BIARYLPYRAZOLE 4-CARBOXAMIDES AS CANNABINOID CB ₁

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 Ca ²⁺ 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 CB ₁ 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 CB ₁ receptors in the limbic system-hypothalamus axis, cannabinoids have an important role in the control of appetite. Moreover, lower levels of CB ₁ 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 CB ₁ 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 CB ₁ 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, CIVCB ₂ 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 CB ₁ 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;

R ₁ and R ₂ are each independently hydrogen, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-12 carbocycle, substituted C _3-12 carbocycle, NR ₃ R ₄ , -CHR ₅ (CO)OR ₇ , -CHR ₅ (CO) NR ₃ R ₄ , or R ₁ and R ₂ 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; R ₃ and R ₄ 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;

R ₅ is hydrogen, C _1-4 alkyl, substituted C _1-4 alkyl, C _3-6 carbocycle, substituted C _3-6 carbocycle, (CH ₂ ) _n -C _3-6 carbocycle or (CH ₂ ) _n -R ₆ , n being 1, 2 or

3; R ₆ is phenyl, furan, thiophene, tetrahydrofuran, tetrahydropyran or dioxane;

R ₇ 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; R ₈ is hydrogen, NR ₃ R ₄ , 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, (CH ₂ ) _m -C _3-6 carbocycle optionally substituted by alkoxy or halogen, or (CH ₂ ) _m -R ₉ , m being 1 or 2; R ₉ 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

R ₁₀ , Rii, Ri ₂ , Ri ₃ , R _H and Ri ₅ 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, R ₁ , R ₂ , R ₈ and Rj ₀ to Ri ₅ 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, SO ₂ , 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, SO ₂ , 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 -OR ₃ , 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 _a R _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) ₂ R _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 -NH ₂ . 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) ₂ NH ₂ . 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) ₂ R _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)R ₀ 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)NH ₂ . 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)NH ₂ .

As used herein, the term "acyl" refers to the group -C(O)R ₆ , 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)R ₆ , 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, R ₁ , R ₂ , R ₈ , R ₁₀ , Rn, Ri ₂ , R ₁₃ , R _H and R ₁₅ 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, R ₁ , R ₂ , R ₈ , Rio ₅ Rn ₅ Ri _2? R _B5 Ri ₄ , and R ₁₅ 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-c hlorophenyl)-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 _J 4-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-c yclobutyl-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-chlo roρhenyl)-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-l ₅ 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- 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-chlorophe nyl)-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-carbo xamide;

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

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

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

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,3 ₅ 4-oxadiazol-2-yl)- N-cyclobutyl-l-(2,4-dichlorophenyl)-lH-pyrazole-4-carboxamid e; 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-carboxam ide; 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 ,3 ₅ 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)-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-carboxam ide; 5-(4-chlorophenyl)-3 -(5-( 1 -(4-chlorophenyl)cyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl) -l-(2 _J 4-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-carboxa mide; 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-carbox amide; 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, R ₁ , R ₂ and R ₈ 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, R ₃ , R ₄ and R ₈ 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, R ₈ 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

R ₈ CO ₂ Me NhH ₂ NH ₂ RλN; ^NH2 (6) ⁽ J)

(11) (12a) (12b)

wherein, R ₃ , R ₄ and R ₈ 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, R ₈ 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, R ₁ , R ₂ and R ₈ 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, R ₈ 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, R ₈ 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 CB ₁ 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 CB ₁ 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,N ₅ N',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.

¹ H 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% CH ₃ CN to 90% CH ₃ CN in H ₂ O. 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 CCl ₄ (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 CH ₂ Cl ₂ and washed with brine. The organic layer was dried over anhydrous MgSO ₄ , 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 MgSO ₄ , 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%).

¹ H NMR (400 MHz ₅ CDCl ₃ ) 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 (S ₅ 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)/H ₂ O (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 MgSO ₄ , filtered and concentrated in vacuo to obtain the desired compound as a solid (1.37g, 95 %), which was used without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) 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

CH ₂ Cl ₂ (5 ml) and stirred at room temperature. The mixture was filtered off.

The filtered white solid was diluted with CH ₂ Cl ₂ (50ml) and washed with brine.

The organic layer was dried over anhydrous MgSO ₄ , 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%).

¹ H NMR (400 MHz, CDCl ₃ ) 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), KH ₂ PO ₄ (2.2 g, 14.7 mmol) and NaClO ₂ (2.4 g, 18.9 mmol in H ₂ O

(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 MgSO ₄ , filtered and concentrated in vacuo to obtain the desired compound as a solide (981 mg, 95 %), which was used without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) 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 CH ₂ Cl ₂ (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 CH ₂ Cl ₂ (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 NaHCO ₃ solution, dried over anhydrous MgSO ₄ , 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%).

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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-c hlorophenyI)-l-(2,4- dichlorophenyI)-lH-pyrazole-4-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ R NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ R NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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-c yclopentyl-l-(2, 4-dichlorophenyl)-lH-pyrazoIe-4-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.72 (d, J = 8.0 Hz ₅ 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 (m ₅ 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

¹ H NMR (400 MHz ₅ CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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, CDCl ₃ ) δ 11.90 (s, IH), 7.78-7.73 (m, 2H), 7.45-7.43 (m, IH), 7.32-7.22 (m ₅ 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-chlorop henyl)-l-(2,4-dic hlorophenyl)-lH-pyrazole-4-carbohydrazide

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.70 (s, IH) ₅ 8.03 (s, IH), 7.46-7.42 (m ₅ IH), 7.31-7.19 (m ₅ 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz ₃ CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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 Hz ₅ 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

¹ H NMR (400 MHz ₅ CDCl ₃ ) δ 9.63 (d, J = 6.4 Hz ₅ IH) ₅ 7.44-7.39 (m ₅ 2H) ₅ 7.32-7.21 (m ₅ 3H) ₅ 7.18-7.10 (m, 2H), 4.18 (m, IH) ₅ 1.48 (s, 9H) ₅ 1.26 (d, J = 6.8 Hz ₅ 6H). MH+ 576.

Example 28

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

1H NMR (400 MHz ₅ CDCl ₃ ) δ 9.06 (s, IH) ₅ 7.45-7.38 (m ₅ 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-cy clopropyl-l-(2 ,4-dichlorophenyl)-lH-pyrazole-4-carboxamide

¹ H NMR (400 MHz ₅ CDCl ₃ ) δ 9.94 (s, IH) ₅ 7.44-7..6 (m ₅ 2H) ₅ 7.31-7.21 (m ₅ 3H) ₅ 7.20-7.11 (m ₅ 2H) ₅ 2.87 (m, IH) ₅ 1.51 (s ₅ 9H) ₅ 0.81-0.72 (m ₅ 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

¹ H NMR (400 MHz ₅ CDCl ₃ ) δ 10.07 (d, J = 6.8 Hz ₅ 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

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.78 (d, J = 6.0 Hz ₅ IH), 7.45-7.39 (m, 2H), 7.31-7.19 (m ₃ 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-cy clohexyl-l-(2,4 -dichlorophenyl)-lH-pyrazole-4-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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-chloro phenyl)-l-(2,4-dich lorophenyl)-lH-pyrazole-4-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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, CDCl ₃ ) 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

¹ H NMR (400 MHz ₅ CDCl ₃ ) δ 10.27 (s, IH), 7.49-7.19 (m, 5H), 7.17-7.09 (m, 2H) ₅ 4.24 (s ₅ 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

¹ H NMR (400 MHz, CDCl ₃ ) 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-carboxa mide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carbo xamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carbox amide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carboxamid e

¹ H NMR (400 MHz, CDCl ₃ ) 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-ca rboxamide

¹ B. NMR (400 MHz, CDCl ₃ ) 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-carboxa mide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carbo xamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carbox amide

¹ H NMR (400 MHz ₅ CDCl ₃ ) δ 9.88 (br d, J = 7.2 Hz ₅ 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 (m ₅ IH) ₅ 2.38-2.27 (m, 2H) ₅ 2.11-1.98 (m, 2H) ₅ 1.85-1.80 (m ₅ 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-carboxamid e

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.69 (s, IH), 7.71 (d, J = 8.0 Hz ₅ 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

¹ H NMR (400 MHz, CDCl ₃ ) 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 (m ₅ 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-carbo xamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carbox amide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carboxamid e

¹ H NMR (400 MHz, CDCl ₃ ) 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-carboxa mide

¹ H NMR (400 MHz, CDCl ₃ ) 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-ca rboxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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

¹ H NMR (400 MHz, CDCl ₃ ) 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-carb oxamide

1H NMR (400 MHz ₅ CDCl ₃ ) 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 (m ₅ 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 (m ₅ 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-carbo xamide

¹ H NMR (400 MHz ₅ CDCl ₃ ) 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 Hz ₅ 2H) ₅ 5.30-4.38 (m, IH) ₅ 2.39-2.32 (m, 3H) ₅ 2.14-2.05 (m ₅ 3H) ₅ 1.88-1.72 (m ₅ 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-carbo xamide

¹ H NMR (400 MHz ₅ CDCl ₃ ) δ 9.68 (br d, J = 7.2 Hz ₅ IH) ₅ 7.45-7.40 (m, 2H) ₅ 7.30 (dd ₅ J = 8.4, 2.4 Hz ₅ IH) ₅ 7.27-7.25 (m, 2H), 7.17-7.14 (m, 2H) ₅ 4.21-4.10 (m ₅ 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-carboxam ide

¹ H NMR (400 MHz ₅ CDCl ₃ ) 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-ca rboxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-c arboxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carboxami de

¹ H NMR (400 MHz, CDCl ₃ ) 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-carbo xamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carb oxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carbox amide

¹ H NMR (400 MHz, CDCl ₃ ) 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-ca rboxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carboxam ide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carb oxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carb oxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-ca rboxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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^-carboxa mide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carboxa mide

1H NMR (400 MHz, CDCl ₃ ) 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-car boxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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 (m ₅ 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-car boxamide

¹ H NMR (400 MHz, CDCl ₃ ) 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-carb oxamide

1H NMR (400 MHz, CDCl ₃ ) 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 CB ₁ and CB ₂ 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 [ ³ H]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 MgCl ₂ and 1 mM EDTA, pH 7.4) at 4 ^" C ₅ 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 [ ³ H]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 CB ₁ receptor was determined there from and compared with that of the control, rimonabant which is known as a cannabinoid CB ₁ receptor antagonist. The results are shown in Table 1. Table 1

As shown in Table 1, the inventive compounds are effective as a cannabinoid CB ₁ 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.