WO2015087995A1 - Cycloalkyl or heterocyclyl pyrazolopyridine derivative - Google Patents

Abstract

A compound which has excellent LCAT activation effects, is useful as an active ingredient of a therapeutic or preventive agent for arteriosclerosis, arteriosclerotic cardiovascular disease, coronary heart disease (including heart failure, myocardial infarction, angina, cardiac ischemia, cardiovascular disorder, and angioplastic restenosis), cerebrovascular disease (including cerebral stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complication), dyslipidemia, low HDL cholesterol, high HDL cholesterol, or kidney disease, in particular, of an anti-arteriosclerosis agent, and is represented by formula (I) (I) [In the formula, R is a C_6-8 cycloalkyl group, a C_6-8 cycloalkenyl group, or a 4 to 7-membered heterocyclyl group which may be substituted.] or a pharmacologically acceptable salt thereof.

Description

Cycloalkyl or heterocyclylpyrazolopyridine derivatives

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

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.

WO2008 / 002591 pamphlet WO2012 / 028243 pamphlet

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 pyrazolopyridine derivative having a specific structure or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and completed the present invention.

The present invention provides a pyrazolopyridine derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing them.

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

[Wherein R is a C _6-8 cycloalkyl group, a C _6-8 cycloalkenyl group, or _4-7 which may be substituted with the same or different 1 to 2 substituents selected from the substituent group A. A membered heterocyclyl group (the heteroatom on the heterocyclyl ring is one or two nitrogen atoms);
Substituent group A includes a C _1-6 alkyl group, a halogen atom, and an optionally substituted aryl group (the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group) , Difluoromethoxy 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) aminocarbonyl group and di (C _1-6 alkyl) amino group are the same or different 1 to 3 groups selected from the group consisting of
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 R is an optionally substituted 4-piperidinyl group, at least one of the 2, 3, 5 and 6 positions of the piperidinyl group has a substituent. Or a pharmacologically acceptable salt thereof,
(2) R is a C _6-8 cycloalkyl group or a C _6-8 cycloalkenyl group, which may be substituted with the same or different one or two substituents selected from Substituent Group A1, Group A1 includes a C _1-6 alkyl group, a halogen atom and 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) (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 a pharmacologically acceptable salt thereof,
(3) R is a cyclohexyl group substituted by one or two different substituents selected from the substituent group A2, and the substituent group A2 includes a C _1-4 alkyl group, a fluorine atom, chlorine An atom and 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 same or different 1 or 2 groups selected from the group consisting of: a compound or a pharmacologically acceptable salt thereof according to (1),
(4) R is a cyclohexyl group substituted with one or two substituents selected from the same or different substituent group A3, and the substituent group A3 includes a C ₁ -C ₄ alkyl group, a fluorine atom, A chlorine atom and 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 (1) or a pharmacologically acceptable salt thereof,
(5) R is a cyclohexyl group substituted by 1 to 2 substituents selected from the same or different substituent group A4, and the substituent group A4 includes a C ₁ -C ₄ alkyl group, a fluorine atom, A chlorine atom and 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). ) Or a pharmacologically acceptable salt thereof,
(6) The compound or pharmacologically acceptable salt thereof according to (1), wherein R is a 4-phenylcyclohexyl group,
(7) R is a 4- to 7-membered heterocyclyl group which may be substituted by the same or different 1 to 2 substituents selected from Substituent Group A5 (the number of heteroatoms on the heterocyclyl ring is 1 or 2 The substituent group A5 includes a C _1-6 alkyl group and an optionally substituted heteroaryl group (the heteroaryl is a 5-membered or 6-membered ring). The hetero atom of is one or two nitrogen atoms, and may further contain one nitrogen atom, oxygen atom or sulfur atom, and the substituent is a halogen atom, a C _1-6 alkyl group, C _{3- 7} cycloalkyl group, a trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano _{group, C 1-6 alkoxy, C 3-7} cycloalkoxy group, a phenyl _{group, C 2-7} an alkoxycarbonyl Boniru group, a benzyloxycarbonyl group, a di (C _1-6 alkyl) aminocarbonyl Moto及busy (C _1-6 alkyl) the same or different 1 or 2 groups selected from the group consisting of amino group.) Or a pharmacologically acceptable salt thereof according to (1),
(8) 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, 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, 4 to 7-membered groups substituted with the same or different 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. heteroatom on the ring of a heterocyclyl group (said heterocyclyl is one or two nitrogen atoms. the heterocyclyl may be further substituted by C _1-6 alkyl group ) Is a compound or a pharmacologically acceptable salt thereof according to (1),
(9) 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 A 4- to 7-membered heterocyclyl group (the heteroatom on the heterocyclyl ring is a nitrogen atom. The heterocyclyl may be further substituted with a methyl group). , The compound according to (1) or a pharmacologically acceptable salt thereof,
(10) 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) 4-7 membered heterocyclyl groups substituted with the same or different 1 or 2 groups, wherein the heteroatom on the ring of the heterocyclyl is a nitrogen atom. The heterocyclyl further comprises a methyl group Or a pharmacologically acceptable salt thereof according to (1), wherein
(11) A 4- to 7-membered heterocyclyl group in which R is substituted with a substituted pyridyl group or pyrazinyl group (the substituent is a trifluoromethyl group) (the heteroatom on the heterocyclyl ring is 1 Or a pharmacologically acceptable salt thereof, wherein the heterocyclyl may be further substituted with a methyl group),
(12) 4-hydroxy-3- (4-phenylcyclohexyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one,
3- {1- [3-Chloro-5- (trifluoromethyl) -2-pyridyl] pyrrolidin-3-yl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro -6H-pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one,
3- {1- [3-Chloro-5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
3- [1- (3,5-Dichloropyridin-2-yl) pyrrolidin-3-yl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [ 3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- {1- [4- (trifluoromethyl) pyrimidin-2-yl] pyrrolidin-3-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one,
4-Hydroxy-3- {2-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl) -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-3-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-3- {3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl) -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-3- {3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl) -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
3- {1- [4- (Difluoromethoxy) phenyl] -3-methylpiperidin-4-yl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] azepan-4-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one, and
4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyrazin-2-yl] pyrrolidin-3-yl} -1,4,5,7-tetrahydro-6H- A compound according to (1) or a pharmacologically acceptable salt thereof selected from the group consisting of pyrazolo [3,4-b] pyridin-6-one;
(13) (4R) -4-hydroxy-4- (trifluoromethyl) -3-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1 , 4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -3-{(3S) -1- [3-Chloro-5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -4-hydroxy-4- (trifluoromethyl)- 1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -3-[(3S) -1- (3,5-dichloropyridin-2-yl) pyrrolidin-3-yl] -4-hydroxy-4- (trifluoromethyl) -1,4,5 7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-4- (trifluoromethyl) -3-{(3S) -1- [4- (trifluoromethyl) pyrimidin-2-yl] pyrrolidin-3-yl} -1,4 5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-3-{(2R, 4R) -2-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl ) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-3-{(2S, 4S) -2-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl ) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-4- (trifluoromethyl) -3-{(3R) -1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-3-yl} -1,4 5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-3-{(3R, 4R) -3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl ) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-3-{(3S, 4S) -3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl ) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -3-{(3R, 4R) -1- [4- (Difluoromethoxy) phenyl] -3-methylpiperidin-4-yl} -4-hydroxy-4- (trifluoromethyl) -1,4 , 5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one, and
(4R) -3-{(3S, 4S) -1- [4- (Difluoromethoxy) phenyl] -3-methylpiperidin-4-yl} -4-hydroxy-4- (trifluoromethyl) -1,4 , 5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one, or a pharmacologically acceptable salt thereof according to (1),
(14) A pharmaceutical composition comprising the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient,
(15) Arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, comprising as an active ingredient the compound according to any one of (1) to (13) 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,
(16) A prophylactic or therapeutic agent for arteriosclerosis comprising the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient,
(17) A prophylactic or therapeutic agent for dyslipidemia comprising the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient,
(18) An agent for preventing 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 (13) or a pharmacologically acceptable salt thereof. Or therapeutic agent,
(19) A prophylactic 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 (13) or a pharmacologically acceptable salt thereof. Or therapeutic agent,
(20) an LCAT activator comprising the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient,
(21) A reversible LCAT activator comprising the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient,
(22) An anti-arteriosclerotic agent comprising the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient,
(23) A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof,
(24) 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 (13) or a pharmacologically acceptable salt thereof,
(25) 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 (13) or a pharmacologically acceptable salt thereof. Method,
(26) For prevention or treatment of dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof. Method,
(27) 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 (13) or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of the disease caused,
(28) 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 (13) or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of the disease caused,
(29) The compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis,
(30) The compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia,
(31) The compound according to any one of (1) to (13) 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
(32) The compound according to any one of (1) to (13) 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 _6-8 cycloalkyl group” is a cyclic saturated hydrocarbon group having 6 to 8 carbon atoms such as cyclohexyl group, cycloheptyl group or cyclooctyl group, Is a cyclohexyl group.

In the compound (I) of the present invention, the “C _6-8 cycloalkenyl group” is a cyclic hydrocarbon group having 6 to 8 carbon atoms having a double bond, such as a cyclohexenyl group, a cycloheptenyl group or a cyclooctenyl group. Yes, preferably a cyclohexenyl group.

In the compound (I) of the present invention, the “4- to 7-membered heterocyclyl group (the heteroatom on the heterocyclyl ring is 1 or 2 nitrogen atoms)” means, for example, an azetidinyl group, a pyrrolidinyl group, a pyrazolidinyl group , An imidazolidinyl group, a piperidinyl group, a tetrahydropyrazinyl group, a tetrahydropyrimidinyl group, a tetrahydropyridazinyl group, a hexahydroazepinyl group, or a tetrahydroimidazo [1,2-a] pyridinyl group, and preferably A 4- to 7-membered heterocyclyl group (the heteroatom on the heterocyclyl ring is one nitrogen atom), and more preferably an azetidinyl group, a pyrrolidinyl group, or a piperidinyl group.

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 “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 _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 “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 _3-7 cycloalkoxy group) to which the “C _3-7 cycloalkyl group” is bonded, and more preferably Cyclobutoxy group.

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, R is as defined above, and R ¹ represents a methyl group or an ethyl group.

Compound (II) includes compound (IIx) which is a tautomer. In the present invention, compound (II) includes all isomers of tautomers. That is, the compound (II) includes all of the compound (II), the compound (IIx), and a mixture of the compound (II) and the compound (IIx) in an arbitrary ratio. In addition, the compound represented by the compound name of compound (II) includes all of compound (II), compound (IIx), and a mixture of compound (II) and compound (IIx) in an arbitrary ratio.

(Process 1)
This step is a step for producing compound (I) by condensing compound (III) with compound (II) by heating in a solvent inert to the reaction or in the absence of a solvent.

Solvents used in this step include organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid; diethyl ether, diisopropyl ether , Tetrahydrofuran, dioxane, dimethoxyethane, or ethers such as tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2 Alcohols such as methoxyethanol, diethylene glycol or glycerol; aromatic hydrocarbons such as benzene, toluene or xylene; or It is a mixed solvent of these, preferably an organic acid, more preferably acetic acid.

The reaction temperature in this step is usually 40 ° C. to 150 ° C., preferably 50 ° C. to 130 ° C., more preferably 60 ° C. to the reflux temperature of the solvent.

The reaction time in this step is usually 5 minutes to 72 hours, preferably 15 minutes to 24 hours, and more preferably 30 minutes to 3 hours.

Manufacturing method 2
The intermediate (II) of the compound of the present invention can be produced, for example, by the following method.

In the formula, R is as defined above, R ² is an alkoxy group or a chlorine atom, ^Ra is one or more amino groups (the amino group is a primary or secondary amino group, A cyclic amino group) or a group having an unsaturated bond and converted to R by Step 2-3.

(Process 2-1)
(I) This step is a step of producing compound (V) by reacting compound (IV) with acetonitrile using a base in an inert solvent when R ² is an alkoxy group.

Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.

The base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide or n-butyllithium. It can be an organometallic base, more preferably sodium hydride or n-butyllithium.

The reaction temperature in this step is preferably −100 ° C. to 0 ° C., and more preferably −78 ° C. to −40 ° C.

The reaction time in this step is preferably 5 minutes to 3 hours, and more preferably 15 minutes to 2 hours.

(Ii) Alternatively, this step is a step of producing compound (V) by reacting compound (IV) with cyanoacetic acid using a base in an inert solvent when R ² is a chlorine atom. is there.

Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.

The base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide or n-butyllithium. It can be an organometallic base, more preferably n-butyllithium.

The reaction temperature in this step is preferably −100 ° C. to 0 ° C., and more preferably −78 ° C. to −40 ° C.

The reaction time in this step is preferably 5 minutes to 3 hours, and more preferably 15 minutes to 2 hours.

Compound (IV) which is a starting material for this step may be a commercially available product, or can be produced by esterification or acid chlorideation of a known benzoic acid compound by a conventional method.

(Step 2-2)
This step is a step for producing compound (II) by reacting compound (V) with a hydrazine compound in an inert solvent.

Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin. Aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably alcohols, more preferably ethanol.

The hydrazine compound used in this step is anhydrous hydrazine, hydrazine monohydrate, hydrazine hydrochloride, hydrazine acetate, hydrazine sulfate, hydrazine nitrate, hydrazine hydrobromide, hydrazine oxalate, or hydrazine phosphate. Preferred is hydrazine monohydrate or hydrazine acetate.

The reaction temperature in this step is preferably 20 ° C. to 120 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.

The reaction time in this step is preferably 10 minutes to 24 hours, and more preferably 1 hour to 5 hours.

(Step 2-3)
(I) In this step, when R ^a has an amino group, the compound (VI) is subjected to Buchwald-Hartwig reaction using a palladium catalyst in an inert solvent in the presence of a ligand and a base in addition to the palladium catalyst. In this step, compound (IV) is produced by reacting with an arylating agent or heteroarylating agent.

The palladium catalyst, ligand, base and reaction conditions used in this step are not particularly limited as long as they are reagents and conditions usually used for the Buchwald-Hartwig reaction. R. Muci, S .; L. Buchwald, Top. Curr. Chem. 2002, 219, p. 131.

The solvent used in this step is an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl-methyl ether; or an aromatic hydrocarbon such as benzene, toluene, or xylene. And preferably toluene or dioxane, more preferably toluene.

The palladium catalyst used in this step is preferably palladium (II) acetate or palladium (0) dibenzylideneacetone.

The ligand used in this step is preferably 2- (di-tert-butylphosphino) biphenyl, tri-tert-butylphosphine, tricyclohexylphosphine, 1,3-bis (diphenylphosphino) propane, 2, 2′-bis (diphenylphosphanyl) 1,1′-binaphthyl, 2- (dicyclohexylphosphino) biphenyl or 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, more preferably 2- (di-tert-butylphosphino) biphenyl, tri-tert-butylphosphine or 2,2′-bis (diphenylphosphanyl) 1,1′-binaphthyl.

The base used in this step is preferably sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium or tert-butoxy potassium, and more preferably tert-butoxy sodium.

The arylating or heteroarylating agent used in this step is a compound having the formula R ^b —Cl, the formula R ^b —Br or the formula R ^b —I, preferably the formula R ^b —Cl or the formula R ^{b 1} -Br 2 (R ^b 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) , 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 Moto及busy (C _1-6 alkyl) is the same or different 1 to 3 groups selected from the group consisting of amino group.), or may be substituted heteroarylene A group (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, and further includes one nitrogen atom, oxygen atom or sulfur atom. comprise may, the substituents are halogen _{atom, C 1-6 alkyl, C 3-7} cycloalkyl group, a trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano _{group, C 1-6} alkoxy group , _{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) group consisting of amino group 1 or 2 groups selected from the same or different.

The reaction temperature in this step is preferably 20 ° C. to 150 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.

The reaction time in this step is preferably 30 minutes to 12 hours, and more preferably 1 hour to 4 hours.

(Ii) Alternatively, in this step, when R ^a has an amino group, the compound (IV) is reacted with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent to give a compound (IV ).

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 ethers such as tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, Amides such as N-methyl-2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably nitriles It is sulfoxides, more preferably, acetonitrile, dimethyl sulfoxide.

The base used in this step is organic such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, N-methylmorpholine, pyridine, dimethylaminopyridine, or 2,6-lutidine. It can be a base and is preferably triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine or dimethylaminopyridine.

The arylating or heteroarylating agent used in this step is a compound having the formula RF, formula R—Cl or formula R—Br, preferably having the formula RF or formula R—Cl. A compound (R is as defined 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.

(Iii) Alternatively, the present step, when R ^a has an unsaturated bond, the compound (VI), the absence of an inert solvent or solvent, by hydrogenation reaction, to produce a compound (IV) It is.

Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol , Tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or alcohols such as glycerin; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, or diethyl carbonate And preferably alcohols, more preferably methanol or ethanol.

Examples of the catalyst used in this step include platinum oxide, palladium-carbon, or palladium hydroxide, and platinum oxide is preferable.

As an additive for accelerating the reaction used in this step, acetic acid, hydrochloric acid, or sulfuric acid can be mentioned, and hydrochloric acid is preferable.

The reaction temperature in this step is preferably 10 ° C. to 50 ° C., and more preferably 20 ° C. to 40 ° C.

The reaction time in this step is preferably 5 hours to 10 days, more preferably 10 hours to 7 days.

Production method 3
Production method 3 is a method for producing compounds (Ib) and (Ic) of the present invention from compound (VII).

In the formula, R ^b is as defined above, Boc represents a tert-butoxycarbonyl group, and R ^C represents a 4- to 7-membered nitrogen-containing cyclyl group. However, when R ^C is may 4-piperidinyl group which is substituted, at least one of 2, 3, 5 and 6 of the piperidinyl group having a substituent.

Compound (VII) can be produced, for example, according to the method described in Reference Example 8, 12, 13, 14, 22, 23, or 29.

(Step 3-1)
This step is a step of producing compound (Ib) by removing the Boc group in compound (VII).

Examples of reagents used for removing Boc in compound (VII) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like which can remove Boc described in the above.

The solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an alkyl halide such as dichloromethane or chloroform; Esters such as toluene; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably ethers or alkyl halides, and even more preferably 1,4- Dioxane.

The reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, and more preferably hydrochloric acid.

The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.

The reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.

(Step 3-2)
This step is a step for producing compound (Ic) by reacting compound (Ib) with an arylating agent or heteroarylating agent.

This step can be performed under the same conditions as in step 2-3 (ii).

Manufacturing method 4
Of the intermediate (II) of the compound of the present invention, the compound represented by the formula (IIc) can be produced, for example, by the following method.

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

(Step 4-1)
This step is a step of producing compound (IIb) by removing the Boc group in compound (IIa).

This step can be performed under the same conditions as in step 3-1.

(Step 4-2)
This step is a step of producing compound (IIc) by reacting compound (IIb) with an arylating agent or heteroarylating agent.

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

Manufacturing method 5
Of the intermediate (II) of the compound of the present invention, the compound represented by the formula (IId) can be produced, for example, by the following method.

In the formula, R ^d represents a 4- to 7-membered azacyclyl group having a cyclic amino group (an azacyclyl group is a heterocyclyl group, and a hetero atom forming the ring is a nitrogen atom).

(Step 5-1)
This step is a step for producing compound (IX) by condensing compound (VIII) and cyanoacetic acid or cyanoacetic acid ester in a solvent inert to the reaction or in the absence of a solvent.

When cyanoacetic acid is used in this step, compound (IX) can be produced by using a condensing agent and reaction conditions that are usually used in an amidation reaction.

When a cyanoacetate is used in this step, the solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; Aromatic hydrocarbons; or a mixed solvent thereof, more preferably alcohols or ethers, and still more preferably ethanol or toluene.

The cyanoacetate used in this step is preferably ethyl cyanoacetate.

The reaction temperature in this step is preferably 0 ° C to 120 ° C, more preferably 20 ° C to 100 ° C.

The reaction time in this step is preferably 1 to 24 hours, and more preferably 5 to 20 hours.

(Step 5-2)
This step is a step of producing compound (X) from compound (IX) 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 mixture thereof. It is a solvent, more preferably ethers or aromatic hydrocarbons, and still more preferably 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.

(Step 5-3)
This step is a step for producing compound (IId) by reacting compound (X) with a hydrazine compound in an inert solvent.

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

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.

Compound (I) of the present invention is isolated and purified as a free compound, a pharmacologically acceptable salt, hydrate, or solvate thereof. The pharmacologically acceptable salt of the compound (I) of the present invention can be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, or various chromatography.

Various isomers can be separated by utilizing differences in physicochemical properties between isomers. 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 administration form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include oral administration by tablet, granule, powder, capsule or syrup, or injection or suppository. Parenteral administration, and the like, and can be administered systemically or locally.

Examples of the oral pharmaceutical form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, Examples include syrups and elixirs. Examples of pharmaceutical forms for parenteral use include injections, ointments, gels, creams, patches, sprays, inhalants, sprays, eye drops, and suppositories. These forms of pharmaceuticals are pharmaceutically acceptable, such as excipients, binders, diluents, stabilizers, preservatives, colorants, solubilizers, suspending agents, buffering agents, or wetting agents. The additive can be prepared according to a conventional method using additives appropriately selected as necessary.

The dosage of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is as follows: symptoms, body weight, age, administration method of the administered person (warm-blooded animal, eg, human) Varies depending on etc. 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, DMF represents N, N′-dimethylformamide, DMSO represents dimethyl sulfoxide, IPA represents 2-propanol, DBU represents 1,8-diazabicyclo [5.4.0] undec-7-ene.

(Reference Example 1) Methyl 4-phenylcyclohexanecarboxylate

To a solution of 4-phenylcyclohexanecarboxylic acid (3.00 g, 14.7 mmol) in DMF (20 mL) was added potassium carbonate (4.10 g, 29.7 mmol) and methyl iodide (1.20 mL, 19.3 mmol). In addition, the mixture was stirred at 60 ° C. for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous 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 / 0-85 / 15 (gradient)] to obtain the title compound (2.48 g, yield: 77%). .

3: 2 diastereomeric mixture:
^{1 H-NMR (400MHz, CDCl} 3) δ: 7.32-7.17 (5H, m), 3.69 (9 / 5H, s), 3.67 (6 / 5H, s), 2.56-1.88 (2H, m), 1.65- 1.42 (8H, m).

(Reference Example 2) 3- (4-Phenylcyclohexyl) -1H-pyrazol-5-amine

N-Butyllithium (2.66M hexane solution, 10.4 mL, 27.7 mmol) was added dropwise to a solution of anhydrous acetonitrile (1.45 mL, 27.7 mmol) in anhydrous THF (80 mL) at −78 ° C., and then at the same temperature. After stirring for 10 minutes, a solution of methyl 4-phenylcyclohexanecarboxylate (1.01 g, 4.76 mmol) prepared in Reference Example 1 in anhydrous THF (20 mL) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. did. 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 = 90 / 10-70 / 30-50 / 50-30 / 70 (gradient)] to obtain a synthetic intermediate.

Hydrazine monohydrate (1.50 mL, 30.9 mmol) was added to a solution of the synthetic intermediate obtained in the above operation in ethanol (30 mL), and the mixture was stirred for 7 hours 30 minutes with heating under reflux. After leaving the reaction solution at room temperature, the solvent of the reaction solution was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent: (i) hexane / ethyl acetate = 50 / 50-0 / 100 (gradient) (ii) ethyl acetate / methanol = 100 / 0-95 / 5 (gradient )] To give the title compound (2.28 g, yield: 86%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 11.13 (1H, brs), 7.35-7.17 (5H, m), 5.23 (1H, s), 4.39 (2H, brs), 2.73-2.54 (1H, m), 2.07-1.81 (4H, m), 1.64-1.18 (5H, m).

(Reference Example 3) 3- (Cyclohex-3-en-1-yl) -1H-pyrazol-5-amine

The reaction was conducted in the same manner as described in Reference Example 2 using (2.08 g, 14.8 mmol) instead of methyl 4-phenylcyclohexanecarboxylate, and the title compound (2.35 g, yield: 94) was obtained. %).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 11.11 (1H, brs), 5.68 (2H, s), 5.20 (1H, s), 4.36 (2H, brs), 2.73-2.61 (1H, m) , 2.28-2.18 (1H, m), 2.12-2.00 (3H, m), 1.92-1.84 (1H, m), 1.60-1.48 (1H, m).

(Reference Example 4) 3-Cyclooctyl-1H-pyrazol-5-amine

To a suspension of cyclooctanecarboxylic acid (1.00 g, 6.40 mmol) in dichloromethane (30 mL), DMF (5 drops of Pasteur pipette) is added, and oxalyl chloride (0.70 mL, 8.02 mmol) is added at 0 ° C. The mixture was stirred at the same temperature for 30 minutes. The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude product.

To a solution of cyanoacetic acid (760 mg, 8.93 mmol) and 2,2′-bipyridyl (3 mg) in anhydrous THF (15 mL) at −78 ° C., n-butyllithium (2.69 M hexane solution, 7.5 mL, 20.2 mmol) was added dropwise and stirred for 20 minutes. Furthermore, the anhydrous THF (15 mL) solution of the crude product obtained by the said operation was dripped at the same temperature, and it stirred for 1 hour and 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with diethyl ether. 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 chromatography [eluent: hexane / ethyl acetate = 100 / 0-80 / 20 (gradient)] to obtain a synthetic intermediate.

Hydrazine monohydrate (0.40 mL, 8.23 mmol) was added to an ethanol (20 mL) solution of the obtained synthetic intermediate, and the mixture was stirred for 2.5 hours under reflux with heating. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography [elution solvent: (i) hexane / ethyl acetate = 50 / 50-0 / 100 (gradient) (ii) ethyl acetate. / Methanol = 100 / 0-90 / 10 (gradient)] to give the title compound (370 mg, yield: 30%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 11.01 (1H, brs), 5.16 (1H, s), 4.35 (2H, brs), 2.74-2.64 (1H, m), 1.82-1.37 (14H, m).

(Reference Example 5) 3- (3-Phenylcyclohexyl) -1H-pyrazol-5-amine

3-Phenylcyclohexanecarboxylic acid can be produced by a method described in WO2011 / 147772 using a racemic mixture of 3-phenylcyclohexanone instead of (R) -3-phenylcyclohexanone.

The reaction was carried out in the same manner as described in Reference Example 4 using 3-phenylcyclohexanecarboxylic acid (1.70 g, 8.32 mmol) instead of cyclooctanecarboxylic acid, and the title compound (950 mg, yield: 47%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 11.09 (1H, brs), 7.31-7.13 (5H, m), 5.19 (1H, s), 4.40 (2H, brs), 2.68-2.57 (2H, m), 1.99-1.76 (4H, m), 1.61-1.25 (4H, m).

(Reference Example 6) 3- (4,4-difluorocyclohexyl) -1H-pyrazol-5-amine

The reaction was conducted in the same manner as described in Reference Example 2 using ethyl 4,4-difluorocyclohexanecarboxylate (2.00 g, 10.4 mmol) instead of methyl 4-phenylcyclohexanecarboxylate to give the title compound (2.20 g, yield: quantitative) was obtained.

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 11.11 (1H, brs), 5.16 (1H, s), 4.41 (2H, brs), 2.59 (1H, t, J = 10Hz), 2.06-1.79 ( 6H, m), 1.60-1.49 (2H, m).

(Reference Example 7) 3- (2-Methylcyclohexyl) -1H-pyrazol-5-amine

Concentrated sulfuric acid (2 mL) was added to a solution of 2-methylcyclohexanecarboxylic acid (4.60 g, 32.4 mmol) in ethanol (50 mL), and the mixture was stirred with heating under reflux for 5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with diethyl ether. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the ethyl ester compound (5. 15 g) was obtained.

The ethyl ester compound (2.00 g) obtained by the above procedure was used in place of methyl 4-phenylcyclohexanecarboxylate in the same manner as in the method described in Reference Example 2, and the title compound (216 mg, Yield: 9%).

MS (ESI) m / z: 180 (M + H) ⁺ .

Reference Example 8 3- [4-Hydroxy-6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-3-ylazetidine- 1-carboxylate tert-butyl

To a solution of tert-butyl 3- (5-amino-1H-pyrazol-3-yl) azetidine-1-carboxylate (a compound described in WO 2011/140488 pamphlet, 555 mg, 2.33 mmol) in acetic acid (6 mL), After adding ethyl trifluoroacetoacetate (686 μL, 4.66 mmol) and stirring at 60 ° C. for 2 hours, the solvent of the reaction solution was distilled off under reduced pressure and azeotroped with toluene. The obtained residue was purified by silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-95 / 5 (gradient)], and further purified by silica gel column chromatography [elution solvent: hexane / Purification by ethyl acetate = 50 / 50-0 / 100 (gradient)] gave the title compound (563 mg, yield: 64%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.70 (1H, s), 10.58 (1H, s), 6.80 (1H, s), 4.09-3.93 (5H, m), 2.87 (1H, d, J = 17Hz), 2.71 (1H, d, J = 17Hz), 1.40 (9H, s).

(Reference Example 9) methyl 1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidine-3-carboxylate

To a solution of methyl pyrrolidine-3-carboxylate hydrochloride (332 mg, 2.00 mmol) in acetonitrile (2 mL) was added N, N-diisopropylethylamine (1.40 mL, 8.04 mmol) and 2-fluoro-5- (trifluoromethyl). ) Pyridine (495 mg, 3.00 mmol) was added and stirred at 70 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-60 / 40 (gradient)] to give the title compound (489 mg, yield: 89%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.39-8.38 (1H, m), 7.61 (1H, dd, J = 9Hz, 2Hz), 6.38 (1H, d, J = 9Hz), 3.79-3.76 (2H , m), 3.74 (3H, s), 3.69-3.63 (1H, m), 3.56-3.49 (1H, m), 3.28-3.21 (1H, m), 2.33 (2H, q, J = 7Hz).

(Reference Example 10) 3- {1- [5- (trifluoromethyl) -2-pyridyl] pyrrolidin-3-yl} -1H-pyrazol-5-amine

Instead of methyl 4-phenylcyclohexanecarboxylate, methyl 1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidine-3-carboxylate (487 mg, 1.78 mmol) prepared in Reference Example 9 was used. Then, the reaction was carried out in the same manner as described in Reference Example 2 to obtain the title compound (489 mg, yield: 92%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.40-8.39 (1H, m), 7.62 (1H, dd, J = 9Hz, 2Hz), 6.39 (1H, d, J = 9Hz), 5.50 (1H, s ), 3.92 (1H, dd, J = 10Hz, 7Hz), 3.75-3.46 (6H, m), 2.47-2.39 (1H, m), 2.20-2.11 (1H, m).

(Reference Example 11) 3- {1- [3-Chloro-5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1H-pyrazol-5-amine

As described in Reference Example 9, 3-chloro-2-fluoro-5- (trifluoromethyl) pyridine (899 mg, 4.51 mmol) was used instead of 2-fluoro-5- (trifluoromethyl) pyridine. Reaction was performed in the same manner as in the method to obtain an aminopyrazole intermediate.

The aminopyrazole intermediate obtained in the above procedure was used in place of methyl 4-phenylcyclohexanecarboxylate in the same manner as in the method described in Reference Example 2, and the title compound (975 mg, yield: 98) was obtained. %).

MS (ESI) m / z: 332 (M + H) ^<+> .

(Reference Example 12) Compound A-1 and Compound A-2

as well as

Similar to the method described in Reference Example 2, using methyl 1- (tert-butoxycarbonyl) -3-pyrrolidinecarboxylate (10.2 g, 44.5 mmol) instead of methyl 4-phenylcyclohexanecarboxylate Reaction was performed to obtain an aminopyrazole intermediate.

As described in Reference Example 8, the aminopyrazole intermediate obtained in the above procedure was used in place of tert-butyl 3- (5-amino-1H-pyrazol-3-yl) azetidine-1-carboxylate. The reaction is performed in the same manner as in the method, and the compound eluting first (hereinafter referred to as Compound A-1) (1.40 g, yield: 8%) and the compound eluting later (hereinafter referred to as Compound A-2) ) (1.16 g, yield: 7%).

Compound A-1:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.40 (1H, s), 10.58 (1H, s), 6.83 (1H, s), 3.71-3.49 (3H, m), 3.32-3.14 (2H, m), 2.91 (1H, d, J = 17Hz), 2.72 (1H, d, J = 17Hz), 2.08-2.06 (2H, m), 1.41-1.40 (9H, m).

Compound A-2:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.40 (1H, s), 10.56 (1H, s), 6.84 (1H, s), 3.71-3.44 (3H, m), 3.29-3.14 (2H, m), 2.91 (1H, d, J = 16Hz), 2.72 (1H, d, J = 16Hz), 2.19-2.06 (2H, m), 1.41-1.40 (9H, m).

(Reference Example 13)

Compound A-1 (1.40 g, 3.59 mmol) produced in Reference Example 12 was added to flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 90/10, flow rate: 12 mL / min] to obtain the target compound (560 mg, yield: 40%).

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate: 1.0 mL / min].

Optical purity 99% or more (retention time: 6.2 minutes).

(Reference Example 14)

Compound A-2 (1.16 g, 2.97 mmol) produced in Reference Example 12 was flash LC [column: Chiralflash IA (30 mm id x 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 91/9, flow rate: 12 mL / min] to obtain the target compound (410 mg, yield: 35%).

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate: 1.0 mL / min].

Optical purity 99% or more (retention time: 5.0 minutes).

(Reference Example 15)

Hydrochloric acid (4M 1,4-dioxane solution, 1.1 mL, 4.4 mmol) was added to the compound produced in Reference Example 14 (86.0 mg, 0.220 mmol), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, acetonitrile was added and azeotroped to obtain the target compound (72.0 mg, yield: quantitative).

MS (ESI) m / z: 291 (M + H) ⁺ .

Reference Example 16 3- {rac- (1R, 5S, 6r) -3- [5- (trifluoromethyl) pyridin-2-yl] -3-azabicyclo [3.1.0] hexane-6-yl } -1H-pyrazol-5-amine

Instead of pyrrolidine-3-carboxylic acid methyl hydrochloride, rac- (1R, 5S, 6r) -3-azabicyclo [3.1.0] hexane-6-carboxylic acid ethyl hydrochloride (CAS number: 174456-77-) (0, 500 mg, 2.61 mmol) was used in the same manner as in the method described in Reference Example 9 to obtain a synthetic intermediate.

The reaction was conducted in the same manner as described in Reference Example 2 using the synthetic intermediate obtained in the above operation instead of methyl 4-phenylcyclohexanecarboxylate to give the title compound (634 mg, yield: 79% )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.38-8.37 (1H, m), 7.75 (1H, dd, J = 9Hz, 2Hz), 6.59 (1H, d, J = 9Hz), 5.11 (1H , brs), 4.36 (1H, brs), 3.82 (2H, d, J = 10Hz), 3.54-3.50 (2H, m), 1.96 (2H, brs).

(Reference Example 17) methyl cis-2-methyl-1- [5- (trifluoromethyl) pyridine-4-carboxylate

Chlorination of methyl 2-chloro-6-methylpyridine-4-carboxylate (compound described in J. Med. Chem., 2010, 53, 7682-7698, 7.39 g, 39.8 mmol) Platinum oxide (1 g) was added to a hydrogen-methanol (5-10%, 150 mL) solution, and the mixture was stirred at room temperature for 8 hours in a hydrogen atmosphere. Furthermore, platinum oxide (1 g) was added, and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. The reaction solution was filtered, and the solvent of the filtrate was distilled off under reduced pressure to obtain a piperidine intermediate (8.79 g).

To a solution of piperidine intermediate (2.41 g) obtained in the above operation in DMSO (20 mL), 2-fluoro-5- (trifluoromethyl) pyridine (1.8 mL, 14.9 mmol) and DBU (4 0.1 mL, 27.4 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: hexane / ethyl acetate = 98 / 2-85 / 15 (gradient)], and further silica gel column chromatography [elution solvent: hexane / ethyl acetate = 98. / 2-85 / 15 (gradient)] to give the title compound (902 mg, yield: 24%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.38-8.35 (1H, m), 7.59 (1H, dd, J = 9Hz, 3Hz), 6.55 (1H, d, J = 9Hz), 4.45 (1H, td , J = 13Hz, 7Hz), 4.19 (1H, dq, J = 14Hz, 3Hz), 3.73 (3H, s), 3.30-3.23 (1H, m), 2.65-2.59 (1H, m), 2.17-1.99 ( 3H, m), 1.96-1.86 (1H, m), 1.15 (3H, d, J = 7Hz).

Reference Example 18 3- {cis-2-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5-amine

Instead of methyl 4-phenylcyclohexanecarboxylate, methyl cis-2-methyl-1- [5- (trifluoromethyl) pyridine-4-carboxylate prepared in Reference Example 17 (0.97 g, 3.21 mmol) The title compound (788 mg, yield: 75%) was obtained in the same manner as in the method described in Reference Example 2.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.37-8.36 (1H, m), 7.59 (1H, dd, J = 9Hz, 3Hz), 6.54 (1H, d, J = 9Hz), 5.48 (1H, s ), 4.33-4.21 (2H, m), 3.33-3.23 (1H, m), 2.85-2.76 (1H, m), 2.26-2.11 (2H, m), 1.87-1.76 (2H, m), 1.16 (3H , d, J = 7Hz).

(Reference Example 19) 3- (2-phenyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-7-yl) -1H-pyrazol-5-amine

Ethyl 2-phenylimidazo [1,2-a] pyridine-7-carboxylate (Reference Eur. J. Med. Chem., 2012, Vol. 52, pp. 137-150, 3.58 g , 13.4 mmol) in ethanol (50 mL) and concentrated hydrochloric acid (5 mL) was added platinum oxide (1.00 g), and the mixture was stirred at room temperature for 6 days in a hydrogen atmosphere. The reaction solution was filtered using Celite (registered trademark), and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: hexane / ethyl acetate = 100 / 0-75 / 25 (gradient)], and further silica gel column chromatography [NH-silica gel, elution solvent: hexane / Purified by ethyl acetate = 100 / 0-75 / 25 (gradient)] and further purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 85 / 15-70 / 30 (gradient)]. A synthetic intermediate was obtained.

The reaction was conducted in the same manner as described in Reference Example 2 using the synthetic intermediate obtained in the above operation instead of methyl 4-phenylcyclohexanecarboxylate, and the title compound (45 mg, yield: 1. 1%) was obtained.

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 11.28 (1H, brs), 7.71 (2H, dd, J = 7Hz, 1Hz), 7.49 (1H, d, J = 2Hz), 7.35-7.30 (2H , m), 7.18-7.14 (1H, m), 5.23 (1H, s), 4.58 (2H, brs), 4.03-4.01 (2H, m), 3.17-3.06 (2H, m), 2.89-2.79 (1H m), 2.26-2.19 (1H, m), 2.06-1.96 (1H, m).

(Reference Example 20) 1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-3-carboxylate

To a solution of ethyl piperidine-3-carboxylate (1.1 g, 7.0 mmol) in DMSO (10 mL), N, N-diisopropylethylamine (1.55 mL, 9.1 mmol) and 2-fluoro-5- (tri Fluoromethyl) pyridine (1.01 mL, 8.4 mmol) was added, stirred at 50 ° C. for 1 hour, and left at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-85 / 15 (gradient)] to give the title compound (1.97 g, yield: 93%). It was.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.39 (1H, brs), 7.61 (1H, dd, J = 9Hz, 3Hz), 6.69 (1H, d, J = 9Hz), 4.44-4.36 (1H, m ), 4.16 (2H, q, J = 7Hz), 4.16-4.09 (1H, m), 3.28 (1H, dd, J = 13Hz, 10Hz), 3.18-3.12 (1H, m), 2.60-2.48 (1H, m), 2.15-2.06 (1H, m), 1.85-1.75 (2H, m), 1.63-1.53 (1H, m), 1.27 (3H, t, J = 7Hz).

(Reference Example 21) 3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} -1H-pyrazol-5-amine

Instead of methyl 4-phenylcyclohexanecarboxylate, ethyl 1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-3-carboxylate prepared in Reference Example 20 (1.97 g, 6.52 mmol) The title compound (1.54 g, yield: 76%) was reacted in the same manner as in the method described in Reference Example 2.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.41-8.39 (1H, m), 7.61 (1H, dd, J = 9Hz, 3Hz), 6.64 (1H, d, J = 9Hz), 5.51 (1H, s ), 4.18 (1H, dd, J = 13Hz, 4Hz), 3.88 (1H, td, J = 9Hz, 4Hz), 3.65 (1H, dd, J = 14Hz, 8Hz), 3.31-3.24 (1H, m), 2.96-2.90 (1H, m), 2.15-2.05 (1H, m), 1.88-1.71 (2H, m), 1.69-1.57 (1H, m).

(Reference Example 22) Compound B-1 and Compound B-2

as well as

Similar to the method described in Reference Example 2, using ethyl 1- (tert-butoxycarbonyl) -3-piperidinecarboxylate (26.4 g, 0.103 mol) instead of methyl 4-phenylcyclohexanecarboxylate Reaction was performed to obtain an aminopyrazole intermediate.

As described in Reference Example 8, the aminopyrazole intermediate obtained in the above procedure was used in place of tert-butyl 3- (5-amino-1H-pyrazol-3-yl) azetidine-1-carboxylate. The reaction was carried out in the same manner as in the above method to obtain a compound eluting first (hereinafter referred to as compound B-1) (5.8 g, yield: 14%) and a compound eluting later (6.0 g). .

The compound (400 mg) that elutes later in the above operation is further added to flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 90/10, flow rate: 12 mL / min. To give compound B-2 (130 mg, yield: 5%).

Compound B-1:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.34 (1H, s), 10.53 (1H, s), 6.78 (1H, brs), 4.20-4.07 (1H, m), 4.05-3.95 (1H, m), 3.12-2.43 (5H, m), 1.86-1.60 (3H, m), 1.49-1.26 (10H, m).

Compound B-2:
The optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate: 1.0 mL / min].

Optical purity 99% ee or more (retention time: 5.9 minutes);
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.36 (1H, s), 10.54 (1H, s), 6.74 (1H, s), 4.10-3.93 (2H, m), 3.13-2.99 (1H, m), 2.96-2.56 (4H, m), 2.00-1.89 (1H, m), 1.77-1.61 (2H, m), 1.43-1.29 (10H, m).

(Reference Example 23)

Compound B-1 (1.5 g) produced in Reference Example 22 was flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 90/10, Purification was performed at a flow rate of 12 mL / min] to obtain the target compound (600 mg, yield: 40%).

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate: 1.0 mL / min].

Optical purity 99% ee or more (retention time: 7.5 minutes).

(Reference Example 24) ethyl cis-3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-4-carboxylate

Instead of ethyl piperidine-3-carboxylate, ethyl cis-3-methylpiperidine-4-carboxylate (compound described in J. Med. Chem., 2010, 53, 7682-7698, 515 mg , 3.01 mmol), and the same procedure as described in Reference Example 20 was performed at room temperature to obtain the title compound (805 mg, yield: 85%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.37-8.35 (1H, m), 7.59 (1H, dd, J = 9Hz, 3Hz), 6.64 (1H, d, J = 9Hz), 4.24-4.02 (4H , m), 3.35 (1H, dd, J = 13Hz, 3Hz), 3.24-3.16 (1H, m), 2.73-2.69 (1H, m), 2.38-2.28 (1H, m), 2.01-1.90 (1H, m), 1.85-1.79 (1H, m), 1.28 (3H, t, J = 7Hz), 0.94 (3H, d, J = 7Hz).

Reference Example 25 3- {cis-3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1H-pyrazol-5-amine

Instead of 4-phenylcyclohexanecarboxylic acid, ethyl cis-3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-4-carboxylate prepared in Reference Example 24 (715 mg, 2.26 mmol) was used in the same manner as described in Reference Example 2 to obtain the title compound (677 mg, yield: 92%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.38-8.35 (1H, m), 7.59 (1H, dd, J = 9Hz, 3Hz), 6.65 (1H, d, J = 9Hz), 5.48 (1H, s ), 4.43-4.34 (1H, m), 4.12-4.05 (1H, m), 3.32 (1H, dd, J = 13Hz, 3Hz), 3.21-3.10 (1H, m), 3.08-3.00 (1H, m) , 2.24-2.14 (1H, m), 2.00-1.83 (2H, m), 0.82 (3H, d, J = 7Hz).

Reference Example 26 ethyl cis-1- [4- (difluoromethoxy) phenyl] -3-methylpiperidine-4-carboxylate

ethyl cis-3-methylpiperidine-4-carboxylate (compound described in J. Med. Chem., 2010, 53, 7682-7698, 1.52 g, 8.87 mmol) and 1 To a solution of bromo-4- (difluoromethoxy) benzene (2.18 g, 9.75 mmol) in toluene (57 mL) was added tert-butoxy sodium (1.07 g, 11.1 mmol), palladium (II) acetate (199 mg, 0 887 mmol) and tri (tert-butyl) phosphine (1.0 M toluene solution, 0.71 mL, 0.709 mmol) were added, and the mixture was stirred at 70 ° C. for 30 minutes in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-95 / 5 (gradient)] to give the title compound (1.58 g, yield: 57%). It was.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.04-7.00 (2H, m), 6.90-6.85 (2H, m), 6.40 (1H, t, J = 75Hz), 4.22-4.12 (2H, m), 3.53-3.47 (1H, m), 3.37-3.33 (1H, m), 2.98-2.93 (1H, m), 2.83-2.77 (1H, m), 2.61-2.56 (1H, m), 2.39-2.32 (1H , m), 2.09-2.00 (1H, m), 1.88-1.82 (1H, m), 1.28 (3H, t, J = 7Hz), 1.06 (3H, d, J = 7Hz).

Reference Example 27 3- {cis-1- [4- (Difluoromethoxy) phenyl] -3-methylpiperidin-4-yl} -1H-pyrazol-5-amine

Instead of methyl 4-phenylcyclohexanecarboxylate, ethyl cis-1- [4- (difluoromethoxy) phenyl] -3-methylpiperidine-4-carboxylate prepared in Reference Example 26 (1.57 g, 5. 00 mmol) was used in the same manner as in the method described in Reference Example 2 to obtain the title compound (1.48 g, yield: 92%).

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 11.10 (1H, brs), 7.05-6.93 (4H, m), 7.02 (1H, t, J = 75Hz), 5.22 (1H, s), 4.43 ( 2H, brs), 3.58-3.51 (1H, m), 3.40-3.34 (1H, m), 2.95-2.90 (1H, m), 2.84-2.75 (2H, m), 2.19-2.10 (1H, m), 1.96-1.85 (1H, m), 1.80-1.72 (1H, m), 0.82 (3H, d, J = 7Hz).

(Reference Example 28) 3-oxo-3- {4- [5- (trifluoromethyl) pyridin-2-yl] piperazin-1-yl} propanenitrile

To 1- [5- (trifluoromethyl) pyridin-2-yl] piperazine (610 mg, 2.64 mmol) was added ethyl cyanoacetate (330 mg, 2.92 mmol), and 3 hours at 40 ° C. and 3 hours at 80 ° C. Further, the mixture was stirred at 100 ° C. for 21 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 60 / 40-0 / 100 (gradient)] to obtain the title compound (520 mg, yield: 66%).

¹ H-NMR (500MHz, CDCl ₃ ) δ: 8.43 (1H, d, J = 2Hz), 7.70 (1H, dd, J = 9Hz, 2Hz), 6.68 (1H, d, J = 9Hz), 3.83 (2H , dd, J = 6Hz, 4Hz), 3.78 (2H, dd, J = 7Hz, 4Hz), 3.67 (2H, dd, J = 7Hz, 4Hz), 3.62 (2H, dd, J = 6Hz, 4Hz), 3.55 (2H, s).

(Reference Example 29) 1-tert-butyl 4-methyl azepane-1,4-dicarboxylate

Using 1- (tert-butoxycarbonyl) azepane-4-carboxylic acid (500 mg, 2.06 mmol) instead of 4-phenylcyclohexanecarboxylic acid, the reaction was carried out in the same manner as described in Reference Example 1, The title compound (523 mg, yield: 99%) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 3.68-3.67 (3H, m), 3.59-3.44 (2H, m), 3.41-3.19 (2H, m), 2.50-2.42 (1H, m), 2.12- 1.75 (4H, m), 1.70-1.57 (2H, m), 1.46-1.46 (9H, m).
Reference Example 30 3- {1- [5- (trifluoromethyl) pyridin-2-yl] azepan-4-yl} -1H-pyrazol-5-amine

Instead of methyl 4-phenylcyclohexanecarboxylate, 1-tert-butyl 4-methyl azepane-1,4-dicarboxylate (523 mg, 2.03 mmol) prepared in Reference Example 29 was used. Reaction was performed in the same manner as described to give an aminopyrazole intermediate.

(3S) -3- [4-Hydroxy-6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-3-yl] pyrrolidine The reaction was carried out in the same manner as described in Reference Example 15 using the aminopyrazole intermediate obtained by the above procedure instead of tert-butyl-1-carboxylate.

To a solution of the obtained residue in DMSO (5 mL), 2-fluoro-5- (trifluoromethyl) pyridine (0.300 mL, 2.44 mmol) and DBU (2.5 mL, 16.7 mmol) were added. For 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-96 / 4 (gradient)] to give the title compound (475 mg, yield: 72%). Got.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.39-8.38 (1H, m), 7.60 (1H, dd, J = 9Hz, 2Hz), 6.52 (1H, d, J = 9Hz), 5.43 (1H, s ), 4.00-3.93 (1H, m), 3.81-3.75 (1H, m), 3.64-3.55 (4H, m), 2.73 (1H, tdd, J = 11Hz, 4Hz, 2Hz), 2.25-2.18 (1H, m), 2.12-2.00 (2H, m), 1.90-1.77 (2H, m), 1.68-1.58 (1H, m).

Example 1 3-Cyclohexyl-4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

To a solution of 3-cyclohexyl-1H-pyrazol-5-amine (250 mg, 1.51 mmol) in acetic acid (5 mL) was added ethyl trifluoroacetoacetate (250 mg, 1.51 mmol), and at 60 ° C. for 3.5 hours. Stir. 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 = 80 / 20-20 / 80 (gradient)] to obtain the title compound (128 mg, yield: 28%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.17 (1H, s), 10.45 (1H, s), 6.61 (1H, s), 3.00-2.91 (1H, m), 2.86 (1H, d, J = 17Hz), 2.70 (1H, d, J = 16Hz), 1.88-1.64 (5H, m), 1.55-1.39 (2H, m), 1.33-1.16 (3H, m);
MS (ESI) m / z: 304 (M + H) ^<+> .

Example 2 3-Cycloheptyl-4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

Reaction similar to that described in Example 1 using 3-cycloheptyl-1H-pyrazol-5-amine (230 mg, 1.28 mmol) instead of 3-cyclohexyl-1H-pyrazol-5-amine To obtain the title compound (141 mg, yield: 35%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.14 (1H, s), 10.44 (1H, s), 6.61 (1H, s), 3.17-3.09 (1H, m), 2.86 (1H, d, J = 16Hz), 2.70 (1H, d, J = 17Hz), 1.89-1.34 (12H, m);
MS (ESI) m / z: 318 (M + H) ^<+> .

Example 3 3-Cyclooctyl-4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

In place of 3-cyclohexyl-1H-pyrazol-5-amine, 3-cyclooctyl-1H-pyrazol-5-amine (370 mg, 1.91 mmol) prepared in Reference Example 4 was used. The reaction is carried out in the same manner as described, and the resulting residue is purified by silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-92 / 8 (gradient)], and further Purification by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-10 / 90 (gradient)] gave the title compound (209 mg, yield: 33%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.14 (1H, s), 10.45 (1H, s), 6.61 (1H, s), 2.88 (1H, d, J = 16Hz), 2.69 (1H, d, J = 16Hz), 1.81-1.44 (15H, m);
MS (ESI) m / z: 332 (M + H) ^<+> .

Example 4 3- (4-tert-butylcyclohexyl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine- 6-on

As described in Example 3, substituting 3- (4-tert-butylcyclohexyl) -1H-pyrazol-5-amine (250 mg, 1.13 mmol) for 3-cyclooctyl-1H-pyrazol-5-amine The reaction was carried out in the same manner as described above to obtain the title compound (142 mg, yield: 35%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.16 (1H, s), 10.46 (1H, s), 6.63 (1H, s), 2.93-2.86 (1H, m), 2.87 (1H, d, J = 17Hz), 2.70 (1H, d, J = 17Hz), 1.95-1.74 (4H, m), 1.56-1.41 (2H, m), 1.06-0.96 (3H, m), 0.85 (9H, s);
MS (ESI) m / z: 360 (M + H) ⁺ .

Example 5 3- (Bicyclo [2.2.1] hept-2-yl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3 , 4-b] Pyridin-6-one

Instead of 3-cyclooctyl-1H-pyrazol-5-amine, 3- (bicyclo [2.2.1] hept-2-yl) -1H-pyrazol-5-amine (250 mg, 1.41 mmol) was used. The reaction was carried out in the same manner as in the method described in Example 3 to obtain the title compound (11 mg, yield: 2%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.03 (1H, s), 10.46 (1H, s), 6.63 (1H, s), 3.10 (1H, t, J = 7Hz), 2.85 (1H, d, J = 17Hz), 2.70 (1H, d, J = 16Hz), 2.34-2.27 (1H, m), 2.11 (1H, s), 1.71-1.41 (5H, m), 1.28-1.11 (3H, m );
MS (ESI) m / z: 316 (M + H) ^<+> .

Example 6 4-Hydroxy-3- (4-phenylcyclohexyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- on

Instead of 3-cyclooctyl-1H-pyrazol-5-amine, 3- (4-phenylcyclohexyl) -1H-pyrazol-5-amine (235 mg, 0.974 mmol) prepared in Reference Example 2 was used. The reaction was conducted in the same manner as described in Example 3 to obtain the title compound (156 mg, yield: 42%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.27 (1 / 2H, s), 12.24 (1 / 2H, s), 10.50 (1 / 2H, s), 10.48 (1 / 2H, s), 7.34-7.14 (5H, m), 6.68 (1 / 2H, s), 6.65 (1 / 2H, s), 3.16 (1 / 2H, t, J = 11Hz), 3.07 (1 / 2H, t, J = 12Hz), 2.92-2.83 (1H, m), 2.74-2.67 (1H, m), 2.65-2.52 (2H, m), 2.03-1.34 (7H, m);
MS (ESI) m / z: 380 (M + H) ⁺ .

Example 7 3- (Cyclohex-3-en-1-yl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b ] Pyridin-6-one

Instead of 3-cyclooctyl-1H-pyrazol-5-amine, 3- (cyclohex-3-en-1-yl) -1H-pyrazol-5-amine prepared in Reference Example 3 (330 mg, 2. The title compound (184 mg, yield: 30%) was obtained in the same manner as described in Example 3.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.24 (1 / 2H, s), 12.23 (1 / 2H, s), 10.51 (1H, s), 6.69 (1H, s), 5.72 (2H, s), 3.22-3.12 (1H, m), 2.89 (1H, d, J = 16Hz), 2.71 (1H, d, J = 16Hz), 2.34-2.04 (4H, m), 1.92-1.67 (2H, m );
MS (ESI) m / z: 302 (M + H) ^<+> .

Example 8 4-Hydroxy-3- (3-phenylcyclohexyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- on

Instead of 3-cyclooctyl-1H-pyrazol-5-amine, 3- (3-phenylcyclohexyl) -1H-pyrazol-5-amine (935 mg, 3.87 mmol) prepared in Reference Example 5 was used. The reaction was conducted in the same manner as described in Example 3 to obtain the title compound (190 mg, yield: 13%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.24 (1H, s), 10.48 (1H, s), 7.32-7.27 (2H, m), 7.22 (2H, d, J = 8Hz), 7.20- 7.16 (1H, m), 6.66 (1H, s), 3.16 (1H, t, J = 12Hz), 2.86 (1H, d, J = 16Hz), 2.70 (1H, d, J = 17Hz), 2.62 (1H , t, J = 10Hz), 2.03-1.65 (6H, m), 1.62-1.36 (2H, m);
MS (ESI) m / z: 380 (M + H) ⁺ .

Example 9 3- (4-Butylcyclohexyl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- on

Instead of 3-cyclooctyl-1H-pyrazol-5-amine, neutralize 3- (4-butylcyclohexyl) -1H-pyrazol-5-amine hydrochloride (595 mg, 2.31 mmol) with saturated aqueous sodium bicarbonate solution Using the compound thus obtained, the reaction was carried out in the same manner as in the method described in Example 3 to obtain the title compound (165 mg, yield: 20%).

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.17 (1H, s), 10.46 (1H, s), 6.62 (1H, s), 2.94-2.88 (1H, m), 2.86 (1H, d, J = 17Hz), 2.70 (1H, d, J = 16Hz), 1.89-1.67 (4H, m), 1.56-1.42 (2H, m), 1.30-1.14 (8H, m), 0.97-0.84 (4H, m );
MS (ESI) m / z: 360 (M + H) ⁺ .

Example 10 3- (4,4-Difluorocyclohexyl) -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine 6-on

Instead of 3-cyclooctyl-1H-pyrazol-5-amine, 3- (4,4-difluorocyclohexyl) -1H-pyrazol-5-amine prepared in Reference Example 6 (2.20 g, 10.9 mmol) The title compound (1.51 g, yield: 41%) was obtained in the same manner as in the method described in Example 3.

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 12.32 (1H, s), 10.50 (1H, s), 6.73 (1H, s), 3.10 (1H, t, J = 12Hz), 2.88 (1H, d, J = 17Hz), 2.71 (1H, d, J = 17Hz), 2.14-2.03 (2H, m), 1.98-1.71 (6H, m);
MS (ESI) m / z: 340 (M + H) ^<+> .

Example 11 4-Hydroxy-3- (2-methylcyclohexyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- On and its diastereomers

as well as

To a solution of 3- (2-methylcyclohexyl) -1H-pyrazol-5-amine (216 mg, 1.2 mmol) prepared in Reference Example 7 in acetic acid (3 mL) was added ethyl trifluoroacetoacetate (355 μL, 2.4 mmol). ) And stirred at 60 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The obtained residue was purified by silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-95 / 5 (gradient)], and further purified by silica gel column chromatography [elution solvent: hexane / Purified with ethyl acetate = 75 / 25-25 / 75 (gradient)], eluting first compound (hereinafter referred to as compound 11-1) (45 mg, yield: 12%), and later eluting Compound (hereinafter referred to as Compound 11-2) (39 mg, yield: 10%) was obtained.

Compound 11-1:
¹ H-NMR (DMSO-d ₆ ) δ: 12.03 (1H, s), 10.47 (1H, s), 6.59 (1H, s), 3.22-3.13 (1H, m), 2.90 (1H, d, J = 17Hz), 2.69 (1H, d, J = 17Hz), 2.28-2.14 (1H, m), 1.95-1.62 (2H, m), 1.60-1.11 (6H, m), 0.77 (3H, d, J = 7Hz );
MS (ESI) m / z: 318 (M + H) ^<+> .

Compound 11-2:
¹ H-NMR (DMSO-d ₆ ) δ: 12.01 (1H, s), 10.45 (1H, s), 6.64 (1H, s), 3.35-3.26 (1H, m), 2.84 (1H, d, J = 16Hz), 2.70 (1H, d, J = 16Hz), 2.11-2.01 (1H, m), 1.94-1.66 (2H, m), 1.63-1.35 (5H, m), 1.33-1.19 (1H, m), 0.83 (3H, d, J = 7Hz);
MS (ESI) m / z: 318 (M + H) ^<+> .

Example 12 4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] azetidin-3-yl} -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

3- [4-Hydroxy-6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine-3 prepared in Reference Example 8 To a suspension of tert-butyl ylazetidine-1-carboxylate (563 mg, 1.50 mmol) in 1,4-dioxane (10 mL) was added hydrochloric acid (4N 1,4-dioxane solution, 2 mL, 8.0 mmol), The mixture was stirred at room temperature for 2 hours, and further stirred at 60 ° C. for 2 hours. Hexane was added to the reaction solution, and the precipitate was collected by filtration to obtain an azetidine intermediate.

To a solution of the obtained azetidine intermediate in DMSO (2 mL), 2-fluoro-5- (trifluoromethyl) pyridine (60 μL, 0.50 mmol) and diisopropylethylamine (156 μL, 0.91 mmol) were added, and the mixture was brought to room temperature. And stirred for 12 hours. Ethyl acetate was added to the reaction mixture, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 75 / 25-0 / 100 (gradient)] to give the title compound (25 mg, yield: 14%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.60 (1H, s), 8.42 (1H, brs), 7.82 (1H, dd, J = 9Hz, 2Hz), 6.87 (1H, s), 6.55 ( 1H, d, J = 9Hz), 4.35 (3H, s), 4.21 (1H, s), 4.09 (1H, s), 2.90 (1H, d, J = 17Hz), 2.74 (1H, d, J = 17Hz );
MS (ESI) m / z: 422 (M + H) ⁺ .

Example 13 4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

as well as

3- {1- [5- (trifluoromethyl) -2-pyridyl] pyrrolidin-3-yl} -1H-pyrazol-5-amine (489 mg, 1.65 mmol) of acetic acid (4 mL) prepared in Reference Example 10 ) To the solution was added ethyl trifluoroacetoacetate (763 mg, 4.14 mmol), and the mixture was stirred at 60 ° C. for 6 hours. After cooling the reaction solution to room temperature, the solvent 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 / 0-90 / 10 (gradient)], and further purified by silica gel column chromatography [elution solvent: ethyl acetate. / Methanol = 100 / 0-95 / 5 (gradient)], eluting first compound (hereinafter referred to as compound 13-1) (173 mg, yield: 24%), and then eluting Compound (hereinafter referred to as Compound 13-2) (170 mg, yield: 24%) was obtained.

Compound 13-1:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.47 (1H, s), 10.58 (1H, s), 8.41-8.39 (1H, m), 7.78 (1H, dd, J = 9Hz, 2Hz), 6.88 (1H, s), 6.59 (1H, d, J = 9Hz), 4.04-3.71 (3H, m), 3.52-3.39 (2H, m), 2.93 (1H, d, J = 16Hz), 2.74 (1H , d, J = 16Hz), 2.31-2.18 (2H, m);
MS (ESI) m / z: 436 (M + H) ^<+> .

Compound 13-2:
¹ H-NMR (400MHz, DMSO-D ₆ ) δ: 12.47 (1H, s), 10.58 (1H, s), 8.41-8.40 (1H, m), 7.78 (1H, dd, J = 9Hz, 2Hz), 6.87 (1H, s), 6.61 (1H, d, J = 9Hz), 3.92-3.72 (3H, m), 3.51-3.40 (2H, m), 2.94 (1H, d, J = 16Hz), 2.74 (1H , d, J = 16Hz), 2.40-2.32 (1H, m), 2.30-2.18 (1H, m);
MS (ESI) m / z: 436 (M + H) ^<+> .

Example 14 3- {1- [3-Chloro-5- (trifluoromethyl) -2-pyridyl] pyrrolidin-3-yl} -4-hydroxy-4- (trifluoromethyl) -1,4 5,7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

as well as

Instead of 3- {1- [5- (trifluoromethyl) -2-pyridyl] pyrrolidin-3-yl} -1H-pyrazol-5-amine, the 3- {1- [ Method described in Example 13 using 3-chloro-5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1H-pyrazol-5-amine (975 mg, 2.94 mmol) The compound eluted first (hereinafter referred to as Compound 14-1) (221 mg, yield: 16%) and the compound to be eluted next (hereinafter referred to as Compound 14-2) ( 220 mg, yield: 16%) was obtained.

Compound 14-1:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.49 (1H, s), 10.57 (1H, s), 8.41-8.40 (1H, m), 8.01 (1H, d, J = 2Hz), 6.85 ( 1H, s), 4.13-4.09 (1H, m), 3.89-3.72 (4H, m), 2.93 (1H, d, J = 16Hz), 2.73 (1H, d, J = 16Hz), 2.24-2.15 (2H , m);
MS (ESI) m / z: 470 (M + H) ^<+> .

Compound 14-2:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.49 (1H, s), 10.58 (1H, s), 8.42-8.40 (1H, m), 8.01 (1H, d, J = 2Hz), 6.87 ( 1H, s), 4.00-3.96 (1H, m), 3.88-3.75 (4H, m), 2.93 (1H, d, J = 16Hz), 2.74 (1H, d, J = 16Hz), 2.33-2.18 (2H , m);
MS (ESI) m / z: 470 (M + H) ^<+> .

(Example 15)

To a solution of the compound prepared in Reference Example 15 (72.0 mg, 0.220 mmol) in DMSO (1 mL), N, N-diisopropylethylamine (310 μL, 1.78 mmol) and 2-fluoro-5- (tri Fluoromethyl) pyridine (30.0 μL, 0.244 mmol) was added and stirred at room temperature for 14 hours. The reaction solution was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 80 / 20-0 / 100 (gradient)]. The obtained crude product was dissolved in a small amount of methanol, water was added, and the precipitate was collected by filtration to obtain the target compound (79.8 mg, yield: 83%).

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: 4.0 minutes);
MS (ESI) m / z: 436 (M + H) ^<+> .

(Example 16)

3- [4-Hydroxy-6-oxo-4- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-3-ylazetidine-1-carboxylic acid tert Using the compound prepared in Reference Example 13 (86.0 mg, 0.220 mmol) instead of -butyl, the reaction was carried out in the same manner as described in Example 12, and the target compound (69.8 mg, Yield: 73%).

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: 4.3 minutes);
MS (ESI) m / z: 436 (M + H) ^<+> .

(Example 17)

As described in Example 15 using 3-chloro-2-fluoro-5- (trifluoromethyl) pyridine (35.1 mg, 0.176 mmol) instead of 2-fluoro-5- (trifluoromethyl) pyridine. The reaction was carried out in the same manner as described above to obtain the target compound (60.8 mg, yield: 81%).

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: 4.3 minutes);
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.50 (1H, s), 10.58 (1H, s), 8.42-8.40 (1H, m), 8.01 (1H, d, J = 2Hz), 6.87 ( 1H, s), 4.00-3.96 (1H, m), 3.88-3.75 (4H, m), 2.93 (1H, d, J = 16Hz), 2.74 (1H, d, J = 16Hz), 2.33-2.17 (2H , m);
MS (ESI) m / z: 470 (M + H) ^<+> .

(Example 18)

Similar to the method described in Example 15 using 3,5-dichloro-2-fluoropyridine (29.2 mg, 0.176 mmol) instead of 2-fluoro-5- (trifluoromethyl) pyridine. The reaction was performed to obtain the target compound (50.7 mg, yield: 73%).

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: 5.0 minutes);
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.48 (1H, s), 10.57 (1H, s), 8.13 (1H, d, J = 2Hz), 7.88 (1H, d, J = 2Hz), 6.85 (1H, s), 3.81-3.67 (5H, m), 2.92 (1H, d, J = 16Hz), 2.73 (1H, d, J = 16Hz), 2.30-2.13 (2H, m);
MS (ESI) m / z: 436 (M + H) ^<+> .

(Example 19)

Instead of 2-fluoro-5- (trifluoromethyl) pyridine, 2-chloro-4- (trifluoromethyl) pyrimidine (32.5 mg, 0.178 mmol) was used as described in Example 15. The reaction was conducted in the same manner to obtain the target compound (46.5 mg, yield: 67%).

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: 4.2 minutes);
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.46 (1H, s), 10.57 (1H, s), 8.71-8.68 (1H, m), 7.04 (1H, d, J = 5Hz), 6.86 ( 1H, s), 3.98-3.77 (3H, m), 3.57-3.44 (2H, m), 2.94 (1H, d, J = 16Hz), 2.74 (1H, d, J = 16Hz), 2.39-2.18 (2H , m);
MS (ESI) m / z: 437 (M + H) ⁺ .

Example 20 4-Hydroxy-4- (trifluoromethyl) -3- {3- [5- (trifluoromethyl) pyridin-2-yl] -3-azabicyclo [3.1.0] hexa-6 -Yl} -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

Instead of 3- {1- [5- (trifluoromethyl) -2-pyridyl] pyrrolidin-3-yl} -1H-pyrazol-5-amine, 3- {rac- ( 1R, 5S, 6r) -3- [5- (trifluoromethyl) pyridin-2-yl] -3-azabicyclo [3.1.0] hexan-6-yl} -1H-pyrazol-5-amine (631 mg , 2.04 mmol) was used in the same manner as described in Example 13. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the precipitate was collected by filtration. The obtained solid was suspended in ethyl acetate, stirred at 60 ° C., and collected by filtration. The suspension was further suspended in ethanol, stirred at 60 ° C., and collected by filtration to obtain the title compound (614 mg, yield: 67%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.08 (1H, s), 10.54 (1H, s), 8.40-8.39 (1H, m), 7.78 (1H, dd, J = 9Hz, 2Hz), 6.75 (1H, s), 6.64 (1H, d, J = 9Hz), 3.84-3.75 (2H, m), 3.59-3.53 (2H, m), 2.85 (1H, d, J = 16Hz), 2.73 (1H , d, J = 16Hz), 2.37-2.33 (1H, m), 2.15-2.11 (1H, m), 1.95 (1H, t, J = 4Hz);
MS (ESI) m / z: 448 (M + H) ^<+> .

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

3- {cis-2-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidine prepared in Reference Example 18 instead of 3-cyclooctyl-1H-pyrazol-5-amine Reaction was carried out in the same manner as described in Example 3 using -4-yl} -1H-pyrazol-5-amine (788 mg, 2.42 mmol) to give the title compound (510 mg, yield: 45%). Got.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.35 (0.5H, s), 12.34 (0.5H, s), 10.51 (1H, s), 8.39-8.36 (1H, m), 7.74 (1H, dd, J = 9Hz, 3Hz), 6.83 (1H, d, J = 9Hz), 6.70 (0.5H, s), 6.67 (0.5H, s), 4.35 (1H, td, J = 14Hz, 7Hz), 4.21 -4.09 (1H, m), 3.36-3.23 (1H, m), 3.13-3.01 (1H, m), 2.87 (1H, d, J = 16Hz), 2.69 (1H, d, J = 16Hz), 2.21- 1.82 (3H, m), 1.79-1.65 (1H, m), 1.19 (3H, d, J = 6Hz);
MS (ESI) m / z: 464 (M + H) ^<+> .

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

as well as

3- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-3 prepared in Reference Example 21 instead of 3- (2-methylcyclohexyl) -1H-pyrazol-5-amine -Il} -1H-pyrazol-5-amine (0.51 g, 1.64 mmol) was used to carry out the reaction in the same manner as described in Example 11, and the previously eluted compound (hereinafter referred to as Compound 22-) 1) (54 mg, yield: 7%) and a compound that elutes later (hereinafter referred to as compound 22-2) (27 mg, yield: 4%) were obtained.

Compound 22-1:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.43 (1H, s), 10.57 (1H, s), 8.41-8.38 (1H, m), 7.76 (1H, dd, J = 9Hz, 2Hz), 6.99 (1H, d, J = 9Hz), 6.85 (1H, s), 4.61 (1H, d, J = 13Hz), 4.49 (1H, d, J = 11Hz), 3.21-3.11 (1H, m), 3.04 (1H, t, J = 12Hz), 2.95 (1H, d, J = 16Hz), 2.85 (1H, t, J = 12Hz), 2.74 (1H, d, J = 16Hz), 1.93-1.76 (3H, m ), 1.54-1.39 (1H, m);
MS (ESI) m / z: 450 (M + H) ^<+> .

Compound 22-2:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.43 (1H, s), 10.55 (1H, s), 8.40-8.37 (1H, m), 7.79 (1H, dd, J = 9Hz, 3Hz), 6.90 (1H, d, J = 9Hz), 6.72 (1H, s), 4.53 (1H, d, J = 12Hz), 4.44 (1H, d, J = 9Hz), 3.16-3.09 (2H, m), 2.93 -2.83 (2H, m), 2.71 (1H, d, J = 16Hz), 2.07-1.97 (1H, m), 1.88-1.75 (2H, m), 1.54-1.40 (1H, m);
MS (ESI) m / z: 450 (M + H) ^<+> .

(Example 23)

To a suspension of the compound prepared in Reference Example 23 (600 mg, 1.48 mmol) in 1,4-dioxane (10 mL), hydrochloric acid (4N 1,4-dioxane solution, 2 mL, 8.0 mmol) was added at room temperature. And stirred at 40 ° C. for 2 hours. The reaction solution was cooled to room temperature, and the solid obtained by filtration was washed with hexane to obtain a piperidine intermediate (580 mg).

4-Hydroxy-3-[(3S) -pyrrolidin-3-yl] -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridine-6- The reaction was carried out in the same manner as described in Example 15 using the piperidine intermediate (164 mg) obtained in the above procedure instead of ON hydrochloride, and the resulting residue was subjected to silica gel column chromatography [elution solvent]. : Hexane / ethyl acetate = 50 / 50-0 / 100 (gradient)] to obtain the target compound (118 mg, yield: 55%)
Got.

MS (ESI) m / z: 450 (M + H) ^<+> .

(Example 24)

The reaction was conducted in the same manner as described in Example 23 using Compound B-2 (120 mg, 0.30 mmol) prepared in Reference Example 22 instead of the compound prepared in Reference Example 23. The target compound (11 mg, yield: 8%) was obtained.

MS (ESI) m / z: 450 (M + H) ^<+> .

(Example 25)

Instead of 2-fluoro-5- (trifluoromethyl) pyridine, 2-chloro-4- (trifluoromethyl) pyrimidine (0.144 mL, 1.20 mmol) was used as described in Example 23. The reaction was conducted in the same manner to obtain the target compound (94 mg, yield: 21%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.43 (1H, s), 10.55 (1H, s), 8.67 (1H, d, J = 5Hz), 7.02 (1H, d, J = 5Hz), 6.77 (1H, s), 4.88-4.70 (2H, m), 3.24-2.82 (4H, m), 2.71 (1H, d, J = 16Hz), 1.94-1.74 (3H, m), 1.54-1.39 (1H , m);
MS (ESI) m / z: 451 (M + H) ^<+> .

(Example 26)

Instead of 2-fluoro-5- (trifluoromethyl) pyridine, 2-chloro-5- (trifluoromethyl) pyrazine (0.136 mL, 1.10 mmol) was used as described in Example 23. Reaction was performed in the same manner to obtain the target compound (43 mg, yield: 10%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.45 (1H, s), 10.57 (1H, s), 8.48 (1H, s), 8.42 (1H, s), 6.93 (1H, s), 4.64 (1H, d, J = 13Hz), 4.54 (1H, d, J = 11Hz), 3.24-3.07 (2H, m), 3.00-2.87 (2H, m), 2.74 (1H, d, J = 16Hz), 2.00-1.80 (3H, m), 1.58-1.43 (1H, m);
MS (ESI) m / z: 451 (M + H) ^<+> .

(Example 27)

Instead of 2-fluoro-5- (trifluoromethyl) pyridine, 2-chloro-4- (trifluoromethyl) pyrimidine (0.165 mL, 1.37 mmol) was used, and the method described in Example 24 was used. The reaction was performed in the same manner to obtain the target compound (201 mg, yield: 49%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.45 (1H, s), 10.55 (1H, s), 8.67 (1H, d, J = 5Hz), 6.99 (1H, d, J = 5Hz), 6.70 (1H, s), 4.76 (2H, d, J = 11Hz), 3.20-3.03 (2H, m), 2.95-2.84 (2H, m), 2.71 (1H, d, J = 16Hz), 2.06-1.97 (1H, m), 1.91-1.77 (2H, m), 1.52-1.34 (1H, m);
MS (ESI) m / z: 451 (M + H) ^<+> .

(Example 28)

Instead of 2-fluoro-5- (trifluoromethyl) pyridine, 2-chloro-5- (trifluoromethyl) pyrazine (0.150 mL, 1.22 mmol) was used to obtain the method described in Example 24. The reaction was performed in the same manner to obtain the target compound (272 mg, yield: 60%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.45 (1H, s), 10.56 (1H, s), 8.48 (1H, s), 8.39 (1H, s), 6.75 (1H, s), 4.63 -4.46 (2H, m), 3.25-3.13 (2H, m), 3.04-2.85 (2H, m), 2.72 (1H, d, J = 16Hz), 2.08-1.98 (1H, m), 1.92-1.78 ( 2H, m), 1.60-1.44 (1H, m);
MS (ESI) m / z: 451 (M + H) ^<+> .

Example 29 4-Hydroxy-3- {3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl) -1,4 , 5,7-Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

as well as

3- {cis-3-methyl-1- [5- (trifluoromethyl) pyridine-2 prepared in Reference Example 25 instead of 3- (2-methylcyclohexyl) -1H-pyrazol-5-amine -Il] piperidin-4-yl} -1H-pyrazol-5-amine (232 mg, 1.15 mmol) was used in the same manner as in the method described in Example 11, and the compound eluted earlier (hereinafter Compound 29-1) (55.1 mg, yield: 17%) and the next eluting compound (hereinafter referred to as compound 29-2) (45.3 mg, yield: 14%) It was.

Compound 29-1:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.13 (1H, s), 10.51 (1H, s), 8.38-8.36 (1H, m), 7.74 (1H, dd, J = 9Hz, 2Hz), 6.99 (1H, d, J = 9Hz), 6.75 (1H, s), 4.63 (1H, d, J = 13Hz), 4.35 (1H, d, J = 13Hz), 3.44 (1H, dt, J = 13Hz, 4Hz), 3.19-3.15 (1H, m), 2.97-2.90 (2H, m), 2.72 (1H, d, J = 16Hz), 2.37-2.29 (1H, m), 2.17-2.07 (1H, m), 1.58-1.51 (1H, m), 0.70 (3H, d, J = 7Hz);
MS (ESI) m / z: 464 [M + H].

Compound 29-2:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.12 (1H, s), 10.50 (1H, s), 8.38-8.37 (1H, m), 7.74 (1H, dd, J = 9Hz, 2Hz), 6.99 (1H, d, J = 9Hz), 6.78 (1H, s), 4.59 (1H, d, J = 13Hz), 4.35 (1H, d, J = 13Hz), 3.57 (1H, dt, J = 13Hz, 4Hz), 3.22-3.17 (1H, m), 2.99-2.85 (2H, m), 2.73 (1H, d, J = 16Hz), 2.20-2.07 (2H, m), 1.63-1.56 (1H, m), 0.77 (3H, d, J = 7Hz);
MS (ESI) m / z: 464 [M + H].

(Example 30)

as well as

Compound 29-1 (192 mg, 0.414 mmol) produced in Example 29 was dissolved in a hexane-IPA (1/1) mixed solution, and flash LC [column: Chiralflash IA (30 mm id × 100 mm); Purified by Daicel, elution solvent: hexane / IPA = 70/30, flow rate: 10 mL / min], eluting first (hereinafter referred to as compound 30-1) (64 mg, yield: 33%) And the compound to be eluted next (hereinafter referred to as compound 30-2) (55 mg, yield: 29%) 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 30-1:
Optical purity 99% or more (retention time: 4.5 minutes);
Compound 30-2:
Optical purity 99% or more (retention time: 8.4 minutes).

(Example 31)

as well as

Compound 29-2 (185 mg, 0.399 mmol) prepared in Example 29 was dissolved in a hexane-IPA (1/1) mixed solution and flash LC [column: Chiralflash IA (30 mm id × 100 mm); Purified by Daicel Corporation, elution solvent: hexane / IPA = 50/50, flow rate: 10 mL / min], and eluting first compound (hereinafter referred to as compound 31-1) (68 mg, yield: 37%) And the compound to be eluted next (hereinafter referred to as Compound 31-2) (58 mg, yield: 31%) 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 31-1:
Optical purity 99% or more (retention time: 10.4 minutes);
Compound 31-2:
Optical purity 99% or more (retention time: 15.8 minutes).

Example 32 3- {1- [4- (Difluoromethoxy) phenyl] -3-methylpiperidin-4-yl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one and its diastereomers

as well as

Instead of 3- (2-methylcyclohexyl) -1H-pyrazol-5-amine, 3- {cis-1- [4- (difluoromethoxy) phenyl] -3-methylpiperidine- prepared in Reference Example 27 Using 4-yl} -1H-pyrazol-5-amine (1.47 g, 4.56 mmol), the reaction was carried out in the same manner as described in Example 11, and the previously eluted compound (hereinafter referred to as Compound 32) -1) (390 mg, yield: 19%) and a compound that elutes later (hereinafter referred to as compound 32-2) (373 mg, yield: 18%) were obtained.

Compound 32-1:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.17 (1H, s), 10.51 (1H, s), 7.05-7.00 (2H, m), 7.03 (1H, t, J = 75Hz), 6.99- 6.94 (2H, m), 6.68 (1H, s), 3.71-3.65 (1H, m), 3.53-3.48 (1H, m), 3.30-3.24 (1H, m), 2.92 (1H, d, J = 16Hz ), 2.86-2.81 (1H, m), 2.72 (1H, d, J = 16Hz), 2.67-2.60 (1H, m), 2.36-2.21 (2H, m), 1.59-1.53 (1H, m), 0.89 (3H, d, J = 7Hz);
MS (ESI) m / z: 461 (M + H) ^<+> .

Compound 32-2:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.15 (1H, s), 10.47 (1H, s), 7.05-7.00 (2H, m), 7.03 (1H, t, J = 75Hz), 6.99- 6.94 (2H, m), 6.71 (1H, s), 3.68-3.62 (1H, m), 3.55-3.50 (1H, m), 3.44-3.38 (1H, m), 2.88-2.82 (2H, m), 2.72 (1H, d, J = 16Hz), 2.68-2.60 (1H, m), 2.31-2.21 (1H, m), 2.18-2.11 (1H, m), 1.64-1.58 (1H, m), 0.95 (3H , d, J = 7Hz);
MS (ESI) m / z: 461 (M + H) ^<+> .

Example 33 4-Hydroxy-4- (trifluoromethyl) -3- {4- [5- (trifluoromethyl) pyridin-2-yl] piperazin-1-yl} -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

3-oxo-3- {4- [5- (trifluoromethyl) pyridin-2-yl] piperazin-1-yl} propanenitrile (520 mg, 1.74 mmol) prepared in Reference Example 28 in THF (10 mL) Lawesson's reagent (400 mg, 0.989 mmol) was added to the solution, and the mixture was stirred at room temperature for 6 hours. The obtained residue was purified by silica gel column chromatography [elution solvent: hexane / ethyl acetate = 50 / 50-0 / 100 (gradient)], and further purified by silica gel column chromatography [elution solvent: hexane / ethyl acetate = 30. / 70-10 / 90 (gradient)] to give a thioamide intermediate.

Hydrazine monohydrate (0.20 mL, 4.12 mmol) was added to an ethanol (5 mL) solution of the thioamide intermediate obtained by the above operation, and the mixture was stirred for 7 hours while heating under reflux. In the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15 (gradient)]. Purification gave the aminopyrazole intermediate.

The reaction was conducted in the same manner as described in Example 3 using the aminopyrazole intermediate obtained by the above procedure in place of 3-cyclooctyl-1H-pyrazol-5-amine to give the title compound (10 mg Yield: 1.3%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.86 (1H, s), 10.44 (1H, s), 8.43 (1H, s), 7.82 (1H, dd, J = 9Hz, 2Hz), 7.03 ( 1H, d, J = 9Hz), 6.86 (1H, s), 3.78-3.66 (4H, m), 3.38-3.24 (4H, m), 2.82 (1H, d, J = 16Hz), 2.73 (1H, d , J = 16Hz);
MS (ESI) m / z: 451 (M + H) ^<+> .

Example 34 4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] azepan-4-yl} -1,4,5,7 -Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one

3- {1- [5- (trifluoromethyl) pyridin-2-yl] azepan-4-yl}-prepared in Reference Example 30 instead of 3-cyclooctyl-1H-pyrazol-5-amine The reaction was carried out in the same manner as described in Example 3 using 1H-pyrazol-5-amine (472 mg, 1.45 mmol) to obtain the title compound (311 mg, yield: 46%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.16-12.15 (m, 1H), 10.48 (1H, s), 8.41-8.40 (1H, m), 7.76 (1H, dd, J = 9Hz, 2Hz ), 6.79 (1H, d, J = 9Hz), 6.67-6.65 (1H, m), 4.14-3.93 (1H, m), 3.78-3.61 (2H, m), 3.47-3.41 (2H, m), 3.19 -3.09 (1H, m), 2.89-2.84 (1H, m), 2.71-2.66 (1H, m), 2.09-1.55 (6H, m);
MS (ESI) m / z: 464 (M + H) ^<+> .

(Example 35)

Trifluoroacetic acid (1.5 mL) was added to a dichloromethane (5 mL) solution of the compound (450 mg, 1.15 mmol) produced in Reference Example 13 at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction solution was added dropwise to a mixed solvent of hexane (40 mL) and diethyl ether (150 mL) at 0 ° C., and the resulting solid was collected by filtration to obtain a synthetic intermediate.

To a solution of the obtained synthetic intermediate in DMSO (3 mL), N, N-diisopropylethylamine (216 μL, 1.3 mmol) and 2-chloro-5- (trifluoromethyl) pyrazine (66 μL, 0.534 mmol) were added. And stirred at room temperature for 30 hours. Ethyl acetate and water were added to the reaction solution for liquid separation, and the organic layer was washed twice with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [NH-silica gel, elution solvent: (i) hexane / ethyl acetate = 50 / 50-0 / 100 (gradient), (ii) ethyl acetate / methanol = 100 / 0-80 / 20 (gradient)] to obtain the target compound (85 mg, yield: 53%).

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 98% or more (retention time: 7.2 minutes);
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.47 (1H, s), 10.60 (1H, s), 8.50 (1H, s), 8.10 (1H, s), 6.91 (1H, s), 4.08 -3.83 (3H, m), 3.62-3.47 (2H, m), 2.93 (1H, d, J = 16Hz), 2.74 (1H, d, J = 16Hz), 2.37-2.15 (2H, m);
MS (ESI) m / z: 437 (M + H) ⁺ .

(Example 36)

Similar to the method described in Example 35, using 2-chloro-5- (trifluoromethyl) pyrazine (66 μL, 0.534 mmol) instead of 2-fluoro-5- (trifluoromethyl) pyridine. The reaction was performed to obtain the target compound (100 mg, yield: 62%).

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: 6.1 minutes);
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.48 (1H, s), 10.60 (1H, s), 8.50 (1H, s), 8.12 (1H, s), 6.89 (1H, s), 3.94 -3.82 (3H, m), 3.60-3.52 (2H, m), 2.95 (1H, d, J = 16Hz), 2.75 (1H, d, J = 16Hz), 2.45-2.18 (2H, m);
MS (ESI) m / z: 437 (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 0.37
Compound of Example 2 0.26
Compound of Example 3 0.37
Compound of Example 4 1.10
Compound of Example 5 0.76
Compound of Example 6 0.14
Compound of Example 7 0.59
Compound of Example 8 0.75
Compound of Example 9 0.39
Compound of Example 10 1.76
Compound 11-1 of Example 11 0.33
Compound 11-2 of Example 11 0.30
Compound of Example 12 0.26
Compound 13-1 of Example 13 0.34
Compound 13-2 of Example 13 0.045
Compound 14-1 of Example 14 0.70
Compound 14-2 of Example 14 0.082
Compound of Example 15 0.028
Compound of Example 16 0.29
Compound of Example 17 0.050
Compound of Example 18 0.078
Compound of Example 19 0.23
Compound of Example 20 0.90
Compound of Example 21 0.21
Compound 22-1 of Example 22 0.43
Compound 22-2 of Example 22 0.66
Compound of Example 23 0.53
Compound of Example 24 0.25
Compound of Example 25 0.44
Compound of Example 26 0.22
Example 27 Compound 0.78
Example 28 Compound 0.37
Compound 29-1 of Example 29 0.018
Compound 29-2 of Example 29 0.011
Compound 30-1 of Example 30 0.016
Compound 30-2 of Example 30 1.46
Compound 31-1 of Example 31 0.006
Compound 31-2 of Example 31 1.48
Compound 32-1 of Example 32 0.042
Compound 32-2 of Example 32 0.004
Compound of Example 33 0.42
Compound of Example 34 0.11
Compound of Example 35 0.66
Compound of Example 36 0.041
――――――――――――――――――――――――――――――

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) It was dissolved in an aqueous methylcellulose solution and orally administered to cynomolgus monkeys for 1 or 7 days. Blood was collected before and after administration on the first or seventh day of administration to obtain plasma. Plasma cholesterol content was measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile was analyzed by HPLC (column: Lipopropak XL, manufactured by Tosoh Corporation). The contents of HDL cholesterol and non-HDL cholesterol were calculated according to the following calculation formula.

HDL cholesterol content = plasma cholesterol content × (HDL cholesterol peak area / sum of each peak)
non-HDL cholesterol content = plasma cholesterol content × (peak area of non-HDL cholesterol / sum of each peak)
The increase rate (%) of HDL after a single administration of 10 mg / kg as compared to before administration was determined from AUC before administration and 24 hours after administration, and the results are shown in Table 2.

Table 2
――――――――――――――――――――――――――――――
Test compound Increased HDL after a single dose -------------
Compound 287 of Example 17
――――――――――――――――――――――――――――――

(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 (32)

Formula (I)

[Wherein R is a C _6-8 cycloalkyl group, a C _6-8 cycloalkenyl group, or _4-7 which may be substituted with the same or different 1 to 2 substituents selected from the substituent group A. A membered heterocyclyl group (the heteroatom on the heterocyclyl ring is one or two nitrogen atoms);
Substituent group A includes a C _1-6 alkyl group, a halogen atom, and an optionally substituted aryl group (the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group) , Difluoromethoxy 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) aminocarbonyl group and di (C _1-6 alkyl) amino group are the same or different 1 to 3 groups selected from the group consisting of
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 R is an optionally substituted 4-piperidinyl group, at least one of the 2, 3, 5 and 6 positions of the piperidinyl group has a substituent. Or a pharmacologically acceptable salt thereof. R is a C _6-8 cycloalkyl group or a C _6-8 cycloalkenyl group, which may be substituted with the same or different 1 or 2 substituents selected from the substituent group A1, and the substituent group A1 is , A C _1-6 alkyl group, a halogen atom and an optionally substituted aryl group (the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy 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) aminocarbonyl group And the same or different 1 to 3 groups selected from the group consisting of di (C _1-6 alkyl) amino groups. Compound or a pharmacologically acceptable salt thereof. R is a cyclohexyl group substituted by one or two different substituents selected from the substituent group A2, and the substituent group A2 includes a C _1-4 alkyl group, a fluorine atom, a chlorine atom, and a substituent. Aryl group (the substituent is selected from the group consisting of chlorine atom, fluorine atom, C _1-3 alkyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group and C _1-3 alkoxy group). Or a pharmacologically acceptable salt thereof. 2. The compound according to claim 1, which is the same or different selected one or two groups. R is a cyclohexyl group substituted by one or two substituents selected from the substituent group A3, and the substituent group A3 includes a C ₁ -C ₄ alkyl group, a fluorine atom, a chlorine atom, and 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) (1 Or a pharmacologically acceptable salt thereof. R is a cyclohexyl group substituted with one or two substituents selected from the same or different substituent group A4, and the substituent group A4 includes a C ₁ -C ₄ alkyl group, a fluorine atom, a chlorine atom, and 2. The 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). Or a pharmacologically acceptable salt thereof. 2. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein R is a 4-phenylcyclohexyl group. R is a 4- to 7-membered heterocyclyl group which may be substituted with the same or different 1 to 2 substituents selected from Substituent Group A5 (the hetero atom on the heterocyclyl ring is 1 or 2 nitrogen atoms) And the substituent group A5 is a C _1-6 alkyl group and an optionally substituted heteroaryl group (the heteroaryl is a 5-membered or 6-membered ring. A heteroatom on the ring of the heteroaryl group) Is one or two nitrogen atoms and may further contain one nitrogen atom, oxygen atom or sulfur atom, and the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano _{group, C 1-6 alkoxy, C 3-7} cycloalkoxy group, a phenyl _{group, C 2-7} alkoxycarbonyl two Group, benzyloxycarbonyl group, di is (C _1-6 alkyl) aminocarbonyl Moto及busy (C _1-6 alkyl) the same or different 1 or 2 groups selected from the group consisting of amino group.) The compound according to claim 1 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, A 4- to 7-membered heterocyclyl group substituted with 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. heteroatom on the ring of the heterocyclyl is one or two nitrogen atoms. the heterocyclyl may be further substituted by C _1-6 alkyl group.) in That is a compound or a pharmacologically acceptable salt thereof according to claim 1. 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 heterocyclyl group is substituted with a 4- to 7-membered heterocyclyl group (the heteroatom on the heterocyclyl ring is a nitrogen atom. The heterocyclyl may be further substituted with a methyl group). 2. The compound according to 1, 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) 4-7 membered heterocyclyl group substituted with different 1 or 2 groups) (the heteroatom on the heterocyclyl ring is a nitrogen atom. The heterocyclyl is further substituted with a methyl group) The compound according to claim 1 or a pharmacologically acceptable salt thereof. R is a substituted 4- to 7-membered heterocyclyl group substituted with a pyridyl group or a pyrazinyl group (the substituent is a trifluoromethyl group) (the heteroatom on the heterocyclyl ring is one nitrogen atom) The compound or pharmacologically acceptable salt thereof according to claim 1, wherein the heterocyclyl may be further substituted with a methyl group. 4-hydroxy-3- (4-phenylcyclohexyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one,
3- {1- [3-Chloro-5- (trifluoromethyl) -2-pyridyl] pyrrolidin-3-yl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro -6H-pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one,
3- {1- [3-Chloro-5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
3- [1- (3,5-Dichloropyridin-2-yl) pyrrolidin-3-yl] -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [ 3,4-b] pyridin-6-one,
4-hydroxy-4- (trifluoromethyl) -3- {1- [4- (trifluoromethyl) pyrimidin-2-yl] pyrrolidin-3-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one,
4-Hydroxy-3- {2-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl) -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-3-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-3- {3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl) -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-hydroxy-3- {3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl) -1,4,5,7- Tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
3- {1- [4- (Difluoromethoxy) phenyl] -3-methylpiperidin-4-yl} -4-hydroxy-4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyridin-2-yl] azepan-4-yl} -1,4,5,7-tetrahydro-6H- Pyrazolo [3,4-b] pyridin-6-one, and
4-Hydroxy-4- (trifluoromethyl) -3- {1- [5- (trifluoromethyl) pyrazin-2-yl] pyrrolidin-3-yl} -1,4,5,7-tetrahydro-6H- 2. The compound according to claim 1 or a pharmacologically acceptable salt thereof selected from the group consisting of pyrazolo [3,4-b] pyridin-6-one. (4R) -4-hydroxy-4- (trifluoromethyl) -3-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1,4 5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -3-{(3S) -1- [3-Chloro-5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -4-hydroxy-4- (trifluoromethyl)- 1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -3-[(3S) -1- (3,5-dichloropyridin-2-yl) pyrrolidin-3-yl] -4-hydroxy-4- (trifluoromethyl) -1,4,5 7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-4- (trifluoromethyl) -3-{(3S) -1- [4- (trifluoromethyl) pyrimidin-2-yl] pyrrolidin-3-yl} -1,4 5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-3-{(2R, 4R) -2-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl ) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-3-{(2S, 4S) -2-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl ) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-4- (trifluoromethyl) -3-{(3R) -1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-3-yl} -1,4 5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-3-{(3R, 4R) -3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl ) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -4-hydroxy-3-{(3S, 4S) -3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -4- (trifluoromethyl ) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one,
(4R) -3-{(3R, 4R) -1- [4- (Difluoromethoxy) phenyl] -3-methylpiperidin-4-yl} -4-hydroxy-4- (trifluoromethyl) -1,4 , 5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one, and
(4R) -3-{(3S, 4S) -1- [4- (Difluoromethoxy) phenyl] -3-methylpiperidin-4-yl} -4-hydroxy-4- (trifluoromethyl) -1,4 The compound according to claim 1 or a pharmacologically acceptable salt thereof, selected from the group consisting of 1,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmacologically acceptable salt thereof as an active ingredient. An arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebrovascular disease, peripheral, comprising the compound according to any one of claims 1 to 13 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 13 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 13 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 13 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 13 or a pharmacologically acceptable salt thereof. An LCAT activator comprising the compound according to any one of claims 1 to 13 or a pharmacologically acceptable salt thereof as an active ingredient. A reversible LCAT activator comprising the compound according to any one of claims 1 to 13 or a pharmacologically acceptable salt thereof as an active ingredient. An anti-arteriosclerotic agent comprising the compound according to any one of claims 1 to 13 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 13 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 13 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 13 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 13 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 13 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, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 13 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 13, 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 13, for use in a method for treatment or prevention of dyslipidemia. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 13, 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 13, 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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