KR101250606B1 - Benzothiazole and benzisothiazole derivatives as antagonist of 5-HT６ receptor, preparation thereof and pharmaceutical composition comprising the same - Google Patents

Abstract

상기 식에서,
R, X 및 Y는 상세한 설명에서 정의된 바와 같다.The present invention provides a novel benzothiazole derivative or a benzisothiazole derivative having a 5-HT ₆ receptor inhibitory activity or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition comprising the same. to provide.
(I)

In this formula,
R, X and Y are as defined in the detailed description.

Description

Benzothiazole and benzisothiazole derivatives as antagonist of 5-HT6 receptor, preparations and pharmaceutical composition comprising the novel benzothiazole and benzisothiazole derivatives having a 5-HT6 receptor inhibitory action same}

The present invention relates to a novel benzothiazole and benzisothiazole derivatives having a 5-HT ₆ receptor inhibitory activity, a preparation method thereof, and a pharmaceutical composition comprising the same.

Serotonin (5-Hydroxytryptamine (5-HT)) is present in high concentrations in enterochromaffin cells of the gastrointestinal tract, platelets, and the central nervous system, and is an effective factor of various kinds of smooth muscles such as the cardiovascular and gastrointestinal tract, and a regulator of platelet function. It is well known as a neurotransmitter in the central nervous system.

In the central nervous system (CNS), serotonin is synthesized and stored in presynaptic neurons (serotonergic neurons, pineal gland, catecholaminergic neurons). The function of serotonin in the CNS is very broad and related to the role of serotonergic neurons in the forebrain, brainstem and cerebellum.

ProJection from rostral nuclei of this CNS helps regulate body temperature, appetite, sleep, vomiting and sexual activity, while proJection from caudal nuclei participates in pain and motor function.

Previous studies have shown that 5-HT is almost all physiological, including emotions, appetite, cognition, vomiting, endocrine system function, digestive system function, motor function, neuropathy, perception, sensory function, sex, sleep and vascular system functions. It appears to have behavioral effects. In particular, most of the recently used drugs for the treatment of psychiatric diseases (depression, manic depression, schizophrenia, autism, OCD, anxiety disorder) are known to work through the serotonergic mechanism, migraine, hypertension, eating disorders, irritable bowel syndrome Diseases such as irritable bowel syndrome (IBS) are associated with 5-HT. The ability of 5-HT to participate in these various functions is due to the large neurites that affect all regions of the central nervous system, while the 5-HT cell body is concentrated in the brainstem raphe nuclei. This is due to the anatomical structure of the serotonergic system and its molecular diversity and characteristic cytological distribution of various 5-HT receptor subtypes present in the cell membrane [Mohammad-Zadeh, LF; Moses, L .; Gwaltney-Brant, S. Serotonin: a review. J. Vet . Pharmacol. Therap . (2008) 31 , 187-199, Glennon, RA; Dukat, M .; Westkaemper, RB Psychopharmacology- The Fourth generation of Progress . ].

5-HT receptors are divided into seven major groups and 14 subtypes according to structural, functional and pharmacological criteria. Except for the 5-HT ₃ receptor, a ligand-gated ion channel, all belong to the G-protein coupled receptor (GPCR).

The 5-HT ₆ receptor is a G-protein coupled receptor positively coupled to the adenylate cyclase belonging to the mammalian 5-HT receptor family. It is a 7-transmembrane-spanning protein consisting of approximately 440 amino acids. % Sequence homology Predominantly in the central nervous system (CNS), such as nucleus accumbens, striatum, hippocampus, olfactory tubercle, and the characteristic location distribution and the 5-HT ₆ receptor antagonist of schizophrenia and castle 5-HT ₆ high affinity for antidepressants receptor Promising and novel targets for CNS-mediated diseases such as Alzheimer's disease (cognitive function), schizophrenia, anxiety, obesity [Holenz, J .; Pauwels, PJ; Diaz, JL; Merce, R .; Codony, X .; Buschmann, H. Medicinal chemistry strategies to 5-HT ₆ receptor ligands as potential cognitive enhancers and antiobesity agents. Drug discovery Today (2006) 11 (7/8), 283-299.

Schizophrenia therapies and antidepressants have significant affinity for the 5-HT ₆ receptor in addition to their main pharmacological targets. Drugs that bind K _i value <50 nM to human 5-HT ₆ receptor include 5-methoxytryptamine, bromocriptine, octoclothepin, neuroleptics clozapine, olanzapine, loxapine, chlorpromazine, and fluphenazine. The first 5-HT ₆ receptor ligand was discovered in the late 1990s by high-throughput screening in Roche and GSK's compound libraries, after which the antagonist tools Ro 04-6790 and Ro 63-0563 were stopped due to insufficient BBB passage, but phenyl -piperazine SB-271046 was first entered into phase I human trial in clinical development.

At the same time, Glennon, one of the pioneers of 5-HT ₆ receptor ligand synthesis, synthesized the first indole-based structures from endogenous 5-HT ligands, and continued to have high affinity and introduced various chemical groups to improve selectivity and functionality. Made. His findings have led to the synthesis of many indole-derived, selective 5-HT ₆ receptor binding structures, such as EMDT, MS-245 (Glennon, Merck Sharp & Dohme), ALX-1161, ALX-1175 (Allelix / NPS Pharmaceutical). Reached.

In addition, it has been found that sulfonamide motifs are important in indole-type structures to sufficiently bind the 5-HT ₆ receptor.

Since the first study on SAR of 5-HT-like structure was published in 1993, much understanding of 5-HT ₆ receptor pharmacophore has been gained recently through receptor-based modeling and ligand-based modeling. The results show that the 5-HT ₆ receptor pharmacophore requires four major key components: positive ionizable atoms (PI), hydrogen bond acceptor groups (HBAs), hydrophobic sites (HYDs), and aromatics that act as proton donors. ring hydrophobic site (AR) [Lopez-Rodriguez, ML; Benhamu, B .; Fuente, T .; Sanz, A .; Pardo, L .; Campillo, M. A three-dimensional pharmacophore model for 5-hydroxytryptamine ₆ (5-HT ₆ ) receptor antagonists. J. Med . Chem (2005) 48 , 4216-4219.

The PI feature is a common pharmacophoric element of most ligands that interact with biogenic amine GPCRs, mainly piperazine or (dimethylamino) ethyl moiety. Protonated piperazine moiety is combined with the Asp ^{3 .32} of the transmembrane (TM) 3.

AR featurisms In most cases, 4-methoxyphenyl, quinoline, indicated by a variously substituted indole ring, the aromatic ring are usually ^{6 .52} Phe in TM 6, part of the TM ⁵ Phe ^5. Interact with ⁴⁷

Cys ³ for compounds containing aromatic rings with additional hydrogen bond donor / acceptor functions ^{. 36} and form a hydrogen bond. HBA feature is formed by a sulfonyl group, the oxygen atom sulfonyl group, acts as a hydrogen bond acceptor in forming the Asn ^{6 .55} and the hydrogen bond interaction from ^.43 Ser ^5, 6 TM TM at 5. On the other hand, NH of the sulfonamide group forms an additional interaction of the TM and Ser ^{5 .43} 5. Finally, the feature is HYD is shown in benzothiene, benzene, naphthalene system, moiety thereof is the interaction takes place in between the hydrophobic moiety of the GPCR (Val and Ala ^{3 .33 5 .42),} and aromatic residues (Phe ^{5 .38).} It is important that the angle between the aromatic ring and the HYD feature of AR is approximately 90 ° [Holenz, J. et. al . Medicinal Chemistry Driven Approaches toward Novel and Selective Serotonin 5-HT ₆ Receptor Ligands. J. Med . Chem (2005) 48 , 1781-1795.

The global market for central nervous system diseases is expanding rapidly. In 2007, among the six therapeutic areas of the global pharmaceutical market, the central nervous system market was the largest, accounting for 17% of the total. In particular, as the number of patients with depression and schizophrenia increases recently, the market in this area is expected to expand further. Among them, 5-HT ₆ receptor is attracting attention as a new target of central nervous system-related diseases, and there is no compound that has been clinically tested. Therefore, if the synthesis of active 5-HT ₆ receptor antagonist leads to product development, high profits will be generated. It is expected to be created.

Therefore Based on the 5-HT ₆ pharmacophore modeling frame, a derivative substituted with a sulfonamide structure in the benzothiazole / benzoisothiazole nucleus was designed for the development of schizophrenia, Alzheimer's disease, and obesity drugs with better efficacy.

It is an object of the present invention to provide novel benzothiazole and benzisothiazole derivatives which are low molecular weight compounds useful as 5-HT ₆ receptor inhibitors.

It is also an object of the present invention to provide a method for producing novel benzothiazole and benzisothiazole derivatives.

It is also an object of the present invention to provide a pharmaceutical composition for the alleviation, prevention and treatment of 5-HT ₆ receptor mediated diseases through compounds including novel benzothiazole and benzisothiazole derivatives.

The present invention provides the following compounds of Formula I, or pharmaceutically acceptable salts thereof.

<Formula I>

Where

R is a phenyl group, naphthalene group or quinoline group which is optionally substituted with one or more selected from the group consisting of C1-6 alkyl, fluoro, chloro, bromo, iodo, nitro and phenyl groups,

X and Y each represent a different element as carbon or nitrogen, i) when X is carbon and Y is nitrogen, the substituent N, N-dimethyl-N'-formimidamide of <Formula I> is bonded to X; and ii) when Y is carbon and X is nitrogen, the substituent N, N-dimethyl-N'-formimidamide of <Formula I> is bonded to Y.

The compound of formula (I) is preferably a compound in which R is a phenyl group, p-methylphenyl group, p-chloro (chloro) phenyl group, 1-naphthalene group, 2-naphthalene group or a pharmaceutically acceptable salt thereof, R It is still more preferable that the compound is a p-methylphenyl group or 2-naphthalene group or a pharmaceutically acceptable salt thereof.

In the present invention, C 1-6 alkyl may be straight, branched or cyclic, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclo Pentyl, cyclohexyl and the like.

In the present invention, when a substituent is substituted for a phenyl group, a naphthalene group or a quinoline group, the substituent may have various positions. For example, when a substituent is substituted in a phenyl group, it may be substituted in the para-, meta-, ortho-position, and para-order is preferable.

The <Formula I> compound is also,

N, N -dimethyl- N ' -(5- (phenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,

N, N -dimethyl- N ' -(5- (4-methylphenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,

N, N -dimethyl- N ' -(5- (4-isopropylphenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,

N, N -dimethyl- N ' -(5- (4-fluorophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,

N, N -dimethyl- N ' -(5- (4-chlorophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,

N, N -dimethyl- N ' -(5- (4-nitrophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,

N, N -dimethyl- N ' -(5- (2,6-difluorophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,

N, N -dimethyl- N ' -(5- (naphthalene-1-sulfonamido) benzo [d] isothiazol-3-yl) formimidamide,

N, N -dimethyl- N ' -(5- (naphthalene-2-sulfonamido) benzo [d] isothiazol-3-yl) formimidamide,

N, N -dimethyl- N ' -(5- (quinolin-8-sulfonamido) benzo [d] isothiazol-3-yl) formimidamide,

N ' -(5- (biphenyl-4-ylsulfonamido) benzo [d] isothiazol-3-yl) -N, N -dimethylformimidamide,

N, N -dimethyl-N '-(6- (naphthalene-1-sulfonamido) benzo [d] thiazol-2-yl) formimidamide and

N, N -dimethyl-N '-(6- (naphthalene-2-sulfonamido) benzo [d] thiazol-2-yl) formimidamide, or a pharmaceutically acceptable salt thereof Desirable,

N, N -dimethyl- N ' -(5- (4-methylphenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide and N, N -dimethyl- N' -(5- ( Even more preferred are compounds selected from naphthalene-2-sulfonamido) benzo [d] isothiazol-3-yl) formimidamide or pharmaceutically acceptable salts thereof.

In the present invention, the pharmaceutically acceptable salts generally mean inorganic and organic acid salts used by pharmaceutical manufacturers to prepare pharmaceuticals. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, and the like may be used. , Acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholineethanesulfonic acid, camphorsulfonic acid, 4- Nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, kalutuuronic acid, emboic acid, glutamic acid, aspartic acid and the like can be used.

In addition, the present invention provides a method for preparing <Formula I> by reacting the following <Formula II> and <Formula III> in the presence of a strong base in an organic solvent (hereinafter referred to as Preparation Method 1.).

<Formula I>

&Lt;

<Formula III>

Where

R, Y and X are as defined for compounds of Formula I and Z is chloro, bromo or iodo.

In the preparation method 1 of the present invention, the strong base is NaH, NaOCH ₃ , NaOCH ₂ CH ₃ , KOCH ₃ , KOCH ₂ CH ₃ , LiOH, NaOH, KOH, RbOH, CsOH, Ca (OH) ₂ , SrOH and Ba (OH Is selected from ₂ ).

In the preparation method 1 of the present invention, the organic solvent is preferably one or more selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and dimethylacetamide.

In the preparation method 1 of the present invention, the reaction temperature may vary depending on the reaction solvent. When the solvent is DMF, about 60 to 120 ° C. is preferable, and about 100 ° C. is more preferable.

In the preparation method 1 of the present invention, the molar ratio of the compound of Formula II and the strong base may vary, but the ratio of 1: 1.1 to 3 mole is preferred, and the ratio of 1: 1.5 to 2. 3 mole ratio saves the reagents and adds the reaction. Even more preferred for reduction.

In the preparation method 1 of the present invention, the molar ratio of the compound of <Formula II> and <Formula III> may vary, but 1: 1.1 to 3 molar ratio is preferred, 1: 1.5 to 2. 3 molar ratio saving reagent And even more preferred for reducing the addition reaction.

In Preparation Method 1 of the present invention, the <Formula III> compound may be commercially available or may be prepared by a known method.

In Preparation Method 1 of the present invention, the <Formula II> compound may be prepared by the <Formula II> Compound Preparation Method provided by the present invention.

Accordingly, the present invention provides a process for preparing a compound of Formula V by reacting a compound of Formula IV with dimethylcarbamylchloride under N-methylmorpholine in an organic solvent, and b. ) A method of preparing a compound of formula (II) by reacting the compound of formula (V) prepared in step a) with a nitro group as an amine group (hereinafter, referred to as preparation method 2).

(IV)

(V)

&Lt;

Where

X and Y are as defined in the compound of Formula I.

In the preparation method 2 of the present invention, the <Formula IV> compound which is a starting material may be commercially available, or may be prepared by a known method.

In step a) of Preparation Method 2 of the present invention, the organic solvent is preferably at least one selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and dimethylacetamide.

In step a) of Preparation Method 2 of the present invention, the reaction temperature may vary depending on the reaction solvent. When the solvent is DMF, about 60 to 120 ° C. is preferable, and about 100 ° C. is more preferable.

In the preparation method 2 of the present invention, the molar ratio of the compound of Formula IV and dimethylcarbamyl chloride may vary, but the molar ratio of 1: 0.9 to 1.5 is preferred, and the molar ratio of 1: 1 reduces the reagents and reduces the addition reaction. More preferred for.

In the preparation method 2 of the present invention, the molar ratio of the compound of Formula IV and N-methylmorpholine may vary, but is preferably 1: 2 to 3 molar ratio, and 1: 2.5 molar ratio to save reagents and reduce addition reaction. More preferred for.

In step b) of Preparation Method 2 of the present invention, the reaction of reducing the nitro group to the amine group refers to a reaction of reducing the nitro group known to those skilled in the organic chemistry group to the amine group. For example, there are reactions carried out under hydrogen gas and palladium catalysts. Palladium catalysts usable here are 5% Pd-C, 10% Pd-C. And the like, and the weight of the catalyst used is preferably about twice the weight of the starting material.

In step b) of Preparation Method 2 of the present invention, the reaction solvent is preferably one or more selected from methanol, ethanol and acetonitrile.

In step b) of Preparation Method 2 of the present invention, the reaction temperature may vary depending on the reaction time, but room temperature is preferred.

In addition, the present invention provides a method for preparing <Formula I> compound comprising Preparation Method 1 and Preparation Method 2 of the present invention.

The present invention also provides a composition for the prevention, alleviation or treatment of 5-HT ₆ receptor mediated diseases or symptoms comprising the compound of the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, 5-HT ₆ receptor mediated disease means Alzheimer's disease (cognitive function), schizophrenia, anxiety disorder or obesity.

In addition, the present invention provides 5-HT by administering an effective amount of a compound of Formula I and a pharmaceutically acceptable salt thereof to a mammal including a human in need of prevention, alleviation or treatment of a 5-HT ₆ receptor mediated disease. ₆ Provide a method for preventing, alleviating or treating a receptor mediated disease.

The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical formulation for the prevention, alleviation or treatment of a 5-HT ₆ receptor mediated disease.

The composition of the present invention may contain one or more active ingredients exhibiting the same or similar functions in addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof.

The composition of the present invention may be prepared by incorporating at least one pharmaceutically acceptable carrier in addition to the above-mentioned components for administration. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, as antioxidants, buffers And other conventional additives such as bacteriostatic agents can be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, it may be preferably formulated according to each disease or component by a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.

The composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex, health status, The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease. The daily dosage of the derivative compound of formula 1 of the present invention is about 0.001 to 1,000 mg / kg, more preferably administered once to several times a day.

The compositions of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy and biological response modifiers for the prevention, alleviation or treatment of 5-HT ₆ receptor mediated diseases.

Since the compound of the present invention has a 5-HT ₆ receptor inhibitory action, it can be usefully used for the prevention, alleviation or treatment of diseases or symptoms mediated by 5-HT ₆ .

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. These Examples and Experiments are for the purpose of illustrating the present invention and the scope of the present invention is not limited to the following Examples and Experimental Examples.

In addition, the reagents and solvents mentioned below are purchased from Aldrich, Alfa Aesar, Acros, or Merck unless otherwise noted, and ¹ H-NMR data are measured by a Unity 400 (Varian) machine. , Mass data is measured by JMS-AX 505wA, JMS-HX / HX 110A and JMS 700 (JEOL) machines.

A. Synthesis

Manufacturing example  One  : N, N -dimethyl- N ' -(5- Nitrobenzo [d] isothiazole -3 days) Form imami De ( N, N - dimethyl - N ' -(5- nitrobenzo [d] isothiazol-3- yl ) formimidamide  Synthesis of (1)

DMF (dimethylformamide) in 10 mL was dissolved 3-amino-5-nitro-benzo isothiazole (3-Amino-5-nitrobenzisothiazole ) 0.4 g (2.04 mmol, 1 eq) N - methyl morpholine (N -methylmorpholine ) 0.56 mL (d = 0.92, 5.10 mmol, 2.5 eq) was added and stirred. 0.19 mL (d = 1.172, 2.04 mmol, 1 eq) of dimethylcarbamyl chloride in 30 mL of DMF was added thereto, followed by heating at 100 ° C. for 16 hours. After the reaction was cooled to room temperature and extracted with 30 mL of ethyl acetate (ethyl acetate). This was washed once with 1N HCl, saturated sodium bicarbonate (sat. NaHCO ₃ ) and finally sat. Washed with NaCl. Water was removed using MgSO ₄ , filtered under reduced pressure, evaporated, and ethyl acetate was separated by column chromatography with an eluent to obtain the title compound.

Red solid (81%), mp 147-148 ° C .: ¹ H NMR (Acetone- d _{6 ,} 400 MHz) δ 7.734 (d, J = 2.4 Hz, 1H), 8.336 (s, 1H), 8.068 (dd, J = 2.4 Hz, 1H), 7.514 (d, J = 9.6 Hz, 1H), 3.350 (s, 3H), 3.302 (s, 3H).

Manufacturing example  2  : N ' -(5- Aminobenzo [d] isothiazole -3 days)- N, N -Dimethylformimidamide ( N ' -(5- aminobenzo [d] isothiazol-3- yl ) - N, N - dimethylformimidamide  (2)) synthesis

Manufactured in Manufacturing Example 1 N, N - dimethyl -N '- (5- nitro-benzo [d] isothiazol-3-yl) form a microporous imide (N, N -dimethyl-N' - (5-nitrobenzo [ 0.1 g (0.38 mmol) of d] isothiazol-3-yl) formimidamide) and about 0.2 g of 5% Pd-C were dissolved in 10 mL of methanol at room temperature, and then dissolved by stirring under H ₂ gas for 16 hours. It was filtered under reduced pressure using celite and then evaporated to yield the title compound.

Brown solid (35%), mp 100-102 ° C .: ¹ H NMR (Acetone- d _{6 ,} 400 MHz) δ 7.973 (s, 1H), 7.231 (d, J = 9.6 Hz, 1H), 6.968 (dd, J = 9.2 Hz, 1H), 7.738 (d, J = 2.4 Hz, 1H), 4.543 (s, 2H), 3.179 (s, 3H), 3.117 (s, 3H).

Example  One  : N, N -dimethyl- N ' - (5- ( Phenylsulfonamido ) Benzo [d] Isothiazole -3 days) Formimidamide ( N, N - dimethyl - N ' - (5- ( phenylsulfonamido ) benzo [d] isothiazol -3-yl) formimidamide Synthesis of (3)

Compound prepared in Preparation Example 2 0.1 g (0.42 mmol, 1 eq) was dissolved in 7 mL of DMF, and 20 mg (0.84 mmol, 2 eq) of sodium hydride was added thereto, followed by heating and stirring at 100 ° C. To this was slowly added benzenesulfonyl chloride (0.84 mmol, 2 eq) in 5 mL of DMF, followed by heating at 100 ° C. for 16 hours. After the reaction, the mixture was cooled to room temperature and sat. Adjust to weak base using NaHCO _3, and add 30 mL of ethyl acetate. Extracted twice. Sat this organic layer. After washing with 30 mL of NaCl, water was removed using MgSO ₄ , filtered under reduced pressure, and evaporated. Finally ethyl acetate was column chromatographed with eluent to afford the title compound.

Yellow oil (19%): ¹ H NMR (Acetone- d _{6 ,} 400 MHz) δ 8.056 (s, 1H), 7.803 (d, J = 8.0 Hz, 2H), 7.611-7.568 (m, 1H), 7.538- 7.481 (m, 3H), 7.314 (d, J = 9.6 Hz, 1H), 7.217 (dd, J = 9.6 Hz, 1H), 3.230 (s, 3H), 3.158 (s, 3H). HR-EI Calcd for C ₁₆ H ₁₇ N ₄ O ₂ S ₂ (M ⁺ + H): 361.0971, Found: 361.0975.

Example  2  : N, N -dimethyl- N ' - (5- (4- Methylphenylsulfonamido ) Benzo [d] Isothiazole -3 days) Formimidamide ( N, N - dimethyl - N ' -(5- (4-methylphenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide  Synthesis of (4)

The title compound was prepared in the same manner as in Example 1, except that 4-methylphenylsulfonylchloride was used instead of benzenesulfonylchloride in Example 1.

Yellow solid (17%), mp 180-182 ° C .: ¹ H NMR (Acetone- d _{6 ,} 400 MHz) δ 8.058 (s, 1H), 7.677 (d, J = 8.0 Hz, 2H), 7.520-7.482 (m , 2H), 7.310 (dd, J = 8.8 Hz, 2H), 7.231 (d, J = 9.2 Hz, 1H), 3.229 (s, 3H), 3.161 (s, 3H), 2.347 (s, 3H). HR-EI Calcd for C ₁₇ H ₁₉ N ₄ O ₂ S ₂ (M ⁺ + H): 375.0949, Found: 375.0947.

Example  3  : N, N -dimethyl- N ' - (5- (4- Isopropylphenylsulfonamido ) Benzo [d] Isothiazole -3 days) Formimidamide (N, N - dimethyl - N ' -(5- (4-isopropylphenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide  (5) synthesis

The title compound was prepared in the same manner as in Example 1, except that 4-isopropylphenylsulfonylchloride was used instead of benzenesulfonylchloride in Example 1.

Yellow solid (41%), mp 159-161 ° C .: ¹ H NMR (Acetone- d ₆ , 400 MHz) δ 8.055 (s, 1H), 7.719 (d, J = 8.4 Hz, 2H), 7.490 (d, J = 2.4 Hz, 1H), 7.384 (d, J = 8.0 Hz, 2H), 7.320 (d, J = 9.2 Hz, 1H), 7.235 (dd, J = 9.6 Hz, 1H), 3.225 (s, 3H), 3.155 (s, 3 H), 2.983-2.914 (m, 1 H), 1.201 (d, J = 6.8 Hz, 6 H). HR-EI Calcd for C ₁₉ H ₂₃ N ₄ O ₂ S ₂ (M ⁺ + H): 403.1262, Found: 403.1265.

Example  4  : N, N -dimethyl- N ' - (5- (4- Fluorophenylsulfonamido ) Benzo [d] Isothiazole -3 days) Formimidamide ( N, N - dimethyl - N ' -(5- (4-fluorophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide  6) Synthesis

The title compound was prepared in the same manner as in Example 1, except that 4-fluorophenylsulfonyl chloride was used instead of benzenesulfonyl chloride in Example 1.

Brown solid (23%), mp 172-174 ° C .: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.785 (s, 1H), 7.772-7.737 (m, 2H), 7.415 (d, J = 8.0 Hz, 2H ), 7.088 (tt, J = 8.8 Hz, 2H), 7.002 (dd, J = 9.2 Hz, 1H), 6.473 (s, 1H), 3.167 (s, 6H)). HR-EI Calcd for C ₁₆ H ₁₆ FN ₄ O ₂ S ₂ (M ⁺ + H): 379.0699, Found: 379.0696.

Example  5 : N, N -dimethyl- N ' - (5- (4- Chlorophenylsulfonamido ) Benzo [d] Isothiazole -3 days) Formimidamide ( N, N - dimethyl - N ' -(5- (4-chlorophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide  Synthesis of 7)

The title compound was prepared in the same manner as in Example 1, except that 4-chlorophenylsulfonyl chloride was used instead of benzenesulfonyl chloride in Example 1-.

Yellow solid (35%), mp 200-201 ° C .: ¹ H NMR (Acetone- d ₆ , 400 MHz) δ 8.071 (s, 1H), 7.781 (d, J = 8.8 Hz, 2H), 7.565 (d, J = 8.8 Hz, 2H), 7.474 (d, J = 1.6 Hz, 1H), 7.330 (d, J = 9.6 Hz, 1H), 7.203 (dd, J = 9.2 Hz, 1H), 3.237 (s, 3H), 3.163 (s, 3 H). HR-EI Calcd for C ₁₆ H ₁₆ ClN ₄ O ₂ S ₂ (M ⁺ + H): 395.0403, Found: 395.0400.

Example  6  : N, N -dimethyl- N ' - (5- (4- Nitrophenylsulfonamido ) Benzo [d] Isothiazole -3 days) Formimidamide ( N, N - dimethyl - N ' -(5- (4-nitrophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide  (8) Synthesis

The title compound was prepared in the same manner as in Example 1, except that 4-nitrophenylsulfonyl chloride was used instead of benzenesulfonyl chloride in Example 1.

Brown solid (11%), mp 213-215 ° C .: ¹ H NMR (Acetone- d ₆ , 400 MHz) δ 8.377 (d, J = 6.8 Hz, 2H), 8.081 (s, 1H), 8.045 (d, J = 6.8 Hz, 2H), 7.499 (s, 1H), 7.334 (d, J = 9.6 Hz, 1H), 7.199 (dd, J = 9.6 Hz, 1H), 3.234 (s, 3H), 3.153 (s, 3H ). HR-EI Calcd for C ₁₆ H ₁₆ N ₅ O ₄ S ₂ (M ⁺ + H): 406.0644, Found: 406.0647.

Example  7  : N, N -dimethyl- N ' -(5- (2,6- Difluorophenylsulfonamido ) Benzo [d] Isothiazole -3 days) Formimidamide ( N, N - dimethyl - N ' -(5- (2,6-difluorophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide  (9) Synthesis

The title compound was prepared in the same manner as in Example 1, except that 2,6-difluoro phenylsulfonyl chloride was used instead of benzenesulfonyl chloride in Example 1. It was.

Yellow solid (12%), mp 217-218 ° C .: ¹ H NMR (Acetone- d ₆ , 400 MHz) δ 8.069 (s, 1H), 7.708-7.635 (m, 1H), 7.610 (d, J = 2.4 Hz , 1H), 7.357 (d, J = 9.2 Hz, 1H), 7.302 (dd, J = 9.2 Hz, 1H), 7.163 (t, J = 10.0 Hz, 2H), 3.236 (s, 3H), 3.174 (s , 3H). HR-EI Calcd for C ₁₆ H ₁₅ F ₂ N ₄ O ₂ S ₂ (M ⁺ + H): 397.0605, Found: 397.0602.

Example  8  : N, N -dimethyl- N ' - (5- ( naphthalene -One- Sulfonamido ) Benzo [d] Isothiazole -3 days) Formimidamide ( N, N - dimethyl - N ' - (5- ( 나프탈렌 -One- sulfonamido ) benzo [d] isothiazol -3- yl ) formimidamide  10) Synthesis

The title compound was prepared in the same manner as in Example 1, except that 1-naphthalenesulfonyl chloride was used instead of benzenesulfonyl chloride in Example 1.

Brown solid (11%), mp 165-167 ° C .: ¹ H NMR (Acetone- d ₆ , 400 MHz) δ 8.866 (d, J = 8.8 Hz, 1H), 8.228 (dd, J = 7.2 Hz, 1H), 8.157 (d, J = 8.4 Hz, 1H), 8.047 (d, J = 8.8 Hz, 1H), 7.993 (s, 1H), 7.706 (t, J = 7.6 Hz, 1H), 7.649 (t, J = 7.6 Hz, 1H), 7.552 (t, J = 8.0 Hz, 1H), 7.359 (d, J = 2.0 Hz, 1H), 7.202 (d, J = 9.6 Hz, 1H), 7.080 (dd, J = 9.2 Hz, 1H), 3.207 (s, 3H), 3.125 (s, 3H). HR-EI Calcd for C ₂₀ H ₁₉ N ₄ O ₂ S ₂ (M ⁺ + H): 411.0949, Found: 411.0951.

Example  9  : N, N -dimethyl- N ' -(5- (naphthalene-2- Sulfonamido ) Benzo [d] Isothiazole -3 days) Formimidamide ( N, N - dimethyl - N ' - (5- ( 나프탈렌 -2-sulfonamido) benzo [d] isothiazol-3-yl) formimidamide  11) Synthesis

The title compound was prepared in the same manner as in Example 1, except that 2-naphthalenesulfonyl chloride was used instead of benzenesulfonyl chloride in Example 1.

Yellow oil (25%): ¹ H NMR (Acetone- d _{6 ,} 400 MHz) δ 8.405 (s, 1H), 8.042 (d, J = 8.0 Hz, 2H), 8.001 (s, 1H), 7.980 (d, J = 8.0 Hz, 1H), 7.826 (dd, J = 8.8 Hz, 1H), 7.687-7.601 (m, 2H), 7.474 (d, J = 2.0 Hz, 1H), 7.288 (d, J = 9.2 Hz, 1H), 7.241 (dd, J = 9.2 Hz, 1H), 3.199 (s, 3H), 3.108 (s, 3H). HR-EI Calcd for C ₂₀ H ₁₉ N ₄ O ₂ S ₂ (M ⁺ + H): 411.1127, Found: 411.1130.

Example  10  : N, N -dimethyl- N ' -(5- (quinoline-8- Sulfonamido ) Benzo [d] Isothiazole -3 days) Formimidamide ( N, N - dimethyl - N ' - (5- ( quinoline -8- sulfonamido ) benzo [d] isothiazol -3-yl) formimidamide Synthesis of 12)

The title compound was prepared in the same manner as in Example 1, except that 8-quinolinesulfonyl chloride was used instead of benzenesulfonyl chloride in Example 1.

Yellow solid (68%), mp 270-272 ° C: ¹ H NMR (DMSO- d _{6 ,} 400 MHz) δ 9.172 (d, J = 4.4 Hz, 1H), 8.532 (d, J = 8.4 Hz, 1H), 8.306 (d, J = 7.2 Hz, 1H), 8.257 (d, J = 8.4 Hz, 1H), 7.742 (q, J = 4.0 Hz, 1H), 7.679 (t, J = 7.8 Hz, 2H), 3.118 ( s, 3H), 3.041 (s, 3H). HR-EI Calcd for C ₁₉ H ₁₈ N ₅ O ₂ S ₂ (M ⁺ + H): 412.1080, Found: 411.1006.

Example  11  : N ' -(5- (biphenyl-4- Il Sulfon amido ) Benzo [d] Isothiazole -3 days)- N, N - Dimethylformimidamide ( N ' - (5- ( biphenyl -4- ylsulfonamido ) benzo [d] isothiazol -3- yl ) - N, N -dimethyl formimidamide Synthesis of 13)

The title compound was prepared in the same manner as in Example 1, except that 1-biphenylsulfonyl chloride was used instead of benzenesulfonyl chloride in Example 1.

Brown solid (15%), mp 104-106 ° C .: ¹ H NMR (Acetone- d ₆ , 400 MHz) δ 8.045 (s, 1H), 7872 (d, J = 8.4 Hz, 2H), 7.801 (d, J = 10.4 7.716-7.661 (m, 2H), 7.514-7.451 (m, 3H), 7.409 (tt, J = 7.6 Hz, 1H), 7.338 (d, J = 9.6 Hz, 1H), 7.268 (dd, J = 9.2 Hz, 1H), 3.205 ( s, 3H), 3.125 (s, 3H) HR-EI Calcd for C 22 H 21 N 4 O 2 s 2 (M + + H):. 437.1106, Found: 437.1102.

Manufacturing example  3  : N, N -dimethyl- N ' - (6- Nitrobenzo [d] thiazole -2 days) Form imami De ( N, N - dimethyl - N ' - (6- nitrobenzo [d] thiazol-2- yl ) formimidamide  Synthesis of 14

Methyl morpholine (N -methylmorpholine) 0.56 mL (d = - 2- amino-5-nitro-benzothiazole (2-amino-5-nitrobenzothiazole ) N was dissolved 0.4 g (2.04 mmol, 1 eq ) in 10 mL DMF 0.92, 5.10 mmol, 2.5 eq) was added and stirred.

0.19 mL (d = 1.172, 2.04 mmol, 1 eq) of dimethylcarbamyl chloride in 30 mL of DMF was added thereto, followed by heating at 100 ° C. for 16 hours. After the reaction was cooled down to room temperature and extracted with 30 mL of ethyl acetate. Once with 1N HCl, sat. Wash with NaHCO ₃ and finally sat. Washed with NaCl.

This was removed with water using MgSO ₄ , filtered under reduced pressure, the solvent was evaporated, and ethyl acetate was purified by column chromatography with eluent to obtain the title compound.

Yellow solid (63%), mp 176-178 ° C: ¹ H NMR (Acetone- d ₆ , 400 MHz) δ 7.728 (d, J = 2.4 Hz, 1H), 8.648 (s, 1H), 8.208 (dd, J = 8.8 Hz, 1H), 7.680 (d, J = 8.8 Hz, 1 H), 3.334 (s, 3 H), 3.173 (s, 1 H).

Manufacturing example  4  : N ' - (6- Aminobenzo [d] thiazole 2-yl) -N, N-dimethylformimidamide ( N ' Synthesis of-(6-aminobenzo [d] thiazol-2-yl) -N, N-dimethylformimidamide (15))

Manufactured in Preparation Example 3 N, N -dimethyl-N '-(6-nitrobenzo [d] thiazol-2-yl) formimidamide ( N, N- dimethyl-N'-(6-nitrobenzo [d] thiazol-2-yl 0.1g (0.38 mmol) and about 0.2 g of 5% Pd-C were dissolved in 10 mL of methanol methanol at room temperature, and then reduced by stirring for 16 hours under H ₂ gas. After filtration under reduced pressure using celite, the solvent was evaporated to obtain the title compound.

Brown solid (31%), mp 103-104 ° C .: ¹ H NMR (Acetone- d ₆ , 400 MHz) δ 8.362 (s, 1H), 7.309 (d, J = 8.8 Hz, 1H), 6.990 (d, J = 2.4 Hz, 1H), 6.702 (dd, J = 8.4 Hz, 1H), 3.195 (s, 3H), 3.045 (s, 3H).

Example  12  : N, N -dimethyl- N ' -(6- (naphthalene-1- Sulfonamido ) Benzo [d] thiazol-2-yl) formimidamide ( N, N - dimethyl - N ' -(6- ( 나프탈렌 -One- sulfonamido ) benzo [d] thiazol -2-yl) formimidamide Synthesis of 16)

Compound prepared in Preparation Example 4 0.1 g (0.42 mmol, 1 eq) was dissolved in 7 mL of DMF, and 20 mg (0.84 mmol, 2 eq) of sodium hydride was added thereto, followed by heating and stirring at 100 ° C. To this was slowly added dropwise 1-naphthalenesulfonyl chloride (0.84 mmol, 2 eq) in 5 mL of DMF, followed by heating at 100 ° C. for 16 hours. After the reaction, the mixture was cooled to room temperature and sat. Adjust to weak base with NaHCO ₃ and 30 mL of ethyl acetate. Extracted twice. Sat this organic layer. After washing with 30 mL of NaCl, water was removed using MgSO ₄ , filtered under reduced pressure, and the solvent was evaporated. Finally ethyl acetate was column chromatographed with eluent to afford the title compound.

Pale brown solid (14%), mp 225-227 ° C: ¹ H NMR (Acetone- d ₆ , 400 MHz) δ 8.827 (d, J = 8.4 Hz, 1H), 8.405 (s, 1H), 8.197 (dd, J = 7.2 Hz, 1H), 8.149 (d, J = 8.4 Hz, 1H), 8.041 (d, J = 8.0 Hz, 1H), 7.713-7.625 (m, 2H), 7.540 (t, J = 8.0 Hz, 1H), 7.476 (d, J = 2.4 Hz, 1H), 7.309 (d, J = 8.4 Hz, 1H), 6.989 (dd, J = 8.4 Hz, 1H), 3.211 (s, 3H), 3.054 (s, 3H). HR-EI Calcd for C ₂₀ H ₁₉ N ₄ O ₂ S ₂ (M ⁺ + H): 410.0871, Found: 410.0869.

Example  13  : N, N -dimethyl- N ' -(6- (naphthalene-2- Sulfonamido ) Benzo [d] thiazol-2-yl) formimidamide ( N, N - dimethyl - N ' -(6- ( 나프탈렌 -2- sulfonamido ) benzo [d] thiazol -2- yl formimidamide Synthesis of 17)

The title compound was prepared in the same manner as in Example 12, except that 2-naphthalenesulfonyl chloride was used instead of 1-naphthalenesulfonyl chloride in Example 12. It was.

Pale brown solid (16%), mp 205-207 ° C: ¹ H NMR (Acetone- d ₆ , 400 MHz) δ 8.420 (s, 1H), 8.364 (d, J = 2.0 Hz, 1H), 8.032 (d, J = 8.4 Hz, 2H), 7.978 (d, J = 8.0 Hz, 1H), 7.767 (dd, J = 8.8 Hz, 1H), 7.687-7.600 (m, 3H), 7.387 (d, J = 8.4 Hz, 1H), 7.133 (dd, J = 8.8 Hz, 1H), 3.218 (s, 3H), 3.061 (s, 3H). HR-EI Calcd for C ₂₀ H ₁₉ N ₄ O ₂ S ₂ (M ⁺ + H): 411.0949, Found: 411.0948.

A. Drug Evaluation

< Experimental Example  1> FDSS6000  Used Ga _S -and( family Serotonin receptor assays assay )

Serotonin receptor activity was measured by intracellular calcium ([Ca ^{2 +} ] _i ) changes induced by 5-HT ₆ by fluorescence imaging using a FDSS6000 high-throughput screening (HTS) instrument. Specifically FDSS6000 is Ca ^{2 +} to all GPCR to search for the fastest ligand to work in GPCR / Gaq / PLC / Ca ^{2 +} signal mechanism by expressing a promiscuous Ga15 protein capable of binding to a variety of GPCR - sensing HTS method [1. Yun HM, Kim S, Kim HJ, Kostenis E, Kim JI, Seong JY, Baik JH, Rhim H. J Biol Chem. 2007. 282 (8): 5496-505, 2. Kim HJ , Yun HM, Kim T, Nam G, Roh EJ, Kostenis E, Choo HY, Pae AN, Rhim H. Comb Chem High Throughput Screen. 2008. 11 (4): 316-24.]

1) of the compound of the present invention HeLa  Serotonin 5- in Cells HT ₆  Confirmation of receptor inhibitory effect

Human recombinant 5-HT ₆ for 5-HT ₆ receptor assay HeLa cells with permanent expression of serotonin receptors were used. Ga15 protein was expressed in HeLa cells for calcium measurement. Fluorine-4 / AM calcium fluorescence labeling dye was used after loading for 1 hour on the day of activity measurement. Compounds used in the present invention for 15 minutes outside the FDSS6000 device was transferred to the FDSS6000 device after pretreatment and treated with 100 nM 5-HT after base line measurement.

After determining the inhibitory effect of the test substance (compound of the present invention) by setting the reaction rate (R ₁ / R ₀ ) of calcium increase by 5-HT measured at 480 nm of the buffer-treated sample instead of the test substance to 100% Concentration-dependent graphs for HeLa cells and IC ₅₀ values were obtained from them, and the results are shown in [Table 1] and [Table 2].

Table 1 Compound 5- of the present invention HT ₆ Inhibition  (%)

Table 2 5- HT ₆ Inhibition  ( IC ₅₀ )

As shown in [Table 1] and [Table 2], the <Formula 1> compound of the present invention shows an excellent 5-HT ₆ inhibitory effect.

2) of the <Formula 1> of the present invention HEK293  Serotonin 5- in Cells HT _{4 ,}  5-HT _6,  5- HT ₇  Selectivity Comparison Between Receptors

For selective experiment for 5-HT receptor of the compounds of the present invention 5- HT _4, 5- HT _6, and a 5- HT ₇ in HEK293 cells After transient expression of the receptor, 5-HT _{4 ,} 5-HT _{6 ,} 5-HT ₇ receptor activity of the compounds of the present invention was measured and then analyzed.

Serotonin receptors, 5- HT _{4 ,} 5- HT _{6 and} 5- HT ₇ in HEK293 cells Each Ga15 gene was transfected with Lipofectamine at a 1: 1 ratio and Ga15 protein was expressed in HEK293 cells for calcium measurement. Fluorine-4 / AM calcium fluorescence labeling dye was used after loading for 1 hour on the day of activity measurement. Compounds used in the present invention for 15 minutes outside the FDSS6000 device was transferred to the FDSS6000 device after pretreatment and treated with 100 nM 5-HT after base line measurement. Instead of the test substance _{, the} ratio of calcium increase (R ₁ / R ₀ ) by 5- HT _{4 ,} 5- HT _{5 , and} 5- HT ₇ measured at 480 nm of the buffer-treated sample was 100%. After determining the inhibitory effect of (Compound of the present invention), the degree of inhibition (% inhibition) for HEK293 cells was calculated, and the results are shown in the following [Table 3].

Table 3 Serotonin Receptor Selectivity

As shown in Table 3, the <Formula 1> compound of the present invention is 5-HT ₆ It exhibits good selectivity for the receptor.

Claims (12)

A compound of Formula I, or a pharmaceutically acceptable salt thereof:
(I)

In this formula,
R is a phenyl group, naphthalene group or quinoline group which is optionally substituted with one or more selected from the group consisting of C1-6 alkyl, fluoro, chloro, bromo, iodo, nitro and phenyl groups,
X and Y each represent a different element as carbon or nitrogen, i) when X is carbon and Y is nitrogen, the substituent N, N-dimethyl-N'-formimidamide of <Formula I> is bonded to X; and ii) when Y is carbon and X is nitrogen, the substituent N, N-dimethyl-N'-formimidamide of <Formula I> is bonded to Y. The compound of formula 1 or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is a phenyl group, p-methylphenyl group, p-chloro (chloro), phenyl group, 1-naphthalene group, 2-naphthalene group. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, which is a p-methylphenyl group or 2-naphthalene group. The method of claim 1,
N, N -dimethyl- N ' -(5- (phenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,
N, N -dimethyl- N ' -(5- (4-methylphenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,
N, N -dimethyl- N ' -(5- (4-isopropylphenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,
N, N -dimethyl- N ' -(5- (4-fluorophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,
N, N -dimethyl- N ' -(5- (4-chlorophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,
N, N -dimethyl- N ' -(5- (4-nitrophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,
N, N -dimethyl- N ' -(5- (2,6-difluorophenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide,
N, N -dimethyl- N ' -(5- (naphthalene-1-sulfonamido) benzo [d] isothiazol-3-yl) formimidamide,
N, N -dimethyl- N ' -(5- (naphthalene-2-sulfonamido) benzo [d] isothiazol-3-yl) formimidamide,
N, N -dimethyl- N ' -(5- (quinolin-8-sulfonamido) benzo [d] isothiazol-3-yl) formimidamide,
N ' -(5- (biphenyl-4-ylsulfonamido) benzo [d] isothiazol-3-yl) -N, N -dimethylformimidamide,
N, N -dimethyl-N '-(6- (naphthalene-1-sulfonamido) benzo [d] thiazol-2-yl) formimidamide and
N, N -dimethyl-N '-(6- (naphthalene-2-sulfonamido) benzo [d] thiazol-2-yl) formimidamide <Formula I> compound or a pharmaceutical thereof Acceptable salts. The N, N -dimethyl- N ' -(5- (4-methylphenylsulfonamido) benzo [d] isothiazol-3-yl) formimidamide according to claim 4 and N, N -dimethyl- N A compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from-(5- (naphthalene-2-sulfonamido) benzo [d] isothiazol-3-yl) formimidamide. Prevention, alleviation or treatment of Alzheimer's disease (cognitive function), schizophrenia, anxiety disorder or obesity comprising the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient Composition. delete The following <Formula II> and <Formula III> to react in the presence of a strong base in an organic solvent to prepare a <Formula I> compound.
(I)

<Formula II>

<Formula III>

In this formula,
R, Y and X are as defined in claim 1,
Z is chloro, bromo or iodo. The method of claim 8, wherein the strong base is NaH, NaOCH ₃ , NaOCH ₂ CH ₃ , KOCH ₃ , KOCH ₂ CH ₃ , LiOH, NaOH, KOH, RbOH, CsOH, Ca (OH) ₂ , SrOH and Ba (OH) ₂ It is selected from the manufacturing method. 10. The process according to claim 9, wherein the organic solvent is selected from dimethylformamide (DMF), dimethylsulfoxide (DMSO) and dimethylacetamide. a) preparing a compound of Chemical Formula V by reacting the following Chemical Formula IV compound with dimethylcarbamylchloride in an organic solvent under N-methylmorpholine; And
b) A method of preparing the compound of Formula 8 according to claim 8 by reducing the compound of Formula V prepared in step a) to a nitro group.
<Formula IV>

<Formula V>

<Formula II>

In this formula,
X and Y are as defined in claim 1. The process according to claim 11, wherein the reaction of reducing the nitro group of step b) to an amine group is carried out under a hydrogen gas and a palladium catalyst.