KR20190115976A - Optically active 2-amino-4-alkoxypyrimidnes derivatives as 5-HT2C agonists - Google Patents

Abstract

The present invention provides an optically active 2-amino-4-alkoxy pyrimidine derivative that has excellent performance as a 5-HT2C agonist but has high selectivity to 2A and 2B. The present invention provides the optically active 2-amino-4-alkoxy pyrimidine derivative having a structure of chemical formula 1.

Description

Optically active 2-amino-4-alkoxypyrimidnes derivatives as 5-HT2C agonists

The present invention relates to an optically active 2-amino-4-alkoxy pyrimidine derivative having activity as a 5-HT2C agonist, and more particularly, to excellent performance as a 5-HT2C agonist, but with high selectivity to 2A and 2B. It relates to an optically active 2-amino-4-alkoxy pyrimidine derivative.

Serotonin is also known as 5-HT (5-hydroxytryptamine). Serotonin is a neurotransmitter and is involved in emotional regulation related to eating, sleeping, awakening, pain control and dreams. Serotonin is synthesized from the amino acid tryptophan, and the enzyme tryptophan hydroxylase (tryptophan hydroxylase) attaches -OH to tryptophan to produce intermediate 5-HTP (5-hydroxytryptophan). Another enzyme 5-HTP decarboxylase then removes -COOH from 5-HTP to complete 5-HT, or serotonin. P-chlorophenylalanine (PCPA) is a synthetic amino acid that is an irreversible inhibitor of tryptophan hydroxylase, a rate limiting enzyme for serotonin synthesis, and induces systemic inhibition of serotonin synthesis.

Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) are the first treatments chosen for the treatment of depression, some form of anxiety and social phobia, which are effective and well tolerated compared to classic tricyclic antidepressants. This is because it has an advantageous safety profile.

However, clinical studies on depression indicate that up to 30% do not substantially respond to SSRIs. Another major neglected factor in antidepressant treatment is the negligible purity, which has a somewhat profound effect on the patient's motivation to continue drug therapy.

First of all, there is a delay in the therapeutic effect of SSRIs. Sometimes symptoms worsen even during the first week of treatment. Second, sexual dysfunction is a common side effect for all SSRIs. Without addressing these issues, it is difficult to make real progress in pharmacotherapy of depression and anxiety disorders.

To overcome no response, psychiatrists sometimes use augmentation strategies. Enhancement of antidepressant therapies can be achieved by co-administration of mood stabilizers such as lithium carbonate or triyodothyronine, or by use of electroshock.

The combined effect of a compound that inhibits serotonin reuptake and a 5-HT1A receptor antagonist has been evaluated in several studies (Innis, RB et al. Eur. J. Pharmacol. 1987, 143, p 1095-204 and Gartside, SE Br. J. Pharmacol. 1995, 115, p 1064-1070, Blier, P. et al. Trends in Pharmacol. Science 1994, 15, 220). In these studies, it was found that 5-HT 1A receptor antagonists eliminated the initial braking of 5-HT neurotransmission induced by serotonin reuptake inhibitors, resulting in immediate elevation of 5-HT delivery and rapid onset of therapeutic action. lost.

Several patent applications have been submitted covering the use of combinations of 5-HT1A antagonists and serotonin reuptake inhibitors for the treatment of depression (see EP-A2-687472 and EP-A2-714663).

Another approach to increasing terminal 5-HT was through blocking of 5-HT1B autoreceptors. Microdialysis experiments in the rats actually showed that the increase in hippocampal 5-HT by citalopram is enhanced by GMC 2-29, an experimental 5-HT1B receptor antagonist.

In addition, several patent applications have been filed that deal with combinations of SSRIs and 5-HT1B antagonists or partial agonists (WO 97/28141, WO 96/03400, EP-A-701819 and WO 99/13877).

It has been demonstrated that the 5-HT2C ligand can affect the release of dopamine (DA) and noradrenaline (NE) in the let frontal cortex. Thus, the 5-HT2C agonist Ro 60-0175 and the selective 5-HT 2C antagonist SB-242084 inhibited and increased both DA and NE levels without altering the levels of serotonin (5-HT), respectively (Millan, MJ et al.). Neuropharmacology 1998, 37, p 953-955). Similar observations were made using SB-206553, a selective 5-HT 2B / 2C antagonist (Gobert, A. et al. Neuropharmacology 1999, 38, p 315-317). Activation of the 5-HT 2C receptor with the selective agonist MK-212 inhibited morphine-induced DA release at the Let nuclear nucleus (Willins, D. L. et al. Brain Res. 1998, 781, p 291-299). Previous reports have demonstrated that quizazine-induced reduction of NE release in the rat hippocampus was offset by ritanserine (Done, C. J. et al. Br. J. Pharmacol. 1992, 107, p 240-245). Thus, the 5-HT 2C receptor exerts an effect upon the release of NE and DA, but not upon the release of 5-HT. In a study by Milan et al. (1998, 1999), 5-HT 2C ligand was injected alone and no effect on 5-HT release was found.

Citalopram and fluoxetine are known to have intermediate affinity for the 5-HT2C receptor (Palvimaki, E. P. Psychopharmacology (Berl.) 1996, 126, p 234-240). Moreover, chronic administration of citalopram, fluoxetine and paroxetine has been reported to lead to functional desensitization of the 5-HT2C receptor (Kennett, GA et al. Neuropharmacology 1994, 33, p 1581-1588, Maj J. et al. Psychopharmacology (Berl.) 1996, 127, p 73-82, and Quested, DJ Psychopharmacology (Berl.) 1997, 133, 305-308). It has also been suggested that this change may contribute to the therapeutic efficacy of depression, anxiety disorders and OCD (OCD).

Recent clinical studies have shown that pindolol and myanserine enhance the efficacy of fluoxetine in the treatment of treatment resistant patients, and that myanserine can shorten the latency period of antidepressant onset when combined with fluoxetine. The effects of myanserine in this study can be explained by at least four different mechanisms regarding the effect of myanserine on noradrenaline replacement, α2-receptor blockade and antagonistic effects on 5-HT2A / 2C receptors (Maes, M J. Clin, Psychopharmacol, 1999, 19,2, p 177-182).

However, in the mice's Forced Swim Test, ritanserine (4 mg / kg intraperitoneal) or ketanserine (8 mg / kg intraperitoneal) was also treated with imipramine prior to administration of the selective 5-HT2A / 2C antagonist. (mg / kg intraperitoneal) and desipramine (16 mg / kg intraperitoneal), but fluoxetine (16 mg / kg intraperitoneal), citalopram (16 mg / kg intraperitoneal) or fluvoxamine (8 mg / kg) kg intraperitoneal) was not reported (Redrobe, JP et al. Eur J Pharmacol. 1997, 325, 129-135).

Currently, the combination of serotonin reuptake inhibitors with compounds having a 5-HT2C antagonist or reverse agonist effect (compounds with negative efficacy at the 5-HT2C receptor), as measured in microdialysis experiments, is determined at the level of 5-HT in the terminal region. It has been found to provide a significant increase. No compound has yet been developed as 5-HT2C agonists and has passed clinical trials for the treatment of schizophrenia. This is because the developed compounds do not show high selectivity for other serotonin (5HT) receptors.

Republic of Korea Patent Publication No. 10-1989-0017244 Japanese Patent No. 5358571

An object of the present invention is to provide an optically active 2-amino-4-alkoxy pyrimidine derivative which is excellent in performance as a 5-HT2C agonist and has high selectivity to 2A and 2B.

It is an object of the present invention to provide optically active 2-amino-4-alkoxy pyrimidine derivatives of novel structures and pharmaceutically acceptable salts thereof.

The present invention also provides a method for preparing the above optically active 2-amino-4-alkoxy pyrimidine derivative compounds by carrying out enzymatic kinetic resolution using an enzymatic reaction. There is a purpose.

In addition, the present invention provides a pharmaceutical composition exhibiting activity as an anti-inflammatory agent of 5-HT2C containing the above-described optically active 2-amino-4-alkoxy pyrimidine derivative compounds and pharmaceutically acceptable salts thereof as an active ingredient. There is another purpose.

In addition, the present invention is a drug for the prevention and treatment of diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ischemic disease, diabetes mellitus, schizophrenia in which the triazole compound and pharmaceutically acceptable salts thereof are included as an active ingredient. There is another purpose to provide.

In order to solve the above problems, the present invention provides an optically active 2-amino-4-alkoxy pyrimidine derivative having the structure of formula (1).

[Formula 1]

(R is hydrogen or C1-10 hydrocarbon, n is an integer of 0-10)

The derivative may have a structure of Formula 2 below.

[Formula 2]

The derivative may have efficacy in diseases of the central nervous system.

The central nervous system disease may be schizophrenia, depression, substance abuse, Parkinson's disease, or obesity.

In another aspect, the present invention provides a method for preparing the 2-amino-4-alkoxy pyrimidine derivative comprising the following steps.

(a) synthesizing (3-fluorophenyl) ethanol having the structure of Formula 3 into the enantiomer;

[Formula 3]

(b) mixing NaO ^t Bu and toluene and then adding (3-fluorophenyl) ethanol prepared in step (a);

(c) adding 2,4-dichloro-5-fluoro pyrimidine to the mixture prepared in step (b) and terminating the reaction by mixing ammonium chloride after 10 minutes to 2 hours;

(d) extracting with a mixture of ethyl acetate and water, and then separating and purifying to obtain a compound having the structure of Formula 4;

[Formula 4]

(e) ( R )-(+)-1-Boc-3-methyl piperazine and toluene are mixed with the compound having the structure of Formula 4, extracted with ethyl acetate and washed to obtain the structure of Formula 5 Obtaining a compound having;

[Formula 5]

(f) mixing the compound having the structure of Formula 5 with dichloromethane, and then adding and stirring trifluoroacetic acid;

(g) extracting the mixture of step (f) using ethyl acetate and water, and then mixing an aqueous sodium hydrogen carbonate solution; And

(h) drying the mixture of step (g) and then separating to obtain a 2-amino-4-alkoxy pyrimidine derivative.

Step (a) may be a step of synthesizing pure enantiomers using enzymatic kinetic resolution.

The enantiomer of step (a) may have the structures of Formulas 3-1 and 3-2.

[Formula 3-1]

[Formula 3-2]

The optically active 2-amino-4-alkoxy pyrimidine derivatives according to the present invention have superior performance as 5-HT2C agonists compared to conventional 5-HT2C inhibitors, but have high selectivity to 2A and 2B to minimize side effects. It can be used as an inhibitor.

Hereinafter, a preferred embodiment of the present invention will be described in detail. In the following description of the present invention, if it is determined that the detailed description of the related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted. Throughout the specification, when a part is said to "include" a certain component, it means that it may further include other components, not to exclude other components, unless otherwise stated.

As the invention allows for various changes and numerous embodiments, particular embodiments will be illustrated and described in detail in the detailed description. However, this is not intended to limit the present invention to specific embodiments, it should be understood to include all transformations, equivalents, and substitutes included in the spirit and scope of the present invention.

The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting of the present invention. Singular expressions include plural expressions unless the context clearly indicates otherwise. In the present invention, the terms including or having are intended to indicate that there is a feature, number, step, operation, component, part, or a combination thereof described in the specification, but one or more other features or numbers, step It is to be understood that the present invention does not exclude in advance the possibility of the presence or the addition of an operation, a component, a part, or a combination thereof.

The present invention relates to an optically active 2-amino-4-alkoxy pyrimidine derivative having the structure of formula (1).

[Formula 1]

(R is hydrogen or C1-10 hydrocarbon, n is an integer of 0-10)

The derivative may have a structure of Formula 2 below.

[Formula 2]

The structure of Chemical Formula 2 relates to a structure in which R is methane and n is 0 in the structure of Chemical Formula 1. In addition, since the structure of Formula 2 may have an optical isomer structure, it may have a structure of the formula 2-1 and 2-2.

[Formula 2-1]

[Formula 2-2]

In addition, the structures of Formulas 2-1 and 2-2 may have a structure of Formulas 2-3 to 2-6, depending on the position of F in the benzene ring.

[Formula 2-3]

[Formula 2-4]

[Formula 2-5]

[Formula 2-6]

The derivative may have efficacy in diseases of the central nervous system. The derivative can be used as an anti-inflammatory agent of 5-HT2C. Therefore, it may have efficacy in various central nervous system diseases caused by the degradation of the 5-HT2C. In this case, the central nervous system disease may be schizophrenia, depression, substance abuse, Parkinson's disease, or obesity, preferably schizophrenia and obesity. .

The present invention also relates to a method for preparing the 2-amino-4-alkoxy pyrimidine derivative comprising the following steps.

(a) synthesizing (3-fluorophenyl) ethanol having the structure of Formula 3 into the enantiomer;

[Formula 3]

(b) mixing NaO ^t Bu and toluene and then adding (3-fluorophenyl) ethanol prepared in step (a);

(c) adding 2,4-dichloro-5-fluoro pyrimidine to the mixture prepared in step (b) and terminating the reaction by mixing ammonium chloride after 10 minutes to 2 hours;

(d) extracting with a mixture of ethyl acetate and water, and then separating and purifying to obtain a compound having the structure of Formula 4;

[Formula 4]

(e) ( R )-(+)-1-Boc-3-methyl piperazine and toluene are mixed with the compound having the structure of Formula 4, extracted with ethyl acetate and washed to obtain the structure of Formula 5 Obtaining a compound having;

[Formula 5]

(f) mixing the compound having the structure of Formula 5 with dichloromethane, and then adding and stirring trifluoroacetic acid;

(g) extracting the mixture of step (f) using ethyl acetate and water, and then mixing an aqueous sodium hydrogen carbonate solution; And

(h) drying the mixture of step (g) and then separating to obtain a 2-amino-4-alkoxy pyrimidine derivative.

As the compound of Formula 3 corresponds to the starting material of the present invention, the compound of Formula 2-1 or 2-2 may be prepared by using the compounds of Formulas 3-1 and 3-2. .

[Formula 3-1]

[Formula 3-2]

Step (a) may be a step of synthesizing pure enantiomers using enzymatic kinetic resolution.

The enzymatic kinetic cleavage utilizes the point that one isomer preferentially reacts with the other in the reaction with a chiral catalyst or reagent (using enzymes or microorganisms). How to separate each. The enzymatic kinetic optical splitting method is a method already known in the art. In the present invention, if a compound capable of splitting or catalyzing at a reaction rate according to stereochemistry can be freely selected and subjected to enzymatic kinetics, the acetylation reaction can be catalyzed at a reaction rate according to the stereochemistry of secondary alcohol. Preference is given to using CAL-B enzyme.

Hereinafter, with reference to the accompanying drawings, preferred embodiments of the present invention will be described to be easily carried out by those of ordinary skill in the art. In addition, in describing the present invention, when it is determined that a detailed description of a related known function or known configuration may unnecessarily obscure the subject matter of the present invention, the detailed description thereof will be omitted. And certain features shown in the drawings are enlarged or reduced or simplified for ease of description, the drawings and their components are not necessarily drawn to scale. However, those skilled in the art will readily understand these details.

Example

(One) ( R ) -1- (3-fluorophenyl) ethane-1-ol (Compound 1)

1- (3-fluorophenyl) ethanol (934 mg, 6.67 mmol) was dissolved in n- hexane (22.2 mL), followed by CAL-B (147 mg), vinyl acetate (0.310 mL, 3.34 mmol) and triethylamine. (0.0540 mL, 0.667 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered to remove impurities and reduced pressure to remove solvent. The mixture was purified by silica gel column chromatography ( n -hexane / EtOAc = 8: 1) to obtain ( R ) -1- (3-fluorophenyl) ethyl acetate (315 mg, 26%) as a pure colorless oil. . The intermediate compound ( R ) -1- (3-fluorophenyl) ethyl acetate was dissolved in methanol (3.45 mL), and then 1M sodium hydroxide (2.6 mL, 2.59 mmol) was added and stirred for 1 hour. The mixture was extracted using ethyl acetate and distilled water. The organic layer was dried with anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f = 0.25 ( n -hexane / EtOAc = 4: 1)) to obtain ( R ) -1- (3-fluorophenyl) ethane-1-ol (156 mg, 17%) as a pure colorless oil. ).

[Formula 6]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.32-7.26 (m, 1H), 7.12-7.07 (m, 2H), 6.97-6.92 (m, 1H), 4.87 (q, J = 6.4 Hz, 1H) , 2.18 (s, 1 H), 1.47 (d, J = 6.4 Hz, 3 H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 163.0 (d, ¹ J = 244 Hz), 148.5 (d, ³ J = 6 Hz), 130.0 (d, ³ J = 8 Hz), 121.0 (d, ⁴ J = 3 Hz), 114.2 (d, ² J = 21 Hz), 112.3 (d, ² J = 21 Hz), 69.8, 25.2

[a] _D ²⁶ + 43.7 ° C (0.7, CHCl ₃ ).

(2) ( S ) -1- (3-fluorophenyl) ethan-1-ol (Compound 2)

1- (3-fluorophenyl) ethanol (934 mg, 6.67 mmol) was dissolved in n- hexane (22.2 mL), and then CAL-B (147 mg), vinyl acetate (1.20 mL, 13.3 mmol) and triethylamine (0.0540 mL, 0.667 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered to remove impurities and reduced pressure to remove solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f = 0.25 ( n -hexane / EtOAc = 4: 1) to obtain ( S ) -1- (3-fluorophenyl) ethan-1-ol (403 mg, 44%) as a pure colorless oil (Formula 7) .

[Formula 7]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.31-7.26 (m, 1H), 7.11-7.06 (m, 2H), 6.96-6.91 (m, 1H), 4.85 (td, J = 5.5, 7.5 Hz, 1H), 2.31 (s, 1H), 1.46 (d, J = 6.5 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 163.0 (d, ¹ J = 245 Hz), 148.6 (d, ³ J = 6 Hz), 130.0 (d, ³ J = 8 Hz), 121.0 (d, ⁴ J = 3 Hz), 114.2 (d, ² J = 21 Hz), 112.3 (d, ² J = 22 Hz), 69.8 (d, ⁴ J = 2 Hz), 25.2.

^{_{[α] D 27 - 46.9 °}} (c 0.4, CHCl 3).

(3) ( R ) -1- (4-fluorophenyl) ethan-1-ol (Compound 3)

1- (4-fluorophenyl) ethanol (1.24 g, 8.85 mmol) was dissolved in n- hexane (29.5 mL), followed by CAL-B (195 mg), vinyl acetate (0.408 mL, 4.43 mmol) and triethylamine. (0.0710 mL, 0.885 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered to remove impurities and reduced pressure to remove solvent. The mixture was purified by silica gel column chromatography ( n -hexane / EtOAc = 8: 1) to obtain ( R ) -1- (4-fluorophenyl) ethyl acetate (511 mg, 32%) as a pure colorless oil. . The intermediate compound ( R ) -1- (4-fluorophenyl) ethyl acetate was dissolved in methanol (5.60 mL), and then 1M sodium hydroxide (4.20 mL, 4.21 mmol) was added and stirred for 1 hour. The mixture was extracted using ethyl acetate and distilled water. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f = 0.25 ( n -hexane / EtOAc = 4: 1)) to obtain ( R ) -1- (4-fluorophenyl) ethan-1-ol (393 mg, 32%) as a pure colorless oil. ).

[Formula 8]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.32-7.26 (m, 2H), 7.03-6.97 (m, 2H), 4.84 (q, J = 6.1 Hz, 1H), 2.34 (s, 1H), 1.44 (d, J = 6.4 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.1 (d, ¹ J = 244 Hz), 141.6 (d, ⁴ J = 3 Hz), 127.1 (d, ³ J = 8 Hz), 115.2 (d, ² J = 21 Hz), 69.7, 25.3.

[a] _D ²⁷ + 51.9 ° (c 0.5, CHCl ₃ ).

(4) ( S ) -1- (4-fluorophenyl) ethan-1-ol (Compound 4)

1- (4-fluorophenyl) ethanol (1.24 g, 8.85 mmol) was dissolved in n- hexane (29.5 mL), followed by CAL-B (195 mg), vinyl acetate (1.60 mL, 17.7 mmol) and triethylamine. (0.0710 mL, 0.885 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered to remove impurities and reduced pressure to remove solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f = 0.25 ( n -hexane / EtOAc = 4: 1)) to obtain ( S ) -1- (4-fluorophenyl) ethan-1-ol (574 mg, 46%) as a pure colorless oil. ).

[Formula 9]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.33-7.30 (m, 2H), 7.04-6.98 (m, 2H), 4.85 (q, J = 6.4 Hz, 1H), 2.16 (s, 1H), 1.45 (d, J = 6.4 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.1 (d, ¹ J = 243 Hz), 141.5 (d, ⁴ J = 3 Hz), 127.1 (d, ³ J = 8 Hz), 115.2 (d, ² J = 21 Hz), 69.8, 25.3.

^{_{[α] D 27 - 49.7 °}} (c 0.6, CHCl 3).

(5) ( R ) -2-chloro-5-fluoro-4- (1- (3-fluorophenyl) ethoxy) pyrimidine (Compound 5)

NaO ^t Bu (137 mg, 1.43 mmol) was added to toluene (7.10 mL) and ( R ) -1- (3-fluorophenyl) ethanol (100 mg, 0.713 mmol) was added dropwise at 0 ° C. Then 2,4-dichloro-5-fluoro pyrimidine (119 mg, 0.713 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was terminated with an aqueous ammonium chloride solution and extracted with ethyl acetate and distilled water. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f = 0.69 ( n -hexane / EtOAc = 4: 1)) to purify ( R ) -2-chloro-5-fluoro-4- (1- (3-fluorophenyl) ethoxy) pyrimidine as a pure colorless oil (139 mg, 72%) was obtained (Formula 10).

[Formula 10]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J = 2.2 Hz, 1H), 7.37-7.31 (m, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.18-7.15 (m , 1H), 7.03-6.99 (m, 1H), 6.30 (q, J = 6.5 Hz, 1H), 1.71 (d, J = 6.6 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.9 (d, ¹ J = 245 Hz), 158.6 (d, ² J = 11 Hz), 153.2 (d, ⁴ J = 5 Hz), 146.0 (d, ¹ J = 263 Hz), 144.4 (d, ² J = 20 Hz), 142.9 (d, ³ J = 7 Hz), 130.3 (d, ³ J = 8 Hz), 122.0 (d, ⁴ J = 3 Hz), 115.3 (d, ² J = 21 Hz), 113.3 (d, ² J = 22 Hz), 75.6 (d, ⁴ J = 2 Hz), 22.2.

[α] _D ²⁶ + 164.1 ° (c 1.0, CHCl ₃ ).

(6) ( R ) -2-chloro-5-fluoro-4- (1- (4-fluorophenyl) ethoxy) pyrimidine (Compound 6)

NaO ^t Bu (151 mg, 1.57 mmol) was added to toluene (7.90 mL) and ( R ) -1- (4-fluorophenyl) ethanol (110 mg, 0.785 mmol) was added dropwise at 0 ° C. Then 2,4-dichloro-5-fluoro pyrimidine (131 mg, 0.785 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was terminated with an aqueous ammonium chloride solution and extracted with ethyl acetate and distilled water. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f ( R ) -2-chloro-5-fluoro-4- (1- (4-fluorophenyl) ethoxy) pyrimidine as a pure colorless oil which has been purified to 0.71 ( n -hexane / EtOAc = 4: 1)). (145 mg, 68%) was obtained (Formula 11).

[Formula 11]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 2.2 Hz, 1H), 7.47-7.42 (m, 2H), 7.08-7.02 (m, 2H), 6.30 (q, J = 6.6 Hz , 1H), 1.71 (d, J = 6.6 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.6 (d, ¹ J = 245 Hz), 158.7 (d, ² J = 11 Hz), 153.1 (d, ⁴ J = 4 Hz), 146.0 (d, ¹ J = 263 Hz), 144.3 (d, ² J = 20 Hz), 136.1 (d, ⁴ J = 4 Hz), 128.4 (d, ³ J = 9 Hz), 115.6 (d, ² J = 22 Hz), 75.9 , 22.2.

[a] _D ²⁷ + 197.3 ° C (c 0.8, CHCl ₃ ).

(7) tert -Butyl- ( R ) -4- (5- Fluoro -4-(( R ) -1- (3- Fluorophenyl ) Ethoxy Pyrimidin-2-yl) -3- methyl  Piperazine-1-carboxylate (Compound 7)

( R ) -2-chloro-5-fluoro-4- (1- (3-fluorophenyl) ethoxy) pyrimidine in a sealed tube (119 mg, 0.440 mmol) and ( R )-(+)-1-Boc-3-methyl piperazine (176 mg, 0.879 mmol) were dissolved in toluene (0.880 mL), followed by stirring at 150 ° C for 12 hours. Let cool. The mixture was extracted with ethyl acetate and washed with aqueous sodium chloride solution. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f 0.41) purified tert -butyl- ( R ) -4- (5-fluoro-4-(( R ) -1- (3-fluorophenyl) ethoxy) pyrimidin-2-yl as a pure colorless oil ) -3-methyl piperazine-1-carboxylate (96.0 mg, 50%) was obtained (Formula 12).

[Formula 12]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 2.8 Hz, 1H), 7.31-7.26 (m, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 9.6 Hz, 1H) 6.96-6.91 (m, 1H), 6.03 (q, J = 6.6 Hz, 1H), 4.58 (bs, 1H), 4.18-3.86 (m, 3H), 3.08-3.01 (m, 2H ), 2.84-2.74 (m, 1H), 1.66 (d, J = 6.6 Hz, 3H), 1.47 (s, 9H), 0.91 (d, J = 6.5 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.9 (d, ¹ J = 245 Hz), 157.1 (d, ² J = 11 Hz), 156.7 (d, ⁴ J = 2 Hz), 155.2, 145.1 (d , ³ J = 7 Hz), 143.4 (d, ² J = 20 Hz), 140.0 (d, ¹ J = 246 Hz), 130.1 (d, ³ J = 8 Hz), 121.2 (d, ⁴ J = 3 Hz ), 114.5 (d, ² J = 21 Hz), 112.7 (d, ² J = 22 Hz), 79.8, 73.9, 48.4, 47.1, 43.9, 42.8, 38.7, 28.4, 23.0, 13.9.

[α] _D ²⁷ + 105.0 ° (c 0.4, CHCl ₃ ).

(8) tert -Butyl- ( R ) -4- (5- Fluoro -4-(( R ) -1- (4- Fluorophenyl ) Ethoxy Pyrimidin-2-yl) -3- methyl  Piperazine-1-carboxylate (Compound 8)

( R ) -2-chloro-5-fluoro-4- (1- (4-fluorophenyl) ethoxy) pyrimidine in a sealed tube (227 mg, 0.839 mmol) and ( R )-(+)-1-Boc-3-methyl piperazine (336 mg, 1.68 mmol) were dissolved in toluene (1.70 mL), followed by stirring at 150 ° C for 12 hours. Let cool. The mixture was extracted with ethyl acetate and washed with aqueous sodium chloride solution. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f 0.33) purified tert -butyl- ( R ) -4- (5-fluoro-4-(( R ) -1- (4-fluorophenyl) ethoxy) pyrimidin-2-yl as a pure colorless oil ) -3-methyl piperazine-1-carboxylate (162 mg, 44%) was obtained (Formula 13).

[Formula 13]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, J = 2.8 Hz, 1H), 7.39-7.33 (m, 2H), 7.04-6.98 (m, 2H), 6.07 (d, J = 6.6 Hz , 1H), 4.60 (bs, 1H), 4.23-3.86 (m, 3H), 3.09-2.77 (m, 3H), 1.65 (d, J = 6.6 Hz, 3H) 1.46 (s, 9H), 0.95 (d , J = 6.6 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.2 (d, ¹ J = 245 Hz), 157.2 (d, ² J = 11 Hz), 156.7 (d, ⁴ J = 2 Hz), 155.2, 143.3 (d, ² J = 19 Hz), 140.0 (d, ¹ J = 247 Hz), 138.1 (d, ⁴ J = 3 Hz), 127.4 (d, ³ J = 8 Hz), 115.4 (d, ² J = 21 Hz) , 79.8, 73.9, 73.9, 48.4, 47.1, 43.7, 42.8, 38.7, 28.4, 23.0, 14.0.

[α] _D ²⁸ + 77.9 ° (c 0.4, CHCl ₃ ).

(9) 5- Fluoro -4-(( R ) -1- (3- Fluorophenyl ) Ethoxy )-2-(( R )-2- Methylpiperazine -1-yl) pyrimidine (compound 9)

tert -butyl- ( R ) -4- (5-fluoro-4-(( R ) -1- (3-fluorophenyl) ethoxy) pyrimidin-2-yl) -3-methyl piperazine-1 Carboxylate (95.6 mg, 0.220 mmol) in dichloromethane (2.20 mL) followed by trifluoroacetic acid (0.337 mL, 4.40 mmol) was added and stirred at 0 ° C for 1 hour. The mixture was extracted using ethyl acetate and distilled water, and then added with an aqueous sodium hydrogen carbonate solution to bring the pH to 8 to remove impurities. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography (DCM / MeOH = 10: 1, R _f 0.32) purified to a pure colorless oil, 5-fluoro-4-(( R ) -1- (3-fluorophenyl) ethoxy) -2-(( R ) -2-methylpiperazin-1-yl Pyrimidine (49.3 mg, 67%) was obtained (Formula 14).

[Formula 14]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 2.4 Hz, 1H), 7.32-7.26 (m, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 9.5 Hz, 1H), 6.97-6.93 (m, 1H), 5.99 (q, J = 6.5 Hz, 1H), 4.88 (bs, 1H), 4.47 (d, J = 13.7 Hz, 1H), 3.41-3.14 (m, 4H), 2.84 (bs, 1H), 1.68 (d, J = 6.6 Hz, 3H), 1.12 (d, J = 6.9 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 163.0 (d, ¹ J = 245 Hz), 157.6 (d, ² J = 11 Hz), 145.2 (d, ⁴ J = 2 Hz), 144.8 (d, ³ J = 7 Hz), 143.1 (d, ² J = 20 Hz), 140.6 (d, ¹ J = 246 Hz), 130.3 (d, ³ J = 8 Hz), 121.0 (d, ⁴ J = 3 Hz), 114.7 (d, ² J = 21 Hz), 112.5 (d, ² J = 23 Hz), 74.7, 47.2. 44.4. 43.1. 35.5. 23.0. 13.2

(10) 5- Fluoro -4-(( R ) -1- (4- Fluorophenyl ) Ethoxy )-2-(( R )-2- Methylpiperazine -1-yl) pyrimidine (compound 10)

tert -butyl- ( R ) -4- (5-fluoro-4-(( R ) -1- (4-fluorophenyl) ethoxy) pyrimidin-2-yl) -3-methyl piperazine-1 Carboxylate (161 mg, 0.371 mmol) in dioxane (3.70 mL) and then 4M hydrogen chloride in dioxane (0.926 mL, 3.71 mmol) was added and stirred at 0 ° C for 2 h 30 min. The mixture was extracted with ethyl acetate and distilled water, and the aqueous solution of sodium bicarbonate was added to pH 8 to remove impurities. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography (DCM / MeOH = 10: 1, R _f 0.25) to purify 5-fluoro-4-(( R ) -1- (4-fluorophenyl) ethoxy) -2-(( R ) -2-methylpiperazin-1-yl as a pure colorless oil Pyrimidine (101 mg, 82%) was obtained (Formula 15).

[Formula 15]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 2.8 Hz, 1H), 7.40-7.34 (m, 2H), 7.04-6.99 (m, 2H), 6.08 (q, J = 6.6 Hz , 1H), 4.60-4.55 (m, 1H), 4.18 (d, J = 3.5 Hz, 1H), 3.06-2.86 (m, 4H), 2.72-2.65 (m, 1H), 2.54 (bs, 1H), 1.65 (d, J = 6.6 Hz, 1H), 1.04 (d, J = 6.8 Hz, 1H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.2 (d, ¹ J = 244 Hz), 157.2 (d, ² J = 11 Hz), 156.9 (d, ⁴ J = 2 Hz), 143.3 (d, ² J = 19 Hz), 139.9 (d, ¹ J = 246 Hz), 138.2 (d, ⁴ J = 3 Hz), 127.5 (d, ³ J = 8 Hz), 115.4 (d, ² J = 21 Hz), 73.8, 50.3, 16.6, 45.8, 39.5, 23.0, 13.6.

(11) ( S ) -2-chloro-5-fluoro-4- (1- (3-fluorophenyl) ethoxy) pyrimidine (Compound 11)

NaO ^t Bu (276 mg, 2.87 mmol) was added to toluene (14.3 mL) and ( S ) -1- (3-fluorophenyl) ethanol (201 mg, 1.43 mmol) was added dropwise at 0 ° C. Then 2,4-dichloro-5-fluoro pyrimidine (239 mg, 1.43 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was terminated with an aqueous ammonium chloride solution and extracted with ethyl acetate and distilled water. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f ( S ) -2-chloro-5-fluoro-4- (1- (3-fluorophenyl) ethoxy) pyrimidine, which is a pure colorless oil that has been purified to 0.69 ( n -hexane / EtOAc = 4: 1)). (211 mg, 55%) was obtained (Formula 16).

[Formula 16]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.18 (d, J = 2.2 Hz, 1H), 7.36-7.31 (m, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.18-7.14 (m , 1H), 7.03-6.98 (m, 1H), 6.30 (q, J = 6.5 Hz, 1H), 1.71 (d, J = 6.6 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.9 (d, ¹ J = 245 Hz), 158.6 (d, ² J = 11 Hz), 153.2 (d, ⁴ J = 4 Hz), 146.0 (d, ¹ J = 262 Hz), 144.4 (d, ² J = 20 Hz), 142.9 (d, ³ J = 7 Hz), 130.3 (d, ³ J = 8 Hz), 122.0 (d, ⁴ J = 3 Hz), 115.3 (d, ² J = 21 Hz), 113.3 (d, ² J = 22 Hz), 75.7 (d, ⁴ J = 1 Hz), 22.2.

^{_{[α] D 27 - 191.4 °}} (c 0.9, CHCl 3).

(12) ( S ) -2-chloro-5-fluoro-4- (1- (4-fluorophenyl) ethoxy) pyrimidine (Compound 12)

NaO ^t Bu (274 mg, 2.85 mmol) was added to toluene (14.3 mL) and ( S ) -1- (4-fluorophenyl) ethanol (200 mg, 1.43 mmol) was added dropwise at 0 ° C. Then 2,4-dichloro-5-fluoropyrimidine (239 mg, 1.43 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was terminated with an aqueous ammonium chloride solution and extracted with ethyl acetate and distilled water. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f = 0.71 (n -hexane / EtOAc = 4: 1)) to give pure colorless oil which ethoxy) (S) -2- chloro-5-fluoro-4- (l- (4-fluorophenyl) pyrimidine (250 mg, 65%) was obtained (Formula 17).

[Formula 17]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 2.2 Hz, 1H), 7.47-7.42 (m, 2H), 7.08-7.02 (m, 2H), 6.30 (q, J = 6.6 Hz , 1H), 1.71 (d, J = 6.6 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.6 (d, ¹ J = 245 Hz), 158.7 (d, ² J = 11 Hz), 153.1 (d, ⁴ J = 4 Hz), 146.0 (d, ¹ J = 263 Hz), 144.3 (d, ² J = 20 Hz), 136.1 (d, ⁴ J = 3 Hz), 128.4 (d, ³ J = 8 Hz), 115.7 (d, ² J = 21 Hz), 75.9 , 22.2.

^{_{[α] D 27 - 204.7 °}} (c 0.8, CHCl 3).

(13) tert -Butyl ( R ) -4- (5- Fluoro -4-(( S ) -1- (3- Fluorophenyl ) Ethoxy Pyrimidin-2-yl) -3- methyl  Piperazine-1-carboxylate (Compound 13)

In a sealed tube, ( S ) -2-chloro-5-fluoro-4- (1- (3-fluorophenyl) ethoxy) pyrimidine (150 mg, 0.554 mmol) and ( R )-(+)-1 -Boc-3-methyl piperazine (222 mg, 1.11 mmol) was dissolved in toluene (1.10 mL) and stirred at 150 ° C for 12 hours, then cooled to room temperature. The mixture was extracted with ethyl acetate and washed with aqueous sodium chloride solution. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f = 0.41) purified tert -butyl ( R ) -4- (5-fluoro-4-(( S ) -1- (3-fluorophenyl) ethoxy) pyrimidin-2-yl) as a pure colorless oil 3-Methyl piperazine-1-carboxylate (137 mg, 57%) was obtained (Formula 18).

[Formula 18]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.95 (d, J = 2.9 Hz, 1H), 7.32-7.26 (m, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.11-7.09 (m , 1H) 6.97-6.93 (m, 1H), 6.06 (q, J = 6.6 Hz, 1H), 4.55 (bs, 1H), 4.22-3.84 (m, 3H), 3.07-2.87 (m, 3H), 1.66 ( d, J = 6.6 Hz, 3H), 1.47 (s, 9H), 1.13 (d, J = 6.6 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 163.0 (d, ¹ J = 245 Hz), 157.1 (d, ² J = 11 Hz), 156.7 (d, ⁴ J = 2 Hz), 155.2, 144.9 (d, ³ J = 7 Hz), 143.5 (d, ² J = 19 Hz), 140.0 (d, ¹ J = 247 Hz), 130.0 (d, ³ J = 8 Hz), 121.4 (d, ⁴ J = 3 Hz) , 114.6 (d, ² J = 21 Hz), 112.8 (d, ² J = 22 Hz), 79.8, 73.8, 48.4, 47.1, 43.9, 42.9, 38.7, 28.4, 22.8, 14.0.

^{_{[α] D 27 - 215.3 °}} (c 0.7, CHCl 3).

(14) tert -Butyl- ( R ) -4- (5- Fluoro -4-(( S ) -1- (4- Fluorophenyl ) Ethoxy Pyrimidin-2-yl) -3- methyl  Piperazine-1-carboxylate (Compound 14)

In a sealed tube, ( S ) -2-chloro-5-fluoro-4- (1- (4-fluorophenyl) ethoxy) pyrimidine (151 mg, 0.558 mmol) and ( R )-(+)-1 -Boc-3-methyl piperazine (224 mg, 1.12 mmol) is dissolved in toluene (1.10 mL) and stirred at 150 ° C for 12 hours, then cooled to room temperature. The mixture was extracted with ethyl acetate and washed with aqueous sodium chloride solution. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography ( n -hexane / EtOAc = 8: 1, R _f 0.33) purified tert -butyl- ( R ) -4- (5-fluoro-4-(( S ) -1- (4-fluorophenyl) ethoxy) pyrimidin-2-yl as a pure colorless oil ) -3-methyl piperazine-1-carboxylate (125 mg, 52%) was obtained (Formula 19).

[Formula 19]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, J = 2.8 Hz, 1H), 7.39-7.32 (m, 2H), 7.04-6.95 (m, 2H), 6.09 (d, J = 6.5 Hz , 1H), 4.59 (bs, 1H), 4.24-3.85 (m, 3H), 3.09-2.88 (m, 3H), 1.65 (d, J = 6.6 Hz, 3H) 1.47 (s, 9H), 1.13 (d , J = 6.4 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.3 (d, ¹ J = 245 Hz), 157.2 (d, ² J = 11 Hz), 156.7 (d, ⁴ J = 3 Hz), 155.2, 143.4 (d , ² J = 19 Hz), 140.0 (d, ¹ J = 247 Hz), 137.9 (d, ⁴ J = 3 Hz), 127.7 (d, ³ J = 8 Hz), 115.4 (d, ² J = 22 Hz ), 79.9, 73.8, 48.4, 47.2, 43.7, 42.9, 38.7, 28.4, 22.8, 14.0.

^{_{[α] D 28 - 212.4 °}} (c 0.5, CHCl 3).

(15) 5- Fluoro -4-(( S ) -1- (3- Fluorophenyl ) Ethoxy )-2-(( R )-2- Methylpiperazine -1-yl) pyrimidine (compound 15)

tert -butyl ( R ) -4- (5-fluoro-4-(( S ) -1- (3-fluorophenyl) ethoxy) pyrimidin-2-yl) -3-methyl piperazine-1- Carboxylate (137 mg, 0.315 mmol) was dissolved in dichloromethane (3.20 mL), trifluoro acetic acid (0.483 mL, 6.31 mmol) was added, and the mixture was stirred at 0 ° C for 1 hour. The mixture was extracted with EtOAc and distilled water, and added with aqueous sodium bicarbonate solution to pH 8 to remove impurities. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography (DCM / MeOH = 10: 1, R _f 0.32) purified to a pure colorless oil, 5-fluoro-4-(( S ) -1- (3-fluorophenyl) ethoxy) -2-(( R ) -2-methylpiperazin-1-yl Pyrimidine (74.4 mg, 71%) was obtained (Formula 20).

[Formula 20]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 2.4 Hz, 1H), 7.34-7.26 (m, 1H), 7.15 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 9.6 Hz, 1H), 7.00-6.95 (m, 1H), 6.03 (q, J = 6.5 Hz, 1H), 4.88-4.85 (m, 1H), 4.53 (d, J = 13.6 Hz, 1H), 3.43 (d, J = 12.1 Hz, 1H), 3.34-2.97 (m, 4H), 1.68 (d, J = 6.6 Hz, 3H), 1.36 (d, J = 7.1 Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 163.0 (d, ¹ J = 245 Hz), 157.7 (d, ² J = 11 Hz), 155.5 (d, ⁴ J = 3 Hz), 144.5 (d, ³ J = 7 Hz), 143.1 (d, ² J = 21 Hz), 140.5 (d, ¹ J = 249 Hz), 130.2 (d, ³ J = 8 Hz), 121.2 (d, ⁴ J = 3 Hz), 114.8 (d, ² J = 21 Hz), 112.7 (d, ² J = 22 Hz), 74.6, 47.0. 44.4. 43.2. 35.7. 22.3. 13.5

(16) 5- Fluoro -4-(( S ) -1- (4- Fluorophenyl ) Ethoxy )-2-(( R )-2- Methylpiperazine -1-yl) pyrimidine (compound 16)

tert -butyl- ( R ) -4- (5-fluoro-4-(( S ) -1- (4-fluorophenyl) ethoxy) pyrimidin-2-yl) -3-methyl piperazine-1 -Carboxylate (76.5 mg, 0.176 mmol) was dissolved in dioxane (1.80 mL), 4M hydrogen chloride in dioxane (0.440 mL, 1.76 mmol) was added, and the mixture was stirred at 0 ° C for 2 hours 30 minutes. The mixture was extracted with ethyl acetate and distilled water, and the aqueous solution of sodium bicarbonate was added to pH 8 to remove impurities. The organic layer was dried over anhydrous MgSO _4, and then dried under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography (DCM / MeOH = 10: 1, R _f 0.25) to purify 5-fluoro-4-(( S ) -1- (4-fluorophenyl) ethoxy) -2-(( R ) -2-methylpiperazin-1-yl as a pure colorless oil Pyrimidine (47.8 mg, 81%) was obtained (Formula 21).

[Formula 21]

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.95 (d, J = 2.9 Hz, 1H), 7.40-7.37 (m, 2H), 7.05-7.00 (m, 2H), 6.11 (q, J = 6.6 Hz , 1H), 4.61-4.57 (m, 1H), 4.27-4.23 (m, 1H), 3.09-2.86 (m, 4H), 2.78-2.71 (m, 1H), 2.59 (bs, 1H), 1.66 (d , J = 6.6 Hz, 1H), 1.23 (d, J = 6.8 Hz, 1H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 162.3 (d, ¹ J = 244 Hz), 157.2 (d, ² J = 11 Hz), 156.9 (d, ⁴ J = 2 Hz), 143.4 (d, ² J = 20 Hz), 140.0 (d, ¹ J = 246 Hz), 137.9 (d, ⁴ J = 3 Hz), 127.7 (d, ³ J = 8 Hz), 115.4 (d, ² J = 21 Hz), 73.7 , 50.2, 46.5, 45.8, 39.5, 22.7, 13.6.

Experimental Example: Measurement of binding affinity for serotonin receptor subtypes

As a receptor, a human genetic recombinant 5-HT subtype receptor expressed in CHO cells or HEK293 cells was used. 50 mM including each reference compound 1 nM, 5-HT subtype receptor membrane (15 ug / well), various concentrations of test drug, 10 mM MgCl ₂ , 0.1 mM EDTA in container. Tris-HCl buffer (pH 7.4) and the like were added to make a reaction volume with a final volume of 0.25 ml and incubated at 25 ° C. for 90 minutes. After incubation, the reaction was terminated by using a Brandel harvester, rapidly filtered through Whatman GF / C glass fiber filter pre-soaked with 0.3% polyethyleneimine, and washed with cold 50 mM Tris-HCl buffer. The filter was covered with MeltiLex, sealed in a sample bag, dried in an oven, and counted in MicroBeta, Wallac. Nonspecific binding was measured in the presence of 0.5 uM Mianserin. The K _i value of the test drug was obtained by calculating the isotherm obtained by repeated experiments of two concentrations of 10-11 step drugs in two test tubes by nonlinear regression analysis (GraphPad Prism Program, San Diego, USA).

Effects and selectivity experiments were carried out on compounds 9, 10, 15, and 16 corresponding to pyrimidine derivatives prepared in Examples 1 to 16, and the results are shown in Tables 1 and 2 below. . As a control, compounds disclosed by Biochemical basis for differences in metabolism-dependent genotoxicity by two diazinylpiperazine-based 5-HT2C receptor agonists (Bioorganic & Medicinal Chemistry Letters 19 (2009) 1559-1563, Amit S. Kalgutkar et al.) Was used.

control Compound 9 Compound 15 Compound 10 Compound 16 5-HT1A % inhibition at 10 μM 89.0 78.0 67.7 10.0 67.3 Ki in nM 353.0 98.0 806.0 X 1117.0 5-HT1B % inhibition at 10 μM 55.1 27.7 3.0 6.4 17.9 Ki in nM 1780.0 X X X X 5-HT1E % inhibition at 10 μM 65.6 37.5 29.5 42.7 redo Ki in nM 1160.0 1161.0 X X X 5-HT2A % inhibition at 10 μM 95.6 93.3 82.4 0.9 64.8 Ki in nM 128.0 222.0 475.0 X 1024.0 5-HT2B % inhibition at 10 μM 97.4 100.2 95.2 99.6 95.3 Ki in nM 7.9 2.6 67.0 19.0 128.0 5-HT2C % inhibition at 10 μM 98.2 98.5 97.7 94.2 97.8 Ki in nM 0.7 1.2 14.0 4.0 23.0 5-HT5A % inhibition at 10 μM 37.4 28.1 22.8 26.7 5.2 Ki in nM ND X X X X 5-HT7 % inhibition at 10 μM 94.7 84.4 56.9 87.6 64.8 Ki in nM 84.0 444.0 766.0 236.0 946.0

control Compound 9 Compound 15 Compound 10 Compound 16 5-HT1A 504.3 81.7 57.63 ND 48.6 5-HT1B 2542.9 ND ND ND ND 5-HT1E 1657.1 967.5 ND ND ND 5-HT2A 182.9 185.0 33.9 ND 44.5 5-HT2B 11.3 2.2 4.8 4.8 5.6 5-HT2C 1.0 1.0 1.0 1.0 1.0 5-HT5A ND ND ND ND ND 5-HT7 120.0 370.0 54.7 59.0 41.1

As shown in Table 1 and Table 2, the compound 10 of the present invention was similar in effect to the existing control (control), but was shown to have a high selectivity against other receptors. In addition, the other compounds 9, 15, 16 also showed the same or excellent efficacy, and in terms of selectivity was shown to have a higher selectivity than the control.

As described above in detail specific parts of the present invention, it will be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. will be. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (7)

An optically active 2-amino-4-alkoxy pyrimidine derivative having the structure of Formula 1
[Formula 1]

(R is hydrogen or C1-10 hydrocarbon, n is an integer of 0-10)
The method of claim 1,
The derivative is a 2-amino-4-alkoxy pyrimidine derivative characterized in that it has the structure of formula (2).
[Formula 2]

The method of claim 1,
2-Amino-4-alkoxy pyrimidine derivative, characterized in that the derivative has an effect on central nervous system diseases.
The method of claim 3,
The central nervous system diseases are schizophrenia, depression, substance abuse, Parkinson's disease, or obesity, 2-amino-4-alkoxy pyrimidine derivatives. .
A method for preparing the 2-amino-4-alkoxy pyrimidine derivative according to any one of claims 1 to 4, comprising the following steps:
(a) synthesizing (3-fluorophenyl) ethanol having the structure of Formula 3 into the enantiomer;
[Formula 3]

(b) mixing NaO ^t Bu and toluene and then adding (3-fluorophenyl) ethanol prepared in step (a);

(c) adding 2,4-dichloro-5-fluoro pyrimidine to the mixture prepared in step (b) and terminating the reaction by mixing ammonium chloride after 10 minutes to 2 hours;
(d) extracting with a mixture of ethyl acetate and water, and then separating and purifying to obtain a compound having the structure of Formula 4;
[Formula 4]

(e) ( R )-(+)-1-Boc-3-methyl piperazine and toluene are mixed with the compound having the structure of Formula 4, extracted with ethyl acetate and washed to obtain the structure of Formula 5 Obtaining a compound having;
[Formula 5]

(f) mixing the compound having the structure of Formula 5 with dichloromethane, and then adding and stirring trifluoroacetic acid;
(g) extracting the mixture of step (f) using ethyl acetate and water, and then mixing an aqueous sodium hydrogen carbonate solution; And
(h) drying the mixture of step (g) and then separating to obtain a 2-amino-4-alkoxy pyrimidine derivative.
The method of claim 5
The step (a) is a method for producing 2-amino-4-alkoxy pyrimidine derivatives, characterized in that the synthesis using pure enantiomers using enzymatic kinetic resolution.
The method of claim 5,
Method of producing a 2-amino-4-alkoxy pyrimidine derivative, characterized in that the enantiomer of step (a) has the structures of formulas 3-1 and 3-2.
[Formula 3-1]

[Formula 3-2]