WO2009078498A1 - Biarylpyrazole 4-carboxamides as cannabinoid cb1 receptor ligands - Google Patents

Abstract

A novel biarylpyrazole 4-carboxamide compound of formula (I) or a pharmaceutically acceptable salt thereof is effective as a cannabinoid CB1 receptor ligand, which is useful for preventing or treating obesity and obesity-related metabolic disorders. The present invention also provide a method for preparing same, a pharmaceutical composition containing same, and a method for preventing or treating obesity and obesity-related metabolic disorders.

Description

BIARYLPYRAZOLE 4-CARBOXAMIDES AS CANNABINOID CB₁

RECEPTOR LIGANDS

FIELD OF THE INVENTION

The present invention relates to a novel biarylpyrazole 4-carboxamide compound which is effective as a cannabinoid CBi receptor ligand.

BACKGROUND OF THE INVENTION

The World Health Organization (WHO) recently reported that obesity has become a global epidemic, posing a serious threat to public health because of the increased risk of associated health problems (see Report of a WHO Consultation on Obesity: Obesity-Preventing and Managing a Global Epidemic; World Health Organization: Geneva, 1997). Obesity is characterized by excess body fat, especially visceral fat, and constitutes a pro-inflammatory state eventually leading to serious health consequences. There are growing evidences that obesity as a chronic disease cannot be cured by short-term dieting or exercise alone, but additional pharmacological treatments would lead to higher success rates.

CBi cannabinoid receptor belongs to G-protein-coupled receptor (GPCR) type and is coupled to inhibitory G proteins (GQJo)) to inhibit certain adenylyl cyclase isozymes, leading to decreased cAMP production, decreased Ca²⁺ conductance, increased K⁺ conductance, and increased mitogen-activated protein kinase activity (see Di Marzo et al, Nat. Rev. Drug Discovery 2004, 3, 771-784; Rhee, M. H. et al., J. Neurochem. 1998, 77, 1525-1534). The major physiological effect of cannabinoids (in the central nervous system (CNS) and neuronal tissues) is the modulation of neurotransmitter release via activation of presynaptic CB₁ receptors located on distinct types of axon terminals throughout the brain (see Howlett, A. C. et al., Neuropharmacology 2004, 47 (Suppl. 1), 345-358).

The CBi receptor is mainly expressed in several brain areas including the limbic system (amygdala, hippocampus), hypothalamus, cerebral cortex, cerebellum, and basal ganglia. In the cerebellum and basal ganglia cannabinoids modulate the locomotor activity. In the limbic system, cannabinoids influence learning, memory, emotion, and motivation, and through activation of CB₁ receptors in the limbic system-hypothalamus axis, cannabinoids have an important role in the control of appetite. Moreover, lower levels of CB₁ receptors can also be found in peripheral tissues including urinary bladder, testis, prostate, GI tract, heart, lung, adrenal gland, parotid gland, bone marrow, uterus, ovary, and adipose tissue (see Cota, D. et al., /. Clin. Invest. 2003, 112, 423-431; Ravinet Trillou, C. et al., Int. J. Obes. Relat. Metab. Disord. 2004, 28, 640-648; Galiegue, S. et al., Eur. J. Biochem. 1995, 232, 54-61; Howlett, A. C. et al., Pharmacol. Rev. 2002, 54, 161-202).

Many preclinical in vitro and in vivo experiments have been shown that CB₁ receptor antagonists can influence energy homeostasis by central and peripheral mechanisms and may represent promising targets to treat diseases that are characterized by impaired energy balance. Already the first published studies with rimonabant (SR141716) in both rodents (see Arnone, M. et al., Psychopharmacology (Berlin) 1997, 132, 104-106) and primates (see Simiand, J.; Keane, M.; Keane, P. E.; Soubrie, P. Behav. Pharmacol. 1998, 9, 179-181) showed clear differentiation, i.e., marked effects on sweet food intake versus marginal effects on regular chow intake or water drinking. Many other preclinical "proof of concept" studies have been performed in the meantime with several CB agonists and antagonists to further uncover the amount and mode of contribution of cannabinergic system modulators to energy homeostasis. Almost all of those studies have been recently reviewed (see Smith, R. A. et al., IDrugs 2005, 8, 53-66).

Considering the important impact of obesity on public health and the lack of any efficient and viable drug to cure it, it is no surprise that CB₁ antagonists are currently the subject of intense studies, which were published in several reviews (see Adam, J. et al., Expert Opin.Ther. Patents, 2002, 12(10), 1475-1489; Hertzog, D. L. Expert Opin.Ther. Patents, 2004, 14(10), 1435-1452; Lange, J. H. M. et al., Drug Discov. Today, 2005, 10, 693-702; Bishop, M. J. J Med. Chem., 2006, 49(14), 4008-4016). On the other hand, CIVCB₂ agonists have been clinically used as an antiemetic agent to stimulate appetite. Potential therapeutic uses of cannabinoid receptor agonists include the management of multiple sclerosis, spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilatation that accompanies advanced cirrhosis and cancer {see Singh, J., Exp. Clin. Pharmacol, 2006, 28(3): 177).

SUMMARY OF THE INVENTION

It is a primary object of the present invention to provide a novel biarylpyrazole 4-carboxamide compound or a pharmaceutically acceptable salt thereof, which is effective as a cannabinoid CB₁ receptor ligand, useful for preventing or treating obesity and obesity-related metabolic disorders.

It is another object of the present invention to provide a method for preparing the inventive compound.

It is another object of the present invention to provide a pharmaceutical composition for preventing or treating obesity and obesity-related metabolic disorders, comprising the inventive compound as an active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof and a method for preparing same:

wherein, Y is O or S;

R₁ and R₂ are each independently hydrogen, C_1-6 alkyl, substituted C_1-6 alkyl, C_3-12 carbocycle, substituted C_3-12 carbocycle, NR₃R₄, -CHR₅(CO)OR₇, -CHR₅(CO) NR₃R₄, or R₁ and R₂ are fused to each other together with the nitrogen atom to which they are bonded to form a 4- to 10-membered saturated or unsaturated heterocyclic ring which is optionally substituted by one or more substituents selected from the group consisting of C_1-3 alkyl, benzyl, phenyl, Ci_-3 alkoxy or halogen; R₃ and R₄ are each independently selected from the group consisting of hydrogen, C_1-7 alkyl, C_3-8 carbocycle, substituted C_3-8 carbocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle and acyl; or are fused to each other together with the nitrogen atom to which they are bonded to form a 5- to 10-membered heterocycle which is unsubstituted or substituted by one or more substituents selected from the group consisting of Q_-4 alkyl, C_1-4 alkoxy and fluoride;

R₅ is hydrogen, C_1-4 alkyl, substituted C_1-4 alkyl, C_3-6 carbocycle, substituted C_3-6 carbocycle, (CH₂)_n-C_3-6 carbocycle or (CH₂)_n-R₆, n being 1, 2 or

3; R₆ is phenyl, furan, thiophene, tetrahydrofuran, tetrahydropyran or dioxane;

R₇ is C_1-4 alkyl, substituted C_1-4 alkyl, C_3-8 carbocycle, substituted C_3-8 carbocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; R₈ is hydrogen, NR₃R₄, C_3-8 carbocycle, substituted C_3-8 carbocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, Ci_-8 alkyl optionally substituted by alkoxy or halogen, C_2-6 alkenyl optionally substituted by alkoxy or halogen, (CH₂)_m-C_3-6 carbocycle optionally substituted by alkoxy or halogen, or (CH₂)_m-R₉, m being 1 or 2; R₉ is phenyl, furanyl, benzofuranyl, thienyl, benzothienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridizinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, 1,4-benzodioxanyl or benzo[l,3]dioxolyl, each having one or more optional substituents selected from the group consisting of halogen, Ci_-3 alkyl and Ci_-2 alkoxy, each having one to three optional fluorine substituents; and

R₁₀, Rii, Ri₂, Ri₃, R_H and Ri₅ are each independently hydrogen, halogen, cyano, Ci_-3 alkyl, Q.₃ alkoxy, C_1-3 sulfanyl or trifluoromethyl.

In accordance with another aspect of the present invention, there is provided a method for preparing the compound of formula (I) of claim 1, which comprises the steps of:

(i) subjecting a compound of formula (II) to bromination using NBS (N-bromosuccinimide) to obtain a compound of formula (III);

(ii) subjecting the compound of formula (III) to a substitution reaction with sodium acetate in an organic solvent to obtain an acetate compound of formula (IV);

(iii) hydrolyzing the compound of formula (IV) to obtain an alcohol compound of formual (V);

(iv) oxidizing the compound of formual (V) in the presence of an oxidant to obtain an aldehyde compound of formula (VI);

(v) further oxidizing the compound of formual (VI) in the presence of sodium chlorite and monobasic potassium phosphate to obtain a carboxylic acid compound of formula (VII);

(vi) chlorinating the compound of formula (VII) with a chlorinating agent to obtain an acid chloride compound of formula (VIII), and

(vii) treating the compound of formula (VIII) with an amine in the presence of a base to obtain the compound of formula (I):

(VI)

wherein, R₁, R₂, R₈ and Rj₀ to Ri₅ have the same meanings as defined above.

As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and hexyl.

As used herein, the term "substituted alkyl" refers to a straight or branched chain saturated hydrocarbon radical, which is optionally substituted by one or more substituents selected from the group consisting of C_1-3 alkyl optionally having one to three fluorine substituents, C_2-3 alkenyl, C_2-3 alkynyl, Ci_-2 alkoxy optionally having one to three fluorine substituents, sulfanyl, sulfinyl, sulfonyl, oxo, hydroxy, mercapto, amino, guanidino, carboxy, aminocarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, aminosulfonyl, sulfonylamino, carboxyamide, ureido, nitro, cyano and halogen. As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond. Examples of "alkenyl" as used herein include, but are not limited to, ethenyl and propenyl. As used herein, the term "substituted alkenyl" refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond, which has optional substituents selected from the group consisting of C_1-3 alkyl optionally having one to three fluorine substituents, amino, aryl, cyano and halogen.

As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond. Examples of "alkynyl" as used herein include, but are not limited to, acetylenyl and 1-propynyl.

As used herein, the term "substituted alkynyl "refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond, optionally having one or more substituents selected from the group consisting of C_1-3 alkyl optionally having one to three fluorine substituents, amino, aryl and halogen.

As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

As used herein, the term "carbocycle" refers to a non-aromatic cyclic hydrocarbon radical composed of three to seven carbon atoms. Five-to seven-membered rings may contain a double bond in the ring structure.

Exemplary "carbocycle" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cycloheptyl.

As used herein, the term "substituted carbocycle" refers to a non-aromatic cyclic hydrocarbon radical composed by three to seven carbon atoms, which is optionally substituted with one or more substituents selected from the group consisting of C_1-3 alkyl optionally having one to three fluorine substituents, C_2-3 alkenyl, C_2-3 alkynyl, C_1-2 alkoxy optionally having one to three fluorine substituents, sulfanyl, sulfϊnyl, sulfonyl, oxo, hydroxy, mercapto, amino, guanidino, carboxy, aminocarbonyl, aryl, aryloxy, heteroaryl, heterocyclic, aminosulfonyl, sulfonylamino, carboxyamide, nitro, ureido, cyano and halogen.

As used herein, the term "aryl" refers to an optionally substituted benzene ring or refers to a ring system which may result by fusing one or more optional substituents. Exemplary optional substituents include substituted Cj_-3 alkyl, substituted C_2-3 alkenyl, substituted C_2-3 alkynyl, heteroaryl, heterocyclic, aryl, alkoxy optionally having one to three fluorine substituents, aryloxy, aralkoxy, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl, sulfinyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide, aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino, nitro, cyano, halogen, or ureido. Such a ring or ring system may be optionally fused to aryl rings (including benzene rings) optionally having one or more substituents, carbocycle rings or heterocyclic rings. Examples of "aryl" groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, indanyl, anthracyl or phenanthryl, as well as substituted derivatives thereof.

As used herein, the term "heteroaryl" refers to an optionally substituted monocyclic five to six-membered aromatic ring containing one or more heteroatomic substitutions selected from S, SO, SO₂, O, N, or N-oxide, or refers to such an aromatic ring fused to one or more rings such as heteroaryl rings, aryl rings, heterocyclic rings, or carbocycle rings (e. g., a bicyclic or tricyclic ring system), each having optional subsituents. Examples of optional substituents are selected from the group consisting of substituted C_1-3 alkyl, substituted C_2-3 alkenyl, substituted C_2-3 alkynyl, heteroaryl, heterocyclic, aryl, C_1-3 alkoxy optionally having one to three fluorine substituents, aryloxy, aralkoxy, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl, sulfinyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide, aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino, nitro, cyano, halogen or ureido. Examples of "heteroaryl" groups used herein include, but are not limited to, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzothiophenyl, benzopyrazinyl, benzotriazolyl, benzo[l,4]dioxanyl, benzofuranyl, 9H-a-carbolinyl, cinnolinyl, furanyl, furo[2,3-b]pyridinyl, imidazolyl, imidazolidinyl, imidazopyridinyl, isoxazolyl, isothiazolyl, isoquinolinyl, indolyl, indazolyl, indolizinyl, naphthyridinyl, oxazolyl, oxothiadiazolyl, oxadiazolyl, phthalazinyl, pyridyl, pyrrolyl, purinyl, pteridinyl, phenazinyl, pyrazolyl, pyridyl, pyrazolopyrimidinyl, pyrrolizinyl, pyridazyl, pyrazinyl, pyrimidyl, 4-oxo-l, 2-dihydro-4H-pyrrolo[3,2,l-ij]-quinolin-4-yl, quinoxalinyl, quinazolinyl, quinolinyl, quinolizinyl, thiophenyl, triazolyl, triazinyl, tetrazolopyrimidinyl, triazolopyrimidinyl, tetrazolyl, thiazolyl, thiazolidinyl, and substituted versions thereof.

As used herein, the term "heterocyclic" refers to a three to seven-membered ring containing one or more heteroatomic moieties selected from S, SO, SO₂, O, N, or N-oxide, optionally substituted with one or more substituents selected from the group which includes substituted C_1-3 alkyl, substituted C_2-3 alkenyl, substituted C_2-3 alkynyl, heteroaryl, heterocyclic, aryl, Ci_-3 alkoxy optionally having one to three fluorine substituents, aryloxy, aralkoxy, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl, sulfmyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide, aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino, mtro, cyano, halogen, and ureido. Such a ring can be saturated or have one or more degrees of unsaturation. Such a ring may be optionally fused to one or more "heterocyclic" ring(s), aryl ring(s), heteroaryl ring(s) or carbocycle ring(s), each having optional substituents. Examples of "heterocyclic" moieties include, but are not limited to,

1,4-dioxanyl, 1,3-dioxanyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, imidazolidine-2,4-dionepiperidinyl, piperazinyl, piperazine-2,5-dionyl, morpholinyl, dihydropyranyl, dihydrocinnolinyl, 2,3-dihydrobenzo [1,4]

-dioxinyl, 3,4-dmydro-2H-benzo[b][l,4]-dioxepinyl, tetrahydropyranyl, 2,3-dihydrofuranyl, 2,3-dihydrobenzofuranyl, dihydroisoxazolyl, tetrahydrobenzodiazepinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydronaphthyridinyl, tetrahydropurinyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, tetrahydroquinoxalinyl, tetrahydropyridinyl, tetrahydrocarbolinyl, 4H-benzo[l,3]-dioxinyl, benzo[l,3]dioxonyl, 2,2-difluorobenzo-[l,3]-dioxonyl, 2,3-dihydro-phthalazine-l, 4-dionyl, and isoindole- 1 ,3-dionyl.

As used herein, the term "alkoxy" refers to the group -OR₃, where R_a is alkyl as defined above. Exemplary alkoxy groups useful in the present invention include, but are not limited to, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy.

As used herein the term "aralkoxy" refers to the group -OR_aR_b, wherein R_a is alkyl and R_b is aryl as defined above. As used herein the term "aryloxy" refers to the group -OR_b, wherein R_b is aryl as defined above.

As used herein, the term "mercapto" refers to the group -SH. As used herein, the term "sulfanyl" refers to the group -SR_C, wherein R_c is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.

As used herein, the term "sulfinyl" refers to the group -S-(O)R_C, wherein R_c is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above. As used herein, the term "sulfonyl" refers to the group -S(O)₂R_C, wherein

R_c is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.

As used herein, the term "oxo" refers to the group =0. As used herein, the term "hydroxy" refers to the group -OH. As used herein, the term "amino" refers to the group -NH₂. The amino group is optionally substituted by substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.

As used herein, the term "cyano" refers to the group -CN. As used herein, the term "aminosulfonyl" refers to the group -S(O)₂NH₂. The aminosulfonyl group is optionally substituted by substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.

As used herein, the term "sulfonylamino" refers to the group -NHS(O)₂R_c wherein R_c is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above. As used herein, the term "carboxyamide" refers to the group -NHC(O)R₀ wherein R_c is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.

As used herein, the term "carboxy" refers to the group -C(O)OH. The carboxy group is optionally substituted by substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.

As used herein, the term "aminocarbonyl" refers to the group -C(O)NH₂. The aminocarbonyl group is optionally substituted by substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.

As used herein, the term "ureido" refers to the group -NHC(O)NHR_d wherein R_d is hydrogen, alkyl, carbocycle or aryl as defined above.

As used herein, the term "guanidino" refers to the group -NHCHSfH)NH₂.

As used herein, the term "acyl" refers to the group -C(O)R₆, wherein R_e is alkyl, carbocycle, or heterocyclic as defined herein.

As used herein, the term "aroyl" refers to the group -C(O)R_b, wherein R_b is aryl as defined herein. As used herein, the term "heteroaroyl" refers to the group -C(O)R_f, wherein R_f is heteroaryl as defined herein.

As used herein, the term "acyloxy" refers to the group -OC(O)R₆, wherein R_e is alkyl, carbocycle, or heterocyclic as defined herein.

As used herein, the term "aroyloxy" refers to the group -OC(O)R_b, wherein R_b is aryl as defined herein.

As used herein, the term "heteroaroyloxy" refers to the group -OC(O)R_f, wherein R_f is heteroaryl as defined herein.

It is to be understood that the present invention also includes a pharmaceutically acceptable salt and an addition salt of the inventive compound, such as a hydrochloride, hydrobromide or trifluoroacetate addition salt and a sodium, potassium and magnesium salt.

The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are incorporated within the scope of the present invention.

One embodiment of the present invention is to provide a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

wherein, R₁, R₂, R₈, R₁₀, Rn, Ri₂, R₁₃, R_H and R₁₅ have the same meanings as defined above.

Another embodiment of the present invention is provide a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

wherein, R₁, R₂, R₈, Rio₅ Rn₅ Ri_2? R_B5 Ri₄, and R₁₅ have the same meanings as defined above.

Preferred compounds useful in the present invention are selected from the group consisting of:

(3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)- 1 -(2,4-dichloroρhenyl

)- 1 H-pyrazol-4-yl)-morpholino-methanone; 3-(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichloroρhenyl)

- 1 H-pyrazole-4-carboxamide;

N-tert-butyl-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dic hlorophenyl)-lH-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl) -N-isopropyl- 1 H-pyrazole-4-carboxamide; 3-(5-tert-butyl-l,3_J4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)

-N-(piperidin- 1-yl)- lH-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-NjN-dimethyl- 1 H-pyrazole-4-carboxamide; 3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N-methyl- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)

-N,N-diethyl- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl) -N-ethyl- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)- 1 -(2,4-dichlorophenyl)

-N-ethyl-N-methyl- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-N-cycloρropyl- 1 -(2,4- dichlorophenyl)- 1 H-pyrazole-4-carboxamide; 3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-N-cyclobutyl-l-(2,4-di chlorophenyl)- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)-N-cyclopentyl- 1 -(2,4-d ichlorophenyl)- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-N-cyclohexyl- 1 -(2,4-di chlorophenyl)- 1 H-pyrazole-4-carboxamide;

(3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl

)-lH-pyrazol-4-yl)(pyrrolidin-l-yl)methanone;

(3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)- 1 -(2,4-dichlorophenyl

)- lH-pyrazol-4-yl)(piρeridin- 1 -yl)methanone; 3-(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N-phenyl- 1 H-pyrazole-4-carboxamide;

N'-acetyl-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)-l-(2,4-dichlo rophenyl)- 1 H-pyrazole-4-carbohydrazide;

3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl) -N'-phenyl- 1 H-pyrazole-4-carbohydrazide;

3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl) -N-(2-oxopropyl)- 1 H-pyrazole-4-carboxamide; 3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl)

-N,N-dimethyl- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophenyl)

-N-methyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l₅3,4-oxadiazol-2-yl)-l-(2,4-dichlorophenyl)

-N-ethyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl) -N-ethyl-N-methyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl)

-N,N-diethyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophenyl)

-N-isopropyl- 1 H-pyrazole-4-carboxamide; 5-(4-bromoρhenyl)-N-tert-butyl-3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)- 1 -(2,4-dic hlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-l-(2,4- dichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-N-cyclobutyl- 1 -(2,4-di chlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-N-cyclopentyl- 1 -(2,4-d ichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-N-cyclohexyl-l-(2,4-di chlorophenyl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophenyl) -N-phenyl- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl) -N-propyl- 1 H-pyrazole-4-carboxamide; N-butyl-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlor ophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromoρhenyl)-3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl> 1 -(2,4-dichlorophenyl) -N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromoρhenyl)-3-(5-tert-butyl- 1 ,3,4-thiadiazol-2-yl)- 1 -(2,4-dichlorophenyl)

-N-phenyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromoρhenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-N-cycloρroρyl-l-(2,4- dichlorophenyl)-lH-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3,4-thiadiazol-2-yl)-N-cyclobutyl- 1 -(2,4-di chlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3 ,4-thiadiazol-2-yl)-N-cyclopentyl- 1 -(2,4- dichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-N-cyclohexyl-l-(2,4-d ichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromoρhenyl)-3-(5-tert-butyl-l,3,4-tbiadiazol-2-yl)-N-cycloheρtyl-l-(2,4- dichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3 ,4-thiadiazol-2-yl)- 1 -(2,4-dichlorophenyl)

-N-(2-fmorophenyl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl)

-N-(2-oxopropyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3,4-thiadiazol-2-yl)- 1 -(2,4-dichlorophenyl)

-N-(2-hydroxypropyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2-yl) - 1 -(2,4-dichlorophenyl)-N-isopropyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)

-N-cyclopropyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)

-N-cyclobutyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)

-l-(2,4-dichlorophenyl)-N-phenyl-lH-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)

- 1 -(2,4-dichlorophenyl)-N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl)-N-isopropyl- 1 H-pyrazole-4-carboxamide;

5-(4-chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)- N-cyclopropyl- 1 -(2,4-dichlorophenyl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3₅4-oxadiazol-2-yl)- N-cyclobutyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3-(5-(l -(4-chlorophenyl)cyclopropyl)- 1 ,3,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl)-N-phenyl- lH-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl)-N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopiOpyl)-l,3,4-thiadiazol-2-yl) -N-cyclopropyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide; 5-(4-biOmophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-thiadiazol-2-yl) -N-cyclobutyl- 1 -(2,4-dichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-thiadiazol-2-yl) - 1 -(2,4-dichlorophenyl)-N-phenyl- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-(l-(4-chloroprienyl)cyclopropyl)-l,3,4-thiadiazol-2-yl) - 1 -(2,4-dichlorophenyl)-N-isopropyl- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-tbiadiazol-2-yl) - 1 -(2,4-dichlorophenyl)-N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromoρhenyl)-3-(5-tert-butyl- 1 ,3,4-thiadiazol-2-yl)- 1 -(2,4-dichlorophenyl) -N-isopropyl- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3,4-thiadiazol-2-yl)- 1 -(2,4-dichlorophenyl) -N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-N-cyclopropyl-l-(2,4-dichlorophenyl)-3-(5-(l-(trifluoromet hyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-N-cyclobutyl- 1 -(2,4-dichlorophenyl)-3 -(5-(I -(trifluorometh yl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)- 1 -(2,4-dichlorophenyl)-N-isopropyl-3-(5-(l -(trifluoromethy l)cyclopropyl)- 1 ,3,4-oxadiazol-2-yl)- lH-pyrazole-4-cai-boxamide; 5-(4-bromophenyl)- 1 -(2,4-dichlorophenyl)-N-phenyl-3-(5-(l -(trifluoromethyl)c yclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-l-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-3-(5-(l-(trifluorom ethyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-chlorophenyl)-3-(5-(l -(4-chlorophenyl)cyclopropyl)- 1 ,3₅4-thiadiazol-2-yl) - 1 -(2,4-dichlorophenyl)-N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-thiadiazol-2-yl) - 1 -(2,4-dichlorophenyl)-N-phenyl- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl) -N-cyclobutyl- 1 -(2,4-dichlorophenyl)- 1 H-pyrazole-4-carboxamide; 5-(4-cMorophenyl)-3-(5-(l-(4-chloroplienyl)cyclopropyl)-l,3,4-thiadiazol-2-yl) -N-cyclopropyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl) -l-(2_J4-dichlorophenyl)-N-isopropyl-lH-pyrazole-4-carboxamide; 5-(4-cMorophenyl)-l-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-3-(5-(l-(trifluorom ethyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-N-phenyl-3-(5-(l-(trifluoromethyl)c yclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-N-cyclobutyl-l-(2,4-dicrilorophenyl)-3-(5-(l-(trifluorometli yl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-N-cyclopropyl- 1 -(2,4-dichlorophenyl)-3-(5-(l -(trifluoromet hyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)-lH-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-N-isopropyl-3-(5-(l-(trifluoromethyl )cyclopropyl)- 1 ,3,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-N-(pyridin-2-yl)-3-(5-( 1 -(trifluorom ethyl)cyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-N-phenyl-3-(5-(l-(trifϊuoromethyl)c yclopropyl)- 1 ,3 ,4-thiadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-N-cyclobutyl- 1 -(2,4-dichlorophenyl)-3 -(5-( 1 -(trifluorometh yl)cyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-N-cyclopropyl- 1 -(2,4-dichlorophenyl)-3-(5-(l -(trifluoromet hyl)cyclopropyl)-l,3,4-thiadiazol-2-yl)-lH-pyrazole-4-carboxamide; and 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-N-isopropyl-3-(5-(l-(trifluoromethyl )cyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl)- 1 H-pyrazole-4-carboxamide.

The compound of formula (Ia) may be illustratively prepared by the synthetic rout shown in Reaction Scheme 1. Reaction Scheme 1

Villa Ia wherein, R₁, R₂ and R₈ have the same meanings as defined above.

Specifically, Reaction Scheme 1 comprises the steps of: (i) subjecting an 1,3,4-oxadiazole compound of formula (Ha) to bromination using NBS (N-bromosuccinimide) to obtain an activated 4-pyrazole intermediate such as the bromomethyl derivative of formula (Ilia);

(ii) subjecting the compound of formula (Ilia) to a substitution reaction with sodium acetate in an organic solvent such as DMF to obtain an acetate compound of formula (IVa);

(iii) hydrolyzing the compound of formula (IVa) to obtain an alcohol compound of formual (Va); (iv) oxidizing the compound of formual (Va) in the presence of an oxidant such as Dess-Martin periodinane to obtain an aldehyde compound of formula (Via);

(v) further oxidizing the compound of formual (Via) in the presence of sodium chlorite and monobasic potassium phosphate to obtain a carboxylic acid compound of formula (Vila);

(vi) chlorinating the compound of formula (Vila) with a chlorinating agent such as oxalyl chloride to obtain an acid chloride compound of formula (VIIIa)₅ and

(vii) treating the compound of formula (Villa) with an amine in the presence of a suitable base such as triethylamine to obtain a compound of formula (Ia).

The 1,3,4-oxadiazole compound of formula (Ha) used as a starting material in preparing the compound of formula (Ia) may be prepared by reacting a carboxylic acid derivative (5) with a hydrazide compound (7) or a semicarbazide compound (12) in the presence of a coupling agent, e.g., EDCI, DMAP; and cyclizing the resulting acyl hydrazide intermediate (9 or 14) using a dehydrating agent, as shown in Reaction Scheme 2.

Reaction Scheme 2

lla-2 wherein, R₃, R₄ and R₈ have the same meanings as defined above.

The cyclization may be conducted using Burgess reagent as a dehydrating agent while applying microwave irradiation thereon (see Leber, J. D. et al., WO 2005/032550), or using triphenylphosphine with carbon tetrachloride and a base such triethylamine in a suitable solvent such as acetonitrile and THF or using phosphorus(III) oxychloride in refluxing 1,4-dioxane.

The acyl hydrazide intermediate (9) used in Reaction Scheme 2 may be also prepared by treating an ester compound of formula (4) with hydrazine in refluxing EtOH and coupling the resulting hydrazide compound (A) with a corresponding acid in the presence of coupling reagents such as DMAP and EDCI, as shown in Reaction Scheme 3.

Reaction Scheme 3

wherein, R₈ has the same meanings as defined above.

The carboxylic acid derivative (5) used in Reaction Scheme 2 may be prepared by a conventional method, e.g., by treating an acetophenone derivative (1) with an organic base such as lithium hexamethyldisilazide (LHMDS) to produce a corresponding alkali metal salt (2); reacting the resulting salt with an equimolar amount of diethyl oxalate to provide a ketoester salt (3); reacting the salt (3) with a hydrazine derivative in refluxing acetic acid to obtain a ρyrazole-3-carboxylic ester (4); and transforming the ester (4) into an acid form (5) using an alkaline agent such as potassium hydroxide or lithium hydroxide, followed by acidification (see Barth, F. et al., US Patent No 5,462,960), as shown in Reaction Scheme 4. Reaction Scheme 4

The hydrazide compound (7) used in Reaction Scheme 2 may be prepared by treating an ester or a carboxylic acid with hydrazine, and also, the semicarbazide compound (12) may be prepared by treating carbamyl chloride or isocynate with hydrazine, as shown in Reaction Scheme 5.

Reaction Scheme 5

R₈ CO₂Me NhH₂NH₂ RΛN;^NH2 (6) ⁽J)

(11) (12a)

(12b) wherein, R₃, R₄ and R₈ have the same meanings as defined above.

In Reaction Scheme 1, the compound of formula (Va) may be also prepared by converting a pyrazole-3-carboxylic ester (4) to a bromide compound (15) using NBS in the presence of a catalytic amount of benzoyl peroxide or AIBN; subjecting the bromide compound (15) to transformation into an alcohol compound (16) by the action of silver nitrate in aqueous acetone; protecting the alcohol compound (16) with TIPSCl (triisopropylsilyl chloride) in the presence of a suitable base such as imidazole and subsequently treating the intermediate with hydrazine to produce a hydrazide compound (17); coupling the hydrazide compound (17) with carboxylic acid in the presence of appropriate coupling reagents such as EDC and HOBt to produce a corresponding acyl hydrazide compound (18); and cyclizing the acyl hydrazide compound (18) using Burgess reagent, followed by deprotecting the silyl group of the resulting compound (19) with TBAF, as shown in Reaction Scheme 6.

Reaction Scheme 6

wherein, R₈ has the same meaning as defined above.

The compound of formula (Ib) may be illustratively prepared by the synthetic rout shown in Reaction Scheme 7.

Reaction Scheme 7

VIIIh wherein, R₁, R₂ and R₈ have the same meanings as defined above.

Specifically, Reaction Scheme 7 comprises the steps of: (i) subjecting a thiadiazole compound of formula (lib) to bromination using NBS (N-bromosuccinimide) to obtain an activated 4-pyrazole intermediate such as the bromomethyl derivative of formula (HIb);

(ii) subjecting the compound of formula (HIb) to reaction with sodium acetate in an organic solvent such as DMF to obtain an acetate compound of formula (IVb);

(iii) hydrolyzing the compound of formula (IVb) to obtain an alcohol compound of formual (Vb);

(iv) oxidizing the compound of formual (Vb) in the presence of an oxidant such as Dess-Martin periodinane to obtain an aldehyde compound of formula (VIb);

(v) further oxidizing the compound of formual (VIb) in the presence of sodium chlorite and monobasic potassium phosphate to obtain a carboxylic acid compound of formula (VIIb);

(vi) chlorinating the compound of formula (VIIb) with a chlorinating agent such as oxalyl chloride to obtain an acid chloride compound of formula (VIIIb), and

(vii) treating the compound of formula (VIIIb) with an amine in the presence of a suitable base such as triethylamine to obtain a compound of formula (Ib).

The thiadiazole compound of formula (lib) used as a starting material in preparing the compound of formula (Ib) may be prepared by reacting a carboxylic acid derivative (5) with a hydrazide compound (7) in the presence of coupling agents, e.g., EDCI, DMAP; and cyclizing the resulting product using a Lawesson's reagent, which can be conducted with microwave irradiation (see Kiryanov, A. A., Sampson, P., Seed, A. J., /. Org. Chem. 2001, 665, 7925-7929), as shown in Reaction Scheme 8.

Reaction Scheme 8

Hb wherein, R₈ has the same meaning as defined above.

In Reaction Scheme 7, the compound of formula (Vb) may be also prepared by cyclizing an acyl hydrazide compound (18) using Lawesson's reagent, followed by deprotecting the silyl group of the resulting compound (20) with TBAF, as shown in Reaction Scheme 9.

Reaction Scheme 9

wherein, R₈ has the same meaning as defined above.

The inventive biarylpyrazole 4-carboxamide compound, i.e., ρyrazole-3-azole-4-carboxamide compound of formula (I) is effective as a cannabinoid CB₁ receptor ligand, thereby preventing or treating obesity and obesity-related metabolic disorders.

Accordingly, the present invention provides a pharmaceutical composition for preventing or treating obesity and obesity-related metabolic disorders, which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

Further, the present invention provides a method for preventing or treating obesity and obesity-related metabolic disorders in a mammal, which comprises administering the compound of formula (I) to the mammal.

Also, the present invention provides a method for inhibiting cannabinoid CB₁ receptor in a mammal, which comprises administering the compound of formula (I) to the mammal.

As used herein, the term "obesity-related metabolic disorders" refers to chronic diseases that require treatment to reduce the excessive health risks associated with obesity and exemplary disorders include type 2 diabetes mellitus, cardiovascular and hypertension, hyperlipidaemia, fibrinolytic abnormalities. The pharmaceutical composition may be administered orally, intramuscularly or subcutaneously. The formulation for oral administration may take various forms such as a syrup, tablet, capsule, cream and lozenge. A syrup formulation will generally contain a suspension or solution of the compound or its salt in a liquid carrier, e.g., ethanol, peanut oil, olive oil, glycerine or water, optionally with a flavoring or coloring agent. When the composition is in the form of a tablet, any one of pharmaceutical carriers routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is in the form of a capsule, any of the routine encapsulation procedures may be employed, e.g., using the aforementioned carriers in a hard gelatin capsule shell. When the composition is formulated in the form of a soft gelatin shell capsule, any of the pharmaceutical carrier routinely used for preparing dispersions or suspensions may be prepared using an aqueous gum, cellulose, silicate or oil. The formulation for intramuscular or subcutaneous administration may take a liquid form such as a solution, suspension and emulsion which includes aqueous solvents such as water, physiological saline and Ringer's solution; or lipophilic solvents such as fatty oil, sesame oil, corn oil and synthetic fatty acid ester. Preferably the composition is formulated in a specific dosage form for a particular patient.

Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg of the compound of formula (I) or its pharmaceutically acceptable salt. The suitable daily dosage for oral administration is about 0.01 mg/Kg to

40 mg/Kg of the compound of formula (I) or its pharmaceutically acceptable salt, may be administered 1 to 6 times a day, depending on the patient's condition.

The present invention is further described and illustrated in Examples provided below, which are, however, not intended to limit the scope of the present invention. EXAMPLES

As used herein the symbols and conventions used describing the 5 processes, schemes and examples of the present invention are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. 0 Hz (Hertz) TLC (thin layer chromatography)

T_r (retention time) RP (reverse phase)

MeOH (methanol) /-PrOH (isopropanol)

TFA (trifluoroacetic acid) TEA (triethylamine)

EtOH (ethanol) THF (tetrahydrofuran) 5 DMSO (dimethylsulfoxide) EtOAc (ethyl acetate)

DCM (dichloromethane) HOAc (acetic acid)

DMF (N,N-dimethylformamide) Ac (acetyl)

CDI (1,1 -carbonyldiimidazole) Bn (benzyl)

HOSu (N-hydroxysuccinimide) O HOBT (1 -hydroxybenzotriazole)

B oc (tert-butyloxycarbonyl) mCPBA (meta-chloroperbenzoic acid)

FMOC (9-fluorenylmethoxycarbonyl)

DCC (dicyclohexylcarbodiimide) 5 Cbz (benzyloxycarbonyl)

ΝMM (Ν-methyl morpholine) HOAt (1 -hydroxy- 7-azabenzotriazole) TBAF (tetra-n-butylammonium fluoride) THP (tetrahydro-2H-pyran-2-yl) O DMAP (4-dimethylaminopyridine)

HPLC (high pressure liquid chromatography) BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride); EDCI (l-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride)

HBTU (O-Benzotriazolel-yl-N,N₅N',N'-tetramethyluronium hexafluorophosphate)

AIBN (2,2'-Azobis(2-methylpropionitrile))

All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in^°C (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted, and all solvents are of the highest available purity unless otherwise indicated.

Microwave reaction was conducted with a Biotage microwave reactor.

¹H NMR spectra were recorded on either a Jeol ECX-400, or a Jeol JNM-LA300 spectrometer. Chemical shifts were expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d(doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).

Mass spectra were obtained with either a Micromass, Quattro LC Triple Quadruple Tandem Mass Spectometer, ESI or Agilent, 1 lOOLC/MSD, ESI. For preparative HPLC, ca 100 mg of a product was injected in 1 ml of

DMSO onto a SunFire™ Prep C18 OBD 5 μm 19xl00mm Column with a 10 min gradient from 10% CH₃CN to 90% CH₃CN in H₂O. Flash chromatography was carried using Merck silica gel 60 (230-400 mesh). Most of the reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light using a 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution.

The following synthetic schemes are merely illustrative of the methods by which the compounds of the invention may be prepared and are not intended to limit the scope of the invention as defined in the appended claims.

Preparation of pyrazoIe-3-azoIe-4-carboxamide compound (formula (R) Example 1

3-(5-tert-Butyl-l,3,4-oxadiazoI-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-N-isopropyI-lH-pyrazole-4-carboxamide

Step 1 : 2-(4-(Bromomethyl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-lH- pyrazol-3-yl)-5-tert-butyI-l,3,4-oxadiazole (Ilia)

2-tert-Butyl-5-(5-(4-chlorophenyl)- 1 -(2,4-dichloroρhenyl)-4-methyl- 1 H- pyrazol-3-yl)-l,3,4-oxadiazole (Ha) (1 g, 2.17 mmol) was dissolved in CCl₄ (50 mL), to which N-bromosuccinimide (422 mg, 2.38 mmol) and catalytic amounts of AIBN. The mixture was heated for 12 hours at 90 "C, cooled to room temperature and filtered off to remove the salts. The filtrate was diluted with CH₂Cl₂ and washed with brine. The organic layer was dried over anhydrous MgSO₄, filtered and concentrated in vacuo to obtain the desired compound as a solid (1.2 g, 100 %), which was used without further purification.

Step 2: 5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazoI-2-yI)-l-(2,4- dichIorophenyI)-lH-pyrazol-4-yl)methyl acetate (IVa)

2-(4-(Bromomethyl)-5-(4-chlorophenyl)- 1 -(2,4-dichloroρhenyl)- IH- pyrazol-3-yl)-5-tert-butyl-l,3,4-oxadiazole (2.7g, 4.614 mmol) obtained in Step 1 above was dissolved in DMF (20 ml), to which sodiumacetate (1.13 mg, 13.842 mmol) was added. The mixture was heated for 12 hours at 60 ^°C, was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (Eluent : Hexane/EtOAc=3/l) to obtain the desired compound as a solid (1.75 g, 76%). ¹H NMR (400 MHz₅ CDCl₃) δ 7.51-7.47 (m, 2H), 7.44-7.39 (m, IH), 7.40-7.38 (m, IH), 7.35-7.32 (m, IH), 7.25-7.06 (m, 2H), 5.30 (s, 2H), 2.03 (s, 3H), 1.49 (S₅ 9H). MH+ 563.

Step 3 : (3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chIorophenyl)-l-(2,4- dichlorophenyl)-lH-pyrazol-4-yl)methanol (Va)

5-(4-Bromoρhenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichloro phenyl)- lH-pyrazol-4-yl)methyl acetate (1.57 g, 3.020 mmol) obtained in Step 2 above was dissolved in THF (9ml)/MeOH (9ml)/H₂O (2ml). Thereto, LiOH monohydrate (380 mg, 9.060 mmol) was added. The mixture was stirred for 12 hours at room temperature, diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO₄, filtered and concentrated in vacuo to obtain the desired compound as a solid (1.37g, 95 %), which was used without further purification.

¹H NMR (400 MHz, CDCl₃) δ 7.45-7.44 (m, IH), 7.34-7.32 (m, 4H), 7.16-7.14 (m, 2H), 4.82-4.78 (m, IH), 4.72-4.70 (m, 2H), 1.51 (s, 9H). MH+ 478.

Step 4: 3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4- dichϊorophenyl)-lH-pyrazole-4-carbaldehyde (Via)

(3-(5-tert-Butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)- 1 -(2,4-dichloro phenyl)- lH-ρyrazol-4-yl)methanol (100 mg, 0.209 mmol) obtained in Step 3 above and Dess-Martin periodinane (132mg, 0.313 mmol) were dissolved in

CH₂Cl₂ (5 ml) and stirred at room temperature. The mixture was filtered off.

The filtered white solid was diluted with CH₂Cl₂ (50ml) and washed with brine.

The organic layer was dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography

(Eluent : Hexane/EtOAc=3/l) to obtain the desired compound as a solid (78 mg,

78%). ¹H NMR (400 MHz, CDCl₃) δ 10.65 (s, IH), 7.46-7.45 (m, IH)₅ 7.38-7.31 (m,

4H), 7.36-7.23 (m, 2H), 1.52 (s, 9H).

MH+ 475.

Step 5: 3-(5-tert-Butyl-l,3,4-oxadiazol-2-yI)-5-(4-chlorophenyl)-l-(2,4- dichlorophenyI)-lH-pyrazole-4-carboxylic acid (Vila)

3-(5-tert~Butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)- 1 -(2,4-dichloro phenyl)- lH-pyrazole-4-carbaldehyde (1.0 g, 2.10 mmol) obtained in Step 4 above was dissolved in t-BuOH (60 ml). Thereto, 2-methyl-2-butene (12.0 ml,

99.0 mmol), KH₂PO₄ (2.2 g, 14.7 mmol) and NaClO₂ (2.4 g, 18.9 mmol in H₂O

(35ml)) were added. The mixture was stirred for 12 hours at room temperature.

The resultant was acidified with AcOH and extracted with EtOAc. The organic layer was dried over anhydrous MgSO₄, filtered and concentrated in vacuo to obtain the desired compound as a solide (981 mg, 95 %), which was used without further purification.

¹H NMR (400 MHz, CDCl₃) δ 7.46-7.45 (m, IH), 7.38-7.31 (m, 4H), 7.36-7.23 (m, 2H), 1.52 (s, 9H). MH+ 491.

Step 6: 3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-N-isopropyl-lH-pyrazole-4-carboxamide (Ia)

3-(5-tert-Butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichloro phenyl)- lH-pyrazole-4-carboxylic (150 mg, 0.31 mmol) obtained in Step 5 above was dissolved in CH₂Cl₂ (5 ml). Thereto, oxalyl chloride (35 μL, 0.37 mmol) and the catalytic amount of DMF were added. The mixture was stirred for 1 hour and concentrated in vacuo. The residue (crude acyl chloride) was diluted with CH₂Cl₂ (10 ml), to which isopropylamine (40 μL, 0.46 mmol) and triethylamine (0.13 ml, 0.93 mmol) were added and stirred for 2 hours at room temperature. The resultant was concentrated in vacuo and diluted with EtOAc. The organic layer was washed with aq. saturated NaHCO₃ solution, dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (Biotage) to obtain the title compound as a solid (103mg, 63%).

¹H NMR (400 MHz, CDCl₃) δ 9.61 (d, J = 7.2 Hz, IH), 7.42 (dd, J = 2.0 Hz, 0.4 Hz, IH), 7.30-7.24 (m, 4H), 7.23-7.19 (m, 2H), 4.18 (septet, J = 7.2 Hz, IH)₅ 1.51 (s, 9H), 1.26 (d, J = 6.4 Hz, 6H). MH+ 532.

The following compounds of Examples 2 to 82 were obtained by using corresponding starting materials and repeating the procedure of Example 1.

Example 2 (3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-lH-pyrazoI-4-yl)-morphoIino-methanone

¹H NMR (400 MHz, CDCl₃) δ 7.52-7 '.47 (m, IH), 7.39-7.25 (m, 5H), 7.23-7.18 (m, 2H), 3.85-3.13 (m, 8H), 1.48 (s, 9H). MH+ 560.

Example 3

3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyI)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.81 (s, IH), 7.43 (dd, J = 2.0 Hz, 0.4 Hz, IH), 7.30-7.25 (m, 4H), 7.23-7.18 (m, 2H), 5.65 (s, IH), 1.51 (s, 9H). MH+ 491.

Example 4

N-tert-Butyl-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyI)-l-(2,4- dichlorophenyI)-lH-pyrazole-4-carboxamide ¹H NMR (400 MHz, CDCl₃) δ 9.05 (s, IH), 7.41 (dd, J = 2.0 Hz, 0.4 Hz, IH), 7.31-7.23 (m, 4H), 7.21-7.17 (m, 2H), 1.51 (s, 9H), 1.44 (s, 9H). MH+ 546.

Example 5

3-(5-tert-Butyl-l,3,4-oxadiazoI-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-N-(piperidin-l-yI)-lH-pyrazole-4-carboxamide

1H NMR (400 MHz, CDCl₃) δ ^~ 10.95 (br s, IH), 7.42 (d, J = 2.0 Hz, IH), 7.31-7.19 (m, 6H), 3.10 (br s, 4H), 1.79 (br s, 4H), 1.52-1.48 (m, HH). MH+ 575.

Example 6 3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichIorophe nyl)-N,N-dimethyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 7.48-7.44 (m, IH), 7.37-7.33 (m, 2H), 7.31-7.26 (m, 2H), 7.22-7 '.17 (m, 2H), 3.10 (s, 3H), 2.92 (s, 3H), 1.48 (s, 9H). MH+ 518.

Example 7

3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-N-methyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.80 (s, IH), 7.42 (dd, J = 2.0 Hz, 0.8 Hz, IH), 7.29-7.24 (m, 4H), 7.23-7.19 (m, 2H), 2.93 (d, J = 4.4 Hz, 3H), 1.51 (s, 9H). MH+ 506.

Example 8

3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-N,N-diethyl-lH-pyrazole-4-carboxamide ¹R NMR (400 MHz, CDCl₃) δ 7.52-7.46 (m, IH), 7.37-7.31 (m, IH), 7.29-7.20 (m, 5H), 3.52 (quartet, J = 7.2 Hz, 2H), 3.21 (quartet, J = 6.4 Hz, 2H), 1.47 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H). MH+ 546.

Example 9

3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-N-ethyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.77 (s, IH), 7.43-7.41 (m, IH), 7.30-7.19 (m, 6H), 3.47-3.38 (m, 2H), 1.50 (s, 9H), 1.25 (t, J - 7.2 Hz, 3H). MH+ 518.

Example 10

3-(5-tert-Butyl-l,3,4-oxadiazoI-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-N-ethyl-N-methyl-lH-pyrazole-4-carboxamide

¹R NMR (400 MHz, CDCl₃) δ 7.47-7.25 (m, 5H), 7.23-7.17 (m, 2H), 3.57 (quartet, J = 7.2 Hz, 2H), 2.86 (s, 3H), 1.45 (s, 9H), 1.18 (t, J = 7.2 Hz, 3H). MH+ 532.

Example 11

3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-N-cyclopropyI-l-(2, 4-dichlorophenyI)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.94 (s, IH), 7.42 (dd, J = 2.0 Hz, 0.8 Hz, IH), 7.30-7.24 (m, 4H), 7.23-7.19 (m, 2H), 2.87 (m, IH), 1.46 (s, 9H), 0.81-0.75 (m, 2H), 0.70-0.64 (m, 2H). MH+ 530.

Example 12 3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-N-cyclobutyl-l-(2,4 -dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ ^~ 10.07 (d, J = 7.2 Hz, IH), 7.43-7.41 (m, IH), 7.29-7.23 (m, 4H)₅ 7.22-7.18 (m, 2H), 4.51-4.49 (m, IH), 2.39-2.30 (m, 2H), 2.15-2.04 (m, 2H), 1.81-1.65 (m, 2H), 1.47 (s, 9H). MH+ 544.

Example 13 3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-N-cyclopentyl-l-(2, 4-dichlorophenyl)-lH-pyrazoIe-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.80 (d, J = 6.0 Hz, IH), 7.42 (d, J = 2.0 Hz, J = 0.8 Hz, IH), 7.31-7.24 (m, 4H), 7.23-7.19 (m, 2H), 4.35-4.27 (m, IH), 2.05-1.95 (m, 2H), 1.85-1.70 (m, 2H), 1.69-1.52 (m, 4H), 1.51 (s, 9H). MH+ 560.

Example 14

3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-N-cyclohexyl-l-(2,4 -dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.72 (d, J = 8.0 Hz₅ IH)₅ 7.43-7.41 (m, IH), 7.30-7.24 (m, 4H)₅ 7.22-7.19 (m, 2H), 3.94-3.83 (m, IH), 2.03-1.91 (m, 2H), 1.75-1.70 (m, 2H)₅ 1.63-1.53 (m, 2H), 1.43 (s, 9H)₅ 1.42-1.21 (m₅ 4H). MH+ 574.

Example 15

(3-(5-tert-Butyl-l,3,4-oxadiazoI-2-yl)-5-(4-chIorophenyl)-l-(2,4-dichIorophe nyl)-lH-pyrazol-4-yl)(pyrrolidin-l-yl)methanone

¹H NMR (400 MHz₅ CDCl₃) δ 7.48-7.46 (m, IH), 7.37-7.33 (m, 2H), 7.28-7.21 (m, 4H), 3.66-3.59 (m, 2H), 3.29-3.19 (m, 2H)₅ 1.95-1.79 (m, 4H), 1.45 (s, 9H). MH+ 546.

Example 16

(3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyI)-l-(2,4-dichlorophe nyI)-lH-pyrazoI-4-yl)(piperidin-l-yl)methanone

¹H NMR (400 MHz, CDCl₃) δ ^~ 7.48-7.44 (m, IH)₅ 7.37-7.24 (m, 4H), 7.22-7.17 (m, 2H), 3.37-3.21 (m, 2H)₅ 1.81-1.45 (m, 6H)₅ 1.46 (s, 9H). MH+ 560.

Example 17

3-(5-tert-ButyI-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichIorophe nyl)-N-phenyl-lH-pyrazole-4-carboxamide

1H NMR (400 MHz, CDCl₃) δ 11.90 (s, IH), 7.78-7.73 (m, 2H), 7.45-7.43 (m, IH), 7.32-7.22 (m₅ 8H), 7.11-7.05 (m, IH), 1.51 (s, 9H). MH+ 566.

Example 18 N'-Acetyl-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dic hlorophenyl)-lH-pyrazole-4-carbohydrazide

¹H NMR (400 MHz, CDCl₃) δ 12.70 (s, IH)₅ 8.03 (s, IH), 7.46-7.42 (m₅ IH), 7.31-7.19 (m₅ 6H)₅ 2.01 (s, 3H), 1.52 (s, 9H). MH+ 547.

Example 19

3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-N'-phenyl-lH-pyrazole-4-carbohydrazide

¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, IH), 7.58-7.53 (m, 2H)₅ 7.49-7.46 (m, IH), 7.42-7.21 (m, 9H), 2.05-1.81 (m, IH), 1.25 (s, 9H). MH+ 581.

Example 20

3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-N-(2-oxopropyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.26 (s, IH), 7.46-7.41 (m, IH), 7.31-7.15 (m, 6H), 4.24 (d, J = 5.2 Hz, 2H), 2.16 (s, 3H), 1.51 (s, 9H). MH+ 548.

Example 21

3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-N-(pyridin-2-yl)-lH-pyrazole-4-carboxamide

1H NMR (400 MHz, CDCl₃) δ 12.32 (s, IH), 8.61 (d, J - 8.8 Hz, IH), 8.27-8.21 (m, IH), 8.10-8.03 (m, IH), 7.47-7.40 (m, IH), 7.38-7.25 (7H), 1.52 (s, 9H). MH+ 567.

Example 22 5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophe nyl)-N,N-dimethyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.42 (m, 3H), 7.39-7.32 (m, 2H), 7.21-7.11 (m, 2H), 3.11 (s, 3H), 2.92 (s, 3H), 1.47 (s, 9H). MH+ 562.

Example 23

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yI)-l-(2,4-dichlorophe nyl)-N-methyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.81 (s, IH), 7.47-7.40 (m, 3H), 7.32-7.24 (m, 2H), 7.19-7.13 (m, 2H), 2.94 (d, J = 4.0 Hz, 3H), 1.52 (s, 9H). MH+ 548.

Example 24

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazoI-2-yl)-l-(2,4-dichlorophe nyl)-N-ethyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz₃ CDCl₃) δ 9.78 (s, IH), 7.45-7.41 (m, 3H), 7.29-7.26 (m, 2H), 7.19-7.13 (m, 2H), 3.48-3.37 (m, 2H), 1.52 (s, 9H), 1.25 (t, J - 7.2 Hz, 3H). MH+ 562.

Example 25

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophe nyl)-N-ethyl-N-methyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 7.48-7.27 (m, 5H), 7.19-7.09 (m, 2H), 3.57 (quartet, J - 7.2 Hz, 2H), 3.05 (s, 3H)₃ 1.45 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H). MH+ 576.

Example 26

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophe nyl)-N,N-diethyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 7.52-7.26 (m, 5H), 7.18-7.12 (m, 2H), 3.52 (quartet, J = 7.2 Hz, 2H), 3.19 (quartet, J = 7.2 Hz, 2H)₃ 1.48 (s, 9H), 1.20 (t, J = 7.2 Hz₅ 3H), 0.84 (t, J = 7.2 Hz, 3H). MH+ 590.

Example 27 5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophe nyl)-N-isopropyl-lH-pyrazole-4-carboxamide ¹H NMR (400 MHz₅ CDCl₃) δ 9.63 (d, J = 6.4 Hz₅ IH)₅ 7.44-7.39 (m₅ 2H)₅ 7.32-7.21 (m₅ 3H)₅ 7.18-7.10 (m, 2H), 4.18 (m, IH)₅ 1.48 (s, 9H)₅ 1.26 (d, J = 6.8 Hz₅ 6H). MH+ 576.

Example 28

5-(4-Bromophenyl)-N-tert-butyl-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4- dichlorophenyl)-lH-pyrazoIe-4-carboxamide

1H NMR (400 MHz₅ CDCl₃) δ 9.06 (s, IH)₅ 7.45-7.38 (m₅ 2H)₅ 7.32-7.19 (m, 3H)₅ 7.16-7.09 (m, 2H)₅ 1.51 (s, 9H)₅ 1.44 (s, 9H). MH+ 590.

Example 29 5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-l-(2 ,4-dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz₅ CDCl₃) δ 9.94 (s, IH)₅ 7.44-7..6 (m₅ 2H)₅ 7.31-7.21 (m₅ 3H)₅ 7.20-7.11 (m₅ 2H)₅ 2.87 (m, IH)₅ 1.51 (s₅ 9H)₅ 0.81-0.72 (m₅ 2H)₅ 0.70-0.62 (m, 2H). MH+ 574.

Example 30

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-N-cyclobutyl-l-(2,4 -dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz₅ CDCl₃) δ 10.07 (d, J = 6.8 Hz₅ IH), 7.45-7.36 (m, 2H)₅ 7.32-7.23 (m, 3H)₅ 7.16-7.10 (m, 2H)₅ 4.53-4.43 (m, IH), 2.40-2.29 (m, 2H)₅ 2.17-2.02 (m, 2H)₅ 1.84-1.63 (m, 2H)₅ 1.47 (s, 9H). MH+ 588.

Example 31 5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-N-cyclopentyl-l-(2, 4-dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.78 (d, J = 6.0 Hz₅ IH), 7.45-7.39 (m, 2H), 7.31-7.19 (m₃ 3H), 7.18-7.11 (m, 2H), 4.36-4.25 (m, IH)₃ 2.05-1.95 (m, 2H), 1.89-1.71 (m, 2H), 1.69-1.53 (m, 4H), 1.51 (s, 9H). MH+ 602.

Example 32 5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yI)-N-cyclohexyl-l-(2,4 -dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.72 (d, J = 7.2 Hz, IH), 7.46-7.39 (m, 2H), 7.31-7.21 (m, 3H), 7.22-7.11 (m, 2H), 3.94-3.82 (m, IH), 2.03-1.91 (m, 2H), 1.79-1.69 (m, 2H), 1.63-1.53 (m, 2H), 1.43 (s, 9H), 1.45-1.19 (m, 4H). MH+ 616.

Example 33

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophe nyl)-N-phenyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.89 (s, IH), 7.79-7.70 (m, 2H), 7.49-7.41 (m, 3H), 7.32-7.22 (m, 4H), 7.21-7.13 (m, 2H), 7.11-7.05 (m, IH), 1.51 (s, 9H). MH+ 610.

Example 34

3-(5-tert-Butyl-l,3,4-oxadiazoI-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophe nyl)-N-propyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.84 (s, IH), 7.42 (d, J = 2.0 Hz, IH), 7.31-7.17 (m, 6H), 3.38-3.29 (m, 2H), 1.87-1.78 (m, 2H), 1.51 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H). MH+ 532.

Example 35

N-Butyl-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dich lorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.76 (br s, IH), 7.42 (d, J = 2.0 Hz, IH), 7.32-7.18 (m, 6H), 3.42-3.35 (m, 2H), 1.67-1.55 (m, 2H), 1.53 (s, 9H), 1.47-1.35 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). MH+ 546.

Example 36

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophe nyl)-N-(pyridin-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.32 (br s, IH), 8.59 (d, J = 8.8 Hz, IH), 8.24 (d,

J = 4.8 Hz, IH), 8.01 (t, J = 7.6 Hz, IH), 7.49-7.40 (m, 3H), 7.37-7.32 (m, IH),

7.30-7.23 (m, 4H), 1.51 (s, 9H).

MH+ 611.

Example 37

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-l-(2,4-dichlorophe nyl)-N-phenyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.46 (s, IH), 7.80-7.75 (m, 2H), 7.45-7.42 (m, 2H), 7.34-7.7.26 (m, 3H), 7.25-7.22 (m, 2H), 7.20-7.17 (m, 2H), 7.09-7.06 (m, IH), 1.55 (s, 9H). MH+ 626.

Example 38

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-N-cyclopropyl-l-(2 ,4-dichlorophenyl)-lH-pyrazole-4-carboxamide ¹H NMR (400 MHz, CDCl₃) δ 10.45 (s, IH), 7.44-7.39 (m, 2H), 7.28-7.25 (m, 2H), 7.22-7.21 (m, IH), 7.17-7.14 (m, 2H), 2.89-2.83 (m, IH), 1.53 (s, 9H), 0.85-0.78 (m, 2H), 0.70-0.66 (m, 2H). MH+ 590.

Example 39

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-N-cyclobutyl-l-(2,

4-dichIorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.55 (s, IH), 7.43-7.38 (m, 2H), 7.29-7.25 (m,

2H), 7.22-7.21 (m, IH), 7.16-7.12 (m, 2H), 4.52-4.44 (m, IH), 2.40-2.32 (m,

2H), 2.18-2.08 (m, 2H), 1.83-1.64 (m, 2H), 1.54 (s, 9H).

MH+ 604.

Example 40

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazoI-2-yl)-N-cyclopentyl-l-(2

,4-dichlorophenyl)-lH-pyrazoIe-4-carboxamide

1H NMR (400 MHz, CDCl₃) δ 10.29 (s, IH), 7.42-7.40 (m, 2H), 7.27-7.24 (m, 2H), 7.23-7.21 (m, IH), 7.17-7.14 (m, 2H), 4.34-4.28 (m, IH), 2.02-1.96 (m, 2H), 1.81-1.79 (m, 2H), 1.69-1.59 (m, 4H), 1.53 (s, 9H). MH+ 618.

Example 41

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-N-cyclohexyl-l-(2, 4-dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.20 (s, IH), 7.43-7.40 (m, 2H), 7.27-7.24 (m, 2H), 7.23-7.20 (m, IH), 7.19-7.13 (m, 2H), 3.89 (bs, IH), 1.99-1.95 (m, 2H), 1.77-1.74 (m, 2H), 1.53 (s, 9H), 1.47-1.24 (m, 6H). MH+ 632. Example 42

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-N-cycloheptyl-l-(2

,4-dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.21 (s, IH)₅ 7.43-7.39 (m, 2H), 7.27-7.24 (m, 2H), 7.20-7.18 (m, IH), 7.17-7.13 (m, 2H), 4.07-4.02 (m, IH), 2.07-1.96 (m, 2H), 1.88-1.37 (m, 10H), 1.55 (s, 9H). MH+ 646.

Example 43

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-l-(2,4-dichIorophe nyl)-N-(2-fluorophenyl)-lH-pyrazole-4-carboxamide

1H NMR (400 MHz, CDCl₃) δ 12.42 (s, IH), 8.19-8.14 (m. IH), 7.45-7.42 (m, 2H), 7.30-7.09 (m, 6H), 7.07-7.02 (m, 2H), 1.55 (s, 9H). MH+ 644.

Example 44 5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichIorophe nyI)-N-(2-oxopropyl)-lH-pyrazoIe-4-carboxamide

¹H NMR (400 MHz₅ CDCl₃) δ 10.27 (s, IH), 7.49-7.19 (m, 5H), 7.17-7.09 (m, 2H)₅ 4.24 (s₅ 2H)₅ 2.16 (s, 3H)₅ 1.47 (s, 9H). MH+ 590.

Example 45

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-l-(2,4-dichIorophe nyl)-N-(2-hydroxypropyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.90 (s, IH), 7.44-7.41 (m, 2H)₅ 7.29-7.20 (m, 3H)₅ 7.16-7.13 (m, 2H)₅ 4.08-4.04 (m, IH)₅ 3.60-3.55 (m, IH)₅ 3.36-3.30 (m, IH), 1.55 (s, 9H), 1.23-1.20 (m, 3H). MH+ 608.

Example 46 5-(4-Bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2- yl)-l-(2,4-dichlorophenyl)-N-isopropyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.41 (d, J = 7.6 Hz, IH), 7.45-7.21 (m, 9H)₅ 7.15-7.08 (m, 2H), 4.21-4.07 (m, IH), 1.84-1.77 (m, 2H), 1.55-1.43 (m, 2H)₅ 1.21 (d, J = 6.4 Hz, 6H). MH+ 670.

Example 47

5-(4-Bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2- yl)-N-cyclopropyl-l-(2,4-dichIorophenyI)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.74 (s, IH), 7.45-7.37 (m, 4H), 7.35-7.30 (m, 2H)₅ 7.29-7.20 (m, 3H), 7.17-7.10 (m, 2H)₅ 2.86-2.77 (m, IH), 1.88-1.78 (m, 2H), 1.55-1.46 (m, 2H), 0.79-0.72 (m, 2H), 0.64-0.58 (m, 2H). MH+ 668.

Example 48

5-(4-BromophenyI)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazoI-2- yl)-N-cyclobutyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.86 (br d, J - 7.2 Hz, IH), 7.45-7.37 (m, 4H), 7.36-7.31 (m, 2H), 7.29-7.20 (m, 3H)₅ 7.15-7.09 (m, 2H)₅ 4.55-4.40 (m, IH), 2.36-2.25 (m, 2H), 2.10-1.97 (m, 2H), 1.87-1.80 (m, 2H), 1.79-1.61 (m, 2H), 1.59-1.47 (m, 2H). MH+ 682.

Example 49 5-(4-Bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazoI-2- yl)-l-(2,4-dichlorophenyl)-N-phenyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.67 (s, IH), 7.70 (d, J = 8.0 Hz, 2H), 7.47-7.40 (m, 4H), 7.35-7.22 (m, 7H), 7.19-7.13 (m, 2H), 7.07 (t, J = 7.2 Hz, IH), 1.90-1.79 (m, 2H), 1.60-1.45 (m, 2H). MH+ 704.

Example 50 5-(4-Bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyI)-l,3,4-oxadiazol-2- yl)-l-(2,4-dichIorophenyl)-N-(pyridin-2-yl)-lH-pyrazole-4-carboxamide

¹B. NMR (400 MHz, CDCl₃) δ 12.25 (s, IH), 8.64 (d, J = 8.8 Hz, IH), 8.44 (d, J = 5.2 Hz, IH), 8.12 (t, J = 8.0 Hz, IH), 7.70-7.33 (m, 13H), 2.11-1.98 (m, 2H), 1.73-1.60 (m, 2H). MH+ 705.

Example 51

5-(4-Chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2- yl)-l-(2,4-dichIorophenyl)-N-isopropyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.42 (d, J = 7.2 Hz, IH), 7.45-7.41 (m, 2H), 7.37-7.33 (m, IH), 7.31-7.24 (m, 6H), 7.22-7.18 (m, 2H), 4.21-4.09 (m, IH), 1.85-1.80 (m, 2H), 1.53-1.47 (m, 2H), 1.22 (d, J = 6.4 Hz, 6H). MH+ 626.

Example 52

5-(4-Chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2- yl)-N-cycIopropyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.76 (s, IH), 7.44-7.40 (m, 3H), 7.37-7.33 (m, 2H), 7.30-7.23 (m, 4H), 7.22-7.19 (m, 2H), 2.87-2.79 (m, IH), 1.85-1.78 (m,

41 2H), 1.53-1.47 (m, 2H)₅ 0.79-0.71 (m, 2H), 0.65-0.58 (m, 2H). MH+ 624.

Example 53 5-(4-Chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2- yl)-N-cyclobutyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz₅ CDCl₃) δ 9.88 (br d, J = 7.2 Hz₅ IH)₅ 7.46-7.41 (m, 3H)₅ 7.38-7.33 (m, 2H)₅ 7.30-7.22 (m, 4H)₅ 7.21-7.17 (m, 2H)₅ 4.53-4.48 (m₅ IH)₅ 2.38-2.27 (m, 2H)₅ 2.11-1.98 (m, 2H)₅ 1.85-1.80 (m₅ 2H), 1.78-1.63 (m, 2H), 1.57-1.49 (m, 2H). MH+ 638.

Example 54 5-(4-ChIorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2- yl)-l-(2,4-dichlorophenyI)-N-phenyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.69 (s, IH), 7.71 (d, J = 8.0 Hz₅ 2H), 7.45-7.40 (m, 3H)₅ 7.38-7.34 (m 2H)₅ 7.32-7.21 (m, 8H)₅ 7.07 (t, J = 7.6 Hz, IH), 1.88-1.72 (m, 2H)₅ 1.57-1.49 (m, 2H). MH+ 660.

Example 55

5-(4-Chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2- yl)-l-(2_?4-dichlorophenyl)-N-(pyridin-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.83 (s, IH), 8.38-8.34 (m, IH), 8.12 (d, J = 8.4 Hz, IH), 7.64-7.57 (m, IH), 7.45-7.38 (m, 3H)₅ 7.34-7.21 (m, 8H)₅ 7.03-6.97 (m₅ IH), 1.88-1.80 (m, 2H), 1.56-1.47 (m, 2H). MH+ 661.

Example 56 5-(4-Bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-thiadiazol-2- yl)-N-cyclopropyl-l-(2,4-dichIorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.35 (s, IH), 7.44-7.39 (m, 5H), 7.36-7.32 (m, 2H), 7.25-7.22 (m, IH), 7.15-7.12 (m, 3H), 2.88-2.83 (m, IH), 1.97-1.94 (m, 2H), 1.60-1.53 (m, 2H), 0.82-0.77 (m, 2H), 0.69-0.65 (m, 2H). MH+ 684.

Example 57 5-(4-Bromophenyl)-3-(5-(l-(4-chlorophenyI)cyclopropyl)-l,3,4-thiadiazoI-2- yl)-N-cyclobutyl-l-(2,4-dichlorophenyI)-lH-pyrazoIe-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.47 (s, IH), 7.45-7.38 (m, 5H), 7.36-7.33 (m, 2H), 7.25-7.21 (m, IH), 7.16-7.10 (m, 3H), 4.53-4.43 (m, IH), 2.40-2.32 (m, 2H), 2.17-2.08 (m, 2H), 2.07-1.83 (m, 2H), 1.79-1.67 (m, 2H), 1.61-1.54 (m, 2H). MH+ 698.

Example 58 5-(4-Bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l ,3,4-thiadiazol-2- yl)-l-(2,4-dichIorophenyl)-N-phenyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 13.39 (s, IH), 7.78-7.76 (m, 2H), 7.46-7.40 (m, 4H), 7.37-7.30 (m, 4H), 7.25-7.19 (m, 2H), 7.18-7.15 (m, 3H), 7.10-7.06 (m, IH), 2.02-1.99 (m, 2H), 1.59-1.55 (m, 2H). MH+ 720.

Example 59

5-(4-Bromophenyl)-3-(5-(l-(4-chlorophenyl)cycIopropyl)-l,3,4-thiadiazol-2- yl)-l-(2,4-dichlorophenyl)-N-isopropyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.07 (s, IH), 7.45-7.41 (m, 5H), 7.40-7.32 (m, 2H), 7.25-7.22 (m, IH), 7.16-7.11 (m, 3H), 4.21-4.13 (m, IH), 2.08-1.95 (m, 2H), 1.56-1.53 (m, 2H), 1.28 (d, J = 6.8 Hz, 4H). MH+ 686.

Example 60

5-(4-Bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-thiadiazol-2- yl)-l-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.79 (s, IH), 8.44-8.43 (m, IH), 8.19-8.17 (m, IH), 7.63-7.51 (m, IH), 7.45-7.39 (m, 4H), 7.36-7.33 (m, IH), 7.27-7.24 (m, 2H), 7.22-7.20 (m, 2H), 7.18-7.13 (m, 2H), 7.02-6.99 (m, IH), 2.09-2.01 (m, 2H), 1.56-1.53 (m, 2H). MH+ 721.

Example 61

5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-l-(2,4-dichlorophe nyl)-N-isopropyHH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.16 (s, IH), 7.44-7.40 (m, 2H), 7.28-7.23 (m, 2H), 7.22-7.15 (m, 3H), 4.21-4.16 (m, IH), 1.55 (s, 9H), 1.30 (d, J = 6.4 Hz, 4H). MH+ 592.

Example 62 5-(4-Bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-l-(2,4-dichlorophe nyl)-N-(pyridin-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.89 (s, IH)₅ 8.45-8.43 (m, IH), 8.20-8.18 (m, IH), 7.64-7.59 (m, IH), 7.47-7.44 (m, 2H), 7.31-7.18 (m, 5H), 7.02-6.99 (m, IH), 1.56 (s, 9H). MH+ 627. Example 63

5-(4-Bromophenyl)-N-cyclopropyl-l-(2,4-dichlorophenyl)-3-(5-(l-(trifluoro methyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)-lH-pyrazole-4-carboxamide

1H NMR (400 MHz₅ CDCl₃) δ 9.54 (br s, IH)₅ 7.45-7.38 (m, 2H)₅ 7.31-7.29 (m, IH)₅ 7.29-7.24 (m₅ 2H)₅ 7.17-7.08 (m, 2H)₅ 2.90-2.83 (m, IH)₅ 1.67-1.62 (m, 4H)₅ 0.81-0.77 (m₅ 2H)₅ 0.67-0.61 (m, 2H). MH+ 626.

Example 64

5-(4-Bromophenyl)-N-cyclobutyl-l-(2,4-dichlorophenyl)-3-(5-(l-(trifluorom ethyl)cycIopropyl)-l,3,4-oxadiazol-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz₅ CDCl₃) δ 9.68 (br d, IH)₅ 7.42 (d, J = 10.8 Hz, 2H)₅ 7.31-7.22 (m, 3H)₅ 7.14 (d, J = 13.2 Hz₅ 2H)₅ 5.30-4.38 (m, IH)₅ 2.39-2.32 (m, 3H)₅ 2.14-2.05 (m₅ 3H)₅ 1.88-1.72 (m₅ 4H). MH+ 640.

Example 65 5-(4-Bromophenyl)-l-(2,4-dichIorophenyl)-N-isopropyI-3-(5-(l-(trifluorom ethyl)cyclopropyl)-l,3,4-oxadiazol-2-yI)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz₅ CDCl₃) δ 9.68 (br d, J = 7.2 Hz₅ IH)₅ 7.45-7.40 (m, 2H)₅ 7.30 (dd₅ J = 8.4, 2.4 Hz₅ IH)₅ 7.27-7.25 (m, 2H), 7.17-7.14 (m, 2H)₅ 4.21-4.10 (m₅ IH)₅ 1.27 (s, 3H), 1.25 (s, 3H)₅ 1.26-1.15 (m, 4H). MH+ 630.

Example 66

5-(4-Bromophenyl)-l-(2,4-dichlorophenyl)-N-phenyl-3-(5-(l-(trifluorometh yl)cyclopropyl)-l,3,4-oxadiazol-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz₅ CDCl₃) δ 11.52 (br s, IH)₅ 7.74 (d, J = 7.6 Hz, 2H), 7.46-7.43 (m, 3H), 7.40-7.28 (m, 5H) 7.19 (d, J = 6.8 Hz, 2H)₃ 7.10 (t, J = 7.2 Hz, IH), 1.64-1.48 (m, 4H). MH+ 664.

Example 67

5-(4-Bromophenyl)-l-(2,4-dichIorophenyl)-N-(pyridin-2-yl)-3-(5-(l-(trifluo romethyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.72 (br s, IH), 7.77 (d, J = 7.4 Hz, 2H), 7.47-7.41 (m, 3H), 7.38-7.31 (m, 4H) 7.22 (d, J = 7.4 Hz, 2H), 7.10 (t, J - 7.1 Hz, IH), 1.63-1.53 (m, 4H). MH+ 665.

Example 68 5-(4-Chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-thiadiazol-2 -yl)-l-(2,4-dichlorophenyI)-N-(pyridin-2-yl)-lH-pyrazoIe-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.74 (s, IH), 8.39-8.33 (m, 2H) ^~, 7.82-7.78 (m, IH), 7.45-7.38 (m, 3H), 7.35-7.32 (m, 2H), 7.29-7.23 (m, 6H), 7.14-7.11 (m, IH), 2.05-2.02 (m, 2H), 1.58-1.51 (m, 2H) MH+ 677.

Example 69

5-(4-ChIorophenyl)-3-(5-(l-(4-chIorophenyl)cyclopropyl)-l,3,4-thiadiazoI-2 -yl)-l-(2,4-dichlorophenyl)-N-phenyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.39 (s, IH), 7.76 (d, J=7.6, 2H) ^~, 7.45-7.40 (m, 3H), 7.37-7.29 (m, 4H), 7.29-7.16 (m, 6H), 7.10-7.06 (m, IH), 2.01-1.98 (m, 2H)₅ 1.58-1.55 (m, 2H). MH+ 676.

Example 70 5-(4-Chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-thiadiazol-2 -yl)-N-cyclobutyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.71 (b, IH), 7.44-7.38 (m, 2H)^~, 7.35-7.31 (m, 2H), 7.25-7.21 (m, 4H), 7.19-7.10 (m, 2H), 4.51-4.44 (m, IH), 2.39-2.34 (m, 2H), 2.20-2.10 (m, 2H), 2.00-1.92 (m, 2H), 1.83-1.66 (m, 2H), 1.55-1.52 (m, 2H). MH+ 654.

Example 71

5-(4-Chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyI)-l,3,4-thiadiazol-2 -yI)-N-cyclopropyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.39 (b, IH), 7.43-7.38 (m, 2H) ^~, 7.35-7.33 (m, 2H), 7.25-7.14 (m, 7H), 2.87-2.84 (m, IH), 1.97-1.94 (m, 2H), 1.56-1.53 (m, 2H), 0.81-0.77 (m, 2H), 0.68-0.64 (m, 2H). MH+ 640.

Example 72 5-(4-Chlorophenyl)-3-(5-(l-(4-chIorophenyl)cycIopropyI)-l,3,4-thiadiazol-2 -yl)-l-(2,4-dichlorophenyI)-N-isopropyl-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.07 (b, IH), 7.43-7.38 (m, 2H) ^~, 7.35-7.33 (m, 2H), 7.25-7.10 (m, 7H), 4.18-4.12 (m, IH), 1.98-1.91 (m, 2H), 1.55-1.50 (m, 2H), 1.27 (d, J=6.4, 6H). MH+ 642.

Example 73

5-(4-Chlorophenyl)-l-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-3-(5-(l-(trifluo romethyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.02 (s, IH), 8.58 (d, J=4.4, 1H)^~, 8.22-8.20 (m, IH), 8.04-8.00 (m, IH), 7.44-7.42 (m, IH), 7.40-7.24 (m, 7H), 1.84-1.77 (m, 2H), 1.68-1.60 (m, 2H). MH+ 619.

Example 74

5-(4-Chlorophenyl)-l-(2,4-dichIorophenyI)-N-phenyl-3-(5-(l-(trifluorometh yl)cyclopropyl)-l,3,4-oxadiazol-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.54 (s, IH), 7.73 (d, J=7.6, 2H) ^~, 7.44 (d, J=2.0, IH), 7.33-7.23 (m, 8H), 7.11-7.07 (m, IH), 1.70 (s, 4H). MH+ 618.

Example 75

5-(4-ChlorophenyI)-N-cyclobutyl-l-(2,4-dichlorophenyl)-3-(5-(l-(trifluoro methyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.68 (m, IH), 7.42 (d, /=2.4, IH) ^~, 7.30-7.24 (m, 5H), 7.21-7.19 (m, IH), 4.53-4.43 (m, IH), 2.39-2.31 (m, 2H), 2.16-2.02 (m, 2H), 1.81-1.66 (m, 2H), 1.83-1.66 (m, 4H), 1.55-1.52 (m, 2H). MH+ 596.

Example 76

5-(4-ChIorophenyl)-N-cycIopropyl-l-(2,4-dichIorophenyl)-3-(5-(l-(trifluoro methyl)cyclopropyl)-l,3,4-oxadiazoI-2-yl)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.55 (b, IH), 7.42 (d, J=2.4, IH)^", 7.30-7.24 (m,

4H), 7.23-7.20 (m, 2H), 2.88-2.82 (m, IH), 1.67 (m, 4H), 0.81-0.76 (m, 2H),

0.67-0.63 (m, 2H).

MH+ 582.

Example 77

5-(4-ChIorophenyl)-l-(2,4-dichIorophenyl)-N-isopropyl-3-(5-(l-(trifluorom ethyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)-lH-pyrazoIe-4-carboxamide

¹H NMR (400 MHz, CDCl₃) O 9.20 (b, IH)₅ 7.42 (d, J=L 6, IH) ^~, 7.31-7.24 (m, 4H), 7.22-7.20 (m, 2H), 4.22-4.10 (m, IH), 1.67 (s, 4H), 1.25 (d, /=6.4, 6H). MH+ 584.

Example 78

5-(4-Chlorophenyl)-l-(2,4-dichlorophenyI)-N-(pyridin-2-yl)-3-(5-(l-(trifluo romethy^cyclopropy^-l^^-thiadiazol-I-yO-lH-pyrazoIe^-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.49 (s, IH), 8.44 (d, /=8.8, IH) ^~, 8.32 (d, IH,

/=5.6), 7.91-7.86 (m, IH), 7.45-7.42 (m, IH), 7.32-7.24 (m, 6H), 7.20-7.16 (m,

IH), 1.85-1.78 (m, 2H), 1.68-1.60 (m, 2H).

MH+ 635.

Example 79

5-(4-Chlorophenyl)-l-(2,4-dichlorophenyl)-N-phenyl-3-(5-(l-(trifluorometh yI)cyclopropyl)-l,3,4-thiadiazol-2-yl)-lH-pyrazole-4-carboxamide

1H NMR (400 MHz, CDCl₃) δ 12.42 (s, IH), 7.74 (d, /=8.8, 2H) ^~, 7.45 (d,

/=2.0, IH), 7.34-7.23 (m, 8H), 7.10-7.07 (m, IH), 1.80-1.73 (m, 2H), 1.69-1.64 (m, 2H). MH+ 634.

Example 80

5-(4-Chlorophenyl)-N-cyclobutyl-l-(2,4-dichlorophenyl)-3-(5-(l-(trifluoro methyl)cyclopropyl)-l,3,4-thiadiazol-2-yI)-lH-pyrazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.33 (b, IH), 7.43 (d, J=2.4, IH) ^~, 7.28-7.25 (m, 4H), 7.22-7.19 (m, 2H), 4.49-4.47 (m, IH)₅ 2.40-2.31 (m, 2H), 2.14-2.06 (m, 2H)₅ 1.83-1.64 (m₅ 6H). MH+ 612. Example 81

5-(4-Chlorophenyl)-N-cyclopropyl-l-(2,4-dichlorophenyl)-3-(5-(l-(trifluoro methyl)cyclopropyI)-l,3,4-thiadiazoI-2-yl)-lH-pyrazoIe-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.22 (b, IH), 7.43 (m, IH)^", 7.29-7.25 (m, 4H), 7.23-7.20 (m, 2H), 2.88-2.86 (m, IH), 1.74-1.71 (m, 2H), 1.70-1.65 (m, 2H), 0.82-0.77 (m, 2H), 0.68-0.64 (m, 2H). MH+ 598.

Example 82

5-(4-ChIorophenyI)-l-(2,4-dichlorophenyI)-N-isopropyl-3-(5-(l-(trifluorom ethyl)cycIopropyI)-l,3,4-thiadiazol-2-yl)-lH-pyrazole-4-carboxamide

1H NMR (400 MHz, CDCl₃) δ 9.91 (b, IH), 7.43 (d, J=2.0, IH) ^~, 7.29-7.25 (m, 4H), 7.23-7.20 (m, 2H), 4.19-4.10 (m, IH), 1.76-1.74 (m, 2H), 1.67-1.64 (m, 2H), 1.27 (d, 7=6.8, 6H). MH+ 600.

Pharmacological Test: In vitro Activity Analysis

The compounds of the present invention were analyzed for their binding characteristics for CB₁ and CB₂ and the pharmacological activity thereof in accordance with the method disclosed in [Devane WA, Dysarz FA 3^rd, Johnson MR, Melvin LS and Howlett AC, Determination and characterization of a cannabinoid receptor in rat brain, MoI. Pharmacol., 34(5): 605-13(1998)]. The analysis was performed using [³H]CP-55940 which is a selectively radioactivity-labeled 5-(l,l-dimethyheptyl)-2[5- hydroxy-2-(3-hydroxyρropyl)-cyclohexyl]-phenol, purchased from PerkinElmer Life Sciences, Inc. (Boston, Massachusetts, U.S.A.), through a rat CB-I receptor binding protocol as follows.

The tissue obtained from the brain of SD rats was homogenized with a Dounce homogenate system in TME(50 mM Tris, 3 mM MgCl₂ and 1 mM EDTA, pH 7.4) at 4^"C₅ and the homogenate was centrifuged at 48,00Og for 30 min. at 4 °C . The pellet was resuspended in 5 ml of TME and the suspension was divided into aliquots and stored at -70 °C until its use in the following assay.

2 μi of the test compound was diluted in dimethylsulphoxide and was added to a deep well of a polypropylene plate, to which 50 μi of [³H]CP-55940 diluted in a ligand buffer solution (0.1 % bovine serum albumin(B AS)-KTME) was added. The tissue concentrations were determined by Bradford protein analysis, and 148 μi of brain tissue of the required concentration was added to the plate. The plate was covered and placed in a 30 °C incubator for 60 min, and then transformed on GF/B filtermat pretreated in polyethylenimine (PEI) using a cell harvester. Each filter was washed five times and dried at 60 ^°C for 1 hr. Then, the degree of radioactivity retained by the filter was measured using Wallac Microbeta™ (PerkinElmer Life Sciences, Inc., Massachusetts, U.S.A.) and the activity of the compound for inhibiting CB₁ receptor was determined there from and compared with that of the control, rimonabant which is known as a cannabinoid CB₁ receptor antagonist. The results are shown in Table 1. Table 1

As shown in Table 1, the inventive compounds are effective as a cannabinoid CB₁ receptor ligand.

While the invention has been described with respect to the specific embodiments, it should be recognized that various modifications and changes may be made by those skilled in the art to the invention which also fall within the scope of the invention as defined as the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

Y is O or S;

R₁ and R₂ are each independently hydrogen, C_1-6 alkyl, substituted C_1-6 alkyl, C_3-12 carbocycle, substituted C_3-12 carbocycle, NR₃R₄, -CHR₅(CO)OR₇, -CHR₅(CO) NR₃R₄, or R₁ and R₂ are fused to each other together with the nitrogen atom to which they are bonded to form a 4- to 10-membered saturated or unsaturated heterocyclic ring which is optionally substituted by one or more substituents selected from the group consisting of Cj_-3 alkyl, benzyl, phenyl, C_1-3 alkoxy or halogen; R₃ and R₄ are each independently selected from the group consisting of hydrogen, C_1-7 alkyl, C_3-8 carbocycle, substituted C_3-8 carbocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle and acyl; or are fused to each other together with the nitrogen atom to which they are bonded to form a 5- to 10-membered heterocycle which is unsubstituted or substituted by one or more substituents selected from the group consisting Of C_1-4 alkyl, C_1-4 alkoxy and fluoride;

R₅ is hydrogen, C_1-4 alkyl, substituted Ci_-4 alkyl, C_3-6 carbocycle, substituted C_3-6 carbocycle, (CH₂)_n-C_3-6 carbocycle or (CH₂)_n-R₆, n being 1, 2 or

3; R₆ is phenyl, furan, thiophene, tetrahydrofuran, tetrahydropyran or dioxane; R₇ is C_1-4 alkyl, substituted C_1-4 alkyl, C_3-8 carbocycle, substituted C_3-8 carbocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle;

R₈ is hydrogen, NR₃R₄, C_3-8 carbocycle, substituted C_3-8 carbocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, Q_-8 alkyl optionally substituted by alkoxy or halogen, C_2-6 alkenyl optionally substituted by alkoxy or halogen, (CH₂)_m-C_3-6 carbocycle optionally substituted by alkoxy or halogen, or (CH₂)_m-R₉, m being 1 or 2;

R₉ is phenyl, furanyl, benzofuranyl, thienyl, benzothienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridizinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, 1,4-benzodioxanyl or benzo[l,3]dioxolyl, each having one or more optional substituents selected from the group consisting of halogen, C_1-3 alkyl and C_1-2 alkoxy, each having one to three optional fluorine substituents; and

R₁₀, Rn, Ri₂, Ri₃, Ri₄ and R₁₅ are each independently hydrogen, halogen, cyano, Ci_-3 alkyl, Ci_-3 alkoxy, Ci_-3 sulfanyl or trifluoromethyl.

2. The compound or pharmaceutically acceptable salt of claim 1, which is selected from the group consisting of:

(3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl )- 1 H-pyrazol-4-yl)-morpholino-methanone;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl) - 1 H-pyrazole-4-carboxamide; N-tert-butyl-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dic hlorophenyl)- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N-isopropyl-lH-pyrazole-4-carboxamide;

3 -(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N-(piperidin- 1 -yl)~ 1 H-pyrazole-4-carboxamide; 3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N,N-dimethyl- 1 H-pyrazole-4-carboxamide;

3 -(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl) -N-methyl- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)-l-(2,4-dichloroρhenyl)

-N,N-diethyl- 1 H-pyrazole-4-carboxamide;

3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4~chlorophenyl)- 1 -(2,4-dichlorophenyl) -N-ethyl- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N-ethyl-N-methyl- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-N-cycloproρyl- 1 -(2,4- dichlorophenyl)- 1 H-pyrazole-4-carboxamide; 3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)-N-cyclobutyl- 1 -(2,4-di chlorophenyl)- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-N-cyclopentyl- 1 -(2,4-d ichlorophenyl)- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)-N-cyclohexyl- 1 -(2,4-di chlorophenyl)- 1 H-pyrazole-4-carboxamide;

(3-(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl

)- 1 H-pyrazol-4-yl)(pyriOlidin- 1 -yl)methanone;

(3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl

)- 1 H-pyrazol-4-yl)(piρeridin- 1 -yl)methanone; 3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N-phenyl- 1 H-pyrazole-4-carboxamide;

N'-acetyl-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4-dichlo rophenyl)- 1 H-pyrazole-4-carbohydrazide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chloroρhenyl)- 1 -(2,4-dichlorophenyl) -N'-phenyl- 1 H-pyrazole-4-carbohydrazide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N-(2-oxopropyl)- 1 H-pyrazole-4-carboxamide;

3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromoρhenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophenyl)

-N_sN-dimethyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromoρhenyl)-3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl) -N-methyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2_;,4-dichlorophenyl)

-N-ethyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl) -N-ethyl-N-methyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophenyl)

-N,N-diethyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3 -(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl)

-N-isopropyl- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-N-tert-butyl-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dic hlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-N-cyclopropyl- 1 -(2,4- dichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromoρhenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-N-cyclobutyl-l-(2,4-di chlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-N-cyclopentyl- 1 -(2,4-d ichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3 -(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)-N-cyclohexyl- 1 -(2,4-di chlorophenyl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2,4-dichlorophenyl)

-N-phenyl- 1 H-pyrazole-4-carboxamide;

3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)

-N-propyl- 1 H-pyrazole-4-carboxamide;

N-butyl-3 -(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-(4-chlorophenyl)- 1 -(2 ,4-dichlor ophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl) -N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3,4-thiadiazol-2-yl)- 1 -(2,4-dichlorophenyl) -N-phenyl- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3 ,4-thiadiazol-2-yl)-N-cyclopropyl- 1 -(2,4- dichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l,3₅4-thiadiazol-2-yl)-N-cyclobutyl-l-(2,4-di chlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l,3₅4-thiadiazol-2-yl)-N-cyclopentyl-l-(2,4- dichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-N-cyclohexyl-l-(2,4-d ichlorophenyl)- lH-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-thiadiazol-2-yl)-N-cycloheρtyl-l-(2,4- dichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromoρhenyl)-3-(5-tert-butyl-l_J3,4-thiadiazol-2-yl)-l-(2,4-dichlorophenyl)

-N-(2-fluorophenyl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-tert-butyl-l,3,4-oxadiazol-2-yl)-l-(2₃4-dichlorophenyl)

-N-(2-oxopropyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromoρhenyl)-3 -(5-tert-butyl- 1 ,3,4-thiadiazol-2-yl)- 1 -(2,4-dichlorophenyl)

-N-(2-hydroxypropyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl) -l-(2,4-dichlorophenyl)-N-isopropyl-lH-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)

-N-cyclopropyl- 1 -(2,4-dichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)

-N-cyclobutyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)

- 1 -(2,4-dichlorophenyl)-N-phenyl- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl) -l-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-lH-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3-(5-(l -(4-chlorophenyl)cyclopropyl)- 1 ,3,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl)-N-isopropyl- 1 H-pyrazole-4-carboxamide;

5-(4-chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)- N-cyclopropyl- 1 -(2,4-dichlorophenyl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3-(5-(l -(4-chlorophenyl)cyclopropyl)- 1 ,3,4-oxadiazol-2-yl)- N-cyclobutyl-l-(2₃4-dichlorophenyl)-lH-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)-

1 -(2,4-dichlorophenyl)-N-phenyl- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3-(5-(l-(4-chloiOphenyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)- 1 -(2,4-dichlorophenyl)-N-(pyridin-2-yl)- lH-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-thiadiazol-2-yl)

-N-cyclopropyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-tbiadiazol-2-yl) -N-cyclobutyl- 1 -(2,4-dichlorophenyl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-1.3,4-thiadiazol-2-yl)

- 1 -(2,4-dichlorophenyl)-N-phenyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-(l -(4-chlorophenyl)cyclopropyl)- 1 ,3,4-tbiadiazol-2-yl)

- 1 -(2,4-dichlorophenyl)-N-isopropyl- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-3-(5-(l -(4-chlorophenyl)cyclopropyl)- 1 ,3,4-thiadiazol-2-yl)

- 1 -(2,4-dichlorophenyl)-N-(pyridm-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-3-(5-tert-butyl- 1 ,3,4-thiadiazol-2-yl)- 1 -(2,4-dichlorophenyl)

-N-isopropyl- 1 H-pyrazole-4-carboxamide;

5-(4-bromoρhenyl)-3-(5-tert-butyl- 1 ,3,4-thiadiazol-2-yl)- 1 -(2,4-dichlorophenyl) -N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-N-cyclopropyl- 1 -(2,4-dichlorophenyl)-3-(5-(l -(trifluoromet hyl)cyclopropyl)- 1 ,3,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromoρhenyl)-N-cyclobutyl-l-(2,4-dichlorophenyl)-3-(5-(l-(trifluorometh yl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-bromophenyl)-l-(2₅4-dichlorophenyl)-N-isopropyl-3-(5-(l-(trifluoromethy l)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)- 1 -(2,4-dichlorophenyl)-N-phenyl-3 -(5-( 1 -(trifluoromethyl)c yclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-bromophenyl)-l-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-3-(5-(l-(trifluorom ethyl)cyclopropyl)-l,3,4-oxadiazol-2-yl)-lH-pyrazole-4-carboxamide;

5-(4-chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-thiadiazol-2-yl)

- 1 -(2,4-dichlorophenyl)-N-(pyridin-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-chlorophenyl)-3-(5-(l -(4-chlorophenyl)cyclopropyl)- 1 ,3₅4-thiadiazol-2-yl)

- 1 -(2,4-dichlorophenyl)-N-phenyl- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3-(5-(l -(4-chlorophenyl)cycloρropyl)- 1 ,3,4-thiadiazol-2-yl)

-N-cyclobutyl-l-(2.4-dichlorophenyl)-lH-pyrazole-4-carboxamide;

5-(4-chlorophenyl)-3-(5-(l-(4-chlorophenyl)cyclopropyl)-l,3,4-thiadiazol-2-yl) -N-cyclopropyl- 1 -(2,4-dichlorophenyl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl) - 1 ~(2,4-dichlorophenyl)-N-isopropyl- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-N-(pyridin-2-yl)-3-(5-( 1 -(trifluorom ethyl)cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-N-phenyl-3-(5-(l-(trifluoromethyl)c yclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-N-cyclobutyl-l-(2,4-dichlorophenyl)-3-(5-(l-(trifluorometh yl)cyclopropyl)-1.3₅4-oxadiazol-2-yl)-lH-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-N-cyclopropyl-l-(2,4-dichlorophenyl)-3-(5-(l-(trifluoromet hyl)cyclopropyl)- 1 ,3, 4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-N-isopropyl-3-(5-(l-(triiluoromethyl )cyclopropyl)- 1 ,3 ,4-oxadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-3-(5-(l-(trifluorom ethyl)cyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl)- 1 H-pyrazole-4-carboxamide;

5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-N-phenyl-3-(5-(l -(trifluoromethyl)c yclopropyl)- 1 ,3,4-thiadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-N-cyclobutyl-l-(2,4-dichlorophenyl)-3-(5-(l-(trifluorometh yl)cyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl)- 1 H-pyrazole-4-carboxamide; 5-(4-chlorophenyl)-N-cyclopropyl- 1 -(2,4-dichloroρhenyl)-3 -(5-( 1 -(trifluoromet hyl)cyclopropyl)-l,3,4-tbiadiazol-2-yl)-lH-pyrazole-4-carboxamide; and 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-N-isopropyl-3-(5-(l-(trifluoromethyl )cyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl)- 1 H-pyrazole-4-carboxamide.

3. A method for preparing the compound of formula (I) of claim 1, which comprises the steps of:

(i) subjecting a compound of formula (II) to bromination using NBS (N-bromosuccimmide) to obtain a compound of formula (III);

(ii) subjecting the compound of formula (III) to a substitution reaction with sodium acetate in an organic solvent to obtain an acetate compound of formula (IV);

(iii) hydrolyzing the compound of formula (IV) to obtain an alcohol compound of formual (V);

(iv) oxidizing the compound of foπnual (V) in the presence of an oxidant to obtain an aldehyde compound of formula (VI);

(v) further oxidizing the compound of formual (VI) in the presence of sodium chlorite and monobasic potassium phosphate to obtain a carboxylic acid compound of formula (VII);

(vi) chlorinating the compound of formula (VII) with a chlorinating agent to obtain an acid chloride compound of formula (VIII), and

(vii) treating the compound of formula (VIII) with an amine in the presence of a base to obtain the compound of formula (I):

wherein, R₁, R₂, Rs and R₁₀ to R_J5 have the same meanings as defined in claim 1.

4. A pharmaceutical composition comprising the compound of formula (I) of claim 1 as an active ingredient and a pharmaceutically acceptable carrier.

5. A method for preventing or treating obesity and obesity-related metabolic disorders in a mammal, which comprises administering the compound of formula (I) of claim 1 to the mammal.

6. A method for inhibiting cannabinoid CB₁ receptor in a mammal, which comprises administering the compound of formula (I) of claim 1 to the mammal.

C07D A61P 3/04(2006.01)1

included in the fields searched

search terms used)

to claim No

1-4 the

1-4

filing date or priority the application but cited to understand relevance, the claimed invention cannot be an inventive alone claimed invention cannot be document is such documents, such combination patent family report

Form PCT/ISA/210 (second sheet) (July 2008)