JP2009051828A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition useful for inhibition of a cholesteryl ester transfer protein (CETP) and effective for prophylaxis and/or treatment of diseases such as arteriosclerotic diseases, hyperlipemia or dyslipidaemias. <P>SOLUTION: The pharmaceutical composition comprises a compound represented by general formula (1) (wherein Y is a methylene group or the like; A is a heterocyclic group or the like which may be substituted; B is a heterocyclic group or the like which may be substituted; R<SP>1</SP>is an alkyl group which may be substituted and further may be substituted with an isocyclic group or the like; R<SP>2</SP>is an amino group or the like which may be substituted) or its pharmacologically permissible derivative as an active ingredient. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to the prevention and / or prevention of diseases such as arteriosclerotic diseases, hyperlipidemia or dyslipidemia, which have cholesteryl ester transfer protein (CETP) inhibitory activity and exhibit HDL cholesterol increasing action and LDL cholesterol lowering action. Or relates to a pharmaceutical composition for treatment.

  Numerous epidemiological studies have shown that hypercholesterolemia, particularly high serum low density lipoprotein (LDL) cholesterol, is a risk factor for atherosclerotic disease. In fact, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and other drugs that lower LDL cholesterol have been used for the purpose of preventing coronary artery disease. A certain effect has been demonstrated. However, its effect on preventing coronary artery disease is limited and still not fully satisfactory.

  On the other hand, many epidemiological studies and large-scale clinical trials have recently revealed that low density of high density lipoprotein (HDL) cholesterol in serum is a strong risk factor for arteriosclerotic diseases. Various anti-arteriosclerotic effects are known for HDL, and as a useful means for the prevention or treatment of arteriosclerotic diseases, the possibility of drugs that increase HDL cholesterol is attracting attention. However, there are currently no drugs that can be used satisfactorily for this purpose. Fibrates and HMG-CoA reductase inhibitors have a low HDL cholesterol-elevating action, and nicotinic acid derivatives significantly increase HDL cholesterol but have serious toleration problems. Therefore, there is a need for a well-tolerated drug that can significantly increase HDL cholesterol and prevent or reverse the progression of arteriosclerotic diseases.

  It is known that various proteins are involved in the mechanism of catabolism of various lipoproteins in serum. Among them, the role of cholesteryl ester transfer protein (CETP) is attracting attention. CETP is a protein that transfers cholesteryl ester (CE) and triglyceride between lipoproteins, and mediates CE transfer from HDL to LDL or very low density lipoprotein (VLDL). Accordingly, CETP activity greatly affects the lipid composition in lipoprotein particles. For example, in rabbits and hamsters, it is known that when an active neutralizing monoclonal antibody against CETP is administered, the HDL cholesterol concentration increases and LDL cholesterol decreases. In addition, in a person whose CETP activity has been decreased / deficient due to a gene mutation, the blood HDL cholesterol concentration is increased and LDL cholesterol is decreased. On the other hand, it is known that HDL cholesterol is decreased and LDL cholesterol concentration is increased in transgenic mice and rats expressing CETP. That is, CETP is considered to contribute greatly to the regulation of serum lipids, resulting in changes in serum lipid profiles such as a decrease in HDL cholesterol and an increase in LDL cholesterol. From these facts, the high value of CETP activity is considered to be atherosclerotic.

  Actually, the CETP activity varies depending on the animal species, and it is known that arteriosclerotic lesions due to cholesterol loading are easily formed in animals with high CETP activity such as rabbits, and conversely, it is difficult to cause in animals with low CETP activity such as rats. . In addition, in rabbits loaded with cholesterol, when antisense oligodeoxynucleotide is administered to continuously suppress CETP activity, effects such as an increase in blood HDL cholesterol concentration and suppression of arteriosclerotic lesions have been confirmed.

  From the above findings, CETP activity is considered to have an inverse correlation with HDL cholesterol, and inhibition of CETP activity is expected to reduce the risk for arteriosclerotic diseases. A compound that inhibits CETP activity inhibits cholesterol transfer from HDL to LDL or VLDL, increases arteriosclerosis-inhibiting HDL cholesterol, and simultaneously reduces arteriosclerosis-induced LDL cholesterol. It is expected to provide an unprecedented useful medical means as a preventive or therapeutic agent for diseases, hyperlipidemia or dyslipidemia.

  Examples of compounds having CETP inhibitory activity include tetrahydroquinoline derivatives (see Patent Document 1, Patent Document 2 and Patent Document 3).

  However, since these compounds have low water solubility, they are poorly absorbed into the body even when administered as a normal oral preparation, and it is difficult to obtain the blood concentration of a drug necessary for achieving a medicinal effect. Yes (see Patent Document 4).

  For this reason, a novel pharmaceutical composition containing a compound that has overcome the above-described drawbacks has been desired, and dibenzylamine type compounds and the like have been intensively studied (see Patent Documents 5, 6, 7, and 8).

International Publication WO00 / 17164 Pamphlet International Publication WO00 / 17165 Pamphlet International Publication WO00 / 17166 Pamphlet International Publication WO03 / 63868 Pamphlet International Publication WO2005 / 100298 Pamphlet International Publication WO2004 / 020393 Pamphlet International Publication WO2006 / 073973 Pamphlet JP2003-221376

  An object of the present invention is to provide a pharmaceutical composition effective for the prevention and / or treatment of diseases such as arteriosclerotic diseases, hyperlipidemia or dyslipidemia, which is effective in inhibiting CETP. is there.

  In order to solve the above-mentioned problems, the present inventors have conducted intensive research, found a pharmaceutical composition having CETP inhibitory activity and exhibiting HDL cholesterol increasing action and LDL cholesterol lowering action, and completed the present invention.

  That is, the present invention is as follows.

（式中、Ｙが、アルキル基およびオキソ基から選ばれる置換基で置換されていてもよいメチレン基または単結合であり、
Ａが、（ｉ）置換されていてもよいアルキニル基、ハロゲン原子、オキソ基、ヒドロキシ基、シアノ基、ニトロ基、カルボキシル基、スルホ基、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルコキシ基、置換されていてもよいアルコキシカルボニル基、置換されていてもよいカルバモイル基、置換されていてもよいカルバムイミドイル基、置換されていてもよいアルキルスルファニル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアミノ基、置換されていてもよいスルファモイル基、置換されていてもよいアルカノイル基、置換されていてもよい同素環基、置換されていてもよい同素環基置換オキシ基、置換されていてもよい同素環基置換カルボニル基、置換されていてもよい複素環基、置換されていてもよい複素環基置換オキシ基、および置換されていてもよい複素環基置換カルボニル基から選ばれる基；
（ｉｉ）前記（ｉ）記載の基から独立して選ばれる１〜５の置換基で置換されていてもよい同素環基；または
（ｉｉｉ）前記（ｉ）記載の基から独立して選ばれる１〜５の置換基で置換されていてもよい複素環基、であり、
Ｂが、以下の置換基から独立して選択される１〜５個の置換基で置換されていてもよい複素環基であり：
置換されていてもよいアルキニル基、ハロゲン原子、オキソ基、ヒドロキシ基、シアノ基、ニトロ基、カルボキシル基、スルホ基、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルコキシ基、置換されていてもよいアルコキシカルボニル基、置換されていてもよいカルバモイル基、置換されていてもよいカルバムイミドイル基、置換されていてもよいアルキルスルファニル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアミノ基、置換されていてもよいスルファモイル基、置換されていてもよいアルカノイル基、置換されていてもよい同素環基、置換されていてもよい同素環基置換オキシ基、置換されていてもよい同素環基置換カルボニル基、置換されていてもよい複素環基、置換されていてもよい複素環基置換オキシ基、置換されていてもよい複素環基置換カルボニル基、およびアルキレン基；
ここにおいて該アルキレン基は窒素原子、硫黄原子および酸素原子より独立して選択される１〜３個のヘテロ原子を有していてもよく、さらに該アルキレン基は置換されていてもよい、
Ｒ^１が水素原子または置換されていてもよいアルキル基であり；該アルキル基は、さらに置換されていてもよい同素環基および置換されていてもよい複素環基から選ばれる置換基で置換されていてもよい、
Ｒ^２が置換されていてもよいアルキニル基、ハロゲン原子、オキソ基、ヒドロキシ基、シアノ基、ニトロ基、カルボキシル基、スルホ基、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルコキシ基、置換されていてもよいアルコキシカルボニル基、置換されていてもよいカルバモイル基、置換されていてもよいカルバムイミドイル基、置換されていてもよいアルキルスルファニル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアミノ基、置換されていてもよいスルファモイル基、置換されていてもよいアルカノイル基、置換されていてもよい同素環基、置換されていてもよい同素環基置換オキシ基、置換されていてもよい同素環基置換カルボニル基、置換されていてもよい複素環基、置換されていてもよい複素環基置換オキシ基、および置換されていてもよい複素環基置換カルボニル基から選ばれる基である）で示される化合物、またはその薬理的に許容しうる誘導体を有効成分として含有することを特徴とする、医薬組成物。 1. General formula (1):

Wherein Y is a methylene group or a single bond optionally substituted with a substituent selected from an alkyl group and an oxo group;
A is (i) an optionally substituted alkynyl group, a halogen atom, an oxo group, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a sulfo group, an optionally substituted alkyl group, or an optionally substituted group. A good cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl Group, optionally substituted carbamimidoyl group, optionally substituted alkylsulfanyl group, optionally substituted alkylsulfinyl group, optionally substituted alkylsulfonyl group, optionally substituted An amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, Optionally substituted homocyclic group, optionally substituted homocyclic group substituted oxy group, optionally substituted homocyclic group substituted carbonyl group, optionally substituted heterocyclic group, substituted A group selected from an optionally substituted heterocyclic group-substituted oxy group, and an optionally substituted heterocyclic group-substituted carbonyl group;
(Ii) a homocyclic group optionally substituted with 1 to 5 substituents independently selected from the groups described in (i); or (iii) selected independently from the groups described in (i). A heterocyclic group optionally substituted with 1 to 5 substituents,
B is a heterocyclic group optionally substituted with 1 to 5 substituents independently selected from the following substituents:
Optionally substituted alkynyl group, halogen atom, oxo group, hydroxy group, cyano group, nitro group, carboxyl group, sulfo group, optionally substituted alkyl group, optionally substituted cycloalkyl group, substituted Alkenyl group which may be substituted, alkoxy group which may be substituted, cycloalkoxy group which may be substituted, alkoxycarbonyl group which may be substituted, carbamoyl group which may be substituted, An optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, a substituted An optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, Good homocyclic group, optionally substituted homocyclic group-substituted oxy group, optionally substituted homocyclic group-substituted carbonyl group, optionally substituted heterocyclic group, optionally substituted A heterocyclic group-substituted oxy group, an optionally substituted heterocyclic group-substituted carbonyl group, and an alkylene group;
Here, the alkylene group may have 1 to 3 heteroatoms independently selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the alkylene group may be further substituted.
R ¹ is a hydrogen atom or an optionally substituted alkyl group; the alkyl group is further substituted with a substituent selected from an optionally substituted homocyclic group and an optionally substituted heterocyclic group May have been,
R ² may be substituted alkynyl group, halogen atom, oxo group, hydroxy group, cyano group, nitro group, carboxyl group, sulfo group, optionally substituted alkyl group, optionally substituted cycloalkyl A group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, a substituted An optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, Optionally substituted sulfamoyl group, optionally substituted alkanoyl group, substituted Allocyclic group which may be substituted, allocyclic group which may be substituted, substituted oxy group, allocyclic group which may be substituted, carbonyl group which may be substituted, heterocyclic group which may be substituted, substituted A compound selected from an optionally substituted heterocyclic group-substituted oxy group and an optionally substituted heterocyclic group-substituted carbonyl group), or a pharmaceutically acceptable derivative thereof as an active ingredient A pharmaceutical composition characterized by the above.

（式中、Ｘ^１およびＸ^３は、それぞれＣＨ_２、ＮＨ、Ｏ、Ｓ、ＳＯ、またはＳＯ_２を表し、Ｘ^２およびＸ^５は、それぞれＣＨ_２、Ｏ、Ｓ、ＳＯ、またはＳＯ_２を表し、Ｘ^４は、ＮＨ、Ｏ、Ｓ、ＳＯ、またはＳＯ_２を表し、Ｘ^６およびＸ^７は、それぞれＯまたはＳを表し、Ｘ^８はＳまたはＳＯを表し、ｎ、ｏ、ｐ、ｑ、およびｒは、それぞれ１〜４の整数を表す）；さらにここにおいて、上記の各基は、さらに以下の群から独立して選ばれる１〜３の置換基で置換されていてもよい：
ハロゲン原子、カルボキシル基、ヒドロキシ基、シアノ基、オキソ基、チオキソ基、アルキル基、ヒドロキシアルキル基、アルコキシカルボニルアルキル基、カルボキシアルキル基、モルホリニルアルキル基、フェニルアルキル基、アルカノイル基、ヒドロキシアルカノイル基、アルコキシアルカノイル基、アルコキシ基、フェニルアルコキシ基、アルコキシカルボニル基、ベンジルオキシカルボニル基、モノ−もしくはジ−アルキルアミノ基、モノ−もしくはジ−アルキルカルバモイル基、モノ−もしくはジ−アルキルスルファモイル基、アルキルスルホニル基、およびテトラゾリル基；
である、１記載の医薬組成物。 2. The homocyclic group is a cycloalkyl group, a phenyl group, or a naphthyl group;
A heterocyclic group is a thienyl group, a furyl group, a pyrrolyl group, a pyrrolinyl group, an oxazolyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, an imidazolinyl group, an isoxazolyl group, an isothiazolyl group, an oxadiazolyl group, a furazanyl group, a thiadiazolyl group, a triazolyl group, Triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazopyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, oxazinyl group, thiazinyl group , Piperazinyl group, triazinyl group, oxatriazinyl group, pyridazinyl group, pyrazinyl group, benzofuranyl group, benzothiazolyl group, benzoxazolyl group, tetrazolopyri Dinyl group, triazolopyridazinyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, dihydroisoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, dihydroindolyl group, indolyl group, quinolidinyl Group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group, acridinyl group, phenanthridinyl group, chromanyl group, benzooxazinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, hexahydroase Pinyl group, imidazolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydrooxazinyl group, dihydropyrazoli Group, an imidazopyridyl group, dihydro pyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group, oxathiadiazolyl group, dihydrooxazolyl group or tetrahydroquinolyl group,
An optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, a substituted An optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, a substituted Alkylsulfonyl group which may be substituted, amino group which may be substituted, sulfamoyl group which may be substituted, alkanoyl group which may be substituted, homocyclic group which may be substituted, Allocyclic group substituted oxy group, which may be substituted allocyclic group substituted carbonyl group, which may be substituted Good heterocyclic group, optionally substituted heterocyclic group-substituted oxy group, optionally substituted heterocyclic group-substituted carbonyl group, optionally substituted phenyl group, optionally substituted alkylsulfonyloxy group 1 to 5 groups, wherein the substituent of the optionally substituted alkynyl group or the optionally substituted alkylene group is independently selected from the group described below:
Cyano group; hydroxy group; nitro group; carboxyl group; oxo group; thioxo group; sulfo group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl A cycloalkyl group optionally substituted by a group; an alkoxycarbonyl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; A carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; Roxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, alkyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, An alkanoyl group optionally substituted by a mono- or di-alkylamino group, phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl An alkoxy group optionally substituted by a group; an aryl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; Canoyloxy group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, alkylsulfanyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, An alkylsulfonyl group optionally substituted by an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group Alkylsulfinyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl Mono- or di-alkylsulfamoyl group which may be substituted with a benzene or morpholinyl group; amino group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group Or a mono- or di-alkylamino group optionally substituted by a morpholinyl group; substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group Mono- or di-alkylsulfamoylamino group which may be substituted; mono optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group - Di-alkylureido group; homocyclic group selected from cycloalkyl group, phenyl group, and naphthyl group; said homocyclic group-substituted oxy group; said homocyclic group-substituted carbonyl group; thienyl group, furyl group, pyrrolyl group , Pyrrolinyl group, oxazolyl group, thiazolyl group, pyrazolyl group, imidazolyl group, imidazolinyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, furazanyl group, thiadiazolyl group, triazolyl group, triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazo Pyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, oxazinyl group, thiazinyl group, piperazinyl group, tri Zinyl group, oxatriazinyl group, pyridazinyl group, pyrazinyl group, benzofuranyl group, benzothiazolyl group, benzoxazolyl group, tetrazolopyridazinyl group, triazolopyridazinyl group, benzoimidazolyl group, quinolyl group, isoquinolyl group Group, dihydroisoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, dihydroindolyl group, indolyl group, quinolidinyl group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group , Acridinyl group, phenanthridinyl group, chromanyl group, benzoxazinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, hexahydroazepinyl group, imidazolidinyl group, oxazolidinyl group, teto Lahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydrooxazinyl group, dihydropyrazolyl group, imidazopyridyl group, dihydropyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group , A heterocyclic group selected from an oxathiadiazolyl group, a dihydrooxazolyl group and a tetrahydroquinolyl group; the heterocyclic group-substituted oxy group; the heterocyclic group-substituted carbonyl group;
And a group represented by the following formula:

Wherein X ¹ and X ³ each represent CH ₂ , NH, O, S, SO, or SO ₂ , and X ² and X ⁵ represent CH ₂ , O, S, SO, or SO ₂ , respectively. X ⁴ represents NH, O, S, SO, or SO ₂ , X ⁶ and X ⁷ each represent O or S, X ⁸ represents S or SO, n, o, p, q , And r each represent an integer of 1 to 4); further, each of the above groups may be further substituted with 1 to 3 substituents independently selected from the following group:
Halogen atom, carboxyl group, hydroxy group, cyano group, oxo group, thioxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group , Alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, alkoxycarbonyl group, benzyloxycarbonyl group, mono- or di-alkylamino group, mono- or di-alkylcarbamoyl group, mono- or di-alkylsulfamoyl group, An alkylsulfonyl group and a tetrazolyl group;
The pharmaceutical composition according to 1, wherein

3. A is the formula:
-A ¹ -A ²
A group represented by
A ¹ is a phenyl group, naphthyl group, pyrimidinyl group, pyridazinyl group, a pyridyl group, triazolyl group, tetrazolyl group, oxadiazolyl group, dihydropyrimidinyl group, a pyrazinyl group, a thiazolyl group, an oxazolyl group, dihydro benzoxazinyl group, an imidazolyl group, pyrazolyl Group or dihydropyrazinyl group,
A ² is carboxyl group; cyano group; nitro group; hydroxy group, cyano group, carboxyl group, alkoxycarbonyl group, alkoxy group, phenylalkoxy group, hydroxyalkoxy group, carboxyalkoxy group, alkylsulfanyl group, alkylsulfonyl group, alkyl Sulfinyl group, amino group, mono- or di-alkylamino group, mono- or di-alkylsulfamoylamino group, mono- or di-alkylureido group optionally substituted with morpholinyl group, oxiranyl group, dialkyldio Substituted with a group selected from a xazolanyl group, a pyrrolidinyl group optionally substituted with a carboxyl group, a piperidyl group optionally substituted with a carboxyl group, a piperazinyl group optionally substituted with an alkyl group, and a morpholinyl group Alkyl group which may be substituted; alkenyl group which may be substituted with carboxyl group; hydroxy group, cyano group, carboxyl group, alkoxycarbonyl group, alkoxy group, phenylalkoxy group, hydroxyalkoxy group, carboxyalkoxy group, alkylsulfanyl Group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono- or di-alkylamino group, mono- or di-alkylsulfamoylamino group, mono- or di-alkylureido optionally substituted with morpholinyl group A group, an oxiranyl group, a dialkyldioxolanyl group, a pyrrolidinyl group optionally substituted with a carboxyl group, a piperidyl group optionally substituted with a carboxyl group, a piperazinyl group optionally substituted with an alkyl group, and An alkoxy group optionally substituted with a group selected from a ruphorinyl group; an alkoxycarbonyl group; a hydroxycarbamimidoyl group; an alkylsulfanyl group; an alkylsulfonyl group optionally substituted with a carboxyl group; a hydroxy group, a carboxyl group, A mono- or di-alkylamino group optionally substituted with an alkoxy group or a mono- or di-alkylamino group; a morpholinyl group optionally substituted with a carboxyl group, an alkyl group, a carboxyalkyl group or an alkoxycarbonyl group An optionally oxidized thiomorpholinyl group; a piperazinyl group optionally substituted with a group selected from an alkyl group, an alkanoyl group, and a hydroxyalkanoyl group; a carboxyl group, an alkyl group, a carboxyalkyl group, or an amine; A pyrrolidinyl group optionally substituted with a alkoxycarbonyl group; a piperidyl group optionally substituted with a carboxyl group, an alkyl group, a carboxyalkyl group, or an alkoxycarbonyl group; an alkyl group, a hydroxyalkyl group, a carboxyalkyl group, or A tetrazolyl group optionally substituted with a morpholinylalkyl group; an oxodihydrooxadiazolyl group; a pyrimidinyl group; or a tetrahydropyranyl group,
R ¹ is the formula:
-R ¹¹ -R ¹²
A group represented by
R ¹¹ is an alkylene group,
R ¹² is phenyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, furyl group, thienyl group, triazolyl group, tetrazolyl group, oxadiazolyl group, dihydropyrimidinyl group, pyrazinyl group, thiazolyl group, oxazolyl group, imidazolyl group, dihydrooxazinyl group A substituent selected from a group, a dihydropyrazinyl group, and a pyrazolyl group;
Here, the substituent is a halogen atom, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono- or di-alkylcarbamoyl group, alkyl group, alkoxy group, hydroxy group, nitro group, cyano group, amino group, mono- or May be substituted with 1 to 4 substituents independently selected from di-alkylamino, alkanoyl, alkylsulfanyl, tetrazolyl, and dihydrooxazolyl groups;
Further, in this case, the alkyl group, alkoxy group, mono- or di-alkylamino group, mono- or di-alkylcarbamoyl group, alkanoyl group, and alkylsulfanyl group are each independently a halogen atom, a hydroxy group, or an alkoxy group. May be substituted with 1 to 5 substituents independently selected from amino group, morpholinyl group, piperidyl group, pyrrolidinyl group, piperazinyl group, alkylpiperazinyl group, and alkanoylpiperazinyl group;
R ² is a halogen atom;
A hydroxy group;
A cyano group;
A nitro group;
Carboxyl group;
A sulfo group;
A cycloalkyl group optionally substituted with a carboxyl group or an alkoxycarbonyl group;
A halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a mono- or di-alkylcarbamoyl group, an alkoxy group (the alkoxy group may be substituted with a phenyl group, a carboxyl group, or a hydroxy group) Alkanoyl group, alkanoyloxy group, alkylsulfanyl group, alkylsulfonyl group, alkylsulfinyl group, mono- or di-alkylamino group optionally substituted with amino group, carboxyl group or alkoxy group, mono- or di -Alkylsulfamoylamino group, mono- or di-alkylureido group optionally substituted with morpholinyl group, oxiranyl group, dioxolanyl group optionally substituted with alkyl group, alkoxycarbonyl group Is a pyrrolidinyl group which may be substituted with a carboxyl group, an alkoxycarbonylalkyl group or a pyrrolidinyl group which may be substituted with a carboxyalkyl group, an alkoxycarbonyl group or a piperidyl group which may be substituted with a carboxyl group, alkoxycarbonylalkyl A piperidyl group optionally substituted with a carboxyalkyl group, a piperazinyl group optionally substituted with an alkyl group, a hexahydroazepinyl group, a morpholinyl group, and a piperidyloxy group optionally substituted with an alkyl group An alkyl group which may be substituted with a group selected from:
An alkenyl group optionally substituted by a group selected from a cyano group, a hydroxy group, a carboxyl group, a benzyloxycarbonyl group, and a tetrazolyl group;
An alkenyloxy group optionally substituted with a carboxyl group;
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group An pyrrolidinylcarbonyl group optionally substituted with an alkoxy group optionally substituted with a group selected from a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
An alkoxycarbonyl group optionally substituted with a phenyl group;
A carbamoyl group;
A mono- or di-alkylcarbamoyl group optionally substituted with a group selected from a carboxyl group, a morpholinyl group, and an alkoxy group;
A hydroxycarbamimidoyl group;
An alkylsulfanyl group optionally substituted with a group selected from a hydroxy group, a carboxyl group, and a mono- or di-alkylcarbamoyl group;
An alkylsulfinyl group;
An alkylsulfonyl group optionally substituted with a group selected from a hydroxy group, a carboxyl group, an alkoxycarbonyl group, and a mono- or di-alkylcarbamoyl group;
An amino group;
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A mono- or di-alkylamino group optionally substituted with a group selected from a pyrrolidinylcarbonyl group optionally substituted with, a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group ;
An alkanoylamino group optionally substituted with a group selected from a hydroxy group, an alkoxy group, a carboxyl group, and an amino group;
A mono- or di-alkylcarbamoylamino group optionally substituted by an alkoxy group;
A morpholinylcarbonylamino group;
A sulfamoyl group;
Mono- or di-alkylsulfamoyl groups;
An alkanoyl group optionally substituted with a group selected from a hydroxy group, a carboxyl group, an alkoxycarbonyl group, an alkoxy group, a mono- or di-alkylamino group, and a morpholinyl group; or
Cycloalkyl group, phenyl group, naphthyl group, thienyl group, furyl group, pyrrolyl group, pyrrolinyl group, oxazolyl group, thiazolyl group, pyrazolyl group, imidazolyl group, imidazolinyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, furazanyl group, thiadiazolyl Group, triazolyl group, triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazopyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, Oxazinyl, thiazinyl, piperazinyl, triazinyl, oxatriazinyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothiazolyl, benzo Xazolyl group, tetrazolopyridazinyl group, triazolopyridazinyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, dihydroisoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, dihydro Indolyl group, indolyl group, quinolidinyl group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group, acridinyl group, phenanthridinyl group, chromanyl group, benzoxazinyl group, phenazinyl group, phenothiazinyl group Group, phenoxazinyl group, hexahydroazepinyl group, imidazolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydroozone Selected from sazinyl group, dihydropyrazolyl group, imidazopyridyl group, dihydropyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group, oxathiadiazolyl group, dihydrooxazolyl group and tetrahydroquinolyl group A cyclic group;
Furthermore, here, the cyclic group may be substituted with a substituent selected from the following group:
A halogen atom, an alkoxyalkyl group, an alkyl group optionally substituted with 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, Cyano group, oxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group, alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, Alkoxycarbonyl, benzyloxycarbonyl, mono- or di-alkylamino, mono- or di-alkylcarbamoyl, mono- or di-alkylsulfamoyl, alkylsulfonyl, Fine-tetrazolyl group;
Further, here, the substituent may be substituted with a substituent selected from the following group:
A halogen atom, an alkoxyalkyl group, an alkyl group optionally substituted with 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, Cyano group, oxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group, alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, Alkoxycarbonyl, benzyloxycarbonyl, mono- or di-alkylamino, mono- or di-alkylcarbamoyl, mono- or di-alkylsulfamoyl, alkylsulfonyl, Fine-tetrazolyl group;
The pharmaceutical composition according to 2, wherein

（式中、記号は前記と同一意味を表す）が

（式中、環Ｗは複素環基を表す）を除くもの；
である、１記載の医薬組成物。 4). Y is a methylene group or a single bond optionally substituted with a group selected from an alkyl group and an oxo group;
A is the formula:
-A ¹ -A ²
A group represented by
A ¹ is a homocyclic group, a heterocyclic group or a single bond,
A ² may be a homocyclic group which may be substituted, an alkylsulfanyl group which may be substituted, an alkylsulfinyl group which may be substituted, an alkylsulfonyl group which may be substituted, a nitro group, a hydroxy group, An optionally substituted alkenyl group, an optionally substituted heterocyclic group, an optionally substituted alkoxy group, a halogen atom, an optionally substituted alkyl group, a cyano group, 1 to 2 substituents An amino group or a hydrogen atom optionally substituted by
B is an oxo group, a cyano group, a carboxyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, a hydroxyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl Group, halogen atom, optionally substituted alkoxy group, optionally substituted alkylsulfanyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, optionally substituted It may be substituted with 1 to 5 groups independently selected from a heterocyclic group, an optionally substituted alkylsulfinyl group, and an amino group optionally substituted with 1 to 2 substituents. A heterocyclic group,
R ¹ is a hydrogen atom or an optionally substituted lower alkyl group; the lower alkyl group may be further substituted with an optionally substituted homocyclic group or optionally substituted heterocyclic group. Often,
R ² is an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, a cyano group, an optionally substituted alkenyl group, 1 to 2 An amino group which may be substituted with a substituent, a halogen atom, an alkoxy group which may be substituted, a carbamoyl group which may be substituted, an oxy group which is substituted with an optionally substituted heterocyclic group, hydroxy A group, an optionally substituted heterocyclic group, an optionally substituted homocyclic group, an oxy group substituted by an optionally substituted homocyclic group, an optionally substituted alkyl group, hydrogen An atom, an optionally substituted alkylcarbonyl group, an optionally substituted alkyl group, an optionally substituted alkoxycarbonyl group or a nitro group;
However, partial structure (1-1) of compound (1):

(Wherein the symbols have the same meaning as above)

(Wherein ring W represents a heterocyclic group);
The pharmaceutical composition according to 1, wherein

5). Y is a methylene group or a single bond optionally substituted with a group independently selected from an alkyl group and an oxo group;
A ¹ is a heterocyclic group or a single bond,
A ² may be substituted with an optionally substituted heterocyclic group, an optionally substituted alkoxy group, a halogen atom, an optionally substituted alkyl group, a cyano group, or 1 to 2 substituents. A good amino group or hydrogen atom,
B is an oxo group, a cyano group, a carboxyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, a hydroxyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl A group, a halogen atom, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted piperidyl group, and 1 to 2 substitutions A heterocyclic group which may be substituted with 1 to 5 groups independently selected from an amino group which may be substituted with a group;
R ¹ is a hydrogen atom, an optionally substituted benzyl group or an optionally substituted phenylethyl group,
R ² is an amino group optionally substituted by 1 to 2 substituents, a halogen atom, an optionally substituted alkoxy group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group An oxy group substituted with a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted homocyclic group, an oxy group substituted with an optionally substituted homocyclic group, hydroxyalkyl A group or a nitro group,
4. The pharmaceutical composition according to 4.

であり、
Ｒ^２が１〜２個の置換基で置換されていてもよいアミノ基、ハロゲン原子、置換されていてもよいアルコキシ基、置換されていてもよいカルバモイル基、置換されていてもよい複素環基で置換されたオキシ基、ヒドロキシ基、置換されていてもよい複素環基、置換されていてもよい同素環基、置換されていてもよい同素環基で置換されたオキシ基、置換されていてもよいアルキル基、水素原子、置換されていてもよいアルキルカルボニル基、置換されていてもよいアルコキシカルボニル基またはニトロ基、
である５記載の医薬組成物。 6). Y is a methylene group or a single bond optionally substituted with a group independently selected from an alkyl group and an oxo group;
A ¹ is a heterocyclic group or a single bond,
A ² may be substituted with an optionally substituted heterocyclic group, an optionally substituted alkoxy group, a halogen atom, an optionally substituted alkyl group, a cyano group, or 1 to 2 substituents. A good amino group or hydrogen atom,
B is an optionally substituted alkyl group, a halogen atom, a hydroxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkoxy group, an optionally substituted alkoxy group, an alkylsulfanyl group, An alkylsulfinyl group, an amino group optionally substituted with 1 to 2 substituents, and a heterocyclic group optionally substituted with 1 to 5 substituents independently selected from an alkylsulfonyl group;
R ¹ is

And
R ² is an amino group optionally substituted by 1 to 2 substituents, a halogen atom, an optionally substituted alkoxy group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group An oxy group substituted with an hydroxy group, an optionally substituted heterocyclic group, an optionally substituted homocyclic group, an optionally substituted homocyclic group, an substituted oxy group, substituted An optionally substituted alkyl group, a hydrogen atom, an optionally substituted alkylcarbonyl group, an optionally substituted alkoxycarbonyl group or a nitro group,
The pharmaceutical composition according to 5, wherein

（式中、Ｘ^１およびＸ^３は、それぞれＣＨ_２、ＮＨ、Ｏ、Ｓ、ＳＯ、またはＳＯ_２を表し、Ｘ^２およびＸ^５は、それぞれＣＨ_２、Ｏ、Ｓ、ＳＯ、またはＳＯ_２を表し、Ｘ^４は、ＮＨ、Ｏ、Ｓ、ＳＯ、またはＳＯ_２を表し、Ｘ^６およびＸ^７は、それぞれＯまたはＳを表し、Ｘ^８はＳまたはＳＯを表し、ｎ、ｏ、ｐ、ｑ、およびｒは、それぞれ１〜４の整数を表す）；さらにここにおいて、上記の各基は、さらに以下の群から独立して選ばれる１〜３の置換基で置換されていてもよい：
ハロゲン原子、カルボキシル基、ヒドロキシ基、シアノ基、オキソ基、チオキソ基、アルキル基、ヒドロキシアルキル基、アルコキシカルボニルアルキル基、カルボキシアルキル基、モルホリニルアルキル基、フェニルアルキル基、アルカノイル基、ヒドロキシアルカノイル基、アルコキシアルカノイル基、アルコキシ基、フェニルアルコキシ基、アルコキシカルボニル基、ベンジルオキシカルボニル基、モノ−もしくはジ−アルキルアミノ基、モノ−もしくはジ−アルキルカルバモイル基、モノ−もしくはジ−アルキルスルファモイル基、アルキルスルホニル基、およびテトラゾリル基、
である６記載の医薬組成物。 7). The homocyclic group is a cycloalkyl group, a phenyl group, or a naphthyl group;
A heterocyclic group is a thienyl group, a furyl group, a pyrrolyl group, a pyrrolinyl group, an oxazolyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, an imidazolinyl group, an isoxazolyl group, an isothiazolyl group, an oxadiazolyl group, a furazanyl group, a thiadiazolyl group, a triazolyl group, Triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazopyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, oxazinyl group, thiazinyl group , Piperazinyl group, triazinyl group, oxatriazinyl group, pyridazinyl group, pyrazinyl group, benzofuranyl group, benzothiazolyl group, benzoxazolyl group, tetrazolopyri Dinyl group, triazolopyridazinyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, dihydroisoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, dihydroindolyl group, indolyl group, quinolidinyl Group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group, acridinyl group, phenanthridinyl group, chromanyl group, benzooxazinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, hexahydroase Pinyl group, imidazolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydrooxazinyl group, dihydropyrazoli Group, an imidazopyridyl group, dihydro pyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group, oxathiadiazolyl group, dihydrooxazolyl group or tetrahydroquinolyl group,
An optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, a substituted An optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, a substituted Alkylsulfonyl group which may be substituted, amino group which may be substituted, sulfamoyl group which may be substituted, alkanoyl group which may be substituted, homocyclic group which may be substituted, Allocyclic group substituted oxy group, which may be substituted allocyclic group substituted carbonyl group, which may be substituted Good heterocyclic group, optionally substituted heterocyclic group-substituted oxy group, optionally substituted heterocyclic group-substituted carbonyl group, optionally substituted phenyl group, optionally substituted alkylsulfonyloxy group 1 to 5 groups, wherein the substituent of the optionally substituted alkynyl group or the optionally substituted alkylene group is independently selected from the group described below:
Cyano group; hydroxy group; nitro group; carboxyl group; oxo group; thioxo group; sulfo group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl A cycloalkyl group optionally substituted by a group; an alkoxycarbonyl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; A carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; Roxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, alkyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, An alkanoyl group optionally substituted by a mono- or di-alkylamino group, phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl An alkoxy group optionally substituted by a group; an aryl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; Canoyloxy group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, alkylsulfanyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, An alkylsulfonyl group optionally substituted by an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group Alkylsulfinyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl Mono- or di-alkylsulfamoyl group which may be substituted with a benzene or morpholinyl group; amino group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group Or a mono- or di-alkylamino group optionally substituted by a morpholinyl group; substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group Mono- or di-alkylsulfamoylamino group which may be substituted; mono optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group - Di-alkylureido group; homocyclic group selected from cycloalkyl group, phenyl group, and naphthyl group; said homocyclic group-substituted oxy group; said homocyclic group-substituted carbonyl group; thienyl group, furyl group, pyrrolyl group , Pyrrolinyl group, oxazolyl group, thiazolyl group, pyrazolyl group, imidazolyl group, imidazolinyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, furazanyl group, thiadiazolyl group, triazolyl group, triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazo Pyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, oxazinyl group, thiazinyl group, piperazinyl group, tri Zinyl group, oxatriazinyl group, pyridazinyl group, pyrazinyl group, benzofuranyl group, benzothiazolyl group, benzoxazolyl group, tetrazolopyridazinyl group, triazolopyridazinyl group, benzoimidazolyl group, quinolyl group, isoquinolyl group Group, dihydroisoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, dihydroindolyl group, indolyl group, quinolidinyl group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group , Acridinyl group, phenanthridinyl group, chromanyl group, benzoxazinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, hexahydroazepinyl group, imidazolidinyl group, oxazolidinyl group, teto Lahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydrooxazinyl group, dihydropyrazolyl group, imidazopyridyl group, dihydropyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group , A heterocyclic group selected from an oxathiadiazolyl group, a dihydrooxazolyl group and a tetrahydroquinolyl group; the heterocyclic group-substituted oxy group; the heterocyclic group-substituted carbonyl group;
And a group represented by the following formula:

Wherein X ¹ and X ³ each represent CH ₂ , NH, O, S, SO, or SO ₂ , and X ² and X ⁵ represent CH ₂ , O, S, SO, or SO ₂ , respectively. X ⁴ represents NH, O, S, SO, or SO ₂ , X ⁶ and X ⁷ each represent O or S, X ⁸ represents S or SO, n, o, p, q , And r each represent an integer of 1 to 4); further, each of the above groups may be further substituted with 1 to 3 substituents independently selected from the following group:
Halogen atom, carboxyl group, hydroxy group, cyano group, oxo group, thioxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group , Alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, alkoxycarbonyl group, benzyloxycarbonyl group, mono- or di-alkylamino group, mono- or di-alkylcarbamoyl group, mono- or di-alkylsulfamoyl group, An alkylsulfonyl group, and a tetrazolyl group,
The pharmaceutical composition according to 6, wherein

8). Y is a methylene group or a single bond,
A ¹ is a pyrimidinyl group, a tetrazolyl group or a single bond,
A ² is substituted with a mono- or di-alkylamino group which may be substituted with a carboxyl group, a piperidyl group which may be substituted with a carboxyl group, a morpholinyl group which may be substituted with a carboxyl group, or a carboxyl group. An optionally substituted alkoxy group, a halogen atom, an alkyl group optionally substituted with a carboxyl group, a hydrogen atom or a cyano group,
B is an isoquinolyl group, a tetrahydroquinolyl group, a quinolyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a dihydroindolyl group, an imidazolyl group, or an imidazolpyridyl group; where these heterocyclic groups are from the groups listed below It may be substituted with 1 to 5 independently selected substituents:
An oxo group; an alkoxy group optionally substituted with 1 to 3 halogen atoms; an alkyl group optionally substituted with 1 to 3 halogen atoms; a halogen atom; a hydroxy group; an alkylsulfanyl group; an alkylsulfinyl group And an amino group optionally substituted by 1 to 2 substituents independently selected from an alkyl group or an alkyl group substituted with a morpholinyl group,
R ¹ is independently selected from a hydrogen atom, an alkoxy group optionally substituted with a cyano group and 1 to 3 halogen atoms, and an alkyl group optionally substituted with 1 to 3 halogen atoms A benzyl group substituted with ~ 3 groups;
R ² is (a) alkyl group, alkoxyalkyl group, cycloalkylalkyl group, alkoxycarbonyl group, alkylcarbonyl group, alkylcarbamoyl group, carboxyalkyl group, carboxyalkyl-substituted cycloalkylalkyl group, hydroxyalkyl group, carboxyalkoxycarbonyl group , Carboxydihydrooxazolyl group, carboxyalkylcarbonyl group, phenylalkyl group, alkoxyalkoxycarbonyl group, alkoxyalkylcarbonyl group, piperidyl group-substituted alkyl group, carboxyalkyl-substituted piperidylalkyl group, and substituted with 1 to 3 halogen atoms It may be substituted with 1 to 2 groups independently selected from an alkyl group substituted with a phenyl group which may be substituted with 1 to 2 alkyl groups which may be substituted Amino groups;
Here, the alkyl group or alkoxy group may be further substituted with 1 to 5 groups independently selected from the following:
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A pyrrolidinylcarbonyl group optionally substituted with a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
(B) a halogen atom;
(C) an alkoxy group optionally substituted with a group selected from a carboxyl group, a cycloalkyl group and an alkoxy group;
Here, the cycloalkyl group or alkoxy group may be further substituted with 1 to 5 groups independently selected from the following:
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A pyrrolidinylcarbonyl group optionally substituted with a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
(D) a carbamoyl group optionally substituted with 1 to 2 substituents independently selected from an alkyl group and a carboxyalkyl group;
Here, the alkyl group may be further substituted with 1 to 5 groups independently selected from the following:
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A pyrrolidinylcarbonyl group optionally substituted with a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
(E) a hydroxy group;
(F) an oxy group substituted with a heterocyclic group selected from a pyrimidinyl group and a tetrahydropyranyl group;
(G) 1-2 pieces independently selected from a pyrimidinyl group, halogen atom, alkyl group, cyano group, mono- or di-alkylamino group, alkoxy group, phenyl group, carboxyl group, carbamoyl group and carboxyalkyl group A heterocyclic group selected from a morpholinyl group, piperidyl group, piperazinyl group, pyrazinyl group, tetrazolyl group, thienyl group, furyl group, dihydroisoquinolyl group, pyridyl group and pyrrolyl group, which may be substituted with a substituent;
Here, the alkoxy group or alkyl group may be further substituted with 1 to 5 groups independently selected from the following:
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A pyrrolidinylcarbonyl group optionally substituted with a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
(H) a phenyl group optionally substituted by 1 to 3 substituents independently selected from a halogen atom, alkyl and alkoxy;
Here, the alkoxy group or alkyl group may be further substituted with 1 to 5 groups independently selected from the following:
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A pyrrolidinylcarbonyl group optionally substituted with a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
(I) an oxy group substituted with a cycloalkyl group;
(J) a hydroxyalkyl group; or (k) a nitro group;
The pharmaceutical composition according to 7, wherein

であり、
Ｒ^２が（ａ）アルキル基、アルコキシアルキル基、シクロアルキルアルキル基、アルコキシカルボニル基、アルキルカルボニル基、アルキルカルバモイル基、カルボキシアルキル基、カルボキシアルキル置換シクロアルキルアルキル基、ヒドロキシアルキル基、カルボキシアルコキシカルボニル基、カルボキシジヒドロオキサゾリル基、カルボキシアルキルカルボニル基、フェニルアルキル基、アルコキシアルコキシカルボニル基、アルコキシアルキルカルボニル基、ピペリジル基置換アルキル基、カルボキシアルキル置換ピペリジルアルキル基、および１〜３個のハロゲン原子で置換されていてもよいアルキル基で１〜２個置換されていてもよいフェニル基で置換されたアルキル基から独立して選ばれる１〜２個の基で置換されていてもよいアミノ基；
（ｂ）ハロゲン原子；
（ｃ）カルボキシル基、シクロアルキル基およびアルコキシ基から選ばれる基で置換されていてもよいアルコキシ基；
（ｄ）アルキル基およびカルボキシアルキル基から独立して選ばれる基１〜２個の置換基で置換されていてもよいカルバモイル基；
（ｅ）ヒドロキシ基；
（ｆ）ピリミジニル基およびテトラヒドロピラニル基から選ばれる複素環基で置換されたオキシ基；
（ｇ）各々アルキル基、ハロゲン原子、フェニル基、アルコキシ基、カルボキシル基およびカルボキシアルキル基から独立して選ばれる１〜３個の置換基で置換されていてもよい、モルホリニル基、ピペリジル基、ピラジニル基、ジヒドロイソキノリル基、ピリジル基、ピリミジニル基、ピペラジニル基、テトラゾリル基およびピロリル基から選ばれる複素環基；
（ｈ）ハロゲン原子、アルキルおよびアルコキシから独立して選ばれる１〜３個の置換基で置換されていてもよいフェニル基；
（ｉ）シクロアルキル基で置換されたオキシ基；
（ｊ）ヒドロキシアルキル基；または
（ｋ）ニトロ基；
である８記載の医薬組成物。 9. Y is a methylene group or a single bond,
A ¹ is a pyrimidinyl group, a tetrazolyl group or a single bond,
A ² is substituted with a mono- or di-alkylamino group which may be substituted with a carboxyl group, a piperidyl group which may be substituted with a carboxyl group, a morpholinyl group which may be substituted with a carboxyl group, or a carboxyl group. An optionally substituted alkoxy group, a halogen atom, an alkyl group optionally substituted with a carboxyl group, a hydrogen atom or a cyano group,
B is an isoquinolyl group, a tetrahydroquinolyl group, a quinolyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a dihydroindolyl group, an imidazolyl group or an imidazolopyridyl group; where these heterocyclic groups are independent of the groups listed below: May be substituted with 1 to 5 substituents selected from:
An oxo group; an alkoxy group optionally substituted with 1 to 3 halogen atoms; an alkyl group optionally substituted with 1 to 3 halogen atoms; a halogen atom; an alkylsulfanyl group; an alkylsulfinyl group; An amino group optionally substituted with 1 to 2 substituents independently selected from a group or an alkyl group substituted with a morpholinyl group,
R ¹ is

And
R ² is (a) alkyl group, alkoxyalkyl group, cycloalkylalkyl group, alkoxycarbonyl group, alkylcarbonyl group, alkylcarbamoyl group, carboxyalkyl group, carboxyalkyl-substituted cycloalkylalkyl group, hydroxyalkyl group, carboxyalkoxycarbonyl group , Carboxydihydrooxazolyl group, carboxyalkylcarbonyl group, phenylalkyl group, alkoxyalkoxycarbonyl group, alkoxyalkylcarbonyl group, piperidyl group-substituted alkyl group, carboxyalkyl-substituted piperidylalkyl group, and substituted with 1 to 3 halogen atoms It may be substituted with 1 to 2 groups independently selected from an alkyl group substituted with a phenyl group which may be substituted with 1 to 2 alkyl groups which may be substituted Amino groups;
(B) a halogen atom;
(C) an alkoxy group optionally substituted with a group selected from a carboxyl group, a cycloalkyl group and an alkoxy group;
(D) a carbamoyl group optionally substituted with 1 to 2 substituents independently selected from an alkyl group and a carboxyalkyl group;
(E) a hydroxy group;
(F) an oxy group substituted with a heterocyclic group selected from a pyrimidinyl group and a tetrahydropyranyl group;
(G) morpholinyl group, piperidyl group, pyrazinyl each optionally substituted by 1 to 3 substituents independently selected from alkyl group, halogen atom, phenyl group, alkoxy group, carboxyl group and carboxyalkyl group A heterocyclic group selected from a group, a dihydroisoquinolyl group, a pyridyl group, a pyrimidinyl group, a piperazinyl group, a tetrazolyl group and a pyrrolyl group;
(H) a phenyl group optionally substituted by 1 to 3 substituents independently selected from a halogen atom, alkyl and alkoxy;
(I) an oxy group substituted with a cycloalkyl group;
(J) a hydroxyalkyl group; or (k) a nitro group;
The pharmaceutical composition according to 8, wherein

であり、
Ｒ^２が（ａ）カルボキシアルキル基、アルコキシアルキル基、ヒドロキシアルキル基、モノ−もしくはジ−アルキルアミノアルキル基、アルキル基、シクロアルキルアルキル基およびアルコキシカルボニル基、から独立して選ばれる１〜２個の基で置換されていてもよいアミノ基、
（ｂ）アルコキシ基、
（ｃ）アルキルもおよびアルコキシから独立して選ばれる１〜２個の置換基で置換されていてもよいフェニル基、
（ｄ）アルコキシ基およびアルキル基から選ばれる１〜２個の置換基で置換されていてもよいピリミジニル基、または
（ｅ）アルコキシ基およびアルキル基から選ばれる１〜２個の置換基で置換されていてもよいピリジル基、
である、９記載の医薬組成物。 10. Y is a methylene group;
A ¹ is a pyrimidinyl group,
A ² is an alkoxy group optionally substituted with a carboxyl group; a piperidyl group optionally substituted with a carboxyl group; substituted with 1 to 2 groups independently selected from a carboxyalkyl group and an alkyl group; An amino group; or an alkyl group substituted with a carboxyl group,
B is a pyrimidinyl group, a pyridyl group, a quinolyl group, a dihydroindolyl group, a pyrazolyl group, an isoquinolyl group, an imidazolyl group or an imidazolpyridyl group, wherein these heterocyclic groups are independently selected from the groups listed below: Optionally substituted with 5 substituents:
An oxo group; an alkoxy group optionally substituted with 1 to 3 halogen atoms; an alkyl group optionally substituted with 1 to 3 halogen atoms; a halogen atom; an alkylsulfanyl group; an alkylsulfinyl group; An amino group optionally substituted with 1 to 2 substituents independently selected from a group or an alkyl group substituted with a morpholinyl group,
R ¹ is

And
1 or ² R ² independently selected from (a) carboxyalkyl group, alkoxyalkyl group, hydroxyalkyl group, mono- or di-alkylaminoalkyl group, alkyl group, cycloalkylalkyl group and alkoxycarbonyl group An amino group optionally substituted by a group of
(B) an alkoxy group,
(C) a phenyl group which may be substituted with 1 to 2 substituents independently selected from alkyl and alkoxy;
(D) a pyrimidinyl group optionally substituted with 1 to 2 substituents selected from an alkoxy group and an alkyl group, or (e) substituted with 1 to 2 substituents selected from an alkoxy group and an alkyl group An optionally pyridyl group,
The pharmaceutical composition according to 9, wherein

（式中、Ａ^１１Ａが、置換されていてもよいピリミジン−２−イル基であり、
Ｒ^１ＡおよびＲ^１Ｂが各々独立して、シアノ基、または１〜３個のハロゲン原子で置換されていてもよいアルキル基であり、
環Ｅが、１〜２個の窒素原子を含む置換されていてもよい複素環基である）
で示される化合物またはその薬理的に許容しうる誘導体を含有する、医薬組成物。 11. As an active ingredient, the formula (IA):

( ^Wherein A ^11A is an ^optionally substituted pyrimidin-2-yl group,
R ^1A and R ^1B are each independently a cyano group or an alkyl group that may be substituted with 1 to 3 halogen atoms,
Ring E is an optionally substituted heterocyclic group containing 1 to 2 nitrogen atoms)
Or a pharmacologically acceptable derivative thereof.

（式中、Ａ^２１Ａが、置換されていてもよいカルバモイル基、置換されていてもよい同素環基、置換されていてもよいアルキルスルファニル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアルキル基、ニトロ基、ヒドロキシ基、シアノ基、置換されていてもよいアルケニル基、置換されていてもよい複素環基、置換されていてもよいアルコキシ基、ハロゲン原子、１〜２個の置換基で置換されていてもよいアミノ基、カルボキシル基、または水素原子であり、
Ｒ^１Ａが、シアノ基、または１〜３個のハロゲン原子で置換されていてもよいアルキル基であり、
Ｂ’が、オキソ基、シアノ基、ハロゲン原子、ヒドロキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいシクロアルコキシ基、置換されていてもよい複素環基、置換されていてもよいアルキルスルファニル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、１〜２個の置換基で置換されていてもよいアミノ基、置換されていてもよいアルキル基、および置換されていてもよいアルコキシ基から独立して選ばれる１〜３個の基で置換されていてもよく、
Ｄが、フェニル基、テトラゾール−５−イル基、ピリミジン−２−イル基、ピリミジン−４−イル基、ピリミジン−５-イル基、ピリミジン−６−イル基、ピリジン−２−イル基、ピリジン−３−イル基、ピリジン−４−イル基、ピリジン−５−イル基、ピリジン−６−イル基、または水素原子であり、
Ｄ’が、ハロゲン原子、アルコキシアルキル基、１〜５個のハロゲン原子で置換されたアルキル基、１〜５個のハロゲン原子で置換されたアルコキシ基、アルケニル基、カルバモイル基、シクロアルキル基、モノ−もしくはジ−アルキルアミノアルキル基、モノ−もしくはジ−アルキルアミノアルコキシ基、カルボキシル基、ヒドロキシ基、シアノ基、オキソ基、アルキル基、ヒドロキシアルキル基、アルコキシカルボニルアルキル基、カルボキシアルキル基、モルホリニルアルキル基、フェニルアルキル基、アルカノイル基、ヒドロキシアルカノイル基、アルコキシアルカノイル基、アルコキシ基、フェニルアルコキシ基、アルコキシカルボニル基、ベンジルオキシカルボニル基、モノ−もしくはジ−アルキルアミノ基、モノ−もしくはジ−アルキルカルバモイル基、モノ−もしくはジ−アルキルスルファモイル基、アルキルスルホニル基、テトラゾリル基、ベンジルオキシアルキル基、シクロアルキルアルキル基、ベンジルオキシ基、アルコキシアルコキシ基、カルボキシアルコキシ基、カルボキシアルケニル基、アルキルカルボニルアミノ基、カルボキシアルコキシアルキル基、モルホリニル基、およびピリジルアルコキシ基から独立して選ばれる基であり、
ｑ^Ａが０〜３の整数であり、
式：

が、以下の基：

から選ばれる基である）
で示される化合物またはその薬理的に許容しうる誘導体を含有する、医薬組成物。 12 As an active ingredient, the formula (IB):

( ^Wherein A ^21A represents an optionally substituted carbamoyl group, an optionally substituted homocyclic group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, a substituted Optionally substituted alkylsulfonyl group, optionally substituted alkyl group, nitro group, hydroxy group, cyano group, optionally substituted alkenyl group, optionally substituted heterocyclic group, optionally substituted A good alkoxy group, a halogen atom, an amino group optionally substituted with 1 to 2 substituents, a carboxyl group, or a hydrogen atom,
R ^1A is a cyano group or an alkyl group which may be substituted with 1 to 3 halogen atoms,
B ′ is an oxo group, a cyano group, a halogen atom, a hydroxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkoxy group, an optionally substituted heterocyclic group, an optionally substituted Alkylsulfanyl group which may be substituted, alkylsulfinyl group which may be substituted, alkylsulfonyl group which may be substituted, amino group which may be substituted with 1 to 2 substituents, alkyl which may be substituted A group, and optionally substituted with 1 to 3 groups independently selected from an optionally substituted alkoxy group,
D represents a phenyl group, a tetrazol-5-yl group, a pyrimidin-2-yl group, a pyrimidin-4-yl group, a pyrimidin-5-yl group, a pyrimidin-6-yl group, a pyridin-2-yl group, a pyridine- A 3-yl group, a pyridin-4-yl group, a pyridin-5-yl group, a pyridin-6-yl group, or a hydrogen atom;
D ′ is a halogen atom, an alkoxyalkyl group, an alkyl group substituted with 1 to 5 halogen atoms, an alkoxy group substituted with 1 to 5 halogen atoms, an alkenyl group, a carbamoyl group, a cycloalkyl group, mono -Or di-alkylaminoalkyl group, mono- or di-alkylaminoalkoxy group, carboxyl group, hydroxy group, cyano group, oxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinyl Alkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group, alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, alkoxycarbonyl group, benzyloxycarbonyl group, mono- or di-alkylamino group, mono- or di- Alkylcarbamoyl group, mono- or di-alkylsulfamoyl group, alkylsulfonyl group, tetrazolyl group, benzyloxyalkyl group, cycloalkylalkyl group, benzyloxy group, alkoxyalkoxy group, carboxyalkoxy group, carboxyalkenyl group, alkylcarbonyl A group independently selected from an amino group, a carboxyalkoxyalkyl group, a morpholinyl group, and a pyridylalkoxy group;
q ^A is an integer from 0 to 3,
formula:

But the following groups:

Is a group selected from
Or a pharmacologically acceptable derivative thereof.

13. A ^21A is, from the group consisting of:
(A) a heterocyclic group selected from a piperidyl group and a morpholinyl group, each of which may be substituted with a substituent selected from a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, and an alkyl group;
(B) a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulfinyl group, a mono- or di-alkylamino group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group, and an alkoxy group An alkoxy group optionally substituted by:
(C) a halogen atom;
(D) Carboxyalkyl group, alkoxycarbonylalkyl group, alkylsulfonylalkyl group, alkylsulfinylalkyl group, hydroxyalkyl group, alkyl group, alkoxyalkyl group, and aminoalkyl optionally substituted by 1 to 2 alkyl groups An amino group optionally substituted by 1 to 2 substituents independently selected from the group;
(E) a hydrogen atom;
(F) a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulfinyl group, a mono- or di-alkylamino group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group, and an alkoxy group An alkyl group optionally substituted by:
(G) a carboxyl group;
(H) a carbamoyl group optionally substituted by a carboxyalkyl group;
(I) an alkenyl group optionally substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, an alkylsulfinyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group, and an alkoxy group;
(J) a morpholinyl group; and
(K) a piperidinyl group optionally substituted by a carboxyl group or a carboxyalkyl group;
Chosen from
B ′ is an oxo group, a halogen atom, an alkyl group which may be substituted with 1 to 3 halogen atoms, an alkoxy group which may be substituted with 1 to 3 halogen atoms, a cyano group, 1 to 3 Alkylsulfanyl group optionally substituted with 1 halogen atom, alkylsulfinyl group optionally substituted with 1 to 3 halogen atoms, amino group, alkoxyalkyl group, benzyloxy group, alkoxyalkoxy group, mono- Or independently selected from a di-alkylaminoalkoxy group, a mono- or di-alkylaminoalkyl group, a cycloalkyl group, a cycloalkoxy group, and an alkylsulfonyl group optionally substituted by 1 to 3 halogen atoms Optionally substituted with 1 to 3 groups,
12. The pharmaceutical composition according to 12.

が、以下の基：

から選ばれる基である、
１３記載の医薬組成物。 14 A ^21A is a morpholinyl group, a carboxyalkoxy group, an alkylsulfonylalkoxy group, a carboxyalkenyl group, a carboxyalkyl group, an alkoxycarbonylalkoxy group, an alkoxycarbonylalkyl group, or a carboxypiperidinyl group,
B ′ is independently selected from a halogen atom, an alkyl group which may be substituted with 1 to 3 halogen atoms, and an alkoxy group which may be substituted with 1 to 3 halogen atoms. May be substituted with
D ′ is a benzyloxyalkyl group, a halogen atom, a cycloalkylalkyl group, an alkyl group that may be substituted with 1 to 3 halogen atoms, and an alkoxy that may be substituted with 1 to 3 halogen atoms A group selected independently from the group;
formula:

But the following groups:

A group selected from
13. The pharmaceutical composition according to 13.

15. A ^21A is a carboxyalkoxy group or a carboxypiperidinyl group,
D is a phenyl group;
D ′ is a group independently selected from a halogen atom, an alkoxy group, or an alkyl group,
14. The pharmaceutical composition according to 14.

が、式：

である、
１４記載の医薬組成物。 16. A ^21A is a carboxyalkoxy group,
1-3 groups independently selected from an alkyl group optionally substituted with 1 to 3 halogen atoms and an alkoxy group optionally substituted with 1 to 3 halogen atoms. May be replaced with
D is a phenyl group;
D ′ is a group independently selected from a halogen atom, an alkoxy group, or an alkyl group, and has the formula:

But the formula:

Is,
14. The pharmaceutical composition according to 14.

  17. A pharmaceutical composition comprising a compound selected from any one of Production Examples 1 to 84 or a pharmaceutically acceptable derivative thereof as an active ingredient.

  18. A pharmaceutical composition comprising a compound selected from any one of Production Examples 52, 54, 55, 57, 58, 60, 63, and 65, or a pharmaceutically acceptable derivative thereof, as an active ingredient.

  19. A pharmaceutical composition comprising as an active ingredient a compound selected from any one of Production Examples 77 to 84, or a pharmaceutically acceptable derivative thereof.

  20. A pharmaceutical composition comprising a compound selected from any one of Production Examples 1, 4, 5, 14, 21, and 23, or a pharmaceutically acceptable derivative thereof, as an active ingredient.

21. As an active ingredient
4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy)- Butanoic acid,
4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy ) -Butanoic acid,
4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[5-chloro-2- (cyclopropylmethyl-propyl-amino) -pyridin-3-ylmethyl] -amino} -pyrimidine-5 -Yloxy) -butanoic acid sodium salt,
1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[8-chloro-2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -pyrimidine-5 -Yl) -piperazine-4-carboxylic acid, and 4- (2-{(3-cyano-5-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -8-methyl A pharmaceutical composition comprising a compound selected from the group consisting of -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy) -butyric acid, or a pharmaceutically acceptable derivative thereof.

  22. The pharmaceutical composition according to any one of 1 to 21, which is an agent for treating or preventing a pathological condition in which inhibition of cholesteryl ester transfer protein is beneficial.

  23. Pathology is atherosclerosis, arteriosclerosis, metabolic syndrome, peripheral vascular disease, dyslipidemia, high beta lipoproteinemia, low alpha lipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial high Cholesterolemia, cardiovascular disorder, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cerebral infarction, stroke, diabetes, diabetic vascular complications, thrombotic disease , Obesity, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, renal vascular disease, kidney disease, visceral vascular disease, intravascular coagulation, fatty liver, steatohepatitis, inflammatory disease, Autoimmune disorders and other systemic disease indications, immune function modulation, lung disease, antioxidants, sexual dysfunction, cognitive impairment, schistosomiasis, cancer, xanthoma regression, Alzheimer's disease And a condition selected from endotoxemia, pharmaceutical composition according to any one of 1 to 22.

（式中、記号は前記と同一意味を表す）
の化合物、またはその薬理的に許容しうる誘導体を含有する医薬組成物。 24. As an active ingredient, general formula (1-2):

(Wherein the symbols have the same meaning as above)
Or a pharmacologically acceptable derivative thereof.

  Where a compound of formula (1) has one or more asymmetric carbon atoms, it can exist as racemates, racemic mixtures and individual enantiomers or diastereomers. All such isomeric forms and mixtures can also be used in the compounds of the present invention.

  Where a compound of the invention contains an alkenyl or alkenylene group, cis (Z) and trans (E) isomerism can occur. The present invention includes the individual stereoisomers of the compound, optionally their individual tautomers, and mixtures thereof.

  Separation of diastereomers, or cis and trans isomers can be achieved in a conventional manner, such as by fractional crystallization, chromatography or HPLC. Alternatively, single stereoisomeric drugs may be prepared from optically pure corresponding intermediates, if necessary, or the corresponding racemates resolved using appropriate chiral supports (e.g., HPLC Or a diastereomeric salt formed by the reaction of the corresponding racemate with a suitable optically active acid or base can be prepared by fractional crystallization. Alternatively, a mixture of enantiomers can be separated by chemical reaction with an appropriate chiral compound to form a new covalent species. For example, coupling of a racemic carboxylic acid with a chiral amine or chiral alcohol yields a diastereomeric mixture (amide or ester, respectively), which is separated by conventional techniques such as column chromatography, HPLC or fractional crystallization. The new covalent bond can then be cleaved with a suitable chemical reaction such as hydrolysis to convert one diastereomer to one enantiomer of the desired compound.

  In the present specification, the “pharmacologically acceptable derivative” means a pharmacologically acceptable salt, solvate, prodrug or the like (eg, ester) of the compound according to the present invention, and these are given to patients. When administered, a compound according to the invention or an active metabolite or residue thereof can be provided (directly or indirectly). Such derivatives can be obtained by one skilled in the art without undue experimentation. See, for example, Burger, Medicinal Chemistry and Drug Discovery, 5th edition, Volume 1, “Principles and Practice”. Preferred pharmacologically acceptable derivatives are salts, solvates, esters, carbamates and phosphates. Particularly preferred pharmacologically acceptable derivatives are salts, solvates and esters. The most preferred pharmacologically acceptable derivatives are salts and esters.

  Those skilled in the field of organic chemistry know that a large number of organic compounds can form or complex with the reaction solvent. These complexes are widely known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates of the compounds according to the invention are also within the scope of the invention.

  In the present specification, the “prodrug” means a compound that is converted into an active form having a pharmacological action by hydrolysis in the body, for example, in blood. Examples of pharmacologically acceptable prodrugs can be found in the literature [T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, “Bioreversible Carriers in Drug Design. ) ”, Edward B. Roche, Ed., American Pharmaceutical Association and Pergamon Press, ACS Symposium Series, Vol. 14, (1987); and D. Fleischer, S. Roman and H. Barbara, “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs, Advanced Drug Delivery Reviews (1996) 19 (2): 115-130)” It is described in.

  Prodrugs are carriers that release a compound of formula (1) that is covalently bound in vivo when administered to a patient. Prodrugs are usually prepared by modifying functional groups such that the modifying moiety is cleaved off by conventional means or in vivo to yield the parent compound. Examples of prodrugs include compounds in which a hydroxy, amine or sulfhydryl group of a compound of the invention is attached to any group that is cleaved to give a hydroxy, amine or sulfhydryl group upon administration to a patient. Accordingly, representative examples of prodrugs include, but are not limited to, the following. Acetate, formate and benzoate derivatives in the alcohol, sulfhydryl and amine functional groups of the compound of formula (1). Furthermore, in the case of carboxylic acid (—COOH), esters such as methyl ester, ethyl ester, and double ester can also be used. Esters are those that are active per se in humans and / or that are hydrolyzed under in vivo conditions, and suitable pharmaceutically acceptable in vivo hydrolyzable ester groups are simple in the human body. And those which are decomposed to liberate the acid of the parent compound or a salt thereof.

  The compounds according to the invention may be in the form of pharmacologically acceptable salts. Suitable salts are reviewed in the literature (Berge et al., J. Pharm. Sci., 66: 1-19 (1977)).

  Usually, a pharmacologically acceptable salt can be easily produced by using a desired acid or base as required. The salt can be recovered by precipitating from solution and filtering or by distilling off the solvent.

  Suitable addition salts are formed with acids that form non-toxic salts. Such salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, Fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, methanesulfonic acid Salts, ethane sulfonates, benzene sulfonates and p-toluene sulfonates are exemplified.

  Salts of pharmaceutically acceptable bases include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium, and primary, secondary and tertiary amines (eg, isopropylamine). , Diethylamine, ethanolamine, trimethylamine, dicyclohexylamine and N-methyl-D-glucamine) and salts with organic bases.

  A halogen atom means fluorine, chlorine, bromine, or iodine.

  The alkyl group or alkyl means a linear or branched saturated hydrocarbon chain having 1 to 10 carbon atoms and a cyclic saturated hydrocarbon chain having 3 to 10 carbon atoms. Are more preferably those having 2 to 10 carbon atoms, especially those having 2 to 6 carbon atoms. A chain alkyl group having 1 to 6 carbon atoms is more preferable, and a chain alkyl group having 1 to 4 carbon atoms is more preferable. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, Hexyl, isohexyl and the like can be mentioned.

  The alkoxy group or alkoxy means a linear or branched alkyloxy group having 1 to 10 carbon atoms and a cyclic alkyloxy group having 3 to 10 carbon atoms. Those having 2 to 10 carbon atoms, particularly those having 2 to 6 carbon atoms are more preferable. A chain alkyloxy group having 1 to 6 carbon atoms is more preferable, and a chain alkyloxy group having 1 to 4 carbon atoms is more preferable. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, and isohexyloxy. It is done.

An alkylene group or alkylene means a saturated hydrocarbon chain obtained by removing a hydrogen atom from each carbon at both ends of a linear hydrocarbon chain. Preferably it is a C1-C6 alkylene, and a methylene, ethylene, trimethylene, tetramethylene, etc. are mentioned as a specific example. In the present invention, when the alkylene group has 1 to 3 heteroatoms independently selected from a nitrogen atom, a sulfur atom and an oxygen atom, —O— (CH ₂ ) _m —O _{-, - S- (CH 2)} m -S -, - NH- (CH 2) m -NH -, - O- (CH 2) include groups represented by the formula, such as m -NH- (wherein , M represents an integer of 1 to 4).

  The alkanoyl group or alkanoyl means a linear or branched alkylcarbonyl group having 1 to 10 carbon atoms, preferably an alkylcarbonyl group having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Of alkylcarbonyl. Examples of the alkanoyl group include an acetyl group, a propionyl group, a butyryl group, a valeryl group, and a pivaloyl group.

  The alkenyl group or alkenyl means a linear or branched hydrocarbon chain having one or more double bonds having 2 to 10 carbon atoms, preferably an alkenyl group having 2 to 6 carbon atoms, more preferably Is an alkenyl group having 2 to 4 carbon atoms. Examples of alkenyl groups include vinyl, 1-propenyl, allyl, isopropenyl, butenyl, butadienyl, pentenyl and the like.

  In the claims and in the description, in the term “mono- or di-alkyl”, when it represents di-alkyl, the alkyl moieties may be the same or each independently an alkyl group. Good.

  In the present invention, the cycloalkyl or cycloalkyl group represents a C3-10 cyclic hydrocarbon group, and examples thereof include C3 such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, and cyclononyl group. -10 cyclic hydrocarbon group, and a C3-6 cyclic hydrocarbon group is preferable.

  In the present invention, the cycloalkoxy or cycloalkoxy group represents a C3-10 cyclic hydrocarbon group-substituted oxy group, for example, a C3-10 cyclic group such as a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, etc. A hydrocarbon group-substituted oxy group is exemplified, and among these, a C3-6 cyclic hydrocarbon group-substituted oxy group is preferable.

  In the present invention, the heterocyclic ring or heterocyclic group includes a 5- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom, and 2 condensed thereto. Examples thereof include a cyclic or tricyclic fused heterocyclic group. Specific examples of the heterocyclic group include, for example, thienyl group, furyl group, pyrrolyl group, pyrrolinyl group, oxazolyl group, thiazolyl group, pyrazolyl group, imidazolyl group, imidazolinyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, and flazanyl group. , Thiadiazolyl group, triazolyl group, triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazopyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl Group, oxazinyl group, thiazinyl group, piperazinyl group, triazinyl group, oxatriazinyl group, pyridazinyl group, pyrazinyl group, benzofuranyl group, benzothiazolyl group, benzoxa Ryl, tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, dihydro Indolyl group, indolyl group, quinolidinyl group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group, acridinyl group, phenanthridinyl group, chromanyl group, benzoxazinyl group, phenazinyl group, phenothiazinyl group Group, phenoxazinyl group, hexahydroazepinyl group, imidazolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydrooxadi Group, dihydropyrazolyl group, imidazopyridyl group, dihydropyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group, oxathiadiazolyl group, dihydrooxazolyl group, tetrahydroquinolyl group, etc. Can be mentioned.

  In the present invention, the homocyclic or homocyclic group includes, for example, a C6-10 aryl group (eg, phenyl, naphthyl etc.), a C3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl). Etc.), a C3-10 cycloalkenyl group (eg, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.) and the like, which may be condensed, etc. are used.

  Compound (1) which is an active ingredient of the pharmaceutical composition of the present invention has CETP inhibitory activity, and exhibits HDL cholesterol increasing action and LDL cholesterol lowering action. Therefore, it is useful for the prevention and treatment of diseases such as arteriosclerosis and hyperlipidemia.

  The pharmaceutical composition of the present invention can be administered orally or parenterally, and can be made into a suitable pharmaceutical preparation using a pharmaceutical carrier usually used for oral or parenteral administration.

  Pharmaceutically acceptable salts of the compound of formula (1) include, for example, alkali metal salts such as lithium, sodium or potassium; alkaline earth metal salts such as calcium or magnesium; and salts with zinc or aluminum; and organic Salts with bases such as ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris (hydroxymethyl) aminomethane, N-methylglucosamine, triethanolamine and dehydroabiethylamine; hydrochloric acid, hydrogen bromide Salts with inorganic acids such as acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid , Citric acid, methanesulfo Acid, ethanesulfonic acid, benzenesulfonic acid, a salt with an organic acid such as toluenesulfonic acid; or aspartic acid, salts with acidic amino acids and glutamic acid.

  Further, the pharmacologically acceptable salt of the compound of the formula (1) includes a quaternary salt of the compound of the formula (1) with an alkyl halide, a halogenated phenylalkyl or the like.

  Suitable pharmaceutical preparations for oral administration of the pharmaceutical composition of the present invention include solid preparations such as tablets, granules, capsules and powders, or liquid preparations such as solutions, suspensions and emulsions. Is mentioned. Suitable pharmaceutical preparations for parenteral administration include injections or infusion preparations using distilled water for injection, physiological saline or aqueous dextrose, suppositories, inhalants and the like.

  These preparations comprise compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier usually used for oral or parenteral administration. Pharmaceutical carriers for oral administration include, for example, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine, etc.), lubrication Examples include agents (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrating agents (potato starch, etc.) and wetting agents (anhydrous sodium sulfate, etc.).

  Moreover, as a pharmaceutical carrier for parenteral administration, it can be set as a parenteral formulation using, for example, distilled water for injection, physiological saline, and aqueous glucose solution.

  The dose of the compound (1) of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, condition or type / degree of disease, but is generally about 0. 0 per day. It is about 001 to 1000 mg / kg, preferably about 0.01 to 100 mg / kg, more preferably about 0.1 to 10 mg / kg.

  The compound (1) of the present invention has CETP inhibitory activity and exhibits HDL cholesterol increasing action and LDL cholesterol lowering action. Therefore, the pharmaceutical composition of the present invention includes atherosclerosis, arteriosclerosis, metabolic syndrome, peripheral vascular disease, lipid metabolism abnormality, high beta lipoproteinemia, low alpha lipoproteinemia, hypercholesterolemia, Hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cerebral infarction, stroke, diabetes, diabetes Vascular complications, thrombotic disease, obesity, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, renal vascular disease, kidney disease, visceral vascular disease, intravascular coagulation, fatty liver, Steatohepatitis, inflammatory diseases, autoimmune disorders and other systemic diseases indications, immune function modulation, lung disease, antioxidant disease, sexual dysfunction, cognitive impairment, schistosomiasis, cancer, xanthoma Regression, Alzheimer's disease, and is useful for the prevention or treatment of a subject suffering from such endotoxemia (particularly mammals including humans).

  The pharmaceutical composition of the present invention may be used together with other drugs useful for the treatment of these diseases. For example, the pharmaceutical composition of the present invention comprises cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors; cholesterol absorption inhibitors such as anion exchange resin preparations; triglyceride lowering agents such as fibrates, niacin, and fish oil; ACE Antihypertensives such as inhibitors, angiotensin receptor blockers, calcium antagonists, beta blockers; central appetite suppressants, lipase inhibitors, CB1 antagonists; insulin resistance improvers, D2 agonists, sulfonyls It can also be used in combination with other anti-diabetic agents such as urea agents, biguanides, α-glucosidase inhibitors, SGLT inhibitors, DPPIV inhibitors; or other cholesterol lowering agents such as ACAT inhibitors.

  Although the compound (1) of this invention can be manufactured with the following method, it is not limited to this.

  Moreover, in each manufacturing method of the compound (1) described below, when protection of the functional group contained in a compound is required, it can implement suitably by a conventional method. General descriptions of protecting groups and their use are described in Green, Protective Groups in Organic Synthesis, John Willey & Sons, New York, 1991.

  Furthermore, in each step, the reaction may be carried out by a usual method, and isolation and purification are carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, column chromatography and preparative HPLC. Just do it.

[Method I]
Compound (1) can be produced by the following method I.

(Step I-1)
Compound (4) can be produced by reacting compound (2) and compound (3) in a solvent in the presence of a base.

  As the solvent used for the reaction, any solvent can be suitably used as long as it does not affect the reaction. For example, ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc. Hydrocarbon solvents such as benzene, toluene, hexane, xylene; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol; ester solvents such as ethyl acetate, methyl acetate, butyl acetate; acetone, N, N -Polar solvents, such as dimethylformamide and dimethyl sulfoxide, etc. are mentioned, These can be used individually or in combination. Preferred solvents for this reaction are ethanol, dioxane, toluene, and N, N-dimethylformamide.

  As the base, a conventional base can be used, for example, an alkali metal hydride such as sodium hydride or potassium hydride; an alkali metal alkoxide such as sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide or the like. Alkyllithium such as n-butyllithium and sec-butyllithium; alkali metal amide such as lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide; alkali metal carbonate such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal phosphates such as sodium phosphate and potassium phosphate; triethylamine, diisopropylethyla Emissions, pyridine, and organic bases such as N- methylmorpholine, preferably triethylamine, sodium bicarbonate, sodium tert- butoxide, diisopropylethylamine, sodium hydride or potassium tert- butoxide.

  As the leaving group, halogen atoms such as fluorine, chlorine atom, bromine atom and iodine atom, and substituted sulfonyloxy groups such as methanesulfonyloxy group, p-toluenesulfonyloxy group and trifluoromethanesulfonyloxy group are used.

(Step I-2)
Compound (1) can be produced by reacting compound (4) and compound (5) in the same manner as in Step I-1 or the following Step I′-1.

[Step I′-1]
Step (I-1) can be replaced by the following step I′-1.

  In step I-1, compound (4) is obtained by reacting compound (2) and compound (3) in a suitable solvent in the presence or absence of a base and in the presence of a metal catalyst such as a palladium catalyst. Can also be manufactured.

  Palladium catalysts include palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (tri-o-tolylphosphine) palladium or bis (triphenylphosphine) Conventional palladium catalysts such as palladium acetate can be used.

  Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert- Alkali metal alkoxides such as butoxide, alkali carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate, alkali metals phosphate such as potassium phosphate, triethylamine, diisopropylethylamine, Amines such as methylpiperidine and dicyclohexylmethylamine, or pyridines such as pyridine and 4-dimethylaminopyridine can be preferably used.

  Furthermore, phosphines may be added to this reaction. Examples of phosphines include triphenylphosphine, tributylphosphine, tritert-butylphosphonium tetrafluoroborate, 1,3-bis (diphenylphosphino) propane, and 2,2′-bis (diphenylphosphino) -1,1 ′. -Binaphthyl, 1,1'-bis (diphenylphosphino) ferrocene, 2- (di-tert-butylphosphino) biphenyl, 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl, 2- (Dicyclohexylphosphino) biphenyl and the like can be suitably used.

  As the solvent used for the reaction, any solvent can be suitably used as long as it does not affect the reaction. For example, ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc. Hydrocarbon solvents such as benzene, toluene, hexane, xylene; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol; ester solvents such as ethyl acetate, methyl acetate, butyl acetate; acetone, N, N -Polar solvents, such as dimethylformamide and dimethyl sulfoxide, etc. are mentioned, These can be used individually or in combination.

(Process I'-2)
Compound (1) can be produced by reacting compound (4) and compound (5) in the same manner as in Step I′-1 or I-1.

[Method II]
Compound (1) can be produced by Method II.

(Step II-1)
Compound (8) can be produced by reacting compound (6) and compound (7) in the same manner as in Step 1-1.

(Process II-2)
Compound (1) can be produced by reacting compound (8) and compound (3) in the same manner as in Step I-1 or I′-1.

（式中、記号は前記と同一意味を表す） [Method III]
Compound (1) can be produced by Method III.

(Wherein the symbols have the same meaning as above)

(Step III-1)
Compound (9) can be produced by reacting compound (3) and compound (7) in the same manner as in Step I-1 or I′-1.

(Step III-2)
Compound (1) can be produced by reacting compound (9) and compound (6) in the same manner as in Step 1-1.

（式中、記号は前記と同一意味を表す）
の化合物は以下のＩＶ法により製造することができる。 [IV method]
In the compound (1), general formula (1-a) in which Y is a methylene group:

(Wherein the symbols have the same meaning as above)
This compound can be produced by the following method IV.

（式中、記号は前記と同一意味を表す）
の化合物、またはその対応するカルボン酸もしくはそのカルボン酸エステルを還元し、一般式（６’’）：

（式中、記号は前記と同一意味を表す）
の化合物とした後、ハロゲン化し、次いで前記化合物（９）と、溶媒中、塩基の存在下に反応させることにより製造することができる。 Compound (1-a) has the general formula (6 ′):

(Wherein the symbols have the same meaning as above)
Or a corresponding carboxylic acid or carboxylic acid ester thereof is reduced to a general formula (6 ″):

(Wherein the symbols have the same meaning as above)
And then halogenated and then reacted with the compound (9) in a solvent in the presence of a base.

  The reduction can be carried out by treating with a reducing agent in a suitable solvent. Examples of the reducing agent include borohydrides (for example, sodium borohydride), aluminum hydrides (lithium aluminum hydride, diisobutyl). An aluminum hydride etc. can be used suitably.

  Halogenation can be produced by treating with a halogenating agent in a suitable solvent. As the halogenating agent, a conventional halogenating agent such as thionyl chloride, phosphorus oxychloride, carbon tetrahalide or the like. (Carbon tetrachloride, carbon tetrabromide, etc.) and phosphines (triphenylphosphine, tolylphosphine, triethylphosphine, etc.) can be preferably used.

  As the base, a conventional base can be used, for example, an alkali metal hydride such as sodium hydride or potassium hydride; an alkali metal alkoxide such as sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide or the like. Alkyllithium such as n-butyllithium and sec-butyllithium; alkali metal amide such as lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide; alkali metal carbonate such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal phosphates such as sodium phosphate and potassium phosphate; triethylamine, diisopropylethyla Emissions, pyridine, and organic bases such as N- methylmorpholine, preferably triethylamine, sodium bicarbonate, sodium tert- butoxide, diisopropylethylamine, sodium hydride or potassium tert- butoxide.

  Any solvent can be suitably used as long as it does not affect the reaction. For example, ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-methoxyethane, diglyme; benzene, Hydrocarbon solvents such as toluene, hexane and xylene; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, N, N-dimethylformamide And polar solvents such as dimethyl sulfoxide, and the like can be used alone or in combination. Preferred solvents for this reaction include ethanol, dioxane, toluene, and N, N-dimethylformamide.

[IV 'method]
Compound (1-a) can also be produced by the following IV ′ method.

（式中、記号は前記と同一意味を表す）
の化合物を製造し、次いで前記工程ＩＩ−２に従って化合物（３）と反応させることによっても製造することができる。 The compound (1-a) is obtained by halogenating the compound (6 ″) according to the above-mentioned method IV and then reacting with the compound (7) in the presence of a base in a solvent.

(Wherein the symbols have the same meaning as above)
And then reacting with compound (3) according to the above step II-2.

[IV '' method]
In the above IV ′ method, compound (8 ′) can be produced by reacting compound (6 ′) with compound (7) in a solvent in the presence of a reducing agent.

  As the solvent used in the reaction, any solvent can be used as long as it does not affect the reaction. Examples thereof include halogen solvents such as 1,2-dichloroethane, dichloromethane, chloroform; diethyl ether, tetrahydrofuran (THF), dioxane, Ether solvents such as 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ethyl acetate, methyl acetate, Examples include ester solvents such as butyl acetate; polar solvents such as acetone, N, N-dimethylformamide, and dimethyl sulfoxide, and these can be used alone or in combination. Particularly preferred solvents for this reaction are 1,2-dichloroethane, dichloromethane and toluene. Examples of the reducing agent include borohydrides such as sodium triacetoxyborohydride and sodium cyanoborohydride, and aluminum hydrides such as lithium aluminum hydride and diisobutylaluminum hydride. Particularly preferred reducing agents in this reaction are sodium triacetoxyborohydride and sodium cyanoborohydride.

（式中、Ｒ^３は、アルキル基を表し、他の記号は前記と同一意味を表す）
の化合物は、化合物（６’）と一般式：
Ｒ^３ＭｇＢｒ
（式中、記号は前記と同一意味を表す）
を通常のグリニヤール反応により一般式（６’’’）：

（式中、記号は前記と同一意味を表す）
の化合物とした後、前記ＩＶ法と同様にハロゲン化し、次いで前記化合物（９）と、溶媒中、塩基の存在下に反応させることにより製造することができる。 [V method]
Among the compounds (1), general formula (1-b) in which Y is a methylene group substituted with an alkyl group:

(Wherein R ³ represents an alkyl group, and other symbols have the same meaning as described above).
The compound of the compound (6 ′) and the general formula:
R ³ MgBr
(Wherein the symbols have the same meaning as above)
By a general Grignard reaction to give a general formula (6 ′ ″):

(Wherein the symbols have the same meaning as above)
And then halogenated in the same manner as in the above-mentioned method IV, and then reacted with the compound (9) in a solvent in the presence of a base.

[V 'method]
Compound (1-b) can also be produced by the following V ′ method.

（式中、記号は前記と同一意味を表す）
の化合物を製造し、次いで前記工程ＩＩ−２に従って化合物（３）と反応させることによっても製造することができる。 The compound (1-b) is obtained by halogenating the compound (6 ′ ″) according to the method V and then reacting with the compound (7) in the presence of a base in a solvent. :

(Wherein the symbols have the same meaning as above)
And then reacting with compound (3) according to the above step II-2.

（式中、記号は前記と同一意味を表す）
の化合物は、化合物（６’）を酸化し、一般式（６’’’’）：

（式中、記号は前記と同一意味を表す）
の化合物とした後、前記ＩＶ法と同様にハロゲン化し、次いで前記化合物（９）と、溶媒中、塩基の存在下に反応させることにより製造することができる。 [VI method]
Among the compounds (1), general formula (1-c) in which Y is a methylene group substituted with an oxo group:

(Wherein the symbols have the same meaning as above)
Compound (6) oxidizes compound (6 ′) to give a general formula (6 ″ ″):

(Wherein the symbols have the same meaning as above)
And then halogenated in the same manner as in the above-mentioned method IV, and then reacted with the compound (9) in a solvent in the presence of a base.

[VI 'method]
Compound (1-c) can also be produced by the following VI ′ method.

（式中、記号は前記と同一意味を表す）
の化合物を製し、次いで前記工程ＩＩ−２に従って化合物（３）と反応させることによっても製造することができる。 The compound (1-c) is obtained by halogenating the compound (6 ″ ″) according to the method VI and then reacting with the compound (7) in the presence of a base in a solvent. '):

(Wherein the symbols have the same meaning as above)
And then reacting with compound (3) according to the above step II-2.

（式中、記号は前記と同一意味を表す）
の化合物を還元し、一般式（６’’’’’’）：

（式中、記号は前記と同一意味を表す）
の化合物とした後、前記化合物（９）と、ＩＶ’’法と同様に反応させることにより一般式（１−ｄ）：

（式中、記号は前記と同一意味を表す）
の化合物とした後、Ｒ^２部分を相互変換することにより製造することができる。 [VII method]
Compound (1-a) can also be produced by the following method VII.
Compound (1-a) has the general formula (6 ′ ″ ″):

(Wherein the symbols have the same meaning as above)
Is reduced to the general formula (6 ''''''):

(Wherein the symbols have the same meaning as above)
Then, the compound (9) is reacted in the same manner as in the method IV ″ to give the general formula (1-d):

(Wherein the symbols have the same meaning as above)
Then, the compound can be produced by interconverting the R ² moiety.

（式中、記号は前記と同一意味を表す）
の化合物を製造し、次いで前記工程ＩＩ−２に従って化合物（３）と反応させることによって化合物（１−ｄ）を製造した後、Ｒ^２部分を相互変換することによっても製造することができる。 [VII 'method]
The compound (1-a) is obtained by reacting the compound (6 ″ ″ ″) with the compound (7) in the same manner as in the IV ″ method:

(Wherein the symbols have the same meaning as above)
Then, the compound (1-d) is produced by reacting with the compound (3) according to the above Step II-2, and then the R ² moiety is interconverted.

Further, the substituents on A, B, R ¹ and R ² may be interconverted by a known method after compound (1) is synthesized by the above-mentioned production method or before compound (1) is synthesized. Good.

A ² can be interconverted by the following methods (EA) to (EL).

  In the following production methods, unless otherwise specified, a conventional base can be used as the base, for example, an alkali metal hydride such as sodium hydride or potassium hydride, sodium hydroxide, potassium hydroxide, etc. Alkali metal hydroxides, alkaline earth metals such as barium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. Alkali metal carbonates, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, methylpiperidine, dimethylaniline, 1,8-diazabicyclo [5.4.0] undecene, 1,4-diazabicyclo [ .2.2] octane, 1,5-diazabicyclo [4.3.0] amines such as nonene, pyridine, pyridines such as dimethylaminopyridine can be preferably used.

  In each of the following production methods, a conventional acid can be used as the acid. Unless otherwise specified, mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, and sulfonic acids (for example, methanesulfonic acid, p-toluenesulfonic acid) , Organic acids represented by trifluoromethanesulfonic acid, etc.) can be preferably used.

  In each of the following production methods, any solvent can be used as long as it does not affect the reaction. Specifically, hydrocarbon solvents such as pentane and hexane, benzene, toluene, nitrobenzene, etc. Aromatic hydrocarbon solvents, halogenated hydrocarbon solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, 1,3-dimethylimidazolidin-2-one, etc. Amide solvents, sulfoxide solvents such as dimethyl sulfoxide, alcohol solvents such as methanol and ethanol, ester solvents such as ethyl acetate and butyl acetate, ketone solvents such as acetone and methyl ethyl ketone, nitrile solvents such as acetonitrile, water , Ma It can be mentioned and mixtures of these solvents.

  In each of the following production methods, the leaving group is a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a substituted sulfonyloxy such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a toluenesulfonyloxy group. Groups.

(EA) A compound in which A ¹ is a tetrazolyl group and A ² is an alkyl group or a substituted alkyl group is a compound in which A ¹ is a tetrazolyl group and A ² is a hydrogen atom in compound (1) Can be produced by alkylation.

Alkylation is carried out in the presence of a base in the presence of a base in a suitable solvent:
A ^2A -Z ²
(Wherein, A ^2A is an alkyl group or substituted alkyl group, Z ² represents a leaving group.)
In the presence of phosphines and azodicarboxylic acid esters in a suitable solvent.
^A2A- OH
(In the formula, the symbols have the same meaning as described above.)
It can implement by making the compound shown by react.
N-alkylation of the compound in which A ¹ is a nitrogen-containing heterocyclic group can be carried out in the same manner as described above.

  This reaction proceeds more suitably by adding a catalytic amount of an alkali metal iodide (for example, potassium iodide, etc.) if desired.

  As the phosphines and azodicarboxylic acid esters, any of those usually used in the Mitsunobu reaction can be preferably used. Examples of phosphines include triphenylphosphine and tributylphosphine, and examples of azodicarboxylic acid esters include diethyl azodicarboxylate and diisopropyl azodiformate.

(EB) A compound in which A ¹ is a 2-oxodihydropyrimidinyl group and A ² is an alkyl group or a substituted alkyl group is a compound represented by compound (1) wherein A ¹ is a 2-hydroxypyrimidinyl group Wherein A ² is a hydrogen atom
A ^2A -Z ²
(In the formula, the symbols have the same meaning as described above.)
It can manufacture by alkylating with the compound shown by these.

  This reaction can be carried out in the same manner as in the above (EA).

（式中、各記号は前記と同一意味を有する。）
で示される基である化合物は、化合物（１）で示される化合物のうち、Ａ^２がハロゲン原子である化合物と、対応するアミン、または、式：

（式中、各記号は前記と同一意味を有する。）
で示される化合物を反応させることにより製造することができる。 (EC) A ² is an optionally substituted amino group or the formula:

(In the formula, each symbol has the same meaning as described above.)
In the compound represented by the formula (1), among the compounds represented by the compound (1), A ² is a halogen atom, a corresponding amine, or a compound represented by the formula:

(In the formula, each symbol has the same meaning as described above.)
It can manufacture by making the compound shown by react.

  This reaction can be carried out by reacting in a suitable solvent in the presence or absence of a base and in the presence or absence of a palladium catalyst.

  Palladium catalysts include palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (tri-o-tolylphosphine) palladium or bis (triphenylphosphine) Conventional palladium catalysts such as palladium acetate can be used.

  Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metals such as sodium methoxide, sodium ethoxide, potassium ethoxide and potassium tert-butoxide. Alkali metal carbonates such as alkoxide, sodium carbonate, potassium carbonate, cesium carbonate, alkali hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal phosphates such as potassium phosphate, triethylamine, diisopropylethylamine, methylpiperidine, dicyclohexylmethyl Amines such as amines or pyridines such as pyridine and 4-dimethylaminopyridine can be preferably used.

  Furthermore, phosphines may be added to this reaction. Examples of phosphines include triphenylphosphine, tributylphosphine, tritert-butylphosphonium tetrafluoroborate, 1,3-bis (diphenylphosphino) propane, and 2,2′-bis (diphenylphosphino) -1,1 ′. -Binaphthyl, 1,1'-bis (diphenylphosphino) ferrocene, 2- (di-tert-butylphosphino) biphenyl, 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl, 2- (Dicyclohexylphosphino) biphenyl and the like can be suitably used.

(ED) The compound in which A ² is an optionally substituted amino group is a compound of the formula (1), wherein A ² is a halogen atom, and a compound represented by the formula:
_{^{(R 20) 3 Sn-NR}} 21 R 22
(Wherein R ²⁰ represents an alkyl group, and NR ²¹ R ²² represents an optionally substituted amino group.)
It can manufacture by coupling the compound shown by these.

  The coupling reaction can be carried out by reacting in a suitable solvent in the presence of a palladium catalyst, in the presence or absence of a base.

  The palladium catalyst, base, and phosphine can be implemented in the same manner as in the above (EC).

(EE) The compound in which A ² is a cyano group can be produced by cyanating a compound in which A ² is a halogen atom among the compounds of the compound (1).

  Cyanation can be carried out by reacting a metal cyanide such as sodium cyanide, potassium cyanide or zinc cyanide in a suitable solvent in the presence of a palladium catalyst.

  The same palladium catalyst as that described in the above (EC) can be preferably used.

(EF) A ² is which do may be alkoxycarbonyl group substituted compounds, among the compounds (1), the alkyl alcohol corresponding to the compounds wherein A ² is a halogen atom, under a carbon monoxide atmosphere, palladium It can manufacture by making it react in a suitable solvent in presence of a base using a catalyst.

  As the palladium catalyst and the base, those similar to the above (EC) can be preferably used.

  Further, this reaction can be carried out more suitably by adding a ligand, and the phosphines mentioned in the above (EC) can be preferably used as the ligand.

(EG) A compound in which A ² is an optionally substituted alkenyl group is produced by coupling, among the compounds of compound (1), a compound in which A ² is a halogen atom and the corresponding alkene. Can do.

  The coupling reaction can be carried out by reacting in a suitable solvent in the presence of a palladium catalyst and in the presence or absence of a base.

  The same palladium catalyst as that described in the above (EC) can be preferably used.

  As the base, the bases mentioned in the above (EC) can be suitably used, and silver carbonate can also be used.

  Further, this reaction can be carried out more suitably by adding a ligand, and the phosphines mentioned in the above (EC) can be preferably used as the ligand.

(EG ') A ² is a alkenyl group which may be substituted compounds can be prepared by dehydration of a compound having a hydroxyalkyl group as a substituent A ^2. The dehydration reaction can be carried out by treating the starting compound with an acid.

  As the acid, a normal acid can be used. For example, inorganic acids (for example, hydrochloric acid, nitric acid, and sulfuric acid) or organic acids (for example, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc.) can be preferably used. .

(EH) A compound in which A ² is a boronic acid ester is obtained by treating a compound in which A ² is a leaving group with a trialkoxyborane (such as trimethoxyboron or triisopropoxyborane), dialkoxyborane ( It can be produced by reacting with pinacolborane or the like, or tetraalkoxy diboron (bis (pinacolato) diboron or the like). Examples of the leaving group include halogen atoms such as chlorine atom, bromine atom and iodine atom, and substituted sulfonyloxy groups such as methanesulfonyloxy group, trifluoromethanesulfonyloxy group, and toluenesulfonyloxy group. This reaction can be carried out in the same manner as in the above (EC).

(EH ′) A compound in which A ² is a hydroxy group can be produced by reacting a compound in which A ² is a boronic acid ester with a peroxide. As the peroxide, a hydrogen peroxide solution, m-chloroperbenzoic acid, OXONE ^{(registered trademark)} (manufactured by DuPont) or the like can be suitably used.

(EI) A compound in which A ² is an alkoxy group or a substituted alkoxy group can be produced by alkoxylating a compound in which A ² is a halogen atom among the compounds of compound (1).

  The alkoxylation can be carried out in a suitable solvent or without a solvent by adding a copper catalyst, if desired, and reacting with the corresponding alcohol in the presence of a base.

  The base mentioned in the above (EC), particularly cesium carbonate, can be preferably used.

  As the copper catalyst, copper iodide, copper bromide, copper chloride, copper acetate, copper trifluoromethanesulfonate, or the like can be suitably used.

  Furthermore, this reaction proceeds more suitably by adding 1,10-phenanthroline, 2-aminopyridine and the like.

(EJ) A ² is optionally substituted alkyl, optionally substituted heterocyclic or compound is optionally substituted aryl group, is, A ² is a leaving group the formula (1) Can be prepared by coupling to a corresponding alkyl, aryl or heterocyclic boronic acid, or a corresponding alkyl, aryl or heterocyclic boronic acid ester.

  Coupling can be carried out by reacting in a suitable solvent in the presence of a palladium catalyst, in the presence or absence of a base.

  This reaction can be carried out in the same manner as in the above (EC).

  The leaving group is the same as defined in (EH) above.

(EJ ') A ² is optionally substituted alkyl, optionally substituted heterocyclic group or compound is also an aryl group substituted in, A ² is boronic acid or boronic acid ester, A certain compound can be produced by coupling an alkyl group having a leaving group, an aryl group, or a heterocyclic group.

  The coupling can be carried out in the presence of a palladium catalyst and in the presence or absence of a base in a suitable solvent. The reaction can be carried out in the same manner as in the above (EC). The leaving group is the same as defined in (EH) above.

(EK) A compound in which A ² is an alkoxycarbonylalkylsulfonyl group is obtained by reacting a compound in which A ² is a halogen atom among the compounds represented by compound (1) with an alkali metal salt of alkoxycarbonylalkylsulfinic acid. Can be manufactured.

  Alkoxycarbonylalkylsulfinic acid alkali metal salts can be produced, for example, according to the method described in Baskin et al., Tetrahedron Letters, Vol. 43, page 8479 (2002). .

  Moreover, this reaction can be implemented by making it react in a suitable solvent in presence of a copper catalyst according to the method of the literature description.

  As the copper catalyst, those similar to the above (EI) can be used, and copper iodide can be particularly preferably used.

で示される基
（記号は前記と同一意味を有する）
である化合物は、Ａ^２がヒドロキシ基である化合物と、式：

（式中、Ｘ^１１はＯ、ＳＯ、ＳＯ_２またはＮＲ^Ｐ（Ｒ^Ｐは保護基）であり、ｑは１〜４の整数である）
で示される化合物を、縮合し、さらに必要によりアミノ基の保護基を除去することにより製造することができる。 (EL) A ² is represented by the formula:

A group represented by (the symbols have the same meaning as described above)
Is a compound wherein A ² is a hydroxy group and a compound of the formula:

(Wherein X ¹¹ is O, SO, SO ₂ or NR ^P ( ^RP is a protecting group), and q is an integer of 1 to 4)
Can be produced by condensing, and if necessary, removing an amino-protecting group.

  As the protecting group, conventional ones such as benzyloxycarbonyl group and tert-butoxycarbonyl group can be used.

  This reaction can be carried out in a suitable solvent in the presence of phosphines and azodicarboxylic acid esters. This reaction can be carried out in the same manner as in the above (EA).

  The removal of the protecting group can be carried out by a conventional method such as catalytic reduction or acid treatment depending on the kind of the protecting group.

If necessary, by applying the same reaction as the reaction according to the conversion of A ² above (EA) ~ (EL), further substituents can also be converted.

  In the compound (1) of the present invention, substituents can be appropriately converted within the range of the compound (1) by the method shown below.

  In each of the following production methods, a conventional base can be used as the base, and the bases mentioned in the above (EA) can be preferably used unless otherwise specified.

  In each of the following production methods, a conventional acid can be used as the acid, and unless otherwise specified, mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, or sulfonic acids (for example, methanesulfonic acid, p-toluenesulfonic acid) Organic acids represented by carboxylic acids (such as acetic acid and trifluoroacetic acid) can be preferably used.

  Furthermore, in each of the following production methods, any solvent can be used as long as it does not affect the reaction. As such, the solvent mentioned in the above (EA) is preferably used. it can.

  Examples of the leaving group include halogen atoms such as chlorine atom, bromine atom and iodine atom, and substituted sulfonyloxy groups such as methanesulfonyloxy group, trifluoromethanesulfonyloxy group and toluenesulfonyloxy group.

（式中、各記号は前記と同一意味を有する。）
で示される基で置換された複素環基である化合物は、Ａが置換されていてもよいアルキルスルホニルオキシ基で置換された複素環基である化合物（１）と、対応するアミン、または、式：

（式中、各記号は前記と同一意味を有する。）
で示される化合物を、パラジウム触媒の存在下、および塩基の存在下または非存在下、適当な溶媒中または無溶媒で反応させることにより製造することができる。 (E1) A is an amino group which may be substituted or a formula:

(In the formula, each symbol has the same meaning as described above.)
The compound which is a heterocyclic group substituted with a group represented by formula (1) is a compound (1) which is a heterocyclic group substituted with an optionally substituted alkylsulfonyloxy group, and the corresponding amine or formula :

(In the formula, each symbol has the same meaning as described above.)
Can be produced by reacting in a suitable solvent or without solvent in the presence of a palladium catalyst and in the presence or absence of a base.

  This reaction can be carried out in the same manner as in the above (EC).

（式中、各記号は前記と同一意味を有する。）
で示される基で置換された複素環基である化合物は、Ａがハロゲン原子または置換されていてもよいアルキルスルホニルオキシ基で置換された複素環基である化合物と、対応するアミン、または、式：

（式中、各記号は前記と同一意味を有する。）
で示される化合物を反応させることにより製造することもできる。 (E2) A is an optionally substituted amino group or formula:

(In the formula, each symbol has the same meaning as described above.)
And a compound in which A is a heterocyclic group substituted with a halogen atom or an optionally substituted alkylsulfonyloxy group, a corresponding amine, or a compound of the formula :

(In the formula, each symbol has the same meaning as described above.)
It can also manufacture by making the compound shown by react.

  This reaction can be carried out in a suitable solvent in the presence or absence of a base, optionally adding a copper catalyst.

  As the copper catalyst, copper iodide, copper bromide, copper chloride, copper acetate, copper trifluoromethanesulfonate, or the like can be suitably used.

  As the base, those similar to the bases mentioned in the above (EC) can be preferably used.

  Furthermore, this reaction proceeds more suitably by adding N, N′-dimethylethylenediamine, 1,10-phenanthroline, ethylene glycol, phenylphenol or the like.

  (E3) The compound in which A is a heterocyclic group substituted with an optionally substituted alkylsulfanyl group is a heterocyclic group substituted with a halogen atom or an optionally substituted alkylsulfonyloxy group It can be produced by reacting a compound with the corresponding alkylsulfanyl.

  This reaction can be carried out in the same manner as in the above (EI), and the reaction proceeds more suitably by adding 1,10-phenanthroline or ethylene glycol.

  (E4) The compound in which A is a heterocyclic group substituted with an optionally substituted heterocyclic group is a heterocyclic group substituted with a halogen atom or an optionally substituted alkylsulfonyloxy group The compound can be produced by coupling a corresponding heterocyclic tin compound or heterocyclic boron compound.

  This reaction can be carried out in the same manner as in the above (ED) or (EI).

  (E5) A compound in which A is a heterocyclic group substituted with an optionally substituted alkoxy group includes a compound in which A is a heterocyclic group substituted with a halogen atom or an alkylsulfonyl group, and a corresponding alkali metal alkoxide. Can be produced by reacting in a suitable solvent. The corresponding alkali metal alkoxide can be obtained by treating the corresponding alkyl alcohol with an alkali metal hydride or alkali metal in the solvent.

  (E6) A compound having an aminoalkyl group as a substituent on A can be produced by catalytic reduction of a compound having a cyano group or a cyanoalkyl group as a substituent on A.

  The catalytic reduction is carried out according to a conventional method using a catalyst in a suitable solvent under a hydrogen atmosphere. Examples of the catalyst include palladium catalysts such as palladium-carbon, nickel catalysts such as Raney nickel, platinum catalysts such as platinum-carbon, and the like.

  (E7) A compound having a mono- or di-alkylsulfamoylaminoalkyl group which may be substituted as a substituent on A corresponds to a compound having an aminoalkyl group as a substituent on A. It can be prepared by reacting with a halogenated mono- or di-alkylsulfamoyl.

  This reaction can be carried out in a suitable solvent in the presence of a base.

  (E8) A compound having a mono-alkylcarbamoylaminoalkyl group which may be substituted as a substituent on A is appropriately selected from a compound having an aminoalkyl group and a corresponding alkyl isocyanate as a substituent on A. It can manufacture by making it react in a solvent.

（式中、Ｒ^９はアルキル基を表し、他の記号は前記と同一意味を有する。）
で示される基を有する化合物は、Ａ上の置換基として、式：

（式中、各記号は前記と同一意味を有する。）
で示される基を有する化合物と、対応するアルキルイソシアネート（Ｒ^９ＮＣＯ）を反応させることにより、製造することができる。本反応は、前記（Ｅ８）と同様にして実施することができる。 (E9) As a substituent on A, the formula:

(Wherein R ⁹ represents an alkyl group, and other symbols have the same meaning as described above.)
A compound having a group represented by the formula:

(In the formula, each symbol has the same meaning as described above.)
A compound having a group represented in, by reacting the corresponding alkyl isocyanate (R 9 ^NCO), it can be produced. This reaction can be carried out in the same manner as in the above (E8).

  (E10) A compound having a mono- or di-alkylcarbamoylaminoalkyl group which may be substituted as a substituent on A is substituted with a compound having an aminoalkyl group as a substituent on A. Further mono- or di-alkylamines can be prepared by condensation using a carbonylating agent in a suitable solvent in the presence or absence of a base.

  As the carbonylating agent, for example, conventional ones such as carbonyldiimidazole, phosgene, triphosgene and the like can be used.

  (E11) A compound having a morpholinylcarbonylamino group as a substituent on A is condensed with a compound having an amino group as a substituent on A and morpholine in a suitable solvent using a carbonylating agent. Can be manufactured. This reaction can be carried out in the same manner as in the above (E10).

（式中、Ｘ^１２は、Ｏ、またはＮＨを表す。）
で示される基を有する化合物は、Ａ上の置換基として式：
Ｈ−Ｘ^１２−ＣＨ_２−ＣＯＮＨ−
（式中、記号は前記と同一意味を有する。）
で示される基を有する化合物を、適当な溶媒中、カルボニル化剤で処理することにより、製造することができる。 (E12) As a substituent on A, the formula:

(In the formula, X ¹² represents O or NH.)
A compound having a group represented by the formula:
H—X ¹² —CH ₂ —CONH—
(In the formula, the symbols have the same meaning as described above.)
It can manufacture by processing the compound which has group shown by a carbonylating agent in a suitable solvent.

  This reaction can be carried out in the same manner as in the above (E10).

（式中、Ｘ^１２はＯまたはＮＨである）
の基を有する化合物は、Ａ上の置換基として、式：Ｈ−Ｘ^１２−ＣＨ_２−ＣＨ_２−ＮＨ−
（式中、記号は上で定義するのと同じ意味を有する）
の基を有する化合物と、適当な溶媒中、カルボニル化剤で処理することにより、製造することができる。 (E12 ′) As a substituent on A, the formula:

(Wherein X ¹² is O or NH)
The compound having a group of the formula: H—X ¹² —CH ₂ —CH ₂ —NH—
(Wherein the symbols have the same meaning as defined above)
It can manufacture by processing with the compound which has these groups, and a carbonylation agent in a suitable solvent.

  This reaction can be carried out in the same manner as in the above (E10).

  (E13) A compound having an optionally substituted carbamoyl group as a substituent on A can be produced by condensing a compound having a carboxyl group as a substituent on A with a desired amine. .

  The condensation can be carried out by treating with a condensing agent in a suitable solvent. As the condensing agent, for example, conventional ones such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, and carbonyldiimidazole can be suitably used.

  Furthermore, the condensation can be more suitably carried out by adding an activator such as 1-hydroxybenzotriazole or 1-hydroxysuccinimide.

（式中、各記号は前記と同一意味を有する。）
で示される基を有する化合物は、Ａ上の置換基としてカルボキシル基を有する化合物と、式：

（式中、各記号は前記と同一意味を有する。）
で示される化合物を縮合させることにより製造することができる。 (E14) As a substituent on A, the formula:

(In the formula, each symbol has the same meaning as described above.)
A compound having a group represented by the formula: a compound having a carboxyl group as a substituent on A, and a compound represented by the formula:

(In the formula, each symbol has the same meaning as described above.)
It can manufacture by condensing the compound shown by these.

  This reaction can be carried out in the same manner as in the above (E13).

  (E15) A compound having a tetrazolyl group as a substituent on A is obtained by reacting a compound having a cyano group as a substituent on A with an alkali metal azide in an appropriate solvent in the presence of an acid. Can be manufactured.

  Examples of the alkali metal azide include sodium azide and lithium azide.

  As the acid, an ammonium salt of hydrogen halide such as ammonium chloride can be preferably used.

  (E16) A compound having an optionally substituted alkyltetrazolyl group as a substituent on A can be produced by alkylating a compound having a tetrazolyl group as a substituent on A.

  The alkylation can be carried out in the same manner as in the above (EA).

（式中、各記号は前記と同一意味を有する。）
で示される基を有する化合物は、Ａ上の置換基として、ハロゲン原子または置換されていてもよいアルキルスルホニルオキシ基を有する化合物と、対応するアミン、または、式：

（式中、各記号は前記と同一意味を有する。）
で示される化合物を反応させることにより製造することができる。 (E17) As a substituent on A, an optionally substituted amino group or formula:

(In the formula, each symbol has the same meaning as described above.)
And a compound having a halogen atom or an optionally substituted alkylsulfonyloxy group as a substituent on A, a corresponding amine, or a compound having the formula:

(In the formula, each symbol has the same meaning as described above.)
It can manufacture by making the compound shown by react.

  This reaction can be preferably carried out in a suitable solvent in the presence or absence of a base.

（式中、Ｒ^１３はヒドロキシ基、アルコキシカルボニル基、モルホリニル基またはフェニル基で置換されていてもよいアルキル基を表し、ｎは前記と同一意味を有する。）
を含む基を有する化合物は、Ａ上の置換基としてアミノ基または式：

（式中、記号は前記と同一意味を有する．）
で示される基を有する化合物と、対応するハロゲン化アルキルまたは対応するスルホン酸アルキルエステル類とを反応させることにより得ることができる。 (E18) As a substituent on A, an optionally substituted alkylamino group or a formula:

(In the formula, R ¹³ represents a hydroxy group, an alkoxycarbonyl group, a morpholinyl group or an alkyl group which may be substituted with a phenyl group, and n has the same meaning as described above.)
A compound having a group containing an amino group as a substituent on A or the formula:

(In the formula, the symbols have the same meaning as described above.)
It can be obtained by reacting a compound having a group represented by the following with a corresponding alkyl halide or a corresponding sulfonic acid alkyl ester.

  As the sulfonic acid alkyl esters, esters with methanesulfonic acid, esters with toluenesulfonic acid, esters with trifluoromethanesulfonic acid, and the like can be suitably used.

  This reaction can be preferably carried out in a suitable solvent in the presence or absence of a base.

（式中、Ｘ^１３は、Ｏ、またはＮＨを表し、他の記号は同一意味を有する。）
で示される基を有する化合物は、Ａ上の置換基として式：
Ｚ^３−（ＣＨ_２）_ｎ−Ｘ^１３−ＣＨ_２−ＣＯＮＨ−
（式中、Ｚ^３は、脱離基を表し、他の記号は前記と同一意味を有する。）
で示される基を有する化合物を閉環することにより、製造することができる。 (E19) As a substituent on A, the formula:

(In the formula, X ¹³ represents O or NH, and other symbols have the same meaning.)
A compound having a group represented by the formula:
Z ³ — (CH ₂ ) _n —X ¹³ —CH ₂ —CONH—
(In the formula, Z ³ represents a leaving group, and other symbols have the same meaning as described above.)
It can manufacture by ring-closing the compound which has group shown by.

  This reaction can be preferably carried out in a suitable solvent in the presence or absence of a base.

  (E20) A compound having a carboxyl group as a substituent on A can be produced by hydrolyzing a compound having an alkoxycarbonyl group as a substituent on A.

  Hydrolysis can be carried out by treatment with a base or an acid in a suitable solvent by a conventional method. As the base, an alkali metal hydroxide can be suitably used.

  (E21) A compound containing a carboxyl group as a substituent on A can also be produced by hydrolyzing a compound containing a cyano group as a substituent on A.

  Hydrolysis can be carried out by treatment with acid or base in a suitable solvent.

  (E22) A compound containing a carbamoyl group as a substituent on A can be produced by hydrolyzing a compound containing a cyano group as a substituent on A.

  Hydrolysis can be carried out by treatment with acid or base in a suitable solvent.

  (E23) A compound having a carboxyalkyl group as a substituent on A is obtained by catalytic reduction of a compound having a carboxyalkenyl group, a benzyloxycarbonylalkenyl group or a benzyloxycarbonylalkyl group as a substituent on A. Can also be manufactured.

  The catalytic reduction can be carried out in the same manner as in the above (E6).

  (E24) A compound having a hydroxy group as a substituent on A can be produced by hydrolyzing a compound in which A has an alkanoyloxy group.

  Hydrolysis can be carried out in the same manner as in the above (E20).

(E25) A compound containing sulfoxide (SO) or sulfone (SO ₂ ) as a substituent on A is a compound having S as a substituent on A (for example, a thiomorpholinyl group or alkylsulfanyl as a substituent on A It can be produced by oxidizing a compound having an alkyl group).

  The oxidation can be carried out by treatment with an oxidizing agent in a suitable solvent.

  As the oxidizing agent, for example, peracids such as hydrogen peroxide, m-chloroperbenzoic acid and peracetic acid can be suitably used.

  (E26) A compound in which an N-oxide is contained in a substituent on A is produced by oxidizing a compound having N as a substituent on A (for example, a compound having a pyridyl group as a substituent on A). be able to.

  The oxidation can be carried out in the same manner as in the above (E25).

  (E27) A compound having a 1,2-dihydroxyalkyl group as a substituent on A is preferably a compound having an alkyl group substituted with a mono- or di-alkyldioxolanyl group as a substituent on A. It can manufacture by processing with an acid in a different solvent.

  As the acid, in addition to those described above, a strongly acidic resin can also be suitably used.

  (E28) A compound having an alkyl group substituted with a hydroxy group and an optionally substituted alkoxy group as a substituent on A corresponds to a compound having an oxiranylalkyl group as a substituent on A. It can be produced by reacting an alkali metal salt of the alcohol to be reacted in an appropriate solvent.

  Examples of the alkali metal salt of alcohol include lithium salt, sodium salt, potassium salt and the like.

  (E29) As a substituent on A, a compound having an alkyl group substituted with a hydroxy group and an amino group, or an alkyl group substituted with a hydroxy group and an optionally substituted mono- or di-alkylamino group is , A can be prepared by reacting a compound having an oxiranylalkyl group as a substituent on A with ammonia or a corresponding mono- or di-alkylamine in a suitable solvent.

  (E30) A compound having a hydroxycarbamimidoyl group as a substituent on A is obtained by reacting a compound having a cyano group as a substituent on A with hydroxylamine or a salt thereof in an appropriate solvent. Can be manufactured. Any solvent can be used as long as it does not affect the reaction. As such, the solvents mentioned in the above (EA) can be preferably used.

  (E31) A compound having an oxodihydrooxadiazolyl group as a substituent on A is obtained by combining a compound having a hydroxycarbamimidoyl group and a carbonylating agent as a substituent on A with a base in a suitable solvent. It can manufacture by making it react in presence or absence.

  As the carbonylating agent, those similar to the above (E10) can be used.

  (E32) A compound having a sulfo group as a substituent on A can be produced by hydrolyzing a compound having an alkoxycarbonylalkylsulfonyl group as a substituent on A.

  Hydrolysis can be carried out in the same manner as in the above (E20).

  (E33) A compound having a sulfamoyl group as a substituent on A can be produced by condensing a compound having a sulfo group as a substituent on A with a desired amine.

  The condensation can be carried out by treating a compound having a sulfo group as a substituent on A with a halogenating agent in a suitable solvent and then reacting with the desired amine in the presence or absence of a base. .

  As the halogenating agent, for example, conventional ones such as thionyl halide and phosphorus oxyhalide can be used.

  (E34) A compound having a hydroxyalkyl group as a substituent on A is prepared by reducing a compound having a carboxyalkyl group as a substituent on A, or once the carboxyl group is acid anhydride or ester It can manufacture by reducing after converting into.

  The step of converting to an acid anhydride can be carried out by reacting with an alkyl halide formate in the presence of a base in a suitable solvent.

  The step of converting to an ester can be carried out by reacting with an alcohol in an appropriate solvent in the presence of a condensing agent. This step can be carried out in the same manner as in the above (E33) except that the desired alcohol is used instead of the amine.

  The reduction can be carried out by treating with a reducing agent in a suitable solvent.

  As the reducing agent, borohydrides (for example, sodium borohydride) and aluminum hydrides (lithium aluminum hydride, diisobutylaluminum hydride, etc.) can be suitably used.

(E35) An aromatic ring group optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom, wherein the substituent on R ¹ is substituted with a cyano group (hereinafter referred to as “an aromatic ring group”). The compound that is an aromatic ring group) can also be produced by cyanating a compound in which the substituent on R ¹ is an aromatic ring group substituted with a halogen atom.

  The cyanation can be carried out in the same manner as in the above (EE).

  (E36) A compound in which A is a hydrogen atom can be produced by acid treatment or reduction of a compound in which A is a tert-butoxycarbonyl group or a compound in which A is a benzyloxycarbonyl group.

  The acid treatment can be carried out in the same manner as in the above (E27) method, and the reduction can be carried out in the same manner as in the above (E23) method.

  (E37) A compound in which A is an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group is obtained by reacting a compound in which A is a hydrogen atom with a carbonylating agent and a desired compound in a suitable solvent. It can be prepared by reacting with an alcohol or the desired amine.

  This reaction can be carried out in the same manner as in the above (E10) method.

  (E38) A compound having an amino group as a substituent on A can be produced by subjecting a compound having a carboxyl group as a substituent on A to a Curtius rearrangement reaction.

  The Curtius reaction can be carried out by using a conventional azidating agent (such as diphenylphosphoryl azide) in a suitable solvent in the presence of a base.

  This reaction may be carried out by further adding an alcohol, producing a compound having an optionally substituted alkoxycarbonylamino group as a substituent on A, and then removing the alkoxycarbonyl group. Good.

  The removal of the alkoxycarbonyl group can be carried out by a conventional method such as acid treatment or reduction depending on the type of the alkoxycarbonyl group to be removed. The acid treatment can be carried out in the same manner as in the above (E27), and the reduction can be carried out in the same manner as in the above (E23).

  (E39) A compound having a hydroxy group as a substituent on A can be produced by catalytic reduction of a compound having a benzyloxy group as a substituent on A. The reduction can be carried out in the same manner as in the above (E23).

  (E40) A compound having an oxo group as a substituent on A can be produced by oxidizing a compound having a hydroxy group as a substituent on A.

  Oxidation can be carried out using an oxidizing agent in a suitable solvent.

  As the oxidizing agent, a conventional oxidizing agent can be used. Chromic acid-pyridine complex, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin reagent (1,1,1-tris (acetoxy) -1,1-dihydro -1,2-benziodooxol-3- (1H) -one), dimethyl sulfoxide and the like.

  (E41) A compound containing an optionally substituted alkoxy group as a substituent on A can be produced by alkylating a compound containing an oxo group or a hydroxy group as the substituent of A.

  Alkylation can be carried out in the same manner as in the above (EA) using the corresponding compound.

  (E41 ′) A compound containing a heterocyclic oxy group which may be substituted or an aryloxy group which may be substituted as a substituent on A is a compound containing a hydroxy group as a substituent on A Can be prepared by coupling with a corresponding aryl compound or heterocyclic compound having a leaving group.

  The coupling reaction can be carried out in the same manner as in the above (EC).

  The leaving group has the same meaning as defined in (EH) above.

  (E42) A compound having an optionally substituted alkanoylamino group as a substituent on A is obtained by condensing a compound having an amino group as a substituent on A with a corresponding carboxylic acid or a reactive derivative thereof. Is obtained.

  The condensation reaction with the corresponding carboxylic acid can be suitably carried out in a suitable solvent in the presence of a condensing agent. This reaction can be carried out in the same manner as in the above (E13).

  In addition, the condensation with the reactive derivative of the corresponding carboxylic acid can be carried out in the presence or absence of a base in a suitable solvent or without a solvent.

  Examples of reactive derivatives include acid halides, acid anhydrides, active esters, and active amides.

（式中、Ｒ^１４はヒドロキシ基またはアルコキシ基で置換されていてもよいアルカノイル基を表し、ｎは前記と同一意味を有する）
で示される基を有する化合物は、Ａ上の置換基として式：

（式中、記号は前記と同一意味を有する）
で示される化合物と対応するカルボン酸もしくはその反応性誘導体を縮合することにより、製造することができる。 (E43) As a substituent on A, the formula:

(Wherein R ¹⁴ represents an alkanoyl group optionally substituted with a hydroxy group or an alkoxy group, and n has the same meaning as described above).
A compound having a group represented by the formula:

(Wherein the symbols have the same meaning as above)
Can be produced by condensing the corresponding carboxylic acid or a reactive derivative thereof.

  This reaction can be carried out in the same manner as in the above (E42).

  (E44) A compound having a maleimide group as a substituent on A can be produced by reacting a compound having an amino group as a substituent on A with maleic anhydride. This reaction can be carried out in a suitable solvent.

  (E45) A compound having an alkyl group substituted with a pyridyl group and a hydroxy group as a substituent on A is a compound having an alkyl group substituted with a pyridyl group in which a nitrogen atom is oxidized as a substituent on A And trifluoroacetic anhydride can be produced. This reaction can be carried out in a suitable solvent.

  (E46) A compound having a halogen atom as a substituent on A can be produced by treating a compound having a hydroxy group as a substituent on A with a halogenating agent.

  As halogenating agents, in addition to conventional halogenating agents such as thionyl chloride and phosphorus oxychloride, carbon tetrahalides (carbon tetrachloride, carbon tetrabromide, etc.) and phosphines (triphenylphosphine, tritolylphosphine, triethyl) Phosphine and the like) can be preferably used.

  (E46 ') A compound having a halogen atom as a substituent on A can be produced by treating the compound with a halogenating agent. As the halogenating agent, a normal halogenating agent such as bromine or N-bromosuccinimide can be suitably used.

  (E47) A compound having a cyanoalkyl group as a substituent on A can be produced by reducing a compound having a cyanoalkenyl group as a substituent on A.

  The reduction can be carried out by treating with a reducing agent in an appropriate solvent or by catalytic reduction.

  The reducing agent may be any reducing agent that reduces only the double bond without reducing the cyano group. For example, sodium bis (2-methoxyethoxy) aluminum hydride is preferably used in the presence of copper bromide. be able to.

  The catalytic reduction can be carried out in the same manner as (E23).

  (E48) Compound (1) having a hydroxyalkyl group as a substituent on A can also be produced by reducing a compound having a formyl group as a substituent on A.

  The reduction can be carried out by treating with a reducing agent in a suitable solvent.

  This reaction can be carried out in the same manner as in the reduction step (E34).

  (E49) A compound in which the substituent on B is a hydroxy group can be produced by demethylating a compound in which the substituent on B is a methoxy group.

  Demethylation can be carried out by treatment with a demethylating agent in a suitable solvent.

  As the demethylating agent, a conventional reagent such as trimethylsilyl iodide, hydrogen bromide / acetic acid, boron tribromide, concentrated sulfuric acid and the like can be used.

  (E50) A compound in which the substituent on B is an optionally substituted alkoxy group can be produced by alkylating a compound in which the substituent on B is a hydroxy group.

  The alkylation can be carried out in the same manner as in the above (EA).

  (E51) A compound in which the substituent on B is an optionally substituted alkylsulfonyloxy group can be produced by alkylsulfonylating a compound in which the substituent on B is a hydroxy group.

  The alkylsulfonylation can be carried out by reacting the corresponding alkylsulfonyl halide or the corresponding alkylsulfonic anhydride in a suitable solvent in the presence or absence of a base.

  (E52) A compound in which the substituent on B is a cyano group can be produced by cyanating a compound in which the substituent on B is an optionally substituted alkylsulfonyloxy group.

  The cyanation can be carried out in the same manner as in the above (EE).

  (E53) A compound in which the substituent on B is an aminoalkyl group can be produced by reducing a compound in which the substituent on B is a cyano group.

  The reduction can be carried out in the same manner as in the above (E6).

  (E54) A compound in which the substituent on B is an alkyl group can be produced by alkylating a compound in which the substituent on B is an optionally substituted alkylsulfonyloxy group.

  Alkylation can be produced by reacting alkylaluminums in a suitable solvent in the presence of a palladium catalyst, a silver catalyst, and a copper catalyst.

  As the palladium catalyst, tetrakis (triphenylphosphine) palladium, silver carbonate as the silver catalyst, and copper (I) chloride as the copper catalyst can be suitably used.

  (E54 ′) A compound in which the substituent on B is an optionally substituted alkyl group can be produced by catalytic reduction of a compound in which the substituent on B is an optionally substituted alkenyl group. it can. This reaction can be carried out in the same manner as in the above (E6).

  (E55) A compound having an imidazolinyl group or an oxazolinyl group as a substituent on A includes (i) a compound containing a cyano group as a substituent on A in the presence of an acid in a suitable solvent or Reaction in the absence of solvent to produce a compound containing an alkoxycarbonimidoyl group as a substituent on A, and then (ii) a compound containing an alkoxycarbonimidoyl group as a substituent on A and 2-aminoethanol Alternatively, it can be produced by reacting ethylenediamine in a suitable solvent or without solvent.

  (E56) A compound having a carboxyl group as a substituent on A is obtained by oxidizing (i) a compound containing a hydroxyalkyl group as a substituent on A in the same manner as in the above (E40). A compound containing an oxo group as a substituent can be obtained, and (ii) it can be produced by oxidizing a compound containing an oxo group as a substituent on A.

  The oxidation in the second step can be carried out using an oxidizing agent in a suitable solvent. As the oxidizing agent, sodium chlorite, silver (I) oxide, sodium periodate and the like can be suitably used.

  (E57) A compound having a carboxyl group as a substituent on A can be directly produced by oxidizing a compound containing a hydroxyalkyl group as a substituent on A.

  The oxidation can be carried out using Jones reagent, potassium permanganate or the like as the oxidizing agent.

  (E58) A compound in which A is a hydrogen atom can be produced by treating a compound in which A is ethoxycarbonyl with a silyl halide or a base. As the silyl halide, trimethylsilyl iodide can be suitably used. Sodium hydroxide can be suitably used as the base.

  In each production method of the compound (1) described above, when protection of a functional group contained in the compound is necessary, it can be appropriately carried out by a conventional method. General descriptions of protecting groups and their use are described in Green, Protective Groups in Organic Synthesis, John Willey & Sons, New York, 1991.

  That is, an amino group protected with a benzyloxycarbonyl group can be removed by catalytic reduction in a suitable solvent under a hydrogen atmosphere.

  A hydroxy group protected with a benzyl group can be similarly removed by catalytic reduction.

  The amino group protected with a tert-butoxycarbonyl group can be removed by treating with an acid (hydrochloric acid, trifluoroacetic acid, toluenesulfonic acid, etc.) in an appropriate solvent.

  Similarly, a hydroxy group protected with a tetrahydropyranyl group can be treated with an acid to remove the protective group.

  In the same manner as in the reactions (E1) to (E58) relating to the conversion of the above groups, other substituents of the compound (1) can be appropriately converted.

[Production Method of Compound (6 ′)]
Compound (6 ′) can be produced according to the following (a) or (b).

（式中、Ｘ^Ａ４は脱離基を表し、他の記号は前記と同一意味を表す）
に、一般式（１１）：
Ｈ−Ｒ^２ （１１）
（式中、記号は前記と同一意味を表す）
を、前記工程Ｉ−１またはＩ’−１と同様にして作用させることにより製造することができる。 (A) Compound (6 ′) is represented by the general formula (10):

(In the formula, X ^A4 represents a leaving group, and other symbols have the same meaning as described above.)
And general formula (11):
HR ² (11)
(Wherein the symbols have the same meaning as above)
Can be produced in the same manner as in Step I-1 or I′-1.

（式中、Ｐはカルボキシル基の保護基を表し、他の記号は前記と同一意味を表す）
に、化合物（１１）を、前記工程Ｉ−１またはＩ’−１と同様にして作用させ、次いで還元することにより化合物（６’’）を得、更に酸化することにより製造することができる。 (B) The compound (6 ′) has the general formula (12):

(Wherein P represents a protecting group for a carboxyl group, and other symbols have the same meaning as described above)
The compound (11) is allowed to act in the same manner as in Step I-1 or I′-1, and then reduced to obtain the compound (6 ″), which can be further oxidized.

  The reduction reaction and oxidation reaction can be performed by a commonly used method.

（式中、記号は前記と同一意味を表す）
とした後、還元反応に付すことにより製造することができる。 [Production Method of Compound (2)]
Compound (2) is obtained by oximation of Compound (6 ′) to give General Formula (13):

(Wherein the symbols have the same meaning as above)
Then, it can be produced by subjecting to a reduction reaction.

  The oximation can be carried out using a method usually used for oxime formation. For example, the compound (6 ′) is converted into a salt of hydroxylamine with an acid or a base, and, for example, an alkyl metal hydroxide, sodium acetate. Alternatively, it can be produced by reacting in alcohol in the presence of pyridine, in acetic acid or in pyridine. The hydroxylamine salt-forming agent may be any acidic substance, but mineral acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid) and organic acids (eg, acetic acid, oxalic acid, Trichloroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid) can be used.

  The subsequent reduction reaction can be carried out by a commonly used method.

  Compound (2) can also be prepared from compound (6 '') using the method of Gabriel synthesis detailed in Mitsunobu, O., Comp. Org. Syn. 1991, 6, 79-85. You can also

（式中、Ｘ^Ａ５は脱離基を表し、他の記号は前記と同一意味を表す）
を用い、通常の遷移金属触媒一酸化炭素挿入によって調製され得る。 [Production method of compound (6 ''''')]
The compound (6 ′ ″ ″) has the general formula (14):

(In the formula, X ^A5 represents a leaving group, and other symbols have the same meaning as described above.)
Can be prepared by conventional transition metal catalyzed carbon monoxide insertion.

  The reaction can be performed in an aprotic solvent such as tetrahydrofuran or DMF. Preferred transition metals are, for example, palladium in the form of a salt such as palladium (II) -acetate or a palladium (0) compound such as tetrakis (triphenylphosphine) palladium. This type of carbon monoxide insertion is described in J. Org. Chem. 1992, 57, 5979 or “Organic Metal Compounds—Synthesis and Use— (Tokyo Kagaku Dojin), Metal-catalyzed Cross-coupling Reaction (WILLY-VCH) , Handbook of Palladium-Catalyzed Organic Reactions (Academic Press) ”and the like.

（式中、記号は前記と同一意味を表す）
の化合物とした後に、アジ化アルカリ金属を反応させることにより製造することができる。 Among the compounds represented by the compound (1-a), a compound in which A ¹ is a tetrazolyl group and A ² is a hydrogen atom, cyanates the compound (8 ′), and has the general formula (8 ″ ″):

(Wherein the symbols have the same meaning as above)
It can manufacture by making alkali metal azide after making it the compound of this.

  Cyanation can be carried out by reacting cyanogen halide in a suitable solvent in the presence of a base.

  As the cyanogen halide, cyanogen bromide is preferable.

  As the base, a conventional base can be preferably used, and an alkali metal carbonate such as potassium carbonate, or an alkali metal hydrogen carbonate such as sodium bicarbonate can be preferably used.

  As the solvent, any solvent can be used as long as it does not affect the reaction, and the solvents mentioned in the above-mentioned method I can be preferably used.

  The conversion from a cyano group to a tetrazolyl group can be produced by reacting a compound having a cyano group and an alkali metal azide in an appropriate solvent in the presence of an acid.

  Examples of the alkali metal azide include sodium azide and lithium azide.

  As the acid, an ammonium salt of hydrogen halide such as ammonium chloride can be preferably used.

  In addition, each said manufacturing method can be performed with reference to international publication WO2004 / 020393 pamphlet, international publication WO2005 / 100298 pamphlet, and Unexamined-Japanese-Patent No. 2003-221376.

  The production method of compound (1) can be used for the production of the corresponding compounds of formulas (IA), (IB) and (1-1).

  Many starting materials and reagents for the preparation of compounds of formula (1) above are either commercially available or published in the literature, or published in the literature or general organic It can be easily produced using a synthesis method.

Experimental Example The following experiment was conducted on the CETP activity inhibitory action of the compound (1) used in the present invention.

(Preparation of acceptor microemulsion)
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (3.5 mg), cholesteryl oleate (3 mg), and a solution of triolein (0.7 mg) in chloroform were mixed, and lipids were added under nitrogen gas reflux. After air drying to remove the solvent, 1,4-dioxane (0.25 ml) was added and stirred to dissolve. While sonicating on an ice bath, the above lipid lysate (0.2 ml) was added to Tris-Saline-EDTA (TSE) buffer [10 mM Tris / HCl (pH 7.4), 0.15 M NaCl, 2 mM EDTA]. Slowly infused using a Hamilton syringe under the water surface (10 ml). Thereafter, the mixture was sonicated for 1 hour on an ice bath and stored at 4 ° C.

(Preparation of donor microemulsion)
A chloroform solution of egg PC (phosphatidylcholine) (0.33 mg) and BODIPY-CE ^{(registered trademark)} (manufactured by Invitrogen) (0.62 mg) was mixed. The lipid was air dried under nitrogen gas reflux to remove the solvent, and then TSE buffer (3 ml) was added and sonicated in an ice bath. This was sterilized by filtration through a 0.22 μm filter and stored at 4 ° C.

(Inhibition of CETP activity in vitro)
The sample solution was prepared using dimethyl sulfoxide as a solvent. 187 μL of healthy human plasma diluted to 0.64% with TSE buffer and 3 μL of the sample solution or solvent alone were added and incubated at 37 ° C. for 24 hours. Then 10 μl of TSE buffer containing 5% donor microemulsion and 5% acceptor microemulsion was added and incubated at 37 ° C. for 3 hours. Ex. Before and after incubation. 550 nm / Em. The fluorescence intensity at 600 nm was measured. The difference in the measured values before and after incubation obtained with only the solvent was defined as CETP activity, and the rate of decrease in the measured value difference between samples was defined as the inhibition rate of CETP activity.
(result)

  Although the manufacturing example and the reference example are given to the following and the manufacturing method of the compound of this invention is demonstrated, this invention is not limited by these manufacturing examples. In the drawings, Me represents a methyl group, and TFA represents trifluoroacetic acid.

Production Example 1
(1) 650 mg of 2-chloroquinoline-3-carboxaldehyde and 576 mg of cyclopropylmethyl-propyl-amine were dissolved in 5 ml of toluene, 1.41 g of potassium carbonate was added, and the mixture was stirred at 120 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and ethyl acetate and water were added for liquid separation. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 5 ml of ethanol, 128 mg of sodium borohydride was added at room temperature, and the mixture was stirred for 1 hour. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 3: 1) to give 350 mg of [2- (cyclopropylmethyl-propyl-amino) -quinolin-3-yl] -methanol. Obtained. MS (m / z): 271 [M + H] ^< +>.

(2) 100 mg of [2- (cyclopropylmethyl-propyl-amino) -quinolin-3-yl] -methanol is dissolved in 1 ml of methylene chloride, 30 μl of thionyl chloride is added under ice cooling, and the mixture is stirred at the same temperature for 10 minutes. did. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. 167 mg of 4- [2- (3,5-bis-trifluoromethyl-benzylamino) -pyrimidin-5-yloxy] -butanoic acid ethyl ester was dissolved in 0.5 ml of N, N-dimethylformamide, and ice-cooled. 14.8 mg of sodium hydride (60%) was added and stirred for 15 minutes. Thereto was added 0.5 ml of a N, N-dimethylformamide solution of the residue obtained above, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 49: 1 → 9: 1) to give 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- 35 mg of (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy) -butanoic acid ethyl ester were obtained. MS (m / z): 704 [M + H] &lt; ⁺ &gt;.

(3) 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -pyrimidine-5 34 mg of yloxy) -butanoic acid ethyl ester was dissolved in 0.5 ml of ethanol, 72 μl of 2N-sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and dilute hydrochloric acid were added to the residue for separation. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4- (2-{( 30 mg of 3,5-bis-trifluoromethyl-benzyl)-[2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy) -butanoic acid was obtained. MS (m / z): 676 [M + H] &lt; ⁺ &gt;.

Production Example 2
The corresponding starting materials were used and treated in the same manner as in Production Example 1 to obtain the compounds listed in Table 1.

Production Example 3
(1) 2-Chloroquinoline-3-carboxaldehyde (330 mg) was dissolved in 1,2-dimethoxyethane (7.5 ml), 2M aqueous sodium carbonate solution (1.72 ml), water (2.5 ml), and ethanol (2.5 ml) were added, and the pressure was reduced. Degassing and nitrogen replacement were performed. Thereto was added 417 mg of 5-isopropyl-2-methoxyphenylboronic acid and 199 mg of tetrakis (triphenylphosphine) palladium, followed by nitrogen replacement again, and set in a microwave reactor up to 150 ° C. by 200 W microwave irradiation. The temperature was raised and allowed to react for 15 minutes. The reaction mixture was allowed to cool to room temperature, and diethyl ether and water were added for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 3: 1) to obtain 493 mg of 2- (5-isopropyl-2-methoxy-phenyl) -quinoline-3-carboxaldehyde. MS (m / z): 306 [M + H] &lt; ⁺ &gt;.

(2) 2- (5-Isopropyl-2-methoxy-phenyl) -quinoline-3-carboxaldehyde (470 mg) was dissolved in ethanol (5 ml), and sodium borohydride (58 mg) was added at room temperature and stirred overnight. A saturated aqueous ammonium chloride solution and diethyl ether were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1) to obtain 415 mg of [2- (5-isopropyl-2-methoxy-phenyl) -quinolin-3-yl] -methanol. It was. MS (m / z): 308 [M + H] &lt; ⁺ &gt;.

(3) 409 mg of [2- (5-isopropyl-2-methoxy-phenyl) -quinolin-3-yl] -methanol is dissolved in 25 ml of methylene chloride, and 107 μl of thionyl chloride is added under ice cooling, followed by stirring at room temperature for 15 minutes. And concentrated under reduced pressure. The residue and 532 mg of (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl) -amine were dissolved in 5 ml of N, N-dimethylformamide, and sodium hydride ( 62%) 103 mg was added and stirred at room temperature overnight. Diethyl ether and water were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidine-2- Yl)-[2- (5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] amine (450 mg) was obtained. MS (m / z): 689/691 [M + H] ^< +>.

Production Example 4
(1) (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-[2- (5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -200 mg of amine dissolved in 3 ml of toluene, 26.6 mg of tris (dibenzylideneacetone) dipalladium, 41.8 mg of sodium tert-butoxide, 34.6 mg of 2- (di-tert-butylphosphino) biphenyl, piperidine-4- 65 μl of carboxylic acid ethyl ester was added, and the mixture was stirred overnight at room temperature under a nitrogen stream. Saturated brine was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 43: 7 → 73: 27), and 1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2 85 mg of-(5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yl) -piperidine-4-carboxylic acid ethyl ester was obtained. MS (m / z): 766 [M + H] ^< +>.

(2) 1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -amino} -pyrimidine- 80 mg of 5-yl) -piperidine-4-carboxylic acid ethyl ester was dissolved in 3 ml of ethanol, 157 μl of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. Diethyl ether, water and 1N-hydrochloric acid were added to the reaction solution so that the pH of the aqueous layer was 4, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 93: 7), and 1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- ( 75 mg of 5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yl) -piperidine-4-carboxylic acid were obtained. MS (m / z): 738 [M + H] &lt; ⁺ &gt;.

Production Example 5
(1) (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-[2- (5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -165 mg of amine, 39 mg of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium methylene chloride complex, 70 mg of potassium acetate, 122 mg of bis (pinacolato) diboron are dissolved in 1.6 ml of dimethyl sulfoxide, and are heated at 80 ° C under a nitrogen atmosphere. And stirred for 1 hour. After returning the reaction solution to room temperature, water and diethyl ether were added for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of tetrahydrofuran, and 0.5 ml of 30% hydrogen peroxide was added dropwise under ice cooling. After 1 hour, a saturated aqueous sodium thiosulfate solution was added under ice cooling to crush excess hydrogen peroxide, and water and diethyl ether were added to separate the layers. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 67: 33), and 2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (5- 116 mg of isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-ol were obtained. MS (m / z): 627 [M + H] ^< +>.

(2) 2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-ol 110 mg and 28 μl of 4-bromobutyric acid ethyl ester were dissolved in 2 ml of N, N-dimethylformamide, 29 mg of potassium carbonate was added, and the mixture was stirred at room temperature overnight. Diethyl ether and saturated brine were added for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 41: 9 → 7: 3), and 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- 71 mg of (5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy) -butanoic acid ethyl ester was obtained. MS (m / z): 741 [M + H] &lt; ⁺ &gt;.

(3) 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -amino} -pyrimidine- 65 mg of 5-yloxy) -butanoic acid ethyl ester was dissolved in 3 ml of ethanol, 132 μl of 2N-sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature overnight. Diethyl ether, water, and 1N-hydrochloric acid were added to separate the aqueous layer so that the pH of the aqueous layer became 4, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 47: 3), and 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- ( 51 mg of 5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy) -butanoic acid was obtained. MS (m / z): 713 [M + H] ^< +>.

Production Example 6
(1) 8.97 g of 2-chloroquinoline-3-carboxaldehyde and 7.95 g of cyclopropylmethyl-propyl-amine were added to 50 ml of toluene, 19.4 g of potassium carbonate was added, and the mixture was stirred at 120 ° C. for 8 hours. After returning the reaction solution to room temperature, water was added for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1) to obtain 9.3 g of 2- (cyclopropylmethyl-propyl-amino) -quinoline-3-carboxaldehyde. It was. MS (m / z): 269 [M + H] ^< +>.

(2) 2- (cyclopropylmethyl-propyl-amino) -quinoline-3-carboxaldehyde (750 mg), 3,5-bis-trifluoromethyl-benzylamine (883 mg) and acetic acid (479 μl) were dissolved in 1,2-dichloroethane (5 ml). At room temperature, 1.18 g of sodium triacetoxyborohydride was added and stirred overnight. Methylene chloride and 1N aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 97: 3 → 17: 3) to obtain {3-[(3,5-bis-trifluoromethyl-benzylamino) -methyl] -quinoline. 1.30 g of -2-yl} -cyclopropylmethyl-propyl-amine was obtained. MS (m / z): 496 [M + H] &lt; ⁺ &gt;.

(3) {3-[(3,5-bis-trifluoromethyl-benzylamino) -methyl] -quinolin-2-yl} -cyclopropylmethyl-propyl-amine (979 mg) was dissolved in 10 ml of ethanol, and sodium hydrogen carbonate 505 mg and 230 mg of cyanogen bromide were added and stirred at room temperature overnight. Diethyl ether and water were added for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 3: 1), and (3,5-bis-trifluoromethyl-benzyl)-[2- (cyclopropylmethyl-propyl) was obtained. 1.02 g of (amino) -quinolin-3-ylmethyl] -cyanamide were obtained. MS (m / z): 521 [M + H] ^< +>.

(4) (3,5-bis-trifluoromethyl-benzyl)-[2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -cyanamide 950 mg, sodium azide 1.186 g, ammonium chloride 976 mg Was added to 10 ml of N, N-dimethylformamide and stirred at 100 ° C. overnight. Diethyl ether and water were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 19: 1), and (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazole- 696 mg of 5-yl) -amino] -methyl} -quinolin-2-yl) -cyclopropylmethyl-propyl-amine were obtained. MS (m / z): 564 [M + H] ^< +>.

Production Example 7
(1) (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl) -amino] -methyl} -quinolin-2-yl) -cyclopropylmethyl-propyl -Amine 250 mg, 2-bromo-2-methyl-propionic acid ethyl ester 195 μl, catalytic amount of potassium iodide, 1 ml of triethylamine was added to 1 ml of N, N-dimethylformamide and stirred at 70 ° C. overnight. After returning the reaction solution to room temperature, diethyl ether and water were added for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 97: 3 → 22: 3), and 2- (5-{(3,5-bis-trifluoromethyl-benzyl)-[ 205 mg of 2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -tetrazol-2-yl) -2-methyl-propionic acid ethyl ester was obtained. MS (m / z): 678 [M + H] ^< +>.

(2) 2- (5-{(3,5-bis-trifluoromethyl-benzyl)-[2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -tetrazole-2- Yl) -2-methyl-propionic acid ethyl ester (200 mg) was dissolved in ethanol (6 ml) and water (1 ml), lithium hydroxide monohydrate (24.8 mg) was added, and the mixture was stirred at room temperature overnight. Diethyl ether, water, and 1N-hydrochloric acid were added so that the pH of the aqueous layer was 4, followed by liquid separation. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 9: 1) to give 2- (5-{(3,5-bis-trifluoromethyl-benzyl)-[2- ( 172 mg of cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -tetrazol-2-yl) -2-methyl-propionic acid were obtained. MS (m / z): 650 [M + H] ^< +>.

Production Example 8
(1) (3-{[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl) -amino] -methyl} -quinolin-2-yl) -cyclopropylmethyl-propyl -250 mg of amine, 94 μl of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester and 193 mg of triphenylphosphine were dissolved in 5 ml of tetrahydrofuran, and 290 μl of a 40% toluene solution of diethyl azodicarboxylate was added at room temperature. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 41: 9) to give 3- (5-{(3,5-bis-trifluoromethyl-benzyl)-[2- 174 mg of (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -tetrazol-2-yl) -2,2-dimethyl-propionic acid methyl ester were obtained. MS (m / z): 678 [M + H] ^< +>.

(2) 3- (5-{(3,5-Bis-trifluoromethyl-benzyl)-[2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -tetrazole-2- Yl) -2,2-dimethyl-propionic acid methyl ester (170 mg) was dissolved in a mixed solution of ethanol (6 ml) and water (1 ml), lithium hydroxide monohydrate (21 mg) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, diethyl ether, water and 1N-hydrochloric acid were added to the residue so that the pH of the aqueous layer was 4, and the mixture was separated. The organic layer was washed with saturated brine, and then dried over magnesium sulfate. And concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 97: 3) to give 3- (5-{(3,5-bis-trifluoromethyl-benzyl)-[2- ( 153 mg of cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -tetrazol-2-yl) -2,2-dimethyl-propionic acid were obtained. MS (m / z): 664 [M + H] ^< +>.

Production Example 9
(1) 2-chloro-6-methoxy-quinoline-3-carboxaldehyde (2.0 g) and cyclopropylmethyl-propyl-amine (1.53 g) are dissolved in 10 ml of toluene, and 3.74 g of potassium carbonate is added at 120 ° C. Stir overnight. The reaction mixture was allowed to cool to room temperature, and water was added for liquid separation. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 99: 1 → 9: 1) to give 2- (cyclopropylmethyl-propyl-amino) -6-methoxy-quinoline-3-carboxaldehyde 2 0.03 g was obtained. MS (m / z): 299 [M + H] ^< +>.

(2) 1.62 g of 2- (cyclopropylmethyl-propyl-amino) -6-methoxy-quinoline-3-carboxaldehyde is dissolved in 10 ml of ethanol, and 205 mg of sodium borohydride is added at room temperature. Stir for 1 hour. To the reaction solution are added a saturated aqueous ammonium chloride solution and diethyl ether, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 7: 3), and [2- (cyclopropylmethyl-propyl-amino) -6-methoxy-quinolin-3-yl] -1.64 g of methanol was obtained. MS (m / z): 301 [M + H] &lt; ⁺ &gt;.

(3) [2- (Cyclopropylmethyl-propyl-amino) -6-methoxy-quinolin-3-yl] -methanol (1.54 g) was dissolved in 5 ml of methylene chloride, and 411 μl of thionyl chloride was added under ice cooling. The mixture was stirred at the same temperature for 15 minutes and concentrated under reduced pressure. The obtained residue and (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl) -amine (2.05 g) were dissolved in N, N-dimethylformamide (10 ml). Sodium hydride (62%) 397 mg was added, and the mixture was stirred at room temperature overnight. Diethyl ether and water were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 99: 1 → 9: 1), and (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo 2.94 g of -pyrimidin-2-yl) -amino] -methyl} -6-methoxy-quinolin-2-yl) -cyclopropylmethyl-propyl-amine were obtained. MS (m / z): 682/684 [M + H] ^< +>.

Production Example 10
The corresponding starting materials were used and treated in the same manner as in Production Example 4 to obtain the compounds listed in Table 2.

Production Example 11
The corresponding starting materials were used and treated in the same manner as in Production Example 9 to give the compounds listed in Table 3.

Production Example 12
The corresponding starting materials were used and treated in the same manner as in Production Example 4 to obtain the compounds listed in Table 3.

Production Example 13
The corresponding starting materials were used and treated in the same manner as in Production Example 9 to give the compounds listed in Table 4.

Production Example 14
The corresponding starting materials were used and treated in the same manner as in Production Example 4 to obtain the compounds listed in Table 4.

Production Example 15
The corresponding starting materials were used and treated in the same manner as in Production Example 6 to obtain the compounds listed in Table 5.

Production Example 16
The corresponding starting materials were used and treated in the same manner as in Production Example 7 to obtain the compounds listed in Table 5.

Production Example 17
The corresponding starting materials were used and treated in the same manner as in Production Example 8 to give the compounds shown in Table 5.

Production Example 18
The corresponding starting materials were used and treated in the same manner as in Production Example 9 to give the compounds shown in Table 5.

Production Example 19
The corresponding starting materials were used and treated in the same manner as in Production Example 4 to obtain the compounds listed in Table 5.

Production Example 20
(1) (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-[5- (cyclopropylmethyl-propyl-amino) -1-methyl-3-trifluoro 500 mg of methyl-1H-pyrazol-4-ylmethyl] -amine is dissolved in 5 ml of 1,4-dioxane, 217 mg of benzyl acrylate, 21.5 mg of tri-tert-butylphosphine tetrafluoroborate, N-ethyldiisopropylamine 155 μl and 34 mg of tris (dibenzylideneacetone) dipalladium were added, and the mixture was stirred overnight at room temperature under a nitrogen stream. Diethyl ether and water were added to the reaction solution to separate the layers. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 91: 9 → 4: 1) to give 3- (2-{(3,5-bis-trifluoromethyl-benzyl)-[5 447 mg of-(cyclopropylmethyl-propyl-amino) -1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl] -amino} -pyrimidin-5-yl) -acrylic acid benzyl ester were obtained. MS (m / z): 755 [M + H] &lt; ⁺ &gt;.

(2) 3- (2-{(3,5-bis-trifluoromethyl-benzyl)-[5- (cyclopropylmethyl-propyl-amino) -1-methyl-3-trifluoromethyl-1H-pyrazole- 4-ylmethyl] -amino} -pyrimidin-5-yl) -acrylic acid benzyl ester (440 mg) was dissolved in a mixture of tetrahydrofuran (5 ml) and ethanol (1 ml), 10% palladium on carbon (50 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. . The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 47: 3) to give 3- (2-{(3,5-bis-trifluoromethyl-benzyl)-[5- ( Cyclopropylmethyl-propyl-amino) -1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl] -amino} -pyrimidin-5-yl) -propionic acid was obtained. MS (m / z): 667 [M + H] ^< +>.

Production Example 21
(1) Dissolve 970 mg of 5-chloro-2-fluoropyridine-3-carboxaldehyde and 1.3 ml of cyclopropylmethyl-propyl-amine in 10 ml of toluene, add 2.52 g of potassium carbonate, and stir at 120 ° C. for 30 minutes. did. The reaction mixture was allowed to cool to room temperature, and ethyl acetate and water were added for liquid separation. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 17: 3) to give 5-chloro-2- (cyclopropylmethyl-propyl-amino) -pyridine-3-carboxaldehyde 1 .49 g was obtained. MS (m / z): 253/255 [M + H] ^< +>.

(2) 1.45 g of 5-chloro-2- (cyclopropylmethyl-propyl-amino) -pyridine-3-carboxaldehyde was dissolved in 10 ml of ethanol, and 217 mg of sodium borohydride was added at room temperature and stirred for 1 hour. . A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 24: 1 → 17: 3), and [5-chloro-2- (cyclopropylmethyl-propyl-amino) -pyridin-3-yl] -1.35 g of methanol was obtained. MS (m / z): 255/257 [M + H] &lt; ⁺ &gt;.

(3) Production Examples 1 (2) and (3) with [5-chloro-2- (cyclopropylmethyl-propyl-amino) -pyridin-3-yl] -methanol obtained in (2) above as a raw material In the same manner 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[5-chloro-2- (cyclopropylmethyl-propyl-amino) -pyridin-3-ylmethyl] -amino}- Pyrimidin-5-yloxy) -butanoic acid sodium salt was synthesized. MS (m / z): 658/660 [M-Na] ^- .

Production Example 22
Using [5-chloro-2- (cyclopropylmethyl-propyl-amino) -pyridin-3-yl] -methanol synthesized in (2) of Production Example 21 as a raw material, in the same manner as in Production Example 9 (3) ( 3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-[5-chloro-2- (cyclopropylmethyl-propyl-amino) -pyridin-3-ylmethyl] -amine Was synthesized. MS (m / z): 636/638 [M + H] ^< +>.

Production Example 23
The corresponding starting materials were used and treated in the same manner as in Production Example 4 to obtain the compounds listed in Table 6.

Production Example 24
(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-[5-chloro-2- (cyclopropylmethyl-propyl-amino) -pyridin-3-yl]- Amine (150 mg) is dissolved in toluene (5 ml) and is itself mixed with 22 mg tris (dibenzylideneacetone) dipalladium, 34 mg sodium tert-butoxide, 2- (di-tert-butylphosphino) biphenyl (28 mg) and morpholine. 31 μl was added and the mixture was stirred overnight at room temperature under a stream of nitrogen. The reaction mixture was washed with saturated brine, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 49: 1 → 87: 13), and (3,5-bis-trifluoromethyl-benzyl)-[5-chloro- 88 mg of 2- (cyclopropylmethyl-propyl-amino) -pyridin-3-ylmethyl]-(5-morpholin-4-yl-pyrimidin-2-yl) -amine were obtained. MS (m / z): 643/645 [M + H] &lt; ⁺ &gt;.

Production Example 25
(1) Dissolve 10.00 g of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester in 120 ml of tetrahydrofuran and add 7.38 ml of cyclopropylmethyl-propyl-amine and 7.19 ml of triethylamine in a water bath. And stirred at room temperature for 1 hour. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 17: 3) to give 4- (cyclopropylmethyl-propyl-amino) -2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester. 07 g was obtained. MS (m / z): 310 [M + H] &lt; ⁺ &gt;.

(2) 4- (cyclopropylmethyl-propyl-amino) -2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (10.58 g) was dissolved in tetrahydrofuran (50 ml), and the resulting solution was dissolved in lithium aluminum hydride (1.30 g). And tetrahydrofuran (50 ml) were added dropwise under ice cooling and stirred at the same temperature for 2 hours. Under ice-cooling, 1 ml of 1M aqueous sodium hydroxide solution and 1.3 ml of water were added to the reaction mixture. After stirring at the same temperature for 30 minutes, the precipitate was filtered, and the resulting filtrate was dried over magnesium sulfate. And concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 4) to give [4- (cyclopropylmethyl-propyl-amino) -2-methylsulfanyl-pyrimidine-5. -Il] -methanol 2.24 g was obtained. MS (m / z): 268 [M + H] &lt; ⁺ &gt;.

(3) 1.49 g of [4- (cyclopropylmethyl-propyl-amino) -2-methylsulfanyl-pyrimidin-5-yl] -methanol was dissolved in 25 ml of chloroform, 5 g of manganese dioxide was added, and the mixture was stirred at room temperature overnight. . Manganese dioxide was removed by filtration, the obtained filtrate was concentrated under reduced pressure, hexane and isopropyl ether were added to the resulting residue, and the mixture was collected by filtration to give 4- (cyclopropylmethyl-propyl-amino) -2-methylsulfanyl. -1.27 g of pyrimidine-5-carbaldehyde was obtained. MS (m / z): 266 [M + H] ^< +>.

(4) 4- (cyclopropylmethyl-propyl-amino) -2-methylsulfanyl-pyrimidine-5-carbaldehyde 1.27 g was dissolved in 1,2-dichloroethane 15 ml, and 3,5-bis (trifluoromethyl) 1.51 g of benzylamine, 0.55 ml of acetic acid, and 2.03 g of sodium triacetoxyborohydride were added and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give {5-[(3,5-bis-trifluoromethyl-benzylamino) -methyl] -2-methylsulfanyl. 2.06 g of -pyrimidin-4-yl} -cyclopropylmethyl-propyl-amine were obtained. MS (m / z): 493 [M + H] ^< +>.

(5) 2.05-g of {5-[(3,5-bis-trifluoromethyl-benzylamino) -methyl] -2-methylsulfanyl-pyrimidin-4-yl} -cyclopropylmethyl-propyl-amine in 15 ml of toluene Then, 3.22 g of 5-bromo-2-chloropyrimidine and 4.34 ml of N, N-diisopropylethylamine were added, and the mixture was stirred at 110 ° C. for 3 days under a nitrogen atmosphere. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Hexane and isopropyl ether are added to the obtained residue, the precipitated insoluble matter is filtered, the filtrate is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 4: 1). (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amino] -methyl} -2-methylsulfanyl-pyrimidine-4- Yl) -cyclopropylmethyl-propyl-amine 2.13 g. MS (m / z): 651/649 [M + H] &lt; ⁺ &gt;.

(6) (5-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amino] -methyl} -2-methylsulfanyl-pyrimidin-4-yl ) -Cyclopropylmethyl-propyl-amine (1.00 g) was dissolved in chloroform (7 ml), m-chloroperbenzoic acid (1.00 g) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1), and (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo 858 mg of -pyrimidin-2-yl) -amino] -methyl} -2-methanesulfonyl-pyrimidin-4-yl) -cyclopropylmethyl-propyl-amine were obtained. MS (m / z): 683/681 [M + H] ^< +>.

(7) (5-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amino] -methyl} -2-methanesulfonyl-pyrimidin-4-yl ) -Cyclopropylmethyl-propyl-amine 500 mg was dissolved in 5 ml of methanol, 231 μl of 28% sodium methoxide methanol solution was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 17: 3 → 7: 3), and (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo 425 mg of -pyrimidin-2-yl) -amino] -methyl} -2-methoxy-pyrimidin-4-yl) -cyclopropylmethyl-propyl-amine were obtained. MS (m / z): 635/633 [M + H] ^< +>.

(8) (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amino] -methyl} -2-methoxy-pyrimidin-4-yl) -422 mg of cyclopropylmethyl-propyl-amine was dissolved in a mixture of 2 ml of dimethyl sulfoxide and 0.5 ml of methylene chloride, degassed, and then [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride 27 mg, 196 mg of potassium acetate and 254 mg of bis (pinacolato) diboron were added, heated to 80 ° C. under a nitrogen stream, and stirred for 45 minutes. The reaction mixture was allowed to cool to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 2.5 ml of tetrahydrofuran, 0.75 ml of 30% aqueous hydrogen peroxide was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium thiosulfate solution was added dropwise to the reaction mixture under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Isopropyl ether was added to the resulting residue, and the precipitated solid was filtered, and 2-{(3,5-bis-trifluoromethyl-benzyl)-[4- (cyclopropylmethyl-propyl-amino) -2-methoxy. 328 mg of -pyrimidin-5-ylmethyl] -amino} -pyrimidin-5-ol were obtained. MS (m / z): 571 [M + H] ^< +>.

(9) 2-{(3,5-bis-trifluoromethyl-benzyl)-[4- (cyclopropylmethyl-propyl-amino) -2-methoxy-pyrimidin-5-ylmethyl] -amino} -pyrimidine-5 -181 mg of ol was dissolved in 2 ml of N, N-dimethylformamide, 132 mg of potassium carbonate and 160 μl of 4-bromobutyric acid ethyl ester were added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 13: 7), and 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[4- 152 mg of (cyclopropylmethyl-propyl-amino) -2-methoxy-pyrimidin-5-ylmethyl] -amino} -pyrimidin-5-yloxy) -butanoic acid ethyl ester were obtained. MS (m / z): 685 [M + H] &lt; ⁺ &gt;.

(10) 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[4- (cyclopropylmethyl-propyl-amino) -2-methoxy-pyrimidin-5-ylmethyl] -amino}- 148 mg of pyrimidine-5-yloxy) -butanoic acid ethyl ester was dissolved in a mixed solution of 1 ml of ethanol and 0.5 ml of tetrahydrofuran, 1 ml of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 10% aqueous citric acid solution and saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Ether was added to the obtained residue, and the precipitated solid was collected by filtration to give 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[4- (cyclopropylmethyl-propyl-amino)- 122 mg of 2-methoxy-pyrimidin-5-ylmethyl] -amino} -pyrimidin-5-yloxy) -butanoic acid was obtained. MS (m / z): 657 [M + H] ^< +>.

Production Example 26
(1) (5-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amino] -methyl} -2-methanesulfonyl-pyrimidin-4-yl ) -Cyclopropylmethyl-propyl-amine (450 mg) was dissolved in ether (3 ml), and 3M-methylmagnesium chloride / tetrahydrofuran solution (286 μl) was added dropwise under ice cooling, followed by stirring at the same temperature for 1.5 hours. Saturated brine and ethyl acetate were added to the reaction mixture, the insoluble material was filtered through celite, the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1), and (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo 346 mg of -pyrimidin-2-yl) -amino] -methyl} -2-methyl-pyrimidin-4-yl) -cyclopropylmethyl-propyl-amine were obtained. MS (m / z): 619/617 [M + H] ^< +>.

(2) (5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amino] -methyl} -2-methyl-pyrimidin-4-yl) 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[] by synthesizing in the same manner as in Production Example 25 (8)-(10) using cyclopropylmethyl-propyl-amine. 4- (Cyclopropylmethyl-propyl-amino) -2-methyl-pyrimidin-5-ylmethyl] -amino} -pyrimidin-5-yloxy) -butanoic acid was obtained. MS (m / z): 641 [M + H] &lt; ⁺ &gt;.

Production Example 27
1.0 g of (6-bromo-pyridin-2-yl) -methanol was dissolved in 10 ml of methylene chloride, and 427 μl of thionyl chloride was added under ice cooling, followed by stirring at the same temperature for 15 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue obtained and 2.12 g of (3,5-bis-trifluoromethyl-benzyl) -5-bromopyrimidin-2-yl) -amine were dissolved in 20 ml of N, N-dimethylformamide and hydrogenated under ice cooling. 226 mg of sodium chloride (62%) was added and stirred overnight at room temperature. Diethyl ether and water were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 19: 1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidine-2- Yl)-(6-bromo-pyridin-2-ylmethyl) -amine (2.7 g) was obtained. MS (m / z): 569/571 [M + H] &lt; ⁺ &gt;.

Production Example 28
(1) Dissolve 2.0 g of 7-formyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in a mixed solvent of 5 ml of toluene and 1 ml of ethanol, add 367 mg of sodium borohydride, and add 2 at room temperature. Stir for hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 83: 17), and 7-hydroxymethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester. 79 g was obtained.

(2) 1.79 g of 7-hydroxymethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester was dissolved in 30 ml of toluene, 630 μl of thionyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 30 ml of N, N-dimethylformamide, 3.4 g of (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amine, tert-butoxy Sodium (830 mg) was added, and the mixture was stirred at room temperature for 3 days. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 17: 3), and 7-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo- Pyrimidin-2-yl) -amino] -methyl} -2,3-dihydro-indole-1-carboxylic acid tert-butyl ester 3.5 g was obtained. MS (m / z): 631/633 [M + H] &lt; ⁺ &gt;.

(3) 7-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amino] -methyl} -2,3-dihydro-indole-1-carvone Dissolve 2.0 g of acid tert-butyl ester in 30 ml of toluene, add 290 mg of tris (dibenzylideneacetone) dipalladium, 380 mg of 2- (di-tert-butylphosphino) biphenyl, 457 mg of sodium tert-butoxy, 415 μl of morpholine, After stirring overnight at room temperature under a nitrogen atmosphere, 290 mg of tris (dibenzylideneacetone) dipalladium, 380 mg of 2- (di-tert-butylphosphino) biphenyl, and 457 mg of tert-butoxy sodium were added to the reaction solution, and the mixture was stirred for 3 hours. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 7: 3), and 7-{[(3,5-bis-trifluoromethyl-benzyl)-(5- Morpholin-4-yl-pyrimidin-2-yl) -amino] -methyl} -2,3-dihydro-indole-1-carboxylic acid tert-butyl ester 1.53 g was obtained. MS (m / z): 638 [M + H] ^< +>.

(4) 7-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl) -amino] -methyl} -2,3-dihydro-indole A carboxylic acid tert-butyl ester (1.53 g) was dissolved in 4 ml of 4N-hydrochloric acid / dioxane solution and stirred at room temperature for 1 hour and 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 2), and (3,5-bis-trifluoromethyl-benzyl)-(2,3-dihydro-1H- 1.15 g of indol-7-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl) -amine were obtained. MS (m / z): 538 [M + H] ^< +>.

Production Example 29
(1) (3,5-bis-trifluoromethyl-benzyl)-(2,3-dihydro-1H-indol-7-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl) -amine Dissolve 450 mg in 10 ml of N, N-dimethylformamide, add 47 mg of sodium hydride (60%) under ice cooling, stir for 30 minutes, add 275 mg of 7-bromo-heptanoic acid ethyl ester, and stir at room temperature overnight. did. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 2), and 7- (7-{[(3,5-bis-trifluoromethyl-benzyl)-(5 95 mg of -morpholin-4-yl-pyrimidin-2-yl) -amino] -methyl} -indol-1-yl) -heptanoic acid ethyl ester were obtained. MS (m / z): 692 [M + H] &lt; ⁺ &gt;.

(2) 7- (7-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl) -amino] -methyl} -indole-1- Yl) -heptanoic acid ethyl ester (90 mg) was dissolved in ethanol (4 ml), 1N aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at room temperature overnight. To the reaction solution are added 1N hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 9: 1), and 7- (7-{[(3,5-bis-trifluoromethyl-benzyl)-(5- Morpholin-4-yl-pyrimidin-2-yl) -amino] -methyl} -indol-1-yl) -heptanoic acid 76 mg was obtained. MS (m / z): 664 [M + H] ^< +>.

Production Example 30
(1) (3,5-bis-trifluoromethyl-benzyl)-(2,3-dihydro-1H-indol-7-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl) -amine 150 mg was dissolved in 5 ml of methylene chloride, 86 mg of 6- (chloroformyl) hexanoic acid ethyl ester and 34 μl of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and chloroform were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2 → 9: 11), and 7- (7-{[(3,5-bis-trifluoromethyl-benzyl)-(5 135 mg of -morpholin-4-yl-pyrimidin-2-yl) -amino] -methyl} -2,3-dihydro-indol-1-yl) -7-oxo-heptanoic acid ethyl ester were obtained. MS (m / z): 708 [M + H] ^< +>.

(2) 7- (7-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl) -amino] -methyl} -2,3- 130 mg of dihydro-indol-1-yl) -7-oxo-heptanoic acid ethyl ester was dissolved in 4 ml of ethanol, 1 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. To the reaction solution are added 1N hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 9: 1), and 7- (7-{[(3,5-bis-trifluoromethyl-benzyl)-(5- 116 mg of morpholin-4-yl-pyrimidin-2-yl) -amino] -methyl} -2,3-dihydro-indol-1-yl) -7-oxo-heptanoic acid were obtained. MS (m / z): 680 [M + H] ^< +>.

Production Example 31
(1) (3,5-bis-trifluoromethyl-benzyl)-(2,3-dihydro-1H-indol-7-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl) -amine 250 mg and 77 μl of triethylamine were dissolved in 8 ml of methylene chloride, and 55 mg of triphosgene was added under ice cooling, followed by stirring at room temperature for 1 hour under a nitrogen atmosphere. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of tetrahydrofuran, 360 μl of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester and 108 mg of sodium hydride (60%) were added, and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 2), and 7-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholine- 86 mg of 4-yl-pyrimidin-2-yl) -amino] -methyl} -2,3-dihydro-indole-1-carboxylic acid 2-methoxycarbonyl-2-methyl-propyl ester were obtained. MS (m / z): 696 [M + H] ^< +>.

(2) 7-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl) -amino] -methyl} -2,3-dihydro-indole -1-Carboxylic acid 2-methoxycarbonyl-2-methyl-propyl ester (80 mg) was dissolved in ethanol (4 ml), 1N-aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at room temperature for 4 hours and 30 minutes. To the reaction solution are added 1N hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2 → 2: 3), and 7-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholine- 25 mg of 4-yl-pyrimidin-2-yl) -amino] -methyl} -2,3-dihydro-indole-1-carboxylic acid 2-carboxy-2-methylpropyl ester was obtained. MS (m / z): 682 [M + H] ^< +>.

Production Example 32
The corresponding starting materials were used and treated in the same manner as in Production Example 5 to give the compounds shown in Table 9.

Production Example 33
1.0 g of 1-benzyl-2-chloromethyl-1H-imidazole hydrochloride and 1.65 g of (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl) -amine are mixed with N, It melt | dissolved in 20 ml of N-dimethylformamide, 318 mg of sodium hydride (60%) was added under ice-cooling, and it stirred at room temperature for 4 hours. Diethyl ether and water were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 2), and (1-benzyl-1H-imidazol-2-ylmethyl)-(3,5-bis-trifluoro) was obtained. 1.94 g of methyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amine were obtained. MS (m / z): 570/572 [M + H] ^< +>.

Production Example 34
The corresponding starting materials were used and treated in the same manner as in Production Example 24 to give the compounds shown in Table 10.

Production Example 35
(1) Dissolve 2.17 g of 2-chloro-3-nitro-pyridine and 2.15 g of (aminomethyl) cyclopropane hydrochloride in 10 ml of N, N-dimethylformamide, add 8.29 g of potassium carbonate and add 6 at room temperature. Stir for hours. The reaction mixture was allowed to cool to room temperature, and ethyl acetate and water were added for liquid separation. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in a mixture of 50 ml of tetrahydrofuran and 10 ml of methanol, Raney nickel was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 100 ml of ethanol, 31.6 g of 2-chloroacetimidic acid ethyl ester hydrochloride was added, and the mixture was stirred at 60 ° C. overnight. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to give 2-chloromethyl-3-cyclopropylmethyl-3H-imidazo [4,5-b] pyridine 2 .92 g was obtained.

(2) 361 mg of (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl) -amine was dissolved in 2 ml of N, N-dimethylformamide, and sodium hydride ( 62%) 45 mg was added and stirred at the same temperature for 30 minutes. Next, 200 mg of 2-chloromethyl-3-cyclopropylmethyl-3H-imidazo [4,5-b] pyridine was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. Diethyl ether and water were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 19: 6) and (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidine-2- Yl)-(1-cyclopropylmethyl-1H-imidazo [4,5-b] pyridin-2-ylmethyl) -amine 390 mg was obtained. MS (m / z): 585/587 [M + H] ^< +>.

Production Example 36
The corresponding starting materials were used and treated in the same manner as in Production Example 4 to obtain the compounds listed in Table 11.

Production Example 37
200 mg of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester was dissolved in 3 ml of N, N-dimethylformamide, 313 mg of 3,5-bis (trifluoromethyl) benzylamine and 360 μl of triethylamine were added, and For 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: hexane: ethyl acetate = 10: 20: 1) to give 4- (3,5-bis-trifluoromethyl-benzylamino) -2-methylsulfanyl-pyrimidine. 340 mg of -5-carboxylic acid ethyl ester was obtained. MS (m / z): 440 [M + H] ^< +>.

Production Example 38
(1) After 1.21 ml of thionyl chloride was added dropwise to 20 ml of methanol under ice-cooling, 1.00 g of 2-amino-3- (3,5-bis-trifluoromethyl-phenyl) -propionic acid was added at room temperature. Stir for 2 days. The reaction mixture was concentrated under reduced pressure, ether and hexane were added to the resulting residue, and the precipitated crystals were collected by filtration to give 2-amino-3- (3,5-bis-trifluoromethyl-phenyl) -propionic acid methyl ester. 1.11 g of hydrochloride was obtained. MS (m / z): 316 [M + H] &lt; ⁺ &gt;.

(2) 4-amino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (300 mg) was dissolved in 4 ml of N, N-dimethylformamide, and 2-amino-3- (3,5-bis-trifluoromethyl- Phenyl) -propionic acid methyl ester hydrochloride (544 mg) and triethylamine (540 μl) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: hexane: ethyl acetate = 10: 12: 1) to give 4- [2- (3,5-bis-trifluoromethyl-phenyl) -1-methoxycarbonyl. -Ethylamino] -2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester 542 mg was obtained. MS (m / z): 512 [M + H] &lt; ⁺ &gt;.

Production Example 39
490 mg of 4- [2- (3,5-bis-trifluoromethyl-phenyl) -1-methoxycarbonyl-ethylamino] -2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester was dissolved in 6 ml of chloroform and iced. Under cooling, 248 mg of m-chloroperbenzoic acid was added and stirred at the same temperature for 10 minutes. The reaction mixture was purified by silica gel column chromatography (chloroform: acetone = 15: 1 → 10: 1) and 4- [2- (3,5-bis-trifluoromethyl-phenyl) -1-methoxycarbonyl-ethyl. 480 mg of amino] -2-methanesulfinyl-pyrimidine-5-carboxylic acid ethyl ester were obtained. MS (m / z): 528 [M + H] ^< +>.

Production Example 40
236 mg of 4- [2- (3,5-bis-trifluoromethyl-phenyl) -1-methoxycarbonyl-ethylamino] -2-methanesulfinyl-pyrimidine-5-carboxylic acid ethyl ester was dissolved in 3 ml of tetrahydrofuran, 28 Five drops of% sodium methoxide / methanol solution was added with a Pasteur pipette and stirred at room temperature for 5 minutes. The reaction mixture was neutralized with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 4- [2- (3,5-bis-trifluoromethyl-phenyl) -1-methoxycarbonyl-ethyl. 55 mg of amino] -2-methoxy-pyrimidine-5-carboxylic acid ethyl ester were obtained. MS (m / z): 496 [M + H] &lt; ⁺ &gt;.

Production Example 41
80 mg of 4- [2- (3,5-bis-trifluoromethyl-phenyl) -1-methoxycarbonyl-ethylamino] -2-methanesulfinyl-pyrimidine-5-carboxylic acid ethyl ester was dissolved in 2 ml of tetrahydrofuran, 1 ml of a% dimethylamine aqueous solution was added and stirred at room temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 13: 7). The obtained residue was dissolved in chloroform, 4N-hydrochloric acid / dioxane solution was added, and the reaction mixture was concentrated under reduced pressure. Ether was added to the obtained residue, and the precipitated crystals were collected by filtration, and 4- [2- (3,5-bis-trifluoromethyl-phenyl) -1-methoxycarbonyl-ethylamino] -2-dimethylamino- Pyrimidine-5-carboxylic acid ethyl ester hydrochloride (64 mg) was obtained. MS (m / z): 509 [M + H] ^< +>.

Production Example 42
The corresponding starting materials were used and treated in the same manner as in Production Example 41 to give the compounds shown in Table 13.

Production Examples 43-49
The corresponding starting materials were used and treated in the same manner as in any of the above production examples to give the compounds listed in Table 14.

Production Example 50
(1) 2-chloroquinoline-3-carboxaldehyde 1.0 g, 2-benzyloxymethyl-5-tributylstannyl-2H-tetrazole 5.0 g, dichlorobis (triphenylphosphine) palladium (II) 366 mg, N, N A mixture of 5 ml of dimethylformamide was stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction solution was returned to room temperature, saturated aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 30 minutes. Insoluble material was removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 62: 38) to give 3- (2-benzyloxymethyl-2H-tetrazol-5-yl) quinoline-3-carboxaldehyde. 237 mg was obtained. MS (m / z): 346 [M + H] ^< +>.

(2) By treating 237 mg of 3- (2-benzyloxymethyl-2H-tetrazol-5-yl) quinoline-3-carboxaldehyde in the same manner as in Production Example 3 (2)-(3) and Production Example 24, [2- (2-Benzyloxymethyl-2H-tetrazol-5-yl) quinolin-3-ylmethyl]-(3,5-bis-trifluoromethylbenzyl)-(5-morpholin-4-yl-pyrimidine-2 -Yl) 59 mg of amine were obtained. MS (m / z): 736 [M + H] &lt; ⁺ &gt;.

Production Example 51
(1) 3.0 g of 2-hydroxymethyl-6-methyl-pyridin-3-ol was dissolved in 40 ml of N, N-dimethylformamide, 3 ml of benzyl bromide and 3.58 g of potassium carbonate were added, and the mixture was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1) to obtain 4.45 g of (3-benzyloxy-6-methyl-pyridin-2-yl) -methanol. MS (m / z): 230 [M + H] &lt; ⁺ &gt;.

(2) 4.45 g of (3-benzyloxy-6-methyl-pyridin-2-yl) -methanol was dissolved in 15 ml of methylene chloride, and under ice cooling, 7.08 g of carbon tetrabromide and 5.34 g of triphenylphosphine. And stirred at 0 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1) to give 3-benzyloxy-2-bromomethyl-6-methyl-pyridine. 85 g was obtained. MS (m / z): 292/294 [M + H] ^< +>.

(3) 6 g of (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amine was dissolved in 50 ml of N, N-dimethylformamide and sodium hydride was cooled with ice. (60%) 720 mg was added and stirred at 0 ° C. for 15 minutes. To the reaction solution, 4.85 g of 3-benzyloxy-2-bromomethyl-6-methyl-pyridine was added and stirred at room temperature for 1.5 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 17: 3), and (3-benzyloxy-6-methyl-pyridin-2-ylmethyl)-(3,5-bis- 8.92 g of trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amine were obtained. 611/613 [M + H] ⁺ .

(4) 1 g of (3-benzyloxy-6-methyl-pyridin-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amine was dissolved in toluene. Dissolve in 15 ml and add 150 mg of tris (dibenzylideneacetone) dipalladium, 236 mg of sodium tert-butoxide, 196 mg of 2- (di-tert-butylphosphino) biphenyl, 380 μl of piperidine-4-carboxylic acid ethyl ester, and under nitrogen flow And stirred at room temperature for 3 days. Saturated sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1 → 1: 1), and 1- {2-[(3-benzyloxy-6-methyl-pyridin-2-ylmethyl) 234 mg of-(3,5-bis-trifluoromethyl-benzyl) -amino] -pyrimidin-5-yl} -piperidine-4-carboxylic acid ethyl ester were obtained. 688 [M + ^H] +.

(5) 1- {2-[(3-Benzyloxy-6-methyl-pyridin-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl) -amino] -pyrimidin-5-yl}- Piperidine-4-carboxylic acid ethyl ester (230 mg) was dissolved in ethanol (5 ml), 10% palladium carbon (50 mg) was added, and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1) to give 1- {2-[(3,5-bis-trifluoromethyl-benzyl)-(3- 152 mg of hydroxy-6-methyl-pyridin-2-ylmethyl) -amino] -pyrimidin-5-yl} -piperidine-4-carboxylic acid ethyl ester were obtained. MS (m / z): 598 [M + H] ^< +>.

(6) 1- {2-[(3,5-bis-trifluoromethyl-benzyl)-(3-hydroxy-6-methyl-pyridin-2-ylmethyl) -amino] -pyrimidin-5-yl} -piperidine 152 mg of -4-carboxylic acid ethyl ester and 31 μl of pyridine were dissolved in 4 ml of methylene chloride, 65 μl of trifluoromethanesulfonic anhydride was added under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour in a nitrogen atmosphere. To the mixture was added 65 μl of romethanesulfonic anhydride, and the mixture was returned to room temperature and stirred for 1 hour. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1 → 3: 2) to give 1- {2-[(3,5-bis-trifluoromethyl-benzyl)-(6 147 mg of -methyl-3-trifluoromethanesulfonyloxy-pyridin-2-ylmethyl) -amino] -pyrimidin-5-yl} -piperidine-4-carboxylic acid ethyl ester were obtained. MS (m / z): 730 [M + H] ^< +>.

(7) 1- {2-[(3,5-bis-trifluoromethyl-benzyl)-(6-methyl-3-trifluoromethanesulfonyloxy-pyridin-2-ylmethyl) -amino] -pyrimidin-5-yl } -Piperidine-4-carboxylic acid ethyl ester 143 mg was dissolved in 1,4-dioxane 4 ml, and 5-isopropyl-2-methoxy-phenylboronic acid 57 mg, [1,1′-bis (diphenylphosphino) ferrocene] dichloro 16 mg of palladium dichloromethane complex and 96 mg of cesium carbonate were added, and the mixture was stirred at 80 ° C. for 2.5 hours under a nitrogen atmosphere. The reaction solution was returned to room temperature, and water and ethyl acetate were added for liquid separation. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1) to give 1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[3- 97 mg of (5-isopropyl-2-methoxy-phenyl) -6-methyl-pyridin-2-ylmethyl] -amino} -pyrimidin-5-yl) -piperidine-4-carboxylic acid ethyl ester was obtained. MS (m / z): 730 [M + H] ^< +>.

(8) 1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[3- (5-isopropyl-2-methoxy-phenyl) -6-methyl-pyridin-2-ylmethyl] -amino } -Pyrimidin-5-yl) -piperidine-4-carboxylic acid ethyl ester (92 mg) was dissolved in ethanol (4 ml), 1N aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at room temperature for 1 day. To the reaction solution are added 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 9: 1) to give 1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[3- (5-isopropyl 73 mg of 2-methoxy-phenyl) -6-methyl-pyridin-2-ylmethyl] -amino} -pyrimidin-5-yl) -piperidine-4-carboxylic acid was obtained. MS (m / z): 702 [M + H] &lt; ⁺ &gt;.

Production Example 52
(1) Preparation of 5 g of (3-benzyloxy-6-methyl-pyridin-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amine By treating in the same manner as in Example 5 (1)-(2), 4- {2-[(3-benzyloxy-6-methyl-pyridin-2-ylmethyl)-(3,5-bis-trifluoromethyl -Benzyl) -amino] -pyrimidin-5-yloxy} -butanoic acid ethyl ester 1.69 g was obtained. MS (m / z): 663 [M + H] ^< +>.

(2) 4- {2-[(3-Benzyloxy-6-methyl-pyridin-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl) -amino] -pyrimidin-5-yloxy}- By treating 1.67 g of butanoic acid ethyl ester in the same manner as in Production Example 51 (5)-(6), 4- {2-[(3,5-bis-trifluoromethyl-benzyl)-(6-methyl There was obtained 1.4 g of -3-trifluoromethanesulfonyloxy-pyridin-2-ylmethyl) -amino] -pyrimidin-5-yloxy} -butanoic acid ethyl ester. MS (m / z): 705 [M + H] &lt; ⁺ &gt;.

(3) 4- {2-[(3,5-bis-trifluoromethyl-benzyl)-(6-methyl-3-trifluoromethanesulfonyloxy-pyridin-2-ylmethyl) -amino] -pyrimidin-5-yloxy By treating 313 mg of} -butanoic acid ethyl ester in the same manner as in Production Example 51 (7)-(8), 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[3- ( 74 mg of 5-isopropyl-2-methoxy-phenyl) -6-methyl-pyridin-2-ylmethyl] -amino} -pyrimidin-5-yloxy) -butanoic acid were obtained. MS (m / z): 677 [M + H] &lt; ⁺ &gt;.

Production Example 53
(1) (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl)-[2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinoline-3 -Ilmethyl] amine 200 mg was dissolved in dioxane 1.5 ml, tris (dibenzylideneacetone) dipalladium 39 mg, tetrafluoroborate tri-tert-butylphosphonium 25 mg, acrylic acid methyl ester 51 μl, N, N-diisopropylethylamine 74 μl. In addition, after degassing under reduced pressure, the mixture was stirred at 50 ° C. for 5 hours under a nitrogen stream. The reaction mixture was allowed to cool to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 91: 9 → 4: 1) to give 3- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2 152 mg of-(5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] amino} -pyrimidin-5-yl) -acrylic acid methyl ester were obtained. MS (m / z): 709 [M + H] ^< +>.

(2) 3- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] amino} -Pyrimidin-5-yl) -acrylic acid methyl ester (149 mg) was dissolved in a mixture of 0.5 ml of methanol and 2 ml of tetrahydrofuran, 0.5 ml of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and 3- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2- 151 mg of methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] amino} -pyrimidin-5-yl) -acrylic acid were obtained. MS (m / z): 695 [M + H] &lt; ⁺ &gt;.

Production Examples 54-56
The corresponding starting materials were used and treated in the same manner as in Production Example 4 to obtain the compounds listed in Table 17.

Production Example 57
(1) (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amino] -methyl} -8-methyl-quinolin-2-yl) -300 mg of cyclopropylmethyl-propyl-amine dissolved in 5 ml of toluene, 41 mg of tris (dibenzylideneacetone) dipalladium, 65 mg of sodium tert-butoxide, 54 mg of 2- (di-tert-butylphosphino) biphenyl, 3-methylamino -107 mg of propionic acid tert-butyl ester was added, and the mixture was stirred overnight at room temperature under a nitrogen stream. Water and diethyl ether were added to the reaction solution for liquid separation, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 85: 15) to give 3-[(2-{(3,5-bis-trifluoromethyl-benzyl)- 121 mg of [2- (cyclopropylmethyl-propyl-amino) -8-methyl-quinolin-3-ylmethyl] -amino} -pyrimidin-5-yl) -methyl-amino] -propionic acid tert-butyl ester were obtained. MS (m / z): 745 [M + H] ^< +>.

(2) 3-[(2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (cyclopropylmethyl-propyl-amino) -8-methyl-quinolin-3-ylmethyl] -amino} 115 mg of -pyrimidin-5-yl) -methyl-amino] -propionic acid tert-butyl ester was dissolved in 3 ml of 4N hydrochloric acid / ethyl acetate solution and stirred at room temperature for 3 hours. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution so that the pH of the aqueous layer was about 4, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 49: 1 → 93: 7) to give 3-[(2-{(3,5-bis-trifluoromethyl-benzyl)-[ 86 mg of 2- (cyclopropylmethyl-propyl-amino) -8-methyl-quinolin-3-ylmethyl] -amino} -pyrimidin-5-yl) -methyl-amino] -propionic acid were obtained. MS (m / z): 689 [M + H] &lt; ⁺ &gt;.

Production Example 58
(1) 2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] amino} -pyrimidine- 88 mg of 5-ol was dissolved in 1 ml of tetrahydrofuran, 25 mg of 2- (methylthio) ethanol and 72 mg of triphenylphosphine were added, 119 μl of 40% diethyl azodicarboxylate / toluene solution was added under water cooling, and the mixture was stirred at room temperature for 2 hours. . Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 4: 1) to give (3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2 117 mg of -methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl]-[5- (2-methylsulfanyl-ethoxy) -pyrimidin-2-yl] -amine were obtained. MS (m / z): 715 [M + H] ^< +>.

(2) (3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl]-[5- (2-methyl 114 mg of sulfanyl-ethoxy) -pyrimidin-2-yl] -amine was dissolved in 2 ml of chloroform, 44 mg of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 and chloroform: methanol = 19: 1) to give (3,5-bis-trifluoromethyl-benzyl)-[2- (5 63 mg of -isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl]-[5- (2-methanesulfonyl-ethoxy) -pyrimidin-2-yl] -amine were obtained. MS (m / z): 747 [M + H] ^< +>.

Production Example 59
(1) 22.7 ml of benzyl alcohol was dissolved in 180 ml of tetrahydrofuran, and 8.76 g of sodium hydride (60%) was gradually added under ice cooling, followed by stirring at room temperature for 20 minutes. A solution prepared by dissolving 15.00 g of 2-chloro-8-methyl-quinoline-3-carbaldehyde in 180 ml of tetrahydrofuran was added to the reaction mixture, and the mixture was stirred at 50 ° C. for 5 hours. A 10% aqueous citric acid solution and saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Ether was added to the resulting residue, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 3: 1). Isopropyl ether was added to the resulting residue, and the precipitated crystals were collected by filtration to obtain 2.62 g of (2-benzyloxy-8-methyl-quinolin-3-yl) -methanol. MS (m / z): 280 [M + H] &lt; ⁺ &gt;.

(2) (2-Benzyloxy-8-methyl-quinolin-3-yl) -methanol (3.59 g) was treated in the same manner as in Production Example 51 (2)-(3) to give (2-benzyloxy-8 5.39 g of -methyl-quinolin-3-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amine were obtained. MS (m / z): 663/661 [M + H] ^< +>.

(3) Using the corresponding starting material, (2-benzyloxy-8-methyl-quinolin-3-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) ) -Amine 4.73 g was treated as in Preparation 52 to give 4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (2,5-dimethoxy-phenyl)]. 66 mg of -8-methyl-quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy) -butyric acid was obtained. MS (m / z): 713 [M-Na] ^- .

Production Example 60
The corresponding starting materials were used and treated in the same manner as in Production Example 59 to give the compounds as shown in Table 18.

Production Example 61
(1) Preparation Example 58 of 700 mg of 2-[(2-benzyloxy-8-methyl-quinolin-3-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl) -amino] -pyrimidin-5-ol To give (2-benzyloxy-8-methyl-quinolin-3-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-[5- (2-methanesulfonyl-ethoxy). -Pyrimidin-2-yl] -amine 607 mg was obtained. MS (m / z): 705 [M + H] &lt; ⁺ &gt;.

(2) (2-Benzyloxy-8-methyl-quinolin-3-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-[5- (2-methanesulfonyl-ethoxy) -pyrimidine-2- Yl] -amine (546 mg) was dissolved in methylene chloride (5 ml), 4N-hydrochloric acid / dioxane solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue for neutralization, 10% aqueous citric acid solution was added to make it weakly acidic, and the mixture was extracted with a mixture of ethyl acetate and a small amount of methylene chloride. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 3-({(3,5-bis-trifluoromethyl-benzyl)-[5- (2-methanesulfonyl-ethoxy)- 530 mg of pyrimidin-2-yl] -amino} -methyl) -8-methyl-quinolin-2-ol were obtained. MS (m / z): 615 [M + H] ^< +>.

(3) 3-({(3,5-bis-trifluoromethyl-benzyl)-[5- (2-methanesulfonyl-ethoxy) -pyrimidin-2-yl] -amino} -methyl) -8-methyl- 462 mg of quinolin-2-ol was dissolved in 8 ml of methylene chloride, 630 μl of triethylamine was added, 380 μl of trifluoromethanesulfonic anhydride was gradually added under water cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 13: 7), and trifluoro-methanesulfonic acid 3-({(3,5-bis-trifluoromethyl-benzyl) There were obtained 427 mg of-[5- (2-methanesulfonyl-ethoxy) -pyrimidin-2-yl] -amino} -methyl) -8-methyl-quinolin-2-yl ester. MS (m / z): 747 [M + H] ^< +>.

(4) Using corresponding raw materials, trifluoro-methanesulfonic acid 3-({(3,5-bis-trifluoromethyl-benzyl)-[5- (2-methanesulfonyl-ethoxy) -pyrimidin-2-yl ] -Amino} -methyl) -8-methyl-quinolin-2-yl ester in the same manner as in Preparation 51 (7) to give (3,5-bis-trifluoromethyl-benzyl)-[2 45 mg of-(2,4-dimethoxy-pyrimidin-5-yl) -8-methyl-quinolin-3-ylmethyl]-[5- (2-methanesulfonyl-ethoxy) -pyrimidin-2-yl] -amine were obtained. . MS (m / z): 737 [M + H] ^< +>.

Production Example 62
(1) (3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl)-obtained by treating in the same manner as in Production Example 6 using the corresponding starting materials. 100 mg of 8-methyl-quinolin-3-ylmethyl]-(1H-tetrazol-5-yl) -amine is dissolved in 10 ml of N, N-dimethylformamide, 67 mg of potassium carbonate and 70 μl of 4-bromobutyric acid ethyl ester are added. Stir at 0 ° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, 10% aqueous citric acid solution and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 99: 1 → 17: 3), and 4- (5-{(3,5-bis-trifluoromethyl-benzyl)-[2- 111 mg of (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] -amino} -tetrazol-2-yl) -butyric acid ethyl ester was obtained. MS (m / z): 729 [M + H] ^< +>.

(2) 4- (5-{(3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] -amino } -Tetrazol-2-yl) -butyric acid ethyl ester 96 mg was treated in the same manner as in Preparation Example 1 (3) to give 4- (5-{(3,5-bis-trifluoromethyl-benzyl)-[2 99 mg of-(5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] -amino} -tetrazol-2-yl) -butyric acid were obtained. MS (m / z): 701 [M + H] &lt; ⁺ &gt;.

Production Example 63
(1) 1.6 M-n-butyllithium / hexane solution (10.9 ml) was added to 30 ml of tetrahydrofuran, and 2.45 ml of diisopropylamine was added dropwise at -78 ° C under a nitrogen atmosphere, followed by stirring at 0 ° C for 1 hour. A solution prepared by dissolving 3.15 g of 2,8-dichloro-quinoline in 10 ml of tetrahydrofuran was dropped into this reaction solution at −78 ° C., and the mixture was stirred at the same temperature for 2 hours. To the reaction solution, 5.1 ml of ethyl formate was added dropwise at −78 ° C., and the mixture was stirred for 1 hour. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. Ethyl acetate and ether were added to the resulting residue, and the precipitated crystals were filtered, and 2,8-dichloro-quinoline-3-carba 1.21 g of aldehyde was obtained. MS (m / z): 228/226 [M + H] ^< +>.

(2) By treating 1.18 g of 2,8-dichloro-quinoline-3-carbaldehyde in the same manner as in Production Example 9 and Production Example 4, 1- (2-{(3,5-bis-trifluoromethyl) -Benzyl)-[8-chloro-2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yl) -piperazine-4-carboxylic acid 87 mg was obtained. MS (m / z): 737/735 [M + H] ^< +>.

Production Example 64
(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) obtained by treating in the same manner as in Production Example 25 (4)-(5) using the corresponding starting material. -By treating 300 mg of quinolin-8-ylmethyl-amine in the same manner as in Preparation Example 4, 1- {2-[(3,5-bis-trifluoromethyl-benzyl) -quinolin-8-ylmethyl-amino]- Pyrimidin-5-yl} -piperidine-4-carboxylic acid 16 mg was obtained. MS (m / z): 590 [M + H] ^< +>.

Production Example 65
(1) [2- (5-Isopropyl-2-methoxy-phenyl) -8-methyl-quinoline-] obtained by treating in the same manner as in Production Example 3 (1)-(2) using the corresponding raw material 3-yl] -methanol (2.06 g) was dissolved in methylene chloride (10 ml), and thionyl chloride (545 μl) was added dropwise at 0 ° C. After stirring at room temperature for 15 minutes, the mixture was concentrated under reduced pressure, and the resulting residue was dissolved in methylene chloride and concentrated again under reduced pressure to give 3-chloromethyl-2- (5-isopropyl-2-methoxy-phenyl) -8-methyl. -2.39 g of quinoline was obtained. MS (m / z): 342/340 [M + H] &lt; ⁺ &gt;.

(2) 3-chloromethyl-2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinoline 2.39 g, N, N-dimethylformamide 12 ml, potassium phthalimide 2.54 g, potassium carbonate 2.58 g And stirred at 80 ° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, saturated brine and 10% aqueous citric acid solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Ether was added to the obtained residue and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 3: 1) to give 2- [2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinoline- 2.35 g of 3-ylmethyl] -isoindole-1,3-dione were obtained. MS (m / z): 451 [M + H] ^< +>.

(3) Dissolve 2.34 g of 2- [2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] -isoindole-1,3-dione in 25 ml of ethanol and dry Hydrazine (200 mg) was added, and the mixture was stirred at 80 ° C. for 3.5 hours. The reaction mixture was allowed to cool to room temperature, brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 19: 1) to give C- [2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinoline-3. -Il] -methylamine 1.54 g was obtained. MS (m / z): 321 [M + H] ^< +>.

(4) 760 mg of C- [2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-yl] -methylamine was dissolved in 12 ml of toluene, and 4- (2-chloro-pyrimidine- 5-yloxy) -butyric acid tert-butyl ester 838 mg, palladium (II) acetate 53 mg, (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthalene 148 mg, tetra-n-butylammonium iodide 175 mg of sodium and 274 mg of sodium tert-butoxide were added, and the mixture was stirred at 85 ° C. overnight under a nitrogen stream. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and 4- (2-{[2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinoline]. -3 ylmethyl] -amino} -pyrimidin-5-yloxy) -butyric acid tert-butyl ester 415 mg was obtained. MS (m / z): 557 [M + H] ^< +>.

(5) 4- (2-{[2- (5-Isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy) -butyric acid tert-butyl ester 187 mg was dissolved in 1.5 ml of N, N-dimethylformamide, 20 mg of sodium hydride (60%) and 266 mg of 3-bromomethyl-5-trifluoromethyl-benzonitrile were added under water cooling, and the mixture was stirred at room temperature for 30 minutes. Again, 60 mg of sodium hydride (60%) and 100 mg of 3-bromomethyl-5-trifluoromethyl-benzonitrile were added, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 4- (2-{(3-cyano-5-trifluoromethyl-benzyl)-[2- (5- 144 mg of isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy) -butyric acid tert-butyl ester were obtained. MS (m / z): 740 [M + H] +.

(6) 4- (2-{(3-Cyano-5-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] -amino } -Pyrimidin-5-yloxy) -butyric acid tert-butyl ester (135 mg) was added with 2 ml of 4N hydrochloric acid / dioxane solution, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 9: 1) to give 4- (2-{(3-cyano-5-trifluoromethyl-benzyl)-[2- 115 mg of (5-isopropyl-2-methoxy-phenyl) -8-methyl-quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy) -butyric acid was obtained. MS (m / z): 684 [M + H] ^< +>.

Production Example 66
(1) 25 g of phthalaldehyde acid was dissolved in 300 ml of N, N-dimethylformamide, 50.8 g of potassium carbonate and 54 g of bromomalonic acid ditert-butyl ester were added, and the mixture was stirred at room temperature overnight. Water and diethyl ether were added to the reaction solution for liquid separation, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 200 ml of 4N hydrochloric acid / ethyl acetate solution and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of acetic acid and 500 ml of 1,4-dioxane, and heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by adding diisopropyl ether to obtain 17.5 g of 1-oxo-1H-isochromene-3-carboxylic acid. MS (m / z): 191 [M + H] &lt; ⁺ &gt;.

(2) 17.5 g of 1-oxo-1H-isochromene-3-carboxylic acid was dissolved in 350 ml of 7N ammonia / methanol solution and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was dissolved in 300 ml of 4N-hydrochloric acid / dioxane solution and stirred at room temperature overnight. The reaction liquid was concentrated under reduced pressure, and 19.0 g of 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid was obtained by adding diisopropyl ether and collecting the precipitated crystals by filtration. MS (m / z): 190 [M + H] &lt; ⁺ &gt;.

(3) A mixture of 19.0 g of 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid, 100 ml of concentrated sulfuric acid, and 500 ml of methanol was heated to reflux overnight. The reaction solution was poured into ice water and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. 15.4 g of 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester was obtained by adding diisopropyl ether and filtering the precipitated crystals. MS (m / z): 204 [M + H] &lt; ⁺ &gt;.

(4) A mixture of 15.3 g of 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester, 10.75 ml of benzyl bromide, 31 g of silver carbonate, and 300 ml of toluene was stirred at 100 ° C. for 2 hours. The insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to obtain 21.3 g of 1-benzyloxy-isoquinoline-3-carboxylic acid methyl ester. MS (m / z): 294 [M + H] ^< +>.

(5) A mixture of 20.6 g of 1-benzyloxy-isoquinoline-3-carboxylic acid methyl ester, 15.9 g of sodium borohydride, and 500 ml of tetrahydrofuran was stirred at 70 ° C. for 15 minutes. Next, 100 ml of methanol was added dropwise to the reaction solution over 1 hour, followed by further stirring for 1 hour. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added to crush excess reagent, and extraction was performed using chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether-hexane to give 17.3 g of (1-benzyloxy-isoquinolin-3-yl) methanol. MS (m / z): 266 [M + H] ^< +>.

(6) 500 mg of (1-benzyloxy-isoquinolin-3-yl) methanol was dissolved in 10 ml of methylene chloride, 151 μl of thionyl chloride was added under ice cooling, and the mixture was stirred at the same temperature for 15 minutes and then concentrated under reduced pressure. The obtained residue and 753 mg of (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl) -amine were dissolved in 5 ml of N, N-dimethylformamide and hydrogenated under ice cooling. 165 mg of sodium (60%) was added and stirred at room temperature overnight. Diethyl ether and water were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 19: 5), and the obtained crude product was recrystallized from diisopropyl ether (1-benzyloxy-isoquinoline-3). 317 mg of -ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amine were obtained. MS (m / z): 647/649 [M + H] ^< +>.

(7) 6.35 g of (1-benzyloxy-isoquinolin-3-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -amine in 100 ml of toluene Dissolve and add 898 mg of tris (dibenzylideneacetone) dipalladium, 1.41 g of sodium tert-butoxide, 1.17 g of 2- (di-tert-butylphosphino) biphenyl, 2.2 ml of isonipecotic acid ethyl ester, and under nitrogen atmosphere And stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 9: 1), and 1- {2-[(1-benzyloxy-isoquinolin-3-ylmethyl)-( 3,4-bis-trifluoromethyl-benzyl) -amino] -pyrimidin-5-yl} -piperidine-4-carboxylic acid ethyl ester (3.04 g) was obtained. MS (m / z): 724 [M + H] ^< +>.

(8) 1- {2-[(1-Benzyloxy-isoquinolin-3-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl) -amino] -pyrimidin-5-yl} -piperidine-4- 2.88 g of carboxylic acid ethyl ester was dissolved in a mixed solvent of 10 ml of ethanol and 30 ml of tetrahydrofuran, 500 mg of 10% -palladium carbon was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 4) to give 1- {2-[(3 , 5-Bis-trifluoromethyl-benzyl)-(1-oxo-1,2-dihydroisoquinolin-3-ylmethyl) -amino] -pyrimidin-5-yl} -piperidine-4-carboxylic acid ethyl ester 1.80 g Got. MS (m / z): 634 [M + H] ^< +>.

(9) 1- {2-[(3,5-Bis-trifluoromethyl-benzyl)-(1-oxo-1,2-dihydroisoquinolin-3-ylmethyl) -amino] -pyrimidin-5-yl}- 100 mg of piperidine-4-carboxylic acid ethyl ester was dissolved in 1 ml of ethanol, 215 μl of 2N-aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. Water and 1N-hydrochloric acid were added to the reaction solution to adjust the pH to about 4, and the mixture was extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to give 1- {2-[(3,5-bis-trifluoromethyl-benzyl)-(1-oxo-1,2-dihydroisoquinolin-3-ylmethyl). 85 mg of -amino] -pyrimidin-5-yl} -piperidine-4-carboxylic acid were obtained. MS (m / z): 606 [M + H] &lt; ⁺ &gt;.

Production Example 67
1- {2-[(1-Benzyloxy-isoquinolin-3-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl) -amino] -pyrimidin-5-yl} -piperidine-4-carboxylate By treating 150 mg of the ester in the same manner as in Production Example 4 (2), 1- {2-[(1-benzyloxy-isoquinolin-3-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)- 127 mg of amino] -pyrimidin-5-yl} -piperidine-4-carboxylic acid were obtained. MS (m / z): 696 [M + H] ^< +>.

Production Example 68
(1) 1- {2-[(3,5-bis-trifluoromethyl-benzyl)-(1-oxo-1,2-dihydroisoquinolin-3-ylmethyl) -amino] -pyrimidin-5-yl}- Piperidine-4-carboxylic acid ethyl ester (300 mg), isopropanol (49 μl) and triphenylphosphine (170 mg) were dissolved in tetrahydrofuran (5 ml), and 40% diethyl azodicarboxylate / toluene solution (255 μl) was added dropwise, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 95: 5) to give 1- {2-[(3,5-bis -Trifluoromethyl-benzyl)-(1-isopropoxy-isoquinolin-3-ylmethyl) -amino] -pyrimidin-5-yl} -piperidine-4-carboxylic acid ethyl ester 281 mg was obtained. MS (m / z): 676 [M + H] &lt; ⁺ &gt;.

(2) 1- {2-[(3,5-bis-trifluoromethyl-benzyl)-(1-isopropoxy-isoquinolin-3-ylmethyl) -amino] -pyrimidin-5-yl} -piperidine-4- Carboxylic acid ethyl ester (275 mg) was dissolved in ethanol (5 ml), 2N aqueous sodium hydroxide solution (610 μl) was added, and the mixture was stirred at room temperature overnight. Water and 1N-hydrochloric acid were added to the reaction solution to adjust the pH to about 4, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 94: 6) to give 1- {2-[(3,5-bis-trifluoromethyl-benzyl)-(1- 215 mg of isopropoxy-isoquinolin-3-ylmethyl) -amino] -pyrimidin-5-yl} -piperidine-4-carboxylic acid were obtained. MS (m / z): 648 [M + H] ^< +>.

Production Example 69
(1) 1- {2-[(3,5-bis-trifluoromethyl-benzyl)-(1-oxo-1,2-dihydroisoquinolin-3-ylmethyl) -amino] -pyrimidin-5-yl}- Piperidine-4-carboxylic acid ethyl ester 300 mg, 2-methoxyethanol 51 μl, triphenylphosphine 170 mg were dissolved in tetrahydrofuran 5 ml, 40% diethyl azodicarboxylate / toluene solution 255 μl was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 93: 7 → 67: 33) to give 1- (2-{(3,5-bis -Trifluoromethyl-benzyl)-[1- (2-methoxy-ethoxy) -isoquinolin-3-ylmethyl] -amino} -pyrimidin-5-yl) -piperidine-4-carboxylic acid ethyl ester 187 mg; MS (m / m z): 692 [M + H] ⁺ , and 1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (2-methoxy-ethyl) -1-oxo-1,2-dihydro 94 mg of isoquinolin-3-ylmethyl] -amino} -pyrimidin-5-yl) -piperidine-4-carboxylic acid ethyl ester were obtained. MS (m / z): 692 [M + H] &lt; ⁺ &gt;.

(2) 1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[1- (2-methoxy-ethoxy) -isoquinolin-3-ylmethyl] -amino}-obtained in (1) 180 mg of pyrimidine-5-yl) -piperidine-4-carboxylic acid ethyl ester was dissolved in 3 ml of ethanol, 390 μl of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. Water and 1N-hydrochloric acid were added to the reaction solution to adjust the pH to about 4, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 93: 7) to give 1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[1- There was obtained 147 mg of (2-methoxy-ethoxy) -isoquinolin-3-ylmethyl] -amino} -pyrimidin-5-yl) -piperidine-4-carboxylic acid. MS (m / z): 664 [M + H] ^< +>.

Production Example 70-72
The corresponding starting materials were used and treated in the same manner as in Production Example 69, to give the compounds as shown in Table 23.

Production Example 73
1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (2-methoxy-ethyl) -1-oxo-1,2-dihydroisoquinoline obtained in Preparation Example 69 (1) 90 mg of -3-ylmethyl] -amino} -pyrimidin-5-yl) -piperidine-4-carboxylic acid ethyl ester was dissolved in 2 ml of ethanol, 195 μl of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. Water and 1N-hydrochloric acid were added to the reaction solution to adjust the pH to about 4, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 99: 1 → 92: 8) to give 1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- 22 mg of (2-methoxy-ethyl) -1-oxo-1,2-dihydroisoquinolin-3-ylmethyl] -amino} -pyrimidin-5-yl) -piperidine-4-carboxylic acid were obtained. MS (m / z): 664 [M + H] ^< +>.

Production Examples 74-76
The corresponding starting materials were used and treated in the same manner as in Production Example 73 to give the compounds listed in Table 24.

Production Example 77-80
The corresponding starting materials were used and treated in the same manner as in any of the above Preparation Examples to give the compounds listed in Table 25.

Production Example 81-84
The corresponding starting materials were used and treated in the same manner as in any of the above Preparation Examples to give the compounds described in Table 26.

Reference example 1
Cyclohexanecarboxaldehyde (38 g), diethylamine hydrochloride (55 g) and acetic acid (29 ml) were dissolved in methylene chloride (500 ml), sodium triacetoxyborohydride (71.8 g) was added at room temperature, and the mixture was stirred at room temperature overnight. To the reaction solution are added a 2N aqueous sodium hydroxide solution and methylene chloride, and the mixture is separated. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product of cyclohexylmethyl-ethyl-amine. 40.1 g was obtained. MS (m / z): 142 [M + H] &lt; ⁺ &gt;.

Reference example 2
Dissolve 10 g of 3,5-bis-trifluoromethyl-benzylamine and 12 g of 5-bromo-2-chloro-pyrimidine in 50 ml of 1,4-dioxane, add 10.7 ml of N, N-diisopropylethylamine, and heat to reflux overnight. did. The reaction solution was returned to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 7: 3) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidine-2- Yl) -amine 10.1 g was obtained. MS (m / z): 713 [M + H] ^< +>.

Reference example 3
(1) 2 g of ethylamine hydrochloride was dissolved in 20 ml of methylene chloride, 6 ml of pyridine and 7.6 g of 6- (chloroformyl) hexanoic acid ethyl ester were added, and the mixture was stirred at room temperature overnight. To the reaction solution is added a saturated aqueous sodium hydrogen carbonate solution, and the mixture is separated, and the organic layer is washed with 1N hydrochloric acid, water, and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 6-ethylcarbamoyl-hexanoic acid. 9.29 g of ethyl ester was obtained as a crude product. MS (m / z): 216 [M + H] ^< +>.

  (2) 9.29 g of a crude product of 6-ethylcarbamoyl-hexanoic acid ethyl ester was dissolved in 50 ml of tetrahydrofuran, and 7.35 g of sodium borohydride was added. The reaction solution was heated to reflux, 11 ml of acetic acid was added dropwise, and the mixture was heated to reflux for 1 hour 30 minutes. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 30 ml of ethanol, 7.6 ml of 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was stirred at room temperature overnight. 2N-aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and 7-ethylamino-heptanoic acid ethyl ester. 98 g were obtained as a crude product. MS (m / z): 216 [M + H] +.

Reference example 4
(1) 5 g of 6-amino-hexanoic acid methyl hydrochloride was dissolved in 20 ml of methylene chloride, 4.5 ml of pyridine and 2 ml of acetyl chloride were added, and the mixture was stirred at room temperature for 1 hour 45 minutes. To the reaction solution are added 1N hydrochloric acid and chloroform, and the mixture is separated. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 5.19 g of 6-acetylamino-hexanoic acid methyl ester as a crude product. Obtained as product. MS (m / z): 188 [M + H] ^< +>.

(2) 5.19 g of a crude product of 6-acetylamino-hexanoic acid methyl ester was dissolved in 50 ml of tetrahydrofuran, and 5.03 g of sodium borohydride was added. The reaction solution was heated to reflux, 7.6 ml of acetic acid was added dropwise, and the mixture was heated to reflux for 1 hour 30 minutes. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 30 ml of ethanol, 7.6 ml of 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was stirred at room temperature overnight. To the reaction solution are added a 2N aqueous sodium hydroxide solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 6-ethylamino-hexanoic acid ethyl ester. 74 g were obtained as a crude product. MS (m / z): 188 [M + H] ^< +>.

Reference Example 5
(1) 10 g of (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl) -amine and 4.18 ml of triethylamine were dissolved in 100 ml of methylene chloride, and triphosgene 2. 97 g was added. The reaction solution was stirred at the same temperature for 30 minutes and then concentrated under reduced pressure. The obtained residue was dissolved in 100 ml of tetrahydrofuran, and 3.88 ml of benzyl alcohol and 10.45 ml of triethylamine were added at room temperature, followed by stirring overnight. Ethyl acetate was added to the reaction solution for dilution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 97: 3 → 9: 1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidine-2- Yl) -carbamic acid benzyl ester (11.58 g) was obtained. MS (m / z): 534/536 [M + H] ^< +>.

(2) 13.5 g of (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) -carbamic acid benzyl ester, [1,1′-bis (diphenylphosphino) ferrocene ] 3.51 g of dichloropalladium dichloromethane complex, 6.33 g of potassium acetate and 10.9 g of bis (pinacolato) diboron were dissolved in 75 ml of dimethyl sulfoxide, heated to 80 ° C. under a nitrogen atmosphere, and stirred for 30 minutes. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, the insoluble material was filtered off through celite, and the phases were separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 100 ml of tetrahydrofuran, and 50 ml of 30% aqueous hydrogen peroxide was added dropwise under ice cooling, followed by stirring for 1 hour. Under ice-cooling, a saturated aqueous sodium thiosulfate solution was added to crush excess hydrogen peroxide, and water and ethyl acetate were added to separate the layers. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 9: 1), and (3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl) was obtained. ) -Carbamic acid benzyl ester 9.70 g was obtained. MS (m / z): 472 [M + H] ^< +>.

  (3) 9.70 g of (3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl) -carbamic acid benzyl ester and 3.53 g of 4-bromobutyric acid ethyl ester were mixed with N, N -It melt | dissolved in 50 ml of dimethylformamide, 3.41 g of potassium carbonate was added, and it stirred at 50 degreeC for 1 hour. Ethyl acetate and saturated brine were added for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1), and 4- {2- [benzyloxycarbonyl- (3,5-bis-trifluoromethyl-benzyl)]. 8.29 g of -amino] -pyrimidin-5-yloxy} -butanoic acid ethyl ester were obtained. MS (m / z): 586 [M + H] +.

(4) Dissolve 3.0 g of 4- {2- [benzyloxycarbonyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -pyrimidin-5-yloxy} -butanoic acid ethyl ester in 20 ml of tetrahydrofuran. 500 mg of 10% palladium carbon was added, and the mixture was stirred at room temperature for 2 hours and 30 minutes in a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1) to give 4- [2- (3,5-bis-trifluoromethyl-benzylamino) -pyrimidine-5. There was obtained 2.22 g of -yloxy] -butanoic acid ethyl ester. MS (m / z): 452 [M + H] &lt; ⁺ &gt;.

Reference Example 6
(1) 6-aminohexanoic acid methyl ester 2.50 g of hydrochloride is dissolved in 50 ml of tetrahydrofuran, 50 ml of water and 3.44 g of sodium hydrogen carbonate are added, and 2.17 ml of chloroformic acid benzyl ester is added dropwise under ice cooling. Stir at warm for 2.5 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4.16 g of 6-benzyloxycarbonylamino-hexanoic acid methyl ester. MS (m / z): 280 [M + H] &lt; ⁺ &gt;.

(2) Dissolve 6.15 g of 6-benzyloxycarbonylamino-hexanoic acid methyl ester in 25 ml of N, N-dimethylformamide, add 552 mg of sodium hydride (63%) under ice cooling, and stir at the same temperature for 1 hour. Then, 1.72 ml of methyl iodide was added, and the mixture was further stirred at the same temperature for 2 hours. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 2.25 g of 6- (benzyloxycarbonyl-methyl-amino) -hexanoic acid methyl ester. MS (m / z): 294 [M + H] ^< +>.

(3) 6.24 g of 6- (benzyloxycarbonyl-methyl-amino) -hexanoic acid methyl ester was dissolved in 35 ml of methanol, 500 mg of 10% palladium carbon was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.11 g of 6-methylamino-hexanoic acid methyl ester. MS (m / z): 160 [M + H] &lt; ⁺ &gt;.

Reference Example 7
0.65 g of propylamine was dissolved in 5 ml of tetrahydrofuran, 0.89 ml of pyridine was added, 1.96 g of methyl adipoyl chloride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 30 ml of tetrahydrofuran, 1.93 g of sodium borohydride was added at room temperature, heated to 65 ° C., 2.92 ml of acetic acid was added dropwise over 1 hour, and the mixture was stirred at the same temperature for 9 hours. Ice-cooled dilute hydrochloric acid was added to the reaction mixture, and the mixture was stirred for 30 minutes and extracted with ethyl acetate. The organic layer was washed with a mixture of saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (15 ml), 4N hydrochloric acid dioxane solution (7.5 ml) was added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution and saturated brine were added to the reaction mixture, and the mixture was extracted 6 times with ethyl acetate. The collected organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 914 mg of 6-propylamino-hexanoic acid methyl ester. It was. MS (m / z): 188 [M + H] ^< +>.

Reference Example 8
(1) Dissolve 2.00 g of piperidin-4-ylmethyl-carbamic acid tert-butyl ester in 10 ml of tetrahydrofuran, add 1.69 ml of triethylamine, drop 1.24 ml of bromoacetic acid ethyl ester dropwise in a water bath, and at room temperature for 2 hours. Stir. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, isopropyl ether was added to the crystalline residue, and the mixture was collected by filtration to give [4- (tert-butoxycarbonylamino-methyl) -piperidine-1]. -Yl] -acetic acid ethyl ester 1.87 g was obtained. MS (m / z): 301 [M + H] &lt; ⁺ &gt;.

(2) 1.86 g of [4- (tert-butoxycarbonylamino-methyl) -piperidin-1-yl] -acetic acid ethyl ester was dissolved in 10 ml of N, N-dimethylformamide and sodium hydride (63%). 19 g and 6.0 ml of ethyl iodide were added, and the mixture was stirred at room temperature for 2 hours. A 10% aqueous citric acid solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture to make it weakly basic and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and {4-[(tert-butoxycarbonyl-ethyl-amino) -methyl] -piperidin-1-yl} -ethyl acetate. 905 mg of ester was obtained. MS (m / z): 329 [M + H] ^< +>.

(3) Dissolve 235 mg of {4-[(tert-butoxycarbonyl-ethyl-amino) -methyl] -piperidin-1-yl} -acetic acid ethyl ester in 1 ml of methylene chloride, add 1 ml of trifluoroacetic acid, and overnight at room temperature. Stir. The reaction mixture was concentrated under reduced pressure to obtain 482 mg of (4-ethylaminomethyl-piperidin-1-yl) -acetic acid ethyl ester ditrifluoroacetate. MS (m / z): 229 [M + H] ^< +>.

Reference Example 9
(1) 2 g of 2-tert-butoxy-ethylamine was dissolved in 10 ml of methylene chloride, 940 μl of pyridine and 1.13 g of 6- (chloroformyl) hexanoic acid ethyl ester were added under ice cooling, and the mixture was stirred at room temperature overnight. To the reaction solution are added 1N hydrochloric acid and chloroform, and the mixture is separated, and the organic layer is washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and 6- (2-tert-ethylcarbamoyl) -hexanoic acid. 2.96 g of ethyl ester was obtained as a crude product. MS (m / z): 288 [M + H] ^< +>.

(2) 2.96 g of a crude product of 6- (2-tert-ethylcarbamoyl) -hexanoic acid ethyl ester was dissolved in 15 ml of tetrahydrofuran, and 1.60 g of sodium borohydride was added. The reaction solution was heated to reflux, 2.4 ml of acetic acid was added dropwise, and the mixture was heated to reflux for 1 hour. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 6 ml of ethanol, 1.5 ml of 4N-hydrochloric acid / ethyl acetate solution was added, and the mixture was stirred at room temperature for 3 days. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. -2.6 g of heptanoic acid ethyl ester was obtained as a crude product. MS (m / z): 274 [M + H] ^< +>.

Reference Example 10
(1) After dissolving 50 g of 3-nitro-5- (trifluoromethyl) benzoic acid in 300 ml of tetrahydrofuran and dropwise adding 300 ml of 1.0 M-borane tetrahydrofuran complex / tetrahydrofuran solution at 0 ° C. over 2 hours under a nitrogen atmosphere. , And stirred at 75 ° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, 1N-hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product of (3-nitro-5-trifluoromethyl-phenyl) -methanol. The obtained crude product was dissolved in 500 ml of methanol, 5 g of 10% palladium carbon was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain a crude product of (3-amino-5-trifluoromethyl-phenyl) -methanol. 500 ml of acetonitrile was added to 53.6 g of copper (II) bromide, and 35.7 ml of tert-butyl nitrite was added dropwise under ice cooling, followed by stirring for 5 minutes in a nitrogen atmosphere. To the reaction mixture, 200 ml of an acetonitrile solution of the above (3-amino-5-trifluoromethyl-phenyl) -methanol crude product was added dropwise over 1 hour and 15 minutes under ice cooling, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. 1N-hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 4: 1) to obtain 40.7 g of (3-bromo-5-trifluoromethyl-phenyl) -methanol. NMR (CDCl ₃ ): 1.90 (1H, t), 4.76 (2H, d), 7.56 (1H, s), 7.68 (1H, s), 7.72 (1H, s) .

(2) 33.9 g of (3-bromo-5-trifluoromethyl-phenyl) -methanol is dissolved in 400 ml of N, N-dimethylformamide, 16.39 g of zinc (II) cyanide, tetrakis (triphenylphosphine) palladium. 7.68 g was added, heated to 120 ° C. under a nitrogen atmosphere, and stirred for 2 hours. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 23.4 g of 3-hydroxymethyl-5-trifluoromethyl-benzonitrile. NMR (CDCl ₃ ): 2.09 (1H, t), 4.85 (2H, d), 7.83 (1H, s), 7.87 (2H, s).

(3) 23.4 g of 3-hydroxymethyl-5-trifluoromethyl-benzonitrile is dissolved in 230 ml of methylene chloride, 42.4 g of carbon tetrabromide is added, and 32.0 g of triphenylphosphine is added under ice cooling. Stir at temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 25.5 g of 3-bromomethyl-5-trifluoromethyl-benzonitrile. _{NMR (CDCl 3): 4.51 (} 2H, s), 7.86 (1H, s), 7.88 (2H, s).

Reference Example 11
(1) 5 g of 2-bromo-pyridin-3-ol was dissolved in 150 ml of water, 6.15 g of sodium carbonate and 7.65 g of iodine were added thereto, and the mixture was stirred at room temperature for 2 hours. 1N-hydrochloric acid and ethyl acetate were added thereto for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 3: 1) to obtain 4.52 g of 2-bromo-6-iodo-pyridin-3-ol. MS (m / z): 300/302 [M + H] ^< +>.

(2) 2.98 g of 2-bromo-6-iodo-pyridin-3-ol is dissolved in 140 ml of N, N-dimethylformamide, to which 16.3 g of cesium carbonate and 1.25 ml of methyl iodide are added, and The mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1) to obtain 2.45 g of 2-bromo-6-iodo-3-methoxy-pyridine. MS (m / z): 314/316 [M + H] ^< +>.

(3) To 0.5M-isopropenylmagnesium bromide / tetrahydrofuran solution, 3.3 ml of trimethylborate was added and the mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. 6N-hydrochloric acid and diethyl ether were added to the reaction solution to separate it. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 818 mg of a crude product of isopropenylboronic acid. 287 mg of the above isopropenyl boronic acid crude product and 800 mg of 2-bromo-6-iodo-3-methoxy-pyridine are dissolved in a mixed solvent of 1,2-dimethoxyethane 8 ml and ethanol 3.2 ml. 6.4 ml of an aqueous solution, 240 mg of tetrakis (triphenylphosphine) palladium were added and the mixture was stirred at 80 ° C. for 5 hours under a nitrogen atmosphere. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 49: 1 → 9: 1), and further purified by NH-silica gel column chromatography (hexane: ethyl acetate = 49: 1 → 9: 1). 138 mg of -bromo-6-isopropenyl-3-methoxy-pyridine were obtained. MS (m / z): 228/230 [M + H] ^< +>.
Reference Example 12
2-Bromo-6-iodo-3-methoxy-pyridine (500 mg) was dissolved in dry toluene (5 ml) and 1.6 M n-butyllithium in hexane (1 mL) was dissolved in -78 under nitrogen atmosphere. Add dropwise at 0 ° C., stir the mixture for 1 hour, add acetone (0.23 ml) to it and stir the mixture overnight. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 2) to give 2- (6-bromo-5-methoxy-pyridin-2-yl) -propan-2- All (197 mg) was obtained. MS (m / z): 246/248 [M + H] ^< +>.

Reference Example 13
250 mg of 5-methoxy-2-methylsulfanyl-pyrimidin-4-ol was dissolved in 7 ml of acetonitrile, 0.7 ml of phosphorus oxychloride and 460 μl of diethylaniline were added, and the mixture was heated to reflux for 5.5 hours. After the reaction solution was azeotroped with toluene three times, an aqueous citric acid solution and chloroform were added to the residue for liquid separation. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 17: 3) to obtain 260 mg of 4-chloro-5-methoxy-2-methylsulfanyl-pyrimidine. MS (m / z): 191/193 [M + H] &lt; ⁺ &gt;.

Reference Example 14
3.89 g of 2-chloropyrimidin-5-ol was dissolved in 50 ml of N, N-dimethylformamide, and 4.98 g of potassium carbonate and 7.36 g of 4-bromobutanoic acid tert-butyl ester were added thereto, and the mixture was allowed to stand overnight at room temperature. Stir. Ethyl acetate and water were added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 24: 1 → 4: 1) to obtain 6.22 g of 4- (2-chloropyrimidin-5-yloxy) bromobutanoic acid tert-butyl ester. MS (m / z): 273 [M + H] ^< +>.
Reference Example 15
2.74 g of 2,5-dibromopyridine was dissolved in 100 ml of toluene, 5.84 g of 3,5-bistrifluoromethylbenzylamine, 449.0 mg of palladium acetate, 2,2′-bis (diphenylphosphino) -1,1 1.25 g of '-binaphthyl, 4.23 g of tert-butoxy sodium were added, and the mixture was stirred at 80 ° C. for 12 hours under a nitrogen atmosphere. The reaction solution is returned to room temperature, a saturated aqueous sodium hydrogen carbonate solution is added thereto, and the mixture is extracted twice with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and dried under reduced pressure. Concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyridin-2-yl) -amine. 2.08 g was obtained. MS (m / z): 399/401 [M + H] ^< +>.

Reference Example 16
3-Bromomethyl-5-trifluoromethyl-benzonitrile (prepared in Reference Example 10) (15.9 g) is dissolved in 7M ammonia / methanol (550 ml) and the mixture is dissolved in 50-60. Stir at 30 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the resulting residue for liquid separation, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0 → 19: 1 → chloroform: methanol: ammonium hydroxide solution = 19: 1: 0.1) to give 3-aminomethyl-5-trifluoro Methyl-benzonitrile (10.4 g) was obtained. MS (m / z): 201 [M + H] &lt; ⁺ &gt;.

Reference Example 17
(1) 4- (2-Chloro-pyrimidin-5-yloxy) -butanoic acid tert-butyl ester (5.0 g) was dissolved in 100 ml of toluene, and paradiu acetate 412 mg, 2,2′-bis (diphenylphosphino) -1 , 1'-binaphthyl was added and the mixture was stirred at 50 ° C for 1 hour under a nitrogen atmosphere. The reaction was returned to room temperature, to which were added 5.35 g of 3,5-bis-trifluoromethyl-benzylamine, 3.88 g of sodium tert-butoxide and the mixture was stirred at 35 ° C. for 2 hours. Ethyl acetate and water were added for liquid separation, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 2: 1) and NH-silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1), and 4- [2- 5.59 g of (3,5-bis-trifluoromethyl-benzylamino) -pyrimidin-5-yloxy] -butanoic acid tert-butyl ester were obtained. MS (m / z): 480 [M + H] &lt; ⁺ &gt;.

Reference Example 18
The corresponding starting materials were treated in the same manner as in Reference Example 17 to give the compounds listed in Table 27.

Reference Example 19
(1) 3-Bromo-4-methoxybenzoic acid (2.00 g) was dissolved in tetrahydrofuran (50 ml), the mixture was cooled to −78 ° C. and itself was added 1.1 M methyllithium in diethyl ether ( 7.7 ml) was added dropwise. The mixture is stirred at −78 ° C. for 5 minutes, to which 1.6 M tert-butyllithium in n-pentane (13.2 ml) is added dropwise and the mixture is stirred at −78 ° C. for 15 minutes. Was allowed to warm to -45 ° C and the mixture was stirred for 45 minutes and then cooled again to -78 ° C. Triisopropylborate was added dropwise thereto, and the mixture was stirred at -78 ° C for 15 minutes and the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 1.5 hours, the mixture was concentrated under reduced pressure, and water and hexane were added thereto. The aqueous layer was adjusted to pH 4 by adding 6N-hydrochloric acid and saturated aqueous sodium bicarbonate solution, and the mixture was extracted twice with ethyl acetate and methanol. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the resulting solid was collected by filtration to give 2-methoxy-5-carboxyphenylboronic acid (1.37 g) as a crude product.

(2) The crude 2-methoxy-5-carboxyphenylboronic acid (370 mg) was dissolved in N, N-dimethylformamide (10 ml) and dissolved in 2.0 M dimethylamine / tetrahydrofuran solution (1.9 ml). 1-hydroxybenzotriazole dihydrate (725 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (579 mg) were added. The mixture was stirred at room temperature for 3 hours and to it was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to obtain 2-methoxy-5-dimethylcarbamoylphenylboronic acid (210 mg). MS (m / z): 224 [M + H] ^< +>.

Reference Example 20
The corresponding starting materials were used and treated in the same manner as in Reference Example 19, to give the compounds as listed in Table 27.

Reference Example 21
(1) 4-sec-Butylphenol (3.0 g) was dissolved in chloroform and bromine (1.02 ml) was added to it, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the solution, followed by liquid separation. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 2-bromo-4-sec-butylphenol (4.57 g). NMR (CDCl ₃ ): 0.81 (3H, t), 1.19 (3H, d), 1.56 (2H, m), 2.51 (1H, m), 5.33 (1H, s) 6.93 (1H, d), 7.02 (1H, d), 7.26 (1H, s).

(2) 2-Bromo-4-sec-butyl-phenol (1.50 g) is dissolved in N, N-dimethylformamide (10 ml) and is itself potassium carbonate (1.18 g) and iodomethane (1.12 g). ) And the mixture was stirred at room temperature overnight. Thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 20: 1) to give 2-bromo-4-sec-butyl-1-methoxy-benzene (1.58 g). NMR (CDCl ₃ ): 0.80 (3H, t), 1.20 (3H, d), 1.55 (2H, m), 2.51 (1H, m), 3.87 (3H, s) 6.82 (1H, d), 7.07 (1 H, d), 7.35 (1 H, s).

(3) 2-Bromo-4-sec-butyl-1-methoxy-benzene (1.15 g) was dissolved in tetrahydrofuran (17 ml) and the mixture was cooled to −78 ° C. to which 1.6 M n was added. -Butyllithium / hexane was added dropwise and the mixture was stirred at -78 ° C for 15 minutes. To the reaction solution was added trimethyl borate (1.47 g) and the reaction mixture was stirred at −78 ° C. for 30 minutes, to which were added saturated aqueous ammonium chloride and ethyl acetate. The mixture was separated and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude 5-sec-butyl-1-methoxy-benzeneboronic acid (950 mg). It was. NMR (CDCl ₃ ): 0.81 (3H, t), 1.22 (3H, d), 1.58 (2H, m), 2.58 (1H, m), 3.90 (3H, s) , 6.25 (2H, s), 6.85 (2H, d), 7.25 (1H, d), 7.65 (1H, s).

Reference Example 22-25
The corresponding starting materials were used and treated in the same manner as in Reference Example 21 to give the compounds shown in Table 27.

  The compound of the present invention represented by the formula (1) and pharmacologically acceptable derivatives thereof have CETP inhibitory activity and exhibit HDL cholesterol increasing action and LDL cholesterol lowering action. Therefore, the pharmaceutical composition of the present invention is useful for the prevention and / or treatment of diseases such as arteriosclerotic diseases, hyperlipidemia or dyslipidemia.

Claims (23)

General formula (1):

Wherein Y is a methylene group or a single bond optionally substituted with a substituent selected from an alkyl group and an oxo group;
A is (i) an optionally substituted alkynyl group, halogen atom, oxo group, hydroxy group, cyano group, nitro group, carboxyl group, sulfo group, optionally substituted alkyl group, or optionally substituted A good cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl Group, optionally substituted carbamimidoyl group, optionally substituted alkylsulfanyl group, optionally substituted alkylsulfinyl group, optionally substituted alkylsulfonyl group, optionally substituted An amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, Optionally substituted homocyclic group, optionally substituted homocyclic group substituted oxy group, optionally substituted homocyclic group substituted carbonyl group, optionally substituted heterocyclic group, substituted A group selected from an optionally substituted heterocyclic group-substituted oxy group, and an optionally substituted heterocyclic group-substituted carbonyl group;
(Ii) an allocyclic group optionally substituted with 1 to 5 substituents independently selected from the groups described in (i); or (iii) selected independently from the groups described in (i) A heterocyclic group optionally substituted with 1 to 5 substituents,
B is a heterocyclic group optionally substituted with 1 to 5 substituents independently selected from the following substituents:
Optionally substituted alkynyl group, halogen atom, oxo group, hydroxy group, cyano group, nitro group, carboxyl group, sulfo group, optionally substituted alkyl group, optionally substituted cycloalkyl group, substituted Alkenyl group which may be substituted, alkoxy group which may be substituted, cycloalkoxy group which may be substituted, alkoxycarbonyl group which may be substituted, carbamoyl group which may be substituted, An optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, a substituted An optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, Good homocyclic group, optionally substituted homocyclic group-substituted oxy group, optionally substituted homocyclic group-substituted carbonyl group, optionally substituted heterocyclic group, optionally substituted A heterocyclic group-substituted oxy group, an optionally substituted heterocyclic group-substituted carbonyl group, and an alkylene group;
Here, the alkylene group may have 1 to 3 heteroatoms independently selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the alkylene group may be further substituted.
R ¹ is a hydrogen atom or an optionally substituted alkyl group; the alkyl group is further substituted with a substituent selected from an optionally substituted homocyclic group and an optionally substituted heterocyclic group May have been,
R ² may be substituted alkynyl group, halogen atom, oxo group, hydroxy group, cyano group, nitro group, carboxyl group, sulfo group, optionally substituted alkyl group, optionally substituted cycloalkyl A group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, a substituted An optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, Optionally substituted sulfamoyl group, optionally substituted alkanoyl group, substituted Allocyclic group which may be substituted, allocyclic group which may be substituted, substituted oxy group, allocyclic group which may be substituted, carbonyl group which may be substituted, heterocyclic group which may be substituted, substituted A compound selected from an optionally substituted heterocyclic group-substituted oxy group and an optionally substituted heterocyclic group-substituted carbonyl group), or a pharmaceutically acceptable derivative thereof as an active ingredient A pharmaceutical composition characterized by the above. The homocyclic group is a cycloalkyl group, a phenyl group, or a naphthyl group;
A heterocyclic group is a thienyl group, a furyl group, a pyrrolyl group, a pyrrolinyl group, an oxazolyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, an imidazolinyl group, an isoxazolyl group, an isothiazolyl group, an oxadiazolyl group, a furazanyl group, a thiadiazolyl group, a triazolyl group, Triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazopyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, oxazinyl group, thiazinyl group , Piperazinyl group, triazinyl group, oxatriazinyl group, pyridazinyl group, pyrazinyl group, benzofuranyl group, benzothiazolyl group, benzoxazolyl group, tetrazolopyri Dinyl group, triazolopyridazinyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, dihydroisoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, dihydroindolyl group, indolyl group, quinolidinyl Group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group, acridinyl group, phenanthridinyl group, chromanyl group, benzooxazinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, hexahydroase Pinyl group, imidazolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydrooxazinyl group, dihydropyrazoli Group, an imidazopyridyl group, dihydro pyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group, oxathiadiazolyl group, dihydrooxazolyl group or tetrahydroquinolyl group,
An optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, a substituted An optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, a substituted Alkylsulfonyl group which may be substituted, amino group which may be substituted, sulfamoyl group which may be substituted, alkanoyl group which may be substituted, homocyclic group which may be substituted, Allocyclic group substituted oxy group, which may be substituted allocyclic group substituted carbonyl group, which may be substituted Good heterocyclic group, optionally substituted heterocyclic group-substituted oxy group, optionally substituted heterocyclic group-substituted carbonyl group, optionally substituted phenyl group, optionally substituted alkylsulfonyloxy group 1 to 5 groups, wherein the substituent of the optionally substituted alkynyl group or the optionally substituted alkylene group is independently selected from the group described below:
Cyano group; hydroxy group; nitro group; carboxyl group; oxo group; thioxo group; sulfo group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl A cycloalkyl group optionally substituted by a group; an alkoxycarbonyl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; A carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; Roxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, alkyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, An alkanoyl group optionally substituted by a mono- or di-alkylamino group, phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl An alkoxy group optionally substituted by a group; an aryl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; Canoyloxy group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, alkylsulfanyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, An alkylsulfonyl group optionally substituted by an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group Alkylsulfinyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl Mono- or di-alkylsulfamoyl group which may be substituted with a benzene or morpholinyl group; amino group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group Or a mono- or di-alkylamino group optionally substituted by a morpholinyl group; substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group Mono- or di-alkylsulfamoylamino group which may be substituted; mono optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group - Di-alkylureido group; homocyclic group selected from cycloalkyl group, phenyl group, and naphthyl group; said homocyclic group-substituted oxy group; said homocyclic group-substituted carbonyl group; thienyl group, furyl group, pyrrolyl group , Pyrrolinyl group, oxazolyl group, thiazolyl group, pyrazolyl group, imidazolyl group, imidazolinyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, furazanyl group, thiadiazolyl group, triazolyl group, triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazo Pyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, oxazinyl group, thiazinyl group, piperazinyl group, tri Zinyl group, oxatriazinyl group, pyridazinyl group, pyrazinyl group, benzofuranyl group, benzothiazolyl group, benzoxazolyl group, tetrazolopyridazinyl group, triazolopyridazinyl group, benzoimidazolyl group, quinolyl group, isoquinolyl group Group, dihydroisoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, dihydroindolyl group, indolyl group, quinolidinyl group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group , Acridinyl group, phenanthridinyl group, chromanyl group, benzoxazinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, hexahydroazepinyl group, imidazolidinyl group, oxazolidinyl group, teto Lahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydrooxazinyl group, dihydropyrazolyl group, imidazopyridyl group, dihydropyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group , A heterocyclic group selected from an oxathiadiazolyl group, a dihydrooxazolyl group and a tetrahydroquinolyl group; the heterocyclic group-substituted oxy group; the heterocyclic group-substituted carbonyl group;
And a group represented by the following formula:

Wherein X ¹ and X ³ each represent CH ₂ , NH, O, S, SO, or SO ₂ , and X ² and X ⁵ represent CH ₂ , O, S, SO, or SO ₂ , respectively. X ⁴ represents NH, O, S, SO, or SO ₂ , X ⁶ and X ⁷ each represent O or S, X ⁸ represents S or SO, n, o, p, q , And r each represent an integer of 1 to 4); further, each of the above groups may be further substituted with 1 to 3 substituents independently selected from the following group:
Halogen atom, carboxyl group, hydroxy group, cyano group, oxo group, thioxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group , Alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, alkoxycarbonyl group, benzyloxycarbonyl group, mono- or di-alkylamino group, mono- or di-alkylcarbamoyl group, mono- or di-alkylsulfamoyl group, An alkylsulfonyl group and a tetrazolyl group;
The pharmaceutical composition according to claim 1, wherein A is the formula:
-A ¹ -A ²
A group represented by
A ¹ is a phenyl group, naphthyl group, pyrimidinyl group, pyridazinyl group, a pyridyl group, triazolyl group, tetrazolyl group, oxadiazolyl group, dihydropyrimidinyl group, a pyrazinyl group, a thiazolyl group, an oxazolyl group, dihydro benzoxazinyl group, an imidazolyl group, pyrazolyl Group or dihydropyrazinyl group,
A ² is carboxyl group; cyano group; nitro group; hydroxy group, cyano group, carboxyl group, alkoxycarbonyl group, alkoxy group, phenylalkoxy group, hydroxyalkoxy group, carboxyalkoxy group, alkylsulfanyl group, alkylsulfonyl group, alkyl Sulfinyl group, amino group, mono- or di-alkylamino group, mono- or di-alkylsulfamoylamino group, mono- or di-alkylureido group optionally substituted with morpholinyl group, oxiranyl group, dialkyldio Substituted with a group selected from a xazolanyl group, a pyrrolidinyl group optionally substituted with a carboxyl group, a piperidyl group optionally substituted with a carboxyl group, a piperazinyl group optionally substituted with an alkyl group, and a morpholinyl group Alkyl group which may be substituted; alkenyl group which may be substituted with carboxyl group; hydroxy group, cyano group, carboxyl group, alkoxycarbonyl group, alkoxy group, phenylalkoxy group, hydroxyalkoxy group, carboxyalkoxy group, alkylsulfanyl Group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono- or di-alkylamino group, mono- or di-alkylsulfamoylamino group, mono- or di-alkylureido optionally substituted with morpholinyl group A group, an oxiranyl group, a dialkyldioxolanyl group, a pyrrolidinyl group optionally substituted with a carboxyl group, a piperidyl group optionally substituted with a carboxyl group, a piperazinyl group optionally substituted with an alkyl group, and An alkoxy group optionally substituted with a group selected from a ruphorinyl group; an alkoxycarbonyl group; a hydroxycarbamimidoyl group; an alkylsulfanyl group; an alkylsulfonyl group optionally substituted with a carboxyl group; a hydroxy group, a carboxyl group, A mono- or di-alkylamino group optionally substituted with an alkoxy group or a mono- or di-alkylamino group; a morpholinyl group optionally substituted with a carboxyl group, an alkyl group, a carboxyalkyl group or an alkoxycarbonyl group An optionally oxidized thiomorpholinyl group; a piperazinyl group optionally substituted with a group selected from an alkyl group, an alkanoyl group, and a hydroxyalkanoyl group; a carboxyl group, an alkyl group, a carboxyalkyl group, or an amine; A pyrrolidinyl group optionally substituted with a alkoxycarbonyl group; a piperidyl group optionally substituted with a carboxyl group, an alkyl group, a carboxyalkyl group, or an alkoxycarbonyl group; an alkyl group, a hydroxyalkyl group, a carboxyalkyl group, or A tetrazolyl group optionally substituted with a morpholinylalkyl group; an oxodihydrooxadiazolyl group; a pyrimidinyl group; or a tetrahydropyranyl group,
R ¹ is the formula:
-R ¹¹ -R ¹²
A group represented by
R ¹¹ is an alkylene group,
R ¹² is phenyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, furyl group, thienyl group, triazolyl group, tetrazolyl group, oxadiazolyl group, dihydropyrimidinyl group, pyrazinyl group, thiazolyl group, oxazolyl group, imidazolyl group, dihydrooxazinyl group A substituent selected from a group, a dihydropyrazinyl group, and a pyrazolyl group;
Here, the substituent is a halogen atom, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono- or di-alkylcarbamoyl group, alkyl group, alkoxy group, hydroxy group, nitro group, cyano group, amino group, mono- or May be substituted with 1 to 4 substituents independently selected from di-alkylamino, alkanoyl, alkylsulfanyl, tetrazolyl, and dihydrooxazolyl groups;
Further, in this case, the alkyl group, alkoxy group, mono- or di-alkylamino group, mono- or di-alkylcarbamoyl group, alkanoyl group, and alkylsulfanyl group are each independently a halogen atom, a hydroxy group, or an alkoxy group. May be substituted with 1 to 5 substituents independently selected from amino group, morpholinyl group, piperidyl group, pyrrolidinyl group, piperazinyl group, alkylpiperazinyl group, and alkanoylpiperazinyl group;
R ² is a halogen atom;
A hydroxy group;
A cyano group;
A nitro group;
Carboxyl group;
A sulfo group;
A cycloalkyl group optionally substituted with a carboxyl group or an alkoxycarbonyl group;
A halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a mono- or di-alkylcarbamoyl group, an alkoxy group (the alkoxy group may be substituted with a phenyl group, a carboxyl group, or a hydroxy group) Alkanoyl group, alkanoyloxy group, alkylsulfanyl group, alkylsulfonyl group, alkylsulfinyl group, mono- or di-alkylamino group optionally substituted with amino group, carboxyl group or alkoxy group, mono- or di -Alkylsulfamoylamino group, mono- or di-alkylureido group optionally substituted with morpholinyl group, oxiranyl group, dioxolanyl group optionally substituted with alkyl group, alkoxycarbonyl group Is a pyrrolidinyl group which may be substituted with a carboxyl group, an alkoxycarbonylalkyl group or a pyrrolidinyl group which may be substituted with a carboxyalkyl group, an alkoxycarbonyl group or a piperidyl group which may be substituted with a carboxyl group, alkoxycarbonylalkyl A piperidyl group optionally substituted with a carboxyalkyl group, a piperazinyl group optionally substituted with an alkyl group, a hexahydroazepinyl group, a morpholinyl group, and a piperidyloxy group optionally substituted with an alkyl group An alkyl group which may be substituted with a group selected from:
An alkenyl group optionally substituted by a group selected from a cyano group, a hydroxy group, a carboxyl group, a benzyloxycarbonyl group, and a tetrazolyl group;
An alkenyloxy group optionally substituted with a carboxyl group;
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group An pyrrolidinylcarbonyl group optionally substituted with an alkoxy group optionally substituted with a group selected from a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
An alkoxycarbonyl group optionally substituted with a phenyl group;
A carbamoyl group;
A mono- or di-alkylcarbamoyl group optionally substituted with a group selected from a carboxyl group, a morpholinyl group, and an alkoxy group;
A hydroxycarbamimidoyl group;
An alkylsulfanyl group optionally substituted with a group selected from a hydroxy group, a carboxyl group, and a mono- or di-alkylcarbamoyl group;
An alkylsulfinyl group;
An alkylsulfonyl group optionally substituted with a group selected from a hydroxy group, a carboxyl group, an alkoxycarbonyl group, and a mono- or di-alkylcarbamoyl group;
An amino group;
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A mono- or di-alkylamino group optionally substituted with a group selected from a pyrrolidinylcarbonyl group optionally substituted with, a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group ;
An alkanoylamino group optionally substituted with a group selected from a hydroxy group, an alkoxy group, a carboxyl group, and an amino group;
A mono- or di-alkylcarbamoylamino group optionally substituted by an alkoxy group;
A morpholinylcarbonylamino group;
A sulfamoyl group;
Mono- or di-alkylsulfamoyl groups;
An alkanoyl group optionally substituted with a group selected from a hydroxy group, a carboxyl group, an alkoxycarbonyl group, an alkoxy group, a mono- or di-alkylamino group, and a morpholinyl group; or
Cycloalkyl group, phenyl group, naphthyl group, thienyl group, furyl group, pyrrolyl group, pyrrolinyl group, oxazolyl group, thiazolyl group, pyrazolyl group, imidazolyl group, imidazolinyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, furazanyl group, thiadiazolyl Group, triazolyl group, triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazopyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, Oxazinyl, thiazinyl, piperazinyl, triazinyl, oxatriazinyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothiazolyl, benzo Xazolyl group, tetrazolopyridazinyl group, triazolopyridazinyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, dihydroisoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, dihydro Indolyl group, indolyl group, quinolidinyl group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group, acridinyl group, phenanthridinyl group, chromanyl group, benzoxazinyl group, phenazinyl group, phenothiazinyl group Group, phenoxazinyl group, hexahydroazepinyl group, imidazolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydroozone Selected from sazinyl group, dihydropyrazolyl group, imidazopyridyl group, dihydropyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group, oxathiadiazolyl group, dihydrooxazolyl group and tetrahydroquinolyl group A cyclic group;
Furthermore, here, the cyclic group may be substituted with a substituent selected from the following group:
A halogen atom, an alkoxyalkyl group, an alkyl group optionally substituted with 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, Cyano group, oxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group, alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, Alkoxycarbonyl, benzyloxycarbonyl, mono- or di-alkylamino, mono- or di-alkylcarbamoyl, mono- or di-alkylsulfamoyl, alkylsulfonyl, Fine-tetrazolyl group;
Further, here, the substituent may be substituted with a substituent selected from the following group:
A halogen atom, an alkoxyalkyl group, an alkyl group optionally substituted with 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, Cyano group, oxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group, alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, Alkoxycarbonyl, benzyloxycarbonyl, mono- or di-alkylamino, mono- or di-alkylcarbamoyl, mono- or di-alkylsulfamoyl, alkylsulfonyl, Fine-tetrazolyl group;
The pharmaceutical composition according to claim 2, wherein Y is a methylene group or a single bond optionally substituted with a group selected from an alkyl group and an oxo group;
A is the formula:
-A ¹ -A ²
A group represented by
A ¹ is a homocyclic group, a heterocyclic group or a single bond,
A ² may be a homocyclic group which may be substituted, an alkylsulfanyl group which may be substituted, an alkylsulfinyl group which may be substituted, an alkylsulfonyl group which may be substituted, a nitro group, a hydroxy group, An optionally substituted alkenyl group, an optionally substituted heterocyclic group, an optionally substituted alkoxy group, a halogen atom, an optionally substituted alkyl group, a cyano group, 1 to 2 substituents An amino group or a hydrogen atom optionally substituted by
B is an oxo group, a cyano group, a carboxyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, a hydroxyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl Group, halogen atom, optionally substituted alkoxy group, optionally substituted alkylsulfanyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, optionally substituted It may be substituted with 1 to 5 groups independently selected from a heterocyclic group, an optionally substituted alkylsulfinyl group, and an amino group optionally substituted with 1 to 2 substituents. A heterocyclic group,
R ¹ is a hydrogen atom or an optionally substituted lower alkyl group; the lower alkyl group may be further substituted with an optionally substituted homocyclic group or optionally substituted heterocyclic group. Often,
R ² is an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, a cyano group, an optionally substituted alkenyl group, 1 to 2 An amino group which may be substituted with a substituent, a halogen atom, an alkoxy group which may be substituted, a carbamoyl group which may be substituted, an oxy group which is substituted with an optionally substituted heterocyclic group, hydroxy A group, an optionally substituted heterocyclic group, an optionally substituted homocyclic group, an oxy group substituted by an optionally substituted homocyclic group, an optionally substituted alkyl group, hydrogen An atom, an optionally substituted alkylcarbonyl group, an optionally substituted alkyl group, an optionally substituted alkoxycarbonyl group or a nitro group;
However, partial structure (1-1) of compound (1):

(Wherein the symbols have the same meaning as above)

(Wherein ring W represents a heterocyclic group);
The pharmaceutical composition according to claim 1, wherein Y is a methylene group or a single bond optionally substituted with a group independently selected from an alkyl group and an oxo group;
A ¹ is a heterocyclic group or a single bond,
A ² may be substituted with an optionally substituted heterocyclic group, an optionally substituted alkoxy group, a halogen atom, an optionally substituted alkyl group, a cyano group, or 1 to 2 substituents. A good amino group or hydrogen atom,
B is an oxo group, a cyano group, a carboxyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, a hydroxyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl A group, a halogen atom, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted piperidyl group, and 1 to 2 substitutions A heterocyclic group which may be substituted with 1 to 5 groups independently selected from an amino group which may be substituted with a group;
R ¹ is a hydrogen atom, an optionally substituted benzyl group or an optionally substituted phenylethyl group,
R ² is an amino group optionally substituted by 1 to 2 substituents, a halogen atom, an optionally substituted alkoxy group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group An oxy group substituted with a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted homocyclic group, an oxy group substituted with an optionally substituted homocyclic group, hydroxyalkyl A group or a nitro group,
The pharmaceutical composition according to claim 4. Y is a methylene group or a single bond optionally substituted with a group independently selected from an alkyl group and an oxo group;
A ¹ is a heterocyclic group or a single bond,
A ² may be substituted with an optionally substituted heterocyclic group, an optionally substituted alkoxy group, a halogen atom, an optionally substituted alkyl group, a cyano group, or 1 to 2 substituents. A good amino group or hydrogen atom,
B is an optionally substituted alkyl group, a halogen atom, a hydroxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkoxy group, an optionally substituted alkoxy group, an alkylsulfanyl group, An alkylsulfinyl group, an amino group optionally substituted with 1 to 2 substituents, and a heterocyclic group optionally substituted with 1 to 5 substituents independently selected from an alkylsulfonyl group;
R ¹ is

And
R ² is an amino group optionally substituted by 1 to 2 substituents, a halogen atom, an optionally substituted alkoxy group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group An oxy group substituted with an hydroxy group, an optionally substituted heterocyclic group, an optionally substituted homocyclic group, an optionally substituted homocyclic group, an substituted oxy group, substituted An optionally substituted alkyl group, a hydrogen atom, an optionally substituted alkylcarbonyl group, an optionally substituted alkoxycarbonyl group or a nitro group,
The pharmaceutical composition according to claim 5. The homocyclic group is a cycloalkyl group, a phenyl group, or a naphthyl group;
A heterocyclic group is a thienyl group, a furyl group, a pyrrolyl group, a pyrrolinyl group, an oxazolyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, an imidazolinyl group, an isoxazolyl group, an isothiazolyl group, an oxadiazolyl group, a furazanyl group, a thiadiazolyl group, a triazolyl group, Triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazopyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, oxazinyl group, thiazinyl group , Piperazinyl group, triazinyl group, oxatriazinyl group, pyridazinyl group, pyrazinyl group, benzofuranyl group, benzothiazolyl group, benzoxazolyl group, tetrazolopyri Dinyl group, triazolopyridazinyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, dihydroisoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, dihydroindolyl group, indolyl group, quinolidinyl Group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group, acridinyl group, phenanthridinyl group, chromanyl group, benzooxazinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, hexahydroase Pinyl group, imidazolidinyl group, oxazolidinyl group, tetrahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydrooxazinyl group, dihydropyrazoli Group, an imidazopyridyl group, dihydro pyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group, oxathiadiazolyl group, dihydrooxazolyl group or tetrahydroquinolyl group,
An optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkoxy group, a substituted An optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, a substituted Alkylsulfonyl group which may be substituted, amino group which may be substituted, sulfamoyl group which may be substituted, alkanoyl group which may be substituted, homocyclic group which may be substituted, Allocyclic group substituted oxy group, which may be substituted allocyclic group substituted carbonyl group, which may be substituted Good heterocyclic group, optionally substituted heterocyclic group-substituted oxy group, optionally substituted heterocyclic group-substituted carbonyl group, optionally substituted phenyl group, optionally substituted alkylsulfonyloxy group 1 to 5 groups, wherein the substituent of the optionally substituted alkynyl group or the optionally substituted alkylene group is independently selected from the group described below:
Cyano group; hydroxy group; nitro group; carboxyl group; oxo group; thioxo group; sulfo group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl A cycloalkyl group optionally substituted by a group; an alkoxycarbonyl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; A carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; Roxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, alkyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, An alkanoyl group optionally substituted by a mono- or di-alkylamino group, phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl An alkoxy group optionally substituted by a group; an aryl group optionally substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; Canoyloxy group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, alkylsulfanyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, An alkylsulfonyl group optionally substituted by an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group; a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group Alkylsulfinyl group optionally substituted by phenyl group or morpholinyl group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl Mono- or di-alkylsulfamoyl group which may be substituted with a benzene or morpholinyl group; amino group; hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group Or a mono- or di-alkylamino group optionally substituted by a morpholinyl group; substituted by a hydroxy group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a mono- or di-alkylamino group, a phenyl group or a morpholinyl group Mono- or di-alkylsulfamoylamino group which may be substituted; mono optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group - Di-alkylureido group; homocyclic group selected from cycloalkyl group, phenyl group, and naphthyl group; said homocyclic group-substituted oxy group; said homocyclic group-substituted carbonyl group; thienyl group, furyl group, pyrrolyl group , Pyrrolinyl group, oxazolyl group, thiazolyl group, pyrazolyl group, imidazolyl group, imidazolinyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, furazanyl group, thiadiazolyl group, triazolyl group, triazinyl group, triazolidinyl group, tetrazolyl group, pyridyl group, imidazo Pyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, oxazinyl group, thiazinyl group, piperazinyl group, tri Zinyl group, oxatriazinyl group, pyridazinyl group, pyrazinyl group, benzofuranyl group, benzothiazolyl group, benzoxazolyl group, tetrazolopyridazinyl group, triazolopyridazinyl group, benzoimidazolyl group, quinolyl group, isoquinolyl group Group, dihydroisoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, dihydroindolyl group, indolyl group, quinolidinyl group, naphthyridinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group , Acridinyl group, phenanthridinyl group, chromanyl group, benzoxazinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, hexahydroazepinyl group, imidazolidinyl group, oxazolidinyl group, teto Lahydrofuranyl group, dioxolanyl group, oxiranyl group, dihydropyrimidinyl group, oxazolinyl group, dihydrooxazinyl group, dihydropyrazolyl group, imidazopyridyl group, dihydropyrazinyl group, tetrahydroquinolyl group, benzothienyl group, dihydrooxazolyl group , A heterocyclic group selected from an oxathiadiazolyl group, a dihydrooxazolyl group and a tetrahydroquinolyl group; the heterocyclic group-substituted oxy group; the heterocyclic group-substituted carbonyl group;
And a group represented by the following formula:

Wherein X ¹ and X ³ each represent CH ₂ , NH, O, S, SO, or SO ₂ , and X ² and X ⁵ represent CH ₂ , O, S, SO, or SO ₂ , respectively. X ⁴ represents NH, O, S, SO, or SO ₂ , X ⁶ and X ⁷ each represent O or S, X ⁸ represents S or SO, n, o, p, q , And r each represent an integer of 1 to 4); further, each of the above groups may be further substituted with 1 to 3 substituents independently selected from the following group:
Halogen atom, carboxyl group, hydroxy group, cyano group, oxo group, thioxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group , Alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, alkoxycarbonyl group, benzyloxycarbonyl group, mono- or di-alkylamino group, mono- or di-alkylcarbamoyl group, mono- or di-alkylsulfamoyl group, An alkylsulfonyl group, and a tetrazolyl group,
The pharmaceutical composition according to claim 6. Y is a methylene group or a single bond,
A ¹ is a pyrimidinyl group, a tetrazolyl group or a single bond,
A ² is substituted with a mono- or di-alkylamino group which may be substituted with a carboxyl group, a piperidyl group which may be substituted with a carboxyl group, a morpholinyl group which may be substituted with a carboxyl group, or a carboxyl group. An optionally substituted alkoxy group, a halogen atom, an alkyl group optionally substituted with a carboxyl group, a hydrogen atom or a cyano group,
B is an isoquinolyl group, a tetrahydroquinolyl group, a quinolyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a dihydroindolyl group, an imidazolyl group, or an imidazolpyridyl group; where these heterocyclic groups are from the groups listed below It may be substituted with 1 to 5 independently selected substituents:
An oxo group; an alkoxy group optionally substituted with 1 to 3 halogen atoms; an alkyl group optionally substituted with 1 to 3 halogen atoms; a halogen atom; a hydroxy group; an alkylsulfanyl group; an alkylsulfinyl group And an amino group optionally substituted by 1 to 2 substituents independently selected from an alkyl group or an alkyl group substituted with a morpholinyl group,
R ¹ is independently selected from a hydrogen atom, an alkoxy group optionally substituted with a cyano group and 1 to 3 halogen atoms, and an alkyl group optionally substituted with 1 to 3 halogen atoms A benzyl group substituted with ~ 3 groups;
R ² is (a) alkyl group, alkoxyalkyl group, cycloalkylalkyl group, alkoxycarbonyl group, alkylcarbonyl group, alkylcarbamoyl group, carboxyalkyl group, carboxyalkyl-substituted cycloalkylalkyl group, hydroxyalkyl group, carboxyalkoxycarbonyl group , Carboxydihydrooxazolyl group, carboxyalkylcarbonyl group, phenylalkyl group, alkoxyalkoxycarbonyl group, alkoxyalkylcarbonyl group, piperidyl group-substituted alkyl group, carboxyalkyl-substituted piperidylalkyl group, and substituted with 1 to 3 halogen atoms It may be substituted with 1 to 2 groups independently selected from an alkyl group substituted with a phenyl group which may be substituted with 1 to 2 alkyl groups which may be substituted Amino groups;
Here, the alkyl group or alkoxy group may be further substituted with 1 to 5 groups independently selected from the following:
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A pyrrolidinylcarbonyl group optionally substituted with a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
(B) a halogen atom;
(C) an alkoxy group optionally substituted with a group selected from a carboxyl group, a cycloalkyl group and an alkoxy group;
Here, the cycloalkyl group or alkoxy group may be further substituted with 1 to 5 groups independently selected from the following:
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A pyrrolidinylcarbonyl group optionally substituted with a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
(D) a carbamoyl group optionally substituted with 1 to 2 substituents independently selected from an alkyl group and a carboxyalkyl group;
Here, the alkyl group may be further substituted with 1 to 5 groups independently selected from the following:
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A pyrrolidinylcarbonyl group optionally substituted with a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
(E) a hydroxy group;
(F) an oxy group substituted with a heterocyclic group selected from a pyrimidinyl group and a tetrahydropyranyl group;
(G) 1-2 pieces independently selected from a pyrimidinyl group, halogen atom, alkyl group, cyano group, mono- or di-alkylamino group, alkoxy group, phenyl group, carboxyl group, carbamoyl group and carboxyalkyl group A heterocyclic group selected from a morpholinyl group, piperidyl group, piperazinyl group, pyrazinyl group, tetrazolyl group, thienyl group, furyl group, dihydroisoquinolyl group, pyridyl group and pyrrolyl group, which may be substituted with a substituent;
Here, the alkoxy group or alkyl group may be further substituted with 1 to 5 groups independently selected from the following:
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A pyrrolidinylcarbonyl group optionally substituted with a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
(H) a phenyl group optionally substituted by 1 to 3 substituents independently selected from a halogen atom, alkyl and alkoxy;
Here, the alkoxy group or alkyl group may be further substituted with 1 to 5 groups independently selected from the following:
Halogen atom, cyano group, hydroxy group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (the mono- or di-alkylcarbamoyl group is a carboxyl group, alkoxycarbonyl group or hydroxy group) An alkoxy group (which may be substituted with a carboxyl group, a formyl group or a hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group. An aminosulfonyl group, an amino group, a carboxyl group or an alkoxy group, which may be substituted with a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, or a morpholinyl group. Mono- or di-alkylureido group which may be substituted, cycloalkyl group which may be substituted with carboxymethyl group, phenyl group which may be substituted with oxiranyl group, alkoxy group or carboxyl group, morpholinyl group, With a pyrrolidinyl group optionally substituted with an alkoxycarbonyl group or a carboxyl group, a pyrrolidinyl group optionally substituted with an alkoxycarbonylalkyl group or a carboxyalkyl group, a pyrrolidinyl group substituted with an oxo group, an alkoxycarbonyl group or a carboxyl group Piperidyl group which may be substituted, piperidyl group which may be substituted with alkoxycarbonylalkyl group or carboxyalkyl group, piperazinyl group which may be substituted with alkyl group, hexahydroa Pinyl group, pyrimidinyl group, pyridyl group, dioxolanyl group which may be substituted with alkyl group, oxadiazolyl group which may be substituted with oxo group, oxathiadiazolyl group which may be substituted with oxo group, carboxyl group A pyrrolidinylcarbonyl group optionally substituted with a piperidyloxy group optionally substituted with an alkyl group and a morpholinylcarbonyl group;
(I) an oxy group substituted with a cycloalkyl group;
(J) a hydroxyalkyl group; or (k) a nitro group;
The pharmaceutical composition according to claim 7. Y is a methylene group or a single bond,
A ¹ is a pyrimidinyl group, a tetrazolyl group or a single bond,
A ² is substituted with a mono- or di-alkylamino group which may be substituted with a carboxyl group, a piperidyl group which may be substituted with a carboxyl group, a morpholinyl group which may be substituted with a carboxyl group, or a carboxyl group. An optionally substituted alkoxy group, a halogen atom, an alkyl group optionally substituted with a carboxyl group, a hydrogen atom or a cyano group,
B is an isoquinolyl group, a tetrahydroquinolyl group, a quinolyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a dihydroindolyl group, an imidazolyl group or an imidazolopyridyl group; where these heterocyclic groups are independent of the groups listed below: May be substituted with 1 to 5 substituents selected from:
An oxo group; an alkoxy group optionally substituted with 1 to 3 halogen atoms; an alkyl group optionally substituted with 1 to 3 halogen atoms; a halogen atom; an alkylsulfanyl group; an alkylsulfinyl group; An amino group optionally substituted with 1 to 2 substituents independently selected from a group or an alkyl group substituted with a morpholinyl group,
R ¹ is

And
R ² is (a) alkyl group, alkoxyalkyl group, cycloalkylalkyl group, alkoxycarbonyl group, alkylcarbonyl group, alkylcarbamoyl group, carboxyalkyl group, carboxyalkyl-substituted cycloalkylalkyl group, hydroxyalkyl group, carboxyalkoxycarbonyl group , Carboxydihydrooxazolyl group, carboxyalkylcarbonyl group, phenylalkyl group, alkoxyalkoxycarbonyl group, alkoxyalkylcarbonyl group, piperidyl group-substituted alkyl group, carboxyalkyl-substituted piperidylalkyl group, and substituted with 1 to 3 halogen atoms It may be substituted with 1 to 2 groups independently selected from an alkyl group substituted with a phenyl group which may be substituted with 1 to 2 alkyl groups which may be substituted Amino groups;
(B) a halogen atom;
(C) an alkoxy group optionally substituted with a group selected from a carboxyl group, a cycloalkyl group and an alkoxy group;
(D) a carbamoyl group optionally substituted with 1 to 2 substituents independently selected from an alkyl group and a carboxyalkyl group;
(E) a hydroxy group;
(F) an oxy group substituted with a heterocyclic group selected from a pyrimidinyl group and a tetrahydropyranyl group;
(G) morpholinyl group, piperidyl group, pyrazinyl each optionally substituted by 1 to 3 substituents independently selected from alkyl group, halogen atom, phenyl group, alkoxy group, carboxyl group and carboxyalkyl group A heterocyclic group selected from a group, a dihydroisoquinolyl group, a pyridyl group, a pyrimidinyl group, a piperazinyl group, a tetrazolyl group and a pyrrolyl group;
(H) a phenyl group optionally substituted by 1 to 3 substituents independently selected from a halogen atom, alkyl and alkoxy;
(I) an oxy group substituted with a cycloalkyl group;
(J) a hydroxyalkyl group; or (k) a nitro group;
The pharmaceutical composition according to claim 8. Y is a methylene group;
A ¹ is a pyrimidinyl group,
A ² is an alkoxy group optionally substituted with a carboxyl group; a piperidyl group optionally substituted with a carboxyl group; substituted with 1 to 2 groups independently selected from a carboxyalkyl group and an alkyl group; An amino group; or an alkyl group substituted with a carboxyl group,
B is a pyrimidinyl group, a pyridyl group, a quinolyl group, a dihydroindolyl group, a pyrazolyl group, an isoquinolyl group, an imidazolyl group or an imidazolpyridyl group, wherein these heterocyclic groups are independently selected from the groups listed below: Optionally substituted with 5 substituents:
An oxo group; an alkoxy group optionally substituted with 1 to 3 halogen atoms; an alkyl group optionally substituted with 1 to 3 halogen atoms; a halogen atom; an alkylsulfanyl group; an alkylsulfinyl group; An amino group optionally substituted with 1 to 2 substituents independently selected from a group or an alkyl group substituted with a morpholinyl group,
R ¹ is

And
1 or ² R ² independently selected from (a) carboxyalkyl group, alkoxyalkyl group, hydroxyalkyl group, mono- or di-alkylaminoalkyl group, alkyl group, cycloalkylalkyl group and alkoxycarbonyl group An amino group optionally substituted by a group of
(B) an alkoxy group,
(C) a phenyl group which may be substituted with 1 to 2 substituents independently selected from alkyl and alkoxy;
(D) a pyrimidinyl group optionally substituted with 1 to 2 substituents selected from an alkoxy group and an alkyl group, or (e) substituted with 1 to 2 substituents selected from an alkoxy group and an alkyl group An optionally pyridyl group,
The pharmaceutical composition according to claim 9, wherein As an active ingredient, the formula (IA):

( ^Wherein A ^11A is an ^optionally substituted pyrimidin-2-yl group,
R ^1A and R ^1B are each independently a cyano group or an alkyl group that may be substituted with 1 to 3 halogen atoms,
Ring E is an optionally substituted heterocyclic group containing 1 to 2 nitrogen atoms)
Or a pharmacologically acceptable derivative thereof. As an active ingredient, the formula (IB):

( ^Wherein A ^21A represents an optionally substituted carbamoyl group, an optionally substituted homocyclic group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, a substituted Optionally substituted alkylsulfonyl group, optionally substituted alkyl group, nitro group, hydroxy group, cyano group, optionally substituted alkenyl group, optionally substituted heterocyclic group, optionally substituted A good alkoxy group, a halogen atom, an amino group optionally substituted with 1 to 2 substituents, a carboxyl group, or a hydrogen atom,
R ^1A is a cyano group or an alkyl group which may be substituted with 1 to 3 halogen atoms,
B ′ is an oxo group, a cyano group, a halogen atom, a hydroxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkoxy group, an optionally substituted heterocyclic group, an optionally substituted Alkylsulfanyl group which may be substituted, alkylsulfinyl group which may be substituted, alkylsulfonyl group which may be substituted, amino group which may be substituted with 1 to 2 substituents, alkyl which may be substituted A group, and optionally substituted with 1 to 3 groups independently selected from an optionally substituted alkoxy group,
D represents a phenyl group, a tetrazol-5-yl group, a pyrimidin-2-yl group, a pyrimidin-4-yl group, a pyrimidin-5-yl group, a pyrimidin-6-yl group, a pyridin-2-yl group, a pyridine- A 3-yl group, a pyridin-4-yl group, a pyridin-5-yl group, a pyridin-6-yl group, or a hydrogen atom;
D ′ is a halogen atom, an alkoxyalkyl group, an alkyl group substituted with 1 to 5 halogen atoms, an alkoxy group substituted with 1 to 5 halogen atoms, an alkenyl group, a carbamoyl group, a cycloalkyl group, mono -Or di-alkylaminoalkyl group, mono- or di-alkylaminoalkoxy group, carboxyl group, hydroxy group, cyano group, oxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinyl Alkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group, alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, alkoxycarbonyl group, benzyloxycarbonyl group, mono- or di-alkylamino group, mono- or di- Alkylcarbamoyl group, mono- or di-alkylsulfamoyl group, alkylsulfonyl group, tetrazolyl group, benzyloxyalkyl group, cycloalkylalkyl group, benzyloxy group, alkoxyalkoxy group, carboxyalkoxy group, carboxyalkenyl group, alkylcarbonyl A group independently selected from an amino group, a carboxyalkoxyalkyl group, a morpholinyl group, and a pyridylalkoxy group;
q ^A is an integer from 0 to 3,
formula:

But the following groups:

Is a group selected from
Or a pharmacologically acceptable derivative thereof. A ^21A is, from the group consisting of:
(A) a heterocyclic group selected from a piperidyl group and a morpholinyl group, each of which may be substituted with a substituent selected from a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, and an alkyl group;
(B) a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulfinyl group, a mono- or di-alkylamino group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group, and an alkoxy group An alkoxy group optionally substituted by:
(C) a halogen atom;
(D) Carboxyalkyl group, alkoxycarbonylalkyl group, alkylsulfonylalkyl group, alkylsulfinylalkyl group, hydroxyalkyl group, alkyl group, alkoxyalkyl group, and aminoalkyl optionally substituted by 1 to 2 alkyl groups An amino group optionally substituted by 1 to 2 substituents independently selected from the group;
(E) a hydrogen atom;
(F) a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulfinyl group, a mono- or di-alkylamino group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group, and an alkoxy group An alkyl group optionally substituted by:
(G) a carboxyl group;
(H) a carbamoyl group optionally substituted by a carboxyalkyl group;
(I) an alkenyl group optionally substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, an alkylsulfinyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group, and an alkoxy group;
(J) a morpholinyl group; and
(K) a piperidinyl group optionally substituted by a carboxyl group or a carboxyalkyl group;
Chosen from
B ′ is an oxo group, a halogen atom, an alkyl group which may be substituted with 1 to 3 halogen atoms, an alkoxy group which may be substituted with 1 to 3 halogen atoms, a cyano group, 1 to 3 Alkylsulfanyl group optionally substituted with 1 halogen atom, alkylsulfinyl group optionally substituted with 1 to 3 halogen atoms, amino group, alkoxyalkyl group, benzyloxy group, alkoxyalkoxy group, mono- Or independently selected from a di-alkylaminoalkoxy group, a mono- or di-alkylaminoalkyl group, a cycloalkyl group, a cycloalkoxy group, and an alkylsulfonyl group optionally substituted by 1 to 3 halogen atoms Optionally substituted with 1 to 3 groups,
The pharmaceutical composition according to claim 12. A ^21A is a morpholinyl group, a carboxyalkoxy group, an alkylsulfonylalkoxy group, a carboxyalkenyl group, a carboxyalkyl group, an alkoxycarbonylalkoxy group, an alkoxycarbonylalkyl group, or a carboxypiperidinyl group,
B ′ is independently selected from a halogen atom, an alkyl group which may be substituted with 1 to 3 halogen atoms, and an alkoxy group which may be substituted with 1 to 3 halogen atoms. May be substituted with
D ′ is a benzyloxyalkyl group, a halogen atom, a cycloalkylalkyl group, an alkyl group that may be substituted with 1 to 3 halogen atoms, and an alkoxy that may be substituted with 1 to 3 halogen atoms A group selected independently from the group;
formula:

But the following groups:

A group selected from
The pharmaceutical composition according to claim 13. A ^21A is a carboxyalkoxy group or a carboxypiperidinyl group,
D is a phenyl group;
D ′ is a group independently selected from a halogen atom, an alkoxy group, or an alkyl group,
The pharmaceutical composition according to claim 14. A ^21A is a carboxyalkoxy group,
1-3 groups independently selected from an alkyl group optionally substituted with 1 to 3 halogen atoms and an alkoxy group optionally substituted with 1 to 3 halogen atoms. May be replaced with
D is a phenyl group;
D ′ is a group independently selected from a halogen atom, an alkoxy group, or an alkyl group, and has the formula:

But the formula:

Is,
The pharmaceutical composition according to claim 14.   A pharmaceutical composition comprising a compound selected from any one of Production Examples 1 to 84 or a pharmaceutically acceptable derivative thereof as an active ingredient.   A pharmaceutical composition comprising a compound selected from any one of Production Examples 52, 54, 55, 57, 58, 60, 63, and 65, or a pharmaceutically acceptable derivative thereof, as an active ingredient.   A pharmaceutical composition comprising as an active ingredient a compound selected from any one of Production Examples 77 to 84, or a pharmaceutically acceptable derivative thereof.   A pharmaceutical composition comprising a compound selected from any one of Production Examples 1, 4, 5, 14, 21, and 23, or a pharmaceutically acceptable derivative thereof, as an active ingredient. As an active ingredient
4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy)- Butanoic acid,
4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy ) -Butanoic acid,
4- (2-{(3,5-bis-trifluoromethyl-benzyl)-[5-chloro-2- (cyclopropylmethyl-propyl-amino) -pyridin-3-ylmethyl] -amino} -pyrimidine-5 -Yloxy) -butanoic acid sodium salt,
1- (2-{(3,5-bis-trifluoromethyl-benzyl)-[8-chloro-2- (cyclopropylmethyl-propyl-amino) -quinolin-3-ylmethyl] -amino} -pyrimidine-5 -Yl) -piperazine-4-carboxylic acid, and 4- (2-{(3-cyano-5-trifluoromethyl-benzyl)-[2- (5-isopropyl-2-methoxy-phenyl) -8-methyl A pharmaceutical composition comprising a compound selected from the group consisting of -quinolin-3-ylmethyl] -amino} -pyrimidin-5-yloxy) -butyric acid, or a pharmaceutically acceptable derivative thereof.   The pharmaceutical composition according to any one of claims 1 to 21, which is a therapeutic or prophylactic agent for a disease state in which inhibition of cholesteryl ester transfer protein is beneficial.   Pathology is atherosclerosis, arteriosclerosis, metabolic syndrome, peripheral vascular disease, dyslipidemia, high beta lipoproteinemia, low alpha lipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial high Cholesterolemia, cardiovascular disorder, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cerebral infarction, stroke, diabetes, diabetic vascular complications, thrombotic disease , Obesity, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, renal vascular disease, kidney disease, visceral vascular disease, intravascular coagulation, fatty liver, steatohepatitis, inflammatory disease, Autoimmune disorders and other systemic disease indications, immune function modulation, lung disease, antioxidants, sexual dysfunction, cognitive impairment, schistosomiasis, cancer, xanthoma regression, Alzheimer's disease And a condition selected from endotoxemia, pharmaceutical composition according to any one of claims 1 to 22.