) m / z: 398.2343 (MH, calculated from CHNO: 398.2317)

Example 58

1-[(5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (2,3-dimethylphenyl) piperazine

1 = [(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (2,3-dimethylphenyl) piperazine was reacted in the same manner as in Example 56 to The compound was obtained.

Yield: 96%

Melting Point: 100-102 ℃

H NMR (CDCl) δ: 1.47 (3H, d), 1.59 (3H, s), 2.25 (3H, s), 2.28 (3H, s), 2.43 (3H, s), 2.93 (4H, t), 3.66 (4H, t), 3.99 (3H, s), 5.05 (1H, q), 6.93 (3H, m), 7.11 (1H, m), 8.48 (1H, s)

Example 59

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-difluorophenyl) piperazine

Reaction of 1-{[5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-difluorophenyl) piperazine in the same manner as in Example 56 To obtain the compound.

Yield: 97%

Melting Point: 184-186 ℃

H NMR (CDCl) δ: 1.48 (3H, d), 2.50 (3H, s), 3.30 (4H, t), 3.70 (4H, t), 4.11 (3H, s), 5.06 (1H, q), 6.33 (1H, q), 6.42 (2H, d), 6.92 (1H, s), 8.54 (1H, s)

Example 60

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl) -4- (3,5-dichlorophenyl) piperazine

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dichlorophenyl) piperazine was reacted in the same manner as in Example 56. The compound was obtained.

Yield: 95%

Melting Point: 197-200 ℃

H NMR (CDCl) δ: 1.46 (3H, d), 2.41 (3H, s), 3.28 (4H, t), 3.66 (4H, t), 3.96 (4H, t), 5.20 (1H, q), 7.02 (3H, m), 8.42 (1H, s)

Example 61

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl) -4- (3,5-methoxyphenyl) piperazine

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3-methoxyphenyl) piperazine

The compound was obtained by reacting in the same manner as in Example 56.

Yield: 97%

Melting Point: 88-90 ℃

H NMR (CDCl) δ: 1.47 (3H, d), 2.42 (3H, s), 3.11 (4H, t), 3.70 (4H, t), 3.89 (3H, s), 3.99 (3H, s), 5.03 (1H, q), 6.89 (3H, m), 6.94 (1H, s), 7.05 (1H, m), 8.48 (1H, s)

Example 62

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl) -4- (3-hydroxylophenyl) piperazine

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-hydroxyphenyl) piperazine was reacted in the same manner as in Example 56. The compound was obtained.

Yield: 87%

Melting Point: 194-196 ℃

H NMR (CDCl) δ: 1.47 (3H, d), 2.41 (3H, s), 3.27 (4H, t), 3.79 (4H, t), 3.98 (3H, s), 5.04 (1H, q), 6.57 (1H, q), 6.90 (1H, s), 7.13 (1H, t), 8.41 (1H, s)

Example 63

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl) -4- (3,5-dimethoxyphenyl) piperazine

Reaction of 1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine in the same manner as in Example 56 To obtain the compound.

Yield: 89%

Melting Point: 189-190 ℃

H NMR (CDCl) δ: 1.47 (3H, d), 2.43 (3H, s), 3.35 (4H, t), 3.78 (6H, s), 3.97 (3H, s), 4.09 (4H, t), 5.05 (1H, q), 6.07 (3H, m), 7.35 (1H, s), 8.42 (1H, s)

Example 64

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl) -4- (3,5-dimethylphenyl) piperazine

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 56 to The compound was obtained.

Yield: 88%

Melting Point: 170-172 ℃

H NMR (CDCl) δ: 1.46 (3H, d), 2.29 (6H, s), 2.43 (3H, s), 3.43 (4H, t), 3.97 (3H, s), 4.10 (4H, t), 5.06 (1H, q), 6.60 (3H, m), 7.37 (1H, s), 8.40 (1H, s)

Example 65

1-{[5- (1-hydroxy-1-methylethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl) -4- (3,5-dimethoxyphenyl) pipe Razin

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (214 mg, 0.50 mmol) After dissolving in hydrofuran (10 milliliters), methylmagnesium bromide (0.50 milliliters, 1.50 mmol) is added slowly and stirred for 15 hours. Concentrated under reduced pressure to remove the solvent, followed by extraction with ethyl acetate and dry filtration, and then purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.

Yield: 84%

Melting Point: 146-148 ℃

H NMR (CDCl) δ: 1.64 (6H, s), 2.64 (3H, s), 3.25 (4H, t), 3.67 (4H, t), 3.78 (6H, s), 3.99 (3H, s), 6.07 (3H, m), 6.86 (1H, s), 8.47 (1H, s)

Example 66

1-{[5- (1-hydroxy-1-methylethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl) -4- (3,5-dimethylphenyl) piperazine

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 65 to The compound was obtained.

Yield: 81%

Melting Point: Oil Phase

H NMR (CDCl) δ: 1.64 (6H, s), 2.29 (6H, s), 2.65 (3H, s), 3.24 (4H, t), 3.67 (4H, t), 3.99 (3H, s), 6.59 (3H, m), 7.05 (1H, s), 8.48 (1H, s)

Example 67

1-{[5- (1-hydroxy-1-methylpropyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl) -4- (3,5-dimethoxyphenyl) pipe Razin

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (214 mg, 0.50 mmol) After dissolving in hydrofuran (10 milliliters), ethylmagnesium bromide (0.50 milliliters, 1.50 mmol) is added slowly and stirred under reflux for 15 hours. Concentrated under reduced pressure, the solvent was removed, extracted with ethyl acetate, dried and filtered. Then, the residue was purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.

Yield: 76%

Melting Point: 127-129 ℃

H NMR (CDCl) δ: 0.83 (3H, t), 1.63 (3H, s), 1.94 (2H, m), 2.61 (3H, s), 3.26 (4H, t), 3.68 (4H, t), 3.79 (6H, s), 3.99 (3H, s), 6.08 (3H, m), 6.86 (1H, s), 8.44 (1H, s)

Example 68

1-{[5- (1-hydroxy-1-methylpropyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl) -4- (3,5-dichlorophenyl) piperazine

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 67 to The compound was obtained.

Yield: 74%

Melting Point: 164-165 ℃

H NMR (CDCl) δ: 0.83 (3H, t), 1.60 (3H, s), 1.95 (2H, m), 2.29 (6H, s), 2.61 (3H, s), 3.23 (4H, t), 3.67 (4H, t), 3.99 (3H, s), 6.59 (3H, m), 6.87 (1H, s), 8.45 (1H, s)

Example 69

1- [5-({[4- (3,5-dimethoxyphenyl) piperazino] carbonyl} amino) -6-butyloxy-2-methylpyridin-3-yl] ethylethanethioate

Triphenylphosphine (262 milligrams, 1.0 mmol) is dissolved in tetrahydrofuran (15 milliliters), diethyl azadicarboxylate (157 microliters, 1.0 mmol) is added, and then stirred at 0 ° C for 30 minutes. 1-{[5- (1- (hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine (213 Milligram, 0.5 mmol) and thiol acetic acid (72 microliters, 1.0 mmol) were dissolved in tetrahydrofuran (15 milliliters) and slowly added, then stirred at 0 ° C. for 1 hour, and stirred at room temperature for 1 hour. The obtained compound was separated and purified by column chromatography (ethyl acetate: hexane = 1: 2).

Yield: 62%

Melting Point: Oil Phase

H NMR (CDCl) δ: 1.55 (3H, d), 2.20 (3H, s), 2.39 (3H, s), 3.15 (4H, t), 3.57 (4H, t), 3.69 (6H, s), 3.90 (3H, s), 4.74 (1H, q), 6.01 (3H, m), 6.89 (1H, s), 8.33 (1H, s)

Example 70

1- [5-({[4- (3,5-dimethylphenyl) piperazino] carbonyl} amino) -6-methoxy-2-methylpyridin-3-yl] ethylethanethioate

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-dimethylphenyl) piperazine with Example 69 Reaction was carried out in the same manner to obtain the compound.

Yield: 60%

Melting Point: Oil Phase

H NMR (CDCl) δ: 1.60 (3H, d), 2.26 (6H, s), 2.52 (3H, s), 3.20 (4H, t), 3.64 (4H, t), 3.96 (3H, s), 4.80 (1H, q), 6.56 (3H, m), 6.91 (1H, s), 8.38 (1H, s)

Example 71

1-{[2-methoxy-6-methyl-5- (1-sulfanylmethyl)] aminocarbonyl]}-4- (3,5-dimethoxyphenyl) piperazine

1- [5-({[4- (3,5-dimethoxyphenyl) piperazino] carbonyl} amino) -6-methoxy-2-methylpyridin-3-yl] ethyl ethanethioate (180 Milligram, 0.37 mmol) was dissolved in tetrahydrofuran (15 milliliters), lithium aluminum hydride (15 milligrams, 0.4 mmol) was added at 0 ° C, and then stirred for 20 minutes. 2Normal-hydrochloric acid is added, followed by concentration under reduced pressure to remove the solvent. The mixture was extracted with dichloromethane, dried, filtered, concentrated under reduced pressure, separated and purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.

Yield: 88%

Melting Point: Oil Phase

H NMR (CDCl) δ: 1.42 (3H, d), 2.39 (3H, s), 3.25 (4H, t), 3.66 (4H, t), 3.76 (6H, s), 3.96 (3H, s), 5.02 (1H, q), 6.17 (3H, m), 6.87 (1H, s), 8.41 (1H, s)

Example 72

1-{[2-methoxy-6-methyl-5- (1-sulfanylmethyl)] aminocarbonyl]}-4- (3,5-dimethylphenyl) piperazine

1- [5-({[4- (3,5-dimethoxyphenyl) piperazino] carbonyl} amino) -6-methoxy-2-methylpyridin-3-yl] ethyl ethanethioate The compound was obtained in the same manner as in Example 71 to obtain the compound.

Yield: 87%

Melting Point: Oil Phase

H NMR (CDCl) δ: 1.43 (3H, d), 2.28 (6H, s), 2.40 (3H, s), 3.25 (4H, t), 3.72 (4H, t), 5.03 (1H, q), 6.64 (3H, m), 6.88 (1H, s), 8.42 (1H, s)

Example 73

1- [2-methoxy-6-methyl-5-vinylpyridin-3-yl) aminocarbonyl]}-4- (3,5-dimethoxyphenyl) piperazine

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine in chloroform ( 15 milliliters) and pyridium paratoluenesulfonate (60 mg, 0.23 mmol) was added and refluxed for 16 hours. The mixture was concentrated under reduced pressure, and chloroform was separated and purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.

Yield: 93%

Melting Point: 140-141 ℃

H NMR (CDCl) δ: 2.43 (3H, s), 3.27 (4H, t), 3.69 (4H, t), 3.79 (6H, s), 4.00 (3H, s), 5.25 (1H, d), 5.65 (1H, d), 6.08 (1H, s), 6.13 (2H, d), 6.82 (1H, d), 6.91 (1H, s), 8.53 (1H, s)

Mass (EI) m / z: 412.2119 (MH, CHNO calculated: 412.2110)

Example 74

1-[(2-methoxy-6-matic-5-vinylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-dimethylphenyl) piperazine with Example 73 Reaction was carried out in the same manner to obtain the compound.

Yield: 94%

Melting Point: 131-132 ℃

H NMR (CDCl) δ: 1.57 (3H, s), 2.31 (6H, s), 2.43 (1H, s), 3.25 (4H, t), 3.68 (4H, t), 4.00 (3H, s), 5.25 (1H, d), 5.65 (1H, d), 6.60 (3H, m), 6.82 (1H, dd), 6.92 (1H, s), 8.53 (1H, s)

Mass (EI) m / z: 380.2236 (MH, calculated CHNO: 380.2212)

Example 75

1-[(2-methoxy-6-methyl-5-vinylpyridin-3-yl) aminocarbonyl] -4- (3,5-diprolophenyl) piperazine

Example 1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-difluorophenyl) piperazine Reaction was carried out in the same manner as 73 to obtain the compound.

Yield: 93%

Melting Point: 160-161 ℃

H NMR (CDCl) δ: 2.44 (3H, s), 3.30 (4H, t, J = 5.5Hz), 3.69 (4H, t, j-5.5Hz) ,, 4.01 (3H, s), 5.26 (1H, d), 5.65 (1H, d), 6.30 (1H, s), 6.39 (2H, s), 6.81 (1H, dd), 8.53 (1H, s)

Example 76

1-[(5-isopropenyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

1-{[5- (1-hydroxy-1-methylethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl) -4- (3,5-dimethoxyphenyl) pipe Razine was reacted in the same manner as in Example 73 to obtain the compound.

Yield: 96%

Melting Point: 83-85 ℃

H NMR (CDCl) δ: 2.01 (3H, s), 2.38 (3H, s), 3.25 (4H, t), 3.66 (4H, t), 3.78 (6H, s), 3.99 (3H, s), 4.86 (1H, s), 5.30 (1H, s), 6.11 (3H, m), 6.90 (1H, s), 8.18 (1H, s)

Example 77

1] [(5-isopropenyl-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

1-{[5- (1-hydroxy-1-methylethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-dimethylphenyl) piperazine In the same manner as in Example 73, the compound was obtained.

Yield: 93%

Melting Point: 140-142 ℃

H NMR (CDCl) δ: 2.01 (3H, s), 2.29 (6H, s), 2.28 (3H, s), 3.23 (4H, t), 3.66 (4H, t), 3.99 (3H, s), 4.86 (1H, s), 5.18 (1H, s), 6.59 (3H, m), 6.91 (1H, s), 8.18 (1H, s)

Example 78

Ethyl-2- {1- [5-({[4- (3,5-dimethoxyphenyl) piperazino] carbonyl} amino) -6-methoxy-2-methylpyridin-3-yl] Toxy} acetate

1-{[5- (1-hydroxy) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine (0.5 mmol) Was dissolved in dimethylformamide (15 milliliters), sodium hydride (18.5 milligrams, 0.5 mmol) was added and stirred at room temperature for 15 minutes. Ethylbromoacetate (83.5 mg, 0.5 mmol) was added and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to remove the solvent, and then separated and purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.

Yield: 89%

Melting Point: Oil Phase

H NMR (CDCl) δ: 1.25 (3H, t), 1.34 (3H, d), 2.42 (3H, s), 3.00 (4H, t), 3.29 (4H, t), 3.74 (6H, s), 3.97 (3H, s), 4.16 (4H, s), 4.53 (1H, q), 6.03 (3H, m), 7.58 (1H, s)

Example 79

4- {1- [5-({[4- (3,5-Dimethoxyphenyl) piperazino] carbonyl} amino) -6-methoxy-2-methylpyridin-3-yl] ethoxy} 4-oxobutanoic acid

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-dimethoxyphenyl) pipezani (107 mg) , 0.25 mmol) and dimethylaminopyridine (3 mg, 0.025 mmol) are dissolved in pyridine, succinic anhydride (50 mg, 0.5 mmol) is added, followed by stirring at room temperature for 5 hours. After adding distilled water and extracting with methylene chloride, the organic layer is washed with 1 normal hydrochloric acid. The solvent was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain the compound.

Yield: 78%

Melting Point: 158-160 ℃

H NMR (CDCl) δ: 1.42 (3H, d), 2.43 (3H, s), 2.61 (4H, m), 3.24 (4H, t), 3.66 (4H, t), 3.76 (6H, s), 3.95 (3H, s), 5.94 (1H, q), 6.04 (3H, m), 6.89 (1H, s), 8.13 (1H, s)

Example 80

4- {1- [5-({[4- (3,5-dimethylphenyl) piperazino] carbonyl} amino) -6-methoxy-2-methylpyridin-3-yl] ethoxy} -4 Oxobutanoic acid

1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminocarbonyl} -4- (3,5-dimethylphenyl) piperazine with Example 79 Reaction was carried out in the same manner to obtain the compound.

Yield: 76%

Melting Point: 138-140 ℃

H NMR (CDCl) δ: 1.43 (3H, d), 2.27 (6H, s), 2.55 (3H, s), 2.65 (4H, m), 3.24 (4H, t), 3.69 (4H, t), 3.95 (3H, s), 5.95 (1H, q), 6.60 (3H, m), 6.88 (1H, s), 8.11 (1H, s)

The anticancer pharmacological activity of the compound of the present invention prepared as above was tested. The anticancer activity of the compounds of the present invention was tested using five human tumor cell lines and two leukemia tumor cell lines by in vitro methods, and the results are shown in the following table. The in vitro test method is as follows.

Experimental Example 1

* In vitro anticancer effect on human tumor cell lines

end. Tumor cell line: A549 (human non-small lung cell)

SKOV-3 (humam ovarian)

HCT-15 (human colon)

XF-498 (human CNS)

SKMEL-2 (human melanoma)

I. SRB Assay Method

a. Human solid tumor cell lines A549 (non-small lung cell), SKMEL-2 (melanoma), HCT-15 (colon), SKOV-3 (ovarian), XF-498 (CNS), etc. RPMI 1640 medium was incubated in 37 ° C., 5% CO 2 incubator and passages were performed 1-2 times a week. Cells were dissolved in 0.25% Trysin and 3 mM CDTA PBS (-) when detached from the adherent surface.

b. 5 × 10³-2 × 10 (cells were added to each well of a 96 well plate (Nunc) and incubated in 37 ° C. and 5% CO 2 incubator for 24 hours.

c. Various drugs were dissolved in a small amount of DMSO and diluted as experimental medium to the desired concentration for the test so that the final DMSO concentration was less than 0.5%.

d. After aspiration to remove all the medium of each well cultured in b. For 24 hours, the drugs prepared in c. Were added to each well 200 μl and incubated for 48 hours. At the time of drug addition, Tz (Time Zero) plates were collected.

e. Tz plates and each incubated plate were subjected to SRB assay method for cell fixing by TCA, staining with 0.4% SRB solution, washing with 1% acetic acid, and dyeing with 10 mM Tris solution to measure OD at 520 nM. .

All. Calculation of results

a. At the beginning of incubation with the addition of the drug, the SRB protein amount was obtained and time zero (Tz) was obtained.

b. The OD value of the wells in which cells were not added was called control value (C).

c. The OD value of drug-treated wells was called drug-treated test value (T).

d. From Tz, C and T, the effects of drugs could be determined by growth stimulation, net growth inhibition and net killing.

e. If T≥Tz, the cellular response function is 100 × (T-T) / (C-T), and for TT, it was calculated as 100 × (T-T) / T. The results are shown in the following table.

[references]

1) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyed. ; Proc. Am. Assoc. Cancer Res., 30,612 (1989)

2) L.V. Rubinstein, R. H. Shoemaker, K. D. Paul, R. M. Simon, S. Tosini, P. Skehan, D. Scudiero, A. Monks and M. R. Boed,; J. Nail. Cancer Inst., 82, 1113 (1990)

3) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1107 (1990)

la. result

The anticancer effect of all compounds was superior to that of Cisplatin, a control drug, in human solid cancer, and the anticancer effect of Adriamycin was higher than that of Adriamycin in most compounds.

Experimental Example 2

* In vitro anticancer effect on animal leukermia cells

end. Experimental material

Tumor Cell Lines: L1210 (mouse leukemia cell)

P388 (mouse lymphoid neoplasma cell)

I. Dye Exclusion Assay

1) L1210 and P388 cells incubated in RPMI 1640 medium containing 10% FBS were adjusted to a concentration of 1 × 10 ⁶ cells / ml.

2) Viable cell numbers were measured within 48 hours by adding drugs at each concentration diluted to a log dose and incubating in 37 ° C and 5% CO ₂ incubator. The viable cell number was measured by dye execlusion test using trypan blue.

3) The concentration of each compound (1C ₅₀ ) showing 50% cell growth inhibition compared to the control was calculated from the measured cell number. The results are shown in the following table.

[references]

1) P. Skhan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; Proc. Am. Assoc. Cancer Res., 30,612 (1989)

2) L.V. Rubinstein, R. H. Shoemaker, K. D. Paul, R. M. Simon, S. Tosini, P. Skehan, D. Scudiero, A. Monks and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1113 (1990)

3) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1107 (1990)

All. result

Compounds of the present invention showed the anticancer effect of L1210, P388 mouse leukemia cells as a result of all the compounds in the table showed more than the anticancer effect than the reference drug Mitomycin C.

Experimental Example 3

* In vivo anticancer effect experiment on mouse P388 cells

end. Experimental material

BDF1 mouse was used.

I. Experimental method]

1) One 6-week-old BDF1 mouse was used as a group, and 1 × 10 P388 cells passaged from DBA / 2 mice to each mouse. Cells / 0.1ml were implanted into the abdominal cavity.

2) The test drug was suspended in 0.5% Tween 80 and injected intraperitoneally at different concentrations for each day of day 1, 5, 9 or everyday 9.

3) The survival rate was measured while observing mice daily, and the anticancer effect was determined by calculating the increased ratio (T / C%) of the mean survival days of the control group to the control group from the median survival time of each experimental group. The results are shown in the following table.

[references]

A. Goldin et al: Europ. Cancer, 17, 129 (1981)

All. result

In vivo experiments using P388 mouse cancer cell showed significant antitumor effect (T / C> 125%) of 8, 15, 16, 20, 56, 73, 74, etc. .

Experimental Example 4

* Acute Toxicity Test (LD)

Experimental method: Richfield-Wilcockson method

Six-week-old ICR mice (male 30 ± 2.0g) were purchased and fed with solid feed and water freely at room temperature 23 ± 1 ℃ and humidity 60 ± 5% before the experiment. Drugs were administered intraperitoneally using 6 animals per group, and the appearance and live death were recorded for 14 days. The mortality was examined by necropsy. LD value was calculated | required by the Richfield-Wilcoxon method. The results are shown in the following table.

The compound moles of the present invention have been found to overcome the problems of the prior art compounds in limiting dosage and toxicity in terms of safety, which is superior to Cisplatin or Adriamycin in acute toxicity.

Claims (2)

Compound represented by the following general structural formula (I) and its pharmaceutically acceptable acid addition salt.

Wherein R ₁ and R ₂ each represent a hydrogen atom, a substituted or unsubstituted C ₁ -C ₈ alkyl group, a C ₃ -C ₈ substituted or unsubstituted 3-6 membered cyclic alkyl group, a substituted or unsubstituted C ₂ -C ₈ unsaturated alkyl group, ketone group, substituted or unsubstituted aryl group, substituted or unsubstituted arylhydroxy group substituted or unsubstituted amine group, C ₁ -C ₄ lower ester group, C ₁ -C ₄ lower thio An ester group, thiol group, substituted or unsubstituted carboxyl group, epoxy group, or R ₁ and R ₂ together form an unsaturated or saturated ring of 3-4 carbon atoms, each of R ₃ , R ₄ , R ₅ , and R ₆ is hydrogen; Atom, halogen atom, hydroxy group, nitro group, C ₁ -C ₄ lower ester group, C ₁ -C ₄ lower alkyl group, substituted or unsubstituted C ₃ -C ₈ unsaturated alkyl group, C ₃ -C ₈ A substituted or unsubstituted 3-6 membered cycloalkyl group, C ₁ -C ₄ lower alkoxy group, C ₁ -C ₄ lower thioalkoxy group, substituted or Unsubstituted aryl group, substituted or unsubstituted aryl lower alkoxy group, substituted or unsubstituted lower alkylamino group, or lower alkyl substituted or unsubstituted carbamate group, or two of R ₃ , R ₄ , R ₅ , R ₆ and R ₇ Two adjacent groups are bonded to each other to form a phenylene ring or a naphthylene ring, X is an oxygen atom, a sulfur atom, a substituted or unsubstituted imine group, Y is an oxygen atom or NH, and Z is a hydrogen atom, a hydroxyl group, C ₁ the lower -C ₈ alkoxy group, a C ₁ -C ₄ lower alkoxy group, a substituted or unsubstituted aryloxy group, a lower alkyl amine group of C ₁ -C4, substitution or which may contain 1 to 5 nitrogen atom It is an unsubstituted cyclic amine group. The following compound of formula (b) prepared by reacting the compound of formula (a) with -C (= X) -donating reagent in the presence of a conventional organic solvent A process for producing the compound of general formula (I) or an acid addition salt thereof.

Wherein R ₁ and R ₂ each represent a hydrogen atom, a substituted or unsubstituted C ₁ -C ₈ alkyl group, a C 3 -C ₈ substituted or unsubstituted 3-6 membered cyclic alkyl group, a substituted or unsubstituted C _2- for C ₈ unsaturated alkyl group, a ketone group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aryl hydroxyl group substituted or unsubstituted amine group, a lower alkylthio-lower esters of the ester group of the _{C 1 -C 4, C 1 -C} 4 Together with the group, thiol group, substituted or unsubstituted carboxyl group, epoxy group, or R ₁ and R ₂ form an unsaturated or saturated ring of 3-4 carbon atoms, R ₃ , R ₄ , R ₅ , R ₆ and R ₇ Hydrogen atom, halogen atom, hydroxy group, nitro group, C ₁ -C ₄ lower ester group, C ₁ -C ₄ lower alkyl group, substituted or unsubstituted C ₃ -C ₈ unsaturated alkyl group, C ₃ -C respectively ₈ substituted or unsubstituted 3-6 membered cycloalkyl group, C ₁ -C ₄ lower alkoxy group, C ₁ -C ₄ lower thioalkoxy group, substitution Or an unsubstituted aryl group, a substituted or unsubstituted aryl lower alkoxy group, a substituted or unsubstituted lower alkylamino group, or a lower alkyl substituted or unsubstituted carbamate group, or in R ₃ , R ₄ , R ₅ , R ₆ and R ₇ Two adjacent groups are bonded to each other to form a phenylene ring or a naphthylene ring, X is an oxygen atom, a sulfur atom, a substituted or unsubstituted imine group, Y is an oxygen atom or NH, and Z is a hydrogen atom, a hydroxyl group, C Lower alkoxy group of _1- C ₈ , lower thioalkoxy group of C ₁ -C ₄ , substituted or unsubstituted aryloxy group, lower alkylamine group of C ₁ -C ₄ , and may contain 1 to 5 nitrogen atoms a substituted or unsubstituted cyclic amine group, ₁ Lie is a leaving group such as a hydrogen atom.