WO2015111545A1 - Condensed pyrazole derivative - Google Patents

Abstract

A compound represented by formula (I) [wherein A represents a group -CH(Y)-, a group -CH₂-CH₂- or a group -NH-; B represents a hydrogen atom or a hydroxy group; X represents an oxygen atom or a sulfur atom; and R represents an aryl group which may be substituted or a heteroaryl group which may be substituted] or a pharmacologically acceptable salt thereof, which has an excellent LCAT-activating activity and is useful as an active ingredient for a therapeutic or prophylactic agent for arteriosclerosis, arteriosclerotic heart diseases, coronary heart diseases (including heart failure, cardiac infarction, angina pectoris, cardiac ischemia, cardiovascular disorders and angioplasty restenosis), cerebrovascular diseases (including stroke and cerebral infarction), peripheral vascular diseases (including diabetic vascular complications), dyslipidemia, low-HDL cholesteremia, high-LDL cholesteremia or renal diseases, particularly an active ingredient for an anti-arteriosclerosis agent.

Description

Condensed pyrazole derivatives

The present invention relates to a condensed pyrazole derivative having an excellent lecithin cholesterol acetyltransferase (hereinafter referred to as LCAT) activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof.

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.

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.

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.

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.

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.

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.

As a compound having a pyrazolopyridine skeleton, a compound described in Patent Document 3 is known. Patent Document 3 describes a GSK-3 inhibitory action, but does not describe an LCAT activation action.

WO2008 / 002591 pamphlet WO2012 / 028243 pamphlet US 2004/0266815 A1

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

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.

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 condensed pyrazole 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 condensed pyrazole derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing them.

That is, the present invention
(1) Formula (I)

[Wherein A represents a formula —CH (Y) — wherein Y represents a hydrogen atom, a C _1-6 alkyl group, a halogen atom, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl C _1- Represents a ₅ alkyl group or a hydroxy C _1-6 alkyl group), a group —CH ₂ —CH ₂ — or a group —NH—,
B represents a hydrogen atom or a hydroxyl group;
X represents an oxygen atom or a sulfur atom, and R represents an aryl group which may be substituted (the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoro group) Methoxy group, trifluoromethoxy group, cyano group, C _1-6 alkoxy group, C _3-7 cycloalkoxy group, phenyl group, C _2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C _1-6 alkyl) Or the same or different 1 to 3 groups selected from the group consisting of an aminocarbonyl group and a di (C _1-6 alkyl) amino group), or
An optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms, and further 1 nitrogen atom, An oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, C _{1-6 alkoxy, C 3-7} cycloalkoxy group, a phenyl _{group, C 2-7} alkoxycarbonyl group, benzyloxycarbonyl group, di _{(C 1-6} alkyl) aminocarbonyl Moto及busy _{(C 1-6} alkyl And the same or different groups selected from the group consisting of amino groups.
However, when B is a hydroxyl group and A is a group represented by the formula —CH (Y) —, Y represents a C _1-6 alkyl group, a halogen atom, a C _1-6 alkoxy group or a hydroxy C _1-6. It is an alkyl group. Or a pharmacologically acceptable salt thereof,
(2) A represents a formula —CH (Y) — (wherein Y represents a hydrogen atom, a C _1-6 alkyl group, a halogen atom, a C _1-6 alkoxy group or a hydroxy C _1-6 alkyl group). A compound represented by (1) or a pharmacologically acceptable salt thereof,
(3) A is a formula —CH (Y) — (wherein Y is a hydrogen atom, a C _1-3 alkyl group, a fluorine atom, a chlorine atom, a C _1-3 alkoxy group or a hydroxy C _1-3 alkyl group) Or a pharmacologically acceptable salt thereof according to (1), which is a group represented by:
(4) The compound or pharmacology thereof according to (1), wherein A is a group represented by the formula —CH (Y) — (wherein Y represents a hydrogen atom, a methyl group or a fluorine atom). Top acceptable salt,
(5) The compound according to any one of (1) to (4), wherein B is a hydrogen atom, or a pharmacologically acceptable salt thereof,
(6) The compound according to any one of (1) to (4), wherein B is a hydroxyl group, or a pharmacologically acceptable salt thereof,
(7) The compound according to any one of (1) to (6), wherein X is an oxygen atom, or a pharmacologically acceptable salt thereof,
(8) R is an aryl group which may be substituted (the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, Cyano group, C _1-6 alkoxy group, C _3-7 cycloalkoxy group, phenyl group, C _2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C _1-6 alkyl) aminocarbonyl group and di (C _{1 -6} alkyl) the same or different 1 to 3 groups selected from the group consisting of amino groups) or the pharmacologically acceptable compound thereof according to any one of (1) to (7) Salt,
(9) R is a substituted aryl group (the substituent is a chlorine atom, a fluorine atom, a C _1-3 alkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, and a C _1- Or a pharmacologically acceptable salt thereof according to any one of (1) to (7), which is the same or different 1 or 2 groups selected from the group consisting of ₃ alkoxy groups). ,
(10) R is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). Or the pharmacologically acceptable salt thereof according to any one of (1) to (7),
(11) R is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). , The compound according to any one of (1) to (7) or a pharmacologically acceptable salt thereof,
(12) R is a heteroaryl group which may be substituted (the heteroaryl is a 5-membered or 6-membered ring. The heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms; It may contain one nitrogen atom, oxygen atom or sulfur atom, and the substituent is a halogen atom, C _1-6 alkyl group, C _3-7 cycloalkyl group, trifluoromethyl group, difluoromethoxy group, trifluoro Methoxy group, cyano group, C _1-6 alkoxy group, C _3-7 cycloalkoxy group, phenyl group, C _2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C _1-6 alkyl) aminocarbonyl group and di (C _1-6 alkyl) one or two groups selected from the group consisting of amino groups, which are the same or different), and any one of (1) to (7) Listed compounds or pharmacologically acceptable salts thereof,
(13) R is a substituted heteroaryl group (the heteroaryl is a 5-membered or 6-membered ring. The heteroatom on the ring of the heteroaryl group is one nitrogen atom, and A nitrogen atom, an oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C _1-3 alkyl group, a C _3-6 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, (1 or 2 groups selected from the group consisting of a cyano group, a C _1-3 alkoxy group, a C _2-4 alkoxycarbonyl group and a benzyloxycarbonyl group). 7) The compound or the pharmacologically acceptable salt thereof according to any one of
(14) R is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C _1-3 alkyl group, a cyclopropyl group, 1 or 2 identical or different selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C _1-3 alkoxy group, C _2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to any one of (1) to (7),
(15) R is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) Or a pharmacologically acceptable salt thereof according to any one of (1) to (7), wherein
(16) 4-hydroxy-5-methyl-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5 , 7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
5-Fluoro-4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -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-4-yl} -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-d] pyrimidin-6-one,
(+)-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one,
4- (Trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3 4-b] pyridin-6-one,
4- (trifluoromethyl) -3- {1- [6- (trifluoromethyl) pyridazin-3-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3 4-b] pyridin-6-one and
4- (trifluoromethyl) -3- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3 4-b] the compound according to (1) or a pharmacologically acceptable salt thereof selected from the group consisting of pyridin-6-one,
(17) A pharmaceutical composition comprising the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient,
(18) Arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, comprising as an active ingredient the compound according to any one of (1) to (16) 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,
(19) A preventive or therapeutic agent for arteriosclerosis comprising the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient,
(20) A prophylactic or therapeutic agent for dyslipidemia comprising the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient,
(21) 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 (16) or a pharmacologically acceptable salt thereof. Or therapeutic agent,
(22) 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 (16) or a pharmacologically acceptable salt thereof. Or therapeutic agent,
(23) An LCAT activator comprising the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient,
(24) A reversible LCAT activator comprising as an active ingredient the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof,
(25) An anti-arteriosclerotic agent comprising the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient,
(26) A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof,
(27) 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 (16) or a pharmacologically acceptable salt thereof,
(28) 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 (16) or a pharmacologically acceptable salt thereof. Method,
(29) For preventing or treating dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof. Method,
(30) 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 (16) or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of the disease caused,
(31) 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 (16) or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of the disease caused,
(32) The compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis,
(33) The compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia,
(34) The compound according to any one of (1) to (16) 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
(35) The compound according to any one of (1) to (16) 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 blood. It is an acceptable salt.

Hereinafter, the definition of the substituent in the compound (I) of the present invention will be described.

Compound (I) of the present invention is a compound represented by formula (I) or a tautomer thereof.

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.

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 3 carbon atoms ( C _1-3 alkyl group), more preferably a methyl group.

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. .

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, an isopropoxy group Alternatively, it may be a butoxy group, preferably an oxygen atom (C _1-3 alkoxy group) to which the “C _1-3 alkyl group” is bonded, and more preferably a methoxy group.

In the compound (I) of the present invention, the “hydroxy C _1-6 alkyl group” is the “C _1-6 alkyl group” substituted with one hydroxyl group, such as a hydroxymethyl group, a 1-hydroxyethyl group. Or a 2-hydroxyethyl group, preferably the above-mentioned “C _1-3 alkyl group” substituted with one hydroxyl group, and more preferably a hydroxymethyl group.

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.

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.

In the compound (I) of the present invention, the “C _3-7 cycloalkoxy group” is an oxygen atom to which the “C _3-7 cycloalkyl group” is bonded, and includes a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group. Group, a cyclohexyloxy group, or a cycloheptyloxy group, preferably an oxygen atom (C _1-3 alkoxy group) to which the “C _1-3 alkyl group” is bonded, more preferably a methoxy group It is.

In the compound (I) of the present invention, the “C _2-7 alkoxycarbonyl group” is a carbonyl group to which the “C _1-6 alkoxy group” is bonded, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group. Or a butoxycarbonyl group, preferably a carbonyl group to which the “C _1-3 alkoxy group” is bonded (C _2-4 alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group. It is.

In the compound (I) of the present invention, the “di (C _1-6 alkyl group) amino group” is an amino group to which two identical or different “C _1-6 alkyl groups” are bonded. Is a dimethylamino group.

In the compound (I) of the present invention, the “di (C _1-6 alkyl group) aminocarbonyl group” is a carbonyl group to which the “di (C _1-6 alkyl group) amino group” is bonded. , A dimethylaminocarbonyl group.

In the compound (I) of the present invention, “a heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The hetero atom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms; 1 nitrogen atom, oxygen atom or sulfur atom may be included.) "Means, for example, pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, pyrrole group, pyrazolyl Group, imidazolyl group, triazolyl group or thiadiazolyl group, preferably a 5- or 6-membered heteroaryl group (the heteroatom on the heteroaryl ring is one nitrogen atom, and one nitrogen atom) More preferably a pyridyl group, a pyrimidyl group, a pyrazinyl group, a pyrida group. An alkylsulfonyl group, thiadiazolyl or thiazolyl group, even more preferably, pyridyl group, pyrimidyl group, a pyrazinyl group or a pyridazinyl group, particularly preferably a pyridyl group or a pyrazinyl group.

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.

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. 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.

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.

Dose response curve for determining 50% effective concentration (EC ₅₀ ) of LCAT activation in Test Examples 1 and 2 of the present invention

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.

Manufacturing method 1
Production method 1 is a method for producing compound (I) of the present invention from compound (II).

In the formula, A, B, X and R are as defined above, and R ¹ represents a benzyl group or diphenylmethyl group which may have a substituent on the aromatic ring.

(Process 1)
This step is a step for producing compound (I) by removing protecting group R ¹ of compound (II) in an inert solvent.

Examples of the reagent used for removing the protecting group in compound (II) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And a reagent capable of removing the protecting group described in the above, preferably hydrochloric acid or trifluoroacetic acid, more preferably trifluoroacetic acid, and triethylsilane, anisole as additives. Alternatively, a compound called a cation scavenger such as thioanisole may be used.

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; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alkyl halides, and still more preferably dichloromethane.

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.

Manufacturing method 2
In the intermediate (II) of the compound of the present invention, X is an oxygen atom, A is a formula —CH (Y ¹ ) — (where Y ¹ is a hydrogen atom, a C _1-6 alkyl group, a halogen atom. Or a group represented by C _1-6 alkoxy group) or the compound (IIa) in the case of the group —CH ₂ CH ₂ — can be produced, for example, by the following method.

In the formula, R and R ¹ are as defined above, R ² is a methyl group or an ethyl group, A ¹ is a formula —CH (Y ¹ ) — (where Y ¹ is a hydrogen atom, C ₁ Represents a _-6 alkyl group, a halogen atom or a C _1-6 alkoxy group.) Or a group —CH ₂ CH ₂ —.

(Process 2-1)
This step is a step for producing compound (IV) by reacting compound (III) with acetonitrile 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; Aliphatic hydrocarbons; 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.

(Step 2-2)
This step is a step for producing compound (V) having protecting group R ¹ by reacting compound (IV) with R ¹ —NH—NH ₂ or a salt thereof 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, and more preferably ethanol.

As R ¹ —NH—NH ₂ used in this step, commercially available products or those produced by methods known in the literature can be used. Moreover, what produced the corresponding benzyl halide by making hydrazine monohydrate in alcohols react can also be used.

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 for producing compound (IIa) by condensing compound (VI) with compound (VI) 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, Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxy Alcohols such as ethanol, diethylene glycol or glycerine; aromatic hydrocarbons such as benzene, toluene or xylene; or these It is a mixed solvent, preferably an organic acid, more preferably acetic acid.

The reaction temperature in this step is usually 40 ° C to 200 ° C, preferably 50 ° C to 160 ° C, and 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.

In order to promote the reaction in this step, in addition to heating the reaction solution, microwaves can be irradiated.

Production method 3
Compound (IIa) which is an intermediate of the compound of the present invention can also be produced, for example, by the following method.

In the formula, R, R ² and A ¹ are as defined above, and Cbz represents a benzyloxycarbonyl group.

(Step 3-1)
This step is a step for producing compound (X) by reacting compound (IX) with acetonitrile in an inert solvent using a base.

This step can be performed in the same manner as step 2-1.

(Step 3-2)
This step is a step for producing compound (XI) by reacting compound (X) with a diphenylmethylhydrazine compound in an inert solvent.

This step can be performed in the same manner as step 2-2.

(Step 3-3)
This step is a step for producing compound (XII) by condensing compound (VI) with compound (VI) by heating in a solvent inert to the reaction or in the absence of a solvent.

This step can be performed in the same manner as step 2-3.

(Step 3-4)
This step is a step of producing compound (XIII) by removing the Cbz group in compound (XII).

Examples of reagents used for removing Cbz in compound (XII) 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 are capable of removing Boc, and the like, and are preferably palladium-activated carbon.

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; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alcohols, and still more preferably ethanol.

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 3-5)
This step is a step for producing compound (IIa) by reacting compound (XIII) with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent.

Solvents used in this step are halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert- Ethers such as butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably sulfoxides More preferably a dimethyl sulfoxide.

The base used in this step is an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, N-methylmorpholine, pyridine, dimethylaminopyridine or 2,6-lutidine. Preferred is diisopropylethylamine or 1,8-diazabicyclo [5.4.0] -7-undecene.

The arylating agent or heteroarylating agent used in this step is a compound represented by the formula RF, formula R-Cl or formula R-Br, and preferably the formula RF or formula R-Cl. (R represents the same meaning as described above).

The reaction temperature in this step is preferably 20 ° C to 200 ° C.

In order to promote the reaction in this step, in addition to heating the reaction solution, microwaves can be irradiated.

The reaction time in this step is preferably 5 minutes to 120 hours, more preferably 10 minutes to 96 hours.

Manufacturing method 4
Production method 4 is a method for producing compound (Ib) from compound (XIV), wherein A is a methylene group, B is a hydrogen atom, and X is an oxygen atom, among compounds (I) of the present invention.

In the formula, R is as defined above.

(Process 4)
This step is a step for producing compound (Ib) by reacting compound (XIV) with trifluoroacetaldehyde equivalent and meldrum acid 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. Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl acetate or propyl acetate; aromatic carbonization such as benzene, toluene or xylene Or a mixed solvent thereof, preferably an alcohol, a halogenated hydrocarbon, an ester, an aromatic hydrocarbon, or a mixed solvent thereof, more preferably The ethanol, or a mixed solvent of dichloromethane, ethyl acetate and toluene.

The trifluoroacetaldehyde equivalent used in this step can be, for example, trifluoroacetaldehyde alkyl hemiacetal or trifluoroacetaldehyde dialkyl acetal, and preferably trifluoroacetaldehyde ethyl hemiacetal.

In this step, triethylamine and molecular sieves 4A (registered trademark) may be used as additives.

The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 20 ° C. to the reflux temperature of the solvent.

The reaction time in this step is preferably 30 minutes to 24 hours, and more preferably 1 hour to 6 hours.

Manufacturing method 5
Production method 5 is a method for producing compound (Ib) from compound (XV), wherein A is a methylene group, B is a hydrogen atom, and X is an oxygen atom, among compounds (I) of the present invention.

In the formula, R represents the same meaning as described above, and Boc represents a tert-butoxycarbonyl group.

(Step 5-1)
This step is a step for producing compound (XVI) by reacting compound (XV) with trifluoroacetaldehyde equivalent and meldrum acid in an inert solvent.

This step can be performed in the same manner as step 4.

(Step 5-2)
This step is a step of producing compound (XVII) by removing the Boc group in compound (XVI).

Examples of reagents used for removing Boc in compound (XVI) 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 are capable of removing Boc, and the like, and are preferably hydrochloric acid or trifluoroacetic acid, and more preferably trifluoroacetic acid.

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; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably alkyl halides, and still more preferably dichloromethane.

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 5-3)
This step is a step for producing compound (Ib) by reacting compound (XVII) with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent.

This step can be performed in the same manner as step 3-5.

Manufacturing method 6
Of the intermediates (II) of the compound of the present invention, A is the formula —CH (Y) — (wherein Y is as defined above) and B is a hydrogen atom. Alternatively, the compound represented by the formula (IId) can be produced, for example, by the following method.

In the formula, R and Y are as defined above, and Y ¹ represents a hydroxy C _1-6 alkyl group.

(Step 6-1)
This step is a step for producing a compound (XIX) by reacting the compound (XVIII) with a trifluoroacetaldehyde equivalent and Meldrum's acid in an inert solvent.

This step can be performed in the same manner as step 4.

(Step 6-2)
This step is a step for producing compound (IIc) by reacting compound (XIX) with a nucleophile in the presence of 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, potassium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide, n-butyl It can be an organometallic base such as lithium, lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, or lithium 2,2,6,6-tetramethylpiperidide, preferably organic A metal base, and more preferably lithium diisopropylamide.

The nucleophile used in this step is preferably an alkylating agent such as methyl iodide, dimethyl sulfate or dimethyl carbonate; a halogenating agent such as N-fluorobenzenesulfonimide; or methyl chlorocarbonate or An alkyl chlorocarbonate such as ethyl chlorocarbonate, more preferably methyl iodide, N-fluorobenzenesulfonimide or ethyl chlorocarbonate.

The reaction temperature in this step is preferably −100 ° C. to 100 ° C., and more preferably −78 ° C. to 30 ° C.

The reaction time in this step is preferably 1 hour to 10 hours, and more preferably 2 hours to 5 hours.

(Step 6-3)
This step is a step for producing compound (IId) by reducing compound (IIc) when Y is a C _1-6 alkoxycarbonyl C _1-5 alkyl group 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; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, alcohols such as tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol or glycerin; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethyl Amides such as phosphorotriamide; ketones such as acetone; or like dichloromethane, dichloroethane or chloroform Alkyl halides are exemplified such, preferably an alcohol, more preferably methanol.

Examples of the reagent used in this step include lithium borohydride, sodium borohydride, lithium aluminum hydride, and the like, and preferably sodium borohydride.

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 5 minutes to 5 hours, and more preferably 30 minutes to 2 hours.

Manufacturing method 7
Among the intermediates (II) of the compound of the present invention, a compound represented by the formula (IIe) in which A is a methylene group and B is a hydrogen atom can be produced, for example, by the following method.

In the formula, R and Boc are as defined above.

(Step 7-1)
This step is a step of producing compound (XXI) by reacting compound (XX) with a diphenylmethylhydrazine compound in an inert solvent.

This step can be performed in the same manner as step 2-2.

(Step 7-2)
This step is a step for producing compound (XXII) by reacting compound (XXI) with a trifluoroacetaldehyde equivalent and Meldrum's acid in an inert solvent.

This step can be performed in the same manner as step 4.

(Step 7-3)
This step is a step of producing compound (XXIII) by removing the Boc group in compound (XXII).

This step can be performed in the same manner as step 5-2.

(Step 7-4)
This step is a step for producing compound (IIe) by reacting compound (XXIII) with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent.

This step can be performed in the same manner as step 3-5.

Manufacturing method 8
Production method 8 is a method for producing compound (Ie) of compound (I) of the present invention wherein A is a group —NH— and B is a hydroxyl group from compound (XVIII).

In the formula, R is as defined above.

(Step 8-1)
This step is a step for producing compound (XXIV) by reacting compound (XVIII) with N, N-dimethylformamide dimethyl acetal in the absence of a solvent.

The reaction temperature in this step is preferably 0 ° C. to 200 ° C., more preferably 20 ° C. to the reflux temperature of N, N-dimethylformamide dimethyl acetal.

The reaction time in this step is preferably 1 hour to 10 hours, and more preferably 2 hours to 5 hours.

(Step 8-2)
This step is a step of producing compound (XXV) by reacting compound (XXIV) with trifluoroacetic anhydride in the presence of a base 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. Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof Obtained, preferably halogenated hydrocarbons, more preferably dichloromethane.

The base used in this step is an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, N-methylmorpholine, pyridine, dimethylaminopyridine or 2,6-lutidine. Preferred is 1,8-diazabicyclo [5.4.0] -7-undecene.

The reaction temperature in this step is preferably −20 ° C. to 100 ° C., more preferably 0 ° C. to 30 ° C.

The reaction time in this step is preferably 10 hours to 2 days, and more preferably 15 hours to 1 day.

(Step 8-3)
This step is a step of producing compound (XXVI) by removing the diphenylmethyl group of compound (XXV) in an inert solvent.

This step can be performed in the same manner as step 1.

(Step 8-4)
This step is a step for producing a compound (XXVI) by converting the imidoformamide group of the compound (XXVI) into an amino group in the presence of a base in an inert solvent.

Solvents used in this step are ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert Alcohols such as butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol or glycerol; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene Aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably Ether such a alcohols, or a mixture of these solvents, more preferably a mixed solvent of tetrahydrofuran and methanol.

The base used in this step can be sodium hydroxide, potassium hydroxide or an aqueous solution thereof, and preferably an aqueous sodium hydroxide solution.

The reaction temperature in this step is preferably 0 ° C. to 120 ° C., more preferably 20 ° C. to the reflux temperature of the solvent.

The reaction time in this step is preferably 30 minutes to 10 hours, and more preferably 1 hour to 2 hours.

(Step 8-5)
This step is a step for producing compound (Id) by reacting compound (XXVII) with potassium cyanate in an inert solvent.

The solvent used in this step is water; 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 Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or 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 glycerine; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chloroben Halogenated hydrocarbons such as ethylene or dichlorobenzene; aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably water, organic acids, ethers or these More preferably, it is a mixed solvent of water, acetic acid and tetrahydrofuran.

The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 10 ° C. to 30 ° C.

The reaction time in this step is preferably 3 hours to 15 hours, and more preferably 5 hours to 10 hours.

Manufacturing method 9
Among the intermediates (II) of the compound of the present invention, compound (IIf) in which X is a sulfur atom can be produced, for example, by the following method.

In the formula, A, B and R are as defined above.

This step is a step of producing compound (IIf) from compound (XXVIII) using a thiocarbonylating reagent.

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 mixed solvent thereof. More preferred are ethers or aromatic hydrocarbons, and still more preferred is tetrahydrofuran.

The thiocarbonylating reagent used in this step is a compound having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as hydrogen sulfide or Lawesson's reagent, preferably Lawesson. It is a reagent.

The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 20 ° C. to 60 ° C.

The reaction time in this step is preferably 1 hour to 10 hours, and more preferably 3 hours to 7 hours.

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.

The 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 performed 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. 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.

Examples of the dosage form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include oral administration such as tablets, granules, powders, capsules or syrups; Parenteral administration by an agent, etc. can be mentioned, and it can administer 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 or 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 additives 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. 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.

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, DMSO represents dimethyl sulfoxide, DBU Represents 1,8-diazabicyclo [5.4.0] -7-undecene.

(Reference Example 1) (4-{[tert-butyl (dimethyl) silyl] oxy} benzyl) hydrazine

To a solution of hydrazine monohydrate (12.5 mL, 257.2 mmol) in methanol (80 mL) was added 4- (tert-butyldimethylsilyloxy) benzyl chloride (a compound described in US2011 / 0244481, 6.67 g, 26.26). 0 mmol) in methanol (20 mL) was added dropwise at 0 ° C., the mixture was stirred at room temperature for 2 hours, and the solvent of the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elution solvent: hexane / ethyl acetate = 100 / 0-70 / 30 (gradient)] to give the title compound (4.85 g, yield: 74). %).

¹ H-NMR (500MHz, CDCl ₃ ) δ: 7.18 (2H, d, J = 8Hz), 6.82 (2H, d, J = 8Hz), 4.86 (1H, brs), 3.84 (2H, s), 0.98 ( 9H, s), 0.19 (6H, s).

(Reference Example 2) 3-Oxo-3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} propanenitrile

N-Butyllithium (2.69 M hexane solution, 18.0 mL, 48.4 mmol) was added dropwise to a solution of anhydrous acetonitrile (3.0 mL, 57.3 mmol) in anhydrous THF (50 mL) at −78 ° C., and then at the same temperature. After stirring for 20 minutes, ethyl 1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-4-carboxylate (compound described in WO2005 / 40119 pamphlet, 5.86 g, 19.4 mmol) Anhydrous THF (50 mL) solution was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 40 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. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-70 / 30 (gradient)] to obtain the title compound (2.60 g, yield: 45%). .

¹ H-NMR (500MHz, CDCl ₃ ) δ: 8.39 (1H, s), 7.63 (1H, dd, J = 9Hz, 2Hz), 6.66 (1H, d, J = 9Hz), 4.43 (2H, dt, J = 14Hz, 3Hz), 3.54 (2H, s), 3.06 (2H, td, J = 13Hz, 3Hz), 2.89 (1H, tt, J = 11Hz, 4Hz), 2.01 (2H, dd, J = 14Hz, 3Hz ), 1.70 (2H, ddd, J = 25Hz, 12Hz, 4Hz).

Reference Example 3 1- (4-{[tert-Butyl (dimethyl) silyl] oxy} benzyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazole-5-amine

(4-{[tert-Butyl (dimethyl) silyl] oxy} benzyl) hydrazine (4.85 g, 19.2 mmol) prepared in Reference Example 1 and 3-oxo-3- {1 prepared in Reference Example 2 A solution of-[5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} propanenitrile (2.60 g, 8.75 mmol) in ethanol (200 mL) was stirred with heating under reflux for 8 hours. After cooling, the solvent of the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-40 / 60 (gradient)] to obtain the title compound (1.06 g, yield: 23%). .

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 8.38 (1H, s), 7.74 (1H, d, J = 9Hz), 7.03 (2H, d, J = 8Hz), 6.95 (1H, d, J = 9Hz), 6.77 (2H, d, J = 8Hz), 5.13 (3H, s), 4.94 (2H, s), 4.38 (2H, d, J = 13Hz), 3.03 (2H, t, J = 12Hz) , 2.70 (1H, t, J = 11Hz), 1.86 (2H, d, J = 11Hz), 1.48 (2H, q, J = 11Hz), 0.93 (9H, s), 0.16 (6H, s).

Reference Example 4 1- (4-{[tert-butyl (dimethyl) silyl] oxy} benzyl) -4-hydroxy-5-methyl-4- (trifluoromethyl) -3- {1- [5- ( Trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

1- (4-{[tert-Butyl (dimethyl) silyl] oxy} benzyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-4 prepared in Reference Example 3 To -yl} -1H-pyrazol-5-amine (480 mg, 0.90 mmol) was added ethyl 2-methyl-4,4,4-trifluoroacetoacetate (2.05 g, 10.35 mmol) at 120 ° C. The mixture was stirred for 1 hour, and the solvent of the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elution solvent: ethyl acetate / methanol = 100 / 0-94 / 6 (gradient)], and further purified by silica gel column chromatography [elution solvent: hexane. / Ethyl acetate = 90 / 10-50 / 50 (gradient)] to give the title compound (360 mg, yield: 58%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 8.38 (1H, s), 7.59 (1H, dd, J = 9Hz, 2Hz), 6.98 (2H, d, J = 8Hz), 6.80 (2H, d , J = 8Hz), 6.66 (1H, d, J = 9Hz), 5.11 (2H, dd, J = 53Hz, 16Hz), 4.51 (2H, dd, J = 19Hz, 14Hz), 3.21-3.13 (1H, m ), 3.07-2.99 (2H, m), 2.94-2.88 (1H, m), 2.04-1.94 (1H, m), 1.86-1.77 (1H, m), 1.33-1.24 (6H, m), 0.97 (9H , s), 0.18 (6H, s).

Reference Example 5 1- (3,4-Dimethoxybenzyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5-amine

3-Oxo-3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} propanenitrile (1.88 g, 6.32 mmol) and (3 , 4-Dimethoxybenzene) hydrazine hydrochloride (compound described in WO 1996/16062 pamphlet, 2.95 g, 13.49 mmol) in ethanol (50 mL) was stirred at 50 ° C. for 3 hours, and the reaction solution was reduced under reduced pressure. The solvent was distilled off. The obtained residue was subjected to silica gel column chromatography [elution solvent: (i) hexane / ethyl acetate = 60 / 40-0 / 100 (gradient), (i) ethyl acetate / methanol = 100 / 0-90 / 10 (gradient). The title compound (655 mg, yield: 22%) was obtained.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.38 (1H, s), 7.75 (1H, dd, J = 9Hz, 3Hz), 6.95 (1H, d, J = 9Hz), 6.86 (1H, d , J = 8Hz), 6.80 (1H, d, J = 2Hz), 6.65 (1H, dd, J = 8Hz, 2Hz), 5.13 (3H, m), 4.93 (2H, brs), 4.38 (2H, d, J = 13Hz), 3.70 (3H, s), 3.66 (3H, s), 3.04 (2H, t, J = 11Hz), 2.76-2.65 (1H, m), 1.86 (2H, d, J = 11Hz), 1.56-1.42 (2H, m).

(Reference Example 6) benzyl 4- [5-amino-1- (diphenylmethyl) -1H-pyrazol-3-yl] piperidine-1-carboxylate

1-benzyl 4-ethyl piperidine-1,4-dicarboxylate instead of ethyl 1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-4-carboxylate (described in WO 2004/78750 pamphlet) Was used in the same manner as described in Reference Example 2 to obtain a synthetic intermediate.

Diphenylmethylhydrazine hydrochloride (2.80 g, 11.9 mmol) was added to an ethanol (20.0 mL) solution of the synthetic intermediate obtained by the above operation, and the mixture was stirred at 50 ° C. for 2.5 hours. Saturated aqueous sodium hydrogen carbonate 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 = 50/50] to give the title compound (2.04 g, yield: 42%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.19 (15H, m), 6.65 (1H, s), 5.39 (1H, s), 5.17 (2H, s), 4.19 (2H, brs), 3.23 -3.20 (2H, m), 2.89 (2H, brs), 2.76-2.68 (1H, m), 1.94-1.85 (2H, m), 1.62-1.50 (2H, m).

(Reference Example 7) Compound A-1 and Compound A-2

as well as,

4,4,4 to 4- [5-amino-1- (diphenylmethyl) -1H-pyrazol-3-yl] piperidine-1-carboxylate (386 mg, 0.827 mmol) prepared in Reference Example 6 -Trifluoro-2-methoxy-3-oxobutanoic acid ethyl (379) mg, 1.77 mmol) was added, and the mixture was stirred at 120 ° C. for 2 hours. The reaction mixture was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-50 / 50 (gradient)] and eluted first (hereinafter referred to as compound A-1) ( 124 mg, yield: 24%) and a compound eluting later (hereinafter referred to as compound A-2) (294 mg, yield: 56%) were obtained.

Compound A-1:
¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.40-7.10 (15H, m), 6.66 (1H, s), 5.12 (2H, s), 4.20 (2H, brs), 3.70 (3H, s), 3.49 (1H, s), 3.09-2.82 (3H, m), 1.95-1.59 (4H, m).

Compound A-2:
¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.40-7.06 (15H, m), 6.93 (1H, brs), 6.70 (1H, s), 5.11 (2H, s), 4.20 (2H, brs), 3.73 (1H, s), 3.56 (3H, s), 3.51 (1H, brs), 3.14-3.02 (1H, m), 2.94-2.82 (2H, m), 1.86-1.63 (4H, m).

(Reference Example 8)

Palladium-activated carbon (10%, 52.4 mg) was added to a solution of compound A-1 (124 mg, 0.195 mmol) prepared in Reference Example 7 in ethanol (3.0 mL), and the mixture was heated at room temperature under a hydrogen atmosphere. For 1.5 hours. The reaction solution was filtered, and the solvent of the filtrate was distilled off under reduced pressure to obtain a piperidine intermediate.

To a DMSO (2.0 mL) solution of the piperidine intermediate obtained by the above operation, 2-fluoro-5- (trifluoromethyl) pyridine (30 μL, 0.249 mmol), and N, N-diisopropylethylamine (70 μL, 0.412 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and 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 = 70 / 30-50 / 50 (gradient)] to obtain the target compound (81.7 mg, yield: 65%). It was.

MS (ESI) m / z: 646 (M + H) ⁺ .

(Reference Example 9)

Using compound A-2 (295 mg, 0.465 mmol) prepared in Reference Example 7 instead of compound A-1, the reaction was carried out in the same manner as in the method described in Reference Example 8, and the target compound (187 mg Yield: 62%).

MS (ESI) m / z: 646 (M + H) ⁺ .

(Reference Example 10) 1- (diphenylmethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5-amine

3-Oxo-3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} propanenitrile (4.52 g, 15.2 mmol) prepared in Reference Example 2 in ethanol To the (100 mL) solution, diphenylmethylhydrazine hydrochloride (4.64 g, 19.8 mmol) was added and stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the resulting residue for separation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure. The solvent was distilled off. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (gradient)] to obtain the title compound (5.44 g, yield: 75%). .

¹ H-NMR (400Hz, CDCl ₃ ) δ: 8.38 (1H, s), 7.59 (1H, dd, J = 9Hz, 2Hz), 7.38-7.27 (6H, m), 7.25-7.18 (4H, m), 6.66 (1H, s), 6.64 (1H, s), 5.41 (1H, s), 4.41 (2H, d, J = 13Hz), 3.23 (2H, s), 3.05-2.98 (2H, m), 2.88- 2.81 (1H, m), 2.01 (2H, dd, J = 13Hz, 3Hz), 1.66 (2H, ddd, J = 25Hz, 13Hz, 4Hz).

Reference Example 11 1- (Diphenylmethyl) -4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl}- 4,5,6,8-tetrahydropyrazolo [3,4-b] azepin-7 (1H) -one

1- (Diphenylmethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5-amine (160 mg) prepared in Reference Example 10 , 0.335 mmol) in acetic acid (2 mL) was added ethyl 5,5,5- (trifluoro) -4-oxopentanoate (164 mg, 0.828 mmol), and the mixture was stirred at 100 ° C. for 5 hours. The reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted 3 times 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. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-60 / 40 (gradient)] to give the title compound (88 mg, yield: 42%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.36 (1H, s), 7.58 (1H, d, J = 9Hz), 7.42-7.18 (8H, m), 7.16-7.04 (3H, m), 6.67- 6.54 (2H, m), 4.40 (2H, d, J = 13Hz), 3.32 (1H, brs), 3.09-2.90 (2H, m), 2.77-2.64 (1H, m), 2.60-2.42 (1H, m ), 2.30-2.18 (2H, m), 2.01-1.82 (3H, m), 1.74-1.62 (1H, m).

Reference Example 12 N ′-[1- (diphenylmethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5-yl] -N, N-dimethylimidoformamide

1- (Diphenylmethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5-amine (1) prepared in Reference Example 10 N, N-dimethylformamide dimethyl acetal (12 mL, 91 mmol) is added to .17 g, 2.45 mmol), and the mixture is stirred for 3 hours under heating and refluxing. After cooling, the solvent of the reaction solution is reduced under reduced pressure. Distilled off. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (gradient)] to obtain the title compound (1.18 g, yield: 90%). .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.38-8.37 (1H, m), 7.69 (1H, s), 7.58 (1H, dd, J = 9Hz, 3Hz), 7.31-7.21 (10H, m), 7.05 (1H, s), 6.64 (1H, d, J = 9Hz), 5.56 (1H, s), 4.41-4.36 (2H, m), 3.06-2.87 (3H, m), 2.97 (6H, s), 2.05-2.00 (2H, m), 1.72-1.62 (2H, m).

Reference Example 13 N, N-dimethyl-N ′-[4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H -Pyrazol-5-yl] imidoformamide

N ′-[1- (diphenylmethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5 prepared in Reference Example 12 -Yl] -N, N-dimethylimidoformamide (1.18 g, 2.22 mmol) in dichloromethane (12 mL) at 0 ° C. with DBU (0.69 mL, 4.6 mmol) and trifluoroacetic anhydride ( 0.62 mL, 4.5 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Further, at 0 ° C., DBU (0.69 mL, 4.6 mmol) and trifluoroacetic anhydride (0.62 mL, 4.5 mmol) were added. ) And stirred at room temperature for 3 hours, and further DBU (0.69 mL, 4.6 mmol) and trifluoroacetic anhydride (0.62 mL, 4.5 mmol) at 0 ° C. , And the mixture was stirred at room temperature for 4 hours. Under reduced pressure, the reaction solution was evaporated, extracted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium bicarbonate, 1N hydrochloric acid and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, The solvent was distilled off under. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-50 / 50 (gradient)] to obtain a synthetic intermediate.

To a dichloromethane (18 mL) solution of the synthetic intermediate obtained by the above operation, a solution of trifluoroacetic acid (5 mL) in dichloromethane (6 mL) was added at 0 ° C. and stirred at room temperature for 6.5 hours. The solvent of the reaction solution was distilled off under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue for separation, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Left. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-0 / 100 (gradient)] to obtain the title compound (0.72 g, yield: 76%). .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 9.52 (1H, brs), 8.39-8.38 (1H, m), 7.70 (1H, brs), 7.61 (1H, dd, J = 9Hz, 2Hz), 6.67 ( 1H, d, J = 9Hz), 4.54-4.49 (2H, m), 3.52-3.44 (1H, m), 3.11-3.04 (2H, m), 3.08 (3H, s), 3.06 (3H, s), 2.11-2.04 (2H, m), 1.76-1.66 (2H, m).

(Reference Example 14) 3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5-amine

Similar to the method described in Reference Example 3 using hydrazine monohydrate (1.00 mL, 20.6 mmol) instead of (4-{[tert-butyl (dimethyl) silyl] oxy} benzyl) hydrazine The title compound (880 mg, yield: 79%) was obtained.

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 11.14 (1H, brs), 8.39 (1H, s), 7.76 (1H, dd, J = 9Hz, 2Hz), 6.98 (1H, d, J = 9Hz ), 5.20 (1H, brs), 4.51-4.25 (4H, m), 3.01 (2H, t, J = 12Hz), 2.78 (1H, brs), 1.90 (2H, d, J = 12Hz), 1.49 (2H , dq, J = 12Hz, 4Hz).

Reference Example 15 4- [6-Oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-3-yl] piperidine-1- Tert-butyl carboxylate

To a suspension of Meldrum's acid (1.5 g, 10 mmol), trifluoroacetaldehyde ethyl hemiacetal (1.6 mL, 14 mmol) and 4AMS (2 g) in dichloromethane (30 mL) was added triethylamine (0.45 mL, 3.2 mmol). After stirring for 5 hours at room temperature, a solution of tert-butyl 4- (5-amino-1H-pyrazol-3-yl) piperidine-1-carboxylate (1.00 g, 3.75 mmol) in ethyl acetate (60 mL) And stirred at 80 ° C. for 1 hour. After the reaction solution was concentrated, toluene (50 mL) was added and stirred at 90 ° C. for 2 hours. The reaction solution is cooled and then filtered, and the solvent of the filtrate is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography [NH-silica gel, elution solvent: (i) hexane / ethyl acetate = 20. / 80-0 / 100 (gradient), (ii) ethyl acetate / methanol = 100 / 0-90 / 10 (gradient)] to give the title compound (720 mg, yield: 47%). .

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.16 (1H, s), 10.44 (1H, s), 4.11-3.93 (3H, m), 2.97-2.67 (5H, m), 1.75-1.51 ( 4H, m), 1.41 (9H, s).

Reference Example 16 4- [6-Oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-3-yl] piperidine-1- Optically active substance of tert-butyl carboxylate

4- [6-Oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-3-yl] piperidine prepared in Reference Example 15 After dissolving tert-butyl-1-carboxylate (3.70 g, 9.52 mmol) in IPA while heating, hexane was added to the solution [HPLC: column: Chiralpak IA (20 mm id x 250 mm); Purified in 8 batches by Daicel, elution solvent: hexane / isopropanol = 80/20 (35 minutes) -0/100, flow rate: 15 mL / min], the target compound (1.34 g, yield: 36%) )

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate 1.0 mL / min].

Optical purity 99% or more (retention time: 11.5 minutes).

(Reference Example 17) 5-Fluoro-N, N-dimethyl-2- (trifluoromethyl) benzamide

To a solution of 5-fluoro-2- (trifluoromethyl) benzoic acid (1.93 g, 9.27 mmol) in dichloromethane (50 mL) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.67 g). 13.93 mmol), 1-hydroxybenzotriazole monohydrate (140 mg, 0.91 mmol) and dimethylamine (2.0 M THF solution, 10.0 mL, 20.0 mmol) were added at room temperature, and the mixture was stirred at room temperature for 5 hours. did. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. 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 / 0-60 / 40 (gradient)] to obtain the title compound (1.32 g, yield 61%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.71 (1H, dd, J = 9Hz, 5Hz), 7.22-7.17 (1H, m), 7.06 (1H, dd, J = 8, 2Hz), 3.13 (3H , s), 2.82 (3H, s).

(Reference Example 18) tert-butyl 4- [5-amino-1- (diphenylmethyl) -1H-pyrazol-3-yl] piperidine-1-carboxylate

To a solution of tert-butyl 4- (cyanoacetyl) piperidine-1-carboxylate (compound described in WO 2004/14910 pamphlet, 7.1 g, 28 mmol) in ethanol (71 mL) was added diphenylmethylhydrazine hydrochloride (8.57 g). 36.5 mmol), and stirred at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the resulting residue for liquid separation, the organic layer was dried over anhydrous magnesium 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 / 5-40 / 60 (gradient)] to obtain the title compound (7.43 g, yield: 59%). .

¹ H-NMR (400Hz, CDCl ₃ ) δ: 7.37-7.19 (10H, m), 6.66 (1H, s), 5.40 (1H, s), 4.11 (1H, brs), 3.23-3.20 (1H, m) , 2.82-2.65 (3H, m), 1.89-1.86 (2H, m), 1.61-1.52 (4H, m), 1.46 (9H, s).

Reference Example 19 4- [1- (Diphenylmethyl) -6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine-3 -Yl] piperidine-1-carboxylate tert-butyl

4- [5-Amino-1- (diphenylmethyl) -1H-pyrazol-3-yl] piperidine-1-carboxylate tert-butyl (2.50 g, 5.78 mmol) prepared in Reference Example 18 and Meldrum To a solution of acid (2.50 g, 17.3 mmol) in ethanol (50 mL) was added trifluoroacetaldehyde ethyl hemiacetal (2.27 mL, 17.3 mmol), and the mixture was stirred with heating under reflux for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [NH-silica gel, elution solvent: hexane / ethyl acetate = 90 / 5-50 / 50 (gradient)]. The title compound (1.48 g, yield: 46%) was obtained.

¹ H-NMR (400Hz, CDCl ₃ ) δ: 7.44-7.12 (10H, m), 6.69 (1H, s), 4.13 (1H, brs), 3.65-3.55 (1H, m), 2.95-2.69 (7H, m), 1.87-1.55 (4H, m), 1.45 (9H, s).

Reference Example 20 1- (Diphenylmethyl) -4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4 5,7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

1- (Diphenylmethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5-amine (4) prepared in Reference Example 10 Trifluoroacetaldehyde ethyl hemiacetal (2.68 g, 18.6 mmol) was added to an ethanol (40 mL) solution of Meldrum's acid (2.65 g, 18.4 mmol) and Meldrum's acid (2.65 g, 18.4 mmol). Stir for 5 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [NH-silica gel, elution solvent: (i) hexane / dichloromethane = 50 / 50-0 / 100 (gradient), (ii ) Dichloromethane / methanol = 100 / 0-90 / 10 (gradient)] to give the title compound (2.85 g, yield: 50%).

¹ H-NMR (400Hz, DMSO-d ₆ ) δ: 11.18 (1H, s), 8.38 (1H, s), 7.75 (1H, dd, J = 9Hz, 2Hz), 7.36-7.16 (10H, m), 6.96 (1H, d, J = 9Hz), 6.81 (1H, s), 4.49-4.41 (2H, m), 4.10-4.00 (1H, m), 3.16-2.89 (4H, m), 1.95-1.46 (4H , m).

Reference Example 21 1- (Diphenylmethyl) -5-methyl-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl}- 1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

To a solution of diisopropylamine (0.11 mL, 0.78 mmol) in anhydrous THF (3 mL) at −78 ° C. was added n-butyllithium (2.6 M hexane solution, 0.30 mL, 0.81 mmol) at the same temperature. After stirring for 10 minutes at 1- (diphenylmethyl) -4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidine prepared in Reference Example 20 -4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one (196 mg, 0.327 mmol) in anhydrous THF (2 mL) was added and added for 30 minutes. Stir. To the reaction solution, methyl iodide (40 μL, 0.64 mmol) was added at the same temperature, the temperature was raised to 0 ° C., and the mixture was stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate, 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 = 70 / 30-30 / 70] to give the title compound (124 mg, yield: 62%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 11.16 (1H, s), 8.37 (1H, s), 7.74 (1H, dd, J = 9Hz, 3Hz), 7.39-7.22 (8H, m), 7.00-6.94 (3H, m), 6.82 (1H, s), 4.50-4.39 (2H, m), 3.94-3.81 (1H, m), 3.11-2.89 (3H, m), 2.75 (1H, q, J = 7Hz), 1.98-1.46 (4H, m), 1.13 (3H, d, J = 7Hz).

Reference Example 22 1- (Diphenylmethyl) -5-fluoro-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl}- 1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

The reaction was conducted in the same manner as described in Reference Example 21 using N-fluorobenzenesulfonimide (200 mg, 0.634 mmol) instead of methyl iodide to give the title compound (175 mg, yield: 85%) Got.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 11.89 (1H, s), 8.38 (1H, s), 7.75 (1H, dd, J = 9Hz, 2Hz), 7.37-7.23 (8H, m), 7.14-7.10 (2H, m), 6.96 (1H, d, J = 9Hz), 6.85 (1H, s), 5.28 (1H, d, J = 44Hz), 4.82-4.68 (1H, m), 4.51-4.40 (2H, m), 3.08-2.93 (3H, m), 1.97-1.46 (4H, m).

Example 1 4-Hydroxy-5-methyl-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4 , 5,7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

1- (4-{[tert-Butyl (dimethyl) silyl] oxy} benzyl) -4-hydroxy-5-methyl-4- (trifluoromethyl) -3- {1- [prepared in Reference Example 4 5- (Trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one (360 mg, 0. 53 mmol) in acetic acid (5.0 mL) was added n-tetrabutylammonium fluoride (1.0 M THF solution, 2.0 mL, 2.0 mmol) at room temperature and stirred at room temperature for 2.5 hours. Stir at 2.5 ° C. for 2.5 hours. Saturated aqueous 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 magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [elution solvent: (i) hexane / ethyl acetate = 70 / 30-0 / 100 (gradient), (ii) ethyl acetate / methanol = 100 / 0-85 / 15 (gradient). The synthetic intermediate was obtained.

To a mixed solution of the synthetic intermediate obtained in the above operation with acetonitrile (15 mL) and water (4 mL), 2,3-dichloro-5,6-dicyano-p-benzoquinone (1.95 g, 8.59 mmol) Was added in 4 portions every 2 hours at 80 ° C., and the mixture was further stirred at the same temperature for 7 hours. Saturated aqueous 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 magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [diol silica gel column, elution solvent: hexane / ethyl acetate = 70 / 30-0 / 100 (gradient)], and further purified by silica gel column chromatography [elution solvent: hexane / Purified by ethyl acetate = 50 / 50-0 / 100 (gradient)], and further silica gel column chromatography [NH-silica gel column, elution solvent: ethyl acetate / methanol = 100 / 0-94 / 6 (gradient) The title compound (44 mg, yield: 18%) was obtained.

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.15 (1H, s), 10.35 (1H, s), 8.42 (1H, s), 7.78 (1H, d, J = 9Hz), 7.00 (1H, d, J = 9Hz), 6.54 (1H, s), 4.58 (2H, d, J = 13Hz), 3.31-3.23 (1H, m), 2.98-2.89 (2H, m), 2.66-2.60 (1H, m ), 1.90 (1H, d, J = 12Hz), 1.76-1.62 (3H, m), 1.15 (3H, d, J = 7Hz);
MS (ESI) m / z: 464 (M + H) ^<+> .

Example 2 5-Fluoro-4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4 , 5,7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

as well as,

1- (3,4-Dimethoxybenzyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5 prepared in Reference Example 5 -Amine (640 mg, 1.39 mmol) to ethyl 2,4,4,4-tetrafluoro-3-oxobutanoate (compound described in literature Heterocycles, 1993, 36, 431-434, 2 .50 g, 12.4 mmol) was added, and the mixture was stirred at 120 ° C. for 40 minutes, and the solvent was distilled off under reduced pressure. Ethyl acetate was added, and the resulting solid was collected by filtration to obtain the desired product. Further, the solvent of the filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: hexane / ethyl acetate = 80 / 20-30 / 70 (gradient)] Combined with the solid obtained by the above operation, a synthetic intermediate was obtained.

Trifluoroacetic acid (5.0 mL) was added to the synthetic intermediate obtained by the above operation, and the mixture was stirred at 60 ° C. for 1.5 hours. Saturated aqueous 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 magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elution solvent: ethyl acetate / methanol = 100 / 0-95 / 5 (gradient)], and further purified by silica gel column chromatography [elution solvent: hexane. / Ethyl acetate = 60 / 40-20 / 80 (gradient)] and elute first (hereinafter referred to as compound 2-1) (175 mg, yield: 36%) and later elute Compound (hereinafter referred to as Compound 2-2) (320 mg, yield: 67%) was obtained.

Compound 2-1
¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.37 (1H, s), 11.03 (1H, s), 8.42 (1H, t, J = 1Hz), 7.79 (1H, dd, J = 9Hz, 3Hz ), 7.30 (1H, s), 7.01 (1H, d, J = 9Hz), 4.96 (1H, d, J = 46Hz), 4.58 (2H, d, J = 12Hz), 3.27-3.18 (1H, m) , 2.98-2.89 (2H, m), 2.00-1.92 (1H, m), 1.76-1.62 (3H, m);
MS (ESI) m / z: 468 (M + H) ⁺ .

Compound 2-2:
¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.38 (1H, s), 10.79 (1H, d, J = 3Hz), 8.42 (1H, d, J = 1Hz), 7.79 (1H, dd, J = 9Hz, 3Hz), 7.37 (1H, s), 7.00 (1H, d, J = 9Hz), 5.43 (1H, d, J = 45Hz), 4.58 (2H, d, J = 13Hz), 3.32-3.28 ( 1H, m), 2.95 (2H, t, J = 12Hz), 1.91 (1H, d, J = 11Hz), 1.74-1.61 (3H, m);
MS (ESI) m / z: 468 (M + H) ⁺ .

(Example 3)

Triethylsilane (110 μL, 0.691 mmol) and trifluoroacetic acid (600 μL) were added at 0 ° C. to a solution of the compound produced in Reference Example 8 (81.7 mg, 0.127 mmol) in dichloromethane (3.0 mL), Stir at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (gradient)] to obtain the desired compound (36.0 mg, yield: 59%). .

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.17 (1H, s), 10.59 (1H, s), 8.42 (1H, s), 7.79 (1H, dd, J = 9Hz, 3Hz), 7.00 ( 1H, d, J = 9Hz), 6.77 (1H, s), 4.61-4.54 (2H, m), 3.55 (2H, s), 3.45 (3H, s), 3.35-3.25 (1H, m), 2.97- 2.88 (2H, m), 1.73-1.61 (4H, m);
MS (ESI) m / z: 480 (M + H) ^<+> .

(Example 4)

Using the compound (187 mg, 0.289 mmol) produced in Reference Example 9 instead of the compound produced in Reference Example 8, the reaction was carried out in the same manner as described in Example 3 to obtain the target compound. (108 mg, yield: 78%) was obtained.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.22 (1H, s), 10.46 (1H, s), 8.41 (1H, s), 7.79 (1H, dd, J = 9Hz, 3Hz), 7.01 ( 1H, d, J = 9Hz), 6.84 (1H, s), 4.61-4.55 (2H, m), 4.15 (1H, s), 3.55 (3H, s), 3.35-3.26 (1H, m), 2.98- 2.85 (2H, m), 1.93-1.58 (4H, m);
MS (ESI) m / z: 480 (M + H) ^<+> .

Example 5 4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4,5,6,8 -Tetrahydropyrazolo [3,4-b] azepine-7 (1H) -one

1- (Diphenylmethyl) -4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-4- prepared in Reference Example 11 Yl} -4,5,6,8-tetrahydropyrazolo [3,4-b] azepin-7 (1H) -one (84 mg, 0.13 mmol) in dichloromethane (2 mL) was added triethylsilane (0.04 mL). , 0.3 mmol) and trifluoroacetic acid (1.96 mL) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate, 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 = 50 / 50-0 / 100 (gradient)] to give the title compound (54 mg, yield: 87%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.45 (1H, s), 9.78 (1H, s), 8.42 (1H, s), 7.79 (1H, dd, J = 9Hz, 3Hz), 7.01 ( 1H, d, J = 9Hz), 6.53 (1H, s), 4.59 (2H, t, J = 10Hz), 3.06-2.86 (3H, m), 2.68-2.55 (1H, m), 2.36-2.16 (3H , m), 1.97-1.49 (4H, m);
MS (ESI) m / z: 464 (M + H) ^<+> .

Example 6 4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-d] pyrimidin-6-one

N, N-dimethyl-N ′-[4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl prepared in Reference Example 13 } -1H-pyrazol-5-yl] imidoformamide (0.72 g, 1.6 mmol) in methanol (5 mL) and THF (5 mL) was added aqueous sodium hydroxide (1N, 3.2 mL) and heated to reflux. Under stirring for 1.5 hours. The solvent of the reaction solution was distilled off under reduced pressure, and ethyl acetate and water were added to separate the layers. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 80 / 20-25 / 75 (gradient)] to obtain an aminopyrazole intermediate.

Water (2.5 mL) and potassium cyanate (190 mg, 2.34 mmol) were added to a mixed solution of the aminopyrazole intermediate obtained in the above operation with acetic acid (1.25 mL) and THF (2.5 mL). The mixture was further stirred at room temperature for 3 hours, and further potassium cyanate (100 mg, 1.23 mmol) was added thereto, followed by stirring for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [elution solvent: (i) hexane / ethyl acetate = 80 / 20-0 / 100 (gradient), (ii) ethyl acetate / methanol = 100 / 0-90 / 10 (gradient). The title compound (0.32 g, yield: 80%) was obtained.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.20 (1H, s), 9.84 (1H, s), 8.42-8.41 (1H, m), 7.82-7.77 (2H, m), 7.70 (1H, s), 7.00 (1H, d, J = 9Hz), 4.60-4.54 (2H, m), 3.23-3.12 (1H, m), 2.97-2.89 (2H, m), 1.93-1.60 (4H, m);
MS (ESI) m / z: 451 (M + H) ^<+> .

Example 7 (+)-4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4 , 5,7-Tetrahydro-6H-pyrazolo [3,4-d] pyrimidin-6-one and (−)-4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoro Methyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-d] pyrimidin-6-one

as well as

4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4 prepared in Example 6 A mixed solution of 5,7-tetrahydro-6H-pyrazolo [3,4-d] pyrimidin-6-one (350 m, 0.777 mmol) in ethyl acetate (1 mL), methanol (1.5 mL), and acetone (1 mL) was added. After adsorbing on silica gel (4 g), the solvent was distilled off under reduced pressure. The obtained powder was purified by flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80 / 20-0 / 100, flow rate: 12 mL / min]. The compound eluting first (hereinafter referred to as compound 7-1). ) (170 mg, yield: 49%) and a compound that elutes later (hereinafter referred to as compound 7-2) (172 mg, yield: 49%) were obtained.

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 50/50, flow rate: 1.0 mL / min].

Compound 7-1:
Optical purity 99% or more (retention time: 4.9 minutes);
[α] _D ²⁵ = -2 ° (DMF, c = 1.0).

Compound 7-2:
Optical purity 99% or more (retention time: 9.5 minutes);
[α] _D ²⁵ = + 2 ° (DMF, c = 1.0).

Example 8 4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridin-6-one

3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5-amine (199 mg, 0.639 mmol) prepared in Reference Example 14, and To a solution of Meldrum's acid (110 mg, 0.763 mmol) in ethanol (5 mL) was added trifluoroacetaldehyde ethyl hemiacetal (460 mg, 3.19 mmol), and the mixture was stirred with heating under reflux for 4 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-0 / 100 (gradient)] to give the title compound ( 42 mg, yield: 15%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.14 (1H, s), 10.45 (1H, s), 8.42 (1H, s), 7.79 (1H, dd, J = 9Hz, 3Hz), 7.01 ( 1H, d, J = 9Hz), 4.57 (2H, t, J = 11Hz), 4.06-3.95 (1H, m), 3.38-3.29 (1H, m), 3.11-2.91 (4H, m), 1.86-1.59 (4H, m);
MS (ESI) m / z: 434 (M + H) ^<+> .

Example 9 (+)-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

4- (Trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-produced in Example 8 Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one (1.40 g, 9.52 mmol) was dissolved in IPA while heating, and then a solution to which hexane was added was added to a HPLC [column: Chiralpak IA. (20 mm id × 250 mm); manufactured by Daicel, elution solvent: hexane / isopropanol = 60/40 (30 minutes) −0/100, flow rate: 15 mL / min], and purified in 8 portions to give the title compound ( 517 mg, yield: 37%).

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 50/50, flow rate 1.0 mL / min].

Optical purity 99% or more (retention time: 16.1 minutes);
[α] _D ²⁵ = + 16 ° (DMF, c = 1.0).

Example 10 4- (Trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridin-6-one

Trifluoroacetic acid (10 mL) was added to a dichloromethane (3 mL) solution of the compound produced in Reference Example 16 (1.35 g, 3.48 mmol) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, poured into diethyl ether (150 mL), and the resulting solid was collected by filtration to obtain a synthetic intermediate (1.43 g).

A portion of the synthetic intermediate obtained by the above operation (98 mg) and 2-chloro-5- (trifluoromethyl) pyrazine (68 mg, 0.37 mmol) in DMSO (2 mL) solution at room temperature with N, N -Diisopropylethylamine (0.13 mL, 0.76 mmol) was added and stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate, 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 = 50 / 50-0 / 100 (gradient)] to give the title compound (92 mg, yield: 87%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.13 (1H, s), 10.45 (1H, s), 8.51 (1H, s), 8.50 (1H, s), 4.63 (2H, t, J = 14Hz), 4.05-3.96 (1H, m), 3.15-2.92 (5H, m), 1.89-1.64 (4H, m);
MS (ESI) m / z: 435 (M + H) ^<+> .

Example 11 4- (Trifluoromethyl) -3- {1- [6- (trifluoromethyl) pyridazin-3-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridin-6-one

Similar to the method described in Example 10 using 3-chloro-6- (trifluoromethyl) pyridazine (70 mg, 0.38 mmol) instead of 2-chloro-5- (trifluoromethyl) pyrazine. Reaction was performed to obtain the title compound (91 mg, yield: 77%).

MS (ESI) m / z: 435 (M + H) ^<+> .

Example 12 2-Methyl-6- {4- [6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine-3 -Il] piperidin-1-yl} pyridine-3-carbonitrile

Trifluoroacetic acid (10 mL) was added to a dichloromethane (3 mL) solution of the compound produced in Reference Example 16 (1.35 g, 3.48 mmol) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, poured into diethyl ether (150 mL), and the resulting solid was collected by filtration to obtain a synthetic intermediate (1.43 g).

A portion of the synthetic intermediate obtained by the above operation (98 mg) and 6-chloro-2-methylpyridine-3-carbonitrile (55 mg, 0.36 mmol) in DMSO (2 mL) were added at room temperature to DBU. (0.13 mL, 0.70 mmol) was added and stirred for 9 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate, 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 = 50 / 50-0 / 100 (gradient)] to give the title compound (82 mg, yield: 83%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.13 (1H, s), 10.45 (1H, s), 7.77 (1H, d, J = 9Hz), 6.82 (1H, d, J = 9Hz), 4.63-4.60 (2H, m), 4.04-3.99 (1H, m), 3.08-2.93 (5H, m), 2.47 (3H, s), 1.86-1.62 (4H, m);
MS (ESI) m / z: 405 (M + H) ^<+> .

Example 13 4-Methyl-6- {4- [6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine-3 -Il] piperidin-1-yl} pyridine-3-carbonitrile

The procedure described in Example 12 was followed using 6-chloro-4-methylpyridine-3-carbonitrile (55 mg, 0.36 mmol) instead of 6-chloro-2-methylpyridine-3-carbonitrile. The reaction was performed in the same manner to obtain the title compound (78 mg, yield: 79%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.13 (1H, s), 10.44 (1H, s), 8.41 (1H, s), 6.93 (1H, s), 4.59 (2H, t, J = 14Hz), 4.05-3.96 (1H, m), 3.12-2.92 (5H, m), 2.34 (3H, s), 1.86-1.59 (4H, m);
MS (ESI) m / z: 405 (M + H) ^<+> .

Example 14 N, N-Dimethyl-5- {4- [6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine -3-yl] piperidin-1-yl} -2- (trifluoromethyl) benzamide

5-Fluoro-N, N-dimethyl-2- (trifluoromethyl) benzamide (89 mg, 0.38 mmol) prepared in Reference Example 17 instead of 6-chloro-2-methylpyridine-3-carbonitrile Was used at 80 ° C. in the same manner as described in Example 12 to obtain the title compound (29 mg, yield: 23%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.20 (1H, s), 10.44 (1H, s), 7.53 (1H, d, J = 9Hz), 7.09-7.07 (1H, m), 6.88 ( 1H, brs), 4.08-3.98 (3H, m), 3.08-2.88 (5H, m), 2.97 (3H, s), 2.75 (3H, s), 1.84-1.71 (4H, m);
MS (ESI) m / z: 504 (M + H) ^<+> .

Example 15 3- {1- [2-Methyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -4- (trifluoromethyl) -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

As described in Example 12, using 4-fluoro-2-methyl-6- (trifluoromethyl) pyrimidine (81 mg, 0.41 mmol) instead of 6-chloro-2-methylpyridine-3-carbonitrile. The reaction was conducted in the same manner as described above to obtain the title compound (80 mg, yield: 77%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 12.12 (1H, s), 10.45 (1H, s), 7.14 (1H, s), 4.73 (2H, brs), 4.05-3.97 (1H, m) , 3.12-2.93 (5H, m), 2.44 (3H, s), 1.87-1.60 (4H, m);
MS (ESI) m / z: 449 (M + H) ^<+> .

Example 16 4- {4- [6-Oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-3-yl] piperidine -1-yl} benzonitrile

The reaction was carried out in the same manner as described in Example 12 using 4-fluorobenzonitrile (49 mg, 0.40 mmol) instead of 6-chloro-2-methylpyridine-3-carbonitrile to give the title compound. (64 mg, yield: 66%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 12.18 (1H, s), 10.44 (1H, s), 7.59-7.56 (2H, m), 7.07-7.04 (2H, m), 4.09-3.96 ( 3H, m), 3.04-2.91 (5H, m), 1.85-1.67 (4H, m);
MS (ESI) m / z: 388 (MH) ^- .

Example 17 4- (Trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyrimidin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridin-6-one

Similar to the method described in Example 12 using 2-chloro-5- (trifluoromethyl) pyrimidine (66 mg, 0.36 mmol) instead of 6-chloro-2-methylpyridine-3-carbonitrile. The title compound (98 mg, yield: 93%) was obtained.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.13 (1H, s), 10.47 (1H, s), 8.73-8.72 (2H, m), 4.89-4.82 (2H, m), 4.08-3.97 ( 1H, m), 3.38-2.93 (5H, m), 1.88-1.54 (4H, m);
MS (ESI) m / z: 433 (MH) ^- .

Example 18 5- {4- [6-Oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-3-yl] piperidine -1-yl} pyrazine-2-carbonitrile

The reaction was conducted in the same manner as described in Example 12 using 5-chloropyrazine-2-carbonitrile (53 mg, 0.38 mmol) instead of 6-chloro-2-methylpyridine-3-carbonitrile. The title compound (74 mg, yield: 82%) was obtained.

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.13 (1H, s), 10.45 (1H, s), 8.58 (1H, d, J = 2Hz), 8.50 (1H, d, J = 2Hz), 4.69-4.61 (2H, m), 4.06-3.97 (1H, m), 3.14-2.93 (5H, m), 1.89-1.54 (4H, m).

Example 19 3- [1- (5-Methylpyridin-2-yl) piperidin-4-yl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] Pyridin-6-one

Similar to the method described in Example 12, using 2-fluoro-5-methylpyridine (65 mg, 0.58 mmol) instead of 6-chloro-2-methylpyridine-3-carbonitrile, biotage. The reaction was carried out using Initiator (registered trademark) manufactured by Seisakusho while irradiating with microwaves at 150 ° C. for 1 hour to obtain the title compound (9.1 mg, yield: 9%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.16 (1H, s), 10.43 (1H, s), 7.95 (1H, s), 7.37 (1H, d, J = 8Hz), 6.79 (1H, d, J = 8Hz), 4.38-4.33 (2H, m), 4.02-3.97 (1H, m), 2.96-2.73 (5H, m), 2.14 (3H, s), 1.81-1.49 (4H, m);
MS (ESI) m / z: 380 (M + H) ⁺ .

Example 20 4- (Trifluoromethyl) -3- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridin-6-one

4- [1- (Diphenylmethyl) -6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] prepared in Reference Example 19 To a mixed solution of tert-butyl pyridin-3-yl] piperidine-1-carboxylate (487 mg, 0.878 mmol) in dichloromethane (1 mL) and acetonitrile (4 mL), chlorotrimethylsilane (0.30 mL, 2.4 mmol) and Sodium iodide (300 mg, 2.00 mmol) was added at room temperature and stirred for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain a synthetic intermediate.

To a solution of the synthetic intermediate obtained in the above operation in DMSO (10 mL), 5-chloro-2- (trifluoromethyl) pyrimidine (319 mg, 1.75 mmol) and DBU (0.50 mL, 3.3 mmol) were added. The mixture was stirred at 70 ° C. for 1 day. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate, 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 / dichloromethane = 50 / 50-0 / 100] to obtain a diphenylmethyl-protected intermediate (190 mg).

1- (diphenylmethyl) -4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4,5,6 , 8-Tetrahydropyrazolo [3,4-b] azepin-7 (1H) -one was replaced with a portion of the diphenylmethyl-protected intermediate obtained in the above procedure (178 mg). To give the title compound (104 mg, yield: 29%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.18 (1H, s), 10.47 (1H, s), 8.67 (2H, s), 4.19-3.99 (3H, m), 3.05-2.93 (5H, m), 1.85-1.72 (4H, m).

Example 21 5-Methyl-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

1- (diphenylmethyl) -4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4,5,6 , 8-Tetrahydropyrazolo [3,4-b] azepin-7 (1H) -one, instead of 1- (diphenylmethyl) -5-methyl-4- (trifluoromethyl) prepared in Reference Example 21 ) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine- The reaction was carried out using 6-one (124 mg, 0.202 mmol) in the same manner as described in Example 5 to obtain the title compound (78 mg, yield: 86%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.16 (1H, s), 10.42 (1H, s), 8.42 (1H, s), 7.79 (1H, d, J = 9Hz), 7.01 (1H, d, J = 9Hz), 4.58 (2H, s), 3.79 (1H, q, J = 10Hz), 3.10-2.92 (3H, m), 2.74-2.62 (1H, m), 1.87-1.59 (4H, m ), 1.15 (3H, d, J = 7Hz);
MS (ESI) m / z: 448 (M + H) ^<+> .

Example 22 5-Fluoro-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

1- (diphenylmethyl) -4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4,5,6 , 8-Tetrahydropyrazolo [3,4-b] azepin-7 (1H) -one, instead of 1- (diphenylmethyl) -5-fluoro-4- (trifluoromethyl) prepared in Reference Example 22 ) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine- The reaction was carried out using 6-one (175 mg, 0.283 mmol) in the same manner as described in Example 5 to obtain the title compound (94 mg, yield: 74%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.38 (1H, s), 11.15 (1H, s), 8.42 (1H, s), 7.80 (1H, dd, J = 9Hz, 2Hz), 7.02 ( 1H, d, J = 9Hz), 5.18 (1H, d, J = 44Hz), 4.73-4.52 (3H, m), 3.20-3.07 (1H, m), 3.03-2.89 (2H, m), 1.87-1.60 (4H, m);
MS (ESI) m / z: 452 (M + H) ^<+> .

Example 23 5- (Hydroxymethyl) -4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4 5,7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

To a solution of diisopropylamidolithium (1.1M hexane-THF mixed solution, 1.10 mL, 1.20 mmol) in anhydrous THF (5 mL) was added 1- (diphenylmethyl) -4- (trifluoro) produced in Reference Example 20. Methyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine -6-one (250 mg, 0.417 mmol) was added and stirred for 30 minutes. To the reaction solution, a solution of ethyl chloroformate (70 μL, 0.74 mmol) in THF (2 mL) was added at the same temperature, stirred for 2 hours, further warmed to 0 ° C. and stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate, 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 = 80 / 20-10 / 90] to give an ethoxycarbonyl adduct.

To a methanol (5 mL) solution of the ethoxycarbonyl adduct obtained by the above operation, sodium borohydride (20 mg, 0.529 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted 3 times 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 = 70 / 30-10 / 90 (gradient)] to obtain a hydroxymethyl intermediate.

1- (diphenylmethyl) -4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4,5,6 , 8-Tetrahydropyrazolo [3,4-b] azepin-7 (1H) -one, but using the hydroxymethyl intermediate obtained in the above procedure, similar to the method described in Example 5. The title compound (6.5 mg, yield: 3%) was obtained.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.18 (1H, s), 10.53 (1H, s), 8.42 (1H, s), 7.79 (1H, d, J = 10Hz), 7.01 (1H, d, J = 9Hz), 5.32 (1H, t, J = 6Hz), 4.57 (2H, s), 3.97-3.87 (1H, m), 3.63-3.53 (1H, m), 3.24-2.92 (3H, m ), 1.85-1.62 (3H, m), 1.30-1.13 (3H, m);
MS (ESI) m / z: 464 (M + H) ^<+> .

Example 24 4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridine-6-thione

1- (Diphenylmethyl) -4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1 prepared in Reference Example 20 , 4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one (205 mg, 0.343 mmol) in anhydrous THF (3 mL) was added Lawesson's reagent (163 mg, 0.403 mmol). In addition, the mixture was stirred for 8 hours with heating under reflux. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-30 / 70 (gradient)]. To obtain a diphenylmethyl protected intermediate.

1- (diphenylmethyl) -4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4,5,6 , 8-tetrahydropyrazolo [3,4-b] azepin-7 (1H) -one, using the diphenylmethyl protected intermediate obtained in the above procedure and the method described in Example 5 The reaction was conducted in the same manner to obtain the title compound (86 mg, yield: 55%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.63 (1H, s), 12.44 (1H, s), 8.43-8.41 (1H, m), 7.79 (1H, dd, J = 9Hz, 2Hz), 7.01 (1H, d, J = 9Hz), 4.62-4.55 (2H, m), 4.05-3.93 (1H, m), 3.26-3.23 (2H, m), 3.12-2.94 (3H, m), 1.86-1.61 (4H, m);
MS (ESI) m / z: 450 (M + H) ^<+> .

(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.

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.

Table 1
――――――――――――――――――――――――――――――
Test compound EC ₅₀ (μM)
――――――――――――――――――――――――――――――
Compound of Example 1 0.072
Compound 2-1 of Example 2 0.052
Compound 2-2 of Example 2 0.084
Compound of Example 3 1.11.
Compound of Example 4 0.75
Compound of Example 5 1.32
Compound of Example 6 0.40
Compound 7-1 of Example 7 0.28
Compound 7-2 of Example 7 1.34
Compound of Example 8 0.29
Compound of Example 9 0.31
Compound of Example 10 0.076
Compound of Example 11 0.27
Compound of Example 12 0.55
Compound of Example 13 0.43
Compound of Example 14 0.88
Compound of Example 15 0.50
Compound of Example 16 1.07
Compound of Example 17 1.25
Compound of Example 18 1.05
Compound of Example 19 1.04
Compound of Example 20 0.23
Compound of Example 21 0.74
Compound of Example 22 0.77
Compound of Example 23 0.42
Compound of Example 24 0.97
――――――――――――――――――――――――――――――

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.

(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.

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.

(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.

(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 is determined from AUC before administration and 24 hours after administration.

(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)
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.

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.

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.

In addition, if desired, apply a coating.

(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.

(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. .

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 (35)

formula

[Wherein A represents a formula —CH (Y) — wherein Y represents a hydrogen atom, a C _1-6 alkyl group, a halogen atom, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl C _1- Represents a ₅ alkyl group or a hydroxy C _1-6 alkyl group), a group —CH ₂ —CH ₂ — or a group —NH—,
B represents a hydrogen atom or a hydroxyl group;
X represents an oxygen atom or a sulfur atom,
R represents an aryl group which may be substituted (the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, C _{1-6 alkoxy, C 3-7} cycloalkoxy group, a phenyl _{group, C 2-7} alkoxycarbonyl group, benzyloxycarbonyl group, di _{(C 1-6} alkyl) aminocarbonyl Moto及busy _{(C 1-6} alkyl ) The same or different 1 to 3 groups selected from the group consisting of amino groups), or
An optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms, and further 1 nitrogen atom, An oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, C _{1-6 alkoxy, C 3-7} cycloalkoxy group, a phenyl _{group, C 2-7} alkoxycarbonyl group, benzyloxycarbonyl group, di _{(C 1-6} alkyl) aminocarbonyl Moto及busy _{(C 1-6} alkyl And the same or different groups selected from the group consisting of amino groups.
However, when B is a hydroxyl group and A is a group represented by the formula —CH (Y) —, Y represents a C _1-6 alkyl group, a halogen atom, a C _1-6 alkoxy group or a hydroxy C _1-6. It is an alkyl group. Or a pharmacologically acceptable salt thereof. A is represented by the formula —CH (Y) — (wherein Y represents a hydrogen atom, a C _1-6 alkyl group, a halogen atom, a C _1-6 alkoxy group or a hydroxy C _1-6 alkyl group). Or a pharmacologically acceptable salt thereof according to claim 1, which is a group represented by the formula: A represents the formula —CH (Y) — (wherein Y represents a hydrogen atom, a C _1-3 alkyl group, a fluorine atom, a chlorine atom, a C _1-3 alkoxy group or a hydroxy C _1-3 alkyl group). The compound or its pharmacologically acceptable salt of Claim 1 which is group represented by this. 2. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein A is a group represented by the formula —CH (Y) — (wherein Y represents a hydrogen atom, a methyl group or a fluorine atom). Salt. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein B is a hydrogen atom. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein B is a hydroxyl group. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 6, wherein X is an oxygen atom. R is an aryl group which may be substituted (the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, C _{1-6 alkoxy, C 3-7} cycloalkoxy group, a phenyl _{group, C 2-7} alkoxycarbonyl group, benzyloxycarbonyl group, di _{(C 1-6} alkyl) aminocarbonyl Moto及busy _{(C 1-6} alkyl 8. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7, wherein the compound is the same or different 1 to 3 groups selected from the group consisting of amino groups. R represents a substituted aryl group (the substituent is a chlorine atom, a fluorine atom, a C _1-3 alkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, and a C _1-3 alkoxy group). The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7, which is the same or different 1 or 2 groups selected from the group consisting of: R is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group and a cyano group). The compound according to any one of claims 1 to 7, or a pharmacologically acceptable salt thereof. R is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). 8. The compound according to any one of 1 to 7 or a pharmacologically acceptable salt thereof. R is an optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatoms on the ring of the heteroaryl group are 1 or 2 nitrogen atoms, and A nitrogen atom, an oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, Cyano group, C _1-6 alkoxy group, C _3-7 cycloalkoxy group, phenyl group, C _2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C _1-6 alkyl) aminocarbonyl group and di (C ₁ The compound according to any one of claims 1 to 7, which is the same or different 1 or 2 groups selected from the group consisting of _-6 alkyl) amino groups. Or a pharmacologically acceptable salt thereof. R is a substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is one nitrogen atom, and further one nitrogen atom, An oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C _1-3 alkyl group, a C _3-6 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, Any one or two groups selected from the group consisting of a C _1-3 alkoxy group, a C _2-4 alkoxycarbonyl group, and a benzyloxycarbonyl group. The compound according to one or a pharmacologically acceptable salt thereof. R is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C _1-3 alkyl group, a cyclopropyl group, trifluoromethyl group) One or two groups selected from the group consisting of a group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, a C _1-3 alkoxy group, a C _2-4 alkoxycarbonyl group and a benzyloxycarbonyl group. The compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof. R is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is the same or selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7, wherein the compound is one or two different groups. 4-hydroxy-5-methyl-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
5-Fluoro-4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -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-4-yl} -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-d] pyrimidin-6-one,
(+)-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one,
4- (Trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3 4-b] pyridin-6-one,
4- (trifluoromethyl) -3- {1- [6- (trifluoromethyl) pyridazin-3-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3 4-b] pyridin-6-one and
4- (trifluoromethyl) -3- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3 The compound or pharmacologically acceptable salt thereof according to claim 1, selected from the group consisting of 4-b] pyridin-6-one. A pharmaceutical composition comprising as an active ingredient the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof. An arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebrovascular disease, peripheral, comprising the compound according to any one of claims 1 to 16 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. A prophylactic or therapeutic agent for arteriosclerosis comprising the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient. A prophylactic or therapeutic agent for dyslipidemia comprising the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient. 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 16 or a pharmacologically acceptable salt thereof. A preventive or therapeutic agent for a disease caused by a decrease in blood HDL cholesterol concentration, comprising as an active ingredient the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof. An LCAT activator comprising as an active ingredient the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof. A reversible LCAT activator comprising the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient. An anti-atherosclerotic agent comprising the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient. A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof. 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 16 or a pharmacologically acceptable salt thereof. 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 16 or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of dyslipidemia, comprising administering an effective amount of the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof to a human. 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 16 or a pharmacologically acceptable salt thereof. Or a method for treatment. Prevention of a disease caused by a decrease in the concentration of HDL cholesterol in the blood, which comprises administering to a human an effective amount of the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof. Or a method for treatment. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 16, for use in a method for the treatment or prevention of arteriosclerosis. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 16, for use in a method for the treatment or prevention of dyslipidemia. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 16, 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. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 16, 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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