KR20220109339A - Pyrazole-carboxamide derivative compounds and uses thereof - Google Patents

Abstract

The novel pyrazole-carboxamide derivative compound provided as one aspect of the present invention exhibits specific antagonist/inverse agonist activity for cannabinoid receptor 1, thereby having a technical effect of effectively preventing or treating related diseases.

Description

Pyrazole-carboxamide derivative compounds and uses thereof

The present invention relates to a novel pyrazole-carboxamide derivative compound and its use for the prevention or treatment of related diseases based on an antagonist/inverse agonist effect specific to cannabinoid receptor 1 thereof.

The endocannabinoid system is composed of endocannabinoids, receptors, transporters, and enzymes, and plays an important role in a wide variety of physiological processes. have. (Howlett, AC, Annu. Pharmacol. Toxicol . 1995, 35, 607-634; Pacher, P. et. al, FEBS J. 2013, 280, 1918-1943; Lu, Y. et. al, Can. J. Physiol. Pharmacol . 2017, 95, 311-327).

Two different subtypes of the human cannabinoid receptor (subtypes, CB1 and CB2) have been isolated, all of which belong to the G protein coupled receptor superfamily. Cannabinoid receptor CB1, together with CB2 receptor and endocanabinoid ligand (endocanabinoid: ex. anandamide, 2-AG, etc.), constitutes an endocanabinoid system that plays an important role in maintaining energy homeostasis. The CB1 receptor is mainly distributed in the central nervous system including the brain of mammals including humans and is known to be involved in energy metabolism and appetite regulation. known to be involved.

The selective CB1 receptor antagonist, rimonabant (SR141716A), effectively reduces body weight in obese patients in clinical trials, and can also alleviate obesity-related metabolic syndrome diseases such as diabetes and cardiovascular disease. and obesity-related metabolic syndrome diseases. However, rimonabant inhibited the activity of CB1 receptors in the central nervous system (CNS) and was withdrawn from the market due to serious side effects such as depression and suicidal ideation (Christensen, R. et al., Lancet , 2013, 23, 4751). -4760). However, appetite regulation by CB1 receptors is not limited to CB1 receptors present in the brain, but appetite is also regulated by CB1 receptors present in peripheral tissues. It has already been verified by many research results (Tam J. et al., Cell Metab . 2012, 16(2), 167-179).

As described above, the previously developed CB1 receptor inhibitors reduce appetite and weight by inhibiting the activity of CB1 receptors in peripheral tissues, and improve glucose homeostasis through insulin resistance and beta cell growth and function, thereby improving type 2 diabetes. looks like However, due to its properties acting on the brain, it caused serious side effects and was withdrawn from the market and clinical trials. For this reason, to develop a CB1 receptor-activator-based type 2 diabetes treatment agent that does not pass through the blood-brain barrier and minimizes side effects by specifically controlling only the activity of CB1 receptors in peripheral tissues. Many studies have been conducted and recently, peripheral tissue-specific CB1 receptor inhibitors have been developed by several research groups (Chorvat, R. et al. Bioorg. Med. Chem. Lett . 2013, 23, 4751-4760; Kunos, G. et al., Br. J. Pharmacol . 2011, 163, 1423-1431). Representative peripheral tissue-specific CB1 receptor inhibitors with high potential for success recently developed are AM6545 and JD5037.

The first candidate, AM6545, was developed by Dr. Developed/reported by the Kunos group. AM6545 was developed through modification of the existing CB1 receptor inhibitor, Rimonabant, and showed a high affinity for the CB1 receptor compared to its parent, rimonabant, while its ability to cross the blood vessel-brain barrier was 14 times lower. It also did not affect the various behavioral effects mediated by CB1 receptors present in the brain. AM6545 improves insulin resistance, fatty liver, and leptin resistance in type 2 diabetes, improves glucose homeostasis and plasma lipid profile, and increases adiponectin production regardless of the weight loss effect. For the first time, it showed the possibility of developing peripheral tissue-specific CB1 receptor inhibitors for the treatment of type 2 diabetes (Tam J. et al., J. Clin Invest . 2010, 120(8), 2953-2966).

JD5037, a second peripheral tissue-specific CB1 receptor inhibitor candidate developed by US venture company Jenrin Discovery, also has a low ability to cross the blood-brain barrier, and various behavioral effects mediated by CB1 receptors in the brain similar to AM6545. It had no effect on type 2 diabetes by improving insulin and leptin resistance and plasma lipid profile (Tam J. et al., Cell Metab . 2012, 16(2)). , 2953-2966).

Therefore, the development of a compound having an antagonist/inverse agonist effect specific for selectively peripheral CB1 receptors is effective in various diseases such as diabetes, metabolic disease, dyslipidemia, alcoholic liver disease or non-alcoholic liver disease without side effects related to the central nervous system. drugs can be developed.

US2018031877A1 (2018.05.10) US9987252B2 (2011.01.27) US20160145333A1 (2016.05.26) US10118900B2 (2018.11.06) WO2018204689A1 (2018.11.08)

It is an object of the present invention to provide a novel pyrazole-carboxamide derivative compound, an isomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof.

It is also an object of the present invention to provide a pharmaceutical composition comprising the novel compound and a pharmaceutically acceptable carrier.

In addition, an object of the present invention is based on the specific inhibitory effect of the novel compound on cannabinoid receptor 1 (CB1), the compound, its isomer, its solvate or a pharmaceutically acceptable salt thereof It is to provide a pharmaceutical composition for the prevention or treatment of diseases caused by overexpression or overactivity of cannabinoid receptor 1, including.

The technical problems to be achieved by the present invention are not limited to the technical problems mentioned above, and other technical problems not mentioned will be clearly understood by those skilled in the art from the following description.

The definitions listed below are definitions of various terms used to describe the present invention. These definitions apply throughout this specification, either individually or as part of terms encompassing them, unless otherwise limited.

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

The term 'alkyl' as used herein, unless otherwise stated, refers to a saturated, straight-chain or branched hydrocarbon radical represented by C _n H _2n+1 , and specifically, between 1 and 6, respectively, 1 to refers to a saturated, straight-chain or branched hydrocarbon radical containing between 8, 1-10, or 1-20 carbon atoms. Examples of these radicals include, but are not limited to, the methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, heptyl, octyl radicals. For example, as used herein, the term 'C ₁ -C ₆ alkyl' refers to a linear or branched hydrocarbon residue having 1 to 6 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

The term 'cycloalkyl' or 'cycloalkyl' as used herein, unless otherwise stated, denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound. For example, as used herein, the term 'C ₃ -C ₆ cycloalkyl' refers to a cyclic hydrocarbon residue having 3 to 6 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

As used herein, unless otherwise stated, the term 'aryl' refers to mono- or poly-cyclic carbocy having 2 to 30 carbon atoms, 6 to 14 carbon atoms, or 1 to 6 carbon atoms, having one or more aromatic rings, fused or non-fused. refers to a click ring system, and examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, andracenyl, and the like.

The term 'heteroaryl' as used herein, unless otherwise stated, includes atoms other than carbon and one or more heteroatoms. Specifically, the heteroatoms are atoms selected from the group consisting of O, N, Se and S. may include one or more. The number of carbon atoms is not particularly limited, but preferably has 2 to 30, 6 to 14, or 1 to 6 carbon atoms, and the heteroaryl group may be monocyclic or polycyclic. Examples of the heteroaryl group include a thiophene group, a furanyl group, a pyrrole group, an imidazolyl group, a thiazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a bipyridyl group, a pyrimidyl group, a triazinyl group, a triazinyl group Jolyl group, acridyl group, pyridazinyl group, pyrazinyl group, quinolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, pyrido pyrimidyl group, pyrido pyrazinyl group, pyrazino pyrazinyl group , isoquinolinyl group, indolyl group, carbazolyl group, benzoxazolyl group, benzimidazolyl group, benzothiazolyl group, benzocarbazolyl group, benzothiophene group, dibenzothiophene group, benzofuranyl group, pe Nonthrolinyl group (phenanthroline), thiazolyl group, isoxazolyl group, oxadiazolyl group, thiadiazolyl group, phenothiazinyl group, dibenzofuranyl group, and the like, but are not limited thereto.

As an aspect of the present invention, there is provided a pyrazole-carboxamide derivative compound represented by the following formula (1), an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

R ₁ is H or halogen,

R ₂ is H, halogen or CN;

R ₃ and R ₄ are each independently H or halogen,

Q is substituted or unsubstituted aryl or heteroaryl,

,

,

,

,

또는

이고, L is

,

,

,

,

or

ego,

L ₁ is C ₁ -C ₆ alkyl,

R' and R'' may each independently be substituted with H or C ₁ -C ₃ alkyl,

Het is a 4-6 membered aromatic or non-aromatic heterocyclic compound unsubstituted or substituted with haloalkyl, and contains N or O in 1 to 4 rings.

Specifically, R ₁ may be H or Cl.

Specifically, R ₂ may be H or CN.

Specifically, R ₃ may be Cl.

Specifically, R ₄ may be H or Cl.

Specifically, the aryl may be any one selected from the following structures;

(In the above structure, X is hydrogen or halogen)

The heteroaryl may be any one selected from the following structures:

(In the above structure, X is hydrogen or halogen).

Specifically, L may be any one selected from the following structures:

(In the above structure, L ₁ is C ₁ -C ₃ alkyl).

Specifically, R' and R'' may be H.

Specifically, Het may be a compound that is unsubstituted or substituted with haloalkyl, and is a 4-6 membered aromatic heterocyclic compound including N or O in 2 to 4 rings.

Specifically, Het may be any one selected from the following structures:

(In the above structure, Y is H or CX ₃ , and X is halogen).

Specifically, the compound may be any one selected from the group consisting of the following compounds:

N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,

N-(3-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,

N-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,

N-(2-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,

N-(3-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,

N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,

(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine;

(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine;

3-(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid;

3-(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid;

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -carboxamide,

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -carboxamide,

(S)-N-(3-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,

(S)-N-(4-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,

N-(2-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,

N-(3-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,

N-(4-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,

N-(3-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,

N-(4-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,3,4-oxadiazole -2-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;

N-(3-amino-3-oxopropyl)-6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,

N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide,

N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-chlorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,

N-(4-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,

N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,

N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) pyrazine-2-carboxamide,

N-(3-amino-3-oxopropyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide,

N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,

N-(3-amino-3-oxopropyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide,

N-(5-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,

N-(3-((3-amino-3-oxopropyl)carbamoyl)-5-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,

N-(3-((3-amino-3-oxopropyl)carbamoyl)-4-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,

N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamide;

N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole- 3-carboxamide,

N-(2-amino-2-oxoethyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide,

N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,

N-(2-amino-2-oxoethyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide, and

N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide.

In one aspect of the present invention, there is provided a pharmaceutical composition comprising the pyrazole-carboxamide derivative compound, an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In addition, as an aspect of the present invention, the pyrazole-carboxamide derivative compound, an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, including overexpression or hyperactivity of cannabinoid receptor 1 It provides a pharmaceutical composition for the prevention or treatment of diseases caused by

In addition, as an aspect of the present invention, the cannabinoid receptor 1 ( To provide a method for preventing or treating diseases caused by overexpression or overactivation of cannabinoid receptor 1).

In addition, as an aspect of the present invention, for the preparation of a medicament for the prevention or treatment of diseases caused by overexpression or overactivity of cannabinoid receptor 1, the pyrazole-carboxamide derivative compound, an isomer thereof , a solvate thereof or a pharmaceutically acceptable salt thereof.

The disease caused by overexpression or overactivity of the cannabinoid receptor 1 may be one or more selected from the group consisting of diabetes, metabolic disease, dyslipidemia, alcoholic liver disease, and non-alcoholic liver disease, but is not limited thereto.

The "prevention" refers to any action that inhibits or delays a disease caused by overexpression or overactivation of cannabinoid receptor 1.

The "treatment" refers to any action in which the symptoms of the suspected and onset individual of a disease caused by overexpression or overactivation of cannabinoid receptor 1 are improved or beneficially changed.

The "pharmaceutically acceptable" means exhibiting properties that are not toxic to cells or humans exposed to the composition.

The "pharmaceutically effective amount" means that the amount of the compound administered is effective in alleviating or reducing to some extent one or more symptoms of the disorder being treated, or delaying the onset of clinical markers or symptoms of a disease requiring prevention. means quantity. Thus, a pharmacologically effective amount may have an effect of 1) reversing the rate of disease progression, 2) inhibiting further progression of the disease to some extent, and/or 3) alleviating to some extent one or more symptoms associated with the disease ( Preferably, it means an amount having the effect of removing). A pharmacologically effective amount can be empirically determined by testing the compound in known in vivo and in vitro model systems for a disease in need of treatment.

The isomers may exist as R or S isomers, racemic compounds, diastereomeric mixtures, or individual diastereomers, depending on the presence of an asymmetric carbon center of the pyrazole-carboxamide derivative compound, all isomers and mixtures of these isomers are included within the scope of the present invention.

The solvate may comprise a stoichiometric or non-stoichiometric amount of a solvent that is bound by non-covalent intermolecular forces. Preferred solvents include nonvolatile, nontoxic, or suitable solvents for human administration, for example, ethanol, methanol, propanol, methylene chloride, and the like, but are not limited thereto.

As the pharmaceutically acceptable salt, the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts prepared from calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, Inorganic acid salts prepared with phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid , glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, mandelic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, Organic acid salts prepared from succinic acid and tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, camphorsulfonic acid, sulfonic acid salts prepared from naphthalenesulfonic acid, glycine, arginine, lysine, etc. There are amino acid salts prepared with , and amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts in the present invention are not limited by these listed salts. For example, the 　 pharmaceutically acceptable salt may be hydrochloric acid as the inorganic acid and methanesulfonic acid as the organic acid.

As the pharmaceutically acceptable carrier, saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components may be mixed and used, and if necessary, an antioxidant , buffers, bacteriostats, and other conventional additives may be added, but the present invention is not limited thereto.

The pharmaceutical composition or pharmaceutical composition may be provided as a pharmaceutical composition including an active ingredient alone, or one or more pharmaceutically acceptable carriers, excipients or diluents.

The pharmaceutical composition or route of administration of the pharmaceutical composition is not limited thereto, but is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal.

The pharmaceutical composition or pharmaceutical composition may be administered orally or parenterally, and when administered parenterally, an injection method for external application or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection is selected. However, it is not limited thereto, and oral administration can be preferably selected from the viewpoint of selecting a more effective absorption route.

The pharmaceutical composition or a preferred dosage of the pharmaceutical composition varies depending on the patient's condition and body weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art. However, for a desirable effect, the composition is preferably administered at 0.01 to 1000 mg/kg/day, preferably 0.1 to 500 mg/kg/day, but is not limited thereto. The administration may be administered once a day, or divided into several administrations. The above dosages are not intended to limit the scope in any way.

When formulating the pharmaceutical composition or pharmaceutical composition, it is prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose. Or it is prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycero geratin and the like can be used.

The compound provided as an embodiment of the present invention may be prepared according to the following preparation method, but is not particularly limited thereto, and may be prepared by a method known in various literatures.

[Scheme 1]

As in Scheme 1, the synthesis of compound (1-6) prepares compound (1-6) as in [Table 1] through a cyclization reaction hydrolysis reaction as previously reported in the literature (Song K. .-S. et al., BMC , 2009, 17, 3080-3092; Kotagiri et al., OPRD 2007 , 11, 910-912).

compound R _One R ₂ R ₃ R ₄ 1-6a Cl H Cl Cl 1-6b H H Cl H 1-6c H CN Cl H

[Scheme 2]

As in Scheme 2, compound (1-6) and various aromatic amines (2-1) Compound (2-2) was obtained through an amide coupling reaction. The ester compound (2-2) was hydrolyzed to obtain compound (2-3) as shown in [Table 2]. Carboxylic acid compounds (2-3) were prepared in Examples 1 to 40 through an amide bond reaction with various amine derivatives (2-4) as shown in [Table 3].

compound intermediate R _One R ₂ R ₃ R ₄ Q 2-3a 1-6a Cl H Cl Cl

2-3b 1-6a Cl H Cl Cl

2-3c 1-6a Cl H Cl Cl

2-3d 1-6a Cl H Cl Cl

2-3e 1-6a Cl H Cl Cl

2-3f 1-6a Cl H Cl Cl

2-3g 1-6a Cl H Cl Cl

2-3h 1-6a Cl H Cl Cl

2-3i 1-6a Cl H Cl Cl

2-3j 1-6a Cl H Cl Cl

2-3k 1-6a Cl H Cl Cl

2-3l 1-6a Cl H Cl Cl

2-3m 1-6a Cl H Cl Cl

2-3n 1-6a Cl H Cl Cl

2-3o 1-6a Cl H Cl Cl

2-3p 1-6b H H Cl H

2-3q 1-6c H CN Cl H

The novel pyrazole-carboxamide derivative compounds of formula (1) may contain one or more asymmetric carbons, and thus racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. It may exist as an isomer. Such isomers can be separated by conventional techniques, for example, column chromatography of the novel pyrazole carboxamide derivative compound of Formula 1 or resolution such as HPLC. Alternatively, stereoisomers of each of the compounds of Formula 1 can be stereospecifically synthesized using optically pure starting materials and/or reagents of a known configuration.

The novel pyrazole-carboxamide derivative compound of Formula 1 can be prepared from pharmaceutically acceptable non-toxic acids derived from inorganic acids and organic acids. The acids are acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloroic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, mucoic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Citric acid, hydrobromoic acid, hydrochloroic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid are particularly preferred.

The novel pyrazole-carboxamide derivative compound provided as an aspect of the present invention exhibits antagonist/inverse agonist activity specific to cannabinoid receptor 1, thereby effectively preventing or treating related diseases. There are technical effects.

However, it is not limited to the above-described effects, and it should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description or claims.

1 is an analysis result of the interaction between CB1 protein and taranabant, known as a CB1 inhibitor (Taranabant, inverse agonist).
2 is a scatter plot showing docking energy score results for 102 compounds of synthetic candidate materials.

Hereinafter, in order to explain in more detail, it will be described in detail with reference to Preparation Examples and Examples. However, the following Preparation Examples and Examples are illustrative, and the scope of the invention is not limited thereto.

manufacturing example. Preparation of intermediate compounds

1. Preparation of compound (1-6a)

(Step 1) Preparation of lithium salt compound (1-3a)

A solution of lithium bis(trimethylsilyl)amide (62.5 mL, 1 M in THF solution, 62.5 mmol) in diethyl ether (250 mL) was mixed with 1-(4-chlorophenyl)propan-1-one (1-1a) (10.5 g, 62.3 mmol) of diethyl ether (50 mL) was slowly added dropwise at -78 °C for 30 min. The reaction mixture was further stirred at the same temperature for 1 hour, and then diethyl oxalate (9.6 mL, 70.8 mmol) was added thereto. After stirring the reaction mixture at room temperature for 16 hours, the white precipitate was filtered, washed with diethyl ether, and dried under vacuum to form a white solid lithium salt compound (1-3a) (5.44 g, 32%) was obtained.

(Step 2) Synthesis of ethyl 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylate (1-5a)

After adding (2,4-dichlorophenyl)hydrazine hydrochloride (1-4a) (5.07 g, 23.7 mmol) to a solution of lithium salt compound (1-3a) (5.44 g, 19.8 mmol) in ethanol (30.2 mL) The mixture was stirred at room temperature for 16 hours. After filtering the precipitate, it was washed with ethanol and diethyl ether in that order, and dried under vacuum to obtain a yellow solid hydrazone compound (4.95 g). This hydrazone compound (4.95 g) was dissolved in acetic acid (39.3 mL) and heated to reflux for 24 hours. The reaction mixture was poured into cold water (200 mL), extracted with ethyl acetate (330 mL), dried with ant sodium sulfate, and concentrated under reduced pressure to give compound (1-5a) (5.0 g, 35%) as a pale yellow solid. obtained in the form

(Step 3) Synthesis of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a)

A solution of the ester compound (1-5a) (5.0 g) in methanol (40 mL) was placed in an aqueous solution of potassium hydroxide (1.7 g) (40 mL), and then heated to reflux for 3 hours. After putting the reaction mixture in cold water (100 mL), it was added dropwise using a 10% aqueous hydrochloric acid solution until the acidity reached 1. The solid precipitate was filtered, washed with water and dried under vacuum to obtain compound (1-6a) (4.4 g, 57%).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 7.34-7.40 (3H, m), 7.65-7.76 (4H, m); LRMS (ESI) m/z 382.6 (M ⁺ +1).

2. Preparation of compound (1-6b)

It was prepared similarly to the process described in the above compound (1-6a) using propiophenone (1-1b) and (4-chlorophenyl)hydrazine (1-4b).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ )δ 2.46 (3H, s), 7.47-7.58 (3H, m), 7.68 (2H, m), 7.76 (2H, d, J = 8.4 Hz) , 7.83 (2H, d, J = 8.4 Hz); LRMS (ESI) m/z 313.8 (M ⁺ +1).

3. Preparation of compound (1-6c)

Using 3-propionylbenzonitrile (1-1c) and (4-chlorophenyl)hydrazine (1-4b), it was prepared similarly to the process described for compound (1-6a) above.

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ )δ 2.50 (3H, s), 7.52-7.66 (2H, m), 7.69-7.86 (5H, m), 8.11 (1H, m); LRMS (ESI) m/z 338.8 (M ⁺ +1).

4. Preparation of compound (2-2a)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) (1.000 g, 2.620 mmol), methyl 2-amino Benzoate (2-1a) (0.436 g, 2.882 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide A solution of hexafluorophosphate (HATU, 1.196 g, 3.144 mmol) and N,N-diisopropylethylamine (0.685 mL, 3.930 mmol) in N,N-dimethylformamide (10 mL) at room temperature was the same The temperature was stirred for 12 hours. Water (5 mL) was added to the reaction mixture, stirred, the precipitated solid was filtered, washed with water, and dried to methyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamido)benzoate (1.180 g, 87.5%) was obtained as a white solid.

Spectroscopy data: LRMS (ESI) m/z 515.8 (M ⁺ +1).

5. Preparation of compound (2-2b)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 3-aminobenzoate (2-1b) was prepared similarly to the process described for compound (2-2a) using

Spectroscopy data: LRMS (ESI) m/z 515.8 (M ⁺ +1).

6. Preparation of compound (2-2c)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 4-aminobenzoate (2-1c) was prepared similarly to the process described for compound (2-2a) using

Spectroscopy data: LRMS (ESI) m/z 515.8 (M ⁺ +1).

7. Preparation of compound (2-2d)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 6-aminonicotinate (2-1d ) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 516.8 (M ⁺ +1).

8. Preparation of compound (2-2e)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 5-aminonicotinate (2-1e ) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 516.8 (M ⁺ +1).

9. Preparation of compound (2-2f)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 5-aminopyrazine-2-carboxylate ( 2-1f) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 517.8 (M ⁺ +1).

10. Preparation of compound (2-2g)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 4-amino-2-chlorobenzoate ( 2-1 g) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 550.2 (M ⁺ +1).

11. Preparation of compound (2-2h)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 4-amino-3-fluorobenzoate (2-1h) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 533.8 (M ⁺ +1).

12. Preparation of compound (2-2i)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 4-amino-2-fluorobenzoate (2-1i) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 533.8 (M ⁺ +1).

13. Preparation of compound (2-2j)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 2-aminoisonicotinate (2- 1j) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 516.8 (M ⁺ +1).

14. Preparation of compound (2-2k)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 5-aminonicotinate (2-1k ) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 516.8 (M ⁺ +1).

15. Preparation of compound (2-2l)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 4-aminonicotinate (2-11) ) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 516.8 (M ⁺ +1).

16. Preparation of compound (2-2m)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 3-amino-4-fluorobenzoate (2-1m) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 533.8 (M ⁺ +1).

17. Preparation of compound (2-2n)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 3-amino-5-fluorobenzoate (2-1n) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 533.8 (M ⁺ +1).

18. Preparation of compound (2-2o)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6a) with methyl 5-amino-2-fluorobenzoate (2-1o) was prepared similarly to the process described for compound (2-2a) above.

Spectroscopy data: LRMS (ESI) m/z 533.8 (M ⁺ +1).

19. Preparation of compound (2-2p)

The above compound (2-) using 1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid (1-6b) and methyl 4-aminobenzoate (2-1c) Prepared similarly to the process described in 2a).

Spectroscopy data: LRMS (ESI) m/z 446.9 (M ⁺ +1).

20. Preparation of compound (2-2q)

Using 1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1-6c) and methyl 4-aminobenzoate (2-1c) Thus, it was prepared similarly to the process described for compound (2-2a).

Spectroscopy data: LRMS (ESI) m/z 471.9 (M ⁺ +1).

21. Preparation of compound (2-3a)

To a solution of lithium hydroxide (0.047 g, 1.943 mmol) in tetrahydrofuran (3 mL)/methanol (1 mL)/water (1 mL) at room temperature, methyl 2-(5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate (2-2a) (0.500 g, 0.971 mmol) was added and stirred at the same temperature for 18 hours. did. The solvent was removed from the reaction mixture under reduced pressure, and water was poured into the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution and purified water in this order, dried with anhydrous magnesium sulfate, and then filtered. Compound (2-3a) (0.350 g, 72.0 %, off-white solid) obtained by concentration under reduced pressure was used without further purification.

Spectroscopy data: LRMS (ESI) m/z 501.8 (M ⁺ +1).

22. Preparation of compound (2-3b)

Using methyl 3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoate (2-2b) Thus, it was prepared similarly to the process described for compound (2-3a).

Spectroscopy data: LRMS (ESI) m/z 501.8 (M ⁺ +1).

23. Preparation of compound (2-3c)

Using methyl 4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoate (2-2c) Thus, it was prepared similarly to the process described for compound (2-3a).

Spectroscopy data: LRMS (ESI) m/z 501.8 (M ⁺ +1).

24. Preparation of compound (2-3d)

Methyl 6- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) nicotinate (2-2d) It was prepared similarly to the process described for compound (2-3a) using

Spectroscopy data: LRMS (ESI) m/z 502.7 (M ⁺ +1).

25. Preparation of compound (2-3e)

Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) picolinate (2-2e) It was prepared similarly to the process described for compound (2-3a) using

Spectroscopy data: LRMS (ESI) m/z 502.7 (M ⁺ +1).

26. Preparation of compound (2-3f)

Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) pyrazine-2-carboxylate (2- 2f) was prepared similarly to the process described for compound (2-3a) above.

Spectroscopy data: LRMS (ESI) m/z 503.7 (M ⁺ +1).

27. Preparation of compound (2-3 g)

Methyl 2-chloro-4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoate (2- 2g) was prepared similarly to the process described for compound (2-3a) above.

Spectroscopy data: LRMS (ESI) m/z 536.2 (M ⁺ +1).

28. Preparation of compound (2-3h)

Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-3-fluorobenzoate (2 -2h) was prepared similarly to the process described for compound (2-3a) above.

Spectroscopy data: LRMS (ESI) m/z 519.8 (M ⁺ +1).

29. Preparation of compound (2-3i)

Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoate (2 -2i) was prepared similarly to the process described for compound (2-3a) above.

Spectroscopy data: LRMS (ESI) m/z 519.8 (M ⁺ +1).

30. Preparation of compound (2-3j)

Methyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)isonicotinate (2-2j) was prepared similarly to the process described for compound (2-3a) using

Spectroscopy data: LRMS (ESI) m/z 502.7 (M ⁺ +1).

31. Preparation of compound (2-3k)

Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) nicotinate (2-2k) It was prepared similarly to the process described for compound (2-3a) using

Spectroscopy data: LRMS (ESI) m/z 502.7 (M ⁺ +1).

32. Preparation of compound (2-3l)

Methyl 4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) picolinate (2-2l) It was prepared similarly to the process described for compound (2-3a) using

Spectroscopy data: LRMS (ESI) m/z 502.7 (M ⁺ +1).

33. Preparation of compound (2-3m)

Methyl 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-4-fluorobenzoate (2 -2m) was prepared similarly to the process described for compound (2-3a) above.

Spectroscopy data: LRMS (ESI) m/z 519.8 (M ⁺ +1).

34. Preparation of compound (2-3n)

Methyl 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-5-fluorobenzoate (2 -2n) was prepared similarly to the process described for compound (2-3a) above.

Spectroscopy data: LRMS (ESI) m/z 519.8 (M ⁺ +1).

35. Preparation of compound (2-3o)

Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) -2-fluorobenzoate (2 -2o) was prepared similarly to the process described for compound (2-3a) above.

Spectroscopy data: LRMS (ESI) m/z 519.8 (M ⁺ +1).

36. Preparation of compound (2-3p)

The above compound (2-3a) using methyl 4-(1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamido)benzoate (2-2p) It was prepared similarly to the process described in

Spectroscopy data: LRMS (ESI) m/z 432.9 (M ⁺ +1).

37. Preparation of compound (2-3q)

methyl 4-(1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate (2-2q) It was prepared analogously to the process described for compound (2-3a).

Spectroscopy data: LRMS (ESI) m/z 457.9 (M ⁺ +1).

The prepared intermediates are summarized in Table 3 below.

intermediate IUPAC Naming and Structural Formula constitutional formula 1-1a 1-(4-chlorophenyl)propan-1-one

1-1b propiophenone

1-1c 3-propionylbenzonitrile

1-4a (2,4-dichlorophenyl)hydrazine

1-4b (4-chlorophenyl)hydrazine

2-1a Methyl 2-aminobenzoate

2-1b Methyl 3-aminobenzoate

2-1c Methyl 4-aminobenzoate

2-1d Methyl 6-aminonicotinate

2-1e Methyl 5-aminonicotinate

2-1f Methyl 5-aminopyrazine-2-carboxylate

2-1 g Methyl 4-amino-2-chlorobenzoate

2-1h Methyl 4-amino-3-fluorobenzoate

2-1i Methyl 4-amino-2-fluorobenzoate

2-1j Methyl 2-aminoisonicotinate

2-1k Methyl 5-aminonicotinate

2-1l Methyl 4-aminonicotinate

2-1m Methyl 3-amino-4-fluorobenzoate

2-1n Methyl 3-amino-5-fluorobenzoate

2-1o Methyl 5-amino-2-fluorobenzoate

2-4a 2-Aminoacetamide

2-4b methyl glycinate

2-4c (S)-pyrrolidine-2-carboxamide

2-4d 2-Aminoethane-1-sulfonamide

2-4e 3-Aminopropanamide

2-4f Methyl 3-aminopropanoate

2-4 g 5-(trifluoromethyl)-1,3,4-oxadiazol-2-amine

2-4h 5-(trifluoromethyl)-1,2,4-oxadiazol-3-amine

2-4i (5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)methanamine

2-4j (1,3,4-oxadiazol-2-yl)methanamine

2-4k (1,2,4-oxadiazol-3-yl)methanamine

1-3a Ethyl4-(4-chlorophenyl)-3-methyl-4-oxido-2-oxobutene-3-oate lithium salt

1-3b Ethyl4-phenyl-3-methyl-4-oxido-2-oxobutene-3-oate lithium salt

1-3c Ethyl4-(3-cyanophenyl)-3-methyl-4-oxido-2-oxobutene-3-oate lithium salt

1-5a Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate

1-5b Ethyl 1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylate

1-5c Ethyl 1- (4-chlorophenyl) -5- (3-cyanophenyl) -4-methyl-1H-pyrazole-3-carboxylate

1-6a 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

1-6b 1-(4-Chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid

1-6c 1-(4-Chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

2-2a Methyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate

2-2b Methyl 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate

2-2c Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate

2-2d Methyl 6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinate

2-2e Methyl 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinate

2-2f Methyl 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)pyrazine-2-carboxylate

2-2g Methyl 2-chloro-4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoate

2-2h Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-3-fluorobenzoate

2-2i Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoate

2-2j Methyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)isonicotinate

2-2k Methyl 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinate

2-2l Methyl 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinate

2-2m Methyl 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-4-fluorobenzoate

2-2n Methyl 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-5-fluorobenzoate

2-2o Methyl 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoate

2-2p Methyl 4-(1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamido)benzoate

2-2q Methyl 4-(1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoate

2-3a 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid

2-3b 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid

2-3c 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid

2-3d 6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinic acid

2-3e 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinic acid

2-3f 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)pyrazine-2-carboxylic acid

2-3g 2-chloro-4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid

2-3h 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-3-fluorobenzoic acid

2-3i 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoic acid

2-3j 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)isonicotinic acid

2-3k 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinic acid

2-3l 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinic acid

2-3m 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-4-fluorobenzoic acid

2-3n 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-5-fluorobenzoic acid

2-3o 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoic acid

2-3p 4-(1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamido)benzoic acid

2-3q 4-(1-(4-Chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid

Example. synthesis of compounds

Example 1

N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3a) (0.100 g, 0.200 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.091 g, 0.240 mmol) and 2-aminoacetamide (2-4a) (0.018) in a solution of N,N-diisopropylethylamine (0.070 mL, 0.399 mmol) in N,N-dimethylformamide (1 mL) at room temperature g, 0.240 mmol) and stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution and purified water in that order, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 5 g cartridge; methanol/dichloromethane = 5 %) and concentrated to N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl )-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (0.080 g, 71.9 %) was obtained as a white solid. .

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 3.72 (2H, s), 7.33-7.45 (4H, m), 7.45 (1H, m), 7.53-7.64 ( 2H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 557.8 (M ⁺ +1).

Example 2

N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and 2-amino It was prepared similarly to the process described above (Example 1) using acetamide (2-4a).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 3.73 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64 7.82 (5H, m), 8.29 (1H, m); LRMS (ESI) m/z 557.7 (M ⁺ +1).

Example 3

N-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 2-amino It was prepared similarly to the process described above (Example 1) using acetamide (2-4a).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 3.71 (2H, s), 7.33-7.40 (3H, m), 7.47-7.58 (4H, m), 7.64- 7.75 (4H, m); LRMS (ESI) m/z 557.9 (M ⁺ +1).

Example 4

N-(2-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3a) and 3-amino Prepared similarly to the process described above (Example 1) using propanamide (2-4e).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.37 (2H, t, J = 6.5 Hz), 7.33-7.45 (4H, m), 7.45 (1H, m), 7.53-7.64 (2H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 571.9 (M ⁺ +1).

Example 5

N-(3-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and 3-amino Prepared similarly to the process described above (Example 1) using propanamide (2-4e).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.32 (3H, s), 2.36 (2H, t, J = 7.0 Hz), 3.42-3.47 (2H, m), 6.85 (s, 1H) , 7.33-7.40 (10H, m), 8.31 (1H, s), 8.44-8.47 (2H, m), 10.31 (1H, s); LRMS (ESI) m/z 571.9 (M ⁺ +1).

Example 6

N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 3-amino Prepared similarly to the process described above (Example 1) using propanamide (2-4e).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.31 (3H, s), 2.35 (2H, t, J = 7.0 Hz), 3.42-3.45 (2H, br m), 6.85 (1H, s) ), 7.27-7.94 (12H, m), 8.42 (1H, br s), 10.40 (1H, s); LRMS (ESI) m/z 571.9 (M ⁺ +1).

Example 7

(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine

3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) (0.150 g, 0.300 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.137 g, 0.359) mmol) and N,N-diisopropylethylamine (0.104 mL, 0.599 mmol) at room temperature with N,N3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) (0.150 g, 0.300 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole Rho[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.137 g, 0.359 mmol) and N,N-diisopropylethylamine (0.104 mL, 0.599 mmol) were mixed with N,N- at room temperature Methyl glycinate (0.032 g, 0.359 mmol) was added to a solution in dimethylformamide (1 mL) and stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Lithium hydroxide (0.014 g, 0.583 mmol) was added to tetrahydrofuran (0.3 mL)/methanol (0.1 mL)/ A solution in water (0.1 mL) was added and stirred at room temperature for 12 hours. The solvent was removed from the reaction mixture under reduced pressure, and water was poured into the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution and purified water in that order, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 5 g cartridge; methanol/dichloromethane = 5 %) and concentrated (3-(5-(4-chlorophenyl)-1-(2,4-) Dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine (0.08 g, 48%) was obtained in the form of a pale yellow solid.

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 3.74 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64 7.82 (5H, m), 8.29 (1H, m); LRMS (ESI) m/z 558.8 (M ⁺ +1)).

Example 8

(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and methyl glycy It was prepared analogously to the process described above (Example 7) using nate (2-4b).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 3.73 (2H, s), 7.33-7.40 (3H, m), 7.42-753 (4H, m), 7.64- 7.75 (4H, m); LRMS (ESI) m/z 558.8 (M ⁺ +1).

Example 9

3-(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid

3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and methyl 3- Prepared analogously to the process described above (Example 7) using aminopropanoate (2-4f).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 2.51 (2H, t, J = 6.7 Hz), 3.42 (2H, t, J = 6.7 Hz), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64-7.81 (5H, m), 8.29 (1H, m); LRMS (ESI) m/z 572.8 (M ⁺ +1).

Example 10

3-(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 3-amino Prepared analogously to the process described above (Example 7) using propanoate (2-4f).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 2.51 (2H, t, J = 6.7 Hz), 3.38 (2H, t, J = 6.7 Hz), 7.33-7.40 (3H, m), 7.46-7.58 (4H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 572.8 (M ⁺ +1).

Example 11

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 - Carboxamide

3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and 2-amino Prepared similarly to the process described above (Example 1) using ethane-1-sulfonamide (2-4d).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.31 (3H, s), 3.25 (2H, t, J = 7.2 Hz), 3.63-3.66 (2H, m), 6.97 (2H, s) , 7.28 (2H, d, J = 8.4 Hz), 7.40-7.93 (8H, m), 8.34 (1H, s), 8.59-8.62 (1H, m), 10.34 (1H, s); LRMS (ESI) m/z 607.9 (M ⁺ +1).

Example 12

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -Carboxamide

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 2-amino Prepared similarly to the process described above (Example 1) using ethane-1-sulfonamide (2-4d).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 3.38 (2H, t, J = 6.3 Hz), 3.52 (2H, t, J = 6.3 Hz), 7.33-7.40 (3H, m), 7.46-7.58 (4H, m), 7.64-7.75 (4H, m); LRMS (ESI) m/z 607.9 (M ⁺ +1).

Example 13

(S)-N-(3-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide

3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and (S) -Pyrrolidine-2-carboxamide (2-4c) was prepared similarly to the process described above (Example 1).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.83-2.18 (4H, m), 2.48 (3H, s), 3.41 (1H, ddd, J = 16.1, 5.4, 1.4 Hz), 3.59 ( 1H, ddd, J = 16.1, 9.3, 5.6 Hz), 4.05 (1H, dd, J = 6.9, 1.8 Hz), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64-7.75 ( 4H, m), 7.79 (1H, m), 8.30 (1H, m); LRMS (ESI) m/z 597.9 (M ⁺ +1).

Example 14

(S)-N-(4-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and (S) -Pyrrolidine-2-carboxamide (2-4c) was prepared similarly to the process described above (Example 1).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.82-2.20 (4H, m), 2.48 (3H, s), 3.41 (1H, ddd, J = 15.1, 5.4, 1.4 Hz), 3.56 ( 1H, ddd, J = 15.1, 9.3, 5.6 Hz), 4.26 (1H, dd, J = 7.4, 7.1 Hz), 7.33-7.40 (3H, m), 7.46 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.64-7.75 (4H, m); LRMS (ESI) m/z 597.9 (M ⁺ +1).

Example 15

N-(2-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide

2- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3a) and (1, Prepared similarly to the process described above (Example 1) using 2,4-oxadiazol-3-yl)methanamine (2-4k).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 4.61 (2H, s), 7.33-7.45 (4H, m), 7.45 (1H, m), 7.53-7.64 ( 2H, m), 7.64-7.75 (4H, m), 8.51 (1H, s); LRMS (ESI) m/z 582.8 (M ⁺ +1).

Example 16

N-(3-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide

3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3b) and (1, Prepared similarly to the process described above (Example 1) using 2,4-oxadiazol-3-yl)methanamine (2-4k).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 4.59 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64 7.82 (5H, m), 8.29 (1H, m), 8.51 (1H, s); LRMS (ESI) m/z 582.8 (M ⁺ +1).

Example 17

N-(4-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide

4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3c) and (1, Prepared similarly to the process described above (Example 1) using 2,4-oxadiazol-3-yl)methanamine (2-4k).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 4.61 (2H, s), 7.33-7.40 (3H, m), 7.47-7.58 (4H, m), 7.64- 7.75 (4H, m), 8.51 (1H, s); LRMS (ESI) m/z 582.8 (M ⁺ +1).

Example 18

N-(3-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide

3- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3b) and (1, Prepared similarly to the process described above (Example 1) using 3,4-oxadiazol-2-yl)methanamine (2-4j).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 4.71 (2H, s), 7.33-7.40 (3H, m), 7.40-7.49 (2H, m), 7.64 7.82 (5H, m), 8.29 (1H, m), 8.45 (1H, s); LRMS (ESI) m/z 582.8 (M ⁺ +1).

Example 19

N-(4-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide

4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3c) and (1, Prepared similarly to the process described above (Example 1) using 3,4-oxadiazol-2-yl)methanamine (2-4j).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.31 (3H, s), 4.19 (2H, s), 7.28 (2H, d, J = 8.4 Hz), 7.36 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 7.58-7.63 (3H, m), 7.80-7.83 (2H, m), 8.02 (2H, d, J = 8.4 Hz), 10.56 (1H, s), 10.99 ( 1H, s); LRMS (ESI) m/z 582.8 (M ⁺ +1).

Example 20

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide

3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3b) and 5-( Prepared analogously to the process described above (Example 1) using trifluoromethyl)-1,2,4-oxadiazol-3-amine (2-4h).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.31 (3H, s), 7.28 (2H, d, J = 8.4 Hz), 7.43-7.68 (4H, m), 7.81-7.84 (2H, m), 8.03 (1H, d, J = 10.0 Hz), 8.53 (1H, d, J = 8.4 Hz), 8.56 (1H, s), 8.75 (1H, d, J = 4.0 Hz), 10.43 91H, s ); LRMS (ESI) m/z 636.8 (M ⁺ +1).

Example 21

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 5-( Prepared analogously to the process described above (Example 1) using trifluoromethyl)-1,2,4-oxadiazol-3-amine (2-4h).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.39 (3H, s), 7.29-7.87 (8H, m), 8.24-8.30 (2H, m), 8.76 (1H, s), 8.86 ( 1H, s); LRMS (ESI) m/z 636.8 (M ⁺ +1).

Example 22

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,3,4-oxadiazole -2-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3c) and 5-( Prepared similarly to the process described above (Example 1) using trifluoromethyl)-1,3,4-oxadiazol-2-amine (2-4 g).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.48 (3H, s), 7.33-7.40 (3H, m), 7.48 (2H, m), 7.56 (2H, m), 7.64-7.75 ( 4H, m); LRMS (ESI) m/z 636.8 (M ⁺ +1).

Example 23

N-(3-amino-3-oxopropyl)-6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide

6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinic acid (2-3d) and 3-amino Prepared similarly to the process described above (Example 1) using propanamide (2-4e).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.40 (2H, t, J = 6.5 Hz), 6.97 (1H) , dd, J = 7.7, 0.5 Hz), 7.33-7.40 (3H, m), 7.64-7.80 (5H, m), 8.56 (1H, dd, J = 1.8, 0.5 Hz); LRMS (ESI) m/z 572.8 (M ⁺ +1).

Example 24

N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide

5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) picolinic acid (2-3e) and 3 -Aminopropanamide (2-4e) was prepared similarly to the process described above (Example 1).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.41 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.59-7.75 (5H, m), 7.89 (1H, d, J = 8.9 Hz), 8.47 (1H, d, J = 1.8 Hz); LRMS (ESI) m/z 572.8 (M ⁺ +1).

Example 25

N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-chlorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide

2-chloro-4- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3 g) and 3-aminopropanamide (2-4e) were prepared similarly to the process described above (Example 1).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.46 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.36 (2H, t, J = 6.5 Hz), 7.04 (1H) , dd, J = 8.2, 1.2 Hz), 7.33-7.40 (3H, m), 7.60 (1H, d, J = 1.2 Hz), 7.64-7.75 (4H, m), 8.16 (1H, d, J = 8.2) Hz); LRMS (ESI) m/z 606.3 (M ⁺ +1).

Example 26

N-(4-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-3-fluorobenzoic acid (2-3h ) and 3-aminopropanamide (2-4e) were prepared similarly to the process described in (Example 1) above.

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.39 (2H, t, J = 6.5 Hz), 6.98 (1H) , d, J = 8.2 Hz), 7.33-7.40 (3H, m), 7.64-7.75 (4H, m), 7.85 (1H, dd, J = 8.2, 1.8 Hz), 7.96 (1H, d, J = 1.8) Hz); LRMS (ESI) m/z 589.8 (M ⁺ +1).

Example 27

N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoic acid (2-3i ) and 3-aminopropanamide (2-4e) were prepared similarly to the process described in (Example 1) above.

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.36 (2H, t, J = 6.5 Hz), 7.28 (1H) , dd, J = 8.2, 1.5 Hz), 7.33-7.40 (3H, m), 7.45 (1H, d, J = 1.5 Hz), 7.64-7.75 (4H, m), 8.16 (1H, d, J = 8.2) Hz); LRMS (ESI) m/z 589.8 (M ⁺ +1).

Example 28

N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) pyrazine-2-carboxamide

5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)pyrazine-2-carboxylic acid (2-3f) and 3-aminopropanamide (2-4e) were prepared similarly to the process described above (Example 1).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (t, 3H, J = 6.5 Hz), 2.48 (3H, s), 3.41 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.64-7.76 (4H, m), 8.73 (1H, s), 9.09 (1H, s); LRMS (ESI) m/z 573.8 (M ⁺ +1).

Example 29

N-(3-amino-3-oxopropyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide

2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)isonicotinic acid (2-3j) and 3- Prepared analogously to the process described above (Example 1) using aminopropanamide (2-4e).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.41 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.58 (1H, dd, J = 4.7, 1.5 Hz), 7.64-7.75 (5H, m), 8.43 (1H, d, J = 4.7 Hz); LRMS (ESI) m/z 572.8 (M ⁺ +1).

Example 30

N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide

5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinic acid (2-3k) and 3-amino Prepared similarly to the process described above (Example 1) using propanamide (2-4e).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.38 (2H, t, J = 7.2 Hz), 2.33 (3H, s), 3.05 (2H, br), 6.87 (1H, s), 7.29 (2H, d, J = 8.8 Hz), 7.39 (1H, s), 7.50 (2H, d, J = 8.8 Hz), 7.62-7.86 (3H, m), 8.73-8.75 (3H, m), 9.09 ( 1H, s), 10.69 (1H, s); LRMS (ESI) m/z 572.8 (M ⁺ +1).

Example 31

N-(3-amino-3-oxopropyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinic acid (2-3l) and 3 -Aminopropanamide (2-4e) was prepared similarly to the process described above (Example 1).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.46 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.42 (2H, t, J = 6.5 Hz), 7.33-7.40 (3H, m), 7.64-7.75 (5H, m), 8.02 (1H, dd, J = 5.1, 1.9 Hz), 8.57 (1H, d, J = 5.1 Hz); LRMS (ESI) m/z 572.8 (M ⁺ +1).

Example 32

N-(5-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide

3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-4-fluorobenzoic acid (2-3m ) and 3-aminopropanamide (2-4e) were prepared similarly to the process described in (Example 1) above.

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.46 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.37 (2H, t, J = 6.5 Hz), 7.30 (1H) , d, J = 8.8 Hz), 7.33-7.40 (3H, m), 7.62-7.75 (5H, m), 8.29 (1H, d, J = 1.9 Hz); LRMS (ESI) m/z 589.8 (M ⁺ +1).

Example 33

N-(3-((3-amino-3-oxopropyl)carbamoyl)-5-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide

3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-5-fluorobenzoic acid (2-3n ) and 3-aminopropanamide (2-4e) were prepared similarly to the process described in (Example 1) above.

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.38 (2H, t, J = 6.5 Hz), 7.21 (1H) , dd, J = 1.8, 1.6 Hz), 7.33-7.40 (3H, m), 7.64-7.77 (5H, m), 8.14 (1H, dd, J = 1.8, 1.3 Hz); LRMS (ESI) m/z 589.8 (M ⁺ +1).

Example 34

N-(3-((3-amino-3-oxopropyl)carbamoyl)-4-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide

5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-2-fluorobenzoic acid (2-3o ) and 3-aminopropanamide (2-4e) were prepared similarly to the process described in (Example 1) above.

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.37 (2H, t, J = 6.5 Hz), 7.29 (1H) , d, J = 8.5 Hz), 7.33-7.40 (3H, m), 7.44 (1H, dd, J = 8.5, 1.5 Hz), 7.64-7.75 (4H, m), 8.28 (1H, d, J = 1.5) Hz); LRMS (ESI) m/z 589.8 (M ⁺ +1).

Example 35

N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamide

4- (1- (4-chlorophenyl) -4-methyl-5-phenyl-1H-pyrazole-3-carboxamido) benzoic acid (2-3p) and 3-aminopropanamide (2-4e) It was prepared similarly to the process described above (Example 1) using

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 3.39 (2H, t, J = 6.5 Hz), 7.46-7.58 (7H, m), 7.66-7.85 (6H, m); LRMS (ESI) m/z 503.0 (M ⁺ +1).

Example 36

N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole- 3-Carboxamide

4-(1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoic acid (2-3q) with 3-aminopropanamide (2-4e) was prepared similarly to the process described above (Example 1).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.45 (2H, t, J = 6.5 Hz), 2.52 (3H, s), 3.39 (2H, t, J = 6.5 Hz), 7.46-7.60 (5H, m), 7.59-7.68 (3H, m), 7.72 (1H, ddd, J = 8.1, 1.8, 1.4 Hz), 7.82 (2H, m), 8.11 (1H, dd, J = 1.9, 1.8 Hz) ); LRMS (ESI) m/z 528.0 (M ⁺ +1).

Example 37

N-(2-amino-2-oxoethyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide

2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)isonicotinic acid (2-3j) and 2- It was prepared similarly to the process described above (Example 1) using aminoacetamide (2-4a).

Spectroscopy data: Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.51 (3H, s), 3.73 (2H, t, J = 6.2 Hz), 7.23 (1H, s), 7.45 (2H, d) , J = 8.4 Hz), 7.53 (1H, s), 7.57 (2H, d, J = 8.4 Hz), 7.67-7.77 (3H, m), 8.43 (2H, d, J = 7.2 Hz), 8.91 (1H) , m), 9.10 (1H, s), 10.7 (1H, s); LRMS (ESI) m/z 557.9 (M ⁺ +1).

Example 38

N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide

5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)nicotinic acid (2-3k) and 2-amino It was prepared similarly to the process described above (Example 1) using acetamide (2-4a).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.33 (3H, s), 3.85 (2H, t, J = 6.0 Hz), 7.09 (1H, s), 7.30 (2H, d, J = 8.4 Hz), 7.45 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 7.62-7.86 (3H, m), 8.78 (2H, d, J = 7.2 Hz), 8.91 (1H, t, J = 5.6 Hz), 9.10 (1H, d, J = 2.0 Hz), 10.7 (1H, s); LRMS (ESI) m/z 557.9 (M ⁺ +1).

Example 39

N-(2-amino-2-oxoethyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide

4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)picolinic acid (2-3l) and 2 -Aminoacetamide (2-4a) was prepared similarly to the process described above (Example 1).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.51 (3H, s), 3.74 (2H, t, J = 6.0 Hz), 7.09 (1H, s), 7.22 (2H, d, J = 8.4 Hz), 7.45 (1H, s), 7.61-7.83 (5H, m), 8.57 (2H, d, J = 7.2 Hz), 8.91 (1H, m), 9.12 (1H, d, J = 2.0 Hz) , 10.5 (1H, s); LRMS (ESI) m/z 557.9 (M ⁺ +1).

Example 40

N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide

5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) picolinic acid (2-3e) and 2 -Aminoacetamide (2-4a) was prepared similarly to the process described above (Example 1).

Spectroscopy data: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.50 (3H, s), 3.73 (2H, t, J = 5.8 Hz), 7.09 (1H, s), 7.39 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz), 7.60-7.95 (4H, m), 8.78-8.91 (3H, m), 9.10 (1H, s), 10.7 (1H, s); LRMS (ESI) m/z 557.9 (M ⁺ +1).

The compounds of Examples 1 to 40 are summarized in Table 4 below.

Example IUPAC Naming and Structural Formula intermediate One

N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

2-3a 2 N-(3-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

2-3b 3 N-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

2-3c 4 N-(2-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

2-3a 5 N-(3-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

2-3b 6 N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide

2-3c 7 (3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine

2-3b 8 (4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine

2-3c 9 3-(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid

2-3b 10 3-(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid

2-3c 11 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -Carboxamide

2-3b 12 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -Carboxamide

2-3c 13 (S)-N-(3-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide

2-3b 14 (S)-N-(4-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide

2-3c 15 N-(2-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide

2-3a 16 N-(3-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide

2-3b 17 N-(4-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide

2-3c 18 N-(3-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide

2-3b 19 N-(4-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide

2-3c 20 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl)carbamoyl)phenyl)-1H-pyrazole-3-carboxamide

2-3b 21 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide

2-3c 22 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,3,4-oxadiazole -2-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide

2-3c 23 N-(3-amino-3-oxopropyl)-6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide

2-3d 24 N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide

2-3e 25 N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-chlorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide

2-3g 26 N-(4-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide

2-3h 27 N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide

2-3i 28 N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) pyrazine-2-carboxamide

2-3f 29 N-(3-amino-3-oxopropyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide

2-3j 30 N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide

2-3k 31 N-(3-amino-3-oxopropyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide

2-3l 32 N-(5-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide

2-3m 33 N-(3-((3-amino-3-oxopropyl)carbamoyl)-5-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide

2-3n 34 N-(3-((3-amino-3-oxopropyl)carbamoyl)-4-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Methyl-1H-pyrazole-3-carboxamide

2-3o 35 N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamide

2-3p 36 N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole- 3-Carboxamide

2-3q 37 N-(2-amino-2-oxoethyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide

2-3j 38 N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide

2-3k 39 N-(2-amino-2-oxoethyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide

2-3l 40 N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide

2-3e

Experimental Example 1. Structure-based virtual screening using molecular docking simulation

Molecular modeling technology was applied to efficiently select compounds that inhibit the CB1 target from synthetic candidates. Computer simulation can be applied according to two main criteria. SBDD (Structure-Based Drug Design), which uses the three-dimensional structure of the protein when the tertiary crystal structure of the target protein is known, and LBDD, which can be applied when only the structure of the ligand is known. (Ligand-Based Drug Design).

Since the x-ray crystal structure of the CB1 target protein has been elucidated, 102 synthetic candidates were evaluated through molecular docking simulation, a protein structure-based method (SBDD).

(1) Protein and Ligand Preparation

The x-ray tertiary crystal structure (PDB code: 　5U09) of the CB1 target protein was obtained from the Protein Data Bank (https://www.rcsb.org) For the protein preparation process, the Discovery Studio program (DASSAULT SYSTEMS) was used. The solvent molecules of the protein were removed, and a structure was obtained in which the protonation of the protein residue was calculated at pH 7.4, and a structure in which the ionization state was calculated based on pH 6.5 to 8.5 of the ligand.

1 is an analysis result of the interaction of CB1 protein with Taranabant (inverse agonist) known as a CB1 inhibitor, forming hydrogen bonds with Ser123 and Ser383, and forming strong hydrophobic pockets (Met103, Asp104, Ile105, Ile119, Phe170, Val196, Trp279). , Trp356, Ala380, Met384, Cys386).

(2) protein-ligand docking

Synthetic candidates 102 compounds were analyzed for binding forms between protein molecules and ligands using the Discovery Studio docking program. 40 kinds of final example compounds were discovered by analysis by docking energy score and visual inspection.

2 is a scatter plot showing docking energy score results for 102 synthetic candidate materials. '- CDOCKER_INTERACTION_ENERGY' means protein-ligand binding energy and is calculated in kcal/mol units. 'LigScore2' means protein-ligand binding affinity, and is calculated in pKi (-log Ki).

Table 5 below shows the protein-ligand binding energy (-CDOCKER_INTERACTION_ENERGY) and protein-ligand binding affinity (LigScore2) for the compounds selected by applying the CADD (Computer-Aided Drug Design) technology.

Example LigScore2 (pKi) -CDOCKER INTERACTION ENERGY
(kcal/mol) One 7.66 64.44 2 7.50 66.71 3 7.25 61.21 4 7.37 67.51 5 7.61 68.04 6 7.53 62.99 7 6.98 54.00 8 6.84 55.05 9 6.87 56.02 10 7.28 58.61 11 7.63 64.28 12 7.51 61.12 13 6.36 45.53 14 4.88 28.99 15 7.62 61.68 16 7.22 54.93 17 7.24 60.38 18 7.19 55.00 19 7.75 64.89 20 7.65 65.14 21 7.53 62.01 22 7.67 64.25 23 5.81 43.57 24 7.14 56.10 25 6.80 56.23 26 7.12 56.20 27 6.95 57.47 28 7.14 56.99 29 7.31 57.98 30 7.52 57.80 31 7.32 59.86 32 6.96 63.64 33 7.04 62.99 34 6.81 61.35 35 6.87 58.03 36 6.78 57.60 37 6.47 54.99 38 6.60 57.02 39 7.22 59.02 40 6.85 57.14

Experimental Example 2. Evaluation of inhibitory activity on cannabinoid receptor 1

In order to evaluate the inhibitory activity of the example compound on cannabinoid receptor 1 (CB1), a cAMP ELISA assay was performed using Rimonabant, an existing developed material, as a control.

Specifically, CHO-GLP1R-CB1R cells were cultured for one day in DMEM medium containing 10% fetal bovine serum (FBS) and 1% antibiotics in an environment of 5% CO ₂ 37 °C. The next day, the cells were cultured in a medium without FBS for 30 minutes, and a CB1 inhibitor compound (including any one of the compounds of Examples 1 to 40) dissolved in DMSO was added and reacted for 30 minutes [compound final concentration (μM)) : 0.1, 1, 2.5, 5, 10, 20]. 10 uM forskolin and 10 nM CP55,940 were added to the cells and incubated for 1 hour. After removing the solution, PBS and 0.1M HCl were added to wash the cells 3 times. The cell extract was centrifuged and 100 uL of the supernatant was used. cAMP was measured using the Direct cAMP ELISA kit (Enzo Life Sciences, Lausen, Switzerland; Catalog # ADI-900-066). Absorbance was measured at 405 nm wavelength using an ELISA reader.

The results are shown in Table 6 below, and the CB1 receptor activity inhibitory effect of the compound was expressed as IC ₅₀ (μM).

Example IC ₅₀ (Rimonabant) 2 2.56 (1.08) 3 1.13 (1.08) 4 7.09 (1.08) 5 5.6 (9.3) 6 6.7 (9.3) 7 0.52 (1.08) 8 0.85 (1.08) 9 0.49 (1.08) 10 0.48 (1.08) 12 1.12 (1.08) 13 0.48 (1.08) 14 0.66 (1.08) 16 1.25 (1.08) 17 10.4 (9.3) 18 2.55 (1.08) 19 2.9 (9.3) 37 1.56 (3.20) 38 3.54 (3.20) 39 4.25 (3.20) 40 2.75 (3.20)

Experimental Example 3. Liver microsomal metabolic stability test

Metabolic stability tests were evaluated in human liver microsomes (UltraPool™ HLM 150, Corning ^® ) and mouse liver microsomes (CD-1 Mouse Pooled Liver Microsomes, Corning ^® ). Prepare the reaction mixture so that the microsomes in the final reaction mixture have a concentration of 0.2 mg/mL protein, and pre-incubate for 5 minutes at 37 ° C with 100 mM phosphate buffer (pH 7.4) and 1 mM NADPH. After giving CB1 inhibitor compounds (Examples 5, 6, 17, 19) or rimonabant (Rimonabant) was added to a final concentration of 1 μM to start the reaction. 1 uM of Verapamil was used as a positive control. At 0 and 30 minutes after the start of the reaction, a stop solution (acetonitrile) containing an internal standard was added to terminate the reaction.

As shown in Table 7 below, the amount of the compound in the reaction mixture was quantified by LC-MS/MS after pretreatment of the liver microsome metabolic stability test result, and expressed as a percentage compared to the initial amount.

Example human
(% remaining) mouse
(% remaining) 5 35.4 67.7 6 51.2 86.2 17 32.5 3.1 19 83.8 59.4 Rimonabant 48.3 8.0 Verapamil 32.2 35.3

Experimental Example 4. Compound brain-vascular barrier (BBB) permeation analysis

The blood-brain barrier (BBB) penetration test of the CB1 inhibitor compound was evaluated in ICR mice. All subjects were fasted for at least 16 hours prior to compound administration. A single dose (10 mg/kg) of a CB1 inhibitor compound (Examples 5, 6, 19) or rimonabant was suspended in 10 mL of a mixed solvent (4% DMSO; 8% Tween 80; 88% saline) and then orally administered to mice. . Mice were sacrificed 1, 2, and 4 hours after compound administration and analyzed. At each autopsy point, the mouse was anesthetized, and about 1 ml of blood was collected by laparotomy. The blood collected was immediately stored in an ice-cold state (about 4°C). After blood collection, the blood was centrifuged at 5,000 rpm for 5 minutes to separate plasma, and then immediately stored in an ice-cooled state. After blood collection, perfusion was performed using saline, and the brain was extracted, and the extracted brain was placed in a tube and stored in a cryogenic freezer. The concentrations of CB1 inhibitor compounds (Examples 5, 6, 19) or rimonabant were measured using LC-MS/MS methods in mouse plasma and brain tissue collected to examine the BBB permeability of the drug.

The brain/plasma ratio of the compound 1, 2, and 4 hours after administration of the compound to the mouse is shown in Table 8 below.

Example 1 hours 2 hours 4 hours 5 0.00 0.00 0.00 6 0.00 0.00 0.01 19 0.08 0.17 0.19 Rimonabant 0.67 0.57 0.52

The scope of the invention is indicated by the claims described below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the invention.

Claims (14)

A pyrazole-carboxamide derivative compound represented by the following formula (1), an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ₁ is H or halogen,
R ₂ is H, halogen or CN;
R ₃ and R ₄ are each independently H or halogen,
Q is substituted or unsubstituted aryl or heteroaryl,
L is

,

,

,

,

or

ego,
L ₁ is C ₁ -C ₆ alkyl,
R' and R'' may each independently be substituted with H or C ₁ -C ₃ alkyl,
Het is a 4-6 membered aromatic or non-aromatic heterocyclic compound unsubstituted or substituted with haloalkyl, and contains N or O in 1 to 4 rings.
The compound of claim 1, wherein R ₁ is H or Cl.
The compound of claim 1, wherein R ₂ is H or CN.
The compound of claim 1, wherein R ₃ is Cl.
The compound of claim 1, wherein R ₄ is H or Cl.
The method according to claim 1,
The aryl is a compound selected from the following structures;

(In the above structure, X is hydrogen or halogen)
The heteroaryl is any one selected from the following structure:

(In the above structure, X is hydrogen or halogen).
The compound of claim 1, wherein L is any one selected from the following structures:

(In the above structure, L ₁ is C ₁ -C ₃ alkyl).
The compound of claim 1, wherein R' and R'' are H.
The compound according to claim 1, wherein Het is a 4-6 membered aromatic heterocyclic compound which is unsubstituted or substituted with haloalkyl, and contains N or O in 2 to 4 rings.
The compound according to claim 1, wherein Het is any one selected from the following structures:

(In the above structure, Y is H or CX ₃ , and X is halogen).
The compound according to claim 1, wherein the compound is any one selected from the group consisting of the following compounds:
N-(2-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
N-(3-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
N-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
N-(2-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
N-(3-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra sol-3-carboxamide,
(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine;
(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzoyl)glycine;
3-(3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid;
3-(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)benzamido)propanoic acid,
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -carboxamide,
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((2-sulfamoylethyl)carbamoyl)phenyl)-1H-pyrazole-3 -carboxamide,
(S)-N-(3-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,
(S)-N-(4-(2-carbamoylpyrrolidine-1-carbonyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,
N-(2-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
N-(3-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
N-(4-(((1,2,4-oxadiazol-3-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
N-(3-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
N-(4-(((1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide,
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(3-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(4-((5-(trifluoromethyl)-1,3,4-oxadiazole -2-yl) carbamoyl) phenyl) -1H-pyrazole-3-carboxamide;
N-(3-amino-3-oxopropyl)-6-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,
N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide,
N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-chlorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl -1H-pyrazole-3-carboxamide,
N-(4-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
N-(4-((3-amino-3-oxopropyl)carbamoyl)-3-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) pyrazine-2-carboxamide,
N-(3-amino-3-oxopropyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide,
N-(3-amino-3-oxopropyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,
N-(3-amino-3-oxopropyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide,
N-(5-((3-amino-3-oxopropyl)carbamoyl)-2-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
N-(3-((3-amino-3-oxopropyl)carbamoyl)-5-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
N-(3-((3-amino-3-oxopropyl)carbamoyl)-4-fluorophenyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide,
N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamide;
N-(4-((3-amino-3-oxopropyl)carbamoyl)phenyl)-1-(4-chlorophenyl)-5-(3-cyanophenyl)-4-methyl-1H-pyrazole- 3-carboxamide,
N-(2-amino-2-oxoethyl)-2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) isonicotinamide,
N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido) nicotinamide,
N-(2-amino-2-oxoethyl)-4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide, and
N-(2-amino-2-oxoethyl)-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox amido)picolinamide.
12. A pharmaceutical composition comprising the compound of any one of claims 1 to 11 and a pharmaceutically acceptable carrier.
A pharmaceutical composition for the prevention or treatment of diseases caused by overexpression or overactivity of cannabinoid receptor 1, comprising the compound of any one of claims 1 to 11.
The pharmaceutical composition according to claim 13, wherein the disease caused by overexpression or overactivity of the cannabinoid receptor 1 is at least one selected from the group consisting of diabetes, metabolic disease, dyslipidemia, alcoholic liver disease, and non-alcoholic liver disease.

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