KR101121662B1 - 3-(Methoxymethyl)pyrazole derivatives as dopamine D3 and D4 receptor antagonists, preparation method thereof and pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention relates to novel 3- (methoxymethyl) pyrazole derivatives, methods for their preparation and pharmaceutical compositions containing them. The novel 3- (methoxymethyl) pyrazole derivatives of the present invention have excellent dopamine D ₃ and D ₄ receptor affinity, and effectively counteract psychopathic behavior (cage climbing) of mice induced with apomorphine. In addition to suppression, the mouse rotarod test has relatively mild side effects, so central nervous system disorders, specifically schizophrenia, attention deficit hyperactivity disorder, depression, stress disorder, panic disorder, phobia, obsessive compulsive disorder, trauma It is useful for the treatment and prevention of post-stress disorders, cognitive disorders, Alzheimer's disease, Parkinson's disease, anxiety, paranoidism, fever, cramps, personality disorders, migraine, drug addiction, alcoholism, obesity, eating disorders and sleep disorders. .

Pyrazole, piperazine, dopamine receptors, central nervous system disease, schizophrenia

Description

Novel 3- (methoxymethyl) pyrazole derivatives that are dopamine D3 and D4 receptor antagonists, methods for their preparation and pharmaceutical compositions comprising the same (3- (Methoxymethyl) pyrazole derivatives as dopamine D3 and D4 receptor antagonists, preparation method compositions containing the same}

The present invention relates to a novel 3- (methoxymethyl) pyrazole derivative, a preparation method thereof, and a pharmaceutical composition containing the same. More specifically, the dopamine D ₃ and D ₄ receptor affinity is excellent, and apomorphine In addition to effectively inhibiting the psychopathic behavior (cage climbing) of the mouse induced by the mouse, as well as relatively mild side effects in the mouse rotarod test, central nervous system diseases, specifically schizophrenia, excessive attention deficit Behavioral disorders, depression, stress disorders, panic disorders, phobias, obsessive-compulsive disorders, post-traumatic stress disorders, cognitive disorders, Alzheimer's disease, Parkinson's disease, anxiety, schizophrenia, fever, cramps, personality disorders, migraines, drug addiction, Piperazinylpropylpyrazole derivatives and their compounds with novel structures useful for the treatment and prevention of alcoholism, obesity, eating disorders and sleep disorders It relates to a method for preparing and a pharmaceutical composition comprising the compound.

Dopamine is a neurotransmitter essential for neurotransmitters found in the brains of animals, including humans. In addition, dopamine antagonists are antipsychotic drugs that inhibit the binding of dopamine and dopamine receptors, and are used as therapeutic agents for central nervous system diseases such as schizophrenia.

Since the antipsychotic effect of Chloropromazine was discovered in 1952, many antipsychotic drugs with various chemical structures have emerged. Typical dopamine D ₂ receptor agonists, such as chloropromazine and haloperidol, have relatively good schizophrenic effects, but include extrapyramidal side effects (EPS), sexual dysfunction, Due to the very serious side effects such as orthostatic hypotension, excessive sedation and weight gain, it makes the normal life of the patient impossible and thus is a big limitation in use. Moreover, these drugs could improve the delusion or hallucination symptoms of schizophrenia, but they did not recover at all in apathy, atrophy and impairment of cognition [Wong, AHC et al., Expert. Opin. Ther. Targets 1999 , 3 , 571-586; Chatterjee, A. et al., Am. J. Psychiat . 1995 , 152 , 1724-1729.

Therefore, there is an urgent need to develop a new class of drugs that can compensate for the shortcomings of these traditional antipsychotics. New forms of drugs that can meet these needs, such as clozapine, olanzapine, risperidone, quetiapine and aripiprazole, which are atypical antipsychotic drugs, have recently been developed. It appeared in The most representative D ₄ receptor antagonist is clozapine, which has a weak affinity for the dopamine D ₂ receptor and high selectivity for the D ₄ receptor, and recently has affinity for a serotonin (5-HT) receptor such as 5-HT _6. It is also reported to be high (Van Tol, HHM et al., Nature 1991 , 350 , 610-614; Oak, JN et al., Eur. J. Pharmacol. 2000 , 405 , 303-327). However, clozapine also has fewer side effects than conventional dopamine D ₂ receptor agonists, but also causes extrapyramidal side effects and shows no efficacy in 30-50% of patients. Research into the development of a more selective dopamine D ₄ receptor antagonist or a D ₄ receptor antagonist with some serotonin 5-HT ₂ receptor affinity (Lober, S. et al., Bioorg. Med. Chem. Lett. 2006) , 16 , 2955-9; Bartolome, JM et al., Bioorg.Med.Chem . Lett. 2005 , 15 , 2898-901; Arora, J. et al., Bioorg.Med.Chem . Lett. 2005 , 15 , 5253-5256; Nakane, M. et al., Neuropharmacology 2005 , 49 , 112-121).

Dopamine receptors have been reported to be closely linked to Parkinson's disease, attention deficit hyperactivity disorder (ADHD), depression, dementia, migraine, aggressiveness and suicidal behavior as well as schizophrenia. (Todd, RD &O'Malley, KL, TIPS 2001 , 55-56; Roth, BL et al., Psychopharmacology 2004 , 174 , 17-24).

Thus, the present inventors synthesized a novel 3- (methoxymethyl) pyrazole compound having excellent affinity for dopamine receptors, and completed the present invention by confirming that these new compounds showed excellent affinity for dopamine D ₃ and D ₄ receptors. .

Accordingly, an object of the present invention is to provide a 3- (methoxymethyl) pyrazole derivative having a novel structure having various substituents introduced therein and a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for producing a novel 3- (methoxymethyl) pyrazole derivative.

In addition, the present invention is a novel 3- (methoxymethyl) pyrazole derivative is included as an active ingredient, it is another object to provide a pharmaceutical composition useful for the treatment and prevention of central nervous system diseases.

In order to achieve the above object, the present invention provides a compound represented by the following formula (1) having a selective antagonistic activity to the dopamine D ₃ and D ₄ receptor and pharmaceutically acceptable salts thereof.

In Chemical Formula 1,

R ¹ represents an alkyl group of C ₁ -C ₁₀ ;

R ² and R ³ are both free of substituents and the other represents a C ₁ -C ₁₀ alkyl group, benzyl group, or a substituted or unsubstituted aryl or heteroaryl group;

R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as or different from each other and represent a hydrogen atom or an alkyl group of C ₁ -C ₁₀ ;

R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same as or different from each other, hydrogen atom, halogen atom, C ₁ -C ₁₀ alkyl group, C ₁ -C ₁₀ alkoxy group, bis (substituted or unsubstituted aryl) alkylene group, benzyl group, knight A ro group, a hydroxyl group, a cyano group, an amino group, a mono or a dialkylamino group, an alkylcarbonylamino group, an aminosulfonyl group, a mono or a dialkylaminosulfonyl group, an alkylcarbonyl group, or an alkyloxycarbonyl group;

은 단일결합선 또는 이중결합을 나타내고, R²와 R³의 치환 유무에 따라 변하나 피라졸 고리의 방향족성을 유지시켜야 하며;

Represents a single bond or double bond and changes depending on whether R ² and R ³ are substituted but must maintain the aromaticity of the pyrazole ring;

In addition, the aryl group represents a phenyl group, a heteroaryl group represents a thio group or a pyridyl, and wherein said substituted aryl or heteroaryl group halogen, nitro, alkoxy of C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ a, a C ₁ -C ₁₀ haloalkyl, and C ₁ is a substituent selected from haloalkoxy of 1 to 3 -C ₁₀ represents a substituted aryl or heteroaryl;

n ₁ is 3 or 4.

In another aspect, the present invention is a method for producing a compound represented by the following formula 1 characterized in that the pyrazole aldehyde derivative represented by the formula (2) and the piperazine derivative represented by the formula (3) by performing a reductive amination reaction To provide.

In Scheme 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined above, respectively, n ₁ is 3 or 4 and n ₂ is 2 or 3.

In another aspect, the present invention provides a pharmaceutical composition for preventing and treating central nervous system diseases comprising the compound represented by the formula (1).

3- (methoxymethyl) pyrazole derivatives represented by Formula 1 according to the present invention have excellent dopamine D ₃ and D ₄ receptor affinity, and effectively prevent psychotic behavior (wire mesh climbing) of apomorphine-induced mice. In addition to suppression, the mouse rotarod test showed relatively mild side effects, such as central nervous system disorders such as schizophrenia, attention deficit hyperactivity disorder, depression, stress disorder, panic disorder, phobia, obsessive compulsive disorder, and post-traumatic stress disorder. It is effective in the treatment and prevention of cognitive disorders, Alzheimer's disease, Parkinson's disease, anxiety, delusional schizophrenia, fever, cramps, personality disorder, migraine, drug addiction, alcoholism, obesity, eating disorders and sleep disorders.

The present invention is characterized by a compound represented by the following formula (1) having a selective antagonistic activity on the dopamine D ₃ and D ₄ receptors and pharmaceutically acceptable salts thereof.

[Formula 1]

In Chemical Formula 1,

R ¹ represents an alkyl group of C ₁ -C ₁₀ ;

R ² and R ³ are both free of substituents and the other represents a C ₁ -C ₁₀ alkyl group, benzyl group, or a substituted or unsubstituted aryl or heteroaryl group;

R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as or different from each other and represent a hydrogen atom or an alkyl group of C ₁ -C ₁₀ ;

R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same as or different from each other, hydrogen atom, halogen atom, C ₁ -C ₁₀ alkyl group, C ₁ -C ₁₀ alkoxy group, bis (substituted or unsubstituted aryl) alkylene group, benzyl group, knight A ro group, a hydroxyl group, a cyano group, an amino group, a mono or a dialkylamino group, an alkylcarbonylamino group, an aminosulfonyl group, a mono or a dialkylaminosulfonyl group, an alkylcarbonyl group, or an alkyloxycarbonyl group;

은 단일결합선 또는 이중결합을 나타내고, R²와 R³의 치환 유무에 따라 변하나 피라졸 고리의 방향족성을 유지시켜야 하며;

Represents a single bond or double bond and changes depending on whether R ² and R ³ are substituted but must maintain the aromaticity of the pyrazole ring;

In addition, the aryl group represents a phenyl group, a heteroaryl group represents a thio group or a pyridyl, and wherein said substituted aryl or heteroaryl group halogen, nitro, alkoxy of C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ a, a C ₁ -C ₁₀ haloalkyl, and C ₁ is a substituent selected from haloalkoxy of 1 to 3 -C ₁₀ represents a substituted aryl or heteroaryl;

n ₁ is 3 or 4.

Hereinafter, the substituent definition of the compound according to the present invention will be described in detail.

"Alkyl" in the present invention means a linear, pulverized or cyclic aliphatic saturated or unsaturated hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. More specifically, it is methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, tert- butyl, n -pentyl, neo-pentyl, cyclopentyl, cyclobutylmethyl, n -hexyl, isohexyl , Cyclohexyl, benzyl, phenylethyl and the like can be included.

In the present invention, "alkoxy" means hydroxy in which a hydrogen atom is substituted by alkyl as defined above. More specifically, this may include methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, i -butoxy, tert -butoxy, benzyloxy, phenylethoxy and the like.

"Aryl" in the present invention refers throughout the aromatic ring. Aryl is a single aromatic ring consisting of at least 5, preferably 5 to 20 carbon atoms or 1 to 5, preferably 1 to 3 further heteroatoms selected from nitrogen, oxygen and sulfur, or The ring is adjacently stabilized. More specifically, it may be phenyl, naphthyl, pyridyl, pyrazine, pyrimidine, pyridazine, triazine, imidazole, triazole, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, oxazole, Examples include isoxazole, thiazole, isothiazole, thiadiazole, oxadiazole, pyrrole, furan, thiophene and the like. Also aryl is alkyl, halogen, alkoxy, phenoxy, nitro, hydroxy, cyano, amino, mono or di alkylamino, alkylcarbonylamino, aminosulfonyl, mono or dialkylaminosulfonyl, alkylcarbonyl, It may have one or more substituents, such as alkyloxycarbonyl.

은 단일결합선 또는 이중결합을 나타내고, R²와 R³의 치환 유무에 따라 변하나 피라졸 고리의 방향족성을 유지시켜야 하며; 또한 상기 치환된 페닐기 또는 피리딜기는 각각 할로겐, 나이트로, C₁-C₁₀의 알킬, C₁-C₁₀의 알콕시, C₁-C₁₀의 할로알킬, 및 C₁-C₁₀의 할로알콕시 중에서 선택된 치환체가 1 내지 3개 치환된 페닐기 또는 피리딜기를 나타내는 화합물이다.In the compound represented by Formula 1 according to the present invention, preferably, R ¹ represents an alkyl group of C ₁ -C ₁₀ ; R ² and R ³ are both free of substituents, and the other represents a C ₁ -C ₁₀ alkyl group, benzyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted pyridyl group; R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as or different from each other and represent a hydrogen atom or methyl; R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each the same or different as represent a hydrogen atom, a halogen atom, an alkoxy group, a bis (substituted or unsubstituted phenyl beach) of the C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkyl group, a benzyl;

Represents a single bond or double bond and changes depending on whether R ² and R ³ are substituted but must maintain the aromaticity of the pyrazole ring; The substituted phenyl group or pyridyl group may also be selected from halogen, nitro, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, and C ₁ -C ₁₀ haloalkoxy. The selected substituent is a compound which represents 1 to 3 substituted phenyl groups or pyridyl groups.

More preferably in the compound represented by Formula 1 according to the present invention, R ¹ is phenyl, 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-thiophenyl, methyl , Ethyl, propyl, isopropyl, butyl, or isobutyl; One of R ² and R ³ is free of substituents, the other is t-butyl, benzyl, phenyl, 3-nitrophenyl, 4-nitrophenyl, 3-chlorophenyl, 4-fluorophenyl, 4 -Methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, or 2-pyridyl; R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as or different from each other and represent a hydrogen atom or methyl; R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different from each other and represent a hydrogen atom, chloro, fluoro, methyl, methoxy, or bis (4-fluorophenyl) methylene.

Particularly preferred when the case of n ₁ of the compound represented by Formula 1 is 3 as follows:

1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -4-phenylpiperazine (Compound 1);

1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -4-phenylpiperazine (Compound 2);

1- (2-fluorophenyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 3);

1- (2-fluorophenyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine (Compound 4);

1- (2,3-dimethylphenyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 5);

1- (2,3-dimethylphenyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine (Compound 6);

1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -4- (pyridin-2-yl) piperazine (Compound 7);

1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -4- (pyridin-2-yl) piperazine (Compound 8);

1- (3,4-dimethylphenyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 9);

1- (3,4-dimethylphenyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine (Compound 10);

1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -4- (2-methoxyphenyl) piperazine (Compound 11);

1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -4- (2-methoxyphenyl) piperazine (Compound 12);

1- (4-fluorophenyl) -4- (3- (5-methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 13);

1- (4-fluorophenyl) -4- (3- (3-methoxymethyl) -1-phenyl-1H-parazol-5-yl) propyl) piperazine (Compound 14);

2- (4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazin-1-yl) pyrimidine (Compound 15);

2- (4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazin-1-yl) pyrimidine (Compound 16);

1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -4- (3-trifluoromethyl) phenyl) piperazine (Compound 17);

1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -4- (3-trifluoromethyl) phenyl) piperazine (Compound 18);

1- (bis (4-fluorophenyl) methyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 19);

1- (bis (4-fluorophenyl) methyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine (Compound 20);

1- (4-chlorophenyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 21);

1- (4-chlorophenyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine (Compound 22);

4- (4-chlorophenyl) -1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -1,2,3,6-tetrahydropyridine (Compound 23);

4- (4-chlorophenyl) -1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -1,2,3,6-tetrahydropyridine (Compound 24);

1- (1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperidin-4-yl) -1H-benzo [d] imidazole- 2 (3H) -one (compound 25)

Also exemplifying the case where n ₁ is 4 is as follows:

1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -4-phenylpiperazine (Compound 26);

1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -4-phenylpiperazine (Compound 27);

1- (2-fluorophenyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 28);

1- (2-fluorophenyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 29);

1- (2,3-dimethylphenyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 30);

1- (2,3-dimethylphenyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 31);

1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -4- (pyridin-2-yl) piperazine (Compound 32);

1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -4- (pyridin-2-yl) piperazine (Compound 33);

1- (3,4-dimethylphenyl) -4- (4- (5-methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 34);

1- (3,4-dimethylphenyl) -4- (4- (3-methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 35);

1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -4- (2-methoxyphenyl) piperazine (Compound 36);

1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -4- (2-methoxyphenyl) piperazine (Compound 37);

1- (4-fluorophenyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 38);

1- (4-fluorophenyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 39);

2- (4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazin-1-yl) pyrimidine (Compound 40);

2- (4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazin-1-yl) pyrimidine (Compound 41);

1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -4- (3- (trifluoromethyl) phenyl) piperazine (Compound 42);

1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -4- (3- (trifluoromethyl) phenyl) piperazine (Compound 43);

1- (bis (4-fluorophenyl) methyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 44);

1- (bis (4-fluorophenyl) methyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 45);

1- (4-chlorophenyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 46);

1- (4-chlorophenyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 47);

4- (4-chlorophenyl) -1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -1,2,3,6-tetrahydropyridine (Compound 48);

4- (4-chlorophenyl) -1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -1,2,3,6, tetrahydropyridine (Compound 49);

1- (1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperidin-4-yl) -1H-benzo [d] imidazole -2 (3H) -one (compound 50);

On the other hand, the present invention includes a method for producing a compound represented by the formula (1).

In the preparation method according to the present invention, as shown in Scheme 1, the pyrazole aldehyde derivative represented by the following Chemical Formula 2 and the piperazine derivative represented by the Chemical Formula 3 are subjected to reductive amination reaction to be represented by Chemical Formula 1 It comprises a method for preparing a compound.

Scheme 1

In Scheme 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined above, respectively, n ₁ is 3 or 4, n ₂ is 2 or 3.

In the reductive amination reaction according to Scheme 1, first, the pyrazole aldehyde derivative and the piperazine derivative dissolved in a solvent were stirred at room temperature with molecular sieves under a nitrogen stream, and then the base was slowly added dropwise, and at room temperature for 30 minutes to 1 hour. After stirring, a reducing agent is added to reduce the compound, which is represented by Chemical Formula 1. The solvent that can be used for the reductive amination reaction according to Scheme 1 is a conventional organic solvent, specifically methylene chloride, chloroform, 1,2-dichloroethane and the like can be used, in the embodiment of the present invention methylene chloride Was used. The molecular sieves used were those having a particle size in the range of 0.1 to 100 mm 3, preferably in the range of 0.1 to 10 mm 3, and in the examples of the present invention, molecular sieves having a particle size of 4 mm 3 were used. Alkyl amines such as triethylamine and diisopropylethylamine, or salts of alkali metals or alkaline earth metals such as Na ₂ CO ₃ and K ₂ CO ₃ may be used as the base, and in the embodiment of the present invention, diisopropyl may be used. Ethylamine was used. The base is used in the amount of 1 to 5 equivalents, preferably 1 equivalent to the reactant. Examples of the reducing agent include NaBH _4, NaBH (OAc) ₃ , and NaBH (OAc) ₃ was used in the examples of the present invention. The amount of the reducing agent used is about 1 to 10 equivalents, preferably about 3 equivalents. The reaction time is about 1 to 24 hours, preferably 12 to 15 hours. The reaction temperature is suitably room temperature. After the reaction is completed, water is added to dissipate the reducing agent, and then pure piperazinylpropylpyrazole derivatives are obtained using a conventional separation method such as column chromatography.

The pyrazolealdehyde derivative represented by Formula 2 and the piperazine derivative represented by Formula 3 used as raw materials in the preparation method according to Scheme 1 can be easily synthesized by a known method as a known compound. In the case of the pyrazole aldehyde derivative represented by the formula (2) it can be synthesized through the reaction of the beta chito ketone and hydrazine. Briefly introducing the synthesis method of the pyrazole aldehyde derivative represented by the formula (2) is shown in Scheme 2.

In Scheme 2, R ¹ , R ² , and R ³ are as defined above, respectively, n ₃ and n ₄ are 3 or 4, n ₅ is 2 or 3.

As shown in Scheme 2, the ketone compound represented by Chemical Formula 4 and gamma butyrolactone are reacted at 30 ° C. to 50 ° C. by adding NaOMe in a benzene solvent to prepare a diquito compound represented by Chemical Formula 5. . A pyrazole alcohol derivative represented by Chemical Formula 6a or 6b is prepared by reacting a dichito compound represented by Chemical Formula 5 with hydrazine. At this time, if R ¹ is an aryl group, only Formula 6a is obtained. If R ¹ is an alkyl group, both Formulas 6a and 6b are obtained. Each pyrazole aldehyde derivative represented by Chemical Formula 2a or Chemical Formula 2b is oxidized by oxidizing each of the pyrazole alcohol derivatives represented by Chemical Formula 6a or Chemical Formula 6b using an oxidizing agent such as PCC (pyridinium chromate chloride). Get

On the other hand, the compound represented by Formula 1 according to the present invention is dopamine D ₂ , D ₃ and It has an excellent selective affinity for the D ₄ receptor, effectively inhibits cage climbing behavior of apomorphine-induced mice, as well as relatively weak side effects in mouse rotarod testing. In particular, central nervous system diseases include schizophrenia, attention deficit hyperactivity disorder, depression, stress disorder, panic disorder, phobia, obsessive compulsive disorder, post-traumatic stress disorder, cognitive impairment, Alzheimer's disease, Parkinson's disease, anxiety, schizophrenia , Fever, cramps, personality disorders, migraines, drug addiction, alcoholism, obesity, eating disorders, sleep disorders and the like can also be usefully used.

Therefore, the present invention contains a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient and includes a pharmaceutical composition effective as an agent for treating and preventing central nervous system diseases.

Pharmaceutically acceptable salts in the present invention may be prepared by conventional methods in the art, for example, with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like. Salts, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gustyic acid, fumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid, or Salts with organic acids such as acetylsalicylic acid (aspirin), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methane Salts with sulfonic acids such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like, metal salts by reaction with alkali metals such as sodium and potassium, or ammonium Salts with ions;

In addition, the pharmaceutical composition of the present invention is a conventional formulation in the pharmaceutical field by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient to the compound represented by the formula (1) or pharmaceutically acceptable salts thereof For example, it may be prepared by oral or parenteral administration such as tablets, capsules, troches, solutions, suspensions, and the like, and may be used for the prevention and treatment of various types of central nervous system diseases.

Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

In addition, the dosage of the compound represented by Formula 1 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, based on an adult patient weighing 70 kg In general, it is generally 0.01 mg to 5000 mg per day, and may be dividedly administered once to several times a day at regular time intervals according to the judgment of a doctor or a pharmacist.

The following examples are examples related to the synthesis of compounds represented by Formula 1 according to Scheme 1 above, and the present invention is by no means limited by these examples.

[Example]

Example 1 1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -4-phenylpiperazine (Compound 1)

0.7 g of a 4 ′ molecular sieve was added to the reaction vessel, followed by 3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol) and 1-phenyl. Piperazine (0.050 mL, 0.327 mmol) was dissolved in 5 mL of CH ₂ Cl _{2 and} stirred. Diisopropylethylamine (DIPEA; 0.086 mL, 0.327 mmol) was added slowly. After stirring at room temperature for 30 minutes, NaBH (OAc) ₃ (243 mg, 1.142 mmol) was added thereto and stirred for 12 hours. Reaction progress and completion was confirmed by TLC. After completion of the reaction, 0.1 mL of water was added to the reaction mixture and stirred for 3 minutes. 82 mg (63%) of the title compound were obtained by column chromatography (EtOAc: Hexane = 4: 1, v / v).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.60-7.47 (m, 5H), 7.33-7.29 (t, 2H, J = 8.4 Hz, 7.6Hz), 7.09-7.07 (d, 2H, J = 8 Hz), 7.02-6.98 (t, 1H, J = 7.4 Hz), 6.57 (s, 1H), 4.40 (s, 1H), 3.85-3.59 (m, 4H), 3.34 (s, 3H), 3.29-3.32 (m, 6H), 2.91-2.87 (t, 2H), 2.25 (m, 2H)

Example 2: 1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -4-phenylpiperazine (Compound 2)

In the same manner as in Example 1, 3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5yl) propanal (80 mg, 0.327 mmol), 1-phenylpiperazine (0.050 mL, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) gave 75 mg (59%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.70-7.59 (m, 5H), 7.28-7.24 (t, 2H), 7.15-7.08 (d, 2H), 7.00 (t, 1H), 6.65 ( s, 1H), 4.59 (s, 1H), 3.85-3.60 (m, 4H), 3.45 (s, 3H), 3.20-3.30 (m, 6H), 2.82 (t, 2H), 2.10-2.12 (m, 2H).

Example 3: 1- (2-fluorophenyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 3)

3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol), 1- (2-fluorophenyl in the same manner as in Example 1 ) 75 mg (59%) of the title compound were obtained using phenylpiperazine (0.052 mL, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.60-7.47 (m, 5H), 7.16-7.01 (m, 4H), 6.47 (s, 1H), 4.40 (s, 2H), 3.52-3.50 ( m, 2H), 3.41 (s, 3H), 3.38-3.16 (m, 8H), 2.89-2.86 (t, 2H), 2.25-2.20 (m, 2H).

Example 4: 1- (2-fluorophenyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine (Compound 4)

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol) and 1- (2-fluorophenyl in the same manner as in Example 1 ) 86 mg (65%) of the title compound were obtained using phenylpiperazine (0.052 mL, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.60-7.49 (m, 5H), 7.13-7.09 (m, 4H), 6.48 (s, 1H), 4.50 (s, 2H), 3.65-3.6 ( m, 4H), 3.41 (s, 3H), 3.33-3.15 (m, 6H), 2.85-2.84 (t, 2H), 2.20-2.10 (m, 2H).

Example 5: 1- (2,3-dimethylphenyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 5)

3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol), 1- (2,3-dimethyl in the same manner as in Example 1 74 mg (54%) of the title compound were obtained using phenyl) piperazine (0.062 mL, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.61-7.50 (m, 5H), 7.09-7.05 (t, 1H, J = 7.6Hz, 8Hz), 6.97 (s, 1H, 6.8Hz), 6.84 (d, 1H, J = 8Hz), 6.49 (s, 1H), 4.40 (s, 2H), 3.69-3.66 (d, 2H), 3.36 (s, 3H), 3.27-3.27 (m, 4H), 3.21 -3.18 (d, 2H), 2.97 (d, 2H), 2.91-2.87 (t, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 2.23-2.20 (m, 2H).

Example 6: 1- (2,3-dimethylphenyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine (Compound 6)

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol), 1- (2,3-dimethyl in the same manner as in Example 1 Phenyl) piperazine (0.062 mL, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) gave 79 mg (58%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.62-7.51 (m, 5H), 7.11-7.07 (t, 1H, J = 7.6 Hz), 6.97 (d, 2H, J = 7.6 Hz), 6.52 (s, 1H), 3.62-3.59 (d, 2H), 3.44 (s, 3H), 3.28-3.20 (m, 6H), 3.11-3.06 (t, 2H), 2.86-2.82 (t, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.18-2.08 (m, 2H).

Example 7: 1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -4- (pyridin-2-yl) piperazine (Compound 7)

3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol), 1- (pyridin-2-yl in the same manner as in Example 1 above ) Piperazine (0.053 mL, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) gave 82 mg (64%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ8.63-8.61 (dd, 1H, J = 5.4Hz, 2Hz), 8.33-8.29 (t, 1H, J = 8.8Hz, 6.8Hz), 8.05-7.90 (m, 5H), 7.61-7.59 (t, J = 8 Hz), 7.42-7.39 (t, 1H, J = 6.8 Hz, 5.6 Hz), 4.60 (s, 2H), 3.80 (s, 3H), 3.78- 3.73 (m, 10 H), 3.34-3.31 (m, 2 H), 2.75-2.69 (m, 2 H).

Example 8 1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -4- (pyridin-2-yl) piperazine (Compound 8)

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol), 1- (pyridin-2-yl in the same manner as in Example 1 above 87 mg (68%) of the title compound was obtained using piperazine (0.053 mL, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ8.14-8.13 (dd, 1H, J = 5.8 Hz, 1.2 Hz), 7.97-7.93 (t, 1H, J = 7.6 Hz, 7.2 Hz), 7.61- 7.48 (m, 5H), 7.27 (d, 1H, J = 8.8 Hz), 7.04-7.00 (t, 1H, J = 6.8 Hz, 6 Hz), 6.48 (s, 1H), 4.48 (s, 2H), 3.80 -3.50 (m, 4H), 3.42 (s, 3H), 3.30-3.18 (m, 6H), 2.83 (t, 2H), 2.18-1.12 (m, 2H).

Example 9: 1- (3,4-dimethylphenyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 9)

3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol), 1- (3,4-dimethyl in the same manner as in Example 1 Phenyl) piperazine (0.062 mL, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) gave 70 mg (51%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.62-7.51 (m, 5H), 7.09 (d, 1H, J = 8.4 Hz), 6.94 (d, 1H, J = 2.4 Hz), 6.86-6.84 (dd, 1H, J = 6Hz, J = 2.4Hz), 6.55 (s, 1H), 3.80-3.60 (m, 4H), 3.38 (s, 3H), 3.25-3.20 (m, 6H), 2.85-2.81 (t, 2H), 2.26 (s, 3H), 2.21 (s, 3H), 2.15-2.11 (m, 2H).

Example 10 1- (3,4-dimethylphenyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine (Compound 10) ;

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol), 1- (3,4-dimethyl in the same manner as in Example 1 74 mg (54%) of the title compound were obtained using phenyl) piperazine (0.062 mL, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.62-7.51 (m, 5H), 7.07-7.05 (d, 1H, J = 8.00 Hz), 6.87 (d, 1H, J = 2.4 Hz), 6.79 -6.77 (dd, 1H, J = 8.2Hz, J = 2.4Hz), 6.50 (s, 1H), 3.76-3.73 (d, 2H, J = 12.4Hz), 3.65-3.62 (d, 2H, J = 12.4 Hz), 3.38 (s, 3H), 3.28-3.10 (m, 6H), 2.85-2.81 (t, 2H), 2.25 (s, 3H), 2.20 (s, 3H), 2.26-2.10 (m, 2H) .

Example 11 1- (3-5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -4- (2-methoxyphenyl) piperazine (Compound 11)

3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol) and 1- (2-methoxyphenyl in the same manner as in Example 1 92 mg (67%) of the title compound was obtained using piperazine (62 mg, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.60-7.45 (m, 5H), 7.10-7.07 (m, 1H), 7.01-6.99 (m, 1H), 6.96-6.90 (m, 2H), 6.48 (s, 1H), 4.41 (s, 2H), 3.87 (s, 3H), 3.36 (s, 3H), 3.37-3.28 (m, 10H), 2.89-2.86 (t, 2H), 2.24-2.20 ( m, 2H).

Example 12 1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -4- (2-methoxyphenyl) piperazine (Compound 12)

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol) and 1- (2-methoxyphenyl in the same manner as in Example 1 102 mg (74%) of the title compound was obtained using piperazine (62 mg, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.62-7.49 (m, 5H), 7.12-7.08 (m, 1H), 7.03-6.99 (m, 2H), 6.97-6.92 (m, 1H), 6.49 (s, 1H), 4.50 (s, 2H), 3.88 (s, 3H), 3.61-3.59 (m, 4H), 3.38 (s, 3H), 3.25-3.00 (m, 6H), 2.85-2.82 ( t, 2H), 2.13-2.09 (m, 2H).

Example 13: 1- (4-fluorophenyl) -4- (3- (5-methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 13)

3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol) and 1- (4-fluorophenyl in the same manner as in Example 1 87 mg (66%) of the title compound was obtained using piperazine dihydrochloride (83 mg, 0.327 mmol), DIPEA (0.172 mL, 0.982 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.59-7.46 (m, 5H), 7.04-6.99 (m, 4H), 6.48 (s, 1H), 4.40 (s, 2H), 3.38 (s, 3H), 3.32-3.28 (m, 10H), 2.89-2.86 (t, 2H), 2.25-2.21 (m, 2H).

Example 14 1- (4-fluorophenyl) -4- (3- (3-methoxymethyl) -1-phenyl-1H-parazol-5-yl) propyl) piperazine (Compound 14)

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol) and 1- (4-fluorophenyl in the same manner as in Example 1 91 mg (68%) of the title compound was obtained using piperazine dihydrochloride (83 mg, 0.327 mmol), DIPEA (0.172 mL, 0.982 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.61-7.48 (m, 5H), 7.05-7.03 (d, 4H, J = 6.4 Hz), 6.47 (s, 1H), 4.49 (s, 2H) , 3.78-3.60 (m, 2H), 3.38 (s, 3H), 3.28-3.18 (m, 8H), 2.85-2.81 (t, 2H), 2.12-2.08 (m, 2H).

Example 15 2- (4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazin-1-yl) pyrimidine (Compound 15)

3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol), 2- (piperazin-1- in the same manner as in Example 1 above Il) 74 mg (58%) of the title compound were obtained using pyrimidine dihydrochloride (78 mg, 0.327 mmol), DIPEA (0.172 mL, 0.982 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol). .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ8.46 (d, 2H, J = 5.2 Hz), 7.57-7.50 (m, 5H), 6.80 (t, 1H, J = 4.8 Hz), 6.48 (s , 1H), 4.40 (s, 2H), 3.72 (d, 2H, J = 12.4 Hz), 3.36 (t, 3H), 3.33-3.28 (m, 6H), 3.20-3.15 (m, 2H), 2.86 ( t, 2H), 2.29-2.20 (m, 2H).

Example 16 2- (4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazin-1-yl) pyrimidine (Compound 16)

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol) and 2- (piperazin-1- in the same manner as in Example 1 Il) 77 mg (60%) of the title compound was obtained using pyrimidine dihydrochloride (78 mg, 0.327 mmol), DIPEA (0.172 mL, 0.982 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol). .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ8.50 (d, 2H, J = 5.2 Hz), 7.62-7.50 (m, 5H), 6.86 (t, 1H, J = 4.8 Hz), 6.52 (s , 1H), 4.51 (s, 2H), 3.67-3.64 (d, 2H, J = 12.4 Hz), 3.36 (s, 3H), 3.25-3.09 (m, 8H), 2.84-2.81 (t, 2H), 2.20-2.15 (m, 2 H).

Example 17 1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -4- (3-trifluoromethyl) phenyl) piperazine (Compound 17)

3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol), 1- (3- (triflo) in the same manner as in Example 1 Romethyl) phenyl) piperazine hydrochloride (87 mg, 0.327 mmol), DIPEA (0.172 mL, 0.982 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) to 72 mg (48%) of the target compound Got.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.59-7.42 (m, 6H), 7.26-7.21 (m, 3H), 6.49 (s, 1H), 4.40 (s, 2H), 3.92-3.89 ( d, 2H, J = 13.6 Hz), 3.75-3.72 (d, 2H, J = 11.6 Hz), 3.36 (s, 3H), 3.28-3.25 (m, 4H), 3.11-3.05 (t, 2H), 2.88 (t, 2H), 2.29-2.21 (m, 2H).

Example 18 1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -4- (3-trifluoromethyl) phenyl) piperazine (Compound 18)

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol), 1- (3- (triflo) in the same manner as in Example 1 Romethyl) phenyl) piperazine hydrochloride (87 mg, 0.327 mmol), DIPEA (0.172 mL, 0.982 mmol) and 76 mg (51%) of the target compound using NaBH (OAc) ₃ (243 mg, 1.142 mmol) Got.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.61-7.46 (m, 6H), 7.28 (d, 2H, J = 6Hz), 7.21 (d, 1H, J = 7.6Hz), 6.49 (s, 1H), 4.49 (s, 2H), 3.94-3.91 (d, 2H, J = 12.4 Hz), 3.67-3.65 (d, 2H, J = 11.2 Hz), 3.37 (s, 3H), 3.28-3.14 (m , 6H), 2.84 (t, 2H), 2.15-2.11 (m, 2H).

Example 19 1- (bis (4-fluorophenyl) methyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine ( Compound 19)

In the same manner as in Example 1, 3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol), 1- (bis (4-flo) 98 mg (58%) of the title compound was obtained using rophenyl) methyl) piperazine (94 mg, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol). .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.66-7.51 (m, 8H), 7.16-7.12 (m, 5H), 6.47 (s, 1H), 4.39 (s, 2H), 3.62-3.43 ( m, 4H), 3.36 (s, 3H), 3.25-3.12 (m, 6H), 2.64 (t, 2H), 2.20-2.17 (m, 2H).

Example 20 1- (bis (4-fluorophenyl) methyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine ( Compound 20)

In the same manner as in Example 1, 3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol), 1- (bis (4-flo) 102 mg (60%) of the title compound was obtained using rophenyl) methyl) piperazine (94 mg, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol). .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.61-7.47 (m, 8H), 7.14-7.10 (m, 5H), 6.47 (s, 1H), 4.48 (s, 2H), 3.61-3.49 (m , 2H), 3.38 (s, 3H), 3.25-3.10 (m, 8H), 2.81-2.78 (t, 2H), 2.18-2.00 (m, 2H).

Example 21 1- (4-chlorophenyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine (Compound 21)

3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol), 1- (4-chlorophenyl) in the same manner as in Example 1 91 mg (66%) of the title compound was obtained using piperazine dihydrochloride (88 mg, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.59-7.45 (m, 5H), 7.28-7.26 (dd, 2H, J = 8Hz, J = 2.4Hz), 6.98-6.96 (dd, 2H, J = 8Hz, J = 2.4Hz), 6.47 (s, 1H), 4.40 (s, 2H), 3.38 (s, 3H), 3.32-3.27 (m, 10H), 2.88 (t, 2H), 2.23-2.19 (m , 2H).

Example 22 1- (4-Chlorophenyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine (Compound 22)

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol), 1- (4-chlorophenyl) in the same manner as in Example 1 97 mg (70%) of the title compound was obtained using piperazine dihydrochloride (88 mg, 0.327 mmol), DIPEA (0.172 mL, 0.982 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.62-7.53 (m, 5H), 7.28-7.25 (dd, 2H, J = 8Hz, J = 2.4Hz), 7.01-6.99 (dd, 2H, J = 8Hz, J = 2.4Hz), 6.58 (s, 1H), 4.54 (s, 2H), 3.82-3.79 (d, 2H, J = 12.8Hz), 3.65-3.62 (d, 2H, J = 12.4Hz), 3.38 (s, 3H), 3.26-3.10 (m, 6H), 2.82 (t, 2H), 2.15-2.11 (m, 2H).

Example 23 4- (4-Chlorophenyl) -1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -1,2,3,6 Tetrahydropyridine (Compound 23)

3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propanal (80 mg, 0.327 mmol), 4- (4-chlorophenyl) in the same manner as in Example 1 83 mg (1,2,3,6-tetrahydropyridine monohydrochloride (75 mg, 0.327 mmol), DIPEA (0.172 mL, 0.982 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) 60%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.55-7.38 (m, 9H), 6.47 (s, 1H), 6.17 (s, 1H), 4.39 (s, 2H), 3.38 (s, 3H), 3.25-3.18 (m, 6H), 2.90-2.81 (m, 4H), 2.25-2.22 (m, 2H).

Example 24 4- (4-chlorophenyl) -1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -1,2,3,6 Tetrahydropyridine (Compound 24)

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol), 4- (4-chlorophenyl) in the same manner as in Example 1 88 mg (1,2,3,6-tetrahydropyridine monohydrochloride (75 mg, 0.327 mmol), DIPEA (0.172 mL, 0.982 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) 64%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.61-7.39 (m, 9H), 6.47 (s, 1H), 6.16 (s, 1H), 4.49 (s, 2H), 3.38 (s, 3H), 3.32-3.22 (m, 6H), 2.84 (m, 4H), 2.14-2.12 (m, 2H).

Example 25 1- (1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperidin-4-yl) -1H-benzo [d Imidazole-2 (3H) -one (compound 25)

3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propanal (80 mg, 0.327 mmol), 1- (piperidine-4 in the same manner as in Example 1 above -Yl) -1H-benzo [d] imidazol-2 (3H) -one (71 mg, 0.327 mmol), DIPEA (0.086 mL, 0.327 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) 107 mg (74%) of the title compound were obtained.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.49-7.30 (m, 4H), 7.22-7.07 (m, 3H), 6.62 (s, 1H), 3.91-3.60 (m, 8H), 3.52-3.39 (m, 2H), 3.11-2.97 (m, 2H), 2.43 (s, 3H), 2.40-2.30 (m, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 1.60 (s, 9H ).

Example 26 1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -4-phenylpiperazine (Compound 26)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol) and 1-phenylpiperazine (0.047 mL in the same manner as in Example 1 above , 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) gave 77 mg (62%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.62-7.49 (m, 5H), 7.30-7.26 (m, 2H), 7.05-7.03 (m, 2H), 6.96-6.93 (t, 1H, J = 7.6 Hz), 6.56 (s, 1H), 4.38 (s, 2H), 3.82-3.48 (m, 4H), 3.30 (s, 3H), 3.29-3.18 (m, 4H), 2.81 (t, 2H), 1.90-1.60 (m, 6 H).

Example 27 1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -4-phenylpiperazine (Compound 27)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol) and 1-phenylpiperazine (0.047 mL in the same manner as in Example 1 above , 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) gave 82 mg (66%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.60-7.50 (m, 5H), 7.28-7.24 (m, 2H), 7.01 (d, 2H, J = 8.8 Hz), 6.94-6.91 (t, 1H , J = 8Hz, 6.8Hz), 6.54 (s, 1H), 4.53 (s, 2H), 3.85-3.78 (d, 2H), 3.61-3.58 (m, 2H), 3.41 (s, 3H), 3.25- 3.08 (m, 4H), 2.76-2.72 (t, 2H), 1.82-1.48 (m, 6H).

Example 28 1- (2-fluorophenyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 28)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol) and 1- (2-fluorophenyl in the same manner as in Example 1 ) Piperazine (0.049 mL, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) gave 97 mg (75%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.58-7.51 (m, 5H), 7.10-7.01 (m, 4H), 6.59 (s, 1H), 4.38 (s, 2H), 3.65-3.62 (d , 2H), 3.56-3.53 (d, 2H), 3.31 (s, 3H), 3.24-3.11 (t, 2H), 1.89-1.81 (m, 6H).

Example 29 1- (2-fluorophenyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 29)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol) and 1- (2-fluorophenyl in the same manner as in Example 1 ) 101 mg (78%) of the title compound was obtained using piperazine (0.049 mL, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.55-7.43 (m, 5H), 7.10-7.01 (m, 4H), 6.39 (s, 1H), 4.44 (s, 2H), 3.62-3.51 (m , 4H), 3.37 (s, 3H), 3.23-3.08 (m, 4H), 2.76-2.72 (t, 2H), 1.80-1.60 (m, 6H).

Example 30 1- (2,3-dimethylphenyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 30)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol) and 1- (2-fluorophenyl in the same manner as in Example 1 92 mg (69%) of the title compound was obtained using piperazine (0.049 mL, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.59-7.44 (m, 5H), 7.11-7.07 (t, 1H, J = 8.0 Hz, 7.6Hz), 6.99-6.95 (t, 2H, J = 6.8 Hz, 7.4 Hz), 6.45 (s, 1H), 4.38 (s, 2H), 3.68-3.63 (t, 2H), 3.38 (s, 3H), 3.31-3.21 (m, 4H), 3.07-3.03 (t , 2H), 2.82-2.78 (t, 2H), 1.89-1.78 (m, 6H).

Example 31 1- (2,3-dimethylphenyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 31)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol), 1- (2,3-dimethyl in the same manner as in Example 1 Phenyl) piperazine (0.059 mL, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) gave 97 mg (73%) of the title compound.

¹ H NMR (400MHz, MeOH-d ₄ ) δ7.56-7.45 (m, 5H), 7.05-7.01 (t, 1H, J = 8Hz, 7.4Hz), 6.92-6.90 (d, 2H, J = 7.6Hz ), 6.43 (s, 1H), 4.46 (s, 2H), 3.62-3.53 (m, 2H), 3.38 (s, 3H), 3.22-3.04 (m, 6H), 2.76-2.73 (t, 2H), 2.22 (s, 3 H), 2.20 (s, 3 H), 1.80-1.60 (m, 6 H).

Example 32 1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -4- (pyridin-2-yl) piperazine (Compound 32)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol) and 1- (pyridin-2-yl in the same manner as in Example 1 73 mg (58%) of the title compound was obtained using piperazine (0.048 mL, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ8.21-8.10 (m, 1H), 8.06-8.04 (m, 1H), 7.60-7.57 (m, 5H), 7.55-7.48 (m, 1H), 7.14 -7.12 (m, 1H), 6.69 (s, 1H), 4.40 (s, 2H), 3.78-3.75 (m, 4H), 3.31 (s, 3H), 3.20-3.26 (m, 4H), 2.86 (t , 2H), 2.10-1.80 (m, 6H).

Example 33 1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -4- (pyridin-2-yl) piperazine (Compound 33)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol) and 1- (pyridin-2-yl in the same manner as in Example 1 75 mg (60%) of the title compound was obtained using piperazine (0.048 mL, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ8.13-8.11 (m, 1H), 8.06-8.04 (m, 1H), 7.55-7.43 (m, 6H), 7.14-7.12 (t, 1H, J = 6.8 Hz), 6.40 (s, 1H), 4.44 (s, 2H), 3.80-3.65 (m, 4H), 3.36 (s, 3H), 3.24-3.16 (m, 4H), 2.75-2.72 (t, 2H ), 1.81-1.77 (m, 2H), 1.69-1.60 (m, 4H).

Example 34 1- (3,4-dimethylphenyl) -4- (4- (5-methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 34)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol), 1- (3,4-dimethyl in the same manner as in Example 1 Phenyl) piperazine (59 mg, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) were used to give 81 mg (61%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.57-7.52 (m, 5H), 7.13-7.11 (d, 1H, J = 8.4 Hz), 7.06-7.05 (d, 1H, J = 2.4 Hz), 6.98-6.96 (d, 1H, J = 8.4 Hz), 6.58 (s, 1H), 4.38 (s, 2H), 3.45-3.40 (m, 8H), 3.31 (s, 3H), 2.84-2.80 (t, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.88-1.80 (m, 6H).

Example 35 1- (3,4-dimethylphenyl) -4- (4- (3-methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 35)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol), 1- (3,4-dimethyl in the same manner as in Example 1 Phenyl) piperazine (59 mg, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) were used to obtain 84 mg (63%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.63-7.54 (m, 5H), 7.12-7.10 (d, 1H, J = 8.4 Hz), 7.03 (s, 1H), 6.95-6.93 (d, 1H , J = 8.0Hz), 6.60 (s, 1H), 4.56 (s, 2H), 3.80-3.65 (m, 4H), 3.45 (s, 3H), 3.22-3.18 (m, 4H), 2.77-2.73 ( t, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.83-1.64 (m, 6H).

Example 36 1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -4- (2-methoxyphenyl) piperazine (Compound 36)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol) and 1- (2-methoxyphenyl in the same manner as in Example 1 78 mg (58%) of the title compound was obtained using piperazine (60 mg, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.59-7.48 (m, 5H), 7.17-7.11 (m, 2H), 7.06-7.04 (d, 1H, J = 8.0Hz), 6.99-6.96 (t , 1H, J = 8.4Hz, 8.6Hz), 6.57 (s, 1H), 4.42 (s, 2H), 3.90 (s, 3H), 3.69 (s, 4H), 3.64 (s, 4H), 3.36 (s , 3H), 2.84 (t, 2H), 2.48-2.45 (t, 2H), 1.88-1.85 (m, 4H).

Example 37 1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -4- (2-methoxyphenyl) piperazine (Compound 37)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol) and 1- (2-methoxyphenyl in the same manner as in Example 1 85 mg (63%) of the title compound was obtained using piperazine (60 mg, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.63-7.54 (m, 5H), 7.30-7.21 (m, 2H), 7.10-7.08 (d, 1H, J = 8.0 Hz), 7.00-6.96 (t , 1H, J = 8.0Hz, 8.4Hz), 6.65 (s, 1H), 4.59 (s, 2H), 3.90 (s, 3H), 3.66-3.63 (m, 8H), 3.38 (s, 3H), 2.76 -2.74 (t, 2H), 1.98 (t, 2H), 1.82-1.65 (m, 4H).

Example 38 1- (4-fluorophenyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 38)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol) and 1- (4-fluorophenyl in the same manner as in Example 1 82 mg (63%) of the title compound was obtained using piperazine dihydrochloride (78 mg, 0.310 mmol), DIPEA (0.162 mL, 0.929 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.55-7.50 (m, 5H), 7.02-6.97 (m, 4H), 6.54 (s, 1H), 4.37 (s, 2H), 3.72-3.62 (m , 4H), 3.32 (s, 3H), 3.27-3.21 (m, 4H), 3.18-3.00 (m, 2H), 2.80 (t, 2H), 1.86-1.79 (m, 4H).

Example 39 1- (4-fluorophenyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 39)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol) and 1- (4-fluorophenyl in the same manner as in Example 1 87 mg (67%) of the title compound was obtained using piperazine dihydrochloride (78 mg, 0.310 mmol), DIPEA (0.162 mL, 0.929 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.59-7.48 (m, 5H), 7.01-6.96 (m, 4H), 6.50 (s, 1H), 4.51 (s, 2H), 3.68-3.65 (d , 2H, J = 13.2 Hz), 3.59-3.56 (d, 2H, J = 12.4 Hz), 3.32 (s, 3H), 3.22-3.00 (m, 6H), 2.76-2.72 (t, 2H), 1.78- 1.65 (m, 4 H).

Example 40 2- (4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazin-1-yl) pyrimidine (Compound 40)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol) and 2- (piperazin-1- in the same manner as in Example 1 Il) 72 mg (58%) of the title compound were obtained using pyrimidine dihydrochloride (73 mg, 0.310 mmol), DIPEA (0.162 mL, 0.929 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol). .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ8.66-8.62 (m, 3H), 7.62-7.58 (m, 5H), 7.12 (t, 1H, J = 4.8 Hz, 5.2 Hz), 6.71 (s, 1H), 3.80-3.73 (m, 8H), 3.28 (s, 3H), 2.90 (t, 2H), 2.42 (t, 2H), 1.81-1.62 (m, 4H).

Example 41 2- (4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazin-1-yl) pyrimidine (Compound 41)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol) and 2- (piperazin-1- in the same manner as in Example 1 Il) 77 mg (62%) of the title compound were obtained using pyrimidine dihydrochloride (73 mg, 0.310 mmol), DIPEA (0.162 mL, 0.929 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol). .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ8.44-8.42 (m, 2H), 7.56-7.44 (m, 5H), 6.79-6.76 (t, 1H, J = 4.8 Hz, 5.2 Hz), 6.40 ( s, 1H), 4.46 (s, 2H), 3.60-3.55 (m, 4H), 3.32 (s, 3H), 3.14-3.02 (m, 4H), 2.75-2.71 (t, 2H), 1.79-1.59 ( m, 6H).

Example 42 1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -4- (3- (trifluoromethyl) phenyl) piperazine ( Compound 42)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol), 1- (3- (triflo) in the same manner as in Example 1 Romethyl) phenyl) piperazine dihydrochloride (82 mg, 0.310 mmol), DIPEA (0.162 mL, 0.929 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) aimed at 82 mg (56%) The compound was obtained.

¹ H NMR (400MHz, MeOH-d ₄ ) δ7.60-7.56 (m, 5H), 7.45 (m, 1H), 7.26 (d, 2H, J = 6Hz), 7.18 (d, 1H, J = 7.2Hz ), 6.65 (s, 1H), 4.41 (s, 2H), 3.92-3.89 (d, 2H, J = 10.8 Hz), 3.70-3.68 (d, 2H, J = 9.6 Hz), 3.33 (s, 3H) , 3.24-3.19 (m, 4H), 1.93-1.86 (m, 6H).

Example 43 1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -4- (3- (trifluoromethyl) phenyl) piperazine ( Compound 43)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol), 1- (3- (triflo) in the same manner as in Example 1 90 mg (63%) using romethyl) phenyl) piperazine dihydrochloride (82 mg, 0.310 mmol), DIPEA (0.162 mL, 0.929 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) The compound was obtained.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.56-7.42 (m, 6H), 7.23-7.22 (d, 2H, J = 5.2 Hz), 7.16-7.14 (d, 1H, J = 8Hz), 6.43 (s, 1H), 4.46 (s, 2H), 3.87-3.85 (d, 2H, J = 10 Hz), 3.61-3.59 (d, 2H, J = 8.8 Hz), 3.36 (s, 3H), 3.21-3.14 (m, 4H), 2.76-2.72 (t, 2H), 177-1.65 (m, 6H).

Example 44 1- (bis (4-fluorophenyl) methyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine ( Compound 44)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol), 1- (bis (4-flo) in the same manner as in Example 1 90 mg (63%) of the title compound were obtained using rophenyl) methyl) piperazine (89 mg, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol). .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.65-7.60 (m, 4H), 7.53-7.43 (m, 5H), 7.12-7.08 (t, 4H, J = 8.4 Hz, J = 8.4 Hz, J = 8.8 Hz), 6.44 (s, 1H), 4.34 (s, 2H), 3.55-3.51 (m, 4H), 3.33 (s, 3H), 3.26-3.19 (m, 4H), 2.75-2.72 (t, 2H), 1.80-1.76 (m, 6H).

Example 45 1- (bis (4-fluorophenyl) methyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine ( Compound 45)

In the same manner as in Example 1, 4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol), 1- (bis (4-flo) 97 mg (59%) of the title compound was obtained using rophenyl) methyl) piperazine (89 mg, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol). .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.69-7.62 (m, 4H), 7.58-7.46 (m, 5H), 7.14-7.10 (m, 4H, J = 8.8 Hz, J = 8.4 Hz), 6.47 (s, 1H), 4.50 (s, 2H), 3.49-3.41 (m, 4H), 3.34 (s, 3H), 3.24-3.12 (m, 4H), 2.73-2.70 (t, 2H), 1.71- 1.62 (m, 6 H).

Example 46 1- (4-chlorophenyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine (Compound 46)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol) and 1- (4-chlorophenyl) in the same manner as in Example 1 88 mg (65%) of the title compound was obtained using piperazine dihydrochloride (83 mg, 0.310 mmol), DIPEA (0.162 mL, 0.929 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol).

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.57-7.53 (m, 5H), 7.24-7.22 (dd, 2H, J = 8.8Hz, J = 2.2Hz), 6.99-6.96 (dd, 2H, J = 8.8Hz, J = 4.0Hz), 6.59 (s, 1H), 4.39 (s, 2H), 3.78 (d, 2H, J = 12.4Hz), 3.62 (d, 2H, J = 12.4Hz), 3.30 ( s, 3H), 3.23-3.02 (m, 6H), 2.82 (t, 2H), 1.86-1.78 (m, 4H).

Example 47 1- (4-chlorophenyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine (Compound 47)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol), 1- (4-chlorophenyl) in the same manner as in Example 1 Piperazine dihydrochloride (83 mg, 0.310 mmol), DIPEA (0.162 mL, 0.929 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) were used to give 98 mg (73%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.61-7.48 (m, 5H), 7.29-7.26 (dd, 2H, J = 8.8 Hz, J = 2.2 Hz), 7.03-7.00 (dd, 2H, J = 8.6Hz, J = 4.0Hz), 6.45 (s, 1H), 4.50 (s, 2H), 3.82-3.79 (d, 2H, J = 12.4Hz), 3.64-3.61 (d, 2H, J = 11.6Hz ), 3.38 (s, 3H), 3.23-3.10 (m, 6H), 2.81-2.77 (t, 2H), 1.85-1.68 (m, 4H).

Example 48 4- (4-chlorophenyl) -1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -1,2,3,6 Tetrahydropyridine (Compound 48)

4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butanal (80 mg, 0.310 mmol) and 4- (4-chlorophenyl) in the same manner as in Example 1 98 mg (1,2,3,6-tetrahydropyridine monohydrochloride (71 mg, 0.310 mmol), DIPEA (0.162 mL, 0.929 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) 73%) of the title compound was obtained.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.62-7.58 (m, 5H), 7.50-7.41 (dd, 2H, J = 8.8 Hz, J = 2.2 Hz), 7.40-7.29 (dd, 2H, J = 8.8Hz, J = 4.0Hz), 6.99 (s, 1H), 6.15 (s, 1H), 4.42 (s, 2H), 4.15-4.12 (d, 2H, J = 12.4Hz), 3.81-3.78 (d , 2H, J = 11.8 Hz), 3.32 (s, 3H), 3.24-3.21 (m, 2H), 2.91-2.71 (m, 4H), 1.98-1.80 (m, 4H).

Example 49 4- (4-chlorophenyl) -1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -1,2,3,6 Tetrahydropyridine (Compound 49)

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol) and 4- (4-chlorophenyl) in the same manner as in Example 1 102 mg (1,2,3,6-tetrahydropyridine monohydrochloride (71 mg, 0.310 mmol), DIPEA (0.162 mL, 0.929 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) 76%) of the title compound.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.60-7.55 (m, 5H), 7.47-7.42 (dd, 2H, J = 8.6 Hz, J = 2.4 Hz), 7.36-7.31 (dd, 2H, J = 8.8Hz, J = 4.2Hz), 6.62 (s, 1H), 6.11 (s, 1H), 4.56 (s, 2H), 4.03-3.99 (d, 2H, J = 12.4Hz), 3.76-3.72 (d , 2H, J = 12.6 Hz), 3.36 (s, 3H), 3.22-3.18 (m, 2H), 2.86-2.65 (m, 4H), 1.86-1.63 (m, 4H).

Example 50 1- (1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperidin-4-yl) -1H-benzo [d ] Imidazole-2 (3H) -one (compound 50);

4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butanal (80 mg, 0.310 mmol) and 1- (piperidine-4 in the same manner as in Example 1 -Yl) -1H-benzo [d] imidazol-2 (3H) -one (67 mg, 0.310 mmol), DIPEA (0.081 mL, 0.310 mmol) and NaBH (OAc) ₃ (243 mg, 1.142 mmol) 103 mg (73%) of the title compound was obtained.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ7.57-7.47 (m, 5H), 7.35-7.34 (d, 1H, J = 6.4 Hz), 7.05 (bs, 3H), 6.46 (s, 1H), 4.48 (s, 2H), 3.68-3.65 (d, 2H, J = 12.4 Hz), 3.39 (s, 3H), 3.23-3.08 (m, 4H), 2.84-2.73 (m, 4H), 2.05-2.01 ( m, 2H), 1.83-1.75 (m, 4H).

 [Reference Example]

The following reference example is an example of the synthesis method of the compound represented by the formula (2) according to the reaction scheme 2, the present invention is not limited by these reference examples.

Reference Example 1 7-hydroxy-1-methoxyheptan-2,4-dione (Formula 5, n ₃ is 3)

NaOMe (6.13 g, 113.47 mmol) was added to 60 mL of benzene under a nitrogen atmosphere, and stirred. 1-methoxypropan-2-one (5.26 mL, 56.74 mmol) was added to 30 mL of benzene and stirred at 40 ° C. for 30 minutes. Gamma butyrolactone (8.72 mL, 113.50 mmol) was added slowly to 30 mL of benzene. Stir at 40 ° C. for 16 h. Reaction progress and completion was confirmed by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. After the mixture was diluted with EtOAc, water was poured and the aqueous layer was extracted with EtOAc, and the organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (EtOAc: Hexane = 1: 1, v / v) to obtain 5.9 g (54%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.80 (s, 1H), 4.05-4.02 (d, 2H, J = 4.6 Hz), 3.98 (s, 3H), 2.50-2.42 (t, 2H, J = 7.6 Hz ), 1.89-1.84 (m, 4H).

Reference Example 2: 8-hydroxy-1-methoxyoctane-2,4, -dione (Formula 5, n ₃ is 4)

NaOMe (6.13 g, 113.47 mmol) was added to 60 mL of benzene under a nitrogen atmosphere, and stirred. 1-methoxypropan-2-one (5.26 mL, 56.74 mmol) was added to 30 mL of benzene and stirred at 40 ° C. for 30 minutes. Gamma valerolactone (10.28 mL, 113.49 mmol) was added slowly to 30 mL of benzene. Stir at 40 ° C. for 16 h. Reaction progress and completion was confirmed by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. After the mixture was diluted with EtOAc, water was poured and the aqueous layer was extracted with EtOAc, and the organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (EtOAc: Hexane = 1: 1, v / v) to obtain 5.9 g (54%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.80 (s, 1H), 4.06-4.03 (d, 2H, J = 4.6 Hz), 3.98 (s, 3H), 2.37-2.32 (m, 4H), 1.70-1.63 (m, 4 H).

Reference Example 3: 3- (5-methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propan-1-ol (Formula 6a, n4 is 3) and 3- (3-methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propan-1-ol (Formula 6b, n ₄ is 3)

7-hydroxy-1-methoxyheptan-2,4-dione (3.5 g, 20.09 mmol) was dissolved in 10 mL of methanol. Ph-NHNH ₂ (2.99 g, 30.13 mmol) was added to 30 mL of methanol, dissolved by stirring, and then placed in a container with 7-hydroxy-1-methoxyheptan-2,4-dione solution. Stir at 40 ° C. for 12 h. Reaction progress and completion was confirmed by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. After the mixture was diluted with EtOAc, water was poured and the aqueous layer was extracted with EtOAc, and the organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (Ether: Hexane = 1: 1, v / v) to give 1.686 g (37%) of the target compound (Formula 6a) and 1.540 g (34%) of the target compound. (Formula 6b) was obtained.

3- (5-methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propan- ¹ -ol: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.60-7.37 (m, 5H), 6.38 (s, 1H), 4.53 (s, 2H), 3.74-3.68 (t, 2H), 3.44 (s, 3H), 2.92 (t, 2H), 2.03-1.97 (m, 2H).

3- (3-methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propan- ¹ -ol: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.58-7.35 (m, 5H), 6.30 (s, 1H), 4.37 (s, 2H), 3.66-3.55 (t, 2H), 3.40 (s, 3H), 2.82-2.70 (t, 2H), 1.88-1.80 (m, 2H).

Reference Example 4: 4- (5-methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butan-1-ol (Formula 6a, n4 is 4) and 4- (3-methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butan-1-ol (Formula 6b, n ₄ is 4)

8-hydroxy-1-methoxyoctane-2,4-dione (3.5 g, 18.59 mmol) was dissolved in 10 mL of methanol. Ph-NHNH ₂ (2.76 g, 27.89 mmol) was added to 30 mL of methanol, dissolved by stirring, and then placed in a container with an 8-hydroxy-1-methoxyoctane-2,4-dione solution. Stir at 40 ° C. for 12 h. Reaction progress and completion was confirmed by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. After the mixture was diluted with EtOAc, water was poured and the aqueous layer was extracted with EtOAc, and the organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (Ether: Hexane = 1: 1, v / v) to give 1.686 g (37%) of the target compound (Formula 6a) and 1.540 g (34%) of the target compound. (Formula 6b) was obtained.

4- (5-methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butan- ¹ -ol: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.56 (d, 2H, J = 7.9 Hz), 7.42 (t, 2H, J = 6.5 Hz, J = 2.4 Hz), 7.28 (m, 1H), 6.23 (s, 1H), 4.28 (s, 2H), 3.61 (m, 2H), 3.38 ( s, 3H), 2.70 (t, 2H) 1.82-1.75 (m, 2H) 1.73-1.68 (m, 2H).

4- (3-methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butan- ¹ -ol: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.52-7.38 (m, 5H), 6.32 (s, 1H), 4.50 (s, 2H), 3.61-3.58 (m, 2H), 3.40 (s, 3H), 3.62 (t, 2H), 1.71-1.68 (m, 2H), 1.65-1.53 (m , 2H).

Reference Example 5: 3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3yl) propanal (Formula 2, n ₂ is 2)

3- (5-methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propan-1-ol (200 mg, 0.812 mmol), PCC (262 mg, 1.218 mmol), SiO ₂ under nitrogen atmosphere 5 mL of CH ₂ Cl ₂ was added to (262 mg), and the mixture was stirred at room temperature for 5 hours. Reaction progress and completion was confirmed by TLC. After the reaction is completed, the reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. After the mixture was diluted with EtOAc, water was poured and the aqueous layer was extracted with EtOAc, and the organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 149 mg (75%) of the title compound by column chromatography (Ether: Hexane = 2: 3, v / v).

¹ H NMR (400 MHz, CDCl ₃ ) δ9.95 (s, 1H), 7.56-7.54 (m, 2H), 7.47-7.45 (m, 2H) 7.43-7.35 (m, 1H), 6.31 (s, 1H) , 4.36 (s, 2H), 3.37 (s, 3H), 3.05-3.01 (m, 2H), 2.90-2.87 (m, 2H).

Reference Example 6: 4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3yl) butanal (Formula 2, n ₂ is 3)

4- (5-methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butan-1-ol (200 mg, 0.768 mmol), PCC (248 mg, 1.152 mmol), SiO ₂ 5 mL of CH ₂ Cl ₂ was added to (248 mg), and the mixture was stirred at room temperature for 5 hours. Reaction progress and completion was confirmed by TLC. After the reaction is completed, the reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. After the mixture was diluted with EtOAc, water was poured and the aqueous layer was extracted with EtOAc, and the organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 149 mg (75%) of the title compound by column chromatography (Ether: Hexane = 2: 3, v / v).

¹ H NMR (400 MHz, CDCl ₃ ) δ9.80 (s, 1H), 7.59 (d, 2H, J = 7.4 Hz), 7.46 (t, 2H, J = 7.2 Hz, J = 2.4 Hz), 7.36 (m , 1H), 6.32 (s, 1H), 4.38 (s, 2H), 3.39 (s, 3H), 2.76 (m, 2H), 2.51 (m, 2H), 2.12 (m, 2H).

[ Experimental Example ]

Experimental Example 1 Measurement of Affinity and Selectivity for Dopamine D ₂ Subtype Family Receptors

Receptor affinity for the dopamine D ₂ , D ₃ and D ₄ receptors was measured for the compounds according to the present invention as follows.

1-1: Measurement of affinity for dopamine D ₂ and D ₃

Dopamine D ₂ and D ₃ receptor affinity was measured using human recombinant recombinant dopamine receptors (PerkinElmer Life and Analytical Scinences, USA) expressed in CHO cells. Receptor membranes (3 and 1 ug / well, respectively), radioisotope [3H] spiferon (0.2 and 1 nM, respectively) and test drug were placed in a certain amount of buffer solution and incubated at 27 ° C. for 60 minutes, followed by Innotech Harvester. The reaction was terminated by rapid filtration through a Wallac GF / C glass fiber filter (Wallac, Finland), pre-soaked in 0.5% PEI, and washed with cold 50 mM Tris-HCl buffer. The filter was covered with MeltiLe, sealed in a sample bag, dried in an oven and counted with MicroBeta Plus (Wallac).

Receptor affinity (IC 50) of the compounds was calculated by nonlinear regression analysis by three replicates in each of two test tubes at 7 to 8 levels of concentration (GraphPad Prism Program, San Diego, USA).

50 mM Tris-HCl (pH 7.4) buffer containing 10 mM MgCl ₂ and 1 mM EDTA was used for dopamine D ₂ receptor affinity measurement, 5 mM MgCl ₂ , 5 mM EDTA, 5 mM KCl for D ₃ receptor test. 50 mM Tris-HCl (pH 7.4) containing 1.5 mM CaCl ₂ and 120 mM NaCl was used. 10 μM of haloperidol was used for nonspecific binding assay.

1-2: Measurement of affinity for dopamine D ₄

Dopamine D ₄ receptor affinity was measured using human recombinant recombinant dopamine D _4.2 receptor (PerkinElmer Life and Analytical Scinences, USA) expressed in CHO-K1 cells, and [ ³ H] Y m- 09151-2 (PerkinElmer) ) Was used. The buffer used for receptor binding assay was 50 mM Tris-HCl (pH 7.4) containing 120 mM NaCl, 5 mM KCl, 5 mM MgCl ₂ and 1 mM EDTA.

[ ³ H] Y m - 09151-2 binding assays were performed in 96-well plates. For drug screening, the final volume was added by adding a compound of the present invention, a D ₄ receptor membrane (43 μg / well), [ ³ H] Y m - 09151-2 (0.1 nM), 50 mM Tris-HCl (pH 7.4), and the like. 0.25 ml of reaction mixture was made and incubated at 25 ° C. for 120 minutes. After incubation, the reaction was terminated by rapid filtration through a Wallac GF / C glass fiber filter (Wallac, Finland) pre-soaked with 0.5% PEI using an Inotech harvester (Inotech) and cold 50 mM Tris-HCl buffer. Washed with solution. The filter was covered with MeltiLe, sealed in a sample bag, dried in an oven and counted with MicroBeta Plus (Wallac). 10 μM of haloperidol was used for nonspecific binding assay.

The affinity results for dopamine of the compounds of the present invention as measured above are shown in Table 1 below.

As shown in Table 1, among the compounds of the present invention, compounds 20, 30, 34, 36, 45, and 49 showed high affinity for the dopamine D ₃ receptor, and compounds 34 and 49 showed affinity for the D ₄ receptor (IC ₅₀ ) Was very good, below 50 nM.

 In general, in order for synthetic compounds to have medicinal properties, it is advantageous to have a low ClogP (octanol / water partition coefficient) value indicating the physicochemical properties of the compounds. Compounds with high ClogP values are disadvantageous in terms of oral absorption needed for future drug development. The compound of the present invention has a suitable ClogP value to have a relatively medicinal properties, it was confirmed that it exhibits very advantageous properties for application as an oral drug.

Claims (9)

delete delete delete 1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -4- (pyridin-2-yl) piperazine, 1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -4- (pyridin-2-yl) piperazine, 2- (4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazin-1-yl) pyrimidine, 2- (4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazin-1-yl) pyrimidine, 1- (bis (4-fluorophenyl) methyl) -4- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) piperazine, 1- (bis (4-fluorophenyl) methyl) -4- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperazine, 4- (4-chlorophenyl) -1- (3- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) propyl) -1,2,3,6-tetrahydropyridine , 4- (4-chlorophenyl) -1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) -1,2,3,6-tetrahydropyridine , 1- (1- (3- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) propyl) piperidin-4-yl) -1H-benzo [d] imidazole- 2 (3H) -on, 1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -4- (pyridin-2-yl) piperazine, 1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -4- (pyridin-2-yl) piperazine, 2- (4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazin-1-yl) pyrimidine, 2- (4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazin-1-yl) pyrimidine, 1- (bis (4-fluorophenyl) methyl) -4- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) piperazine, 1- (bis (4-fluorophenyl) methyl) -4- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperazine, 4- (4-chlorophenyl) -1- (4- (5- (methoxymethyl) -1-phenyl-1H-pyrazol-3-yl) butyl) -1,2,3,6-tetrahydropyridine , 4- (4-chlorophenyl) -1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) -1,2,3,6, tetrahydropyridine , 1- (1- (4- (3- (methoxymethyl) -1-phenyl-1H-pyrazol-5-yl) butyl) piperidin-4-yl) -1H-benzo [d] imidazole- 2 (3H) -on, and And a pharmaceutically acceptable salt thereof. The method of claim 4, wherein Wherein said pharmaceutically acceptable salt is a salt produced by reaction with an inorganic acid, an organic acid, an amino acid, a sulfonic acid, an alkali metal or an ammonium ion. delete delete Schizophrenia, attention deficit hyperactivity disorder, depression, stress disorder, panic disorder, phobia, obsessive compulsive disorder, post traumatic stress disorder, cognitive disorder, Alzheimer's disease, comprising the compound of claim 4 or 5 as an active ingredient, A pharmaceutical composition for treating central nervous system diseases selected from Parkinson's disease, anxiety, schizophrenia, fever, cramps, personality disorder, migraine, drug addiction, alcoholism, obesity, eating disorders and sleep disorders. delete