JP2012158535A - Pyrazole derivative and medical drug use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound having 11β-HSD1 inhibitory activity, to provide a curative for diabetes having a reduced side effect and a novel mechanism and to provide an improving drug having insulin resistance.SOLUTION: A pyrazole derivative represented by general formula (I) and a salt thereof pharmaceutically permitted are provided.

Description

  The present invention relates to pyrazole derivatives and pharmaceutical uses thereof.

  Diabetes is a metabolic disease group mainly characterized by chronic hyperglycemia due to insufficient insulin action, and is roughly classified into type 1 and type 2. Type 1 diabetes develops mainly due to a decrease in insulin secretion due to destruction or loss of pancreatic islets of Langerhans that synthesize and secrete insulin, whereas type 2 diabetes has a decrease in insulin secretion and insulin It develops with multiple genetic factors, including predisposing factors for resistance, with environmental factors such as overeating (especially high fat diet), lack of exercise, obesity, and stress, and aging.

  In addition, the long-lasting hyperglycemic state due to diabetes has a high risk of leading to blindness and cardiovascular disorders in addition to diabetic retinopathy, diabetic nephropathy and diabetic neuropathy, which are said to be the three major complications of diabetes. It is known. For this reason, at the onset of diabetes, QOL (quality of life) is to improve the glucose tolerance, postprandial hyperglycemia, fasting hyperglycemia, etc. by controlling the blood sugar level to lead to an appropriate level. It is thought that it is important also from a viewpoint (nonpatent literature 1).

  Currently used therapeutic agents for diabetes include insulin preparations, sulfonylureas such as glibenclamide, biguanides such as metformin, α-glucosidase inhibitors such as voglibose, and thiazolidinedione drugs such as pioglitazone (Non-patent Document 1). ~ 5).

  Insulin preparations have a hypoglycemic effect, but are also known to often cause severe hypoglycemia or weight gain, and require administration by injection, which has a demerit that places a heavy burden on patients. Although sulfonylurea has a blood glucose lowering effect, it similarly causes severe hypoglycemia and weight gain, and it is known that deterioration of blood glucose level control called secondary ineffectiveness occurs in the case of long-term administration. . Biquanides have a hypoglycemic effect and an insulin resistance-improving effect, but may cause gastrointestinal disorders such as diarrhea or bloating, and there is also a risk of causing severe lactic acidosis. It is contraindicated in patients with dysfunction. An α-glucosidase inhibitor has an action of suppressing postprandial blood glucose increase (postprandial hyperglycemia), but is known to cause gastrointestinal disorders such as abdominal pain, diarrhea or bloating. Thiazolidinedione drugs have a hypoglycemic effect through improved insulin resistance, but often cause weight gain, edema, and liver damage, and are not suitable for patients with heart failure or those with a history of heart failure. Regular liver function tests are required.

  Insulin resistance, on the other hand, refers to a state in which insulin action commensurate with the concentration of insulin in the blood cannot be obtained. It is known that symptoms of insulin resistance are also observed in borderline humans who do not suffer from diabetes. ing. Insulin resistance is a basic pathological condition of metabolic syndrome as well as visceral fat-type obesity, and it has been clarified that it is closely related to the pathogenesis of arteriosclerosis, obesity, hypertension, and abnormal lipid metabolism. Here, metabolic syndrome is a concept based on the assumption that obesity-based, mainly lipid metabolism abnormalities (high triglycerides and low HDL cholesterol), high blood pressure, and impaired glucose tolerance increase the risk of developing ischemic cardiovascular disease. It is.

  For this reason, improvement of insulin resistance is considered to be important not only for improvement of glucose metabolism abnormality but also for treatment of metabolic syndrome, cardiovascular disorder, and cerebrovascular disorder (Non-patent Document 1).

  In addition, 11β-hydroxysteroid dehydrogenase 1 (11β-hydroxysteroid dehydrogenase type 1; hereinafter referred to as “11β-HSD1”) is an inactive glucocorticoid (cortisone in humans and 11-dehydrocorticosterone in rodents). It is an enzyme that converts intracellularly into glucocorticoid (cortisol in humans and corticosterone in rodents) and is highly expressed in liver, adipose tissue and skeletal muscle (Non-patent Document 6). Active glucocorticoids have been reported to cause metabolic abnormalities such as hyperglycemia by enhancing gluconeogenesis in the liver and suppressing glycolysis or suppressing sugar uptake in adipose tissue and muscle (Non-patent Document 7). ). In 11β-HSD1 knockout mice, hepatic gluconeogenic enzymes (PEPCK, G6Pase, etc.) are not induced against stress load and high fat diet load, and show obvious resistance to the onset of diabetes, and visceral organs due to high fat diet load It has been reported that since fat accumulation is selectively suppressed, it is resistant to the onset and progression of metabolic syndrome (Non-patent Document 8).

  Patent Documents 1 to 5 disclose pyrazole derivatives having 11β-HSD1 inhibitory action.

International Publication No. 08/099145 International Publication No. 09/060232 International Publication No. 09/099851 International Publication No. 10/088770 International Publication No. 09/010416

Japan Diabetes Society, Diabetes Treatment Guide 2008-2009, 2008 Moller, Nature, 2001, 414, p. 821-827 Skyler, Journal of Medicinal Chemistry, 2004, 47, p. 4113-4117 Ross et al., Chemical Review, 2004, 104, p. 1255-1282 Stumvol et al., Lancet, 2005, 365, p. 1333-1346 Seckl et al., Endocrinology, 2001, 142, p. 1371 Tsuchida et al., Japanese Clinical, 2002, Volume 60, Special Issue 7, p. 280 Kotelevtsev et al., Proceedings of the National Academy of Sciences of the United States of America, 1997, Vol. 94, p. 14924-14929

  However, as described above, all of the existing antidiabetic drugs are effective, but they have various drawbacks and side effects. At present, it is desired to create an easy-to-use anti-diabetic drug that can be administered to patients with diseases and can be administered for a long time.

  In addition, since a compound having an 11β-HSD1 inhibitory action can inhibit the conversion of inactive glucocorticoid and attenuate the action of active glucocorticoid in tissues, a new mechanism compared to existing pharmaceuticals. Is expected to suppress hyperglycemia and hepatic gluconeogenesis, and to be effective in improving insulin resistance and metabolic syndrome. However, it still has an 11β-HSD1 inhibitory action and improves insulin resistance. The drug is not approved as a medicinal product.

  Accordingly, an object of the present invention is to provide a compound having a remarkable 11β-HSD1 inhibitory activity, and to provide a therapeutic agent for diabetes and a drug for improving insulin resistance with a new mechanism with reduced side effects.

  As a result of intensive studies to achieve the above object, the present inventors have found that a novel pyrazole derivative or a pharmaceutically acceptable salt thereof has a potent 11β-HSD1 inhibitory activity, and improves diabetes and insulin resistance. As a result, the present invention has been completed.

That is, the present invention provides the following general formula (I)
[Wherein, R ¹ represents alkyl having 1 to 6 carbon atoms (the alkyl may be substituted with 1 to 5 halogen atoms or hydroxy), cycloalkyl having 3 to 10 carbon atoms (the cyclo Alkyl may be substituted with 1 to 5 halogen atoms or hydroxy.), Alkyloxy having 1 to 3 carbon atoms (the alkyloxy may be substituted with one or more halogen atoms). , A halogen atom or a hydrogen atom, k represents an integer of 1 to 5, R ² represents an alkyl having 1 to 6 carbon atoms (the alkyl is substituted with 1 to 5 halogen atoms or hydroxy). Or a cycloalkyl having 3 to 10 carbon atoms (the cycloalkyl may be substituted with 1 to 5 halogen atoms or hydroxy), and R ³ represents carbon. Numbers 1-6 Kill, a cycloalkyl or a hydrogen atom having 3 to 6 carbon atoms, R ⁴ is alkyl of 1 to 6 carbon atoms (the alkyl may be substituted with 1-5 halogen atoms.), Carbon Formula 1-6 alkyloxy (the alkyloxy may be substituted with 1 to 5 halogen atoms), hydroxy, cyano, halogen atom, hydrogen atom, —O— (CH ₂ ) _n —R ⁵ , —SO ₂ —R ⁶ , —SO ₂ —OR ⁶ , —NR ⁶ (C═O) R ⁶ , —NR ⁶ (SO ₂ ) R ⁶ , —NR ⁷ R ⁸ , — (C═O) — NR ⁷ R ⁸ , —O— (C═O) —NR ⁷ R ⁸ or —SO ₂ —NR ⁷ R ⁸ is shown, R ⁵ is an alkyloxy having 1 to 3 carbon atoms (the alkyloxy is 1 to 5 halogen atoms may be substituted.), hydroxy, ^-NR 7 ^{R 8} Is - (C = O) indicates ^-NR 7 ^{R 8, R 6} are each independently alkyl (the alkyl having 1 to 3 carbon atoms may be substituted with 1 to 3 halogen atoms Or a hydrogen atom, and R ⁷ and R ⁸ each independently represent an alkyl or hydrogen atom having 1 to 6 carbon atoms, or R ⁷ , R ⁸ and a nitrogen atom are combined to form pyrrolidyl , Piperidyl, morpholyl, piperazyl or 4-alkylpiperazin-1-yl (the carbon number of the alkyl constituting the 4-alkylpiperazin-1-yl is 1 to 3), and m and n are each independently And an integer of 1-4. Or a pharmaceutically acceptable salt thereof.

The R ³ preferably represents a hydrogen atom, and the R ⁴ is hydroxy, —NR ⁶ (C═O) R ⁶ , — (C═O) —NR ⁷ R ⁸ or —O— (C ═O) —NR ⁷ R ⁸ is preferable, and hydroxy, —NR ⁶ (C═O) R ⁶ or — (C═O) —NR ⁷ R ⁸ is more preferable. At that time, m preferably represents 1.

R ² represents alkyl having 1 to 6 carbons (the alkyl may be substituted with 1 to 5 halogen atoms, but excluding methyl) or cycloalkyl having 3 to 6 carbons. It is preferable that 2-propyl or 2-methyl-2-propyl is more preferable.

Further, R ¹ is alkyl having 1 to 3 carbon atoms (the alkyl may be substituted with 1 to 5 halogen atoms or hydroxy), alkyloxy having 1 to 3 carbon atoms (the alkyloxy is 1 may be substituted with one or more halogen atoms), preferably a halogen atom or a hydrogen atom. In that case, it is preferable that said k shows the integer of 1-3.

  The present invention also provides an 11β-hydroxysteroid dehydrogenase 1 inhibitor (11β-HSD1 inhibitor) containing the above-mentioned pyrazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

  The present invention also provides a therapeutic or prophylactic agent for diabetes containing the above-mentioned pyrazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. More preferably, the diabetes is type 2 diabetes.

  The present invention also provides an insulin resistance ameliorating agent comprising the above-mentioned pyrazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

  The pyrazole derivative of the present invention or a pharmaceutically acceptable salt thereof exhibits a remarkable 11β-HSD1 inhibitory activity, and has a remarkable therapeutic effect from a diabetic disease to a disease accompanied by insulin resistance. In addition, the therapeutic agent for diabetes and the drug for improving insulin resistance of the present invention have reduced side effects such as weight gain observed with existing therapeutic agents for diabetes, and administration to patients with chronic diseases or complex diseases and long-term administration. Can be expected to be possible.

FIG. 4 is a graph showing the insulin resistance improving action of the compound of Example 2. It is a figure which shows the insulin resistance improvement effect of the compound of Example 7. It is a figure which shows the insulin resistance improvement effect of the compound of Example 8. It is a figure which shows the insulin resistance improvement effect of the compound of Example 23. FIG. 4 is a graph showing the insulin resistance improving action of the compound of Example 2. FIG. 4 is a graph showing an inhibitory effect on hepatic gluconeogenesis of the compound of Example 2. FIG. 4 is a graph showing an inhibitory effect on hepatic gluconeogenesis of the compound of Example 2.

  The following terms used in this specification are defined as follows unless otherwise specified.

  “Alkyl” means a straight or branched saturated hydrocarbon such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 1, Examples include 1-dimethylethyl, 1-pentyl, 2-pentyl, 3-pentyl or 1-hexyl.

  “Cycloalkyl” means a saturated alicyclic hydrocarbon which may partially have an unsaturated bond or may form a bridged ring or a spiro ring, such as cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, bicyclo [2,2,1] hexane-1-yl, bicyclo [2,2,1] heptan-2-yl, bicyclo [3,1,1] heptan-3-yl , Bicyclo [2,2,2] octan-1-yl, adamantyl (adamantan-1-yl or adamantane-2-yl) or norbornyl.

  “Alkyloxy” means a functional group in which alkyl is bonded to an oxygen atom, and examples thereof include methoxy, ethoxy, 1-propoxy, 2-propoxy and 1-butoxy.

  “Halogen” means fluorine, chlorine, bromine or iodine.

  “Diabetes” means a pathological condition that meets diagnostic criteria such as the World Health Organization (WHO), the Japan Diabetes Society, the American Diabetes Association, or the European Diabetes Association, such as type 1 diabetes, type 2 diabetes, or gestational diabetes. It is done.

  “Insulin resistance” refers to the insulin resistance index (fasting blood glucose (mg / dL) × fasting insulin (μU / mL) ÷ 405), glucose clamp method, etc. It means a disease state where a suitable insulin action cannot be obtained, and syndrome X is also included in this.

  “Therapeutic or prophylactic agents” include not only those used for treatment or prevention but also those used simultaneously for both treatment and prevention.

The pyrazole derivative of the present invention has the following general formula (I)
[Wherein, R ¹ represents alkyl having 1 to 6 carbon atoms (the alkyl may be substituted with 1 to 5 halogen atoms or hydroxy), cycloalkyl having 3 to 10 carbon atoms (the cyclo Alkyl may be substituted with 1 to 5 halogen atoms or hydroxy.), Alkyloxy having 1 to 3 carbon atoms (the alkyloxy may be substituted with one or more halogen atoms). , A halogen atom or a hydrogen atom, k represents an integer of 1 to 5, R ² represents an alkyl having 1 to 6 carbon atoms (the alkyl is substituted with 1 to 5 halogen atoms or hydroxy). Or a cycloalkyl having 3 to 10 carbon atoms (the cycloalkyl may be substituted with 1 to 5 halogen atoms or hydroxy), and R ³ represents carbon. Numbers 1-6 Kill, a cycloalkyl or a hydrogen atom having 3 to 6 carbon atoms, R ⁴ is alkyl of 1 to 6 carbon atoms (the alkyl may be substituted with 1-5 halogen atoms.), Carbon Formula 1-6 alkyloxy (the alkyloxy may be substituted with 1 to 5 halogen atoms), hydroxy, cyano, halogen atom, hydrogen atom, —O— (CH ₂ ) _n —R ⁵ , —SO ₂ —R ⁶ , —SO ₂ —OR ⁶ , —NR ⁶ (C═O) R ⁶ , —NR ⁶ (SO ₂ ) R ⁶ , —NR ⁷ R ⁸ , — (C═O) — NR ⁷ R ⁸ , —O— (C═O) —NR ⁷ R ⁸ or —SO ₂ —NR ⁷ R ⁸ is shown, R ⁵ is an alkyloxy having 1 to 3 carbon atoms (the alkyloxy is 1 to 5 halogen atoms may be substituted.), hydroxy, ^-NR 7 ^{R 8} Is - (C = O) indicates ^-NR 7 ^{R 8, R 6} are each independently alkyl (the alkyl having 1 to 3 carbon atoms may be substituted with 1 to 3 halogen atoms Or a hydrogen atom, and R ⁷ and R ⁸ each independently represent an alkyl or hydrogen atom having 1 to 6 carbon atoms, or R ⁷ , R ⁸ and a nitrogen atom are combined to form pyrrolidyl , Piperidyl, morpholyl, piperazyl or 4-alkylpiperazin-1-yl (the carbon number of the alkyl constituting the 4-alkylpiperazin-1-yl is 1 to 3), and m and n are each independently And an integer of 1-4. It is characterized by being represented.

R ¹ is alkyl having 1 to 3 carbon atoms (the alkyl may be substituted with 1 to 5 halogen atoms or hydroxy), alkyloxy having 1 to 3 carbon atoms (the alkyloxy is It may be substituted with one or more halogen atoms.), Preferably represents a halogen atom or a hydrogen atom, more preferably represents a methyl, methoxy, trifluoromethyl, chlorine, fluorine or hydrogen atom. In that case, k is preferably an integer of 1 to 3, and more preferably 1 or 2.

R ² is an alkyl having 1 to 6 carbon atoms other than methyl (the alkyl may be substituted with 1 to 5 halogen atoms, but excluding methyl) or a cycloalkyl having 3 to 6 carbon atoms. Is preferable, and 2-propyl or 2-methyl-2-propyl is more preferable.

R ³ preferably represents an alkyl having 1 to 4 carbon atoms or a hydrogen atom, and more preferably represents a hydrogen atom.

R ⁴ preferably represents hydroxy, —NR ⁶ (C═O) R ⁶ , — (C═O) —NR ⁷ R ⁸ or —O— (C═O) —NR ⁷ R ⁸ , More preferably, -NR < ⁶ > (C = O) R < ⁶ > or-(C = O) -NR < ⁷ > R < ⁸ >. In that case, m is preferably 1 or 2, and more preferably 1. The substitution position is preferably the 4-position from the carbon to which the nitrogen atom is bonded, and the relative arrangement is preferably trans to each other on the adamantane ring.

R ⁵ preferably represents hydroxy, —NR ⁷ R ⁸ or — (C═O) —NR ⁷ R ^8, and more preferably represents hydroxy or —NR ⁷ R ⁸ .

R ⁶ preferably represents a hydrogen atom or alkyl having 1 to 3 carbon atoms, and more preferably represents a methyl or hydrogen atom.

R ⁷ and R ⁸ are each independently preferably a hydrogen atom or alkyl having 1 to 3 carbon atoms, and more preferably a hydrogen atom.

  In addition, the pyrazole derivative represented by the general formula (I) may have a stereoisomer such as an enantiomer, a racemate, or a diastereomer depending on the case. However, all the stereoisomers are present in the pyrazole derivative of the present invention. And mixtures of the respective isomers.

Specific examples of the pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof are represented by the general formula (Ia). Examples of preferred combinations of substituents in the compound represented by the general formula (Ia) are shown in Tables 1 to 17. In Tables 1 to 17, the wavy line in the structural formula indicates that the position is substituted, i-Pr indicates 2-propyl, and t-Bu indicates 2-methyl-2-propyl. .

  The “pharmaceutically acceptable salt” of the pyrazole derivative represented by the general formula (I) includes, for example, hydrochloride, sulfate, nitrate, bromide when the pyrazole derivative has a basic substituent. Inorganic acid salts such as hydrogenate, hydroiodide or phosphate, acetate, trifluoroacetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate Acid, mandelate, maleate, benzoate, organic carboxylate such as phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate or camphorsulfonate Organic sulfonates such as salts or acidic amino acid salts such as aspartate or glutamate, including hydrochloride, hydrobromide, phosphate, trifluoroacetate, Enoic acid, fumaric acid, tartaric acid salt or methanesulfonic acid salt.

  When the pyrazole derivative has an acidic substituent, for example, an alkali metal salt such as sodium salt or potassium salt, an alkaline earth metal salt such as calcium salt or magnesium salt, an aluminum salt, an ammonium salt, a trimethylamine salt, Organic base salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, dicyclohexylamine salt or N, N-dibenzylethylenediamine salt, or bases such as arginine salt, lysine salt or ornithine salt Amino acid salts, sodium salts, potassium salts and ethanolamine salts are preferred.

  The pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof can be produced by appropriately combining synthesis methods known in the literature. Scheme 1 illustrates a typical production method. The meanings of symbols in each reaction formula are as defined above unless otherwise specified.

  The pyrazole derivative represented by the general formula (I) obtained by the following production method can be isolated and purified by a known means. Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.

When the pyrazole derivative represented by the general formula (I) contains an optical isomer or a stereoisomer, each isomer can be obtained as a single compound by a known method.

  In Scheme 1, X represents alkyl having 1 to 6 carbon atoms.

[First step]
As the pyrazole-4-carboxylic acid represented by the general formula (III), a commercially available compound is used, or the pyrazole-4-carboxylic acid ester represented by the general formula (II) is obtained under acidic or basic conditions. It can be synthesized by hydrolysis reaction.

  The above hydrolysis reaction may be carried out according to Green's method (Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons., 1999) or experimental chemistry course (4th edition, volume 22, p.271-309). It can be carried out according to the method described.

  0.5-100 equivalent is preferable with respect to the pyrazole-4-carboxylic acid ester represented by general formula (II), and, as for the quantity of the acid or base used for said hydrolysis reaction, 1-30 equivalent is more preferable.

  The reaction solvent used in the hydrolysis reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, ethers such as tetrahydrofuran (hereinafter “THF”), 1,4-dioxane, ethylene glycol dimethyl ether, or dimethoxyethane are used. Solvents, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, N, N-dimethylformamide (hereinafter “DMF”) or dimethyl sulfoxide (hereinafter “ Aprotic polar solvents such as DMSO "), ketone solvents such as acetone or methyl ethyl ketone, nitrile solvents such as acetonitrile or propionitrile, protic properties such as methanol, ethanol or 2-propanol Alcohol solvents or water, or is a mixture thereof, ether solvents, aprotic polar solvents, protic alcohol solvents or water or a mixed solvent thereof preferred.

  The concentration of the pyrazole-4-carboxylic acid ester represented by the general formula (II) in the reaction solution at the start of the hydrolysis reaction is preferably in the range of 0.01 mM to 1M.

  The hydrolysis reaction temperature is preferably −78 to 200 ° C., more preferably −20 to 100 ° C.

  The hydrolysis reaction time is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 30 hours.

[Second step]
A pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof includes a pyrazole-4-carboxylic acid represented by the general formula (III), an adamantaneamine represented by the general formula (IV), and It can be synthesized by the condensation reaction.

  The above condensation reaction can be performed by a general peptide synthesis method ("Experimental Chemistry Course (Vol. 16) Synthesis of Organic Compounds IV", 5th Edition, p.258-270, etc.) or a general carboxylic acid amide synthesis method ( "Experimental Chemistry (Vol. 16) Synthesis of Organic Compounds IV", p. 118-134; Benz, Comprehensive Organic Synthesis, 1991, Vol. 6, p. 381-417, Pergamon Press; Association Journal, 2004, 62, p. 1249-1259; Montalbetti et al., Tetrahedron, 2005, 61, p. 10827-10852, etc.).

  Examples of the reagent used in the above condensation reaction (hereinafter, “condensing agent”) include cyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride, N, N-carbodiimidazole, O- (7- Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate or ortho- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluro Nium hexafluorophosphate (hereinafter “HBTU”) is preferred, and HBTU is more preferred.

  The amount of the condensing agent is preferably 1 to 10 equivalents and more preferably 1 to 3 equivalents with respect to the pyrazole-4-carboxylic acid represented by the general formula (III).

  The solvent suitable for the above condensation reaction varies depending on the type of the above condensing agent. For example, ether solvents such as THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxyethane, dichloromethane, chloroform or 1,2-dichloroethane. And halogen solvents such as DMF or DMSO, nitrile solvents such as acetonitrile or propionitrile, halogen solvents or aprotic polar solvents are preferred, and halogen solvents are more preferred. .

  The concentration of pyrazole-4-carboxylic acid represented by the general formula (III) in the reaction solution at the start of the condensation reaction is preferably in the range of 0.01 mM to 1M.

  The condensation reaction temperature is preferably −78 to 200 ° C., more preferably 0 to 100 ° C.

  The condensation reaction time is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 6 to 48 hours.

  The pyrazole-4-carboxylic acid ester represented by the general formula (II), which is a starting material for the production method exemplified in Scheme 1, can be synthesized by, for example, the method shown in Scheme 2. The meanings of symbols in each reaction formula are as defined above unless otherwise specified.

As the phenylhydrazine compound represented by the general formula (VII) in Scheme 2, a salt such as hydrochloride may be used.

[First step]
The compound represented by the general formula (VI) can be synthesized by an aminomethylation reaction in which dimethylformamide dimethyl acetal is allowed to act on a commercially available acetoacetate represented by the general formula (V).

  1-20 equivalent is preferable with respect to the acetoacetate ester represented with general formula (V), and, as for the quantity of the dimethylformamide dimethyl acetal used for said aminomethylation reaction, 3-10 equivalent is more preferable.

  The aminomethylation reaction is preferably carried out without using a reaction solvent. On the other hand, when a reaction solvent is used for the aminomethylation reaction, the reaction solvent is appropriately selected from solvents that do not normally inhibit the reaction. Examples of such solvents include ether solvents such as THF, 1,4-dioxane or ethylene glycol dimethyl ether, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, and aromatic hydrocarbons such as benzene or toluene. Solvent, aprotic polar solvent such as DMF or DMSO, protic alcohol solvent such as methanol, ethanol or 2-propanol, water or mixed solvent, halogen solvent, aromatic hydrocarbon solvent, aprotic Polar solvents or protic alcohol solvents are preferred.

  The concentration of the acetoacetate ester represented by the general formula (V) in the reaction solution at the start of the aminomethylation reaction is preferably in the range of usually 0.1 mM to 10M.

  The aminomethylation reaction temperature is preferably 0 to 200 ° C, more preferably 20 to 120 ° C.

  The aminomethylation reaction time is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 0.5 to 12 hours.

[Second step]
The pyrazole-4-carboxylic acid ester represented by the general formula (II) can be synthesized by a cyclization reaction in which the phenylhydrazine compound represented by the general formula (VII) is allowed to act on the compound represented by the general formula (VI). .

  1-10 equivalent is preferable with respect to the acetoacetate ester represented with general formula (V), and, as for the quantity of the phenylhydrazine compound used for said cyclization reaction, 1-5 equivalent is more preferable.

  The reaction solvent used for the cyclization reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, an aprotic polar solvent such as DMF or DMSO, or a protic alcohol solvent such as methanol, ethanol, or 2-propanol. Nitrile solvents such as acetonitrile or propionitrile, organic carboxylic acids such as formic acid, acetic acid or propionic acid, or water or a mixed solvent thereof. Among them, a protic alcohol solvent or a nitrile solvent is preferable, and a protic alcohol solvent. Is more preferable.

  The concentration of the compound represented by the general formula (VI) at the start of the cyclization reaction is usually preferably in the range of 0.01 mM to 10M.

  The cyclization reaction temperature is preferably 0 to 200 ° C, more preferably 20 to 120 ° C.

  The cyclization reaction time is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 12 hours.

Formula (IV)
An adamantaneamine compound represented by the formula (Tetrahedron Letters, 2006, 47, 46, p.8063-8067; Journal of Medicinal Chemistry, 2007, 50, No. 1, p.149-164).

  The 11β-HSD1 inhibitor, the therapeutic and prophylactic agent for diabetes and the insulin amelioration agent of the present invention include the pyrazole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof. It is characterized by containing as an active ingredient.

  The effects of the 11β-HSD1 inhibitor, the therapeutic and prophylactic agent for diabetes and the insulin ameliorating agent are as follows: blood glycohemoglobin level (HbA1c), fasting blood glucose level, oral glucose tolerance test (OGTT; oral glucose tolerance) test) blood glucose 2-hour value, blood c-peptide value, blood glycoalbumin value, 1,5-AG (1,5-anhydroglucitol), blood hollow abdominal insulin value, HOMA-IR ( Sugar injection rate (GIR), glucose production rate (HGP) in homeostasis model assessment of insulance, glucose clamp (euglycemic-hyperinsulinic clamp) test epatic glucose production), insulin tolerance test (ITT; insulin tolerance test) or pyruvate tolerance test (PTT; Pyruvate tolerance test) can be evaluated and the like.

  The pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is effective in improving diabetes, particularly type 2 diabetes, specifically, HbA1c, glycoalbumin, fructosamine, 1, 5-AG, hyperglycemia at any time, fasting hyperglycemia, impaired glucose tolerance, increased hepatic gluconeogenesis, improvement of GIR and HGP in HOMA-IR and glucose clamp tests can be expected. Furthermore, since the pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof can be used for improving insulin resistance, it is suitable as a therapeutic or prophylactic agent for metabolic syndrome.

  When the pyrazole derivative represented by the general formula (I) is clinically administered as a therapeutic or prophylactic agent for diabetes or insulin resistance, the free form of the pyrazole derivative represented by the general formula (I) Pharmaceutically acceptable salts may be administered as they are, and additives such as excipients, stabilizers, preservatives, buffers, solubilizers, emulsifiers, diluents or isotonic agents are mixed as appropriate. May be administered. Examples of the administration form include oral administration such as tablets, capsules, granules, powders or syrups, parenteral administration such as injections, suppositories or liquids, ointments, creams or patches. Topical administration.

  The preparation of each of the above dosage forms can be prepared by a known production method, but contains 0.00001 to 90% by weight of the pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Is preferable, and 0.0001 to 70% by weight is more preferable.

  The dose of the pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is appropriately selected according to symptoms, age, body weight, administration method, etc. When administered, the amount of active ingredient is preferably 1 μg to 10 g per day, and can be administered once or divided into several times.

  A medicine containing a pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, that is, a therapeutic or prophylactic agent for diabetes or insulin resistance includes other therapeutic agents for diabetes, dyslipidemia It may be used in combination with a therapeutic drug, a therapeutic drug for obesity, or a therapeutic drug for metabolic syndrome (hereinafter referred to as “concomitant drug”).

  At this time, there is no limitation on the timing of administration of the pharmaceutical comprising the pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof and the concomitant drug, and these are administered simultaneously in combination or combination. Alternatively, administration may be performed with a time difference. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the combined volume ratio or combination ratio of the drug containing the pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient and the concomitant drug is the subject of administration, dosage form, symptom or It can be appropriately selected depending on the combination of each drug.

  Examples of the concomitant drugs include insulin preparations (super-fast-acting insulin preparations, fast-acting insulin preparations, mixed-type insulin preparations, intermediate-type insulin preparations, continuous-type insulin preparations, sustained-release dissolved insulin preparations, transpulmonary insulin preparations, Oral insulin preparations), insulin sensitizers (pioglitazone), rosiglitazone, netoglitazone, farglitazar, riboglitazone, riboglitaglitazone α-glucosidase inhibitors (acarbose, voglibose, miglitol, Glycate (emitlite), biguanide agents (metformin, metformin, etc.), sulfonylurea agents (tolbutamide, acetohexamide, chlorpropamamide, chlorpropramide) Clopyramide (glyclozide), glipidone (glypideon), glyidone (glypideon), glyidone (glyidone) linide, repaglinide, mitiglinide, etc.), GLP-1 agonist (exenatide), liraglutide, etc., amylin agonist (pramlintide-IV) inhibitor, pramlintide-IV inhibitor, etc. Vildagliptin, Sitagliptin, Saxagliptin, Alogliptin, Denagliptin, Gemiliptin, Gemiliptin, Gemiliptin, Gemiliptin mira egron), KRP-204, etc.), fructose-1,6-bisphosphatase inhibitor (MB-6322, MB-07803 etc.), SGLT (sodium-dependent renal glucose transporter) inhibitor (sergliflozin), remogliflozin (Remogloflozin), AVE-2268, TS-033, KGA-2727, SAR-7226, etc.), 11β-HSD1 inhibitor (BVT-3498, AMG-221, INCB-13739, INCB-20817, JTT-654, PF-) 915275 etc.), PTP-1B (protein tyrosine phosphatase-1B) inhibitors (ISIS-1113715, JTT-551 etc.) , GSK3β (glycogen synthase kinase 3β) inhibitors (such as SAR-502250), glucagon antagonists (such as BAY-27-9955, NN-2501), glycogen phosphorylase inhibitors (such as isofagomine, PSN-357), (Carnitine O-palmitoyltransferase 1) inhibitors (eg, teglicar), glucocorticoid antagonists (eg, mifepristone, KB-3305), HMG-CoA reductase inhibitors (pravastatin), simvastatin (Simvastatin), fluvastatin, atorvastatin Pitavastatin (such as pitavastatin), anion exchange resin (such as cholestyramine), colestimide (such as colestimide), fibrate (clofibrate), clinofibrate (binofibate), bezafibrate (b) )), Nicotinic acid drugs (tocopherol nicotinate), CB1 (cannabinoid 1) antagonist (rimonabant, surinabant, taranabant, drinabanze inhibitor, etc.) (Orlistat ( orlistat) or a central appetite suppressant (such as mazindol, fenfluramine, dexfenfluramine or sibutramine, phentermine).

  EXAMPLES Hereinafter, although an Example is shown and this invention is explained in full detail, this invention is not limited to these.

Example 1
Synthesis of 1-phenyl-5-trifluoromethyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter the compound of Example 1):
[First step]
Synthesis of trans-5-hydroxy-2-adamantylamine (hereinafter referred to as Reference Compound 1):
5-Hydroxy-2-adamantanone (3.00 g, 18.1 mmol) was dissolved in toluene (60 mL), (-)-1-phenylethylamine (2.4 mL, 19 mmol), aluminum isopropoxide (3.69 g). , 18.1 mmol) and palladium hydroxide (0.25 g, 1.2 mmol) were added, and the mixture was stirred at 50 ° C. in a hydrogen atmosphere. After 16 hours, the reaction solution was filtered through Celite and concentrated to obtain an oily crude product. The obtained composition organism was dissolved in methanol (130 mL), palladium hydroxide (0.15 g, 0.72 mmol) was added, and the mixture was stirred at room temperature in a hydrogen atmosphere. After 14 hours, the reaction solution was filtered through Celite and concentrated to give a crude product (1.78 g, 96%) as a white solid. Recrystallization was performed using hexane / ethyl acetate as a solvent to obtain 0.98 g (55%) of the title compound as a white solid.

[Second step]
Synthesis of the compound of Example 1:
To a solution of 1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.10 g, 0.39 mmol) in chloroform (4 mL), trans-5-hydroxy-2-adamantylamine (0.065 g) , 0.39 mmol), diisopropylethylamine (0.34 mL, 2.0 mmol), and HBTU (0.091 g, 0.39 mmol) were added, and the mixture was stirred at room temperature. After 16 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 97/3 to 89/11) to obtain 0.15 g (95%) of the title compound as a white solid.

(Example 2)
Synthesis of 5-isopropyl-1-phenyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter the compound of Example 2):
[First step]
Synthesis of ethyl 5-isopropyl-1-phenyl-1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 2):
Dimethylformaldehyde dimethyl acetal (61.0 mL, 460 mmol) was added to ethyl 4-methyl-3-oxopentanoate (15 g, 92 mmol), and the mixture was stirred at 90 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (320 mL), phenylhydrazine (13 g, 63 mmol) was added, and the mixture was stirred at room temperature. After 2 hours, 1N HCl (63 mL, 63 mmol) was added and stirred at 90 ° C. After 2 hours, the mixture was cooled to room temperature, concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 100/0 to 87/13) to obtain 15 g (93%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 2:
To a solution of ethyl 5-isopropyl-1-phenyl-1H-pyrazole-4-carboxylate (15 g, 59 mmol) in methanol (180 mL) was added 1N NaOH (180 mL, 180 mmol), and the mixture was stirred at 50 ° C. After 8 hours, the mixture was concentrated and extracted with chloroform, 1N HCl was added to the aqueous layer to adjust to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 81/19 to 26/74). Chloroform (65 mL), trans-5-hydroxy-2-adamantylamine (5.5 g, 33 mmol), diisopropylethylamine (17 mL, 98 mmol) and HBTU (7.7 g, 33 mmol) were added to the purified product and stirred at room temperature. did. After 16 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was subjected to slurry washing with ethyl acetate to obtain 8.0 g (36%) of the title compound as a white solid (non-crystal).

(Example 3)
Synthesis of 5-cyclopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide (hereinafter the compound of Example 3):
To a solution of 5-cyclopropyl-1-phenyl-1H-pyrazole-4-carboxylic acid (0.10 g, 0.44 mmol) in chloroform (2 mL), trans-5-hydroxy-2-adamantylamine (0.073 g, 0 .44 mmol), diisopropylethylamine (0.12 mL, 0.66 mmol), and HBTU (0.17 g, 0.46 mmol) were added and stirred at room temperature. After 16 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 95/5) to obtain 0.13 g (76%) of the title compound as a white solid.

Example 4
Synthesis of 1- (4-chlorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 4):
[First step]
Synthesis of ethyl 1- (4-chlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 3):
Dimethylformaldehyde dimethyl acetal (0.76 mL, 5.7 mmol) was added to ethyl 4-methyl-3-oxopentanoate (0.30 g, 1.9 mmol), and the mixture was stirred at 100 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), 4-chlorophenylhydrazine hydrochloride (0.34 g, 1.9 mmol) and triethylamine (0.79 mL, 5.7 mmol) were added, and the mixture was stirred at 80 ° C. After 2 hours, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 0.40 g (72%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 4:
To a solution of ethyl 1- (4-chlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (0.40 g, 1.4 mmol) in methanol (8 mL) was added 1N NaOH (2.8 mL, 2.8 mmol). In addition, the mixture was stirred at 60 ° C. After 2 hours, the mixture was cooled to room temperature, 1N HCl (2.8 mL, 2.8 mmol) was added, and the mixture was concentrated. To the obtained crude product, chloroform (15 mL), trans-5-hydroxy-2-adamantylamine (0.23 g, 1.4 mmol), and HBTU (0.52 g, 1.4 mmol) were added, and the mixture was stirred at room temperature. After 60 hours, the crude product obtained by concentration was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain 0.21 g (37%) of the title compound as a white solid.

(Example 5)
1- (4-Fluorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter synthesis of the compound of Example 5:
[First step]
Synthesis of ethyl 1- (4-fluorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (hereinafter referred to as reference compound 4):
Dimethylformaldehyde dimethyl acetal (0.76 mL, 5.7 mmol) was added to ethyl 4-methyl-3-oxopentanoate (0.30 g, 1.9 mmol), and the mixture was stirred at 100 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), 4-fluorophenylhydrazine hydrochloride (0.31 g, 1.9 mmol) and triethylamine (0.79 mL, 5.7 mmol) were added, and the mixture was stirred at 80 ° C. After 2 hours, it was cooled to room temperature and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 0.38 g (73%) of the title compound as a yellow liquid.

[Second step]
Synthesis of 1- (4-fluorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 5):
To a solution of ethyl 1-isopropyl-5- (4-fluorophenyl) -1H-pyrazole-4-carboxylate (0.38 g, 1.4 mmol) in methanol (8 mL) is added 1N NaOH (2.8 mL, 2.8 mmol). And stirred at 60 ° C. After 2 hours, the mixture was cooled to room temperature, 1N HCl (2.8 mL, 2.8 mmol) was added, and the mixture was concentrated. The obtained crude product was chloroform (15 mL), trans-5-hydroxy-2-adamantylamine (0.23 g, 1.4 mmol), diisopropylethylamine (0.73 mL, 4.2 mmol), HBTU (0.53 g, 1.4 mmol) was added and stirred at room temperature. After 60 hours, the crude product obtained by concentration was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain 0.065 g (12%) of the title compound as a white solid.

(Example 6)
Synthesis of 5-cyclopentyl-1-phenyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 6):
[First step]
Synthesis of ethyl 5-cyclopentyl-1-phenyl-1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 5):
Dimethylformaldehyde dimethyl acetal (0.65 mL, 4.9 mmol) was added to ethyl 3-cyclopentyl-3-oxopropanoate (0.30 g, 1.6 mmol), and the mixture was stirred at 100 ° C. After 1 hour, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), phenylhydrazine hydrochloride (0.24 g, 1.6 mmol) and triethylamine (0.68 mL, 4.9 mmol) were added, and the mixture was stirred at 80 ° C. After 2 hours, it was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 0.43 g (93%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 6:
1N NaOH (3.1 mL, 3.1 mmol) was added to a solution of ethyl 5-cyclopentyl-1-phenyl-1H-pyrazole-4-carboxylate (0.43 g, 1.5 mmol) in methanol (8 mL) at 60 ° C. Stir with. After 2 hours, the mixture was cooled to room temperature, and 1N HCl (3.1 mL, 3.1 mmol) was added and concentrated. The obtained crude product was chloroform (15 mL), trans-5-hydroxy-2-adamantylamine (0.25 g, 1.5 mmol), diisopropylethylamine (0.80 mL, 4.6 mmol), HBTU (0.58 g, 1.5 mmol) was added and stirred at room temperature. After 60 hours, the crude product obtained by concentration was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain 0.17 g (28%) of the title compound as a white solid.

(Example 7)
Synthesis of 5- (tert-butyl) -1-phenyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 7):
[First step]
Synthesis of methyl 5- (tert-butyl) -1-phenyl-1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 6):
Dimethylformaldehyde dimethyl acetal (7.6 mL, 57 mmol) was added to methyl 4,4-dimethyl-3-oxopentanoate (3.0 g, 19 mmol), and the mixture was stirred at 100 ° C. After 4 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (50 mL), phenylhydrazine (2.1 g, 19 mmol) was added, and the mixture was stirred at 80 ° C. After 5 hours, the mixture was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 1.6 g (32%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 7:
To a solution of methyl 5- (tert-butyl) -1-phenyl-1H-pyrazole-4-carboxylate (1.6 g, 6.1 mmol) in methanol (80 mL) was added 1N NaOH (12 mL, 12 mmol), NaOH (0. 73 g, 18 mmol) was added and stirred at 80 ° C. After 2 hours, the mixture was cooled to room temperature, 1N HCl was added to adjust to pH = 4, and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The obtained crude product was chloroform (30 mL), trans-5-hydroxy-2-adamantylamine (0.67 g, 4.0 mmol), diisopropylethylamine (1.7 mL, 10 mmol), HBTU (1.5 g, 4. mmol). 0 mmol) was added and stirred at room temperature. After 11 hours, 1N HCl was added and extracted with chloroform. The organic layer was dried and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to chloroform / methanol = 10/1) to give 0.83 g (42%) of the title compound as a white solid (non-crystal). Obtained.

(Example 8)
Synthesis of 1- (3-chlorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 8):
[First step]
Synthesis of ethyl 1- (3-chlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 7):
Dimethylformaldehyde dimethyl acetal (4.2 mL, 32 mmol) was added to ethyl 4-methyl-3-oxopentanoate (1.0 g, 6.3 mmol), and the mixture was stirred at 90 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (32 mL), 3-chlorophenylhydrazine sulfate (1.5 g, 6.3 mmol) was added, and the mixture was stirred at 80 ° C. After 2 hours, 1N HCl (6.3 mL, 6.3 mmol) was added and stirred again at 80 ° C. After 2 hours, the mixture was cooled to room temperature, concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 96/4 to 86/14) to obtain 1.8 g (97%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 8:
To a solution of ethyl 1- (3-chlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (1.8 g, 6.1 mmol) in methanol (18 mL) was added 1N NaOH (18 mL, 18 mmol) and 50 ° C. Stir with. After 5 hours, the mixture was concentrated and extracted with chloroform. Then, 1N HCl was added to the aqueous layer to adjust to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was mixed with chloroform (14 mL), trans-5-hydroxy-2-adamantylamine (1.0 g, 6.1 mmol), diisopropylethylamine (3.2 mL, 18 mmol), HBTU (1.4 g, 6 0.1 mmol) and stirred at room temperature. After 14 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 97/3) to obtain 0.81 g (32%) of the title compound as a white solid (non-crystal).

Example 9
Synthesis of 1- (3-fluorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 9):
[First step]
Synthesis of ethyl 1- (3-fluorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 8):
Dimethylformaldehyde dimethyl acetal (4.2 mL, 32 mmol) was added to ethyl 4-methyl-3-oxopentanoate (1.0 g, 6.3 mmol), and the mixture was stirred at 90 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (32 mL), 3-fluorophenylhydrazine hydrochloride (1.0 g, 6.3 mmol) was added, and the mixture was stirred at 80 ° C. After 2 hours, 1N HCl (6.3 mL, 6.3 mmol) was added and stirred again at 80 ° C. After 2 hours, the mixture was cooled to room temperature, concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 96/4 to 86/14) to obtain 1.5 g (88%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 9:
To a solution of ethyl 1- (3-fluorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (1.5 g, 5.5 mmol) in methanol (18 mL) was added 1N NaOH (18 mL, 18 mmol) and 50 Stir at ° C. After 5 hours, the mixture was concentrated and extracted with chloroform. Then, 1N HCl was added to the aqueous layer to adjust to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by using chloroform (14 mL), trans-5-hydroxy-2-adamantylamine (1.0 g, 6.2 mmol), diisopropylethylamine (3.2 mL, 18 mmol), HBTU (1.4 g, 6 0.2 mmol) and stirred at room temperature. After 14 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 97/3) to obtain 0.60 g (27%) of the title compound as a white solid.

(Example 10)
Synthesis of 1- (2-fluorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 10):
[First step]
Synthesis of ethyl 1- (2-fluorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (hereinafter referred to as reference compound 9):
Dimethylformaldehyde dimethyl acetal (4.2 mL, 32 mmol) was added to ethyl 4-methyl-3-oxopentanoate (1.0 g, 6.3 mmol), and the mixture was stirred at 90 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (32 mL), 2-fluorophenylhydrazine hydrochloride (1.0 g, 6.3 mmol) was added, and the mixture was stirred at 80 ° C. After 2 hours, 1N HCl (6.3 mL, 6.3 mmol) was added and stirred again at 80 ° C. After 2 hours, the mixture was cooled to room temperature, concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 96/4 to 86/14) to obtain 1.5 g (88%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 10:
To a solution of ethyl 1- (2-fluorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (1.5 g, 5.5 mmol) in methanol (18 mL) was added 1N NaOH (18 mL, 18 mmol) and 50 Stir at ° C. After 5 hours, the mixture was concentrated and extracted with chloroform. Then, 1N HCl was added to the aqueous layer to adjust to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was mixed with chloroform (14 mL), trans-5-hydroxy-2-adamantylamine (1.0 g, 6.2 mmol), diisopropylethylamine (3.2 mL, 18 mmol), HBTU (1.5 g, 6 0.2 mmol) and stirred at room temperature. After 14 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 97/3) to obtain 0.70 g (32%) of the title compound as a white solid.

(Example 11)
Synthesis of 5-isopropyl-1- (4-methoxyphenyl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 11):
[First step]
Synthesis of ethyl 5-isopropyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 10):
Dimethylformaldehyde dimethyl acetal (0.76 mL, 5.7 mmol) was added to ethyl 4-methyl-3-oxopentanoate (0.30 g, 1.9 mmol), and the mixture was stirred at 100 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), 4-methoxyphenylhydrazine hydrochloride (0.33 g, 1.9 mmol) and triethylamine (0.79 mL, 5.7 mmol) were added, and the mixture was stirred at 80 ° C. After 2 hours, it was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 0.44 g (80%) of the title compound as a yellow solid.

[Second step]
Synthesis of the compound of Example 11:
To a solution of ethyl 5-isopropyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxylate (0.44 g, 1.5 mmol) in methanol (8 mL) was added 1N NaOH (3.1 mL, 3.1 mmol). And stirred at 80 ° C. After 2 hours, NaOH (0.25 g, 6.3 mmol) was added, and the mixture was further stirred at 80 ° C. for 1 hour. After cooling to room temperature, 1N HCl was added to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The obtained crude product was chloroform (5 mL), trans-5-hydroxy-2-adamantylamine (0.26 g, 1.5 mmol), diisopropylethylamine (0.80 mL, 4.6 mmol), HBTU (0.58 g, 1.5 mmol) was added and stirred at room temperature. After 12 hours, 1N HCl was added and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 0.59 g (94%) of the title compound as a white solid.

(Example 12)
5-isopropyl-1- (3- (trifluoromethyl) phenyl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter referred to as the compound of Example 12) Synthesis:
[First step]
Synthesis of ethyl 5-isopropyl-1- (3- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 11):
Dimethylformaldehyde dimethyl acetal (0.76 mL, 5.7 mmol) was added to ethyl 4-methyl-3-oxopentanoate (0.30 g, 1.9 mmol), and the mixture was stirred at 100 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), 3- (trifluoromethyl) phenylhydrazine (0.33 g, 1.9 mmol) and triethylamine (0.79 mL, 5.7 mmol) were added, and the mixture was stirred at 80 ° C. did. After 2 hours, it was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 0.46 g (74%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 12:
To a solution of ethyl 5-isopropyl-1- (3- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxylate (0.46 g, 1.4 mmol) in methanol (8 mL) was added 1N NaOH (2.8 mL, 2.8 mmol) was added and stirred at 80 ° C. After 2 hours, NaOH (0.25 g, 6.3 mmol) was added, and the mixture was further stirred at 80 ° C. for 1 hour. After cooling to room temperature, 1N HCl was added to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The obtained crude product was mixed with chloroform (5 mL), trans-5-hydroxy-2-adamantylamine (0.24 g, 1.4 mmol), diisopropylethylamine (0.74 mL, 4.2 mmol), HBTU (0.53 g, 1.4 mmol) was added and stirred at room temperature. After 12 hours, 1N HCl was added and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 0.59 g (95%) of the title compound as a white solid.

(Example 13)
Synthesis of 5-isopropyl-1- (meth-tolyl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 13):
[First step]
Synthesis of ethyl 5-isopropyl-1- (meth-tolyl) -1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 12):
Dimethylformaldehyde dimethyl acetal (0.76 mL, 5.7 mmol) was added to ethyl 4-methyl-3-oxopentanoate (0.30 g, 1.9 mmol), and the mixture was stirred at 100 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), 3-tolylhydrazine hydrochloride (0.30 g, 1.9 mmol) and triethylamine (0.79 mL, 5.7 mmol) were added, and the mixture was stirred at 80 ° C. After 2 hours, it was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 0.40 g (77%) of the title compound as a yellow solid.

[Second step]
Synthesis of 5-isopropyl-1- (meth-tolyl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 13):
To a solution of ethyl 5-isopropyl-1- (meth-tolyl) -1H-pyrazole-4-carboxylate (0.40 g, 1.5 mmol) in methanol (8 mL) was added 1N NaOH (2.9 mL, 2.9 mmol). In addition, the mixture was stirred at 80 ° C. After 2 hours, NaOH (0.25 g, 6.3 mmol) was added, and the mixture was further stirred at 80 ° C. for 1 hour. After cooling to room temperature, 1N HCl was added to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The obtained crude product was diluted with chloroform (5 mL), DMF (2 mL), trans-5-hydroxy-2-adamantylamine (0.24 g, 1.5 mmol), diisopropylethylamine (0.80 mL, 4.4 mmol), HBTU. (0.55 g, 1.5 mmol) was added and stirred at room temperature. After 12 hours, 1N HCl was added and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 0.51 g (88%) of the title compound as a white solid.

(Example 14)
Synthesis of 5-isopropyl-1- (2-methoxyphenyl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 14):
[First step]
Synthesis of ethyl 5-isopropyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 13):
Dimethylformaldehyde dimethyl acetal (0.76 mL, 5.7 mmol) was added to ethyl 4-methyl-3-oxopentanoate (0.30 g, 1.9 mmol), and the mixture was stirred at 100 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), 2-methoxyphenylhydrazine hydrochloride (0.33 g, 1.9 mmol) and triethylamine (0.79 mL, 5.7 mmol) were added, and the mixture was stirred at 80 ° C. After 9 hours, the mixture was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 0.37 g (68%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 14:
To a solution of ethyl 5-isopropyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxylate (0.37 g, 1.3 mmol) in methanol (8 mL) was added 1N NaOH (2.6 mL, 2.6 mmol). And stirred at 80 ° C. After 2 hours, NaOH (0.25 g, 6.3 mmol) was added, and the mixture was further stirred at 80 ° C. for 1 hour. After cooling to room temperature, 1N HCl was added to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The obtained crude product was diluted with chloroform (5 mL), DMF (2 mL), trans-5-hydroxy-2-adamantylamine (0.22 g, 1.3 mmol), diisopropylethylamine (0.70 mL, 3.9 mmol), HBTU. (0.49 g, 1.3 mmol) was added and stirred at room temperature. After 12 hours, 1N HCl was added and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 0.53 g (100%) of the title compound as a white solid.

(Example 15)
5-isopropyl-1- (2- (trifluoromethyl) phenyl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter referred to as the compound of Example 15) Synthesis:
[First step]
Synthesis of ethyl 5-isopropyl-1- (2- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 14):
Dimethylformaldehyde dimethyl acetal (0.76 mL, 5.7 mmol) was added to ethyl 4-methyl-3-oxopentanoate (0.30 g, 1.9 mmol), and the mixture was stirred at 100 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), and 2- (trifluoromethyl) phenylhydrazine hydrochloride (0.40 g, 1.9 mmol) and triethylamine (0.79 mL, 5.7 mmol) were added thereto at 80 ° C. Stir with. After 9 hours, the mixture was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to obtain 0.40 g (65%) of the title compound as a yellow solid.

[Second step]
Synthesis of the compound of Example 15:
To a solution of ethyl 5-isopropyl-1- (2- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxylate (0.40 g, 1.2 mmol) in methanol (8 mL) was added 1N NaOH (2.5 mL, 2.5 mmol) was added and stirred at 80 ° C. After 2 hours, NaOH (0.25 g, 6.3 mmol) was added, and the mixture was further stirred at 80 ° C. for 1 hour. After cooling to room temperature, 1N HCl was added to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The obtained crude product was diluted with chloroform (5 mL), DMF (2 mL), trans-5-hydroxy-2-adamantylamine (0.21 g, 1.2 mmol), diisopropylethylamine (0.64 mL, 3.7 mmol), HBTU. (0.47 g, 1.2 mmol) was added and stirred at room temperature. After 12 hours, 1N HCl was added and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 8/1) to obtain 0.48 g (87%) of the title compound as a white solid.

(Example 16)
5-Isopropyl-1- (ortho-tolyl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter synthesis of the compound of Example 16:
[First step]
Synthesis of ethyl 5-isopropyl-1- (ortho-tolyl) -1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 15):
Dimethylformaldehyde dimethyl acetal (0.76 mL, 5.7 mmol) was added to ethyl 4-methyl-3-oxopentanoate (0.30 g, 1.9 mmol), and the mixture was stirred at 100 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), ortho-tolylhydrazine hydrochloride (0.30 g, 1.9 mmol) and triethylamine (0.79 mL, 5.7 mmol) were added, and the mixture was stirred at 80 ° C. After 9 hours, the mixture was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 0.27 g (52%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 16:
To a solution of ethyl 5-isopropyl-1- (ortho-tolyl) -1H-pyrazole-4-carboxylate (0.27 g, 0.99 mmol) in methanol (8 mL) was added 1N NaOH (2.0 mL, 2.0 mmol). In addition, the mixture was stirred at 80 ° C. After 2 hours, NaOH (0.25 g, 6.3 mmol) was added, and the mixture was further stirred at 80 ° C. for 1 hour. After cooling to room temperature, 1N HCl was added to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The obtained crude product was diluted with chloroform (5 mL), DMF (2 mL), trans-5-hydroxy-2-adamantylamine (0.17 g, 0.99 mmol), diisopropylethylamine (0.52 mL, 3.0 mmol), HBTU. (0.37 g, 0.99 mmol) was added and stirred at room temperature. After 12 hours, 1N HCl was added and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 0.39 g (100%) of the title compound as a white solid.

(Example 17)
Synthesis of 1- (2-chlorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, the compound of Example 17):
[First step]
Synthesis of ethyl 1- (2-chlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 16):
Dimethylformaldehyde dimethyl acetal (4.2 mL, 32 mmol) was added to ethyl 4-methyl-3-oxopentanoate (1.0 g, 6.3 mmol), and the mixture was stirred at 90 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (32 mL), 2-chlorophenylhydrazine hydrochloride (1.1 g, 6.3 mmol) was added, and the mixture was stirred at 80 ° C. After 2 hours, 1N HCl (6.3 mL, 6.3 mmol) was added and stirred again at 80 ° C. After 2 hours, the mixture was cooled to room temperature, concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 96/4 to 86/14) to obtain 1.7 g (95%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 17:
To a solution of ethyl 1- (2-chlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (1.7 g, 5.9 mmol) in methanol (18 mL) was added 1N NaOH (18 mL, 18 mmol) at 50 ° C. Stir with. After 4 hours, the mixture was concentrated and extracted with chloroform. Then, 1N HCl was added to the aqueous layer to adjust to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was chloroform (14 mL), trans-5-hydroxy-2-adamantylamine (0.99 g, 5.9 mmol), diisopropyethylamine (3.1 mL, 18 mmol), HBTU (1.4 g, 5 0.9 mmol) and stirred at room temperature. After 14 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 97/3) to obtain 0.89 g (36%) of the title compound as a white solid.

(Example 18)
1-phenyl-5- (2-hydroxypropan-2-yl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter referred to as the compound of Example 18) Synthesis:
[First step]
Synthesis of ethyl 4- (benzyloxy) -4-methyl-3-oxopentanoate (hereinafter referred to as Reference Compound 17):
Ethyl 2-hydroxy-2-methylpropanoate (1.0 g, 7.6 mmol) in DMF (7.6 mL) was added to sodium hydride (0.40 g, 9.1 mmol), benzyl bromide (0.86 mL, 7.2 mmol) was added and stirred at room temperature. After 1 hour, water was added to the reaction solution and extracted with diethyl ether. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was dissolved in methanol (20 mL), 1N NaOH (21 mL, 21 mmol) was added, and the mixture was stirred at room temperature. After 16 hours, 1N HCl (25 mL, 25 mmol) was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was dissolved in acetonitrile (40 mL), carbonyldiimidazole (1.2 g, 7.6 mmol) was added, and the mixture was stirred at room temperature (this is liquid A). Magnesium chloride (4.1 g, 32 mmol) was dissolved in acetonitrile (20 mL), ethyl potassium malonate (2.6 g, 15 mmol) and triethylamine (10 mL, 72 mmol) were added, and the mixture was stirred at room temperature. To do). After 2 hours, solution A was added to solution B and stirred at 90 ° C. After 2 hours, the mixture was cooled to room temperature, 1N HCl was added, and the mixture was stirred at room temperature. After 1 hour, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 96/4 to 86/14) to obtain 1.3 g (68%) of the title compound as a yellow liquid.

[Second step]
Synthesis of ethyl 1-phenyl-5- (2- (benzyloxy) propan-2-yl) -1H-pyrazole-4-carboxylate (hereinafter referred to as reference compound 18):
Dimethylformaldehyde dimethyl acetal (2.7 mL, 20 mmol) was added to ethyl 4- (benzyloxy) -4-methyl-3-oxopentanoate (1.1 g, 4.0 mmol), and the mixture was stirred at 80 ° C. After 6 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (34 mL), phenylhydrazine (0.35 mL, 3.6 mmol) was added, and the mixture was stirred at 80 ° C. After 4 hours, the mixture was cooled to room temperature, 1N HCl (6.3 mL, 6.3 mmol) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0-60 / 40) to obtain 0.70 g (56%) of the title compound as a yellow liquid.

[Third step]
Synthesis of the compound of Example 18:
Ethyl 1-phenyl-5- (2- (benzyloxy) propyl-2-yl) -1H-pyrazole-4-carboxylate (0.20 g, 0.55 mmol) was dissolved in methanol (1.8 mL), and 1N NaOH (1.3 mL, 1.3 mmol) was added and stirred at 50 ° C. After 6 hours, 1N HCl (2.0 mL, 2.0 mmol) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated, and the resulting crude product was chloroform (5.5 mL). In the mixture, trans-5-hydroxy-2-adamantylamine (0.10 g, 0.60 mmol), diisopropylethylamine (0.35 mL, 2.0 mmol) and HBTU (0.31 g, 82 mmol) were added and stirred at room temperature. did. After 16 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was dissolved in ethanol (5.0 mL), palladium hydroxide (0.073 g, 0.52 mmol) was added, and the mixture was stirred at room temperature in a hydrogen atmosphere. After 2 hours, the reaction solution was filtered through Celite, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (chloroflum / methanol = 100/0 to 80/20) to obtain 0.16 g (76%) of the title compound as a white solid.

(Example 19)
1-phenyl-5- (1-hydroxypropan-2-yl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter referred to as the compound of Example 19) Synthesis:
[First step]
Synthesis of ethyl 1-phenyl-5- (1- (4-methoxybenzyloxy) propan-2-yl) -1H-pyrazole-4-carboxylate (hereinafter referred to as reference compound 19):
Methyl 3-hydroxy-2-methylpropanoate (0.90 g, 7.6 mmol) was dissolved in dichloromethane (18 mL) and 1,1,1-trichloro-4- (4-methoxyphenyl) butan-2-imine was dissolved. (2.4 g, 8.4 mmol), 10-camphorsulfonic acid (0.18 g, 0.76 mmol) was added and stirred at room temperature. After 4 hours, the mixture was filtered, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was dissolved in methanol (47 mL), 1.5 N NaOH (7.8 mL, 12 mmol) was added, and the mixture was stirred at room temperature. After 16 hours, the mixture was concentrated and extracted with ethyl acetate. Then, 1N HCl was added to the aqueous layer to adjust to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated to give a crude product of 3- (4-methoxybenzyloxy) -2-methylpropanoyl acid. The obtained 3- (4-methoxybenzyloxy) -2-methylpropanoyl acid was dissolved in acetonitrile (12 mL), carbonyldiimidazole (1.0 g, 6.1 mmol) was added, and the mixture was stirred at room temperature. A liquid). Magnesium chloride (1.2 g, 13 mmol) was dissolved in acetonitrile (12 mL), ethyl potassium malonate (2.1 g, 12 mmol) and triethylamine (3.7 mL, 26 mmol) were added, and the mixture was stirred at room temperature. Liquid). After 2 hours, solution A was added to solution B and stirred at 90 ° C. After 4 hours, the mixture was cooled to room temperature, adjusted to pH = 5 with 1N HCl, stirred for 0.5 hours, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. Dimethylformamide dimethyl acetal (3.9 mL, 29 mmol) was added to the obtained crude product, and the mixture was stirred at 90 ° C. After 2 hours, it was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (58 mL), phenylhydrazine (1.1 mL, 12 mmol) was added, and the mixture was stirred at room temperature for 2 hours, and then stirred at 90 ° C. After 3 hours, 1N HCl was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 94/6 to 86/14) to obtain 1.2 g (40%) of the title compound.

[Second step]
Synthesis of 1-phenyl-5- (1- (4-methoxybenzyloxy) propan-2-yl) -1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 20):
Dissolve ethyl 1-phenyl-5- (1- (4-methoxybenzyloxy) propan-2-yl) -1H-pyrazole-4-carboxylate (0.2 g, 0.51 mmol) in methanol (2.5 mL). 1N NaOH (2.5 g, 2.5 mmol) was added and stirred at 60 ° C. After 6 hours, the mixture was concentrated and extracted with ethyl acetate. Then, 1N HCl was added to the aqueous layer to adjust to pH = 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 91/9 to 79/21) to obtain 0.14 g (76%) of the title compound.

[Third step]
1-phenyl-5- (1- (4-methoxybenzyloxy) propan-2-yl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter referred to as reference) Synthesis of compound 21):
To a chloroform solution (4.0 mL) of 1-phenyl-5- (1- (4-methoxybenzyloxy) propan-2-yl) -1H-pyrazole-4-carboxylate (0.38 g, 0.38 mmol) , Trans-5-hydroxy-2-adamantylamine (0.10 g, 0.38 mmol), diisopropylethylamine (0.20 mL, 1.1 mmol), HBTU (0.09 g, 0.38 mmol) were added and stirred at room temperature. . After 16 hours, water was added and extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 97/3) to obtain 0.16 g (81%) of the title compound as a white solid.

[Fourth step]
Synthesis of the compound of Example 19:
1-phenyl-5- (1- (4-methoxybenzyloxy) propan-2-yl) -N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (0.08 g , 0.16 mmol) in ethanol solution (1.5 mL), 20% palladium hydroxide-carbon (0.022 g, 0.032 mmol) was added and stirred at room temperature for 4 hours in a hydrogen atmosphere, and then stirred at 50 ° C. After 4 hours, the reaction solution was filtered through celite and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 93/7) to obtain 0.045 g (73%) of the title compound as a white solid.

(Example 20)
Synthesis of 1-phenyl-5-isopropyl-N- (trans-5-acetamidoadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter the compound of Example 20):
To a solution of 1-phenyl-5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (0.14 g, 0.37 mmol) in acetonitrile (3.7 mL), Concentrated sulfuric acid (0.019 mL, 0.37 mmol) was added and stirred at 70 ° C. After 4 hours, the mixture was cooled to room temperature, 1N NaOH (1.5 mL, 1.5 mmol) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 90/10) to obtain 0.14 g (88%) of the title compound as a white solid.

(Example 21)
Synthesis of 1-phenyl-5-isopropyl-N- (trans-5-carbamoyladamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter the compound of Example 21):
To a solution of 1-phenyl-5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (0.35 g, 0.92 mmol) in fuming sulfuric acid (7.5 mL) Formic acid (6.50 mL, 168 mmol) was added and stirred at 60 ° C. After 2 hours, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was dissolved in chloroform (3.1 mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.15 g, 0.80 mmol), 1-hydroxybenzotriazole (0 .12 g, 0.80 mmol) was added and stirred at room temperature. After 3 hours, an ammonia saturated chloroform solution (15 mL) was added, and the mixture was stirred at room temperature. After 16 hours, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 90/10) to obtain 0.33 g (89%) of the title compound as a white solid. It was.

(Example 22)
Synthesis of trans-4- (5-isopropyl-1-phenyl-1H-pyrazole-4-carboxamido) adamantane-1-carbamate (hereinafter the compound of Example 22):
Under an argon atmosphere, 1-phenyl-5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (0.50 g, 1.3 mmol) was added to THF (6.5 mL). ), Chlorosulfonyl isocyanate (0.13 mL, 1.5 mmol) was added, and the mixture was stirred at room temperature. After 4 hours, a saturated aqueous sodium carbonate solution was added to neutralize, and the mixture was stirred at room temperature for 1 hour, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 89/11) to obtain 0.099 g (18%) of the title compound as a white solid.

(Example 23)
Synthesis of 1- (3-chlorophenyl) -5-isopropyl-N- (trans-5- (aminocarbonyl) aminoadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter the compound of Example 23) :
trans-5- (1- (3-chlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxamido) adamantane-2-carboxylic acid (0.50 g, 1.1 mmol) was dissolved in dichloromethane (20 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.19 g, 1.2 mmol), 1-hydroxybenzotriazole monohydrate (0.17 g, 1.2 mmol), triethylamine (0.79 mL) 5.7 mmol) and stirred at room temperature. After 4 hours, a saturated ammonia-chloroform solution (5 mL) was added, and the mixture was further stirred for 3 hours. Distilled water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 91/9) to obtain 0.31 g (62%) of the title compound as a white solid (non-crystal).

(Example 24)
Synthesis of trans-4- (1- (3-chlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxamido) adamantane-1-carbamate (hereinafter the compound of Example 24):
1- (3-Chlorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (0.40 g, 0.97 mmol) in THF under argon atmosphere. (10 mL), chlorosulfonyl isocyanate (0.13 mL, 1.4 mmol) was added, and the mixture was stirred at room temperature. After 4 hours, a saturated aqueous sodium carbonate solution was added for neutralization, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 91/9) to obtain 0.29 g (66%) of the title compound as a white solid.

(Example 25)
Synthesis of 1- (3-chlorophenyl) -5-isopropyl-N- (trans-5-acetylaminoadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter the compound of Example 25):
1- (3-Chlorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (0.40 g, 0.97 mmol) in acetonitrile under an argon atmosphere (6 mL), concentrated sulfuric acid (3 mL) was added, and the mixture was stirred at room temperature. After 16 hours, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 96/4) to obtain 0.40 g (92%) of the title compound as a white solid.

(Example 26)
1- (2-Chloro-5-trifluoromethylphenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter the compound of Example 26) ) Synthesis:
[First step]
Synthesis of methyl 1- (2-chloro-5-trifluoromethylphenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (hereinafter referred to as reference compound 22):
Dimethylformaldehyde dimethyl acetal (0.33 mL, 2.5 mmol) was added to methyl 4-methyl-3-oxopentanoate (0.072 g, 0.50 mmol), and the mixture was stirred at 90 ° C. After 2 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), 2-chloro-5-trifluoromethylphenylhydrazine (0.11 g, 0.50 mmol) was added, and the mixture was stirred at 80 ° C. After 3 hours, it was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain 0.16 g (92%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 26:
To a solution of methyl 1- (2-chloro-5-trifluoromethylphenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (0.16 g, 0.46 mmol) in methanol (3 mL) was added 1N NaOH (1. 15 mL, 1.15 mmol) was added and stirred at 50 ° C. overnight. Thereafter, 1N NaOH (1.15 mL, 1.15 mmol) was further added, and the mixture was stirred at 50 ° C. After 3 hours, the mixture was cooled to room temperature, and 1N HCl (2.3 mL, 2.3 mmol) was added and concentrated. The obtained crude product was chloroform (5 mL), trans-5-hydroxy-2-adamantylamine (0.077 g, 0.46 mmol), diisopropylethylamine (0.12 mL, 0.69 mmol), HBTU (0.18 g, 0.46 mmol) was added and stirred at room temperature. After 20 hours, the crude product obtained by concentration was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain 0.20 g (88%) of the title compound as a white solid.

(Example 27)
1- (3,5-bistrifluoromethylphenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter referred to as the compound of Example 27) Synthesis:
[First step]
Synthesis of methyl 1- (3,5-bistrifluoromethylphenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 23):
Dimethylformaldehyde dimethyl acetal (0.33 mL, 2.5 mmol) was added to methyl 4-methyl-3-oxopentanoate (0.072 g, 0.50 mmol), and the mixture was stirred at 90 ° C. After 2 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), 3,5-bistrifluoromethylphenylhydrazine (0.12 g, 0.49 mmol) was added, and the mixture was stirred at 80 ° C. After 2.5 hours, it was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain 0.17 g (88%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 27:
To a solution of methyl 1- (3,5-bistrifluoromethylphenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (0.17 g, 0.44 mmol) in methanol (3 mL) was added 1N NaOH (1.11 mL, 1.11 mmol) was added and stirred at 50 ° C. for 4 hours. Thereafter, 1N NaOH (1.11 mL, 1.11 mmol) was further added, and the mixture was stirred at 50 ° C. After 4 hours, the mixture was cooled to room temperature, 1N HCl (2.22 mL, 2.22 mmol) was added, and the mixture was concentrated. The obtained crude product was mixed with chloroform (5 mL), trans-5-hydroxy-2-adamantylamine (0.074 g, 0.44 mmol), diisopropylethylamine (0.12 mL, 0.67 mmol), HBTU (0.17 g, 0.44 mmol) was added and stirred at room temperature. After 72 hours, the crude product obtained by concentration was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 0.22 g (94%) of the title compound as a white solid.

(Example 28)
1- (2-chloro-4-fluorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter the compound of Example 28) Synthesis:
[First step]
Synthesis of methyl 1- (2-chloro-4-fluorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 24):
Dimethylformaldehyde dimethyl acetal (0.33 mL, 2.5 mmol) was added to methyl 4-methyl-3-oxopentanoate (0.072 g, 0.50 mmol), and the mixture was stirred at 90 ° C. After 2 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), 2-chloro-4-fluorophenylhydrazine hydrochloride (0.099 g, 0.50 mmol) was added, and the mixture was stirred at 80 ° C. After 3 hours, it was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain 0.12 g (79%) of the title compound as a yellow liquid.

[Second step]
The following synthesis of the compound of Example 28:
To a solution of methyl 1- (2-chloro-4-fluorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (0.12 g, 0.39 mmol) in methanol (3 mL) was added 1N NaOH (0.99 mL, 0.99 mmol) was added and the mixture was stirred at 50 ° C. for 4 hours. Thereafter, 1N NaOH (0.99 mL, 0.99 mmol) was further added, and the mixture was stirred at 50 ° C. After 4 hours, the mixture was cooled to room temperature, 1N HCl (1.98 mL, 1.98 mmol) was added, and the mixture was concentrated. The obtained crude product was chloroform (5 mL), trans-5-hydroxy-2-adamantylamine (0.066 g, 0.39 mmol), diisopropylethylamine (0.10 mL, 0.59 mmol), HBTU (0.15 g, 0.39 mmol) was added and stirred at room temperature. After 72 hours, the crude product obtained by concentration was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 0.14 g (84%) of the title compound as a white solid.

(Example 29)
Synthesis of 1- (3,4-dichlorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter the compound of Example 29):
[First step]
Synthesis of methyl 1- (3,4-dichlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (hereinafter referred to as Reference Compound 25):
Dimethylformaldehyde dimethyl acetal (0.33 mL, 2.5 mmol) was added to methyl 4-methyl-3-oxopentanoate (0.072 g, 0.50 mmol), and the mixture was stirred at 90 ° C. After 2 hours, the reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethanol (5 mL), 3,4-dichlorophenylhydrazine hydrochloride (0.11 g, 0.50 mmol) was added, and the mixture was stirred at 80 ° C. After 2.5 hours, it was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain 0.14 g (91%) of the title compound as a yellow liquid.

[Second step]
Synthesis of the compound of Example 29:
To a solution of methyl 1- (3,4-dichlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylate (0.14 g, 0.46 mmol) in methanol (5 mL) is added 1N NaOH (2.29 mL, 2.29 mmol). ) And stirred at 50 ° C. overnight. Thereafter, 1N NaOH (1.15 mL, 1.15 mmol) was further added, and the mixture was stirred at 50 ° C. After 24 hours, the mixture was cooled to room temperature, 1N HCl (3.44 mL, 3.44 mmol) was added, and the mixture was concentrated. The obtained crude product was chloroform (5 mL), trans-5-hydroxy-2-adamantylamine (0.076 g, 0.46 mmol), diisopropylethylamine (0.12 mL, 0.69 mmol), HBTU (0.17 g, 0.46 mmol) was added and stirred at room temperature. After 72 hours, the crude product obtained by concentration was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 0.19 g (93%) of the title compound as a white solid.

(Comparative Example 1)
Synthesis of 1-phenyl-5-methyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (hereinafter, compound of Comparative Example 1):
To a solution of 1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid (0.10 g, 0.50 mmol) in chloroform (5 mL), trans-5-hydroxy-2-adamantylamine (0.083 g, 0 .50 mmol), diisopropyethylamine (0.26 mL, 1.5 mmol) and HBTU (0.12 g, 0.50 mmol) were added and stirred at room temperature. After 16 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 93/7) to obtain 0.11 g (61%) of the title compound as a white solid.

(Comparative Example 2)
Synthesis of trans-4- (1-phenyl-5-isopropyl-1H-pyrazole-4-carboxamido) adamantane-1-carboxylic acid (hereinafter, compound of Comparative Example 2):
Fuming sulfuric acid heated to 60 ° C. (8.4 mL) was added to 1-phenyl-5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide (0.20 g, 0.53 mmol) of formic acid (2 mL) was slowly added and stirred. After 4 hours, the reaction solution was cooled to 0 ° C., water was added, and the mixture was stirred at room temperature. After 16 hours, saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 3, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 91/9), and then slurry washed with ethyl acetate and hexane to give 0.016 g (7.0%) of the title compound. Was obtained as a white solid.

(Comparative Example 3)
Synthesis of trans-4- (1- (3-chlorophenyl) -5-isopropyl-1H-pyrazole-4-carboxamido) adamantane-1-carboxylic acid (hereinafter, compound of Comparative Example 3):
Fuming sulfuric acid (8.4 mL) heated to 60 ° C. was added to 1- (3-chlorophenyl) -5-isopropyl-N- (trans-5-hydroxyadamantan-2-yl) -1H-pyrazole-4-carboxamide ( 1.0 g, 2.4 mmol) of formic acid (8.4 mL) was slowly added and stirred. After 4 hours, the reaction solution was cooled to 0 ° C., water was added, and the mixture was stirred at room temperature. After 1 hour, saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 3, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 75/25) to obtain 1.0 g (96%) of the title compound as a white solid.

(Comparative Example 4)
Synthesis of 4- (4-((5-hydroxyadamantan-2-yl) carbamoyl) -5-isopropyl-1H-pyrazol-1-yl) benzoic acid (hereinafter, compound of Comparative Example 4):
[First step]
Synthesis of N- (5-hydroxyadamantan-2-yl) -4-methyl-3-oxopentanamide (hereinafter referred to as Reference Compound 26):
To a solution of methyl 4-methyl-3-oxopentanoate (1.7 mL, 12 mmol) in toluene (18 mL) was added trans-5-hydroxy-2-adamantylamine (2.0 g, 12 mmol), and the mixture was stirred at 90 ° C. . After 16 hours, the reaction solution was cooled to room temperature, 1N HCl was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10-70 / 30) to obtain 0.90 g (36%) of the title compound as a white solid.

[Second step]
Synthesis of methyl 4- (4-((5-hydroxyadamantan-2-yl) carbamoyl) -5-isopropyl-1H-pyrazol-1-yl) benzoate (hereinafter reference compound 27):
Dimethylformamide dimethyl acetal (2.2 mL, 16 mmol) was added to N- (5-hydroxyadamantan-2-yl) -4-methyl-3-oxopentanamide (0.90 g, 3.22 mmol), and the mixture was stirred at 90 ° C. did. After 5 hours, the reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried and concentrated. Ethanol (10 mL) and 4-hydrazinobenzoic acid methyl ester hydrochloride (0.38 g, 1.9 mmol) were added to the obtained crude product, and the mixture was stirred at 80 ° C. After 35 hours, the reaction solution was cooled to room temperature, 1N HCl was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10-50 / 50) to give 0.48 g (59%) of the title compound as a white solid.

[Third step]
Synthesis of the compound of Comparative Example 4:
Methyl 4- (4-((5-hydroxyadamantan-2-yl) carbamoyl) -5-isopropyl-1H-pyrazol-1-yl) benzoate (0.48 g, 1.1 mmol) in methanol (10 mL), 1N NaOH (5.5 mL, 5.55 mmol) was added and the mixture was stirred at 80 ° C. After 2 hours, the reaction solution was cooled to room temperature, concentrated with 1N HCl. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol = 90/10) to obtain 0.38 g (81%) of the title compound as a white solid.

  Tables 18 to 20 show the compounds of Examples 1 to 29, Tables 21 to 23 show the reference compounds 1 to 27, and Table 24 shows the structural formulas, 1H-NMR data, and mass spectrometry data of the compounds of Comparative Examples 1 to 4, respectively. .

Example 30 11β-HSD1 Inhibition Experiment: Cell-free Evaluation System Using a cell extract (hereinafter “lysate”) prepared by transiently introducing a human 11β-HSD1 gene expression vector into HEK293H cells (Invitrogen) The 11β-HSD1 inhibitory action of the pyrazole derivative of the present invention or a pharmaceutically acceptable salt thereof (hereinafter referred to as “compound group of examples”) was evaluated.

1. Test method a. Enzyme source M.M. A. G. A DNA fragment containing human 11β-HSD1 was amplified by PCR using plasmid DNA containing human 11β-HSD1 (inserted into pCMV-SPORT6 vector) prepared from E clone (clone ID: 5193867, Invitrogen) as a template. And subcloned into pTA2 (Toyobo). A positive clone which was confirmed to have no mutation by analyzing the nucleotide sequence was cleaved with restriction enzymes XhoI and XbaI, and a DNA fragment containing human 11β-HSD1 was inserted into the XhoI and XbaI cleavage sites of pCI-neo (Promega). A human 11β-HSD1 gene expression vector h11β-HSD1 / pCI-neo was obtained.

Cell lysate was prepared by the following method. The number of HEK293H cells was counted, seeded at 2 × 10 ⁶ cells / 5 mL / 6 cm dish, and cultured overnight at 37 ° C. in a 5% CO ₂ incubator. On the second day, the culture solution was changed (2 mL culture solution / dish), and h11β-HSD1 / pCI-neo was transfected into the cells using FuGENE HD Transfection Reagent (Roche Applied Science). Transfection was performed according to the preparation method attached to the reagent. That is, 5.0 μg of h11β-HSD1 / pCI-neo per dish was prepared in an amount of 50 μL using Opti-MEM (Invitrogen) in a tube, and 20 μL of FuGENE HD Transfection Reagent was added thereto at room temperature. After allowing to stand for minutes, the mixture was added to the cells, and cultured overnight in an incubator at 37 ° C. and 5% CO ₂ . On day 3, the cells were suspended in PBS and collected in a tube, and centrifuged at 1,000 rpm for 5 minutes at 4 ° C. The supernatant was removed and the cell mass was frozen with liquid nitrogen. Cells were suspended in 200 μL of lysis buffer (0.25 mol / L sucrose, 1 mmol / L EDTA · 2Na, 10 mmol / L Tris-HCl, pH 7.4, 1% protease inhibitor cocktail) per plate, and freeze-thawed 3 times. Repeatedly. Protein quantification was performed by Bradford method using protein assay (Bio-Rad), glycerol was added to 10% glycerol, and the sample was stored frozen at −80 ° C. until use.

b. Enzyme inhibition experiment The reaction was carried out using a 384 well black plate (Corning). The test compound was prepared to 100 times the final concentration in DMSO and diluted to 8 times the final concentration in assay buffer (20 mmol / L HEPES (pH 6.0), 5 mmol / L EDTA, 0.1% BSA). . 12 μL of human 11β-HSD1-expressing cell lysate (final protein concentration 100-200 μg / mL) diluted to 2.67 times the final concentration in assay buffer was added to a 96-well V-bottom plate, and assay buffer or diluted test was added thereto 4 μL of the compound solution was added and incubated at 37 ° C. for 10 minutes. Coenzyme NADPH (final concentration 0.2 mmol / L, sigma) and cortisone (final concentration 200 nmol / L, sigma) were each diluted to 4 times the final concentration in the assay buffer and mixed in equal amounts, and the substrate was mixed. 5 μL of the solution was added to a 384 well black plate. 5 μL of preincubated lysate was added to the 384 well black plate and incubated at 37 ° C. for 2 hours. Cortisol produced was detected using Cortisol kit, and 5 μL each of anti-cortisol cryptate and cortisol-XL665 was added and incubated at room temperature for 2 hours, followed by fluorescence of the reaction solution (excitation wavelength 340 nm, fluorescence wavelength) 615 nm and 665 nm) were measured using a multi-label reader (Arvo SX, Perkin Elmer). A calibration curve for cortisol was prepared, and the concentration of cortisol converted from cortisone in the sample was calculated.

From the measurement results, the inhibition rate (% of inhibition) was determined for each concentration of each test compound. The method for obtaining the inhibition rate is shown below.
Ratio = (A _{665 nm} / B _{615 nm} ) × 10 ⁴
A _{665 nm} : measured value at ₆₆₅ nm, B _{615 nm} : measured value at ₆₁₅ nm Inhibition rate (% of inhibition) = ((Ratio of test compound−Ratio without test compound) / (Ratio without cell lysate and without test compound) -Ratio without test compound))) x 100

2. Results The compound concentration that inhibits the enzyme activity by 50% was calculated as the IC ₅₀ value. The results are shown in Table 25. The compound group of the Example shown in Table 25 showed strong 11 (beta) -HSD1 inhibitory activity. On the other hand, the compounds of Comparative Examples 1 to 4 used as comparative control compounds showed only a slight 11β-HSD1 inhibitory activity.

(Example 31) 11β-HSD1 inhibition experiment (cell evaluation system)
Using the human 11β-HSD1 gene stable expression cell line, the 11β-HSD1 inhibitory action of the compound group of the example was evaluated.

1. Test method a. Human 11β-HSD1 gene stable expression cell line A stable expression cell line was established by the following method. The cells were rat liver cancer cell line H4-II-E-C3 (American Type Culture Collicon (ATCC)), and MEM containing 10% FBS, 0.1 mmol / L Non essential amino acid and 1 mmol / L sodium pyruvate. The medium was subcultured in a CO ₂ incubator as a medium. The cells were seeded in a 3.5 cm dish at 0.8 or 1.0 × 10 ⁶ cells / 2 mL culture solution / dish, and cultured overnight at 37 ° C. in a 5% CO ₂ incubator. On the second day, the culture solution was changed (2 mL culture solution / dish), and h11β-HSD1 / pCI-neo was transfected. Transfection was performed by the following preparation method. Prepare 0.5 μg of h11β-HSD1 / pCI-neo and 2.5 μL of FuGENE HD Transfection Reagent per dish in 25 μL using Opti-MEM (Invitrogen) in a tube, and let stand at room temperature for 20 minutes. The mixed solution was added to the solution, and the cells were cultured in an incubator at 37 ° C. and 5% CO ₂ for 2 days. The cells were washed with PBS, peeled with trypsin / EDTA, suspended in 10 mL of medium, and G418 was added to 0.5 or 0.6 mg / mL. The culture solution was changed every few days, and the cell mass that became G418 resistant was picked up from the culture plate using a 20 μL pipetman to obtain human 11β-HSD1 gene stably expressing cells.

b. Measurement of 11β-HSD1 activity To evaluate 11β-HSD1 activity, cortisone was added to cells stably expressing human 11β-HSD1 gene seeded in a 96-well plate, and the amount of cortisol produced in the culture supernatant was used as an index. First, cells were seeded on a first day in a 96-well plate at 1.2 × 10 ⁵ cells / well, and after 7 hours, the medium was serum-free medium (MEM, 1% Non essential amino acid, 1 mmol / L sodium pyruvate). And 0.1% BSA) and cultured overnight. On the second day, the cells were washed with PBS and then replaced with glucose-free and phenol red-free DMEM medium (Sigma; D-5030) supplemented with 100 nmol / L cortisone and 20 mmol / L sodium pyruvate for 4 hours. Cultured. Test compounds were pre-diluted (0.1% DMSO) to the final concentration in the aforementioned medium and treated. 10 μL / well of culture supernatant was collected and used as a sample. Cortisol produced was detected using Cortisol kit, and 5 μL each of anti-cortisol cryptate and cortisol-XL665 was added and incubated at room temperature for 2 hours, followed by fluorescence of the reaction solution (excitation wavelength 340 nm, fluorescence wavelength) 615 nm and 665 nm) were measured using a multi-label reader (Arvo SX, Perkin Elmer). A calibration curve for cortisol was prepared, and the concentration of cortisol converted from cortisone in the sample was calculated. The inhibition rate of the test compound was expressed as an inhibition rate (% of inhibition) with 100% activity when no test compound was added and no cortisone was added, and 0% activity when no test compound was added and when cortisone was added.

2. Results The compound concentration that inhibits the enzyme activity by 50% was calculated as the IC ₅₀ value. The results are shown in Table 26. The compound group of the Example shown in Table 26 showed strong 11 (beta) -HSD1 inhibitory activity. On the other hand, the compound of Comparative Example 4 used as a comparative control compound showed only a slight 11β-HSD1 inhibitory activity.

(Example 32) Insulin resistance improving action and effect on body weight in pathological model Using mouse DIO (Diet induced-obesity) model (hereinafter "DIO mouse"), improvement of insulin resistance of compound group of Example The effect was evaluated.

1. Test method C57BL / 6N mice (male, Japanese Charles River) are received at the age of 4 weeks, fed with a normal diet (CRF-1) for 1 week, and then a solid diet containing 60% fat (D12492, Research Diet) or They were bred for 12 to 13 weeks on normal feed.

  The compound group of Example and pioglitazone were suspended in 0.5% methylcellulose (MC) using an agate mortar to 1 or 3 mg / mL. The drug solution for administration was prepared at the time of use, and was administered using a disposable syringe (1 mL size, Terumo) and a sonde for oral administration. The administered drug solution was dosed at 10 or 30 mg / kg once a day in the evening by gavage without anesthesia. The control vehicle group received 0.5% MC. The administration start day was set as day 0 and administration was continued until day 13. The grouping was performed so that the weights of each group (n = 8) were equal on the day before the start of administration (day -1). DIO mice bred with a solid feed containing 60% fat were subject to grouping of individuals whose body weights were within the mean value ± 2SD (standard deviation). The mice of a normal feed mouse group (hereinafter referred to as “normal group”) were weighed, and 8 mice were randomly selected for the experiment. The body weight was measured every day until the 13th day.

  On the morning of the 14th day, blood was collected from a mouse that had been fasted overnight in a five-fold fast cage. For blood, the mouse tail vein (about 3 cm from the tip of the tail) was injured with a lancet (MEDIpoint), injection needle or equivalent, and collected from the same site using a heparinized capillary tube (50-70 μL). At the time of blood collection, blood glucose measurement was simultaneously performed using a simple blood glucose measurement device (Medisense Precision Exceed, Abbott Japan). The collected blood was centrifuged (10000 rpm, 7 min, centrifuged in a low temperature chamber) with a hematocrit centrifuge (Kubota Seisakusho), and plasma was collected and stored frozen until use. For insulin measurement, an insulin measurement kit (Levis Insulin-Mouse T, Shibayagi) was used. Details followed the kit instructions. Samples were diluted as necessary and measured again.

  HOMA-IR (homeostasis model of insulin resistance), which is an index of insulin resistance, was calculated by the formula of fasting blood glucose level × plasma insulin level / 22.5.

  Insulin tolerance test (ITT) was performed on day 14 after a fasting of 20 hours or more. On the afternoon of the 14th day, the blood glucose level was measured again, and then an insulin solution was intraperitoneally administered (0.3 unit / kg). The insulin solution was prepared by diluting a 100 unit / mL solution (Humarin R injection, Eli Lily) to 0.06 unit / mL with 0.1% BSA-containing physiological saline. Blood glucose levels were measured at 30, 60 and 120 minutes after insulin loading. The blood glucose level was measured as described above.

  The effects of the compound group of Example and pioglitazone on body weight were evaluated by the body weight (g) at the 13th day after the start of administration and the amount of change (g) from the administration start date (day 0).

  Statistical analysis between the solvent administration group of DIO mice (hereinafter referred to as “solvent group”) and the compound group administration group of Examples was performed using the following method. The two groups were tested by confirming equidispersity (F test) and then selecting Student's t test or Welch test. Dose responsiveness was assessed by parametric or non-parametric Williams test after confirmation of equidispersity (Bartlett test). In the Williams test, a P value of less than 0.025 (lower side) was judged to be statistically significant when the P value of the two groups was less than 0.05.

2. Result The effect | action with respect to the HOMA-IR value of the compound representing the compound group of an Example is shown to FIGS. The symbol * in the figure indicates that the comparison with the solvent group is statistically significant. As a result of the experiment, the administration groups of the compounds of Examples 2, 7, 8 and 23 significantly decreased the HOMA-IR value as compared with the solvent group.

  In ITT, the insulin-sensitive blood glucose lowering effect of the compound of Example 2 and pioglitazone, which is one of thiazolidinediones, was evaluated. FIG. 5 shows a normal group (□), a solvent group (■), a 10 mg / kg administration group (◯) of the compound of Example 2, a 30 mg / kg administration group (●) of the compound of Example 2, and a 30 mg / kg administration group of pioglitazone ( (△) shows blood glucose level transition after insulin load. The symbol * or # in the figure indicates that the compound administration group or the pioglitazone administration group of Example 2 is statistically significant in comparison with the solvent group, respectively. * (10, 30) indicates that the dose of the compound of Example 2 is statistically significant in both the groups of 10 and 30 mg / kg. * (10) indicates that the dose of the compound of Example 2 is 10 mg. It is statistically significant in the / kg group. As shown in FIG. 5, the blood glucose level at 30 minutes and 60 minutes after the insulin load in the compound administration group of Example 2 was significantly lower than that in the solvent group. Moreover, the blood glucose level transition of the compound administration group of Example 2 was comparable with the pioglitazone administration group.

  From these results, it was shown that the compound groups of Examples have an insulin resistance improving action.

  Table 27 shows the body weight at the 13th day after the start of administration and the amount of change (weight change) from the start date of administration (day 0) (average values of 8 cases ± standard error). The solvent group was shown to be obese relative to the normal group. The body weight of the compound administration group of Example 2 was lower than that of the solvent group, and the body weight change amount showed a significant change (decrease). On the other hand, body weight increased by pioglitazone administration. From the above results, it was shown that the compound groups of Examples have an effect of improving obesity and have no side effects of weight gain.

(Example 33) Liver gluconeogenesis inhibitory action in a pathological model Using the DIO mouse, the liver gluconeogenesis inhibitory action of the compound group of an Example was evaluated.

1. Test method C57BL / 6N mice (male, Japanese Charles River) are received at the age of 4 weeks, fed with a normal diet (CRF-1) for 1 week, and then a solid diet containing 60% fat (D12492, Research Diet) or They were raised for 13 weeks on normal feed. In addition, the mouse | mouth of the solid feed containing 60% fat was made into the DIO mouse | mouth, and the mouse | mouth of the normal feed was made into the mouse | mouth of a normal group.

  Preparation, administration, grouping, blood collection method, blood glucose level measurement and statistical analysis of the compound of Example 2 and pioglitazone were performed in the same manner as described in Example 32. The administration start day was day 0 and administration was continued until day 13.

  Evaluation of the hepatic gluconeogenesis inhibitory effect was performed by a pyruvate tolerance test (PTT). In the afternoon of the 14th day, blood glucose levels of mice fasted for 20 hours were measured, and then a sodium pyruvate solution was immediately intraperitoneally administered (2 g / kg). A sodium pyruvate solution was prepared by diluting to 0.2 g / mL with PBS (−). Blood glucose levels were measured 30, 60, 90, 120 and 180 minutes after pyruvate loading.

2. Results FIG. 6 shows a normal group (□), a solvent group (■), a 10 mg / kg administration group (◯) of the compound of Example 2, a 30 mg / kg administration group (●) of the compound of Example 2, and a 30 mg / kg administration group of pioglitazone. (△) shows the blood glucose level transition after pyruvic acid administration (the pyruvic acid loading time is 0 minute). Moreover, in FIG. 7, the blood glucose level AUC (Area under the curve) from 0 to 180 minutes after pyruvic acid load is shown. The symbol * or # in the figure indicates that the compound administration group or the pioglitazone administration group of Example 2 is statistically significant in comparison with the solvent group, respectively. * (10, 30) indicates that the dose of the compound of Example 2 is statistically significant in both the groups of 10 and 30 mg / kg. * (30) indicates that the dose of the compound of Example 2 is 30 mg. It is statistically significant in the / kg group. As shown in FIG. 6, the blood glucose level of the solvent group was higher than that of the normal group, and the blood glucose level did not fall completely even after 180 minutes of pyruvate load. The blood glucose level in the compound administration group of Example 2 significantly decreased after 60 minutes of pyruvate load compared to the solvent group, and decreased to the same level as the pyruvate load time point (0 minute) after 180 minutes. Moreover, as shown in FIG. 7, the compound administration group of Example 2 significantly reduced the blood glucose level AUC as compared with the solvent group, and its efficacy was stronger than that of the pioglitazone administration group. From the above result, it was shown that the compound group of an Example has a hepatic gluconeogenesis suppression effect.

  Since the pyrazole derivative of the present invention or a pharmaceutically acceptable salt thereof exhibits a remarkable 11β-HSD1 inhibitory activity and has reduced side effects, it has a therapeutic and prophylactic agent for diabetes and insulin resistance in the pharmaceutical field. It can be used as an improving agent.

Claims (11)

The following general formula (I)
[Wherein, R ¹ represents alkyl having 1 to 6 carbon atoms (the alkyl may be substituted with 1 to 5 halogen atoms or hydroxy), cycloalkyl having 3 to 10 carbon atoms (the cyclo Alkyl may be substituted with 1 to 5 halogen atoms or hydroxy.), Alkyloxy having 1 to 3 carbon atoms (the alkyloxy may be substituted with one or more halogen atoms). , A halogen atom or a hydrogen atom, k represents an integer of 1 to 5, R ² represents an alkyl having 1 to 6 carbon atoms (the alkyl is substituted with 1 to 5 halogen atoms or hydroxy). Or a cycloalkyl having 3 to 10 carbon atoms (the cycloalkyl may be substituted with 1 to 5 halogen atoms or hydroxy), and R ³ represents carbon. Numbers 1-6 Kill, a cycloalkyl or a hydrogen atom having 3 to 6 carbon atoms, R ⁴ is alkyl of 1 to 6 carbon atoms (the alkyl may be substituted with 1-5 halogen atoms.), Carbon Formula 1-6 alkyloxy (the alkyloxy may be substituted with 1 to 5 halogen atoms), hydroxy, cyano, halogen atom, hydrogen atom, —O— (CH ₂ ) _n —R ⁵ , —SO ₂ —R ⁶ , —SO ₂ —OR ⁶ , —NR ⁶ (C═O) R ⁶ , —NR ⁶ (SO ₂ ) R ⁶ , —NR ⁷ R ⁸ , — (C═O) — NR ⁷ R ⁸ , —O— (C═O) —NR ⁷ R ⁸ or —SO ₂ —NR ⁷ R ⁸ is shown, R ⁵ is an alkyloxy having 1 to 3 carbon atoms (the alkyloxy is 1 to 5 halogen atoms may be substituted.), hydroxy, ^-NR 7 ^{R 8} Is - (C = O) indicates ^-NR 7 ^{R 8, R 6} are each independently alkyl (the alkyl having 1 to 3 carbon atoms may be substituted with 1 to 3 halogen atoms Or a hydrogen atom, and R ⁷ and R ⁸ each independently represent an alkyl or hydrogen atom having 1 to 6 carbon atoms, or R ⁷ , R ⁸ and a nitrogen atom are combined to form pyrrolidyl , Piperidyl, morpholyl, piperazyl or 4-alkylpiperazin-1-yl (the carbon number of the alkyl constituting the 4-alkylpiperazin-1-yl is 1 to 3), and m and n are each independently And an integer of 1-4. ]
Or a pharmaceutically acceptable salt thereof. The pyrazole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ represents a hydrogen atom. R ⁴ represents hydroxy, —NR ⁶ (C═O) R ⁶ , — (C═O) —NR ⁷ R ⁸ or —O— (C═O) —NR ⁷ R ⁸ , and m represents 1 The pyrazole derivative or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein The R ⁴ represents hydroxy, —NR ⁶ (C═O) R ^6, or — (C═O) —NR ⁷ R ⁸ , and the m represents 1. 4. Or a pharmaceutically acceptable salt thereof. R ² represents alkyl having 1 to 6 carbons (the alkyl may be substituted with 1 to 5 halogen atoms, but excluding methyl) or cycloalkyl having 3 to 6 carbons; The pyrazole derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4. The R ² represents 2-propyl or 2-methyl-2-propyl, the pyrazole derivative according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. R ¹ is alkyl having 1 to 3 carbon atoms (the alkyl may be substituted with 1 to 5 halogen atoms or hydroxy), alkyloxy having 1 to 3 carbon atoms (the alkyloxy is And optionally substituted with one or more halogen atoms.), Represents a halogen atom or a hydrogen atom, and k represents an integer of 1 to 3, or a pyrazole derivative thereof according to any one of claims 1 to 6; A pharmaceutically acceptable salt.   An 11β-hydroxysteroid dehydrogenase 1 inhibitor comprising the pyrazole derivative according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.   A therapeutic or prophylactic agent for diabetes comprising the pyrazole derivative according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.   The therapeutic or preventive agent for diabetes according to claim 9, wherein the diabetes is type 2 diabetes.   A drug for improving insulin resistance comprising the pyrazole derivative according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.