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WO2015076353A1 - 3-alkylpyrazolopyridine derivative - Google Patents

3-alkylpyrazolopyridine derivative Download PDF

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Publication number
WO2015076353A1
WO2015076353A1 PCT/JP2014/080847 JP2014080847W WO2015076353A1 WO 2015076353 A1 WO2015076353 A1 WO 2015076353A1 JP 2014080847 W JP2014080847 W JP 2014080847W WO 2015076353 A1 WO2015076353 A1 WO 2015076353A1
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Prior art keywords
compound
group
trifluoromethyl
ethyl
pyridin
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French (fr)
Japanese (ja)
Inventor
雅巳 荒井
小林　英樹
秀樹 窪田
直生 寺坂
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • C07D263/18—Oxygen atoms
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    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pyrazolopyridine derivative having a superior lecithin cholesterol acetyltransferase (hereinafter referred to as LCAT) activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof.
  • LCAT superior lecithin cholesterol acetyltransferase
  • cardiovascular diseases for example, heart disease, cerebrovascular disease, kidney disease, etc.
  • hypertension for example, hypertension, dyslipidemia, diabetes, etc.
  • Antihypertensive drugs, antilipidemia drugs, and antidiabetic drugs are used for the treatment of hypertension, dyslipidemia, and hyperglycemia, respectively.
  • ⁇ and ⁇ blockers, diuretics, calcium antagonists, ACE inhibitors, and A-II antagonists are used as antihypertensive agents, and HMG-CoA reductase inhibitors, Insulin, sulfonylureas, metformin, glitazones, DPP4 inhibitors, and the like are used as antidiabetics such as ion exchange resins, nicotinic acid derivatives, probucol, and fibrates.
  • These drugs contribute to the regulation of blood pressure and blood lipid or blood glucose levels.
  • mortality due to heart disease, cerebrovascular disease and kidney disease has not been greatly improved even by the use of these drugs, and development of better therapeutic agents for these diseases is desired.
  • a direct risk factor for cardiovascular disease is arteriosclerosis accompanied by thickening of the arterial wall, and the cause of the thickening is due to accumulation of oxidized low density lipoprotein (hereinafter referred to as LDL) cholesterol in macrophages in the arterial wall. It is the formation of plaque (Non-Patent Documents 1 and 2). This plaque inhibits blood flow and promotes thrombus formation.
  • LDL oxidized low density lipoprotein
  • Non-Patent Document 3 An increase in the concentration of LDL cholesterol in the blood and a decrease in the concentration of high-density lipoprotein (hereinafter referred to as HDL) cholesterol are both risk factors for coronary artery disease.
  • HDL high-density lipoprotein
  • Peripheral tissue cholesterol is extracted by HDL and esterified by LCAT on HDL to become cholesteryl ester.
  • Increased LCAT activity promotes the withdrawal of cholesterol from macrophages (for example, Non-Patent Documents 4 and 5). Therefore, it is considered that a drug that enhances LCAT activity is useful as a medicament for treating or preventing diseases such as dyslipidemia and arteriosclerosis.
  • Non-patent Document 6 examples of known drugs that enhance LCAT activity include peptide compounds (for example, Non-patent Document 6) and, as small molecules, for example, compounds described in Patent Document 1.
  • Patent Document 2 As the compound having a pyrazolopyridine skeleton, the compound described in Patent Document 2 is known. Patent Document 2 describes an anti-LPA receptor action, but does not describe an LCAT activation action.
  • the present inventors have conducted various synthetic studies aiming at obtaining new anti-arteriosclerotic drugs by having an excellent LCAT activation action and promoting cholesterol withdrawal directly from macrophages. As a result, the present inventors have found that a pyrazolopyridine derivative having a specific structure or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and completed the present invention.
  • the present invention provides a pyrazolopyridine derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing them.
  • R 2 and R 3 both represent a hydrogen atom, or together with the carbon atom to which they are bonded form a cyclopropyl ring or a cyclobutyl ring, and R 1 represents a group selected from the following group Q1:
  • X represents a single bond, or R 3 represents a hydrogen atom
  • R 1 and R 2 are the same or different and represent a group selected from the following group Q1, X represents a single bond, an oxygen atom, a sulfur atom or a group SO 2 ;
  • Q1 group includes an aryl group, a substituted aryl group, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a heteroaryl group (the heteroaryl may be condensed with a benzene ring), a substituted heteroaryl A group consisting of a group (the heteroaryl may be fused with a benzene ring), a heterocyclyl group and a substitute
  • the substituent is the same or different 1 to 2 substituents selected from the group consisting of a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group and a C 1 -C 6 alkoxy group) It is.
  • R 2 and R 3 are both hydrogen atoms
  • X is a single bond
  • R 1 is a benzyl group.
  • R 2 and R 3 both represent a hydrogen atom
  • R 1 represents a group selected from the following group Q2
  • X represents a single bond
  • R 3 represents a hydrogen atom
  • R 1 and R 2 are the same or different and represent a group selected from the following group Q2, X represents a single bond, an oxygen atom, a sulfur atom or a group SO 2
  • Group Q2 is a group consisting of a substituted aryl group, a C 1 -C 6 alkyl group and a substituted heterocyclyl group
  • the substituent in the Q2 group is a substituted heteroaryl group (the substituent on the heteroaryl is a group consisting of a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, and a C 1 -C 6 alkoxy group)
  • a pharmacologically acceptable salt thereof according to (1) which is the same or different 1 or 2
  • Or therapeutic agent (10) A preventive agent for a disease caused by a decrease in the concentration of HDL cholesterol in blood, comprising as an active ingredient the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof.
  • Or therapeutic agent (11) An LCAT activator comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient, (12) a reversible LCAT activator comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient, (13) An anti-arteriosclerosis agent comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient, (14) A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof, (15) A method for preventing or treating a disease, comprising administering to a human an effective amount of the compound according to any one
  • a method for the prevention or treatment of the disease caused (20) The compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis, (21) The compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia, (22) The compound according to any one of (1) to (4) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by an increase in the concentration of LDL cholesterol in blood Acceptable salts, and (23) The compound according to any one of (1) to (4) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by a decrease in the concentration of HDL cholesterol in the blood It is an acceptable salt.
  • Compound (I) of the present invention is a compound represented by formula (I) or a tautomer thereof.
  • the compound (I) containing any tautomer is represented by the structural formula of the formula (I) and the corresponding chemical name.
  • any isomer of the other tautomer (amide-imidic acid) of the compound (I) of the present invention is contained in the present compound (I).
  • the compound (I ) Is also represented by the structural formula represented by formula (I) and the corresponding chemical name.
  • the “C 3-7 cycloalkyl group” is a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms (C 3-6 cycloalkyl group) is preferable, and a cyclopropyl group is more preferable.
  • the “aryl group” is, for example, a phenyl group or a naphthyl group, and is preferably a phenyl group.
  • the “C 1-6 alkyl group” is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, It may be an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group, or a hexyl group, and is preferably a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms ( C 1-4 alkyl group), more preferably a methyl group.
  • the “heteroaryl group (the heteroaryl may be condensed with a benzene ring)” is, for example, a pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, furyl group, thienyl group.
  • Benzofuryl group benzothienyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, pyrrole group, pyrazolyl group, imidazolyl group, triazolyl group, benzoxazolyl group or benzothiazolyl group, preferably 5 members Or a 6-membered heteroaryl group (the heteroatoms on the heteroaryl ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) (“heteroaryl More preferably a pyridyl group, pyrazinyl group, pyrimidyl group, Group, a thienyl group, a thiazolyl group or a pyrazolyl group.
  • the “heterocyclyl group” is a monocyclic or bicyclic 3 to 10 member containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • a saturated or unsaturated heterocyclic group such as aziridinyl group, azetidinyl group, pyrrolidinyl group, morpholinyl group, pyrrolyl group, furyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isothiazolyl group, pyranyl group, Pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, benzimidazolyl group, benzoxazolyl group, quinolyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, dihydropyridyl group, tetrahydropyridyl group, etc. Or a 6-membered heterocyclyl group, more preferably Enyl group, a pyridyl group, a tetrahydropyranyl group, an isoxazo
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom.
  • the “C 1-6 haloalkyl group” is the above “C 1-6 alkyl group” substituted with the same or different 1 to 3 “halogen atoms”, for example, , Fluoromethyl group, chloromethyl group, bromomethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, trifluoromethyl group, trichloromethyl group or 2,2,2-trifluoroethyl group, preferably A C 1-3 alkyl group substituted with 1 to 3 chlorine atoms or 1 to 3 fluorine atoms, and more preferably a trifluoromethyl group.
  • the “C 1-6 alkoxy group” is an oxygen atom to which the “C 1-6 alkyl group” is bonded.
  • a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group Preferably, it is an oxygen atom (C 1-3 alkoxy group) to which the “C 1-3 alkyl group” is bonded, and more preferably a methoxy group.
  • the “aryloxy group” is an oxygen atom to which the “aryl group” is bonded, and may be, for example, a phenoxy group or a naphthyloxy group, and is preferably a phenoxy group.
  • the “aralkyl group” is the “C 1-6 alkyl group” substituted with the “aryl group”, for example, a benzyl group or a phenethyl group, preferably , A phenyl-C 1-3 alkyl group, and more preferably a benzyl group.
  • “pharmacologically acceptable salts” include, for example, hydrohalides such as hydrofluoric acid salts, hydrochlorides, hydrobromides, hydroiodides; nitrates, perchlorates.
  • Inorganic salts such as sulfates and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salts; organic acid salts such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, succinate, maleate; and amino acid salts such as ornithate, glutamate, aspartate Can be mentioned.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may absorb water and become a hydrate when left in the atmosphere, and such a hydrate is also included in the present invention. Is done.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may be taken out from the solvent and become a solvate by leaving it in a solvent, and such a solvate is also encompassed in the present invention. Is done.
  • Compound (I) of the present invention has an optical isomer based on an asymmetric center in the molecule. Unless otherwise specified, in the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers.
  • Compound (I) of the present invention may also contain an unnatural proportion of atomic isotopes at one or more of the atoms constituting the compound.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound may be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activating action, and is arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (heart failure). , Including myocardial infarction, angina pectoris, cardiac ischemia, cardiovascular disorder and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications), lipid abnormalities It is useful as an active ingredient of a therapeutic or prophylactic agent for renal disease, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease, particularly an anti-arteriosclerotic agent.
  • Production method 1 is a method for producing compound (I) of the present invention from compound (II).
  • X, R 1 , R 2 , and R 3 are as defined above, and R 4 represents a methyl group or an ethyl group.
  • Compound (II) includes compound (IIx) which is a tautomer.
  • compound (II) includes all isomers of tautomers. That is, the compound (II) includes all of the compound (II), the compound (IIx), and a mixture of the compound (II) and the compound (IIx) in an arbitrary ratio.
  • the compound represented by the compound name of compound (II) includes all of compound (II), compound (IIx), and a mixture of compound (II) and compound (IIx) in an arbitrary ratio.
  • This step is a step for producing compound (I) by condensing compound (III) with compound (II) by heating in a solvent inert to the reaction or in the absence of a solvent.
  • Solvents used in this step include organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid; diethyl ether, diisopropyl ether , Tetrahydrofuran, dioxane, dimethoxyethane, or ethers such as tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2 Alcohols such as methoxyethanol, diethylene glycol or glycerol; aromatic hydrocarbons such as benzene, toluene or xylene; or It is a
  • the reaction temperature in this step is usually 40 ° C. to 150 ° C., preferably 50 ° C. to 130 ° C., more preferably 60 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is usually 5 minutes to 72 hours, preferably 15 minutes to 24 hours, and more preferably 30 minutes to 3 hours.
  • Manufacturing method 2 The intermediate (II) of the compound of the present invention can be produced, for example, by the following method.
  • R 5 is an alkoxy group, a chlorine atom or an oxazolidinone auxiliary group
  • the oxazolidinone auxiliary group is, for example, 2-oxo A -4-substituted-1,3-oxaloridin-3-yl group, preferably a chiral-2-oxo-4-isopropyl-1,3-oisazolidin-3-yl group, and so on.
  • R a has one or more amino groups (the amino group is a primary or secondary amino group, including a cyclic amino group) or a carbonyl group, and is converted to R 1 by Step 2-3. Represents a group.
  • Compound (IV), which is a starting material for this step may be a commercially available product, or can be produced by esterifying, amidating, or acidifying a known benzoic acid compound by a conventional method. .
  • compound (IV) is produced by reacting compound (IV) with acetonitrile in an inert solvent using a base. It is a process.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.
  • the base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide or n-butyllithium. It can be an organometallic base, more preferably sodium hydride or n-butyllithium.
  • the reaction temperature in this step is preferably ⁇ 100 ° C. to 0 ° C., and more preferably ⁇ 78 ° C. to ⁇ 40 ° C.
  • the reaction time in this step is preferably 5 minutes to 3 hours, and more preferably 15 minutes to 2 hours.
  • this step is a step of producing compound (V) by reacting compound (IV) with cyanoacetic acid using a base in an inert solvent when R 5 is a chlorine atom. is there.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.
  • the base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide or n-butyllithium. It can be an organometallic base, more preferably n-butyllithium.
  • the reaction temperature in this step is preferably ⁇ 100 ° C. to 0 ° C., and more preferably ⁇ 78 ° C. to ⁇ 40 ° C.
  • the reaction time in this step is preferably 5 minutes to 3 hours, and more preferably 15 minutes to 2 hours.
  • Step 2-2 This step is a step for producing compound (II) by reacting compound (V) with a hydrazine compound in an inert solvent.
  • Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably alcohols, more preferably ethanol.
  • the hydrazine compound used in this step is anhydrous hydrazine, hydrazine monohydrate, hydrazine hydrochloride, hydrazine acetate, hydrazine sulfate, hydrazine nitrate, hydrazine hydrobromide, hydrazine oxalate, or hydrazine phosphate.
  • Preferred is hydrazine monohydrate or hydrazine acetate.
  • the reaction temperature in this step is preferably 20 ° C. to 120 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is preferably 10 minutes to 24 hours, and more preferably 1 hour to 5 hours.
  • Step 2-3 This step is a step of producing compound (IV) by reacting compound (VI) with a heteroarylating agent in the presence of a base in an inert solvent when R a has an amino group. is there.
  • Solvents used in this step include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Alcohols; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; or ketones such as acetone.
  • Examples of the base used in this step include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Potassium.
  • the reaction temperature in this step is preferably ⁇ 30 ° C. to 100 ° C., and more preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is preferably 30 minutes to 24 hours, and more preferably 1 hour to 10 hours.
  • the heteroarylating agent used in this step is a compound having the formula R b —Cl, the formula R b —Br or the formula R b —I, preferably the formula R b —Br or the formula R b —I (R b represents a heteroaryl group or a substituted heteroaryl in the Q1 group).
  • R a of compound (VI) has a carbonyl group
  • compound (VI) is reduced by reducing compound (VI) in an inert solvent or in the absence of a solvent. Is a process of manufacturing.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol , Tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or alcohols such as glycerin; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, Or amides such as hexamethylphosphorotriamide; ketones such as acetone; or dichloromethane, dichloroethane, chloroform Alkyl halides can be mentioned a, preferably, ethers, amides,
  • Examples of the combination of reagents used in this step include palladium-carbon and hydrogen, aluminum chloride and lithium aluminum hydride, or triethylsilane and trifluoroacetic acid, and preferably triethylsilane and trifluoroacetic acid.
  • the reaction temperature in this step is preferably ⁇ 30 ° C. to 50 ° C., and more preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is preferably 30 minutes to 48 hours, and more preferably 5 hours to 24 hours.
  • Production method 3 is a method for producing compound (I) of the present invention from compound (V).
  • Step 3-1 This step is a step for producing compound (IIa) by reacting compound (V) with a diphenylmethylhydrazine compound in an inert solvent.
  • Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably alcohols, more preferably ethanol.
  • the diphenylmethyl hydrazine compound used in this step can be anhydrous diphenylmethyl hydrazine, diphenylmethyl hydrazine hydrochloride, diphenylmethyl hydrazine acetate, etc., and is preferably diphenylmethyl hydrazine hydrochloride or diphenylmethyl hydrazine acetate.
  • the reaction temperature in this step is preferably 20 ° C. to 120 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is preferably 10 minutes to 24 hours, and more preferably 1 hour to 5 hours.
  • Step 3-2 In this step, compound (Ia) is produced by condensing compound (III) with compound (III) by heating in a solvent inert to the reaction or in the absence of a solvent.
  • This step can be performed under the same conditions as in step 1.
  • Step 3-3 This step is a step for producing compound (I) by removing the diphenylmethyl group of compound (Ia) in an inert solvent.
  • Examples of the reagent used for removing the diphenylmethyl group in the compound (IIa) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like, which can remove the trityl group described in the above.
  • Solvents used in this step are preferably alcohols such as methanol or ethanol: ethers such as tetrahydrofuran or 1,4-dioxane; alkyl halides such as dichloromethane or chloroform; ethyl acetate Esters such as toluene; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alkyl halides, and still more preferably dichloromethane.
  • alcohols such as methanol or ethanol: ethers such as tetrahydrofuran or 1,4-dioxane; alkyl halides such as dichloromethane or chloroform; ethyl acetate Esters such as toluene; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alkyl halides, and still more preferably dichloromethane.
  • the reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, more preferably trifluoroacetic acid, and a compound called a cation scavenger such as triethylsilane, anisole or thioanisole as an additive. It may be used.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.
  • the reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.
  • X, R 1 and R 2 are as defined above, and R 6 represents a hydroxyl group, an alkoxy group, or an oxazolidinone auxiliary group.
  • This step is a step for producing compound (IVa) by reacting compound (VII) with an alkylating agent using a base in an inert solvent.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.
  • the base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide, n-butyllithium, lithium diisopropyl It can be an organometallic base such as amide, lithium hexamethylene disilazide, sodium hexamethylene disilazide or potassium hexamethylene disilazide, more preferably lithium diisopropylamide or lithium hexamethylene disilazide.
  • the alkylating agent used in this step can be preferably methyl iodide, ethyl iodide or dimethyl sulfate, and more preferably methyl iodide.
  • the reaction temperature in this step is preferably ⁇ 100 ° C. to 0 ° C., and more preferably ⁇ 78 ° C. to 5 ° C.
  • the reaction time in this step is preferably 30 minutes to 5 hours, and more preferably 30 minutes to 2 hours.
  • the compound represented by the formula (IVb) can be produced, for example, by the following method.
  • R 1 is as defined above, R 7 is a methyl group or an ethyl group, R 8 is a hydrogen atom, a methyl group, or an ethyl group, X a is a chlorine atom, a bromine atom, And an iodine atom.
  • Step 5-1 This step is a step for producing compound (X) by reacting compound (VIII) with malonic ester compound (IX) using a palladium catalyst.
  • Step 5-2 This step is a step of producing compound (IVb) from compound (X) under acidic conditions or basic conditions.
  • the solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an aromatic hydrocarbon such as toluene; or a mixture thereof. It is a solvent, more preferably an alcohol or an ether, and still more preferably ethanol or 1,4-dioxane.
  • the reagent used in this step is preferably hydrochloric acid or a sodium hydroxide aqueous solution.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 20 ° C. to 70 ° C.
  • the reaction time in this step is preferably 1 hour to 10 hours, and more preferably 2 minutes to 6 hours.
  • R 1 is as defined above, R 7 represents a methyl group or an ethyl group, and X b represents a chlorine atom, a bromine atom, or an iodine atom.
  • Step 6 This step is a step for producing compound (IVc) by reacting compound (XI) with compound (XII) in the presence of a base in an inert solvent.
  • Solvents used in this step include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Alcohols; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; or ketones such as acetone.
  • Examples of the base used in this step include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Cesium.
  • the reaction temperature in this step is preferably ⁇ 30 ° C. to 150 ° C., and more preferably 20 ° C. to 100 ° C.
  • the reaction time in this step is preferably 30 minutes to 24 hours, and more preferably 1 hour to 10 hours.
  • R 2 and R 3 are as defined above, and X 1 is a chlorine atom, a bromine atom, an iodine atom, or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
  • R 9 represents an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group in the Q1 group
  • X 2 represents B (OH) 2 , a bromine atom, or Indicates an iodine atom.
  • Step 7 a halogenated compound (IIb) in which X 1 is a chlorine atom, a bromine atom, or an iodine atom is converted into an organoboron compound in which X 2 is B (OH) 2 by a Suzuki-Miyaura reaction using a palladium catalyst.
  • compound (IIc) is produced by reacting with halogenated compound (XIII) wherein X 2 is bromine atom or iodine atom by Suzuki-Miyaura reaction.
  • the palladium catalyst, ligand, base and reaction conditions used in this step are not particularly limited as long as they are reagents and conditions used in the usual Suzuki-Miyaura reaction. Miyaura, A .; Suzuki, Chem. Rev. 1995, volume 95, p. 2457 and the like.
  • Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; water; or a mixed solvent thereof And is preferably a mixed solvent of ethers and water, and more preferably a mixed solvent of 1,4-dioxane and water.
  • the palladium catalyst used in this step is preferably tetrakistriphenylphosphine palladium or [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct.
  • the base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate, or an organic metal base such as sodium tert-butoxide or potassium tert-butoxide. More preferably, it is potassium carbonate.
  • Manufacturing method 8 is a method for producing compounds (Ic) and (Id) of the present invention from compound (XIV).
  • R x represents an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group in the Q1 group, and Boc is tert. -Represents a butoxycarbonyl group.
  • Step 8-1 This step is a step of producing compound (Ic) by removing the Boc group in compound (XIV).
  • reagents used for removing Boc in compound (XIV) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like which can remove Boc described in the above.
  • the solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an alkyl halide such as dichloromethane or chloroform; Esters such as toluene; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alkyl halides, and still more preferably dichloromethane.
  • an alcohol such as methanol or ethanol
  • an ether such as tetrahydrofuran or 1,4-dioxane
  • an alkyl halide such as dichloromethane or chloroform
  • Esters such as toluene
  • aromatic hydrocarbons such as toluene
  • a mixed solvent thereof more preferably alkyl halides, and still more preferably dichloromethane.
  • the reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, and more preferably trifluoroacetic acid.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.
  • the reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.
  • Step 8-2 This step is a step for producing compound (Id) by reacting compound (Ic) with an arylating agent or heteroarylating agent.
  • This step can be performed under the same conditions as in step 2-3 (i).
  • the product of each of the above steps is a free compound or a salt thereof, after completion of the reaction, if necessary, a conventional method, for example, (1) a method of concentrating the reaction solution as it is, or (2) filtering insoluble matter such as a catalyst. (3) A method in which water and a solvent immiscible with water (for example, dichloroethane, diethyl ether, ethyl acetate, toluene, etc.) are added to the reaction solution, and the product is extracted (4) )
  • the crystallized or precipitated product can be isolated from the reaction mixture, such as by filtration.
  • the isolated product can be purified by a conventional method such as recrystallization, reprecipitation, various chromatographies and the like, if necessary.
  • the product of each step can be used in the next step without isolation or purification.
  • Compound (I) of the present invention is isolated and purified as a free compound, a pharmacologically acceptable salt, hydrate, or solvate thereof.
  • the pharmacologically acceptable salt of the compound (I) of the present invention can be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, or various chromatography.
  • Various isomers can be separated by utilizing differences in physicochemical properties between isomers.
  • a racemic mixture can be converted to an optically pure isomer, such as by fractional crystallization leading to a diastereomeric salt with an optically active base or acid, or chromatography using a chiral column.
  • the diastereo mixture can be separated by fractional crystallization or various chromatographies.
  • An optically active compound can also be produced by using an appropriate optically active raw material.
  • Examples of the administration form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include oral administration by tablet, granule, powder, capsule or syrup, or injection or suppository. Parenteral administration, and the like, and can be administered systemically or locally.
  • Examples of the oral pharmaceutical form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, Examples include syrups and elixirs.
  • Examples of pharmaceutical forms for parenteral use include injections, ointments, gels, creams, patches, sprays, inhalants, sprays, eye drops, and suppositories. These forms of pharmaceuticals are pharmaceutically acceptable, such as excipients, binders, diluents, stabilizers, preservatives, colorants, solubilizers, suspending agents, buffering agents, or wetting agents.
  • the additive can be prepared according to a conventional method using additives appropriately selected as necessary.
  • the dosage of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is as follows: symptoms, body weight, age, administration method of the administered person (warm-blooded animal, eg, human) Varies depending on etc.
  • the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). It is desirable to administer one to several times a day depending on the symptoms.
  • the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). Is preferably administered one to several times per day depending on the symptoms.
  • hexane represents n-hexane
  • THF represents tetrahydrofuran
  • IPA 2-propanol
  • DMF represents N, N′-dimethylformamide
  • DMSO dimethyl sulfoxide
  • n-butyllithium (2.69 M hexane solution, 100 mL, 0.269 mol) was added dropwise at ⁇ 78 ° C. and stirred for 15 minutes. Further, at the same temperature, a solution of the crude product obtained in the above operation in anhydrous THF (100 mL) was added dropwise and stirred for 1 hour. 2M hydrochloric acid was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • N-Butyllithium (2.69 M hexane solution, 32.6 mL, 87.7 mmol) was added dropwise at ⁇ 78 ° C. to a solution of anhydrous acetonitrile (4.60 mL, 87.9 mmol) in anhydrous THF (200 mL) at the same temperature. After stirring for 30 minutes, a solution of methyl 2- (4-chlorophenyl) propionate (1.01 g, 4.76 mmol) in anhydrous THF (200 mL) was added dropwise at ⁇ 78 ° C., and the mixture was stirred at the same temperature for 45 minutes.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • reaction solution was allowed to cool to room temperature and filtered, and then the solvent of the filtrate was distilled off under reduced pressure.
  • N-Butyllithium (2.69 M hexane solution, 5.80 mL, 15.6 mmol) was added dropwise at ⁇ 78 ° C. to a solution of anhydrous acetonitrile (0.85 mL, 16.2 mmol) in anhydrous THF (25 mL) at the same temperature. After stirring for 30 minutes, a solution of ethyl 2- (1-benzofuran-2-yl) propionate (1.13 g, 5.18 mmol) prepared in Reference Example 45 in anhydrous THF (25 mL) was added dropwise at ⁇ 78 ° C. And stirred for 45 minutes at the same temperature.
  • reaction solution was allowed to stand at room temperature, water was added, extraction was performed with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure.
  • Potassium carbonate (2.70 g, 19.5 mmol) was added to a mixed solution of the crude product obtained in the above operation in ethanol (50 mL) and water (25 mL), and stirred for 18 hours while heating under reflux. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the carboxylic acid compound Got.
  • Test Example 1 Measurement of LCAT activity (in vitro) A density gradient centrifugation was performed to obtain a fraction composed of HDL3 (1.125 ⁇ specific gravity ⁇ 1.210 g / mL) from plasma of a healthy person. The obtained fraction was dialyzed with phosphate buffered saline (pH 7.4) and used as an enzyme source and acceptor of LCAT. The test drug was prepared by dissolving in dimethyl sulfoxide.
  • the radioactivity of the portion corresponding to cholesterol oleate was measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Samples to which no test drug was added were similarly processed and measured. Using the following equation, compared with no addition of test drug was calculated EC 50 values of LCAT activation. The results are shown in Table 1.
  • X represents the logarithm of the concentration of the test drug
  • Y represents the response of the test drug (LCAT activity)
  • Top indicates the maximum value (maximum plateau)
  • Bottom indicates a minimum value (minimum flat area);
  • EC 50 indicates a 50% effective concentration.
  • the compound of the present invention has an excellent LCAT activation action and is useful as a medicament for the treatment or prevention of diseases such as dyslipidemia and arteriosclerosis.
  • Test Example 2 Measurement of LCAT activity (plasma) Human, cynomolgus monkey or human LCAT transgenic mouse plasma is used as an enzyme source and acceptor for LCAT.
  • the test drug is prepared by dissolving in dimethyl sulfoxide. [14C] cholesterol containing DTNB (Ielman's reagent, final concentration 0.5 mM), mercaptoethanol (final concentration 12.5 mM), and 0.6% bovine serum albumin was added to 5 ⁇ L of each plasma and 45 ⁇ L of PBS. Add the test drug at a concentration to make the total volume 80 ⁇ L. After incubating this mixture at 37 ° C.
  • X represents the logarithm of the concentration of the test drug
  • Y represents the response of the test drug (LCAT activity)
  • Top indicates the maximum value (maximum plateau)
  • Bottom indicates a minimum value (minimum flat area);
  • EC 50 indicates a 50% effective concentration.
  • DTNB Ielman's reagent, final concentration 0.26 mM
  • mercaptoethanol final concentration 2 mM
  • bovine serum albumin 0.6% bovine serum albumin
  • the radioactivity of the portion corresponding to cholesterol oleate is measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Compared with the LCAT activity before administration, the rate of change in LCAT activation at each time point is calculated.
  • Test Example 4 Cynomolgus monkey efficacy test
  • the test drug was propylene glycol (Sigma-Aldrich) -Tween 80 (Sigma-Aldrich) mixed solution [4/1 (v / v)] or 0.5% (w / v) Dissolve in aqueous methylcellulose and administer orally to cynomolgus monkeys for 1 or 7 days. Blood is collected before and after administration on the 1st or 7th day of administration to obtain plasma. The cholesterol content in plasma is measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile is analyzed by HPLC (column: Lipopropak XL, Tosoh). The content of HDL cholesterol and non-HDL cholesterol is calculated according to the following calculation formula.
  • HDL cholesterol content plasma cholesterol content ⁇ (HDL cholesterol peak area / sum of each peak)
  • non-HDL cholesterol content plasma cholesterol content ⁇ (peak area of non-HDL cholesterol / sum of each peak)
  • the increase rate (%) of HDL after a single administration of 10 mg / kg as compared to before administration was determined from AUC before administration and 24 hours after administration, and the results are shown in Table 2.
  • Test Example 5 Human LCAT transgenic mouse drug efficacy test The test drug was dissolved in polypropylene glycol-Tween 80 mixed solution [4/1 (v / v)] or 0.5% (w / v) methylcellulose aqueous solution, Human LCAT transgenic mice are orally administered for 1, 4 or 7 days. Blood is collected before and after administration on the first, fourth or seventh day of administration to obtain plasma. The cholesterol content in plasma is measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile is analyzed by HPLC (column: Lipopropak XL, Tosoh). The content of HDL cholesterol and non-HDL cholesterol is calculated according to the following calculation formula.
  • HDL cholesterol content plasma cholesterol content ⁇ (HDL cholesterol peak area / sum of each peak)
  • non-HDL cholesterol content plasma cholesterol content ⁇ (peak area of non-HDL cholesterol / sum of each peak)
  • Formulation Example 1 Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.
  • Formulation Example 3 Tablet According to conventional methods, 100 mg of the compound of Example 3, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg Manufactured using lactose.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and in particular, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease.
  • arteriosclerosis arteriosclerotic heart disease
  • coronary heart disease including acute coronary syndrome, heart failure, myocardial infarction, angina, cardiac ischemia, cardiovascular disorders and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (peripheral arterial disease, Treatment of diabetic vascular complications), dyslipidemia, LCAT deficiency, low HDL cholesterolemia, high LDL cholesterolemia, diabetes, hypertension, metabolic syndrome, Alzheimer's disease, corneal opacity, or renal disease or It is useful as an active ingredient of prophylactic agents, particularly anti-arteriosclerotic agents.

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Abstract

　A compound represented by the formula (in the formula, R2 and R3 both represent hydrogen atoms or, together with the binding carbon atoms, form a cyclopropyl ring or cyclobutyl ring, R1 represents a group selected from group Q1, and X represents a single bond; or R3 represents a hydrogen atom, and R1 and R2 are the same or different and represent groups selected from group Q1), or a pharmaceutically acceptable salt thereof, the compound and salts exhibiting an exceptional LCAT activating effect and being useful as an active ingredient of an agent for the treatment or prevention of arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (including heart failure, myocardial infarction, angina pectoris, cardiac ischemia, cardiovascular disorders, and angioplasty restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications), dyslipidemia, low HDL cholesterol, or renal disease, and especially being useful as an anti-arteriosclerotic.

Description

３－アルキルピラゾロピリジン誘導体3-alkylpyrazolopyridine derivatives

　本発明は、優れたレシチンコレステロールアセチルトランスフェラーゼ（以下、ＬＣＡＴという）活性化作用（好適には、可逆的なＬＣＡＴ活性化作用）を有するピラゾロピリジン誘導体又はその薬理上許容される塩に関する。 The present invention relates to a pyrazolopyridine derivative having a superior lecithin cholesterol acetyltransferase (hereinafter referred to as LCAT) activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof.

　先進文明国では、高血圧症、脂質異常症、糖尿病などにより引き起こされる循環器疾患（例えば、心疾患、脳血管疾患、腎疾患等）が、大きな問題になっている。これら高血圧症、脂質異常症及び高血糖症の治療には、それぞれ抗高血圧薬、抗脂質異常薬及び抗糖尿病薬が用いられている。臨床では、抗高血圧薬として、α及びβ遮断薬、利尿剤、カルシウム拮抗剤、ＡＣＥ阻害剤、及び、Ａ－ＩＩ拮抗剤等が、抗脂質異常薬として、ＨＭＧ－ＣｏＡ還元酵素阻害剤、陰イオン交換樹脂、ニコチン酸誘導体、プロブコール、及び、フィブラート類等が、抗糖尿病薬として、インシュリン、スルホニル尿素類、メトフォルミン、グリタゾン類、及び、ＤＰＰ４阻害剤等が用いられている。これらの薬剤は、血圧及び血中の脂質又は血糖レベルの調節に寄与している。しかし、心疾患、脳血管疾患及び腎疾患による死亡率は、これらの医薬の使用によっても、大きく改善されてはおらず、より優れたこれらの疾患の治療薬の開発が望まれている。 In advanced civilized countries, cardiovascular diseases (for example, heart disease, cerebrovascular disease, kidney disease, etc.) caused by hypertension, dyslipidemia, diabetes, etc. are a major problem. Antihypertensive drugs, antilipidemia drugs, and antidiabetic drugs are used for the treatment of hypertension, dyslipidemia, and hyperglycemia, respectively. Clinically, α and β blockers, diuretics, calcium antagonists, ACE inhibitors, and A-II antagonists are used as antihypertensive agents, and HMG-CoA reductase inhibitors, Insulin, sulfonylureas, metformin, glitazones, DPP4 inhibitors, and the like are used as antidiabetics such as ion exchange resins, nicotinic acid derivatives, probucol, and fibrates. These drugs contribute to the regulation of blood pressure and blood lipid or blood glucose levels. However, mortality due to heart disease, cerebrovascular disease and kidney disease has not been greatly improved even by the use of these drugs, and development of better therapeutic agents for these diseases is desired.

　循環器疾患の直接の危険因子は、動脈壁の肥厚を伴う動脈硬化であり、その肥厚の原因は、酸化低密度リポ蛋白（以下、ＬＤＬという）コレステロールの動脈壁中のマクロファージなどへの蓄積によるプラークの形成である（非特許文献１及び２）。このプラークは血液の流れを阻害し、血栓の生成を促進する。 A direct risk factor for cardiovascular disease is arteriosclerosis accompanied by thickening of the arterial wall, and the cause of the thickening is due to accumulation of oxidized low density lipoprotein (hereinafter referred to as LDL) cholesterol in macrophages in the arterial wall. It is the formation of plaque (Non-Patent Documents 1 and 2). This plaque inhibits blood flow and promotes thrombus formation.

　血清リポ蛋白の濃度は、脂質異常症、動脈硬化症等の疾患と関連することが、多くの疫学的調査の結果より示されている（例えば、非特許文献３）。血中のＬＤＬコレステロールの濃度の増加、及び、高比重リポ蛋白（以下、ＨＤＬという）コレステロールの濃度の減少は、いずれも冠状動脈性疾患の危険因子である。 The results of many epidemiological studies show that the serum lipoprotein concentration is associated with diseases such as dyslipidemia and arteriosclerosis (for example, Non-Patent Document 3). An increase in the concentration of LDL cholesterol in the blood and a decrease in the concentration of high-density lipoprotein (hereinafter referred to as HDL) cholesterol are both risk factors for coronary artery disease.

　末梢組織のコレステロールは、ＨＤＬにより引き抜かれ、ＨＤＬ上でＬＣＡＴによりエステル化されてコレステリルエステルとなる。ＬＣＡＴ活性の亢進は、マクロファージ中からのコレステロールの引き抜きを促進させる（例えば、非特許文献４及び５）。したがって、ＬＣＡＴ活性を亢進する薬剤は、脂質異常症及び動脈硬化症等の疾患の治療若しくは予防のための医薬として有用であると考えられる。 Peripheral tissue cholesterol is extracted by HDL and esterified by LCAT on HDL to become cholesteryl ester. Increased LCAT activity promotes the withdrawal of cholesterol from macrophages (for example, Non-Patent Documents 4 and 5). Therefore, it is considered that a drug that enhances LCAT activity is useful as a medicament for treating or preventing diseases such as dyslipidemia and arteriosclerosis.

　ＬＣＡＴ活性を亢進する薬剤は、ペプチド化合物（たとえば、非特許文献６）や、低分子としては、例えば、特許文献１に記載の化合物が知られている。 Examples of known drugs that enhance LCAT activity include peptide compounds (for example, Non-patent Document 6) and, as small molecules, for example, compounds described in Patent Document 1.

　ピラゾロピリジン骨格を有する化合物としては、特許文献２に記載の化合物が知られている。特許文献２には抗ＬＰＡ受容体作用が記載されているが、ＬＣＡＴ活性化作用は記載されていない。 As the compound having a pyrazolopyridine skeleton, the compound described in Patent Document 2 is known. Patent Document 2 describes an anti-LPA receptor action, but does not describe an LCAT activation action.

ＷＯ２００８／００２５９１号パンフレットWO2008 / 002591 pamphlet ＷＯ２０１２／０２８２４３号パンフレットWO2012 / 028243 pamphlet

Ｒｏｓｓ，Ｒ．，Ａｎｎｕ．Ｒｅｖ．Ｐｈｙｓｉｏｌ．１９９５年，第５７巻，第７９１－８０４頁Ross, R.A. , Annu. Rev. Physiol. 1995, 57, 791-804 Ｓｔｅｉｎｂｅｒｇ，Ｄ．，Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．１９９７年，第２７２巻，第２０９６３－２０９６６頁Steinberg, D.C. , J .; Biol. Chem. 1997, 272, 20963-20966 Ｂａｄｉｍｏｎ，Ｊ．Ｃｌｉｎ．Ｉｎｖｅｓｔ．，１９９０年，第８５巻，第１２３４－１２４１頁Badimon, J .; Clin. Invest. 1990, vol. 85, p. 1234-1241. Ｍａｔｓｕｕｒａ，Ｆ．，Ｊ．Ｃｌｉｎ．Ｉｎｖｅｓｔ．２００６年，第１１６巻，第１４３５－１４４２頁Matsuura, F.A. , J .; Clin. Invest. 2006, 116, 1434-1442. Ｙｖａｎ－Ｃｈａｒｖｅｔ，Ｌ．，Ａｒｔｅｒｉｏｓｃｌｅｒ．Ｔｈｒｏｍｂ．Ｖａｓｃ．Ｂｉｏｌ．２００７年，第２７巻，第１１３２－１１３８頁Yvan-Charvet, L.M. , Arterioscler. Thromb. Vasc. Biol. 2007, 27, 1132-1138 Ｉｗａｔａ，Ａ．，Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ．２０１１年，第２１８巻，第３００－３０７頁Iwata, A .; , Atherosclerosis. 2011, Vol. 218, pp. 300-307

　現在知られているＬＣＡＴ活性化作用を有する化合物は、安全性及び有効性の面で満足できるものではなく、安全性及び有効性に優れたＬＣＡＴ活性化剤が切望されていた。 Currently known compounds having an LCAT activating action are not satisfactory in terms of safety and effectiveness, and LCAT activators having excellent safety and effectiveness have been desired.

　本発明者らは、優れたＬＣＡＴ活性化作用を有し、マクロファージより直接的にコレステロールの引き抜きを促進させることによる新しい抗動脈硬化薬の獲得を目指して種々の合成検討を行った。その結果、特定の構造を有するピラゾロピリジン誘導体又はその薬理上許容される塩が、優れたＬＣＡＴ活性化作用を有することを見出し、本発明を完成した。 The present inventors have conducted various synthetic studies aiming at obtaining new anti-arteriosclerotic drugs by having an excellent LCAT activation action and promoting cholesterol withdrawal directly from macrophages. As a result, the present inventors have found that a pyrazolopyridine derivative having a specific structure or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and completed the present invention.

　本発明は、優れたＬＣＡＴ活性化作用（好適には、可逆的なＬＣＡＴ活性化作用）を有するピラゾロピリジン誘導体又はその薬理上許容される塩及びこれらを含有する医薬を提供する。 The present invention provides a pyrazolopyridine derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing them.

　すなわち、本発明は、
（１）式 That is, the present invention
(1) Formula

Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002

［式中、Ｒ２及びＲ３は共に水素原子を表し、又は、それらが結合する炭素原子と一緒になってシクロプロピル環若しくはシクロブチル環を形成し、Ｒ１は下記Ｑ１群から選ばれる基を表し、Ｘは単結合を表し、或いは、
Ｒ３は水素原子を表し、Ｒ１及びＲ２は同一又は異なって下記Ｑ１群から選ばれる基を表し、Ｘは単結合、酸素原子、硫黄原子又は基ＳＯ２を表し、
Ｑ１群は、アリール基、置換アリール基、Ｃ１－Ｃ６アルキル基、Ｃ３－Ｃ７シクロアルキル基、ヘテロアリール基（当該ヘテロアリールはベンゼン環と縮合していてもよい）、置換ヘテロアリール基（当該ヘテロアリールはベンゼン環と縮合していてもよい）、ヘテロシクリル基及び置換ヘテロシクリル基からなる群であり、
Ｑ１群における置換基は、ハロゲン原子、Ｃ１－Ｃ６ハロアルキル基、Ｃ１－Ｃ６アルコキシ基、アリール基、アリールオキシ基、アラルキル基、ヘテロアリール基又は置換ヘテロアリール基（当該ヘテロアリール上の置換基は、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ハロアルキル基及びＣ１－Ｃ６アルコキシ基からなる群から選ばれる同一又は異なった１～２個の置換基である）である。但し、Ｒ２及びＲ３が共に水素原子であり、Ｘが単結合であり、Ｒ１がベンジル基である場合を除く。］で表される化合物又はその薬理上許容される塩、
（２）Ｒ２及びＲ３は共に水素原子を表し、Ｒ１は下記Ｑ２群から選ばれる基を表し、Ｘは単結合を表し、或いは、
Ｒ３は水素原子を表し、Ｒ１及びＲ２は同一又は異なって下記Ｑ２群から選ばれる基を表し、Ｘは単結合、酸素原子、硫黄原子又は基ＳＯ２を表し、
Ｑ２群は、置換アリール基、Ｃ１－Ｃ６アルキル基及び置換ヘテロシクリル基からなる群であり、
Ｑ２群における置換基は、置換ヘテロアリール基（当該ヘテロアリール上の置換基は、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ハロアルキル基及びＣ１－Ｃ６アルコキシ基からなる群から選ばれる同一又は異なった１～２個の置換基である）である、（１）に記載の化合物又はその薬理上許容される塩、
（３）４－ヒドロキシ－３－（１－フェニルエチル）－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　３－［１－（４－ブチルフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　３－（１－シクロヘキシルエチル）－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－３－［１－（５－メチルチオフェン－２－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－４－（トリフルオロメチル）－３－（１－｛３－［６－（トリフルオロメチル）ピリジン－３－イル］フェニル｝エチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－４－（トリフルオロメチル）－３－｛１－［４’－（トリフルオロメチル）ビフェニル－３－イル］エチル｝－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－３－｛１－［３－（２－イソプロポキシピリミジン－５－イル）フェニル］エチル｝－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－４－（トリフルオロメチル）－３－（１－｛３－［５－（トリフルオロメチル）ピラジン－２－イル］フェニル｝エチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－４－（トリフルオロメチル）－３－（｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル｝メチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－４－（トリフルオロメチル）－３－［１－｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル］エチル｝－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－３－｛１－［３－（６－メトキシピリジン－３－イル）フェニル］エチル｝－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、
　３－｛１－［３－（２，６－ジフルオロピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オンからなる群から選ばれる、（１）に記載の化合物又はその薬理上許容される塩、
（４）（４Ｒ）－４－ヒドロキシ－３－［（１Ｓ）－１－フェニルエチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　（４Ｒ）－３－｛（１Ｓ）－１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　（４Ｒ）－４－ヒドロキシ－４－（トリフルオロメチル）－３－（｛（３Ｒ）－１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル｝メチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　（４Ｒ）－４－ヒドロキシ－４－（トリフルオロメチル）－３－［（１Ｓ）－１－｛（３Ｒ）－１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル］エチル｝－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン
　（４Ｒ）－４－ヒドロキシ－３－｛（１Ｓ）－１－［３－（６－メトキシピリジン－３－イル）フェニル］エチル｝－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、
　（４Ｒ）－３－｛（１Ｓ）－１－［３－（２、６－ジフルオロピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オンからなる群から選ばれる、（１）に記載の化合物又はその薬理上許容される塩、
（５）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物、
（６）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、動脈硬化症、動脈硬化性心疾患、冠状動脈性心疾患、脳血管疾患、末梢血管疾患、脂質異常症、低ＨＤＬコレステロール血症、高ＬＤＬコレステロール血症、又は、腎疾患の予防若しくは治療のための医薬組成物、
（７）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、動脈硬化症の予防剤若しくは治療剤、
（８）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、脂質異常症の予防剤若しくは治療剤、
（９）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血中のＬＤＬコレステロールの濃度の増加により引き起こされる疾患の予防剤若しくは治療剤、
（１０）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血中のＨＤＬコレステロールの濃度の減少により引き起こされる疾患の予防剤若しくは治療剤、
（１１）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、ＬＣＡＴ活性化剤、
（１２）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、可逆的ＬＣＡＴ活性化剤、
（１３）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、抗動脈硬化剤、
（１４）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、ＬＣＡＴ活性化方法、
（１５）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、疾患の予防若しくは治療のための方法、
（１６）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、動脈硬化症の予防若しくは治療のための方法、
（１７）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、脂質異常症の予防若しくは治療のための方法、
（１８）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、血中のＬＤＬコレステロールの濃度の増加により引き起こされる疾患の予防若しくは治療のための方法、
（１９）（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、血中のＨＤＬコレステロールの濃度の減少により引き起こされる疾患の予防若しくは治療のための方法、
（２０）動脈硬化症の治療又は予防のための方法における使用のための、（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（２１）脂質異常症の治療又は予防のための方法における使用のための、（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（２２）血中のＬＤＬコレステロールの濃度の増加により引き起こされる疾患の治療又は予防のための方法における使用のための、（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩、及び、
（２３）血中のＨＤＬコレステロールの濃度の減少により引き起こされる疾患の治療又は予防のための方法における使用のための、（１）～（４）のいずれか１項に記載の化合物又はその薬理上許容される塩である。 [Wherein, R 2 and R 3 both represent a hydrogen atom, or together with the carbon atom to which they are bonded form a cyclopropyl ring or a cyclobutyl ring, and R 1 represents a group selected from the following group Q1: X represents a single bond, or
R 3 represents a hydrogen atom, R 1 and R 2 are the same or different and represent a group selected from the following group Q1, X represents a single bond, an oxygen atom, a sulfur atom or a group SO 2 ;
Q1 group includes an aryl group, a substituted aryl group, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a heteroaryl group (the heteroaryl may be condensed with a benzene ring), a substituted heteroaryl A group consisting of a group (the heteroaryl may be fused with a benzene ring), a heterocyclyl group and a substituted heterocyclyl group;
The substituent in the Q1 group is a halogen atom, a C 1 -C 6 haloalkyl group, a C 1 -C 6 alkoxy group, an aryl group, an aryloxy group, an aralkyl group, a heteroaryl group or a substituted heteroaryl group (on the heteroaryl). The substituent is the same or different 1 to 2 substituents selected from the group consisting of a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group and a C 1 -C 6 alkoxy group) It is. However, R 2 and R 3 are both hydrogen atoms, X is a single bond, and R 1 is a benzyl group. Or a pharmacologically acceptable salt thereof,
(2) R 2 and R 3 both represent a hydrogen atom, R 1 represents a group selected from the following group Q2, X represents a single bond, or
R 3 represents a hydrogen atom, R 1 and R 2 are the same or different and represent a group selected from the following group Q2, X represents a single bond, an oxygen atom, a sulfur atom or a group SO 2 ;
Group Q2 is a group consisting of a substituted aryl group, a C 1 -C 6 alkyl group and a substituted heterocyclyl group,
The substituent in the Q2 group is a substituted heteroaryl group (the substituent on the heteroaryl is a group consisting of a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, and a C 1 -C 6 alkoxy group) Or a pharmacologically acceptable salt thereof according to (1), which is the same or different 1 or 2 substituents selected from
(3) 4-hydroxy-3- (1-phenylethyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
3- [1- (4-Butylphenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- on,
3- (1-cyclohexylethyl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-Hydroxy-3- [1- (5-methylthiophen-2-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] Pyridin-6-one,
3- {1- [3- (6-Fluoropyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- (1- {3- [6- (trifluoromethyl) pyridin-3-yl] phenyl} ethyl) -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- {1- [4 '-(trifluoromethyl) biphenyl-3-yl] ethyl} -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] pyridin-6-one,
4-hydroxy-3- {1- [3- (2-isopropoxypyrimidin-5-yl) phenyl] ethyl} -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [ 3,4-b] pyridin-6-one,
4-Hydroxy-4- (trifluoromethyl) -3- (1- {3- [5- (trifluoromethyl) pyrazin-2-yl] phenyl} ethyl) -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3-({1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} methyl) -1,4,5,7-tetrahydro -6H-pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- [1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl] ethyl} -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-Hydroxy-3- {1- [3- (6-methoxypyridin-3-yl) phenyl] ethyl} -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] pyridin-6-one, and
3- {1- [3- (2,6-Difluoropyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo The compound according to (1) or a pharmacologically acceptable salt thereof selected from the group consisting of [3,4-b] pyridin-6-one;
(4) (4R) -4-Hydroxy-3-[(1S) -1-phenylethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4 b] pyridin-6-one,
(4R) -3-{(1S) -1- [3- (6-Fluoropyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-4- (trifluoromethyl) -3-({(3R) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} methyl) -1 , 4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-4- (trifluoromethyl) -3-[(1S) -1-{(3R) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-3- Yl] ethyl} -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one (4R) -4-hydroxy-3-{(1S) -1- [3- (6-methoxypyridin-3-yl) phenyl] ethyl} -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one, and ,
(4R) -3-{(1S) -1- [3- (2,6-Difluoropyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5 , 7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one, or a pharmacologically acceptable salt thereof according to (1),
(5) A pharmaceutical composition comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient,
(6) Arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, comprising as an active ingredient the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof, A pharmaceutical composition for the prevention or treatment of cerebrovascular disease, peripheral vascular disease, dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease,
(7) A prophylactic or therapeutic agent for arteriosclerosis comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient,
(8) A prophylactic or therapeutic agent for dyslipidemia containing the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient,
(9) A preventive agent for a disease caused by an increase in the concentration of LDL cholesterol in blood, comprising as an active ingredient the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof. Or therapeutic agent,
(10) A preventive agent for a disease caused by a decrease in the concentration of HDL cholesterol in blood, comprising as an active ingredient the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof. Or therapeutic agent,
(11) An LCAT activator comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient,
(12) a reversible LCAT activator comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient,
(13) An anti-arteriosclerosis agent comprising the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient,
(14) A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof,
(15) A method for preventing or treating a disease, comprising administering to a human an effective amount of the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof,
(16) For the prevention or treatment of arteriosclerosis, comprising administering to a human an effective amount of the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof. Method,
(17) For preventing or treating dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof. Method,
(18) By increasing the concentration of LDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of the disease caused,
(19) By reducing the concentration of HDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of the disease caused,
(20) The compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis,
(21) The compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia,
(22) The compound according to any one of (1) to (4) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by an increase in the concentration of LDL cholesterol in blood Acceptable salts, and
(23) The compound according to any one of (1) to (4) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by a decrease in the concentration of HDL cholesterol in the blood It is an acceptable salt.

　以下に、本発明の化合物（Ｉ）における置換基の定義を説明する。 Hereinafter, the definition of the substituent in the compound (I) of the present invention will be described.

　本発明の化合物（Ｉ）は、式（Ｉ）で表される化合物、及び、その互変異性体である式 Compound (I) of the present invention is a compound represented by formula (I) or a tautomer thereof.

Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003

で表される化合物の両方を含む。本願では、特に断りのない限り、便宜上、いずれの互変異性体を含む化合物（Ｉ）をも、式（Ｉ）の構造式、及び、それに対応する化学名で表す。また、本発明化合物（Ｉ）のその他の互変異性体（アミド－イミド酸）のいずれの異性体も本願化合物（Ｉ）に含有され、本願では、便宜上、いずれの異性体を含む化合物（Ｉ）をも、式（Ｉ）で表される構造式、及び、それに対応する化学名で表す。 Including both compounds represented by: In the present application, unless otherwise specified, for convenience, the compound (I) containing any tautomer is represented by the structural formula of the formula (I) and the corresponding chemical name. In addition, any isomer of the other tautomer (amide-imidic acid) of the compound (I) of the present invention is contained in the present compound (I). In the present application, for convenience, the compound (I ) Is also represented by the structural formula represented by formula (I) and the corresponding chemical name.

　本発明の化合物（Ｉ）において、「Ｃ３－７シクロアルキル基」は、シクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基のような炭素数３～７個の環状飽和炭化水素基であり、好適には、炭素数３～６個の環状飽和炭化水素基（Ｃ３－６シクロアルキル基）であり、より好適には、シクロプロピル基である。 In the compound (I) of the present invention, the “C 3-7 cycloalkyl group” is a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms (C 3-6 cycloalkyl group) is preferable, and a cyclopropyl group is more preferable.

　本発明の化合物（Ｉ）において、「アリール基」は、例えば、フェニル基又はナフチル基であり、好適には、フェニル基である。 In the compound (I) of the present invention, the “aryl group” is, for example, a phenyl group or a naphthyl group, and is preferably a phenyl group.

　本発明の化合物（Ｉ）において、「Ｃ１－６アルキル基」は、炭素数１～６個の直鎖又は分枝鎖飽和炭化水素基であり、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、イソブチル基、ペンチル基又はヘキシル基であり得、好適には、炭素数１～４個の直鎖又は分枝鎖飽和炭化水素基（Ｃ１－４アルキル基）であり、より好適には、メチル基である。 In the compound (I) of the present invention, the “C 1-6 alkyl group” is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, It may be an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group, or a hexyl group, and is preferably a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms ( C 1-4 alkyl group), more preferably a methyl group.

　本発明の化合物（Ｉ）において、「ヘテロアリール基（当該ヘテロアリールはベンゼン環と縮合していてもよい）」は、例えば、ピリジル基、ピラジニル基、ピリミジル基、ピリダジニル基、フリル基、チエニル基、ベンゾフリル基、ベンゾチエニル基、オキサゾリル基、チアゾリル基、イソキサゾリル基、イソチアゾリル基、ピロール基、ピラゾリル基、イミダゾリル基、トリアゾリル基、ベンゾオキサゾリル基又はベンゾチアゾリル基であり得、好適には、５員又は６員ヘテロアリール基（当該ヘテロアリール環上の複素原子は、窒素原子、酸素原子及び硫黄原子からなる群から選ばれる同一又は異なった１～２個の複素原子である。）（「ヘテロアリール基」）であり、より好適には、ピリジル基、ピラジニル基、ピリミジル基、フリル基、チエニル基、チアゾリル基又はピラゾリル基である。 In the compound (I) of the present invention, the “heteroaryl group (the heteroaryl may be condensed with a benzene ring)” is, for example, a pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, furyl group, thienyl group. , Benzofuryl group, benzothienyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, pyrrole group, pyrazolyl group, imidazolyl group, triazolyl group, benzoxazolyl group or benzothiazolyl group, preferably 5 members Or a 6-membered heteroaryl group (the heteroatoms on the heteroaryl ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) (“heteroaryl More preferably a pyridyl group, pyrazinyl group, pyrimidyl group, Group, a thienyl group, a thiazolyl group or a pyrazolyl group.

　本発明の化合物（Ｉ）において、「ヘテロシクリル基」は、窒素原子、酸素原子及び硫黄原子からなる群より選択される１～３個の原子を含有する単環若しくは二環性の３～１０員の飽和若しくは不飽和の複素環基であり、例えば、アジリジニル基、アゼチジニル基、ピロリジニル基、モルホリニル基、ピロリル基、フリル基、チエニル基、ピラゾリル基、イミダゾリル基、オキサゾリル基、イソチアゾリル基、ピラニル基、ピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基、ベンゾイミダゾリル基、ベンゾオキサゾリル基、キノリル基、ピロリニル基、イミダゾリニル基、ピラゾリニル基、ジヒドロピリジル基、テトラヒドロピリジル基などが挙げられ、好適には、５若しくは６員ヘテロシクリル基であり、より好適には、チエニル基、ピリジル基、テトラヒドロピラニル基、イソオキサゾリル基である。 In the compound (I) of the present invention, the “heterocyclyl group” is a monocyclic or bicyclic 3 to 10 member containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. A saturated or unsaturated heterocyclic group such as aziridinyl group, azetidinyl group, pyrrolidinyl group, morpholinyl group, pyrrolyl group, furyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isothiazolyl group, pyranyl group, Pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, benzimidazolyl group, benzoxazolyl group, quinolyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, dihydropyridyl group, tetrahydropyridyl group, etc. Or a 6-membered heterocyclyl group, more preferably Enyl group, a pyridyl group, a tetrahydropyranyl group, an isoxazolyl group.

　本発明の化合物（Ｉ）において、「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子又はヨウ素原子であり、好適には、フッ素原子又は塩素原子であり、より好適には、塩素原子である。 In the compound (I) of the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom. .

　本発明の化合物（Ｉ）において、「Ｃ１－６ハロアルキル基」は、同一又は異なった１～３個の前記「ハロゲン原子」で置換された前記「Ｃ１－６アルキル基」であり、例えば、フルオロメチル基、クロロメチル基、ブロモメチル基、ジフルオロメチル基、ジクロロメチル基、ジブロモメチル基、トリフルオロメチル基、トリクロロメチル基又は２，２，２－トリフルオロエチル基であり得、好適には、１～３個の塩素原子又は１～３個のフッ素原子で置換されたＣ１－３アルキル基であり、より好適には、トリフルオロメチル基である。 In the compound (I) of the present invention, the “C 1-6 haloalkyl group” is the above “C 1-6 alkyl group” substituted with the same or different 1 to 3 “halogen atoms”, for example, , Fluoromethyl group, chloromethyl group, bromomethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, trifluoromethyl group, trichloromethyl group or 2,2,2-trifluoroethyl group, preferably A C 1-3 alkyl group substituted with 1 to 3 chlorine atoms or 1 to 3 fluorine atoms, and more preferably a trifluoromethyl group.

　本発明の化合物（Ｉ）において、「Ｃ１－６アルコキシ基」は、前記「Ｃ１－６アルキル基」が結合した酸素原子であり、例えば、メトキシ基、エトキシ基、プロポキシ基又はイソプロポキシ基であり得、好適には、前記「Ｃ１－３アルキル基」が結合した酸素原子（Ｃ１－３アルコキシ基）であり、より好適には、メトキシ基である。 In the compound (I) of the present invention, the “C 1-6 alkoxy group” is an oxygen atom to which the “C 1-6 alkyl group” is bonded. For example, a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group Preferably, it is an oxygen atom (C 1-3 alkoxy group) to which the “C 1-3 alkyl group” is bonded, and more preferably a methoxy group.

　本発明の化合物（Ｉ）において、「アリールオキシ基」は、前記「アリール基」が結合した酸素原子であり、例えば、フェノキシ基又はナフチルオキシ基であり得、好適には、フェノキシ基である。 In the compound (I) of the present invention, the “aryloxy group” is an oxygen atom to which the “aryl group” is bonded, and may be, for example, a phenoxy group or a naphthyloxy group, and is preferably a phenoxy group.

　本発明の化合物（Ｉ）において、「アラルキル基」は、前記「アリール基」で置換された前記「Ｃ１－６アルキル基」であり、例えば、ベンジル基又はフェネチル基であり得、好適には、フェニル－Ｃ１－３アルキル基であり、より好適には、ベンジル基である。 In the compound (I) of the present invention, the “aralkyl group” is the “C 1-6 alkyl group” substituted with the “aryl group”, for example, a benzyl group or a phenethyl group, preferably , A phenyl-C 1-3 alkyl group, and more preferably a benzyl group.

　本発明の化合物（Ｉ）は、塩基性基を有するため、薬理上許容される酸との酸付加塩とすることができる。本発明において「その薬理上許容される塩」としては、例えばフッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩等のハロゲン化水素酸塩；硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩等の低級アルカンスルホン酸塩；ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩等のアリールスルホン酸塩；酢酸、リンゴ酸、フマル酸塩、コハク酸塩、クエン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及びオルニチン酸塩、グルタミン酸塩、アスパラギン酸塩等のアミノ酸塩を挙げることができる。 Since the compound (I) of the present invention has a basic group, it can be converted into an acid addition salt with a pharmacologically acceptable acid. In the present invention, “pharmacologically acceptable salts” include, for example, hydrohalides such as hydrofluoric acid salts, hydrochlorides, hydrobromides, hydroiodides; nitrates, perchlorates. Inorganic salts such as sulfates and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salts; organic acid salts such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, succinate, maleate; and amino acid salts such as ornithate, glutamate, aspartate Can be mentioned.

　本発明の化合物（Ｉ）又はその薬理上許容される塩は、大気中に放置されることにより水分を吸収し、水和物になる場合があり、そのような水和物も本発明に包含される。 The compound (I) of the present invention or a pharmacologically acceptable salt thereof may absorb water and become a hydrate when left in the atmosphere, and such a hydrate is also included in the present invention. Is done.

　本発明の化合物（Ｉ）又はその薬理上許容される塩は、溶媒中に放置されることにより、溶媒から取り出して溶媒和物になる場合があり、そのような溶媒和物も本発明に包含される。 The compound (I) of the present invention or a pharmacologically acceptable salt thereof may be taken out from the solvent and become a solvate by leaving it in a solvent, and such a solvate is also encompassed in the present invention. Is done.

　本発明の化合物（Ｉ）には、分子内の不斉中心に基づく光学異性体が存在する。特に断りのない限り、本発明の化合物においては、これらの異性体及びこれらの異性体の混合物が全て単一の式、すなわち一般式（Ｉ）で示されている。従って、本発明はこれらの異性体及びこれらの異性体の混合物をも全て含むものとする。 Compound (I) of the present invention has an optical isomer based on an asymmetric center in the molecule. Unless otherwise specified, in the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers.

　本発明の化合物（Ｉ）は、化合物を構成する原子の１以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素（２Ｈ）、トリチウム（３Ｈ）、ヨウ素－１２５（１２５Ｉ）、又は炭素－１４（１４Ｃ）等が挙げられる。また、前記化合物は、例えば、トリチウム（３Ｈ）、ヨウ素－１２５（１２５Ｉ）、又は炭素－１４（１４Ｃ）等の放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 Compound (I) of the present invention may also contain an unnatural proportion of atomic isotopes at one or more of the atoms constituting the compound. Examples of atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like. In addition, the compound may be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

　本発明の一般式（Ｉ）で表される化合物又はその薬理上許容される塩は、優れたＬＣＡＴ活性化作用を有し、動脈硬化症、動脈硬化性心疾患、冠状動脈性心疾患（心不全、心筋梗塞、狭心症、心虚血、心血管障害及び血管形成性再狭窄を含む）、脳血管疾患（脳卒中及び脳梗塞を含む）、末梢血管疾患（糖尿病血管合併症を含む）、脂質異常症、低ＨＤＬコレステロール血症、高ＬＤＬコレステロール血症、又は、腎疾患の治療剤又は予防剤、特に、抗動脈硬化剤の有効成分として有用である。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activating action, and is arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (heart failure). , Including myocardial infarction, angina pectoris, cardiac ischemia, cardiovascular disorder and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications), lipid abnormalities It is useful as an active ingredient of a therapeutic or prophylactic agent for renal disease, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease, particularly an anti-arteriosclerotic agent.

本発明の試験例１及び２におけるＬＣＡＴ活性化の５０％効果濃度（ＥＣ５０）を求めるため用量反応曲線Dose response curve for determining 50% effective concentration (EC 50 ) of LCAT activation in Test Examples 1 and 2 of the present invention

　以下に、本発明の化合物（Ｉ）及び本発明の化合物（Ｉ）の製造に使用する原料化合物の代表的な製造方法について説明するが、本発明はこれらの方法に限定されるものではない。 Hereinafter, typical methods for producing the compound (I) of the present invention and the starting compound used for the production of the compound (I) of the present invention will be described, but the present invention is not limited to these methods.

　製造法１
　製造法１は、化合物（ＩＩ）から本発明の化合物（Ｉ）を製造する方法である。 Manufacturing method 1
Production method 1 is a method for producing compound (I) of the present invention from compound (II).

Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004

　式中、Ｘ、Ｒ１、Ｒ２、及び、Ｒ３は前記と同意義を示し、Ｒ４はメチル基又はエチル基を示す。 In the formula, X, R 1 , R 2 , and R 3 are as defined above, and R 4 represents a methyl group or an ethyl group.

Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005

　化合物（ＩＩ）には、互変異性体である化合物（ＩＩｘ）が存在する。本発明においては、化合物（ＩＩ）は互変異性体による異性体をもすべて包含する。すなわち、化合物（ＩＩ）は、化合物（ＩＩ）、化合物（ＩＩｘ）、並びに、化合物（ＩＩ）及び化合物（ＩＩｘ）の任意の割合の混合物をもすべて含む。また、化合物（ＩＩ）の化合物名で表される化合物は、化合物（ＩＩ）、化合物（ＩＩｘ）、並びに、化合物（ＩＩ）及び化合物（ＩＩｘ）の任意の割合の混合物をもすべて包含する。 Compound (II) includes compound (IIx) which is a tautomer. In the present invention, compound (II) includes all isomers of tautomers. That is, the compound (II) includes all of the compound (II), the compound (IIx), and a mixture of the compound (II) and the compound (IIx) in an arbitrary ratio. In addition, the compound represented by the compound name of compound (II) includes all of compound (II), compound (IIx), and a mixture of compound (II) and compound (IIx) in an arbitrary ratio.

　（工程１）
　本工程は、化合物（ＩＩ）に、化合物（ＩＩＩ）を、反応に不活性な溶媒中又は溶媒の非存在下、加熱して縮合させることにより、化合物（Ｉ）を製造する工程である。 (Process 1)
This step is a step for producing compound (I) by condensing compound (III) with compound (II) by heating in a solvent inert to the reaction or in the absence of a solvent.

　本工程に用いられる溶媒としては、酢酸、ギ酸、シュウ酸、メタンスルホン酸、ｐ－トルエンスルホン酸、カンファースルホン酸、トリフルオロ酢酸、若しくはトリフルオロメタンスルホン酸のような有機酸類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、若しくはｔｅｒｔ－ブチルメチルエーテルのようなエーテル類；メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔｅｒｔ－ブタノール、イソアミルアルコール、オクタノール、シクロヘキサノール、２－メトキシエタノール、ジエチレングリコール、若しくはグリセリンのようなアルコール類；ベンゼン、トルエン、若しくはキシレンのような芳香族炭化水素類；又は、これらの混合溶媒であり得、好適には、有機酸類であり、より好適には、酢酸である。 Solvents used in this step include organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid; diethyl ether, diisopropyl ether , Tetrahydrofuran, dioxane, dimethoxyethane, or ethers such as tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2 Alcohols such as methoxyethanol, diethylene glycol or glycerol; aromatic hydrocarbons such as benzene, toluene or xylene; or It is a mixed solvent of these, preferably an organic acid, more preferably acetic acid.

　本工程の反応温度は、通常、４０℃乃至１５０℃であり、好適には、５０℃乃至１３０℃であり、より好適には、６０℃乃至溶媒の還流温度である。 The reaction temperature in this step is usually 40 ° C. to 150 ° C., preferably 50 ° C. to 130 ° C., more preferably 60 ° C. to the reflux temperature of the solvent.

　本工程の反応時間は、通常、５分間乃至７２時間であり、好適には、１５分間乃至２４時間であり、より好適には、３０分間乃至３時間である。 The reaction time in this step is usually 5 minutes to 72 hours, preferably 15 minutes to 24 hours, and more preferably 30 minutes to 3 hours.

　製造法２
　本発明の化合物の中間体（ＩＩ）は、例えば次の方法で製造することができる。 Manufacturing method 2
The intermediate (II) of the compound of the present invention can be produced, for example, by the following method.

Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006

　式中、Ｘ、Ｒ１、Ｒ２、及び、Ｒ３は前記と同意義を示し、Ｒ５はアルコキシ基、塩素原子又はオキサゾリジノン補助基（本発明において、オキサゾリジノン補助基は、例えば、２－オキソ－４－置換－１，３－オキサロリジン－３－イル基であり、好適にはキラル－２－オキソ－４－イソプロピル－１，３－オイサゾリジン－３－イル基である。以下同様。）を示し、Ｒａは１個以上のアミノ基（当該アミノ基は、１級又は２級アミノ基であり、環状アミノ基を含む）又は、カルボニル基を有し、工程２－３によりＲ１に変換される基を示す。 In the formula, X, R 1 , R 2 and R 3 are as defined above, and R 5 is an alkoxy group, a chlorine atom or an oxazolidinone auxiliary group (in the present invention, the oxazolidinone auxiliary group is, for example, 2-oxo A -4-substituted-1,3-oxaloridin-3-yl group, preferably a chiral-2-oxo-4-isopropyl-1,3-oisazolidin-3-yl group, and so on. R a has one or more amino groups (the amino group is a primary or secondary amino group, including a cyclic amino group) or a carbonyl group, and is converted to R 1 by Step 2-3. Represents a group.

　（工程２－１）
　本工程の出発物質である化合物（ＩＶ）は、市販のものを用いるか、又は、公知の安息香酸化合物を常法によりエステル化、アミド化、若しくは、酸クロリド化することにより製造することができる。 (Process 2-1)
Compound (IV), which is a starting material for this step, may be a commercially available product, or can be produced by esterifying, amidating, or acidifying a known benzoic acid compound by a conventional method. .

　（ｉ）本工程は、Ｒ５がアルコキシ基、又はオキサゾリジノン補助基である場合、化合物（ＩＶ）を、不活性溶媒中、塩基を用いてアセトニトリルと反応させることにより、化合物（Ｖ）を製造する工程である。 (I) In this step, when R 5 is an alkoxy group or an oxazolidinone auxiliary group, compound (IV) is produced by reacting compound (IV) with acetonitrile in an inert solvent using a base. It is a process.

　本工程に用いられる溶媒としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、若しくはｔｅｒｔ－ブチルメチルエーテルのようなエーテル類；ベンゼン、トルエン、若しくはキシレンのような芳香族炭化水素類；ヘキサンのような脂肪族炭化水素類；又は、これらの混合溶媒であり得、好適には、エーテル類であり、より好適には、テトラヒドロフランである。 Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.

　本工程に用いられる塩基としては、好適には、水素化ナトリウム、炭酸ナトリウム、炭酸カリウム若しくは炭酸セシウムのような無機塩基；又は、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシド若しくはｎ－ブチルリチウムのような有機金属塩基であり得、より好適には、水素化ナトリウム又はｎ－ブチルリチウムである。 The base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide or n-butyllithium. It can be an organometallic base, more preferably sodium hydride or n-butyllithium.

　本工程の反応温度は、好適には、－１００℃乃至０℃であり、より好適には、－７８℃乃至－４０℃である。 The reaction temperature in this step is preferably −100 ° C. to 0 ° C., and more preferably −78 ° C. to −40 ° C.

　本工程の反応時間は、好適には、５分間乃至３時間であり、より好適には、１５分間乃至２時間である。 The reaction time in this step is preferably 5 minutes to 3 hours, and more preferably 15 minutes to 2 hours.

　（ｉｉ）或いは、本工程は、Ｒ５が塩素原子である場合、化合物（ＩＶ）を、不活性溶媒中、塩基を用いてシアノ酢酸と反応させることにより、化合物（Ｖ）を製造する工程である。 (Ii) Alternatively, this step is a step of producing compound (V) by reacting compound (IV) with cyanoacetic acid using a base in an inert solvent when R 5 is a chlorine atom. is there.

　本工程に用いられる溶媒としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、若しくはｔｅｒｔ－ブチルメチルエーテルのようなエーテル類；ベンゼン、トルエン、若しくはキシレンのような芳香族炭化水素類；ヘキサンのような脂肪族炭化水素類；又は、これらの混合溶媒であり得、好適には、エーテル類であり、より好適には、テトラヒドロフランである。 Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.

　本工程に用いられる塩基としては、好適には、水素化ナトリウム、炭酸ナトリウム、炭酸カリウム若しくは炭酸セシウムのような無機塩基；又は、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシド若しくはｎ－ブチルリチウムのような有機金属塩基であり得、より好適には、ｎ－ブチルリチウムである。 The base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide or n-butyllithium. It can be an organometallic base, more preferably n-butyllithium.

　本工程の反応温度は、好適には、－１００℃乃至０℃であり、より好適には、－７８℃乃至－４０℃である。 The reaction temperature in this step is preferably −100 ° C. to 0 ° C., and more preferably −78 ° C. to −40 ° C.

　本工程の反応時間は、好適には、５分間乃至３時間であり、より好適には、１５分間乃至２時間である。 The reaction time in this step is preferably 5 minutes to 3 hours, and more preferably 15 minutes to 2 hours.

　（工程２－２）
　本工程は、化合物（Ｖ）を、不活性溶媒中、ヒドラジン化合物と反応させることにより、化合物（ＩＩ）を製造する工程である。 (Step 2-2)
This step is a step for producing compound (II) by reacting compound (V) with a hydrazine compound in an inert solvent.

　本工程に用いられる溶媒は、メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔｅｒｔ－ブタノール、イソアミルアルコール、オクタノール、シクロヘキサノール、２－メトキシエタノール、ジエチレングリコール、若しくはグリセリンのようなアルコール類；ベンゼン、トルエン、若しくはキシレンのような芳香族炭化水素類；又は、これらの混合溶媒であり得、好適には、アルコール類であり、より好適には、エタノールである。 Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin. Aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably alcohols, more preferably ethanol.

　本工程に用いられるヒドラジン化合物は、無水ヒドラジン、ヒドラジン一水和物、ヒドラジン塩酸塩、ヒドラジン酢酸塩、ヒドラジン硫酸塩、ヒドラジン硝酸塩、ヒドラジン臭化水素酸塩、ヒドラジンシュウ酸塩、又はヒドラジンリン酸塩などであり得、好適にはヒドラジン一水和物又はヒドラジン酢酸塩である。 The hydrazine compound used in this step is anhydrous hydrazine, hydrazine monohydrate, hydrazine hydrochloride, hydrazine acetate, hydrazine sulfate, hydrazine nitrate, hydrazine hydrobromide, hydrazine oxalate, or hydrazine phosphate. Preferred is hydrazine monohydrate or hydrazine acetate.

　本工程の反応温度は、好適には、２０℃乃至１２０℃であり、より好適には、５０℃乃至溶媒の還流温度である。 The reaction temperature in this step is preferably 20 ° C. to 120 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.

　本工程の反応時間は、好適には、１０分間乃至２４時間であり、より好適には、１時間乃至５時間である。 The reaction time in this step is preferably 10 minutes to 24 hours, and more preferably 1 hour to 5 hours.

　（工程２－３）
　（ｉ）本工程は、Ｒａがアミノ基を有する場合、化合物（ＶＩ）を、不活性溶媒中、塩基存在下、ヘテロアリール化剤と反応させることにより、化合物（ＩＶ）を製造する工程である。 (Step 2-3)
(I) This step is a step of producing compound (IV) by reacting compound (VI) with a heteroarylating agent in the presence of a base in an inert solvent when R a has an amino group. is there.

　本工程に用いられる溶媒としては、メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔｅｒｔ－ブタノール、イソアミルアルコール、オクタノール、シクロヘキサノール、２－メトキシエタノール、ジエチレングリコール、若しくはグリセリンのようなアルコール類；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリジノン、若しくはヘキサメチルホスホロトリアミドのようなアミド類；又は、アセトンのようなケトン類が挙げられ、好適には、アルコール類又はアミド類であり、より好適には、Ｎ，Ｎ－ジメチルホルムアミドである。 Solvents used in this step include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin. Alcohols; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; or ketones such as acetone. Are alcohols or amides, and more preferably N, N-dimethylformamide.

　本工程に用いられる塩基としては、水素化ナトリウム、水素化カリウムのような水素化アルカリ金属；炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムのようなアルカリ金属炭酸塩であり、好適には、炭酸カリウムである。 Examples of the base used in this step include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Potassium.

　本工程の反応温度は、好適には、－３０℃乃至１００℃であり、より好適には、０℃乃至３０℃である。 The reaction temperature in this step is preferably −30 ° C. to 100 ° C., and more preferably 0 ° C. to 30 ° C.

　本工程の反応時間は、好適には、３０分間乃至２４時間であり、より好適には１時間乃至１０時間である。 The reaction time in this step is preferably 30 minutes to 24 hours, and more preferably 1 hour to 10 hours.

　本工程に用いられるヘテロアリール化剤は、式Ｒｂ－Ｃｌ、式Ｒｂ－Ｂｒ又は式Ｒｂ－Ｉを有する化合物であり、好適には、式Ｒｂ－Ｂｒ又は式Ｒｂ－Ｉを有する化合物である（Ｒｂは、Ｑ１群のうち、ヘテロアリール基又は置換ヘテロアリールを示す。）。
（ｉｉ）或いは、本工程は、化合物（ＶＩ）のＲａがカルボニル基を有する場合、化合物（ＶＩ）を、不活性な溶媒中又は溶媒の非存在下、還元することにより、化合物（ＩＶ）を製造する工程である。 The heteroarylating agent used in this step is a compound having the formula R b —Cl, the formula R b —Br or the formula R b —I, preferably the formula R b —Br or the formula R b —I (R b represents a heteroaryl group or a substituted heteroaryl in the Q1 group).
(Ii) Alternatively, in this step, when R a of compound (VI) has a carbonyl group, compound (VI) is reduced by reducing compound (VI) in an inert solvent or in the absence of a solvent. Is a process of manufacturing.

　本工程に用いられる溶媒としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、若しくはｔｅｒｔ－ブチルメチルエーテルのようなエーテル類；メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔｅｒｔ－ブタノール、イソアミルアルコール、オクタノール、シクロヘキサノール、２－メトキシエタノール、ジエチレングリコール、若しくはグリセリンのようなアルコール類；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリジノン、若しくはヘキサメチルホスホロトリアミドのようなアミド類；アセトンのようなケトン類；又は、ジクロロメタン、ジクロロエタン、クロロホルムのようなハロゲン化アルキル類が挙げられ、好適には、エーテル類、アミド類、又は、ハロゲン化アルキル類であり、より好適には、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド、若しくはジクロロメタンである。 Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol , Tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or alcohols such as glycerin; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, Or amides such as hexamethylphosphorotriamide; ketones such as acetone; or dichloromethane, dichloroethane, chloroform Alkyl halides can be mentioned a, preferably, ethers, amides, or a halogenated alkyls, more preferably, tetrahydrofuran, N, N- dimethylformamide, or dichloromethane.

　本工程に用いられる試薬の組み合わせとしては、パラジウム－炭素と水素、塩化アルミニウムと水素化リチウムアルミニウム、若しくは、トリエチルシランとトリフルオロ酢酸などが挙げられ、好適には、トリエチルシランとトリフルオロ酢酸である。 Examples of the combination of reagents used in this step include palladium-carbon and hydrogen, aluminum chloride and lithium aluminum hydride, or triethylsilane and trifluoroacetic acid, and preferably triethylsilane and trifluoroacetic acid. .

　本工程の反応温度は、好適には、－３０℃乃至５０℃であり、より好適には、０℃乃至３０℃である。 The reaction temperature in this step is preferably −30 ° C. to 50 ° C., and more preferably 0 ° C. to 30 ° C.

　本工程の反応時間は、好適には、３０分間乃至４８時間であり、より好適には５時間乃至２４時間である。 The reaction time in this step is preferably 30 minutes to 48 hours, and more preferably 5 hours to 24 hours.

　製造法３
　製造法３は、化合物（Ｖ）から、本発明の化合物（Ｉ）を製造する方法である。 Production method 3
Production method 3 is a method for producing compound (I) of the present invention from compound (V).

Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007

　式中、Ｘ、Ｒ１、Ｒ２、Ｒ３、及び、Ｒ４は前記と同意義を示す。 In the formula, X, R 1 , R 2 , R 3 , and R 4 are as defined above.

　（工程３－１）
　本工程は、化合物（Ｖ）を、不活性溶媒中、ジフェニルメチルヒドラジン化合物と反応させることにより、化合物（ＩＩａ）を製造する工程である。 (Step 3-1)
This step is a step for producing compound (IIa) by reacting compound (V) with a diphenylmethylhydrazine compound in an inert solvent.

　本工程に用いられる溶媒は、メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔｅｒｔ－ブタノール、イソアミルアルコール、オクタノール、シクロヘキサノール、２－メトキシエタノール、ジエチレングリコール、若しくはグリセリンのようなアルコール類；ベンゼン、トルエン、若しくはキシレンのような芳香族炭化水素類；又は、これらの混合溶媒であり得、好適には、アルコール類であり、より好適には、エタノールである。 Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin. Aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably alcohols, more preferably ethanol.

　本工程に用いられるジフェニルメチルヒドラジン化合物は、無水ジフェニルメチルヒドラジン、ジフェニルメチルヒドラジン塩酸塩、ジフェニルメチルヒドラジン酢酸塩などであり得、好適にはジフェニルメチルヒドラジン塩酸塩又はジフェニルメチルヒドラジン酢酸塩である。 The diphenylmethyl hydrazine compound used in this step can be anhydrous diphenylmethyl hydrazine, diphenylmethyl hydrazine hydrochloride, diphenylmethyl hydrazine acetate, etc., and is preferably diphenylmethyl hydrazine hydrochloride or diphenylmethyl hydrazine acetate.

　本工程の反応温度は、好適には、２０℃乃至１２０℃であり、より好適には、５０℃乃至溶媒の還流温度である。 The reaction temperature in this step is preferably 20 ° C. to 120 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.

　本工程の反応時間は、好適には、１０分間乃至２４時間であり、より好適には、１時間乃至５時間である。 The reaction time in this step is preferably 10 minutes to 24 hours, and more preferably 1 hour to 5 hours.

　（工程３－２）
　本工程は、化合物（ＩＩａ）に、化合物（ＩＩＩ）を、反応に不活性な溶媒中又は溶媒の非存在下、加熱して縮合させることにより、化合物（Ｉａ）を製造する工程である。 (Step 3-2)
In this step, compound (Ia) is produced by condensing compound (III) with compound (III) by heating in a solvent inert to the reaction or in the absence of a solvent.

　本工程は、工程１と同様の条件で行うことができる。 This step can be performed under the same conditions as in step 1.

　（工程３－３）
　本工程は、化合物（Ｉａ）のジフェニルメチル基を、不活性溶媒中、除去することにより、化合物（Ｉ）を製造する工程である。 (Step 3-3)
This step is a step for producing compound (I) by removing the diphenylmethyl group of compound (Ia) in an inert solvent.

　化合物（ＩＩａ）におけるジフェニルメチル基の除去に使用される試薬としては、例えば、Ｐ．Ｇ．Ｗｕｔｓ，Ｔ．Ｗ．Ｇｒｅｅｎｅ，Ｇｒｅｅｎｅ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ．Ｔｈｉｒｄ　Ｅｄｉｔｉｏｎ，２００６年，Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，Ｉｎｃ．などに記載されているトリチル基の除去が可能な試薬などが挙げられる。 Examples of the reagent used for removing the diphenylmethyl group in the compound (IIa) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like, which can remove the trityl group described in the above.

　本工程に用いられる溶媒は、好適には、メタノール、若しくはエタノールのようなアルコール類：テトラヒドロフラン、若しくは１，４－ジオキサンのようなエーテル類；ジクロロメタン、若しくはクロロホルムのようなハロゲン化アルキル類；酢酸エチルのようなエステル類；トルエンのような芳香族炭化水素類；又は、これらの混合溶媒であり、より好適には、ハロゲン化アルキル類であり、更により好適には、ジクロロメタンである。 Solvents used in this step are preferably alcohols such as methanol or ethanol: ethers such as tetrahydrofuran or 1,4-dioxane; alkyl halides such as dichloromethane or chloroform; ethyl acetate Esters such as toluene; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alkyl halides, and still more preferably dichloromethane.

　本工程に用いられる試薬は、好適には、塩酸、トリフルオロ酢酸であり、より好適には、トリフルオロ酢酸であり、添加剤として、トリエチルシラン、アニソール又はチオアニソールなどのカチオンスカベンジャーと呼ばれる化合物を用いてもよい。 The reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, more preferably trifluoroacetic acid, and a compound called a cation scavenger such as triethylsilane, anisole or thioanisole as an additive. It may be used.

　本工程の反応温度は、好適には、０℃乃至１００℃であり、より好適には、０℃乃至５０℃である。 The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.

　本工程の反応時間は、好適には、５分間乃至２４時間であり、より好適には、１０分間から６時間である。 The reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.

　製造法４
　本発明の化合物の中間体（ＩＶ）のうち、式（ＩＶａ）で表される化合物は、例えば次の方法で製造することができる。 Manufacturing method 4
Of the intermediate (IV) of the compound of the present invention, the compound represented by the formula (IVa) can be produced, for example, by the following method.

Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008

　式中、Ｘ、Ｒ１、及び、Ｒ２は前記と同意義を示し、Ｒ６は水酸基、アルコキシ基、又はオキサゾリジノン補助基を示す。 In the formula, X, R 1 and R 2 are as defined above, and R 6 represents a hydroxyl group, an alkoxy group, or an oxazolidinone auxiliary group.

　（工程４）
　本工程は、化合物（ＶＩＩ）を、不活性溶媒中、塩基を用いてアルキル化剤と反応させることにより、化合物（ＩＶａ）を製造する工程である。 (Process 4)
This step is a step for producing compound (IVa) by reacting compound (VII) with an alkylating agent using a base in an inert solvent.

　本工程に用いられる溶媒としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、若しくはｔｅｒｔ－ブチルメチルエーテルのようなエーテル類；ベンゼン、トルエン、若しくはキシレンのような芳香族炭化水素類；ヘキサンのような脂肪族炭化水素類；又は、これらの混合溶媒であり得、好適には、エーテル類であり、より好適には、テトラヒドロフランである。 Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.

　本工程に用いられる塩基としては、好適には、水素化ナトリウム、炭酸ナトリウム、炭酸カリウム若しくは炭酸セシウムのような無機塩基；又は、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムジイソプロピルアミド、リチウムヘキサメチレンジシラジド、ナトリウムヘキサメチレンジシラジド若しくはカリウムヘキサメチレンジシラジドのような有機金属塩基であり得、より好適には、リチウムジイソプロピルアミド又はリチウムヘキサメチレンジシラジドである。 The base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide, n-butyllithium, lithium diisopropyl It can be an organometallic base such as amide, lithium hexamethylene disilazide, sodium hexamethylene disilazide or potassium hexamethylene disilazide, more preferably lithium diisopropylamide or lithium hexamethylene disilazide.

　本工程に用いられるアルキル化剤としては、好適には、ヨウ化メチル、ヨウ化エチル若しくはジメチル硫酸であり得、より好適には、ヨウ化メチルである。 The alkylating agent used in this step can be preferably methyl iodide, ethyl iodide or dimethyl sulfate, and more preferably methyl iodide.

　本工程の反応温度は、好適には、－１００℃乃至０℃であり、より好適には、－７８℃乃至５℃である。 The reaction temperature in this step is preferably −100 ° C. to 0 ° C., and more preferably −78 ° C. to 5 ° C.

　本工程の反応時間は、好適には、３０分間乃至５時間であり、より好適には、３０分間乃至２時間である。 The reaction time in this step is preferably 30 minutes to 5 hours, and more preferably 30 minutes to 2 hours.

　製造法５
　本発明の化合物の中間体（ＩＶ）のうち、式（ＩＶｂ）で表される化合物は、例えば次の方法で製造することができる。 Manufacturing method 5
Among the intermediates (IV) of the compound of the present invention, the compound represented by the formula (IVb) can be produced, for example, by the following method.

Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009

　式中、Ｒ１は前記と同意義を示し、Ｒ７はメチル基、又はエチル基を示し、Ｒ８は水素原子、メチル基、又はエチル基を示し、Ｘａは、塩素原子、臭素原子、及び、ヨウ素原子を示す。 In the formula, R 1 is as defined above, R 7 is a methyl group or an ethyl group, R 8 is a hydrogen atom, a methyl group, or an ethyl group, X a is a chlorine atom, a bromine atom, And an iodine atom.

　（工程５－１）
　本工程は、化合物（ＶＩＩＩ）とマロン酸エステル化合物（ＩＸ）を、パラジウム触媒を用いて反応させることより、化合物（Ｘ）を製造する工程である。 (Step 5-1)
This step is a step for producing compound (X) by reacting compound (VIII) with malonic ester compound (IX) using a palladium catalyst.

　本工程は、例えば、Ｎ．Ａ．Ｂｅａｒｅ,Ｊ．Ｆ．Ｈａｒｔｗｉｇ，Ｊ．Ｏｒｇ．Ｃｈｅｍ．、２００２年、第６７巻、第５４１－５５５頁に記載されている方法に準じて行うことができる。 This process is, for example, N. A. Beare, J .; F. Hartwig, J. et al. Org. Chem. , 2002, Vol. 67, pp. 541-555.

　（工程５－２）
　本工程は、化合物（Ｘ）を、酸性条件下、若しくは、塩基性条件下にて、化合物（ＩＶｂ）を製造する工程である。 (Step 5-2)
This step is a step of producing compound (IVb) from compound (X) under acidic conditions or basic conditions.

　本工程に用いられる溶媒は、好適には、メタノール、若しくはエタノールのようなアルコール類；テトラヒドロフラン、若しくは１，４－ジオキサンのようなエーテル類；トルエンのような芳香族炭化水素類；又はこれらの混合溶媒であり、より好適には、アルコール類又はエーテル類であり、更により好適には、エタノール、又は１，４－ジオキサンである。 The solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an aromatic hydrocarbon such as toluene; or a mixture thereof. It is a solvent, more preferably an alcohol or an ether, and still more preferably ethanol or 1,4-dioxane.

　本工程に用いられる試薬は、好適には、塩酸、水酸化ナトリウム水溶液である。 The reagent used in this step is preferably hydrochloric acid or a sodium hydroxide aqueous solution.

　本工程の反応温度は、好適には、０℃乃至１００℃であり、より好適には、２０℃乃至７０℃である。 The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 20 ° C. to 70 ° C.

　本工程の反応時間は、好適には、１時間乃至１０時間であり、より好適には、２分間から６時間である。 The reaction time in this step is preferably 1 hour to 10 hours, and more preferably 2 minutes to 6 hours.

　製造法６
　本発明の化合物の中間体（ＩＶ）のうち、Ｘが酸素原子である式（ＩＶｃ）で表される化合物は、例えば次の方法で製造することができる。 Manufacturing method 6
Among the intermediates (IV) of the compound of the present invention, the compound represented by the formula (IVc) in which X is an oxygen atom can be produced, for example, by the following method.

Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010

　式中、Ｒ１は前記と同意義を示し、Ｒ７はメチル基、又はエチル基を示し、Ｘｂは塩素原子、臭素原子、又はヨウ素原子を示す。 In the formula, R 1 is as defined above, R 7 represents a methyl group or an ethyl group, and X b represents a chlorine atom, a bromine atom, or an iodine atom.

　（工程６）
本工程は、化合物（ＸＩ）と化合物（ＸＩＩ）を、不活性溶媒中、塩基存在下反応させることによる、化合物（ＩＶｃ）を製造する工程である。 (Step 6)
This step is a step for producing compound (IVc) by reacting compound (XI) with compound (XII) in the presence of a base in an inert solvent.

　本工程に用いられる溶媒としては、メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔｅｒｔ－ブタノール、イソアミルアルコール、オクタノール、シクロヘキサノール、２－メトキシエタノール、ジエチレングリコール、若しくはグリセリンのようなアルコール類；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリジノン、若しくはヘキサメチルホスホロトリアミドのようなアミド類；又は、アセトンのようなケトン類が挙げられ、好適には、アルコール類又はアミド類であり、より好適には、Ｎ，Ｎ－ジメチルホルムアミドである。 Solvents used in this step include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin. Alcohols; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; or ketones such as acetone. Are alcohols or amides, and more preferably N, N-dimethylformamide.

　本工程に用いられる塩基としては、水素化ナトリウム、水素化カリウムのような水素化アルカリ金属；炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムのようなアルカリ金属炭酸塩であり、好適には、炭酸セシウムである。 Examples of the base used in this step include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Cesium.

　本工程の反応温度は、好適には、－３０℃乃至１５０℃であり、より好適には、２０℃乃至１００℃である。 The reaction temperature in this step is preferably −30 ° C. to 150 ° C., and more preferably 20 ° C. to 100 ° C.

　本工程の反応時間は、好適には、３０分間乃至２４時間であり、より好適には１時間乃至１０時間である。 The reaction time in this step is preferably 30 minutes to 24 hours, and more preferably 1 hour to 10 hours.

　製造法７
　本発明の化合物の中間体（ＩＩ）のうち、式（ＩＩｃ）で表される化合物は、例えば次の方法で製造することができる。 Manufacturing method 7
Of the intermediate (II) of the compound of the present invention, the compound represented by the formula (IIc) can be produced, for example, by the following method.

Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011

　式中、Ｒ２、及び、Ｒ３は前記と同意義を示し、Ｘ１は、塩素原子、臭素原子、ヨウ素原子、又は４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル基を示し、Ｒ９は、Ｑ１群のうち、アリール基、置換アリール基、ヘテロアリール基、又は置換ヘテロアリール基を示し、Ｘ２は、Ｂ（ＯＨ）２、臭素原子、又はヨウ素原子を示す。 In the formula, R 2 and R 3 are as defined above, and X 1 is a chlorine atom, a bromine atom, an iodine atom, or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Represents a -2-yl group, R 9 represents an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group in the Q1 group, and X 2 represents B (OH) 2 , a bromine atom, or Indicates an iodine atom.

　（工程７）
　本工程は、Ｘ１が塩素原子、臭素原子、又はヨウ素原子であるハロゲン化化合物（ＩＩｂ）を、パラジウム触媒を用いた鈴木－宮浦反応により、Ｘ２がＢ（ＯＨ）２である有機ホウ素化合物（ＸＩＩＩ）と反応させる、若しくは、Ｘ１が４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル基である有機ホウ素化合物（ＩＩｂ）を、パラジウム触媒を用いた鈴木－宮浦反応により、Ｘ２が臭素原子、又は、ヨウ素原子であるハロゲン化化合物（ＸＩＩＩ）と反応させ、化合物（ＩＩｃ）を製造する工程である。 (Step 7)
In this step, a halogenated compound (IIb) in which X 1 is a chlorine atom, a bromine atom, or an iodine atom is converted into an organoboron compound in which X 2 is B (OH) 2 by a Suzuki-Miyaura reaction using a palladium catalyst. (XIII) or an organoboron compound (IIb) in which X 1 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group using a palladium catalyst In this step, compound (IIc) is produced by reacting with halogenated compound (XIII) wherein X 2 is bromine atom or iodine atom by Suzuki-Miyaura reaction.

　本工程に用いられるパラジウム触媒、リガンド、塩基ならびに反応条件は、通常の鈴木－宮浦反応に使用される試薬および条件であれば特に限定されないが、例えば、Ｎ．Ｍｉｙａｕｒａ，Ａ．Ｓｕｚｕｋｉ，Ｃｈｅｍ．Ｒｅｖ．１９９５年，９５巻，ｐ．２４５７などに記載されている。 The palladium catalyst, ligand, base and reaction conditions used in this step are not particularly limited as long as they are reagents and conditions used in the usual Suzuki-Miyaura reaction. Miyaura, A .; Suzuki, Chem. Rev. 1995, volume 95, p. 2457 and the like.

　本工程に用いられる溶媒は、メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔｅｒｔ－ブタノール、イソアミルアルコール、オクタノール、シクロヘキサノール、２－メトキシエタノール、ジエチレングリコール、若しくはグリセリンのようなアルコール類；ベンゼン、トルエン、若しくはキシレンのような芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、若しくはｔｅｒｔ－ブチルメチルエーテルのようなエーテル類；水；又は、これらの混合溶媒であり得、好適には、エーテル類及び水の混合溶媒であり、更により好適には、１，４－ジオキサン及び水の混合溶媒である。 Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin. Aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; water; or a mixed solvent thereof And is preferably a mixed solvent of ethers and water, and more preferably a mixed solvent of 1,4-dioxane and water.

　本工程に用いられるパラジウム触媒としては、好適には、テトラキストリフェニルホスフィンパラジウム又は［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロロメタン付加物である。 The palladium catalyst used in this step is preferably tetrakistriphenylphosphine palladium or [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct.

　本工程に用いられる塩基としては、好適には、水素化ナトリウム、炭酸ナトリウム、炭酸カリウム若しくは炭酸セシウムのような無機塩基や、ナトリウムｔｅｒｔ－ブトキシド、若しくはカリウムｔｅｒｔ－ブトキシドのような有機金属塩基であり得、より好適には、炭酸カリウムである。 The base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate, or an organic metal base such as sodium tert-butoxide or potassium tert-butoxide. More preferably, it is potassium carbonate.

　製造法８
　製造法８は、化合物（ＸＩＶ）から本発明の化合物（Ｉｃ）及び（Ｉｄ）を製造する方法である。 Manufacturing method 8
Production method 8 is a method for producing compounds (Ic) and (Id) of the present invention from compound (XIV).

Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012

　式中、Ｘ、Ｒ２、又はＲ３は前記と同意義を示し、Ｒｘは、Ｑ１群のうち、アリール基、置換アリール基、ヘテロアリール基、又は置換ヘテロアリール基を示し、Ｂｏｃはｔｅｒｔ－ブトキシカルボニル基を示す。 In the formula, X, R 2 or R 3 is as defined above, R x represents an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group in the Q1 group, and Boc is tert. -Represents a butoxycarbonyl group.

　（工程８－１）
　本工程は、化合物（ＸＩＶ）におけるＢｏｃ基を、除去することにより、化合物（Ｉｃ）を製造する工程である。 (Step 8-1)
This step is a step of producing compound (Ic) by removing the Boc group in compound (XIV).

　化合物（ＸＩＶ）におけるＢｏｃの除去に使用される試薬としては、例えば、Ｐ．Ｇ．Ｗｕｔｓ，Ｔ．Ｗ．Ｇｒｅｅｎｅ，Ｇｒｅｅｎｅ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ．Ｔｈｉｒｄ　Ｅｄｉｔｉｏｎ，２００６年，Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，Ｉｎｃ．などに記載されているＢｏｃの除去が可能な試薬などが挙げられる。 Examples of reagents used for removing Boc in compound (XIV) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like which can remove Boc described in the above.

　本工程に用いられる溶媒は、好適には、メタノール、若しくはエタノールのようなアルコール類；テトラヒドロフラン、若しくは１，４－ジオキサンのようなエーテル類；ジクロロメタン、若しくはクロロホルムのようなハロゲン化アルキル類；酢酸エチルのようなエステル類；トルエンのような芳香族炭化水素類；又はこれらの混合溶媒であり、より好適には、ハロゲン化アルキル類であり、更により好適には、ジクロロメタンである。 The solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an alkyl halide such as dichloromethane or chloroform; Esters such as toluene; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alkyl halides, and still more preferably dichloromethane.

　本工程に用いられる試薬は、好適には、塩酸、トリフルオロ酢酸であり、より好適には、トリフルオロ酢酸である。 The reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, and more preferably trifluoroacetic acid.

　本工程の反応温度は、好適には、０℃乃至１００℃であり、より好適には、０℃乃至５０℃である。 The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.

　本工程の反応時間は、好適には、５分間乃至２４時間であり、より好適には、１０分間から６時間である。 The reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.

　（工程８－２）
　本工程は、化合物（Ｉｃ）を、アリール化剤若しくはヘテロアリール化剤と反応させることにより、化合物（Ｉｄ）を製造する工程である。 (Step 8-2)
This step is a step for producing compound (Id) by reacting compound (Ic) with an arylating agent or heteroarylating agent.

　本工程は、工程２－３の（ｉ）と同様の条件で行うことができる。 This step can be performed under the same conditions as in step 2-3 (i).

　上記各工程の生成物は、遊離化合物又はその塩として、反応終了後、必要に応じて、常法、例えば、（１）反応液をそのまま濃縮する方法、（２）触媒等の不溶物をろ過により除去し、ろ液を濃縮する方法、（３）反応液に水及び水と混和しない溶媒（例えば、ジクロロエタン、ジエチルエーテル、酢酸エチル、トルエン等）を加え、生成物を抽出する方法、（４）結晶化した又は沈殿した生成物をろ取する方法等により、反応混合物から単離することができる。単離された生成物は、必要に応じて、常法、例えば、再結晶、再沈殿、各種クロマトグラフィー等により、精製することができる。又は、各工程の生成物は、単離又は精製することなく次の工程に用いることもできる。 The product of each of the above steps is a free compound or a salt thereof, after completion of the reaction, if necessary, a conventional method, for example, (1) a method of concentrating the reaction solution as it is, or (2) filtering insoluble matter such as a catalyst. (3) A method in which water and a solvent immiscible with water (for example, dichloroethane, diethyl ether, ethyl acetate, toluene, etc.) are added to the reaction solution, and the product is extracted (4) ) The crystallized or precipitated product can be isolated from the reaction mixture, such as by filtration. The isolated product can be purified by a conventional method such as recrystallization, reprecipitation, various chromatographies and the like, if necessary. Alternatively, the product of each step can be used in the next step without isolation or purification.

　本発明の化合物（Ｉ）は、遊離化合物、その薬理上許容される塩、水和物、又は溶媒和物の物質として単離され、精製される。本発明の化合物（I）の薬理上許容される塩は、常法の造塩反応に付すことにより、製造することができる。単離、精製は、抽出、濃縮、留去、結晶化、ろ過、再結晶、又は各種クロマトグラフィー等の通常の化学操作を適用して行われる。 Compound (I) of the present invention is isolated and purified as a free compound, a pharmacologically acceptable salt, hydrate, or solvate thereof. The pharmacologically acceptable salt of the compound (I) of the present invention can be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, or various chromatography.

　各種の異性体は、異性体間の物理化学的性質の差を利用して分離することができる。例えば、ラセミ混合物は、光学活性な塩基若しくは酸とのジアステレオマー塩に導く分別結晶化又はキラルカラムを用いたクロマトグラフィー等により、光学的に純粋な異性体に導くことができる。又、ジアステレオ混合物は、分別結晶化又は各種クロマトグラフィー等により分離できる。又、光学活性な化合物は適当な光学活性な原料を用いることにより製造することもできる。 Various isomers can be separated by utilizing differences in physicochemical properties between isomers. For example, a racemic mixture can be converted to an optically pure isomer, such as by fractional crystallization leading to a diastereomeric salt with an optically active base or acid, or chromatography using a chiral column. Further, the diastereo mixture can be separated by fractional crystallization or various chromatographies. An optically active compound can also be produced by using an appropriate optically active raw material.

　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩の投与形態としては、例えば、錠剤、顆粒剤、散剤、カプセル剤若しくはシロップ剤等による経口投与、又は注射剤若しくは坐剤等による非経口投与を挙げることができ、全身的又は局所的に投与することができる。 Examples of the administration form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include oral administration by tablet, granule, powder, capsule or syrup, or injection or suppository. Parenteral administration, and the like, and can be administered systemically or locally.

　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩の経口用の医薬の形態としては、錠剤、丸剤、顆粒剤、散剤、カプセル剤、液剤、懸濁剤、乳剤、シロップ剤、又はエリキシル剤等が挙げられる。非経口用の医薬の形態としては、注射剤、軟膏剤、ゲル剤、クリーム剤、貼付剤、噴霧剤、吸入剤、スプレー剤、点眼剤、又は坐剤等が挙げられる。これらの形態の医薬は、賦形剤、結合剤、希釈剤、安定化剤、防腐剤、着色剤、溶解補助剤、懸濁化剤、緩衝剤、又は湿潤化剤等の薬学的に許容される添加剤から、必要に応じて適宜選択した添加剤を用いて、常法に従って調製することができる。 Examples of the oral pharmaceutical form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, Examples include syrups and elixirs. Examples of pharmaceutical forms for parenteral use include injections, ointments, gels, creams, patches, sprays, inhalants, sprays, eye drops, and suppositories. These forms of pharmaceuticals are pharmaceutically acceptable, such as excipients, binders, diluents, stabilizers, preservatives, colorants, solubilizers, suspending agents, buffering agents, or wetting agents. The additive can be prepared according to a conventional method using additives appropriately selected as necessary.

　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩の投与する際の投与量は、その投与される者（温血動物、例えばヒト）の症状、体重、年齢、投与方法等により異なる。例えば、経口投与の場合には、１回当たり、下限として０．０１ｍｇ／ｋｇ体重（好ましくは、０．０３ｍｇ／ｋｇ体重）、上限として、３００ｍｇ／ｋｇ体重（好ましくは、１００ｍｇ／ｋｇ体重）を、１日当たり１乃至数回、症状に応じて投与することが望ましい。また、静脈内投与の場合には、１回当たり、下限として０．０１ｍｇ／ｋｇ体重（好ましくは、０．０３ｍｇ／ｋｇ体重）、上限として、３００ｍｇ／ｋｇ体重（好ましくは、１００ｍｇ／ｋｇ体重）を１日あたり１乃至数回、症状に応じて投与することが望ましい。 The dosage of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is as follows: symptoms, body weight, age, administration method of the administered person (warm-blooded animal, eg, human) Varies depending on etc. For example, in the case of oral administration, the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). It is desirable to administer one to several times a day depending on the symptoms. In the case of intravenous administration, the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). Is preferably administered one to several times per day depending on the symptoms.

 
　以下、実施例、試験例及び製剤例を挙げて本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。以下の実施例において、ヘキサンは、ｎ－ヘキサンを示し、ＴＨＦはテトラヒドロフランを示し、ＩＰＡは２－プロパノールを示し、ＤＭＦはＮ，Ｎ’－ジメチルホルムアミドを示し、ＤＭＳＯはジメチルスルホキシドを示す。
EXAMPLES Hereinafter, although an Example, a test example, and a formulation example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these. In the following examples, hexane represents n-hexane, THF represents tetrahydrofuran, IPA represents 2-propanol, DMF represents N, N′-dimethylformamide, and DMSO represents dimethyl sulfoxide.

　（参考例１）３－（ビフェニル－４－イル）－３－オキソブタンニトリル (Reference Example 1) 3- (Biphenyl-4-yl) -3-oxobutanenitrile

Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013

　４－ビフェニル酢酸（１．０１ｇ、４．７６ｍｍｏｌ）のジクロロメタン（２０ｍＬ）懸濁液に、ＤＭＦ（パスツールピペット３滴）を加え、塩化オキサリル（２．０８ｍｌ、２３．８ｍｍｏｌ）を加え、室温にて1時間攪拌した。反応液は、減圧下にて、溶媒を留去し、粗生成物（１．１５ｇ）を得た。 To a suspension of 4-biphenylacetic acid (1.01 g, 4.76 mmol) in dichloromethane (20 mL) is added DMF (3 drops of Pasteur pipette), oxalyl chloride (2.08 ml, 23.8 mmol) is added, and the mixture is brought to room temperature. And stirred for 1 hour. In the reaction solution, the solvent was distilled off under reduced pressure to obtain a crude product (1.15 g).

　シアノ酢酸（４２５ｍｇ、５．００ｍｍｏｌ）、２，２’－ビピリジル（１ｍｇ）の無水ＴＨＦ（２０ｍＬ）溶液に、－７８℃にてｎ－ブチルリチウム（１．６７Ｍヘキサン溶液、６．０ｍＬ、１０．０ｍｍｏｌ）を滴下し１５分間攪拌した。更に同温度にて、上記操作で得られた粗生成物（５７６ｍｇ）の無水ＴＨＦ（５ｍＬ）溶液を滴下し、３０分間攪拌した。反応液をジエチルエーテル、１Ｍ塩酸の２層液に加えよく攪拌し、得られた有機層を無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣を酢酸エチル、ヘキサンを用い粉末化し、標記化合物（４４０ｍｇ、収率：７５％）を得た。 To a solution of cyanoacetic acid (425 mg, 5.00 mmol) and 2,2′-bipyridyl (1 mg) in anhydrous THF (20 mL) at −78 ° C., n-butyllithium (1.67 M hexane solution, 6.0 mL, 10. 0 mmol) was added dropwise and stirred for 15 minutes. Further, at the same temperature, a solution of the crude product (576 mg) obtained in the above operation in anhydrous THF (5 mL) was added dropwise and stirred for 30 minutes. The reaction solution was added to a two-layer solution of diethyl ether and 1M hydrochloric acid and stirred well. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was triturated with ethyl acetate and hexane to give the title compound (440 mg, yield: 75%).

　1H-NMR (400MHz, CDCl3) δ: 7.63-7.55 (4H, m), 7.48-7.42 (2H, m), 7.39-7.34 (1H, m), 7.32-7.28 (2H, m), 3.92 (2H, s), 3.51 (2H, s)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.63-7.55 (4H, m), 7.48-7.42 (2H, m), 7.39-7.34 (1H, m), 7.32-7.28 (2H, m), 3.92 ( 2H, s), 3.51 (2H, s).

　（参考例２）３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミン (Reference Example 2) 3- (Biphenyl-4-ylmethyl) -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014

　参考例１にて製造された３－（ビフェニル－４－イル）－３－オキソブタンニトリル（４４０ｍｇ、１．８７ｍｍｏｌ）のエタノール（５ｍＬ）溶液に、ヒドラジン一水和物（０．１８２ｍＬ、３．７４ｍｍｏｌ）を加え、加熱還流下３時間攪拌した。反応液を室温で放置し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル／メタノール＝１００／０－９０／１０（グラジェント）］で精製し、標記化合物（３１６ｍｇ、収率：６８％）を得た。 To a solution of 3- (biphenyl-4-yl) -3-oxobutanenitrile (440 mg, 1.87 mmol) prepared in Reference Example 1 in ethanol (5 mL), hydrazine monohydrate (0.182 mL, 3. 74 mmol) was added, and the mixture was stirred for 3 hours under heating to reflux. The reaction solution was allowed to stand at room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-90 / 10 (gradient)] to obtain the title compound (316 mg, yield: 68%).

　1H-NMR (400MHz, CDCl3) δ: 7.60-7.52 (4H, m), 7.47-7.41 (2H, m), 7.37-7.32 (1H, m), 7.30-7.26 (2H, m), 5.52 (1H, s), 3.94 (2H, s)。
（参考例３）３－（ビフェニル－３－イルメチル）－１Ｈ－ピラゾール－５－アミン 1 H-NMR (400MHz, CDCl 3 ) δ: 7.60-7.52 (4H, m), 7.47-7.41 (2H, m), 7.37-7.32 (1H, m), 7.30-7.26 (2H, m), 5.52 ( 1H, s), 3.94 (2H, s).
Reference Example 3 3- (Biphenyl-3-ylmethyl) -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015

　４－ビフェニル酢酸の代わりに、３－ビフェニル酢酸（８４９ｍｇ、４．００ｍｍｏｌ）を用いて、参考例１に記載された方法と同様に反応を行い、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝９０／１０－５０／５０（グラジェント）］で精製して、合成中間体を得た。 The reaction was conducted in the same manner as described in Reference Example 1 using 3-biphenylacetic acid (849 mg, 4.00 mmol) instead of 4-biphenylacetic acid, and silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (gradient)] to obtain a synthetic intermediate.

　３－（ビフェニル－４－イル）－３－オキソブタンニトリルの代わりに、上記操作にて得られた合成中間体（４２０ｍｇ）を用いて、参考例２に記載された方法と同様に反応を行い、標記化合物（２５４ｍｇ、収率：４０％）を得た。 The reaction was conducted in the same manner as described in Reference Example 2 using the synthetic intermediate (420 mg) obtained by the above procedure in place of 3- (biphenyl-4-yl) -3-oxobutanenitrile. The title compound (254 mg, yield: 40%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 7.58-7.53 (2H, m), 7.50-7.32 (6H, m), 7.21-7.17 (1H, m), 5.51 (1H, s), 3.96 (2H, s)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.58-7.53 (2H, m), 7.50-7.32 (6H, m), 7.21-7.17 (1H, m), 5.51 (1H, s), 3.96 (2H, s).

　（参考例４）３－オキソ－４－フェニルペンタンニトリル (Reference Example 4) 3-Oxo-4-phenylpentanenitrile

Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016

　２－フェニルプロピオン酸（１．００ｇ、６．６６ｍｍｏｌ）のジクロロメタン（２０ｍＬ）溶液に、ＤＭＦ（パスツールピペット２滴）を加え、塩化オキサリル（２．９ｍｌ、３３．３ｍｍｏｌ）を加え、室温にて１時間攪拌した。反応液は、減圧下にて、溶媒を留去し、粗生成物（１．１２ｇ）を得た。 To a solution of 2-phenylpropionic acid (1.00 g, 6.66 mmol) in dichloromethane (20 mL) was added DMF (2 drops of Pasteur pipette), oxalyl chloride (2.9 ml, 33.3 mmol) was added, and at room temperature. Stir for 1 hour. In the reaction solution, the solvent was distilled off under reduced pressure to obtain a crude product (1.12 g).

　シアノ酢酸（５１０ｍｇ、６．００ｍｍｏｌ）、２，２’－ビピリジル（１ｍｇ）の無水ＴＨＦ（２０ｍＬ）溶液に、－７８℃にてｎ－ブチルリチウム（１．６７Ｍヘキサン溶液、７．２ｍＬ、１２．０ｍｍｏｌ）を滴下し１５分間攪拌した。更に同温度にて、上記操作で得られた粗生成物（５０６ｍｇ）の無水ＴＨＦ（５ｍＬ）溶液を滴下し、３０分間攪拌した。反応液をエチルエーテル、１Ｍ塩酸の２層液に加えよく攪拌し、得られた有機層を無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝９５／５－７５／２５（グラジェント）］で精製して、標記化合物（３８７ｍｇ、収率：７４％）を得た。 To a solution of cyanoacetic acid (510 mg, 6.00 mmol) and 2,2′-bipyridyl (1 mg) in anhydrous THF (20 mL) at −78 ° C., n-butyllithium (1.67 M hexane solution, 7.2 mL, 12. 0 mmol) was added dropwise and stirred for 15 minutes. Further, at the same temperature, a solution of the crude product (506 mg) obtained in the above operation in anhydrous THF (5 mL) was added dropwise and stirred for 30 minutes. The reaction solution was added to a two-layer solution of ethyl ether and 1M hydrochloric acid and stirred well. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-75 / 25 (gradient)] to give the title compound (387 mg, yield: 74%).

　1H-NMR (400MHz, CDCl3) δ: 7.42-7.30 (3H, m), 7.24-7.20 (2H, m), 3.91 (1H, q, J=7Hz), 3.37 (2H, s), 1.46 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.42-7.30 (3H, m), 7.24-7.20 (2H, m), 3.91 (1H, q, J = 7Hz), 3.37 (2H, s), 1.46 ( 3H, d, J = 7Hz).

　（参考例５）３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミン (Reference Example 5) 3- (1-Phenylethyl) -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017

　参考例４にて製造された３－オキソ－４－フェニルペンタンニトリル（３８７ｍｇ、２．２３ｍｍｏｌ）のエタノール（５ｍＬ）溶液に、ヒドラジン一水和物（２１７μＬ、４．４７ｍｍｏｌ）を加え、加熱還流下３時間攪拌した。反応液を室温で放置し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル］で精製し、標記化合物（３５８ｍｇ、収率：８６％）を得た。 To a solution of 3-oxo-4-phenylpentanenitrile (387 mg, 2.23 mmol) prepared in Reference Example 4 in ethanol (5 mL) was added hydrazine monohydrate (217 μL, 4.47 mmol), and heated under reflux. Stir for 3 hours. The reaction solution was allowed to stand at room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate] to obtain the title compound (358 mg, yield: 86%).

　1H-NMR (400MHz, CDCl3) δ: 7.34-7.28 (2H, m), 7.26-7.19 (3H, m), 5.54-5.53 (1H, m), 4.03 (1H, q, J=7Hz), 1.59 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.34-7.28 (2H, m), 7.26-7.19 (3H, m), 5.54-5.53 (1H, m), 4.03 (1H, q, J = 7Hz), 1.59 (3H, d, J = 7Hz).

　（参考例６）４－（３－ブロモフェニル）－３－オキソペンタンニトリル (Reference Example 6) 4- (3-Bromophenyl) -3-oxopentanenitrile

Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018

　２－フェニルプロピオン酸の代わりに、２－（３－ブロモフェニル）プロピオン酸（２．７７ｇ、１２．１ｍｏｌ）を用いて、参考例４に記載された方法と同様に反応を行い、標記化合物（１．８４ｇ、収率：６３％）を得た。 The reaction was conducted in the same manner as described in Reference Example 4 using 2- (3-bromophenyl) propionic acid (2.77 g, 12.1 mol) instead of 2-phenylpropionic acid, and the title compound ( 1.84 g, yield: 63%).

　1H-NMR (400MHz, CDCl3) δ: 7.49-7.45 (1H, m), 7.38 (1H, t, J=2Hz), 7.29-7.24 (1H, m), 7.18-7.14 (1H, m), 3.89 (1H, q, J=7Hz), 3.40 (2H, s), 1.45 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.49-7.45 (1H, m), 7.38 (1H, t, J = 2Hz), 7.29-7.24 (1H, m), 7.18-7.14 (1H, m), 3.89 (1H, q, J = 7Hz), 3.40 (2H, s), 1.45 (3H, d, J = 7Hz).

　（参考例７）３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミン (Reference Example 7) 3- [1- (3-Bromophenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019

　３－オキソ－４－フェニルペンタンニトリルの代わりに、参考例６にて製造された４－（３－ブロモフェニル）－３－オキソペンタンニトリル（１．８４ｇ、７．３０ｍｍｏｌ）を用いて、参考例５に記載された方法と同様に反応を行い、標記化合物（１．８５ｇ、収率：９５％）を得た。 In place of 3-oxo-4-phenylpentanenitrile, 4- (3-bromophenyl) -3-oxopentanenitrile (1.84 g, 7.30 mmol) prepared in Reference Example 6 was used. The reaction was conducted in the same manner as described in 5, to give the title compound (1.85 g, yield: 95%).

　1H-NMR (400MHz, CDCl3) δ: 7.39-7.34 (2H, m), 7.21-7.11 (2H, m), 5.52 (1H, s), 4.01 (1H, q, J=7Hz), 1.57 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.39-7.34 (2H, m), 7.21-7.11 (2H, m), 5.52 (1H, s), 4.01 (1H, q, J = 7Hz), 1.57 ( 3H, d, J = 7Hz).

　（参考例８）３－[１－（３－クロロフェニル）エチル]－１Ｈ－ピラゾール－５－アミン (Reference Example 8) 3- [1- (3-Chlorophenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020

　２－フェニルプロピオン酸の代わりに、２－（３－クロロフェニル）プロピオン酸（１．１３ｇ、６．１２ｍｍｏｌ）を用いて、参考例４に記載された方法と同様に反応を行い、合成中間体を得た。 Using 2- (3-chlorophenyl) propionic acid (1.13 g, 6.12 mmol) in place of 2-phenylpropionic acid, the reaction was carried out in the same manner as described in Reference Example 4, and the synthetic intermediate was obtained. Obtained.

　３－オキソ－４－フェニルペンタンニトリルの代わりに、上記操作で得られた合成中間体を用いて、参考例５に記載された方法と同様に反応を行い、標記化合物（３２９ｍｇ、収率：２４％）を得た。 The reaction was conducted in the same manner as described in Reference Example 5 using the synthetic intermediate obtained in the above operation instead of 3-oxo-4-phenylpentanenitrile to give the title compound (329 mg, yield: 24 %).

　1H-NMR (400MHz, CDCl3) δ: 7.24-7.18 (3H, m), 7.10-7.07 (1H, m), 5.51 (1H, s), 4.01 (1H, q, J=7Hz), 1.57 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.24-7.18 (3H, m), 7.10-7.07 (1H, m), 5.51 (1H, s), 4.01 (1H, q, J = 7Hz), 1.57 ( 3H, d, J = 7Hz).

　（参考例９）３－[１－（４－メトキシフェニル）エチル]－１Ｈ－ピラゾール－５－アミン (Reference Example 9) 3- [1- (4-Methoxyphenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021

　２－（３－クロロフェニル）プロピオン酸の代わりに、２－（４－メトキシフェニル）プロピオン酸（１．１７ｇ、６．３２ｍｏｌ）を用いて、参考例８に記載された方法と同様に反応を行い、標記化合物（４０８ｍｇ、収率：３０％）を得た。 The reaction was conducted in the same manner as described in Reference Example 8 using 2- (4-methoxyphenyl) propionic acid (1.17 g, 6.32 mol) instead of 2- (3-chlorophenyl) propionic acid. The title compound (408 mg, yield: 30%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 7.16-7.11 (2H, m), 6.88-6.83 (2H, m), 5.53 (1H, s), 4.00 (1H, q, J=7Hz), 3.80 (3H, s), 1.56 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.16-7.11 (2H, m), 6.88-6.83 (2H, m), 5.53 (1H, s), 4.00 (1H, q, J = 7Hz), 3.80 ( 3H, s), 1.56 (3H, d, J = 7Hz).

　（参考例１０）３－[１－（３－メトキシフェニル）エチル]－１Ｈ－ピラゾール－５－アミン Reference Example 10 3- [1- (3-Methoxyphenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022

　２－（３－クロロフェニル）プロピオン酸の代わりに、２－（３－メチルフェニル）プロピオン酸（１．２７ｇ、６．６２ｍｏｌ）を用いて、参考例８に記載された方法と同様に反応を行い、標記化合物（７２０ｍｇ、収率：５０％）を得た。 Using 2- (3-methylphenyl) propionic acid (1.27 g, 6.62 mol) instead of 2- (3-chlorophenyl) propionic acid, the reaction was conducted in the same manner as described in Reference Example 8. The title compound (720 mg, yield: 50%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 7.24 (1H, t, J=8Hz), 6.83-6.74 (3H, m), 5.55 (1H, s), 4.02 (1H, q, J=7Hz), 3.79 (3H, s), 1.59 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.24 (1H, t, J = 8Hz), 6.83-6.74 (3H, m), 5.55 (1H, s), 4.02 (1H, q, J = 7Hz), 3.79 (3H, s), 1.59 (3H, d, J = 7Hz).

　（参考例１１）３－[１－（ビフェニル－３－イル）エチル]－１Ｈ－ピラゾール－５－アミン (Reference Example 11) 3- [1- (Biphenyl-3-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023

　２－（３－クロロフェニル）プロピオン酸の代わりに、２－（ビフェニル－３－イル）プロピオン酸（１．３５ｇ、５．９５ｍｏｌ）を用いて、参考例８に記載された方法と同様に反応を行い、標記化合物（６７８ｍｇ、収率：４３％）を得た。 Using 2- (biphenyl-3-yl) propionic acid (1.35 g, 5.95 mol) in place of 2- (3-chlorophenyl) propionic acid, the reaction was conducted in the same manner as described in Reference Example 8. The title compound (678 mg, yield: 43%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 7.57-7.52 (2H, m), 7.48-7.31 (6H, m), 7.20-7.16 (1H, m), 5.56 (1H, s), 4.09 (1H, q, J=7Hz), 1.62 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.57-7.52 (2H, m), 7.48-7.31 (6H, m), 7.20-7.16 (1H, m), 5.56 (1H, s), 4.09 (1H, q, J = 7Hz), 1.62 (3H, d, J = 7Hz).

　（参考例１２）３－[１－（３－フェノキシフェニル）エチル]－１Ｈ－ピラゾール－５－アミン (Reference Example 12) 3- [1- (3-phenoxyphenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024

　２－（３－クロロフェニル）プロピオン酸の代わりに２－（３－フェノキシフェニル）プロピオン酸（７６０ｍｇ、３．１４ｍｏｌ）を用いて、参考例８に記載された方法と同様に反応を行い、標記化合物（４８８ｍｇ、収率：５６％）を得た。 Using 2- (3-phenoxyphenyl) propionic acid (760 mg, 3.14 mol) instead of 2- (3-chlorophenyl) propionic acid, the reaction was carried out in the same manner as described in Reference Example 8 to obtain the title compound (488 mg, yield: 56%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 7.37-7.30 (2H, m), 7.29-7.23 (1H, m), 7.13-7.08 (1H, m), 7.02-6.89 (4H, m), 6.87-6.82 (1H, m), 5.53-5.53 (1H, m), 4.01 (1H, q, J=7Hz), 1.58 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.37-7.30 (2H, m), 7.29-7.23 (1H, m), 7.13-7.08 (1H, m), 7.02-6.89 (4H, m), 6.87- 6.82 (1H, m), 5.53-5.53 (1H, m), 4.01 (1H, q, J = 7Hz), 1.58 (3H, d, J = 7Hz).

　（参考例１３）３－[１－（ナフタレン－１－イル）エチル]－１Ｈ－ピラゾール－５－アミン (Reference Example 13) 3- [1- (Naphthalen-1-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025

　２－（３－クロロフェニル）プロピオン酸の代わりに、２－（ナフタレン－１－イル）プロピオン酸（１．０９ｇ、５．４４ｍｏｌ）を用いて、参考例８に記載された方法と同様に反応を行い、標記化合物（４７８ｍｇ、収率：３７％）を得た。 Using 2- (naphthalen-1-yl) propionic acid (1.09 g, 5.44 mol) instead of 2- (3-chlorophenyl) propionic acid, the reaction was conducted in the same manner as described in Reference Example 8. Then, the title compound (478 mg, yield: 37%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 8.02-7.96 (1H, m), 7.85-7.79 (1H, m), 7.70 (1H, d, J=8Hz), 7.50-7.41 (2H, m), 7.41-7.34 (1H, m), 7.30 (1H, d, J=7Hz), 5.54 (1H, s), 4.79 (1H, q, J=7Hz), 1.69 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.02-7.96 (1H, m), 7.85-7.79 (1H, m), 7.70 (1H, d, J = 8Hz), 7.50-7.41 (2H, m), 7.41-7.34 (1H, m), 7.30 (1H, d, J = 7Hz), 5.54 (1H, s), 4.79 (1H, q, J = 7Hz), 1.69 (3H, d, J = 7Hz).

　（参考例１４）３－［１－（３－ベンジルフェニル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 14) 3- [1- (3-Benzylphenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026

　２－（３－ベンゾイルフェニル）プロピオン酸（５４０ｍｇ、２．１２ｍｍｏｌ）のトリフルオロ酢酸（３ｍＬ）溶液に、氷冷下、トリエチルシラン（１．０１ｍｌ、６．３７ｍｍｏｌ）を加え、室温にて一晩攪拌した。反応液は、減圧下にて、溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝７５／２５－０／１００（グラジェント）］で精製し、合成中間体を得た。 To a solution of 2- (3-benzoylphenyl) propionic acid (540 mg, 2.12 mmol) in trifluoroacetic acid (3 mL) was added triethylsilane (1.01 ml, 6.37 mmol) under ice cooling, and overnight at room temperature. Stir. The reaction solution was purified by silica gel column chromatography [elution solvent: hexane / ethyl acetate = 75 / 25-0 / 100 (gradient)] by distilling off the solvent under reduced pressure. An intermediate was obtained.

　２－（３－クロロフェニル）プロピオン酸の代わりに、上記操作で得られた合成中間体を用いて、参考例８に記載された方法と同様に反応を行い、標記化合物（２０３ｍｇ、収率：３６％）を得た。 The reaction was conducted in the same manner as described in Reference Example 8 using the synthetic intermediate obtained in the above operation instead of 2- (3-chlorophenyl) propionic acid, and the title compound (203 mg, yield: 36) %).

　1H-NMR (400MHz, CDCl3) δ: 7.31-7.14 (6H, m), 7.07-7.01 (3H, m), 5.52 (1H, s), 4.00 (1H, t, J=7Hz), 3.95 (2H, s), 1.56 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.31-7.14 (6H, m), 7.07-7.01 (3H, m), 5.52 (1H, s), 4.00 (1H, t, J = 7Hz), 3.95 ( 2H, s), 1.56 (3H, d, J = 7Hz).

　（参考例１５）３－［１－（２，３－ジクロロフェニル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 15) 3- [1- (2,3-Dichlorophenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027

　２－（３－クロロフェニル）プロピオン酸の代わりに、２－（２，３－ジクロロフェニル）プロピオン酸（１．０７ｇ、４．８８ｍｏｌ）を用いて、参考例８に記載された方法と同様に反応を行い、標記化合物（７７０ｍｇ、収率：６１％）を得た。 Using 2- (2,3-dichlorophenyl) propionic acid (1.07 g, 4.88 mol) instead of 2- (3-chlorophenyl) propionic acid, the reaction was conducted in the same manner as described in Reference Example 8. The title compound (770 mg, yield: 61%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 7.35 (1H, dd, J=8Hz, 2Hz), 7.14 (1H, t, J=8Hz), 7.07 (1H, dd, J=8Hz, 2Hz), 5.56 (1H, s), 4.62 (1H, q, J=7Hz), 1.57 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.35 (1H, dd, J = 8Hz, 2Hz), 7.14 (1H, t, J = 8Hz), 7.07 (1H, dd, J = 8Hz, 2Hz), 5.56 (1H, s), 4.62 (1H, q, J = 7Hz), 1.57 (3H, d, J = 7Hz).

　（参考例１６）３－［（１Ｓ）－１－フェニルエチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 16) 3-[(1S) -1-phenylethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028

　（Ｓ）－（＋）－２－フェニルプロピオン酸（１０．０ｇ、６６．６ｍｍｏｌ）のジクロロメタン（１００ｍＬ）溶液に、ＤＭＦ（パスツールピペット５滴）、塩化オキサリル（７．０ｍｌ、７９．９ｍｍｏｌ）を加え、室温にて1時間攪拌した。反応液は減圧下にて、溶媒を留去し、粗生成物を得た。 To a solution of (S)-(+)-2-phenylpropionic acid (10.0 g, 66.6 mmol) in dichloromethane (100 mL), DMF (5 drops of Pasteur pipette), oxalyl chloride (7.0 ml, 79.9 mmol) And stirred at room temperature for 1 hour. The reaction solution was distilled under reduced pressure to obtain a crude product.

　シアノ酢酸（１１．３３ｇ、０．１３３ｍｏｌ）の無水ＴＨＦ（４００ｍＬ）溶液に、－７８℃にてｎ－ブチルリチウム（２．６９Ｍヘキサン溶液、１００ｍＬ、０．２６９ｍｏｌ）を滴下し１５分間攪拌した。更に同温度にて、上記操作で得られた粗生成物の無水ＴＨＦ（１００ｍＬ）溶液を滴下し、１時間攪拌した。反応液に２Ｍ塩酸を加え室温に昇温し、エーテルで抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣のエタノール（１００ｍＬ）溶液に、ヒドラジン酢酸塩（９．２０ｇ、９９．９ｍｍｏｌ）を加え、５０℃にて１５分間攪拌した。反応液を減圧下にて濃縮し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル］で精製し、標記化合物（７．４９ｇ、収率：６０％）を得た。 To a solution of cyanoacetic acid (11.33 g, 0.133 mol) in anhydrous THF (400 mL), n-butyllithium (2.69 M hexane solution, 100 mL, 0.269 mol) was added dropwise at −78 ° C. and stirred for 15 minutes. Further, at the same temperature, a solution of the crude product obtained in the above operation in anhydrous THF (100 mL) was added dropwise and stirred for 1 hour. 2M hydrochloric acid was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hydrazine acetate (9.20 g, 99.9 mmol) was added to a solution of the obtained residue in ethanol (100 mL), and the mixture was stirred at 50 ° C. for 15 minutes. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate]. The title compound (7.49 g, yield: 60%) was obtained.

　光学純度はＨＰＬＣ［カラム：Ｃｈｉｒａｌｐａｋ　ＯＪ（４．６ｍｍ　ｉ．ｄ．ｘ１５０ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝４０／６０、流速：１．０ｍＬ／分］を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak OJ (4.6 mm id x 150 mm); manufactured by Daicel, elution solvent: hexane / IPA = 40/60, flow rate: 1.0 mL / min].

　光学純度９４％（保持時間：７．３分）。 Optical purity 94% (retention time: 7.3 minutes).

　（参考例１７）４－（４－フルオロフェニル）－３－オキソペンタンニトリル (Reference Example 17) 4- (4-Fluorophenyl) -3-oxopentanenitrile

Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029

　２－フェニルプロピオン酸の代わりに、２－（４－フルオロフェニル）プロピオン酸（３３６ｍｇ、２．００ｍｏｌ）を用いて、参考例４に記載された方法と同様に反応を行い、標記化合物（１３０ｍｇ、収率：３４％）を得た。 The reaction was conducted in the same manner as described in Reference Example 4 using 2- (4-fluorophenyl) propionic acid (336 mg, 2.00 mol) instead of 2-phenylpropionic acid, and the title compound (130 mg, Yield: 34%).

　1H-NMR (400MHz, CDCl3) δ: 7.23-7.17 (2H, m), 7.11-7.04 (2H, m), 3.93 (1H, q, J=7Hz), 3.38 (2H, s), 1.44 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.23-7.17 (2H, m), 7.11-7.04 (2H, m), 3.93 (1H, q, J = 7Hz), 3.38 (2H, s), 1.44 ( 3H, d, J = 7Hz).

　（参考例１８）３－［１－（４－フルオロフェニル）エチル］－１Ｈ－ピラゾール－５－アミン Reference Example 18 3- [1- (4-Fluorophenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030

　参考例１７にて製造された４－（４－フルオロフェニル）－３－オキソペンタンニトリル（１３０ｍｇ、０．６８ｍｏｌ）のエタノール（３ｍＬ）溶液に、ヒドラジン酢酸塩（９４ｍｇ、１．０２ｍｍｏｌ）を加え、５０℃にて３０分間攪拌した。反応液を減圧下にて濃縮し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル／メタノール＝１００／０－９０／１０（グラジェント）］で精製し、標記化合物（７４ｍｇ、収率：５３％）を得た。 To a solution of 4- (4-fluorophenyl) -3-oxopentanenitrile (130 mg, 0.68 mol) prepared in Reference Example 17 in ethanol (3 mL) was added hydrazine acetate (94 mg, 1.02 mmol), Stir at 50 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10 (gradient)] to give the title compound (74 mg, yield: 53%).

　1H-NMR (400MHz, CDCl3) δ: 7.20-7.14 (2H, m), 7.03-6.97 (2H, m), 5.52 (1H, s), 4.03 (1H, q, J=7Hz), 3.88-3.14 (3H, m), 1.57 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.20-7.14 (2H, m), 7.03-6.97 (2H, m), 5.52 (1H, s), 4.03 (1H, q, J = 7Hz), 3.88- 3.14 (3H, m), 1.57 (3H, d, J = 7Hz).

　（参考例１９）３－［１－（３－フルオロフェニル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 19) 3- [1- (3-Fluorophenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031

　２－フェニルプロピオン酸の代わりに、２－（３－フルオロフェニル）プロピオン酸（５１５ｍｇ、３．０６ｍｏｌ）を用いて、参考例４に記載された方法と同様に反応を行い、合成中間体を得た。 Using 2- (3-fluorophenyl) propionic acid (515 mg, 3.06 mol) instead of 2-phenylpropionic acid, the reaction was carried out in the same manner as described in Reference Example 4 to obtain a synthetic intermediate. It was.

　４－（４－フルオロフェニル）－３－オキソペンタンニトリルの代わりに上記操作にて得られた合成中間体を用いて、参考例１８に記載された方法と同様に反応を行い、標記化合物（１１９ｍｇ、収率：１９％）を得た。 The reaction was conducted in the same manner as described in Reference Example 18 using the synthetic intermediate obtained in the above operation instead of 4- (4-fluorophenyl) -3-oxopentanenitrile to give the title compound (119 mg Yield: 19%).

　1H-NMR (400MHz, CDCl3) δ: 7.30-7.22 (1H, m), 7.01-6.88 (3H, m), 5.52 (1H, s), 4.04 (1H, q, J=7Hz), 1.58 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.30-7.22 (1H, m), 7.01-6.88 (3H, m), 5.52 (1H, s), 4.04 (1H, q, J = 7Hz), 1.58 ( 3H, d, J = 7Hz).

　（参考例２０）３－［１－（４－クロロフェニル）エチル］－１Ｈ－ピラゾール－５－アミン Reference Example 20 3- [1- (4-Chlorophenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032

　無水アセトニトリル（４．６０ｍＬ、８７．９ｍｍｏｌ）の無水ＴＨＦ（２００ｍＬ）溶液にｎ－ブチルリチウム（２．６９Ｍヘキサン溶液、３２．６ｍＬ、８７．７ｍｍｏｌ）を－７８℃で滴下した後、同温度で３０分間攪拌した後、２－（４－クロロフェニル）プロピオン酸メチル（１．０１ｇ、４．７６ｍｍｏｌ）の無水ＴＨＦ（２００ｍＬ）溶液を－７８℃で滴下し、同温度で４５分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去した。 N-Butyllithium (2.69 M hexane solution, 32.6 mL, 87.7 mmol) was added dropwise at −78 ° C. to a solution of anhydrous acetonitrile (4.60 mL, 87.9 mmol) in anhydrous THF (200 mL) at the same temperature. After stirring for 30 minutes, a solution of methyl 2- (4-chlorophenyl) propionate (1.01 g, 4.76 mmol) in anhydrous THF (200 mL) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 45 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

　得られた残渣のエタノール（２００ｍＬ）溶液に、ヒドラジン一水和物（５．００ｍＬ、１０３ｍｍｏｌ）を加え、加熱還流下４時間２０分攪拌した。反応液を室温で放置した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：（ｉ）ヘキサン／酢酸エチル＝６０／４０－０／１００（グラジェント）（ｉｉ）酢酸エチル／メタノール＝１００／０－８５／１５（グラジェント）］で精製し、標記化合物（６．６０ｇ、収率：定量的）を得た。 Hydrazine monohydrate (5.00 mL, 103 mmol) was added to a solution of the obtained residue in ethanol (200 mL), and the mixture was stirred with heating under reflux for 4 hours and 20 minutes. After leaving the reaction solution at room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Distilled off. The obtained residue was subjected to silica gel column chromatography [elution solvent: (i) hexane / ethyl acetate = 60 / 40-0 / 100 (gradient) (ii) ethyl acetate / methanol = 100 / 0-85 / 15 (gradient )] To give the title compound (6.60 g, yield: quantitative).

　1H-NMR (500MHz, DMSO-d6) δ: 11.31-11.00 (1H, m), 7.41-7.22 (4H, m), 5.30-4.73 (1H, m), 4.39 (1H, brs), 4.16-3.89 (2H, m), 1.48 (3H, d, J=7Hz)。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 11.31-11.00 (1H, m), 7.41-7.22 (4H, m), 5.30-4.73 (1H, m), 4.39 (1H, brs), 4.16- 3.89 (2H, m), 1.48 (3H, d, J = 7Hz).

　（参考例２１）３－［１－（ビフェニル－４－イル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 21) 3- [1- (Biphenyl-4-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033

　２－フェニルプロピオン酸の代わりに、２－（ビフェニル－４－イル）プロピオン酸（文献Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．、２００２年、第１０巻、第２６４１－２６５６頁に記載された化合物、１．２４ｇ、５．４８ｍｍｏｌ）を用いて、参考例４に記載された方法と同様に反応を行い、合成中間体を得た。 Instead of 2-phenylpropionic acid, 2- (biphenyl-4-yl) propionic acid (Reference Bioorg. Med. Chem., 2002, Vol. 10, pages 2641-2656, 1.24 g (5.48 mmol) was used in the same manner as in the method described in Reference Example 4 to obtain a synthetic intermediate.

　３－オキソ－４－フェニルペンタンニトリルの代わりに、上記操作で得られた合成中間体を用いて、参考例５に記載された方法と同様に反応を行い、標記化合物（５２０ｍｇ、収率：３６％）を得た。 The reaction was conducted in the same manner as described in Reference Example 5 using the synthetic intermediate obtained in the above operation instead of 3-oxo-4-phenylpentanenitrile to give the title compound (520 mg, yield: 36 %).

　1H-NMR (400MHz, CDCl3)δ: 7.59-7.28 (9H, m), 5.56 (1H, s), 4.09 (1H, q, J=7Hz), 1.63 (3H, d, J=7Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.59-7.28 (9H, m), 5.56 (1H, s), 4.09 (1H, q, J = 7 Hz), 1.63 (3H, d, J = 7 Hz).

　（参考例２２）３－［１－（ナフタレン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 22) 3- [1- (Naphthalen-2-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、２－（ナフタレン－２－イル）プロピオン酸（文献Ｔｅｔｒａｈｅｄｒｏｎ、２０１１年、第６７巻、第３４７０－３４７５頁に記載された化合物、１．２７ｇ、６．３４ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（２５６ｍｇ、収率：１７％）を得た。 Instead of 2- (biphenyl-4-yl) propionic acid, 2- (naphthalen-2-yl) propionic acid (the compound described in the document Tetrahedron, 2011, Vol. 67, pages 3470-3475; (27 g, 6.34 mmol), and the reaction was carried out in the same manner as described in Reference Example 21 to obtain the title compound (256 mg, yield: 17%).

　1H-NMR (400MHz, DMSO-d6)δ: 7.90-7.71 (4H, m), 7.52-7.38 (3H, m), 5.21 (2H, brs), 4.50 (1H, s), 4.14 (1H, q, J=7Hz), 1.57 (3H, d, J=7Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 7.90-7.71 (4H, m), 7.52-7.38 (3H, m), 5.21 (2H, brs), 4.50 (1H, s), 4.14 (1H, q, J = 7Hz), 1.57 (3H, d, J = 7Hz).

　（参考例２３）（３－ｔｅｒｔ－ブチルフェニル）（メチル）プロパン二酸ジエチル (Reference Example 23) (3-tert-butylphenyl) (methyl) diethyl propanedioate

Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035

　１－ブロモ－３－ｔｅｒｔ－ブチルベンゼン（１．５０ｇ、７．０４ｍｍｏｌ）、マロン酸ジエチル（１．３２ｍＬ、８．７４ｍｍｏｌ）、２－（ジ－ｔｅｒｔ－ブチルホスフィノ）－２’－メチルビフェニル（１８０ｍｇ、０．５７６ｍｍｏｌ）、及び、リン酸カリウム（６．０２ｇ、２８．４ｍｍｏｌ）のＴＨＦ（１５ｍＬ）懸濁液に、酢酸パラジウム（６０ｍｇ、０．２６７ｍｍｏｌ）を加え、７０℃で１５時間攪拌した後、ヨウ化メチル（１．８０ｍＬ、２８．９ｍｍｏｌ）を加え、更に同温で５時間攪拌した。反応液を室温まで放冷し、ろ過した後、減圧下、ろ液の溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝１００／０－８５／１５（グラジェント）］で精製し、標記化合物（１．８６ｇ、収率：８６％）を得た。 1-bromo-3-tert-butylbenzene (1.50 g, 7.04 mmol), diethyl malonate (1.32 mL, 8.74 mmol), 2- (di-tert-butylphosphino) -2′-methylbiphenyl To a suspension of (180 mg, 0.576 mmol) and potassium phosphate (6.02 g, 28.4 mmol) in THF (15 mL) was added palladium acetate (60 mg, 0.267 mmol), and the mixture was stirred at 70 ° C. for 15 hours. After that, methyl iodide (1.80 mL, 28.9 mmol) was added, and the mixture was further stirred at the same temperature for 5 hours. The reaction solution was allowed to cool to room temperature and filtered, and then the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-85 / 15 (gradient)] to obtain the title compound (1.86 g, yield: 86%). .

　1H-NMR (400MHz, DMSO-d6) δ: 7.35-7.26 (3H, m), 7.14-7.11 (1H, m), 4.17 (4H, q, J=7Hz), 1.75 (3H, s), 1.27 (9H, s), 1.17 (6H, t, J=7Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 7.35-7.26 (3H, m), 7.14-7.11 (1H, m), 4.17 (4H, q, J = 7Hz), 1.75 (3H, s), 1.27 (9H, s), 1.17 (6H, t, J = 7Hz).

　（参考例２４）２－（３－ｔｅｒｔ－ブチルフェニル）プロピオン酸 (Reference Example 24) 2- (3-tert-butylphenyl) propionic acid

Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036

　参考例２３にて製造された（３－ｔｅｒｔ－ブチルフェニル）（メチル）プロパン二酸ジエチル（１．８６ｇ、６．０７ｍｍｏｌ）の１，４－ジオキサン（４０ｍＬ）溶液に、１Ｎ水酸化ナトリウム水溶液（２０ｍＬ）を加え、６０℃で６時間攪拌した。反応液に２Ｎ塩酸を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣をジエチルエーテルに溶解させた後に飽和炭酸水素ナトリウムを加え分液し、水層を酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去して、標記化合物（８８０ｍｇ、収率：７０％）を得た。 To a solution of diethyl (3-tert-butylphenyl) (methyl) propanedioate (1.86 g, 6.07 mmol) prepared in Reference Example 23 in 1,4-dioxane (40 mL), a 1N aqueous sodium hydroxide solution ( 20 mL) was added and stirred at 60 ° C. for 6 hours. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in diethyl ether, and saturated sodium hydrogen carbonate was added for liquid separation, the aqueous layer was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (880 mg, yield: 70%).

　1H-NMR (400MHz, DMSO-d6) δ: 7.39-7.05 (4H, m), 3.65 (1H, q, J=7 Hz), 1.34 (3H, d, J=7Hz), 1.27 (9H, s)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 7.39-7.05 (4H, m), 3.65 (1H, q, J = 7 Hz), 1.34 (3H, d, J = 7 Hz), 1.27 (9H, s).

　（参考例２５）３－［１－（３－tert－ブチルフェニル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 25) 3- [1- (3-tert-butylphenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、参考例２４にて製造された２－（３－ｔｅｒｔ－ブチルフェニル）プロピオン酸（８８０ｍｇ、４．２７ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（２２３ｍｇ、収率：２１％）を得た。 Instead of 2- (biphenyl-4-yl) propionic acid, 2- (3-tert-butylphenyl) propionic acid (880 mg, 4.27 mmol) prepared in Reference Example 24 was used. The reaction was performed in the same manner as described to give the title compound (223 mg, yield: 21%).

　1H-NMR (400MHz, DMSO-d6) δ: 7.24 (1H, s), 7.18-7.12 (2H, m), 6.99 (1H, dt, J=6Hz, 2Hz), 5.13 (1H, s), 3.91 (1H, q, J=7Hz), 1.43 (3H, d, J=7Hz), 1.23 (9H, s)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 7.24 (1H, s), 7.18-7.12 (2H, m), 6.99 (1H, dt, J = 6Hz, 2Hz), 5.13 (1H, s), 3.91 (1H, q, J = 7Hz), 1.43 (3H, d, J = 7Hz), 1.23 (9H, s).

　（参考例２６）４－（４－ブチルフェニル）－３－オキソペンタンニトリル (Reference Example 26) 4- (4-Butylphenyl) -3-oxopentanenitrile

Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038

　１－ブロモ－３－ｔｅｒｔ－ブチルベンゼンの代わりに、１－ブチル－４－ヨードベンゼン（１．５０ｇ、５．７７ｍｍｏｌ）を用いて、参考例２３に記載された方法と同様に反応を行い、合成中間体を得た。 Using 1-butyl-4-iodobenzene (1.50 g, 5.77 mmol) instead of 1-bromo-3-tert-butylbenzene, the reaction was carried out in the same manner as described in Reference Example 23, A synthetic intermediate was obtained.

　（３－tert－ブチルフェニル）（メチル）プロパン二酸ジエチルの代わりに、上記操作にて得られた合成中間体を用いて、参考例２４に記載された方法と同様に反応を行い、カルボン酸化合物を得た。 The reaction was carried out in the same manner as described in Reference Example 24 using the synthetic intermediate obtained by the above procedure in place of diethyl (3-tert-butylphenyl) (methyl) propanedioate. A compound was obtained.

　２－フェニルプロピオン酸の代わりに、上記操作で得られたカルボン酸化合物を用いて、参考例４に記載された方法と同様に反応を行い、標記化合物（４５３ｍｇ、収率：３４％）を得た。 The reaction was conducted in the same manner as described in Reference Example 4 using the carboxylic acid compound obtained in the above operation instead of 2-phenylpropionic acid to give the title compound (453 mg, yield: 34%). It was.

　1H-NMR (400MHz, CDCl3)δ: 7.19 (2H, d, J=8Hz), 7.11 (2H, d, J=8Hz), 3.86 (1H, q, J=7Hz), 3.37 (2H, s), 2.60 (2H, t, J=8Hz), 1.43 (3H, d, J=7Hz), 1.41-1.24 (4H, m), 0.96-0.90 (3H, m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.19 (2H, d, J = 8Hz), 7.11 (2H, d, J = 8Hz), 3.86 (1H, q, J = 7Hz), 3.37 (2H, s ), 2.60 (2H, t, J = 8Hz), 1.43 (3H, d, J = 7Hz), 1.41-1.24 (4H, m), 0.96-0.90 (3H, m).

　（参考例２７）３－［１－（４－ブチルフェニル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 27) 3- [1- (4-Butylphenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039

　３－オキソ－４－フェニルペンタンニトリルの代わりに、参考例２６にて製造された４－（４－ブチルフェニル）－３－オキソペンタンニトリル（４５３ｍｇ、１．９８ｍｍｏｌ）を用いて、参考例５に記載された方法と同様に反応を行い、標記化合物（２４８ｍｇ、収率：１７％）を得た。 Instead of 3-oxo-4-phenylpentanenitrile, 4- (4-butylphenyl) -3-oxopentanenitrile (453 mg, 1.98 mmol) prepared in Reference Example 26 was used. Reaction was performed in the same manner as described to give the title compound (248 mg, yield: 17%).

　1H-NMR (400MHz, DMSO-d6)δ: 7.16-7.05 (4H, m), 5.14 (1H, s), 3.91 (1H, q, J=7Hz), 2.59-2.49 (2H, m), 1.55-1.46 (2H, m), 1.45 (3H, d, J=7Hz), 1.34-1.23 (2H, m), 0.88 (3H, t, J=7Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 7.16-7.05 (4H, m), 5.14 (1H, s), 3.91 (1H, q, J = 7Hz), 2.59-2.49 (2H, m), 1.55-1.46 (2H, m), 1.45 (3H, d, J = 7Hz), 1.34-1.23 (2H, m), 0.88 (3H, t, J = 7Hz).

　（参考例２８）３－［１－（２－クロロフェニル）エチル］－１Ｈ－ピラゾール－５－アミン Reference Example 28 3- [1- (2-Chlorophenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、２－（２－クロロフェニル）プロピオン酸（文献Ｔｅｔｒａｈｅｄｒｏｎ、２０１１年、第６７巻、第３４７０－３４７５頁に記載された化合物、１．６７ｇ、９．０４ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（４４６ｍｇ、収率：２２％）を得た。 Instead of 2- (biphenyl-4-yl) propionic acid, 2- (2-chlorophenyl) propionic acid (the compound described in Tetrahedron, 2011, Vol. 67, pages 3470-3475, 1.67 g, 9.04 mmol) was used in the same manner as in the method described in Reference Example 21 to obtain the title compound (446 mg, yield: 22%).

　1H-NMR (400MHz, DMSO-d6) δ: 7.37 (1H, d, J=8Hz), 7.27-7.15 (3H, m), 5.12 (1H, s), 4.36 (1H, q, J=7Hz), 1.42 (3H, d, J=7Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 7.37 (1H, d, J = 8Hz), 7.27-7.15 (3H, m), 5.12 (1H, s), 4.36 (1H, q, J = 7Hz ), 1.42 (3H, d, J = 7Hz).

　（参考例２９）３－［１－（２－ブロモフェニル）エチル］－１Ｈ－ピラゾール－５－アミン Reference Example 29 3- [1- (2-Bromophenyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041

　ジイソプロピルアミン（４．５５ｍＬ、３２．４ｍｍｏｌ）の無水ＴＨＦ（４０ｍＬ）溶液に、０℃でｎ－ブチルリチウム（２．６９Ｍヘキサン溶液、１１．５ｍＬ、３０．９ｍｍｏｌ）を滴下し、同温で４０分間攪拌した後に、（２－ブロモフェニル）酢酸（３．００ｇ、１４．０ｍｍｏｌ）の無水ＴＨＦ（４０ｍＬ）溶液を滴下し、１．５時間攪拌した。反応液に、０℃でヨウ化メチル（１．２０ｍＬ、１９．３ｍｍｏｌ）の無水ＴＨＦ（２０ｍＬ）溶液を加え、室温で１時間攪拌した。反応液に２Ｎ塩酸水溶液を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去して、メチル化された生成物を得た。 To a solution of diisopropylamine (4.55 mL, 32.4 mmol) in anhydrous THF (40 mL), n-butyllithium (2.69 M hexane solution, 11.5 mL, 30.9 mmol) was added dropwise at 0 ° C. After stirring for minutes, a solution of (2-bromophenyl) acetic acid (3.00 g, 14.0 mmol) in anhydrous THF (40 mL) was added dropwise and stirred for 1.5 hours. To the reaction solution, a solution of methyl iodide (1.20 mL, 19.3 mmol) in anhydrous THF (20 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. 2N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to methylate. Product was obtained.

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、上記操作で得られたメチル化生成物を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（９８０ｍｇ、収率：２６％）を得た。 Using the methylated product obtained by the above procedure instead of 2- (biphenyl-4-yl) propionic acid, the reaction was carried out in the same manner as described in Reference Example 21, and the title compound (980 mg, yield) was obtained. Rate: 26%).

　1H-NMR (400MHz, DMSO-d6)δ: 7.55 (1H, d, J = 8 Hz), 7.31-7.19 (2H, m), 7.13-7.08 (1H, m), 5.13 (1H, s), 4.33 (1H, q, J=7 Hz), 1.42 (3H, d, J=7Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 7.55 (1H, d, J = 8 Hz), 7.31-7.19 (2H, m), 7.13-7.08 (1H, m), 5.13 (1H, s) , 4.33 (1H, q, J = 7 Hz), 1.42 (3H, d, J = 7 Hz).

　（参考例３０）３－オキソ－４－フェノキシペンタンニトリル (Reference Example 30) 3-Oxo-4-phenoxypentanenitrile

Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042

　シアノ酢酸（８３０ｍｇ、９．７６ｍｍｏｌ）、２，２’－ビピリジル（１ｍｇ）の無水ＴＨＦ（１５ｍＬ）溶液に、－７８℃にてｎ－ブチルリチウム（２．６９Ｍヘキサン溶液、７．６ｍＬ、２０．４ｍｍｏｌ）を滴下し２０分間攪拌した。更に同温度にて、２－フェノキシプロピオニルクロリド（市販）（１．５０ｇ、８．１２ｍｍｏｌ）の無水ＴＨＦ（１５ｍＬ）溶液を滴下し、４０分間攪拌した。反応液に２Ｎ塩酸を加え、エチルエーテルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝１００／０－８０／２０（グラジェント）］で精製し、標記化合物（１．３１ｇ、収率：８５％）を得た。 To a solution of cyanoacetic acid (830 mg, 9.76 mmol), 2,2′-bipyridyl (1 mg) in anhydrous THF (15 mL) at −78 ° C., n-butyllithium (2.69 M hexane solution, 7.6 mL, 20. 4 mmol) was added dropwise and stirred for 20 minutes. Furthermore, at the same temperature, a solution of 2-phenoxypropionyl chloride (commercially available) (1.50 g, 8.12 mmol) in anhydrous THF (15 mL) was added dropwise and stirred for 40 minutes. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-80 / 20 (gradient)] to obtain the title compound (1.31 g, yield: 85%). .

　1H-NMR (400MHz, CDCl3) δ: 7.35-7.30 (2H, m), 7.07-7.01 (1H, m), 6.94-6.84 (2H, m), 4.81 (1H, q, J=7Hz), 3.85 (1H, d, J=20Hz), 3.60 (1H, d, J=20Hz), 1.56 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.35-7.30 (2H, m), 7.07-7.01 (1H, m), 6.94-6.84 (2H, m), 4.81 (1H, q, J = 7Hz), 3.85 (1H, d, J = 20Hz), 3.60 (1H, d, J = 20Hz), 1.56 (3H, d, J = 7Hz).

　（参考例３１）３－（１－フェノキシエチル）－１Ｈ－ピラゾール－５－アミン (Reference Example 31) 3- (1-phenoxyethyl) -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043

　３－オキソ－４－フェニルペンタンニトリルの代わりに、参考例３０にて製造された３－オキソ－４－フェノキシペンタンニトリル（１．３１ｇ、６．９２ｍｍｏｌ）を用いて、参考例５に記載された方法と同様に反応を行い、標記化合物（８８０ｍｇ、収率：６３％）を得た。 It was described in Reference Example 5 by using 3-oxo-4-phenoxypentanenitrile (1.31 g, 6.92 mmol) prepared in Reference Example 30 instead of 3-oxo-4-phenylpentanenitrile. Reaction was performed in the same manner as in the method to obtain the title compound (880 mg, yield: 63%).

　1H-NMR (400MHz, DMSO-d6) δ: 11.56-11.19 (1H, m), 7.31-7.17 (2H, m), 6.97-6.81 (3H, m), 5.43-5.15 (1H, m), 4.89 (1H, brs), 4.50-4.41 (1H, m), 1.51 (3H, d, J=6Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.56-11.19 (1H, m), 7.31-7.17 (2H, m), 6.97-6.81 (3H, m), 5.43-5.15 (1H, m), 4.89 (1H, brs), 4.50-4.41 (1H, m), 1.51 (3H, d, J = 6Hz).

　（参考例３２）３－［メトキシ（フェニル）メチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 32) 3- [Methoxy (phenyl) methyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、メトキシ（フェニル）酢酸（１．５９ｇ、９．５７ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（６０３ｍｇ、収率：３１％）を得た。 The reaction was conducted in the same manner as described in Reference Example 21 using methoxy (phenyl) acetic acid (1.59 g, 9.57 mmol) instead of 2- (biphenyl-4-yl) propionic acid, and the title compound (603 mg, yield: 31%) was obtained.

　1H-NMR (400MHz, DMSO-d6) δ: 7.40-7.22 (5H, m), 5.15-5.09 (2H, m), 3.22 (3H, s)。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.40-7.22 (5H, m), 5.15-5.09 (2H, m), 3.22 (3H, s).

　（参考例３３）３－［シクロヘキシル（フェニル）メチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 33) 3- [Cyclohexyl (phenyl) methyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、シクロヘキシル（フェニル）酢酸（２．０８ｇ、９．５３ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（８４２ｍｇ、収率：３５％）を得た。 The reaction was conducted in the same manner as described in Reference Example 21 using cyclohexyl (phenyl) acetic acid (2.08 g, 9.53 mmol) instead of 2- (biphenyl-4-yl) propionic acid, and the title compound (842 mg, yield: 35%) was obtained.

　1H-NMR (400MHz, DMSO-d6) δ: 7.35-7.21 (6H, m), 7.19-7.11 (1H, m), 5.29 (1H, s), 4.44 (2H, brs), 3.44-3.36 (1H, m), 1.97-0.67 (10H, m)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 7.35-7.21 (6H, m), 7.19-7.11 (1H, m), 5.29 (1H, s), 4.44 (2H, brs), 3.44-3.36 ( 1H, m), 1.97-0.67 (10H, m).

　（参考例３４）３－（２－メチル－１－フェニルプロピル）－１Ｈ－ピラゾール－５－アミン (Reference Example 34) 3- (2-Methyl-1-phenylpropyl) -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、３－メチル－２－フェニルブタン酸（１．５０ｇ、８．４２ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（５３０ｍｇ、収率：２９％）を得た。 Using 3-methyl-2-phenylbutanoic acid (1.50 g, 8.42 mmol) instead of 2- (biphenyl-4-yl) propionic acid, the reaction was conducted in the same manner as described in Reference Example 21. The title compound (530 mg, yield: 29%) was obtained.

　1H-NMR (500MHz, DMSO-d6) δ: 11.26 (1H, brs), 7.36-7.20 (4H, m), 7.19-7.12 (1H, m), 5.30 (1H, s), 4.45 (2H, brs), 2.32-2.17 (2H, m), 0.87 (3H, d, J=7Hz), 0.69 (3H, d, J=7Hz)。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 11.26 (1H, brs), 7.36-7.20 (4H, m), 7.19-7.12 (1H, m), 5.30 (1H, s), 4.45 (2H, brs), 2.32-2.17 (2H, m), 0.87 (3H, d, J = 7Hz), 0.69 (3H, d, J = 7Hz).

　（参考例３５）３－［１－（チオフェン－３－イル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 35) 3- [1- (thiophen-3-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、２－（チオフェン－３－イル）プロピオン酸（１．００ｇ、６．４０ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（３８０ｍｇ、収率：３１％）を得た。 Similar to the method described in Reference Example 21, using 2- (thiophen-3-yl) propionic acid (1.00 g, 6.40 mmol) instead of 2- (biphenyl-4-yl) propionic acid. Reaction was performed to obtain the title compound (380 mg, yield: 31%).

　1H-NMR (400MHz, DMSO-d6) δ: 11.18 (1H, brs), 7.42 (1H, dd, J=5Ha, 3Hz), 7.15 (1H, d, J=2Hz), 7.00 (1H, d, J=4Hz), 5.13 (1H, s), 4.43 (2H, brs), 4.03 (1H, q, J=7Hz), 1.47 (3H, d, J=7Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.18 (1H, brs), 7.42 (1H, dd, J = 5Ha, 3Hz), 7.15 (1H, d, J = 2Hz), 7.00 (1H, d , J = 4Hz), 5.13 (1H, s), 4.43 (2H, brs), 4.03 (1H, q, J = 7Hz), 1.47 (3H, d, J = 7Hz).

　（参考例３６）３－［（メチルスルファニル）（フェニル）メチル］－１Ｈ－ピラゾール－５－アミン Reference Example 36 3-[(Methylsulfanyl) (phenyl) methyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、（メチルスルファニル）（フェニル）酢酸（１．００ｇ、５．４９ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（２２０ｍｇ、収率：１８％）を得た。 The reaction was carried out in the same manner as described in Reference Example 21 using (methylsulfanyl) (phenyl) acetic acid (1.00 g, 5.49 mmol) instead of 2- (biphenyl-4-yl) propionic acid. The title compound (220 mg, yield: 18%) was obtained.

　1H-NMR (500MHz, DMSO-d6) δ: 11.30 (1H, brs), 7.41 (2H, d, J=8Hz), 7.34-7.29 (2H, m), 7.25-7.20 (1H, m), 5.31 (1H, s), 4.91 (1H, s), 4.73 (2H, brs), 1.90 (3H, s)。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 11.30 (1H, brs), 7.41 (2H, d, J = 8Hz), 7.34-7.29 (2H, m), 7.25-7.20 (1H, m), 5.31 (1H, s), 4.91 (1H, s), 4.73 (2H, brs), 1.90 (3H, s).

　（参考例３７）３－［１－（チオフェン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 37) 3- [1- (thiophen-2-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、２－（チオフェン－２－イル）プロピオン酸（１．００ｇ、６．４０ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（３９５ｍｇ、収率：３２％）を得た。 Similar to the method described in Reference Example 21, using 2- (thiophen-2-yl) propionic acid (1.00 g, 6.40 mmol) instead of 2- (biphenyl-4-yl) propionic acid. Reaction was performed to obtain the title compound (395 mg, yield: 32%).

　1H-NMR (400MHz, DMSO-d6) δ: 11.23 (1H, brs), 7.30 (1H, dd, J=5Hz, 1Hz), 6.92 (1H, dd, J=5Hz, 4Hz), 6.87 (1H, dd, J=4Hz, 1Hz), 5.17 (1H, s), 4.57 (2H, brs), 4.23 (1H, q, J=7Hz), 1.53 (3H, d, J=7Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.23 (1H, brs), 7.30 (1H, dd, J = 5Hz, 1Hz), 6.92 (1H, dd, J = 5Hz, 4Hz), 6.87 (1H , dd, J = 4Hz, 1Hz), 5.17 (1H, s), 4.57 (2H, brs), 4.23 (1H, q, J = 7Hz), 1.53 (3H, d, J = 7Hz).

　（参考例３８）３－［１－（フェニルスルファニル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 38) 3- [1- (Phenylsulfanyl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、２－（フェニルスルファニル）プロピオン酸（１．００ｇ、５．４９ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、標記化合物（４６９ｍｇ、収率：３９％）を得た。 Using 2- (phenylsulfanyl) propionic acid (1.00 g, 5.49 mmol) instead of 2- (biphenyl-4-yl) propionic acid, the reaction was carried out in the same manner as described in Reference Example 21. The title compound (469 mg, yield: 39%) was obtained.

　1H-NMR (500MHz, DMSO-d6) δ: 11.26 (1H, brs), 7.37-7.16 (5H, m), 5.26 (1H, s), 4.66 (2H, brs), 4.42 (1H, q, J=7Hz), 1.47 (3H, d, J=7Hz)。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 11.26 (1H, brs), 7.37-7.16 (5H, m), 5.26 (1H, s), 4.66 (2H, brs), 4.42 (1H, q, J = 7Hz), 1.47 (3H, d, J = 7Hz).

　（参考例３９）２－（５－メチルフラン－２－イル）プロピオン酸メチル (Reference Example 39) Methyl 2- (5-methylfuran-2-yl) propionate

Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051

　２－（５－メチルフラン－２－イル）プロピオン酸（１．００ｇ、６．４９ｍｍｏｌ）、及び、炭酸カリウム（１．４５ｇ、１０．５ｍｍｏｌ）のＤＭＦ（３０ｍＬ）懸濁液に、ヨウ化メチル（０．５７ｍＬ、９．１６ｍｍｏｌ）を室温で加え、同温で６．５時間攪拌した。反応液に水を加え、ジエチルエーテルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝１００／０－３０／７０（グラジェント）］で精製し、標記化合物（９２０ｍｇ、収率：８４％）を得た。 To a suspension of 2- (5-methylfuran-2-yl) propionic acid (1.00 g, 6.49 mmol) and potassium carbonate (1.45 g, 10.5 mmol) in DMF (30 mL) was added methyl iodide. (0.57 mL, 9.16 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 6.5 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-30 / 70 (gradient)] to obtain the title compound (920 mg, yield: 84%).

　1H-NMR (500MHz, CDCl3) δ: 6.04 (1H, d, J=3Hz), 5.89 (1H, d, J=3Hz), 3.77 (1H, q, J=7Hz), 3.71 (3H, s), 2.26 (3H, s), 1.49 (3H, d, J=7Hz)。 1 H-NMR (500MHz, CDCl 3 ) δ: 6.04 (1H, d, J = 3Hz), 5.89 (1H, d, J = 3Hz), 3.77 (1H, q, J = 7Hz), 3.71 (3H, s ), 2.26 (3H, s), 1.49 (3H, d, J = 7Hz).

　（参考例４０）３－［１－（５－メチルフラン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 40) 3- [1- (5-Methylfuran-2-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052

　２－（４－クロロフェニル）プロピオン酸メチルの代わりに、参考例３９にて製造された２－（５－メチルフラン－２－イル）プロピオン酸メチル（９２０ｍｇ、５．４７ｍｍｏｌ）を用いて、参考例２０に記載された方法と同様に反応を行い、標記化合物（１．０２ｇ、収率：９７％）を得た。 Instead of methyl 2- (4-chlorophenyl) propionate, methyl 2- (5-methylfuran-2-yl) propionate (920 mg, 5.47 mmol) prepared in Reference Example 39 was used. The reaction was conducted in the same manner as described in 20 to obtain the title compound (1.02 g, yield: 97%).

　1H-NMR (500MHz, DMSO-d6) δ: 11.17 (1H, brs), 5.92 (2H, s), 5.11 (1H, s), 4.52 (2H, brs), 3.93 (1H, q, J=7Hz), 2.19 (3H, s), 1.42 (3H, d, J=7Hz)。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 11.17 (1H, brs), 5.92 (2H, s), 5.11 (1H, s), 4.52 (2H, brs), 3.93 (1H, q, J = 7Hz), 2.19 (3H, s), 1.42 (3H, d, J = 7Hz).

　（参考例４１）２－（６－メトキシピリジン－２－イル）プロピオン酸エチル Reference Example 41 Ethyl 2- (6-methoxypyridin-2-yl) propionate

Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053

　１－ブロモ－３－ｔｅｒｔ－ブチルベンゼンの代わりに、２－ブロモ－６－メトキシピリジン（３．００ｇ、１６．０ｍｍｏｌ）を用いて、参考例２３と同様に反応を行い、合成中間体を得た。 The reaction was carried out in the same manner as in Reference Example 23 using 2-bromo-6-methoxypyridine (3.00 g, 16.0 mmol) instead of 1-bromo-3-tert-butylbenzene to obtain a synthetic intermediate. It was.

　上記操作で得られた合成中間体のエタノール（２０ｍＬ）溶液に、１Ｎ塩酸（４０ｍＬ）を加え、６０℃で１０時間攪拌した。反応液に飽和炭酸水素ナトリウムを加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝１００／０－８５／１５（グラジェント）］で精製し、標記化合物（４３０ｍｇ、収率：１３％）を得た。 1N hydrochloric acid (40 mL) was added to an ethanol (20 mL) solution of the synthetic intermediate obtained by the above operation, and the mixture was stirred at 60 ° C. for 10 hours. Saturated sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-85 / 15 (gradient)] to obtain the title compound (430 mg, yield: 13%).

　1H-NMR (500MHz, CDCl3) δ: 7.53-7.49 (1H, m), 6.82 (1H, d, J=7Hz), 6.60 (1H, d, J=8Hz), 4.16 (2H, q, J=7Hz), 3.90 (3H, s), 3.81 (1H, q, J=7Hz), 1.52 (3H, d, J=7Hz), 1.22 (3H, t, J=7Hz)。 1 H-NMR (500MHz, CDCl 3 ) δ: 7.53-7.49 (1H, m), 6.82 (1H, d, J = 7Hz), 6.60 (1H, d, J = 8Hz), 4.16 (2H, q, J = 7Hz), 3.90 (3H, s), 3.81 (1H, q, J = 7Hz), 1.52 (3H, d, J = 7Hz), 1.22 (3H, t, J = 7Hz).

　（参考例４２）３－［１－（６－メトキシピリジン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン Reference Example 42 3- [1- (6-Methoxypyridin-2-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054

　２－（４－クロロフェニル）プロピオン酸メチルの代わりに、参考例４１にて製造された２－（６－メトキシピリジン－２－イル）プロピオン酸エチル（４３０ｍｇ、２．０６ｍｍｏｌ）を用いて、参考例２０に記載された方法と同様に反応を行い、標記化合物（４６０ｍｇ、収率：定量的）を得た。 Instead of methyl 2- (4-chlorophenyl) propionate, ethyl 2- (6-methoxypyridin-2-yl) propionate prepared in Reference Example 41 (430 mg, 2.06 mmol) was used. The reaction was performed in the same manner as described in 20 to obtain the title compound (460 mg, yield: quantitative).

　1H-NMR (500MHz, DMSO-d6) δ: 11.17 (1H, brs), 8.92 (1H, brs), 7.61-7.54 (1H, m), 6.77 (1H, d, J=7Hz), 6.61 (1H, d, J=8Hz), 5.21 (1H, s), 4.37 (1H, brs), 4.03-3.96 (1H, m), 3.85 (3H, s), 1.50 (3H, d, J=7Hz)。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 11.17 (1H, brs), 8.92 (1H, brs), 7.61-7.54 (1H, m), 6.77 (1H, d, J = 7Hz), 6.61 ( 1H, d, J = 8Hz), 5.21 (1H, s), 4.37 (1H, brs), 4.03-3.96 (1H, m), 3.85 (3H, s), 1.50 (3H, d, J = 7Hz).

　（参考例４３）２－（５－メチルチオフェン－２－イル）プロピオン酸エチル (Reference Example 43) Ethyl 2- (5-methylthiophen-2-yl) propionate

Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055

　２－（５－メチルフラン－２－イル）プロピオン酸の代わりに、２－（５－メチルチオフェン－２－イル）プロピオン酸（１．００ｇ、５．８８ｍｍｏｌ）を、ヨウ化メチルの代わりにヨウ化エチル（０．６２ｍＬ、７．７１ｍｍｏｌ）用いて、参考例３９に記載された方法と同様に反応を行い、標記化合物（１．０５ｇ、収率：９０％）を得た。 Instead of 2- (5-methylfuran-2-yl) propionic acid, 2- (5-methylthiophen-2-yl) propionic acid (1.00 g, 5.88 mmol) was used instead of methyl iodide. Reaction was carried out in the same manner as described in Reference Example 39 using ethyl iodide (0.62 mL, 7.71 mmol) to obtain the title compound (1.05 g, yield: 90%).

　1H-NMR (400MHz, CDCl3) δ: 6.71 (1H, d, J=4Hz), 6.59-6.57 (1H, m), 4.20-4.10 (2H, m), 3.89 (1H, q, J=7Hz), 2.44 (3H, s), 1.53 (3H, t, J=4Hz), 1.25 (3H, t, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 6.71 (1H, d, J = 4Hz), 6.59-6.57 (1H, m), 4.20-4.10 (2H, m), 3.89 (1H, q, J = 7Hz ), 2.44 (3H, s), 1.53 (3H, t, J = 4Hz), 1.25 (3H, t, J = 7Hz).

　（参考例４４）３－［１－（５－メチルチオフェン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 44) 3- [1- (5-Methylthiophen-2-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056

　２－（４－クロロフェニル）プロピオン酸メチルの代わりに、参考例４３にて製造された２－（５－メチルチオフェン－２－イル）プロピオン酸エチル（１．０５ｇ、５．３０ｍｍｏｌ）を用いて、参考例２０に記載された方法と同様に反応を行い、標記化合物（１．００ｇ、収率：９１％）を得た。 Instead of methyl 2- (4-chlorophenyl) propionate, ethyl 2- (5-methylthiophen-2-yl) propionate prepared in Reference Example 43 (1.05 g, 5.30 mmol) was used. The reaction was performed in the same manner as described in Reference Example 20 to obtain the title compound (1.00 g, yield: 91%).

　1H-NMR (400MHz, DMSO-d6) δ: 11.24 (1H, brs), 6.62 (1H, s), 6.57 (1H, s), 5.22 (1H, s), 4.38 (2H, brs), 4.15 (1H, s), 2.35 (3H, s), 1.49 (3H, d, J=7Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.24 (1H, brs), 6.62 (1H, s), 6.57 (1H, s), 5.22 (1H, s), 4.38 (2H, brs), 4.15 (1H, s), 2.35 (3H, s), 1.49 (3H, d, J = 7Hz).

　（参考例４５）２－（１－ベンゾフラン－２－イル）プロピオン酸エチル (Reference Example 45) Ethyl 2- (1-benzofuran-2-yl) propionate

Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057

　２－（５－メチルチオフェン－２－イル）プロピオン酸の代わりに、２－（１－ベンゾフラン－２－イル）プロピオン酸（１．００ｇ、５．２６ｍｍｏｌ）を用いて、参考例４３に記載された方法と同様に反応を行い、標記化合物（１．１３ｇ、収率：９８％）を得た。 As described in Reference Example 43, 2- (1-benzofuran-2-yl) propionic acid (1.00 g, 5.26 mmol) was used instead of 2- (5-methylthiophen-2-yl) propionic acid. The reaction was conducted in the same manner as described above to obtain the title compound (1.13 g, yield: 98%).

　1H-NMR (400MHz, CDCl3) δ: 7.53-7.50 (1H, m), 7.46-7.42 (1H, m), 7.26-7.17 (2H, m), 6.58-6.57 (1H, m), 4.20 (2H, q, J=7Hz), 3.94 (1H, q, J=7Hz), 1.62 (3H, d, J=7Hz), 1.26 (3H, t, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.53-7.50 (1H, m), 7.46-7.42 (1H, m), 7.26-7.17 (2H, m), 6.58-6.57 (1H, m), 4.20 ( 2H, q, J = 7Hz), 3.94 (1H, q, J = 7Hz), 1.62 (3H, d, J = 7Hz), 1.26 (3H, t, J = 7Hz).

　（参考例４６）４－（１－ベンゾフラン－２－イル）－３－オキソペンタンニトリル (Reference Example 46) 4- (1-benzofuran-2-yl) -3-oxopentanenitrile

Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058

　無水アセトニトリル（０．８５ｍＬ、１６．２ｍｍｏｌ）の無水ＴＨＦ（２５ｍＬ）溶液にｎ－ブチルリチウム（２．６９Ｍヘキサン溶液、５．８０ｍＬ、１５．６ｍｍｏｌ）を－７８℃で滴下した後、同温度で３０分攪拌した後、参考例４５にて製造された２－（１－ベンゾフラン－２－イル）プロピオン酸エチル（１．１３ｇ、５．１８ｍｍｏｌ）の無水ＴＨＦ（２５ｍＬ）溶液を－７８℃で滴下し、同温度で４５分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝１００／０－７０／３０（グラジェント）］で精製し、標記化合物（７５５ｍｇ、収率：６８％）を得た。 N-Butyllithium (2.69 M hexane solution, 5.80 mL, 15.6 mmol) was added dropwise at −78 ° C. to a solution of anhydrous acetonitrile (0.85 mL, 16.2 mmol) in anhydrous THF (25 mL) at the same temperature. After stirring for 30 minutes, a solution of ethyl 2- (1-benzofuran-2-yl) propionate (1.13 g, 5.18 mmol) prepared in Reference Example 45 in anhydrous THF (25 mL) was added dropwise at −78 ° C. And stirred for 45 minutes at the same temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-70 / 30 (gradient)] to obtain the title compound (755 mg, yield: 68%).

　1H-NMR (400MHz, CDCl3) δ: 7.56 (1H, dd, J=7Hz, 1Hz), 7.46 (1H, dd, J=8Hz, 1Hz), 7.33-7.23 (2H, m), 6.67 (1H, s), 4.11 (1H, q, J=7Hz), 3.57 (2H, d, J=1Hz), 1.59 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.56 (1H, dd, J = 7Hz, 1Hz), 7.46 (1H, dd, J = 8Hz, 1Hz), 7.33-7.23 (2H, m), 6.67 (1H , s), 4.11 (1H, q, J = 7Hz), 3.57 (2H, d, J = 1Hz), 1.59 (3H, d, J = 7Hz).

　（参考例４７）３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン (Reference Example 47) 3- {1- [3- (6-Fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059

　参考例７にて製造された３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミン（２．１５ｇ、８．０８ｍｍｏｌ）、６－フルオロ－３－ピリジニルボロン酸（１．２５g、８．８９ｍｍｏｌ）及び、炭酸カリウム（２．４６ｇ、１７．８ｍｍｏｌ）の１，４－ジオキサン（３０ｍＬ）、及び、水（１５ｍＬ）の混合溶液に、窒素雰囲気下［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロロメタン付加物（６６０ｍｇ、０．８１ｍｍｏｌ）を加え、８０℃で２時間攪拌した。反応液を室温まで放置し、水を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル／メタノール＝１００／０－９０／１０（グラジェント）］で精製し、標記化合物（２．２９ｇ、収率：定量的）を得た。 3- [1- (3-Bromophenyl) ethyl] -1H-pyrazol-5-amine (2.15 g, 8.08 mmol), 6-fluoro-3-pyridinylboronic acid (1. 25 g, 8.89 mmol) and potassium carbonate (2.46 g, 17.8 mmol) in 1,4-dioxane (30 mL) and water (15 mL) under a nitrogen atmosphere [1,1′-bis (Diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (660 mg, 0.81 mmol) was added and stirred at 80 ° C. for 2 hours. The reaction solution was allowed to stand at room temperature, water was added, extraction was performed with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10 (gradient)] to obtain the title compound (2.29 g, yield: quantitative). .

　1H-NMR (400MHz, CDCl3) δ: 8.36 (1H, d, J=3Hz), 7.91 (1H, td, J=8Hz, 2Hz), 7.43-7.33 (3H, m), 7.28-7.24 (1H, m), 6.98 (1H, dd, J=8Hz, 3Hz), 5.55 (1H, s), 4.12 (1H, q, J=7Hz), 1.63 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.36 (1H, d, J = 3Hz), 7.91 (1H, td, J = 8Hz, 2Hz), 7.43-7.33 (3H, m), 7.28-7.24 (1H , m), 6.98 (1H, dd, J = 8Hz, 3Hz), 5.55 (1H, s), 4.12 (1H, q, J = 7Hz), 1.63 (3H, d, J = 7Hz).

　（参考例４８）３－（１－｛３－［６－（トリフルオロメチル）ピリジン－３－イル］フェニル｝エチル）－１Ｈ－ピラゾール－５－アミン (Reference Example 48) 3- (1- {3- [6- (trifluoromethyl) pyridin-3-yl] phenyl} ethyl) -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060

　６－フルオロ－３－ピリジニルボロン酸の代わりに、２－トリフルオロメチルピリジル－５－ボロン酸（１．８１ｇ、９．４６ｍｍｏｌ）を用いて、参考例４７に記載された方法と同様に反応を行い、標記化合物（２．６０ｇ、収率：９１％）を得た。 The reaction was carried out in the same manner as described in Reference Example 47 using 2-trifluoromethylpyridyl-5-boronic acid (1.81 g, 9.46 mmol) instead of 6-fluoro-3-pyridinylboronic acid. The title compound (2.60 g, yield: 91%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 8.88 (1H, s), 7.98 (1H, d, J=8Hz), 7.73 (1H, d, J=8Hz), 7.49-7.38 (3H, m), 7.35-7.28 (1H, m), 5.55 (1H, s), 4.14 (1H, q, J=7Hz), 1.63 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.88 (1H, s), 7.98 (1H, d, J = 8Hz), 7.73 (1H, d, J = 8Hz), 7.49-7.38 (3H, m), 7.35-7.28 (1H, m), 5.55 (1H, s), 4.14 (1H, q, J = 7Hz), 1.63 (3H, d, J = 7Hz).

　（参考例４９）３－｛１－［３－（ピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン (Reference Example 49) 3- {1- [3- (Pyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061

　６－フルオロ－３－ピリジニルボロン酸の代わりに、３－ピリジルボロン酸（１４３ｍｇ、１．１７ｍｍｏｌ）を用いて、参考例４７に記載された方法と同様に反応を行い、標記化合物（２０９ｍｇ、収率：７５％）を得た。 The reaction was conducted in the same manner as described in Reference Example 47 using 3-pyridylboronic acid (143 mg, 1.17 mmol) instead of 6-fluoro-3-pyridinylboronic acid, and the title compound (209 mg, yield) : 75%).

　1H-NMR (400MHz, CDCl3) δ: 8.72 (1H, d, J=2Hz), 8.55 (1H, dd, J=5Hz, 2Hz), 7.80 (1H, dt, J=8Hz, 2Hz), 7.42-7.36 (3H, m), 7.32 (1H, dd, J=8Hz, 5Hz), 7.26-7.21 (1H, m), 5.55 (1H, s), 4.11 (1H, q, J=7Hz), 1.62 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.72 (1H, d, J = 2Hz), 8.55 (1H, dd, J = 5Hz, 2Hz), 7.80 (1H, dt, J = 8Hz, 2Hz), 7.42 -7.36 (3H, m), 7.32 (1H, dd, J = 8Hz, 5Hz), 7.26-7.21 (1H, m), 5.55 (1H, s), 4.11 (1H, q, J = 7Hz), 1.62 ( 3H, d, J = 7Hz).

　（参考例５０）３－｛１－［３－（６－メトキシピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン (Reference Example 50) 3- {1- [3- (6-Methoxypyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062

　６－フルオロ－３－ピリジニルボロン酸の代わりに、２－メトキシピリジン－５－ボロン酸（２４０ｍｇ、１．５７ｍｍｏｌ）を用いて、参考例４７に記載された方法と同様に反応を行い、標記化合物（３７６ｍｇ、収率：８９％）を得た。 The reaction was carried out in the same manner as described in Reference Example 47 using 2-methoxypyridine-5-boronic acid (240 mg, 1.57 mmol) instead of 6-fluoro-3-pyridinylboronic acid, and the title compound ( 376 mg, yield: 89%).

　1H-NMR (400MHz, CDCl3) δ: 8.34 (1H, d, J=2Hz), 7.74 (1H, dd, J=9Hz, 2Hz), 7.41-7.36 (2H, m), 7.34 (1H, s), 7.22-7.16 (1H, m), 6.80 (1H, d, J=9Hz), 5.56 (1H, s), 4.09 (1H, q, J=7Hz), 3.97 (3H, s), 1.62 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.34 (1H, d, J = 2Hz), 7.74 (1H, dd, J = 9Hz, 2Hz), 7.41-7.36 (2H, m), 7.34 (1H, s ), 7.22-7.16 (1H, m), 6.80 (1H, d, J = 9Hz), 5.56 (1H, s), 4.09 (1H, q, J = 7Hz), 3.97 (3H, s), 1.62 (3H , d, J = 7Hz).

　（参考例５１）３－｛１－［３－（２，６－ジフルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン Reference Example 51 3- {1- [3- (2,6-difluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063

　６－フルオロ－３－ピリジニルボロン酸の代わりに、２，６－ジフルオロピリジン－３－ボロン酸（２２５ｍｇ、１．４２ｍｍｏｌ）を用いて、参考例４７に記載された方法と同様に反応を行い、標記化合物（２７６ｍｇ、収率：７１％）を得た。 The reaction was conducted in the same manner as described in Reference Example 47 using 2,6-difluoropyridine-3-boronic acid (225 mg, 1.42 mmol) instead of 6-fluoro-3-pyridinylboronic acid. The compound (276 mg, yield: 71%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 7.96-7.88 (1H, m), 7.43-7.33 (3H, m), 7.28-7.24 (1H, m), 6.91 (1H, dd, J=8Hz, 3Hz), 5.55 (1H, s), 4.10 (1H, q, J=7Hz), 1.62 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.96-7.88 (1H, m), 7.43-7.33 (3H, m), 7.28-7.24 (1H, m), 6.91 (1H, dd, J = 8Hz, 3Hz ), 5.55 (1H, s), 4.10 (1H, q, J = 7Hz), 1.62 (3H, d, J = 7Hz).

　（参考例５２）３－｛１－［４’－（トリフルオロメチル）ビフェニル－３－イル］エチル｝－１Ｈ－ピラゾール－５－アミン Reference Example 52 3- {1- [4 '-(trifluoromethyl) biphenyl-3-yl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064

　６－フルオロ－３－ピリジニルボロン酸の代わりに、４－トリフルオロメチルフェニルボロン酸（２９０ｍｇ、１．５３ｍｍｏｌ）を用いて、参考例４７に記載された方法と同様に反応を行い、標記化合物（３７８ｍｇ、収率：８２％）を得た。 The reaction was conducted in the same manner as described in Reference Example 47 using 4-trifluoromethylphenylboronic acid (290 mg, 1.53 mmol) instead of 6-fluoro-3-pyridinylboronic acid, and the title compound (378 mg Yield: 82%).

　1H-NMR (400MHz, CDCl3) δ: 7.67 (2H, d, J=8Hz), 7.63 (2H, d, J=8Hz), 7.48-7.37 (3H, m), 7.27-7.23 (1H, m), 5.55 (1H, s), 4.11 (1H, q, J=7Hz), 1.63 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.67 (2H, d, J = 8Hz), 7.63 (2H, d, J = 8Hz), 7.48-7.37 (3H, m), 7.27-7.23 (1H, m ), 5.55 (1H, s), 4.11 (1H, q, J = 7Hz), 1.63 (3H, d, J = 7Hz).

　（参考例５３）３－｛１－［３－（２－フルオロ－６－メトキシピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン Reference Example 53 3- {1- [3- (2-Fluoro-6-methoxypyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065

　６－フルオロ－３－ピリジニルボロン酸の代わりに、２－フルオロ－６－メトキシピリジン－３－ボロン酸（２５４ｍｇ、１．４９ｍｍｏｌ）を用いて、参考例４７に記載された方法と同様に反応を行い、標記化合物（１９４ｍｇ、収率：４６％）を得た。 The reaction was conducted in the same manner as described in Reference Example 47 using 2-fluoro-6-methoxypyridine-3-boronic acid (254 mg, 1.49 mmol) instead of 6-fluoro-3-pyridinylboronic acid. The title compound (194 mg, yield: 46%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 7.73 (1H, dd, J=10Hz, 8Hz), 7.42-7.33 (3H, m), 7.23-7.17 (1H, m), 6.70 (1H, dd, J=8Hz, 1Hz), 5.58 (1H, brs), 4.11 (1H, q, J=7Hz), 3.96 (3H, s), 3.61 (1H, brs), 1.63 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.73 (1H, dd, J = 10Hz, 8Hz), 7.42-7.33 (3H, m), 7.23-7.17 (1H, m), 6.70 (1H, dd, J = 8Hz, 1Hz), 5.58 (1H, brs), 4.11 (1H, q, J = 7Hz), 3.96 (3H, s), 3.61 (1H, brs), 1.63 (3H, d, J = 7Hz).

　（参考例５４）３－｛１－［３－（６－フルオロ－２－メチルピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン Reference Example 54 3- {1- [3- (6-Fluoro-2-methylpyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066

　６－フルオロ－３－ピリジニルボロン酸の代わりに、６－フルオロ－２－メチルピリジン－３－ボロン酸（２３９ｍｇ、１．５５ｍｍｏｌ）を用いて、参考例４７に記載された方法と同様に反応を行い、標記化合物（３４９ｍｇ、収率：８４％）を得た。 The reaction was conducted in the same manner as described in Reference Example 47 using 6-fluoro-2-methylpyridine-3-boronic acid (239 mg, 1.55 mmol) instead of 6-fluoro-3-pyridinylboronic acid. The title compound (349 mg, yield: 84%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 7.57 (1H, t, J=8Hz), 7.38 (1H, t, J=8Hz), 7.28-7.21 (1H, m), 7.19-7.10 (2H, m), 6.79 (1H, dd, J=8Hz, 3Hz), 5.54 (1H, s), 4.10 (1H, q, J=7Hz), 2.40 (3H, s), 1.62 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.57 (1H, t, J = 8Hz), 7.38 (1H, t, J = 8Hz), 7.28-7.21 (1H, m), 7.19-7.10 (2H, m ), 6.79 (1H, dd, J = 8Hz, 3Hz), 5.54 (1H, s), 4.10 (1H, q, J = 7Hz), 2.40 (3H, s), 1.62 (3H, d, J = 7Hz) .

　（参考例５５）３－オキソ－４－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］ペンタンニトリル Reference Example 55 3-Oxo-4- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] pentanenitrile

Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067

　参考例６にて製造された４－（３－ブロモフェニル）－３－オキソペンタンニトリル（５２１ｍｇ、２．０７ｍｍｏｌ）、及び、ビス（ピナコラト）ジボロン（５７７ｍｇ、２．２７ｍｍｏｌ）の１，４－ジオキサン（１０ｍＬ）溶液に、窒素雰囲気下［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロロメタン付加物（１６９ｍｇ、０．２１ｍｍｏｌ）、酢酸カリウム（４４６ｍｇ、４．５５ｍｍｏｌ）を加え、８０℃で２時間攪拌した。反応液を室温まで放置し、水を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝９５／５－７５／２５（グラジェント）］で精製し、標記化合物（４１５ｍｇ、収率：７６％）を得た。 4- (3-Bromophenyl) -3-oxopentanenitrile (521 mg, 2.07 mmol) and bis (pinacolato) diboron (577 mg, 2.27 mmol) of 1,4-dioxane prepared in Reference Example 6 (10 mL) To the solution was added [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (169 mg, 0.21 mmol), potassium acetate (446 mg, 4.55 mmol) under a nitrogen atmosphere, Stir at 80 ° C. for 2 hours. The reaction mixture was allowed to stand at room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-75 / 25 (gradient)] to obtain the title compound (415 mg, yield: 76%).

　1H-NMR (400MHz, CDCl3) δ: 7.78-7.75 (1H, m), 7.65-7.62 (1H, br m), 7.39 (1H, t, J=7Hz), 7.31-7.27 (1H, m), 3.87 (1H, q, J=7Hz), 3.39-3.36 (2H, m), 1.46 (3H, d, J=7Hz), 1.35 (12H, s)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.78-7.75 (1H, m), 7.65-7.62 (1H, br m), 7.39 (1H, t, J = 7Hz), 7.31-7.27 (1H, m) , 3.87 (1H, q, J = 7Hz), 3.39-3.36 (2H, m), 1.46 (3H, d, J = 7Hz), 1.35 (12H, s).

　（参考例５６）３－｛１－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン (Reference Example 56) 3- {1- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068

　４－（４－フルオロフェニル）－３－オキソペンタンニトリルの代わりに、参考例５５にて製造された３－オキソ－４－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］ペンタンニトリル（４１５ｍｇ、１．３９ｍｏｌ）を用いて、参考例１８に記載された方法と同様に反応を行い、標記化合物（３２６ｍｇ、収率：７５％）を得た。 Instead of 4- (4-fluorophenyl) -3-oxopentanenitrile, 3-oxo-4- [3- (4,4,5,5-tetramethyl-1,3 prepared in Reference Example 55 was used. , 2-Dioxaborolan-2-yl) phenyl] pentanenitrile (415 mg, 1.39 mol), and the reaction was carried out in the same manner as described in Reference Example 18 to obtain the title compound (326 mg, yield: 75%). Got.

　1H-NMR (400MHz, CDCl3) δ: 7.71-7.66 (2H, m), 7.34-7.27 (2H, m), 5.53 (1H, s), 4.04 (1H, q, J=7Hz), 1.59 (3H, d, J=7Hz), 1.34 (12H, s)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.71-7.66 (2H, m), 7.34-7.27 (2H, m), 5.53 (1H, s), 4.04 (1H, q, J = 7Hz), 1.59 ( 3H, d, J = 7Hz), 1.34 (12H, s).

　（参考例５７）３－｛１－［３－（５－フルオロピリジン－２－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン (Reference Example 57) 3- {1- [3- (5-fluoropyridin-2-yl) phenyl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069

　参考例５６にて製造された３－｛１－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン（１０６ｍｇ、０．３４ｍｍｏｌ）、２－クロロ－５－フルオロピリジン（３８μＬ、０．３７ｍｍｏｌ）の１，４－ジオキサン：水（２：１、２ｍＬ）の混合溶液に、窒素雰囲気下［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロロメタン付加物（２８ｍｇ、０．０３４ｍｍｏｌ）、炭酸ナトリウム（７９ｍｇ、０．７４ｍｍｏｌ）を加え、８０℃で１時間攪拌した。反応液を室温まで放置し、水を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル／メタノール＝１００／０－９５／０５（グラジェント）］で精製し、標記化合物（７３ｍｇ、収率：７６％）を得た。 3- {1- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethyl} -1H-pyrazole-5 prepared in Reference Example 56 -A mixed solution of amine (106 mg, 0.34 mmol), 2-chloro-5-fluoropyridine (38 μL, 0.37 mmol) in 1,4-dioxane: water (2: 1, 2 mL) under a nitrogen atmosphere [1 , 1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (28 mg, 0.034 mmol) and sodium carbonate (79 mg, 0.74 mmol) were added, and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was allowed to stand at room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0-95 / 05 (gradient)] to obtain the title compound (73 mg, yield: 76%).

　1H-NMR (400MHz, CDCl3) δ: 8.49 (1H, d, J=3Hz), 7.81-7.78 (1H, m), 7.75-7.71 (1H, m), 7.65 (1H, dd, J=9Hz, 4Hz), 7.44 (1H, td, J=8Hz, 3Hz), 7.37 (1H, t, J=8Hz), 7.22 (1H, d, J=8Hz), 5.54 (1H, s), 4.10 (1H, q, J=7Hz), 1.61 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.49 (1H, d, J = 3Hz), 7.81-7.78 (1H, m), 7.75-7.71 (1H, m), 7.65 (1H, dd, J = 9Hz , 4Hz), 7.44 (1H, td, J = 8Hz, 3Hz), 7.37 (1H, t, J = 8Hz), 7.22 (1H, d, J = 8Hz), 5.54 (1H, s), 4.10 (1H, q, J = 7Hz), 1.61 (3H, d, J = 7Hz).

　（参考例５８）３－｛１－［３－（２－メトキシピリミジン－５－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン (Reference Example 58) 3- {1- [3- (2-methoxypyrimidin-5-yl) phenyl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070

　２－クロロ－５－フルオロピリジンの代わりに、５－ブロモ－２－メトキシピリミジン（１７１ｍｇ、０．９０ｍｏｌ）を用いて、参考例５７に記載された方法と同様に反応を行い、標記化合物（１８４ｍｇ、収率：７６％）を得た。 The reaction was conducted in the same manner as described in Reference Example 57 using 5-bromo-2-methoxypyrimidine (171 mg, 0.90 mol) instead of 2-chloro-5-fluoropyridine to give the title compound (184 mg Yield: 76%).

　1H-NMR (400MHz, CDCl3) δ: 8.67 (2H, s), 7.45-7.36 (2H, m), 7.34-7.32 (1H, m), 7.28-7.25 (1H, m), 5.57 (1H, s), 4.13 (1H, q, J=7Hz), 4.06 (3H, s), 1.64 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.67 (2H, s), 7.45-7.36 (2H, m), 7.34-7.32 (1H, m), 7.28-7.25 (1H, m), 5.57 (1H, s), 4.13 (1H, q, J = 7Hz), 4.06 (3H, s), 1.64 (3H, d, J = 7Hz).

　（参考例５９）３－｛１－［３－（２－イソプロポキシピリミジン－５－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン (Reference Example 59) 3- {1- [3- (2-Isopropoxypyrimidin-5-yl) phenyl] ethyl} -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071

　２－クロロ－５－フルオロピリジンの代わりに、５－ブロモ－２－イソプロポキシピリミジン（２１６ｍｇ、０．９９ｍｏｌ）を用いて、参考例５７に記載された方法と同様に反応を行い、標記化合物（２７３ｍｇ、収率：９３％）を得た。 The reaction was conducted in the same manner as described in Reference Example 57 using 5-bromo-2-isopropoxypyrimidine (216 mg, 0.99 mol) in place of 2-chloro-5-fluoropyridine, and the title compound ( 273 mg, yield: 93%).

　1H-NMR (400MHz, CDCl3) δ: 8.65 (2H, s), 7.44-7.31 (3H, m), 7.27-7.23 (1H, m), 5.56 (1H, s), 5.36-5.27 (1H, m), 4.12 (1H, q, J=7Hz), 1.63 (3H, d, J=7Hz), 1.43 (6H, d, J=6Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.65 (2H, s), 7.44-7.31 (3H, m), 7.27-7.23 (1H, m), 5.56 (1H, s), 5.36-5.27 (1H, m), 4.12 (1H, q, J = 7Hz), 1.63 (3H, d, J = 7Hz), 1.43 (6H, d, J = 6Hz).

　（参考例６０）３－（１－｛３－［５－（トリフルオロメチル）ピラジン－２－イル］フェニル｝エチル）－１Ｈ－ピラゾール－５－アミン (Reference Example 60) 3- (1- {3- [5- (trifluoromethyl) pyrazin-2-yl] phenyl} ethyl) -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072

　２－クロロ－５－フルオロピリジンの代わりに、２－ブロモ－５－（トリフルオロメチル）ピラジン（１７６ｍｇ、０．９７ｍｏｌ）を用いて、参考例５７に記載された方法と同様に反応を行い、標記化合物（２３４ｍｇ、収率：８０％）を得た。 Using 2-bromo-5- (trifluoromethyl) pyrazine (176 mg, 0.97 mol) instead of 2-chloro-5-fluoropyridine, the reaction was carried out in the same manner as described in Reference Example 57, The title compound (234 mg, yield: 80%) was obtained.

　1H-NMR (400MHz, CDCl3) δ: 9.06 (1H, d, J=1Hz), 8.95 (1H, d, J=1Hz), 7.96-7.92 (1H, m), 7.92-7.88 (1H, m), 7.48 (1H, t, J=8Hz), 7.38 (1H, d, J=8Hz), 5.56 (1H, s), 4.16 (1H, q, J=7Hz), 1.65 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 9.06 (1H, d, J = 1Hz), 8.95 (1H, d, J = 1Hz), 7.96-7.92 (1H, m), 7.92-7.88 (1H, m ), 7.48 (1H, t, J = 8Hz), 7.38 (1H, d, J = 8Hz), 5.56 (1H, s), 4.16 (1H, q, J = 7Hz), 1.65 (3H, d, J = 7Hz).

　（参考例６１）３－（１－｛３－［５－（トリフルオロメチル）ピリジン－２－イル］フェニル｝エチル）－１Ｈ－ピラゾール－５－アミン (Reference Example 61) 3- (1- {3- [5- (trifluoromethyl) pyridin-2-yl] phenyl} ethyl) -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073

　２－クロロ－５－フルオロピリジンの代わりに、２－ブロモ－５－（トリフルオロ）ピリジン（３１５ｍｇ、１．３９ｍｍｏｌ）を用いて、参考例５７に記載された方法と同様に反応を行い、標記化合物（３８３ｍｇ、収率：９９％）を得た。 The reaction was conducted in the same manner as described in Reference Example 57 using 2-bromo-5- (trifluoro) pyridine (315 mg, 1.39 mmol) instead of 2-chloro-5-fluoropyridine. The compound (383 mg, yield: 99%) was obtained.

　1H-NMR (500MHz, DMSO-d6) δ: 11.20 (1H, brs), 9.04 (1H, s), 8.28 (1H, dd, J=8Hz, 2Hz), 8.17 (1H, d, J=8Hz), 8.05 (1H, s), 7.96 (1H, d, J=8Hz), 7.52-7.36 (2H, m), 5.20 (1H, s), 4.50 (2H, brs), 4.09 (1H, q, J=7Hz), 1.54 (3H, d, J=7Hz)。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 11.20 (1H, brs), 9.04 (1H, s), 8.28 (1H, dd, J = 8Hz, 2Hz), 8.17 (1H, d, J = 8Hz ), 8.05 (1H, s), 7.96 (1H, d, J = 8Hz), 7.52-7.36 (2H, m), 5.20 (1H, s), 4.50 (2H, brs), 4.09 (1H, q, J = 7Hz), 1.54 (3H, d, J = 7Hz).

　（参考例６２）３－（１－｛３－［６－（トリフルオロメチル）ピリジン－２－イル］フェニル｝エチル）－１Ｈ－ピラゾール－５－アミン Reference Example 62 3- (1- {3- [6- (trifluoromethyl) pyridin-2-yl] phenyl} ethyl) -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074

　２－クロロ－５－フルオロピリジンの代わりに、２－ブロモ－６－（トリフルオロ）ピリジン（５２０ｍｇ、２．３０ｍｍｏｌ）を用いて、参考例５７に記載された方法と同様に反応を行い、標記化合物（３６０ｍｇ、収率：８１％）を得た。 The reaction was conducted in the same manner as described in Reference Example 57 using 2-bromo-6- (trifluoro) pyridine (520 mg, 2.30 mmol) instead of 2-chloro-5-fluoropyridine. The compound (360 mg, yield: 81%) was obtained.

　1H-NMR (400MHz, DMSO-d6) δ: 11.23 (1H, brs), 8.26 (1H, d, J=8Hz), 8.20-8.15 (1H, m), 7.99 (1H, s), 7.94 (1H, d, J=8Hz), 7.86 (1H, d, J=8Hz), 7.48-7.43 (1H, m), 7.38 (1H, d, J=8Hz), 5.20 (1H, s), 4.51 (2H, brs), 4.09 (1H, q, J=7Hz), 1.54 (3H, d, J=7Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.23 (1H, brs), 8.26 (1H, d, J = 8Hz), 8.20-8.15 (1H, m), 7.99 (1H, s), 7.94 ( 1H, d, J = 8Hz), 7.86 (1H, d, J = 8Hz), 7.48-7.43 (1H, m), 7.38 (1H, d, J = 8Hz), 5.20 (1H, s), 4.51 (2H , brs), 4.09 (1H, q, J = 7Hz), 1.54 (3H, d, J = 7Hz).

　（参考例６３）２－（１－フェニル－１Ｈ－ピラゾール－４－イル）プロピオン酸メチル (Reference Example 63) Methyl 2- (1-phenyl-1H-pyrazol-4-yl) propionate

Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075

　ジイソプロピルアミン（１．２０ｍＬ、８．５４ｍｍｏｌ）の無水ＴＨＦ（３５ｍＬ）溶液に、－７８℃でｎ－ブチルリチウム（２．６９Ｍヘキサン溶液、３．１５ｍＬ、８．４７ｍｍｏｌ）を滴下し、同温で３０分間攪拌した後に、（１－フェニル－１Ｈ－ピラゾール－４－イル）酢酸メチル（１．５１ｇ、６．９８ｍｍｏｌ）の無水ＴＨＦ（３５ｍＬ）溶液を滴下し、２０分間攪拌した。反応液に、ヨウ化メチル（０．４５ｍＬ、７．２３ｍｍｏｌ）を加え、同温で２．５時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝１００／０－７５／２５（グラジェント）］で精製し、標記化合物（１．１０ｇ、収率：６８％）を得た。 To a solution of diisopropylamine (1.20 mL, 8.54 mmol) in anhydrous THF (35 mL), n-butyllithium (2.69 M hexane solution, 3.15 mL, 8.47 mmol) was added dropwise at −78 ° C. at the same temperature. After stirring for 30 minutes, a solution of methyl (1-phenyl-1H-pyrazol-4-yl) acetate (1.51 g, 6.98 mmol) in anhydrous THF (35 mL) was added dropwise and stirred for 20 minutes. To the reaction solution was added methyl iodide (0.45 mL, 7.23 mmol), and the mixture was stirred at the same temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-75 / 25 (gradient)] to obtain the title compound (1.10 g, yield: 68%). .

　1H-NMR (500MHz, CDCl3) δ: 7.87 (1H, s), 7.67 (3H, d, J=8Hz), 7.48-7.42 (2H, m), 7.30-7.26 (1H, m), 3.77 (1H, q, J=7Hz), 3.72 (3H, s), 1.54 (3H, d, J=6Hz)。 1 H-NMR (500MHz, CDCl 3 ) δ: 7.87 (1H, s), 7.67 (3H, d, J = 8Hz), 7.48-7.42 (2H, m), 7.30-7.26 (1H, m), 3.77 ( 1H, q, J = 7Hz), 3.72 (3H, s), 1.54 (3H, d, J = 6Hz).

　（参考例６４）３－［１－（１－フェニル－１Ｈ－ピラゾール－４－イル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 64) 3- [1- (1-Phenyl-1H-pyrazol-4-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076

　２－（４－クロロフェニル）プロピオン酸メチルの代わりに、参考例６３にて製造された２－（１－フェニル－１Ｈ－ピラゾール－４－イル）プロピオン酸メチル（１．１０ｇ、４．７８ｍｍｏｌ）を用いて、参考例２０に記載された方法と同様に反応を行い、標記化合物（１．０７ｇ、収率：８８％）を得た。 Instead of methyl 2- (4-chlorophenyl) propionate, methyl 2- (1-phenyl-1H-pyrazol-4-yl) propionate (1.10 g, 4.78 mmol) prepared in Reference Example 63 was used. And the reaction was carried out in the same manner as described in Reference Example 20 to obtain the title compound (1.07 g, yield: 88%).

　1H-NMR (400MHz, DMSO-d6) δ: 11.19 (1H, brs), 8.29 (1H, s), 7.80-7.76 (2H, m), 7.57 (1H, s), 7.49-7.44 (2H, m), 7.29-7.24 (1H, m), 5.19 (1H, s), 4.37 (2H, brs), 4.03 (1H, q, J=7Hz), 1.50 (3H, d, J=7Hz)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.19 (1H, brs), 8.29 (1H, s), 7.80-7.76 (2H, m), 7.57 (1H, s), 7.49-7.44 (2H, m), 7.29-7.24 (1H, m), 5.19 (1H, s), 4.37 (2H, brs), 4.03 (1H, q, J = 7Hz), 1.50 (3H, d, J = 7Hz).

　（参考例６５）２－（２－フェニル－１，３－チアゾール－４－イル）プロピオン酸メチル (Reference Example 65) Methyl 2- (2-phenyl-1,3-thiazol-4-yl) propionate

Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077

　ジイソプロピルアミン（２．８２ｍＬ、２０．１ｍｍｏｌ）の無水ＴＨＦ（２５ｍＬ）溶液に、０℃でｎ－ブチルリチウム（２．６９Ｍヘキサン溶液、７．３５ｍＬ、１９．８ｍｍｏｌ）を滴下し、同温で３０分間攪拌した後に、２－フェニル－１，３－チアゾール－４－イル）酢酸（市販）（２．００ｇ、９．１２ｍｍｏｌ）の無水ＴＨＦ（２５ｍＬ）溶液を滴下し、３５分間攪拌した。反応液に、ヨウ化メチル（０．７５ｍＬ、１２．１ｍｍｏｌ）を加え、同温で４５分間攪拌した。反応液に１Ｎ塩酸を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去し、メチル化化合物を得た。 To a solution of diisopropylamine (2.82 mL, 20.1 mmol) in anhydrous THF (25 mL), n-butyllithium (2.69 M hexane solution, 7.35 mL, 19.8 mmol) was added dropwise at 0 ° C., and 30 ° C. at the same temperature. After stirring for 5 minutes, a solution of 2-phenyl-1,3-thiazol-4-yl) acetic acid (commercially available) (2.00 g, 9.12 mmol) in anhydrous THF (25 mL) was added dropwise and stirred for 35 minutes. To the reaction solution was added methyl iodide (0.75 mL, 12.1 mmol), and the mixture was stirred at the same temperature for 45 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a methylated compound. It was.

　上記操作で得られたメチル化化合物、及び、炭酸カリウム（２．８０ｇ、２０．３ｍｍｏｌ）のＤＭＦ（２０ｍＬ）懸濁液に、ヨウ化エチル（１．０５ｍＬ、１３．１ｍｍｏｌ）を室温で加え、同温で５０分間攪拌した。反応液に水を加え、ジエチルエーテルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝１００／０－７５／２５（グラジェント）］で精製し、標記化合物（１，７９ｇ、収率：７５％）を得た。 Ethyl iodide (1.05 mL, 13.1 mmol) was added to a DMF (20 mL) suspension of the methylated compound obtained in the above operation and potassium carbonate (2.80 g, 20.3 mmol) at room temperature, The mixture was stirred at the same temperature for 50 minutes. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-75 / 25 (gradient)] to obtain the title compound (1,79 g, yield: 75%). .

　1H-NMR (500MHz, CDCl3) δ: 7.95-7.92 (2H, m), 7.45-7.40 (3H, m), 7.11 (1H, s), 4.20 (2H, q, J=7Hz), 4.05 (1H, q, J=7Hz), 1.61 (3H, d, J=7Hz), 1.27 (3H, t, J=7Hz)。 1 H-NMR (500MHz, CDCl 3) δ: 7.95-7.92 (2H, m), 7.45-7.40 (3H, m), 7.11 (1H, s), 4.20 (2H, q, J = 7Hz), 4.05 ( 1H, q, J = 7Hz), 1.61 (3H, d, J = 7Hz), 1.27 (3H, t, J = 7Hz).

　（参考例６６）３－［１－（２－フェニル－１，３－チアゾール－４－イル）エチル］－１Ｈ－ピラゾール－５－アミン Reference Example 66 3- [1- (2-Phenyl-1,3-thiazol-4-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078

　２－（４－クロロフェニル）プロピオン酸メチルの代わりに、参考例６５にて製造された２－（２－フェニル－１，３－チアゾール－４－イル）プロピオン酸メチル（１．７９ｇ、６．８５ｍｍｏｌ）を用いて、参考例２０に記載された方法と同様に反応を行い、標記化合物（１．７４ｇ、収率：９４％）を得た。
1H-NMR (400MHz, DMSO-d6) δ: 11.22 (1H, brs), 7.93-7.90 (2H, m), 7.52-7.41 (3H, m), 7.28 (1H, s), 5.22 (1H, s), 4.40 (2H, brs), 4.26-4.11 (1H, m), 1.56 (3H, d, J=7Hz)。 Instead of methyl 2- (4-chlorophenyl) propionate, methyl 2- (2-phenyl-1,3-thiazol-4-yl) propionate prepared in Reference Example 65 (1.79 g, 6.85 mmol) The title compound (1.74 g, yield: 94%) was obtained in the same manner as in the method described in Reference Example 20.
1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.22 (1H, brs), 7.93-7.90 (2H, m), 7.52-7.41 (3H, m), 7.28 (1H, s), 5.22 (1H, s), 4.40 (2H, brs), 4.26-4.11 (1H, m), 1.56 (3H, d, J = 7Hz).

　（参考例６７）２－（６－フェニルピリジン－２－イル）プロピオン酸エチル (Reference Example 67) Ethyl 2- (6-phenylpyridin-2-yl) propionate

Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079

　１－ブロモ－３－ｔｅｒｔ－ブチルベンゼンの代わりに、２－ブロモ－６－フェニルピリジン（３．０２ｇ、１２．９ｍｍｏｌ）を用いて、参考例２３に記載された方法と同様に反応を行い、粗生成物を得た。 Using 2-bromo-6-phenylpyridine (3.02 g, 12.9 mmol) instead of 1-bromo-3-tert-butylbenzene, the reaction was carried out in the same manner as described in Reference Example 23, A crude product was obtained.

　上記操作にて得られた粗生成物のエタノール（５０ｍＬ）、水（２５ｍＬ）混合溶液に、炭酸カリウム（２．７０ｇ、１９．５ｍｍｏｌ）を加え、加熱還流下１８時間攪拌した。反応液に１Ｎ塩酸を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去して、カルボン酸化合物を得た。 Potassium carbonate (2.70 g, 19.5 mmol) was added to a mixed solution of the crude product obtained in the above operation in ethanol (50 mL) and water (25 mL), and stirred for 18 hours while heating under reflux. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the carboxylic acid compound Got.

　上記操作にて得られたカルボン酸化合物のエタノール（４０ｍＬ）溶液に、濃塩酸（６ｍＬ）を０℃で加え、室温で２４時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液に注ぎ、ジエチルエーテルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝１００／０－８５／１５（グラジェント）］で精製し、標記化合物（１．１３ｇ、収率：３４％）を得た。 Concentrated hydrochloric acid (6 mL) was added to an ethanol (40 mL) solution of the carboxylic acid compound obtained by the above operation at 0 ° C., and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-85 / 15 (gradient)] to give the title compound (1.13 g, yield: 34%). .

　1H-NMR (400MHz, CDCl3) δ: 8.04-8.01 (2H, m), 7.71 (1H, dd, J=8Hz, 7Hz), 7.61 (1H, dd, J=8Hz, 1Hz), 7.48-7.36 (3H, m), 7.22 (1H, dd, J=8Hz, 1Hz), 4.18 (2H, q, J=7Hz), 4.01 (1H, q, J=7Hz), 1.60 (3H, d, J=7Hz), 1.23 (3H, t, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.04-8.01 (2H, m), 7.71 (1H, dd, J = 8Hz, 7Hz), 7.61 (1H, dd, J = 8Hz, 1Hz), 7.48-7.36 (3H, m), 7.22 (1H, dd, J = 8Hz, 1Hz), 4.18 (2H, q, J = 7Hz), 4.01 (1H, q, J = 7Hz), 1.60 (3H, d, J = 7Hz ), 1.23 (3H, t, J = 7Hz).

　（参考例６８）３－［１－（６－フェニルピリジン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン (Reference Example 68) 3- [1- (6-Phenylpyridin-2-yl) ethyl] -1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080

　２－（４－クロロフェニル）プロピオン酸メチルの代わりに、参考例６７にて製造された２－（６－フェニルピリジン－２－イル）プロピオン酸エチル（１．１３ｇ、４．４３ｍｍｏｌ）を用いて、参考例２０に記載された方法と同様に反応を行い、標記化合物（９８５ｍｇ、収率：８４％）を得た。 Instead of methyl 2- (4-chlorophenyl) propionate, ethyl 2- (6-phenylpyridin-2-yl) propionate prepared in Reference Example 67 (1.13 g, 4.43 mmol) was used. The reaction was carried out in the same manner as described in Reference Example 20 to obtain the title compound (985 mg, yield: 84%).

　1H-NMR (500MHz, DMSO-d6) δ: 11.28 (1H, brs), 8.11 (2H, d, J=7Hz), 7.78 (2H, s), 7.52-7.47 (2H, m), 7.45-7.41 (1H, m), 7.20-7.15 (1H, m), 5.26 (1H, s), 4.37 (2H, brs), 4.17 (1H, s), 1.59 (3H, d, J=7Hz)。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 11.28 (1H, brs), 8.11 (2H, d, J = 7Hz), 7.78 (2H, s), 7.52-7.47 (2H, m), 7.45- 7.41 (1H, m), 7.20-7.15 (1H, m), 5.26 (1H, s), 4.37 (2H, brs), 4.17 (1H, s), 1.59 (3H, d, J = 7Hz).

　（参考例６９）｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル酢酸エチル (Reference Example 69) {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl ethyl acetate

Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081

　２－（３－ピペリジル）酢酸エチル（７６０ｍｇ、４．４４ｍｏｌ）、２－フルオロ－５－（トリフルオロメチル）ピリジン（５８８μＬ、４．８８ｍｏｌ）、及び、ジイソプロピルエチルアミン（９８１μＬ、５．７７ｍｏｌ）のＤＭＳＯ（１０ｍＬ）懸濁液を、５０℃にて２時間攪拌した。反応液に水を加え酢酸エチルにて抽出し、酢酸エチル層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて、溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝９５／５－７５／２５（グラジェント）］で精製し、標記化合物（１．３３ｇ、収率：９５％）を得た。 2- (3-piperidyl) ethyl acetate (760 mg, 4.44 mol), 2-fluoro-5- (trifluoromethyl) pyridine (588 μL, 4.88 mol), and diisopropylethylamine (981 μL, 5.77 mol) in DMSO The (10 mL) suspension was stirred at 50 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-75 / 25 (gradient)] to give the title compound (1. 33 g, yield: 95%).

　1H-NMR (400MHz, CDCl3) δ: 8.38-8.35 (1H, m), 7.59 (1H, dd, J=9Hz, 2Hz), 6.66 (1H, d, J=9Hz), 4.32-4.21 (2H, m), 4.16 (2H, q, J=7Hz), 3.07-2.98 (1H, m), 2.80 (1H, dd, J=13Hz, 10Hz), 2.36-2.22 (2H, m), 2.13-2.01 (1H, m), 1.96-1.88 (1H, m), 1.79-1.71 (1H, m), 1.64-1.52 (1H, m), 1.37-1.29 (1H, m), 1.28 (3H, t, J=7Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.38-8.35 (1H, m), 7.59 (1H, dd, J = 9Hz, 2Hz), 6.66 (1H, d, J = 9Hz), 4.32-4.21 (2H , m), 4.16 (2H, q, J = 7Hz), 3.07-2.98 (1H, m), 2.80 (1H, dd, J = 13Hz, 10Hz), 2.36-2.22 (2H, m), 2.13-2.01 ( 1H, m), 1.96-1.88 (1H, m), 1.79-1.71 (1H, m), 1.64-1.52 (1H, m), 1.37-1.29 (1H, m), 1.28 (3H, t, J = 7Hz ).

　（参考例７０）４－（｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル｝メチル－１Ｈ－ピラゾール－５－アミン Reference Example 70 4-({1- [5- (Trifluoromethyl) pyridin-2-yl] piperidin-3-yl} methyl-1H-pyrazol-5-amine

Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082

　２－（４－クロロフェニル）プロピオン酸メチルの代わりに、参考例６９にて製造された｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル酢酸エチル（１．３３ｇ、４．２０ｍｍｏｌ）を用い、ヒドラジン一水和物の代わりにヒドラジン酢酸塩を用いて、参考例２０に記載された方法と同様に反応を行い、標記化合物（１．０１ｇ、収率：７４％）を得た。 Instead of methyl 2- (4-chlorophenyl) propionate, ethyl {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl acetate prepared in Reference Example 69 (1.33 g 4.20 mmol), and using hydrazine acetate instead of hydrazine monohydrate, the reaction was carried out in the same manner as described in Reference Example 20, and the title compound (1.01 g, yield: 74%) was obtained. )

　1H-NMR (400MHz, CDCl3) δ: 8.43-8.40 (1H, m), 7.59 (1H, dd, J=9Hz, 2Hz), 6.61 (1H, d, J=9Hz), 5.47 (1H, s), 4.03-3.96 (1H, m), 3.89 (1H, td, J=9Hz, 4Hz), 3.28-3.17 (2H, m), 2.61 (1H, dd, J=15Hz, 8Hz), 2.47 (1H, dd, J=15Hz, 5Hz), 1.94-1.83 (2H, m), 1.80-1.71 (1H, m), 1.62-1.50 (1H, m), 1.47-1.35 (1H, m)。 1 H-NMR (400MHz, CDCl 3) δ: 8.43-8.40 (1H, m), 7.59 (1H, dd, J = 9Hz, 2Hz), 6.61 (1H, d, J = 9Hz), 5.47 (1H, s ), 4.03-3.96 (1H, m), 3.89 (1H, td, J = 9Hz, 4Hz), 3.28-3.17 (2H, m), 2.61 (1H, dd, J = 15Hz, 8Hz), 2.47 (1H, dd, J = 15Hz, 5Hz), 1.94-1.83 (2H, m), 1.80-1.71 (1H, m), 1.62-1.50 (1H, m), 1.47-1.35 (1H, m).

　（参考例７１）（３Ｓ）－３－（｛［４－ヒドロキシ－６－オキソ－４－（トリフルオロメチル）－４，５，６，７－テトラヒドロ－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－３－イル］メチル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（以下、化合物Ａとする） Reference Example 71 (3S) -3-({[4-Hydroxy-6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] Pyridin-3-yl] methyl} piperidine-1-carboxylate (hereinafter referred to as Compound A)

Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083

　｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル酢酸エチルの代わりに、（３Ｓ）－３－（２－メトキシ－２－オキソエチル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（０．９５ｇ、３．６９ｍｍｏｌ）を用いて、参考例７０に記載された方法と同様に反応を行い、アミノピラゾール中間体を得た。 {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl instead of ethyl acetate, (3S) -3- (2-methoxy-2-oxoethyl) piperidine-1-carboxylic acid tert The reaction was carried out in the same manner as described in Reference Example 70 using -butyl (0.95 g, 3.69 mmol) to obtain an aminopyrazole intermediate.

　３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミンの代わりに、上記操作にて得られたアミノピラゾール中間体を用いて、実施例１に記載された方法と同様に反応を行い、ジアステレオマー混合物（化合物Ａ、０．５０ｇ、収率：３２％）を得た。 Using the aminopyrazole intermediate obtained by the above procedure in place of 3- (biphenyl-4-ylmethyl) -1H-pyrazol-5-amine, the reaction was carried out in the same manner as described in Example 1. , A diastereomeric mixture (Compound A, 0.50 g, yield: 32%) was obtained.

　上記操作にて得られたジアステレオマー混合物をフラッシュＬＣ［カラム：Ｃｈｉｒａｌｆｌａｓｈ　ＩＡ（３０ｍｍ　ｉ．ｄ．ｘ１００ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝８９／１１、流速：１２ｍＬ／分］で精製して、先に溶出する標記化合物（以下、化合物Ａ－１とする、２３０ｍｇ、収率：４６％）を得た。 The diastereomer mixture obtained by the above operation was flash LC [column: Chiralflash IA (30 mm id x 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 89/11, flow rate: 12 mL / min]. Purification gave the title compound (hereinafter referred to as Compound A-1, 230 mg, yield: 46%) eluting first.

　化合物Ａ－１：
　光学純度はＨＰＬＣ［カラム：Ｃｈｉｒａｌｐａｋ　ＩＡ（４．６ｍｍ　ｉ．ｄ．ｘ２５０ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝８０／２０、流速：１．０ｍＬ／分］を用いて測定した。 Compound A-1:
The optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate: 1.0 mL / min].

　光学純度９９％以上（保持時間：６．８分）；
　1H-NMR (400MHz, DMSO-d6) δ: 12.20 (1H, s), 10.51 (1H, s), 6.66 (1H, s), 3.89-3.66 (2H, m), 2.87 (1H, d, J=16Hz), 2.80-2.65 (2H, m), 2.62-2.37 (2H, m), 1.91-1.75 (1H, m), 1.74-1.66 (1H, m), 1.66-1.57 (1H, m), 1.41-1.01 (12H, m)。 Optical purity 99% or more (retention time: 6.8 minutes);
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.20 (1H, s), 10.51 (1H, s), 6.66 (1H, s), 3.89-3.66 (2H, m), 2.87 (1H, d, J = 16Hz), 2.80-2.65 (2H, m), 2.62-2.37 (2H, m), 1.91-1.75 (1H, m), 1.74-1.66 (1H, m), 1.66-1.57 (1H, m), 1.41-1.01 (12H, m).

　（参考例７２）（３Ｒ）－３－（｛［４－ヒドロキシ－６－オキソ－４－（トリフルオロメチル）－４，５，６，７－テトラヒドロ－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－３－イル］メチル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（以下、化合物Ｂとする） Reference Example 72 (3R) -3-({[4-Hydroxy-6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] Pyridin-3-yl] methyl} piperidine-1-carboxylate (hereinafter referred to as Compound B)

Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084

　４－（｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル｝メチル－１Ｈ－ピラゾール－５－アミンの代わりに、（３Ｒ）－３－（２－メトキシ－２－オキソエチル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（１．００ｇ、３．８９ｍｍｏｌ）を用いて、参考例７１に記載された方法と同様に反応を行い、ジアステレオマー混合物（化合物Ｂ、０．４２ｇ、収率：２６％）を得た。 Instead of 4-({1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} methyl-1H-pyrazol-5-amine, (3R) -3- (2-methoxy- The reaction was carried out in the same manner as described in Reference Example 71 using tert-butyl 2-oxoethyl) piperidine-1-carboxylate (1.00 g, 3.89 mmol), and a diastereomeric mixture (compound B, 0 .42 g, yield: 26%).

　上記操作にて得られたジアステレオマー混合物をフラッシュＬＣ［カラム：Ｃｈｉｒａｌｆｌａｓｈ　ＩＡ（３０ｍｍ　ｉ．ｄ．ｘ１００ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝９１／９、流速：１２ｍＬ／分］で精製して、先に溶出する標記化合物（以下、化合物Ｂ－１とする、１４０ｍｇ、収率：３３％）を得た。 The diastereomeric mixture obtained by the above operation was flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 91/9, flow rate: 12 mL / min]. Purification gave the title compound (hereinafter referred to as Compound B-1, 140 mg, yield: 33%) eluting first.

　光学純度はＨＰＬＣ［カラム：Ｃｈｉｒａｌｐａｋ　ＩＡ（４．６ｍｍ　ｉ．ｄ．ｘ２５０ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝８０／２０、流速：１．０ｍＬ／分］を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate: 1.0 mL / min].

　化合物Ｂ－１：
　光学純度９９％以上（保持時間：６．０分）；
　1H-NMR (400MHz, DMSO-d6) δ: 12.21 (1H, s), 10.50 (1H, s), 6.65 (1H, s), 3.93-3.66 (2H, m), 2.86 (1H, d, J=16Hz), 2.78-2.65 (2H, m), 2.62-2.40 (2H, m), 1.90-1.75 (1H, m), 1.72-1.55 (2H, m), 1.42-1.17 (11H, m), 1.15-1.00 (1H, m)。 Compound B-1:
Optical purity 99% or more (retention time: 6.0 minutes);
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.21 (1H, s), 10.50 (1H, s), 6.65 (1H, s), 3.93-3.66 (2H, m), 2.86 (1H, d, J = 16Hz), 2.78-2.65 (2H, m), 2.62-2.40 (2H, m), 1.90-1.75 (1H, m), 1.72-1.55 (2H, m), 1.42-1.17 (11H, m), 1.15-1.00 (1H, m).

　（参考例７３）（３Ｓ）－３－｛（２Ｓ）－１－オキソ－１－［（４Ｓ）－２－オキソ－４－イソプロピル－１，３－オキサゾリジン－３－イル］プロパン－２－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 73 (3S) -3-{(2S) -1-oxo-1-[(4S) -2-oxo-4-isopropyl-1,3-oxazolidine-3-yl] propan-2-yl } Tip-butyl piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085

　参考例７３は、文献Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．、１９８２年、第１０４巻、第１７３７－１８３９頁、または、Ｄ．Ａ．Ｅｖａｎｓ著、ｉｎ　Ａｓｙｍｍｅｔｒｉｃ　Ｓｙｎｔｈｅｓｉｓ、Ｊ．Ｄ．Ｍｏｒｒｉｓｏｎ編、１９８４年、第３巻、Ａｃａｄｅｍｉｃ　Ｐｒｅｓｓ、Ｎｅｗ　Ｙｏｒｋなどに記載されている方法に準じて合成した。即ち、２－（１－ｔｅｒｔ-ブトキシカルボニル－３－ピペリジル）酢酸、（４Ｓ）－（－）－イソプロピル－２－オキサゾリジノン、及び、ヨウ化メチルを用いたＥｖａｎｓの不斉アルキル化反応を行い、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝９５／５－７５／２５（グラジェント）］で精製し、先に溶出する標記化合物を得た。 Reference Example 73 is a document J.P. Am. Chem. Soc. 1982, 104, 1737-1839; A. By Evans, in Asymmetric Synthesis, J.A. D. Synthesis was performed according to the method described in Morrison, 1984, Volume 3, Academic Press, New York, and the like. That is, an asymmetric alkylation reaction of Evans using 2- (1-tert-butoxycarbonyl-3-piperidyl) acetic acid, (4S)-(−)-isopropyl-2-oxazolidinone, and methyl iodide was performed. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-75 / 25 (gradient)] to obtain the title compound eluted earlier.

　1H-NMR (400MHz, CDCl3) δ: 4.54-4.43 (1H, m), 4.38-4.27 (1H, m), 4.24-4.14 (1H, m), 3.89-3.69 (1H, m), 3.52-3.00 (2H, m), 2.41-2.29 (1H, m), 2.03-1.55 (3H, m), 1.54-1.36 (2H, m), 1.43 (9H, s), 1.19 (3H, d, J=7Hz), 0.92 (3H, d, J=7Hz), 0.88 (3H, d, J=7Hz)。 1 H-NMR (400MHz, CDCl 3) δ: 4.54-4.43 (1H, m), 4.38-4.27 (1H, m), 4.24-4.14 (1H, m), 3.89-3.69 (1H, m), 3.52- 3.00 (2H, m), 2.41-2.29 (1H, m), 2.03-1.55 (3H, m), 1.54-1.36 (2H, m), 1.43 (9H, s), 1.19 (3H, d, J = 7Hz ), 0.92 (3H, d, J = 7Hz), 0.88 (3H, d, J = 7Hz).

　（参考例７４） (Reference example 74)

Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086

　｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル酢酸エチルの代わりに、参考例７３にて製造された（３Ｓ）－３－｛（２Ｓ）－１－オキソ－１－［（４Ｓ）－２－オキソ－４－イソプロピル－１，３－オキサゾリジン－３－イル］プロパン－２－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（２．８８ｇ、７．８２ｍｍｏｌ）を用い、ヒドラジン酢酸塩の代わりにジフェニルメチルヒドラジン酢酸塩を用いて、参考例７０に記載された方法と同様に反応を行い、アミノピラゾール中間体を得た。 {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl (3S) -3-{(2S) -1-oxo prepared in Reference Example 73 instead of ethyl acetate Tert-Butyl-1-[(4S) -2-oxo-4-isopropyl-1,3-oxazolidine-3-yl] propan-2-yl} piperidine-1-carboxylate (2.88 g, 7.82 mmol) And using diphenylmethylhydrazine acetate instead of hydrazine acetate, the reaction was carried out in the same manner as described in Reference Example 70 to obtain an aminopyrazole intermediate.

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、上記操作にて得られたアミノピラゾール中間体を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（６７４ｍｇ、１．１３ｍｍｏｌ）のジクロロメタン（７ｍＬ）溶液に、氷冷下、トリエチルシラン（８９７μＬ、５．５８ｍｍｏｌ）、及び、トリフルオロ酢酸（２ｍＬ）を加え、室温にて1時間攪拌した。反応液をジエチルエーテルに注加し、ヘキサンを加え、析出した固体を濾取し、目的化合物（４８９ｍｇ、収率：１５％）を得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, the aminopyrazole intermediate obtained in the above procedure was used. Reaction was carried out in the same manner as described in Example 44, and a solution of the previously eluted compound (674 mg, 1.13 mmol) in dichloromethane (7 mL) was added with triethylsilane (897 μL, 5.58 mmol) under ice cooling, and Trifluoroacetic acid (2 mL) was added and stirred at room temperature for 1 hour. The reaction solution was poured into diethyl ether, hexane was added, and the precipitated solid was collected by filtration to obtain the target compound (489 mg, yield: 15%).

　MS (ESI) m/z: 333 (M+H)+。 MS (ESI) m / z: 333 (M + H) <+> .

　（参考例７５） (Reference example 75)

Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087

　２－[（３Ｒ）－１－ｔｅｒｔ-ブトキシカルボニル－３－ピペリジル]酢酸（２．００ｇ、８．２２ｍｍｏｌ）を用いて、参考例７３及び参考例７４に記載された方法に準じて反応を行い、目的化合物（１８２ｍｇ、収率：５％）を得た。 2-[(3R) -1-tert-butoxycarbonyl-3-piperidyl] acetic acid (2.00 g, 8.22 mmol) was used for the reaction according to the methods described in Reference Example 73 and Reference Example 74. The target compound (182 mg, yield: 5%) was obtained.

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.34 (1H, brs), 10.53 (1H, s), 8.81-8.65 (1H, m), 8.37-8.20 (1H, m), 6.72 (1H, s), 3.43 (1H, d, J=11Hz), 3.18 (1H, d, J=11Hz), 3.06-2.97 (1H, m), 2.90 (1H, d, J=16Hz), 2.83-2.55 (3H, m), 2.07-1.92 (1H, m), 1.80-1.68 (1H, m), 1.56-1.37 (2H, m), 1.17 (3H, d, J=7Hz), 1.14-1.03 (1H, m)。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.34 (1H, brs), 10.53 (1H, s), 8.81-8.65 (1H, m), 8.37-8.20 (1H, m), 6.72 (1H, s), 3.43 (1H, d, J = 11Hz), 3.18 (1H, d, J = 11Hz), 3.06-2.97 (1H, m), 2.90 (1H, d, J = 16Hz), 2.83-2.55 (3H , m), 2.07-1.92 (1H, m), 1.80-1.68 (1H, m), 1.56-1.37 (2H, m), 1.17 (3H, d, J = 7Hz), 1.14-1.03 (1H, m) .

　（参考例７６）（４Ｓ）－３－［（２Ｓ）－２－（３－ブロモフェニル）プロパノイル］－４－イソプロピル－１，３－オキサゾリジン－２－オン Reference Example 76 (4S) -3-[(2S) -2- (3-bromophenyl) propanoyl] -4-isopropyl-1,3-oxazolidine-2-one

Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088

　（３－ブロモフェニル）酢酸を用いて、参考例７３に準じて反応を行い、標記化合物を得た。 (3-Bromophenyl) acetic acid was used according to Reference Example 73 to obtain the title compound.

　1H-NMR (500MHz, CDCl3) δ: 7.50 (1H, t, J=2Hz), 7.39-7.37 (1H, m), 7.29 (1H, dt, J=8Hz, 2Hz), 7.18 (1H, t, J=8Hz), 5.12 (1H, q, J=7Hz), 4.40-4.37 (1H, m), 4.20-4.17 (2H, m), 2.43 (1H, td, J=7Hz, 4Hz), 1.51 (3H, d, J=7Hz), 0.93 (3H, d, J=7Hz), 
0.91 (3H, d, J=7Hz)。 1 H-NMR (500MHz, CDCl 3 ) δ: 7.50 (1H, t, J = 2Hz), 7.39-7.37 (1H, m), 7.29 (1H, dt, J = 8Hz, 2Hz), 7.18 (1H, t , J = 8Hz), 5.12 (1H, q, J = 7Hz), 4.40-4.37 (1H, m), 4.20-4.17 (2H, m), 2.43 (1H, td, J = 7Hz, 4Hz), 1.51 ( 3H, d, J = 7Hz), 0.93 (3H, d, J = 7Hz),
0.91 (3H, d, J = 7Hz).

　（参考例７７）（４Ｓ）－４－（３－ブロモフェニル）－３－オキソペンタンニトリル (Reference Example 77) (4S) -4- (3-Bromophenyl) -3-oxopentanenitrile

Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089

　２－（１－ベンゾフラン－２－イル）プロピオン酸エチルの代わりに、参考例７６にて製造された（４Ｓ）－３－［（２Ｓ）－２－（３－ブロモフェニル）プロパノイル］－４－イソプロピル－１，３－オキサゾリジン－２－オン（４．２３ｇ、１２．４ｍｍｏｌ）を用いて、参考例４５に記載された方法と同様に反応を行い、標記化合物（２．９８ｇ、収率：９５％）を得た。 Instead of ethyl 2- (1-benzofuran-2-yl) propionate, (4S) -3-[(2S) -2- (3-bromophenyl) propanoyl] -4- prepared in Reference Example 76 was used. The reaction was conducted in the same manner as described in Reference Example 45 using isopropyl-1,3-oxazolidine-2-one (4.23 g, 12.4 mmol), and the title compound (2.98 g, yield: 95) was obtained. %).

　光学純度はＨＰＬＣ［カラム：Ｃｈｉｒａｌｐａｋ　ＡＳ（４．６ｍｍ　ｉ．ｄ．ｘ１５０ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝５０／５０－０／１００（グラジェント）、流速：０．８ｍＬ／分］を用いて測定した。 The optical purity is HPLC [column: Chiralpak AS (4.6 mm id x 150 mm); manufactured by Daicel, elution solvent: hexane / IPA = 50 / 50-0 / 100 (gradient), flow rate: 0.8 mL / min ] And measured.

　光学純度９３．８％（保持時間：５．９分）。 Optical purity 93.8% (retention time: 5.9 minutes).

　（実施例１）３－（ビフェニル－４－イルメチル）－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 1 3- (biphenyl-4-ylmethyl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6 -on

Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090

　参考例２にて製造された３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミン（１２５ｍｇ、０．５０ｍｍｏｌ）の酢酸（２ｍＬ）溶液に、トリフルオロアセト酢酸エチル（０．２２２ｍＬ、１．５０ｍｍｏｌ）を加え、６０℃で２時間攪拌した。反応液を減圧下にて濃縮し、トルエンにて共沸した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル］で精製し、更に酢酸エチルに溶解し、ヘキサンを加え粉末化し、標記化合物（１０２ｍｇ、収率：５３％）を得た。 To a solution of 3- (biphenyl-4-ylmethyl) -1H-pyrazol-5-amine (125 mg, 0.50 mmol) prepared in Reference Example 2 in acetic acid (2 mL), ethyl trifluoroacetoacetate (0.222 mL, 1.50 mmol) was added and the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure and azeotroped with toluene. The obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate], further dissolved in ethyl acetate, and pulverized with hexane to obtain the title compound (102 mg, yield: 53%).

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.33 (1H, s), 10.55 (1H, s), 7.64 (2H, d, J=8Hz), 7.60 (2H, d, J=8Hz), 7.45 (2H, t, J=8Hz), 7.38-7.32 (3H, m), 6.83 (1H, s), 4.11 (1H, d, J=16Hz), 4.03 (1H, d, J=16Hz), 2.95 (1H, d, J=16Hz), 2.75 (1H, d, J=16Hz)；
　MS (ESI) m/z: 388 (M+H)+。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.33 (1H, s), 10.55 (1H, s), 7.64 (2H, d, J = 8 Hz), 7.60 (2H, d, J = 8 Hz), 7.45 (2H, t, J = 8Hz), 7.38-7.32 (3H, m), 6.83 (1H, s), 4.11 (1H, d, J = 16Hz), 4.03 (1H, d, J = 16Hz), 2.95 (1H, d, J = 16Hz), 2.75 (1H, d, J = 16Hz);
MS (ESI) m / z: 388 (M + H) <+> .

　（実施例２）３－（ビフェニル－３－イルメチル）－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 2 3- (biphenyl-3-ylmethyl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6 -on

Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091

　３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミン代わりに、参考例３にて製造された３－（ビフェニル－３－イルメチル）－１Ｈ－ピラゾール－５－アミン（９２ｍｇ、０．３７ｍｍｏｌ）を用いて、実施例１に記載された方法と同様に反応を行い、標記化合物（５６ｍｇ、収率：３９％）を得た。 Instead of 3- (biphenyl-4-ylmethyl) -1H-pyrazol-5-amine, 3- (biphenyl-3-ylmethyl) -1H-pyrazol-5-amine prepared in Reference Example 3 (92 mg, 0. 37 mmol) was used to carry out the reaction in the same manner as described in Example 1 to obtain the title compound (56 mg, yield: 39%).

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.35 (1H, s), 10.54 (1H, s), 7.67-7.61 (2H, m), 7.59 (1H, brs), 7.52-7.44 (3H, m), 7.41-7.34 (2H, m), 7.28 (1H, d, J=7Hz), 6.85 (1H, s), 4.14 (1H, d, J=16Hz), 4.05 (1H, d, J=16Hz), 2.95 (1H, d, J=16Hz), 2.74 (1H, d, J=16Hz)；
　MS (ESI) m/z: 388 (M+H)+。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.35 (1H, s), 10.54 (1H, s), 7.67-7.61 (2H, m), 7.59 (1H, brs), 7.52-7.44 (3H, m), 7.41-7.34 (2H, m), 7.28 (1H, d, J = 7Hz), 6.85 (1H, s), 4.14 (1H, d, J = 16Hz), 4.05 (1H, d, J = 16Hz ), 2.95 (1H, d, J = 16Hz), 2.74 (1H, d, J = 16Hz);
MS (ESI) m / z: 388 (M + H) <+> .

　（実施例３）４－ヒドロキシ－３－（１－フェニルエチル）－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 3 4-Hydroxy-3- (1-phenylethyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- on

Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092

　参考例５にて製造された３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミン（１１５ｍｇ、０．６１ｍｍｏｌ）の酢酸（２ｍＬ）溶液に、トリフルオロアセト酢酸エチル（２７１μＬ、１．８４ｍｍｏｌ）を加え、７０℃で２時間攪拌した。反応液を室温まで放冷し、減圧下にて濃縮し、トルエンにて共沸した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル］で精製し、更にシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝２５：７５－０：１００（グラジェント）］で精製し、標記化合物（２８ｍｇ、収率：１３％）を得た。 To a solution of 3- (1-phenylethyl) -1H-pyrazol-5-amine (115 mg, 0.61 mmol) prepared in Reference Example 5 in acetic acid (2 mL) was added ethyl trifluoroacetoacetate (271 μL, 1.84 mmol). ) And stirred at 70 ° C. for 2 hours. The reaction solution was allowed to cool to room temperature, concentrated under reduced pressure, and azeotroped with toluene. The obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate], and further purified by silica gel column chromatography [elution solvent: hexane / ethyl acetate = 25: 75-0: 100 (gradient)] The title compound (28 mg, yield: 13%) was obtained.

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.41 (1H, s), 10.51 (1H, s), 7.32-7.25 (4H, m), 7.21-7.16 (1H, m), 6.80 (1H, s), 4.03 (1H, q, J=7Hz), 2.91 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.56 (3H, d, J=7Hz)；
　MS (ESI) m/z: 326 (M+H)+。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.41 (1H, s), 10.51 (1H, s), 7.32-7.25 (4H, m), 7.21-7.16 (1H, m), 6.80 (1H, s), 4.03 (1H, q, J = 7Hz), 2.91 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.56 (3H, d, J = 7Hz);
MS (ESI) m / z: 326 (M + H) <+> .

　（実施例４）３－［１－（３－ブロモフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 4 3- [1- (3-Bromophenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one and its diastereomer

Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093

及び as well as

Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094

　参考例７にて製造された３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミン（２４８ｍｇ、０．９３ｍｍｏｌ）の酢酸（５ｍＬ）溶液に、トリフルオロアセト酢酸エチル（４１２μＬ、２．８０ｍｍｏｌ）を加え、６０℃で３時間攪拌した。反応液を減圧下にて濃縮し、トルエンにて共沸した。得られた残渣をシリカゲルカラムクロマトグラフィー［ＮＨ－シリカゲル、溶出溶媒：酢酸エチル／メタノール＝１００／０－９０／１０（グラジェント）］で精製し、更にシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝５０／５０－０／１００（グラジェント）］で精製して、先に溶出する化合物（以下、化合物４－１とする）（６５ｍｇ、収率：１７％）、及び、後に溶出する化合物（以下、化合物４－２とする）（７４ｍｇ、収率：２０％）をそれぞれ得た。 To a solution of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine (248 mg, 0.93 mmol) prepared in Reference Example 7 in acetic acid (5 mL), ethyl trifluoroacetoacetate ( 412 μL, 2.80 mmol) was added, and the mixture was stirred at 60 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure and azeotroped with toluene. The obtained residue was purified by silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10 (gradient)], and further silica gel column chromatography [elution solvent: hexane / acetic acid. Purified with ethyl = 50 / 50-0 / 100 (gradient)] and eluting first compound (hereinafter referred to as compound 4-1) (65 mg, yield: 17%) and later eluting compound (Hereinafter referred to as Compound 4-2) (74 mg, yield: 20%) was obtained.

　化合物４－１：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.47 (1H, s), 10.54 (1H, s), 7.61-7.57 (1H, m), 7.44-7.38 (2H, m), 7.30-7.25 (1H, m), 6.84 (1H, s), 4.53 (1H, q, J=7Hz), 2.96 (1H, d, J=17Hz), 2.70 (1H, d, J=17Hz), 1.54 (3H, d, J=7Hz)；
　MS (ESI) m/z: 404 (M+H)+。 Compound 4-1
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.47 (1H, s), 10.54 (1H, s), 7.61-7.57 (1H, m), 7.44-7.38 (2H, m), 7.30-7.25 ( 1H, m), 6.84 (1H, s), 4.53 (1H, q, J = 7Hz), 2.96 (1H, d, J = 17Hz), 2.70 (1H, d, J = 17Hz), 1.54 (3H, d , J = 7Hz);
MS (ESI) m / z: 404 (M + H) <+> .

　化合物４－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.50 (1H, s), 10.55 (1H, s), 7.46 (1H, s), 7.42-7.38 (1H, m), 7.30-7.22 (2H, m), 6.86 (1H, s), 4.56 (1H, q, J=7Hz), 2.92 (1H, d, J=16Hz), 2.72 (1H, d, J=16Hz), 1.56 (3H, d, J=7Hz)；
　MS (ESI) m/z: 404 (M+H)+。 Compound 4-2:
1 H-NMR (400MHz, DMSO -d 6) δ: 12.50 (1H, s), 10.55 (1H, s), 7.46 (1H, s), 7.42-7.38 (1H, m), 7.30-7.22 (2H, m), 6.86 (1H, s), 4.56 (1H, q, J = 7Hz), 2.92 (1H, d, J = 16Hz), 2.72 (1H, d, J = 16Hz), 1.56 (3H, d, J = 7Hz);
MS (ESI) m / z: 404 (M + H) <+> .

　（実施例５）３－［１－（３－クロロフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 5 3- [1- (3-Chlorophenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] Pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095

及び as well as

Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミン代わりに、参考例８にて製造された３－[１－（３－クロロフェニル）エチル]－１Ｈ－ピラゾール－５－アミン（３２９ｍｇ、１．４８ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物５－１とする）（６２ｍｇ、収率：１２％）、及び、後に溶出する化合物（以下、化合物５－２とする）（１１７ｍｇ、収率：２２％）をそれぞれ得た。 3- [1- (3-chlorophenyl) ethyl] -1H-pyrazole-5 prepared in Reference Example 8 instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine -Reaction using amine (329 mg, 1.48 mmol) in the same manner as described in Example 4, and eluting compound (hereinafter referred to as compound 5-1) (62 mg, yield: 12) %) And a compound that elutes later (hereinafter referred to as compound 5-2) (117 mg, yield: 22%) were obtained.

　化合物５－１：
　MS (ESI) m/z: 360 (M+H)+。 Compound 5-1
MS (ESI) m / z: 360 (M + H) + .

　化合物５－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.50 (1H, s), 10.55 (1H, s), 7.35-7.26 (3H, m), 7.20 (1H, d, J=7Hz), 6.86 (1H, s), 4.57 (1H, q, J=7Hz), 2.92 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.56 (3H, d, J=7Hz)；
　MS (ESI) m/z: 360 (M+H)+。 Compound 5-2:
1 H-NMR (400MHz, DMSO -d 6) δ: 12.50 (1H, s), 10.55 (1H, s), 7.35-7.26 (3H, m), 7.20 (1H, d, J = 7Hz), 6.86 ( 1H, s), 4.57 (1H, q, J = 7Hz), 2.92 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.56 (3H, d, J = 7Hz);
MS (ESI) m / z: 360 (M + H) + .

　（実施例６）４－ヒドロキシ－３－［１－（４－メトキシフェニル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 6 4-Hydroxy-3- [1- (4-methoxyphenyl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミン代わりに、参考例９にて製造された３－[１－（４－メトキシフェニル）エチル]－１Ｈ－ピラゾール－５－アミン（４０８ｍｇ、１．８８ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（８３ｍｇ、収率：１２％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- [1- (4-methoxyphenyl) ethyl] -1H-pyrazol-5-amine prepared in Reference Example 9 (408 mg) , 1.88 mmol) in the same manner as described in Example 3 to obtain the title compound (83 mg, yield: 12%).

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.35 (1H, s), 10.50 (1H, s), 7.18 (2H, d, J=9Hz), 6.85 (2H, dd, J=7Hz, 2Hz), 6.79 (1H, s), 4.50 (1H, q, J=7Hz), 3.71 (3H, s), 2.91 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.53 (3H, d, J=7Hz)；
　MS (ESI) m/z: 356 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.35 (1H, s), 10.50 (1H, s), 7.18 (2H, d, J = 9Hz), 6.85 (2H, dd, J = 7Hz, 2Hz ), 6.79 (1H, s), 4.50 (1H, q, J = 7Hz), 3.71 (3H, s), 2.91 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.53 (3H, d, J = 7Hz);
MS (ESI) m / z: 356 (M + H) <+> .

　（実施例７）４－ヒドロキシ－３－［１－（３－メトキシフェニル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 7 4-Hydroxy-3- [1- (3-methoxyphenyl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミン代わりに、参考例１０にて製造された３－[１－（３－メトキシフェニル）エチル]－１Ｈ－ピラゾール－５－アミン（７２０ｍｇ、３．３１ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（１６３ｍｇ、収率：１４％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- [1- (3-methoxyphenyl) ethyl] -1H-pyrazol-5-amine prepared in Reference Example 10 (720 mg) 3.31 mmol) was used in the same manner as described in Example 3 to obtain the title compound (163 mg, yield: 14%).

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.39 (1H, s), 10.51 (1H, s), 7.20 (1H, t, J=8Hz), 6.86-6.74 (4H, m), 4.52 (1H, q, J=7Hz), 3.72 (3H, s), 2.92 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.55 (3H, d, J=7Hz)；
　MS (ESI) m/z: 356 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.39 (1H, s), 10.51 (1H, s), 7.20 (1H, t, J = 8Hz), 6.86-6.74 (4H, m), 4.52 ( 1H, q, J = 7Hz), 3.72 (3H, s), 2.92 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.55 (3H, d, J = 7Hz);
MS (ESI) m / z: 356 (M + H) <+> .

　（実施例８）３－［１－（ビフェニル－３－イル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 8 3- [1- (biphenyl-3-yl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4 b] Pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099

及び as well as

Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミン代わりに、参考例１１にて製造された３－[１－（ビフェニル－３－イル）エチル]－１Ｈ－ピラゾール－５－アミン（６７８ｍｇ、２．５７ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物８－１とする）（１６２ｍｇ、収率：１６％）、及び後に溶出する化合物（以下、化合物８－２とする）（１９０ｍｇ、収率：１８％）をそれぞれ得た。 3- [1- (Biphenyl-3-yl) ethyl] -1H-pyrazole prepared in Reference Example 11 instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine The reaction was carried out in the same manner as described in Example 4 using -5-amine (678 mg, 2.57 mmol), and the previously eluted compound (hereinafter referred to as Compound 8-1) (162 mg, yield) : 16%) and a compound eluting later (hereinafter referred to as compound 8-2) (190 mg, yield: 18%).

　化合物８－１：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.51 (1H, s), 10.53 (1H, s), 7.73 (1H, s), 7.66 (2H, d, J=7Hz), 7.51-7.34 (6H, m), 6.83 (1H, s), 4.63 (1H, q, J=7Hz), 2.97 (1H, d, J=17Hz), 2.71 (1H, d, J=17Hz), 1.62 (3H, d, J=7Hz)；
　MS (ESI) m/z: 402 (M+H)+。 Compound 8-1:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.51 (1H, s), 10.53 (1H, s), 7.73 (1H, s), 7.66 (2H, d, J = 7Hz), 7.51-7.34 ( 6H, m), 6.83 (1H, s), 4.63 (1H, q, J = 7Hz), 2.97 (1H, d, J = 17Hz), 2.71 (1H, d, J = 17Hz), 1.62 (3H, d , J = 7Hz);
MS (ESI) m / z: 402 (M + H) <+> .

　化合物８－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.49 (1H, s), 10.53 (1H, s), 7.63 (2H, d, J=7Hz), 7.58 (1H, s), 7.53-7.43 (3H, m), 7.43-7.33 (2H, m), 7.29 (1H, d, J=8Hz), 6.86 (1H, s), 4.64 (1H, q, J=7Hz), 2.94 (1H, d, J=16Hz), 2.73 (1H, d, J=16Hz), 1.63 (3H, d, J=7Hz)；
　MS (ESI) m/z: 402 (M+H)+。 Compound 8-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.49 (1H, s), 10.53 (1H, s), 7.63 (2H, d, J = 7Hz), 7.58 (1H, s), 7.53-7.43 ( 3H, m), 7.43-7.33 (2H, m), 7.29 (1H, d, J = 8Hz), 6.86 (1H, s), 4.64 (1H, q, J = 7Hz), 2.94 (1H, d, J = 16Hz), 2.73 (1H, d, J = 16Hz), 1.63 (3H, d, J = 7Hz);
MS (ESI) m / z: 402 (M + H) <+> .

　（実施例９）４－ヒドロキシ－３－［１－（３－フェノキシフェニル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及びそのジアステレオマー Example 9 4-Hydroxy-3- [1- (3-phenoxyphenyl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101

及び as well as

Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミン代わりに、参考例１２にて製造された３－[１－（３－フェノキシフェニル）エチル]－１Ｈ－ピラゾール－５－アミン（４８８ｍｇ、１．７５ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物９－１とする）（１４２ｍｇ、収率：１９％）、及び、後に溶出する化合物（以下、化合物９－２とする）（１７７ｍｇ、収率：２４％）をそれぞれ得た。 Instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine, 3- [1- (3-phenoxyphenyl) ethyl] -1H-pyrazole- prepared in Reference Example 12 Using 5-amine (488 mg, 1.75 mmol), the reaction was carried out in the same manner as in the method described in Example 4, and the previously eluted compound (hereinafter referred to as Compound 9-1) (142 mg, yield: 19%) and a compound eluting later (hereinafter referred to as compound 9-2) (177 mg, yield: 24%) were obtained.

　化合物９－１：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.42 (1H, s), 10.52 (1H, s), 7.42-7.35 (2H, m), 7.30 (1H, t, J=8Hz), 7.22-7.10 (3H, m), 7.02-6.97 (2H, m), 6.81-6.75 (2H, m), 4.54 (1H, q, J=7Hz), 2.95 (1H, d, J=16Hz), 2.70 (1H, d, J=16Hz), 1.55 (3H, d, J=7Hz)；
　MS (ESI) m/z: 418 (M+H)+。 Compound 9-1:
1 H-NMR (400MHz, DMSO -d 6) δ: 12.42 (1H, s), 10.52 (1H, s), 7.42-7.35 (2H, m), 7.30 (1H, t, J = 8Hz), 7.22- 7.10 (3H, m), 7.02-6.97 (2H, m), 6.81-6.75 (2H, m), 4.54 (1H, q, J = 7Hz), 2.95 (1H, d, J = 16Hz), 2.70 (1H , d, J = 16Hz), 1.55 (3H, d, J = 7Hz);
MS (ESI) m / z: 418 (M + H) <+> .

　化合物９－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.43 (1H, s), 10.52 (1H, s), 7.42-7.27 (3H, m), 7.16-7.03 (2H, m), 7.00-6.91 (3H, m), 6.85-6.77 (2H, m), 4.55 (1H, q, J=7Hz), 2.91 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.56 (3H, d, J=7Hz)；
　MS (ESI) m/z: 418 (M+H)+。 Compound 9-2:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.43 (1H, s), 10.52 (1H, s), 7.42-7.27 (3H, m), 7.16-7.03 (2H, m), 7.00-6.91 ( 3H, m), 6.85-6.77 (2H, m), 4.55 (1H, q, J = 7Hz), 2.91 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.56 (3H , d, J = 7Hz);
MS (ESI) m / z: 418 (M + H) <+> .

　（実施例１０）４－ヒドロキシ－３－［１－（ナフタレン－１－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 10 4-Hydroxy-3- [1- (naphthalen-1-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4 b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミン代わりに、参考例１３にて製造された３－[１－（ナフタレン－１－イル）エチル]－１Ｈ－ピラゾール－５－アミン（４７８ｍｇ、２．０１ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（１４４ｍｇ、収率：１９％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- [1- (naphthalen-1-yl) ethyl] -1H-pyrazol-5-amine prepared in Reference Example 13 ( 478 mg, 2.01 mmol) was used in the same manner as described in Example 3 to obtain the title compound (144 mg, yield: 19%).

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.54 (1H, s), 10.56 (1H, s), 8.09 (1H, d, J=8Hz), 7.93 (1H, d, J=8Hz), 7.78 (1H, d, J=8Hz), 7.60-7.49 (2H, m), 7.44 (1H, t, J=8Hz), 7.26 (1H, d, J=7Hz), 6.86 (1H, s), 5.40 (1H, q, J=7Hz), 2.93 (1H, d, J=16Hz), 2.70 (1H, d, J=16Hz), 1.66 (3H, d, J=7 Hz)；
　MS (ESI) m/z: 376 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.54 (1H, s), 10.56 (1H, s), 8.09 (1H, d, J = 8Hz), 7.93 (1H, d, J = 8Hz), 7.78 (1H, d, J = 8Hz), 7.60-7.49 (2H, m), 7.44 (1H, t, J = 8Hz), 7.26 (1H, d, J = 7Hz), 6.86 (1H, s), 5.40 (1H, q, J = 7Hz), 2.93 (1H, d, J = 16Hz), 2.70 (1H, d, J = 16Hz), 1.66 (3H, d, J = 7 Hz);
MS (ESI) m / z: 376 (M + H) <+> .

　（実施例１１）３－［１－（３－ベンジルフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 11 3- [1- (3-Benzylphenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one and its diastereomer

Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104

及び as well as

Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミン代わりに、参考例１４にて製造された３－［１－（３－ベンジルフェニル）エチル］－１Ｈ－ピラゾール－５－アミン（２０３ｍｇ、０．７３ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物１１－１とする）（６４ｍｇ、収率：２１％）、及び、後に溶出する化合物（以下、化合物１１－２とする）（５８ｍｇ、収率：１９％）をそれぞれ得た。 3- [1- (3-Benzylphenyl) ethyl] -1H-pyrazole- prepared in Reference Example 14 instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine Using 5-amine (203 mg, 0.73 mmol), the reaction was carried out in the same manner as described in Example 4, and the compound eluting first (hereinafter referred to as Compound 11-1) (64 mg, yield: 21%) and a compound eluting later (hereinafter referred to as compound 11-2) (58 mg, yield: 19%) were obtained.

　化合物１１－１：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.40 (1H, s), 10.50 (1H, s), 7.38 (1H, s), 7.30-7.16 (7H, m), 7.01 (1H, d, J=7Hz), 6.75 (1H, s), 4.51 (1H, q, J=7Hz), 3.90 (2H, s), 2.94 (1H, d, J=16Hz), 2.70 (1H, d, J=16Hz), 1.53 (3H, d, J=7Hz)；
　MS (ESI) m/z: 416 (M+H)+。 Compound 11-1:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.40 (1H, s), 10.50 (1H, s), 7.38 (1H, s), 7.30-7.16 (7H, m), 7.01 (1H, d, J = 7Hz), 6.75 (1H, s), 4.51 (1H, q, J = 7Hz), 3.90 (2H, s), 2.94 (1H, d, J = 16Hz), 2.70 (1H, d, J = 16Hz ), 1.53 (3H, d, J = 7Hz);
MS (ESI) m / z: 416 (M + H) <+> .

　化合物１１－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.38 (1H, s), 10.50 (1H, s), 7.29-7.09 (8H, m), 7.02 (1H, d, J=8Hz), 6.79 (1H, s), 4.52 (1H, q, J=7Hz), 3.89 (2H, s), 2.91 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.54 (3H, d, J=7Hz)；
　MS (ESI) m/z: 416 (M+H)+。 Compound 11-2:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.38 (1H, s), 10.50 (1H, s), 7.29-7.09 (8H, m), 7.02 (1H, d, J = 8Hz), 6.79 ( 1H, s), 4.52 (1H, q, J = 7Hz), 3.89 (2H, s), 2.91 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.54 (3H, d , J = 7Hz);
MS (ESI) m / z: 416 (M + H) <+> .

　（実施例１２）３－［１－（２，３－ジクロロフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 12 3- [1- (2,3-Dichlorophenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4 b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミン代わりに、参考例１５にて製造された３－［１－（２，３－ジクロロフェニル）エチル］－１Ｈ－ピラゾール－５－アミン（３００ｍｇ、１．１７ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（８９ｍｇ、収率：１９％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- [1- (2,3-dichlorophenyl) ethyl] -1H-pyrazol-5-amine prepared in Reference Example 15 ( 300 mg, 1.17 mmol) was used to carry out the reaction in the same manner as described in Example 3 to obtain the title compound (89 mg, yield: 19%).

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.73 (1H, s), 10.58 (1H, s), 7.49 (1H, dd, J=8Hz, 2Hz), 7.29 (1H, t, J=8Hz), 7.08 (1H, dd, J=8Hz, 2Hz), 6.80 (1H, s), 5.07 (1H, q, J=7Hz), 2.87 (1H, d, J=16Hz), 2.68 (1H, d, J=16Hz), 1.53 (3H, d, J=7Hz)；
　MS (ESI) m/z: 394 (M+H)+。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.73 (1H, s), 10.58 (1H, s), 7.49 (1H, dd, J = 8Hz, 2Hz), 7.29 (1H, t, J = 8Hz ), 7.08 (1H, dd, J = 8Hz, 2Hz), 6.80 (1H, s), 5.07 (1H, q, J = 7Hz), 2.87 (1H, d, J = 16Hz), 2.68 (1H, d, J = 16Hz), 1.53 (3H, d, J = 7Hz);
MS (ESI) m / z: 394 (M + H) <+> .

　（実施例１３）（４Ｒ）－４－ヒドロキシ－３－［（１Ｓ）－１－フェニルエチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 13 (4R) -4-hydroxy-3-[(1S) -1-phenylethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 4-b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミン代わりに、参考例１６にて製造された３－［（１Ｓ）－１－フェニルエチル］－１Ｈ－ピラゾール－５－アミン（２７．８７ｇ、０．１４９ｍｏｌ）を用いて、実施例１に記載された方法と同様に反応を行い、得られた残渣をシリカゲルカラムクロマトグラフィー［ＮＨ－シリカゲル、溶出溶媒：酢酸エチル／メタノール＝１００／０－９５／５（グラジェント）］で精製し、更にシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝５０／５０－０／１００（グラジェント）］で精製して、標記化合物（９．６６ｇ、収率：２０％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3-[(1S) -1-phenylethyl] -1H-pyrazol-5-amine prepared in Reference Example 16 (27. 87 g, 0.149 mol), and the reaction was carried out in the same manner as described in Example 1, and the obtained residue was subjected to silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100/0. -95/5 (gradient)] and further purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (gradient)] to give the title compound (9.66 g Yield: 20%).

　光学純度はＨＰＬＣ［カラム：Ｃｈｉｒａｌｐａｋ　ＩＡ（４．６ｍｍ　ｉ．ｄ．ｘ１５０ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝６０／４０、流速：１．０ｍＬ／分］を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 150 mm); manufactured by Daicel, elution solvent: hexane / IPA = 60/40, flow rate: 1.0 mL / min].

　光学純度９９％以上（保持時間：４．６分）；
　[α]D 25 = -105°(DMF, c=1.00)。 Optical purity 99% or more (retention time: 4.6 minutes);
[α] D 25 = -105 ° (DMF, c = 1.00).

　（実施例１４）４－ヒドロキシ－３－（１－フェニルシクロプロピル）－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 14 4-Hydroxy-3- (1-phenylcyclopropyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6 -on

Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108

　３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミン代わりに、３－（１－フェニルシクロプロピル）－１Ｈ－ピラゾール－５－アミン（ＷＯ２００３／４４９７号パンフレットに記載された化合物、２３２ｍｇ、１．１６ｍｍｏｌ）を用いて、実施例１に記載された方法と同様に反応を行い、標記化合物（６０ｍｇ、収率：１５％）を得た。 Instead of 3- (biphenyl-4-ylmethyl) -1H-pyrazol-5-amine, 3- (1-phenylcyclopropyl) -1H-pyrazol-5-amine (compound described in WO2003 / 4497 pamphlet, 232 mg , 1.16 mmol) was used in the same manner as described in Example 1 to obtain the title compound (60 mg, yield: 15%).

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.63 (1H, s), 10.58 (1H, s), 7.24-7.18 (2H, m), 7.14-7.08 (1H, m), 7.07-7.02 (2H, m), 6.47 (1H, s), 2.80 (1H, d, J=16Hz), 2.73 (1H, d, J=16Hz), 1.63-1.53 (1H, m), 1.38-1.28 (2H, m), 1.17-1.09 (1H, m)；
　MS (ESI) m/z: 338 (M+H)+。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.63 (1H, s), 10.58 (1H, s), 7.24-7.18 (2H, m), 7.14-7.08 (1H, m), 7.07-7.02 ( 2H, m), 6.47 (1H, s), 2.80 (1H, d, J = 16Hz), 2.73 (1H, d, J = 16Hz), 1.63-1.53 (1H, m), 1.38-1.28 (2H, m ), 1.17-1.09 (1H, m);
MS (ESI) m / z: 338 (M + H) <+> .

　（実施例１５）３－［１－（４－フルオロフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 15 3- [1- (4-Fluorophenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例１８にて製造された３－［１－（４－フルオロフェニル）エチル］－１Ｈ－ピラゾール－５－アミン（７３ｍｇ、０．３６ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（２１ｍｇ、収率：１７％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- [1- (4-fluorophenyl) ethyl] -1H-pyrazol-5-amine prepared in Reference Example 18 ( 73 mg, 0.36 mmol) was used in the same manner as described in Example 3 to obtain the title compound (21 mg, yield: 17%).

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.44 (1H, s), 10.53 (1H, s), 7.33-7.25 (2H, m), 7.17-7.08 (2H, m), 6.83 (1H, s), 4.56 (1H, q, J=7Hz), 2.92 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.55 (3H, d, J=7Hz)；
　MS (ESI) m/z: 344(M+H)+。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.44 (1H, s), 10.53 (1H, s), 7.33-7.25 (2H, m), 7.17-7.08 (2H, m), 6.83 (1H, s), 4.56 (1H, q, J = 7Hz), 2.92 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.55 (3H, d, J = 7Hz);
MS (ESI) m / z: 344 (M + H) <+> .

　（実施例１６）３－［１－（３－フルオロフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 16 3- [1- (3-Fluorophenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one and its diastereomer

Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110

及び as well as

Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、参考例１９にて製造された（１１９ｍｇ、０．５８ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物１６－１とする）（４５ｍｇ、収率：２３％）、及び、後に溶出する化合物（以下、化合物１６－２とする）（３６ｍｇ、収率：１８％）をそれぞれ得た。 As described in Example 4, using (119 mg, 0.58 mmol) prepared in Reference Example 19 instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine The compound eluted first (hereinafter referred to as compound 16-1) (45 mg, yield: 23%) and the compound eluted later (hereinafter referred to as compound 16-2) (36 mg, yield: 18%) was obtained.

　化合物１６－１：
　MS (ESI) m/z: 344 (M+H)+。 Compound 16-1:
MS (ESI) m / z: 344 (M + H) <+> .

　化合物１６－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.47 (1H, s), 10.54 (1H, s), 7.34 (1H, td, J=8Hz, 7Hz), 7.12-7.00 (3H, m), 6.85 (1H, s), 4.58 (1H, q, J=7Hz), 2.92 (1H, d, J=16Hz), 2.72 (1H, d, J=16Hz), 1.56 (3H, d, J=7Hz)；
　MS (ESI) m/z: 344(M+H)+。 Compound 16-2:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.47 (1H, s), 10.54 (1H, s), 7.34 (1H, td, J = 8Hz, 7Hz), 7.12-7.00 (3H, m), 6.85 (1H, s), 4.58 (1H, q, J = 7Hz), 2.92 (1H, d, J = 16Hz), 2.72 (1H, d, J = 16Hz), 1.56 (3H, d, J = 7Hz) ;
MS (ESI) m / z: 344 (M + H) <+> .

　（実施例１７）３－［１－（４－クロロフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 17 3- [1- (4-Chlorophenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112

　参考例２０にて製造された３－［１－（４－クロロフェニル）エチル］－１Ｈ－ピラゾール－５－アミン（６．６０ｇ、２９．８ｍｍｏｌ）の酢酸（５０ｍＬ）溶液に、トリフルオロアセト酢酸エチル（１４．８ｇ、８０．４ｍｍｏｌ）を加え、６０℃で１．５時間攪拌した。反応液を室温まで放冷し、減圧下にて濃縮し、トルエンにて共沸した。得られた残渣をシリカゲルカラムクロマトグラフィー［ＮＨ－シリカゲル、溶出溶媒：酢酸エチル／メタノール＝１００／０－９０／１０（グラジェント）］で精製し、更にシリカゲルカラムクロマトグラフィー［溶出溶媒：（ｉ）ヘキサン／酢酸エチル＝７０／３０－０／１００（グラジェント）（ｉｉ）酢酸エチル／メタノール＝１００／０－９４／６（グラジェント）］で精製して、標記化合物（２．６１、収率：２４％）を得た。 To a solution of 3- [1- (4-chlorophenyl) ethyl] -1H-pyrazol-5-amine (6.60 g, 29.8 mmol) prepared in Reference Example 20 in acetic acid (50 mL) was added ethyl trifluoroacetoacetate. (14.8 g, 80.4 mmol) was added and stirred at 60 ° C. for 1.5 hours. The reaction solution was allowed to cool to room temperature, concentrated under reduced pressure, and azeotroped with toluene. The obtained residue was purified by silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10 (gradient)], and further silica gel column chromatography [elution solvent: (i) Hexane / ethyl acetate = 70 / 30-0 / 100 (gradient) (ii) ethyl acetate / methanol = 100 / 0-94 / 6 (gradient)] to give the title compound (2.61, yield) : 24%).

　1H-NMR (500MHz, DMSO-d6)δ: 12.48 (1H, s), 10.56 (1H, s), 7.39 (2H, d, J=8Hz), 7.29 (2H, d, J=8Hz), 6.86 (1H, s), 4.58 (1H, q, J=7Hz), 2.94 (1H, d, J=17Hz), 2.74 (1H, d, J=17Hz), 1.58 (3H, d, J=7Hz)；
　MS (ESI) m/z: 360 (M+H)+。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 12.48 (1H, s), 10.56 (1H, s), 7.39 (2H, d, J = 8Hz), 7.29 (2H, d, J = 8Hz), 6.86 (1H, s), 4.58 (1H, q, J = 7Hz), 2.94 (1H, d, J = 17Hz), 2.74 (1H, d, J = 17Hz), 1.58 (3H, d, J = 7Hz) ;
MS (ESI) m / z: 360 (M + H) + .

　（実施例１８）３－［１－（ビフェニル－４－イル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 18 3- [1- (Biphenyl-4-yl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4 b] Pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113

及び as well as

Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、参考例２１にて製造された３－［１－（ビフェニル－４－イル）エチル］－１Ｈ－ピラゾール－５－アミン（５２０ｍｇ、１．９７ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物１８－１とする）（１４２ｍｇ、収率：１８％）、及び、後に溶出する化合物（以下、化合物１８－２とする）（１６６ｍｇ、収率：２１％）をそれぞれ得た。 Instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine, 3- [1- (biphenyl-4-yl) ethyl] -1H- prepared in Reference Example 21 Using pyrazole-5-amine (520 mg, 1.97 mmol), a reaction was carried out in the same manner as in the method described in Example 4, and the previously eluted compound (hereinafter referred to as Compound 18-1) (142 mg, yield) Rate: 18%) and a compound that elutes later (hereinafter referred to as compound 18-2) (166 mg, yield: 21%).

　化合物１８－１：
　1H-NMR (400MHz, DMSO-d6)δ: 12.46 (1H, s), 10.53 (1H, s), 7.64-7.58 (4H, m), 7.46 (4H, dt, J=14Hz, 7Hz), 7.37-7.33 (1H, m), 6.80 (1H, s), 4.59 (1H, q, J=7Hz), 2.96 (1H, d, J=17Hz), 2.70 (1H, t, J=12Hz), 1.58 (3H, d, J=7Hz)；
　MS (ESI) m/z: 402 (M+H)+。 Compound 18-1:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.46 (1H, s), 10.53 (1H, s), 7.64-7.58 (4H, m), 7.46 (4H, dt, J = 14Hz, 7Hz), 7.37-7.33 (1H, m), 6.80 (1H, s), 4.59 (1H, q, J = 7Hz), 2.96 (1H, d, J = 17Hz), 2.70 (1H, t, J = 12Hz), 1.58 (3H, d, J = 7Hz);
MS (ESI) m / z: 402 (M + H) <+> .

　化合物１８－２：
　1H-NMR (400MHz, DMSO-d6)δ: 12.43 (1H, s), 10.50 (1H, s), 7.62-7.55 (4H, m), 7.41 (2H, t, J=8Hz), 7.34-7.29 (3H, m), 6.82 (1H, s), 4.57 (1H, q, J=7Hz), 2.90 (1H, d, J=16Hz), 2.69 (1H, d, J=16Hz), 1.56 (3H, d, J=7Hz)；
　MS (ESI) m/z: 402 (M+H)+。 Compound 18-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.43 (1H, s), 10.50 (1H, s), 7.62-7.55 (4H, m), 7.41 (2H, t, J = 8Hz), 7.34- 7.29 (3H, m), 6.82 (1H, s), 4.57 (1H, q, J = 7Hz), 2.90 (1H, d, J = 16Hz), 2.69 (1H, d, J = 16Hz), 1.56 (3H , d, J = 7Hz);
MS (ESI) m / z: 402 (M + H) <+> .

　（実施例１９）４－ヒドロキシ－３－［１－（ナフタレン－２－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 19 4-Hydroxy-3- [1- (naphthalen-2-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4 b] Pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115

及び as well as

Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、参考例２２にて製造された３－［１－（ナフタレン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン（２５６ｍｇ、１．０８ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物９－１とする）（７３ｍｇ、収率：１８％）、及び、後に溶出する化合物（以下、化合物９－２とする）（８６ｍｇ、収率：２１％）をそれぞれ得た。 Instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine, 3- [1- (naphthalen-2-yl) ethyl] -1H- prepared in Reference Example 22 Using pyrazole-5-amine (256 mg, 1.08 mmol), the reaction was carried out in the same manner as in the method described in Example 4, and the previously eluted compound (hereinafter referred to as Compound 9-1) (73 mg, yield) Rate: 18%) and a compound that elutes later (hereinafter referred to as compound 9-2) (86 mg, yield: 21%).

　化合物９－１：
　1H-NMR (400MHz, DMSO-d6)δ: 12.46 (1H, s), 10.53 (1H, s), 7.88-7.83 (4H, m), 7.60 (1H, dd, J=9Hz, 2Hz), 7.52-7.44 (2H, m), 6.81 (1H, s), 4.72 (1H, q, J=7Hz), 2.96 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.65 (3H, d, J=7Hz)；
　MS (ESI) m/z: 376 (M+H)+。 Compound 9-1:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.46 (1H, s), 10.53 (1H, s), 7.88-7.83 (4H, m), 7.60 (1H, dd, J = 9Hz, 2Hz), 7.52-7.44 (2H, m), 6.81 (1H, s), 4.72 (1H, q, J = 7Hz), 2.96 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.65 (3H, d, J = 7Hz);
MS (ESI) m / z: 376 (M + H) <+> .

　化合物９－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.44 (1H, s), 10.51 (1H, s), 7.85-7.79 (3H, m), 7.70 (1H, s), 7.48-7.38 (3H, m), 6.83 (1H, s), 4.70 (1H, q, J=7Hz), 2.91 (1H, d, J=16Hz), 2.69 (1H, d, J=16Hz), 1.62 (3H, d, J=7Hz)；
　MS (ESI) m/z: 376 (M+H)+。 Compound 9-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.44 (1H, s), 10.51 (1H, s), 7.85-7.79 (3H, m), 7.70 (1H, s), 7.48-7.38 (3H, m), 6.83 (1H, s), 4.70 (1H, q, J = 7Hz), 2.91 (1H, d, J = 16Hz), 2.69 (1H, d, J = 16Hz), 1.62 (3H, d, J = 7Hz);
MS (ESI) m / z: 376 (M + H) <+> .

　（実施例２０）３－［１－（３－ｔｅｒｔ－ブチルフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 20 3- [1- (3-tert-Butylphenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4 -B] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117

及び as well as

Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、参考例２５にて製造された３－［１－（３－ｔｅｒｔ－ブチルフェニル）エチル］－１Ｈ－ピラゾール－５－アミン（２１６ｍｇ、０．８８８ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物２０－１とする）（５９ｍｇ、収率：１７％）、及び、後に溶出する化合物（以下、化合物２０－２とする）（６５ｍｇ、収率：１９％）をそれぞれ得た。 3- [1- (3-tert-butylphenyl) ethyl] -1H prepared in Reference Example 25 instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine Using -pyrazol-5-amine (216 mg, 0.888 mmol), the reaction was carried out in the same manner as in the method described in Example 4, and the previously eluted compound (hereinafter referred to as Compound 20-1) (59 mg, Yield: 17%) and a compound that elutes later (hereinafter referred to as Compound 20-2) (65 mg, yield: 19%) were obtained.

　化合物２０－１：
　MS (ESI) m/z: 382 (M+H)+。 Compound 20-1:
MS (ESI) m / z: 382 (M + H) <+> .

　化合物２０－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.39 (1H, s), 10.50 (1H, s), 7.29-7.15 (4H, m), 6.82 (1H, s), 4.54 (1H, q, J=7Hz), 2.92 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.57 (3H, d, J=7Hz), 1.23 (9H, s)；
　MS (ESI) m/z: 382 (M+H)+。 Compound 20-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.39 (1H, s), 10.50 (1H, s), 7.29-7.15 (4H, m), 6.82 (1H, s), 4.54 (1H, q, J = 7Hz), 2.92 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.57 (3H, d, J = 7Hz), 1.23 (9H, s);
MS (ESI) m / z: 382 (M + H) <+> .

　（実施例２１）３－［１－（４－ブチルフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 21 3- [1- (4-Butylphenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one and its diastereomer

Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119

及び as well as

Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、参考例２７にて製造された３－［１－（４－ブチルフェニル）エチル］－１Ｈ－ピラゾール－５－アミン（２４０ｍｇ、０．９８６ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物２１－１とする）（５８ｍｇ、収率：１５％）、及び、後に溶出する化合物（以下、化合物２１－２とする）（５９ｍｇ、収率：１６％）をそれぞれ得た。 3- [1- (4-Butylphenyl) ethyl] -1H-pyrazole prepared in Reference Example 27 instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine The reaction was carried out in the same manner as described in Example 4 using -5-amine (240 mg, 0.986 mmol), and the previously eluted compound (hereinafter referred to as Compound 21-1) (58 mg, yield) : 15%) and a compound eluting later (hereinafter referred to as Compound 21-2) (59 mg, yield: 16%).

　化合物２１－１：
　MS (ESI) m/z: 382 (M+H)+。 Compound 21-1:
MS (ESI) m / z: 382 (M + H) <+> .

　化合物２１－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.36 (1H, s), 10.51 (1H, s), 7.17 (2H, d, J=8Hz), 7.10 (2H, d, J=8Hz), 6.79 (1H, s), 4.51 (1H, q, J=8Hz), 2.91 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 2.55-2.50 (2H, m), 1.54-1.46 (2H, m), 1.54 (3H, d, J=7Hz), 1.28 (2H, td, J=15Hz, 7Hz), 0.88 (3H, t, J=7Hz)；
　MS (ESI) m/z: 382 (M+H)+。 Compound 21-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.36 (1H, s), 10.51 (1H, s), 7.17 (2H, d, J = 8Hz), 7.10 (2H, d, J = 8Hz), 6.79 (1H, s), 4.51 (1H, q, J = 8Hz), 2.91 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 2.55-2.50 (2H, m), 1.54 -1.46 (2H, m), 1.54 (3H, d, J = 7Hz), 1.28 (2H, td, J = 15Hz, 7Hz), 0.88 (3H, t, J = 7Hz);
MS (ESI) m / z: 382 (M + H) <+> .

　（実施例２２）３－［１－（２－クロロフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 22 3- [1- (2-Chlorophenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例２８にて製造された３－［１－（２－クロロフェニル）エチル］－１Ｈ－ピラゾール－５－アミン（４４６ｍｇ、２．０１ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（１１０ｍｇ、収率：１５％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- [1- (2-chlorophenyl) ethyl] -1H-pyrazol-5-amine prepared in Reference Example 28 (446 mg) 2.01 mmol), and the reaction was carried out in the same manner as described in Example 3 to obtain the title compound (110 mg, yield: 15%).

　1H-NMR (400MHz, DMSO-d6) δ: 12.70 (1H, s), 10.57 (1H, s), 7.41 (1H, dd, J=8Hz, 2Hz), 7.27-7.18 (2H, m), 7.12 (1H, d, J=8Hz), 6.76 (1H, s), 2.86 (1H, d, J=17Hz), 2.67 (1H, d, J=16Hz), 1.51 (3H, d, J=7Hz)；
　MS (ESI) m/z: 360 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.70 (1H, s), 10.57 (1H, s), 7.41 (1H, dd, J = 8Hz, 2Hz), 7.27-7.18 (2H, m), 7.12 (1H, d, J = 8Hz), 6.76 (1H, s), 2.86 (1H, d, J = 17Hz), 2.67 (1H, d, J = 16Hz), 1.51 (3H, d, J = 7Hz) ;
MS (ESI) m / z: 360 (M + H) + .

　（実施例２３）３－（１－シクロヘキシルエチル）－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、３－（シクロヘキシルメチル）－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 23 3- (1-Cyclohexylethyl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- ON and 3- (cyclohexylmethyl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122

及び as well as

Figure JPOXMLDOC01-appb-C000123
Figure JPOXMLDOC01-appb-C000123

　ジイソプロピルアミン（６．５５ｍＬ、４６．６ｍｍｏｌ）の無水ＴＨＦ（４０ｍＬ）溶液に、－７８℃でｎ－ブチルリチウム（２．６９Ｍヘキサン溶液、１７．６ｍＬ、４６．５ｍｍｏｌ）を滴下し、同温で３０分間攪拌した後に、－２０℃でシクロヘキシル酢酸（３．００ｇ、２１．１ｍｍｏｌ）の無水ＴＨＦ（４０ｍＬ）溶液を滴下し、０℃で１．５時間攪拌した。反応液に、０℃でヨウ化メチル（１．７５ｍＬ、２８．１ｍｍｏｌ）の無水ＴＨＦ（２０ｍＬ）溶液を加え、室温で１．５時間攪拌した。反応液に２Ｎ塩酸水溶液を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去して、粗生成物を得た。 To a solution of diisopropylamine (6.55 mL, 46.6 mmol) in anhydrous THF (40 mL), n-butyllithium (2.69 M hexane solution, 17.6 mL, 46.5 mmol) was added dropwise at −78 ° C. at the same temperature. After stirring for 30 minutes, a solution of cyclohexylacetic acid (3.00 g, 21.1 mmol) in anhydrous THF (40 mL) was added dropwise at −20 ° C., and the mixture was stirred at 0 ° C. for 1.5 hours. To the reaction solution, a solution of methyl iodide (1.75 mL, 28.1 mmol) in anhydrous THF (20 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added 2N aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. Got.

　２－（ビフェニル－４－イル）プロピオン酸の代わりに、上記操作で得られた粗生成物を用いて、参考例２１に記載された方法と同様に反応を行い、アミノピラゾール化合物を得た。 Using the crude product obtained by the above operation instead of 2- (biphenyl-4-yl) propionic acid, the reaction was carried out in the same manner as described in Reference Example 21 to obtain an aminopyrazole compound.

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、上記操作で得られたアミノピラゾール化合物を用いて、実施例４に記載された方法と同様に反応を行い、得られた残渣をシリカゲルカラムクロマトグラフィー［ＮＨ－シリカゲル、溶出溶媒：酢酸エチル／メタノール＝１００／０－８５／１５（グラジェント）］で精製し、更に、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝７０／３０－０／１００（グラジェント）］で精製し、二番目に溶出したフラクションをシリカゲルカラムクロマトグラフィー［ＮＨ－シリカゲル、溶出溶媒：（ｉ）ヘキサン／酢酸エチル＝３０／７０－０／１００（グラジェント）、（ｉｉ）酢酸エチル／メタノール＝１００／０－９４／６（グラジェント）］で精製して、先に溶出する化合物（以下、化合物２３－１とする）（８８ｍｇ、収率：１．３％）、及び、後に溶出する化合物（以下、化合物２３－２とする）（１１ｍｇ、収率：０．１６％）をそれぞれ得た。 Using the aminopyrazole compound obtained in the above procedure in place of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine, the reaction was carried out in the same manner as described in Example 4. The resulting residue was purified by silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-85 / 15 (gradient)], and further purified by silica gel column chromatography [elution solvent. : Hexane / ethyl acetate = 70 / 30-0 / 100 (gradient)], and the second eluted fraction was subjected to silica gel column chromatography [NH-silica gel, elution solvent: (i) hexane / ethyl acetate = 30 / 70-0 / 100 (gradient), (ii) ethyl acetate / methanol = 100 / 0-94 / 6 The compound eluting first (hereinafter referred to as compound 23-1) (88 mg, yield: 1.3%), and the compound eluting later (hereinafter referred to as compound 23-2) (11 mg, yield: 0.16%).

　化合物２３－１：
　1H-NMR (400MHz, DMSO-d6) δ: 12.09 (1H, s), 10.45 (1H, s), 6.58 (1H, s), 2.87 (1H, d, J=16Hz), 2.69 (1H, d, J=16Hz), 1.97-1.89 (1H, m), 1.78-1.70 (1H, m), 1.65-1.55 (3H, m), 1.37-1.29 (1H, m), 1.26-1.05 (4H, m), 1.13 (3H, d, J=7Hz), 0.92-0.71 (2H, m)；
　MS (ESI) m/z: 332 (M+H)+。 Compound 23-1:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.09 (1H, s), 10.45 (1H, s), 6.58 (1H, s), 2.87 (1H, d, J = 16Hz), 2.69 (1H, d, J = 16Hz), 1.97-1.89 (1H, m), 1.78-1.70 (1H, m), 1.65-1.55 (3H, m), 1.37-1.29 (1H, m), 1.26-1.05 (4H, m ), 1.13 (3H, d, J = 7Hz), 0.92-0.71 (2H, m);
MS (ESI) m / z: 332 (M + H) <+> .

　化合物２３－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.14 (1H, s), 10.48 (1H, s), 6.59 (1H, s), 2.87 (1H, d, J=16Hz), 2.70 (1H, d, J=16Hz), 1.79-1.52 (7H, m), 1.26-1.03 (4H, m), 1.03-0.83 (2H, m)；
　MS (ESI) m/z: 318 (M+H)+。 Compound 23-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.14 (1H, s), 10.48 (1H, s), 6.59 (1H, s), 2.87 (1H, d, J = 16Hz), 2.70 (1H, d, J = 16Hz), 1.79-1.52 (7H, m), 1.26-1.03 (4H, m), 1.03-0.83 (2H, m);
MS (ESI) m / z: 318 (M + H) <+> .

　（実施例２４）３－［１－（２－ブロモフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 24 3- [1- (2-Bromophenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000124

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例２９にて製造された３－［１－（２－ブロモフェニル）エチル］－１Ｈ－ピラゾール－５－アミン（４１０ｍｇ、１．５４ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（１２５ｍｇ、収率：２０％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- [1- (2-bromophenyl) ethyl] -1H-pyrazol-5-amine prepared in Reference Example 29 ( 410 mg, 1.54 mmol) was used in the same manner as in Example 3 to obtain the title compound (125 mg, yield: 20%).

　1H-NMR (400MHz, DMSO-d6) δ: 12.73 (1H, s), 10.57 (1H, s), 7.58 (1H, dd, J=8Hz, 1Hz), 7.31-7.26 (1H, m), 7.14-7.07 (2H, m), 6.75 (1H, s), 5.00 (1H, q, J=7Hz), 2.86 (1H, d, J=16Hz), 2.67 (1H, d, J=16Hz), 1.50 (3H, d, J=7Hz)；
　MS (ESI) m/z: 404 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.73 (1H, s), 10.57 (1H, s), 7.58 (1H, dd, J = 8Hz, 1Hz), 7.31-7.26 (1H, m), 7.14-7.07 (2H, m), 6.75 (1H, s), 5.00 (1H, q, J = 7Hz), 2.86 (1H, d, J = 16Hz), 2.67 (1H, d, J = 16Hz), 1.50 (3H, d, J = 7Hz);
MS (ESI) m / z: 404 (M + H) <+> .

　（実施例２５）４－ヒドロキシ－３－（１－フェノキシエチル）－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 25 4-Hydroxy-3- (1-phenoxyethyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- on

Figure JPOXMLDOC01-appb-C000125
Figure JPOXMLDOC01-appb-C000125

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例３１にて製造された３－（１－フェノキシエチル）－１Ｈ－ピラゾール－５－アミン（８８０ｍｇ、４．３３ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（２８１ｍｇ、収率：１９％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- (1-phenoxyethyl) -1H-pyrazol-5-amine prepared in Reference Example 31 (880 mg, 4.33 mmol) The title compound (281 mg, yield: 19%) was obtained in the same manner as described in Example 3.

　1H-NMR (400MHz, DMSO-d6) δ: 12.67 (1H, s), 10.60 (1H, s), 7.30-7.24 (2H, m), 6.96-6.89 (4H, m), 5.62 (1H, q, J=6Hz), 2.94 (1H, d, J=16Hz), 2.74 (1H, d, J=16Hz), 1.61 (3H, d, J=6Hz)；
　MS (ESI) m/z: 342 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.67 (1H, s), 10.60 (1H, s), 7.30-7.24 (2H, m), 6.96-6.89 (4H, m), 5.62 (1H, q, J = 6Hz), 2.94 (1H, d, J = 16Hz), 2.74 (1H, d, J = 16Hz), 1.61 (3H, d, J = 6Hz);
MS (ESI) m / z: 342 (M + H) <+> .

　（実施例２６）４－ヒドロキシ－３－（１－フェニルプロピル）－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 26 4-Hydroxy-3- (1-phenylpropyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- On and its diastereomers

Figure JPOXMLDOC01-appb-C000126
Figure JPOXMLDOC01-appb-C000126

及び as well as

Figure JPOXMLDOC01-appb-C000127
Figure JPOXMLDOC01-appb-C000127

　２－（ビフェニル－４－イル）プロピオン酸の代わりに２－フェニル酪酸（市販）（１．０６ｇ、６．４６ｍｍｏｌ）を用いて、参考例２１に記載された方法と同様に反応を行い、アミノピラゾール化合物を得た。 Using 2-phenylbutyric acid (commercially available) (1.06 g, 6.46 mmol) instead of 2- (biphenyl-4-yl) propionic acid, the reaction was carried out in the same manner as described in Reference Example 21, and amino A pyrazole compound was obtained.

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、上記操作で得られたアミノピラゾール化合物を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物２６－１とする）（１１５ｍｇ、収率：５％）、及び、後に溶出する化合物（以下、化合物２６－２とする）（１２２ｍｇ、収率：６％）をそれぞれ得た。 Using the aminopyrazole compound obtained in the above procedure in place of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine, the reaction was carried out in the same manner as described in Example 4. The compound eluting first (hereinafter referred to as compound 26-1) (115 mg, yield: 5%) and the compound eluting later (hereinafter referred to as compound 26-2) (122 mg, yield: 6%) were obtained.

　化合物２６－１：
　MS (ESI) m/z: 340 (M+H)+。 Compound 26-1:
MS (ESI) m / z: 340 (M + H) <+> .

　化合物２６－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.46 (1H, s), 10.50 (1H, s), 7.35-7.26 (4H, m), 7.21-7.16 (1H, m), 6.77 (1H, s), 4.28 (1H, t, J=8Hz), 2.92 (1H, d, J=16Hz), 2.70 (1H, d, J=16Hz), 2.04-1.90 (2H, m), 0.77 (3H, t, J=7Hz)；
　MS (ESI) m/z: 340 (M+H)+。 Compound 26-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.46 (1H, s), 10.50 (1H, s), 7.35-7.26 (4H, m), 7.21-7.16 (1H, m), 6.77 (1H, s), 4.28 (1H, t, J = 8Hz), 2.92 (1H, d, J = 16Hz), 2.70 (1H, d, J = 16Hz), 2.04-1.90 (2H, m), 0.77 (3H, t , J = 7Hz);
MS (ESI) m / z: 340 (M + H) <+> .

　（実施例２７）４－ヒドロキシ－３－［メトキシ（フェニル）メチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 27 4-Hydroxy-3- [methoxy (phenyl) methyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6 -on

Figure JPOXMLDOC01-appb-C000128
Figure JPOXMLDOC01-appb-C000128

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例３２にて製造された３－［メトキシ（フェニル）メチル］－１Ｈ－ピラゾール－５－アミン（６０３ｍｇ、２．９７ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（６８ｍｇ，収率：７％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- [methoxy (phenyl) methyl] -1H-pyrazol-5-amine prepared in Reference Example 32 (603 mg, 2. 97 mmol) was used to carry out the reaction in the same manner as described in Example 3 to obtain the title compound (68 mg, yield: 7%).

　1H-NMR (400MHz, DMSO-d6) δ: 12.59 (1H, s), 10.57 (1H, s), 7.40-7.26 (5H, m), 6.94 (1H, s), 5.63 (1H, s), 3.25 (3H, s), 2.99 (1H, d, J=16Hz), 2.72 (1H, d, J=16Hz)；
　MS (ESI) m/z: 340 (M-H)-。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.59 (1H, s), 10.57 (1H, s), 7.40-7.26 (5H, m), 6.94 (1H, s), 5.63 (1H, s) , 3.25 (3H, s), 2.99 (1H, d, J = 16Hz), 2.72 (1H, d, J = 16Hz);
MS (ESI) m / z: 340 (MH) - .

　（実施例２８）３－［シクロヘキシル（フェニル）メチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 28 3- [Cyclohexyl (phenyl) methyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6 -on

Figure JPOXMLDOC01-appb-C000129
Figure JPOXMLDOC01-appb-C000129

　３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例３３にて製造された３－［シクロヘキシル（フェニル）メチル］－１Ｈ－ピラゾール－５－アミン（８４２ｍｇ、３．２９ｍｍｏｌ）を用いて、実施例１に記載された方法と同様に反応を行い、標記化合物（２６０ｍｇ、収率：２０％）を得た。 Instead of 3- (biphenyl-4-ylmethyl) -1H-pyrazol-5-amine, 3- [cyclohexyl (phenyl) methyl] -1H-pyrazol-5-amine prepared in Reference Example 33 (842 mg, 3 .29 mmol) was used in the same manner as described in Example 1 to obtain the title compound (260 mg, yield: 20%).

　1H-NMR (400MHz, DMSO-d6)δ: 12.50 (1/2H, s), 12.45 (1/2H, s), 10.47 (1/2H, s), 10.45 (1/2H, s), 7.42-7.13 (6H, m), 6.71 (1/2H, s), 6.64 (1/2H, s), 4.06 (1/2H, d, J=12Hz), 3.93 (1/2H, d, J=12Hz), 2.99-2.83 (1H, m), 2.73-2.59 (1H, m), 2.26-1.96 (2H, m), 1.73-0.64 (8H, m)；
　MS (ESI) m/z: 394 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.50 (1 / 2H, s), 12.45 (1 / 2H, s), 10.47 (1 / 2H, s), 10.45 (1 / 2H, s), 7.42-7.13 (6H, m), 6.71 (1 / 2H, s), 6.64 (1 / 2H, s), 4.06 (1 / 2H, d, J = 12Hz), 3.93 (1 / 2H, d, J = 12Hz), 2.99-2.83 (1H, m), 2.73-2.59 (1H, m), 2.26-1.96 (2H, m), 1.73-0.64 (8H, m);
MS (ESI) m / z: 394 (M + H) <+> .

　（実施例２９）４－ヒドロキシ－３－（２－メチル－１－フェニルプロピル）－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 29 4-Hydroxy-3- (2-methyl-1-phenylpropyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] Pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000130
Figure JPOXMLDOC01-appb-C000130

及び as well as

Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、参考例３４にて製造された３－（２－メチル－１－フェニルプロピル）－１Ｈ－ピラゾール－５－アミン（５３０ｍｇ、２．４６ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物２９－１とする）（７３ｍｇ、収率：８％）、及び、後に溶出する化合物（以下、化合物２９－２とする）（６９ｍｇ、収率：８％）をそれぞれ得た。 Instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine, 3- (2-methyl-1-phenylpropyl) -1H-pyrazole- prepared in Reference Example 34 Using 5-amine (530 mg, 2.46 mmol), the reaction was carried out in the same manner as in the method described in Example 4, and the previously eluted compound (hereinafter referred to as Compound 29-1) (73 mg, yield: 8%) and a compound eluting later (hereinafter referred to as compound 29-2) (69 mg, yield: 8%) were obtained.

　化合物２９－１：
　1H-NMR (400MHz, DMSO-d6) δ: 12.53 (1H, s), 10.46 (1H, s), 7.43 (2H, d, J=8Hz), 7.31-7.24 (2H, m), 7.20-7.14 (1H, m), 6.67 (1H, s), 3.87 (1H, d, J=12Hz), 2.89 (1H, d, J=16Hz), 2.64 (1H, d, J=16Hz), 2.57-2.51 (1H, m), 0.81 (3H, d, J=6Hz), 0.68 (3H, d, J=7Hz)；
　MS (ESI) m/z: 354 (M+H)+。 Compound 29-1:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.53 (1H, s), 10.46 (1H, s), 7.43 (2H, d, J = 8Hz), 7.31-7.24 (2H, m), 7.20- 7.14 (1H, m), 6.67 (1H, s), 3.87 (1H, d, J = 12Hz), 2.89 (1H, d, J = 16Hz), 2.64 (1H, d, J = 16Hz), 2.57-2.51 (1H, m), 0.81 (3H, d, J = 6Hz), 0.68 (3H, d, J = 7Hz);
MS (ESI) m / z: 354 (M + H) <+> .

　化合物２９－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.48 (1H, s), 10.48 (1H, s), 7.39 (2H, d, J=7Hz), 7.33-7.25 (2H, m), 7.22-7.14 (1H, m), 6.74 (1H, s), 3.97 (1H, d, J=12Hz), 2.93 (1H, d, J=16Hz), 2.70 (1H, d, J=16Hz), 2.42-2.30 (1H, m), 0.85 (3H, t, J=6Hz), 0.67 (3H, d, J=7Hz)；
　MS (ESI) m/z: 354 (M+H)+。 Compound 29-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.48 (1H, s), 10.48 (1H, s), 7.39 (2H, d, J = 7Hz), 7.33-7.25 (2H, m), 7.22- 7.14 (1H, m), 6.74 (1H, s), 3.97 (1H, d, J = 12Hz), 2.93 (1H, d, J = 16Hz), 2.70 (1H, d, J = 16Hz), 2.42-2.30 (1H, m), 0.85 (3H, t, J = 6Hz), 0.67 (3H, d, J = 7Hz);
MS (ESI) m / z: 354 (M + H) <+> .

　（実施例３０）４－ヒドロキシ－３－［１－（チオフェン－３－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 30 4-Hydroxy-3- [1- (thiophen-3-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4 b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000132
Figure JPOXMLDOC01-appb-C000132

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例３５にて製造された３－［１－（チオフェン－３－イル）エチル］－１Ｈ－ピラゾール－５－アミン（３８０ｍｇ、１．９７ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（１３２ｍｇ、収率：２０％）を得た。 3- [1- (thiophen-3-yl) ethyl] -1H-pyrazol-5-amine prepared in Reference Example 35 instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine (380 mg, 1.97 mmol) was used in the same manner as in Example 3 to obtain the title compound (132 mg, yield: 20%).

　1H-NMR (500MHz, DMSO-d6) δ: 12.32 (1H, s), 10.52 (1H, s), 7.45 (1H, d, J=3Hz), 7.17 (1H, s), 7.01 (1H, d, J=5Hz), 6.81 (1H, s), 4.58 (1H, q, J=7Hz), 2.92 (1H, d, J=17Hz), 2.73 (1H, d, J=17Hz), 1.55 (3H, d, J=7Hz)；
　MS (ESI) m/z: 332 (M+H)+。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 12.32 (1H, s), 10.52 (1H, s), 7.45 (1H, d, J = 3Hz), 7.17 (1H, s), 7.01 (1H, d, J = 5Hz), 6.81 (1H, s), 4.58 (1H, q, J = 7Hz), 2.92 (1H, d, J = 17Hz), 2.73 (1H, d, J = 17Hz), 1.55 (3H , d, J = 7Hz);
MS (ESI) m / z: 332 (M + H) <+> .

　（実施例３１）４－ヒドロキシ－３－［（メチルスルファニル）（フェニル）メチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 31 4-Hydroxy-3-[(methylsulfanyl) (phenyl) methyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] Pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133

及び as well as

Figure JPOXMLDOC01-appb-C000134
Figure JPOXMLDOC01-appb-C000134

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、参考例３６にて製造された３－［（メチルスルファニル）（フェニル）メチル］－１Ｈ－ピラゾール－５－アミン（２２０ｍｇ、１．００ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物３１－１とする）（５２ｍｇ、収率：１５％）、及び、後に溶出する化合物（以下、化合物３１－２とする）（４１ｍｇ、収率：１１％）をそれぞれ得た。 Instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine, 3-[(methylsulfanyl) (phenyl) methyl] -1H-pyrazole- prepared in Reference Example 36 Using 5-amine (220 mg, 1.00 mmol), the reaction was carried out in the same manner as in the method described in Example 4, and the previously eluted compound (hereinafter referred to as Compound 31-1) (52 mg, yield: 15%) and a compound eluting later (hereinafter referred to as compound 31-2) (41 mg, yield: 11%) were obtained.

　化合物３１－１：
　1H-NMR (400MHz, DMSO-d6) δ: 12.80 (1H, s), 10.57 (1H, s), 7.53 (2H, d, J=7Hz), 7.36-7.31 (2H, m), 7.29-7.24 (1H, m), 6.85 (1H, s), 5.41 (2H, s), 2.94 (1H, d, J=16Hz), 2.67 (1H, d, J=16Hz), 1.94 (3H, s)。 Compound 31-1:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.80 (1H, s), 10.57 (1H, s), 7.53 (2H, d, J = 7Hz), 7.36-7.31 (2H, m), 7.29- 7.24 (1H, m), 6.85 (1H, s), 5.41 (2H, s), 2.94 (1H, d, J = 16Hz), 2.67 (1H, d, J = 16Hz), 1.94 (3H, s).

　化合物３１－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.76 (1H, s), 10.58 (1H, s), 7.47 (2H, d, J=7Hz), 7.36-7.31 (2H, m), 7.29-7.26 (1H, m), 6.99 (1H, s), 5.50 (1H, s), 3.01 (1H, d, J=16Hz), 2.72 (1H, d, J=16Hz), 1.98 (3H, s)。 Compound 31-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.76 (1H, s), 10.58 (1H, s), 7.47 (2H, d, J = 7Hz), 7.36-7.31 (2H, m), 7.29- 7.26 (1H, m), 6.99 (1H, s), 5.50 (1H, s), 3.01 (1H, d, J = 16Hz), 2.72 (1H, d, J = 16Hz), 1.98 (3H, s).

　（実施例３２）４－ヒドロキシ－３－［（メチルスルホニル）（フェニル）メチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 32 4-Hydroxy-3-[(methylsulfonyl) (phenyl) methyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135

　実施例３１にて製造された４－ヒドロキシ－３－［（メチルスルファニル）（フェニル）メチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン（３０ｍｇ、０．０８４ｍｍｏｌ）のジクロロメタン（５ｍＬ）溶液に、３－クロロ過安息香酸（含量６５％、５５ｍｇ、０．２０７ｍｍｏｌ）を０℃で加え、室温で２時間攪拌した。反応液に１Ｎ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝７０／３０－１０／９０（グラジェント）］で精製し、標記化合物（１２ｍｇ、収率：３７％）を得た。 4-Hydroxy-3-[(methylsulfanyl) (phenyl) methyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4] prepared in Example 31 -B] To a solution of pyridin-6-one (30 mg, 0.084 mmol) in dichloromethane (5 mL) was added 3-chloroperbenzoic acid (content 65%, 55 mg, 0.207 mmol) at 0 ° C., and 2 hours at room temperature. Stir. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-10 / 90 (gradient)] to obtain the title compound (12 mg, yield: 37%).

　1H-NMR (400MHz, DMSO-d6) δ: 12.98 (1H, s), 10.74 (1H, s), 7.67 (2H, t, J=4Hz), 7.49-7.25 (4H, m), 3.15 (1H, d, J=16Hz), 2.92 (3H, s), 2.75 (1H, d, J=16Hz)；
　MS (ESI) m/z: 388 (M-H)-。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.98 (1H, s), 10.74 (1H, s), 7.67 (2H, t, J = 4Hz), 7.49-7.25 (4H, m), 3.15 ( 1H, d, J = 16Hz), 2.92 (3H, s), 2.75 (1H, d, J = 16Hz);
MS (ESI) m / z: 388 (MH) - .

　（実施例３３）４－ヒドロキシ－３－［１－（チオフェン－２－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 33 4-Hydroxy-3- [1- (thiophen-2-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4 b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例３７にて製造された３－［１－（チオフェン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン（３９５ｍｇ、２．０４ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（１２０ｍｇ、収率：１８％）を得た。 3- [1- (thiophen-2-yl) ethyl] -1H-pyrazol-5-amine prepared in Reference Example 37 instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine (395 mg, 2.04 mmol) was used in the same manner as in Example 3 to obtain the title compound (120 mg, yield: 18%).

　1H-NMR (400MHz, DMSO-d6) δ: 12.40 (1H, s), 10.54 (1H, s), 7.34 (1H, d, J=5Hz), 6.95 (1H, dd, J=5Hz, 4Hz), 6.89 (1H, d, J=3Hz), 6.85 (1H, s), 4.74 (1H, q, J=7Hz), 2.93 (1H, d, J=16Hz), 2.73 (1H, d, J=16Hz), 1.63 (3H, d, J=7Hz)；
　MS (ESI) m/z: 332 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.40 (1H, s), 10.54 (1H, s), 7.34 (1H, d, J = 5Hz), 6.95 (1H, dd, J = 5Hz, 4Hz ), 6.89 (1H, d, J = 3Hz), 6.85 (1H, s), 4.74 (1H, q, J = 7Hz), 2.93 (1H, d, J = 16Hz), 2.73 (1H, d, J = 16Hz), 1.63 (3H, d, J = 7Hz);
MS (ESI) m / z: 332 (M + H) <+> .

　（実施例３４）４－ヒドロキシ－３－［１－（フェニルスルファニル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 34 4-Hydroxy-3- [1- (phenylsulfanyl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine -6-on

Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例３８にて製造された３－［１－（フェニルスルファニル）エチル］－１Ｈ－ピラゾール－５－アミン（４６９ｍｇ、２．１４ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（１５２ｍｇ、収率：２０％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- [1- (phenylsulfanyl) ethyl] -1H-pyrazol-5-amine prepared in Reference Example 38 (469 mg, 2.14 mmol) was used in the same manner as in Example 3 to obtain the title compound (152 mg, yield: 20%).

　1H-NMR (500MHz, DMSO-d6) δ: 12.64 (1H, s), 10.56 (1H, s), 7.39-7.22 (5H, m), 6.84 (1H, s), 4.72 (1H, q, J=7Hz), 2.90 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.56 (3H, d, J=7Hz)；
　MS (ESI) m/z: 358 (M+H)+。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 12.64 (1H, s), 10.56 (1H, s), 7.39-7.22 (5H, m), 6.84 (1H, s), 4.72 (1H, q, J = 7Hz), 2.90 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.56 (3H, d, J = 7Hz);
MS (ESI) m / z: 358 (M + H) <+> .

　（実施例３５）４－ヒドロキシ－３－（ペンタン－２－イル）－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 35 4-Hydroxy-3- (pentan-2-yl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6 -on

Figure JPOXMLDOC01-appb-C000138
Figure JPOXMLDOC01-appb-C000138

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、３－（ペンタン－２－イル）－１Ｈ－ピラゾール－５－アミン（５２０ｍｇ、３．３９ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（１２６ｍｇ、収率：１３％）を得た。 Example using 3- (pentan-2-yl) -1H-pyrazol-5-amine (520 mg, 3.39 mmol) instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine The reaction was performed in the same manner as described in 3 to obtain the title compound (126 mg, yield: 13%).

　1H-NMR (500MHz, DMSO-d6) δ: 12.19 (1H, s), 10.49 (1H, s), 6.64 (1H, s), 3.19-3.13 (1H, m), 2.91 (1H, d, J=16Hz), 2.73 (1H, d, J=16Hz), 1.66-1.49 (2H, m), 1.34-1.13 (2H, m), 1.20 (3H, d, J=7Hz), 0.86 (3H, t, J=7Hz)；
　MS (ESI) m/z: 292 (M+H)+。 1 H-NMR (500 MHz, DMSO-d 6 ) δ: 12.19 (1H, s), 10.49 (1H, s), 6.64 (1H, s), 3.19-3.13 (1H, m), 2.91 (1H, d, J = 16Hz), 2.73 (1H, d, J = 16Hz), 1.66-1.49 (2H, m), 1.34-1.13 (2H, m), 1.20 (3H, d, J = 7Hz), 0.86 (3H, t , J = 7Hz);
MS (ESI) m / z: 292 (M + H) <+> .

　（実施例３６）３－（ヘプタン－３－イル）－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 36 3- (Heptan-3-yl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6 -On and its diastereomers

Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139

及び as well as

Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、３－（ヘプタン－３－イル）－１Ｈ－ピラゾール－５－アミン（５１０ｍｇ、２．８１ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物３６－１とする）（５４ｍｇ、収率：６％）、及び、後に溶出する化合物（以下、化合物３６－２とする）（６８ｍｇ、収率：８％）をそれぞれ得た。 Instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine, 3- (heptan-3-yl) -1H-pyrazol-5-amine (510 mg, 2.81 mmol) The compound eluted in the same manner as described in Example 4 and the compound eluting first (hereinafter referred to as compound 36-1) (54 mg, yield: 6%) and the compound eluting later ( (Hereinafter referred to as Compound 36-2) (68 mg, yield: 8%).

　化合物３６－１：
　1H-NMR (500MHz, DMSO-d6) δ: 12.10 (1H, s), 10.44 (1H, s), 6.54 (1H, s), 3.00-2.92 (1H, m), 2.89 (1H, d, J=16Hz), 2.69 (1H, d, J=16Hz), 1.65-1.51 (4H, m), 1.28-1.07 (4H, m), 0.83 (3H, t, J=7Hz), 0.75 (3H, t, J=8Hz)；
　MS (ESI) m/z: 320 (M+H)+。 Compound 36-1:
1 H-NMR (500MHz, DMSO-d 6 ) δ: 12.10 (1H, s), 10.44 (1H, s), 6.54 (1H, s), 3.00-2.92 (1H, m), 2.89 (1H, d, J = 16Hz), 2.69 (1H, d, J = 16Hz), 1.65-1.51 (4H, m), 1.28-1.07 (4H, m), 0.83 (3H, t, J = 7Hz), 0.75 (3H, t , J = 8Hz);
MS (ESI) m / z: 320 (M + H) <+> .

　化合物３６－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.11 (1H, s), 10.45 (1H, s), 6.54 (1H, s), 3.01-2.92 (1H, m), 2.89 (1H, d, J=16Hz), 2.69 (1H, d, J=16Hz), 1.64-1.49 (4H, m), 1.29-1.04 (4H, m), 0.82 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz)；
　MS (ESI) m/z: 320 (M+H)+。 Compound 36-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.11 (1H, s), 10.45 (1H, s), 6.54 (1H, s), 3.01-2.92 (1H, m), 2.89 (1H, d, J = 16Hz), 2.69 (1H, d, J = 16Hz), 1.64-1.49 (4H, m), 1.29-1.04 (4H, m), 0.82 (3H, t, J = 7Hz), 0.78 (3H, t , J = 7Hz);
MS (ESI) m / z: 320 (M + H) <+> .

　（実施例３７）４－ヒドロキシ－３－［１－（５－メチルフラン－２－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 37 4-Hydroxy-3- [1- (5-methylfuran-2-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例４０にて製造された３－［１－（５－メチルフラン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン（１．０２ｇ、５．３３ｍｍｏｌ）を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（４２５ｍｇ、収率：２４％）を得た。 Instead of 3- (1-phenylethyl) -1H-pyrazol-5-amine, 3- [1- (5-methylfuran-2-yl) ethyl] -1H-pyrazole- prepared in Reference Example 40 The reaction was carried out in the same manner as described in Example 3 using 5-amine (1.02 g, 5.33 mmol) to obtain the title compound (425 mg, yield: 24%).

　1H-NMR (500MHz, DMSO-d6) δ: 12.30 (1H, s), 10.52 (1H, s), 6.79 (1H, s), 5.95 (1H, d, J=3Hz), 5.92 (1H, d, J=3Hz), 4.49 (1H, q, J=7Hz), 2.91 (1H, d, J=16Hz), 2.72 (1H, d, J=16Hz), 2.20 (3H, s), 1.51 (3H, d, J=7Hz)；
　MS (ESI) m/z: 330 (M+H)+。 1 H-NMR (500MHz, DMSO-d 6 ) δ: 12.30 (1H, s), 10.52 (1H, s), 6.79 (1H, s), 5.95 (1H, d, J = 3Hz), 5.92 (1H, d, J = 3Hz), 4.49 (1H, q, J = 7Hz), 2.91 (1H, d, J = 16Hz), 2.72 (1H, d, J = 16Hz), 2.20 (3H, s), 1.51 (3H , d, J = 7Hz);
MS (ESI) m / z: 330 (M + H) <+> .

　（実施例３８）４－ヒドロキシ－３－［１－（６－メトキシピリジン－２－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 38 4-Hydroxy-3- [1- (6-methoxypyridin-2-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000142

　３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例４２にて製造された３－［１－（６－メトキシピリジン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン（４５８ｍｇ、２．１０ｍｍｏｌ）を用いて、実施例１に記載された方法と同様に反応を行い、標記化合物（１７５ｍｇ、収率：２３％）を得た。 3- [1- (6-Methoxypyridin-2-yl) ethyl] -1H-pyrazole prepared in Reference Example 42 instead of 3- (biphenyl-4-ylmethyl) -1H-pyrazol-5-amine Reaction was carried out in the same manner as described in Example 1 using -5-amine (458 mg, 2.10 mmol) to obtain the title compound (175 mg, yield: 23%).

　1H-NMR (400MHz, DMSO-d6) δ: 12.30 (2/5H, s), 12.24 (3/5H, s), 10.51 (1H, s), 7.64-7.58 (1H, m), 6.87-6.78 (1H, m), 6.71-6.61 (1H, m), 4.61-4.53 (1H, m), 3.89 (3*2/5H, s), 3.86 (3*3/5H, s), 2.98-2.90 (1H, m), 2.75-2.67 (1H, m), 1.63-1.55 (3H, m)；
　MS (ESI) m/z: 357 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.30 (2 / 5H, s), 12.24 (3 / 5H, s), 10.51 (1H, s), 7.64-7.58 (1H, m), 6.87- 6.78 (1H, m), 6.71-6.61 (1H, m), 4.61-4.53 (1H, m), 3.89 (3 * 2 / 5H, s), 3.86 (3 * 3 / 5H, s), 2.98-2.90 (1H, m), 2.75-2.67 (1H, m), 1.63-1.55 (3H, m);
MS (ESI) m / z: 357 (M + H) <+> .

　（実施例３９）４－ヒドロキシ－３－［１－（５－メチルチオフェン－２－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 39 4-Hydroxy-3- [1- (5-methylthiophen-2-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143

及び as well as

Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、参考例４４にて製造された３－［１－（５－メチルチオフェン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン（１．００ｇ、４．８２ｍｍｏｌ）を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物３９－１とする）（３５１ｍｇ、収率：２１％）、及び、後に溶出する化合物（以下、化合物３９－２とする）（３８４ｍｇ、収率：２３％）をそれぞれ得た。 3- [1- (5-methylthiophen-2-yl) ethyl prepared in Reference Example 44 instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine] Using 1H-pyrazol-5-amine (1.00 g, 4.82 mmol) in the same manner as in the method described in Example 4, the previously eluted compound (hereinafter referred to as Compound 39-1) ) (351 mg, yield: 21%) and a compound that elutes later (hereinafter referred to as compound 39-2) (384 mg, yield: 23%).

　化合物３９－１：
　MS (ESI) m/z: 346 (M+H)+。 Compound 39-1:
MS (ESI) m / z: 346 (M + H) <+> .

　化合物３９－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.34 (1H, s), 10.53 (1H, s), 6.81 (1H, s), 6.64 (1H, d, J=3Hz), 6.61 (1H, dd, J=3Hz, 1Hz), 4.64 (1H, q, J=7Hz), 2.92 (1H, d, J=17Hz), 2.72 (1H, d, J=16Hz), 2.36 (3H, s), 1.58 (3H, d, J=7Hz)；
　MS (ESI) m/z: 346 (M+H)+。 Compound 39-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.34 (1H, s), 10.53 (1H, s), 6.81 (1H, s), 6.64 (1H, d, J = 3Hz), 6.61 (1H, dd, J = 3Hz, 1Hz), 4.64 (1H, q, J = 7Hz), 2.92 (1H, d, J = 17Hz), 2.72 (1H, d, J = 16Hz), 2.36 (3H, s), 1.58 (3H, d, J = 7Hz);
MS (ESI) m / z: 346 (M + H) <+> .

　（実施例４０）３－［１－（１－ベンゾフラン－２－イル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 40 3- [1- (1-Benzofuran-2-yl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145

及び as well as

Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000146

　３－（ビフェニル－４－イル）－３－オキソブタンニトリルの代わりに、参考例４６にて製造された４－（１－ベンゾフラン－２－イル）－３－オキソペンタンニトリル（７５５ｍｇ、３．５４ｍｍｏｌ）を用いて、参考例２に記載された方法と同様に反応を行い、アミノピラゾール化合物を得た。 Instead of 3- (biphenyl-4-yl) -3-oxobutanenitrile, 4- (1-benzofuran-2-yl) -3-oxopentanenitrile prepared in Reference Example 46 (755 mg, 3.54 mmol) ) Was used in the same manner as in the method described in Reference Example 2 to obtain an aminopyrazole compound.

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、上記操作にて製造されたアミノピラゾール化合物を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物４０－１とする）（２１６ｍｇ、収率：１７％）、及び、後に溶出する化合物（以下、化合物４０－２とする）（２５５ｍｇ、収率：２２％）をそれぞれ得た。 Similar to the method described in Example 4 using the aminopyrazole compound prepared by the above procedure instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine. The reaction was carried out and the compound eluting first (hereinafter referred to as compound 40-1) (216 mg, yield: 17%) and the compound eluting later (hereinafter referred to as compound 40-2) (255 mg, yield) : 22%) respectively.

　化合物４０－１：
　1H-NMR (500MHz, DMSO-d6) δ: 12.54 (1H, s), 10.58 (1H, s), 7.58 (1H, d, J=8Hz), 7.50 (1H, d, J=8Hz), 7.27-7.19 (2H, m), 6.81 (1H, s), 6.61 (1H, s), 4.74 (1H, q, J=8Hz), 2.99 (1H, d, J=17Hz), 2.72 (1H, d, J=17Hz), 1.62 (3H, d, J=8Hz)；
　MS (ESI) m/z: 366 (M+H)+。 Compound 40-1:
1 H-NMR (500MHz, DMSO-d 6 ) δ: 12.54 (1H, s), 10.58 (1H, s), 7.58 (1H, d, J = 8Hz), 7.50 (1H, d, J = 8Hz), 7.27-7.19 (2H, m), 6.81 (1H, s), 6.61 (1H, s), 4.74 (1H, q, J = 8Hz), 2.99 (1H, d, J = 17Hz), 2.72 (1H, d , J = 17Hz), 1.62 (3H, d, J = 8Hz);
MS (ESI) m / z: 366 (M + H) <+> .

　化合物４０－２：
　1H-NMR (500MHz, DMSO-d6) δ: 12.51 (1H, s), 10.58 (1H, s), 7.57 (1H, d, J=8Hz), 7.49 (1H, d, J=8Hz), 7.26-7.18 (2H, m), 6.90 (1H, s), 6.56 (1H, s), 4.72 (1H, q, J=7Hz), 2.95 (1H, d, J=16Hz), 2.75 (1H, d, J=16Hz), 1.65 (3H, d, J=7Hz)；
　MS (ESI) m/z: 366 (M+H)+。 Compound 40-2:
1 H-NMR (500MHz, DMSO-d 6 ) δ: 12.51 (1H, s), 10.58 (1H, s), 7.57 (1H, d, J = 8Hz), 7.49 (1H, d, J = 8Hz), 7.26-7.18 (2H, m), 6.90 (1H, s), 6.56 (1H, s), 4.72 (1H, q, J = 7Hz), 2.95 (1H, d, J = 16Hz), 2.75 (1H, d , J = 16Hz), 1.65 (3H, d, J = 7Hz);
MS (ESI) m / z: 366 (M + H) <+> .

　（実施例４１）４－ヒドロキシ－４－（トリフルオロメチル）－３－｛１－［４－（トリフルオロメチル）フェノキシ］エチル｝－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 41 4-Hydroxy-4- (trifluoromethyl) -3- {1- [4- (trifluoromethyl) phenoxy] ethyl} -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147

及び as well as

Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148

　４－（トリフルオロメチル）フェノール（１．６２ｇ、９．９９ｍｍｏｌ）、２－ブロモプロピオン酸エチル（１．４２ｍＬ、１１．０ｍｍｏｌ）、及び、炭酸セシウム（６．６０ｇ、２０．３ｍｍｏｌ）のＤＭＦ（３０ｍＬ）懸濁液を、９０℃で７時間攪拌した。反応液に水を加え、ジエチルエーテルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝１００／０－８０／２０（グラジェント）］で精製し、粗生成物を得た。 4- (Trifluoromethyl) phenol (1.62 g, 9.99 mmol), ethyl 2-bromopropionate (1.42 mL, 11.0 mmol), and cesium carbonate (6.60 g, 20.3 mmol) in DMF ( (30 mL) The suspension was stirred at 90 ° C. for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-80 / 20 (gradient)] to obtain a crude product.

　２－（４－クロロフェニル）プロピオン酸メチルの代わりに、上記操作により得られた粗生成物を用いて、参考例２０に記載された方法と同様に反応を行い、アミノピラゾール化合物を得た。 Using the crude product obtained by the above operation instead of methyl 2- (4-chlorophenyl) propionate, the reaction was carried out in the same manner as described in Reference Example 20 to obtain an aminopyrazole compound.

　３－[１－（３－ブロモフェニル）エチル]－１Ｈ－ピラゾール－５－アミンの代わりに、上記操作により得られたアミノピラゾール化合物を用いて、実施例４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物４１－１とする）（２３３ｍｇ、収率：６％）、及び、後に溶出する化合物（以下、化合物４１－２とする）（３１０ｍｇ、収率：８％）をそれぞれ得た。 Using the aminopyrazole compound obtained by the above procedure instead of 3- [1- (3-bromophenyl) ethyl] -1H-pyrazol-5-amine, the reaction was carried out in the same manner as described in Example 4. The compound eluting first (hereinafter referred to as compound 41-1) (233 mg, yield: 6%) and the compound eluting later (hereinafter referred to as compound 41-2) (310 mg, yield: 8%) respectively.

　化合物４１－１：
　1H-NMR (500MHz, DMSO-d6) δ: 12.78 (1H, s), 10.62 (1H, s), 7.59 (2H, d, J=9Hz), 7.24 (2H, d, J=9Hz), 7.23 (1H, s), 5.81 (1H, q, J=7Hz), 3.06 (1H, d, J=17Hz), 2.77 (1H, d, J=16Hz), 1.61 (3H, d, J=7Hz)；
　MS (ESI) m/z: 410 (M+H)+。 Compound 41-1:
1 H-NMR (500MHz, DMSO-d 6 ) δ: 12.78 (1H, s), 10.62 (1H, s), 7.59 (2H, d, J = 9Hz), 7.24 (2H, d, J = 9Hz), 7.23 (1H, s), 5.81 (1H, q, J = 7Hz), 3.06 (1H, d, J = 17Hz), 2.77 (1H, d, J = 16Hz), 1.61 (3H, d, J = 7Hz) ;
MS (ESI) m / z: 410 (M + H) <+> .

　化合物４１－２：
　1H-NMR (500MHz, DMSO-d6) δ: 12.80 (1H, s), 10.66 (1H, s), 7.68 (2H, d, J=9Hz), 7.12 (2H, d, J=9Hz), 7.01 (1H, s), 5.79 (1H, q, J=6Hz), 2.98 (1H, d, J=16 Hz), 2.78 (1H, d, J=16Hz), 1.68 (3H, d, J=7Hz)；
　MS (ESI) m/z: 410 (M+H)+。 Compound 41-2:
1 H-NMR (500MHz, DMSO-d 6 ) δ: 12.80 (1H, s), 10.66 (1H, s), 7.68 (2H, d, J = 9Hz), 7.12 (2H, d, J = 9Hz), 7.01 (1H, s), 5.79 (1H, q, J = 6Hz), 2.98 (1H, d, J = 16 Hz), 2.78 (1H, d, J = 16Hz), 1.68 (3H, d, J = 7Hz );
MS (ESI) m / z: 410 (M + H) <+> .

　（実施例４２）４－ヒドロキシ－４－（トリフルオロメチル）－３－｛１－［３－（トリフルオロメチル）フェノキシ］エチル｝－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 42 4-Hydroxy-4- (trifluoromethyl) -3- {1- [3- (trifluoromethyl) phenoxy] ethyl} -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000149
Figure JPOXMLDOC01-appb-C000149

及び as well as

Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000150

　４－（トリフルオロメチル）フェノールの代わりに、３－（トリフルオロメチル）フェノール（１．７８ｇ、１０．９８ｍｍｏｌ）を用いて、実施例４１に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物４２－１とする）（１２７ｍｇ、収率：３％）、及び、後に溶出する化合物（以下、化合物４２－２とする）（１４８ｍｇ、収率：３％）をそれぞれ得た。 The reaction was carried out in the same manner as described in Example 41 using 3- (trifluoromethyl) phenol (1.78 g, 10.98 mmol) instead of 4- (trifluoromethyl) phenol. The eluting compound (hereinafter referred to as compound 42-1) (127 mg, yield: 3%) and the later eluting compound (hereinafter referred to as compound 42-2) (148 mg, yield: 3%) Obtained.

　化合物４２－１：
　1H-NMR (400MHz, DMSO-d6) δ: 12.74 (1H, s), 10.60 (1H, s), 7.46-7.39 (2H, m), 7.32-7.29 (2H, m), 7.23 (1H, d, J=7Hz), 5.75 (1H, q, J=7Hz), 2.87 (1H, d, J=17Hz), 2.77 (1H, d, J=16Hz), 1.57 (2H, d, J=7Hz)；
　MS (ESI) m/z: 410 (M+H)+。 Compound 42-1:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.74 (1H, s), 10.60 (1H, s), 7.46-7.39 (2H, m), 7.32-7.29 (2H, m), 7.23 (1H, d, J = 7Hz), 5.75 (1H, q, J = 7Hz), 2.87 (1H, d, J = 17Hz), 2.77 (1H, d, J = 16Hz), 1.57 (2H, d, J = 7Hz) ;
MS (ESI) m / z: 410 (M + H) <+> .

　化合物４２－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.69 (1H, s), 10.62 (1H, s), 7.55-7.49 (1H, m), 7.30 (1H, d, J=7Hz), 7.24 (1H, dd, J=8Hz, 2Hz), 7.15 (1H, s), 6.99 (1H, s), 5.68 (1H, q, J=6Hz), 2.96 (1H, d, J=17Hz), 2.74 (1H, d, J=16Hz), 1.65 (3H, d, J=6Hz)；
　MS (ESI) m/z: 410 (M+H)+。 Compound 42-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.69 (1H, s), 10.62 (1H, s), 7.55-7.49 (1H, m), 7.30 (1H, d, J = 7Hz), 7.24 ( 1H, dd, J = 8Hz, 2Hz), 7.15 (1H, s), 6.99 (1H, s), 5.68 (1H, q, J = 6Hz), 2.96 (1H, d, J = 17Hz), 2.74 (1H , d, J = 16Hz), 1.65 (3H, d, J = 6Hz);
MS (ESI) m / z: 410 (M + H) <+> .

　（実施例４３）３－［１－（４－フルオロフェノキシ）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 43 3- [1- (4-Fluorophenoxy) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000151

　２－（４－クロロフェニル）プロピオン酸メチルの代わりに、２－（４－フルオロフェノキシ）プロピオン酸メチル（１．００ｇ、５．５０ｍｍｏｌ）を用いて、参考例２０に記載された方法と同様に反応を行い、アミノピラゾール化合物を得た。 Using methyl 2- (4-fluorophenoxy) propionate (1.00 g, 5.50 mmol) instead of methyl 2- (4-chlorophenyl) propionate, the reaction was carried out in the same manner as described in Reference Example 20. The aminopyrazole compound was obtained.

　３－（１－フェニルエチル）－１Ｈ－ピラゾール－５－アミンの代わりに、上記操作で得られたアミノピラゾール化合物を用いて、実施例３に記載された方法と同様に反応を行い、標記化合物（１４８ｍｇ、収率：７％）を得た。 Using the aminopyrazole compound obtained by the above procedure in place of 3- (1-phenylethyl) -1H-pyrazol-5-amine, the reaction was carried out in the same manner as described in Example 3 to obtain the title compound (148 mg, yield: 7%) was obtained.

　1H-NMR (400MHz, DMSO-d6) δ: 12.69 (1H, s), 10.60 (1H, s), 7.13-7.07 (2H, m), 6.96-6.91 (3H, m), 5.55 (1H, q, J=6 Hz), 2.93 (1H, d, J=17Hz), 2.73 (1H, d, J=16Hz), 1.60 (3H, d, J=6Hz)；
　MS (ESI) m/z: 304 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.69 (1H, s), 10.60 (1H, s), 7.13-7.07 (2H, m), 6.96-6.91 (3H, m), 5.55 (1H, q, J = 6 Hz), 2.93 (1H, d, J = 17 Hz), 2.73 (1H, d, J = 16 Hz), 1.60 (3H, d, J = 6 Hz);
MS (ESI) m / z: 304 (M + H) <+> .

　（実施例４４）３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 44 3- {1- [3- (6-Fluoropyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro- 6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000152

及び as well as

Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000153

　参考例４７にて製造された３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン（３０１ｍｇ、１．０７ｍｍｏｌ）の酢酸（３ｍＬ）溶液に、トリフルオロアセト酢酸エチル（０．４７１ｍｌ、３．２０ｍｍｏｌ）を加え、６０℃で２時間攪拌した。反応液を減圧下にて濃縮し、トルエンにて共沸した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝５０／５０－０／１００（グラジェント）］で精製し、先に溶出する化合物（以下、化合物４４－１とする）（８４ｍｇ、収率：１９％）、及び、後に溶出する化合物（以下、化合物４４－２とする）（１００ｍｇ、収率：２２％）をそれぞれ得た。 3- {1- [3- (6-Fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine (301 mg, 1.07 mmol) prepared in Reference Example 47 (3 mL) To the solution was added ethyl trifluoroacetoacetate (0.471 ml, 3.20 mmol), and the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure and azeotroped with toluene. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (gradient)], and the compound eluted first (hereinafter referred to as compound 44-1) ( 84 mg, yield: 19%) and a compound that elutes later (hereinafter referred to as compound 44-2) (100 mg, yield: 22%) were obtained.

　化合物４４－１：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.49 (1H, s), 10.52 (1H, s), 8.55 (1H, d, J=2Hz), 8.28 (1H, td, J=8Hz, 3Hz), 7.77 (1H, s), 7.55 (1H, dt, J=7Hz, 2Hz), 7.50-7.40 (2H, m), 7.31 (1H, dd, J=9Hz, 3Hz), 6.84 (1H, s), 4.63 (1H, q, J=7Hz), 2.96 (1H, d, J=16Hz), 2.71 (1H, d, J=16Hz), 1.61 (3H, d, J=7Hz)；
　MS (ESI) m/z: 419 (M-H)-。 Compound 44-1:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.49 (1H, s), 10.52 (1H, s), 8.55 (1H, d, J = 2Hz), 8.28 (1H, td, J = 8Hz, 3Hz ), 7.77 (1H, s), 7.55 (1H, dt, J = 7Hz, 2Hz), 7.50-7.40 (2H, m), 7.31 (1H, dd, J = 9Hz, 3Hz), 6.84 (1H, s) , 4.63 (1H, q, J = 7Hz), 2.96 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 1.61 (3H, d, J = 7Hz);
MS (ESI) m / z: 419 (MH) - .

　化合物４４－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.49 (1H, s), 10.54 (1H, s), 8.54 (1H, d, J=2Hz), 8.26 (1H, td, J=8Hz, 3Hz), 7.68 (1H, s), 7.56 (1H, d, J=8Hz), 7.43 (1H, t, J=8Hz), 7.34-7.28 (2H, m), 6.88 (1H, s), 4.65 (1H, q, J=7Hz), 2.94 (1H, d, J=16Hz), 2.74 (1H, d, J=16Hz), 1.63 (3H, d, J=7Hz)；
　MS (ESI) m/z: 419 (M-H)-。 Compound 44-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.49 (1H, s), 10.54 (1H, s), 8.54 (1H, d, J = 2Hz), 8.26 (1H, td, J = 8Hz, 3Hz ), 7.68 (1H, s), 7.56 (1H, d, J = 8Hz), 7.43 (1H, t, J = 8Hz), 7.34-7.28 (2H, m), 6.88 (1H, s), 4.65 (1H , q, J = 7Hz), 2.94 (1H, d, J = 16Hz), 2.74 (1H, d, J = 16Hz), 1.63 (3H, d, J = 7Hz);
MS (ESI) m / z: 419 (MH) - .

　（実施例４５） (Example 45)

Figure JPOXMLDOC01-appb-C000154
Figure JPOXMLDOC01-appb-C000154

　実施例４４にて製造された化合物４４－２（２００ｍｇ、０．４８ｍｍｏｌ）のヘキサン－ＩＰＡ（１／１）混合溶液に溶解し、ＨＰＬＣ［カラム：Ｃｈｉｒａｌｐａｋ　ＩＡ（２０ｍｍ　ｉ．ｄ．ｘ２５０ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝６５／３５、流速：１５ｍＬ／分]で精製して、目的化合物（７６ｍｇ、収率：３８％）を得た。 The compound 44-2 (200 mg, 0.48 mmol) produced in Example 44 was dissolved in a hexane-IPA (1/1) mixed solution, and HPLC [column: Chiralpak IA (20 mm id x 250 mm); Daicel The product was purified by an elution solvent: hexane / IPA = 65/35, flow rate: 15 mL / min] to obtain the target compound (76 mg, yield: 38%).

　光学純度はＨＰＬＣ［カラム：Ｃｈｉｒａｌｐａｋ　ＩＡ（４．６ｍｍ　ｉ．ｄ．ｘ２５０ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝６０／４０、流速：１．０ｍＬ／分］を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 60/40, flow rate: 1.0 mL / min].

　光学純度９９％以上（保持時間：４．６分）。 Optical purity 99% or more (retention time: 4.6 minutes).

　（実施例４６）４－ヒドロキシ－４－（トリフルオロメチル）－３－（１－｛３－［６－（トリフルオロメチル）ピリジン－３－イル］フェニル｝エチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 46 4-Hydroxy-4- (trifluoromethyl) -3- (1- {3- [6- (trifluoromethyl) pyridin-3-yl] phenyl} ethyl) -1,4,5 7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000155
Figure JPOXMLDOC01-appb-C000155

及び as well as

Figure JPOXMLDOC01-appb-C000156
Figure JPOXMLDOC01-appb-C000156

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例４８にて製造された３－（１－｛３－［６－（トリフルオロメチル）ピリジン－３－イル］フェニル｝エチル）－１Ｈ－ピラゾール－５－アミン（２９６ｍｇ、０．８７ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出した化合物（以下、化合物４６－１とする）（７３ｍｇ、収率：１７％）、及び、次に溶出した化合物（以下、化合物４６－２とする）（９０ｍｇ、収率：２１％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, 3- (1- {3- [6- (Trifluoromethyl) pyridin-3-yl] phenyl} ethyl) -1H-pyrazol-5-amine (296 mg, 0.87 mmol) was used to react in the same manner as described in Example 44. The first eluted compound (hereinafter referred to as Compound 46-1) (73 mg, yield: 17%) and the next eluted compound (hereinafter referred to as Compound 46-2) (90 mg, yield: 21%) were obtained respectively.

　化合物４６－１：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.51 (1H, s), 10.54 (1H, s), 9.10 (1H, d, J=2Hz), 8.36 (1H, dd, J=8Hz, 2Hz), 8.02 (1H, d, J=8Hz), 7.87 (1H, s), 7.67 (1H, d, J=7Hz), 7.58-7.46 (2H, m), 6.85 (1H, s), 4.66 (1H, q, J=7Hz), 2.97 (1H, d, J=17Hz), 2.72 (1H, d, J=17Hz), 1.63 (3H, d, J=7Hz)；
　MS (ESI) m/z: 469 (M-H)-。 Compound 46-1:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.51 (1H, s), 10.54 (1H, s), 9.10 (1H, d, J = 2Hz), 8.36 (1H, dd, J = 8Hz, 2Hz ), 8.02 (1H, d, J = 8Hz), 7.87 (1H, s), 7.67 (1H, d, J = 7Hz), 7.58-7.46 (2H, m), 6.85 (1H, s), 4.66 (1H , q, J = 7Hz), 2.97 (1H, d, J = 17Hz), 2.72 (1H, d, J = 17Hz), 1.63 (3H, d, J = 7Hz);
MS (ESI) m / z: 469 (MH) - .

　化合物４６－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.50 (1H, s), 10.54 (1H, s), 9.08 (1H, d, J=2Hz), 8.34 (1H, dd, J=8Hz, 2Hz), 8.02 (1H, d, J=8Hz), 7.78 (1H, s), 7.67 (1H, d, J=8Hz), 7.48 (1H, t, J=8Hz), 7.37 (1H, d, J=8Hz), 6.89 (1H, s), 4.68 (1H, q, J=7Hz), 2.95 (1H, d, J=17Hz), 2.73 (1H, d, J=17Hz), 1.65 (3H, d, J=7Hz)；
　MS (ESI) m/z: 469 (M-H)-。 Compound 46-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.50 (1H, s), 10.54 (1H, s), 9.08 (1H, d, J = 2Hz), 8.34 (1H, dd, J = 8Hz, 2Hz ), 8.02 (1H, d, J = 8Hz), 7.78 (1H, s), 7.67 (1H, d, J = 8Hz), 7.48 (1H, t, J = 8Hz), 7.37 (1H, d, J = 8Hz), 6.89 (1H, s), 4.68 (1H, q, J = 7Hz), 2.95 (1H, d, J = 17Hz), 2.73 (1H, d, J = 17Hz), 1.65 (3H, d, J = 7Hz);
MS (ESI) m / z: 469 (MH) - .

　（実施例４７）４－ヒドロキシ－３－｛１－［３－（ピリジン－３－イル）フェニル］エチル｝－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 47 4-Hydroxy-3- {1- [3- (pyridin-3-yl) phenyl] ethyl} -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000157

及び as well as

Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000158

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例４９にて製造された３－｛１－［３－（ピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン（２０９ｍｇ、０．７８ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物４７－１とする）（３６ｍｇ、収率：１１％）、及び、後に溶出する化合物（以下、化合物４７－２とする）（３２ｍｇ、収率：１０％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, the 3- {1- [3- Compound that elutes first by reacting in the same manner as described in Example 44 using (pyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine (209 mg, 0.78 mmol) (Hereinafter referred to as Compound 47-1) (36 mg, yield: 11%) and a compound that elutes later (hereinafter referred to as Compound 47-2) (32 mg, yield: 10%) were obtained.

　化合物４７－１：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.50 (1H, s), 10.53 (1H, s), 8.93-8.89 (1H, m), 8.58 (1H, dd, J=5Hz, 2Hz), 8.09-8.05 (1H, m), 7.79 (1H, s), 7.58-7.42 (4H, m), 6.84 (1H, s), 4.63 (1H, q, J=8Hz), 2.96 (1H, d, J=16Hz), 2.70 (1H, d, J=16Hz), 1.62 (3H, d, J=8Hz)；
　MS (ESI) m/z: 403 (M+H)+。 Compound 47-1:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.50 (1H, s), 10.53 (1H, s), 8.93-8.89 (1H, m), 8.58 (1H, dd, J = 5Hz, 2Hz), 8.09-8.05 (1H, m), 7.79 (1H, s), 7.58-7.42 (4H, m), 6.84 (1H, s), 4.63 (1H, q, J = 8Hz), 2.96 (1H, d, J = 16Hz), 2.70 (1H, d, J = 16Hz), 1.62 (3H, d, J = 8Hz);
MS (ESI) m / z: 403 (M + H) <+> .

　化合物４７－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.50 (1H, s), 10.54 (1H, s), 8.89-8.87 (1H, m), 8.58 (1H, dd, J=5Hz, 2Hz), 8.05 (1H, dt, J=8Hz, 2Hz), 7.67 (1H, s), 7.57 (1H, d, J=8Hz), 7.50 (1H, dd, J=8Hz, 5Hz), 7.43 (1H, t, J=8Hz), 7.31 (1H, d, J=8Hz), 6.88 (1H, s), 4.65 (1H, q, J=7Hz), 2.94 (1H, d, J=16Hz), 2.73 (1H, d, J=16Hz), 1.63 (3H, d, J=7Hz)；
　MS (ESI) m/z: 403 (M+H)+。 Compound 47-2:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.50 (1H, s), 10.54 (1H, s), 8.89-8.87 (1H, m), 8.58 (1H, dd, J = 5Hz, 2Hz), 8.05 (1H, dt, J = 8Hz, 2Hz), 7.67 (1H, s), 7.57 (1H, d, J = 8Hz), 7.50 (1H, dd, J = 8Hz, 5Hz), 7.43 (1H, t, J = 8Hz), 7.31 (1H, d, J = 8Hz), 6.88 (1H, s), 4.65 (1H, q, J = 7Hz), 2.94 (1H, d, J = 16Hz), 2.73 (1H, d , J = 16Hz), 1.63 (3H, d, J = 7Hz);
MS (ESI) m / z: 403 (M + H) <+> .

　（実施例４８）４－ヒドロキシ－３－｛１－［３－（６－メトキシピリジン－３－イル）フェニル］エチル｝－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 48 4-Hydroxy-3- {1- [3- (6-methoxypyridin-3-yl) phenyl] ethyl} -4- (trifluoromethyl) -1,4,5,7-tetrahydro- 6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000159
Figure JPOXMLDOC01-appb-C000159

及び as well as

Figure JPOXMLDOC01-appb-C000160
Figure JPOXMLDOC01-appb-C000160

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例５０にて製造された３－｛１－［３－（６－メトキシピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン（３７６ｍｇ、１．２８ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物４８－１とする）（９８ｍｇ、収率：１７％）、及び、後に溶出する化合物（以下、化合物４８－２とする）（１２３ｍｇ、収率：２２％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, the 3- {1- [3- (6-Methoxypyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine (376 mg, 1.28 mmol) was used to carry out the reaction in the same manner as described in Example 44. Eluting compound (hereinafter referred to as compound 48-1) (98 mg, yield: 17%) and later eluting compound (hereinafter referred to as compound 48-2) (123 mg, yield: 22%) Obtained.

　化合物４８－１：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.49 (1H, s), 10.53 (1H, s), 8.50-8.48 (1H, m), 8.01 (1H, dd, J=9Hz, 2Hz), 7.72 (1H, s), 7.50-7.46 (1H, m), 7.46-7.37 (2H, m), 6.93 (1H, d, J=9Hz), 6.84 (1H, s), 4.62 (1H, q, J=7Hz), 3.90 (3H, s), 2.97 (1H, d, J=17Hz), 2.72 (1H, d, J=17Hz), 1.61 (3H, d, J=7Hz)；
　MS (ESI) m/z: 433 (M+H)+。 Compound 48-1:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.49 (1H, s), 10.53 (1H, s), 8.50-8.48 (1H, m), 8.01 (1H, dd, J = 9Hz, 2Hz), 7.72 (1H, s), 7.50-7.46 (1H, m), 7.46-7.37 (2H, m), 6.93 (1H, d, J = 9Hz), 6.84 (1H, s), 4.62 (1H, q, J = 7Hz), 3.90 (3H, s), 2.97 (1H, d, J = 17Hz), 2.72 (1H, d, J = 17Hz), 1.61 (3H, d, J = 7Hz);
MS (ESI) m / z: 433 (M + H) <+> .

　化合物４８－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.48 (1H, s), 10.54 (1H, s), 8.46 (1H, d, J=2Hz), 7.98 (1H, dd, J=9Hz, 2Hz), 7.59 (1H, s), 7.50 (1H, d, J=8Hz), 7.39 (1H, t, J=8Hz), 7.27 (1H, d, J=8Hz), 6.94 (1H, d, J=9Hz), 6.87 (1H, s), 4.64 (1H, q, J=7Hz), 3.90 (3H, s), 2.94 (1H, d, J=16Hz), 2.74 (1H, d, J=16Hz), 1.63 (3H, d, J=7Hz)；
　MS (ESI) m/z: 433(M+H)+。 Compound 48-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.48 (1H, s), 10.54 (1H, s), 8.46 (1H, d, J = 2Hz), 7.98 (1H, dd, J = 9Hz, 2Hz ), 7.59 (1H, s), 7.50 (1H, d, J = 8Hz), 7.39 (1H, t, J = 8Hz), 7.27 (1H, d, J = 8Hz), 6.94 (1H, d, J = 9Hz), 6.87 (1H, s), 4.64 (1H, q, J = 7Hz), 3.90 (3H, s), 2.94 (1H, d, J = 16Hz), 2.74 (1H, d, J = 16Hz), 1.63 (3H, d, J = 7Hz);
MS (ESI) m / z: 433 (M + H) <+> .

　（実施例４９）３－｛１－［３－（２，６－ジフルオロピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 49 3- {1- [3- (2,6-difluoropyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000161
Figure JPOXMLDOC01-appb-C000161

及び as well as

Figure JPOXMLDOC01-appb-C000162
Figure JPOXMLDOC01-appb-C000162

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例５１にて製造された３－｛１－［３－（２，６－ジフルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン（３７６ｍｇ、１．２８ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出した化合物（以下、化合物４９－１とする）（７４ｍｇ、収率：１８％）、及び、次に溶出した化合物（以下、化合物４９－２とする）（１２３ｍｇ、収率：２３％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, the 3- {1- [3- (2,6-Difluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine (376 mg, 1.28 mmol) was used to carry out the reaction in the same manner as described in Example 44. The previously eluted compound (hereinafter referred to as compound 49-1) (74 mg, yield: 18%) and the next eluted compound (hereinafter referred to as compound 49-2) (123 mg, yield: 23%) ) Respectively.

　化合物４９－１：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.47 (1H, s), 10.53 (1H, s), 8.36-8.27 (1H, m), 7.65 (1H, s), 7.54-7.41 (3H, m), 7.33 (1H, dd, J=8Hz, 2Hz), 6.81 (1H, s), 4.62 (1H, q, J=8Hz), 2.95 (1H, d, J=17Hz), 2.70 (1H, d, J=17Hz), 1.60 (3H, d, J=8Hz)；
　MS (ESI) m/z: 439 (M+H)+。 Compound 49-1:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.47 (1H, s), 10.53 (1H, s), 8.36-8.27 (1H, m), 7.65 (1H, s), 7.54-7.41 (3H, m), 7.33 (1H, dd, J = 8Hz, 2Hz), 6.81 (1H, s), 4.62 (1H, q, J = 8Hz), 2.95 (1H, d, J = 17Hz), 2.70 (1H, d , J = 17Hz), 1.60 (3H, d, J = 8Hz);
MS (ESI) m / z: 439 (M + H) <+> .

　化合物４９－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.46 (1H, s), 10.54 (1H, s), 8.33-8.24 (1H, m), 7.52 (1H, brs), 7.48-7.29 (4H, m), 6.87 (1H, s), 4.64 (1H, q, J=7Hz), 2.94 (1H, d, J=16Hz), 2.73 (1H, d, J=16Hz), 1.62 (3H, d, J=7Hz)；
　MS (ESI) m/z: 439(M+H)+。 Compound 49-2:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.46 (1H, s), 10.54 (1H, s), 8.33-8.24 (1H, m), 7.52 (1H, brs), 7.48-7.29 (4H, m), 6.87 (1H, s), 4.64 (1H, q, J = 7Hz), 2.94 (1H, d, J = 16Hz), 2.73 (1H, d, J = 16Hz), 1.62 (3H, d, J = 7Hz);
MS (ESI) m / z: 439 (M + H) <+> .

　（実施例５０）４－ヒドロキシ－４－（トリフルオロメチル）－３－｛１－［４’－（トリフルオロメチル）ビフェニル－３－イル］エチル｝－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 50 4-Hydroxy-4- (trifluoromethyl) -3- {1- [4 ′-(trifluoromethyl) biphenyl-3-yl] ethyl} -1,4,5,7-tetrahydro- 6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000163
Figure JPOXMLDOC01-appb-C000163

及び as well as

Figure JPOXMLDOC01-appb-C000164
Figure JPOXMLDOC01-appb-C000164

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例５２にて製造された３－｛１－［４’－（トリフルオロメチル）ビフェニル－３－イル］エチル｝－１Ｈ－ピラゾール－５－アミン（３７８ｍｇ、１．１４ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物５０－１とする）（１１０ｍｇ、収率：２３％）、及び、後に溶出する化合物（以下、化合物５０－２とする）（１２５ｍｇ、収率：２７％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, the 3- {1- [4 ′ -(Trifluoromethyl) biphenyl-3-yl] ethyl} -1H-pyrazol-5-amine (378 mg, 1.14 mmol) was used to carry out the reaction in the same manner as described in Example 44. The eluting compound (hereinafter referred to as Compound 50-1) (110 mg, yield: 23%) and the later eluting compound (hereinafter referred to as Compound 50-2) (125 mg, yield: 27%) Obtained.

　化合物５０－１：
　MS (ESI) m/z: 468 (M-H)-。 Compound 50-1:
MS (ESI) m / z: 468 (MH) - .

　化合物５０－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.52 (1H, s), 10.55 (1H, s), 7.87 (2H, d, J=9Hz), 7.84 (2H, d, J=9Hz), 7.67 (1H, brs), 7.58 (1H, d, J=8Hz), 7.45 (1H, t, J=8Hz), 7.35 (1H, d, J=8Hz), 6.88 (1H, s), 4.67 (1H, q, J=7Hz), 2.95 (1H, d, J=17Hz), 2.74 (1H, d, J=17Hz), 1.64 (3H, d, J=7Hz)；
　MS (ESI) m/z: 468 (M-H)-。 Compound 50-2:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.52 (1H, s), 10.55 (1H, s), 7.87 (2H, d, J = 9 Hz), 7.84 (2H, d, J = 9 Hz), 7.67 (1H, brs), 7.58 (1H, d, J = 8Hz), 7.45 (1H, t, J = 8Hz), 7.35 (1H, d, J = 8Hz), 6.88 (1H, s), 4.67 (1H , q, J = 7Hz), 2.95 (1H, d, J = 17Hz), 2.74 (1H, d, J = 17Hz), 1.64 (3H, d, J = 7Hz);
MS (ESI) m / z: 468 (MH) - .

　（実施例５１）３－｛１－［３－（２－トリフルオロ－６－メトキシピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 51 3- {1- [3- (2-trifluoro-6-methoxypyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5 , 7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-C000165

及び as well as

Figure JPOXMLDOC01-appb-C000166
Figure JPOXMLDOC01-appb-C000166

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例５３にて製造された３－｛１－［３－（２－フルオロ－６－メトキシピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン（１９４ｍｇ、０．６２ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物５１－１とする）（４４ｍｇ、収率：１６％）、及び、後に溶出する化合物（以下、化合物５１－２とする）（４３ｍｇ、収率：１５％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, the 3- {1- [3- (2-Fluoro-6-methoxypyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine (194 mg, 0.62 mmol) was used to react in the same manner as described in Example 44. The compound eluting first (hereinafter referred to as compound 51-1) (44 mg, yield: 16%) and the compound eluting later (hereinafter referred to as compound 51-2) (43 mg, yield: 15) %) Respectively.

　化合物５１－１：
　MS (ESI) m/z: 451 (M＋H)+。 Compound 51-1:
MS (ESI) m / z: 451 (M + H) <+> .

　化合物５１－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.44 (1H, s), 10.53 (1H, s), 7.99 (1H, dd, J=10Hz, 8Hz), 7.46 (1H, brs), 7.42-7.37 (2H, m), 7.34-7.28 (1H, m), 6.91 (1H, dd, J=8Hz, 1Hz), 6.85 (1H, s), 4.62 (1H, q, J=7Hz), 3.88 (3H, s), 2.93 (1H, d, J=16Hz), 2.72 (1H, d, J=16Hz), 1.61 (3H, d, J=7Hz)；
　MS (ESI) m/z: 451 (M＋H)+。 Compound 51-2:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.44 (1H, s), 10.53 (1H, s), 7.99 (1H, dd, J = 10Hz, 8Hz), 7.46 (1H, brs), 7.42- 7.37 (2H, m), 7.34-7.28 (1H, m), 6.91 (1H, dd, J = 8Hz, 1Hz), 6.85 (1H, s), 4.62 (1H, q, J = 7Hz), 3.88 (3H , s), 2.93 (1H, d, J = 16Hz), 2.72 (1H, d, J = 16Hz), 1.61 (3H, d, J = 7Hz);
MS (ESI) m / z: 451 (M + H) <+> .

　（実施例５２）３－｛１－［３－（６－トリフルオロ－２－メチルピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 52 3- {1- [3- (6-Trifluoro-2-methylpyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5 , 7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000167
Figure JPOXMLDOC01-appb-C000167

及び as well as

Figure JPOXMLDOC01-appb-C000168
Figure JPOXMLDOC01-appb-C000168

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例５４にて製造された３－｛１－［３－（６－フルオロ－２－メチルピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン（３４９ｍｇ、１．１８ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物５２－１とする）（９６ｍｇ、収率：１９％）、及び、後に溶出する化合物（以下、化合物５２－２とする）（１０８ｍｇ、収率：２１％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, the 3- {1- [3- (6-Fluoro-2-methylpyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine (349 mg, 1.18 mmol) was used to react in the same manner as described in Example 44. The compound eluting first (hereinafter referred to as compound 52-1) (96 mg, yield: 19%) and the compound eluting later (hereinafter referred to as compound 52-2) (108 mg, yield: 21) %) Respectively.

　化合物５２－１：
　MS (ESI) m/z: 435 (M＋H)+。 Compound 52-1:
MS (ESI) m / z: 435 (M + H) <+> .

　化合物５２－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.45 (1H, s), 10.53 (1H, s), 7.78 (1H, t, J=8Hz), 7.41 (1H, t, J=8Hz), 7.33-7.21 (3H, m), 7.08 (1H, dd, J=8Hz, 3Hz), 6.84 (1H, s), 4.63 (1H, q, J=7Hz), 2.93 (1H, d, J=16Hz), 2.72 (1H, d, J=16Hz), 2.33 (3H, s), 1.61 (3H, d, J=7Hz)；
　MS (ESI) m/z: 435 (M＋H)+。 Compound 52-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.45 (1H, s), 10.53 (1H, s), 7.78 (1H, t, J = 8Hz), 7.41 (1H, t, J = 8Hz), 7.33-7.21 (3H, m), 7.08 (1H, dd, J = 8Hz, 3Hz), 6.84 (1H, s), 4.63 (1H, q, J = 7Hz), 2.93 (1H, d, J = 16Hz) , 2.72 (1H, d, J = 16Hz), 2.33 (3H, s), 1.61 (3H, d, J = 7Hz);
MS (ESI) m / z: 435 (M + H) <+> .

　（実施例５３）３－｛１－［３－（５－フルオロピリジン－２－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 53 3- {1- [3- (5-Fluoropyridin-2-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro- 6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000169
Figure JPOXMLDOC01-appb-C000169

及び as well as

Figure JPOXMLDOC01-appb-C000170
Figure JPOXMLDOC01-appb-C000170

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例５７にて製造された３－｛１－［３－（５－フルオロピリジン－２－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン（７３ｍｇ、０．２６ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物５３－１とする）（１４ｍｇ、収率：１３％）、及び、後に溶出する化合物（以下、化合物５３－２とする）（１９ｍｇ、収率：１７％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, the 3- {1- [3- Using (5-fluoropyridin-2-yl) phenyl] ethyl} -1H-pyrazol-5-amine (73 mg, 0.26 mmol), the reaction was carried out in the same manner as described in Example 44. The eluting compound (hereinafter referred to as Compound 53-1) (14 mg, yield: 13%) and the later eluting compound (hereinafter referred to as Compound 53-2) (19 mg, yield: 17%) Obtained.

　化合物５３－１：
　MS (ESI) m/z: 421 (M＋H)+。 Compound 53-1.
MS (ESI) m / z: 421 (M + H) <+> .

　化合物５３－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.52 (1H, s), 10.53 (1H, s), 8.66 (1H, d, J=3Hz), 8.01 (1H, dd, J=9Hz, 4Hz), 7.97 (1H, s), 7.89-7.81 (2H, m), 7.41 (1H, t, J=8Hz), 7.32 (1H, d, J=8Hz), 6.85 (1H, s), 4.66 (1H, q, J=7Hz), 2.93 (1H, d, J=16Hz), 2.72 (1H, d, J=16Hz), 1.62 (3H, d, J=7Hz)；
　MS (ESI) m/z: 421 (M＋H)+。 Compound 53-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.52 (1H, s), 10.53 (1H, s), 8.66 (1H, d, J = 3Hz), 8.01 (1H, dd, J = 9Hz, 4Hz ), 7.97 (1H, s), 7.89-7.81 (2H, m), 7.41 (1H, t, J = 8Hz), 7.32 (1H, d, J = 8Hz), 6.85 (1H, s), 4.66 (1H , q, J = 7Hz), 2.93 (1H, d, J = 16Hz), 2.72 (1H, d, J = 16Hz), 1.62 (3H, d, J = 7Hz);
MS (ESI) m / z: 421 (M + H) <+> .

　（実施例５４）４－ヒドロキシ－３－｛１－［３－（２－メトキシピリミジン－５－イル）フェニル］エチル｝－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 54 4-Hydroxy-3- {1- [3- (2-methoxypyrimidin-5-yl) phenyl] ethyl} -4- (trifluoromethyl) -1,4,5,7-tetrahydro- 6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000171
Figure JPOXMLDOC01-appb-C000171

及び as well as

Figure JPOXMLDOC01-appb-C000172
Figure JPOXMLDOC01-appb-C000172

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例５８にて製造された３－｛１－［３－（２－メトキシピリミジン－５－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン（１８４ｍｇ、０．６２ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物５４－１とする）（４７ｍｇ、収率：１７％）、及び、後に溶出する化合物（以下、化合物５４－２とする）（５３ｍｇ、収率：２０％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, the 3- {1- [3- (2-Methoxypyrimidin-5-yl) phenyl] ethyl} -1H-pyrazol-5-amine (184 mg, 0.62 mmol) was used to carry out the reaction in the same manner as described in Example 44. Eluting compound (hereinafter referred to as compound 54-1) (47 mg, yield: 17%) and later eluting compound (hereinafter referred to as compound 54-2) (53 mg, yield: 20%) Obtained.

　化合物５４－１：
　MS (ESI) m/z: 434 (M+H)+。 Compound 54-1:
MS (ESI) m / z: 434 (M + H) <+> .

　化合物５４－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.47 (1H, s), 10.53 (1H, s), 8.92 (2H, s), 7.70 (1H, s), 7.57 (1H, d, J=8Hz), 7.42 (1H, t, J=8Hz), 7.27 (1H, d, J=8Hz), 6.87 (1H, s), 4.64 (1H, q, J=7Hz), 3.97 (3H, s), 2.94 (1H, d, J=17Hz), 2.73 (1H, d, J=17Hz), 1.62 (3H, d, J=7Hz)；
　MS (ESI) m/z: 434 (M+H)+。 Compound 54-2:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.47 (1H, s), 10.53 (1H, s), 8.92 (2H, s), 7.70 (1H, s), 7.57 (1H, d, J = 8Hz), 7.42 (1H, t, J = 8Hz), 7.27 (1H, d, J = 8Hz), 6.87 (1H, s), 4.64 (1H, q, J = 7Hz), 3.97 (3H, s), 2.94 (1H, d, J = 17Hz), 2.73 (1H, d, J = 17Hz), 1.62 (3H, d, J = 7Hz);
MS (ESI) m / z: 434 (M + H) <+> .

　（実施例５５）４－ヒドロキシ－３－｛１－［３－（２－イソプロポキシピリミジン－５－イル）フェニル］エチル｝－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 55 4-Hydroxy-3- {1- [3- (2-isopropoxypyrimidin-5-yl) phenyl] ethyl} -4- (trifluoromethyl) -1,4,5,7-tetrahydro -6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000173
Figure JPOXMLDOC01-appb-C000173

及び as well as

Figure JPOXMLDOC01-appb-C000174
Figure JPOXMLDOC01-appb-C000174

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例５９にて製造された３－｛１－［３－（２－イソプロポキシピリミジン－５－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミン（２７３ｍｇ、０．８４ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物５５－１とする）（６５ｍｇ、収率：１７％）、及び、後に溶出する化合物（以下、化合物５５－２とする）（７８ｍｇ、収率：２０％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, the 3- {1- [3- (2-Isopropoxypyrimidin-5-yl) phenyl] ethyl} -1H-pyrazol-5-amine (273 mg, 0.84 mmol) was used to carry out the reaction in the same manner as described in Example 44. (65 mg, yield: 17%) eluting into the compound (hereinafter referred to as compound 55-2) (78 mg, yield: 20%) I got each.

　化合物５５－１：
　MS (ESI) m/z: 462 (M+H)+。 Compound 55-1:
MS (ESI) m / z: 462 (M + H) <+> .

　化合物５５－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.47 (1H, s), 10.53 (1H, s), 8.90 (2H, s), 7.70 (1H, s), 7.56 (1H, d, J=8Hz), 7.41 (1H, t, J=8Hz), 7.26 (1H, d, J=8Hz), 6.87 (1H, s), 5.30-5.21 (1H, m), 4.64 (1H, q, J=7Hz), 2.94 (1H, d, J=16Hz), 2.73 (1H, d, J=16Hz), 1.62 (3H, d, J=7Hz), 1.35 (6H, d, J=6Hz)；
　MS (ESI) m/z: 462 (M+H)+。 Compound 55-2:
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.47 (1H, s), 10.53 (1H, s), 8.90 (2H, s), 7.70 (1H, s), 7.56 (1H, d, J = 8Hz), 7.41 (1H, t, J = 8Hz), 7.26 (1H, d, J = 8Hz), 6.87 (1H, s), 5.30-5.21 (1H, m), 4.64 (1H, q, J = 7Hz ), 2.94 (1H, d, J = 16Hz), 2.73 (1H, d, J = 16Hz), 1.62 (3H, d, J = 7Hz), 1.35 (6H, d, J = 6Hz);
MS (ESI) m / z: 462 (M + H) <+> .

　（実施例５６）４－ヒドロキシ－４－（トリフルオロメチル）－３－（１－｛３－［５－（トリフルオロメチル）ピラジン－２－イル］フェニル｝エチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 56 4-Hydroxy-4- (trifluoromethyl) -3- (1- {3- [5- (trifluoromethyl) pyrazin-2-yl] phenyl} ethyl) -1,4,5 7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000175
Figure JPOXMLDOC01-appb-C000175

及び as well as

Figure JPOXMLDOC01-appb-C000176
Figure JPOXMLDOC01-appb-C000176

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例６０にて製造された３－（１－｛３－［５－（トリフルオロメチル）ピラジン－２－イル］フェニル｝エチル）－１Ｈ－ピラゾール－５－アミン（２３４ｍｇ、０．７０ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物５６－１とする）（５９ｍｇ、収率：１８％）、及び、後に溶出する化合物（以下、化合物５６－２とする）（６５ｍｇ、収率：２０％）を得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, 3- (1- {3- [5- (Trifluoromethyl) pyrazin-2-yl] phenyl} ethyl) -1H-pyrazol-5-amine (234 mg, 0.70 mmol) was used in the same manner as described in Example 44. The compound eluting first (hereinafter referred to as compound 56-1) (59 mg, yield: 18%) and the compound eluting later (hereinafter referred to as compound 56-2) (65 mg, yield: 20) %).

　化合物５６－１：
　MS (ESI) m/z: 472 (M+H)+。 Compound 56-1:
MS (ESI) m / z: 472 (M + H) <+> .

　化合物５６－２：
　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.55 (1H, s), 10.55 (1H, s), 9.46 (1H, d, J=1Hz), 9.25 (1H, d, J=1Hz), 8.18 (1H, s), 8.08 (1H, d, J=8Hz), 7.53 (1H, t, J=8Hz), 7.46 (1H, d, J=8Hz), 6.88 (1H, s), 4.70 (1H, q, J=7Hz), 2.94 (1H, d, J=16Hz), 2.72 (1H, d, J=16Hz), 1.65 (3H, d, J=7Hz)；
　MS (ESI) m/z: 472 (M+H)+。 Compound 56-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.55 (1H, s), 10.55 (1H, s), 9.46 (1H, d, J = 1Hz), 9.25 (1H, d, J = 1Hz), 8.18 (1H, s), 8.08 (1H, d, J = 8Hz), 7.53 (1H, t, J = 8Hz), 7.46 (1H, d, J = 8Hz), 6.88 (1H, s), 4.70 (1H , q, J = 7Hz), 2.94 (1H, d, J = 16Hz), 2.72 (1H, d, J = 16Hz), 1.65 (3H, d, J = 7Hz);
MS (ESI) m / z: 472 (M + H) <+> .

　（実施例５７）４－ヒドロキシ－４－（トリフルオロメチル）－３－（１－｛３－［５－（トリフルオロメチル）ピリジン－２－イル］フェニル｝エチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 57 4-Hydroxy-4- (trifluoromethyl) -3- (1- {3- [5- (trifluoromethyl) pyridin-2-yl] phenyl} ethyl) -1,4,5 7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000177
Figure JPOXMLDOC01-appb-C000177

及び as well as

Figure JPOXMLDOC01-appb-C000178
Figure JPOXMLDOC01-appb-C000178

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例６１にて製造された３－（１－｛３－［５－（トリフルオロメチル）ピリジン－２－イル］フェニル｝エチル）－１Ｈ－ピラゾール－５－アミン（３８３ｍｇ、１．１５ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物５７－１とする）（９４ｍｇ、収率：１７％）、及び、後に溶出する化合物（以下、化合物５７－２とする）（１０１ｍｇ、収率：１９％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, 3- (1- {3- [5- (Trifluoromethyl) pyridin-2-yl] phenyl} ethyl) -1H-pyrazol-5-amine (383 mg, 1.15 mmol) was used to react in the same manner as described in Example 44. The compound eluting first (hereinafter referred to as compound 57-1) (94 mg, yield: 17%) and the compound eluting later (hereinafter referred to as compound 57-2) (101 mg, yield: 19) %) Respectively.

　化合物５７－１：
　MS (ESI) m/z: 471 (M+H)+。 Compound 57-1:
MS (ESI) m / z: 471 (M + H) <+> .

　化合物５７－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.54 (1H, s), 10.54 (1H, s), 9.05 (1H, s), 8.31 (1H, dd, J=9Hz, 2Hz), 8.17 (1H, d, J=9Hz), 8.09 (1H, s), 7.99 (1H, d, J=8Hz), 7.50-7.39 (2H, m), 6.87 (1H, s), 4.68 (1H, q, J=7Hz), 2.94 (1H, d, J=16Hz), 2.72 (1H, d, J=16Hz), 1.63 (3H, d, J=7Hz)；
　MS (ESI) m/z: 471 (M+H)+。 Compound 57-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.54 (1H, s), 10.54 (1H, s), 9.05 (1H, s), 8.31 (1H, dd, J = 9Hz, 2Hz), 8.17 ( 1H, d, J = 9Hz), 8.09 (1H, s), 7.99 (1H, d, J = 8Hz), 7.50-7.39 (2H, m), 6.87 (1H, s), 4.68 (1H, q, J = 7Hz), 2.94 (1H, d, J = 16Hz), 2.72 (1H, d, J = 16Hz), 1.63 (3H, d, J = 7Hz);
MS (ESI) m / z: 471 (M + H) <+> .

　（実施例５８）４－ヒドロキシ－４－（トリフルオロメチル）－３－（１－｛３－［６－（トリフルオロメチル）ピリジン－２－イル］フェニル｝エチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、そのジアステレオマー Example 58 4-Hydroxy-4- (trifluoromethyl) -3- (1- {3- [6- (trifluoromethyl) pyridin-2-yl] phenyl} ethyl) -1,4,5 7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

Figure JPOXMLDOC01-appb-C000179
Figure JPOXMLDOC01-appb-C000179

及び as well as

Figure JPOXMLDOC01-appb-C000180
Figure JPOXMLDOC01-appb-C000180

　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－１Ｈ－ピラゾール－５－アミンの代わりに、参考例６２にて製造された３－（１－｛３－［６－（トリフルオロメチル）ピリジン－２－イル］フェニル｝エチル）－１Ｈ－ピラゾール－５－アミン（３６０ｍｇ、１．０８ｍｍｏｌ）を用いて、実施例４４に記載された方法と同様に反応を行い、先に溶出する化合物（以下、化合物５８－１とする）（９５ｍｇ、収率：１９％）、及び、後に溶出する化合物（以下、化合物５８－２とする）（１０４ｍｇ、収率：２０％）をそれぞれ得た。 Instead of 3- {1- [3- (6-fluoropyridin-3-yl) phenyl] ethyl} -1H-pyrazol-5-amine, 3- (1- {3- [6- (Trifluoromethyl) pyridin-2-yl] phenyl} ethyl) -1H-pyrazol-5-amine (360 mg, 1.08 mmol) was used to react in the same manner as described in Example 44. The compound eluting first (hereinafter referred to as compound 58-1) (95 mg, yield: 19%) and the compound eluting later (hereinafter referred to as compound 58-2) (104 mg, yield: 20) %) Respectively.

　化合物５８－１：
　MS (ESI) m/z: 471 (M+H)+。 Compound 58-1:
MS (ESI) m / z: 471 (M + H) <+> .

　化合物５８－２：
　1H-NMR (400MHz, DMSO-d6) δ: 12.48 (1H, s), 10.53 (1H, s), 8.27-8.17 (2H, m), 8.04 (1H, s), 7.96 (1H, d, J=7Hz), 7.86 (1H, d, J=7Hz), 7.51-7.46 (1H, m), 7.43-7.39 (1H, m), 6.89 (1H, s), 4.68 (1H, q, J=7Hz), 2.94 (1H, d, J=17Hz), 2.73 (1H, d, J=16Hz), 1.64 (3H, d, J=7Hz)；
　MS (ESI) m/z: 471 (M+H)+。 Compound 58-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.48 (1H, s), 10.53 (1H, s), 8.27-8.17 (2H, m), 8.04 (1H, s), 7.96 (1H, d, J = 7Hz), 7.86 (1H, d, J = 7Hz), 7.51-7.46 (1H, m), 7.43-7.39 (1H, m), 6.89 (1H, s), 4.68 (1H, q, J = 7Hz ), 2.94 (1H, d, J = 17Hz), 2.73 (1H, d, J = 16Hz), 1.64 (3H, d, J = 7Hz);
MS (ESI) m / z: 471 (M + H) <+> .

　（実施例５９）４－ヒドロキシ－３－［１－（１－フェニル－１Ｈ－ピラゾール－４－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 59 4-Hydroxy-3- [1- (1-phenyl-1H-pyrazol-4-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one

Figure JPOXMLDOC01-appb-C000181
Figure JPOXMLDOC01-appb-C000181

　３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例６４にて製造された３－［１－（１－フェニル－１Ｈ－ピラゾール－４－イル）エチル］－１Ｈ－ピラゾール－５－アミン（１．０７ｇ、４．２２ｍｍｏｌ）を用いて、実施例１に記載された方法と同様に反応を行い、標記化合物（５５８ｍｇ、収率：３４％）を得た。 Instead of 3- (biphenyl-4-ylmethyl) -1H-pyrazol-5-amine, 3- [1- (1-phenyl-1H-pyrazol-4-yl) ethyl]-prepared in Reference Example 64 The reaction was carried out in the same manner as described in Example 1 using 1H-pyrazol-5-amine (1.07 g, 4.22 mmol) to obtain the title compound (558 mg, yield: 34%).

　1H-NMR (400MHz, DMSO-d6) δ: 12.34 (1/2H, s), 12.31 (1/2H, s), 10.53 (1H, s), 8.31 (1/2H, s), 8.28 (1/2H, s), 7.80-7.73 (2H, m), 7.65-7.45 (3H, m), 7.31-7.25 (1H, m), 6.84 (1/2H, s), 6.77 (1/2H, s), 4.57-4.48 (1H, m), 3.01-2.91 (1H, m), 2.78-2.70 (1H, m), 1.60-1.55 (3H, m)；
　MS (ESI) m/z: 392 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.34 (1 / 2H, s), 12.31 (1 / 2H, s), 10.53 (1H, s), 8.31 (1 / 2H, s), 8.28 ( 1 / 2H, s), 7.80-7.73 (2H, m), 7.65-7.45 (3H, m), 7.31-7.25 (1H, m), 6.84 (1 / 2H, s), 6.77 (1 / 2H, s ), 4.57-4.48 (1H, m), 3.01-2.91 (1H, m), 2.78-2.70 (1H, m), 1.60-1.55 (3H, m);
MS (ESI) m / z: 392 (M + H) <+> .

　（実施例６０）４－ヒドロキシ－３－［１－（２－フェニル－１、３－チアゾール－４－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 60 4-Hydroxy-3- [1- (2-phenyl-1,3-thiazol-4-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro- 6H-pyrazolo [3,4-b] pyridin-6-one

Figure JPOXMLDOC01-appb-C000182
Figure JPOXMLDOC01-appb-C000182

　３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例６６にて製造された３－［１－（２－フェニル－１，３－チアゾール－４－イル）エチル］－１Ｈ－ピラゾール－５－アミン（１．７４ｇ、６．４４ｍｍｏｌ）を用いて、実施例１に記載された方法と同様に反応を行い、標記化合物（１．１４ｇ、収率：４３％）を得た。 3- [1- (2-Phenyl-1,3-thiazol-4-yl) ethyl prepared in Reference Example 66 instead of 3- (biphenyl-4-ylmethyl) -1H-pyrazol-5-amine ] -1H-pyrazol-5-amine (1.74 g, 6.44 mmol) was used in the same manner as described in Example 1 to give the title compound (1.14 g, yield: 43%). Got.

　1H-NMR (400MHz, DMSO-d6) δ: 12.46 (2/5H, s), 12.37 (3/5H, s), 10.56 (2/5H, s), 10.54 (3/5H, s), 7.99-7.93 (2H, m), 7.54-7.44 (3H, m), 7.35 (2/5H, d, J=1Hz), 7.22 (3/5H, s), 7.18 (2/5H, s), 6.91 (3/5H, s), 4.76-4.67 (1H, m), 3.01-2.90 (1H, m), 2.77-2.70 (1H, m), 1.68-1.63 (3H, m)；
　MS (ESI) m/z: 409 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.46 (2 / 5H, s), 12.37 (3 / 5H, s), 10.56 (2 / 5H, s), 10.54 (3 / 5H, s), 7.99-7.93 (2H, m), 7.54-7.44 (3H, m), 7.35 (2 / 5H, d, J = 1Hz), 7.22 (3 / 5H, s), 7.18 (2 / 5H, s), 6.91 (3 / 5H, s), 4.76-4.67 (1H, m), 3.01-2.90 (1H, m), 2.77-2.70 (1H, m), 1.68-1.63 (3H, m);
MS (ESI) m / z: 409 (M + H) <+> .

　（実施例６１）４－ヒドロキシ－３－［１－（６－フェニルピリジン－２－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 61 4-Hydroxy-3- [1- (6-phenylpyridin-2-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] Pyridin-6-one

Figure JPOXMLDOC01-appb-C000183
Figure JPOXMLDOC01-appb-C000183

　３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例６８にて製造された３－［１－（６－フェニルピリジン－２－イル）エチル］－１Ｈ－ピラゾール－５－アミン（９８５ｍｇ、３．７３ｍｍｏｌ）を用いて、実施例１に記載された方法と同様に反応を行い、標記化合物（６３０ｍｇ、収率：４２％）を得た。 3- [1- (6-Phenylpyridin-2-yl) ethyl] -1H-pyrazole prepared in Reference Example 68 instead of 3- (biphenyl-4-ylmethyl) -1H-pyrazol-5-amine The reaction was carried out in the same manner as described in Example 1 using -5-amine (985 mg, 3.73 mmol) to obtain the title compound (630 mg, yield: 42%).

　1H-NMR (400MHz, DMSO-d6) δ: 12.43 (2/5H, s), 12.41 (3/5H, s), 10.53 (1H, s), 8.18-8.12 (2H, m), 7.84-7.77 (2H, m), 7.53-7.41 (3H, m), 7.27 (2/5H, dd, J=7Hz, 2Hz), 7.10 (3/5H, dd, J=5Hz, 4Hz), 6.95 (2/5H, s), 6.91 (3/5H, s), 4.77-4.68 (1H, m), 2.93 (1H, d, J=16Hz), 2.75-2.66 (1H, m), 1.67 (3H, d, J=7Hz)；
　MS (ESI) m/z: 403 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.43 (2 / 5H, s), 12.41 (3 / 5H, s), 10.53 (1H, s), 8.18-8.12 (2H, m), 7.84- 7.77 (2H, m), 7.53-7.41 (3H, m), 7.27 (2 / 5H, dd, J = 7Hz, 2Hz), 7.10 (3 / 5H, dd, J = 5Hz, 4Hz), 6.95 (2 / 5H, s), 6.91 (3 / 5H, s), 4.77-4.68 (1H, m), 2.93 (1H, d, J = 16Hz), 2.75-2.66 (1H, m), 1.67 (3H, d, J = 7Hz);
MS (ESI) m / z: 403 (M + H) <+> .

　（実施例６２）４－ヒドロキシ－４－（トリフルオロメチル）－３－（｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル｝メチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン Example 62 4-Hydroxy-4- (trifluoromethyl) -3-({1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} methyl) -1,4 5,7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

Figure JPOXMLDOC01-appb-C000184
Figure JPOXMLDOC01-appb-C000184

　３－（ビフェニル－４－イルメチル）－１Ｈ－ピラゾール－５－アミンの代わりに、参考例７０にて製造された４－（｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル｝メチル－１Ｈ－ピラゾール－５－アミン（１．０１ｇ、３．１０ｍｍｏｌ）を用いて、実施例１に記載された方法と同様に反応を行い、標記化合物（７６６ｍｇ、収率：５４％）を得た。 4-({1- [5- (trifluoromethyl) pyridin-2-yl] piperidine produced in Reference Example 70 instead of 3- (biphenyl-4-ylmethyl) -1H-pyrazol-5-amine The reaction was carried out in the same manner as described in Example 1 using -3-yl} methyl-1H-pyrazol-5-amine (1.01 g, 3.10 mmol), and the title compound (766 mg, yield: 54%).

　1H-NMR (400MHz, DMSO-d6) δ: 12.24 (1H, s), 10.52 (1H, s), 8.40-8.36 (1H, m), 7.79-7.72 (1H, m), 6.87 (1H, t, J=9Hz), 6.67 (1H, s), 4.38-4.25 (2H, m), 2.98-2.85 (2H, m), 2.76-2.60 (4H, m), 2.02-1.90 (1H, m), 1.81-1.67 (2H, m), 1.45-1.16 (2H, m)；
　MS (ESI) m/z: 464 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.24 (1H, s), 10.52 (1H, s), 8.40-8.36 (1H, m), 7.79-7.72 (1H, m), 6.87 (1H, t, J = 9Hz), 6.67 (1H, s), 4.38-4.25 (2H, m), 2.98-2.85 (2H, m), 2.76-2.60 (4H, m), 2.02-1.90 (1H, m), 1.81-1.67 (2H, m), 1.45-1.16 (2H, m);
MS (ESI) m / z: 464 (M + H) <+> .

　（実施例６３） (Example 63)

Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000185

　参考例７１にて製造された化合物Ａ－１（２３０ｍｇ、０．５５ｍｍｏｌ）のジオキサン（３ｍＬ）溶液に、４Ｎ塩酸－ジオキサン溶液（１ｍＬ）を加え、４０℃にて２時間攪拌した。反応液を減圧下濃縮し、得られた残渣のＤＭＳＯ（２ｍＬ）溶液に、２－フルオロ－５－（トリフルオロメチル）ピリジン（８６μＬ、０．７１ｍｏｌ）、及び、ジイソプロピルエチルアミン（２８０μＬ、１．６５ｍｏｌ）を加え、５０℃にて２時間攪拌した。反応液に酢酸エチルを加え、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［ＮＨ－シリカゲル、溶出溶媒：酢酸エチル／メタノール＝１００／０－９５／０５（グラジェント）］で精製し、目的化合物（８７ｍｇ、収率：３４％）を得た。 4N Hydrochloric acid-dioxane solution (1 mL) was added to a dioxane (3 mL) solution of compound A-1 (230 mg, 0.55 mmol) produced in Reference Example 71, and the mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the obtained residue in DMSO (2 mL) was added to 2-fluoro-5- (trifluoromethyl) pyridine (86 μL, 0.71 mol) and diisopropylethylamine (280 μL, 1.65 mol). ) And stirred at 50 ° C. for 2 hours. Ethyl acetate was added to the reaction solution, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-95 / 05 (gradient)] to obtain the target compound (87 mg, yield: 34%). Obtained.

　1H-NMR (400MHz, DMSO-d6) δ: 12.24 (1H, s), 10.52 (1H, s), 8.40-8.36 (1H, m), 7.76 (1H, dd, J=9Hz, 3Hz), 6.86 (1H, d, J=9Hz), 6.68 (1H, s), 4.29 (2H, d, J=13Hz), 2.98-2.85 (2H, m), 2.76-2.58 (4H, m), 2.03-1.90 (1H, m), 1.81-1.67 (2H, m), 1.46-1.20 (2H, m)；
　MS (ESI) m/z: 464 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.24 (1H, s), 10.52 (1H, s), 8.40-8.36 (1H, m), 7.76 (1H, dd, J = 9Hz, 3Hz), 6.86 (1H, d, J = 9Hz), 6.68 (1H, s), 4.29 (2H, d, J = 13Hz), 2.98-2.85 (2H, m), 2.76-2.58 (4H, m), 2.03-1.90 (1H, m), 1.81-1.67 (2H, m), 1.46-1.20 (2H, m);
MS (ESI) m / z: 464 (M + H) <+> .

　（実施例６４） (Example 64)

Figure JPOXMLDOC01-appb-C000186
Figure JPOXMLDOC01-appb-C000186

　化合物Ａ－１の代わりに、参考例７２にて製造された化合物Ｂ－１（１４０ｍｇ、０．３３ｍｍｏｌ）を用いて、実施例６３に記載された方法と同様に反応を行い、目的化合物（１７ｍｇ、収率：１１％）を得た。 Using the compound B-1 (140 mg, 0.33 mmol) prepared in Reference Example 72 instead of the compound A-1, the reaction was carried out in the same manner as described in Example 63, and the target compound (17 mg Yield: 11%).

　1H-NMR (400MHz, DMSO-d6) δ: 12.24 (1H, s), 10.52 (1H, s), 8.40-8.37 (1H, m), 7.76 (1H, dd, J=9Hz, 3Hz), 6.88 (1H, d, J=9Hz), 6.67 (1H, s), 4.33 (2H, d, J=13Hz), 2.97-2.84 (2H, m), 2.76-2.65 (3H, m), 2.58-2.49 (1H, m), 2.02-1.90 (1H, m), 1.75-1.66 (2H, m), 1.44-1.14 (2H, m)；
　MS (ESI) m/z: 464 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.24 (1H, s), 10.52 (1H, s), 8.40-8.37 (1H, m), 7.76 (1H, dd, J = 9Hz, 3Hz), 6.88 (1H, d, J = 9Hz), 6.67 (1H, s), 4.33 (2H, d, J = 13Hz), 2.97-2.84 (2H, m), 2.76-2.65 (3H, m), 2.58-2.49 (1H, m), 2.02-1.90 (1H, m), 1.75-1.66 (2H, m), 1.44-1.14 (2H, m);
MS (ESI) m / z: 464 (M + H) <+> .

　（実施例６５） (Example 65)

Figure JPOXMLDOC01-appb-C000187
Figure JPOXMLDOC01-appb-C000187

　参考例７４にて製造された化合物（９４ｍｇ、０．２１ｍｍｏｌ）のＤＭＳＯ（２ｍＬ）溶液に、２－フルオロ－５－（トリフルオロメチル）ピリジン（３０．４μＬ、０．２５ｍｍｏｌ）、ジイソプロピルエチルアミン（１０７μＬ、０．６３ｍｍｏｌ）を加え、混合溶液を室温にて終夜放置した。反応液に酢酸エチルを加え、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン／酢酸エチル＝７５／２５－０／１００（グラジェント）］で精製し、目的化合物（７８ｍｇ、収率：７８％）を得た。 To a solution of the compound prepared in Reference Example 74 (94 mg, 0.21 mmol) in DMSO (2 mL) was added 2-fluoro-5- (trifluoromethyl) pyridine (30.4 μL, 0.25 mmol), diisopropylethylamine (107 μL). , 0.63 mmol) was added and the mixture was left at room temperature overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 75 / 25-0 / 100 (gradient)] to obtain the desired compound (78 mg, yield: 78%).

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.26 (1H, s), 10.54 (1H, s), 8.37-8.33 (1H, m), 7.75 (1H, dd, J=9Hz, 3Hz), 6.68 (1H, s), 6.63 (1H, d, J=9Hz), 4.37 (1H, d, J=13Hz), 4.04 (1H, d, J=13Hz), 3.01-2.68 (4H, m), 2.51-2.44 (1H, m), 2.07 (1H, d, J=13Hz), 1.91-1.73 (2H, m), 1.42-1.37 (1H, m), 1.29-1.23 (1H, m), 1.18 (3H, d, J=7Hz)；
　MS (ESI) m/z: 478 (M+H)+。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.26 (1H, s), 10.54 (1H, s), 8.37-8.33 (1H, m), 7.75 (1H, dd, J = 9Hz, 3Hz), 6.68 (1H, s), 6.63 (1H, d, J = 9Hz), 4.37 (1H, d, J = 13Hz), 4.04 (1H, d, J = 13Hz), 3.01-2.68 (4H, m), 2.51 -2.44 (1H, m), 2.07 (1H, d, J = 13Hz), 1.91-1.73 (2H, m), 1.42-1.37 (1H, m), 1.29-1.23 (1H, m), 1.18 (3H, d, J = 7Hz);
MS (ESI) m / z: 478 (M + H) <+> .

　（実施例６６） (Example 66)

Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000188

　２－フルオロ－５－（トリフルオロメチル）ピリジンの代わりに、２－クロロ－５－（トリフルオロメチル）ピラジン（２７．９μＬ、０．２３ｍｍｏｌ）を用いて、実施例６５に記載された方法と同様に反応を行い、目的化合物（７６ｍｇ、収率：８４％）を得た。 Using the method described in Example 65 using 2-chloro-5- (trifluoromethyl) pyrazine (27.9 μL, 0.23 mmol) instead of 2-fluoro-5- (trifluoromethyl) pyridine. The reaction was performed in the same manner to obtain the target compound (76 mg, yield: 84%).

　1H-NMR (400MHz, DMSO-ｄ6) δ: 12.28 (1H, s), 10.55 (1H, s), 8.44 (1H, s), 8.14 (1H, s), 6.69 (1H, s), 4.39 (1H, d, J=12Hz), 4.10 (1H, d, J=12Hz), 3.03-2.88 (3H, m), 2.72 (1H, d, J=16Hz), 2.62-2.51 (1H, m), 2.13-2.02 (1H, m), 1.95-1.74 (2H, m), 1.53-1.36 (1H, m), 1.35-1.21 (1H, m), 1.19 (3H, d, J=7Hz)；
　MS (ESI) m/z: 479 (M+H)+。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.28 (1H, s), 10.55 (1H, s), 8.44 (1H, s), 8.14 (1H, s), 6.69 (1H, s), 4.39 (1H, d, J = 12Hz), 4.10 (1H, d, J = 12Hz), 3.03-2.88 (3H, m), 2.72 (1H, d, J = 16Hz), 2.62-2.51 (1H, m), 2.13-2.02 (1H, m), 1.95-1.74 (2H, m), 1.53-1.36 (1H, m), 1.35-1.21 (1H, m), 1.19 (3H, d, J = 7Hz);
MS (ESI) m / z: 479 (M + H) <+> .

　（実施例６７） (Example 67)

Figure JPOXMLDOC01-appb-C000189
Figure JPOXMLDOC01-appb-C000189

　参考例７４にて製造された化合物の代わりに、参考例７５にて製造された化合物（１７０ｍｇ、０．３８ｍｍｏｌ）を用いて、実施例６５に記載された方法と同様に反応を行い、目的化合物（１６４ｍｇ、収率：９０％）を得た。 Using the compound (170 mg, 0.38 mmol) produced in Reference Example 75 instead of the compound produced in Reference Example 74, the reaction was carried out in the same manner as described in Example 65 to obtain the target compound. (164 mg, yield: 90%) was obtained.

　1H-NMR (400MHz, DMSO-d6) δ: 12.13 (1H, s), 10.48 (1H, s), 8.42 (1H, s), 7.78 (1H, d, J=9Hz), 6.96 (1H, d, J=9Hz), 6.65 (1H, s), 4.66 (1H, d, J=13Hz), 4.31 (1H, d, J=13Hz), 3.01-2.82 (3H, m), 2.74-2.63 (2H, m), 1.91-1.79 (1H, m), 1.68-1.58 (1H, m), 1.51-1.43 (1H, m), 1.40-1.28 (1H, m), 1.25 (3H, d, J=7Hz), 1.15-1.02 (1H, m)；
　MS (ESI) m/z: 479 (M+H)+。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 12.13 (1H, s), 10.48 (1H, s), 8.42 (1H, s), 7.78 (1H, d, J = 9Hz), 6.96 (1H, d, J = 9Hz), 6.65 (1H, s), 4.66 (1H, d, J = 13Hz), 4.31 (1H, d, J = 13Hz), 3.01-2.82 (3H, m), 2.74-2.63 (2H , m), 1.91-1.79 (1H, m), 1.68-1.58 (1H, m), 1.51-1.43 (1H, m), 1.40-1.28 (1H, m), 1.25 (3H, d, J = 7Hz) , 1.15-1.02 (1H, m);
MS (ESI) m / z: 479 (M + H) <+> .

　（実施例６８） (Example 68)

Figure JPOXMLDOC01-appb-C000190
Figure JPOXMLDOC01-appb-C000190

　３－（ビフェニル－４－イル）－３－オキソブタンニトリルの代わりに、参考例７７にて製造された（４Ｓ）－４－（３－ブロモフェニル）－３－オキソペンタンニトリル（３．２４ｇ、１２．９ｍｍｏｌ）を用いて、参考例２に記載された方法と同様に反応を行い、アミノピラゾール化合物（３．１８ｇ）を得た。 Instead of 3- (biphenyl-4-yl) -3-oxobutanenitrile, (4S) -4- (3-bromophenyl) -3-oxopentanenitrile prepared in Reference Example 77 (3.24 g, 12.9 mmol) was used in the same manner as in the method described in Reference Example 2 to obtain an aminopyrazole compound (3.18 g).

　アミノピラゾール化合物の一部（５０４ｍｇ）を用い、６－フルオロ－３－ピリジニルボロン酸の代わりに、２－メトキシピリジン－５－ボロン酸を用いて、参考例４７、実施例３に記載された方法に準じて反応を行い、目的化合物（８０ｍｇ、収率：９％）を得た。 A part of the aminopyrazole compound (504 mg) was used, and 2-methoxypyridine-5-boronic acid was used instead of 6-fluoro-3-pyridinylboronic acid, and the method described in Reference Example 47 and Example 3 was used. The reaction was carried out in the same manner to obtain the target compound (80 mg, yield: 9%).

　光学純度はＨＰＬＣ［カラム：Ｃｈｉｒａｌｐａｋ　ＩＡ（４．６ｍｍ　ｉ．ｄ．ｘ１５０ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝５０／５０、流速：１．０ｍＬ／分］を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 150 mm); manufactured by Daicel, elution solvent: hexane / IPA = 50/50, flow rate: 1.0 mL / min].

　光学純度９９％以上（保持時間：１０．２分）。 Optical purity 99% or more (retention time: 10.2 minutes).

　（実施例６９） (Example 69)

Figure JPOXMLDOC01-appb-C000191
Figure JPOXMLDOC01-appb-C000191

　２－メトキシピリジン－５－ボロン酸の代わりに、２，６－ジフルオロピリジン－３－ボロン酸を用いて、実施例６８に記載された方法と同様に反応を行い、目的化合物（１６０ｍｇ、収率：９％）を得た。 The reaction was conducted in the same manner as described in Example 68 using 2,6-difluoropyridine-3-boronic acid instead of 2-methoxypyridine-5-boronic acid, and the target compound (160 mg, yield) : 9%).

　光学純度はＨＰＬＣ［カラム：Ｃｈｉｒａｌｐａｋ　ＡＤ（４．６ｍｍ　ｉ．ｄ．ｘ１５０ｍｍ）；ダイセル社製、溶出溶媒：ヘキサン／ＩＰＡ＝８０／２０－２０／８０（グラジェント）、流速：１．５ｍＬ／分］を用いて測定した。 The optical purity is HPLC [column: Chiralpak AD (4.6 mm id x 150 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80 / 20-20 / 80 (gradient), flow rate: 1.5 mL / min ] And measured.

　光学純度９６．６％（保持時間：５．３分）。 Optical purity 96.6% (retention time: 5.3 minutes).

　（試験例１）ＬＣＡＴ活性の測定（ｉｎ　ｖｉｔｒｏ）
　密度勾配遠心分離を行い、健常人の血漿よりＨＤＬ３からなる画分（１．１２５＜比重＜１．２１０ｇ／ｍＬ）を得た。得られた画分をリン酸緩衝生理食塩水（ｐＨ７．４）で透析して、ＬＣＡＴの酵素源及びアクセプターとして使用した。被検薬はジメチルスルホキシドに溶解して調製した。１ｍｇ／ｍＬのＨＤＬ３を含むリン酸緩衝生理食塩水（ｐＨ７．４）に、ＤＴＮＢ（イールマン試薬、最終濃度０．５ｍＭ）、メルカプトエタノール（最終濃度１２．５ｍＭ）、及び０．６％牛血清アルブミンを含む［１４Ｃ］コレステロールを加え、さらにこれに各種濃度の被検薬を加え全量を８０μＬとした。この混合物を３７℃で約１６時間インキュベートした後、ヘキサンとイソプロパノールの混合液（混合比＝３：２）を加え反応を停止した。攪拌後ヘキサン層を採取し、これを濃縮乾固した。これにクロロホルム溶液（濃度１０ｍｇ／ｍＬ）を加え、シリカゲル薄層板にスポットし、ヘキサン、ジエチルエーテルおよび酢酸エチルの混合液（混合比＝８５：１５：２）で展開した。コレステロールオレエートに相当する部分の放射能活性をイメージングアナライザーＢＡＳ－２５００（富士フィルム社製）で測定した。被検薬を加えない試料についても同様に処理、測定した。下記の式を用いて、被検薬を加えない場合と比較し、ＬＣＡＴ活性化のＥＣ５０値を算出した。その結果を表１に示す。 (Test Example 1) Measurement of LCAT activity (in vitro)
A density gradient centrifugation was performed to obtain a fraction composed of HDL3 (1.125 <specific gravity <1.210 g / mL) from plasma of a healthy person. The obtained fraction was dialyzed with phosphate buffered saline (pH 7.4) and used as an enzyme source and acceptor of LCAT. The test drug was prepared by dissolving in dimethyl sulfoxide. Phosphate buffered saline (pH 7.4) containing 1 mg / mL HDL3, DTNB (Ielman reagent, final concentration 0.5 mM), mercaptoethanol (final concentration 12.5 mM), and 0.6% bovine serum albumin [ 14 C] cholesterol containing, and various concentrations of test drug were added to make the total volume 80 μL. After this mixture was incubated at 37 ° C. for about 16 hours, a mixture of hexane and isopropanol (mixing ratio = 3: 2) was added to stop the reaction. After stirring, the hexane layer was collected and concentrated to dryness. Chloroform solution (concentration 10 mg / mL) was added thereto, spotted on a silica gel thin layer plate, and developed with a mixed solution of hexane, diethyl ether and ethyl acetate (mixing ratio = 85: 15: 2). The radioactivity of the portion corresponding to cholesterol oleate was measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Samples to which no test drug was added were similarly processed and measured. Using the following equation, compared with no addition of test drug was calculated EC 50 values of LCAT activation. The results are shown in Table 1.

Figure JPOXMLDOC01-appb-M000192
Figure JPOXMLDOC01-appb-M000192

　式中、Ｘは、被検薬の濃度の対数を示し、
　Ｙは、被検薬の応答性（ＬＣＡＴ活性）を示し、
　Ｔｏｐは、最大値（最大平坦域）を示し、
　Ｂｏｔｔｏｍは、最小値（最小平坦域）を示し、
　ＥＣ５０は、５０％有効濃度を示す。 In the formula, X represents the logarithm of the concentration of the test drug,
Y represents the response of the test drug (LCAT activity),
Top indicates the maximum value (maximum plateau),
“Bottom” indicates a minimum value (minimum flat area);
EC 50 indicates a 50% effective concentration.

　表１
――――――――――――――――――――――――――――――
試験化合物　　　　　　　　　　　　　　　ＥＣ５０（μＭ）
――――――――――――――――――――――――――――――
実施例１の化合物　　　　　　　　　　　　０．５３
実施例２の化合物　　　　　　　　　　　　０．５３
実施例３の化合物　　　　　　　　　　　　０．３８
実施例４の化合物４－１　　　　　　　　　０．９９
実施例４の化合物４－２　　　　　　　　　０．５０
実施例５の化合物５－１　　　　　　　　　１．４９
実施例５の化合物５－２　　　　　　　　　０．３９
実施例６の化合物　　　　　　　　　　　　１．４９
実施例７の化合物　　　　　　　　　　　　０．６８
実施例８の化合物８－１　　　　　　　　　０．３８
実施例８の化合物８－２　　　　　　　　　０．３０
実施例９の化合物９－１　　　　　　　　　０．５８
実施例９の化合物９－２　　　　　　　　　０．７５
実施例１０の化合物　　　　　　　　　　　０．５０
実施例１１の化合物１１－１　　　　　　　０．６１
実施例１１の化合物１１－２　　　　　　　０．２８
実施例１２の化合物　　　　　　　　　　　０．５５
実施例１３の化合物　　　　　　　　　　　０．１３
実施例１４の化合物　　　　　　　　　　　０．６５
実施例１５の化合物　　　　　　　　　　　０．７８
実施例１６の化合物１６－１　　　　　　　１．６７
実施例１６の化合物１６－２　　　　　　　０．２０
実施例１７の化合物　　　　　　　　　　　０．４９
実施例１８の化合物１８－１　　　　　　　０．４９
実施例１８の化合物１８－２　　　　　　　０．８５
実施例１９の化合物１９－１　　　　　　　０．６８
実施例１９の化合物１９－２　　　　　　　０．３２
実施例２０の化合物２０－１　　　　　　　０．７６
実施例２０の化合物２０－２　　　　　　　０．４０
実施例２１の化合物２１－１　　　　　　　０．４７
実施例２１の化合物２１－２　　　　　　　０．１８
実施例２２の化合物　　　　　　　　　　　０．２６
実施例２３の化合物２３－１　　　　　　　０．１７
実施例２３の化合物２３－２　　　　　　　１．１３
実施例２４の化合物　　　　　　　　　　　０．５０
実施例２５の化合物　　　　　　　　　　　１．８３
実施例２６の化合物２６－１　　　　　　　１．４９
実施例２６の化合物２６－２　　　　　　　０．２０
実施例２７の化合物　　　　　　　　　　　１．７８
実施例２８の化合物　　　　　　　　　　　０．２４
実施例２９の化合物２９－１　　　　　　　０．６３
実施例２９の化合物２９－２　　　　　　　０．２５
実施例３０の化合物　　　　　　　　　　　０．３７
実施例３１の化合物３１－１　　　　　　　０．４６
実施例３１の化合物３１－２　　　　　　　０．２８
実施例３２の化合物　　　　　　　　　　　０．８７
実施例３３の化合物　　　　　　　　　　　０．２０
実施例３４の化合物　　　　　　　　　　　１．３５
実施例３５の化合物　　　　　　　　　　　０．８６
実施例３６の化合物３６－１　　　　　　　０．４６
実施例３６の化合物３６－２　　　　　　　０．３０
実施例３７の化合物　　　　　　　　　　　０．７４
実施例３８の化合物　　　　　　　　　　　１．７１
実施例３９の化合物３９－１　　　　　　　１．１６
実施例３９の化合物３９－２　　　　　　　０．１６
実施例４０の化合物４０－１　　　　　　　０．６４
実施例４０の化合物４０－２　　　　　　　０．６３
実施例４１の化合物４１－１　　　　　　　１．５６
実施例４１の化合物４１－２　　　　　　　０．８０
実施例４２の化合物４２－１　　　　　　　１．０３
実施例４２の化合物４２－２　　　　　　　１．２１
実施例４３の化合物　　　　　　　　　　　０．７５
実施例４４の化合物４４－１　　　　　　　０．４１
実施例４４の化合物４４－２　　　　　　　０．２０
実施例４５の化合物　　　　　　　　　　　０．１１
実施例４６の化合物４６－１　　　　　　　０．２６
実施例４６の化合物４６－２　　　　　　　０．１５
実施例４７の化合物４７－１　　　　　　　０．９１
実施例４７の化合物４７－２　　　　　　　０．５１
実施例４８の化合物４８－１　　　　　　　０．３８
実施例４８の化合物４８－２　　　　　　　０．３０
実施例４９の化合物４９－１　　　　　　　０．５１
実施例４９の化合物４９－２　　　　　　　０．３１
実施例５０の化合物５０－１　　　　　　　０．１４
実施例５０の化合物５０－２　　　　　　　０．１４
実施例５１の化合物５１－１　　　　　　　０．４６
実施例５１の化合物５１－２　　　　　　　０．６２
実施例５２の化合物５２－１　　　　　　　０．４１
実施例５２の化合物５２－２　　　　　　　０．９８
実施例５３の化合物５３－１　　　　　　　１．１０
実施例５３の化合物５３－２　　　　　　　０．６０
実施例５４の化合物５４－１　　　　　　　０．５４
実施例５４の化合物５４－２　　　　　　　０．５８
実施例５５の化合物５５－１　　　　　　　０．６０
実施例５５の化合物５５－２　　　　　　　０．１７
実施例５６の化合物５６－１　　　　　　　０．５０
実施例５６の化合物５６－２　　　　　　　０．０７６
実施例５７の化合物５７－１　　　　　　　０．３２
実施例５７の化合物５７－２　　　　　　　０．３０
実施例５８の化合物５８－１　　　　　　　０．６３
実施例５８の化合物５８－２　　　　　　　０．６５
実施例５９の化合物　　　　　　　　　　　０．７４
実施例６０の化合物　　　　　　　　　　　０．４８
実施例６１の化合物　　　　　　　　　　　０．３６
実施例６２の化合物　　　　　　　　　　　０．３０
実施例６３の化合物　　　　　　　　　　　０．３５
実施例６４の化合物　　　　　　　　　　　０．０９６
実施例６５の化合物　　　　　　　　　　　０．６４
実施例６６の化合物　　　　　　　　　　　０．５８
実施例６７の化合物　　　　　　　　　　　０．０２１
実施例６８の化合物　　　　　　　　　　　０．２１
実施例６９の化合物　　　　　　　　　　　０．１９
――――――――――――――――――――――――――――――。 Table 1
――――――――――――――――――――――――――――――
Test compound EC 50 (μM)
――――――――――――――――――――――――――――――
Compound of Example 1 0.53
Compound of Example 2 0.53
Compound of Example 3 0.38
Compound 4-1 of Example 4 0.99
Compound 4-2 of Example 4 0.50
Compound 5-1 of Example 5 1.49
Compound 5-2 of Example 5 0.39
Compound of Example 6 1.49
Compound of Example 7 0.68
Compound 8-1 of Example 8 0.38
Compound 8-2 of Example 8 0.30
Compound 9-1 of Example 9 0.58
Compound 9-2 of Example 9 0.75
Compound of Example 10 0.50
Compound 11-1 of Example 11 0.61
Compound 11-2 of Example 11 0.28
Compound of Example 12 0.55
Compound of Example 13 0.13
Compound of Example 14 0.65
Compound of Example 15 0.78
Compound 16-1 of Example 16 1.67
Compound 16-2 of Example 16 0.20
Compound of Example 17 0.49
Compound 18-1 of Example 18 0.49
Compound 18-2 of Example 18 0.85
Compound 19-1 of Example 19 0.68
Compound 19-2 in Example 19 0.32
Compound 20-1 of Example 20 0.76
Compound 20-2 of Example 20 0.40
Compound 21-1 of Example 21 0.47
Compound 21-2 of Example 21 0.18
Compound of Example 22 0.26
Compound 23-1 of Example 23 0.17
Compound 23-2 of Example 23 1.13
Compound of Example 24 0.50
Compound of Example 25 1.83
Compound 26-1 of Example 26 1.49
Compound 26-2 of Example 26 0.20
Compound of Example 27 1.78
Compound of Example 28 0.24
Compound 29-1 of Example 29 0.63
Compound 29-2 of Example 29 0.25
Compound of Example 30 0.37
Compound 31-1 of Example 31 0.46
Compound 31-2 of Example 31 0.28
Compound of Example 32 0.87
Compound of Example 33 0.20
Compound of Example 34 1.35
Compound of Example 35 0.86
Compound 36-1 of Example 36 0.46
Compound 36-2 of Example 36 0.30
Example 37 Compound 0.74
Compound of Example 38 1.71
Compound 39-1 of Example 39 1.16
Compound 39-2 of Example 39 0.16
Compound 40-1 of Example 40 0.64
Compound 40-2 of Example 40 0.63
Compound 41-1 of Example 41 1.56
Compound 41-2 of Example 41 0.80
Compound 42-1 of Example 42 1.03
Compound 42-2 of Example 42 1.21
Compound of Example 43 0.75
Compound 44-1 of Example 44 0.41
Compound 44-2 of Example 44 0.20
Example 45 Compound 0.11
Compound 46-1 of Example 46 0.26
Compound 46-2 of Example 46 0.15
Compound 47-1 of Example 47 0.91
Compound 47-2 of Example 47 0.51
Compound 48-1 of Example 48 0.38
Compound 48-2 of Example 48 0.30
Compound 49-1 of Example 49 0.51
Compound 49-2 of Example 49 0.31
Compound 50-1 of Example 50 0.14
Compound 50-2 of Example 50 0.14
Compound 51-1 of Example 51 0.46
Compound 51-2 of Example 51 0.62
Compound 52-1 of Example 52 0.41
Compound 52-2 of Example 52 0.98
Compound 53-1 of Example 53 1.10
Compound 53-2 of Example 53 0.60
Compound 54-1 of Example 54 0.54
Compound 54-2 of Example 54 0.58
Compound 55-1 of Example 55 0.60
Compound 55-2 of Example 55 0.17
Compound 56-1 of Example 56 0.50
Compound 56-2 of Example 56 0.076
Compound 57-1 of Example 57 0.32
Compound 57-2 of Example 57 0.30
Compound 58-1 of Example 58 0.63
Compound 58-2 of Example 58 0.65
Compound of Example 59 0.74
Compound of Example 60 0.48
Compound of Example 61 0.36
Compound of Example 62 0.30
Compound of Example 63 0.35
Compound of Example 64 0.096
Example 65 Compound 0.64
Compound of Example 66 0.58
Compound of Example 67 0.021
Compound of Example 68 0.21
Compound of Example 69 0.19
――――――――――――――――――――――――――――――

　以上より、本発明化合物は、優れたＬＣＡＴ活性化作用を有し、脂質異常症及び動脈硬化症等の疾患の治療若しくは予防のための医薬として有用である。 As described above, the compound of the present invention has an excellent LCAT activation action and is useful as a medicament for the treatment or prevention of diseases such as dyslipidemia and arteriosclerosis.

　（試験例２）ＬＣＡＴ活性の測定（血漿）
　ヒト、カニクイサル又はヒトＬＣＡＴトランスジェニックマウスの血漿を、ＬＣＡＴの酵素源及びアクセプターとして使用する。被検薬はジメチルスルホキシドに溶解して調製する。各血漿５μＬとＰＢＳ４５μＬに、ＤＴＮＢ（イールマン試薬、最終濃度０．５ｍＭ）、メルカプトエタノール（最終濃度１２．５ｍＭ）、及び０．６％牛血清アルブミンを含む［１４Ｃ］コレステロールを加え、さらにこれに各種濃度の被検薬を加え全量を８０μＬとする。この混合物を３７℃で約１６時間インキュベートした後、ヘキサン及びイソプロパノールの混合液（混合比＝３：２）を加え反応を停止する。水を加え攪拌後ヘキサン層を採取し、これを濃縮乾固する。これにクロロホルム溶液（濃度１０ｍｇ／ｍＬ）を加え、シリカゲル薄層板にスポットし、ヘキサン、ジエチルエーテル及び酢酸エチルの混合液（混合比＝８５：１５：２）で展開する。コレステロールオレエートに相当する部分の放射能活性をイメージングアナライザーＢＡＳ－２５００（富士フィルム社製）で測定する。被検薬を加えない試料についても同様に処理、測定する。下記の式を用いて、被検薬を加えない場合と比較し、ＬＣＡＴ活性化のＥＣ５０値を算出する。 (Test Example 2) Measurement of LCAT activity (plasma)
Human, cynomolgus monkey or human LCAT transgenic mouse plasma is used as an enzyme source and acceptor for LCAT. The test drug is prepared by dissolving in dimethyl sulfoxide. [14C] cholesterol containing DTNB (Ielman's reagent, final concentration 0.5 mM), mercaptoethanol (final concentration 12.5 mM), and 0.6% bovine serum albumin was added to 5 μL of each plasma and 45 μL of PBS. Add the test drug at a concentration to make the total volume 80 μL. After incubating this mixture at 37 ° C. for about 16 hours, the reaction is stopped by adding a mixture of hexane and isopropanol (mixing ratio = 3: 2). After adding water and stirring, the hexane layer is collected and concentrated to dryness. Chloroform solution (concentration 10 mg / mL) is added to this, spotted on a silica gel thin layer plate, and developed with a mixed solution of hexane, diethyl ether and ethyl acetate (mixing ratio = 85: 15: 2). The radioactivity of the portion corresponding to cholesterol oleate is measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). The same processing and measurement is performed for the sample to which the test drug is not added. Using the following formula, the EC 50 value of LCAT activation is calculated in comparison with the case where no test drug is added.

Figure JPOXMLDOC01-appb-M000193
Figure JPOXMLDOC01-appb-M000193

　式中、Ｘは、被検薬の濃度の対数を示し、
　Ｙは、被検薬の応答性（ＬＣＡＴ活性）を示し、
　Ｔｏｐは、最大値（最大平坦域）を示し、
　Ｂｏｔｔｏｍは、最小値（最小平坦域）を示し、
　ＥＣ５０は、５０％有効濃度を示す。 In the formula, X represents the logarithm of the concentration of the test drug,
Y represents the response of the test drug (LCAT activity),
Top indicates the maximum value (maximum plateau),
“Bottom” indicates a minimum value (minimum flat area);
EC 50 indicates a 50% effective concentration.

　（試験例３）ＬＣＡＴ活性の測定（Ｅｘ　ｖｉｖｏ）
　被検薬を投与したカニクイサル又はヒトＬＣＡＴトランスジェニックマウスの血漿中のＬＣＡＴ活性を測定する。各血漿２５μＬに、ＤＴＮＢ（イールマン試薬、最終濃度０．２６ｍＭ）、メルカプトエタノール（最終濃度２ｍＭ）、及び０．６％牛血清アルブミンを含む［１４Ｃ］コレステロールを加え、全量を４０μＬとする。この混合物を３７℃で１時間インキュベートした後、ヘキサン及びイソプロパノールの混合液（混合比＝３：２）を加え反応を停止する。水を加え攪拌後ヘキサン層を採取し、これを濃縮乾固する。これにクロロホルム溶液（濃度１０ｍｇ／ｍＬ）を加え、シリカゲル薄層板にスポットし、ヘキサン、ジエチルエーテル及び酢酸エチルの混合液（混合比＝８５：１５：２）で展開する。コレステロールオレエートに相当する部分の放射能活性をイメージングアナライザーＢＡＳ－２５００（富士フィルム社製）で測定する。投与前のＬＣＡＴ活性と比較し、各時点でのＬＣＡＴ活性化の変化率を算出する。 (Test Example 3) Measurement of LCAT activity (Ex vivo)
LCAT activity in plasma of cynomolgus monkeys or human LCAT transgenic mice administered with the test drug is measured. [25C] Each plasma is added with [14C] cholesterol containing DTNB (Ielman's reagent, final concentration 0.26 mM), mercaptoethanol (final concentration 2 mM), and 0.6% bovine serum albumin to a total volume of 40 μL. This mixture is incubated at 37 ° C. for 1 hour, and then the reaction is stopped by adding a mixture of hexane and isopropanol (mixing ratio = 3: 2). After adding water and stirring, the hexane layer is collected and concentrated to dryness. Chloroform solution (concentration 10 mg / mL) is added to this, spotted on a silica gel thin layer plate, and developed with a mixed solution of hexane, diethyl ether and ethyl acetate (mixing ratio = 85: 15: 2). The radioactivity of the portion corresponding to cholesterol oleate is measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Compared with the LCAT activity before administration, the rate of change in LCAT activation at each time point is calculated.

　（試験例４）カニクイサル薬効試験
　被検薬をｐｒｏｐｙｌｅｎｅ　ｇｌｙｃｏｌ（Ｓｉｇｍａ－Ａｌｄｒｉｃｈ）－Ｔｗｅｅｎ　８０（Ｓｉｇｍａ－Ａｌｄｒｉｃｈ）混合溶液［４／１（ｖ／ｖ）］又は、０．５％（ｗ／ｖ）メチルセルロース水溶液に溶解し、カニクイサルに、１又は７日間経口投与する。投与１又は７日間目の投与前及び投与後の血液を採取し、血漿を得る。血漿中コレステロール含有量は、市販の測定キット（コレステロール－Ｅワコー、和光純薬）を用いて測定する。リポタンパク質プロファイルを、ＨＰＬＣ（カラム：ＬｉｐｏｐｒｏｐａｋＸＬ、東ソー製）によって分析する。ＨＤＬコレステロール、及び、ｎｏｎ－ＨＤＬコレステロールの含有量は、以下の計算式にしたがって算出する。 (Test Example 4) Cynomolgus monkey efficacy test The test drug was propylene glycol (Sigma-Aldrich) -Tween 80 (Sigma-Aldrich) mixed solution [4/1 (v / v)] or 0.5% (w / v) Dissolve in aqueous methylcellulose and administer orally to cynomolgus monkeys for 1 or 7 days. Blood is collected before and after administration on the 1st or 7th day of administration to obtain plasma. The cholesterol content in plasma is measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile is analyzed by HPLC (column: Lipopropak XL, Tosoh). The content of HDL cholesterol and non-HDL cholesterol is calculated according to the following calculation formula.

　ＨＤＬコレステロール含有量＝血漿中コレステロール含有量×（ＨＤＬコレステロールのピーク面積／各ピークの和）
　ｎｏｎ－ＨＤＬコレステロール含有量＝血漿中コレステロール含有量×（ｎｏｎ－ＨＤＬコレステロールのピーク面積／各ピークの和）
　投与前に比べて１０ｍｇ／ｋｇ１回投与後のＨＤＬの上昇率（％）を、投与前及び投与後２４時間のＡＵＣから求め、その結果を表２に示す。 HDL cholesterol content = plasma cholesterol content × (HDL cholesterol peak area / sum of each peak)
non-HDL cholesterol content = plasma cholesterol content × (peak area of non-HDL cholesterol / sum of each peak)
The increase rate (%) of HDL after a single administration of 10 mg / kg as compared to before administration was determined from AUC before administration and 24 hours after administration, and the results are shown in Table 2.

　表２
――――――――――――――――――――――――――――――
試験化合物　　　　　　　　　　　　１回投与後のＨＤＬの上昇率
――――――――――――――――――――――――――――――
実施例３の化合物　　　　　　　　　　　　６２３
実施例１３の化合物　　　　　　　　　　　５４６
実施例４４の化合物４４－２　　　　　　　４５８
実施例４６の化合物４６－２　　　　　　　２１１
実施例６８の化合物　　　　　　　　　　　１１７
――――――――――――――――――――――――――――――。 Table 2
――――――――――――――――――――――――――――――
Test compound Increased HDL after a single dose -------------
Compound 623 of Example 3
Compound 546 of Example 13
Compound 44-2 458 of Example 44
Compound 46-2 of Example 46 211
Compound of Example 68
――――――――――――――――――――――――――――――

　（試験例５）ヒトＬＣＡＴトランスジェニックマウス薬効試験
　被検薬をｐｒｏｐｙｌｅｎｅ　ｇｌｙｃｏｌ－Ｔｗｅｅｎ　８０混合溶液［４／１（ｖ／ｖ）］又は、０．５％（ｗ／ｖ）メチルセルロース水溶液に溶解し、ヒトＬＣＡＴトランスジェニックマウスに、１、４又は７日間経口投与する。投与１、４又は７日間目の投与前及び投与後の血液を採取し、血漿を得る。血漿中コレステロール含有量は、市販の測定キット（コレステロール－Ｅワコー、和光純薬）を用いて測定する。リポタンパク質プロファイルを、ＨＰＬＣ（カラム：ＬｉｐｏｐｒｏｐａｋＸＬ、東ソー製）によって分析する。ＨＤＬコレステロール、及び、ｎｏｎ－ＨＤＬコレステロールの含有量は、以下の計算式にしたがって算出する。 (Test Example 5) Human LCAT transgenic mouse drug efficacy test The test drug was dissolved in polypropylene glycol-Tween 80 mixed solution [4/1 (v / v)] or 0.5% (w / v) methylcellulose aqueous solution, Human LCAT transgenic mice are orally administered for 1, 4 or 7 days. Blood is collected before and after administration on the first, fourth or seventh day of administration to obtain plasma. The cholesterol content in plasma is measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile is analyzed by HPLC (column: Lipopropak XL, Tosoh). The content of HDL cholesterol and non-HDL cholesterol is calculated according to the following calculation formula.

　ＨＤＬコレステロール含有量＝血漿中コレステロール含有量×（ＨＤＬコレステロールのピーク面積／各ピークの和）
　ｎｏｎ－ＨＤＬコレステロール含有量＝血漿中コレステロール含有量×（ｎｏｎ－ＨＤＬコレステロールのピーク面積／各ピークの和）
　以上のように、本発明の化合物は、優れたＬＣＡＴ活性化作用を示し、脂質異常症及び動脈硬化症等の疾患の治療若しくは予防のための医薬として有用である。

　（製剤例１）ハ－ドカプセル剤
　標準二分式ハ－ドゼラチンカプセルの各々に、１００ｍｇの粉末状の実施例１の化合物、１５０ｍｇのラクト－ス、５０ｍｇのセルロ－ス及び６ｍｇのステアリン酸マグネシウムを充填することにより、単位カプセルを製造し、洗浄後、乾燥する。 HDL cholesterol content = plasma cholesterol content × (HDL cholesterol peak area / sum of each peak)
non-HDL cholesterol content = plasma cholesterol content × (peak area of non-HDL cholesterol / sum of each peak)
As described above, the compound of the present invention exhibits an excellent LCAT activation action and is useful as a medicament for the treatment or prevention of diseases such as dyslipidemia and arteriosclerosis.

Formulation Example 1 Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.

　（製剤例２）ソフトカプセル剤
　消化性油状物、例えば、大豆油、綿実油又はオリ－ブ油中に入れた、実施例２の化合物の混合物を調製し、正置換ポンプでゼラチン中に注入して、１００ｍｇの活性成分を含有するソフトカプセルを得、洗浄後、乾燥する。 Formulation Example 2 Soft Capsules A mixture of the compound of Example 2 in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected into gelatin with a positive displacement pump, Soft capsules containing 100 mg of active ingredient are obtained, washed and dried.

　（製剤例３）錠剤
　常法に従って、１００ｍｇの実施例３の化合物、０．２ｍｇのコロイド性二酸化珪素、５ｍｇのステアリン酸マグネシウム、２７５ｍｇの微結晶性セルロ－ス、１１ｍｇのデンプン及び９８．８ｍｇのラクト－スを用いて製造する。 Formulation Example 3 Tablet According to conventional methods, 100 mg of the compound of Example 3, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg Manufactured using lactose.

　なお、所望により、剤皮を塗布する。 In addition, if desired, apply a coating.

　（製剤例４）懸濁剤
　５ｍＬ中に、１００ｍｇの微粉化した実施例４の化合物、１００ｍｇのナトリウムカルボキシメチルセルロ－ス、５ｍｇの安息香酸ナトリウム、１．０ｇのソルビト－ル溶液（日本薬局方）及び０．０２５ｍＬのバニリンを含有するように製造する。 (Formulation example 4) Suspension agent In 5 mL, 100 mg of the compound of Example 4 finely divided, 100 mg sodium carboxymethyl cellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution (Japanese Pharmacopoeia ) And 0.025 mL of vanillin.

　（製剤例５）注射剤　１．５重量％の実施例６の化合物を、１０重量％のプロピレングリコール中で撹拌し、次いで、注射用水で一定容量に調整した後、滅菌して注射剤とする。 (Formulation Example 5) Injection: 1.5% by weight of the compound of Example 6 is stirred in 10% by weight of propylene glycol, adjusted to a certain volume with water for injection, and then sterilized to give an injection. .

　本発明の一般式（Ｉ）で表される化合物又はその薬理上許容される塩は、優れたＬＣＡＴ活性化作用を有し、特に、動脈硬化症、動脈硬化性心疾患、冠状動脈性心疾患（急性冠症候群、心不全、心筋梗塞、狭心症、心虚血、心血管障害及び血管形成性再狭窄を含む）、脳血管疾患（脳卒中及び脳梗塞を含む）、末梢血管疾患（末梢動脈疾患、糖尿病血管合併症を含む）、脂質異常症、ＬＣＡＴ欠損症、低ＨＤＬコレステロール血症、高ＬＤＬコレステロール血症、糖尿病、高血圧症、メタボリックシンドローム、アルツハイマー病、角膜混濁、又は、腎疾患の治療剤又は予防剤、特に、抗動脈硬化剤の有効成分として有用である。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and in particular, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease. (Including acute coronary syndrome, heart failure, myocardial infarction, angina, cardiac ischemia, cardiovascular disorders and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (peripheral arterial disease, Treatment of diabetic vascular complications), dyslipidemia, LCAT deficiency, low HDL cholesterolemia, high LDL cholesterolemia, diabetes, hypertension, metabolic syndrome, Alzheimer's disease, corneal opacity, or renal disease or It is useful as an active ingredient of prophylactic agents, particularly anti-arteriosclerotic agents.

Claims (23)

　式
Figure JPOXMLDOC01-appb-C000001
［式中、Ｒ２及びＲ３は共に水素原子を表し、又は、それらが結合する炭素原子と一緒になってシクロプロピル環若しくはシクロブチル環を形成し、Ｒ１は下記Ｑ１群から選ばれる基を表し、Ｘは単結合を表し、或いは、
Ｒ３は水素原子を表し、Ｒ１及びＲ２は同一又は異なって下記Ｑ１群から選ばれる基を表し、Ｘは単結合、酸素原子、硫黄原子又は基ＳＯ２を表し、
Ｑ１群は、アリール基、置換アリール基、Ｃ１－Ｃ６アルキル基、Ｃ３－Ｃ７シクロアルキル基、ヘテロアリール基（当該ヘテロアリールはベンゼン環と縮合していてもよい）、置換ヘテロアリール基（当該ヘテロアリールはベンゼン環と縮合していてもよい）、ヘテロシクリル基及び置換ヘテロシクリル基からなる群であり、
Ｑ１群における置換基は、ハロゲン原子、Ｃ１－Ｃ６ハロアルキル基、Ｃ１－Ｃ６アルコキシ基、アリール基、アリールオキシ基、アラルキル基、ヘテロアリール基又は置換ヘテロアリール基（当該ヘテロアリール上の置換基は、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ハロアルキル基及びＣ１－Ｃ６アルコキシ基からなる群から選ばれる同一又は異なった１～２個の置換基である）である。但し、Ｒ２及びＲ３が共に水素原子であり、Ｘが単結合であり、Ｒ１がベンジル基である場合を除く。］で表される化合物又はその薬理上許容される塩。 formula
Figure JPOXMLDOC01-appb-C000001
[Wherein, R 2 and R 3 both represent a hydrogen atom, or together with the carbon atom to which they are bonded form a cyclopropyl ring or a cyclobutyl ring, and R 1 represents a group selected from the following group Q1: X represents a single bond, or
R 3 represents a hydrogen atom, R 1 and R 2 are the same or different and represent a group selected from the following group Q1, X represents a single bond, an oxygen atom, a sulfur atom or a group SO 2 ;
Q1 group includes an aryl group, a substituted aryl group, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a heteroaryl group (the heteroaryl may be condensed with a benzene ring), a substituted heteroaryl A group consisting of a group (the heteroaryl may be fused with a benzene ring), a heterocyclyl group and a substituted heterocyclyl group;
The substituent in the Q1 group is a halogen atom, a C 1 -C 6 haloalkyl group, a C 1 -C 6 alkoxy group, an aryl group, an aryloxy group, an aralkyl group, a heteroaryl group or a substituted heteroaryl group (on the heteroaryl). The substituent is the same or different 1 to 2 substituents selected from the group consisting of a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group and a C 1 -C 6 alkoxy group) It is. However, R 2 and R 3 are both hydrogen atoms, X is a single bond, and R 1 is a benzyl group. Or a pharmacologically acceptable salt thereof. 　Ｒ２及びＲ３は共に水素原子を表し、Ｒ１は下記Ｑ２群から選ばれる基を表し、Ｘは単結合を表し、或いは、
Ｒ３は水素原子を表し、Ｒ１及びＲ２は同一又は異なって下記Ｑ２群から選ばれる基を表し、Ｘは単結合、酸素原子、硫黄原子又は基ＳＯ２を表し、
Ｑ２群は、置換アリール基、Ｃ１－Ｃ６アルキル基及び置換ヘテロシクリル基からなる群であり、
Ｑ２群における置換基は、置換ヘテロアリール基（当該ヘテロアリール上の置換基は、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ハロアルキル基及びＣ１－Ｃ６アルコキシ基からなる群から選ばれる同一又は異なった１～２個の置換基である）である、請求項１に記載の化合物又はその薬理上許容される塩。 R 2 and R 3 both represent a hydrogen atom, R 1 represents a group selected from the following group Q2, X represents a single bond, or
R 3 represents a hydrogen atom, R 1 and R 2 are the same or different and represent a group selected from the following group Q2, X represents a single bond, an oxygen atom, a sulfur atom or a group SO 2 ;
Group Q2 is a group consisting of a substituted aryl group, a C 1 -C 6 alkyl group and a substituted heterocyclyl group,
The substituent in the Q2 group is a substituted heteroaryl group (the substituent on the heteroaryl is a group consisting of a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, and a C 1 -C 6 alkoxy group) The compound or a pharmacologically acceptable salt thereof according to claim 1, wherein the compound is the same or different 1 to 2 substituents selected from 　４－ヒドロキシ－３－（１－フェニルエチル）－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　３－［１－（４－ブチルフェニル）エチル］－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　３－（１－シクロヘキシルエチル）－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－３－［１－（５－メチルチオフェン－２－イル）エチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　３－｛１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－４－（トリフルオロメチル）－３－（１－｛３－［６－（トリフルオロメチル）ピリジン－３－イル］フェニル｝エチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－４－（トリフルオロメチル）－３－｛１－［４’－（トリフルオロメチル）ビフェニル－３－イル］エチル｝－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－３－｛１－［３－（２－イソプロポキシピリミジン－５－イル）フェニル］エチル｝－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－４－（トリフルオロメチル）－３－（１－｛３－［５－（トリフルオロメチル）ピラジン－２－イル］フェニル｝エチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－４－（トリフルオロメチル）－３－（｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル｝メチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－４－（トリフルオロメチル）－３－［１－｛１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル］エチル｝－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　４－ヒドロキシ－３－｛１－［３－（６－メトキシピリジン－３－イル）フェニル］エチル｝－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、
　３－｛１－［３－（２，６－ジフルオロピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オンからなる群から選ばれる、請求項１に記載の化合物又はその薬理上許容される塩。 4-hydroxy-3- (1-phenylethyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
3- [1- (4-Butylphenyl) ethyl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- on,
3- (1-cyclohexylethyl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-Hydroxy-3- [1- (5-methylthiophen-2-yl) ethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] Pyridin-6-one,
3- {1- [3- (6-Fluoropyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- (1- {3- [6- (trifluoromethyl) pyridin-3-yl] phenyl} ethyl) -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- {1- [4 '-(trifluoromethyl) biphenyl-3-yl] ethyl} -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] pyridin-6-one,
4-hydroxy-3- {1- [3- (2-isopropoxypyrimidin-5-yl) phenyl] ethyl} -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [ 3,4-b] pyridin-6-one,
4-Hydroxy-4- (trifluoromethyl) -3- (1- {3- [5- (trifluoromethyl) pyrazin-2-yl] phenyl} ethyl) -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3-({1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} methyl) -1,4,5,7-tetrahydro -6H-pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- [1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl] ethyl} -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-Hydroxy-3- {1- [3- (6-methoxypyridin-3-yl) phenyl] ethyl} -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] pyridin-6-one, and
3- {1- [3- (2,6-Difluoropyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo 2. The compound according to claim 1 or a pharmacologically acceptable salt thereof selected from the group consisting of [3,4-b] pyridin-6-one. 　（４Ｒ）－４－ヒドロキシ－３－［（１Ｓ）－１－フェニルエチル］－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　（４Ｒ）－３－｛（１Ｓ）－１－［３－（６－フルオロピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　（４Ｒ）－４－ヒドロキシ－４－（トリフルオロメチル）－３－（｛（３Ｒ）－１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル｝メチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、
　（４Ｒ）－４－ヒドロキシ－４－（トリフルオロメチル）－３－［（１Ｓ）－１－｛（３Ｒ）－１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－３－イル］エチル｝－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン
　（４Ｒ）－４－ヒドロキシ－３－｛（１Ｓ）－１－［３－（６－メトキシピリジン－３－イル）フェニル］エチル｝－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オン、及び、
　（４Ｒ）－３－｛（１Ｓ）－１－［３－（２、６－ジフルオロピリジン－３－イル）フェニル］エチル｝－４－ヒドロキシ－４－（トリフルオロメチル）－１，４，５，７－テトラヒドロ－６Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－オンからなる群から選ばれる、請求項１に記載の化合物又はその薬理上許容される塩。 (4R) -4-Hydroxy-3-[(1S) -1-phenylethyl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine -6-on,
(4R) -3-{(1S) -1- [3- (6-Fluoropyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-4- (trifluoromethyl) -3-({(3R) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} methyl) -1 , 4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-4- (trifluoromethyl) -3-[(1S) -1-{(3R) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-3- Yl] ethyl} -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one (4R) -4-hydroxy-3-{(1S) -1- [3- (6-methoxypyridin-3-yl) phenyl] ethyl} -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one, and ,
(4R) -3-{(1S) -1- [3- (2,6-Difluoropyridin-3-yl) phenyl] ethyl} -4-hydroxy-4- (trifluoromethyl) -1,4,5 The compound according to claim 1, or a pharmacologically acceptable salt thereof, selected from the group consisting of, 7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising as an active ingredient the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、動脈硬化症、動脈硬化性心疾患、冠状動脈性心疾患、脳血管疾患、末梢血管疾患、脂質異常症、低ＨＤＬコレステロール血症、高ＬＤＬコレステロール血症、又は、腎疾患の予防若しくは治療のための医薬組成物。 An arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebrovascular disease, peripheral, comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient A pharmaceutical composition for the prevention or treatment of vascular disease, dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、動脈硬化症の予防剤若しくは治療剤。 A prophylactic or therapeutic agent for arteriosclerosis comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、脂質異常症の予防剤若しくは治療剤。 A prophylactic or therapeutic agent for dyslipidemia comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血中のＬＤＬコレステロールの濃度の増加により引き起こされる疾患の予防剤若しくは治療剤。 A preventive or therapeutic agent for a disease caused by an increase in the concentration of LDL cholesterol in blood, comprising as an active ingredient the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血中のＨＤＬコレステロールの濃度の減少により引き起こされる疾患の予防剤若しくは治療剤。 A preventive or therapeutic agent for a disease caused by a decrease in the concentration of HDL cholesterol in blood, comprising as an active ingredient the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、ＬＣＡＴ活性化剤。 An LCAT activator comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、可逆的ＬＣＡＴ活性化剤。 A reversible LCAT activator comprising as an active ingredient the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、抗動脈硬化剤。 An anti-arteriosclerotic agent comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、ＬＣＡＴ活性化方法。 A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、疾患の予防若しくは治療のための方法。 A method for preventing or treating a disease, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、動脈硬化症の予防若しくは治療のための方法。 A method for the prevention or treatment of arteriosclerosis, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、脂質異常症の予防若しくは治療のための方法。 A method for the prevention or treatment of dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、血中のＬＤＬコレステロールの濃度の増加により引き起こされる疾患の予防若しくは治療のための方法。 Prevention of a disease caused by an increase in the concentration of LDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. Or a method for treatment. 　請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、血中のＨＤＬコレステロールの濃度の減少により引き起こされる疾患の予防若しくは治療のための方法。 Prevention of a disease caused by a decrease in the concentration of HDL cholesterol in the blood, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. Or a method for treatment. 　動脈硬化症の治療又は予防のための方法における使用のための、請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4, for use in a method for treating or preventing arteriosclerosis. 　脂質異常症の治療又は予防のための方法における使用のための、請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4, for use in a method for the treatment or prevention of dyslipidemia. 　血中のＬＤＬコレステロールの濃度の増加により引き起こされる疾患の治療又は予防のための方法における使用のための、請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof for use in a method for the treatment or prevention of a disease caused by an increase in the concentration of LDL cholesterol in blood. 　血中のＨＤＬコレステロールの濃度の減少により引き起こされる疾患の治療又は予防のための方法における使用のための、請求項１～４のいずれか１項に記載の化合物又はその薬理上許容される塩。
  The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4, for use in a method for the treatment or prevention of a disease caused by a decrease in the concentration of HDL cholesterol in the blood.
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JPH02142728A (en) * 1988-08-25 1990-05-31 Merrell Dow Pharmaceut Inc Pyrazolopyridine derivative as anti-atheroscelerosis agent and anti-hypercholesteremia agent
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JPH02142728A (en) * 1988-08-25 1990-05-31 Merrell Dow Pharmaceut Inc Pyrazolopyridine derivative as anti-atheroscelerosis agent and anti-hypercholesteremia agent
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