KR101070176B1 - 1H-pyrazole-3-amide derivatives having CB1-antagonistic activity and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a novel compound having CB1 antagonistic activity, and specifically relates to a 1H-pyrazole-3-amide-based compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

In addition, the present invention relates to a pharmaceutical composition comprising the 1H-pyrazole-3-amide-based compound of Formula 1 having a CB1 antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient.

Cannabinoid-1, CB-1, CB1, antagonist, acrylamide, oxoacetamide

Description

1H-pyrazole-3-amide-based compound or 1H-pyrazole-3-oxoacetamide-based chemical derivative having antagonistic activity at Ck 1 and pharmaceutical composition comprising same {1H-pyrazole-3-amide derivatives having CB1-antagonistic activity and pharmaceutical composition comprising the same}

The present invention relates to a novel compound having CB1 antagonistic activity, and specifically relates to a 1H-pyrazole-3-amide-based compound of Formula 1 or a pharmaceutically acceptable salt thereof. In addition, the present invention relates to a pharmaceutical composition comprising the 1H-pyrazole-3-amide-based compound of Formula 1 having a CB1 antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

Obesity is a major public health concern due to its increasing spread and associated health risks. Increased obesity is associated with excessive health risks associated with obesity, such as coronary heart disease, seizures, hypertension, type 2 diabetes, dyslipidemia, sleep apnea, osteoarthritis, gallbladder disease, depression, and some forms of cancer, for example It is important because it causes cancer of the endometrium, breast, prostate and colon (McGinnis M, Foege WH., JAMA, 270, 2207-2212 (1993)). Prescription drugs currently available for the management of obesity generally reduce weight by inducing satiety or by reducing dietary fat absorption. Satiety is achieved by increasing synaptic levels of norepinephrine, serotonin, or both. For example, stimulation of serotonin receptor subtypes 1B, 1D and 2C and 1- and 2-adrenergic receptors reduces food intake by modulating satiety [Bray GA, Obes Res., 3 (suppl 4), 415s-7s (1995)]. Adrenaline agonists such as diethylpropion, benzpetamine, pendimethazine, marginol or phentermine act by regulating central norepinephrine and dopamine receptors through the promotion of catecholamine release. Adrenergic weight loss drugs that are strongly involved in the dopamine pathway, such as amphetamine, metamphetamine, phenmetrazine, are no longer recommended because of their risk of misuse. Serotonin agonists used to control appetite, such as fenfluramine and dexfenfluramine, are no longer used.

Delta-9-tetrahydrocannabinol, a major component of Cannabis sativa (marijuana), has recently been tested for food control, immunosuppression, analgesia, inflammation, vomiting, anti-nocioception, sedation, And members of a broad group of lipophilic compounds (cannabinoids) that mediate physiological and psychological effects, including intraocular pressure. Two forms of cannabinoids have been cloned in receptors, which are CB1 [LAMatsuda, et al., Nature 346,561-564 (1990)], and CB2 [S. Munro, et al., Nature, 365, 61- 65 (19930). Cannabinoids act through selective binding to G-protein coupled cannabinoid receptors and their activation. CB1 receptors are highly expressed in the central and peripheral nervous systems (M, Glass, et al., Neuroscience, 77, 299-318 (1997)), but CB2 receptors are highly expressed in immune tissues, especially in the spleen and tonsils. . There is substantial evidence that cannabinoids control appetite behavior. Stimulating CB1 activity with anandamide or delta-9 THC results in increased food intake and weight loss in various species, including humans (Williams and Kirkham, Psychopharm., 143, 135-137 (1999)). Gene knockout of CB1 was informed and dried compared to natural mice from litter (DiMarzo, et al., Nature, 410, 822-825 (2001)). A published study of CB1 small molecule antagonists demonstrated the reduction of food intake and body weight in rats (Trillou, et. Al., A77 Jplzysiol. Regul. Integr. Comp. Physiol., R345-R353, (2003)). Chronic administration of CB1 antagonist AM-251 for two weeks results in substantial weight loss and a decrease in adipose tissue mass (Hilderbrandt, et. Al., Eur. J. Pharm, 462, 125-132 (2003)). In addition, a number of studies have examined the anorexic effect of SR-141716, a Sanobisa CB1 antagonist (Rowland, et. Al., Pyschopharm., 159-11-116 (2001); Colombo, et. Al., LifeSci) , 63, 113-117 (1998). There are at least two CB1 antagonists as clinical trials for appetite control, including SR-141716 from Sanofi and SLV-319 from Solvay. Published Phase IIb data showed that SR-141716 reduced body weight in human subjects regardless of dose during the 16 week trial period.

While many studies are underway as described above, there is still a need for more effective and safe treatments for the reduction or prevention of weight gain.

It is an object of the present invention to provide a 1H-pyrazole-3-amide compound or a pharmaceutically acceptable salt thereof, which is a novel compound having antagonistic activity on CB1.

It is also an object of the present invention to provide a pharmaceutical composition having antagonistic activity against CB1 containing a novel 1H-pyrazole-3-amide-based compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a novel 1H-pyrazole-3-amide compound or a pharmaceutically acceptable salt thereof as an active ingredient for the treatment of weight loss, obesity, bulimia or attention deficit behavioral disorder, Parkinson's disease, Alzheimer's disease, nodule It is an object of the present invention to provide a pharmaceutical composition for treating dementia, vascular dementia, and alcoholism.

The present invention relates to a novel compound having an antagonistic activity on CB1, specifically provides a 1H-pyrazole-3-amide compound of formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

또는

이고;[In Formula 1, A is

or

ego;

R ₁ is hydrogen, (C ₁ -C 10) alkyl, (C 3 -C 7) cycloalkyl, (C 6 -C 20) aryl or (C 6 -C 20) ar (C 1 -C 10) alkyl;

R ₂ and R ₃ independently of one another are hydrogen, (C 1 -C 10) alkyl, (C 6 -C 20) aryl, (C 6 -C 20) ar (C 1 -C 10) alkyl, (C 3 -C 7) cycloalkyl, N, O and (C3-C7) heterocycloalkyl, adamantyl, piperidino or pyrrolidino containing one or more heteroatoms selected from S or R ₂ and R ₃ are linked to (C3-C7) alkylene to form a ring May be substituted with one or more carbon atoms of the alkylene NR ₆ , O or S;

R ₄ and R ₅ are independently of each other hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl or (C6-C20) aryl;

R ₆ is hydrogen, (C 1 -C 10) alkyl or (C 1 -C 10) alkoxycarbonyl;

The alkyl, aryl, aralkyl, cycloalkyl, adamantyl or heterocycloalkyl of R ₁ , R ₂ and R ₃ may be halogen, (C 1 -C 10) alkyl, halo (C 1 -C 10) alkyl, (C 1 -C 10) Alkoxy, mono or di- (C1-C10) alkylamino, mono or di- (C6-C20) arylamino, (C3-C7) cycloalkyl, (C2-C20) heteroaryl, hydroxy, N, O and S May be further substituted with one or more substituents selected from (C3-C7) heterocycloalkyl, pyrrolidino or piperidino comprising one or more heteroatoms selected from;

Provided that R ₂ and R ₃ are not simultaneously hydrogen.]

The present invention also provides a pharmaceutical composition having CB-1, CB1 antagonistic activity containing the above formula 1H-pyrazole-3-amide-based compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Diseases, symptoms, and / or disorders controlled by cannabinoid receptor antagonists include eating disorders (eg, habitual overeating, anorexia and bulimia), weight loss or control (eg, reducing calorie or food intake, and / or suppressing appetite). ), Obesity, depression, atypical depression, bipolar disorder, psychosis, schizophrenia, behavioral addiction, suppression of reward-related behavior (eg, conditional place repellence, such as cocaine and morphine-induced conditional place suppression), drug abuse, Addiction disorders, impulses, alcoholism (eg, alcohol abuse, addiction and / or dependence, such as alcoholism, treatment to reduce the need for alcohol intake and relapse), tobacco abuse (eg, smoking addiction, withdrawal symptoms and / or dependence) For example, to reduce the need for tobacco smoking and prevent relapses, dementia (loss of memory, Alzheimer's disease, aging dementia, vascular dementia, mild cognition) Deterioration, cognitive impairment due to aging and mild neurocognitive impairment, etc.), sexual dysfunction in men (eg erectile dysfunction), seizure disorders, epilepsy, inflammation, digestive tract disorders (eg gastrointestinal or intestinal peristaltic dysfunction), Attention deficit behavioral disorder (ADD / ADHD), Parkinson's disease, and type 2 diabetes. In a preferred embodiment, the composition is used for the treatment of weight loss, obesity, bulimia, or attention deficit behavioral disorder (ADD / ADHD), Parkinson's disease, Alzheimer's disease, aging dementia, vascular dementia and alcoholism.

The compounds of the present invention are particularly suitable for the treatment of obesity, for example, by loss of appetite and weight, maintenance of weight loss, and prevention of repulsion.

Hereinafter, the present invention will be described in more detail.

The present invention provides the 1H-pyrazole-3-amide-based compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

또는

이고;[In Formula 1, A is

or

ego;

R ₁ is hydrogen, (C ₁ -C 10) alkyl, (C 3 -C 7) cycloalkyl, (C 6 -C 20) aryl or (C 6 -C 20) ar (C 1 -C 10) alkyl;

R ₂ and R ₃ independently of one another are hydrogen, (C 1 -C 10) alkyl, (C 6 -C 20) aryl, (C 6 -C 20) ar (C 1 -C 10) alkyl, (C 3 -C 7) cycloalkyl, N, O and (C3-C7) heterocycloalkyl, adamantyl, piperidino or pyrrolidino containing one or more heteroatoms selected from S or R ₂ and R ₃ are linked to (C3-C7) alkylene to form a ring May be substituted with one or more carbon atoms of the alkylene NR ₆ , O or S;

R ₄ and R ₅ are independently of each other hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl or (C6-C20) aryl;

R ₆ is hydrogen, (C 1 -C 10) alkyl or (C 1 -C 10) alkoxycarbonyl;

The alkyl, aryl, aralkyl, cycloalkyl, adamantyl or heterocycloalkyl of R ₁ , R ₂ and R ₃ may be halogen, (C 1 -C 10) alkyl, halo (C 1 -C 10) alkyl, (C 1 -C 10) Alkoxy, mono or di- (C1-C10) alkylamino, mono or di- (C6-C20) arylamino, (C3-C7) cycloalkyl, (C2-C20) heteroaryl, hydroxy, N, O and S May be further substituted with one or more substituents selected from (C3-C7) heterocycloalkyl, pyrrolidino or piperidino comprising one or more heteroatoms selected from;

Provided that R ₂ and R ₃ are not simultaneously hydrogen.]

More preferably, R ₁ is (C1-C10) alkyl, R ₂ and R ₃ are independently of each other hydrogen, (C1-C10) alkyl, (C6-C20) aryl, (C6-C20) ar (C1- C10) alkyl, (C3-C7) cycloalkyl, piperidino, adamantyl, piperidinyl, or R ₂ and R ₃ may be linked to (C2-C7) alkylene to form a ring, said alkyl The carbon atom of the lene may be substituted one or more with NR ₆ , O or S; R ₄ and R ₅ are hydrogen; R ₆ is hydrogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxycarbonyl; Alkyl, aryl, aralkyl, cycloalkyl or adamantyl of R ₁ , R ₂ and R ₃ may be halogen, (C 1 -C 10) alkyl, halo (C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, mono or It may be further substituted with one or more substituents selected from di- (C 1 -C 10) alkylamino, (C 3 -C 7) cycloalkyl, (C 2 -C 20) heteroaryl, hydroxy or piperidino.

In addition, the 1H-pyrazole-3-amide compound of Formula 1 includes the following compound.

(1) (E) -N- (4-chlorophenyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3 -Ryl) acrylamide;

(2) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-yl) -N-phenylacrylamide ;

(3) (E) -N- (3-chlorobenzyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3 -Ryl) acrylamide;

(4) (E) -N- (2-chlorobenzyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1 H-pyrazole-3 -Ryl) acrylamide;

(5) (E) -N-benzyl-3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-yl) acrylamide ;

(6) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-yl) -N- (4- Methoxybenzyl) acrylamide;

(7) (E) -N- (4-chlorobenzyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3 -Ryl) acrylamide;

(8) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1 H-pyrazol-3-yl) -N- (4- Fluorobenzyl) acrylamide;

(9) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (3- Fluorobenzyl) acrylamide;

(10) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-yl) -N-isopropylacrylic Amides;

(11) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (3- Chloropropyl) acrylamide;

(12) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-hexyl acrylamide ;

(13) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (cyclohexyl Methyl) acrylamide;

(14) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (3- (Trifluoromethyl) benzyl) acrylamide;

(15) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (4- Trifluoromethyl) benzyl) acrylamide;

(16) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1 H-pyrazole-3-yl) -N- (4- (Dimethylamino) benzyl) acrylamide;

(17) (E) -N- (3-chlorophenethyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1 H-pyrazole- 3-ryl) acrylamide;

(18) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (piperi Din-1-yl) acrylamide;

(19) (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1 H-pyrazol-3-yl) -N- (furan- 3-ylmethyl) acrylamide;

(20) (E) -4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -1- (piperi Din-4-yl) acrylamide;

(21) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N-phenylacetamide ;

(22) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-methyl-2-oxo-N -Phenylacetamide;

(23) N- (3-chlorobenzyl) -2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl)- 2-oxoacetamide;

(24) N- (3-chlorophenethyl) -2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) 2-oxoacetamide;

(25) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-cyclopentyl-2-oxoacet Amides;

(26) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-cyclohexyl-2-oxoacet Amides;

(27) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-cycloheptyl-2-oxoacet Amides;

(28) 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- (pyrrolidine-1- Yl) ethane-1,2-dione;

(29) 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- (piperidine-1- Yl) ethane-1,2-dione;

(30) 1- (azpan-1-yl) -2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl ) Ethane-1,2-dione;

(31) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N- (piperi Din-1-yl) acetamide;

(32) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (cyclohexylmethyl) -2 Oxoacetamide;

(33) 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl ) Ethane-1,2-dione;

(34) tert-butyl 4- (2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo Acetyl) piperazine-1-carboxylate;

(35) 1- (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- (4-methylpiperazin- 1-yl) ethane-1,2-dione;

(36) 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl)-2-morpholinoethane-1,2 -Dione;

(37) 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-thiomorpholinoethane-1, 2-dione;

(38) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-adamantyl-2-oxo Acetamide;

(39) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N, N-dicyclohexyl-2 Oxoacetamide;

(40) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N, N-dihexyl-2- Oxoacetamide;

(41) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-ethyl-2-oxoacetamide ;

(42) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N-propylacetamide ;

(43) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-isopropyl-2-oxoacet Amides;

(44) N-butyl-2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetamide ;

(45) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-isobutyl-2-oxoacet Amides;

(46) N-tert-butyl-2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo Acetamide;

(47) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N-pentylacetamide ;

(48) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-hexyl-2-oxoacetamide ;

(49) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-heptyl-2-oxoacetamide ;

(50) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-octyl-2-oxoacetamide ;

(51) 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (2-hydroxyethyl) 2-oxoacetamide.

The compound of Chemical Formula 1 according to the present invention may be prepared by the preparation method of Scheme 1 below. However, it is not limited to the following preparation method and can be variously prepared using a known organic synthesis reaction.

Scheme 1

)은 화학식 (Ⅷ)의 아크릴산 화합물과 아민 화합물을 사용하여 상온에서 반응하여 얻었다. 화학식 (Ⅴ)의 알콜 화합물을 합성한 후 사브롬화탄소와 트리페닐포스핀을 사용하여 화학식 (IX)의 알킬 브로마이드 화합물을 얻었다. 이렇게 얻은 화학식 (Ⅸ)의 알킬 브로마이드 화합물을 시안화나트륨을 이용하여 화학식 (Ⅹ)의 시안화 화합물을 얻었다. 화학식 (Ⅹ)의 시안화 화합물을 산화시켜 화학식 (XI)의 카르복실산 화합물을 얻었고, 염화티오닐과 에탄올을 반응시켜 화학식 (XII)의 에스테르 화합물을 얻었다. 산화셀레늄을 이용하여 디케토 에스테르 화합물인 화학식 (XIII)을 얻었고, 통상의 염기 가수분해를 통하여 화학식 (XIV)의 화합물을 얻은 후 목적 화합물인 화학식 1의 옥소아세트 아마이드 구조의 화합물(A=

)은 화학식 (XIV)의 디케토산 화합물과 아민 화합물을 사용하여 상온에서 반응하여 얻었다.Manganese dioxide was used to oxidize the alcohol compound of formula (V) to give an aldehyde compound (VI). Thus obtained compound of formula (VI) was obtained by using triethylphosphonoacetate. After obtaining a carboxylic acid compound of formula (VII) through conventional base hydrolysis, a compound of acrylamide structure of formula (I) as the target compound (A =

) Was obtained by reacting at room temperature using an acrylic acid compound of formula (VII) and an amine compound. After synthesizing the alcohol compound of Formula (V), an alkyl bromide compound of Formula (IX) was obtained using carbon tetrabromide and triphenylphosphine. The alkyl bromide compound of formula (VII) thus obtained was obtained using sodium cyanide to obtain a cyanide compound of formula (VII). The cyanated compound of formula (VII) was oxidized to obtain a carboxylic acid compound of formula (XI), and thionyl chloride and ethanol were reacted to obtain an ester compound of formula (XII). Compound (XIII), which is a diketo ester compound, was obtained using selenium oxide, and the compound of formula (1), which is an oxoacetamide structure of formula (I), was used as a target compound (A =

) Was obtained by reaction at room temperature using a diketosan compound of formula (XIV) and an amine compound.

The compound of formula (V) which is a starting material of Scheme 1 may be prepared by the following Scheme 2.

Scheme 2

The diketone compound of formula (II) and the hydrazine compound were reacted to obtain a hydrazone compound represented by formula (III). The hydrazone compound of formula (III) was refluxed in acetic acid to obtain a compound of pyrazole form represented by formula (IV). Alcohol compounds of formula (V) were obtained using lithium aluminum hydride which is the usual reducing conditions in formula (IV).

In the present invention, "pharmaceutically acceptable salts" include pharmaceutically acceptable acid-addition salts. Suitable pharmaceutically acceptable salts of compounds of formula 1 include, for example, acid-addition salts of sufficiently basic compounds of formula 1, such as inorganic or organic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid or Maleic acid). Representative salts include hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, triple luoroacetate, oxalate, besylate, palmitate, pamoate, malonate, stearate, lau Laterate, malate, borate, lactate, phosphate, hexafluorophosphate, mesylate, benzoate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, glucohepto Nate, lactobionate and laurylsulfonate salts and the like.

Throughout the specification and the appended claims, the chemical formulas or chemical names given encompass all mixtures of these stereoisomers, enantiomers, optical isomers and racemates, as well as separate enantiomers in different proportions, where such isomers and enantiomers are present. And solvates (eg hydrates) thereof.

In addition, the present invention provides a pharmaceutical composition having an antagonistic activity against CB1 containing a novel 1H-pyrazole-3-amide-based compound or a pharmaceutically acceptable salt thereof as an active ingredient, and comprising a cannabinoid receptor antagonist It is useful for treating a disease, condition, or disorder that is controlled. Diseases, symptoms, and / or disorders controlled by cannabinoid receptor antagonists include eating disorders (eg, habitual overeating, anorexia and bulimia), weight loss or control (eg, reducing calorie or food intake, and / or suppressing appetite). ), Obesity, depression, atypical depression, bipolar disorder, psychosis, schizophrenia, behavioral addiction, suppression of reward-related behavior (eg, conditional place repellence, such as cocaine and morphine-induced conditional place suppression), drug abuse, Addiction disorders, impulses, alcoholism (eg, alcohol abuse, addiction and / or dependence, such as alcoholism, treatment to reduce the need for alcohol intake and relapse), tobacco abuse (eg, smoking addiction, withdrawal symptoms and / or Dependence, such as treatment to reduce the need for tobacco smoking and prevent recurrence, dementia (loss of memory, Alzheimer's disease, aging dementia, vascular dementia, mild cognition Deterioration, cognitive impairment due to aging and mild neurocognitive impairment, etc.), sexual dysfunction in men (eg erectile dysfunction), seizure disorders, epilepsy, inflammation, digestive tract disorders (eg gastrointestinal or intestinal peristaltic dysfunction), Attention deficit behavioral disorder (ADD / ADHD), Parkinson's disease, and type 2 diabetes. In a preferred embodiment, the pharmaceutical composition is used for the treatment of weight loss, obesity, bulimia or attention deficit behavioral disorder, Parkinson's disease, Alzheimer's disease, aging dementia, vascular dementia, alcoholism.

The compounds of the present invention are particularly suitable for the treatment of obesity, for example, by loss of appetite and weight, maintenance of weight loss, and prevention of repulsion.

The patient may be administered at a dosage of about 0.1 mg to about 1,000 mg per day of the compound of the present invention. For normal adults weighing about 70 kg, dosages of about 0.01 mg to about 100 mg / kg body weight are usually sufficient. However, the general dosage range may need to vary in part depending on the age and weight of the subject to be treated, the route of administration, the particular compound to be administered, and the like. Dosage ranges and optimal dosages for particular patients can be determined within the discretion of those skilled in the art having the benefit of the present disclosure. In addition, the compounds of the present invention can be used in sustained release, controlled release and delayed release formulations, which forms are also well known to those skilled in the art.

As discussed above, the compounds of the present invention are useful for treating diseases, conditions, and / or disorders controlled by cannabinoid receptor antagonists, and thus other embodiments of the present invention provide therapeutically effective amounts of the compounds and pharmaceuticals of the present invention. It is a pharmaceutical composition comprising an acceptable excipient, diluent or carrier. Alternatively, the compounds of the present invention may be administered with at least one additional pharmaceutical agent, which is also preferably administered in the form of a pharmaceutical composition. The compounds or pharmaceutical compositions of the invention may be conventionally applied to any oral, rectal, transdermal, parenteral (eg intravenous, intramuscular, or subcutaneous), intracranial, vaginal, intraperitoneal, bladder, topical (eg Powder, ointment or mucus), or oral, nasal dosage forms.

Oral administration is generally preferred, and solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms the compound of the present invention is mixed with at least one pharmaceutically acceptable excipient, diluent or carrier. Suitable excipients, diluents or carriers include sodium citrate or dicalcium phosphate or (a) fillers or extenders (eg, starch, lactose, sugar, mannitol, silicic acid, etc.); (b) binders (eg, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sugar, acacia, etc.); (c) humectants (eg, glycerol, etc.); (d) disintegrants (eg, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain composite silicates, sodium carbonate, etc.); (e) solution retardants (eg, paraffin, etc.); (f) absorption accelerators (eg, quaternary ammonium compounds); (g) wetting agents (eg, cetyl alcohol, glycerol monostearate, etc.); (h) adsorbents (eg kaolin, bentonite, etc.); And / or (i) lubricants (eg, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and the like). In addition, in the case of capsules and tablets, the dosage form may comprise a buffer. Solid compositions of a similar type can also be used as fillers in soft or hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules and granules can be prepared using coatings and shells such as enteric coatings and others well known in the art. They may also contain a suspending agent and may be compositions which release the compounds of the invention and / or further pharmaceutical agents in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The drug may also be present in microcapsule form with one or more of the aforementioned excipients as appropriate.

The novel 1H-pyrazole-3-amide compounds according to the present invention have an excellent inhibitory effect on cannabinoid receptor 1 (CB1). Therefore, a pharmaceutical composition comprising as an active ingredient a novel 1H-pyrazole-3-amide-based compound or a pharmaceutically acceptable salt thereof according to the present invention is effective in treating weight loss, obesity, bulimia, and attention deficit behavioral disorder, It is expected to have excellent effects in the treatment of Parkinson's disease, Alzheimer's disease, aging dementia, vascular dementia and alcoholism.

Hereinafter, the embodiment of the present invention will be described in more detail, but the scope of the present invention is not limited by the following examples.

[ Manufacturing example  1] lithium 1- (4- Chlorophenyl )-4- Methoxy -2- methyl -3,4- Dioxobutan -1-oleate ( lithium  1- (4- chlorophenyl )-4- methoxy -2- methyl -3,4- dioxobutan -One- olate Manufacturing

1- (4-chlorophenyl) propan-1-one (1- (4-chlorophenyl) propan-1-one) (15.10 g, 88.85 mmol) was dissolved in 100 mL by diethylether. After cooling the above solution to -78 ℃ 98 mL of LiHMDS / THF solution was diluted with diethyl ether 200 mL and then carefully added dropwise and stirred for 1 hour. After adding dimethyl oxalate (11.54 g, 97.74 mmol) and stirred for 18 hours at room temperature. After completion of the reaction and distillation under reduced pressure to remove the solvent, the resulting solid was washed with diethyl ether to obtain 17.81 g of the target compound, and the next reaction was carried out without purification.

[ Manufacturing example  2] (Z)- methyl  4- (4- Chlorophenyl ) -2- (2- (2,4- Dichlorophenyl ) Hydrazone ) -3- methyl 4-oxobutanoate ((Z)- methyl  4- (4- chlorophenyl ) -2- (2- (2,4- dichlo rophenyl ) hydrazono ) -3- methyl -4-oxobutanoate)

Lithium 1- (4-chlorophenyl) -4-methoxy-2-methyl-3,4-dioxobutan-1-oleate (10.05 g, 38.02 mmol), a compound of Preparation Example 1, was dissolved in 150 mL of methanol. After 2- (2,4-dichlorophenyl) hydrazinium chloride (8.97 g, 42.12 mmol) was added, the reaction was terminated after stirring at room temperature for 21 hours. After distillation under reduced pressure to remove the solvent, the resulting solid was washed with diethyl ether to obtain 5.32 g of the title compound.

Melting point: 172 캜; ¹ H NMR (CDCl ₃ ): δ 7.88 (d, 2H), 7.42 (d, 3H), 7.26 (d, 1H), 7.15 (q, 1H), 4.69 (q, 1H), 3.77 (s, 3H) , 1.49 (d, 3 H); ¹³ C NMR (CDCl ₃ ): δ 198.49, 162.48, 139.09, 138.25, 134.33, 129.58, 129.55, 128.83, 128.66, 127.82, 126.35, 118.99, 125.03, 52.17, 44.81, 15.22.

[ Manufacturing example  3] methyl  5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-carboxylate ( methyl  5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazole -3- carboxylate Manufacturing

Compound (Z) -Methyl 4- (4-chlorophenyl) -2- (2- (2,4-dichlorophenyl) hydrazone) -3-methyl-4-oxobutanoate of Preparation Example 2 (5.30) g, 13.02 mmol) was dissolved in 80 mL of acetic acid and refluxed for 21 hours. After completing the reaction, the mixture was extracted with ethyl acetate, and then the water layer was extracted twice with ethyl acetate. After removing water with anhydrous sodium sulfate, the oil obtained by distillation under reduced pressure was subjected to column chromatography to obtain 4.01 g of the target compound.

Melting point: 135 ° C; ¹ H NMR (CDCl ₃ ): δ 7.37 (d, 1H), 7.32 (m, 4H), 7.08 (m, 2H), 3.95 (s, 3H), 2.34 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 162.75, 142.65, 142.31, 135.82, 135.59, 134.79, 132.75, 130.62, 130.42, 129.87, 128.67, 127.56, 126.69, 119.05, 51.92, 9.63.

[ Manufacturing example  4] (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) methanol ((5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) methanol Manufacturing

LiAlH ₄ (0.14 g, 3.80 mmol) was dissolved in 10 mL of diethyl ether and cooled to −18 ° C., followed by methyl 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl of Preparation Example 3. ) -4-methyl-1H-pyrazole-3-carboxylate (1.02 g, 2.53 mmol) was diluted in 10 mL with diethyl ether and then carefully added dropwise. After stirring for 30 minutes at room temperature, the reaction was terminated with 20 mL of 1N HCl. Extraction with ethyl acetate twice, removal of water with anhydrous sodium sulfate, distillation under reduced pressure and removal of solvent gave recrystallization of the oil to obtain 0.77 g of the target compound.

Melting point: 118 ° C; ¹ H NMR (CDCl ₃ ): δ 7.28 (t, 1H), 7.17 (m, 4H), 6.96 (m, 2H), 4.65 (s, 2H), 2.04 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 152.02, 141.66, 136.02, 135.16, 134.26, 132.72, 130.47, 130.30, 129.97, 128.62, 127.75, 127.63, 113.71, 57.49, 8.39

[ Manufacturing example  5] 5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole 3-carbaldehyde (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H-pyrazole-3-carbaldehyde)

(5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) methanol (3.02 g, 8.16 mmol) of Preparation Example 4 was subjected to chloroform. Dissolved in 50 mL and cooled to -18 ° C. Manganese dioxide (14.18 g, 163.2 mmol) was added and stirred at room temperature for 17 hours, after which the reaction was terminated. The manganese dioxide was filtered off, extracted with ethyl acetate, distilled under reduced pressure to remove the solvent, and the obtained oil was crystallized to obtain 2.31 g of the target compound.

Melting point: 201 ° C .; ¹ H NMR (CDCl ₃ ): δ 10.07 (s, 1H), 7.41 (m, 1H), 7.29 (m, 5H), 7.09 (m, 2H), 2.34 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 187.27, 149.34, 142.93, 135.87, 135.39, 134.79, 132.37, 130.44, 130.07, 129.96, 128.64, 127.68, 126.17, 117.11, 8.96

[ Manufacturing example  6] (E) -ethyl 3- (5- (4- Chlorophenyl ) -1- (2,4,- Dichlorophenyl )-4- methyl -1H-pyrazol-3-yl) Acrylate ((E)- ethyl  3- (5- (4- chlorophenyl ) -1- (2,4- dichloro phenyl )-4- methyl -1H- pyrazol Preparation of -3-yl) acrylate)

5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carbaldehyde (3.50 g, 9.75 mmol) of Preparation Example 5 was added to tetrahydrofuran. It was dissolved in 50 mL, triethylphosphonoacetate (2.58 g, 11.49 mmol) and lithium hydroxide (0.69 g, 28.72 mmol) were added thereto, and the reaction was terminated after reflux for 3 hours. After distillation under reduced pressure to remove the solvent, the mixture was extracted twice with ethyl acetate. After distillation under reduced pressure to remove the solvent, the following reaction was carried out without any further purification.

[ Manufacturing example  7] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4,- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) acrylic acid ((E) -3- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H-pyrazol-3-yl) acrylic acid Manufacturing

(E) -ethyl 3- (5- (4-chlorophenyl) -1- (2,4, -dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) acrylate of Preparation Example 6 ( 3.10 g, 7.11 mmol) and sodium hydroxide (0.71 g, 17.79 mmol) were dissolved in 10 mL of tetrahydrofuran and 10 mL of distilled water, and the reaction was terminated after 5 hours of reflux. Extracted twice with ethyl acetate and distilled under reduced pressure to remove the solvent. The resulting oil was crystallized to give 2.8 g target compound.

Melting point: 256 ° C .; _{^{1 H NMR (DMSO- d 6)}} : δ 7.56 (m, 3H), 7.49 (q, 1H), 7.39 (d, 2H), 7.18 (d, 2H), 6.46 (d, 1H), 2.15 (s, 3H); ¹³ C NMR (DMSO- d ₆ ): δ 167.15, 146.34, 141.98, 135.73, 134.73, 134.08, 133.56, 131.74, 131.46, 130.97, 129.49, 128.58, 128.16, 127.10, 120.19, 115.58, 8.90

[ Manufacturing example  8] 3- ( Bromoethyl ) -5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H-pyrazole (3- ( bromomethyl ) -5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl ) -4-methyl-1H-pyrazole)

Triphenylphosphine (58 g, 223 mmol) and carbon tetrabromide (37 g, 111 mmol) were dissolved in 50 mL of acetonitrile 100 mL dichloromethane and then (5- (4-chlorophenyl) of Preparation Example 4 -1- (2,4-Dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) methanol (27.3 g, 74.3 mmol) was slowly added thereto, followed by stirring at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and then the produced solid was subjected to column chromatography to obtain 14 g of the target compound.

Melting point 93 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.36 (s, 1H), 7.20-7.30 (m, 4H), 7.00-7.18 (d, 2H), 4.56 (s, 2H) 2.15 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 148.53, 141.71, 135.79, 135.14, 134.27, 132.56, 130.35, 130.22, 129.85, 128.53, 127.51, 127.40, 114.46, 24.01, 8.53

[ Manufacturing example  9] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3 days) Acetonitrile (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H-pyrazol-3-yl) acetonitrile)

3- (Bromoethyl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole of Preparation Example 8 was subjected to N, N-dimethylformamide. After dissolving in 30 mL sodium cyanide (4.78 g, 97.5 mmol) was added. This solution was heated at 50 ° C. for 30 min and extracted with ethyl acetate after completion of reaction. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent to obtain 11.9 g of the target compound.

Melting point 140 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.37 (s, 1H), 7.24-7.30 (m, 4H), 7.02-7.08 (d, 2H), 3.80 (s, 2H), 2.15 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 142.12, 141.77, 135.65, 135.32, 134.49, 132.58, 130.38, 130.25, 129.90, 128.62, 127.60, 127.17, 116.16, 113.71, 16.35, 8.41

[ Manufacturing example  10] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) acetic acid (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H-pyrazol-3-yl) acetic acid Manufacturing

100 mL of 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) acetonitrile of Preparation Example 9 in H ₂ O With H ₂ SO ₄ Suspended in 200 mL and refluxed this solution for 4 hours. After the reaction was completed, the resulting solid was cooled to room temperature and filtered. The solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to obtain 12.5 g of the target compound.

Melting point 148 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.35-7.38 (d, 1H), 7.22-7.30 (m, 4H), 7.02-7.10 (m, 2H), 3.80 (s, 2H), 2.06 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 174.55, 145.73, 141.56, 135.66, 135.19, 134.29, 132.74, 130.54, 130.32, 129.91, 128.57, 127.58, 127.53, 114.51, 32.76, 8.62

[ Manufacturing example  11] ethyl 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H-pyrazol-3-yl) acetate ( ethyl  2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl  )-4- methyl -1H- pyrazol -3- yl ) acetate Manufacturing

2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) acetic acid (12.5 g, 31.6 mmol) of Preparation Example 10 was prepared. After dissolving in 200 mL of ethanol, thionyl chloride (6.90 mL, 94.8 mmol) was slowly added dropwise and the solution was heated at 50 ° C. for 3 hours. After completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent to obtain 13 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 7.33-7.38 (d, 1H), 7.22-7.32 (m, 4H), 7.03-7.10 (d, 2H), 4.15-4.25 (q, 2H), 3.75 (s, 2H ), 2.09 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 169.76, 146.01, 141.07, 136.00, 134.71, 133.85, 132.55, 130.38, 130.14, 129.64, 128.31, 127.77, 127.34, 114.20, 458.03, 32.99, 15.21, 8.55

[ Manufacturing example  12] ethyl 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -2-oxoacetate ( ethyl  2- (5- (4- chlorophenyl ) -1- (2,4- dichlo rophenyl )-4- methyl -1H- pyrazol -3- yl ) -2-oxoacetate)

Ethyl 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) acetate of Preparation Example 11 (13 g, 30.7 mmol) After dissolving in 150 mL of pyridine was added SeO ₂ (17 g, 153 mmol) and refluxed for 24 hours. After the reaction was completed, 1N HCl aqueous solution was added to neutralize the pyridine, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and then distilled under reduced pressure. This solid was chromatographed to give 10.5 g of the target compound.

Melting point 131 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.38-7.42 (d, 1H) 7.26-7.34 (m, 4H), 7.00-7.08 (d, 2H), 4.30-4.50 (q, 2H), 2.35 (s, 3H) , 1.25-1.75 (t, 3 H); ¹³ C NMR (CDCl ₃ ): δ 182.81, 163.75, 145.71, 143.02, 136.07, 135.36, 135.08, 132.54, 130.66, 130.24, 130.13, 128.83, 127.73, 126.17, 119.62, 62.11, 14.16, 9.53

[ Manufacturing example  13] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -2-oxoacetic acid (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl ) -4- methyl -1H- pyrazol -3- yl )-2- oxoacetic  acid)

Ethyl 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetate of Preparation Example 12 (5.5 g , 12.6 mmol) was dissolved in 50 mL of THF, and then 37.7 mL of 1 N aqueous sodium hydroxide solution and 50 mL of water were refluxed for 6 hours. After the reaction was terminated, the mixture was cooled to room temperature, and added with 1 N aqueous hydrogen chloride solution, extracted with ethyl acetate. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and then distilled under reduced pressure to obtain 5.1 g of the target compound.

Melting point 215 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.70-7.85 (m, 2H), 7.50-7.60 (q, 1H), 7.40-7.45 (d, 2H), 7.20-7.25 (d, 2H), 2.28 (s, 3H ); ¹³ C NMR (CDCl ₃ ): δ 185.06, 165.38, 144.77, 143.21, 135.49, 135.09, 134.11, 131.61, 131.54, 131.30, 129.66, 128.75, 128.41, 125.97, 118.36, 9.19

[ Example  1] (E) -N- (4- Chlorophenyl ) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3- reel) Acrylamide ((E) -N- (4- chlorophenyl ) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) acrylamide)

4-chloroaniline (75.27 mg, 0.59 mmol) and triethylamine (118 mg, 1.18 mmol) were dissolved in 20 mL of dichloromethane, and then Compound (E) -3- (5- (4-chlorophenyl) ) -1- (2,4, -dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) acrylic acid (240 mg, 0.59 mmol) was dissolved in 10 mL of thionyl chloride, refluxed for 3 hours, distilled under reduced pressure to remove the thionyl chloride, diluted with dichloromethane, and added dropwise. After stirring at room temperature for 30 minutes, the mixture was extracted twice with dichloromethane. After distillation under reduced pressure to remove the solvent, the resulting oil was purified by column chromatography to obtain 0.13 g of the target compound.

Melting point: 225 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.73 (d, 1H), 7.52 (d, 2H), 7.35 (d, 2H), 7.24 (t, 6H), 7.04 (d, 2H), 6.78 (d, 1H) , 2.20 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 163.62, 147.29, 142.24, 136.40, 135.94, 135.63, 134.69, 132.71, 131.86, 130.49, 130.37, 130.16, 128.93, 128.78, 127.75, 127.24, 121.63, 120.88, 116.37, 8.

[ Example  2] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N-phenylacrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-phenylacrylamide)

0.12 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that aniline (24.95 mg, 0.59 mmol) was used.

Melting point: 270 ° C; ¹ H NMR (CDCl ₃ ): δ 10.25 (s, 1H), 7.76 (t, 1H), 7.66 (m, 3H), 7.54 (m, 2H), 7.44 (d, 2H), 7.31 (t, 2H) , 7.21 (d, 2 H), 6.95 (m, 2 H), 2.21 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 163.94, 147.63, 142.60, 139.83, 136.60, 135.36, 134.22, 132.46, 132.26, 131.76, 130.84, 130.29, 129.44, 129.38, 128.96, 128.02, 124.21, 124.01, 119.72, 119.72.

[ Example  3] (E) -N- (3- Chlorobenzyl ) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3- reel) Acrylamide ((E) -N- (3- chlorobenzyl ) -3- (5- (4-  chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) acrylamide)

0.12 g of the target compound was obtained by the same method and conditions as in Example 1 except for using 3-chlorobenzylamine (83.54 mg, 0.59 mmol).

Melting point: 192 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.62 (d, 1H), 7.31 (d, 1H), 7.26 (s, 1H), 7.24 (s, 1H), 7.20 (m, 3H), 7.15 (m, 2H) , 7.11 (m, 1H), 7.01 (d, 2H), 6.93 (t, 1H), 6.71 (d, 1H), 4.46 (d, 2H), 2.12 (S, 3H); ¹³ C NMR (CDCl ₃ ): δ 165.64, 147.35, 141.87, 140.21, 135.78, 135.26, 134.36, 133.96, 132.40, 130.54, 130.32, 130.24, 129.85, 129.52, 128.53, 127.53, 127.30, 127.15, 127.15, 127.07. , 115.87, 42.90, 14.14, 8.82

[ Example  4] (E) -N- (2- Chlorobenzyl ) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3- reel) Acrylamide ((E) -N- (2- chlorobenzyl ) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) acrylamide)

0.17 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that 2-chlorobenzylamine (83.54 mg, 0.59 mmol) was used.

Melting point: 163 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.64 (d, 1H), 7.40 (m, 1H), 7.38 (s, 1H), 7.33 (m, 1H), 7.27 (d, 1H), 7.24 (m, 3H) , 7.20 (m, 2H), 7.02 (d, 2H), 6.67 (d, 1H), 6.06 (t, 1H), 4.63 (d, 2H), 2.17 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 165.48, 147.46, 142.06, 136.00, 135.50, 135.42, 134.57, 133.44, 133.44, 130.70, 130.48, 130.39, 130.16, 130.10, 129.35, 128.82, 128.72, 127.71, 127.35, 127.35. , 116.10, 41.79, 8.91

[ Example  5] (E) -N-benzyl-3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H-pyrazole-3-yl) Acrylamide ((E) -N- benzyl -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) acrylamide)

0.11 g of the target compound was obtained by the same method and conditions as in Example 1 except for using benzylamine (63.22 mg, 0.59 mmol).

Melting point: 177 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.66 (d, 1H), 7.37 (t, 1H), 7.28 (m, 5H), 7.24 (m, 4H), 7.03 (m, 2H), 6.66 (d, 1H) , 5.92 (t, 1 H), 4.55 (d, 2 H), 2.17 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 165.45, 147.50, 142.04, 138.00, 136.00, 135.47, 134.55, 132.71, 130.64, 130.48, 130.39, 130.08, 128.71, 128.56, 127.68, 127.60, 127.37, 121.67, 116.05, 43.05, 43.

[ Example  6] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- (4-methoxybenzyl) Acrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (methoxybenzyl) acrylamide)

0.15 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that 4-methoxybenzylamine (56.20 mg, 0.59 mmol) was used.

Melting point: 172 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.64 (d, 1H), 7.35 (d, 1H), 7.24 (m, 4H), 7.19 (d, 2H), 7.02 (m, 2H), 6.81 (m, 2H) , 6.42 (d, 1 H), 6.07 (t, 1 H), 4.46 (d, 2H), 3.77 (s, 3H), 2.16 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 165.70, 159.05, 147.87, 142.32, 136.32, 135.74, 134.84, 132.99, 130.79, 130.71, 130.48, 130.36, 129.28, 129.01, 127.99, 127.69, 122.23, 116.30, 114.30, 114.30. , 9.27

[ Example  7] (E) -N- (4- Chlorobenzyl ) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3- reel) Acrylamide ((E) -N- (4- chlorobenzyl ) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) acrylamide)

0.18 g of the title compound was obtained in the same manner and in the same manner as in Example 1 except that 4-chlorobenzylamine (83.54 mg, 0.59 mmol) was used.

Melting point: 206 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.64 (d, 1H), 7.36 (d, 1H), 7.24 (m, 6H), 7.18 (d, 2H), 7.02 (d, 2H), 6.66 (d, 1H) , 6.13 (t, 1 H), 4.49 (d, 2 H), 2.15 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 165.57, 147.43, 142.08, 136.65, 135.97, 135.50, 134.58, 133.04, 132.68, 130.83, 130.46, 130.36, 130.07, 128.89, 128.71, 128.61, 127.68, 127.31, 121.49, 127.07. , 8.90

[ Example  8] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- (4- Fluorobenzyl ) Acrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (4-fluorobenzyl) acrylamide)

0.15 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that 4-fluorobenzylamine (73.83 mg, 0.59 mmol) was used.

Melting point: 166 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.64 (d, 1H), 7.36 (t, 1H), 7.27 (t, 1H), 7.21 (m, 5H), 7.02 (m, 2H), 6.94 (m, 2H) , 6.66 (d, 1 H), 6.19 (t, 1 H), 4.49 (d, 2H), 2.15 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 165.86, 163.40, 160.96, 147.78, 142.38, 136.29, 135.80, 134.88, 134.25, 132.99, 131.04, 130.78, 130.69, 130.38, 129.60, 129.52, 129.24, 129.02, 128.00 263 128.00 , 116.36, 115.76, 115.55, 43.37, 9.23

[ Example  9] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- (3- Fluorobenzyl ) Acrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (3-fluorobenzyl) acrylamide)

0.14 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that 3-fluorobenzylamine (73.83 mg, 0.59 mmol) was used.

Melting point: 191 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.67 (d, 1H), 7.38 (s, 1H), 7.24 (m, 5H), 7.03 (t, 3H), 6.92 (m, 2H), 6.68 (d, 1H) , 6.01 (s, 1 H), 4.55 (d, 2 H), 2.17 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 165.58, 147.43, 142.09, 135.99, 135.51, 134.59, 132.72, 130.94, 130.48, 130.38, 130.23, 130.10, 130.01, 128.72, 128.56, 127.70, 127.33, 123.02, 122.99, 121.40, 121.40 , 114.50, 114.35, 114.28, 114.14, 43.23, 8.93

[ Example  10] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N-isopropylacrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-isopropylacrylamide)

0.12 g of the target compound was obtained by the same method and conditions as in Example 1 except for using isopropylamine (34.87 mg, 0.59 mmol).

Melting point: 187 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.60 (d, 1H), 7.38 (s, 1H), 7.26 (d, 3H), 7.03 (d, 2H), 6.61 (d, 1H), 5.59 (d, 1H) , 4.16 (m, 1 H), 2.17 (s, 3 H), 1.19 (d, 6 H); ¹³ C NMR (CDCl ₃ ): δ 164.66, 147.58, 141.93, 135.99, 135.37, 134.46, 132.66, 130.44, 130.38, 130.01, 129.85, 128.65, 127.64, 127.35, 122.40, 115.86, 41.55, 22.85, 8.93

[ Example  11] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- (3- Chloropropyl ) Acrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (3-chloropropyl) acrylamide)

0.11 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that 3-chloropropylamine (76.71 mg, 0.59 mmol) was used.

Melting point: 198 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.17 (d, 1H), 7.38 (m, 1H), 7.25 (m, 4H), 7.03 (q, 2H), 6.65 (d, 1H), 5.98 (t, 1H) , 3.58 (t, 2H), 3.51 (q, 2H), 2.17 (s, 3H), 2.02 (m, 2H); ¹³ C NMR (CDCl ₃ ): δ 165.85, 147.43, 142.04, 135.94, 135.48, 134.53, 132.67, 130.45, 130.38, 130.07, 128.69, 127.70, 127.29, 121.60, 116.05, 42.59, 37.22, 32.06, 8.90

[ Example  12] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N-hexylacrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-hexylacrylamide)

0.11 g of the target compound was obtained by the same method and conditions as in Example 1 except for using hexylamine (59.70 mg, 0.59 mmol).

Melting point: 167 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.61 (d, 1H), 7.37 (d, 1H), 7.24 (m, 4H), 7.03 (d, 2H), 6.64 (d, 1H), 5.79 (t, 1H) , 3.33 (q, 2H), 2.17 (s, 3H), 1.50 (m, 2H), 1.29 (m, 6H), 0.86 (t, 3H); ¹³ C NMR (CDCl ₃ ): δ 165.46, 147.58, 141.93, 135.98, 135.38, 134.46, 132.65, 130.42, 130.38, 130.01, 129.84, 128.65, 127.65, 127.34, 122.15, 115.91, 39.75, 31.51, 29.62, 26.61, 26.61. , 14.11, 8.89

[ Example  13] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- blood Razol-3-yl) -N- ( Cyclohexylmethyl ) Acrylamide ((E) -3- (5- (4-chlorophenyl) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -N- ( cyclohexylmethyl ) acrylamide)

0.13 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that cyclohexylmethylamine (66.79 mg, 0.59 mmol) was used.

Melting point: 120 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.61 (d, 2H), 7.38 (s, 1H), 7.26 (t, 2H), 7.03 (d, 2H), 6.66 (d, 1H), 5.87 (t, 1H) , 3.20 (t, 2H), 2.17 (s, 3H), 1.64 (m, 5H), 1.48 (m, 1H), 1.12 (m, 4H), 0.86 (m, 3H); ¹³ C NMR (CDCl ₃ ): δ 165.56, 147.58, 141.90, 135.97, 135.36, 134.43, 132.64, 130.40, 130.36, 129.99, 129.85, 128.62, 127.62, 127.32, 122.19, 115.88, 45.87, 38.06, 30.83, 26.4185 , 8.87

[ Example  14] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- (3- ( Trifluoromethyl )benzyl) Acrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -N- (3- (trifluoromethyl) benzyl) acrylamide)

0.13 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that 3- (trifluoromethyl) benzylamine (100 mg, 0.59 mmol) was used.

Melting point: 185 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.67 (d, 1H), 7.46 (t, 3H), 7.37 (m, 2H), 7.25 (m, 4H), 7.02 (d, 2H), 6.69 (d, 1H) , 6.19 (t, 1 H), 4.60 (d, 2 H), 2.17 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 165.69, 147.36, 142.06, 139.16, 137.41, 135.86, 135.57, 134.53, 132.94, 132.58, 130.95, 130.83, 130.50, 130.42, 130.32, 130.32, 128.94, 128.68, 127.67, 127.15, 127.67 , 124.05, 124.01, 122.46, 121.32, 119.76, 116.10, 43.15, 8.87

[ Example  15] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- (4- ( Trifluoromethyl )benzyl) Acrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -N- (4- (trifluoromethyl) benzyl) acrylamide)

0.13 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that 4- (trifluoromethyl) benzylamine (100 mg, 0.59 mmol) was used.

Melting point: 247 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.68 (d, 1H), 7.55 (d, 2H), 7.38 (d, 3H), 7.24 (m, 4H), 7.03 (d, 2H), 6.70 (d, 1H) , 6.07 (t, 1 H), 4.61 (d, 2 H), 2.17 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 165.99, 147.67, 142.44, 136.26, 135.86, 134.92, 133.01, 131.42, 130.78, 130.67, 130.42, 129.05, 128.03, 127.97, 127.57, 125.80, 125.77, 121.46, 116.22.

[ Example  16] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- (4- ( Dimethylamino )benzyl) Acrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -N- (4- (dimethylamino) benzyl) acrylamide)

0.13 g of the title compound was obtained in the same manner as the Example 1 except for using 4- (aminomethyl) -N, N-dimethylbenzeneamine (88.63 mg, 0.59 mmol).

Melting point: 208 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.64 (d, 1H), 7.35 (s, 1H), 7.24 (m, 4H), 7.14 (d, 2H), 7.02 (d, 2H), 6.61 (t, 3H) , 5.94 (s, 1H), 4.43 (d, 2H), 2.91 (s, 6H), 2.16 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 165.20, 149.81, 147.54, 141.90, 135.94, 135.33, 134.42, 132.61, 130.42, 130.36, 130.21, 129.98, 128.76, 128.62, 127.62, 127.34, 122.03, 115.89, 112.52, 43.42, 43.42. , 8.94

Example 17 (E) -N- (3-chlorophenylethyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyra Sol-3-yl) acrylamide ((E) -N- (3-chlorophenylethyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol- Preparation of 3-yl) acrylamide)

0.13 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that 3-chlorophenylethylamine (91.82 mg, 0.59 mmol) was used.

Melting point: 70 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.61 (d, 1H), 7.36 (s, 1H), 7.25 (t, 4H), 7.17 (m, 3H), 7.02 (t, 3H), 6.60 (d, 1H) , 5.92 (t, 1 H), 3.59 (q, 2 H), 2.82 (t, 2 H), 2.16 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 165.94, 147.78, 142.35, 141.04, 136.28, 135.79, 134.85, 134.50, 132.98, 130.78, 130.72, 130.57, 130.38, 130.06, 129.02, 129.00, 128.03, 127.63, 127.14, 127.14, 127.14 , 116.39, 40.96, 35.71, 9.23

[ Example  18] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- (piperidin-1-yl) Acrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (piperidin-1-yl) acrylamide)

0.13 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that 1-aminopiperidine (59.10 mg, 0.59 mmol) was used.

Melting point: 184 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.68 (d, 1H), 7.38 (d, 1H), 7.30 (s, 1H), 7.27 (m, 1H), 7.26 (q, 1H), 7.24 (s, 1H) , 7.23 (d, 1H), 7.05 (d, 1H), 7.03 (d, 1H), 3.56 (d, 4H), 2.19 (s, 3H), 1.64 (m, 6H); ¹³ C NMR (CDCl ₃ ): δ 164.86, 147.99, 141.86, 136.04, 135.38, 134.41, 132.74, 131.16, 130.47, 130.42, 130.01, 128.60, 127.64, 127.45, 118.60, 115.93, 46.92, 43.31, 26.83, 25.83, 25.83. , 8.76

[ Example  19] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- ( Furan -3- Yl methyl ) Acrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (furan-3-ylmethyl) acrylamide)

0.13 g of the title compound was obtained in the same manner and in the same manner as in Example 1, except that furan-3-ylmethanamine (57.30 mg, 0.59 mmol) was used.

mp 123 ° C .; ¹ H NMR (CDCl ₃ ): δ 7.70 (d, 1H), 7.37 (t, 1H), 7.33 (m, 9H), 7.04 (q, 2H), 6.69 (d, 1H), 5.95 (t, 1H) , 4.56 (d, 2 H), 2.17 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 165.452, 147.501, 142.040, 137.998, 135.996, 135.473, 134.547, 132.712, 130.642, 130.475, 130.391, 130.080, 128.708, 128.564, 127.684, 127.600, 127.365, 121.670, 116.05094.

[ Example  20] (E) -3- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- (piperidin-4-yl) Acrylamide ((E) -3- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (piperidin-4-yl) acrylamide)

0.13 g of the target compound was obtained by the same method and conditions as in Example 1 except for using piperidin-4-ylmethanamine (59.09 mg, 0.59 mmol).

Melting point: 248 ° C .; ¹ H NMR (CDCl ₃ ): δ 9.23 (d, 2H), 7.60 (d, 1H), 7.35 (s, 1H), 7.25 (d, 4H), 7.01 (d, 2H), 6.79 (s, 1H) , 3.24 (s, 2H), 2.86 (s, 3H), 2.14 (s, 3H), 1.91 (s, 3H), 1.66 (s, 2H); ¹³ C NMR (CDCl ₃ ): δ 166.271, 147.546, 142.253, 135.806, 135.609, 134.616, 132.583, 130.520, 130.414, 130.035, 128.693, 127.851, 127.130, 122.519, 166.005, 44.389, 44.055, 34.067, 26.604267.

[ Example  21] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -2-oxo-N-phenylacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- p yrazol-3-yl) -2-oxo-N-phenylacetamide)

2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetic acid of Preparation Example 13 (150 mg, 0.366 mmol) was dissolved in 10 mL of dichloromethane, oxalyl chloride 2 M solution in dichloromethane (0.545 mL, 1.10 mmol) was added thereto, and the mixture was refluxed for 2 hours. The solution was distilled under reduced pressure, and then dissolved in 5 mL of dichloromethane. Then, aniline (106 μl, 1.10 mmol) was slowly added dropwise to the solution dissolved in 5 mL of dichloromethane. After completion of the reaction, the solvent was distilled off under reduced pressure and column chromatography gave 80 mg of the title compound.

¹ H NMR (CDCl ₃ ): δ 7.66-7.72 (d, 2H), 7.42-7.46 (d, 1H), 7.30-7.65 (m, 5H), 7.10-7.20 (t, 2H), 7.04-7.09 (d , 2H), 2.35 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 181.40, 168.65, 157.88, 146.64, 146.41, 142.87, 136.79, 136.22, 135.22, 135.17, 132.45, 130.74, 130.25, 128.90, 127.89, 126.08, 124.95, 121.08, 119.119, 119.119.

[ Example  22] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- methyl 2-oxo-N- Phenylacetamide (2- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-methyl-2-oxo-N-phenylacetamide)

70 mg of the target compound were obtained by the same method and conditions as in Example 21, except that N-methylaniline (120 μl, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 2.08 (s, 3H), 3.36 (s, 3H), 6.87-6.92 (d, 2H), 7.16-7.20 (m, 7H), 7.23-7.27 (m, 2H), 7.34-7.38 (d, 1 H); ¹³ C NMR (CDCl ₃ ): δ 186.78, 166.76, 146.58, 142.67, 141.16, 136.06, 135.47, 134.92, 132.77, 130.60, 130.46, 130.03, 129.13, 128.85, 128.73, 127.71, 127.12, 126.18, 118.18.

Example 23 N- (3-chlorobenzyl) -2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3- Japan) -2-oxoacetamide (N- (3-chlorobenzyl) -2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetamide)

130 mg of the target compound were obtained by the same method and conditions as in Example 21, except using 3-chlorobenzylamine (134 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.32-7.40 (m, 3H), 7.25-7.30 (m, 4H), 7.18-7.24 (m, 3H), 7.02-7.08 (d, 2H), 4.52-4.62 (d , 2H), 2.39 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 162.26, 144.32, 142.88, 140.28, 135.75, 135.56, 134.68, 134.17, 132.61, 130.57, 130.26, 130.07, 129.67, 128.69, 127.69, 127.60, 127.31, 126.86, 125.74, 125.74, 125.74 , 9.56

[ Example  24] N- (3- Chlorophenethyl ) -2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3- days) -2- Oxoacetamide (N- (3- chlorophenethyl ) -2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetamide)

110 mg of the target compound were obtained by the same method and conditions as in Example 21, except that 2- (3-chlorophenyl) ethylamine (153 μl, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.27-7.33 (d, 1H), 7.04-7.20 (m, 7H), 6.93-7.02 (m, 4H), 3.40-3.60 (t, 2H), 2.70-2.90 (t , 2H), 2.29 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 162.35, 144.48, 142.72, 140.78, 135.63, 135.56, 134.60, 133.95, 132.61, 130.54, 130.22, 130.05, 129.56, 128.72, 128.65, 127.64, 126.89, 126.77, 126.38. , 35.74, 9.50

[ Example  25] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- Cyclopentyl -2- Oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-cyclopentyl-2-oxoacetamide)

85 mg of the target compound were obtained by the same method and conditions as in Example 21, except for using cyclopentylamine (109 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.92-8.06 (d, 1H), 7.24-7.34 (m, 2H), 7.12-7.22 (m, 3H), 6.90-7.00 (d, 2H), 4.15-4.30 (m , 1H), 2.17 (s, 3H), 1.80-1.90 (m, 2H), 1.55-1.60 (m, 2H), 1.40-1.50 (m, 4H); ¹³ C NMR (CDCl ₃ ): δ 182.07, 160.25, 146.22, 142.27, 135.60, 134.87, 134.65, 131.92, 130.39, 130.08, 129.69, 128.45, 127.50, 125.86, 120.05, 51.07, 32.51, 23.40, 9.61

[ Example  26] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- Cyclohexyl -2- Oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-cyclohexyl-2-oxoacetamide)

130 mg of the target compound were obtained by the same method and conditions as in Example 21 except for using cyclohexylamine (127 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.90-8.00 (d, 1H), 7.40-7.46 (d, 1H), 7.28-7.38 (m, 4H), 7.04-7.10 (d, 2H), 3.85-3.98 (m , 1H), 2.31 (s, 3H), 1.90-2.00 (m, 2H), 1.68-1.75 (m, 2H), 1.55-1.65 (m, 1H), 1.25-1.45 (m, 5H); ¹³ C NMR (CDCl ₃ ): δ 182.40, 172.97, 159.81, 146.39, 142.37, 135.75, 135.03, 134.81, 132.13, 130.50, 130.11, 129.90, 128.60, 127.60, 126.02, 120.26, 48.25, 32.31, 25.26, 24.26, 24.26

Example 27 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-cycloheptyl-2 Preparation of oxoacetamide (2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-cycloheptyl-2-oxoacetamide)

60 mg of the target compound were obtained by the same method and conditions as in Example 21, except for using cycloheptylamine (140 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.74-7.88 (d, 1H), 7.43 (s, 1H), 7.24-7.34 (m, 4H) 7.00-7.10 (d, 2H) 3.80-3.90 (m, 1H), 1.90-2.05 (m, 2H), 1.45-1.70 (m, 10H)

Example 28 1- (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- (pyrrolidine- 1-yl) ethane-1,2-dione (1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- ( Preparation of pyrrolidin-1-yl) ethane-1,2-dione)

60 mg of the target compound were obtained by the same method and conditions as in Example 21, except for using pyrrolidine (97 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.38-7.42 (s, 1H), 7.29-7.32 (m, 1H), 7.26-7.28 (m, 2H), 7.23-7.25 (m, 2H), 7.00-7.05 (d , 2H), 3.58-3.65 (t, 2H), 3.46-3.52 (t, 2H), 2.36 (s, 3H), 1.90-2.00 (m, 4H)

[ Example  29] 1- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -2- (piperidin-1-yl) ethane-1,2- Dion (1- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol Preparation of -3-yl) -2- (piperidin-1-yl) ethane-1,2-dione)

80 mg of the target compound were obtained by the same method and condition as in Example 21, except for using piperidine (108 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.39 (s, 1H), 7.23-7.32 (m, 4H), 7.00-7.08 (d, 2H), 3.60-3.70 (t, 2H), 3.30-3.40 (t, 2H ), 2.37 (s, 3H), 1.60-1.70 (m, 6H)

[ Example  30] 1- ( Azepan -1-yl) -2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl ) -4-methyl-1H- Pyrazole -3-yl) ethane-1,2- Dion (One-( azepan -One- yl ) -2- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) ethane-1,2-dione)

70 mg of the target compound were obtained by the same method and conditions as in Example 21, except that hexamethyleneimine (124 µl, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.40-7.50 (d, 1H), 7.26-7.32 (m, 4H), 7.02-7.08 (d, 2H), 3.00-3.12 (t, 4H), 2.55-2.68 (t , 4H), 2.18 (s, 3H), 2.05 (s, 3H)

Example 31 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N- ( Piperidin-1-yl) acetamide (2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N Preparation of-(piperidin-1-yl) acetamide)

90 mg of the target compound were obtained by the same method and conditions as in Example 21, except that aminopiperidine (119 μl, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.32 (s, 1H), 7.15-7.25 (m, 4H), 6.92-7.00 (d, 2H), 3.50-3.70 (t, 2H), 3.20-3.40 (t, 2H ), 2.30 (s, 3H), 1.50-1.60 (m, 6H)

[ Example  32] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- ( Cyclomethyl ) -2-oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl Preparation of -1H-pyrazol-3-yl) -N- (cyclohexylmethyl) -2-oxoacetamide)

80 mg of the target compound were obtained by the same method and conditions as in Example 21 except for using cyclohexylmethylamine (143 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.42 (s, 1H), 7.27-7.30 (m, 4H), 7.02-7.06 (m, 2H), 3.70-3.80 (m, 2H), 3.40-3.50 (m, 2H ), 2.48-2.53 (m, 2H), 2.40-2.45 (m, 2H), 2.37 (s, 3H), 2.30-2.35 (d, 4H); ¹³ C NMR (CDCl ₃ ): δ 182.17, 160.91, 146.61, 142.66, 136.06, 135.20, 135.09, 132.44, 130.65, 130.20, 130.10, 128.82, 127.74, 126.13, 120.58, 45.87, 37.62, 30.76, 26.29, 25.78, 25.78

[ Example  33] 1- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -2- (piperazin-1-yl) ethane-1,2- Dion (1- (5- (4-chlorophenyl) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl )-2-( piperazin -One- yl ) ethane -1,2- dione Manufacturing

Tert-butyl 4- (2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetyl) pipe Razine-1-carboxylate (150 mg, 0.260 mmol) was dissolved in 10 mL of 4 N HCl in dioxane and reacted for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure and column chromatography was carried out to obtain 20 mg of the target compound.

¹ H NMR (CDCl ₃ ): δ 7.40 (s, 1H), 7.25-7.32 (m, 4H), 7.00-7.06 (d, 2H), 3.64-3.72 (t, 2H), 3.36-3.44 (t, 2H ), 2.90-2.96 (t, 2H), 2.80-2.90 (t, 2H), 2.36 (s, 3H); ¹³ C NMR (CDCl ₃ ): δ 187.74, 165.29, 146.42, 143.08, 136.05, 135.33, 135.04, 132.52, 130.61, 130.32, 130.07, 128.83, 127.71, 126.14, 119.16, 47.29, 45.93, 45.47, 42.27, 53.53

[ Example  34] Tert - Butyl  4- (2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl ) -4-methyl-1H- Pyrazole -3- days) -2- Oxoacetyl Piperazine-1- Carboxylate ( tert - butyl  4- (2- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetyl) piperazine-1-carboxylate)

300 mg of the target compound was obtained in the same manner and in the same manner as in Example 21, except that tert-butyl 1-piperazinecarboxylate (409 mg, 2.20 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.38-7.43 (m, 1H), 7.25-7.32 (m, 4H), 7.03-7.08 (m, 2H), 3.68 (s, 2H), 3.41 (s, 2H), 2.37 (s, 3 H), 1.47 (s, 9 H); ¹³ C NMR (CDCl ₃ ): δ 187.25, 165.28, 153.98, 146.25, 143.11, 135.97, 135.16, 134.95, 132.39, 130.51, 130.19, 129.94, 128.71, 127.63, 125.94, 119.08, 80.17, 45.74, 40.95, 26.95

[ Example  35] 1- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -2- (4- Methylpiperazine -1-yl) ethane-1,2- Dion (1- (5- (4- chlorophenyl Preparation of) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- (4-methylpiperazin-1-yl) ethane-1,2-dione)

80 mg of the target compound were obtained by the same method and condition as in Example 21, except for using 1-methylpiperazine (122 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.47 (s, 1H), 7.38-7.43 (d, 1H), 7.26-7.35 (m, 4H), 7.02-7.07 (m, 2H), 2.30 (s, 3H), 2.06-2.35 (m, 10H), 1.66-1.76 (m, 6H)

[ Example  36] 1- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3- days) -2- Morpholinoethane -1,2- Dion (1- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -2-morpholinoethane-1,2-dione)

90 mg of the target compound were obtained by the same method and conditions as in Example 21, except that morpholine (97 µl, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.32 (s, 1H), 7.14-7.22 (m, 4H), 6.92-7.00 (d, 6H), 3.56-3.90 (m, 6H), 3.30-3.40 (m, 2H ), 2.27 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 187.26, 165.11, 146.19, 143.04, 135.93, 135.12, 134.90, 132.33, 130.49, 130.19, 129.91, 128.69, 127.62, 125.89, 119.01, 66.31, 46.20, 41.34, 29.56, 9.35

[ Example  37] 1- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3- days) -2- Thiomorpholinoethane -1,2- Dion (1- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-thiomorpholinoethane-1,2-dione)

105 mg of the target compound were obtained by the same method and conditions as in Example 21, except that thiomorpholine (104 µl, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.32 (s, 1H), 7.16-7.25 (m, 4H), 6.93-7.00 (d, 2H), 3.87 (s, 4H), 3.55-3.65 (m, 2H), 2.55-2.70 (s, 4 H), 2.28 (s, 3 H); ¹³ C NMR (CDCl ₃ ): δ 187.32, 165.39, 146.22, 143.10, 136.01, 135.15, 134.96, 132.36, 130.51, 130.22, 129.99, 128.73, 127.68, 125.94, 119.12, 47.63, 43.49, 27.49, 27.08, 42.42

[ Example  38] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole  -3-yl) -N- Adamantyl 2-oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3-yl) -N-adamantyl-2-oxoacetamide)

60 mg of the target compound were obtained by the same method and conditions as in Example 21, except that 1-adamantylamine (150 mg, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.92-8.06 (d, 1H), 7.24-7.34 (m, 2H), 7.12-7.22 (m, 3H), 6.90-7.00 (d, 2H), 4.15-4.30 (m , 1H), 2.17 (s, 3H), 1.80-1.90 (m, 2H), 1.55-1.60 (m, 2H), 1.40-1.50 (s 4H); ¹³ C NMR (CDCl ₃ ): δ 183.18, 159.37, 146.59, 142.42, 135.91, 135.37, 134.95, 132.45, 130.68, 130.31, 130.10, 128.78, 127.73, 126.38, 120.56, 52.43, 14.05, 36.24, 29.34, 10.08

[ Example  39] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N, N- Dicyclohexyl -2- Oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -N, N- dicyclohexyl -2-oxoacetamide)

100 mg target compound was obtained by the same method and condition as in Example 21, except for using dicyclohexylamine (171 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.28-7.35 (m, 1H), 7.25-7.28 (m, 2H), 7.23-7.27 (m, 2H), 7.00-7.10 (d, 2H), 2.05 (s, 3H ), 1.50-1.65 (m, 10H), 1.00-1.20 (m, 10H)

[ Example  40] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N, N- Dihexyl -2- Oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3-yl) -N, N-dihexyl-2-oxoacetamide)

90 mg of the target compound were obtained by the same method and condition as in Example 21, except for using dihexylamine (260 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.36-7.40 (t, 1H), 7.27-7.31 (m, 2H), 7.23-7.26 (m, 2H), 7.00-7.04 (d, 2H), 3.40-3.50 (t , 2H), 3.15-3.25 (t, 2H), 2.37 (s, 3H), 1.55-1.65 (m, 3H), 1.30-1.40 (m, 3H), 1.20-1.30 (m, 10H), 0.80-0.90 (q, 6H)

[ Example  41] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N-ethyl-2-oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -N-ethyl-2-oxoacetamide)

90 mg of the target compound were obtained by the same method and conditions as in Example 21, except that ethyl amine (0.564 mL, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.83 (s, 1H), 7.30-7.35 (d, 1H), 7.25-7.29 (d, 1H), 7.18-7.24 (d, 3H), 6.92-7.00 (d, 2H ), 3.30-3.40 (q, 2H), 2.22 (s, 3H), 1.10-1.20 (t, 3H); ¹³ C NMR (CDCl ₃ ): δ 182.40, 160.90, 146.40, 142.55, 135.92, 135.11, 134.92, 132.33, 130.59, 130.24, 129.97, 128.69, 127.68, 126.07, 120.38, 34.51, 14.43, 9.85

[ Example  42] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -2-oxo-N-propylacetamide (2- (5- (4- chlorophenyl ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N-propylacetamide)

70 mg of the target compound were obtained in the same manner as the Example 21, except for using propylamine (90 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.96 (s, 1H), 7.30-7.34 (d, 1H), 7.24-7.30 (d, 1H), 7.14-7.24 (m, 3H), 6.92-7.02 (d, 2H ), 3.20-3.40 (q, 2H), 2.22 (s, 3H), 1.50-1.60 (m, 2H), 0.80-0.90 (t, 3H); ¹³ C NMR (CDCl ₃ ): δ 182.23, 160.96, 146.42, 142.55, 135.91, 135.07, 134.91, 132.29, 130.57, 130.20, 129.94, 128.67, 127.67, 126.02, 120.38, 41.24, 22.38, 11.37, 9.84

[ Example  43] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- Isopropyl -2- Oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H-pyrazol-3-yl) -N-isopropyl-2-oxoacetamide)

60 mg of the target compound were obtained by the same method and conditions as in Example 21, except for using isopropylamine (94 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.58-7.66 (d, 1H), 7.30-7.36 (d, 1H), 7.16-7.24 (m, 4H), 6.94-7.00 (d, 2H), 4.05-4.20 (q , 1H), 2.15-2.30 (s, 3H), 1.10-1.20 (d, 6H); ¹³ C NMR (CDCl ₃ ): δ 182.60, 160.01, 146.46, 142.47, 135.88, 135.16, 134.93, 132.28, 130.60, 130.18, 130.04, 128.72, 127.69, 126.15, 120.41, 41.83, 22.40, 9.89

[ Example  44] N-butyl-2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -2-oxoacetamide (N- butyl -2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H-pyrazol-3-yl) -2-oxoacetamide)

60 mg of the target compound were obtained by the same method and conditions as in Example 21, except that butylamine (109 μl, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.85 (s, 1H), 7.40-7.45 (d, 1H), 7.26-7.32 (m, 4H), 7.02-7.06 (d, 2H), 3.38-3.46 (q, 2H ), 2.33 (s, 3H), 1.54-1.60 (q, 2H), 1.36-1.42 (q, 2H), 0.90-0.96 (t, 3H); ¹³ C NMR (CDCl ₃ ): δ 182.20, 160.93, 146.41, 142.56, 135.91, 135.08, 134.91, 132.29, 130.57, 130.21, 129.92, 128.67, 127.65, 126.02, 120.36, 39.29, 31.03, 19.98, 13.63, 9.81

[ Example  45] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- Isobutyl -2- Oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3-yl) -N-isobutyl-2-oxoacetamide)

70 mg of the target compound were obtained by the same method and conditions as in Example 21 except for using isobutylamine (108 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 8.13 (s, 1H), 7.25-7.33 (m, 2H), 7.16-7.24 (d, 3H), 6.93-7.02 (d, 2H), 3.10-3.20 (s, 2H ), 2.20 (s, 3H), 1.70-1.80 (m, 1H), 0.80-1.90 (d, 6H); ¹³ C NMR (CDCl ₃ ): δ 181.94, 160.87, 146.33, 142.48, 135.79, 134.94, 134.80, 132.13, 130.48, 130.13, 129.80, 128.56, 127.59, 125.89, 120.25, 46.74, 28.09, 19.95, 9.74

[ Example  46] N- Tert - Butyl -2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -2-oxoacetamide (N- tert - butyl -2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl ) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetamide)

80 mg of the target compound were obtained by the same method and conditions as in Example 21, except that tertbutylamine (115 μl, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.70 (s, 1H), 7.28-7.33 (m, 1H), 7.16-7.26 (m, 4H), 6.92-7.00 (m, 2H), 2.20 (s, 3H), 1.34 (s, 9 H); ¹³ C NMR (CDCl ₃ ): δ 182.72, 159.56, 146.45, 142.35, 135.78, 135.16, 134.81, 132.23, 130.56, 130.19, 129.92, 128.64, 127.63, 126.16, 120.39, 51.59, 28.30, 9.90

[ Example  47] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -2-oxo-N- Pentylacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -2-oxo-N-pentylacetamide)

80 mg of the target compound were obtained by the same method and conditions as in Example 21, except for using pentylamine (128 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.98 (s, 1H), 7.40-7.45 (d, 1H), 7.27-7.35 (m, 4H), 7.03-7.10 (d, 2H), 3.36-3.46 (q, 2H ), 2.32 (s, 3H), 1.54-1.62 (t, 2H), 1.28-1.36 (q, 4H), 0.80-0.88 (t, 3H); ¹³ C NMR (CDCl ₃ ): δ 182.27, 160.89, 146.55, 142.64, 136.03, 135.19, 135.03, 132.44, 130.64, 130.24, 130.06, 128.78, 127.72, 126.13, 120.50, 39.64, 29.05, 28.80, 22.30, 13.98 9.

[ Example  48] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- Hexyl 2-oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -N-hexyl-2-oxoacetamide)

70 mg of the target compound were obtained by the same method and conditions as in Example 21, except that hexylamine (145 μl, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 7.86 (s, 1H), 7.38-7.42 (m, 1H), 7.24-7.32 (m, 4H), 7.02-7.08 (q, 2H), 3.35-3.45 (1, 2H ), 2.32 (s, 3H), 1.53-1.63 (q, 2H), 1.30-1.37 (m, 2H), 1.20-1.28 (m, 4H), 0.80-0.90 (t, 3H); ¹³ C NMR (CDCl ₃ ): δ 181.99, 160.93, 146.28, 142.46, 135.78, 134.96, 134.78, 132.14, 130.48, 130.19, 129.74, 128.53, 127.56, 125.89, 120.18, 39.44, 31.17, 28.83, 26.39, 22.39, 22. , 9.68

[ Example  49] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- Heptyl -2- Oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -N-heptyl-2-oxoacetamide)

70 mg of the target compound were obtained by the same method and conditions as in Example 21, except that heptylamine (163 μl, 1.10 mmol) was used.

¹ H NMR (CDCl ₃ ): δ 8.00 (s, 1H), 7.25-7.33 (m, 2H), 7.16-7.23 (d, 3H), 6.95-7.05 (d, 2H), 3.25-3.40 (q, 2H ), 2.21 (s, 3H), 1.45-1.55 (q, 2H), 1.10-1.25 (m, 8H), 0.70-0.80 (t, 3H); ¹³ C NMR (CDCl ₃ ): δ 182.21, 160.85, 146.58, 142.66, 136.06, 135.19, 135.06, 132.46, 130.66, 130.23, 130.11, 128.81, 127.76, 126.13, 120.58, 39.70, 31.75, 29.14, 28.95, 26.9561 26 , 14.15, 9.97

[ Example  50] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- Octyl -2- Oxoacetamide (2- (5- (4- chlorophenyl ) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -N-octyl-2-oxoacetamide)

80 mg of the target compound were obtained by the same method and conditions as in Example 21, except for using octylamine (182 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 7.95 (s, 1H), 7.30-7.36 (d, 1H), 7.25-7.29 (d, 1H), 7.18-7.24 (m, 3H), 6.93-7.00 (d, 2H ), 3.25-3.40 (q, 2H), 2.22 (s, 3H), 1.45-1.55 (q, 2H), 1.10-1.30 (m, 10H), 0.70-0.80 (t, 3H); ¹³ C NMR (CDCl ₃ ): δ 182.09, 160.83, 146.45, 142.57, 135.94, 135.09, 134.94, 132.32, 130.58, 130.22, 129.96, 128.69, 127.68, 126.02, 120.42, 39.61, 31.68, 29.14, 29.03, 26.89, 26.89 , 14.08, 9.87

[ Example  51] 2- (5- (4- Chlorophenyl ) -1- (2,4- Dichlorophenyl )-4- methyl -1H- Pyrazole -3-yl) -N- (2-hydroxyethyl) -2- Oxoacetamide (2- (5- (4-chlorophenyl) -1- (2,4- dichlorophenyl )-4- methyl -1H- pyrazol -3- yl ) -N- (2- hydroxyethyl ) -2-oxoacetamide)

20 mg of the target compound were obtained by the same method and condition as in Example 21, except for using 2-aminoethanol (66 μl, 1.10 mmol).

¹ H NMR (CDCl ₃ ): δ 8.06 (s, 1H), 7.34 (s, 1H), 7.18-7.26 (m, 4H), 6.94-7.02 (d, 2H), 3.70-3.80 (t, 2H), 3.45-3.55 (q, 2H), 2.25 (s, 3H)

[ Test Example ] CB1 Inhibitory effect on

The cannabinoid receptor 1 (CB1) fraction was applied in detail by Wiley et al. (J Pharmacol Exp Ther. 1998, 285 (3): 9951004). To briefly explain the acquisition process of the receptor protein fraction, 10-week-old SpragueDawley rats were bleeded to death, and CB1 was used to isolate the cerebral cortex by removing the brain except the cerebellum. The isolated organs were added to the buffer at 5 times volume, crushed, homogenized, and centrifuged to obtain final receptor protein fractions.

As the receptor binding ability test method, Rinaldi Carmona et al. (J Pharmacol Exp Ther. 2004, 310 (3): 90514.) And Ruju et al. (J Pharmacol Exp Ther. 2003, 306 (1): 36370) were used. It was. In the case of the cannabinoid 1 receptor, 50 ug of total protein per reaction was added to various concentrations of drug and PerkinElmer's [3H] CP 55,940 to 1 nM, and then the total reaction volume was 200 uL for 1 hour in a 30 ° C water bath. A cell harvestor was used to filter the GF / C filter paper, and a total of 10 washes were performed by adding 250 ul per reaction with a buffer containing 0.25% bovine serum albumin. The filter paper was dried for 1 hour, and 50 ul of flash cocktail was added thereto for 1 hour, and the radioactivity was measured for 1 hour.

At this time, it was prepared by dissolving in dimethyl sulfoxide (DMSO) at a concentration corresponding to 2000 times the final concentration of each drug, and diluted again in a buffer to prepare a concentration 10 times the final concentration. The radioactivity of nonspecific binding was reflected in all the results of Tocris CP 55,940 treated with 5 uM. When 100% of [3H] CP 55,940 binds to the cannabinoid receptor, the relative% inhibition rate of each drug against the radioactivity was calculated, and the 50% inhibition concentration by the drug was calculated based on this.

The inhibitory effect on CB1 of the compounds according to the present invention prepared in Examples 1 to 51 was measured by the method described above and the results are shown in Table 1 below.

TABLE 1

According to the results of Table 1, it can be seen that the 1H-pyrazole-3-amide compound of Formula 1 according to the present invention has an excellent CB1 inhibitory effect, among others Example 3, Example 14, Example The effect of the compounds of 32 and Example 43 was the best.

Claims (7)

1H-pyrazole-3-amide compound of Formula 1 or a pharmaceutically acceptable salt thereof. [Formula 1]

[In Formula 1, A is

or

ego; R ₁ is (C1-C10) alkyl; R ₂ and R ₃ independently of one another are hydrogen, (C 1 -C 10) alkyl, (C 6 -C 20) aryl, (C 6 -C 20) ar (C 1 -C 10) alkyl, (C 3 -C 7) cycloalkyl, N, O and (C3-C7) heterocycloalkyl, adamantyl or piperidino containing one or more heteroatoms selected from S or R ₂ and R ₃ may be linked to (C3-C7) alkylene to form a ring, The carbon atom of the alkylene may be substituted one or more with NR ₆ , O or S; R ₄ and R ₅ are independently of each other hydrogen; R ₆ is hydrogen, (C 1 -C 10) alkyl or (C 1 -C 10) alkoxycarbonyl; Alkyl, aryl or aralkyl of R ₂ and R ₃ is halogen, (C 1 -C 10) alkyl, halo (C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, mono or di- (C 1 -C 10) alkylamino, May be further substituted with one or more substituents selected from (C3-C7) cycloalkyl, (C2-C20) heteroaryl or hydroxy; Provided that R ₂ and R ₃ are not simultaneously hydrogen.] The method of claim 1, R ₁ is (C ₁ -C 10) alkyl, R ₂ and R ₃ are independently of each other hydrogen, (C 1 -C 10) alkyl, (C 6 -C 20) aryl, (C 6 -C 20) ar (C 1 -C 10) alkyl, ( C3-C7) cycloalkyl, piperidino, adamantyl, piperidinyl, or R ₂ and R ₃ may be linked to (C4-C6) alkylene to form a ring, wherein the carbon atom of the alkylene is NR One or more may be substituted with ₆ , O or S; R ₄ and R ₅ are hydrogen; R ₆ is hydrogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxycarbonyl; Alkyl, aryl or aralkyl of R ₂ and R ₃ is halogen, (C 1 -C 10) alkyl, halo (C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, mono or di- (C 1 -C 10) alkylamino, 1H-pyrazole-3-amide compound or a pharmaceutically acceptable thereof, which may be further substituted with one or more substituents selected from (C3-C7) cycloalkyl, (C2-C20) heteroaryl or hydroxy Salts thereof. The method of claim 2, 1H-pyrazole-3-amide compound or a pharmaceutically acceptable salt thereof, which is selected from the following compounds. (E) -N- (4-chlorophenyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) Acrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-phenylacrylamide; (E) -N- (3-chlorobenzyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) Acrylamide; (E) -N- (2-chlorobenzyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) Acrylamide; (E) -N-benzyl-3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-yl) acrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (4-methoxybenzyl ) Acrylamide; (E) -N- (4-chlorobenzyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) Acrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (4-fluorobenzyl ) Acrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (3-fluorobenzyl ) Acrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-isopropylacrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (3-chloropropyl) Acrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-hexylacrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (cyclohexylmethyl) acrylic Amides; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (3- (trifluoro Rhomethyl) benzyl) acrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (4-trifluoro Methyl) benzyl) acrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (4- (dimethyl Amino) benzyl) acrylamide; (E) -N- (3-chlorophenethyl) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl ) Acrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (piperidine-1 -Yl) acrylamide; (E) -3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (furan-3-yl Methyl) acrylamide; (E) -4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -1- (piperidine-4 -Yl) acrylamide. The method of claim 2, 1H-pyrazole-3-amide compound or a pharmaceutically acceptable salt thereof, which is selected from the following compounds. 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N-phenylacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-methyl-2-oxo-N-phenylacet Amides; N- (3-chlorobenzyl) -2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo Acetamide; N- (3-chlorophenethyl) -2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- Oxoacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-cyclopentyl-2-oxoacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-cyclohexyl-2-oxoacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-cycloheptyl-2-oxoacetamide; 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- (pyrrolidin-1-yl) ethane -1,2-dione; 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- (piperidin-1-yl) ethane -1,2-dione; 1- (Azepan-1-yl) -2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) ethane- 1,2-dione; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N- (piperidine-1 -Yl) acetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (cyclohexylmethyl) -2-oxoacet Amides; 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) ethane- 1,2-dione; Tert-butyl 4- (2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetyl) pipe Razin-1-carboxylate; 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2- (4-methylpiperazin-1-yl ) Ethane-1,2-dione; 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-morpholinoethane-1,2-dione ; 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-thiomorpholinoethane-1,2-da ion; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-adamantyl-2-oxoacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N, N-dicyclohexyl-2-oxoacet Amides; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N, N-dihexyl-2-oxoacetamide ; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-ethyl-2-oxoacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N-propylacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-isopropyl-2-oxoacetamide; N-butyl-2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-isobutyl-2-oxoacetamide; N-tert-butyl-2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxoacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -2-oxo-N-pentylacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-hexyl-2-oxoacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-heptyl-2-oxoacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N-octyl-2-oxoacetamide; 2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-yl) -N- (2-hydroxyethyl) -2- Oxoacetamide. delete A pharmaceutical for treating or preventing weight loss, obesity or bulimia, comprising as an active ingredient the 1H-pyrazole-3-amide-based compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. Composition. Attention deficit behavioral disorder, Parkinson's disease, Alzheimer's disease, furnace comprising the 1H-pyrazole-3-amide compound of any one selected from claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for treating or preventing dementia, vascular dementia or alcoholism.