KR20210027218A - 2,5-disubstituted pyrimidines and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to the synthesis and biological evaluation of disubstituted pyrimidine derivatives and pharmaceutically acceptable salts having activity as selective 5-HT2A, 5-HT2B and 5-HT4 agonists. In the present invention, disubstituted pyrimidine derivatives are derived by substituting a fluorophenyl alkoxy group at position 5 and introducing various cyclic amines at position 2, and the 2,5-disubstituted pyrimidine compound of the present invention acts as an agonist selectively binding to 5-HT2A, 5-HT2B and 5-HT4 receptors, and thus it is useful as a drug for treating diseases derived from dysfunction of 5-HT2A, 5-HT2B and 5-HT4 receptors.

Description

{2,5-disubstituted pyrimidines and pharmaceutical composition comprising the same}

The present invention relates to a 2,5-disubstituted pyrimidine derivative and a pharmaceutical composition comprising the same.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that is widely distributed throughout the body in both the central and peripheral nervous systems. 95% of serotonin is found in the digestive tract and the remaining 5% is found in the brain. do. Serotonin receptors are present in the intestinal nerves, intestinal chromophilic cells, digestive tract smooth muscles, and immune tissues, and there are 14 serotonin receptors. According to amino acid sequence and function, the GPCR, 5-HT1 (A, B, D. ,E), 5-HT2(A,B,C), 5-HT3, 5-HT4, 5-HT5A, 5-HT6, 5-HT7, etc.

The interaction of these various receptors with serotonin is linked to various physiological functions, and there has been substantial interest in the development of therapeutic agents targeting specific serotonin receptor subtypes.

The 5-HT2A receptor is a subtype of the 5-HT2 receptor and corresponds to the major excitatory receptor subtype among GPCRs for serotonin. This receptor was first noted for its importance as a target of serotonin hallucinogenic drugs such as LSD and psilocybin mushroom, and since it is known to mediate the action of antipsychotic drugs, 5-HT2A receptor agonists are used in the treatment of psychiatric disorders such as depression. It has been found to have potential usefulness. In addition, 5-HT2B receptor antagonists are also known to be useful in the treatment or prevention of various diseases including epilepsy, migraine, renal ischemia, stroke, myocardial infarction, pneumonia, depression, anxiety neurosis, or obesity.

The 5-HT4 receptor binds to adenylate cyclase in the long muscle plexus and induces acetylcholine release. It is located in the presynaptic nerve ending of the intermediate cholinergic neuron and motor neuron in the intestine. The main afferent nerve cells in the intestine have 5-HT4 receptors, which are involved in peristaltic reflex. The response to 5-HT4 receptor stimulation differs depending on the species. In rats, the esophagus and ileum are relaxed, in guinea pigs the stomach, ileum, and colon contract, and in humans, the cricoid muscle of the colon is relaxed.

As such, the identification of 5-HT4 receptors and the identification of pharmaceutical substances that interact with them have become the core of recent important activities. 5-HT4 receptor agonists not only treat gastrointestinal motility disorders such as irritable bowel syndrome, constipation, indigestion, delayed gastric emptying, gastroesophageal reflux disease, gastric paralysis, and intestinal obstruction, as well as Alzheimer's disease (AD), schizophrenia, and depression. , Attention deficit hyperactivity disorder, Huntington's disease, Parkinson's disease, and a number of other psychiatric disorders.

The 5-HT4 agonists developed to date include benzofuran carboxamide-based prucalopride (EP0445862), aminoguanidine-based tegaserod (US5510353), benzamide-based cisapride (Cisapride, US4962115), and mosapride. (Mosapride, EP0243959), etc., and this compound has been reported to stimulate gastrointestinal motility.

Despite the development of many potential 5-HT agonists, 5-HT agonists are known to stimulate human ether-a-go-go related gene (hERG) channels and cause cardiac arrhythmia and sudden death. Accordingly, it is necessary to develop a new structured best in class compound.

Langlois, M.; Fischmeister, R. J. Med. Chem. 2003, 46, 319-344. Caroline Lanthier, Patrick Dallemagne, Cedric Lecoutey, Sylvie Claeysen, Christophe Rochais EXPERT OPINION ON THERAPEUTIC PATENTS 2020, 30(7), 495-508.

An object of the present invention is to provide a 2,5-disubstituted pyrimidine derivative having a novel structure excellent in stimulating effects against 5-HT2A, 5-HT2B and 5-HT4.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems that are not mentioned will be clearly understood by those skilled in the art from the following description.

In order to solve the above problems, the present invention provides a 2,5-disubstituted pyrimidine derivative or salt thereof represented by the following formula (1).

[Formula 1]

In Formula 1, n is an integer of 0 to 2, and R is a substituted or unsubstituted heterocyclic group.

As an exemplary embodiment of the present invention, the substituted or unsubstituted heterocyclic group in Formula 1 may be at least one selected from the group consisting of piperazine, methylpiperazine, and diaazepain.

In another embodiment of the present invention, the 2,5-disubstituted pyrimidine derivative is 4-(5-(3-fluorophenoxy)pyrimidin-2-yl)piperazine-1-ium hydrochloride (chemical formula 10);

4-(5-(4-fluorophenoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 11);

( R) -4-(5-(3-fluorophenoxy)pyrimidin-2-yl)-3-methylpiperazine-1-ium hydrochloride (Chemical Formula 12);

( R )-4-(5-(4-fluorophenoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Chemical Formula 13);

4-(5-(3-fluorophenoxy)pyrimidin-2-yl)-1,4-diazephen-1-ium hydrochloride (Chemical Formula 14);

4-(5-(4-fluorophenoxy)pyrimidin-2-yl)-1,4-diazephen-1-ium hydrochloride (Chemical Formula 15);

4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 22);

4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 23);

( R )-4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Chemical Formula 24);

( R )-4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-3-methylpiperazine-1-ium hydrochloride (Chemical Formula 25);

4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazephen-1-ium hydrochloride (Chemical Formula 26);

4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride (Chemical Formula 27);

4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 34);

4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 35);

( R )-4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Chemical Formula 36);

( R )-4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Chemical Formula 37);

4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)-1,4-diazephen-1-ium hydrochloride (Chemical Formula 38); And

It may be at least one selected from the group consisting of 4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride (Chemical Formula 39); .

In another embodiment of the present invention, the 2,5-disubstituted pyrimidine derivative or salt thereof represented by Formula 1 is directed to at least one receptor selected from the group consisting of 5-HT2A, 5-HT2B, and 5-HT4. It is characterized by having an activity as an agonist.

In addition, the present invention provides a pharmaceutical composition for preventing or treating central nervous system diseases, comprising as an active ingredient a 2,5-disubstituted pyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a pharmaceutical composition for preventing or treating gastrointestinal diseases, comprising as an active ingredient a 2,5-disubstituted pyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method for preventing or treating central nervous system diseases comprising administering to an individual a 2,5-disubstituted pyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method for preventing or treating gastrointestinal diseases comprising administering to an individual a 2,5-disubstituted pyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a use of a 2,5-disubstituted pyrimidine derivative represented by Formula 1 for the manufacture of a drug for preventing or treating central nervous system diseases.

In addition, the present invention provides a use of a 2,5-disubstituted pyrimidine derivative represented by Formula 1 for the manufacture of a drug for preventing or treating gastrointestinal diseases.

As an embodiment of the present invention, the central nervous system disease is Alzheimer's disease, epilepsy, migraine, renal ischemia, stroke, myocardial infarction, schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), Huntington's disease. , Substance abuse, Parkinson's disease (Parkinson diseases), urinary incontinence (urinary incontinence), and may be one or more selected from the group consisting of obesity (obesity).

In another embodiment of the present invention, the gastrointestinal disease is irritable bowel syndrome (IBS), constipation, indigestion, delayed gastric emptying, gastroesophageal reflux disease (GERD), Gastric paralysis, post-operative ileus, intestinal peusdo-obstruction, and drug-induced delayed transit. .

The 2,5-disubstituted alkoxy pyrimidine derivatives and pharmaceutically acceptable salts thereof represented by the above formula according to the present invention are useful as treatment and prevention of 5-HT2A, 5-HT2B and 5-HT4 receptor-mediated diseases. Can be used.

5-HT2A, 5-HT2B and 5-HT4 receptor-mediated diseases that can be prevented and treated from the compounds according to the present invention include, for example, Alzheimer's disease, epilepsy, migraine, renal ischemia, stroke, myocardial infarction, schizophrenia, Depression, attention deficit hyperactivity disorder, Huntington's disease, substance abuse, Parkinson's disease, urinary incontinence, obesity, irritable bowel syndrome, constipation, indigestion, delayed gastric emptying, gastroesophageal reflux disease, gastric paralysis, postoperative intestinal obstruction, pseudo intestine Obstruction, and drug-induced delayed passage, and the like.

5-HT is 3-(beta-aminoethyl)-5-hydroxyindole, which acts as an important neurotransmitter. As 5-HT plays a role as a neurotransmitter, while studying a compound having an activity as a 5-HT agonist, a fluorophenyl alkoxy group was substituted at the 5th position, and various cyclic amines were introduced at the 2nd position. Thus, the present invention was completed by confirming that the disubstituted pyrimidine derivative has an activity as a 5-HT agonist.

The 2,5-disubstituted pyrimidine compound of the present invention acts as an agonist that selectively binds to 5-HT2A, 5-HT2B, and 5-HT4 receptors, especially among 5-HT receptors, so 5-HT2A, 5-HT2B , And 5-HT4 receptors are useful as drugs for treating diseases derived from dysfunction.

Accordingly, the present invention aims to provide a 2,5-disubstituted pyrimidine derivative or salt thereof represented by the following formula (1).

[Formula 1]

In Formula 1, n is an integer of 0 to 2, and R is a substituted or unsubstituted heterocyclic group.

As an embodiment of the present invention, the substituted or unsubstituted heterocyclic group in Formula 1 may be at least one selected from the group consisting of piperazine, methylpiperazine, and diaazepain.

The compound of Formula 1 includes 4-(5-(3-fluorophenoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 10);

4-(5-(4-fluorophenoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 11);

( R) -4-(5-(3-fluorophenoxy)pyrimidin-2-yl)-3-methylpiperazine-1-ium hydrochloride (Chemical Formula 12);

( R )-4-(5-(4-fluorophenoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Chemical Formula 13);

4-(5-(3-fluorophenoxy)pyrimidin-2-yl)-1,4-diazephen-1-ium hydrochloride (Chemical Formula 14);

4-(5-(4-fluorophenoxy)pyrimidin-2-yl)-1,4-diazephen-1-ium hydrochloride (Chemical Formula 15);

4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 22);

4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 23);

( R )-4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Chemical Formula 24);

( R )-4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-3-methylpiperazine-1-ium hydrochloride (Chemical Formula 25);

4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazephen-1-ium hydrochloride (Chemical Formula 26);

4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride (Chemical Formula 27);

4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 34);

4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Chemical Formula 35);

( R )-4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Chemical Formula 36);

( R )-4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Chemical Formula 37);

4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)-1,4-diazephen-1-ium hydrochloride (Chemical Formula 38); And

It may be at least one selected from the group consisting of 4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride (Chemical Formula 39); .

The 2,5-disubstituted pyrimidine derivative represented by Formula 1 or a salt thereof has an activity as an agonist against at least one receptor selected from the group consisting of 5-HT2A, 5-HT2B, and 5-HT4. The activity as an agonist against the 5-HT2A receptor is particularly excellent in the compounds of Formulas 12, 13, 22, 23, 24, 25, 34, 35, 36 and 37, and the activity as an agonist against the 5-HT2B receptor is particularly It is excellent in the compounds of 22, 23, 24, 25, 34, 35, 36, 37 and 38, and the activity as an agonist against the 5-HT4 receptor is especially the formulas 10, 11, 14, 15, 22, 23, 24, 25 , 27, 34, 35, 36, 37, 38 and 39 are excellent.

In addition, the present invention comprises a 2,5-disubstituted pyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition for the prevention or treatment of central nervous system diseases or gastrointestinal diseases Can provide.

In addition, the present invention provides a method for preventing or treating central nervous system diseases or gastrointestinal diseases comprising administering to an individual a 2,5-disubstituted pyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof. do.

In the present invention, "individual" means a subject in need of treatment or prevention of a disease, and more specifically, human or non-human primates, mice (mouse, dogs, cats, horses and cattle, etc. do.

In addition, the present invention provides a use of a 2,5-disubstituted pyrimidine derivative represented by Formula 1 for the manufacture of a drug for preventing or treating central nervous system diseases.

In addition, the present invention provides a use of a 2,5-disubstituted pyrimidine derivative represented by Formula 1 for the manufacture of a drug for preventing or treating gastrointestinal diseases.

As an embodiment of the present invention, the central nervous system disease is Alzheimer's disease, epilepsy, migraine, renal ischemia, stroke, myocardial infarction, schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), Huntington's disease. , Substance abuse, Parkinson's disease (Parkinson diseases), urinary incontinence (urinary incontinence), and may be one or more selected from the group consisting of obesity (obesity).

In another embodiment of the present invention, the gastrointestinal diseases include irritable bowel syndrome (IBS), constipation, indigestion, delayed gastric emptying, gastroesophageal reflux disease (GERD), Gastric paralysis, post-operative ileus, intestinal peusdo-obstruction, and drug-induced delayed transit. .

The pharmaceutical composition according to the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, but are not limited thereto. In addition, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be additionally included in addition to the above components.

The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenous, subcutaneous, intraperitoneal or topical application) according to a desired method, and the dosage is It depends on the degree, drug form, administration route and time, but may be appropriately selected by those skilled in the art.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type of disease, severity, drug activity, Sensitivity to drugs, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field can be determined. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or administered in combination with another therapeutic agent, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.

Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient in the body, inactivation rate and excretion rate, the type of disease, and the drug to be used in combination. 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since it can be increased or decreased according to the route of administration, the severity of obesity, sex, weight, age, etc., the dosage amount is not limited by any method.

In the present invention, various transformations can be applied and various embodiments may be applied. Hereinafter, specific embodiments will be illustrated in the drawings and described in detail in the detailed description. However, this is not intended to limit the present invention to a specific embodiment, it should be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, when it is determined that a detailed description of a related known technology may obscure the subject matter of the present invention, a detailed description thereof will be omitted.

[Example]

<Experiment method>

All reactions were carried out under an oven-dried glassware under a nitrogen atmosphere. All commercially available reagents were purchased and used without further purification. The solvent and gas were dried according to the standard procedure, and the organic solvent was evaporated under reduced pressure using a rotary evaporator. Following the reaction, analytical thin layer chromatography (TLC) analysis was performed using a glass plate pre-coated with silica gel (0.25 mm). The TLC plate was visualized by exposure to UV light (UV) and then visualized with KMnO ₄ or p-anisaldehyde staining, followed by heating on a hot plate for a while. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) with the indicated solvent. The 1H-NMR spectrum was measured at 400 MHz and the 13C-NMR spectrum was measured at 100 MHz using _{CDCl 3} and CD _{3 OD.} 1H NMR spectra were expressed as chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integral and binding constant (J) in Hertz (Hz) units.

1 H NMR chemical shift was _{reported relative to CDCl 3} (7.26 ppm). 13C NMR was recorded for the center line (77.0 ppm) of CDCl3, high resolution mass spectra (LR-MS) were obtained using positive electron spray ionization, and the mass/charge (m/z) ratio was in atomic mass units. Reported.

Serotonin receptor binding affinity assay

Analysis was performed in standard binding buffer (50mM Tris(hydroxymethyl)-aminomethane-HCl (Tris-HCl), 10mM MgCl ₂ , 1mM ethylenediaminetetraacetate (EDTA)). Radioligands (1A, 1B, 1D, 1E, 2A, 2B, 2C, 3, 4, 5A, 6, 7, Table 1) were diluted 5 times the assay concentration in standard binding buffer, and aliquots of radioligand (50 μL) was dispensed into the wells of a 96-well plate containing 100 μL of standard binding buffer, and three aliquots (50 μL) of test and reference compound dilutions were added. Finally, the crude membrane fraction (50 μL) of cells (HEK293 or CHO) expressing the human recombinant receptor was distributed to each well. A total of 250 μL of the reaction mixture was incubated at room temperature, blocked from light for 1.5 hours, and then harvested by rapid filtration through a Whatman GF/B glass fiber filter pre-soaked with 0.3% polyethyleneimine using a 96-well Brandel harvester.

Four rapid washes were performed with cooled standard binding buffer (500 μL) to reduce non-specific binding. The filter was placed in a 6 mL scintillation tube and dried overnight. The next day, 4 ml of EcoScint scintillation cocktail (National Diagnostics) was added to each tube. Tubes were capped, labeled and counted by liquid scintillation counting. The filter mat was dried, the scintillant was dissolved in the filter, and the radioactivity remaining in the filter was counted on a Microbeta scintillation counter. IC50 values were obtained using the Prism 4.0 program (GraphPad Software, San Diego, CA) and converted to Ki values. Each compound was tested at least three times.

Receptor subtype Radioligand Reference compound 1A ^[3 H] Way100635 8-OH-DPAT 1B [ ³ H]5-CT Ergotamine 1D [ ³ H]5-CT Ergotamine 1E ^[3 H] 5-HT 5-HT 2A ^[3 H] Ketanserin Clozapine 2B ^[3 H] LSD SB206553 2C ^[3 H] Mesulergine Ritanserin 3 ^[3 H] GR65630 Zacopride 4 ^[3 H] GR113808 SDZ205557 5A ^[3 H] LSD Ergotamine 6 ^[3 H] LSD Clozapine 7 ^[3 H] LSD Clozapine

<Derivative preparation and results>

Example 1. Synthesis of 2,5-disubstituted pyrimidine derivatives

Reagents and conditions: (a) N-Boc-protected amines, K ₂ CO ₃ , CH ₃ CN, 80° C., 88-97%; (b) 3- or 4-fluorophenol/benzyl alcohol/phenethyl alcohol, CuI or CuO ₂ , Bromopyrimidine, Cs ₂ CO ₃ , toluene, 110° C., 42-85%; (c) TFA, CH ₂ Cl ₂ , 0° C., 52-67%.

(One) tert -Butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (Compound A)

Aceto 2,5-dibromo pyrimidine (1.2 g, 5.04 mmol), 1-Boc-piperazine (940 mg, 5.04 mmol), and potassium carbonate (1.8 g, 13.1 mmol) in a round bottom flask filled with argon gas. After dissolving in nitrile (12 mL), the mixture was stirred at 80 °C for 12 hours. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 50 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Hexane = 1:8), and the target compound tert -butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate as a pure white solid. (1.5 g, 88%) was obtained.

[Formula A]

¹ H-NMR (400MHz, CDCl3): δ 8.29 (s, J = 2.0 Hz, 2H), 3.76 (t, J = 5.2 Hz, 4H), 3.48 (t, J = 5.2 Hz, 4H), 1.48 (s , 9H).

(2) tert -Butyl (R)-4-(5-bromopyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (Compound B)

In a round bottom flask filled with argon gas, 2,5-dibromo pyrimidine (850 mg, 3.37 mmol), ( R )-1-Boc-methylpiperazine (1.07 g, 5.36 mmol), potassium carbonate (1.28 g, 9.29 mmol) was dissolved in acetonitrile (9.0 mL) and stirred at 80° C. for 12 hours. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 50 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Hexane = 1:8) to obtain the pure white solid tert -butyl (R)-4-(5-bromopyrimidin-2-yl)-3- Methylpiperazine-1-carboxylate (1.1 g, 92%) was obtained.

[Formula B]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.28 (s, J = 2.0 Hz, 1H), 4.81-4.70 (m, 1H), 4.39-4.36 (m, 1H), 4.15-3.90 (m, 2H) , 3.19-3.08 (m, 1H), 3.08-2.90 (m, 2H), 1.47 (s, 9H), 1.16 (d, J = 6.7 Hz, 3H).

(3) tert -Butyl 4-(5-bromopyrimidin-2-yl)-1,4-diazepain-1-carboxylate (Compound 3)

To a round bottom flask filled with argon gas, 2,5-dibromo pyrimidine (1.0 g, 4.2 mmol), 1-Boc-homopiperazine (1.6 mL, 8.4 mmol), and potassium carbonate (1.5 g, 10.9 mmol) were added. After dissolving in acetonitrile (10 mL), the mixture was stirred at 80 °C for 12 hours. After cooling at room temperature, confirm the reaction using TLC, and then add ammonium chloride aqueous solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 50 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Hexane = 1:8), and the target compound tert -butyl 4-(5-bromopyrimidin-2-yl)-1,4-diase as a pure white solid. Paine-1-carboxylate (1.4 g, 97%) was obtained.

[Formula 3]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.28 (s, 2H), 3.86-3.80 (m, 2H), 3.72 (t, J = 6.2 Hz, 2H), 3.54 (t, J = 5.3 Hz, 2H ), 3.37 (t, J = 5.9 Hz, 1H), 3.27 (t, J = 6.1 Hz, 1H), 1.96-1.90 (m, 2H), 1.42 (d, J = 8.5 Hz, 9H).

(4) tert -Butyl 4-(5-(3-fluorophenoxy)pyrimidin-2-yl)piperazine-1-carboxylate (compound 4)

In a microwave vacuum tube filled with argon gas, tert -butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (200 mg, 0.58 mmol), 3-fluorophenol (0.31 mL, 3.48) mmol), cesium carbonate (566 mg, 1.74 mmol), copper(I) oxide (8 mg, 0.058 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (27 mg, 0.116 mmol ) Is dissolved in toluene (1.1 mL) and stirred in a microwave for 6 hours at 130° C., 200 W, and 250 psi. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography separation method (EtOAc/Acetone/Hexane=1:0.5:18), and the target compound tert -butyl 4-(5-(3-fluorophenoxy)pyrimidine-2 as a pure white solid. -Yl) piperazine-1-carboxylate (47 mg, 21%) was obtained.

[Formula 4]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.17 (s, 2H), 7.27-7;21 (m, 1H), 6.77-6.73 (m, 1H), 6.71-6.62 (m, 2H), 3.80 ( t, J = 5.1 Hz, 4H), 3.52 (t, J = 5.0 Hz, 4H), 1.49 (s, 9H).

(5) tert -Butyl 4-(5-(4-fluorophenoxy)pyrimidin-2-yl)piperazine-1-carboxylate (Compound 5)

In a microwave vacuum tube filled with argon gas, tert -butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (200 mg, 0.58 mmol), 4-fluorophenol (0.31 mL, 3.48) mmol), cesium carbonate (566 mg, 1.74 mmol), copper(I) oxide (8 mg, 0.058 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (27 mg, 0.116 mmol ) Is dissolved in toluene (1.1 mL) and stirred in a microwave for 6 hours at 130° C., 200 W, and 250 psi. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Acetone/Hexane=1:0.5:18), and the target compound tert -butyl 4-(5-(4-fluorophenoxy)pyrimidine-2 as a pure white solid. -Yl) piperazine-1-carboxylate (47 mg, 21%) was obtained.

[Formula 5]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.17 (s, 2H), 7.03-6.99 (m, 2H), 6.92-6.89 (m, 2H), 3.80 (t, J = 5.2 Hz, 4H), 3.52 (t, J = 5.2 Hz, 4H), 1.49 (s, 9H).

(6) tert -Butyl ( R )-4-(5-(3-fluorophenoxy)pyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (compound 6)

In a microwave vacuum tube filled with argon gas, tert -butyl ( R )-4-(5-bromopyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.56 mmol), 3- Fluorophenol (0.36 mL, 3.92 mmol), cesium carbonate (547 mg, 1.68 mmol), copper(I) oxide (8 mg, 0.056 mmol), 3,4,7,8-tetramethyl-1,10-phenane After dissolving troline (26 mg, 0.112 mmol) in toluene (1.1 mL), the mixture was stirred at 130° C. for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Acetone/Hexane=1:0.5:18), and the target compound tert -butyl ( R )-4-(5-(3-fluorophenoxy) as a pure white solid. Pyrimidine-2-yl)-3-methylpiperazine-1-carboxylate (37 mg, 17%) was obtained.

[Formula 6]

^OneH-NMR (400MHz, CDCl₃):δ8.18 (s, 2H), 7.27-7.22 (m, 1H), 6.78-6.70 (m, 2H), 6.65-6.63 (m, 1H), 4.90-4.84 (m, 1H), 4.43-4.40 (m, 1H), 4.18-3.93 (m, 2H), 3.24-3.18 (m, 1H), 3.13-2.94 (m, 2H), 1.49 (s, 9H), 1.20 (d,J= 6.8 Hz, 3H).

(7) tert -Butyl (R)-4-(5-(4-fluorophenoxy)pyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (compound 7)

In a microwave vacuum tube filled with argon gas, tert -butyl ( R )-4-(5-bromopyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.56 mmol), 4- Fluorophenol (0.36 mL, 3.92 mmol), cesium carbonate (547 mg, 1.68 mmol), copper(I) oxide (8 mg, 0.056 mmol), 3,4,7,8-tetramethyl-1,10-phenane After dissolving troline (26 mg, 0.112 mmol) in toluene (1.1 mL), the mixture was stirred at 130° C. for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add ammonium chloride aqueous solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Acetone/Hexane=1:0.5:18), and the target compound tert -butyl (R)-4-(5-(4-fluorophenoxy) as a pure white solid. Pyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (37 mg, 27%) was obtained.

[Formula 7]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.17 (s, 2H), 7.02-6.98 (m, 2H), 6.91-6.89 (m, 2H), 4.90-4.83 (m, 1H), 4.43-4.39 (m, 1H), 4.18-3.92 (m, 3H), 3.25-3.18 (m, 1H), 3.15-2.93 (m, 2H), 1.49 (s, 9H), 1.20 (d, J = 6.7 Hz, 3H).

(8) tert -Butyl 4-(5-(3-fluorophenoxy)pyrimidin-2-yl)-1,4-diazepine-1-carboxylate (compound 8)

In a microwave vacuum tube filled with argon gas, tert -butyl 4-(5-bromopyrimidin-2-yl)-1,4-diazepain-1-carboxylate (200 mg, 0.58 mmol), 3-fluoro Phenol (0.31 mL, 3.48 mmol), cesium carbonate (566 mg, 1.74 mmol), copper(I) oxide (8 mg, 0.058 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (27 mg, 0.116 mmol) was dissolved in toluene (1.1 mL) and stirred in a microwave for 6 hours at 130° C., 200 W, and 250 psi. After cooling at room temperature, confirm the reaction using TLC, and then add ammonium chloride aqueous solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography separation method (EtOAc/Acetone/Hexane=1:0.5:18), and the target compound tert -butyl 4-(5-(3-fluorophenoxy)pyrimidine-2 as a pure white solid. -Yl)-1,4-diazepain-1-carboxylate (41 mg, 19%) was obtained.

[Formula 8]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.17 (s, 2H), 7.28-7.22 (m, 1H), 6.78-6.70 (m, 2H), 6.71 (m, 1H), 6.65-6.60 (m, 1H), 3.90-3.88 (m, 2H), 3.80-3.78 (m, 2H), 3.59-3.58 (m, 2H), 3.40-3.39 (m, 1H), 3.33-3.30 (m , 1H), 1.99-1.96 (m, 2H), 1.44 (s, 9H).

(9) tert -Butyl 4-(5-(4-fluorophenoxy)pyrimidin-2-yl)-1,4-diazepine-1-carboxylate (Compound 9)

In a microwave vacuum tube filled with argon gas, tert -butyl 4-(5-bromopyrimidin-2-yl)-1,4-diazepain-1-carboxylate (200 mg, 0.58 mmol), 4-fluoro Phenol (0.31 mL, 3.48 mmol), cesium carbonate (566 mg, 1.74 mmol), copper(I) oxide (8 mg, 0.058 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (27 mg, 0.116 mmol) was dissolved in toluene (1.1 mL) and stirred in a microwave for 6 hours at 130° C., 200 W, and 250 psi. After cooling at room temperature, confirm the reaction using TLC, and then add ammonium chloride aqueous solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Acetone/Hexane=1:0.5:18), and the target compound tert -butyl 4-(5-(4-fluorophenoxy)pyrimidine-2 as a pure white solid. -Yl)-1,4-diazepain-1-carboxylate (68 mg, 31%) was obtained.

[Formula 9]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.14 (s, 2H), 7.01-6.96 (m, 2H), 6.87-6.75 (m, 2H), 3.89-3.84 (m, 2H), 3.76-3.73 ( m, 2H), 3.58-5.55 (m, 2H), 3.39 (t, J = 6.0 Hz, 1H), 3.31 (d, J = 6.0 Hz, 1H), 3.31 (t, J = 6.0 Hz, 1H), 1.98-1.92 (m, 2H), 1.44 (s, 9H).

(10) 4-(5-(3-fluorophenoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Compound 10)

Piperazine carboxylate (57 mg, 0.15 mmol) was dissolved in dichloromethane (1.5 mL) in a vial filled with argon gas, and TFA (0.23 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the title compound (28 mg, 21%) as a pure white solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 10]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.17 (s, 2H), 7.24 (dd, J = 15.4, 7.5 Hz, 1H), 6.75 (td, J = 6.2, 4.9 Hz, 1H), 6.70 (d , J = 8.4 Hz, 1H), 6.64 (d, J = 10.2 Hz, 1H), 3.89 (t, J = 4.5 Hz, 4H), 3.07 (t, J = 4.7 Hz, 4H).

¹³ C-NMR (100 MHz, MeOD): δ 162.4 (d, ¹ J = 259 Hz), 159.7, 152.3, 152.0, 144.5, 132.2 (d, ³ J = 9 Hz), 113.4 (d, ⁴ J = 3 Hz), 110.9 (d, ² J = 21 Hz), 105.4 (d, ² J = 25 Hz), 44.4, 42.5.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₄ H ₁₅ FN ₄ O: 274.30, found: 274.30.

(11) 4-(5-(4-fluorophenoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (compound 11)

Piperazine carboxylate (90 mg, 0.24 mmol) was dissolved in dichloromethane (2.5 mL) in a vial filled with argon gas, and TFA (0.36 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the title compound (40 mg, 60%) as a pure white solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 11]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.15 (s, 2H), 7.02-6.98 (m, 2H), 6.91-6.88 (m, 2H), 3.77 (t, J = 5.2 Hz, 4H), 3.51 (t, J = 5.1 Hz, 4H).

¹³ C-NMR (100 MHz, MeOD): δ 158.9 (d, ¹ J = 241 Hz), 157.9, 153.8, 150.1, 144.4, 118.6 (d, ³ J = 8 Hz), 116.6 (d, ² J = 23 Hz), 43.4, 41.5.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₄ H ₁₅ FN ₄ O: 274.30, found: 274.30.

(12) ( R) -4-(5-(3-Fluorophenoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Compound 12)

To a vial filled with argon gas, methylpiperazine carboxylate (50 mg, 0.13 mmol) was dissolved in dichloromethane (1.3 mL), and TFA (0.20 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the title compound (8 mg, 21%) as a pure white solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 12]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.18 (s, 2H), 7.27-7.21 (m, 1H), 6.77-6.65 (m, 2H), 6.63-6.62 (m, 1H), 4.78-4.75 ( m, 1H), 4.41-4.38 (m, 1H), 3.16-3.08 (m, 2H), 3.04-3.00 (m, 1H), 2.92-2.89 (m, 1H), 2.83-2.76 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H).

¹³ C-NMR (100 MHz, MeOD): δ 159.3, 152.1, 146.9, 144.3, 132.2 (d, ³ J = 9 Hz), 131.8, 113.4, 110.8 (d, ² J = 21 Hz), 105.4 (d, ² J = 25 Hz), 45.8, 44.8, 36.9, 35.9, 13.7.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₅ H ₁₇ FN ₄ O: 288.33, found: 288.33

(13) ( R )-4-(5-(4-fluorophenoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Compound 13)

To a vial filled with argon gas, methylpiperazine carboxylate (60 mg, 0.15 mmol) was dissolved in dichloromethane (1.5 mL), and TFA (0.23 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the title compound (17 mg, 39%) as a pure white solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 13]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.15 (s, 2H), 7.01-6.96 (m, 2H), 6.91-6.87 (m, 2H), 4.79-4.76 (m, 1H), 4.42-4.38 (m, 1H), 3.16-3.09 (m, 2H), 3.05-3.01 (m, 1H), 2.94-2.91 (m, 1H), 2.84-2.77 (m, 1H), 2.77-2.70 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H).

¹³ C-NMR (100 MHz, MeOD): δ 160.1 (d, ¹ J = 239 Hz), 159.0, 155.5, 155.5 (d, ⁴ J = 2 Hz), 145.5, 119.8 (d, ³ J = 8 Hz) , 117.4 (d, ² J = 24 Hz), 45.9, 44.9, 37.2, 30.9, 30.7, 13.5.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₅ H ₁₇ FN ₄ O: 288.33, found: 288.33

(14) 4-(5-(3-fluorophenoxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride (Compound 14)

Diaazepain carboxylate (68 mg, 0.17 mmol) was dissolved in dichloromethane (1.8 mL) in a vial filled with argon gas, and TFA (0.24 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the title compound (27 mg, 40%) as a pure white solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 14]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.17 (s, 2H), 7.26-7.22 (m, 1H), 6.77-6.73 (m, 1H), 6.70-6.67 (m, 1H), 6.65-6.62 (m, 1H), 4.08-4.01 (s, 2H), 3.90 (t, J = 6.3 Hz, 2H), 3.36-3.27 (m, 2H), 3.16-3.15 (m, 2H), 2.16- 2.14 (m, 2H).

¹³ C-NMR (100 MHz, MeOD): δ 165.0 (d, ¹ J = 244 Hz), 159.6, 152.3, 143.9, 132.1 (d, ³ J = 10 Hz), 131.6 (d, ³ J = 8 Hz) , 113.3, 110.7 (d, ² J = 21 Hz), 105.2 (d, ² J = 25 Hz), 46.8, 46.5, 44.7, 26.8.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₅ H ₁₇ FN ₄ O: 288.33, found: 288.33

(15) 4-(5-(4-fluorophenoxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride (Compound 15)

Diaazepain carboxylate (68 mg, 0.17 mmol) was dissolved in dichloromethane (1.8 mL) in a vial filled with argon gas, and TFA (0.24 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the title compound (17 mg, 34%) as a pure white solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 15]

¹ H-NMR (400MHz, CDCl ₃ ) δ 8.14 (s, 2H), 7.00-6.96 (m, 2H), 6.90-6.87 (m, 2H), 4.10-4.01 (m, 2H), 3.98-3.88 (m, 1H), 3.38-3.30 (m, 2H), 3.27-3.20 (m, 2H), 2.20-2.15 (m, 2H).

¹³ C-NMR (100 MHz, MeOD): δ 163.9 (d, ¹ J = 244 Hz), 157.9, 147.9, 147.1, 134.1, 131.0 (d, ³ J = 8 Hz), 116.3 (d, ² J = 21 Hz), 72.4, 47.1, 46.6, 46.5, 44.5, 26.8.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₅ H ₁₇ FN ₄ O: 288.33, found: 288.33

(16) tert -Butyl 4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (compound 16)

In a microwave vacuum tube filled with argon gas, tert -butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (30 mg, 0.58 mmol), 3-fluoro benzyl alcohol (87 μ￥ μL, 0.8 mmol), cesium carbonate (39 mg, 0.12 mmol), copper iodide (2 mg, 0.008 mmol), 1,10-phenanthroline (3 mg, 0.016 mmol) dissolved in toluene (0.16 mL) After 12 hours, the mixture was stirred at 110°C. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Hexane = 1:10), and the target compound tert -butyl 4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl as a pure colorless oil. ) Piperazine-1-carboxylate (26 mg, 79%) was obtained.

[Formula 16]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.11 (s, 2H), 7.37-7.32 (m, 1H), 7.17-7.11 (m, 2H), 7.05-6.99 (m, 1H), 5.01 (s, 2H), 3.71 (t, J = 5.2 Hz, 4H), 3.49 (t, J = 5.2 Hz, 4H), 1.48 (s, 9H).

(17) tert -Butyl 4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (compound 17)

In a microwave vacuum tube filled with argon gas, tert -butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (30 mg, 0.08 mmol), 4-fluoro benzyl alcohol (87 μ￥ μL, 0.8 mmol), cesium carbonate (39 mg, 0.12 mmol), copper iodide (2 mg, 0.008 mmol), 1,10-phenanthroline (3 mg, 0.016 mmol) dissolved in toluene (0.16 mL) After 12 hours, the mixture was stirred at 110°C. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography separation method (EtOAc/Acetone/Hexane = 1:1:15), and the target compound t ert -butyl 4-(5-((4-fluorobenzyl)oxy) pyrid was purified as a pure colorless oil. Midin-2-yl) piperazine-1-carboxylate (13 mg, brsm 76%) was obtained.

[Formula 17]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.10 (s, 1H), 7.37 (dd, J = 8.7, 5.3 Hz, 2H), 7.09-7.05 (m, 2H), 4.98 (s, 2H), 3.71 (t, J = 5.2 Hz, 4H), 3.49 (t, J = 5.2 Hz, 4H), 1.48 (s, 1H).

(18) tert -Butyl ( R )-4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (compound 18)

In a microwave vacuum tube filled with argon gas, tert -butyl ( R )-4-(5-bromopyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.56 mmol), 3- Fluorobenzyl alcohol (0.18 mL, 1.68 mmol), cesium carbonate (273 mg, 0.84 mmol), copper iodide (10 mg, 0.056 mmol), 1,10-phenanthroline (20 mg, 0.112 mmol) toluene After dissolving in (1.1 mL), the mixture is stirred at 130 °C for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add ammonium chloride aqueous solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 50 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography separation method (EtOAc/Acetone/Hexane = 1:1:15), and the target compound tert -butyl ( R )-4-(5-((3-fluorobenzyl) as a pure white solid) Oxy)pyrimidin-2-yl)-3-methylpiperazin-1-carboxylate (96 mg, 43%) was obtained.

[Formula 18]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.11 (s, 2H), 7.37-7.32 (m, 1H), 7.15-7.11 (m, 2H), 7.04-6.99 (m, 1H), 5.01 (s, 2H), 4.81-4.75 (m, 1H), 4.32-4.29 (m, 1H), 4.16-3.87 (m, 2H, broad), 3.17-3.10 (m , 2H), 3.10-2.91 (m, 1H), 1.48 (s, 9H), 1.14 (d, J = 6.7 Hz, 3H).

(19) tert -Butyl ( R )-4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (compound 19)

In a microwave vacuum tube filled with argon gas, tert -butyl ( R )-4-(5-bromopyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.56 mmol), 4- Fluorobenzyl alcohol (0.18 mL, 1.68 mmol), calcium carbonate (273 mg, 0.84 mmol), copper iodide (10 mg, 0.056 mmol), 1,10-phenanthroline (20 mg, 0.112 mmol) toluene After dissolving in (1.1 mL), the mixture is stirred at 130 °C for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 50 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography separation method (EtOAc/Acetone/Hexane = 1:1:15), and the target compound tert -butyl ( R )-4-(5-((4-fluorobenzyl)oxy) as a white solid. )Pyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (93 mg, 41%) was obtained.

[Formula 19]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.10 (s, 2H), 7.37 (dd, J = 8.5, 5.4 Hz, 2H), 7.09-7.05 (m, 2H), 4.97 (s, 2H), 4.80-4.74 (m, 1H), 4.32-4.28 (m, 1H), 4.15-3.89 (m, 3H), 3.17-3.10 (m, 1H), 3.10-2.90 (m, 2H) ), 1.48 (s, 9H), 1.14 (d, J = 6.7 Hz, 3H).

(20) tert -Butyl 4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepine-1-carboxylate (compound 20)

In a microwave vacuum tube filled with argon gas, tert -butyl 4-(5-bromopyrimidin-2-yl)-1,4-diazepine-1-carboxylate (40 mg, 0.11 mmol), 3-fluoro Benzyl alcohol (36 uL, 0.33 mmol), cesium carbonate (52 mg, 0.16 mmol), copper iodide (6 mg, 0.03 mmol), 1,10-phenanthroline (11 mg, 0.06 mmol) toluene (0.3 mL) and stirred at 130° C. for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 50 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Acetone/Hexane = 1:1:15), and the compound tert -butyl 4-(5-((3-fluorobenzyl)oxy)pyrimidine- as a sticky white oil. 2-yl)-1,4-diazepain-1-carboxylate (35 mg, 79%) was obtained.

[Formula 20]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.09 (s, 2H), 7.37-7.32 (m, 1H), 7.17-7.11 (m, 2H), 7.04-6.99 (m, 1H), 4.99 (s, 2H), 3.84-3.78 (m, 2H), 3.71-3.68 (m, 2H), 3.53 (s, 2H), 3.35 (t, J = 5.8 Hz, 1H), 3.25 (t, J = 5.9 Hz, 1H), 1.96-1.90 (m, 2H), 1.42 (d, J = 11.9 Hz, 9H).

(21) tert -Butyl 4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepine-1-carboxylate (compound 21)

Tert -butyl 4-(5-bromopyrimidin-2-yl)-1,4-diazepain-1-carboxylate (140 mg, 0.39 mmol), 4-fluoro in a microwave vacuum tube filled with argon gas Benzyl alcohol (127 μL, 1.17 mmol), cesium carbonate (189 mg, 0.58 mmol), copper iodide (22 mg, 0.12 mmol), 1,10-phenanthroline (42 mg, 0.24 mmol) toluene (0.78 mL) and stirred at 130° C. for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 50 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography separation method (EtOAc/Acetone/Hexane = 1:1:18), and the yellow oil compound tert -butyl 4-(5-((4-fluorobenzyl)oxy)pyrimidine-2 -Yl)-1,4-diazepain-1-carboxylate (64 mg, mixture) was obtained.

[Formula 21]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.08 (s, 2H), 7.38-7.31 (m, 10H), 7.09-7.02 (m, 10H), 4.99 (s, 2H), 4.66 (s, 8H), 3.84-3.78 (m, 2H), 3.71-3.68 (m, 2H), 3.58-3.50 (m, 2H), 3.34 (t, J = 5.8 Hz, 1H), 3.25 (t, J = 6.1 Hz, 1H), 1.96-1.90 (m, 2H), 1.43 (d, J = 11.5 Hz, 9H).

(22) 4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Compound 22)

Piperazine carboxylate (35 mg, 0.09 mmol) was dissolved in dioxane (2.3 mL) in a vial filled with argon gas, and 4 M HCl/dioxane (2.0 mL) was slowly added. After stirring at room temperature for 3 hours, after confirming the reaction using TLC, extraction was performed with distilled water (3 x 20 mL), and an aqueous sodium hydrogen carbonate solution was added to the remaining separated organic layer until the pH of the mixture became 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain a pure white solid compound (15 mg, 58%). The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 22]

¹ H-NMR (400MHz, MeOD): δ 8.23 (s, 1H), δ 7.42-7.37 (m, 1H), δ 7.25-7.17 (m, 2H), δ 7.06 (td, J = 8.5, 2.4 Hz, 1H), δ 7.07-7.02 (m, 1H), δ 5.12 (s, 2H), δ 3.95 (t, J = 5.3 Hz, 4H), δ 3.23 (t, J = 5.3 Hz, 4H).

¹³ C-NMR (100 MHz, MeOD): δ 164.3 (d, ¹ J = 243 Hz), 158.2, 147.7, 147.4, 140.8 (d, ³ J = 7 Hz), 131.5 (d, ³ J = 8 Hz), 124.4 (d, ⁴ J = 3 Hz), 115.8 (d, ² J = 21 Hz), 115.3 (d, ² J = 22 Hz), 71.9, 44.3, 42.6.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₅ H ₁₇ FN ₄ O: 288.33, found: 288.33

(23) 4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Compound 23)

Piperazine carboxylate (280 mg, 0.635 mmol) was dissolved in dichloromethane (1.1 mL) in a vial filled with argon gas, and TFA (7.3 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 50 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain a pure white solid compound (122 mg, two-step yield 67%). The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 23]

¹ H-NMR (400MHz, MeOD): δ 8.22 (s, 2H), 7.47-7.43 (m, 2H), 7.13-7.08 (m, 2H), 5.08 (s, J = 2.5 Hz, 2H), 3.95 ( t, J = 5.3 Hz, 4H), 3.24 (t, J = 5.2 Hz, 4H).

¹³ C-NMR (100 MHz, MeOD): δ 164.0 (d, ¹ J = 243 Hz), 158.4, 147.4, 134.0 (d, ⁴ J = 3 Hz), 132.3, 131.0 (d, ³ J = 8 Hz), 116.3 (d, ² J = 22 Hz), 72.1, 44.7, 43.3.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₅ H ₁₇ FN ₄ O: 288.33, found: 288.33

(24)( R )-4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Compound 24)

To a vial filled with argon gas, methylpiperazine carboxylate (55 mg, 0.136 mmol) was dissolved in dichloromethane (1.3 mL), and TFA (0.2 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain a pure yellow solid compound (29 mg, 70%). The compound was obtained in the form of a salt after treatment with 4 M HCl/diethyl ether.

[Formula 24]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.12 (s, 2H), 7.37-7.33 (m, 1H), 7.17-7.11 (m, 2H), 7.03 (td, J = 8.4, 2.3 Hz, 1H) , 5.01 (s, 1H), 4.85-4.82 (m, 1H), 4.45-4.40 (m, 1H), 3.23-3.17 (m, 2H), 3.10-3.01 (m, 2H), 2.89-2.82 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H).

¹³ C-NMR (100 MHz, MeOD): δ 165.6 (d, ¹ J = 244 Hz), 157.8, 147.4, 140.8, 131.4 (d, ³ J = 9 Hz), 124.3, 115.8 (d, ² J = 20 Hz), 115.3 (d, ² J = 22 Hz), 71.9, 45.8, 44.8, 37.2, 13.4 .

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₆ H ₁₉ FN ₄ O: 302.35, found 302.35

(25) ( R )-4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Compound 25)

To a vial filled with argon gas, methylpiperazine carboxylate (50 mg, 0.12 mmol) was dissolved in dichloromethane (1.2 mL), and TFA (0.2 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain a pure yellow solid compound (27 mg, 73%). The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 25]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.11 (s, 2H), 7.39-7.35 (m, 2H), 7.09-7.05 (m, 2H), 4.98 (s, 2H), 4.94-4.89 (m, 1H), 4.64-4.61 (m, 1H), 3.48-3.39 (m, 2H), 3.28-3.25 (m, 1H), 3.20-3.12 (m, 1H), 3.01-2.94 (m, 1H), 1.42 ( d, J = 7.0 Hz, 3H).

¹³ C-NMR (100 MHz, MeOD): δ 162.8 (d, ¹ J = 245 Hz), 156.4, 146.4, 146.1, 131.9, 129.7 (d, ³ J = 8 Hz), 115.8 (d, ² J = 21 Hz), 71.5, 47.2, 44.3, 43.3, 35.7, 14.0.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₆ H ₁₉ FN ₄ O _: 302.35, found: 302.35

(26) 4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride (compound 26)

Azepane carboxylate (185 mg, 0.56 mmol) was dissolved in dichloromethane (5.6 mL) in a vial filled with argon gas, and TFA (0.86 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 30 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain a pure yellow solid compound (90 mg, two-step yield: 53%). The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 26]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.10 (s, 2H), 7.38-7.32 (m, 1H), 7.17-7.11 (m, 2H), 7.05-7.01 (m, 1H), 5.01 (s, 2H), 3.92-3.90 (m, 2H), 3.81-3.77 (m, 2H), 3.76-3.71 (m, 2H), 3.58 (t, J = 6.0 Hz, 1H), 3.52 (t, J = 6.0 Hz , 1H), 2.07-1.97 (m, 2H).

¹³ C-NMR (100 MHz, MeOD): δ 164.4 (d, ¹ J = 243 Hz), 157.9, 147.8, 147.1, 140.9 (d, ³ J = 7 Hz), 131.4 (d, ³ J = 8 Hz) , 124.3 (d, ⁴ J = 3 Hz), 115.8 (d, ² J = 21 Hz), 115.3 (d, ² J = 22 Hz), 72.1, 72.1, 47.0, 46.6, 44.6, 26.9.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₆ H ₁₉ FN ₄ O _: 302.35, found: 302.35

(27) 4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride (Compound 27)

Azepane carboxylate (93 mg, 0.56 mmol) was dissolved in dichloromethane (5.6 mL) in a vial filled with argon gas, and TFA (0.86 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 30 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain a pure yellow solid compound 8f (12 mg, two-step yield: 7%). The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 27]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.11 (s, 2H), 7.37 (dd, J = 8.4, 5.4 Hz, 2H), 7.08 (t, J = 8.6 Hz, 2H), 4.97 (s, 2H ), 4.07-4.03 (s, 2H), 3.89-3.86 (m, 2H), 3.35-3.29 (m, 2H), 3.20-3.17 (m, 2H), 2.23-2.22 (m, 2H).

¹³ C-NMR (100 MHz, MeOD): δ 165.4 (d, ¹ J = 243 Hz), 155.0, 147.0, 146.8, 133.5, 131.2 (d, ³ J = 8 Hz), 116.4 (d, ² J = 21 Hz), 72.5, 47.2, 46.9, 46.6, 27.0

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₆ H ₁₉ FN ₄ O: 302.35, found: 302.35

(28) tert -Butyl 4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)piperazine-1-carboxylate (compound 28)

Tert -butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (150 mg, 0.437 mmol), 2-(3-fluorophenylethyl) in a microwave vacuum tube filled with argon gas Alcohol (170 μL, 4.37 mmol), cesium carbonate (211 mg, 0.65 mmol), copper iodide (25 mg, 0.13 mmol), 1,10-phenanthroline (61 mg, 0.26 mmol) in toluene (0.87 mL) ) And stirred at 110 °C for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 40 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Acetone/Hexane = 1:1:15), and the white solid compound tert -butyl 4-(5-(3-fluorophenethoxy)pyrimidine-2- Il) piperazine-1-carboxylate (75 mg, 46%) was obtained.

[Formula 28]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.05 (s, 1H), 7.24-7.20 (m, 2H), 7.02-6.98 (m, 2H), 4.12 (t, J = 6.8 Hz, 2H), 3.69 (t, J = 5.2 Hz, 2H), 3.48 (t, J = 5.2 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H), 1.48 (s, 1H).

(29) tert -Butyl 4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)piperazine-1-carboxylate (compound 29)

Tert -butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (200 mg, 0.58 mmol), 2-(4-fluorophenylethyl) in a microwave vacuum tube filled with argon gas Alcohol (291 μL, 2.33 mmol), cesium carbonate (283 mg, 0.87 mmol), copper iodide (32 mg, 0.17 mmol), 1,10-phenanthroline (63 mg, 0.34 mmol) toluene (1.2 mL ) And stirred at 130° C. for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add ammonium chloride aqueous solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Acetone/Hexane = 1:1:15), and the target compound tert -butyl 4-(5-(4-fluorophenethoxy)pyrimidine- as a yellow sticky solid- 2-yl) piperazine-1-carboxylate (125 mg, 54%) was obtained.

[Formula 29]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.05 (s, 1H), 7.24-7.20 (m, 2H), 7.02-6.98 (m, 2H), 4.12 (t, J = 6.8 Hz, 2H), 3.70 (t, J = 5.2 Hz, 2H), 3.48 (t, J = 5.2 Hz , 2H), 3.03 (t, J = 6.8 Hz, 2H), 1.48 (s, 1H).

(30) tert -Booty ( R )-4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (compound 30)

In a microwave vacuum tube filled with argon gas, tert -butyl ( R )-4-(5-bromopyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (150 mg, 0.42 mmol), 2- (3-Fluorophenylethyl) alcohol (0.52 mL, 4.20 mmol), cesium carbonate (205 mg, 0.63 mmol), copper iodide (24 mg, 0.126 mmol), 3,4,7,8-tetramethyl- 1,10-phenanthroline (79 mg, 0.252 mmol) was dissolved in toluene (0.5 mL) and stirred at 130° C. for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add aqueous ammonium chloride solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Acetone/Hexane = 1:1:20) and the target compound tert -buty ( R )-4-(5-(3-fluorophenethoxy) as a yellow oil. Pyrimidine-2-yl)-3-methylpiperazine-1-carboxylate (42 mg, 24%) was obtained.

[Formula 30]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.06 (s, 2H), 7.30-7.26 (m, 1H), 7.04-7.02 (m, 1H), 6.98-6.91 (m, 2H), 4.98 (s, 2H), 4.80-4.70 (m, 1H), 4.31-4.28 (m, 1H), 4.14 (t, J = 6.7 Hz, 2H), 3.97-3.90 (m, 2H), 3.17-3.10 (m, 2H), 3.06 (t, J = 6.7 Hz, 2H), 3.00-2.80 (m. 2H), 1.48 (s, 9H), 1.14 (d, J = 6.7 Hz, 3H).

(31) tert -Butyl ( R )-4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (compound 31)

In a microwave vacuum tube filled with argon gas, tert -butyl ( R )-4-(5-bromopyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.56 mmol), 2- (4-fluorophenylethyl) alcohol (0.28 mL, 2.24 mmol), cesium carbonate (273 mg, 0.84 mmol), copper iodide (32 mg, 0.17 mmol), 3,4,7,8-tetramethyl- 1,10-phenanthroline (79 mg, 0.34 mmol) was dissolved in toluene (1.1 mL) and stirred at 130 °C for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add ammonium chloride aqueous solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Acetone/Hexane = 1:1:20), and the target compound tert -butyl ( R )-4-(5-(4-fluorophenethoxy) as a yellow oil Pyrimidine-2-yl)-3-methylpiperazine-1-carboxylate (90 mg, 39%) was obtained.

[Chemical Formula 31]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.05 (s, 2H), 7.23-7.20 (m, 2H), 7.02-6.98 (m, 2H), 4.80-4.70 (m, 1H), 4.30-4.27 (m, 1H), 4.12 (t, J = 6.9 Hz, 2H), 3.98-3.87 (m, 2H), 3.17-3.09 (m, 1H), 3.03 (t, J = 6.8 Hz, 2H), 3.01-2.89 (m, 2H), 1.48 (s, 9H), 1.14 (d, J = 6.7 Hz, 3H).

(32) tert -Butyl 4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)-1,4-diazepine-1-carboxylate (compound 32)

Tert -butyl 4-(5-bromopyrimidin-2-yl)-1,4-diaazepain-1-carboxylate (200 mg, 0.56 mmol), 2-(3) in a microwave vacuum tube filled with argon gas. -Fluorophenylethyl) alcohol (0.42 mL, 3.36 mmol), cesium carbonate (273 mg, 0.84 mmol), copper iodide (32 mg, 0.17 mmol), 3,4,7,8-tetramethyl-1, After dissolving 10-phenanthroline (79 mg, 0.34 mmol) in toluene (1.1 mL), the mixture was stirred at 130° C. for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add ammonium chloride aqueous solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (EtOAc/Acetone/Hexane = 1:0.5:18), and the colorless oil compound tert -butyl 4-(5-(3-fluorophenethoxy)pyrimidine-2- Day)-1,4-diazepain-1-carboxylate (273 mg, mixture) was obtained.

[Formula 32]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.04 (s, 2H), 7.29-7.24 (m, 5H), 7.01-6.99 (m, 10H), 6.95-6.90 (m, 20H), 4.13 (t, J = 6.7 Hz, 2H), 3.87 (t, J = 6.1 Hz, 20H), 3.78-3.69 (m, 2H), 3.54-3.52 (m, 2H), 3.34 (t, J = 5.8 Hz, 1H), 3.24 (t, J = 6.0 Hz, 1H), 3.06-3.03 (t, J = 6.7 Hz, 2H), 2.87 (t, J = 6.5 Hz, 20H), 1.95-1.92 (m, 2H), 1.43 (d, J = 11.8 Hz, 9H).

(33) tert -Butyl 4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)-1,4-diazepine-1-carboxylate (Compound 33)

Tert -butyl 4-(5-bromopyrimidin-2-yl)-1,4-diazepine-1-carboxylate (200 mg, 0.56 mmol), 2-(4) in a microwave vacuum tube filled with argon gas. -Fluorophenylethyl) alcohol (0.42 mL, 3.36 mmol), cesium carbonate (273 mg, 0.84 mmol), copper iodide (32 mg, 0.17 mmol), 3,4,7,8-tetramethyl-1, After dissolving 10-phenanthroline (79 mg, 0.34 mmol) in toluene (1.1 mL), the mixture was stirred at 130° C. for 20 hours. After cooling at room temperature, confirm the reaction using TLC, and then add ammonium chloride aqueous solution (10 mL) to terminate the reaction. Extracted with EtOAc (3 x 60 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography separation method (EtOAc/Acetone/Hexane = 1:0.5:18), and the yellow oil compound tert -butyl 4-(5-(4-fluorophenethoxy)pyrimidine-2- Day)-1,4-diazepain-1-carboxylate (264 mg, mixture) was obtained.

[Formula 33]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.01 (s, 2H), 7.17 (dd, J = 8.3, 5.6 Hz, 20H), 6.98 (dd, J = 11.9, 5.4 Hz, 20H), 4.09 (t , J = 6.8 Hz, 2H), 3.79 (t, J = 3.3 Hz, 20H), 3.69 (t, J = 5.4 Hz, 2H), 3.52 (t, J = 5.4 Hz, 2H), 3.32-3.23 (m , 2H), 3.01 (t, J = 6.7 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 1.94-1.89 (m, 2H), 1.41 (d, J = 10.7 Hz, 9H).

(34) 4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Compound 34)

Piperazine carboxylate (43 mg, 0.166 mmol) was dissolved in dichloromethane (1.7 mL) in a vial filled with argon gas, and TFA (0.25 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the target compound (23 mg, two-step yield: 46%) as a pure white solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 34]

¹ H-NMR (400MHz, MeOD): δ 8.17 (s, 2H), 7.34-7.29 (m, 1H), 7.13 (d, J = 8 Hz, 1H), 7.07 (d, J = 10.1 Hz, 1H) , 6.96 (td, J = 8.7, 2.3 Hz, 1H), 4.25 (t, J = 6.5 Hz, 2H), 3.97 (t, J = 5.2 Hz, 4H), 3.27 (t, J = 5.2 Hz, 4H) , 3.09 (t, J = 6.5 Hz, 2H).

¹³ C-NMR (100 MHz, MeOD) δ 164.3 (d, ¹ J = 242 Hz), 158.1, 148.2, 146.8, 142.5 (d, ³ J = 7 Hz), 131.1 (d, ³ J = 8 Hz), 125.9 (d, ⁴ J = 3 Hz), 116.7 (d, ² J = 21 Hz), 114.3 (d, ² J = 21 Hz), 71.28, 44.3, 42.7, 36.4, 36.4.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₆ H ₁₉ FN ₄ O: 302.35, found: 302.35

(35) 4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride (Compound 35)

Piperazine carboxylate (150 mg, 0.482 mmol) was dissolved in dichloromethane (3.7 mL) in a vial filled with argon gas, and TFA (0.57 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 40 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the target compound (78 mg, two-step yield: 53%) as a pure white solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 35]

¹ H-NMR (400MHz, MeOD): δ 8.16 (s, 2H), 7.32-7.28 (m, 2H), 7.04-6.99 (m, 2H), 4.21 (t, J = 6.6 Hz, 2H), 3.95 ( t, J = 5.1 Hz, 4H), 3.27 (t, J = 5.1 Hz, 4H), 3.05 (t, J = 6.6 Hz, 2H).

¹³ C-NMR (100 MHz, MeOD): δ 163.1 (d, ¹ J = 241 Hz), 158.6, 147.7, 146.8, 135.51, 131.7 (d, ³ J = 8 Hz), 116.0 (d, ² J = 21 Hz), 71.7, 45.3, 44.5, 35.9.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₆ H ₁₉ FN ₄ 302.35, found 302.35

(36)( R )-4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Compound 36)

To a vial filled with argon gas, methylpiperazine carboxylate (111 mg, 0.42 mmol) was dissolved in dichloromethane (4.2 mL), and TFA (8.4 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 40 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the target compound (32 mg, two-step yield: 37%) as a pure yellow oil. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Chemical Formula 36]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.06 (s, 2H), 7.28 (dd, J = 13.9, 7.9 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.98-6.91 (m, 2H), 4.86 (s, 2H), 4.45 (d, J = 12.4 Hz, 1H), 4.15 (t, J = 6.7 Hz, 2H), 3.28-3.14 (m, 2H), 3.11-3.08 (m, 1H), 3.06 (t, J = 6.7 Hz, 2H), 2.87 (td, J = 12.6, 4.1 Hz, 2H), 1.26 (d, J = 6.9 Hz, 2H).

¹³ C-NMR (100 MHz, MeOD): δ 163.10 (d, ¹ J = 245 Hz), 157.6, 147.9, 146.1, 142.5 (d, ³ J = 7 Hz), 131.1 (d, ³ J = 8 Hz), 125.9 (d, ⁴ J = 3 Hz), 116.7 (d, ² J = 21 Hz), 114.2 (d, ² J = 21 Hz), 71.3, 45.6, 44.6, 36.7, 36.4, 30.9, 13.3.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₇ H ₂₁ FN ₄ O: 316.38, found: 316.38

(37)( R )-4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride (Compound 37)

To a vial filled with argon gas, methylpiperazine carboxylate (60 mg, 0.144 mmol) was dissolved in dichloromethane (1.4 mL), and TFA (0.22 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 20 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the title compound 10d (39 mg, 85%) as a pure yellow solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Chemical Formula 37]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.06 (s, 2H), 7.22 (dd, J = 8.4, 5.5 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H), 4.87-4.85 (m, 1H), 4.46-4.42 (m, 1H), 4.12 (t, J = 6.8 Hz, 2H), 3.27-3.16 (m, 2H), 3.09-3.05 (m, 2H), 3.03 (t, J = 6.7 Hz, 2H), 2.90-2.84 (m, 1H), 1.37 (d, J = 7.0 Hz, 3H).

¹³ C-NMR (100 MHz, MeOD): δ 163.08 (d, ¹ J = 241 Hz), 157.7, 147.8, 146.9, 135.5 (d, ⁴ J = 3 Hz), 131.7 (d, ³ J = 8 Hz), 116.0 (d, ² J = 21 Hz), 71.7, 45.8, 44.8, 37.2, 35.9, 30.9 , 30.7, 13.3.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₇ H ₂₁ FN ₄ 316.38, found 316.38

(38) 4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride (Compound 38)

Azepane carboxylate (273 mg, 0.56 mmol) was dissolved in dichloromethane (5.6 mL) in a vial filled with argon gas, and TFA (0.86 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 50 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the target compound (11 mg, two-step yield: 6.5%) as a pure white solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Formula 38]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.04 (s, 2H), 7.30-7.28 (m, 2H), 7.04-7.03 (m, 1H), 6.99-6.94 (m, 2H), 4.15 (t, J = 6.6 Hz, 2H), 3.91-3.89 (m, 2H), 3.79-3.77 (m, 2H), 3.75-3.72 (m, 2H), 3.57-3.55 (m, 1H), 3,50-3.49 ( m, 1H), 3.06 (t, J = 6.5 Hz, 2H), 2.05-1.98 (m, 2H).

¹³ C-NMR (100 MHz, MeOD): δ 147.4, 147.3, 147.2, 131.1, 131.0, 125.9, 125.9, 116.8, 116.6, 114.2, 114.0, 71.59, 47.7, 46.66, 46.5, 36.5, 25.9.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₇ H ₂₁ FN ₄ O: 316.38, found: 316.38

(39) 4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride (Compound 39)

Azepane carboxylate (250 mg, 0.56 mmol) was dissolved in dichloromethane (5.6 mL) in a vial filled with argon gas, and TFA (0.86 mL) was slowly added at 0 °C. After the mixture was stirred for 3 hours, after confirming the reaction using TLC, an aqueous sodium hydrogen carbonate solution was added until the pH of the mixture reached 8. Extracted with EtOAc (3 x 50 mL) and washed with water and brine. The organic layer was dried with anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (MeOH/DCM = 1:15) to obtain the target compound (6 mg, two-step yield: 3.5%) as a pure white solid. The compound was obtained in the form of salt after treatment with 4 M HCl/diethyl ether.

[Chemical Formula 39]

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.04 (s, 2H), 7.22 (dd, J = 8.4, 5.5 Hz, 2H), 7.01 (t, J = 8.6 Hz, 2H), 4.12 (t, J = 6.8 Hz, 2H), 3.92-3.89 (m, 2H), 3.81-3.77 (m, 2H), 3.75-3.71 (m, 2H), 3.57 (t, J = 6.0 Hz, 1H), 3.51 (t, J = 6.0 Hz, 1H), 3.03 (t, J = 6.7 Hz, 2H), 2.07-1.96 (m , 2H).

¹³ C-NMR (100 MHz, MeOD): δ 156.4, 146.2, 145.8, 134.2, 130.3 (d, ³ J = 8 Hz), 114.6 (d, ² J = 21 Hz), 70.5, 60.1, 45.6, 45.2, 43.2, 34.6, 29.5, 25.5.

LRMS-EI ( m/z ): [M-HCl] ⁺ calcd for C ₁₇ H ₂₁ FN ₄ O: 316.38, found: 316.38

Example 2. Measurement of binding affinity to 5-HT receptor subtypes

The binding affinity of the 2,5-disubstituted pyrimidine derivative synthesized in Example 1 to the 5-HT receptor subtype was measured. The results are shown in Table 2 below.

1A 1B 1D 1E 2A 2B 2C 3 4 5A 6 7 compound
number %inhibition at 10 uM %inhibition at 10 uM %inhibition at 10 uM %inhibition at 10 uM %inhibition at 10 uM %inhibition at 10 uM %inhibition at 10 uM %inhibition at 10 uM %inhibition at 10 uM %inhibition at 10 uM %inhibition at 10 uM %inhibition at 10 uM 10 -2.35 32.14 6.33 4.23 47.88 7.18 8.61 59.36 70.6 -27.21 10.91 -11.68 11 23.17 29.71 -2.62 10.23 49.59 25.26 19.19 53.07 55.17 -2.87 12.45 -2.91 12 -3.03 27.04 -19.1 12.34 68.78 36.54 10.43 32.32 48.52 -8.94 52.43 10.11 13 16.86 26.73 11.76 23.64 85.71 46.06 13.62 56.7 32.89 6.77 21.58 21.31 14 2.92 22.7 -7.61 -2.54 32.05 20.21 21.01 67.97 54.74 6.02 0.38 -13.01 15 16.13 20.76 17.59 -0.62 34.8 27.83 20.07 33.39 55.23 16.41 11.1 54 22 6.21 30.56 31.36 11.72 80.45 82.98 19.94 51.34 67.44 13.25 58.56 23.74 23 6.58 35.42 20.1 12.76 62.46 67.74 22.76 44.17 75.91 -0.79 31.53 17.92 24 23.23 41.72 -9.04 40.34 92.52 85.15 31.84 75.43 62.18 4.61 87.86 10.68 25 14.51 41.13 46.99 43.36 83.09 65.27 10.8 48.83 69.28 22.48 56.51 -1.33 26 -12.21 17.37 2.91 12.99 12.27 28.09 7.79 17.56 39.12 6.27 12.11 9.39 27 -7.52 15.09 22.63 -2.79 15.42 23.51 20.76 24.22 52.9 6.03 6.99 30.41 34 2.87 27.31 17.77 18.74 72.96 52.19 26.58 45.46 95.53 22.89 24.67 6.86 35 13.18 28.07 27.01 24.31 51.26 58.01 12.93 54.74 97.47 16.99 32.53 1.57 36 7.25 27.23 24.68 26.87 80.12 61.97 68.17 54.29 89.99 6.65 26.8 0.81 37 11.76 22.95 24.96 24.95 69.71 69.8 66.16 44.5 90.72 1.12 28.76 30.55 38 2.69 32.64 8.51 4.94 21.66 69.08 34.25 36.1 85.19 -4.26 17.53 11.25 39 3.92 41.75 8.74 1.6 21.17 29.69 28.69 32.93 85.21 -2.61 19.3 3.1

As described above, specific parts of the present invention have been described in detail, and for those of ordinary skill in the art, it is obvious that this specific technique is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Therefore, it will be said that the practical scope of the present invention is defined by the appended claims and their equivalents.

Claims (8)

A 2,5-disubstituted pyrimidine derivative represented by the following formula (1) or a salt thereof:
[Formula 1]

In Formula 1, n is an integer of 0 to 2, and R is a substituted or unsubstituted heterocyclic group.
The method of claim 1,
The substituted or unsubstituted heterocyclic group in Formula 1 is characterized in that at least one selected from the group consisting of piperazine, methylpiperazine, and diaazepain, a pyrimidine derivative or a salt thereof.
The method of claim 1,
The 2,5-disubstituted pyrimidine derivatives include 4-(5-(3-fluorophenoxy)pyrimidin-2-yl)piperazine-1-ium hydrochloride;
4-(5-(4-fluorophenoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride;
( R) -4-(5-(3-fluorophenoxy)pyrimidin-2-yl)-3-methylpiperazine-1-ium hydrochloride;
( R )-4-(5-(4-fluorophenoxy)pyrimidin-2-yl)-3-methylpiperazine-1-ium hydrochloride;
4-(5-(3-fluorophenoxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride;
4-(5-(4-fluorophenoxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride;
4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride;
4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride;
( R )-4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride;
( R )-4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-3-methylpiperazine-1-ium hydrochloride;
4-(5-((3-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride;
4-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride;
4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride;
4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)piperazin-1-ium hydrochloride;
( R )-4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride;
( R )-4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)-3-methylpiperazin-1-ium hydrochloride;
4-(5-(3-fluorophenethoxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride; And
4-(5-(4-fluorophenethoxy)pyrimidin-2-yl)-1,4-diazepen-1-ium hydrochloride; characterized in that at least one selected from the group consisting of, pyri Mydin derivatives or salts thereof.
The method of claim 1,
The 2,5-disubstituted pyrimidine derivative represented by Formula 1 or a salt thereof is characterized in that it has an activity as an agonist against at least one receptor selected from the group consisting of 5-HT2A, 5-HT2B, and 5-HT4. To, a pyrimidine derivative or a salt thereof.
A pharmaceutical composition for preventing or treating central nervous system diseases, comprising a 2,5-disubstituted pyrimidine derivative represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In Formula 1, n is an integer of 0 to 2, and R is a substituted or unsubstituted heterocyclic group.
The method of claim 5,
The central nervous system disease is selected from the group consisting of Alzheimer's disease, epilepsy, migraine, renal ischemia, stroke, myocardial infarction, schizophrenia, depression, attention deficit hyperactivity disorder, Huntington's disease, substance abuse, Parkinson's disease, urinary incontinence, and obesity. It is characterized in that at least one disease, pharmaceutical composition.
A pharmaceutical composition for preventing or treating gastrointestinal diseases, comprising a 2,5-disubstituted pyrimidine derivative represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In Formula 1, n is an integer of 0 to 2, and R is a substituted or unsubstituted heterocyclic group.
The method of claim 7,
The gastrointestinal disease is one selected from the group consisting of irritable bowel syndrome, constipation, indigestion, delayed gastric emptying, gastroesophageal reflux disease, gastric paralysis, postoperative ileus, pseudo-intestinal obstruction, and drug-induced delayed passage The pharmaceutical composition, characterized in that the above disease.