Title of Invention	TRISUBSTITUTED AMINE COMPOUNDS AS INHIBITORS OF CHOLESTERYL ESTER TRANSFER PROTEIN CETP
Abstract	The present invention relates to a compound of the general formula wherein, Y is a methylene group, and the like; A is an optionally substituted heterocyclic group, and the like; B is an optionally substituted phenyl group, and the like; R1 is an optionally substituted alkyl group, and the like; and R2 is an optionally substituted amino group, and the like; or a pharmaceutically acceptable derivative thereof, which has an inhibitory activity against cholesteryl ester transfer protein (CETP), thereby being useful for prophylaxis and/or treatment of arteriosclerotic diseases, hyperlipemia or dyslipidemia, and the like.

Title of Invention

TRISUBSTITUTED AMINE COMPOUNDS AS INHIBITORS OF CHOLESTERYL ESTER TRANSFER PROTEIN CETP

Abstract

The present invention relates to a compound of the general formula wherein, Y is a methylene group, and the like; A is an optionally substituted heterocyclic group, and the like; B is an optionally substituted phenyl group, and the like; R1 is an optionally substituted alkyl group, and the like; and R2 is an optionally substituted amino group, and the like; or a pharmaceutically acceptable derivative thereof, which has an inhibitory activity against cholesteryl ester transfer protein (CETP), thereby being useful for prophylaxis and/or treatment of arteriosclerotic diseases, hyperlipemia or dyslipidemia, and the like.

Full Text	DESCRIPTION TRISUBSTITUTED AMINE COMPOUND TECHNICAL FIELD The present invention relates to a compound having an inhibitory activity against cholesteryl ester transfer protein (CETP) and showing an activity of increasing HDL cholesterol level and an activity of decreasing LDL cholesterol level, thereby being useful for prophylaxis and/or treatment of arteriosclerotic diseases, hyperlipemia or dysllpidemia. BACKGROUND ART Hypercholesterolemia, especially high serum level of low-density lipoprotein (LDL) cholesterol, has been revealed to be a risk factor of arteriosclerotic diseases by a number of epidemiological surveys. Actually, drugs capable of decreasing LDL cholesterol level such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been used with the aim of preventing coronary artery diseases, and demonstrated to have some benefits in many large scale clinical tests. However, their preventive effect on coronary diseases is limited to some extent, and is not satisfactory enough yet. Recently, low serum level of high density lipoprotein (HDL) cholesterol has been revealed to be a potent risk factor of arteriosclerotic diseases by a number of epidemiological surveys and large scale clinical tests. HDL is known to have various antiarteriosclerotic effects and attention is focused on the potentiality of drugs increasing HDL cholesterol level as a means for prevention or treatment of arteriosclerotic diseases. However, there are no drugs that can be used in a satisfactory manner for this purpose. Fibrates and HMG-CoA reductase inhibitors have only low activity of increasing HDL cholesterol level; nicotinic acid derivatives can significantly increase HDL cholesterol level, but have serious toleration issues. Accordingly, there has been a demand for a well-tolerated agent which can significantly elevate HDL cholesterol level, thereby preventing or reversing the progression of atherosclerosis. It is known that many proteins are involved in the regulation mechanism for catabolism of various lipoproteins. Among them, the role of cholesteryl ester transfer protein (CETP) became to draw attention. CETP is a protein responsible for transfer of cholesteryl ester (CE) and triglyceride between lipoproteins, and mediate the transfer of CE from HDL to LDL or to very low density lipoprotein (VLDL). Accordingly, CETP activity affects greatly the lipid composition in lipoprotein particles. For example, it is known that administration of an active neutralizing monoclonal antibody against CETP to rabbit or hamster elevates HDL cholesterol level and lower LDL cholesterol level. Furthermore, human being having decreased or eliminated CETP activity due to gene mutation shows raised blood HDL cholesterol level and lowered blood LDL cholesterol level. On the other hand, it is known that transgenic mice and rats made to express CETP show lowered HDL cholesterol level and raised LDL cholesterol level. Thus, it is considered that CETP greatly contribute to the regulation of serum lipids, and thereby affecting the change of serum lipid profile such as decrease of HDL cholesterol level and increase of LDL cholesterol level. Accordingly, it is assumed that a high value of CETP activity would induce arteriosclerosis. In fact, CETP activity varies depending on animal species. It is known that, arteriosclerotic lesions are readily formed by cholesterol loading in animals with high CETP activity such as rabbits, whereas such lesions hardly occur in animals with low CETP activity such as rats. Furthermore, it is confirmed that continuous suppressioii of CETP activity by administration of antisense oligodeoxynuclotide resulted in effects such as increase of blood HDL cholesterol level and reduction in arteriosclerotic lesions in cholesterol-fed rabbits. The above findings indicate that CETP activity is in negative correlation with HDL cholesterol, and that inhibition of CETP activity would decrease the degree of risk for arteriosclerotic diseases. It is therefore expected that compounds capable of inhibiting CETP activity can block the transfer of cholesterol from HDL to LDL or VLDL, and thereby increasing HDL cholesterol that tends to prevent arteriosclerosis while lowering LDL cholesterol that tends to promote arteriosclerosis. In this way, such compounds can serve as a useful preventive or therapeutic agent for arteriosclerotic diseases, hyperlipemia or dyslipidemia and provide effective medical treatment for the first time. Examples of compounds having CETP inhibitory activity include tetrahydroquinoline derivatives. See, PCT International Publication WOOO/17164 pamphlet, PCT International Publication WOOO/17165 pamphlet and PCT International Publication WOOO/17166 pamphlet. However, these compounds have defects. That is, they are poorly soluble in water and cannot be absorbed enough in vivo, a sufficient blood level for taking medicinal effect can hardly be achieved even when administered as an ordinary formulation for oral administration. See, WO03/63868. Accordingly, it has been demanded to find a novel compound which eliminates the above-mentioned defects and intensive studies have been done on dibenzylamine type compounds, and the like. See, PCT International Publication WO05/100298 pamphlet, PCT International Publication WO04/020393 pamphlet, PCT International Publication WO 06/056854 pamphlet and JP 2003-221376 A. DISCLOSURE OF INVENTION The present invention provides compounds having an excellent inhibitory activity against CETP, thereby useful for prophylaxis and/or treatment of arteriosclerotic diseases, hyperlipemia or dyslipidemia. The present inventors have intensively studied in order to achieve the above-mentioned objects, and have found a compound having an inhibitory activity against CETP and showing an activity of increasing HDL cholesterol level and an activity of decreasing LDL cholesterol level, and have accomplished the present invention. BEST MODES FOR CARRYING OUT THE INVENTION That is, the present invention provides the following embodiments: 1. A compound of the general formula (1): ) wherein, Y is a methylene group optionally substituted by a substituent(s) selected from an alkyl group and an oxo group, or a single bond; A is (i) a group selected from 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, an optionally substituted 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, 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, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxy group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxy group substituted by optionally substituted heterocyclic group, and a carbonyl group substituted by optionally substituted heterocyclic group; (ii) a homocyclic group optionally substituted by 1 to 5 substituents selected independently from the groups as defined above in (i); or (iii) a heterocyclic group optionally substituted by 1 to 5 substituents selected independently from the groups as defined above in (i); B is a phenyl group optionally substituted by 1 to 4 substituents selected independently from the following groups: an optionally substituted allqnyl group, a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a sulfo group, an optionally substituted alkyl group, an optionally substituted cycloalbyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkojQ' group, am optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionally substituted all^^lsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an o^ group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxy group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, and an all^lene group; wherein said alkylene group may have 1 to 3 heteroatoms selected independentiy from oxygen, sulfur and nitrogen atoms and further optionally may have a substituent(st; Ri is a hydrogen atom or an optionally substituted alkyl group; wherein the alkyl group further may optionally be substituted by a substituent(s) selected from an optionally substituted homocyclic group and an optionally substituted heterocyclic group; R2 is a group selected from an optionally substituted allqaiyl 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, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalko?^ group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionsdly substituted allcylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxo group substituted by optionally substituted heterocyclic group, and a carbonyl group substituted by optionally substituted heterocyclic group, or a pharmaceutically acceptable derivative thereof. 2. The compound of the above embodiment 1 wherein the homocyclic group is a cycloall^l group, a phenyl group or a naphthyl group; the heterocyclic group is a thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl, tetrazolyl, pjoidyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl, TOorpholinyl, triazinyl, pyrroUdinyi, piperidyl, pyranyl, tetrahydropyrsinyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, p5Tazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnoiinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl, naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidazolidinyl, oxazoiidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dJhydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropjo-azolyl, iijiidazopyridyl, dihydropjn-azinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl or tetrahydroquinolyl group; a substituent(s) for 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, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted all^lsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic groxip, an oxo group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted alkylsulfonyloxy group, an optionally substituted alkynyl group or an optionally substituted alkylene group is/are 1 to 5 groups selected independentiy from the following groups: a halogen atom; a cyano group; a hydroxy group; a nitro group; a carboxyl group; an oxo group; a thioxo group; a sulfo group; a cycloalkyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoxycarbonyl group optionally substituted by hydrojQ' group, halogen atom, carboxyl group, alko:^carbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an aUcanoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyloxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-all^lamino group, phenyl group or morpholinyl group; an alkylsuKanyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkylsulfonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-all^'laniino group, phenyl group or morpholinyl group; an alkylsulfinyl group optionally substituted by hydro?^ group, halogen atom, carbojQ'l group, alkoxycarbonyl group, mono- or di-allQ'laniino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamolyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an amino group; a mono- or di-alkylamino group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoJQ^carbonyl group, mono- or di-allcylamino group, phenyl group or morpholinyl group; a mono- or di-allQ'lsulfamoylamino group optionally substituted by hydroxy group, halogen atom, carbojcyl group, alkoJ^carbonyl group, mono- or di-all^lamino group, phenyl group or morpholinyl group; a mono- or di-alkylureido group optionally substituted by hydroxy group, halogen atom, carbo3cyl group, aUcoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a homocyclic group selected from a cycloalkyl group, a phenyl group and a naphthyi group; an o3ty group substituted by the homocyclic group as defined above; a carbonyl group substituted by the homocyclic group as defined above; a heterocyclic group selected from a thienyl, furyl, pyrrolyl, P5TTolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, trieizolyl, triazinyl, triazolidinyl, tetrazolyl, pyridyl, imidazopjTidyl, p5Timidinyl, thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl, benzofiiiyl, benzothiazolyl, benzoxazolyl, tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyi, cinnolinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl, naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups; an oxy group substituted by the heterocyclic group as defined above; a carbonyl group substituted by the heterocyclic group as defined wherein X^ and X3 are each independently CH2, NH, O, S, SO or SO2; X2 and X5 are each independently CH2, O, S, SO or SO2; X"* is NH, O, S, SO or SO2; X6 and X^ are each independently O or S; X^ is S or SO; and n, 0, p, q and r are each independently an integer of 1 to 4, and further each of the above groups may optionally be substituted by 1 to 3 substituents selected from the following groups: halogen atom, carboxyl group, hydroxy group, cyano group, 0x0 group, thioxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group, alkoxyalkanoyl group, alkojcy group, phenylalko)^ group, alkoxycarbonyl group, benzyloxycarbonyl group, mono- or di-alkylamino group, mono- or di- alkylcarbamoyl group, mono- or di-all^^lsulfamoyl group, alkylsulfonyl group and tetrazolyl group; or a pharmaceutically acceptable derivative thereof. 3. The compound of the above embodiment 2 wherein A is a group of a formula: -A1-A2; wherein Ai is a phenyl, naphthyl, pyrimidinyl, pyridazinyl, pyridyl, triazolyl. tetrazolyl, oxadiazolyl, dihydropyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, dihydrooxazinyl, imidazolyl, pyrazolyl or dihydropyrazinyl group; A2 is a carboxyl group; a cyano group; a nitro group; an alkyl group optionally substituted by a group selected from a hydroxy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkoxy group, a phenylalkoxy group, a hydrojQ^alkoxy group, a carboxyalkoxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, an oxiranyl group, a dialkyldioxolanyl group, a p3TTolidinyl group optionally substituted by carboxyl group, a piperidyl group optionally substituted by carbojQ'l group, a piperazinyl group optionally substituted by alkyl group, and a morpholinyl group; an alkenyl group optionally substituted by carbo^l group; an alkoxy group optionally substituted by a group selected from a hydrojcy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkoxy group, a phenylalkoxy group, a hydroxyalkoxy group, a carboxyalkoxy group, an all^lsulfanyl group, an eilkylsulfonyl group, an aUQ^lsulfinyl group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, an oxiranyl group, a dialkyldioxolanyl group, a pjTrolidinyl group optionally substituted by carboxyl group, a piperidyl group optionally substituted by carboxyl group, a piperazinyl group optionally substituted by alkyl group, and a morpholinyl group; an alkoxycarbonyl group; a hydroxycarbamimidoyl group; an alkylsulfanyl group; an alkylsulfonyl group optionally substituted by carboxyl group; a mono- or di-alkylamino group optionally substituted by hydroxy group, carboxyl group, alko:^ group or mono- or di-alkylamino group; a morpholinyl group optionally substituted by carboxyl group, alkyl group, carboxyalkyl group or alkoxycarbonyl group; an optionally oxidized thiomorpholinyl group; a piperazinyl group optionally substituted by a group selected from an alkyl group, alkanoyl group and hydroxyalkanoyl group; a pyrrolidinyl group optionally substituted by carboxyl group, alkyl group, carbojtyalkyl group or alkoxycarbonyl group; a piperidyl group optionally substituted by carboxyl group, alkyl group, carboxyall^l group or alkoxycarbonyl group; a tetrazolyl group optionally substituted by alkyl group, hydroxyall^l group, carboxyalkyl group or morpholinylall^l group; an oxodihydrooxadiazolyl group; a p3Tiinidinyl group; or a tetrahydropyranyl group; Ri is a group of a formula: -R11-R12, wherein Rn is an alkylene group; R12 is a substituent(s) selected from a phenyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, thienyl, triazolyl, tetrazolyl, oxadiazolyl, dihydropyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, dlhydrooxazinyl, dihydropyra^inyl and pjTazolyl group; wherein said substituent(s) may optionally be substituted by 1 to 4 substituents selected independently from halogen atom, carboxyl group, alkoj^carbonyl group, carbamoyl group, mono- or di-alkyl carbamoyl group, alkyl group, alkoxy group, hydroxy group, nitro group, cyano group, amino group, mono- or di-alkylamino group, alkanoyl group, alkylsulfanyl group, tetrazolyl group and dihydrooxazolyl group; and further each of said alkyl group, alkoxy group, mono- or di-alkylamino group, mono- or di-alkylcarbamoyl group, alkanoyl group and alkylsulfanyl group independentiy may optionally be substituted by 1 to 5 substituents selected independently from halogen atom, hydroxy group, alkoxy group, amino group, morpholinyl group, piperidyl group, p3aTolidinyl group, piperazinyl group, alkylpiperazinyl group and alkanoylpiperazinyl group; R2 is a halogen atom; a hydroxy group; a cyano group; a nitro group; a carboxyl group; a sulfo group; a cycloalkyl group optionally substituted by carboxyl group or alkoxycarbonyl group; an alkyl group optionally substituted by a group selected from a halogen atom, a cyano group, a hydro?^ group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a mono- or di-allcylcarbainoyl group, an alkoxy group (said alkoxy group may optionally be substituted by phenyl group, carboxyl group or hydroxy group), an aJkanoyl group, an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsuifinyl group, an amino, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di- alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, an oxiranyl group, a dioxolanyl group optionally substituted by alkyl group, pyrrolldinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a morpholinyl group, and a piperidyloxy group optionally substituted by alkyl group; 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 by carboxyl group; an alko^ group optionally substituted by a group selected from a halogen atom, a cyano group, a hydros^ group, a carboxyl group, an alkoxycarhanyl group, a tetrazolyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carboj^l graup, alkoxycarbonyl group or hydroxy group), an aOcoxy group (said alkoxy group may optionally be substituted by carboj^l group, formyl group or hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an aikylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carbojqTnethyl group, an oxiranyl group, a phenyl group optionaily substituted by alkoxy group or carboxyl group, a morpholinyl group, a pjTTolidinyl group optionally substituted by alkoxycarbonyl group or carboj^l group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a pyrrolidinyl group optionally substituted by oxo group, a piperidyl group optionally substituted by edkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a pipera2inyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a p3rrimidinyl group, a pjn-idyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidylo;^^ group optionally substituted by alkyl group and a morpholinylcarbonyl group; an alkoxycarbonyl group optionally substituted by phenyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by a group selected from a carboj^l group, a morpholinyl group and an alkoxy group; a hydroxycarbamim.idoyl; an alkylsulfanyl group optionally substituted by a group selected from hydroxy group, carhoxyl group and mono- or di-aJkylcarbamoy] group; an alkylsuliinyl group; an all^lsulfonyl group optionally substituted by a group selected from hydroxy group, carboxyl group, alkoscycarbonyl group and mono- or di-alkylcarbamoyl group; an amino group; a mono- or di-alkylamino group optionally substituted by a group selected from a hydrogen atom, a cyano group, a hydroxy group, a carboxyl group, an alko^carbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyi group (said mono- or di-aikyicarbamoyl group may optionally be substituted by carhoxyl group, alkoxycarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino optionally substituted by carboj^I group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by eilkoxy group or carboj^l group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylall^] or carboxyalkyl group, a pyrrolidinyl group substituted by oxo group, a piperidyl group optionadly substituted by sdkoxycarbonyl group or ceirboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optioneilly substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a morpholinylcarbonyl group; an alkanoylamino group optionally substituted by a group selected from hydroxy group, alkoxy group, carboxyl group and amino group; a mono- or di-alkylcarbamoylamino group optionally substituted by alkoxy group; a morpholinylcarbonylamino group; a sulfamolyl group; a mono- or di-allQrlsuIfamolyl group; an alkanoyl group optionally substituted by a group selected from hydroxy group, carbojQrl group, alkoxycarbonyl group, alkoxy group, mono- or di- alkylamino group and morpholinyl group; or a cyclic group selected from a cycloall^l, phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyrroUnyl, oxazolyl, thiazolyl, pjTazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazoHdinyl, tetrazolyl, p3Tidyl, imidazopyridyl, pyrimidinyl, thiomorphoUnyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, pjoidazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolopyridazinyl, triazolop3n-idazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinoHzinyl, naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidazolidinyl, oxazolidinyl, tetrahydrofurainyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropjTazolyl, imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups; wherein said cyclic group may optionally be substituted by the following groups: a halogen atom, an alkojQ'allq'l group, an allQ'l group optionally substituted by 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyi group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, a cyano group, an oxo group, an alkyl group, a hydroxyallcyl group, an alkoxycarbonylalkyl group, a carboxyallQ'l group, a morpholinylalkyl group, a phenylalkyl group, an alkanoyl group, a hydroj^alkanoyl group, an alkoxyalkanoyl group, an alkoxy group, a phenylalkoxy group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a mono- or di-all^lamino group, a mono- or di-alkylcarbamoyl group, a mono- or di-alkylsulfamolyl group, an allcylsulfonyl group and a tetrazolyl group; wherein the substituents defined as above may further be substituted by a substituent(s) selected from the following groups: a halogen atom, an alkoj^aZkyl group, an alkyl group optionally substituted by 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, a cyano group, an oxo group, an aUcyl group, a hydroxyalkyl group, an alkoxycarbonylall^l group, a carboxyalkyl group, a morpholinylalkyl group, a phenylalkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkoxyalkanoyl group, an alkoxy group, a phenylalkoxy group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a mono- or di-alkylamino group, a mono- or di-alkylcarbamoyl group, a mono- or di-alkylsulfamolyl group, an alkylsulfonyl group and a tetrazolyl group, or a pharmaceutically acceptable derivative thereof. 4. The compound of the above embodiment 1 wherein Y is a methylene group optionally substituted by a substituent{s) selected from an all^l group and an oxo group, or a single bond; A is a group of a formula: -A1-A2; wherein A^ is a heterocyclic group or a homocyclic group; A2 is an optionally substituted homocyclic group, an optionally substituted allq^lsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted allcylsulfonyl group, an optionally substituted alkyl group, a nitro group, a hydroxy group, a cyano group, an optionally substituted alkenyl group, an optionally substituted heterocyclic group, a substituted alkoxy group, a halogen atom, an amino group substituted by 1 to 2 substituents, or a hydrogen atom; B is a phenyl group optionally substituted by 1 to 4 substituents selected independently from a cyano group, a halogen atom, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfmyl group, an optionally substituted alkylsulfonyl group, an amino group substituted by 1 to 2 substituents, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted cycloalkoxy group, a carboxyl group, an optionally substituted cycloalkyl group, an optionally substituted carbeunoyl group, an optionally substituted alkyl group, and an optionally substituted alkoxy group; Ri is a hydrogen atom, an ailkyl group substituted by a heterocyclic group or an alkyl group substituted by a homocyclic group; wherein said heterocyclic group, homocyclic group or alkyl group may further have a substituent(s); R2 is an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted all^lsulfonyl group, a cyano group, an optionally substituted alkenyl group, an amino group optionally substituted by 1 to 2 substituents, a halogen atom^, an optionally substituted alko?^ group, an optionally substituted carbamoyl group, an oxy group optionally substituted by optionally substituted heterocyclic group, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted homocyclic group, an oxo group optionally substituted by optionally substituted homocycUc group, an optionally substituted alkyl group or a nitro group; provided that when Y is a methylene group and A^ is a halogen atom, a hydrogen atom, a nitro group, a hydroxy group or a cyano group, then R^ is not an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkoj^ group, or an amino group optionally substituted by 1 to 2 substituents, or a pharmaceutically acceptable derivative thereof. 5. The compound of the above embodiment 4 wherein Y is a methylene group optionally substituted by a substituent(s) selected from an alkyl group and an oxo group; Ai is a heterocyclic group; A2 is an optionally substituted heterocyclic group, an optionally substituted alkyl group, a substituted alkoxy group, a halogen atom, an amino group optionally substituted by 1 to 2 substituents, or a hydrogen atom; B is a phenyl group optionally substituted by 1 to 4 groups selected independently from a cyano group, a halogen atom, a hydroxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkoxy group, an optionally substituted piperidyl group, a cycloalkyl group, a cycloalkoxy group, an optionally substituted alkyl group and an optionally substituted alkoxy group; Ri is a hydrogen atom, or an alkyl group substituted by a phenyl group that is substituted by 1 to 2 groups selected independently from an alkoxy group optionally substituted by 1 to 3 halogen atoms, an alkyl group optionally substituted by 1 to 3 halogen atoms and a cyano group; R2 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 oxy group substituted by optionally substituted heterocyclic group, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted horaocyclic group, an oxy group substituted by optionally substituted homocyclic group, a hydroj^alkyl group or a nitro group, or a pharmaceutically acceptable derivative thereof. 6. The compound of the above embodiment 5 wherein the homocyclic group is a cycloalkyl group, a phenyl group or a naphthyl group; the heterocyclic group is a thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl, tetrazolyl, pj^idyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl, thiop3^anyl, oxadinyl, thJadinyl, piperazinyl, triazinyl, oxotriazinyl, pjT-idazinyl, pjTazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl, naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropyrazolyl, imidazopjTidyl, dihydrop5T-azinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl or tetrahydroquinolyl group; a substituent(s) for an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloeilkoxy group, 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, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxo group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted alkylsulfonyloxy group, an optionally substituted alkynyl group or an optionally substituted aUcylene group is/are 1 to 5 groups selected independently from the following groups: a halogen atom; a cyano group; a hydroxy group; a nitro group; a carboxyl group; an oxo group; a thioxo group; a sulfo group; a cycloalkyi group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, m.ono- or di-ajkylamino group, phenyl group or morpholinyl group; an alkoxycarbonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoj^ group optionally substituted by hydroicy group, halogen atom, carboxyl group, alkoT^carbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyloxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-aU^lamino group, phenyl group or morpholinyl group; an aikylsulfanyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an aHQflsulfonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoj^carbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkylsulfinyl group optionally substituted by hydroxy group, halogen atom^, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamolyl group optionally substituted by hydroscy group, halogen atom, carboJ^l group, alkojcycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an amino group; a mono- or di-alkylamino group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamoylamino group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylureido group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a homocycUc group selected from a cycloalkyl group, a phenyl group and a naphthyl group; an oxy group substituted by the homocycUc group as defined above; a carbonyl group substituted by the homocyclic group as defined above; a heterocyclic group selected from a thienyl, furyl, pyrrolyl, pyrroliny], oxazolyl, thia^olyl, pyrazolyl, imidazolyl, imidazolinyl, Jsoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl, tetrazolyl, pyridyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, pjnrolidinyl, piperidyl, pyranyl. tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl, naphthjTidinyl, purinyl, pteridinyl, dtbenzofuranyl, benzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxasMlinyl, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropjrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups; an oxy group substituted by the heterocyclic group as defined above; a carbonyl group substituted by the heterocyclic group as defined wherein X^ and X^ are each independently CH2, NH, O, S, SO or SO2; X^ and X5 are each independently CH2, O, S, SO or SO2; X-^ is NH, O, S, SO or SOa; X& and X^ are each independently O or S; X^ is S or SO; and n, o, p, q and r are each independently an integer of 1 to 4, and further wherein each of the above groups may optionally be substituted by 1 to 3 substituents selected from the following groups: halogen atom, carboxyl group, hydroxy group, cyano group, oxo group, thioxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyall^l group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group, alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, alkoxycarbonyl group, benzyloxyceirbonyl group, mono- or di-alkylaxnino group, mono- or di-alkylcarbamoyl group, mono- or di-allq^lsulfamoyl group, alkylsulfonyl group and tetrazolyl group; or a pharmaceutically acceptable derivative thereof. 7. The compound of the above embodiment 6 wherein A^ is a pyrimidinyl group or a pyridyl group; A^ is (a) a heterocyclic group selected from a piperidy] group and a morpholinyl group, respectively optionally substituted by a substituent(s) selected from a carboxyl group, a carbojcyalkyl group and an alkyl group; (b) aji alkoxy group substituted by a group selected from a carboxyl group, a hydroxy group, an alkojcy group and a cyano group; (c) a halogen atom; (d) an amino group optionally substituted by 1 to 2 substituents independently selected from a carboxyalkyl group, a hydroxyalkyl group, an aUcyl group, an alkoxyall^l group and an aminoalkyl group optionally substituted by 1 to 2 all^l groups; (e) a hydrogen atom; B is a phenyl group optionally substituted by 1 to 4 groups selected independently from halogen atom, hydroxy group, alkyl group optionally substituted by 1 to 3 halogen atoms and alkoxy group optionally substituted by 1 to 3 halogen atoms; Ri is a hydrogen atom, or a benzyl group substituted by 1 to 3 groups selected independently from an alkoxy group optionally substituted by 1 to 3 halogen atoms, an alkyl group optionally substituted by 1 to 3 halogen atoms and a cyano group; R2 is (a) an amino group optionally substituted by 1 to 2 groups independently selected from an alkyl group, an alkoxyalkyl group, a cycloalkylalkyl group, an alko^tycarbonyl group, an alkylcarbonyl group, an alkylcarbamoyl group, a carbojQ^alkyl group, a cycloalkylalkyl group substituted by carboxyalkyl group, a hydrojq'all^I group, a carboxyalkoxycarbonyl group, a carbo^dihydrooxazolyl group, a carboxyalkylcarbonyl group, a phenylalkyl group, an alkoxyalkoxycarbonyl group, an alkoxyalkylcarbonyl group, an alkyl group substituted by piperidyl group, a piperidylalkyl group substituted by carboxyalkyl group, and an alkyl group substituted by phenyl that is optionally substituted by 1 to 2 alkyl groups (said alkyl group may optionally substituted by 1 to 3 halogen atoms); wherein said all^l group or alkoxy group may further optionally be substituted by 1 to 5 groups selected independently from the following groups: a halogen atom, a cyano group, a hydroj^ group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group {said mono- or di-alkylcarbamoyl group may optionally be substituted by carboxyl group, alkoxycarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxy group, an all^lsulfeinyl group, an allq^lsulfonyl group, an alkylsulfmyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di-allqrlsulfainoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoj^ group or carboJ^l group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkojQrcarbonylalkyl group or carboxyalkyl group, a pyrrolidinyl group optionally substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pjTimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by all^l group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by aUcyl group and a morpholinylcarbonyl group; (b) a halogen atom; (c) an alkoxy optionally substituted by a group selected from carboxyl group, cycloalkyl group and alkoxy group; wherein said cycloalkyl group or alkoxy group may optionally be substituted by 1 to 5 groups selected independently from the following groups: a halogen atom, a cyano group, a hydros^ group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-aJkylcarbamoyI group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carboxyl group, alko^Q'carbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carbojQ'l group, formyl group or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alk/lureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyi group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrroUdinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperidyl group optionally substituted by oxo group, a piperidyl group optionally substituted by aUcoxycarobonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alky] group and a morpholinylcarbonyl group; (d) a carbamoyl group optionally substituted by 1 to 2 substituents selected independently from alkyl group and carboityalkyl group, wherein said all^l group may optionally be substituted by 1 to 5 groups selected independently from the following groups: a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may be substituted by carbojcyl, alkoxycarbonyl or hydroxy group), an alkoxy group (said alkoxy group may be substituted by carboxyl, formyl or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyJ group, an alkylsulfmy] group, an amincsulfonyl group, an amino group, a mono- or di-allQ'lamino optionally substituted by carboxyl or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxjmiethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy or carboxyl group, a morpholiny] group, a pyrroMiny] optionally substituted by alkoxycarhonyl or carboxyl group, a pyrrolidinyl optionally substituted by alkoxycarbonylalkyl or carboxyalkyl group, a pyrrolidinyl substituted by oxo group, a piperidyl optionally substituted by alkoscycarbonyl or carboxyl cup, a piperidyl optionally substituted by alkoxycarbonylalkyl or irboxyalkyl group, a piperazinyl optionally substituted by alkyl group, a ixahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolany oup optionally substituted by alkyl group, an oxadiazolyl group Jtionedly substituted by oxo group, an oxathiadiazolyl group optionally ibstituted by oxo group, a pyrroUdinylcarbonyl group optionally ibstituted by carboxyl group, a piperidyloxy group optionally substituted f alkyl group and a morpholinylcairbonyl group; (e) a hydrojo^ group; (f) an oxy group substituted by a heterocyclic group selected from ^midiny] group and tetrahydropyranyl group; (g) a heterocyclic group selected from a morpholinyl, pyrimidinyl, iperidyl, piperazinyl, pyrazinyl, tetrazolyl, thienyl, fury, dihydroisoquinolyl, yiidyl and pyrrolyl group, which are each optionally substituted by 1 to 3 abstituents selected independently from pjoimidinyl group, alkyl group, alogen atom, cyano group, mono- or di-alkylamino group, alkoxy group, henyl group, carbojQrl group, carbamoyl group and carboxyalkyl group; herein said alkoxy group or alkyl group may optionally be substituted by to 5 groups selected independently from the following groups: a halogen atom, a cyano group, a hydroxy group, a carboj^l group, n alkoxycarhonyl group, a tetrazolyl group, a carbamoyl group, a mono-r di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may ptionaliy be substituted by carboj^l group, alkoxycarhonyl group or ydroxy group), an alkoxy group (said alkoxy group may optionally be ubstituted by carboxyl group, formyl group or hydroxy group), an Ikanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoicy group or carboxyl group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a p57rrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a pyrrolidinyl group substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carbojq'l group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolany] group optionally substituted by alky] group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a phenyl group optionally substituted by morpholinyl group; (h) a phenyl group optionally substituted by 1 to 3 substituents selected independently from halogen atom, alkyl group and alkoxy group; wherein said alkoxy group or alkyl group may further optionally be substituted by 1 to 5 groups selected independently from the following groups: a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group (said mono- or di-all^lcarbamoyl group may optionally be substituted by carboxyl group, alkoxycarbonyl group or hydroxy group), an alkoj^ group (said alko^Q^ group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an gimino group, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrroUdinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrroUdinyl group optionally substituted by alkojQ^carbonylallq'l group, a pyrroUdinyl group substituted by oxo group, a piperidyl group optionaUy substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylall^l group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionaUy substituted by alkyl group, an oxadiazolyl group optionaUy substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrroUdinylcarbonyl group optionaUy substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a morphoUnylcarbonyl group; (i) an oxo group substituted by cycloailkyl group; (]') a hydroxyallq^l group; or (k) a nitro group; or a pharmaceuticaUy acceptable derivative thereof. 8. The compound of the above embodiment 7 wherein A^ is a pyrimidinyl group or a pyridyl group; A2 is (a) a heterocyclic group selected from piperidyl group and morpholinyl group, which are each optionally substituted by a substituent(s) selected from a carboxyl group, carboxyalkyl group or alkyl group; (b) an alkoxy group substituted by a group selected from carboxi group, hydroxy group, alkoxy group and cyano group; (c) a halogen atom; (d) an amino group optionally substituted by 1 to 2 substitueni selected independently from carboxyalkyl group, hydrojcyalkyl group, aOv group, alkoxyalkyl group and aminoalkyl group, respectively optional] substituted by 1 to 2 alkyl groups; (e) a hydrogen atom; B is a phenyl group optionally substituted by 1 to 4 groups selecte independently from alkyl group optionally substituted by 1 to 3 haloge atoms and alkoxy group optionally substituted by 1 to 3 halogen atoms; R2 is (a) an amino group optionally substituted by 1 to 2 grouj selected independently from an allcyl group, an alkoxyalkyl group, cycloalkylallcy] group, an alkoxycarbonyi group, an alkylcarbonyl group, an alkylcarbamoyl group, a carboxyalkyl group, a cycloalkylalkyl group substituted by carbojtyall^l group, a hydroxyalkyl group, a carboxyalkoxycarbonyl group, a carboxydihydrooxazolyl group, a carboxyalkylcarbonyl group, a phenylalkyl group, an alkoxyalkoxycarbonyl group, an alkoxyalkylcarbonyl group, an alkyl group substituted by piperidyl group, a piperidylalkyl group substituted by carboj^all^l group and an alkyl group substituted by phenyl group that is optionally substituted by 1 to 2 alkyl groups (said all^^l group may optionally be substituted by 1 to 3 halogen atoms); (b) a halogen atom; (c) an alkoxy group optionally substituted by a group selected from a carboxyl group, a cycloalkyl group and an alkoxy group; (d) a carbamoyl group optionally substituted by 1 to 2 substituents selected independently from alkyl group and carboxyalkyl group; fe) a hydrojQ' group; (f) an oxQ group substituted by a heterocyclic group selected from a pyrimidinyl group and a tetrahydropyranyl group; (g) a heterocyclic group selected from a p3T-imidinyI, pyridyl, morpholinyl, piperidyl, piperazinyl, tetrazolyl, dihydroisoquinolyl and P3'rrolyl group, which are each optionally substituted by 1 to 2 substituents selected independently from alkyl group, alkoxy group, phenyl group, carboxyl group, carboxyalkoxy group and carboxyalkyl group; (h) a phenyl group optionally substituted by 1 to 3 substituents selected independently from halogen atom, alkyl group and alkoxy group; (i) an oxo group substituted by cycloalkyl group; (i) a hydroxyalkyl group; (k) a nitro group; or a pharmaceutically acceptable derivative thereof. 9. The compound of the above embodiment 8 wherein A2 is an amino group substituted by 1 to 2 groups selected independently from a piperidyl group optionally substituted by carboxyl group; a morpholinyl group optionally substituted by carboxyl group; ain alkoxy group substituted by a group selected from carboxyl group, hydroxy group, alkoxy group and cyano group; an amino group substituted by 1 to 2 groups selected independently from carboxyalkyl group and alkyl group; B is a phenyl group optionally substituted by an alkyl group optionally substituted by 1 to 3 halogen atoms; R2 is (a) an amino group optionally substituted by 1 to 2 groups selected independently from an alkyl group, a cycloalkylalkyl group, an alkoxycarbonyl group, a carboxyalkyl group and a cycloalkylalkyl group substituted by carboxyalkyl group; (b) an alkoxy group; {c} a phenyl group optionally substituted by a group selected from a halogen atom, an alkyl group and an alkoxy group; (d) a pyridyl group optionally substituted by a group selected from a halogen atom, an aUc^l group and an alkoxy group; or a pharmaceutically acceptable derivative thereof. 10. A compound described in anyone of examples No. 7, 24, 75, 57, 13, 54, 12, 65, 63 and 64, or a pharmaceutically acceptable derivative thereof. 11. A compound of the formula (1-A): wherein AiiA is an optionally substituted pyrimidin-2-yl group or an optionally substituted pyridin-2-yl group; R^A and R^^ are independently a cyano group or an alkyl group optionailly substituted by 1 to 3 halogen atoms; Ring E is an optionally substituted phenyl group; F is an optionally substituted cyclic group; or a pharmaceutically acceptable derivative thereof. 12. A compound of the formula (I-B): ZA is N or CH; A21A is an optionally substituted homocyclic group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl group, a nitro group, a hydroxy group, a cyano group, an optionally substituted alkenyl group, an optionally substituted heterocyclic group, an optionally substituted alkoxy group, a halogen atom, an amino group optionally substituted by 1 to 2 substituents, a carbamoyl group optionally substituted by 1 to 2 substituents, a carboxyl group or a hydrogen atom; RiA is a cyano group or an alkyl group optionally substituted by 1 to 3 halogen atoms; B' is a group selected independently from an oxo group, a cyano group, a halogen atom, an optionally substituted all^lsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted all^lsulfonyl group, an amino group optionally substituted by 1 to 2 substituents, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted cycloalkoxy group, an optionally substituted cycloalkyl group, a carboj^l group, a carbamoyl group optionally substituted by 1 to 2 substituents, an optionally substituted alkyl group or an optionally substituted alkoxy group; pA is an integer of 0 to 3; D is a pyrimidinyl group, a pyridyl group, a phenyl group, a pyrimidinyloxy group, a tetrazolyl group or ain oxazolidinyl group; D' is a group selected independently from a halogen atom, an alkoxyalkyl group, an alkyl group substituted by 1 to 5 halogen atoms, an aUcoxy group substituted by 1 to 5 halogen atoms, an alkenyl group, a carbamoyl group, a cycloalkyl group, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, a cyano group, an oxo group, an alkyl group, a hydroxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkyl group, a morpholinylalkyl group, a phenylalkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkojcyalkanoyl group, an alkoxy group, a phenylalko3cy group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a mono- or di-alkylamino group, a mono- or di-alkylcarbamoyl group, a mono- or di-alkylsulfamolyl group, an alkylsulfonyl group, a tetrazolyl group, benzyloxyalkyl group, a cycloall^lalkyl group, an benzyloxy group, an alkoxyalkoxy group, a carboxyalkoxy group, a carboxyalkenyl group, an alkylcarbonylamino group, a carboxyalkoxyalkyl group, a morpholinyl group or a pyridylalkojfy group; qA is an integer of 0 to 3; or a pharmaceutically acceptable derivative thereof. 13. The compound of the above embodiment 12 wherein A21A is selected from the following group (a) a heterocyclic group selected from a piperidyl group and a morpholinyl group, respectively optionally substituted by a substitutent(s) selected from a carbojQ^l group, an alkoxycarbonyl group, a carboxyalkyl group or an alkyl group; (b) an alkoxy group optionally substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulflnyl group, a mono- or di-allQrlamino group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an all^lsulfanyl group, a hydroxy group or an alkoxy group; (c) a halogen atom; (d) an amino group optionally substituted by 1 to 2 substituents independently selected from a carboj^alkyl group, an alko^^carbonyleilkyl group, an alkylsulfonylalkyl group, an alkylsuliinylalkyl group, a hydroxyalkyl group, an alkyl group, an alkoxyalkyl group or an aminoall^l group optionally substituted by 1 to 2 alkyl groups; (e) a hydrogen atom; (f) an alkyl group optionally substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulfmyl group, a mono- or di-alkylamino group, a cyano group, a t:etra2olyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group or an alkoxy group; (g) a carboxyl group; (h) a carbamoyl group optionally substituted by a carboxyalkyl group; or (i) an alkenyl group substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, an all^lsulfmyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group or an alkoxy group; [j) a morpholinyl group; (k) a piperidinyl group optionally substituted by a carboxyl group or a carbojo^alkyl group; B' is a group selected independently from an oxo group, a halogen atom, an allQ'I group optionally substituted by 1 to 3 halogen atoms, an alkoxy group optionally substituted by 1 to 3 halogen atoms, a cyano group, a hydroxy group, a cycloalkyl group, an alkoxyalkyl group, a cycloalkoxy group, an alkylsulfanyl group optionally substituted by 1 to 3 halogen atoms, an alkylsulfmyl group optionally substituted by 1 to 3 halogen atoms or an alkylsulfonyl group optionally substituted by 1 to 3 halogen atoms; or a pharmaceutically acceptable derivative thereof. 14. The compound of the above embodiment 13 wherein A21A is an alkoxy group optionally substituted by 1 to 2 groups selected from a carboxyl group, a halogen atom, an alkoxycarbonyl group, an alkoxyl group, a hydroxy group, a mono or di-aikylamino group, an alkylsuliinyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl group and an aikylsuifanyl group; an alkyl group optionally substituted by 1 to 2 groups selected from a carboxyl group, a halogen atom, an alkojcycarbonyl group, an alkoxyl group, a hydroxy group, a mono or di-alkylamino group, an alkylsulfinyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl group and an aikylsuifanyl group; a morpholinyl group; a carboxyl group or a carboxj'piperidinyl group; B' is a group selected independently from a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms or an alkoxy group optionally substituted by 1 to 3 halogen atoms; D' is a group selected independently from an alkoxy group optionally substituted by 1 to 3 halogen atoms, a halogen atom, a cyano group, an aikylsuifanyl group, a mono or di-alkylamino group, an alkenyl group, an alkyl group optionally substituted by 1 to 3 halogen atoms, a carboxyl group, a hydroxy group, a carbo:cyalkoxy group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an oxo group, a cycloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylcarbonylamino group, a morpholinyl group or a carboxyaJkoxyalkyl group; or a pharmaceutically acceptable derivative thereof. 15. The compound of the above embodiment 14, wherein Z^ is a N, or a pharmaceutically acceptable derivative thereof. 16. The compound of the above embodiment 14, wherein R^^ is an alkyl group optionally substituted by 1 to 3 halogen atoms, or a pharmaceutically acceptable derivative thereof. 17. The compound of the above embodiment 14, wherein D is a phenyl group, or a pharmaceutically acceptable derivative thereof. IS. The compound of the above embodiment 14, wherein D' is a group selected independently from a halogen atom, an alkoxy group or an alkyl group, or a pharmaceutically acceptable derivative thereof. 19. The compound of the above embodiment 14, wherein A^IA is a morpholinyl group or an alkoxyl group substituted by a carbojo'l group, or a pharmaceutically acceptable derivative thereof. 20. A compound described in anyone of examples No. 91, 94, 96, 112, 114, 118 to 123, 131, 133, 136, 138 to 140, 142 to 153, 158 to 163, 165 to 169, 173 to 177, 179 to 182, 185, 186, 190 to 194, 198, 203, 208 to 216, 218 to 223, 231, 239, 240, 241 or a pharmaceutically acceptable derivative thereof. 21. A compound described in anyone of examples No. 154 to 157, 164, 170 to 172, 178, 183, 184, 187 to 189, 195 to 197, 199 to 202, 204 to 207, 217, 224 to 230, 232 to 238, 242 to 252 or a pharmaceutically acceptable derivative thereof. 22. A pharmaceutical composition, which comprises as an active ingredient a compound according to any one of the above embodiments 1 to 21, or a pharmaceutically acceptable derivative thereof. 23. A method for prophylaxis or treatment of arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hjTierbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hj'percholesterolemia, cardiovascular diseases, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, cerebral stroke, diabetes, vascular complication of diabetes, thrombotic diseases, obesity, endotoxemia, metabolic s3Tidrome, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, reno-vascular disease, renal disease, splanchnic vascular disease, vascular hemostatic disease. fatty liver disease, steatohepatitis, inflammatory disease, autoimmune disorders and other systemic disease indications, immune function modulation, pulmonary disease, anti-oxidant disease, sexual dysfunction, cognitive dysfunction, schistosomiasis, cancer, regression of xanthoma or Alzheimer's disease, which comprises administering an effective amount of a compound according to any one of the above embodiments 1 to 21, or a pharmaceutically acceptable derivative thereof, to a patient in need thereof. 24. Use of a compound according to any one of the above embodiments 1 to 21, or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament in treatment of patients suffering from arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular diseases, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, cerebral stroke, diabetes, vascular complication of diabetes, thrombotic diseases, obesity, endotoxemia, metabolic syndrome, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhj^thmia, pulmonary vascular disease, reno-vascular disease, renal disease, splanchnic vascular disease, vascular hemostatic disease, fatly liver disease, steatohepatitis, inflam.matory disease, autoimmune disorders and other systemic disease indications, immune function modulation, pulmonary disease, anti-oxidant disease, sexual dysfunction, cognitive dysfunction, schistosomiasis, cancer, regression of xanthoma or Alzheimer's disease. 25. A compound of a general formula (1-1): wherein the sjnnbols have the same meanings as defined above, or a pharmaceutically acceptable derivative thereof. When the compound (1) has one or more asymmetric carbon atoms, the compound (1) of the present invention encompasses racemate, racemic mixture, individual enantiomers or diastereomers. The present compounds also include all such isomers and a mixture thereof. Also, when the present compound has an alkenyl or all^Tiyl group, CIS (Z)- and trans (Ej- forms may occur. In addition, the present compounds include individual stereoisomer of the compound and optionally, individual tautomeric forms thereof and a mixture thereof. Separation of diastereomer or cis- and trans- isomers can be achieved by the conventional method such as fractional crystallization, chromatography and HPLC method, and the like. Also the drug containing the individual stereoisomer as needed can be prepared from a corresponding optically active intermediate or alternatively by resolving the corresponding racemate by using the suitable chiral support (e.g. HPLC) or by performing a fractional crystallization of diastereomeric salt formed by reacting a corresponding racemate and a suitable optically active acid or base. Alternatively, the resolution of the mixture of enantiomers can be done by forming on a novel covalently bounded species formed by means of reacting it with a suitable chiral compound. For example, at first, the coupling reaction between a racemic carbojQ^lic acid and a chiral amine or a chiral alcolol gives a mixture of diastereoisomers (amide or ester, respectively) and then it is isolated by the conventional technique such as chromatography, HPLC or fractional crystallization, and the like. Thereafter, the resulting one diastereoisomer can be converted into one enantiomer of the desired compound by cleaving the new covaJent binding with a suitable chemical reaction such as hydrolysis, and the like. As used herein, the term "pharmaceutically acceptable derivative" represents a pharmaceutical acceptable salt, solvate or prodrug (e.g. ester) of the present compound, and which can provide (directly or indirectly} the compound of the present invention or an active metabohte or a residue thereof. Such derivatives can be obtained by a person skilled in the art without undue experimentation. See, for example, Burger's Medicinal Chemistry and Drug Discovery 5th ed., vol. 1st, "Principles and Practice". Preferred pharmaceutically acceptable derivative is a salt, a solvate, an ester, a carbamlnic ester and a phosphoric ester. Especially preferred pharmaceutically acceptable derivative is a salt, a solvate and an ester. Most preferred pharmaceutically acceptable derivative is a salt and an ester. A person skilled in the art of organic chemisty knows that m^any organic compounds can be formed a complex with a solvent of reaction system and which can be precipitated out or crystallized out from the solvent. These complexes are widely known as a "solvate". For example, the complex with water is known as a "hydrate". The solvate of the compound of the present invention falls within the scope of the invention. As used herein, the "prodrug" represent a compound which convert to the active form having a pharmacological activity by a hydrolysis in vivo (such as in a blood). The example of the pharamaceutically acceptable prodrug is described in the literature: T. Higuchi and V. Stera, Prodrugs as Novel Delivery Systems, "Bioreversible Carriers in Drug Design", Edward B. Roche ed., American Pharmaceutical Association and Pergamon Press, A.C.S. Symposium Series, vol. 14th, (1987); and D. Freisher, S. Roman and H. Barbara, Improved oral drug delivery: solubility limitations overcome by the use of prodrugs, Adveinced Drug Delivery Reviews (1996) 19(2): 115-130). A prodrug is a carrier that releases the compound of the formula (1) which is bound covalently in vivo when administered to a patient. In general, the prodrug is prepared by the conventional m^ethod or by modifying a functional group such that the moidified moiety is cleaved in vivo to give a parent compound. Examples of the prodrug include the CQjnpound wherein a hydroJQ^, amine or sulfhydiyl group binds to an optional group such that provide a hydroxy, amine or sulfhydiyl group by cleaving it when administered to a patient. Thus the representative exam.ples of prodrug are the following ones, but not limited thereto; i. e. the derivatives with acetic ester, formic ester and benzoic ester at the functional groups such as alcohol, sulfhydiyl or amine of the compound of the formula (1). In addition, when the functional group is a carboxylic acid, esters such as methyl ester, ethyl ester and double ester, and the like can be used. The esters exhibit inherently the activity in a human body and/or are hydrolyzed under in vivo condition to the active sompound. The suitable pharmaceutically acceptable esters capable of hydrolyzing in vivo include those which are decomposed easily in the human body to release the parent acid compound or a salt thereof. The compound of the present invention may be a pharmacetically acceptable salt form thereof. The suitable salt is outlined in literature (Berge et. al., J. Pharm. Sci., 66: 1-19 (1977)). In general, the pharmaceutically acceptable salts can be easily prepared with a desirable acid or base as needed. The resulting salts can be recovered by filtering aifter precipitating it out from the solution or distilling the solvent off. The suitable additive salts may be formed with an acid forming a nontoxic salt. Examples of the salt include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccarate, benzoate, methanesulfonate, ethane sulfonate, benzenesulfonate and p-toluenesulfonate. Examples of the pharmaceutically acceptable salt with a base include alkaline metal salts including ammonium salt, sodium salt and potassium salt; alkaline earth metal salts including calcium salt and magnesium salt as well as salts with organic bases including a primary, secondary and tertiary amine (e.g. isopropylamine, diethylamine, ethanolamine, trimethlamine, dicyclohej^lamine and N-methyl-D-glucamine). The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "alkyl group" or "alkyl" means a straight or branched saturated hydrocarbon chain having 1 to 10 carbon atoms and a cyclic saturated hydrocarbon chain having 3 to 10 carbon atoms. As a straight or branched hydrocarbon chain, those having 2 to 10 carbon atoms are preferred and those having 2 to 6 carbons are more preferred. More preferred exeimples are stradght chain alkyl groups having 1 to 6 carbon atoms, especially those having 1 to 4 carbon atoms. Examples of alkyl group include methyl, ethyl, propyl, isopropyl, butyl, sec-bulyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-penlyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl and isohexyl groups, and the like. The term "aUcoxy group" or "alkoxy" means a straight or branched alkyloxy group having 1 to 10 carbon atoms and a cyclic alkyloxy group having 3 to 10 carbon atoms. As a straight or branched hydrocarbon chain, those having 2 to 10 carbon atoms are preferred and those having 2 to 6 carbons are more preferred. More preferred examples are straight chain alkoxy groups having 1 to 6 carbon atoms, especially those having 1 to 4 carbon atoms. Examples of alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutojQ', tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy, hexoxy and isohexoxy groups, and the like. The term "alkylene group" or "alkylene" means a saturated hydrocarbon chain wherein a hydrogen atom is removed from each of the terminal carbons of a straight hydrocarbon chain. Preferred examples include an alkylene group having 1 to 6 carbon atoms, specifically, methylene, ethylene, trimethylene and tetramethylene groups, and the like. When an alkylene group herein used contains 1 to 3 heteroatoms selected independently from nitrogen, sulfur and oxygen atoms, the term "aikylene" includes a group of the formula:-0-fCH2)m-0-, -S-(CH2)m-S-, -NH-(CH2}m-NH-, or -0-(CH2)m-NH- (wherein m is an integer of 1 to 4}, or the like. The term "alkanoyl group" or "alkanoyl" means a straight or branched alkylcarbonyl group having 1 to 10 carbon atoms, preferably an alkylcarbonyl group having 1 to 6 carbon atoms, more preferably an alkylcarbonyl group having 1 to 4 carbon atoms. Examples of alkanoyl group include acetyl, propionyl, bulyryl, valeryl and pivaloyl groups, and the like. The term "alkenyl group" or "alkenyl" means a straight or branched hydrocarbon chain having 2 to 10 carbon atoms and containing at least one double bond, preferably an alkenyl group having 2 to 6 carbon atoms, more preferably an alkenyl group having 2 to 4 carbon atoms Examples of alkenyl group include vinyl, l-propenyl, allyl, isopropenyl, butenyi, butadienyl and pentenyl groups, and the like. The term "alkynyl group" or "alkjniyr' means a straight or branched hydrocarbon chain having 2 to 10 carbon atoms and containing at least one triple bond, preferably an alkynyl group having 2 to 6 carbon atoms, more preferably an all^Tiyl group having 2 to 4 carbon atoms Examples of alkynyl group include ethinyl, 1-propynyl, isopropynyl, and pentynyl groups, and the like. As herein used throughout the claims and specification, when the term "mono- or di-alkyl" refers to di-alkyl, the all^^l moieties may be the same or independent from each other. The cycloalkyl or cycloEilkyl group as used herein is C3-10 cyclic hydroncarbon group and includes for example, cyclopropyl, cyclobutyl, cyclopentyl, cycohecyl, cycloheptyl, cyclooctyl, cyclononyl groups, and the like and preferably C3-6 cyclic hydrocarbon group. The cycloalkoxy and cycloalkoxy group as used herein is oxy group substituted by C3-10 cyclic hydrocarbon and includes, for example cyclopropyloxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and the like and preferably oxy group substituted by C3-6 cyclic hydrocarbon group. The heterocycle or heterocycic group as used herein includes 5 to 8 membered heterocyclic group including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms and dicyclic or tricyclic fused heterocyclic group fused thereto. Specific examples of the heterocycic group include, for example, a thienyl, furyl, p5Trolyl, pyrroUnyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazoUdinyl, tetrazolyl, pyridyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl, morphoUnyl, triazinyl, pyrroUdinyl, piperidyl, pyranyl, tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl, benzofuiyl, benzothiazolyl, benzoxazolyl, tetrazolopjTidazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indoiyl, quinolizinyl, naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl or tetrahydroquinolyl group, and the like. The homocycle or homocyclic group as used herein includes, for example, 3 to 7 membered carbocyclic group optionally fused, such as C6-10 aryl group (e.g. phenyl and napthyl group, and the like), C3-10 cycloalkyl group (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepthyl, and the like), C3-10 cycloalkenyl group (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cycohexenyl, cycloheptenyl, and the like). The cyclic group as used herein includes the heterocyclic group and the homocycUc group mentioned above. EFFECT OF THE INVENTION The compound (1) of the present invention has an inhibitory activity against CETP and shows the effects on increasing HDL cholesterol level and decreasing LDL choresterol. Thus the compound is useful in a prophylaxis and a treatment of diseases such as arteriosclerosis and hyperlipidemia, and the like. The present compound (1) can be administered either orally or parenterally, and can be formulated into a suitable pharmaceutical preparations with a conventional pharmaceuticailly acceptable carriers used therefor. The pharmaceutically acceptable salts of the compound (1) include, for example, alkali metal salts such as lithium, sodium or potassium salt; alkali earth metal salts such as calcium or magnesium salt; salts with zinc or aluminum; salts with organic bases such as ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucosamie, triethanolamine or dehydroabiethylamine; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methane sulfonic acid, ethanesulfonic acid, benzene sulfonic acid or toluenesulfonic acid; or salts derived from acidic amino acids such as aspartic acid or glutamic acid. Additionally, the pharmaceutically acceptable salts of the compound of the formula (1) include, for example, quaternary salts formed between a compound of the formula (1) and an alkyl halide or a phenylalkyl halide. Preferred pharmaceutical preparations for oral administration of the present compound include solid formulations such as tablets, granules, capsules or powders; and liquid formulations such as solutions, suspensions or emulsions. Preferred pharmaceutical preparations for parenteral administration include injections or infusions formulated with injectable distilled-water, physiological saline or aqueous glucose solution; suppository; or inhalation preparation, and the like. These pharmaceutical preparations comprise a compound (1) of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier which is usually used for oral or parenteral administration. The pharmaceutically acceptable carriers for oral administration include, for example, a binder (syrup, gum acacia, gelatin, sorbit, tragacanth, polj^nylpyrrolidone, and the like), an excipient (lactose, sugar, cornstarch, potassium phosphate, sorbit, glycine, and the like), a lubricant (magnesium stearate, talc, polyethylene glycol, silica, and the like), a disintegrant (potato starch, and the like), and a wetting agent (anhydrous sodium lauryl sulfate, and the like). Also the pharmaceutically acceptable carriers for parenteral administration include, for example, injectable distilled-water, physiological saline and aqueous glucose solution. The dose of a compound (1) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration route, age, body weight, disease, and condition/severity, of the patient It however can usually be in the range of about 0.001 - 1,000 mg/kg/day, preferably in the range of about 0.01 - 100 mg/kg/day, more preferably in the range of about 0.1 - 10 mg/kg/day. The compounds (1) of the present invention have an inhibitory activity against CETP and show an activi^ of increasing HDL cholesterol level and an activity of lowering LDL cholesterol level. Accordingly, they are useful in the prophylaxis or treatment of a subject (particularly, mammal including hum.an) suffering from arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular diseases, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, cerebral stroke, diabetes, vascular complication of diabetes, thrombotic diseases, obesity, endotoxemia, metabolic syndrome, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhj^mia, pulmonary vascular disease, reno-vasculEir disease, renal disease, splanchnic vascular disease, vascular hemostatic disease, fatty liver disease, steatohepatitis, inflammatory disease, autoimmune disorders and other systemic disease indications, immune function modulation, pulmonary disease, anti-oxidant disease, sexual dysfunction, cognitive dysfunction, schistosomiasis, cancer, regression of xanthoma, Alzheimer's disease, or the like. In addition, the compounds of the present invention may be used in combination with other drugs useful for treatment of these diseases. For example, a compound of the present invention may be used in combination with an inhibitor of cholesterol ssmthesis such as HMG-CoA reductase inhibitor; an inhibitor of cholesterol absorption such as anion exchange resin; a triglyceride lowering agent such as fibrates, niacin and fish oil; an antihypertensive such as ACE inhibitor, angiotensin receptor blocker, calcium antagonist and beta blocker; an antiobesity agent such as central anorectic, lipase inhibitor and CBl antagonist; an antidiabetic agent such as insulin sensitizer, D2 agonist, sulfonylurea, biguanide, a-glucosidase inhibitor, SGLT inhibitor and DPPIV inhibitor; or other cholesterol reducer such as ACAT inhibitor. The compound (1) of the present invention may be prepared by the 49 following methods, which should not be construed to be limited thereto. In each process for preparing a compound of the formula fl) described above, when protection of a functional group contained in any compound is needed, the protection can be carried out in a conventional manner ad libitum. General statement related to protecting groups and their use is provided by Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991. Further in each process, the reaction can be carried out by the conventional method and a procedure for isolation and the purification may be selected from the conventional method such as crystallization, recrystallization and chromatography and preparative HPLC, and the like as appropriate, or may be combined with one another. wherein the X^i and X^ are a leaving group and the other symbols have the same meanings as defined above (Process I-l) The compound (4) can be prepared by reacting the compound (2) with the compound (3) in a solvent in the presence of a base. Any solvent which dose not disturb the reaction can be preferably used as a solvent used, and include, for example, ethers including diethylether, tetrahydrofuran (THF), dioxane, l,2-methoxyeth£ine, diglyme; hydrocarbons including benzene, toluene, hexane, xylene; alcohols including methanol, ethanol, isopropyl alcohol, tert-butanol; esters including ethyl acetate, methyl acetate, butyl acetate; polar solvents including acetone, N,N-dimethylformamide, dimethyl sulfoxide, which can 50 be used alone or in a combination thereof. Prefered solvents in this reaction include ethanol, dioxane, toluene and N,N-dimethylforniamide. A conventional base may be used as a base, aind includes for example, alkaline metal hydride including sodium hydride and potassium hydride; alkaline metal alkoxide including sodium ethoxide, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide; alkyl lithium including n-butyl lithium and sec-bulyl lithium; alkaline metal amide including lithium diisopropylamide, sodium amide and lithium bis(trimethylsilyl)amide; alkaline metal carbonate including sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkaline metal hydroxide including lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline metal phosphate including sodium and phosphate potassium phosphate; organic base including triethylamine, diisopropylethylamine, pyridine and N- methylmorpholine; preferably triethylamine, sodium bicarbonate, sodium, tert-butoxide, diisopropylethylamine, sodium hydride and potassium tert-butoxide. The leaving group includes a halogen atom including chlorine atom, bromine atom, iodine atom, and a substituted sulfonyloxy group including methanesulfonyloxy group, p-toluenesulfonyloxy group and trifluoro-methanesulfonyloxy group. (Process 1-2) The compound (1) can be prepared by reacting the compound (4) with the compound (5) in a same manner as in process I-l or I'-l described below. (Process I'-l) The process (I-l) may be replaced by the following process I'-l. In the above process 1-1, the compound (4) can also be prepared by reacting the compound (2) with the compound (3) in the presence or absence of a base or in the presence of a metal catalyst such as palladium catalyst in a suitable solvent. 51 A conventional palladmm catalyst can be used as a palladium catalyst, and include palladium acetate, tetrakis(triphenylphosphine)-palladium, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenyI-phosphine) palladium, dichlorobis{tri-o-tolylphosphine)palladiuni, bis-(triphenylphosphine)palladium acetate, or the like. As the base, alkaline metal hydroxide including sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxide including barium hydroxide; alkaline metal alkoxide including sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline metal carbonate including sodium carbonate, potassium carhonate, cesium carbonate; alkaline metal bicarbonate including sodium bicarbonate, potassium bicarbonate; alkaline metal phosphate including potassium phosphate; amines including triethyiamine, diisopropyl-ethyiamine, methylpiperidine, dicyclohexyhnethylaimine; and pyridines including pyridine, 4-dimethylaininopyridine can be preferably used. Additionally, phosphines may be added in the present reaction. As the phosphines, triphenylphosphine, tributylphosphine, tri-tert-butylphosphonium tetrafluoroborate, l,3-bis{diphenylphosphino)propane, 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, l,r-bis(diphenylphosphino}-ferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohejcylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-(dicyc]ohexylphosphino)biphenyl, and the like can be preferably used. Any solvent which dose not disturb the reaction can be preferably used as a solvent used in the reaction, and include, for example, ethers including diethylether, tetrahydrofuran (THF), dioxane, 1,2-methoxyethane, diglyme; hydrocarbons including benzene, toluene, hexane, xylene; alcohols including methanol, ethanol, isopropyl alcohol, tert-butanol; esters including ethyl acetate, methyl acetate, butyl acetate; polar solvents including acetone, N,N-dimethylformamide, dimethyl sulfoxide, and which can be used alone or in a combination thereof. 52 (Process V-2) The compound (1) can be prepared by reacting the compound (4) with the compound (5) in a same manner as in process I'-l or I-l. (Method II] wherein the X^ is a leaving group and the other symbols have the same meanings as defined above (Process II-l) The compound (8) can be prepared by reacting the compound (6) with the compound (7) in a same manner as process I-l. (Process II-2) The compound (1) can be prepared by reacting the compound (8) with the compound (3) in a same manner as in process I-l or T-l. [Method III] The compound (1) can be prepared by a method III. wherein the symbols have the same meanings as defined above (Process III-1) The compound (9) can be prepared by reacting the compound (3) with the compound (7) in a same meinner as in process I-l or process I'-l. (Process III-2) The compound (1) can be prepared by reacting the compound (9) 53 with the compound (6) in a same manner as in process I-l. [Method IV] The compound of the general formula (1-a): wherein the symbols have the same meanings as defined above , that is, those wherein Y is a methylene group in the compound of the formula (1), can be prepared by a following method IV. The compound (1-a) can be prepared by reducing the compound of a general formula (6'): wherein the symbols have the same meanings as defined above, or its corresponding carboj^lic acid or its corresponding carboxylic acid ester to provide the compound of a general formula (6"): wherein the symbols have the same meanings as defined above, followed by halogenating the resulting compound and then reacting the resulting compound with the above compound (9) in a solvent in the presence of a base. The reduction can be carried out by treating a starting compound with a reducing agent in a suitable solvent. Boron hydrides (sodium borohydride, and the like) and aluminum hydrides (lithium aluminum hydride, diisobutylaluminum hydride, £ind the like) can be preferably used as a reducing agent. The hologenation can be carried out by treating a starting compound with a halogenating agent in a suitable solvent. As the halogenating agent, 54 a conventional halogenating agent including thionyl chloride, phosphorus oxychloride, as well as carbon tetrahalide (e.g., carbon tetrachloride, carbon tetrabromide, and the like) and phosphines (e.g., triphenylphosphine, tritolylphosphine, triethylphosphine, and the like) can be preferably used. A conventional base may be used as a base and include for example, alkaline metal hydride including sodium hydride and potassium hydride; alkaline metal alkoxide including sodium ethoxide, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide; alkyl lithium including n-butyl lithium and sec-bulyl lithium; alkaline metal amide including lithium diisopropylamide, sodium amide and lithium bis(trimethylsilyl) amide; alkaline metal carbonate including sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkaline metal hydroxide including lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline metal phosphate including sodium and phosphate potassium phosphate; organic base including triethylamine, diisopropylethylamine, pyridine and N- methylmorpholine; preferably triethylamine, sodium bicarbonate, sodium tert-butoxide, diisopropylethylamine, sodium hydride and potassium tert-butoxide. Any solvent which dose not disturb the reaction can be preferably used as a solvent used, and include, for example, ethers including diethylether, tetrahydrofuran (THF), dioxane, 1,2-methoxyethaiie, diglyme; hydrocarbons including benzene, toluene, hexane, xylene; alcohols including methanol, ethanol, isopropyl alcohol, tert-butanol; esters including ethyl acetate, methyl acetate, buty] acetate; polar solvents including acetone, N,N-dimethylformamide, dimethyl sulfoxide, which can be used alone or in a combination thereof. Prefered solvents in this reaction include ethanol, dioxane, toluene and N,N-dimethylformamide. [Method IV] The compound (1-a) can also be prepared by the following method 55 IV'. The compound (l-a) can also be prepared by halogenating the above compound (6") according to the above method IV, foUowd by reacting the resulting compound with the above compound (7) in a solvent in the presence of a base to provide the compound of a general formula (8') wherein the sjnnbols have the same meanings as defined above, then reacting the resulting compound with the compound (3) acccording to the above process II-2. [Method IV"] In the above method IV', the compound (8) can be prepared by reacting the compound (6") with the compound {7) in a solvent in the presence of a reducing agent. Any solvent which dose not disturb the reaction can be preferably used as a solvent used in the reaction, and include for example, halogens including 1,2-dichloroethane, dichloromethane, chloroform, ethers including diethylether, tetrahydrofuran (THF), dioxane, 1,2-methoxyethane, diglyme; hydroceirbons including benzene, toluene, hexane, xylene; alcohols including methanol, ethanol, isopropyl alcohol, tert-butanol; esters including ethyl acetate, methyl acetate, butyl acetate; polar solvents including acetone, N,N-dimethylformamide, dimethyl sulfoxide, and which can be used alone or in a combination thereof. Especially prefered solvent in this reaction includes l,2-dich2oroethane, dichloromethane and toluene. The reducing reagent includes sodium borohydrides including sodium triacetoxyborohydride, sodium cyanoborohydride; and aluminum hydrides including lithium aluminium hydride and diisobutylaluminium hydride. [Method V] 56 The compound of a general formula (1-b): wherein R^ is an alkyl group aind the other symbols have the same meanings as defined above, those wherein Y is an alkyl group in the compound (1), can be prepared by undergoing a conventional Grignard reaction of the compound (6') with a reagent of a general formula: R^MgBr wherein the symbol has the same meaning as defined above, to provide the compound of a general formula (6'")' wherein the symbols have the same meanings as defined above, followed by halogenating the resulting compound in a same manner as in the above method IV, then reacting the resulting compound with the above compound (9) in a solvent in the presence of a base. [Method V) The compound (1 -b) can also be prepared by the following method V. The compound (1-b) can also be prepared by haogenating the above compound (6'"} according to the above method V, followed by reacting the resulting compound with the above compound (7) in a solvent in the presence of a base, to provide a compound of a general formula (8"): wherein the S3Tnbo]s have the same meanings as defined above, then reacting the resulting compound with the compound (3) according to the 57 above process II-2. [Method VI] The compound of a general formula f 1-c): wherein the symbols have the same meanings as defined above, those wherein Y is an methylene group substituted by an oxo group in the compound (1), can be prepared by oxidating the compound {6') to provide the compound of a general formula (6""): wherein the symbols have the same meanings as defined above, followed by halogenating the resulting compound according to the above method IV, then reacting the resulting compound with the above compound (9) in a solvent in the presence of a base. [Method Vr] The compound (1-c) can also be prepared by the following method VI'. The compound (1-c) can be prepared by halogenating the above compound (6"") according to the above method VI, followed by reacting the resulting compound with the above compound (7) in a solvent in the presence of a base, to provide a compound of a general formula (8"'): wherein the ss^mbols have the same meanings as defined above, then reacting the resulting compound with the compound (3) according to the above process II-2. 58 [Method VII] The compound (1-a) can be prepared by the following method VII. The compound (l-a) can also be prepared by reducing the compound wherein the symbols have the same meeinings as defined above, to provide the compound of a general formula (6""")- wherein the symbols have the same meanings as defined above, then reacting the resulting compound with the above compound (9\| in a same manner as in the method IV", to provide the compound of a general wherein the symbols have the same meanings as defined above, and interconverting on R2 moiety. [Method VII'] The compound (1-a) can also be prepared by reacing the above compound (6""") with the above compound (7) in a same manner as in the above method IV" to provide the compound of a general formula (8"); 59 wherein the symbols have the same meanings as defined above, followed by-reacting the resulting compound with the compound (3) according to the above process 11-2 to provide the compound (1-d), then interconverting on R2 moiety. In addition, substituents on the A, B, R^ and R2 may be further interconverted according to the known method after or before a s3Tithesis of the compound (1). A2 can be interconverted by the following methods (EA) to (EL\|. In the following each process, unless otherwise specified, a conventional base can be used as the base, and for example, alkaline metal hydride including sodium hydride, potassium hydride; alkaline metal hydroxide including sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxide including barium hydroxide; alkaline metal alkoxide including sodium m^ethoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide; alkaline metal carbonate including sodium carbonate, potassium carbonate, cesium carbonate; alkaline metal bicarbonate including sodium bicarbonate, potassium bicarbonate; amines including triethylamine, diisopropylethylamine, methylpiperidine, dimethylaniline, l,8-diazabicyclo[5.4.0]undecene, 1,4- diazabicyclol2.2.2]octane, l,5-diazabicyclo[4.3.0]nonene; p5THdines including pyridine, dimethylaminopyridine can be preferably used. Also in the following each process, a conventional acid can be used as the acid, and for example, unless otherwise specified, an inoroganic acid (e.g. hydrochloric acid, nitric acid and sulfuric acid; origanic acid represented by sulfonic acids (e.g. methane sulfonic acid, p-toluene sulfonic acid and trifluoromethane sulfonic acid, and the like) can be 60 preferably used. Also in the following each process, any solvent which dose not disturb the reaction can be used as the solvent and specifically include hydrocarbons including pentane, hexane; aromatic hydrocarbons including benzene, toluene, nitrobenzene; halogenated hydrocarbons including dichloro me thane, chloroform; ethers including diethylether, tetraihydrofuran amides including dimethylformamide, N-methylpyrrolidone, l,3-dimethylimidazolidin-2-one; sulfoxides including dimethyl sulfoxide; alcohols including methanol, ethanol; esters including ethyl acetate, butyl acetate; ketones including acetone, methyl ethyl ketone; nitriles including acetonitrile; water, or a mixed solvent thereof. Also in the following each process, the leaving group includes a halogen atom including chlorine atom, bromine atom, iodine atom, and a substituted sulfonyloiQ' group including methanesulfonyloxy group, trifluoromethanesulfonyloxy group and toluenesulfonyloxy group. (EA) The compound wherein A^ is a tetrazolyl group and A^ is an alkyl group or a substituted all^l group can be prepared by alkylating a compound wherein A^ is a tetrazolyl group and A^ is a hydrogen atom. The alkylation can be carried out by reacting with a compound of the formula: A2A-Z2 wherein A^A is an alkyl group or a substituted alkyl group and Z^ is a leaving group, in a suitable solvent in the presence or absence of a base, or by reacting with a compound of the formula: A2^0H wherein the symbol has the same meaning as defined above, in a suitable solvent in the presence of phosphines eind azodicarboxylic esters. N-alkylation of a compound wherein A^ is a nitrogen-containing heterocyclic group can be carried out in a similar manner as above. The reaction proceeds more preferably when a catalj^c amount of an 51 alkaline metal iodide (e.g., potassium iodide, and the like) is added. Both phosphines and azodicarboxylic esters which usually employed in Mitsunobu reaction can be preferably used. Phosphines include, for example, triphenylphosphine, tribulylphosphine, and the like, and azodicarboxylic esters include diethyl azodicarboxylate, diisopropyl azodiformate, and the like. (EB) The compound wherein Ai is 2-oxodihydropyrimidinyl group and A2 is an alkyl group or a substituted alkyl group can be prepared by alkylating a compound of the formula (1) wherein A^ is 2- hydroxypyrimidinyl group and A^ is a hydrogen atom, with a compound of the formula: A2^Z2 wherein the symbols have the same meeining as defined above. The reaction can be carried out in the same manner as in the above (EA). (EC) The compound wherein A2 is an optionally substituted amino group or a group of the formula: wherein the symbols have the same meaning as defined above, can be prepared by reacting a compound of the formula (1) wherein A^ is a halogen atom, with a corresponding amine or a compound of the formula: wherein the symbols have the same meanings as defined above. The reaction can be carried out in the presence or absence of a base, and in the presence or absence of a palladium catalyst in a suitable solvent. As the palladium catalyst, a conventional palladium catalyst 62 including palladium acetate, tetrakis(triphenylphosphine) palladium, tris{diben^lideneacetone)dipalladium, dichlorobis(triphenylphosphine)- palladium, dichlorobis(tri-o-tolylphosphine)palladiuin, bis- (triphenylphosphine)palladium acetate, or the like can be used. As the base, alkaline metal hydroxide including sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxide including barium hydroxide; alkaline metal alkoxide including sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide; alkaline metal carbonate including sodium carbonate, potassium carbonate, cesium carbonate; alkaline metal bicarbonate including sodium bicarbonate, potassium bicarbonate; alkaline metal phosphate including potassium phosphate; amines including triethylamine, diisopropylethylamine, methylpiperidine, dicyclohexylmethylamine; and pjoidines including pyridine, 4-dimethylaminop3Tidine can be preferably used. Additionally, phosphines may be added in the present reaction. As the phosphines, triphenylphosphine, tributylphosphine, tri-tert-butylphosphonium tetrafluoroborate, 1,3-bis(diphenylphosphino)propane, 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, l,r-bis(diphenylphosphino)-ferrocene, 2-{di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylam,ino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, and the like can be preferably used as the phosphines. (EDJ The compound wherein A2 is an optionally substituted amino group can be prepared by coupling a compound of the formula (1} wherein A2 is a halogen atom with a compound of the formula: (R20)3Sn-NR2iR22 wherein R2o is an all^l group and NR21R22 is an optionally substituted amino group. The coupling reaction can be carried out in the presence of a palladium catalyst in the presence or absence of a base in a suitable solvent. 63 The palladium catalysts, bases, and phosphines described in the above (EC) can be used in the same manner as in the above (EC). (EE) The compound wherein A^ is a cyano group can be prepared by cyanating a compound of the formula (1) wherein A^ is a halogen atom. The cyanation can be carried out by reacting a starting compound with a metal cyanide including sodium cyanide, potassium cyanide, or zinc cyanide in the presence of a palladium catalyst in a suitable solvent. The same palladium catalyst as that described in the above (EC) can be preferably used. (EF) The compound wherein A^ is an optionally substituted alkoxycarbonyl group can be prepared by reacting a compound of the formula (1) wherein A2 is a halogen atom, with a corresponding alkylalcohol under carbon monoxide atmosphere using a palladium catalyst in the presence of a base in a suitable solvent. The same palladium catalyst and base as those described in the above (EC) can be preferably used. Additionally, the reaction can be more preferably carried out by adding a ligand, and phosphines described in the above (EC) can be preferably used as the ligand. (EG) The compound wherein A2 is an optionally substituted alkenyl group can be prepared by coupling a compound of the formula (1) wherein A^ is a halogen atom with a corresponding alkene. The coupling reaction can be carried out in the presence of a palladium catalyst in the presence or absence of a base in a suitable solvent. The same palladium catalyst as that described in the above (EC) can be preferably used. The same base as that described in the above (EC) can be preferably used and silver carbonate can also be used. Additionally, the reaction can be more preferably carried out by 64 adding a ligand, and phosphines described in the above (EC) can be preferably used as the ligand. {EG') The compound wherein A^ is an optionally substituted ajkenyl group can be prepared by dehydration reaction of a compound having a hydroxyalkyl group in a substituent A^. The dehydration reaction can be carried out by treating a starting compound with acid. As the acid, a conventional acid can be used. For example, an inoroganic acid (e.g. hydrochloric acid, nitric acid and sulfuric acid) or an origanic acid (e.g. methane sulfonic acid, p-toluene sulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethane sulfonic acid, and the like) can be preferably used. (EH) The compound wherein A^ is a boronic acid ester can be prepared by reacting with the compound wherein Pfi is a leaving group with a trialkoxyborane (trimethoxyborane, triisoprGpojQrborane, and the like), a dialkoxyborane (pinacolborane, and the like) or a tetraalkoxydiboron {bis(pinacolato)diboron, and the like) in the presence of palladium catalyst. The leaving group includes a halogen atom including chlorine atom, bromine atom, iodine atom, and a substituted sulfonyloxy group including methane sulfonyloxy group, trifluoromethanesulfonyloxy group, and toluenesulfonyloj^ group. The reaction can be carried out in the same manner as in the above (EC). (EH) The compound wherein A^ is a hydroxy group can be prepared by reacting the compound wherein A^ is a boronic acid ester with the peroxide. Aqueous hydrogen peroxide, m-chloroperbenzoic acid and OXONETM (DuPont Co. Ltd), and the like can be perferably used as the peroxide. (El) The compound wherein A2 is an alkoxy group or a substituted alkoxy group can be prepared by alko^lating the compound (1) wherein A^ is a halogen atom. The alkoxylation can be carried out by optionally adding a copper 65 catalyst to react with a corresponding alcohol in a suitable solvent or solvent-free in the presence of a base. The same base as described in the above (EC), in particular, cesium carbonate can be preferably used. The copper catalyst including copper iodide, copper bromide, copper chloride, copper acetate, copper trifluoromethanesulfonate, and the like can be preferably used. Additionally, this reaction proceeds more preferably when 1,10-phenanthroline, 2-aminopyridine, or the like is added. (EJ) The compound wherein A^ is an optionally substituted alkyl group, an optionally substituted heterocyclic group or an optionally substituted aryl group can be prepared by coupling a compound of the formula (1) wherein A^ is a leaving group with a corresponding alkyl, aryl or heterocyclic boronic acid or a corresponding alkyl, aiyl or heterocyclic boronic acid ester. 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. This reaction can be carried out in the same manner as in the above (EC). The leaving group is the same as defined above (EH). (EJ') The compound wherein A^ is an optionally substituted alkyl group, an optionally substituted heterocyclic group or an optionally substituted aiyl group can be prepared by coupling a compound of the formula (1) wherein A^ is a boronic acid or a boronic acid ester with an alkyl, an aryl or a heterocyclic group which have a leaving 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 meinner as in the above (EC). The leaving group is the same as defined above (EH). (EK) The compound wherein A^ is an alkoxycarbonylalkylsulfonyl 66 group can be prepared by reacting a compound of the formula (1) wherein A2 is a halogen atom with an alkoxycarbonylalkylsulfinic acid alkaline metal salt. The alkoxycarbonylalkylsulfinic acid alkaline metal salt can be prepared according to the method described, for example, in Baskin et. al., Tetrahedron Lett., 43, 8479 (2002). Additionally, this reaction can be carried out in the presence of a copper catalyst in a suitable solvent according to the method described in the said literature. The same copper catalyst as described in (EI) above can be used, and in particular, copper iodide can be preferably used. (EL) The compound wherein A^ is a group of the formula: wherein the symbols have the same meaning as defined above, can be prepared by condensing a compound wherein A^ is a hydroxy group with a compound of the formula: wherein X^i is O, SO, SO2 or NRP (RP is a protecteing group) and q is an integer from 1 to 4, and as needed, removing the protecting group for amino group. As a protecting group, a conventional protecting group including benzyloxycarbonyl group, tert-butoxycarbonyl group, and the like can be used. The reaction can be carried out in a suitable solvent in the presence of phosphines and azodicarbojiylic esters. The reaction can be carried out in the same manner as in the above (EA). The removal of a protecting group can be carried out in a conventional manner including catalj^tic reduction, acid-treatment, and the 67 like, depending on the type of a protecting group. The same manner as in the above reactions (EA) to (EL) for conversions of A^ can also be applied for conversion of the other substituent as needed. Additionally, a substituent(s) of a compound (1) of the present invention can be converted into different one(s) within the scope of the compound (1) according to the following methods as appropriate. In the following each process, a conventional base can be used as the base, and unless otherwise specified, the base described in the above (EA) can be preferably used. Additionally, in the following each process, a conventional acid can be used as the acid, and unless otherwise specified, a mineral acid including hydrochloric acid, nitric acid, sulfuric acid, or an organic acid represented by sulfonic acids (e.g., methane sulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid) or carbojQrUc acids (e.g., acetic acid, trifluoroacetic acid) can be preferably used. Further additionally, in the following each process, any solvent which dose not disturb the reaction can be used, and as such, the solvent described in the above (EA) can be preferably used. The leaving group includes a halogen atom including chlorine atom, bromine atom, iodine atom, and a substituted sulfonyloxy group including m ethane sulfonyloj^ group, trifluoromethane sulfonyloxy group, and toluenesulfonyloj^ group. (El) The compound wherein A is a heterocyclic group substituted by an optionally substituted amino group or a group of the formula: wherein the symbols have the same meanings as defined above, can be prepared by reacting a compound (1) wherein A is a heterocyclic group 68 substituted by an optionally substituted alkylsulfonyloxy group, with a corresponding amine or a compound of the formula: wherein the symbols have the same meaning as defined above in the presence of a palladium catalyst, and in the presence or absence of a base in a suitable solvent or solvent-free. The reaction can be carried out in the same manner as in the above (EC). (E2) The compound wherein A is a heterocyclic group substituted by an optionally substituted amino group or a group of the formula: wherein the ssnnbols have the same meanings as defmed above, can also be prepared by reacting a compound wherein A is a heterocyclic group substituted by a halogen atom or an optionally substituted alkylsulfonyloxy group, with a corresponding amine or a compound of the formula: wherein the symbols have the same meanings as defined above. The reaction can be carried out by optionally adding a copper catalyst in the presence or absence of a base in a suitable solvent. Copper iodide, copper bromide, copper chloride, copper acetate, copper trifluoromethanesulfonate, and the like can be preferably used as the copper catalyst. The same base as that described in the above (EC) cein be preferably 69 used. Additionally, the reaction proceeds more preferably when N,N'- dimethylethylenediamine, 1,10-phenanthroline, ethylene glycol, phenylphenol, and the like is added. (E3) The compound wherein A is a heterocyclic group substituted by an optionally substituted alkylsulfanyl group can be prepared by reacting a compound wherein A is a heterocyclic group substituted by a halogen atom or an optionally substituted alkylsulfonyloxy group with a corresponding alkylthiol. The reaction can be carried out in the same manner as in that described in the above (EI) and more preferably facilitated by adding 1,10-phenanthroline or ethylene glycol. (E4) The compound wherein A is a heterocyclic group substituted by an optionally substituted heterocyclic group can be prepared by coupling a compound wherein A is a heterocyclic group substituted by a halogen atom or an optionally substituted allq^lsulfonylojQr group with a corresponding heterocyclic tin compound or a corresponding heterocyclic boron compound. The reaction can be carried out in the same manner as in the above (ED) or (EI). (E5) The compound wherein A is a heterocyclic group substituted by an alko3^ group can be prepared by reacting a compound wherein A is a heterocyclic group substituted by a halogen atom or an alkylsulfonyl group with a corresponding alkaline metal alkoxide in a suitable solvent. The corresponding alkaline metal alkoxide can be obtained by treating a corresponding alltylalcohol with alkaline metal hydride or alkaline metal in the said solvent. (E6) The compound having an aminoall^l group as a substituent on A can be prepared by catalytically reducing a compound having a cyano group or a cyanoall^l group as a substituent on A. 70 The catalytic reduction can be carried out by using a catalyst under hydrogen atmosphere in a suitable solvent in a conventional majiner. The catalyst includes a palladium catalyst including palladium-carbon, a nickel catalyst including Raney nickel, a platinum catalyst including platinum-carbon, and the like. (E?) The compound having an optionally substituted mono- or di-alkylsulfamoylaminoalkyl group as a substituent on A can be prepared by reacting a compound having an aminoalkyl group as a substituent on A with a corresponding halogenated mono- or di-alkylsulfamoyl. The reaction can be carried out in a suitable solvent in the presence of a base. (E8) The compound having an optionally substituted mono-alkylcarbamoylaminoalkyl group as a substituent on A can be prepared by reacting a compound having an aminoalkyl group as a substituent on A with a corresponding alkyl isocyanate in a suitable solvent. (E9) The compound having a group of the formula: wherein R9 is an all^l group and the other symbols have the same meanings as defined above as a substituent on A can be prepared by reacting a compound having a group of the formula; wherein the symbols have the same meanings as defined above as a substituent on A with a corresponding alkyl isocyanate (R^IMCO). The reaction can be carried out in the same manner as in the above (E8). (ElO) The compound having an optionally substituted mono- or di- 71 alkylcarbamoylaminoalkyl group as a substituent on A can be prepared by condensing a compound having an aminoalkyl group as a substituent on A with an optionally substituted mono- or di-alkylamine using a carbonylating agent in a suitable solvent in the presence or absence of a base. A conventional carbonylating agent such as carbonyldiimidazole, phosgene, triphosgene, and the like can be used. (Ell) The compound having a morpholinylcarbonylamino group as a substituent on A can be prepared by condensing a compound having an amino group as a substituent on A with morpholine using a carbonylating agent in a suitable solvent. The reaction can be carried out in the same manner as in the above (E ] 0). (E12) The compound having a group of the formula: wherein X12 is O or NH, as a substituent on A can be prepared by treating a compound having a group of the formula; H-X12-CH2-CONH- wherein the symbols have the same meanings as defined above as a substituent on A with a carbonylating agent in a suitable solvent. The reaction can be carried out in the same manner as in the above (ElO). (E12') The compound having a group of the formula: wherein X^^ is O or NH, as a substituent on A can be prepared by treating a compound having a group of the formula; 72 H-X12-CH2- CH2-NH- wherein the symbols have the same meanings as defined above as a substituent on A with a carbonylating agent in a suitable solvent. The reaction can be carried out in the same manner as in the above (ElO). (El3) The compound having an optionally substituted carbamoyl group as a substituent on A can be prepared by condensing a compound having a carboxyl group as a substituent on A with a desirable amine. The condensation can be carried out using a condensing agent in a suitable solvent. A conventional condensing agent such as dicyclohexylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl}carbodiimide, carbonyldiimidazole, and the like can be preferably used. Additionally, the condensation can be more preferably carried out by adding an activating agent including 1-hydroxybenzotriazole, 1-hydroxysuccinimide, and the like. (El4) The compound having a group of the formula: wherein the symbols have the same meanings as defined above as a substituent on A can be prepared by condensing a compound having a carboxyl group as a substituent on A with a compound of the formula: wherein the symbols have the same meanings as defined above. The reaction can be carried out in the same manner as in the above (E13). (El5) The compound having a tetrazolyl group as a substituent on A can be prepared by reacting a compound having a cyano group as a substituent on A with an alkaline metal azide in the presence of an acid in 73 a suitable solvent. The alkaline metal azide includes sodium azide, lithium azide, and the like. An ammonium salt of a halogenated hydrogen including ammonium chloride can be preferably used as the acid. (E16) The compound having an optionally substituted alkyl tetrazolyl group as a substituent on A can be prepared by alkylating a com^pound having a tetrazolyl group as a substituent on A. The alkylation can be carried out in the same manner as in the above (EA). (E17) The compound having an optionally substituted amino group or a group of the formula: wherein the symbols have the same meanings as defined above as a substituent on A can be prepared by reacting a compound having a halogen atom or an optionally substituted alkylsulfonyloxy group as a substituent on A with a corresponding amine or a compound of the wherein the s3Tnbols have the same meanings as defined above. The reaction can be preferably carried out in the presence or absence of a base in a suitable solvent. (E18) The compound having an optionally substituted alkylamino group or a group of the formula: 74 wherein R^^ is an alkyl group optionally substituted by a hydroxy group, an alkoxycarbonyl group, a morpholinyl group or a phenyl group, and n has the same meaning as defined above, as a substituent on A can be obtained by reacting a compound having an amino group or a group of the formula: wherein the symbols have the same meanings as defined above as a substituent on A with a corresponding allq'l halide or a corresponding sulfonic alkyl esters. The sulfonic alkyl esters including methane sulfonic ester, toluenesulfonic ester, trifluoromethanesulfonic ester, and the like can be preferably used. The reaction can be preferably carried out in the presence or absence of a base in a suitable solvent. (E19) The compound having a group of the formula: wherein Xi3 is O or NH, and the other symbol has the same meaning as defined above as a substituent on A, can be prepared by ring-closing a compound having a group of the formula: Z3-(CH2)n-X13-CH2-CONH- wherein Z^ is a leaving group and the other S5Tnbols have the same meanings as defined above, as a substituent on A. The reaction can be preferably carried out in the presence or absence of a base in a suitable solvent. (E20) The compound having a carboxyl group as a substituent on A can be prepared by hydrolyzing a compound having an alkoxycarbonyl group as a substituent on A. The hydrolysis can be carried out by treating a starting compound 75 with a base or an acid in a suitable solvent according to a conventional manner. An alkaline metal hydroxide can be preferably used as the base. (E21) The compound conteiining a carboxyl group as a substituent on A can be prepared by hydrolyzing a compound containing a cyano group as a substituent on A. The hydrolysis can be carried out by treating a starting compound with an acid or a base in a suitable solvent. (E22) The compound containing a carbamoyl group as a substituent on A can be prepared by hydrolyzing a compound containing a cyano group as a substituent on A. The hydrolysis can be carried out by treating a starting compound with an acid or a base in a suitable solvent. (E23) The compound having a carboxyalkyl group as a substituent on A can also be prepared by catal5^cally reducing a compound having a carboxyalkenyl group, a benzyloxycarbonylalkenyl group or a benzyloxycarbonylalkyl group as a substituent on A. The catalytic reduction can be carried out in the same manner as in the above {E6}. {E24) The compound having a hydroxy group as a substituent on A can be prepared by hydrolyzing a compound wherein A has an alkanoylo3cy group. The hydrolysis can be carried out in the same manner as in the above (E20). (E25) The compound containing sulfoxide (SO) or sulfone {S02) in a substituent on A can be prepared by oxidizing a compound having S in a substituent on A (e.g., a compound having a thiomorpholinyl group or an alkylsulfanylallq'l group as a substituent on A). The oxidation can be carried out by treating a starting compound with an oxidizing agent in a suitable solvent. Peroxides such as hydrogen peroxide, m-chloroperbenzoic acid, 76 acetyl hydroperoxide, and the like can be preferably used as the oxidizing agent. (E26) The compound containing N-oxide in a substituent on A can be prepared by oxidizing a compound having N in a substituent on A (e.g., a compound having a pyridyl group as a substituent on A). The oxidation can be carried out in the same manner as in the above (E25). fE27) The compound having a 1,2-dihydroxyalkyl group as a substituent on A can be prepared by treating a compound having an alkyl group substituted by mono- or di-alkyldioxolanyl group as a substituent on A with an acid in a suitable solvent. A strongly acidic resin can also be preferably used as the acid, in addition to those previously described. (E28) The compound having an alkyl group substituted by a hydroxy group and an optionally substituted alkoxy group as substituents on A can be prepared by reacting a compound having an oxylanylalkyl group as a substituent on A with an alkaline metal salt of the corresponding alcohol in a suitable solvent. The alkaline metal salt of alcohol includes a lithium salt, a sodium salt, a potassium salt, and the like. (E29) The compound having an alkyl group substituted by a hydroxy group and an amino group, or an alkyl group substituted by a hydroxy group and an optionally substituted mono- or di-alkylamino group as substituents on A can be prepared by reacting a compound having an OJ^lanylalkyl group as a substituent on A with ammonia or a corresponding mono- or di-alkylamines in a suitable solvent. (E30) The compound having a hydro^carbamimidoyl group as a substituent on A can be prepared by reacting a compound having a cyano group as a substituent on A with hydroxylamine or a salt thereof in a suitable solvent. Any solvent which does not disturb the reaction can be 77 used, and as such, the solvent described in the above (EA) can be preferably used. (E31) The compound having an oxodihydrooxadiazolyl group as a substituent on A can be prepared by reacting a compound having a hydroxycarbamimidoyl group as a substituent on A with a carbonylating agent in a suitable solvent in the presence or absence of a base. The same carbonylating agent as that described in the above (ElO) can be used. (E32) The compound having a sulfo group as a substituent on A can be prepared by hydrolyzing a compound having an alkoxycarbonylalkylsulfonyl group as a substituent on A. The hydrolysis can be carried out in the same manner as in the above (E20). (E33) The compound having a sulfamoyl group as a substituent on A can be prepared by condensing a compound having a sulfo group as a substituent on A with a desirable 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, followed by reacting the resulting compound with a desirable amine in the presence or absence of a base. A conventional halogenating agent including thionyl halide, phosphorus oxyhalide, or the like can be used. (E34) The compound having a hydroJ^allQ^l group as a substituent on A can be prepared by reducing a compound having a carboj^alkyl group as a substituent on A, or by converting the carboxyl group into an acid anhydride or an ester and then reducing the resulting compound. A process for conversion into an acid anhydride can be carried out by reacting a starting compound with a halogenated alkyl formate in a suitable solvent in the presence of a base. A process for conversion into an ester can be carried out by reacting 78 a starting compound with an alcohol in the presence of a condensing agent in a suitable solvent. This process can be carried out in the same manner as in (E33) except that a desirable alcohol is used in place of amine. The reduction can be carried out by treating the resulting compound with a reducing agent in a suitable solvent. Boron hydrides (e.g. sodium borohydride), aluminum hydrides (lithium aluminum hydride, diisobutylaluminum hydride, and the like) can be preferably used as the reducing agent. (E35) The compound having an aromatic group substituted by a cyano group as a substituent on Ri, optionally having one to three heteroatoms independently selected from oxygen atom, sulfur atom and nitrogen atom (hereinafter, referred to as "an aromatic group"), can also be prepared by cyanating a com.pound having an aromatic group substituted by a halogen atom as a substituent on Ri. The cyanation can be carried out in the same manner as in the above (EE). (E36) The compound wherein A is a hydrogen atom can be prepared by acid-treatment or reduction of a compound wherein A is a tert-butoxycarbonyl group or a benzyloxycarbonyl group. The acid-treatment can be carried cut 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). (E37) The compound wherein A is an optionally substituted alkoxycarbonyl group, or an optionally substituted carbamoyl group can be prepared by reacting a compound wherein A is a hydrogen atom with a carbonylating agent, or a desirable alcohol or a desirable simine in a suitable solvent. The reaction can be carried out in the same manner as in the above (ElO). (ESS) The compound having an amino group as a substituent on A 79 can be prepared by undergoing a Curtius rearrangement reaction of a compound having a carboxyl group as a substituent on A. Curtius rearrangement reaction can be carried out using a conventional azidating agent (e.g., diphenylphosphorylazide, and the like) in a suitable solvent in the presence of a base. The reaction may also be carried out by adding alcohols to provide a compound having an optionally substituted alkoxycarbonylamino group as a substituent on A, followed by removing the alkoxycarbonyl group. The removal of the alkoxycarbonyl group can be carried out in a conventional manner such as an acid-treatment or a reduction depending on the type of 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 meinner as in the above (E23). (E39) The compound having a hydroxy group as a substituent on A can be prepared by cataljTically reducing a compound having a benzyloj^ group as a substituent on A. The reduction can be carried out in the same manner as in the above (E23). (E40) The compound having an oxo group as a substituent on A can be prepared by oxidizing a compound having a hydroxy group as a substituent on A. The oxidation can be carried out by using an oxidizing agent in a suitable solvent. A conventional oxidizing agent can be used as the oxidizing agent, such as chromate-pyridine complex, pjridinium chlorochromate, pyridinium dichromate, Dess-Martin reagent (1,1.1 -tris(acetoxy) -1,1-dihydro-l,2-ben2iodoxol-3-(lH)-one), dimethylsulfoxide, and the like. (E41) The compound containing an optionally substituted alkoxy group as a substituent on A can be prepared by alkylating a compound containing an oxo group or a hydroxy group as a substituent on A. The alkylation can be carried out by using a corresponding 80 compound in the same manner as in the above (EA). (E41 ■) The compound containing an optionally substituted heterocyclyloxy group or an optionally substituted aryloj^ group as a substituent on A can be prepared by coupling a compound containing a hydro;^ group as a substituent on A with a corresponding aiyl compound or a heterocyclic compounds which have a leaving group. The coupling can be carried out in the same manner as in the above (EC). The leaving group have the same meaning as defined above (EH). (E42) The compound having an optionally substituted alkanoylamino group as a substituent on A can be prepared by condensing a compound having an amino group as a substituent on A with a corresponding carbojcylic acid or a reactive derivative thereof. The condensation with the corresponding carboxylic acid can be preferably carried out in a suitable solvent in the presence of a condensing agent. The reaction can be carried out in the same manner as in the above (E13). Additionally, the condensation with the reactive derivative of the corresponding carboxylic acid can be carried out in a suitable solvent or solvent-free in the presence or absence of a base. The reactive derivative includes an acid halide, an acid anhydride, an activated ester, an activated amide, and the like. (E43) The compound having a group of the formula: wherein R^t is an alkanoyl group optionally substituted by a hydrojq' group or an alkoxy group, and n has the same meaning as defined above, as a substituent on A can be prepared by condensing a compound of a group of the formula: 81 wherein the symbol has the same meaning as defined above, as a substituent on A with a corresponding carboxylic acid or a reactive derivative thereof. The reaction can be carried out in the seime manner as in the above (E42). (E44\| The compound having a maleimide group as a substituent on A can be prepared by reacting a compound having an amino group as a substituent on A with a maleic anhydride. The reaction can be carried out in a suitable solvent. (E45) The compound having an sJkyl group substituted by a pyridyl group and a hydroxy group as substituents on A can be prepared by reacting a compound having an all^l group substituted by a p3Tidyl group of which nitrogen atom is oxidized as a substituent on A with a trifluoroacetic anhydride. The reaction can be carried out in a suitable solvent. (E46) The compound having a halogen atom as a substituent on A can be prepared by treating a compound having a hydroxy group as a substituent on A with a halogenating agent. As the halogenating agent, a conventional halogenating agent including thionyl chloride, phosphorus oxychloride, as well as carbon tetrahalide (e.g., carbon tetrachloride, carbon tetrabromide, and the like) and phosphines (e.g., triphenylphosphine, tritolylphosphine, triethylphosphine, and the like) can be preferably used. (E46') The compound having a halogen atom as a substituent on A can be prepared by treating a compound with a halogenating agent. As the halogenating agent, a conventional halogenating agent such as bromine, N-bromosuccinimide, and the like can be preferably used. (E47) The compound having a cyanoalkyl group as a substituent on 82 A can be prepared by reducing a compound having a cyanoalkenyl group as a substituent on A. The reduction can be carried out by treating a starting compound with a reducing agent or by catalytically reducing in a suitable solvent. Any reducing agent can be used subject that it reduces only a double bond without affecting a cyano group. For example, sodium bis{2-metho3^ethoxy}aluminum hydride in the presence of a copper bromide can be preferably used. The catal3^c reduction can be carried out in the same manner as in the above (E23). (E4S) The compound (1) having a hydroj^all^l group as a substituent on A can be prepared by reducing a compound having a formyl group as a substituent on A. The reduction can be carried out by treating a starting compound with a reducing agent in a suitable solvent. The reaction can be carried out in the same manner as in the process for reducing in the above {E34}. (E49) The compound wherein a substituent on B is a hydroxy group can be prepared by demethylating a compound wherein the substituent on B is a methoxy group. The demethylation can be carried out by treating a starting compound with a demethylating agent in a suitable solvent. A conventional reagent including trimethylsilyl iodide, hydrogen bromide/acetic acid, boron tribromide, concentrated sulfuric acid, and the like can be used as the demethylating agent. (E50) The compound wherein a substituent on B is an optionally substituted alkoxy group can be prepared by allQ'lating a compound wherein the substituent on B is a hydrojQr group. The all^lation can be carried out in the same manner as in the above (EA). 83 (E51) The compound wherein a substituent on B is an optionally substituted alkylaulfonyloxy group can be prepared by alkylsulfonylating a coinpound wherein the substituent on B is a hydroxy group. The alkylsulfonylation can be carried out by reacting a corresponding all^Isulfonyl halide or a corresponding alkylsulfonic anhydride in a suitable solvent in the presence or absence of a base. (E52) The compound wherein a substituent on B is a cyano group can be prepared by cyanating a compound wherein 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) The compound wherein a substituent on B is an aminoalkyl group can be prepared by reducing a compound wherein the substituent on B is a cyano group. The reduction can be carried out in the same manner as in the above (E6). (E54} The compound wherein a substituent on B is an alkyl group can be prepared by alkylating a compound wherein the substituent on B is an optionally substituted alkylsulfonyloxy group. The alkylation can be carried out by reacting alkyl aluminums in the presence of a palladium catalyst, a silver catalyst and a copper catalyst in a suitable solvent. Tetrakis(triphenylphosphine}palladium as the palladium catalyst, silver carbonate as the silver catalyst, copper (I) chloride as the copper catalyst can be preferably used. (£54) The compound wherein a substituent on B is an optionally substituted alkyl group can be prepared by catalytically reducing a compound wherein a substituent on B is an optionally substituted alkenyl group. The reaction can be carried out in the same manner as in the above (E6). 84 (E55) The compound having an imidazolinyl group or an oxazolinyl group as a substituent on A can be prepared by (i) reacting a compound containing a cyano group as a substituent on A with a desirable alcohol in the presence of an acid in a suitable solvent or solvent-free to provide a compound containing an alkoxycarbonimidoyl group as a substituent on A, and (ii) reacting the compound containing an alkoxycarbonimidoyl group as a substituent on A with 2-aminoethanol or ethylene diamine in a suitable solvent or solvent-free. {E56i The compound having a carboxyl group as a substituent on A can be prepared by (i) oxidizing a compound containing a hydroxyalkyl group as a substituent on A in the same manner as in the above (E40) to provide a compound containing an oxo group as a substituent on A, and (ii) oxidizing the compound containing an oxo group as a substituent on A. The oxidization for the second process can be carried out by using an oxidizing agent in a suitable solvent. Sodium^ chlorite, Silver(I) oxide, Sodium periodate and the like can be preferably used as the oxidizing agent. (E57) The compound having a carbojQ^l group as a substituent on A can be directly prepared by oxidizing a compound containing a hydroxyalkyl group as a substituent on A. The oxidization can be carried out by using Jones reagent, potassium permanganate, and the like as the oxidizing agent. (ESS) The compound wherein A is hydrogen atom can be prepared by treating a compound wherein A is ethoxycarbonyl group with a silyl halide or a base. Trimethylsilyl iodide can be preferably used as the silyl halide. Sodium hydroxide can be preferably used as the base. In each process for preparing a compound (1) described above, when protection of a functional group contained in any compound is needed, the protection can be carried out in a conventional manner as appropriate. General statement related to protecting groups aind their use is provided by 85 Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991. When an amino group is protected by a benzyloxycarbonyl group, the protecting group can be removed by a catalj^c reduction under hydrogen atmosphere in a suitable solvent. When a hydroxy group is protected by a benzyl group, the protecting group can also be removed by a catal5^c reduction in a similar manner as above. When an amino group is protected by a tert-butoxycarbonyl group, the protecting group can be removed by treating a starting compound with an acid (e.g., hydrochloric acid, trifluoroacetic acid, toluenesulfonic acid, and the like) in a suitable solvent. When a hydroxy group is protected by a tetrahydropyranyl group, the protecting group can also be removed by treating a starting com.pound with an acid in a similar manner as above. Other substituents of the present compouind (1) can also be converted in the same manner as in the reactions (El) to (E58) for conversion of the above groups. [Preparation of a compound (6')] The compound (6") can be prepared according to the following method (a) or (b). (a) The compound (6") can be prepared by reacting the compound of wherein X^t is a leaving group and the other symbols have the same meanings as defined above, with the compound of a general formula (11): H-R2 (11) wherein the symbol has the same meaning defined above, in the same manner as in the above process I-l or process I'-l. 86 (b) The compound {6) can be prepared by reacting the compound of wherein P is a protecting group for a carboxyl group and the other symbols have the same meanings as defined above, with the compound fll) in the same manner as in the above process I-l or process I'-l, followed by reducing the resulting compound to provide the compound {6") and further oxidizing the resulting compound. The reduction and oxidation in the above methods can be carried out by the conventional method. [Preparation of a compound (2)] The compound (2) can be prepared by oximating the compound (6") to provide the compound of a general formula (13): wherein the symbols have the same meanings as defined above, followed by reducing the resulting compound. The oximation can be carried out by the conventional oximation methods, for example, by treating the compound (6') with a salt of hydroj^lamine in the presence of an acid or a base such as alkaline metal hydroxide, sodium acetate or pyridine in an alcohol, acetic acid or pyridine. Also einy acidic material can be used as the agent for preparing a salt of hjdroxyl amine, for example, a mineral acid (e.g. sulfuric acid, phosphoric acid, hydrogen bromide and hydrogen iodide), and organic acid (e.g. acetic cid, oxalic acid, trichloroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, 1,5-naphthalenedisulfonic acid). The subsequent reduction reaction can be carried out in a conventional manner. 87 The compound (2) can aJso be prepared from the compound {6") using the method of Gabriel synthesis, described in detail in Mitsunobu, O. Comp. Org. Syn. 1991, 6, 79-85. [Preparation of a compound (6'"")] The compound (6'"") can be prepared from the compound of a general formula (14): wherein X^s is a leaving group and the other symbols have the same meanings as defined above, by a conventional insertion reaction of carbon monoxide aith a transition metal catalyst. The reaction can be carried out in an aprotic solvent such as tetrahydrofuran or DMF, and the like. Preferred transition metal includes, for example, a salt form of palladium such as palladium {II)-acetate, and the like or a palladium (0) compound such as tetrakis(triphenylphosphine)palladium, and the like. This kind of an insertion reaction of carbon monoxide can be carried out by the method described in detail in J. Org. Chem. 1992, 57, 5979 or "Organometallic compound-Synthesis and Application-(Tokyo Kagaku Dozin Co., Ltd.), Metal-catalyEed Cross-coupling Reaction (WILLY-VCH), Handbook of Palladium-Catalyzed Organic Reactions (Academic Press)", and the like. The compound (1-a) wherein A^ is tetrazolyl group and A^ is a hydrogen atom can be prepared by cyanidating the above compound (8') to provide the compound of a general formula (8""); wherein the symbols have the same meanings as defined above, folowed by reacting with an alkaline metal azide. 88 The cyanidation can be carried out by reacting a starting compound with cyanogen halide in the presence of a base in a suitable solvent. The cyanogen halide is preferably cyanogen bromide. The conventional base can be preferably used as a base, such as alkaline metal carbonate (e.g. potassium carbonate) or an alkaline metal bicarbonate (e.g. sodium bicarbonate). Any solvent which dose not disturb the reaction can be used as a solvent and the solvent illustrated in the above method I can be preferably used. The conversion of a cyano group into a tetrazolyl group can be achieved by reacting the compound having a cyano group with an alkaline metal azide in the presence of an acid in a suitable solvent. The alkaline metal azide includes sodium azide and lithium azide, and the like. The ammonium salt of halogenated hydrogen such as ammonium chloride can be preferably used as an acid. In addition, for performing the above methods, there can be referred to PCX International Publication WO04/020393 pamphlet, WO05/100298 pamphlet and JP. 2003-221376 A. The methods for preparation of the compound (1) are applicable to preparation of the corresponding compounds of formula (I-A), (I-B) and (1- !)■ Many of starting materials and reagents for preparation of the aforementioned compound of the formula 1 are either commercially available or disclosed in literatures, or can be readily prepared by a method that is disclosed in literatures or used generally in the organic synthesis. Experiment The inhibitory activily of the compounds of the present invention against CETP was tested in this experiment. Preparation of Acceptor Microemulsion 89 A solution of l-Palimtoyl-2-oleoyl-sn-gIycero-3-phosphocholine (3.5 mg), cholesteryl oleate (Smg) and triolein (0.7 mg) in chloroform was mixed and lipid was air-dried under nitrogen gas to remove solvent. 1,4-Dioxane (0.25 ml) was then added and the mixture was stirred for dissolution. The resultant lipid solution (0.2 ml) was slowly injected under the surface of Tris-saline-EDTA(TSE) buffer solution [lOmM Tris/HCl (pH 7.4), 0.15M NaCl, 2mM EDTA] (10 ml) with Hamilton syringe, while sonicating in ice-bath. After 1-hour-sonication in ice-bath, the solution was stored at 4 "C. Preparation of Donor Microemulsion A solution of egg PC (phosphatidylcholine) (0.33 mg) and BODIFY-CE (0.62 mg) in chloroform was mixed. After removing solvent by air-drying lipid under nitrogen gas, TSE buffer solution (3 ml) was added and the solution was sonicated in ice-bath. This solution was filtered to sterilize through 0.22 pm filter and stored at 4 °C. Inhibitory Activity against CETP in vitio A test solution was prepared using dimethyl sulfoxide as a solvent. Plasma from a healthy volunteer was diluted to 0.64 % with TSE buffer, and to the resultant plasma solution (187 \|il) was added a test solution (3 \x\] or the solvent alone followed by incubation at 37 °C for 24 hours. After addition of TSE buffer solution (10 \d) containing 5 % donor micro-emulsion and 5 % acceptor microemulsion, the mixture was incubated at 37 °C for 3 hours. Before and after the incubation, the fluorescence intensity was measured at Ex.550nm/Em.600nm. CETP activity was defined as the difference between the measurements obtained before incubation and after incubation. The decreasing rate of the difference in the sample was defined as the inhibition rate of CETP activity. ICso for each sample was calculated from the inhibition rate of CETP activity. Using this protocol, compounds given in Examples were shown to exhibit a CETP inhibitory activity with an ICso of less than or equal to 50 ]iM. EXAMPLES 90 The present invention is illustrated in more detail by Examples and Reference Examples, but the present invention should not be construed to be limited thereto. Example 1 (1) 2-Fluoro-5-trifluoromethyl-benzaldehyde {2.7g) and ethyl-(2-methoxy-ethyl)-amine (2.18g) are dissolved in toluene (20ml), and thereto is added potassium carbonate (5.83g) and the mxture is stirred at 120°C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated brine and the mixture is separated, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—4:1) to give 2-[ethyl-(2-methoxy-ethyl}-amino]-5-trifluoromethyl-benzaldehyde (3.75g). MS (m/z): 276 [M+H]+ (2) 2-[Ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzaldehyde (3.7g), 3,5-bis-trifluoromethyl-benzylamine (4.23g), acetic acid (1.15ml) are dissolved in 1,2-dichloroethane (SOml), and thereto is added triacetoxy sodium borohydride (5.68g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution are added methylene chloride and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—»4:1) to give (2-[(3,5-bis-trifIuoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-ethyl-(2-methoxy-ethyl)-amine (3.3Sg). MS (m/z)i 503 [M+H]+. (3) {2-[(3,5-Bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-ethyl-(2-methoxy-ethyl)-amine (3.37g), 5-bromo-2-chlorop3a4midine (2.6g) and N-ethyldiisopropylamine (3.51ml) are dissolved in toluene (50ml) and the mixture is stirred at 120°C overnight. The reaction solution is 91 cooled to room temperature, and thereto are added ethyl acetate and water and the mixture is separated, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—>19:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromop5Timidin-2-yl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-aniine (4.06g). MS (m/z): 659/661 [M+H]* (4) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-{2-[ethyI-(2-methoxy-ethyl)-ainino]-5-trifluoromethyl-benzyl}-amine (350mg) is dissolved in toluene {5ml) and tris(dibenzylideneacetone)dipalladium (49ing), sodium tert-butoxide (77mg), 2-(di-tert-butylphosphino)biphenyl f63nig) and ethyl piperidine-4-carboxylate (119ial) and the mixture is stirred under nitrogen flow at room temperature overnight. To the reaction solution is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^3:1} to give ethyl l-[2-{(3,5-bis-trifluoromethyl-ben^yl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (212mg). MS (m/z): 7:36 [M+HJ+ (5) Ethyl l-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-{2-methoxy-ethyl)-aminoi-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carbo;^late (205mg) is dissolved in ethanol (2ml) and thereto is added 2N-aqueous sodium hydroxide solution (418^1) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated aqueous citric acid solution, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 92 1:1^0:1) to give l-[2-((3,5-bis-trifluoromethy]-benzy])-{2-jethy]-(2-methoxy-ethyI)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid (155mg). The resulting carbojq'lic acid is dissolved in ethanol (1ml) and thereto is added 2N-aqueous sodium hydroxide solution (llOpl) and the reaction solution is concentrated under reduced pressure to give l-[2-{(3,5-bis-trifluoromethyI-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino] - 5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid sodium salt (159mg). MS (m/z): 706 [M-Na]-Example 2 (1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (5.0g) and butyl-ethyl-amine (3.95g) are dissolved in toluene (50ml) and thereto is added potassium carhonate (10.78g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—4:1) to give 2-(butyl-ethyl-amino)-5-trifluoromethyl-benzaldehyde (6.54g). MS (m/z): 274 [M+H]- (2) 2-(Bu1yl-ethyl-£imino)-5-trifluoromethyl-benzaldehyde (5.5g), 3,5-bis-trifluoromethyl-ben^lamine (7.52g), acetic acid (2.04ml) are dissolved in 1,2-dichloroethane (50ml), and thereto is added triacetoxy sodium borohydride (10. Ig) at room temperature and the mixture is stirred for 2 hours. To the reaction solution are added IN-aqueous sodium hydroxide solution and methylene chloride, and the mixture is separated, and the organic layer is washed with a saturated brine and dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^4:1) to give {2-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-butyl-ethyl-amine (10.48g). MS (m/z); 501 [M+H]+ 93 (3) {2-[(3,5-Bis-trifluoromethyl-benzylaiiiino)-methyl]-4-trifluoromethyl-phenylj-butyl-ethyl-amine (4.6g), 5-bromo-2-chloropyriniidine (3.56g) and N-ethyldiisopropylethylamine (4.8ml) are dissolved in toluene (lOOml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-9:1) to give (3,5-bis-trifluoromethyl-ben^l) - (5-bromo-pyrimidin-2-yl) - [2 - (butyl-ethyl-amino) - 5-trilluoromethyl-benzyl]-amine (5.24g). MS (m/z): 657/659 [M+H]* (4) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl)-[2-(butyl-ethyl-ainino)-5-trifluoromethyl-benzyl]-amine (3.0g), [1,1'-bis(diphenylphosphino)ferrocenejdichloropalladium methylene chloride complex {112mg), potassium acetate (1.34g) and bis(pinacolate)diboron (1.74g) are dissolved in dimethylsulfoxide (20ml) and the mixture is heated to 80°C under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is dissolved in tetrahydrofuran (70ml) and thereto is added dropwdse a 30 % aqueous hydrogen peroxide solution (15ml) under ice-cooling. On hour thereafter, thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consum.e the excess hydrogen peroxide, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1->3:1) to give 2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)- 94 5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (263mg). MS (m/z): 595 [M+H]^ (5) 2-{(3,5-Bis-trifluoromethyl-benzyl}-[2-(buQ^l-ethy]-amino)-5-trifluoroinethyl-benzyll-ainino}-pyriinidin-5-ol (150mg) and ethyl 4-bromobutyrate (44vil) are dissolved in N,N-dimethylformamide (3ml) and thereto is added potassium carbonate (42mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—3:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-ben2yl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyll-amino}-pyrimidin-5-yloj^)-butyrate (117mg). MS (m/z): 709 [M+H]^ (6) Ethyl 4-(2-{{3,5-bis-trifluoromethyl-benzyl}-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-am.ino}-pjTiniidin-5-yloxy)-butyrate (1 lOmg) is dissolved in ethanol (2ml) and thereto is added a 2N-aqueous sodium hydroxide solution (233pl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated aqueous citric acid solution, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1 to 7:3) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl) - [2-(butyl-ethyl-amino) - 5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (69mg). The resulting carboxylic acid is dissolved in ethanol (0.2mL) and thereto is added 2N-aqueous sodium hydroxide solution (SOpl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-l2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (70mg). MS (m/z): 679 [M-Na]- 95 Example 3 (1) 2-((3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethy-ethyl-ainino)-5~trifluoroinethyl-benzyl]-aniino}-pyriniidin-5-ol (250mg) and 3-bromo-l-propanol (43ial) are dissolved in N^N-dimethylformamide (1ml) and thereto is added potassium carbonate (65mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mbcture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—3:1) to give 3-(2-{(3,5-bis-trifluorom ethyl-benzyl) - [2-(cyclohej^lmethy-ethyl-amino)-5 - trifluoromethyl-benzyl]-amino}-p3aimidin-5-yloxy}-propan-l-ol (150g). MS (m/z): 693 [M+H]+ (2) 3-(2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethy-ethyI-ainino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ylojcy)-propan-l-ol (140mg) is dissolved in methylene chloride (2ml), and thereto is added l,l,l-tris(acetyloj^)-l,l-dihydro-l,2-benziodoxoI-3-(lH)-one (188mg) at room temperature and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, 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 resulting residue is dissolved in the mixed solvent of tert-butanol (4ml) ad water (1ml) and thereto are added 2-methyl-2-butene (128iil), sodium dihydrogenphosphate dihydrate (44mg) and sodium chlorite (73mg) and the mixture is stirred at room temperature for 30 minutes. Thereto are added ethyl acetate and a IN-hydrochloric acid, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—2:3) to give 3-(2-{(3,5-bis- 96 lTifluoromethyl-benzyl)-[2-(cyclohexylmethy-ethyl-amino)-5-trifluoromethyl-benzyl]-ainino}-pyrimidin-5-yloxy)-propiomc acid (60ing). The resulting carboxylic acid is dissolved in ethanol {0.5ml), and thereto is added IN-aqueous sodium hydroxide solution (85\|il) and the reaction solution is concentrated under reduced pressure to give 3-(2-{(3,5-bis-trifluoromethyl-ben^l)-[2-(cyclohexylmethy-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-S-yloxy)-propionic acid sodium salt (60mg). MS (m/z): 705 [M-Na]-. Example 4 (1) Ethyl 4-{2-[[2-{benzyl-ethyl-ainino)-5-trifluoromethyl-benzyl]-(3,5-bis-trifluoromethyl-benzyl)-ainino]-pyrimidin-5-yloxy}-butyrate (4.07g) is dissolved in ethanol (60ml), and thereto is added 10% palladium-carbon {500mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 30 minutes. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1-17;3) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl}-(2-ethylaniino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyTate (S.lg). MS (m/z): 653 [M+Hj* (2) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trif]uoromethyl-benzyl)-amino]-pyrimid2n-5-yloxy}-butyrate (200rog) and pjnidine (371 pi) are dissolved in methylene chloride {5ml) , and thereto is added ethyl chlorocarbonate (293vil) under ice-cooling. The reaction solution is stirred at room temperature overnight and the organic solvent is concentrated under reduced pressure. To the residue are added ethyl acetate and an aqueous citric acid solution, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2- 97 (ethoxycarbonyl-ethyl -amino) -5-trifluoromethyl- benzyl]-aininoj- pyrimidin-5-yloxy)-butyrate (176mg). MS (m/z): 725 [M+H]* (3) Ethyl 4-(2-{(3,5-bis-txifluoromethyl-benzyl}-[2-(ethoxycarbonyl-ethyl-amino)-5-triflu oromethyl-benzyl j-ainino}-p3Timidin-5-yloxy)-butyrate fl70mg) is dissolved in ethanol (2ml), and thereto is added 2N-aqueous sodium hydroxide solution (352ial) and the mixture is stirred at room temperature for 1.5 hours and concentrated under reduced pressure. To the residue are added ethyl acetate and a IN-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-aniino)-5 - trifluoromethyl-benzyl]-arnino}-p>Timidin-5-yloxy)-butyric acid (147mg). The resulting carboxylic acid is dissolved in ethainol (1ml) and thereto is added 2N-aqueous sodium hydroxide solution {106pl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-ben^I]-amino}-pjT-imidin-5-yloxy)-butyric acid sodium salt (ISlmg). MS (m/z): 695 [M-Na]-Example 5 (1) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5- trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloj^}-bu^ate (lOOmg) and p5Tidine (19pl) are dissolved in methylene chloride (1ml) and thereto is added butyryl chloride (19^1} at room temperature. The reaction solution is stirred at room temperature for 30 minutes, and thereto are added methylene chloride and IN-hydrochloric acid, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-am.ino}-p3Timidin-5-yloxy)-butyrate 98 (84mg). MS (m/z): 723 [M+H]^ (2) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-aniino)-5-trifluoroinethyl-benzyl]-aiiiino}-pyrimidin-5-yloxy)-bufyrate (78ing) is dissolved in ethanol (Iml) and tiiereto is added a 2N-aqueous sodium hydroxide solution (162^1) and the mixture is stirred at room temperature for 3 hours. Thereto are added ethyl acetate and a IN-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{{3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl] - amino}-pyrimidin-5-yloxy}-butyric acid (66mg). The resulting carboxylic acid is dissolved in ethanol (0.5ml), and thereto is added 2N-aqueous sodium hydroxide solution (47fi]) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-triflu oromethyl-benzyl) - [2 - (bulyryl-ethyl-amino)-S-trifluoromethyl-ben^l]-amino\|-pyrimidin-5-yloxy)-butyric acid sodium salt (68mg). MS (m/z): 693 [M-Na]' Exam.ple 6 (1) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5- trifluoromethyl-benzyl)-amino]-p5nrimidin-5-yloxy}-butyrate (200mg) and triethylamine (51ial) are dissolved in methylene chloride (1ml), and thereto is added triphosgene (36mg) in a small amount at room temperature. The reaction solution is stirred at room temperature for 10 minutes and concentrated under reduced pressure. The residue is dissolved in tetrahydrofuran (1 ml) and therero is added a 2M ethylamine in tetrahydrofuran (1ml) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution are added ethyl acetate and a IN-hydrochloric acid, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—»■ 1:1) to give 99 ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(l,3-diet±iyllureido)-5- trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (ISlmg). MS (m/z): 724 [M+H] (2) Ethyl 4-(2-{{3,5-bis-trifluoroinethyl-benzyl)-[2-(l,3-diethyllureido)-5- trifluoromethyl-benzyl]-ainino}-pyrimidin-5-yloxy)-butyrate (165mg) is dissolved in ethanol (3inl) and thereto is added 2N-aqueous sodium hydroxide solution (342^1) and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl acetate and a IN- hydrochloric acid, 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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—17:3) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(l,3-diethyllureido}-5- trifluoromethyl-benzyll-amino}-p5Timidin-5-yloxy)-butyric acid (68mg). MS (m/z): 696 [M+H] Example 7 (1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (l-3g) and cyclopropylmethyl-propyl-amine (1.15g) are dissolved in toluene (13ml), and thereto is added potassium carbonate (2.81g) and the mixture is stirred at 120'C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = l:0->97:3) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-ben2aldehyde {l-7g). MS (m/z): 286 [M+H]+ (2) 2-(Cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (1.69g} is dissolved in ethanol (10ml) and thereto is added sodium borohydride (224mg) and the mixture is stirred for 15 minutes. To the 100 reaction solution are added a saturated aqueous ammonium chloride 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 resulting residue is dissolved in methylene chloride (10ml) and thereto is added thionyl chloride (492\|il) under ice-cooling, and the mixture is stirred for 10 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate 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. (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yI)-amine {2.7g) is dissolved in N,N-dimethylformamide (10ml) and thereto is added sodium hydride (62%) (343mg) at room temperature and the mixture is stirred for 30 minutes. Thereto are added dropwise a solution of a residue obtained above in N,N-dimethylformamide (10ml) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-p5Timidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyll-amine (3.38g). MS (m/z): 669/671 [M+H] (3) (3,5-Bis-trifluoromethyl-ben^l}-(5-bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-ben2ylj-amine (3.35g) [l,l'-bis(diphenylphosphino)ferroceneldichloropalladium dichloromethane complex (817mg), potassium acetate (1.47g), bis(pinacolate)diboron (2.54g) are dissolved in dimethylsulfoxide (20ml) and the mixture is heated to 80°C under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the insoluble materials is removed by filtration through Celite^'M and 101 the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (20ml\|, and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (lOml) under ice-cooling. One hour thereafter, thereto is added a saturated aqueous sodium thiosuifate solution under ice-cooling to consume the excess hydrogen peroxide, and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—4:1) to give 2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-triftuoromethyl-benzyl]-amino}-pyrimidin-5-ol {1.8g). MS (m/z): 607 [M+H]+ (4) 2-{{3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropylm ethyl-pro pyl-an3ino)-5-trifluoromethyl-ben2yl]-aminD}-pyrimidin-5-o] (SOOmg) and ethyl 4-bromobutyrate (SS^il) are dissolved in N,N-dimethylformamide (1ml) and thereto is added potassium carbonate (82mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, 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 resulting residue is purified by silica ge] column chromatography (hexane ; ethyl acGtate = 97:3—17:3) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cycloprQpylmethyl-propyl-amino) - 5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (296mg). MS (m/z): 721 [M+Hj* (5) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (290mg) is dissolved in ethanol (5ml) and thereto is added a 2N-aqueous sodium hydroxide solution (604\|ilj and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a IN- 102 hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropyImethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid {277mg). The resulting carboxylic acid is dissolved in ethanol (Imi) and thereto is added 2N-aqueous sodium hydroxide solution (200vil), and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoro methyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino) - 5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy}-butyric acid sodium salt (278mg). MS (m/z); 691 [M-Na]-Example 8 (1) To toluene (Sml) are added 2-fluoro-5-trifluoromethyl-benzaldehyde (650mg) and dimethylamine hydrochloride (2.76g), followd by addition of potassium carbonate {l-4g), and the mixture is stirred at 120'C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1^4:1} to give 2-dimethylamino-5-triiluoromethyl-ben2aldehyde (529mg). MS (m/z): 218 [M+H]* (2) 2-Dimethylamino-5-trifluoromethyl-benzaldehyde (144mg) is dissolved in ethanol (10ml) and thereto is added sodium borohydride (224mg) at room temperature and the mixture is stirred for 15 minutes. To the reaction solution are added a saturated aqueous ammonium chloride 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 resulting residue is dissolved in methylene chloride (2ml) and thereto is added thionyl chloride (58pl) under 103 ice-cooling and the mixture is stirred at room temperature for 10 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate 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. Ethyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-ylo:qr]-butyrate (200mg) is dissolved in N,N-dimethylformaniide (1.5ml) and thereto is added sodium hydride (62%) {26mg) under ice-cooling, and the mixture is stirred for 15 minutes. Thereto is added a solution of a residue obtained above in N,N-dimethylformamide (1.5ml), and the mixture is stirred at the same temperature for 15 minutes. To the reaction solution are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—t-9:l) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-dimethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-bu1yrate (97mg). MS (m/z): 653 [M+H]* (3) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-dimethylamino-5- trifiuoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (QOmg) is dissolved in ethanol (2ml), and thereto is added a 2N-aqueous sodium hydroxide solution (207^1), and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a IN-hydrochloric acid, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—1:4) to give 4-{2-[(3,5-bis-triiluoromethyl-benzyl)-(2-dimethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (29mg). The resulting carboxylic acid is dissolved in ethanol (0.5ml) and thereto is added a 2N-aqueous sodium 104 hydroxide solution (23vil} and the reaction solution is concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyI-benzyl)-(2-dimethylamino-5-trifluoromethyl-ben^l)-amino]-pyrimidin-5-yloxy}-butyric acid ethyl ester sodium salt (30mg). MS (m/z): 623 [M-Na]-Example 9 (1) 2-Fluoro-5-trifluoromethyl-benzylamine (2.0g) is dissolved in 1,4-dioxane (lOml) and thereto are added N.N-diisopropylethylamine (2.7ml) and 5-bromo-2-chloropyrimidine (3.02g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1 to 7:3) to give (5-bromo-p3Timidin-2-yl)-(2-fluoro-5-triiluoromethyl-benzyl)-amine (1.69g). MS [m/z): 350/352 [M+H] (2) (5-Bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (2.10g) is dissolved in N,N-dimethylformamide (10ml) and thereto is added sodium hydride (62.7%) (345mg) under ice-cooling and the mixture is stirred for 30 minutes, and thereto is added l-bromomethyl-3,5-bis-trifluoromethyl-benzene (2.76g) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixtrure is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0^9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-iluoro-5-trifluoromethyl-benzylj-amine (3.30g). MS (m/z): 576/578 [M+H]^ (3) (3,5-Bis-trifluorQmethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-eimine (300mg) is dissolved in toluene (5ml) and tris(dibenzylideneacetone)dipalladium (48mg), 2-(di-tert-butylphosphino)biphenyl (62mg), sodium tert-butoxide (75mg) and 105 morpholine (68^1) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by NH-silica gel column chromatography {hexane : ethyl acetate = 19:l-9:l) to give {3,5-bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl-benzyl)-(5-morphDlin-4-yl-pyrimidin-2-yl)-amine {176mg). MS (m/z): 583 [M+H] Example 10 (1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyTimidin-2-yl)-(2-fluoro- 5-trifluoromethyl-benzyl)-amine (300mg) is dissolved in toluene {5ml) and thereto are added tris(dibenzylideneacetone)dipalladium (48mg), 2-(di-tert-butylphosphinojbiphenyl (62mg), sodium tert-butoxide (75mg) and ethyl piperidine-4-carboxylate (120pl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by NH-silica gel column chromatography (hexane ; ethyl acetate = 19:1—9:1) to give l-{2-[(3,5-bis-trifluoromethyl-ben^l)-{2-fluoro-5-trifluoromethyl-ben^l)-amino]-pyrimidin-5-yl}-ethyl piperidine-4-CEirboxylate (Hlmg). MS (m/z): 653 [M+H] (2) l-{2-[(3,5-Bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl- benzyl)-amino]-pyrimidin-5-yl}-ethyl piperidine-4-carboxylate (105mg) is dissolved in ethanol (4ml) and thereto is added a IN-aqueous sodium hydroxide solution {2ml), and the mixture is stirred at room temperature for 2 hour. To the reaction solution are added IN-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is 106 washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = liO-^Qil) to give l-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl- ben^I)-aminoI-pyrimidin-5-yI}-piperidine-4-carboj^Iic acid (Slmg). MS (m/z): 625 [M+H]-^ Example 11 (1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trif!uoromethy]-benzy])-amine f300mg) is dissolved in tetrahydrofuran {3ml) and thereto are added ethyl-carbamic ethyl ester (67mg) and sodium hydride (60%) (23mg) and the mixture is stirred at 120°C under a condition of 192W by a microwave instrument for 1 hour and thereto are added ethyl-carbamic ethyl ester (134mg) and sodium hydride (60%) (46mg) and the mixture is stirred at 120°C under a condition of 192W by a microwave instrument for an additional 1 hour. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—'9:1) to give (3,5-bis-trifluoromethyl-ben^l)-(5-bromo-pyrimidin-2-yl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amine (220mg). MS (m/z): 602/604 [M+H]^ (2) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amine (210mg) is dissolved in toluene (5ml} and thereto are added tris(dibenzylideneacetone)dipalladium (32mg), 2-(di-tert-bulylphosphino)biphenyl (42mg), sodium tert-butoxide (50mg) and ethyl piperidine-4-carboxylate (SOiol) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 107 reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = l:0- (3) Ethyl l-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethoxy-5- trifluoromethyl-benzyl}-amino]-pyrimidin-5-yl}-piperidine-4-carboxylate (llOmg) is dissolved in ethanol (4nil) and thereto is added a iN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = l:0--9:l) to give l-{2-[(3,5-bis-trinuoromethyl-benzyl}-(2-ethoxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carboxylic acid (63mg). MS (m/z): 651 [M+H]+ Example 12 (1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (Ig) is dissolved in toluene (5ml) and thereto are added ethyl 7-ethylamino-heptanoate (3.98g) and potassium carbonate (2.88g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 97:3-»83:17) to give ethyl 7-[ethyl-(2-formyl-4-trifiuoromethyl-phenyl)-amino]-heptanoate (1.29g). MS (m/z): 374 [M+H]^ (2) Ethyl 7-[ethyl-(2-formyl-4-trifluoromethyl-phenyl)-amino]-heptanoate (1.29g) is dissolved in a mixed solvent of toluene {5ml) and etheinol (1ml), 108 and thereto is added sodium borohydride {156mg) and the mixture is stirred for 2 hours and 30 minutes. To the reaction solution are added a saturated aqueous ammonium chloride 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—3:1) to give ethyl 7-[ethyl-(2-hydroxymethyl-4-trifluoromethyl-phenyl)-amino]-heptanoate (589mg). MS (m/z): 376 [M+H] + (3) Ethyl 7-[ethyl-(2-hydroxymethyl-4-trifluoromethyl-phenyl)-amino]-heptanoate {580mg) is dissolved in toluene (10ml) and thereto is added thionyl chloride (135pl) under ice-cooling, and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added water 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 resulting residue is dissolved in N,N-dimethylformamide (10ml), and thereto are added (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (740mg) and sodium tert-butoxide (178mg) and the mixture is stirred at room temperature overnight. To the reaction solution are added a saturated aqueous ammonium chloride 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 resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 23 : 2-41: 9) to give ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoate (760mg). MS (m/z): 757/759 [M+H]+ (4) Ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) - amino]-me thy l}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoate (300mg) is dissolved in toluene (5ml) and thereto are added 109 tris(dibenzyiideneacetone)dipalladmm (37ing), 2-(di-tert- but7lphosphino}biphenyl (48mg), sodium tert-butoxide (58mg), and morpholine (53>il) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is sepeirated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-sHica gel column chromatography (hexane : ethyl acetate = 9:1-»4:1) to give ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yI-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyI-phenyl)-ethyl-amino]-heptanoate (254mg). MS (m/z): 764 [M+H] (5) Ethyl 7-\|(2-{[{3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl- p3T-imidin-2-yl)-aminol-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]- heptanoate (250mg) is dissolved in ethanol (4ml), and thereto is added a IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution are added a IN-hydrochloric acid and ethyl acetate, and the mixture is separated, eind the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-19:1) to give 7-l(2-{[(3,5-bis-trifluoromethyl- benzyl}-(5-morpholin-4-yl-pyTimidin-2-yl)-amino]-methyl}-4- trifluoromethyl-phenyl)-ethylaminoj-heptanoic add (ISlmg). The resulting 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)- aminol-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoic acid {131mg) is dissolved in ethanol (1ml), and thereto is added a IN-aqueous sodium hydroxide solution (178^1), and concentrated under reduced pressure to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]- heptanoic acid sodium salt (133mg). MS (m/z): 734 [M-Na]-Example 13 (1) Ethyl trans-(4-{[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino J-me thyl}-4-trifluoromethyl-phenyll-ethyl-amino]-methyl}-cyclohexyl)-acetate (which is prepared by treating the corresponding starting compound in a same manner as in Example 12 (1)-(3)) (2.6g) is dissolved dimethylsulfoxide (15ml), and thereto are added [l,r-bis(diphenylphosphtno}ferrocene]dichloropalladium dichloromethane complex (73mg), potassium acetate (977mg) and bis(pinacolate)diboron (1.26g), and the mixture is heated to 80°C under nitrogen atmosphere and stirred for 2 hours. The reaction solution is cooled to room temperature and thereto are added a saturated brine and ethyl acetate, and the mixture is separated and the organic layer is washed with a saturated brine again, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (30ml) and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (30ml) under ice-cooling. The mixture is stirred for 1 hour, and thereto is added a saturated aqueous sodium thiosulfate solution to consume the excess hydrogen peroxide and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1 to 7:3) to give ethyl trans-(4-{l(2-{[{3,5-bis-trifluoromethyl-benzyl) -(5 -hydroxy-pjTimidin- 2 -yl)-amino) -methyl}-4-trifluoromethyl-phenyl)-ethylaminol-methyl}-cyclohexyl)-acetate (1.29g). MS (m/z): 721 [M+H]+ (2) Ethyl trans-(4-{[(2-{({3,5-bis-trifluoromethyl-benzyI)-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-4-trinuoromethyl-phenyl)-ethyl-amino]-methyl}-cyclohexyl)-acetate (300mg) is dissolved in N,N-dimethylformamide (4ml), and thereto are added 2-bromoethanol (87\|il) and potassium carbonate (172nig), and tiie mixture is stirred at 60°C for 1 day. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 7:3—»1:1} to give ethyl trans-[4-({[2-({(3,5-bis-trifluoromethyl-ben2yl)-[5-(2-hydroxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-ajTiino}-methyl)-cyclohexyl]-acetate (138mg). MS (m/z): 765 [M+H] (3) Ethyl trans-[4-({[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-hydroxy-ethoxy)-p5Timidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-methyl)-cyclohexyl]-acetate (122nig) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (Iml) and the mixture is stirred at 60°C for 2 hours. The reaction solution is cooled to room temperature, and thereto are added IN-hydrochloric acid and ethyl acetate, and the mixture is separated, and the orgeinic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 7:3- Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-propionate (which is prepared by treating the corresponding starting compound in a same manner as in Example 12(l}-(4)) (205mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (5ml} and the mixture is stirred at room temperature for 2 hour. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:1^0:1) to give 3-[(2-{[(3,5-bis-trifluoroniethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl}-aniino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-propiomc acid (133mg}. MS (m/z): 680 [M+H]* Example 15 (1} Ethyl 7-[(2-{l(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl- pyrimidin-2-yl}-amino]-methyl}-4-trifluoromethyl-phenyl)-(2-tert-buto3^-ethyl)-aniino]-heptanaate (which is prepared by treating the corresponding starting compound in a same manner as in Example 12(l)-(4)) (260mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (4ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over ma^esium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:l-»3:2) to give ethyl 7-[(2-acetoxy-ethyl)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl} - amino]-methyl}-4-trifluoromethyl-phenyl) - amino]-heptanoate (162mg). MS (m/z): 822 [M+H]+ (2) Ethyl 7-[(2-acetoxy-ethyl)-(2-{[{3,5-bis-trifluorQmethyl.benzyl)-(5- morpholin-4-yl-pyrimidin-2-yl)-£imino]-methyl}-4-trifluoromethyl-phenyl)-amino]-heptanoate (156mg) is dissolved in ethanol (4ml), and thereto is added iN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 4 hours. To the reaction solution are added IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-^19:1) to give 7-[(2-acetoxy-ethyl)-(2-{\|(3,5- bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-p3T:imidin-2-yl)-amino]- methyl}-4-trifluoromethyl-phenyl)-amino]-heptanoic acid (144mg). The resulting 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl- pyTimidin-2-yl)-amino]-methyl}-4-triftuoromethyl-phenyl}-(2-hydroxy-ethyl}-aminoj-heptanoic acid (144mg) is dissolved in ethanol flml), and thereto is added a IN-aqueous sodium hydroxide solution (172vil ), and concentrated under reduced pressure to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl}-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-triauoromethyl-phenyl)-(2-hydroxy-ethyl)-amino]-heptanoic acid sodium salt (ISSmg). MS (m/z): 750 [M-Na]-Example 16 (1) Ethyl 6-[(2-{[{3,S-bis-trifluoromethyl-ben^l)-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-hexaiioate (120mg) is dissolved in tetrahydrofuran (1ml), emd thereto are added 2-methoxyethanol (21^1) and triphenylphosphine (69mg), and thereto is added dropwise 40% diethyl azodicarbojQ'late in toluene (llSpl) under water-cooling, and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 6:1) to give ethyl 6-{[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methojcy-ethoxy}-pyrimidin-2-yl]-amino}-methyl}-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanQate (120mg). MS (m/z): 739 [M+H]* (2) Ethyl 6-{[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoate (113mg) is dissolved in a mixed solvent of ethanol {2nil) and tetrahydrofuran (1ml), and thereto is added IM-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 2 hours. The reaction solution is made weakly acidic with a 10 % aqueous citric acid solution, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—49:1} to give 6-{[2-({{3,5-bis-trifluoromethyl-ben3yl)-[5-(2-methoxy-ethoxy)- pyrimidin-2-yl]-ainino}-methyl)-4-trifluQromethyl-phenyl]-ethyl-aniino}-hexanoic acid (lllmg). MS (m/z): 711 [M+H] (3) 6-{[2-({{3,5-Bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl)-ainino}-methyl)-4-trifluoromethyl~phenyl]-ethyl-aniino}-hexanoic acid (105mg) is dissolved in ethanol (1ml), and thereto is added a 2M-aqueous sodium hydroxide solution (74\|il), and the mixture is stirred at room temperature for 5 minutes. The reaction solution is concentrated under reduced pressure to give 6-{I2-({(3,5-bis-trifluorom ethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoic acid sodium salt (102mg). MS (m/z): 709 [M-NaJ-Example 17 (1) (2-Bromo-trifluoromethyl-phenyl}-methanol (5g) is dissolved in N,N-dimethylformamide (45ml) and thereto are added palladium acetate (440mg), l,r-bis(diphenylphosphino)ferrocene {2.17g) and triethylamine (2 (5ml), and the mixture is stirred under carbon monooxide flow at room temperature for 5 minutes and at 90°C for 1 day. The reaction solution is cooled to room temperature, and thereto are added a IN-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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1^^3:2) to give 6-trifluoromethyI-3H-isobenzofuran-l-one (2.77g). MS (m/zj: 203 [M+H]* (2) 6-Trifluoromethyl-3H-isoben2ofuran-l-one (1.77g) is dissolved in methylene chloride (20ml) and the mixture is cooled to -78'^C, and thereto is added a l.OM diisobutylaluminum hydride in toluene (19.5ml) and the mixture is stirred for 1 hour and 20 minutes. The reaction solution is cooled to room temperature, and thereto are added a saturated aqueous ammonium chloride solution and ethyl acetate, and the m^ixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—3:2) to give 6-trifluoromethyl-l,3-dihydro-isobenzofuran-l-ol(1.36g\|. MS (m/z): 187 [M+H-H20i (3) 6-Trifluoromethyl-l,3-dihydro-isobenzofuran-l-ol (4.12g) is dissolved in 1,2-dichloroethane (75ml), and thereto are added 3,5-bis-trifluoromethyl-benzylamine (5.89g), triacetoxy-sodium borohydride (9.0g) and acetic acid (2.3ml), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 7:3^1:1) to give {2-[(3,5-bis-trifluoromethyl-ben2ylainino)-methyl]-4-trifluoromethyl-phenyl}--methanol (7.06g). MS (m/z): 432 [M+H]* (4) {2-[(3,5-Bis-ti-ifluoromethyl-ben2ylamino)-methyl]-4-trifluoromethyI-phenyl}-n]ethanol (7.0g) is dissolved in toluene (70ml) and thereto are added 5-bromo-2-chloro-pyrimidine {4.7g) and N,N-diisopropylethylamine (4.23ml) and the mixture is heated under reflux for 3 days. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—3;2) to give (2-{[(3,5-bis-trifluoromethyI-benzy2)-(5-bromo-pyrimidin-2-yl)-amino)-methyl}-4-trifluorcmethyl-phenyl)-methanol (7.37g). MS (m/z): 588/590 [M+H]+ (5) (2-{[(3,5-Bis-trifluoromethyl-benzyl}-(5-bromo-pyrimidin-2-yl)-aniino]-niethyl}-4-trifluoromethyl-phenyl)-methanol (225mg) is dissolved in acetone (5ml), and thereto is added 1.94M Jones reagent {290pl} under ice-coolitig, and the mixture is stirred for 30 minutes. To the reaction solution are added sodium hydrogenesulfite, water 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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-»9:1) to give 2-{[(3,5-bis-trifluorotnethyl-benzyl)-(5-bromo-p5T-imidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoic acid (ISlmg). MS (m/z): 602/604 [M+H]+ (6} 2-{[(3,5-Bis-trifluoromethyl-benzyl}-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyI-benzoic acid (Ig) is dissolved in tetrahydrofuran (10ml), and thereto are added diphenoj^^jhosphinylazide (540pl), triethylamine (695pl) and ethanol (6ml) and the mixture is heated at 60°C for 3 days with stirring. The reaction solution is cooled to room temperature, and thereto are added IN-hydrochloric acid and ethyl acetate, £ind the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0^4: l-»chloroform : methanol = 4:1) to give ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl}-carbamate (660mg). MS (m/z): 645/647 {M+H] (7) Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyriniidin-2-yl)- amino]-niethyl}'4-trifluoromethyl-phenyl}-carbamate (980mg) is dissolved in N,N-dimethylformamide (lOml), and thereto is added sodium hydride (60%) (91mg) under ice-cooiing, and the mixture is stirred for 30 minutes and thereto is added ethyl iodide (182^1) and the mixture is stirred at room temperature overnight. Thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^^4:1) to give ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methylS-4-trifluoromethyl-phenyl)-ethyl-carbamate (425mg). MS (m/z): 673/675 [M+H]* (8) Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbainate (412mg) is dissolved in toluene (5ml) , and thereto are added tris(dibenzylideneacetone)dipalladium (112mg), 2-(di-tert-butylphosphino)biphenyl (146mg), sodium tert-butoxide (176mg) and ethyl piperidine-4-carboxylate (140\|il), and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—-4:l) to give l-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-ainino}-pyrimidin-5-yl}-ethyl piperidine-4-carboxylate (72mg). MS (m/z): 750 [M+H]+ (9) l-(2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trinuoromethyl-benzyl]-amino}-pyrimidin-5-jl)-ethyl piperidine-4-carbo3cylate (70mg) is dissolved in ethanol (4ml), and thereto is added IN- aqueous sodium hydroxide solution flml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution aire added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—9:1) to give l-{2-{(3,5-bis-trifluoroinethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-triflu oromethyl-benzyl]-amino}-pyrimidin-5-yll-piperidine-4-carboj^lic acid (44mg). The resulting l-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-aniino)-5-trifluoromethyl-benzyl]-amino)-pyrimidin-5-yl}-piperidine-4-carboxylic acid (44mg) is dissolved in ethanol (1ml), and thereto is added IN-aqueous sodium hydroxide solution (44\|il), and then the mixture is concentrated under reduced pressure to give l-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trinuoromethyl-benryl]-amino}-p5T-imidin-5-yl)-piperidine-4-carboxylic acid sodium salt (45mg). MS (m/z): 720 [M-Na]-Example 18 (1) Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)- amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (614mg) is dissolved in toluene (6.5ml), and thereto are added tris(diben2ylideneacetone)dipalladium(0) (87mg), 2-(di-tert- butylphosphino)biphenyl (114mg), morpholine (166]il) and sodium tert-butoxide (183mg) and the mixture is stirred under nitrogen flow at 60°C for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 9:1-^4:1) to give ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl)-4-trifluoromethyl-phenyl)-carbamate (476mg). MS (m/z): 652 [M+H] + (2) Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-{5-morpholin-4-yl-pyrimidin-2-yl) - amino]-inethyl}-4-trifluoromethyl-phenyl) - carbamate (140mg) is dissolved in N,N-dimethylformainide (Iml), and thereto is added sodium hydride (63%) (12mg) under ice-cooling, and the mixture is stirred at the same temperature for 30 minutes. To the reaction mixture is added ethyl 5-bromo-pentanoate {68iil), and the mixture is stirred at 0°C to room temperature overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give ethyl 5-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-me thy l}-4-trifluoromethyl-phenyl}-ethoxycarbonyl-aminol-pentanoate (137mg). MS (m/z): 780 [M+H]* (3) Ethyl 5-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethoxycarbonyl-amino]-pentanate (134mg) is dissolved in methanol (1ml), and thereto is added IM-aqueous sodium hydroxide solution (Iml), and the mixture is stirred at room temperature for 1 hour and a half. The reaction solution is made weakly acidic with a 10 % aqueous citric acid solution, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 19:1) to give 5-[(2-{[(3,5-bis-trifluoromethyl-ben^l)-(5-morpholin-4-yl-p5n-imidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethoxycarbonyl-amino]-pentanoic acid (123mg). MS (m/z): 752 [M+H]* Example 19 (1) 2-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyriniidin-2-yl)-amino]- methy]}-4-trifluoromethyl'benzoic acid (2,5g) is dissolved in tetrahydrofuran (25ml), and thereto are added diphenoxyphosphinylazide (1.34ml), triethylamine (174ml) and benzyl alcohol (1.3ml) and the mixture is heated at 60°C overnight with stirring. The reaction solution is cooled to room temperature, and thereto is added a IN-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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—9:1—♦4:1) to give benzyl (2-([(3,5-bis-trifluoromethyl-ben2yl)-(5-bromo-pyrimidin-2-yl)-aminol-methyl}-4-trifluoromethyl-phenyl)-carbamate (2.66g}. MS (m/z): 707/709 [M+H]+ (2} Benzyl (2-([(3,5-bis-trifIuoromethyI-benzyI(-(5-bronio-pyrimidin-2-yI)-aminol-methyl}-4-trifluoromethyl-phenyl)-carbamate (1.5g) is dissolved in NjN-dimethylformamide (15ml}, and thereto is sodium hydride (60%) (127mg} under ice-cooling, and the mixture is stirred for 30 minutes and thereto is added ethyl iodide (255pl), and the mixture is stirred at room temperature overnight. Thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—>17:3) to give benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl) - (5 - bromo-pyrimidin-2-yl}-amino]-methyI}-4-trifluoromethyl-phenyl)-ethyl-carbamate (1.30g). MS (m/z): 735/737 [M+H] (3) Benzyl (2-{[(3,5-bis-trifluoromethyI-benzylj-(5-bromo-pyrimidin-2-ylj- amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamate (1.28g) is dissolved in toluene (15ml), and thereto are added tris(diben2yIideneacetone)dipalladium [159mg), 2-(di-tert- butylphosphino)biphenyl (208mg), sodium tert-butoxide (250mg) and morpholine (230)il) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added tris(diben^lideneacetone)dipalladium (159mg), 2- (di-tert- butylphosphinojbiphenyl (208mg) and sodium tert-butoxide (250mg) and the mixture is stirred for 3 hours and a half. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the orgeinic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—4:1) to give benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl}-ethyl-carbamate (724nig). MS (m/z): 742 [M+H] (4) Benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamate (720mg) is dissolved in ethanol (10ml), and thereto is added 10% palladium-carbon (200mg), and the mixture is stirred under hydrogen atmosphere at room temperature for 2 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 9:1 to 7:3) to give (3,5-bis-trifluoromethyI-benzyl)-(2-ethylamino-5-trifluoromethy}-benzyl)-(5-morpholin-4-yl-pyrimidin-2-y])-amine (569mg). MS (m/z): 608 [M+H]* (5) (3,5-Bis-trifluoromethyl-ben2yl)-(2-ethylamino-5-trifluoromethyl-benzyl}-[5-morpholin-4-yl-pyrimidin-2-yl)-aniine (200mg) and triethylamine {55]il) is dissolved in methylene chloride (5ml) , and thereto is added triphosgene (39mg) under ice-cooling, and the mixture is stirred under nitrogen atmosphere at room temperature for 30 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is dissolved in tetrahydrofuran (5ml), and thereto are added tert-butyl 3-hydrojQ'-propionate (73vil) and sodium hydride (60%) (20mg), and the mixture is stirred at room temperature overnight. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1 to 7:3) to give tert-bulyl 3-[(2-{[{3,5-bis-trifluoromethyl-benzyl)-{5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyloxy]-propionate (120mg). MS (m/z): 780 [M+H]* (5) Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyloxy]-propionate (114mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (5ml), and the mixture is stirred at room temperature for 1 hour and 30 minutes. Thereto are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-19:1) to give 3-((2-{[(3,5-bis-trifluoromethyl-bensyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoylojcy]-propionic acid (81mg). The resulting 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyriniidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbainoyloxyl-propionic acid (Slmg) is dissolved in ethanol (1ml), and thereto is added IN-aqueous sodium hydroxide solution (115pl) and concentrated under reduced pressure to give 3-[(2-{[(3,5-bis-trifluQromethyl-ben^l)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethylcarbainoylo3ty]-propionic acid sodium salt (78mg). MS (m/z): 722 [M-Na]- Example 20 (1) (3,5-Bis-trifluoromethyl-benzyl)-{2-ethylamino-5-trifluoromethyl-ben2yl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (400mg) is dissolved in methylene chloride {5nil}, and thereto is added triethylamine (llOpl) and triphosgene (78mg) under ice-cooling, and the mixture is stirred under nitrogen atmosphere at room temperature for 2 hours. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is dissolved in tetrahydrofuran (5ml), and thereto are added (S)-2-amino-3-tert-butojq'-propionic acid methyl ester hydrochloride (279mg) and triethylainine {183pl), and the mixture is stirred at room temperature for 1 day. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:1—3:7) to give methyl (S)-2-[3-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl'phenyl\|-3-ethyl-ureido]-3-tert-butoxy-propionate (462mg). MS (m/z): 809 [M+H] (2) Methyl (S)-2-[3-(2-{[(3,5-bis-trinuoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-aniino]-methyl}-4-trifluoromethyl-phenyl)-3-ethyl-ureido]-3-tert-buto^-propionate (455mg) is dissolved in a 4N-hydrochloric acid in dioxane (5ml), and the mixture is stirred at room temperature for 8 hours. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 1:1-»0:1) to give methyl {S)-2-[3-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyiimidin-2-yl)-amino]-methyl}-4-triflu oromethyl-phenyl)-3-ethyl-ureidol-3-hydroxy-propionate (285mg). MS (m/z): 753 [M+H]* (3) Methyl (S}-2-[3-(2-{l(3,5-bis-tri{luoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-3-ethyl-ureido]-3-hydroxy-propionate (280mg) and pyridine (72ial} is dissolved in methylene chloride (5ml), and the mixture is cooled to -20'C, and thereto is added trifluoromethane sulfonic acid anhydride (150pl) and the mixture is stirred at -20'C for 1 hour and 30 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 4:1—-l:l) to give methyl {S)-2-l(2-{[(3,5-bis-trifluoromethy]-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-aminD]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxBzole'4-carhoxy\ate (197mg). MS (m/z): 735 [M+H]' (4) Methyl fS)-2-[(2-{f(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yJ-pyrimidin-2-yl}-amino]-methyI)-4-trifluoromethyl-phenyl)-ethyI-aminoj-4,5-dihydro-oxazole-4-carboxyiate (190mg) is dissolved in methanol (4ml) and thereto is added a IN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-»4:1) to give (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morphoUn-4-yl-pyriinidin-2-yl)-amino]-methyl}-4-triflu oromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carbojqrUc acid (130mg). The resulting (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl}-(5- morpholm-4-yl-p5Timidin-2-yl)-ainino]-niethyl}-4-trifluoroinethyl-phenyl)-ethyl-aininol-4,5-dihydro-oxazole-4-carboxylic acid (130mg) is dissolved in ethanol (1ml), and thereto is added IN-aqueous sodium hydroxide solution (180]al} and concentrated under reduced pressure to give (S)-2-l(2-{j(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyTimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid sodium salt (120mg). MS {m/z}: 729 [M-Na]-Example 21 (1) (3,5-Bis-trifIuoromethyl-benzyl)-(2-ethylamino-5-trifluoromethy]-ben2yl)-(5-morpholin-4-yl-p5Timidin-2-y!)-amine (164mg) is dissolved in methylene chloride (5ml), and thereto are added ethyl 6-(chloroformyl)hexanoate (67mg) and triethylamine (26]al}, and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 17:3-»7:3) to give ethyl 6-[{2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morphoUn-4-yl-pyTimidin-2-yl)-aniino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyl]-hexanoate (147mg). MS (m/z): 778 [M+H] (2) Ethyl 6-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyl]-hexanoate (140mg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 2 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = l-.0-9:l) to give 6-[(2-{[(3,5-bis-trifluoromethyl-ben2yl)-(5-niorpholin-4-yl-pyrimidin-2-yl)-amino]-me thyl}-4-trifluoromethy]-phenyl)-ethyl-car barnoyl) -hexanoic acid (137mg). MS (m/z): 750 [M+HJ+ Example 22 (1) 2-{[{3,5-Bis-trifluoromethyl-benzyl)-(S-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoic acid (250mg) is dissolved in tetrahydrofuran (5ml), and thereto are added tert-butyl 3 -ethylamino-propionate {103mg)> l-hydroxybenzotriazole dihydrate (81mg), l-ethy-3-(3-dimethylaininopropyl)carbodiimide hydrochloride (114mg) and triethylamine (83iil), and the mixture is stirred at room temperature overnight. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^4:1) to give tert-butyl 3-[(2-{[ (3,5-bis-trifluoromethyl-benzyl) - {5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoyl)-ethyl-amino]-propionate (310mg). MS (m/z): 757/759 [M+H\| (2) Tert-butyl 3-[(2-{[{3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-me thy l}-4-trifluoromethyl-benzoyl)-ethyl-amino]-propionate (300mg) is dissolved in toluene {5ml), and thereto are added tris(dibenzylideneacetone)dipalladium (36mg), 2-(di-tert-butylphosphinojbiphenyl (47mg), sodium tert-butoxide (57mg) and morpholine {52jil\|, and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 17:3-^7:3) and further by silica gel column chromatography (hexane : ethyl acetate = 4:1—3:2) to give tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morphDlin-4-yl-pyriniidm-2-yl}-aminol-methyl}-4-trifluoromethyl-benzoyl}-ethyl-ammo]-propionate (13.3mg). MS (m/z); 764 1M+HJ+ (3) Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoyl)-ethyl-aniino]-propionate (13.3mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (2ml), and the mixture is stirred at room temperature for 4 hours. Thereto are added a saturated aqueous sodium bicairbonate 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 to give 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-p5Timidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoyl)-ethyl-amino]-propionic acid (12mg). MS (m/z): 780 [M+H]+ Example 23 (1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyTimidin-2-yl)-amine (8.55g) is dissolved in N,N-dimethylformainide (20ml), and thereto is added sodium hydride (60%) (855mg) under ice-cooling, and the mixture is stirred for 15 minutes. To the reaction solution are added 2-bromomethyl-l-fluoro-4-trifluoromethyl-benzene (5g), and the mixture is stirred at room temperature overnight. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—»9:1) to give (3,5-bis-trifluoromethyl-benzyI\|-(5-bromo-pyrimidin-2-yI)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (11.Ig). MS (m/z); 576/578 [M+H] (2) (3,5-Bis-trifluoromethyl-benzyI)-(5-bromo-pyrimidin-2-yI)-(2-fluaro-5-trifluoromethyl-ben^l)-amine (11. Ig) is dissolved in tetrahydrofuran (20ml), and thereto are added benzyl alcohol (6ml) and sodium hydride (60%) (2.32g), and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 97:3^^9:1) to give (2-benzy]oxy-5-trifluoromethyl-ben^y])-(3,5-bis-trifluoromethyl-ben2yl)-(5-bromo-pyrimidin-2-yl)-amine (12.9g}. MS (m/z): 664/666 [M+H]* (3) (2-Ben^yloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-ben^I\|-(5-bromo-pyrimidin-2-yi}-amine (12.9g) is dissolved in dimethylsulfoxide (150ml), and thereto are added 11,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (3.17g), potassium acetate (5.71g) and bis(pinacolate)diboron (9.S5g), and the miirture is heated to SO°C under nitrogen atmosphere for 1 hour and 30 minutes. The reaction solution is cooled to room temperature, and thereto are added a saturated brine and ethyl acetate, and the mixture is separated, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (150ml), and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (40ml) under ice-cooling. Two hours thereafter, thereto is added a saturated aqueous sodium thiosulfate solution to consume the excess hydrogen peroxide, and thereto is added ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1 to 7:3) to give 2-[(2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-ol (7.68g). MS (m/z): 602 [M+H]* (4) 2-[(2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethy]-benzyl)-aniino]-pyrimidin-5-ol (7.68g) is dissolved in N,N- dimethylformamide (lOOml) and thereto are added ethyl 4-bromo-butyrate (2.3ml} and potassium carbonate (2.22g), and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl 4-bromo-butyrate (2.3ml) and potassium carbonate (2.22g), and the mixture is stirred at room temperature 3 days. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1^^4:1) to give ethyl 4-{2-l(2-benzylo3q'-5-triiluoromethyl-benzyl}-(3,5-bis-trifluoromethyl-beniyl)-amino]-pyriniidin-5-ylo)cy}-bulyrate as crude product (11.3g). MS (m/z): 716 [M+H]^ (5) Crude ethyl 4-{2-[(2-benzylo3qr-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-aininol-pyrimidin-5-yloxyS-butyrate (11.3g) is dissolved in ethanol (lOOml) £ind thereto is added 10% palladium-carbon (3g), and the mixture is stirred under hydrogen atmosphere at room temperature for 2 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-^4:1) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimi din-5-yloxy}-butyrate (6.03g). MS (m/z): 626 [M+Hl* (6) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-ylDxy}-butyrate {200mg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroforni : methanol = 1:0—19:1\| to give 4-{2-[(3,5-bis-trifluoroniethyI-beii2yI)-(2-hydro^-5-trifIuoromethyI- benzy])-amino)-pyrimidin-5-yloxy^}-butyric acid (182mg). The resulting 4-{2-\|(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-aiiiino]-pyrimidin-5-yloxy}-butyric acid (184mg) is dissolved in ethanol {5ml), and thereto is added IN-aqueous sodium hydroxide solution (305pl},and concentrated under reduced pressure to give 4-{2-((3,5-bis-trifluoromethyl-ben2ylj - (2 - hydroxy-5-trifluoromethyl-benzyl)-amino)-pyrimidin-5-yIoxy}-buQTric acid sodium salt (lS4mg\|. MS (m/z): 598 IM+H]+ Example 24 (1) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-ainino]-p5T:imidin-5-yloxy}-butyrate (300mg) and 3-pentanol (63mg) are dissolved in tetrahydrofuran (4ml}, and thereto are added dropwise triphenylphosphine (lS9mg) and a 40% diethyl azodicarboxylate in toluene (ISOpl) under ice-cooling, and the mixture is stirred at room temperature overnight. Thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0^9:1} to give ethyl 4-(2-{(3,5-bis-trif3uoromethyI-benzyl)-[2-(l-ethyl-propoxy)-5-trifluoromethy]-benzyl)-amino}-pyrimidin-5-ylojQr)-butyrate (195mg). MS (m/z): 696 [M+H)+ (2) Ethyl 4-(2-{(3,5-bis-trinuoromethyl-beiizyl)-I2-(l-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyriiiiidin-5-yloxy)-but5Tate (190mg) is dissolved in ethanol {5ml), and thereto is added a IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = l:0-»93 : 7) to give 4-(2-{{3,5-bis-trifluoromethyl-benzyl)-[2-(l-ethylpropoxy)-5-trifluoromethyl-benzyl]-ainino}-pyriniidin-5-yloxy)-butyric acid (158mg). The resulting 4-(2-{(3,5-bis-trifluoromethyI-benzyl)-[2-(l-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy}-butyric acid (158mg) is dissolved in ethanol (Iml), and thereto is added IN-aqueous sodium hydroxide solution (237\|al) and concentrated under reduced pressure to give 4-(2-{{3,5-bis-trifluoromethyl-benzyl)-{2-(l-ethyl-propoxy}-5-trifluoromethyl-benzyll-amino}-p3T-imidin-5-yloxy)-butyric acid sodium salt (149mg). MS (m/z): 656 [M-Na]-Example 25 (1) Ethyl 4-{2-[{3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifIuoromethyI-benzyl}-ainino]-p3rrimidin-5-yIo3cy}-butyrate (200mg) is dissolved in N,N-dimethylformamide (3ml), and thereto are added 2-chloropyrimidine (45mg) and potassium carbonate (55mg), and the mixture is stirred at 85°C overnight. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 41:9—13:7) to give ethyl 4-(2-{(3,5-bis-trifl.uoromethyl-benzyl) - [2-(pyrimidin-2-ylojq'} - 5-trifluoromethyl-ben2yl]-amino}-pyrimidin-5-yloj^)-butyrate (120mg). MS (m/z): 704 [M+H]* (2) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-ben2yl)-[2-(pyrimidin-2-yloxy}-5-trifluoromethy]-ben2y]]-amino}-pyrimidin-5-yloxy)-butyrate (115mg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0^^9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(p5T-imidin-2-yloxy)-5- trifluoromethyl-benzyl]-am.ino}-pyrimidin-5-yloxy}-butyTic acid (96nig). MS (m/z): 676 [M+H]+ Example 26 (1) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (3g) and pyridine (580vil) are dissolved in methylene chloride (45ml), and thereto is added trifluoromethane sulfonic acid anhydride (1.2ml) under ice-cooling, and the mixture is stirred under nitrogen atmosphere for 2 hours. The reaction solution is cooled to room temperature, and thereto are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—»^4:1) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl) - (2-trifluoromethane sulfonyloxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (3.44g). MS (m/z): 758 [M+H]* (2) Ethyl 4-{2-[{3,5-bis-trinuoromethyI-benzyl\|-(2-trifluoromethanesulfonyloxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200mg) is dissolved in 1,4-dioxajie (3ml), and thereto are added phenyl borate (64mg), [1>1'-bis(diphenylphosphino)ferrocenejdichloropalladium dichloromethane complex (22mg) and cesium carbonate {172mg), and the mixture is stirred under nitrogen atmosphere at 80°C overnight. To the reaction solution are added water 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1^17:3) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl\|-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pjrrimidin-5-yloxy}-butyrate (192mg). MS (m/z): 686 [M+H]* (3) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl- biphenyl-2-ylmethyl)-amino]-p5Timidin-2-ylmethyl}-ainino)-p3Timidin-5-yloxy}-butyrate (185mg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml), and the m.ixture is stirred at room temperature for 2 hours. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0^19:1} to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-p5Timidin-5-yloxy}-butyric acid (160mg). The resulting 4-{2-[(3,5-bis-trifluoromethyl-ben2yl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-p3T^midin-5-ylox3^-butyric acid (160mg) is dissolved in ethanol (1ml) and thereto is added IN-aqueous sodium hydroxide solution (245pl) and concentrated under reduced pressure to give 4-{2-[(3,5-bis-trinuoromethyl-benzyl) - (4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (158mg). MS (m/z): 656 [M-Naj- Example 27 (1) (2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoroniethyl-benzyl}-(5-bromo-pyrim.idin-2-yl)-amine (3.75g) is dissolved in toluene (50ml) and thereto are added tris(dibenzylideneacetone)dipalladium (516mg), 2-(di-tert-butylphosphino)biphenyl (673mg), sodium tert-butoxide (813mg) and morpholine (740ial), and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the orgeinic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 9:1-^4:1) to give (2-benzyIoxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl}-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (2.46g). MS (m/z): 671 [M+H]'^ (2) (2-Ben2yIoxy-5-trifluoromethyl-benzyI)-(3,5-bis-trifluoromethy]-ben^l)-{5-morpholin-4-yl-pyrimidin-2-yl)-am.ine (2.46g) is dissolved in ethanol (35ml), and thereto is added 10% palladium-carbon (750mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 hour and 30 minutes. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—3:2) to give 2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl}-aminol-methyl}-4-trifluoromethyl-phenol (1.53g). MS (m/z): 581 [M+H] (3) 2-{[(3,5-Bis-trifluoromethyl-ben2yl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenol (150mg) is dissolved in N,N-dimethylformamide (4ml), and thereto are added ethyl 4-bromo-butyrate (74p.l) and potassium carbonate (71mg) and the mixture is stirred at SO^C overnight. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 22:3^^7:3) to give ethyl 4-(2-{[(3,5-bis-triftuoromethyl-ben2yl)-(5-morpholin-4-yl-pyriniidin-2-yl\|-aminoJ-methyl}-4-trifluoromethyl-phenoxy)-butyrate (123mg). MS (m/z): 695 fM+Hj* (4) Ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl}-(5-morpholin-4-yl- pyrimidin-2-yl)-ainino]-methyl}-4-triiluoroniethyl-phenoxy)-butyrate (llSmg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 4 hours. To the reaction solution are added a IN- 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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—•■19:1) to give 4-(2-{[(3,5-bis-trifluoromethyl-ben2yl)-(5-morpholin-4-yl- pyTimidin-2-yl)-amino]-methyl}-4-trifluorom ethyl-phenoj^)-butyric acid (lOSmg). MS (m/z): 667 [M+H]* Example 28 (1) 2-{[(3,5-Bis-trifluoromethyl-ben2yl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-triiluoromethyl-phenol (300mg) and pjTidine (50^1) are dissolved in methylene chloride (Smlj and thereto is added trifluoromethanesulfonic acid anhydride (104pl) under ice-cooling, and the mixture is stirred under nitrogen atmosphere for 1 hour. The reaction solution is cooled to room temperature, and thereto are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 9:1 to 7:3) to give trifluoromethanesulfonic acid 2-{[(3,5-bis-trifiuoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl ester (330mg). MS (m/z): 713 [M+H]* (2) Trifluoromethanesulfonic acid 2-{[(3,5-bis-trifluoromethyI-benzyl)-(5-morpholin-4-yl-pyriniidin-2-yl)-ainino]-methyl}-4-trifluoromethyl-phenyl ester (200mg) is dissolved in 1,4-dioxane (3ml), and thereto are added phenyl borate (69mg), [!> 1'-bis(diphenylphosphino)ferroceneldichloropalladium dichloromethane complex (23mg) and cesium carbonate (183mg), gind the mixture is stirred under nitrogen atmosphere at 80°C for 1 day. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—♦4:1) to give (3,5-bis-trifluoromethyl-benzyl}-(5-morpholin-4-yl-pyTimidin-2-yl)-(4-triiluoromethyl-biphenyl-2-ylmethyl)-amine (52mg). MS (m/z): 641 [M+HJ* Examples 29 to 35 The corresponding starting compounds are treated in a similar manner to Example 1 to give the compounds as listed in Table 1. Example 36 The corresponding starting compound is treated in a similar manner to Example l(l)-(3) to give the compound as listed in Table 1-Examples 37 to 46 The corresponding starting compounds are treated in a similar manner to Example 2 to give the compounds as listed in Table 1. Examples 47 to 48 The corresponding starting compounds are treated in a similar manner to Example 4 to give the compounds as listed in Table 1. Example 49 The corresponding starting compound is treated in a similar manner to Example 5 to give the compound as listed in Table 1. Examples 50 to 53 The corresponding starting compounds are treated in a similar manner to Example 8 to give the compounds as listed in Table 1. Examples 54 to 60 The corresponding starting compounds are treated in a similar manner to Example 12 to give the compounds as listed in Table 1. Examples 61 to 62 The corresponding starting compounds are treated in a similar manner to Example 12{l)-(3) to give the compounds as listed in Table 1. Examples 63 to 64 The corresponding starting compounds are treated in a similar manner to Example 13 to give the compounds as listed in Table 1. Example 65 The corresponding starting compound is treated in a similar manner to Example 16 to give the compound as listed in Table 1. Example 66 The corresponding starting compound is treated in a similar manner to Example 18 to give the compounds as listed in Table I. Example 67 The corresponding starting compound is treated in a similar manner to Example 20 to give the compound as listed in Table 1. Examples 68 to 71 The corresponding starting compounds are treated in a similar manner to Example 24 to give the compounds as listed in Table I. Examples 72 to 75 The comssponding starting compounds are treated in a similar manner to Example 26 to give the compounds as listed in Table 1. Example 76 (1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (5g) and cyclopropylmethyl-propyl-amine (5.57ml) is dissolved in toluene (50ml), and thereto is added potassium carbonate (10.7g) and the mixture is stirred at 120'C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate emd water, 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 resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 20:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (6.8g). MS (m/z): 286 [M+H] (2) To ethanol are added (30ml)2-(cyclopropylm ethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (5.8g), hydroxylamine hydrochloride {1.66g) and sodium acetate (1.95g) and the mixture is stirred at room temperature overnight. Ethanol is removed by evaporating under reduced pressure and thereto is added chloroform and water, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 10:1—»2:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde oxime {5.78g). MS (m/z): 301 [M+H1+ (3) Lithium aluminum hydride (1.4g) is suspended in tetrahydrofuran (50ml} and thereto is added dropwise a 2-(cyclopropylmethyl-propyl-aniino)-5-trifluoromethyl-benzaldehyde oxime {5.7g) in tetrahydrofuran (20ml) under ice-cooUng, and the mixture is stirred at room temperature overnight. To the reaction solution are added water (1.4ml), a 2N-aqueous sodium hydroxide solution (2.8ml) and water (2.8inl) successively under ice-cooling, and the insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (; chloroform : ethyl acetate= 10:1) to give (2-aminomethyl-4-trifluoromethyl-phenyl)-cyclopropylmethyl-propyl-amine as a crude product (5.1g). (4) The crude (2-aminomethyl-4-trifluoromethyl-phenyl)-cyclopropylmethyl-propyl-amine obtained in (3) (5.06g) is dissolved in dioxane (25ml), and thereto are added N-ethyldiisopropylethylamine (9.19ml) and 5-bromo-2-chlorop3Timidine (8.48g), and the mixture is heated under reflux for 4 hours and 20 minutes. The insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 15:1) to give (S-bromo-pjrrimidin-2-yl) - [2 - (cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amine (6.33g). MS (m/z): 443/445 [M+H]+ (5) (5-Bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amine (2.33g) is dissolved in N,N-dimethylformamide (16.8ml) and thereto is added sodium hydride (60%) (273mg) under ice-cooling. Twenty minutes thereafter, thereto is added 3-bromomethyl-5-trifluoromethyl-benzonitrile (2.08g) and the mixture is stirred at room temperature for 1 hour and 15 minutes. To the reaction solution are added acetic acid to consume the excess sodium hydride, and thereto are added ethyl acetate and water, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1) to give 3-({(5-bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino) - 5-trifluoromethyl-benzyl]-aminQ}-methyl) - 5-trifluoromethyl-benzonitrile (2.81g). MS (m/z): 626/628 [M+H]* (6) 3-({(5-Bromo-p5Timidin-2-yl}-[2-(cyclopropylmethyl-propyl-amino)-5- triflu oromethyl-benzyl] - aminoj-methyl) - 5-trifluoromethyl-benzonitrile (2.81g) is dissolved in dimethylsulfoxide (12.6ml) and the mixture is degassed under reduced pressure and flushed with nitrogen gas. Thereto are added potassium acetate {1.32g), bis(pinacolate)diboron (2.88g} and [ 1, l'-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (732mg) and the mixture is heated at 80°C under nitrogen atmosphere and stirred for 1 hour and 40 minutes. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (26ml) and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (15.7ml) under ice-cooling. Two hours thereafter, thereto is added a saturated aqueous sodium thiosulfate under ice-cooling to consume the excess hydrogen peroxide, and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1) to give 3-{[[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (1.94g). MS (m/z): 564 (M+HJ. (7) Ethyl 3-{[ [2-(cyclopropylmethyl-propyl-amino) - 5-trifluoromethyl-ben^ll-(5-hydroxy-pyrimidin-2-yl)-aininol-methyl}-5-trifluoromethyl-benzonitrile (250mg) and 4-bromobutyrate (76.9^11) is dissolved in N,N-dimethylformamide (3.7mi) and thereto is added potassium carbonate (74mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated, and the organic layer is washed with a saturated brine, dried and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 8:1) to give ethyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino) - 5-trifluoromethyl-benzyl] - amino}-p3Timidin-5-yloxy)-butyrate (220mg). MS (m/z): 678 [M+H] (8) Ethyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ylo:ty)-butyrate (240mg) is dissolved in tetrahydrofuran (2.6ml}, and thereto is added IN-aqueous sodium hydroxide solution (2.6ml) and the mixture is stirred at 40°C for additional 30 minutes and warmed to 50°C and stirred for 3 hours. Thereto is added a 2N-aqueous sodium hydroxide solution (650\|il) and the mixture is stirred at 50°C for 20 minutes. The reaction solution is cooled to room temperature and thereto are added ethyl acetate and a IN-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 19:1) to give 4-(2-{(3-cyano- 5-triflu oromethyl -ben2yl) -[2 -(cyclopropylmethyl -propyl -amino)- 5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-but5T-ic acid (189mg). MS (m/2): 650 \|M+H]^ Example 77 The corresponding starting compound is treated in a similar manner to Example 76 to give the compounds as listed in Table 2. Example 78 (1) {2-[(3,5-Bis-trifluoromethyl-ben2ylamino)-methyl]-4-trifluoromethyl-phenyl}-butyl-ethyl-amine (2.0g), 4,6-dichloropyrinudine (1.19g) and N-ethyldiisopropylamine (2.09ml) are dissolved in toluene (lOml) and the mixture is heated under reilux for 3 hours. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-17:3) to give (3,5-bis-trifluoromethyl-benzyl)-{2-(butyl-ethyl-amino)-5-trifluoromethyl-benzylJ-(6-chloropyrimidin-4-yl)-amine (1.8g). MS (m/z): 613 [M+H]^ (2) (3,5-Bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino}-5-trifluorom ethyl-benzyl]-(6-chloropyrimidin-4-yl)-amine (SOOmg) is dissolved in toluene (5ml), and thereto are added 3-aininopropionic acid tert-butyl ester hydrochloride {888mg) and N-ethyldiisopropylamine (1.7ml), and the mixture is stirred at 120°C overnight. To the reaction solution are added ethyl acetate and a IN-hydrochloric acid, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (hexane : ethyl acetate = 9:1—3:1) to give tert-butyl 3-(6-{(3,5-bis-trifluoromethyl-benzyl}-[2-(bulyl-ethyl-ainino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-4-ylamino)-propionate (TOmg). MS (m/z): 722 [M+H]- (3) Tert-butyl 3-(6-{(3,5-bis-trifluoromethyl-benzyl}-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-p3Timidin-4-ylamino)-propionate (60mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (0.5ml) and the mixture is stirred at room temperature for 1.5 hours. To the reaction solution are added ethyl acetate and water, and foUwed by a further addition of a saturated aqueous sodium bicarbonate solution to make the pH of aqueous layer to be about 4, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and the mixture is concentrated under reduced pressure to give 3-{6-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluororoethyl-ben2yl]-amino}-pyrimidin-4-ylamino)-propionic acid (57mg), MS (m/z): 666 [M+H]+ Examples 79 to 83 The corresponding starting compounds are treated in a similar manner to Example 78(2) to give the compounds as listed in Table 3. solution (0.80ml) and acetic acid (2.1ml), followed by an addition of ti^acetoxy-sodium borohydride (13. Ig) at room temperature over 1 hour with stirring. After the mixture is stirred at room, temperature for additional 30 minutes, to the reaction mixture is added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1) to give (3,5-bis-trifluoromethyl-benzyl)-ethyl-amine (1.52gj. MS (m/z): 272 [M+H]* (2} (3,5-Bis-trifluoromethyl-benzyl)-ethyl-amine (1.03g) is dissolved in N, N-dimethylformamide (1 Oml), and thereto are added 2 -fluoro-5-triiluoromethyl-benzaldehyde (1.45g) and potassium carbonate (1.48g), and the mixture is stirred under nitrogen atmosphere at 90°C for 3 hours and at room temperature overnight. To reaction mixture is added a saturated brine and water, and the mixture is extracted five times with ethyl acetate and the organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1} to give 2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyI-benzaldehyde (282mg). MS (m/z): 444 [M+H]+ (3) 2-[{3,5-Bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehyde (275mg) is dissolved in ethanol (2.5ml) and thereto are added hydro^lammonium chloride (86mg) and sodium acetate (102mg), and the mixture is stirred at eCC under nitrogen atmosphere for 1 hour and a half. To the reaction solution are added a saturated brine and water, and the mixture is extracted with ethyl acetate, aind the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 24:1—»83:17) to give 2-[(3,5-bis-trifluoromethyl-ben^l}-ethyl-aininol-5-trifluoromethyl-benzaldehydeoxime (244mg). MS (m/z): 459 [M+H]-^ (4) 2-[(3,5-Bis-trinuQromethyl-benzyl)-ethyl-aiiiino]-5-trifluoromethyl-benzaldehydeoxime (241mg) is dissolved in methanol (lOml) and thereto is added Raney nickel {0.5g) and the mixture is stirred under hydrogen atmosphere at room temperature overnight. Raney nickel is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—•■O:!) to give (2-aminomethyl-4-trifluoromethyl-phenyl)-(3,5-bis-trifluoromethyl-benzyl)-ethyl-amine {210mg). MS (m/z): 445 [M+H]^ (5) (2-Aminomethyl-4-trifluoromethyl-phenyI)-(3,5-bis-trifluoromethyl-benzyl)-ethyl-amine (165mg) is dissolved in toluene (3ml) and thereto are added tert-butyl 4-(2-chloro-p5aimidin-5-ylo3cy)-butyrate (202mg), tris(dibenzylideneacetone)dipalladium(0) (68mg), (±)-2,2'-bis(diphenylphosphino)-l,l'-binaphthalene (92mg) and sodium tert-butoxide (71mg), and the mixture is stirred under nitrogen flow at SCC for 5 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 7:1) to give tert-butyl 4-(2-{2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-triflu oromethyl-benzylamino}-pyrimidin-5-yloxy)-butyrate (73mg). MS (m/z): 681 [M+H]' (6) To tert-butyl 4-(2-{2-[[3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzylamino}-pyTimidin-5-yloxy)-but5Tate (84mg) is added a 4N-hydrochloric acid in dioxane (1.5ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution and made weakly acidic with 10% aquous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 19:1} to give 4-(2-{2-[(3,5-bis-trifluoromethyl-benzy])-ethy]-amino]-5-trifluoromethyl-benzylainino}-p3Timidin-5-y]oxy)-butyric acid (47mg). MS (m/z): 625 [M+H]* Example 85 (1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (5.38g) and cyclopropylmethyl-propyl-amine (4.75g) is dissolved in toluene (50ml), and thereto are added potassium carbonate (11.6g) and the mixture is stirred at 120°C for 4 hours. The reaction solution is cooled to room temperature, and thereto is added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-+4:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (S.Og). MS (m/z): 286 [M+H]* (2) 2-(Cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (5.0g) is dissolved in diethylether ISOml} and thereto is added a 2M methyl magnesium bromide in diethylether (7.35ml) under nitrogen flow at -70'C. The mixture is stirred at the sam.e temperature for 30 minutes, and the reaction solution is quenched with a saturated aqueous ammonium chloride solution and the mixture is extracted with diethylether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—►3:2) to give l-[2-(cyclopropylmethyl-propyl-amino}-5-trif]uoromethyl-phenylj-ethanol (5.43g). MS (m/z): 302 [M+H]* (3) l-[2-(Cyclopropylinethy]-propyl-amino)-5-trifluoromethy]-phenyl\|-ethanol (500mg) is dissolved in methylene chloride (5ml) and thereto is added thionyl chloride (133pl) under ice-cooling and the mixture is stirred at room temperature for 15 minutes. To the reaction solution are added methylene chloride and a saturated aqueous sodium bicarbonate solution, 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 resulting residue and ethyl 4-\|2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxyl-butyrate (749mg) are dissolved in N,N-dimethylformamide (5ml) and thereto is added sodium hydride (62%) (64mg) under ice-cooling and the mixture is stirred for 1 hour. Thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1-+4:1) to give ethyl 4-[2-((3,5-bis-trifluoromethyl-benzyl}-{l-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-ainino)-p3TTmidin-5-yloxy]-butyrate (144mg) as a crude product. The resulting ester is dissolved in ethanol (2ml) and thereto is added a 2N-aqueous sodium hydroxide solution (SOOiil) and the mixture is stirred at room temperature for 2 hour and concentrated under reduced pressure. To the residue is added ethyl acetate and a dilute hydrochloric acid 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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-.24:1} to give 4-[2-((3,5-bis- trifluoroniethyl-benzyl)-{l-[2-(cyclopropylmethyl-propyl-amino)-5- trifluoromethyl-phenyll-ethyl}-amino)-pyrimidin-5-yloxy]-but5Tic acid (llmg). MS (m/z): 707 [M+H]* Example 86 l-[2-(Cyclapropylmethyl-propyl-amino)-5-trifluoromethyl-phenyll-ethanol (l.Og) is dissolved in methylene chloride (10ml) and thereto is added thionyl chloride (266pl) under ice-cooling, and the mixture is stirred for 30 minutes and concentrated under reduced pressure. (3,5-bis-trifluoromethyJ-benzyI)-{5-bromo-pyrimidin-2-yl)-amine (1.33g) is dissolved in N,N-dimethylformamide (5ml) and thereto is added sodium hydride (62%) (142mg) under ice-cooUng, and the mixture is stirred for 15 minutes. Thereto are added a solution of a residue obtained above in N,N-dimethylformamide (5ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—49:1) to give (3,5-bis-trifluoromethyl-benzyl}-(5-bromo-pyrimidin-2-yl)-{l-[2-(cyclopropylmethyl-propyI-aniino)-5-trifluoroniethyI-phenyl]-ethy]}-amine {S15mg). MS (m/z): 683/685 [M+H] Example 87 (1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-p5Timidin-2-yl}-{l-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-amine (200mg) is dissolved in toluene (3ml), and thereto are added tris(dibenzylideneacetone)dip£illadium (27mg), sodium tert-butoxide (42mg), 2-(di-tert-butylphosphino)biphenyl (35mg) and ethyl piperidine-4-carboxylate (66)il) and the mixture is stirred at room temperature under nitrogen flow overnight. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (hexane : ethyl acetate = 19:1^^21:4) to give ethyl l-(2-((3,5-bis-trifluoromethyl-ben2yl)-{l-[2-(cyclopropylmethyl-propyl-amino) - 5-triflu oromethyl-phenyl]-ethyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (78mg). MS (m/z): 760 IM+H]^ (2) Ethyl l-\|2-((3,5-bis-trifluoromethyl-benzyl)-{l-[2-fcyclopropylmethyl- propyl-amino) - 5-trifluorom ethyl-phenyl)-ethyl}-ainino)-pyriniidin-5-yl]- piperJdine-4-carboxylate (75mg) is dissolved in ethanol (1ml), and thereto is added a 2N-aqueous sodium hydroxide solution (148pl), and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a dilute hydrochloric acid 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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0->49:1} to give l-12-((3,5-bis-trifluoromethyl-benzyl}-{l-[2- (cycl op ropylmethyl-propyl-amino) - 5 -trifluoromethyl-phenyl] -ethyl} -amino) -P3a-imidin-5-yl]-piperidine-4-carboxylic acid (54mg). MS (m/z): 732 [M+H]* Example 88 (1) 2-(Butyl-ethyl-amino)-5-fxifluoromethyl-benzaldehyde (l-72g) is dissolved in a mixed solvent of tert-butanol (8ml) and water (2ml), and thereto are added 2-methyI-2-butene (4ml), sodium dihydrogenphosphate dihydrate (1.37g) and sodium chlorite (l.S2g) under ice-cooling, and the mixture is stirred for 2 hours. Thereto are added ethyl acetate and a IN-hydrochloric acid 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 resulting residue is purified by silica gel column chromatography (chlorofonn : methanol = 1:0—♦9:1) to give 2-(butyl-ethyl-amino)-5-trifluoromethyl-benzoxc acid (1.29mg). MS (m/z): 290 [M+H]* (2) 2-(Butyl-ethyl-amino)-5-trifluoromethyl-benzoic acid (l-28g) is dissolved in methylene chloride (lOml) and thereto are added oxalyl chloride (578ial) and a catalj^c amount of N,N-dimethylformamide under ice-cooling, and the mixture is stirred for 30 minutes and evaporated under reduced pressure to dryness. The resulting residue is dissolved in methylene chloride (10ml) again and thereto are added dropwise a solution of (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl)-amine (1.77g) and triethylamine (924pl) under ice-cooling. The reaction solution is stirred at room temperature overnight and the mixture is washed with a IN-hydrochloric acid and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—9:1) to give N-{3,5-bis-trifluoromethyl-benzyl)-N-(5-bromo-p3Timidin-2-yl)-2-(butyl-ethyl-amino)-5-trifluoromethylben0amide (842mg). MS (m/z): 671/673 [M+H]+ The corresponding starting compounds are treated in a similar manner to any of the above Examples to give the compounds as listed in Table 7. Example 103 (1) Ethyl 4-{2-[(3,5-bis-txifluoromethyl-benzyl)-(2-txifluoro- methariesulforiyloxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (I.Og) is dissolved in 1,4-dioxane (lOml) and thereto are added [ 1, r -bis(diphenylphosphino)ferTocene]dichloropalladium dichloromethane complex (216mg), bis(pinacolate\|diboron (670mg) and potassium acetate (389mg), and the mixture is stirred under nitrogen atmosphere at 80°C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:l->-4:l) to give ethyl 4-(2-{(3,5-bis-triiluoromethyl- benzyl)-[2-(4,4,5,5-tetrainethyl-(l,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (805mg). MS (m/z): 73&{M+H]-^o (2) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-(4,4,5,5-tetramethyl-[I,3,2]dioxaboroIan2-yI)-5-trifluoroinethyI-benzyI]-ammo}-p5T:iniidin-5-yloxy)-bu1yrate (200mg) is dissolved in 1,4-dioxane (4inl) and thereto are added 2-bromo-4-methyl-pyridine (70mg), [1.1-bis(diphenylphosphino)ferroceneldichloropalladium dichloromethane complex (22mg) and cesium carbonate (133mg), and the mixture is stirred under nitrogen atmosphere at 80°C for 5 days. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—4:1) to give ethyl 4-(2-((3,5-bis-trifLuoromethyI-benzyI)-[2-(4-methyI-pyridin-2-yI)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (85mg). MS (m/z): 701 [M+H]* (3) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-5-trifIuoromethyl-beniyl]-amino}-p3Timidin-5-ylo^}-bu1yrate (SSmg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (Iml) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—23:2) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-\|2-(4-methylpyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (68mg). The resulting carboxylic acid is dissolved in ethanol (1ml), and thereto is added ]^jii ,,n ^rt^i,-i„ h-^rAfnv^Af dnintinn noinll. and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis- trifluoromethyl-benzyl) - [2 - (4-methyl-pyridin-2-yl) - 5-trifluoromethyl-benzyl]- amino}-pyrimidin-5-yloxy)-bu1yric acid sodium salt (69mg). MS (m/z): 671 [M-Na]- Examples 104 to 112 The corresponding starting compounds are treated in a similar manner to Example 103 to give the compounds as listed in Table 9. Example 113 (1) Trifluoro-methanesulfonic acid 2-{\|{3,5-bis-trifluoromethyl-ben^l)- {5-morphoUn-4-yl-pyrimidin-2-yl)-ainino]-methyl}-4-triflu oromethyl-phenyl ester (1.19g) is dissolved in 1,4-dioxane (10ml) and thereto are added [1,1'- bis(diphenylphasphino)ferrocene]dichloropaUadium dichloromethane complex (273mg), bis(pinacolate)diboron (848mg) and potassium acetate [492mg), and the mixture is stirred under nitrogen atmosphere at SCC overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate and the insoluble materials are removed by filtration through CelitefM. The filtrate is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1^7:3) to give (3,5-bis-trifluoromethyI-benzyl)-(5-morphoUn-4-yl-pyrimidin-2-yl)-[2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amine (648mg). MS (m/z); 691 [M+H]+ (2) f3,5-Bis-trinuoromethyl-ben2yl)-(5-morpholin-4-yl-pyrimidin-2-yl}-[2- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolaii-2-yl)-5-trifluoromethyl-benzyl]- amine {250mg) is dissolved in 1,4-dioxane (5ml) and thereto are added ethyl 4-chloro-2-trifluoromethyl-pyriniidine-5-carboxylate (140nig), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (30mg) and cesium carbonate (177mg), and the mixture is stirred under nitrogen atmosphere at SCC overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate £ind the insoluble materials are removed by filtration through CeliteTM. The filtrate is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by sUica gel column chromatography (hexane : ethyl acetate = 9:1-^4:1) to give ethyl 4-(2-{[(3,5-bis- trifiuoromethyl-ben2yl}-{5-morpholin-4-yl-p3'rimidin-2-yl)-amino]-methyl}- 4-trifluoromethyl-phenyl) - 2-trinuoromethyl-pyrimidine - 5-carboxylate (199mg). MS (m/z): 783 IM+H] (3) Ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-{5-morpholin-4-yl- pjTiimidin- 2 -yl) -amino] -methyl}-4 -trifluoromethyl-phenyl) -2 -trifiuoromethyl- pyrimidine-5-carboxylate (194mg) is dissolved in ethanol (4m.l), and thereto is added IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1 N-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 resulting residue is purified by silica gel column chromatography 172 (chloroform : methanol = 1:0^7:3) to give 4-(2-{[(3,5-bis-trifluoromethyl- benzyl)-(5-morpholin-4-yl-p5Timidin-2-yl)-amino]-methyl}-4- trifluoromethyl-phenyl)-2-trifluoromethyl-pyrimidine-5-carboxylic acid (165mg). MS (m/z): 755 [M+H]* Example 114 1) Ethyl 4-(2-{(3,5-bis-trinuoromethyI-benzyl)-[2-(4,4,5,5-tetramethyl-l,3,21dioxaborolan-2-yl)-5-trifluoromethyl-ben2yll-amino}-p5T-imidin-5-'loxy)-butyrate (SOOmg) is dissolved in 1,4-dioxane (5m^l) and thereto are idded 4-chloro-5-methoj!y-2-methylsulfanil-pyrimidine (117mg), [1,1'-)is{diphenylphosphino) ferrocene] dichloropalladium dichloromethane ;oinplex (33mg) and cesium carbonate (199mg), and the mixture is stirred inder nitrogen atmosphere at 80°C overnight. The reaction solution is ;ooled to room temperature, and thereto are added chloroform and water, uid the insoluble materials are removed by filtration through Celite^^. The iltrate is separated, and the organic layer is dried and concentrated under ■educed pressure. The resulting residue is purified by silica gel column :hromatography {hexane : ethyl acetate = 9:l-7:3) to give ethyl 4-(2-{(3,5-3is-trifluoromethyl-benzyl)-[2-(5-methoxy-2-methylsulfanil-p3Tiniidin-4-yl}-S-trifluoromethyl-benzyl]-aniino}-pyrimidin-5-ylo7^)-butyrate (165mg). MS m/z): 764 [M+H]+ 2) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-(5-methoxy-2-nethylsulfanil-pyrimidin-4-yl)-5-trifluoromethyl-benzyl] - amino}-pyrimidin-5-ylo3^)-bu1yrate (162mg) is dissolved in chloroform (5ml) and thereto is idded m-chloro perbenzoic acid (70%) (63mg) and the mixture is stirred at -oom temperature for 30 minutes. To the reaction solution are added saturated aqueous sodium thiosulfate solution and chloroform, and the nixture is separated, and the organic layer is washed with a saturated Drine, dried over magnesium sulfate, and concentrated under reduced Dressure. The resulting residue is purified by silica gel column :hromatography (hexane : ethyl acetate = 1:0^19:1) to give ethyl 4-(2-{(3,5- 173 bis-trifluoromethyl-benzyi) - [2 - (2-methanesulfinyl-5-methoxy-pyrimidin-4 -yl)-5-trifluQromethyl-benzyl]-ainino}-p3Timidin-5-yloxy)-butyrate (143mg). MS (m/z): 780 [M+H] (3) Ethyl 4-(2-{(3,5-bis-trifluoroinethyl-benzyl)-[2-(2-methanesulfmyl-5-methoxy-pyrimidin-4-yl)-5-trifluoromethyl-ben2yl]-ainino}-pyrimidin-5-yloxy}-butyrate (139ing) is dissolved in methanol (5ml) and thereto is added sodium methoxide (48mg} and the mixture is stirred at room temperature overnight and further thereto is added sodium methoxide (48mg), and the mixture is stirred overnight. The reaction solution is concentrated under reduced pressure, and to the residue is added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over ma^esium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 7:3—tl;l) to give methyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2,5-dimethoxy-pyrimidin-4-yl)-5-trifluoromethyI-ben^l]-amino}-pyrimidin-5-yla3^)-butyrate (54mg). MS (m/z): 734 [M+Hi+ (4} Methyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2,5-dimethoxy- pyrimidin-4-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-y]oxy}-bu^ate (52mg) is dissolved in methanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2,5-dimethoxy-pyrimidin-4-yl) - 5-trifluorom ethyl-benzyl] - amino}-pyrimidin-5-yloxy)-butyric acid {49mg). MS (m/z): 720 [M+H]^ Example 115 174 (1) Trifluoro-methanesulfonic acid 2-{[(3,5-bis-trifiuoromethyl-benzyl}-(5-morphoUn-4-yl-pyrimidin-2-yl)-amino]-metiiyl}-4-trifluoromethyl-phenyl ester (620ing) is dissolved in 1,4-dioxane (10ml) and thereto are added 2-benzyloxyphenyl boronic acid (398mg), [1,1'-bis{diphenylphosphino)ferrocene)dichloropalladium dichloromethane complex (142mg) and cesium carbonate (567mg), and the mixture is stirred under nitrogen atmosphere at 80°C overnight, The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the insoluble materials are removed by filtration through CeliteTM. The filtrate is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—»4:1) to give {2'-benzyloxy4-trifluoromethyl-biphenyl-2-ylmethyl}-(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-ainine (617mg). MS (m/z): 747 [M+H]+ (2) (2'-Benzyloxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(3,5-bis-trifiuoromethyl-benzyl)-(5-morpholin-4-yl-p5T-imidin-2-yl)-amine (606mg) is dissolved in ethanol (lOml), and thereto is added 10% palladium-carbon (lOOmg) and the mixture is stirred under hydrogen atmosphere at room temperature for 3.5 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:l-7:3) to give 2'-{[(3,5-bis-trifluoromethyl-benzyl)-{5-morpholin-4-yl-pyrimidin-2-yl)-ainino]-methyI}-4'-trifluoromethyl-biphenyl-2-ol (374mg). MS (m/z): 657 \|M+H1+ Example 116 (1) 2'-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4'-trifluoromethyl-biphenyl-2-ol (ISOing) is dissolved in N,N-dimethylformamide (3ml) and thereto are added ethyl 4-bromobu1yrate (SOpl) and potassium carbonate (47mg), and the mixture is stirred at room 175 temperature for 2 hours and at 80°C for 2 hours. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, £ind concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—»'4:1) to give ethyl 4-(2'-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yI-pyrimidin-2-yl)-amino]-niethyl}-4'-trifluoromethyl-biphenyl-2-yloxy)-butyrate (163mg). MS (m/z): 771 [M+H]* (2) Ethyl 4-(2'-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl- pyrimiditi-2-yl)-amino]-methyl}-4'-trifluoromethyl-biphenyl-2-yloxy)-bulyrate (157mg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 2 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0^9:1) to give 4-(2'-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-P5Tim,idin-2-yl}-amino]-methyl}-4'-trifluoromethyl-biphenyl-2-ylo3ty)-butyric acid (146mg). The resulting carboxylic acid is dissolved in ethanol (Iml), and thereto is added IN-aqueous sodium hydroxide solution H97ial) and the reaction solution is concentrated under reduced pressure to give 4-(2'-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-p5mmidin-2-yl)-amino]-methyl}-4'-trifluoromethyl-biphenyl-2-yloxy)-butyric acid sodium salt (146mg). MS (m/z): 741 [M-Na]-Example 117 (1) 2-Chloro-5-(trifluoromethyl)benzaldehyde (12.00g) is dissolved in toluene (200ml) and the mixture is degassed under reduced pressure. To this soluton are added tetrakis(triphenylphosphine)palladium (13.29g), 5- 176 isopropyl-2-methoxybenzene boronic acid (14.51g), ethanol {26ml), distilled water (ISml) and a 2M-aqueous sodium carbonate solution (57.5ml), aind the m,Lxture is degassed under reduced pressure and heated at SS^C under nitrogen atmosphere and stirred overnight. The reaction solution is allowed cool to room temperature, and thereto is added a saturated brine and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 99:1— give 5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde {14.25g). MS (m/z): 323 [M+H]* (2) 5'-lsopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (5.0g) is dissolved in 1,2-dichloroethane {20ml) and thereto are added 3,5-bis-{trifluoromethyI)ben^lamine (3.8g), acetic acid (1.1ml) and triacetoxy-sodium borohydride {4.0g), and the mixture is stirred at room temperature overnight. To reaction mixture is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with chloroform. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 10:1) to give {3,5-bis-trifluoromethyl-benzyl}-{5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine {7.2g). MS {m/z): 550 [M+H]+ {3) (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (3.0g} is dissolved in toluene {20ml) and thereto are added 5-bromo-2-chlorop5Timidine {1.6g) and N,N-diisopropylethylamine (1.4ml) and the mixture is heated under reflux overnight. The reaction solution is allowed cool to room temperature, and thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue 177 is purified by silica gel column chromatography (hexane : ethyl acetate = 40:1) to give f3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethy]-biphenyJ-2-yImethyl)-amme (2.6g). MS (m/z); 708/706 [M+HJ+ (4) {3,5-Bis-trifluoromethyl-benzyl)-{5-bromo-pyrimidin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine {1.2g} is dissolved in N,N-dimethylformam.ide (6ml) £ind thereto are added palladium acetate (II) (76mg), l,r-bis(diphenylphosphino}ferrocene (376mg), ethanol (4.0ml) and triethylamine (4.8nil), and the mixture is stirred under carbon monoxide at 90*C overnight. The reaction solution is allowed cool to room temperature, and thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 20:1^^10:1) to give ethyl 2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carboxyIate (l.lg). MS (m/z): 700 [M+H]+ (5) Ethyl 2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methojQ'-4-trifluoromethyl-biphenyl-2-ylniethyl)-amino]-pyrimidine-5-carboxylate (l.lg) is dissolved in a mixed solvent of ethanol (18ml) and tetrahydrofuran (20ml) and thereto is added a 2M-aqueous sodium hydroxide solution (3ml), and the mixture is stirred at 50°C for 1 hour and a half. The reaction solution is concentrated under reduced pressure and thereto is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 25:1) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carbo3^1ic acid 178 (TOOmg). MS (m/z): 672 [M+H] Example 118 (1) 2-[(3,5-Bis-trifluoromethyl-ben2yI)-(5'-isopropyl-2'-raethoxy-4-trifluoroinethyl-bipheny]-2-ylinethyl)-ainino]-pyrmiidine-5-carboxylic acid (200ing) is dissolved in N,N-dimethylformamide (5ml) and thereto are dded l-(3-dimethylaininopropyl)-3-ethylcarbodiimide hydrochloride 56mg), 1-hydroxy-benzotriazole (60mg), triethylamine (125^11) and 4-minobutyric acid ethyl ester hydrochloride {75mg), and the mixture is tirred at room temperature overnight. To reaction mixture is added a aturated aqueous sodium bicarbonate solution and the mixture is xtracted with ethyl acetate. The organic layer is washed with a saturated irine, dried over magnesium sulfate, and concentrated under reduced iressure. The resulting residue is purified by silica gel column hromatography (hexane : ethyl acetate = 5:2) to give ethyl 4-({2-[(3,5-bis-rifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trTfluoromethyl-iiphenyl-2-ylmethyl)-amino]-p5Tnmidine-5-carbonyl}-amino)-but5^ate 230mg). MS (m/z): 785 [M+H)* 2) Ethyl 4-{{2-[(3,5-bis-trinuoromethyl-benzyl)-(5'-isopropyl-2'-methoxy--trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carbonyl}-imino)-butyrate (230mg) is dissolved in ethanol (5ml) and thereto is added L 2M-aqueous sodium hydroxide solution (1ml) and the mixture is stirred it room temperature for 1 hour and a half. To reaction mixture is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The irganic layer is washed with a saturated brine, dried over magnesium ulfate, and concentrated under reduced pressure. The resulting residue s purified by silica gel column chromatography (chloroform : methanol = 25:1) to give 4-({2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carbonyl}-amino)-butyric acid (220mg). MS (m/z): 757 [M+H]^ Example 119 179 (1) (3,5-Bis-txifIuoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-aiiiine (1.06g) is dissolved in dimethylsulfoxide (5ml), and the mixture is degassed and thereto are added [ 1, l'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (61mg), potassium acetate (442mg) and bis(pinacoIate)diboron (571mg). The mixture is degassed and heated to 80°C under nitrogen flowe and stirred for 45 minutes. The reaction solution is allowed cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (5ml), and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (1.5ml) under ice-cooling and stirred at the same temperature for 1 hour and a half. To reaction mixture is added dropwise saturated aqueous sodium thiosulfate solution under ice-cooling, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4: l-»3:1) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyTimidin-5-ol (866mg). MS (m/z): 644 [M+H]^ (2) 2-{(3,5-Bis-trifluoromethyl-benzyl)-[4-(cyclopropylmethyl-propyl-amino)-2-methoxy-pyrimidin-5-ylmethyl]-amino}-pyrimidin-5-ol (300mg) is dissolved in N,N-dimethylformamide (2ml) and thereto are added potassium carbonate (193mg) and 4-bromo-butyronitrile (139pl), and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The 180 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 17:3^3:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl- 2' -metho5^-4-trifiuoromethyl-biphenyl-2 -ylmethyi) -amino j -pyrimidin-5-yloxy}-bu1yronitrlle (308mg). MS (m/z): 711 [M+H]+ Example 120 4-{2-l(3,5-Bis-trifluoromethyl-beiizyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyronitrile (240mg) is dissolved in N,N-dimethylformamide (7.5ml), and the mixture is degassed and thereto are added sodium azide (220mg) and ammonium chloride (ISlmg) and the mixture is heated to 110°C and stirred overnight. The reaction solution is allowed cool to room temperature, and thereto are added a saturated brine and 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by siEca gel column chromatography (chloroform : methanol = 99:1-19:1) to give (3,5-bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-methojQ'-4-trifluoromethyl-biphenyl-2-ylmethyl)-{5-[3-(lH-tetrazol-5-yl)-propo:^]-pyrimidin-2-yl}-amine (127mg). MS (m/z): 754 [M+H]- Example 121 (1) 2-{(2-Benzyloxy-5-trifiuoromethyl-benzyl}-(3,5-bis-trifluoromethyl-benzyl}-amino]-p3Timidin-5-ol (1.33g) is dissolved in tetrahydrofuran (20ml), and thereto are added 2-methylsulfanil-ethanol (290vil), triphenyJphosphine (S70mg) and 40% diethyl azodicarboxylate/toluene solution (1.5ml) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added water 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 99:1—9:1) to give (2-benzyloxy-5- 181 trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methylsialfanil-ethojq')-pyrimidin.-2-yl]-amine (1.2 Ig). MS (m/z); 676 [M+H]+ (2) (2-Benzyloxy-5-trifluoromethyl-benzyl}-(3,5-bis-trifluoromethyl-beiizyl)-[5-(2-inethylsulfanii-ethoxy)-pyriinidin-2-yl]-ainine {1.2 Ig) is dissolved in chloroform (ISml) and diereto is added m-chloro perbenzoic acid (75%) (906nig) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added saturated aqueous sodium thiosulfate 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—7:3) to give (2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methanesulfonyl-etho3cy}-pyriniidin-2-ylj-amine(1.09g). MS (m/z): 708 [M+H]* (3) (2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-ainine (1.07g) is dissolved in ethanol (15ml) and thereto is added 10% palladium-carbon (320mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 7 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give 2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-£imino}-methyl)-4-trifluoromethyl-phenol (400mg). MS (m/z): 618 [M+H1+ (4) 2-({t3,5-Bis-trifluoromethyl-ben2yl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trinuoromethyl-phenol (400mg) and pyridine (79pl) are dissolved in methylene chloride (10ml) and thereto is added trifluoromethanesulfonic acid anhydride (ISSjil) under ice-cooling and the mixture is stirred under nitrogen atmosphere at 0°C for 30 182 minutes. The reaction solution is cooled to room temperature and stirred for 50 minutes, and thereto is added trifiuoromethane sulfonic acid anhydride (Sljal) and the mixture is stirred for 10 minutes. Thereto are added a saturated aqueous sodium bicarbonate 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 is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1^2:1) to give trifiuoromethane sulfonic acid 2-({(3,5-bis-trifluoromethyl-benzyl)-[5-{2-methanesulfonyl-ethoxy)-pyrimidin-2-yl] - amino}-methyl)-4-trifluoromethyl-phenyl ester (386mg). MS (m/z): 750 [M+H]* (5) Trifiuoromethanesulfonic acid 2-({(3,5-bis-trifluoromethyl-benzyl}-[5-(2-methanesulfonyl-ethoxy}-p3Timidin-2-yl]-amino}-methyl}-4-trifluoromethyl-phenyl ester (llOmg) is dissolved in 1,4-dioxane (2ml) and thereto are added 2,4-dimethoxy-pyrimidine-5-boronic acid (70mg), palladium acetate (13.2mg), 1,1 '-bis(di-tert-butylphosphino)ferrocene (28mg) and tripotassium phosphate (62mg) and the mixture is stirred under nitrogen atmosphere at SCC for 4 hours. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give (3,5-bis-trifluoromethyl-benzyl)-[2-(2,4-dimetha3^-pyrimidin-5-yl)-5-trifluoromethyl-benzyl]-[5-(2-methanesulfonyl-ethoxy)-p5TTmidin-2-yl]-amine (34mg}. MS (m/z): 740 [M+H]* Example 122 The corresponding starting compound is treated in a similar manner to Example 121 to give the compound as listed in Table 10. 183 Sxample 123 1) Ethyl 4-(2-{(3,5-bis-triiluoromethyl-benzyl)-12-(6-isopropenyl-3- nelJioxy-p5aidm-2-yl)-5-trifluoromethyl-benzyl]-airiino}-pyrimidin-5-yloxy)- 3utyrate (76mg) is dissolved in ethanol (5ml), and thereto is added 10% Dalladium-carbon (15mg) and the mixture is stirred under hydrogen itmosphere for 1.5 hours. The catalyst is removed by filtration, and the iltrate is concentrated under reduced pressure to give ethyl 4-(2-{(3,5-bis- Tifluoromethyl-benzyl)-[2-(6-isopropyl-3-metho3Q'-p5Tidin-2-yl)-5- Tifluoromethyl-benzyl]-amino}-p5Timidin-5-yloxy)-butyrate {70mg). MS m/z): 759 [M+H]* 2) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3- nethoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy}- 185 butyrate (70mg) is dissolved in ethanol (2ml), and thereto is added IN-aqueous sodium hydroxide solution (0.5ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a IN-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 resulting residue is puriiied by silica gel column chromatography (chloroform : methanol = 1:0->9:1) to give 4'(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-(6-isopropyl-3-methoxy-pyridin'2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (62mg). The resulting carboxylic acid is dissolved in ethanol (1ml), and thereto is ^dded IN-aqueous sodium hydroxide solution (85vil) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trinuoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-ben^l)-amino}-pyrimidin-5-yloxy}-butyric acid sodium salt (729mg). MS (m/2): 729 [M-Na)-Example 124 (1) Ethyl 4-{2-((3,5-bis-trifluoromethyl-benzyl)-(2-hydrojcy-5- trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-but3Tate (300mg) is dissolved in N,N-dimethylformamide (5ml) and thereto are added sodium hydride (60%) (29mg) and 4,6-dichloro-p5T-imidine (107mg) under ice-cooling, and the mijtture is stirred for 30 minutes, and the reaction solution is cooled to room temperature, and thereto is added 4,5-dichloro-pyrimidine (107mg), and the mixture is stirred for 30 minutes. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1-17:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-(6-chloro-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy}-butyrate (244mg). MS (m/z): 738/740 [M+Hj^ 186 (2) Ethyl 4-(2-\|(3,5-bis-trifluoromethyl-benzyl)-[2-(6-chIoro-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl j-amino}-pyrimidin-5-yloxy)-bulyrate (170mg) is dissolved in toluene {5ml), and thereto are added diisopropylethylamine (136\|al), 2.0M-dunethylamine/tetrahydrofuran solution (0.4ml) and the mixture is stirred at 50°C for 1 day. The reaction solution is cooled to room temperature, and thereto are added aqueous citric acid solution and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1->2:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-(6-dimethylamino-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-bu^ate (llSmg). MS (m/z): 747 [M+H]+ (3) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-dimethylamino-pyTimidin-4~yloxy)-5-trifluoromethyl-ben2yl]-amino}-pyrimidin-5-yloxy)-butyrate (llOmg) is dissolved in ethanol (Sml) and thereto is added IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 2 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0^9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-ben^l)-[2-(6-dimethylamino-p5?rimidin-4-yloxy)-5-trifluoromethyl-ben2ryll-amino}-pyrimidin-5-yloxy)-butyric acid (107mg). MS (m/z): 719 [M+H]+ Example 125 The corresponding starting compound is treated in a similar manner to Example 124 to give the compound as listed in Table 11. 187 Example 126 (1) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-trifluoro- methanesulfonyloxy-5-trifluoromet±iyl-benzyl)-ainino]-p5T-imidin-5-yloxy}- butyrate (260mg) is dissolved in 1,2-dimethoxyethane (1ml) and thereto are added (S)-l-(tert-butyl-dimethyl-silanyloxymethyl)-propylamine (140mg), tris(dibenzyIideneacetone)dipalladium (31mg}, 2-(di-tert- butylphosphino}biphenyl (41mg) and tripotassium phosphate (l46ing), and the mixture is degassed under reduced pressure and stirred under nitrogen atmosphere at SCC overnight. The reaction solution is allowed cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column 188 chromatography (hexane ; ethyl acetate = 1:0^-10:1) to give ethyl 4-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-I(S)-l-(tert-butyl-diniethyI-sil£inylox5TTiethyl)-propylamino]-5-trifluoromethyl-benzyl}-amino)-p3n-imidin-5-ylo:^]-butjTate (186ing). MS (m/z): 811 [M+H] (2) Ethyl 4-[2-((3,5-bis-trinuoroinethyl-benzyl)-{2-[(S)-l-(tert-butyl-dimethyl-silanyloxymethyl)-propylamino] - 5-trifluoromethyl-benzyl}-ainino)-pyrimidin-5-yloxy]-but3Tate (183mg) is dissolved in tetrahydrofuran (SmL) and thereto is added IM-tetrabutylammonium fluoride/tetrahydrofuran solution (1ml) and the mixture is stirred at room temperature for 20 minutes. The reaction solution is concentrated under reduced pressure and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4: l-2:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-((S)-l-hydroxymethyl-propylam.ino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-but3Taet (93mg). MS (m/z): 697 [M+H]+ (3) Ethyl 4-(2-{(3,5-bis-trinuoromethyl-benzyl)-[2-((S)-l-hydroxymethyl-propylamino)-5-trifluoromethyl-benzyl]-aniino}-pyrimidin-5-yloxy')-butyrate (40mg) is dissolved in a mixed solvent of methanol (0.3ml) and tetrahydrofuran (1ml) and thereto is added a IM-aqueous sodium hydroxide solution (0.5ml), and the mixture is stirred at room temperature for 30 minutes. To reaction mixture is added a 10% aqueous citric acid solution and a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-({S)-l-hydro30T^ethyl-propylamino)-5-trinuoromethyl-benzyI]-amino}-pyrimidin-5-yloj^)-butyric acid (41mg). MS (m/z): 669 [M+H]^ 189 Example 127 (1) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-l-hydroxymethyl-propyl-amino) - 5-trinuoromethyl-ben2yl]-amino}-pyrimidin-5-yloxy)-butyrate (102mg) is dissolved in methylene chloride (1.5ml) and thereto is added triethylamine (31}il), followed by an addition of triphosgene (17mg) under water-cooling, and the mixture is stirred at room temperature overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (hexane:ethyl acetate = 9:l--»7:3) to give ethyl 4-{2-{(3,5-bis-trinuoromethyl-benzyl)-[2-((S)-4-ethyl-2-oxo-oxazolidin-3-yl)-5-trifluoromethyl-benzyl]-amino}-p5T-imidin-5-yloxy}-butyrate (94mg). MS (m/z): 723 [M+H]+ (2) Ethyl 4-(2-{(3,5-bis-triiluoromethyl-benzyl)-[2-{(S)-4-ethyl-2-oxo-oxazolidin-3-yl}-5-trifluoromethyl-benzyl]-amino}-pyTimidin-5-yloxy)-butyrate (90mg} is dissolved in a mixed solvent of a methanol (0.5mL) and tetrahydrofuran (1ml) and thereto is added IM-aqueous sodium hydroxide solution (0.5mL) and the mixture is stirred at room temperature for 1 hour. The reaction mixture is made acidic with 10% aqueous citric acid solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = l:0- 190 Example 128 (1) 2-[(3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methojcy-4-trifluoromethyl-biphenyl-2-ylmethyl)-ainino]-p3T-imidin-5-ol (300mg) is dissolved in tetrahydrofuran (2mL), and thereto are added 2-(methylthio)ethanol (162]il} and triphenylphosphine (488mg}, and thereto is added dropwise a 40% diethyl azodicarboj^late/toluene solution (424\|il) under water-cooling, and the mixture is stirred at 50°C overnight. Further thereto are added 2-{methylthio)ethanol (243nl) and triphenylphosphine (244mg), and thereto is added dropwise diisopropyl azodicarboxylate (361vil} under water-cooling, and the mixture is stirred at 60°C for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 99:1—♦Q:!) to give (3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[5-(2-methylsulfanil-ethoxy)-pyrimidin-2-yl]-amine (300mg). MS (m/z): 718 [M+H]+ 191 (2) (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-metho3cy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-(2-methylsulfanil-ethoxy)-pyrimidin-2-yl]-amine (296mg) is dissolved in chloroform (3ml) and thereto is added m-chloro perbenzoic acid (152ing), and the mixture is stirred at room temperature for 1 hour. To the reaction solution is added a saturated aqueous sodium bicarbonate solution and the mixture is stirred at room temperature for 10 minutes and extracted with chloroform, and the organic layer is washed successively a saturated aqueous sodium bicarbonate solution and a brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 19:1—»2:1, and chloroform : methanol = 97:3^19:1) to give (3,5-bis-trifluoromethyl-benzyI}-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-amine (203mg) (MS (m/z): 750 [M+H]^), and (3,5-bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-methoxy-4-triflu oromethyl-biphenyU2-ylmethyl) - [5-(2-metheinesulfinyl-ethoxy)-pyrimidin-2-yl]-aniine (65mg) (MS (m/z): 734 [M+H]+}. 192 fl) (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethy]-biphenyl-2-ylmet±iyl)-ainine (2.0g) is dissolved in ethanol (20ml), and thereto are added cyanogen bromide (578ing) and sodium bicarbonate (928mg) and the mixture is stirred at room temperature for 2 hours. To reaction mixture is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by sUica gel column chromatography (hexane : ethyl acetate = 10:1—5:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5'-isoprDpyl-2'-methoj^-4-trifluoromethyl-biphenyl-2-ylmethyl}-cyanamide (1.8g). MS (m/z): 575 [M+H]* (2) (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-cyanamide (l.Sg) is dissolved in N,N-dimethylformamide (10ml), eind thereto are added sodium azide (407mg) and ammonium chloride (335mg), and the mixture is heated to 100°C and starred for 6 hours. The reaction solution is allowed cool to room temperature, and thereto is added a 10% aqueous citric acid solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 30:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoroinethyl-biphenyl-2-ylmethyl)-(2H-tetrazol-5-yl)-amine (1.9g). MS (m/z): 618 [M+H]* (3) (3,5-Bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-methoxy-4-trifiuoromethyl-biphenyl-2-ylmethyl)-(2H-tetra2ol-5-yl}-amine (400mg) is dissolved in N.N-dimethylformamide (3ml) and thereto are added triethylamine (2ml) and ethyl 4-bromobutyrae (278^^1) and the mixture is stirred at 50°C for 3 hours. To reaction mixture is added water, and 193 extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1) to give ethyl 4-{5-[(3,5-bis-trifluoro methyl-benzyl} - (5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-aminol-tetrazol-2-yl}-butyrate (360mg) MS (m/z): 732 [M+H]* (4) Ethyl 4-{5-[(3,5-bis-trifluorGmethyl-benzyl}-(5'-isopropyl-2'-metho^-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyrate (180mg) is dissolved in ethanol (3ml), and thereto is added a 2M-aqueous sodium hydroxide solution {0.5mL) and the mixture is stirred at room temperature for 1 hour and a half. The reaction mixture is made acidic with a IN-hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 20:1) to give 4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyric acid (160mg). MS (m/z): 704 [M+H]* (5) 4-{5-[(3,5-Bis-trifluaromethyl-benzyl}-{5'-isopropyl-2'-metho:^-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyric acid (154mg) is dissolved in ethanol (3ml), and thereto is added IM-aqueous sodium hydroxide solution (225}il), and concentrated under reduced pressure to give 4-{5-[(3,5-bis-triiluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl- 2 -ylmethyl) -amino] -tetrazol-2 -yl}-butyric acid sodium salt (153mg). MS (m/z): 702 [M-Na] * Example 130 (1) (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-triiluoromethyl-biphenyl-2-ylmethyl)-(2 H-tetrazol-5-yl)-amine (300mg) is dissolved in tetrahydrofuran (5ml) and thereto are added 194 triphenylphosphine (l91mg), 2-(methylthio)ethanol (631^1), a 40% diethyl azodicarboxylate/toluene solution (332)^1) and the mixture is stirred at room temperature for 2 hours and a half. To reaction mixture is added water and the mixture is extracted with ether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 12:1) to give (3,5-bis-trifluoromethyl-benzyl]-(5'-isopropyl-2'-methoxy-4-trinuoromethyl-biphenyl-2-ylmethyl)-[2-(2-methylsulfanil-ethyl)-2H-tetrazol-5-yl]-amine (270mg). MS (m/z): 692 [M+H]* (2) (3,5-Bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-metho3^-4-trifluoromethyl-biphenyl- 2-ylmethyl) - [ 2 -(2 -methylsulfanil-ethyl) -2 H -tetrazol-5-yl]-amine (270mg) is dissolved in chloroform (3ml), and thereto is added m-chloro perbenzoic acid (168mg), and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate, and the organic layer is washed with a brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 40:1) to give (3,5-bis-trifluoromethyl-ben^l)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methanesulfmyl-ethyl)-2H-tetrazol-5-yl]-amine (157mg). MS (m/z): 708 [M+H]+ 195 Example 131 (1) 5'-Isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (S.OOg) is dissolved in ethanol (40inl) and thereto are added hydroxyl ammonium chloride (1.29g) and sodium acetate (1.53g), and the mixture is stirred under nitrogen atmosphere at 60°C for 1 hour and a half. The reaction solution is concentrated under reduced pressure, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue (3.3g) is dissolved in methanol (40ml), and thereto is added Raney nickel {5g) £ind the mixture is stirred under hydrogen atmosphere at room temperature overnight. Raney nickel is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—♦19:1) to give C-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2- 196 yl)-methylaniine (1.57g). MS (m/z): 324 [M+H]^ (2) C-(5'-isopropyl-2'-methojq'-4-txifluoromethyl-biphenyl-2-yl)-methylajnine (1.54g) is dissolved in toluene (25ml), and thereto are added tert-butyl 4-(2-chloro-pyTimidin-5-yloxy)-biityrate (1.96g), palladium acetate {II} (I95mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (543nig), tetra-n-bulyl ammomum iodide {359mg) and sodium tert-butoxide (560mg), and the mixture is stirred under nitrogen flow at 85°C overnight. The reaction solution is allowed cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 47:3—3:1) to give tert-butyl 4-{2-[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-bu1yrate (895mg). MS (m/z): 560 [M+H] (3) Tert-butyl 4-{2-[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloJ^}-but5T:ate (ISOmg) is dissolved in N,N-dimethyIfGrmamide (1.0ml), and thereto is added l,3-dichloro-5-chloromethyl-benzene (252mg), followed by an addition of sodium hydride (60%) (34mg) under ice-cooling and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-9:1) to give tert-butyl 4-{2-[(3,5-dichloro-benzyl)-{5'-isopropyl-2'-methojq'-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (184mg). MS (m/z): 720/718 [M+H] (4) TQ tert-butyl 4-{2-[(3,5-dichloro-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethy 1-bipheny 1-2 -ylmethyl) -amino] -pyrimidin-5 -yloxy}-butyrate 197 (ISOmg) is added 4N-hydrochloric acid/dioxane solution (2ml} and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : m.ethanol = 1:0-19:1) to give 4-{2-[(3,5-dichlorobenzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl}-amino]-pyrimidin-5-yloxy}-butyric acid (136mg}. MS (m/z): 664/662 [M+H]+ Examples 132 to 133 The corresponding starting compounds are treated in a similar manner to Example 131 to give the compounds as listed in Table 15. 198 dimethylxanthene (62mg) and palladium acetate (II) (16mg) and the mixture is stirred under nitrogen atmosphere at room temperature for 5 minutes. To the mixed solvent is added the mixed solution of tert-butyl 4-{2-[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (200mg), l-bromo-3,5-bis-trifluoromethyl-benzene (126mg) and toluene (1.5ml), and the mixture is degassed under reduced pressure and thereto is added sodium tert-butoxide (51mg) and the mixture is stirred under nitrogen flow at 80°C overnight. The reaction solution is allowed cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 10:1) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-pheny])-(5'-isopropyI-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino j-pyrimidin-5-yloxyj-butyrate (204mg), MS (m/z): 772 [M+H] (2) To tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-phenyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (197mg) is added a 4N-hydrochloric acid in dioxane (2.5ml) and the mixture is stirred at room temperature for 3 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chrom,atography (chloroform : methanol = 1:0-+19:1) to give 4-{2-[(3,5-bis-trifluoromethyI-phenyl)-(5'-isopropyl-2'-methojqr-4-trifluoromethyl-biphenyl-2-ylmethyl)-aminol-p5n:imidin-5-yloxy}-butyric acid (104mg). MS (m/z): 716 [M+H]* Example 135 (1) C-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine {3.47g) is dissolved in dioxane (50ml), and thereto are added 199 5-bromo-2-chloropyriinidine (5.30g) and N,N-diisopropylethylainine {5.74ml) and the mixture is stirred at lOCC for 2 hours and a half. The reaction solution is allowed cool to room temperature, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 50:1—22:3) to give (5-bromo-pyrimidin-2-yl)-(5'-isopropyl-2'-niethoxy-4-trifluoroinethyl-biphenyl-2-ylmethyl)-amine {4.82g). MS (m/z): 482/480 [M+H]+ (2} (5-Bromo-p3Timidin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl- biphenyl-2-ylmethyl)-amine {3.30g) is dissolved in toluene fSOml), and thereto are added tris(dibenzylideneacetone)dipalladium (1.26g), 2-(di-tert- butylphosphino}biphenyl (1.23g), morpholine (2.4ml) and sodium tert- butoxide (1.32g) and the mixture is degassed under reduced pressure and stirred under nitrogen flow at 50°C overnight. To the reaction mixture is added a saturated brine, and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-+3:1) to give (5'-isopropyl-2'-methoxy-4-trinuoromethyl-biphenyl-2-ylmethyl)-(5- morpholin-4-yl-pyrimidin-2-yl)-amine (l.llg). MS (m/z): 487 [M+H] (3) (5'-Isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5- morpholin-4-yl-pyrimidin-2-yl}-amine (500mg) is dissolved in N,N- dimethylformamide {3ml), and thereto is added 3-fluoro-5-(trifluoromethyl- )benzylbromide (528mg) and thereto is added sodium hydride (60%) {82mg) under ice-cooling, and the mixture is stirred at room temperature for 2 hours and a half. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1—22:3) to give (3-fluoro-5-trifluoromethyl-benzyl)-{5'-isopropyl-2'-methoj^-4- 200 tTifluoroinet±iyl-biphenyl-2-ylniethyl)-(5-morpholin-4-yl-pyrimidin-2-yl}-amine (440mg). MS (m/z): 663 [M+H]^ (4) To tetrahydrofuran (6ml) is added sodium hydride (60%) (390mg) under nitrogen atmosphere, followed by an addition dropwise of benzyl alcohol (l.Olml) under water-cooling, and the mixture is stirred at the same temperature for 30 minutes. To this reaction mixture is added a mixture of (3-fIuoro-5-triftuoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - (5-morpholin-4-yl-pyrimidin-2-yl)-amine (430mg) and tetrahydrofuran (4ml) and the mixture is stirred under nitrogen atmosphere at 70'C overnight. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 97:3^^17:3) to give (3-benzyloxy-5-trifluoromethyl-benzyl}-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylinethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (221mg). MS (m/z): 751 [M+H] (5) (3-Benzyloxy-5-trifIuoromethyl-benzyI)-(5'-isopropyI-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - (5-morpholin-4-yl-pyrimidin-2-yl)-amine {215mg) is dissolved in methanol (10.5ml), and thereto is added 10% palladium-carbon and the mixture is stirred under hydrogen atmosphere at room temperature for 1 hour. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 4:1—1:2, and chloroform : methanol 19:1—♦9:1) to give 3-{[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morphoIin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenol {98mg). MS (m/z): 661 [M-1-H1+ (6) 3-{[(5'-Isopropyl-2'-methoxy-4-trifluoromethyI-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yI)-amino]-methyl}-5-trifluoromethyl-phenol 201 (95mg) is dissolved in N,N-dimethylformamide (1ml), and thereto are added potassium carbonate (90mg) and ethyl 4-bromobutyrate (93vil) and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1^4:1) to give ethyl 4-(3-([(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2 -ylmethyl) - (5 -morpholin- 4-yl-pyrimidin- 2 -yl) -aniino]-methyl}-5-trifluoromethyl-pheno3^)but5T-ate (92mg). MS (m/z): 775 [M+H]^ (7) Ethyl 4-{3-{[(5'-isopropyl-2'-methoxy-4-triiluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-pheno3^)butyrate (88mg) is dissolved in a mixed solvent of ethanol (Iml) and tetrahydrofuran (Iml) and thereto is added a IM-aqueous sodium hydroxide solution (Iml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is made acidic with 10% aqueous citric, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—1:1) to give 4-(3-{[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - (5-morpholin-4-yl-p3^rimidin-2-yl)-amino]-methyl)-5-trifluoromethyl-phenoxy)butyric acid (71mg). MS (m/z): 747 (M+HJ^ (S) 4-(3-{[(5'-Isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - (5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenoxy)butyric acid (69mg) is dissolved in ethanol (1ml) and thereto is added a IM-aqueous sodium hydroxide solution (92^1) and the mixture is stirred at room temperature for 3 minutes, and concentrated under reduced pressure to give 4-(3-{[(5'-isopropyl-2'-methoxy-4- 202 tTifluoromethyI-biphenyl-2-ylmethyl)-(5-rnorpholin-4-y]-pyrirni din--2-71)-aniino]-methyl}-5-trifluoromethyl-phenojq^)butyric acid sodium salt (66mg). MS (m/z): 745 [M-Na] * Example 136 (1) (2-Benzyloxy-3-chloro-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-p3n-imidiii-2-yl)-ainine (which is prepared by treating the corresponding starting compound in a same manner as in Example 23 (l)-(2)} (700mg) is treated in a similar manner to Example 87 (1) to give l-{2-[(2-benzylojQ'-3-chloro-5-trifluoromethyl-ben^l)-(3,5-bis- trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-ethyl piperidine-4- carboxylate (422mg). MS (m/z): 775/777 [M+H]^ (2) Ethyl l-{2-[(2-benzyloxy-3-chloro-5-trifluoromethyl-benzyl)-(3,5-bis- triflu oromethyl-benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carboxy late (412mg) is treated in a similar meinner to Example 23 (5) to give ethyl l-{2- [(3,5-bis-trifluoromethyl-ben^l)-(3-chloro2-hydro3^-5-trifluoromethyl- benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carbojiylate (277mg). MS (m/z): 685/687 [M+H]* 203 trifluoroinethyl-benzyl}-amino]-pyriniidin-5-yl}-piperidine-4-carboxylate (274mg) is treated with the corresponding starting compound in a similar manner to Example 26 to give l-{2-[(3,5-bis-trifluoromethyl-benzyl)-(6-chloro-3'-isopropyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-ainino]-P5TT.midin-5-yI}-piperidine-4-carboxylic acid (180mg). MS (m/z): 759/761 [M+Hj^ Example 137 The corresponding starting compound is treated in a similar manner to Example 136 to give the compound as listed in Table 17. Example 138 (1) (2-Benzyloxy-3-chloro-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-p5T-imidin-2-yl)-amine (2.11g) is treated in a similar manner to Example 23(3)-(5) to give ethyl 4-{2-{(3,5-bis-trifluoromethyl-benzyl) - {3-chloro-2-hydros^'-5-trifIuoromethyl-benzyl}- 204 amino]-pyrimidin-5-yloxy}-butyrate (163mg). MS (m/z): 660/662 [M+H]' (2) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-ben0yl)-{3-chloro-2-hydroxy-5-trifluoromethyl-benzyl)-amino]-p3Timidin-5-yloxy}-butyrate (160mg) is treated with the corresponding starting compound in a similar manner to Example 26 to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(6-chloro-3'-isopropyl-4-trifluoromethyl-biphenyl-2-yhnethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (87mg). MS (m/z): 762/764 fM-Na]-Example 139 (1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-p5T-imidin-2-yl)-(5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amine (which is prepared in a similar manner to Example 117(l)-(3)) (532mg) is treated with the corresponding starting compound in a similar manner to Exainple 2(4} to give 2-((3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-p3Timidin-5-ol (371mg). MS (m/z): 636 [M+H]^ (2) 2-[(3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-4,5,2'-trimetho3cy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ol (160mg) is treated in a similar manner to Example 2(5)-(6) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yl05cy}-butyric acid sodium salt (128mg). MS (m/z): 720 [M-Na]-Examole 140 (1) Ethyl 4-{2-[(3,5-bis-trinuoromethyl-benzyl)-(2-hydroxy-5- trifluoromethyl-benzyl)-amino]-p3Timidin-5-yloxy}-butyrate (1.39g) is dissolved in chloroform (20ml) and thereto is added N-bromosuccinicimide (475mg} and the mbrture is stirred at room temperature for 2 hours and the reaction solution is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-4:1} to give ethyl 4-{2-[(3,5-bis-trifluoromethyI-benzyl) - (3-bromo-2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxyj-butyrate (1.29g). MS (m/z): 704/706 [M+Hj 205 (2) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-ben;yl)-(3-bromo-2-hydroxy-5-trifluoroinethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (1.29g) and pyridine (220vil) are dissolved in methylene chloride (15ml) and thereto is added trifluoromethanesulfonic acid anhydride (460ial( under ice-cooling, and the mixture is stirred under nitrogen atmosphere at 0°C for 45 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:l-t4:l) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(3-bromo-2-trif!uoromethanesulfonyloxy-5-trifluoroniethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (907mg). MS (m/z): 836/838 [M+H]* (3) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(3-bromo-2-trifluoro-methanesuIfonyloxy-5-trifluoromethyl-benzyl)-amino]-p5Timidin-5-ylo^}-butyrate {300mg) is dissolved in 1,4-dioxane (4ml) and thereto are added [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex {58mg), methyl boric acid (32mg) and cesium carbonate (175mg) and the mixture is stirred under nitrogen atmosphere at SO°C for 3 days. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, £ind the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = IQrl^'lTiS) to give the crude product containing ethyl 4-(2-[(3,5-bis-trifluoromethyI-benzyI)-(3-methyl-2-trifluoro-methanesulfonyloxy-5-trifluoromethyl-ben^l)-amino]-pyrimidin-5-yloxyj-butyrate (207mg]. The resulting crude product (200mg) is dissolved in 1,4-dioxane (4ml) and thereto are added [1,1'-bis(diphenylphosphino)ferrocene\|dicWoropal]adium dichloromethane 206 complex (42mg\|, 5-isopropyI-2-methoxyphenyl borate (ISOmg) and cesium carbonate (127mg) and the mixture is stirred under nitrogen atmosphere at SO^C overnight. The reaction solution is cooled to room temperature, and thereto are added ethy] acetate and a saturated aqueous sodium bicarbonate solution, 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 49:1—17:3), followed by Gel Permeation Chromatography (JiUGEL; chloroform) to give ethyl 4-{2-\|(3,5-bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-methoxy-6- methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate {20mg). MS (m/z): 772 [M+HI (4) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-metho3ty-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pjT-imidin-5-y]oxy}-but5T-ate (20mg) is dissolved in ethanol (2ml), and thereto is added a IN-aqueous sodium hydroxide solution (0.5ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-9:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-6-methyI-4-trifluoromethyI-biphenyJ-2-ylmethyl\|-amino]-pyrimidin-5-yloxy}-butyric acid (21mg). The resulting carboxylic acid is dissolved in ethanol (Iml) and thereto is added IN-aqueous sodium hydroxide solution {28p}) and the reaction solution is concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-m.ethoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylinethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (19mg). MS (m/z): 742 \|M-Na]- 207 Example 141 (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - [ 2-(2-methane sulfinyl-ethyl)-2 H-tetra2ol-5-yl]-amine (129mg) is dissolved in chloroform (2ml), and thereto is added m-chloroperbenzoic acid (50mg) and the mixture is stirred at room temperature overnight. To the reaction solution is added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give (3,5-bis-trinuoromethyl-benzyI)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2 -ylmethyl) -(2 - (2 -methane sulfonyl-ethyl}-2H-tetrazol-5-yl]-amine (81mg). MS (m/z): 724 [M+H] 208 Example 142 (1) Tert-buty] 4-(2-chloropyrimidin-5-yloxy)-butjTate {5.0g) is dissolved in toluene (100ml) and thereto are added palladium acetate (412mg) and 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (1.26g}, and the mixture is stirred under nitrogen atmosphere at 50 °C for 1 hour. The reaction solution is cooled to room temperature, and thereto are added 3,5-bis-trifluoromethyl-henzylamine (5.35g) and sodium tert-butoxide (3.8Sg) andthe mixture is stirred at 35°C for 2 hours. Thereto are added ethyl acetate and water, 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 is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1->2:I) and NH-silica gel column chromatography (hexane : ethyl acetate = 4:1--2:1) to give tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate (5.59g}. MS (m/z): 480 [M+H] (2) (2-Bromo-4,5-dimethoxy-phenyl}-methanol (2.47g) is dissolved in methylene chloride (30ml) and thereto is added thionyl chloride (875pl} and, the mixture is stirred at room temperature for 30 minutes. The reaction 209 solution is concentrated under reduced pressure, and thereto is added to hexane and the resulting crystal is filtered to give l-broino-2-chloromethyl-4,5-dimethoxy-benzene (2.25g). MS (m/z): 229/231 (3) Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-ben2yl-amino)-pyrimidin-5-yloxyl-butyrate (lOOmg) is dissolved in DMF (1ml) and thereto is added sodium hydride (60%) (lO.Smg) under ice-cooling, and the mixture is stirred under ice-cooling for 15 minutes. Thereto is added l-bromo-2-chloromethyl-4,5-dimethoxybenzene (83.1mg) and the mixture is stirred under ice-cooling for 1 hour. To the reaction solution are added aqueous ammonium chloride 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 residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1—4:1) to give tert-bulyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl}-(2-bromo-4,5-dimethoxy-benzyl)-amino]-pyrimidin-5-yloxy}-but5Tate (116mg). MS (m/z): 708/710 [M+H] (4) Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-4,5-dimethoxy-ben2yl)-amino]-p5T-imidin-5-yloxy}-butyrate (150mg) is dissolved in 1,4-dioxane (3ml) and thereto are added {4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (128mg), [1.1'-bis(diphenyIphosphino)ferrocene]dichloropalIadium dichloromethane complex (32mg) and cesium carbonate (196mg), and the mixture is stirred under nitrogen atmosphere at BO^C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the orgainic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—17:3) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (140mg). MS 210 (m/z): 796 [M+H]+ (5) To tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4'-nuoro-5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl}-aminol-pyriinidin-5-yloxy}-butyrate (129mg) is added a 4N-hydrogen chloride/dioxane solution (Sml) and the mixture is stirred at room temperature for 7 hours. To the reaction solution are added a. saturated aqueous sodium hydroxide 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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-.9:1} to give 4-{2-[(3,5-bis-trinuoromethyl-beiizyl)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ylojcy}-butyric acid (lOOmg). MS (m/z): 740 [M+H]^ (6) The resulting carbojc^lic acid obtained in the above (5) is dissolved in ethanol (1ml) and thereto is added IN-aqueous sodium hydroxide solution (128vil), and the reaction solution is concentrated under reduced pressure to give 4-{2-\|(3,5-bis-trifluoromethyl-ben^l)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-but^c acid sodium salt (lOOmg). MS (m/z): 738 [M-Na]-Examples 143 to 152 The corresponding starting compounds are treated in a similar manner to Example 142 to give the compounds as listed in Table 20. Example 153 The corresponding starting compound is treated in a similar manner to Example 159 to give the compounds as listed in Table 20. Examples 154 to 157 The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 20. Table 20 211 to Example 117(1) and Example 131 to give the compound as listed in Table 21. Example 159 (1) Tert-bulyryl 4-{2-[(2-bromo-4,5-dimethoxy-benzyl)-(3-cyano-5- trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (which is prepared by treating the corresponding starting compound in a similar manner to Example 142(l)-(3)} (l.Og) is dissolved in 1,4-dioxane (10ml) and thereto are added [l,l'-bis(diphenylphosphino)ferrocene]dichloropaUadium dichloromethane complex (252mg), bis(pinacolate)diboron (782mg) and potassium acetate (453mg) and the mixture is stirred under nitrogen atmosphere at 80°C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 80:20-^70:30) to give tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (769mg). MS (m/z): 713 1M+H]+ (2) Tert-butyryl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[4,5-dimethGxy- 2-(4,4,5,5-tetramethyl-[l,3,2jdioxaborolan-2-yl)-benzyl]-amino}-pyrimidin- 5-yloxy}-but3Tate (60mg) is dissolved in 1,4-dioxane (1.5ml) and thereto are added 2-bromo-6-isDprDpenyl-3-methoxy-pyridme (38mg), [1,1'- bis(diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (7mg) and cesium carbonate (55mg), and the mixture is stirred 214 under nitrogen atmosphere at 80°C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated and the organic layer is filtered by NH- silica gel and the mixture is extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 85:15—70;30) to give tert-butyl 4-(2-{{3-cyano-5-trifluoromethyl-benzyl)-[2-{6-isopropenyl-3-methoxy-pyridin-2-yl)-4,5-dimethoxy-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (17mg). MS (m/z): 734 [M+H]+ (3) Tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropenyl-3-methoxy-p3T-idin-2-yI)-4,5-dimethojQ'-benzylj-amino}-pyriinidin-5-yloxy)-butyrate (36mg) is treated in a similar manner to Example 142(5) to give 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropenyl-3-methoxy-pyridin-2-yl)-4,5-dimethoxy-ben2yl]-amino}-pyrimidin-5-yloxy)-butyric acid (24.5mg). MS (m/z): 678 [M+H] (4) 4-(2-{(3-Cyano-5-trifiuoromethyl-benzyl)-[2-(6-isopropenyl-3-methoxy-pyridin-2-yl}-4,5-dimethoj^-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (24.5mg) is dissolved in methanol (2ml), and thereto is added 10% palladium-carbon (lOmg) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 hour. The insoluble material is removed by Alteration and the fiJtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform : methanol = 100:0^85:15) to give 4-(2-{(3-cyano-5-trifIuoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-4,5-dimetho:^-benzyl]-amino}-p3Timidin-5-yloxy)-butyric acid (21mg). MS (m/z): 680 [M+H]+ (5) 4-(2-{(3-Cyano-5-trifluoromethyl-benzyl)-[2-(5-isopropyl-3-methoxy-pyridin-2-yl)-4,5-dimethojQ'-benzyl]-amino}-p5TTniidin-5-yloxy)-butyric acid (21mg) is treated in a similar manner to Example 142(6) to give 4-(2-{(3-cyano-5-trifluoromethyl-benzyl) - (2 - (6-isopropyl3-methoxy-pyridine2-yl)- 215 4,5-dimethoxy-benzyl]-amino}-p3Timidin-5-yloxy)-butyric acid sodium salt (22mg). MS fm/z): 678 [M-Na]-Example 160 Tert-butyryl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl}-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl}-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (195mg) and l-bromo-5-isopropyl-2-methoxy-4-methyl-benzene (130mg) is treated in a similar manner to Examples 159(2),(3) and (5) to give 4-{2-[(3-cyano-5-trifluoromethyl-ben2yl)-(5'-isopropyl-4,5,2'-trimetho3cy-4'-methyl-biphenyl-2-ylmethyl)-amino]-p5T-imidin-5-yloxy}-butyric acid sodium salt (66mg). MS (m/z): 691 [M-Na]-Examples 161 to 162 The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 21. 216 The corresponding starting compounds are treated in a similar manner to Example 142 to give the compounds as listed in Table 22. Enample 169 (1) Tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl}-[2-(6-isopropenyl-3-methoxy-pyTidine-2-yl)-5-trifluorometyl-benzyl]-amino}-pyrimidine -5-yloxy)-butyrate (which is prepared in a similar manner to Example 142(2}-(3) and Example 159(l)-(2))(73mg) is treated in a similar manner to Exeimple 159(4) to give tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methojQ'-p5T4dine-2-yl)-5-trifluorometyl-benzyl]-amino}-pyrimidine-5-yloxy)-butyrate (70mg). MS (m/z): 744 [M+H]+ (2) Tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-ben2yl)-[2-(6-isopropyl-3-methoxy-p3Tidine-2-yl)-5-trifluorometyl-benzyl]-amino}-pyrimidine -5-yloxy)-butyrate (70mg) is treated in a similar manner to Example 142(5)-(6) to give 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridine-2-yl) - 5-trifluorometyl-benzyl] - amino}-pyrimidine-5-yloxy)-butylic acid sodium salt (40mg). MS (m/z): 686 [M-Na]-. Examples 170 to 172 The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 22. 217 The corresponding starting compounds are treated in a similar manner to Example 142 to give the compounds as listed in Table 23. Example 178 The corresponding starting compound is treated in a similar manner to Example 169 to give the compound as listed in Table 23. 219 (1) 1 -Methoxy-5-methyl-4-nitro-2-trifiuoromethyl-benzene (lOg) is dissolved in methanol (lOOml), and thereto is added 10% palladium-carbon (Ig) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 day. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give 4-methoxy-2-methyl-5-trifluoromethyl-phenylamine (9.07g). MS (m/z): 206 [M+H]+ (2) To copper (II) bromide (ll.Sg) is added acetonitrile (50ml) and followed by addition dropwise of tert-butyl nitrite (8.5ml) under ice-cooling and the mixture is stirred under nitrogen atmosphere for 5 minutes. To 220 reaction mixture is added dropwise a solution of 4-methoxy-5-trifluoromethyl-phenylamine (9.07g) in acetonitrile {20ml) under ice-cooling over 20 minutes and the mixture is stirred at room tem^perature under nitrogen atmosphere overnight. Reaction mixture is concentrated under reduced pressure. To the resulting residure is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1—'0:1) eind NH-silica gel column chromatography (hexane ; ethyl acetate = 1:0—9:1) to give l-bromo-4-methoxy-2-methyl-5-trifluoromethyl-benzene (3.61g). (3) l-Bromo-4-methoxy-2-methyl-5-trifluoromethyl-benzene (l.Og), 2,2'-azobisisobutyronitrile (61mg) and N-bromosuccinimide {795mg) are dissolved in carbon tetrachloride (15ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0^^9:1) to give l-bromo-2-bromomethyl-4-metho^-5-trifluoromethyl-benzene (732mg). (4) Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzyIamino)-pyrimidin-5-ylox/J-butyrate (300mg} is dissolved in N,N-dimethylformamide (4ml) and thereto is added sodium hydride (60%) (33mg) under ice-cooling, and the mixture is stirred for 15 minutes and thereto is added l-bromo-2-bromomethyl-4-methoj{y-5-trifluoromethyl-ben2ene (327mg) and the mixture is stirred at room temperature overnight. Thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—17:3) to give tert-butyl 4-{2-[(3,5-bis-triiluoromethyl-benzyl)-(2-bromo-5-methoxy-4- 221 trifluoromethyl-benzyl)-amino)-pyrimid.in-5-yloxy}-bu1yrate (256mg). MS (m/z): 746/748 [M+H]* (5) Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5- methoxy-4-trinuoroinethyl-benzyl}-ainino]-p5Timidin-5-yloxy}-butyrate (120mg) is treated in a similar manner to Example 142(4)-(5) to give 4-{2- [(3,5-bis-trifluoromethyl-benzyl)-{4'-fluoro-5'-isopropyl-4,2'-dimethojQ'-5- trillUGromethyl-biphenyl-2-ylmethyl) - amiono]-pjTimidin-5-yloxy}-butyric acid sodium salt (53mg). MS (m/z): 776 [M-Na]- Example 180 The corresponding starting compound is treated in a similar manner to Example 179 to give the compound as listed in Table 24. Example 181 The corresponding starting compound is treated in a similar manner to Exam.ple 169 to give the compound as listed in Table 24. Examples 182 to 184 The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 24. 222 The corresponding starting compounds are treated in a similar manner to Example 179 to give the compounds as listed in Table 25. Example 187 The corresponding starting compound is treated in a similar manner to Example 169 to give the compound as listed in Table 25. Examples 188 to 189 The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 25. Table 25 223 (1) 5-Methoxy-2-nitro-4-trifluoromethyl-phenol (5g) and pyridine (2.6ml) are dissolved in methylene chloride {150ml), and the mixture is cooled to 0°C, and thereto is added trifluoromethane sulfonic acid anhydride (5.3ml} and the mixture is stirred at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and 224 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^^4:1) to give trifluoro-methanesulfonic acid 5-methojty-2-nitro-4-trifluoromethyl-phenyl ester (5.3g). (2) Trifluoro-methanesulfonic acid 5-methoxy-2-nitro-4-trifluoromethyl-phenyl ester (2.6gJ is dissolved in 1,4-dioxane (20ml) and thereto is added 5-isopropyl-2-methoxy benzene boronic acid (l-5g), [1>1'-bis(diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (575mg) and cesium carbonate {3.44g), and the mixture is stirred under nitrogen atmosphere at 80°C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1—^17:3) to give 5'-isopropyl-5,2'-dimethoxy-2-nitro-4-trifluoromethyl-biphenyl (2.35g). MS (m/z): 370 [M+H]* (3) 5'-Isopropyl-5,2'-dimethoxy-2-nitro-4-trifluoromethyl-biphenyl (2.35g) is dissolved in a mixed solvent of tetrahydrofuran (20ml} and methanol (30ml), and thereto is added 10% palladium-carbon (SOOmg) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 day. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—4:1) to give 5'-isopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-ylamine (1.88g). MS (m/z): 340 [M+H] (4) To copper (II) bromide (l.lTg) is added acetonitrile (5ml) and followed by addition dropwise of tert-butyl nitrite (0.835ml) under ice-cooling and 225 the mixture is stirred under nitrogen atmosphere for 5 minutes. To reaction mixture is added dropwise a solution of 5'-isopropyl-5,2'-dimetho3^-4'trifluoromethyl-biphenyl-2-ylamine (1.48g) in acetonitrile (2ml) under ice-cooling and the mixture is stirred at room temperature under nitrogen atm.osphere overnight. Reaction mixture is concentrated under reduced pressure. To the resulting residure is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = l:0-^-9:1) to give 2-bromo-5'-isopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl (1.29g). (5) 2-Bromo-5'-isopropyI-5,2'-dimethoxy-4-trifluoromethyl-biphenyl (1.29g} is dissolved in dry tetrahydrofuran (30ml) and thereto is added dropwise 1.6M n-butyllithium in hexanes at -78°C, and the mixture is stirred for 1 hour and thereto is added N,N-dimethylformamide (1.2ml), and the mixture is stirred for 1.5 hours. To the reaction solution are added a saturated aqueous ammonium chloride solution eind 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1-17:3) to give 5'-isopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (733mg). MS (m/z): 353 [M+H]+ (6) 5'-lsopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde {692mg) is dissolved in a mixed solvent of tetrahydrofuran (12ml), ethanol (3.5ml} and methylene chloride (1ml), and thereto is added sodium borohydride (82mg) and the mixture is stirred at room temperature for 40 minutes. The reaction solution is concentrated under reduced pressure and thereto are added ethyl acetate and water, and the mixture is 226 separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—4:1) to give (5'-isopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-yl)-methanol (566mg). MS (m/z): 337 [M+H-H201^ (7) (5'-lsopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-yl)-methanol (200mg) is dissolved in toluene (5ml) and thereto is added thionyl chloride (60pl) under ice-cooling, and the mixture is stirred for 3 hours. To the reaction solution are added water 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. 4-[2-(3,5-Bis-trifluoromethyl-ben2ylamino)-pyrimidin-5-y]o3cy]-bmyric acid tert-butyl ester {246mg) is dissolved in N,N-dimethylformainide (5ml) and thereto is added sodium hydride (60%) (23mg) under.ice-cooling, and the mixture is stirred for 20 minutes. Thereto are added a solution of a residue obtained above in N,N-dimethylformamide (Sml) and the mixture is stirred at room temperature 3 hours and 20 minutes. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-»17:3) to give tert-butyl 4-{2-[(3,5-bis-trinuoromethyl-benzyl)-{5'-isopropyl-5,2'-dimethojqr-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (74mg). MS (m/z): 816 [M+H]+ (8) Tert-butyl 4-{2-l(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - amino]-pjniimidin-5-yloxyj-butyrate (68mg) is treated in a similar manner to Example 142(5)-(5) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-5,2'-dimethoxy-4- 227 tiiiluorome thy 1-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt {23mg). MS (m/z): 758 [M-Na]-Examples 191 The corresponding starting compound is treated in a similar manner to Example 190 to give the compounds as listed in Table 26. The corresponding starting compounds are treated in a similar manner to Example 142 to give the compounds as listed in Table 27. Examples 201 to 205 The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 27. Examples 206 to 207 The corresponding starting compounds are treated in a similar manner to any of the above Examples to give the compounds as listed in 228 (1) 2-[(3,5-Bis-trifluoroniethyl-beniyl)-(5'-isopropyl-4,5,2'-trimethoxy- biphenyl-2-ylmethyl)-amino]-pyriinidin-5-ol (60mg) is dissolved in tetrahydrofuran (1ml) and thereto are added tert-butyl 3-hydroxy- propionate (336nig), triphenylphosphine (592mg), and thereto is added dropwise diisopropyl azodicarboj^late {447vil) and the mixture is stirred at 60°C overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. To the resulting residue is added isopropylether and the insoluble material is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—>2:1) and NH-silica gel column chromatography (hexane : ethyl acetate = 9:1—•4:1) to give tert- butyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-4,5,2'-trimethoxy- biphenyl-2-ylmethyl)-£unino]-p3Timidin-5-yloxy}-propionate (43mg). MS (m/z): 764 [M+H]* (2) To tert-butyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl- 4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ylo3^}- propionate (41mg) is added a 4N-hydrochloric acid/dioxane (4ml) and the mixture is stirred at room temperature for 9 hours. The reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution and the mixture is made weakly acidic with a 10 % aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column 231 chromatography (hexane : ethyl acetate = 4:1—1:3) and the resulting purified product is dissolved in ethanol (0.5ml) and thereto is added IM-aqueous sodium hydroxide solution (24JJ1) and the mixture is concentrated under reduced pressure to give 3-{2-[(3,5-bis-trifluoroinethyl-benzyl)-(5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyriinidin-5-yloxy}-propionic acid sodium salt (18mg). MS (m/z): 706 [M-Na]-Example 209 Methyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-4,5,2'- trimethoxy-biphenyl-2-ylmethyl)-aininol-pyrimidin-5-yloxy}-2,2-dimethyl-propionate (which is prepared by treating the corresponding starting compound in a similar manner to Example 208(1)) (85mg) is treated in a similar manner to Example 103(3) to give 3-{2-[(3,5-bis-trifluoromethyl-ben2yl)-(5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-ainino]-pyrimidin-5-yloxy}-2,2-dimethyl-propionic acid sodium salt (52ing). MS (m/z): 734 [M-Na]-Example 210 The corresponding starting compounds is treated in a similar manner to Example 139(2) to give the compound as listed in Table 28. 232 The corresponding starting compound is treated in a similar manner to Example 208 to give the compound as listed in Table 29. Example 212 The corresponding starting compound is treated in a similar manner to Example 209 to give the compound as listed in Table 29. Example 213 The corresponding starting compound is treated in a similar manner to Example 139(2) to give the compound as listed in Table 29. 233 (1) 5'-Isopropenyl-2'-methoxy-4-trifluoroniethyl-biphenyl-2- carbaldehyde (5.0g) is dissolved in a mixed solvent of tetrahydrofuran (100ml), ethanol (30ml) and methylene chloride (10ml), and thereto is added sodium borohydride {646m^g) and the mixture is stirred at room temperature for 10 minutes. The reaction solution is concentrated under reduced pressure and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1—^:1) to give (5'-isopropenyl- 2'-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methanol (4.73g). MS (m/z): 307 [M+H]+ (2) (5'-Isopropenyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-yl)- methanol (500mg) is dissolved in methylene chloride (3ml), and thereto is added dropwise thionyl chloride (248^1) under nitrogen atmosphere under ice-cooling and the mixture is stirred at room temperature for 15 minutes 234 and the reaction, solution is ice-cooled and thereto is added dropwise triethylamine (647{J1). TO the reaction solution are added diethylether and a saturated brine, and the mixture is separated, and the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The residue and (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-p3Tidin-2-yI)-amine (799mg\| is dissolved in N,N-dimethylformamide and thereto is added sodium hydride (123mg) and the mixture is stirred at SCC for 2 hours and a half. The reaction solution is cooled to room temperature, and thereto is added diethylether and water, and the mixture is separated and the organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by sUica gel colum.n chromatography (hexane : ethyl acetate = 49:1—9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (4Slmg}. IVIS (m/z): 705/707 [M+H\* (3) (3,5-Bis-trifluoromethyl-ben2yl)-(5-bromo-pyridin-2-yl)-{5'-isopropyl-2'-methoxy-4-trifiuoromethyl-biphenyl-2-ylinethyl)-amine (475mg), [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium methylene chloride complex (55mg), potassium acetate (198mg) and bis(pinacolate)diboron (256mg) are dissolved in dimethyl sulfoxide (2ml), and the mixture is heated to sec under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed twdce with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (10ml), and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (0.75ml) under ice-cooling. The reaction solution is stirred at room temperature overnight, and thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, followed by an addition of water 235 and diethylether, and the mixture is separated. The organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-»4:1) to give 6-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylinethyl)-aniinoj-P3rridin-3-ol (141mg). MS (m/z): 643 [M+H]+ (4) 6-[(3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trtfluoromethyl-biphenyl-2-ylmethyl)-amino]-p5T-idin-3-ol (14lmg) is dissolved in N,N-dimethylformamide (1ml), and thereto is added 60% sodium hydride (lOmg) under ice-cooling and the mixture is stirred for 5 minutes and thereto is added ethyl 4-bromobutyrate (48>il), and the mixture is stirred at room temperature for 1 hour. To the reaction solution is added water under ice-cooling, and the mixture is extracted with methylene chloride, and the organic layer is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^4:1) to give ethyl 4-{6-[(3,5-bis-trifluoromethyl-benzyl) - (5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-buty^ate (154. Img). MS (m/z): 757 [M+H]+ (5) Ethyl 4-{6-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl- 2 -ylmethyl)-amino] -p5Tidin- 3-yloxy}-butyrate (150mg) is dissolved in a mixed solvent of ethanol (1ml) and tetrahydrofuran (2ml) and thereto is added a 2N-aqueous sodium hydroxide solution (0.3ml) and the mixture is stirred at 50°C for 3 hours and 20 minutes. The reaction solution is cooled to room temperature and neutralized with a 2N-hydrochloric acid (0.3ml), and thereto are added methylene chloride and a saturated brine and the mixture Is separated, and the organic layer is concentrated under reduced pressure. The resulting residue is purified by LCMS (column: CAPCELPACK MG2 C18, 236 eluate: a lOpM aqueous carbonic acid solution/acetonitrile 55/45—40/60) to give 4-{6-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoroinethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloJ^}-butyric acid (31.4mg). The resulting carboxylic acid is dissolved in ethanol (1ml) and thereto is added a 2N-aqueous sodium hydroxide solution (42pl) and the reaction solution is concentrated under reduced pressure to give 4-{6-[(3,5-bis-trifluoromethyl-benzyI)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylm ethyl)-amino]-pyridin-3-yloxy}-butyric acid sodium salt (30.6mg). MS (m/z): 727 [M-Na]-Example 215 The corresponding starting compound is treated in a similar manner to Example 214 to give the compound as listed in Table 30. 237 (1) 5'-Isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (S.Og), hydroxylamine hydrochloride (3.45g) and pyridine (28ml) are dissolved in ethanol (140nil), and the mxture is stirred at 80°C for 1 hour. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a IN-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a IN-hydrochloric acid, a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (100ml), and thereto is added Raney nickel, and the mixture is stirred under hydrogen atmosphere at room temperature for 30 minutes and SO^C overnight. The reaction solution is cooled to room temperature, and Raney nickel is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—23:2) to give C-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (5.50g). MS (m/z): 324 [M+H]+ (2) C-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (107mg) is dissolved in toluene (3ml), and thereto Eire added tris(dibenzylideneacetone)dipalladium (30mg), 1,3- 238 bis(diphenylphosphino)propane (27mg) and sodium tert-butoxide (44mg), and the mixture is stirred under nitrogen atmosphere at 80°C overnight. The reaction solution is cooled to room temperature, and to the reaction solution are added methylene chloride and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1—4:1) to give (5-bromo-pyridin-2-yl}-(5'-isopropyl-2'-methoxy-4-trifiuoromethyl- biphenyI-2-ylmethyl)-amine (41.3mg). MS (m/zj: 479/481 [M+H1^ (3) (5-Bromo-pyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine {700mg), is dissolved in N,N-dimethylformamide (5ml), and thereto is added sodium hydride (60%) (88mg) under nitrogen atmosphere at -10°C, and the mixture is stirred at the same temperature for 5 minutes, and 3-bromomethyl-5-triiluoromethyl-benzonitrile (77lmg), and the mixture is stirred under ice-cooling for 1 hour and 40 minutes. To the reaction solution are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated, and the organic layer is washed twice with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—17:3) and (hexane : ethyl acetate = 49:1—t9:l). The residue is dissolved in diethyl ether, and filtered. The filtrate is concentrated under reduced pressure, and the residue obtained above (630mg) is dissolved in tetrahydrofuran (3ml), and thereto are added morphoUne (119ial) and triethyamine (190>il), and the mixture is stirred at 50°C for 4 hours, and the reaction solution is cooled to room temperature, and stirred at same temperature overnight. To the reaction solution are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with water and a saturated brine, and the mixture is dried over magnesium sulfate and is 239 concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—vlTiS) to give 3-{[(5-bromo-pyridin-2-yl}-(5'-isopropyl-2'-methoj^-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-S-trifluoromethyl-benzonitrile (440mg). MS (m/z): 662/664 [M+H]* (4) 3-{[(5-Bromo-pyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyI-2-yhnethyl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (435mg) is treated in a similar manner to Example 214(3) to give 3-{[(5-hydroxy-pyridin-2-yl)-(5'-isopropyl-2'-methGxy-4-trif]uoromethyl-biphenyl-2-ylmethyl\|-amino]-methyl}-5-trifluoromethyl-benzonitrile (251mg). MS (m/z): 600 [M+H]* (5) 3-{i(5-Hydroxy-p3T-idin-2-yl)-(5'-isopropyl-2'-metho5Q'-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-5-trifiu oromethyl-benzonitrile (150mg) is dissolved in N,N-dimethyifonnamide (2.5ml), and thereto is added 60% sodium hydride (12mg) under ice-cooling and the mixture is stirred for 30 minutes and thereto is added tert-butyl 4-bromobutyrate (85mg), and the mixture is stirred at room temperature for 6 hours. To the reaction solution is added water under ice-cooling, and the mixture is extracted with methylene chloride, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 9: l--3:1) to give tert-butyl 4-{6-[(3-cyano-5-trifluoromethyl-benzyl)-(5'-isopropyl-2'-metho;Q'-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyrate (169mg). MS (m/z): 742 [M+H] (6) Tert-butyl 4-{6-[(3-cyano-5-trifluoromethyl-benzyl)-{5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-p5Tidin-3-yloxy}-butyrate (165mg) is treated in a similar manner to Example l42(5)-{6) to give 4-{6-[(3-cyano-5-trifluoromethyl-ben^l)-(5'-isoprGpyl-2'-methoJ^-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-p5Tidin-3-yloxy}-but5Tic acid 240 sodium salt (113.5mg). MS (m/z): 684 (M-Na]-Example 217 The corresponding starting compound is treated in a similar manner to any of the above Examples to give the compound as listed in Table 31. The corresponding starting compounds are treated in a similar manner to Example 142 to give the compounds as listed in Table 32. Example 220 (1) 5-Benzyloxy-2-bromo-benzaldehyde (l.Og) is dissolved in 1,4-dioxane (30ml) and thereto are added [l,r-bis(diphenylphosphino\|ferrocene]-dichloropalladium dichloromethane complex {280mg), (5-isopropyl-2-methoxyphenyl)boronic acid (800mg) and cesium carbonate (1.68g) and the m^ixture is stirred under nitrogen atmosphere at 80°C for 6 hours. The reaction mixture is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over m^nesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—>4:1) to give 4-benzyloxy-5'- 241 isopropyI-2'-raethoxy-biphenyI-2-carbaldehyde (1.19g}. MS (m/z): 361 [M+H](2) 4-Beiizylo3gr-5'-isopropyl-2'-metho?cy-biphenyl-2-carbaldehyde (1.16g) is dissolved in ethanol (15ml) and thereto is added sodium borohydride (122mg) and the mixture is stirred at room temperature for 10 minutes. Thereto are added a saturated aqueous ammonium chloride 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 to give (4-benzyloxy-5'-isopropyl-2'-methoxy-biphenyl-2-yl)-methanol (1.26g). MS (m/z): 345 (3) (4-Benzyloxy-5'-isopropyl-2'-niethoxy-biphenyl-2-yl)-methanol (l.lOg) is dissolved in methylene chloride (10ml), and thereto is added thionyl chloride (332pl) and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0^9:1) to give 4-ben^loxy-2-chloromethyl-5'-isopr opyl-2'-methoxy-biphenyl (1.15g). MS (m/z): 345 (4) Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxyj-butyrate (l.llg) and 4-benzylo;^-2-chloromethyl-5'-isopropyl-2'-methoxy-biphenyl (805mg) are dissolved in N,N-dimethylformamide (10ml) and thereto is added sodium hydride (60%) (120mg) under ice-cooling, and the mixture is stirred under ice-cooling for 2 hours, and then is stirred at room temperature for 30 minutes. Thereto are added a saturated aqueous ammonium chloride 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—4;1\| to give tert-butyl 4-{2-[(4-benzyIoxy-5'-isopropyl-2'-methoxy-biphenyI-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (1.14g). MS (m/z): 824 [M+H\|242 (5) Tert-butyl 4-{2-[(4-benzyloxy-5'-isopropyl-:(i'-metnoxy-Dipnenyl-2-ylmethyl) - f 3, S-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxyj-butyrate (80mg) is treated in a similar manner to Example 142(5)-(6) to give 4-{2-[(4-benzyloxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylniethyl)-(3,5-b is-trifluQromethyl-benzyl)-aminol-pyrimidin-5-ylo5^}-butyric acid sodium salt(59.5mg). MS (m/z): 766 [M-Na]-Example 221 (1) Tert-butyl 4-{2-[(4-benzyloxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl}-amino]-pyrimidin-5-yloxy}-butyrate (l.Og) is dissolved in ethanol (20ml), and thereto is added 10% palladium-carbon (200mg), and the mixture is stirred under hydrogen atmosphere at room temperature for 4 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure, and thereto is added hexane and the resulting crystal is filtered to give tert-butyl 4-{2-[(3,5-bis-trifluorom ethyl-benzyl)-(4-hydroxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl}-amino]-p5rrimidin-5-yloxy}-butyrate (835mg). MS (m/z): 734 [M+Hj (2) Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-hydroxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-amino]-p3Timidin-5-yloxy}-butyrate (70mg) is treated in a similar manner to Example 142{5)-(6) to give 4-{2-[(3,5-Bis-trifluoromethyl-benzyl)-(4-hydroxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (55.4mg). MS (m/z): 676 [M-Na]- Example 222 (1) Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-ben^l)-(4-hydroxy-5'- isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-ainino]-pyTimidin-5-yloxy}- butyrate (70mg) is dissolved in N,N-dimethylformamide (3ml) and thereto is added potassium carbonate (26.4mg) and iodoethane (29.8mg) and the mixture is stirred at 50°C for 8 hours. Thereto are added ethyl acetate and a water, and the mixture is separated, and the organic layer is washed 243 with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 1:0^^9: l)to give tert- butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-ethoxy-5'-isopropyl-2'- methoxy-hiphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (60.5mg). MS (m/z): 762 [M+H]+ (2) Tert-butyl 4-{2-[(3,5-bis-triiluoromethyl-benzyl)-f4-ethoxy-5'- isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-aniino]-pyrimidin-5-yloxy}-butyrate (59mg) is treated in a similar manner to Example 142(5)-(6) to give 4-{2-[(3,5-bis-trifLuoromethyl-benzyl)-(4-etho3^-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-but5Tic acid sodium salt (48.2mg). MS (m/z): 704 [M-Naj-Example 223 The corresponding starting compound is treated in a similar manner to Example 222 to give the compound as listed in Table 32. Examples 224 to 230 The corresponding starting compounds are treated in a similar manner to any of the above Examples to give the compounds as listed in 244 (1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-p5Tiniidin-2-yl)-ainine (315mg) and 4-ben^loxy-2-chloromethyl-5'-isopropyl-2'-methoxy-biphenyl (300mg) are dissolved in N.N-dimethylformamide (5ml) and thereto is added sodium hydride (60%) (40.9mg) under ice-cooUng, and the mixture is stirred at room temperature overnight. Thereto are added a saturated aqueous ammonium chloride 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 resulting residue is purified by silica gel column chromatography (hexane : Sethyl acetate = 1:0—»-97;3) to give (4-benzyloj^-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-ben2yl)-(5-bromo-pyrimidin-2-yl)-amine (458mg). MS (m/z): 744/746 [M+H]. 246 (2) {4-Benzyloxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl}-(3,5-bis-trifluoromethyl-benzyl}-(5-bronio-p3TTmidin-2-yl)-ainine (433mg) is dissolved in toluene (Sml) and trisfdibenzylideneacetonejdipaUadium (107mg), sodium tert-butoxide (168mg), 2-(di-tert-butylphosphino)biphenyl (69.4mg) and morpholine (152mg) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 9:1—♦2:1} to give {4-benzylQxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-{3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (3S4mg). MS (m/z): 751 [M+H] (3) (4-Benzyloxy-5'-isopropyl-2'-methojcy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine is treated in a similar manner to Example 221 and 222 to give 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-{5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5'-isopropyl-2'-methoxy-biphenyl-4-yloxy)-butyric acid sodium salt. MS (m/z): 745 [M-Na]- Example 232 The corresponding starting compound is treated in a similar manner to Example 231 to give the compound as listed in Table 33. Examples 233 to 234 The corresponding starting compounds are treated in a similar manner to any of the above Examples to give the compounds as listed in Table 33. Table 33 The corresponding starting compounds are treated in a similar manner to any of the above Examples to give the compounds as listed in Table 34. Example 239 The corresponding starting compound is treated in a similar manner to Example 142 to give the compound as listed In Table 35. 248 Cyclohexanecarboxaldehyde (38g), diethylamine hydrochloride (55g) and acetic acid (29ml) are dissolved in methylene chloride (500ml) and thereto is added triacetoxy sodium borohydride (71.8g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution are added a 2N-aqueous sodium hydroxide solution 254 and methylene chloride, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and the mixture is concentrated under reduced pressure to give cycIohejQrimethy-ethyl-amine (40. Ig) as a crude product. MS (m/z): 142 [M+Hj^ Reference Example 2 3,5-Bis-trifluoromethyl-benzylamine (lOg) and 5-bromo-2-chloro- pyrimidine (12g) is dissolved in 1,4-dioxane (50ml} and thereto is added N,N-diisopropylethylamine (10.7ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 9:1 to 7:3) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyriinidin-2-yl)-amine (10. Ig). MS (m/z): 713 [M+H]* Reference Example 3 (1) Ethylamine hydrochloride (2g) is dissolved in methylene chloride (20ml) and thereto are added pyridine (6ml) and ethyl 6-(chloroformyl)hexanoate (7.6g) and the mixture is stirred at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and the mixture is separated, and the organic layer is washed successively with a IN-hydrochloric acid, water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give ethyl 6-ethylcarbamoyl hexanoate (9.29g) as a crude product. MS (m/z): 216 [M+H]+ (2) Crude ethyl 6-ethylcarbamoyl hexanoate (9.29g) is dissolved in tetrahydrofuran (50ml) and thereto is added sodium borohydride (7.35g). The reaction solution is heated under reflux and thereto is added dropwise acetic acid (11ml) and the mixture is heated under reflux for 1 hour and a half. To the reaction solution is added water under ice-cooling eind the mixture is extracted with ethyl acetate. The organic layer is washed with a 255 saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in ethanol (SOml), and thereto is added a 4N-hydrochloric acid in ethyl acetate (7.6nil), and the mixture is 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 a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give ethyl 7-ethylamino-heptanoate (3.98g) as a crude product. MS(m/z): 216 [M+H]-Reference Example 4 (1) 6-Aminohexanoic acid methyl ester hydrochloride (5g) is dissolved in methylene chloride (20ml) and thereto are added pjn-idine (4.5ml) and acetyl chloride (2ml), and the mixture is stirred at room temperature for 1 hour and 45 minutes. To the reaction solution are added a IN-hydrochloric acid 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 to give methyl 6-acetylamino-hexanoate (5.19g) as a crude product. MS (m/z): 188 [M+H]+ (2) Crude methyl 6-acetylainino-hexanoate (5.19g) is dissolved in tetrahydrofuran (50ml) and thereto is added sodium borohydride (5.03g). The reaction solution is heated under reflux and thereto is added dropwise acetic acid {7.6ml) and the mixture is heated under reflux for 1 hour and 30 minutes. To the reaction solution are added water under ice-cooling and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in ethanol (30ml) and thereto is added a 4N-hydrochloric acid in ethyl acetate (7.6ml) and the mixture is 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 256 washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give ethyl 6-ethylaniino-hexanoate (1.74g) as a crude product. MS (m/z): 188 [M+H]* Reference Example 5 (1) (3,5-Bis-trifluoroniethyl-benzyl)-(5-broino-pyriniidin-2-yl)-anune (lOg) and triethylamine (4.18ml) are dissolved in methylene chloride (lOOmL) and thereto is added triphosgene (2.97g) under ice-cooling. The reaction solution is stirred at the same temperature for 30 minutes and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofurein (lOOmL) and thereto are added benzyl alcohol (3.88ml) and triethylamine (10.45ml) at room temperature and the mixture is stirred overnight. The reaction solution is diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution ^nd a IN-hydrochloric acid. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 97:3~>9:1) to give benzyl (3,5-bis-trifli4oromethyl-benzyI)-(5-bromo-pyrimidin-2-yl)-carbamate (11.58g). MS (m/a): 534/536 [M+H]* (2) Benzyl (3,5-bis-trifluoromethyl-benzyl}-(5-bromo-pyrimidin-2-yI)-carbamate (11. 5g), [ 1,1 '-bis(diphenylphosphinQ)ferrocenel-dichloropalladium dichloromethane complex (3.51g), potassium acetate (6.33g) and bis(pinacolate)diboron (10.9g) are dissolved in dimethylsulfoxide (75ml), and the mixture is heated to 80°C under nitrogen atmosphere and stirred for 30 minutes. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the insoluble materials are removed by filtration through Celite'^M^ 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 resulting residue is dissolved in tetrahydrofuran (100ml) 257 and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (50ml) under ice-cooling and the mixture is stirred for 1 hour. Thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, followed by an addition of water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0^9:1) to give benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl}-carbamate (9.70g). MS (m/z): 472 [M+H]* (3) Benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-hydro>^-p5rrimidin-2-yl)-carbamate (9.70g) and ethyl 4-bromobutyrate (3-53g) are dissolved in N,N-dimethylformamide (50mL) and thereto is added potassium carbonate (3.41g) and the mixture is stirred at 50°C for 1 hour. Thereto are added ethyl acetate and a saturated brine, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—* 1:1) to give ethyl 4-{2-[benzyloxycarbonyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloJ0^}-butyrate (8.29g). MS (m/z): 586 [M+H]+ (4) Ethyl 4-{2-[benzyloxycarbonyl-(3,5-bis-trifluoromethyl-ben2yl)-aminol-pyrimidin-S-yloxyl-butyrate (3.0g) is dissolved in tetrahydrofuran {20ml) and thereto is added 10% palladium-carbon (SOOmg) and the mixture is stirred under hydrogen atmosphere at room temperature for 2 hours and 30 minutes. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—1:1) to give ethyl 4-[2-(3,5-bis-trifluoromethy!-benzylamino)-pyrimidin-5-yloxy]-butyrate (2.22g). MS (m/z): 452 [M+H]^ Reference Example 6 258 (1) 6-Aminohexanoic acid methyl ester hydrochloride (2.50g) is dissolved in tetrahydrofuran (50ml) and thereto are added water (50ml) and sodium bicarbonate (3.44g), followed by an addition dropwise of benzyl chloroformate (2.17ml) under ice-cooling, and the mixture is stirred at the same temperature for 2 hours and a half. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 6-benzyloxycarbonylamino hexanoate (4.16g). MS (m/z): 280 [M+H]^ (2) Methyl 6-benzyloxycarbonylamino-hexanoate (4.15g) is dissolved in N,N-dime thy Iformamide (2.5mL) ans thereto is added sodium hydride (63%) (552mg) under ice-cooling and the mixture is stirred at the same temperature for 1 hour and thereto is added methyl iodide (1.72ml), and the mixture is stirred at the same temperature for an additional 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1} to give methyl 6-(benzylo3cycarbonyl-methyl-aniino)-hexanoate (2.25g). MS (m/z): 294 [M+H]^ (3) Methyl 6-(ben^lojQ'carbonyl-methyl-amino)-hexanoate (2.24g) is dissolved in methanol (35ml) and thereto is added 10% palladium-carbon (500mg) and the mixture is stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to give methyl 6-methylamino hexanoate (l.llg). MS (m/z): 160 [M+H]^ Reference Example 7 Propylamine (0.65g) is dissolved in tetrahydrofuran (5ml) and thereto is added pyridine (0.89ml), followed by an addition dropwise of methyl 259 adipoyi chloride (1.96g) under ice-cooling and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (30ml) and thereto is added sodium borohydride (1.93g) at room temperature and the mixture is heated to 65°C and thereto is added dropwise acetic acid (2.92ml) over 1 hour and the mixture is stirred at the same temperature for 9 hours. To reaction mixture is added an ice-cooled dilute hydrochloric acid, and the mixture is stirred for 30 minutes and extracted with ethyl acetate, and the organic layer is washed with a mixed solution of a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in methanol (Sml) and thereto is added a 4N-hydrochloric acid in dioxane (7.5mL) and the mixture is stirred at room temperature overnight. To the reaction mixture is added a saturated aqueous sodium bicarbonate solution and a saturated brine, and the mixture is extracted six times with ethyl acetate and the collected organic layer is dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 6-propylamino-hexanoate (914mg). MS (m/z): 188 [M+H] Reference Example 8 (1) Tert-butyl piperidine-4-ylmethyI-carbamate [2.00g) is dissolved in tetrahydrofuran (10ml), and thereto is added triethylamine (1.69ml), followed by an addition dropwise of ethyl bromoacetate (1.24mL) in water bath and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure, and to the resulting crystalline residue is added isopropylether 260 and tne mixture is tiitered to give etiiyl \|4-(tert-butoxy-carbonylammo-methyl)-piperidin-l-ylj-acetate (1.87g). MS (m/z): 301 [M+H]+ (2) Ethyl [4-(tert-butoxycarbonylainino-niethyl)-piperidin-l-yl]-acetate (1.86g) is dissolved in N,N-dimethylformainide (10ml), and thereto are added sodium hydride (63%) (1.19g) and ethyl iodide (6.0ml), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is made weak basic with a 10% aqueous citric acid solution and a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give ethyl {4-[(tert-butojqfcarbonyl-ethyl-amino)-methyl]-piperidine-l-yl}-acetate (905mg). MS (m/z): 329 [M+H]* (3) Ethyl {4-[(tert-buto3q^carbonyl-ethyl-amino)-methyl]-piperidine-1 -yl}-acetate (235mg) is dissolved in methylene chloride (1ml) and thereto is added trifluoroacetic acid (1ml) and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to give (4-ethylaminomethyl-piperidin-l-yl)-acetic acid ethyl ester bistrifluoroacetic acid salt (482mg). MS (m/z): 229 [M+H]* Reference Example 9 (1) 2-Tert-butoxy-ethylaraine (2g} is dissolved in methylene chloride (10ml) and thereto are added p3T-idine (940vil) and ethyl 6-(chloroformyl)hexanoate (1.13g) under ice-cooling and the mixture is stirred at room temperature overnight. To the reaction solution are added a IN-hydrochioric acid 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 to give ethyl 6-(2-tert-ethylcarbamoyl)-hexanoate as a crude product (2.96g). MS (m/z): 288 [M+H]+ (2) Crude ethyl 6-{2-tert-ethylcarbamDyl)-hexanoate (2.96g) is dissolved 261 in tetrahydrofuran {15ml) and thereto is added sodium borohydride (1.60g). The reaction solution is heated under reflux and thereto is added dropwise acetic acid {2.4mL) and the mixure is heated under reflux for 1 hour. To the reaction solution is added water under ice-cooling and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, guid concentrated under reduced pressure. The resulting residue is dissolved in ethanol (6ml) and thereto is added a 4N-hydrochloric acid in ethyl acetate (1.5ml) and the mixture is stirred at room temperature for 3 days. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 to give ethyl 7-(2-tert-butoxy-ethylamino)-heptanoate as a crude product (2.6g). MS (m/z): 274 [M+H]+ Reference Example 10 (1) 2-Bromo-pyridine-3-ol (5g) is dissolved in water (150ml) and thereto are added sodium carbonate (6.15g) and iodine (7.65g) and the mixture is stirred at room temperature for 2 hours. Thereto are added a IN-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 is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1^3:1) to give 2-bromo-6-iodD-pyridin-3-ol (4.52g). MS (m/z): 300/302 [M+H]-^ (2) 2-Bromo-6-iodo-pyrid:n-3-ol (2.98g) is dissolved in N,N-dimethylformamide (140ml) and thereto are added cesium carbonate (16.3g) and methyl iodide (1.25mL) and the mixture is stirred at room temperature overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the oi^anic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column 262 chromatography (hexane : ethyl acetate = 19:1^4:1) to give 2-bromo-6-iodo-S-methoxy-pyridine (2.45g). MS (m/z); 314/316 [M+H]+ (3) To 0.5M-isopropenyl magnesium bromide/tetrahydrofuran is added trimethyl borate (3.3ml) and the mixture is stirred under nitrogen atmosphere at room temperature for 30 minutes. To the reaction solution are added 6N-hydrochloric acid and diethylether, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give isopropenylboric acid as a crude product (818mg). The above crude isopropenyl boric acid (287mg) and 2-bromo-6-iodo-3-methoxy-pyridine (SOOmg) are dissolved in a mixed solvent of l,2-diinetho3Q'-ethane (8ml) and ethanol (3.2ml) and thereto are added a IM-aqueous sodium carbonate solution {6.4ml) and tetrakis(triphenylphosphine)palladium (240mg) and the mixture is stirred under nitrogen atmosphere at 80°C for 5 hours. To the reaction solution are added water 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 is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1—-9:l), followed by NH-silica gel column chromatography (hexane : ethyl acetate = 49:1^^9:1) to give 2-bromo-6-isopropenyl-3-methoxy-pyridine (138mg). MS (m/z): 228/230 [M+H] Reference Example 11 5-Methoxy-2-methylsulfanil-p5Timidin-4-ol (250mg) is dissolved in acetonitrile (7ml) and thereto are added phoshporus oxychloride (0.7ml) and diethyl aniline {460pl) and the mixture is heated under reflux for 5.5 hours. The reaction solution is evaporated azeotropically with toluene three times, and to the residue are added aqueous citric acid solution and chloroform, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel 263 column chromatography (hexane : ethyl acetate = 19:1^^17:3) to give 4- chloro-5-methoxy-2-methyl sulfanil-pyrimidine (260mg). MS (m/z): 191/293 [M+HJ + Reference Example 12 (1} 3-Nitro-5-(trifluoromethyl)benzoic acid (50g) is dissolved in tetrahydrofuran (300ml) and thereto is added dropwise a l.OM-borane tetrahydrofuran complex/tetrahydrofuran (300ml) at 0°C under nitrogen atmosphere over 2 hours and the mixture is stirred at 75°C for 1 hour and a half. The reaction solution is allowed cool to room temperature and concentrated under reduced pressure, and thereto is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude (3-nitro-5-trifluoromethyl-phenyl)-methanol. This product is dissolved in methanol (500mL) and thereto is added 10% palladium-carbon (5g) and the mixture is stirred under hydrogen atmosphere at room temperature overnight. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give crude (3-amino-5-trifluoromethyl-phenyl)-methanol. To copper (II) bromide (53.6g) is added acetonitrile (500ml), followed by an addition dropwise of tert-butyl nitrite (35.7ml) under ice-cooling and the mixture is stirred under nitrogen atmosphere for 5 minutes. To reaction mixture is added dropwise a solution of the above crude (3-amino-5-trifluoromethyl-phenyl)-methanol in acetonitrile (200ml) under ice-cooling over 1 hour and 15 minutes and the mixture is stirred at room temperature under nitrogen atmosphere overnight. To reaction mixture is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively vi^th a IN-hydrochloric acid, water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography 264 (hexane : etiiy! acetate = 7:1— (2) (3-Bromo-5-trifIuoromethyl-phenyl)-methanol (33.9g) is dissolved in N,N-dimethylformamide (400mL) and thereto are added zinc(II) cyanide (16.39g) and tetrakis(triphenylphosphine)palladium (7.68g) and the mixture is heated under nitrogen atmosphere at 120°C for 2 hours. The reaction solution is allowed cool to room temperature, and filtered through CeliteTM, and the filtrate is concentrated under reduced pressure. Thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give 3-hydrox3Tnethyl-5-trifluoromethyl-benzonitrile (23.4g). NMR (CDCI3): 2.09 (lH,t), 4.85 (2H,d), 7.83 (IH.s), 7.87 (2H,s) (3) S-HydrojqTnethyl-S-triftuoromethyl-benzonitrile (23.4g) is dissolved in methylene chloride (230mL) and thereto is added carbon tetrabromide (42.4g), followed by an addition of triphenylphosphine (32.Og) under ice-cooling and the mixture is stirred at the same temperature for 30 minutes. The reaction solution is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1) to give 3-bromo-methyl5-trifluoromethyl-benzonitrile (25.5g). NMR (CDCI3): 4.51 (2H,s), 7.86 (lH,s), 7.88 (2H,s) Reference Example 13 2-Chloropyrimidin-5-ol (3.89g) is dissolved in N,N-dimethylformamide (50ml) and thereto are added potassium carbonate (498g) and tert-butyl 4-bromo-bu1yrate (7.36g) and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and 265 concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 24:1-4:1\| to give tert-butyl 4-(2-chloropyTiinidin-5-yloxy)bromobutyrate (6.22g}. MS fm/z): 273 [M+H]-Reference Example 14 2,5-Dibromopyridine (4.74g) is dissolved in toluene (100ml) and thereto are added 3,5-bis-trifluoromethyl-benzylainine (5.84g) and palladium acetate (449.Omg), 2,2'-bis{diphenylphosphino)-l,l'-binaphthyl (1.25g) and sodium tert-butoxide (4.23g) and the mixture is stirred under nitrogen atmosphere at 80°C for 12 hours. The reaction solution is cooled to room temperature, and thereto is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate twice, and the organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^4:1) to give (3,5-bis-triftuoromethyl-benzyl)-(5-bromopyridin-2-yl)-amine (2.08g). MS (m/z): 399/401 [M+H]+ Reference Example 15 3-Bromomethyl-5-trifiuorometyl-benzonitrile (which is prepared in Referrence Example 12) (15.9g) is dissolved in 7M-ammonia/methanol (550ml), and the mixture is stirred at 50-60°C for 30 minuites. The reaction solution is concentrated under reduced pressure. To the resulting residue are added a saturated aqueous sodium bicarbonate solution and chloroform, and the mixture is separated, and the organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—19:1—•■chloroform ; methanol : ammonium hydroxyide solution = 19:1:0.1) to give 3-aminomethyl-5-trifluorometyl-benzonitrile {10.4g). MS (m/z): 201 [M+HJ+ 266 Reference Example 16 The corresponding starting compound is treated in a similar manner to Example 142(1) to give the compound. Reference Example 17 (1) 3-Bromo-4-methoxybenzoic acid (2.00g) is dissolved in tetrahydrofuran (50ml), and the mixture is cooled to -78°C, and thereto is added dropwise a I.IM methyllithium in diethyl ether (7.7ml). The mixture is stirred at -78°C for 5 minutes, and thereto is added dropwise a 1.6M tert-butyllithium in n-pentane (13.2ml), and the mixture is stirred at -78'C for 15 minutes, and the mixture is allowed to warm to -45°C, and the mixture is stirred for 45 minutes, and then again cooled to -78°C. Thereto is added dropwise triisopropylborate, and the mixture is stirred at -78°C for 15 minutes, and the mbiture is allowed to warm to room temperature. The mixture is stirred at room temperature for 1.5 hours, and the mixture is concentrated under reduced pressure, and thereto are added water and hexane. The aqueous layer is adjusted pH to 4 by addition of a 6N-hydrochloric acid and a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate and methanol twice. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To the resulting residue is added diethyl ether, and the resulting solids are collected by filteration to give 2-methojQ'-5-carbojtyphenylboronic acid (1.37g) as a crude product. (2) The crude 2-metho3ty-5-carboxyphenylboronic acid (370mg) is dissolved in N,N-dimethylformamide (10ml), and thereto are added 2.0M-dimethylamine/tetrahydrofuran solution (1.9ml), 1-hydroxybenzotriazole dihydrate (725mg), l-ethy-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (579mg). The mbiture is stirred at room temperature for 3 hours, and thereto is added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate twice. The organic layer is dried over magnesium sulfate and concentrated under reduced 267 pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 19:1) to give 2-methoxy-5-dimethylcarbamoylphenylboronic acid (210mg). MS (m/z): 224 [M+H]+ Reference Example 18 The corresponding starting compound is treated in a similar manner to Reference_Example,17 to give the compound. Reference Example 19 (1) 4-sec-Butyl-phenol (3.0g) is dissolved in chloroform and thereto is added bromine (1.02ml) and the mixture is stirred at room temperature for 30 minutes. Thereto are added a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and conscentrated under reduced pressure to give 2-bromo-4-sec-butyl-phenol (4.57g). NMR (CDCI3): 0.81 (3H,t). 1.19 (3H,d), 1.56 (2H,m), 2.51 (lH,m), 5.33 (lH,s), 6.93 (lH,d), 7.02 (lH,d), 7.26 (lH,s). (2) 2-Bromo-4-sec-butyl-phenol (1.50g) is dissolved in N,N-dimethylformamide (10ml) and thereto is added potassium carbonate (l.lSg) and iodomethane (1.12g) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 1:0-»20:1) to give 2-bromo-4-sec-butyl-1-methoxy-benzene (l.SSg). NMR (CDCI3): 0.80 (3H,t), 1.20 (3H,d), 1.55 (2H,m), 2.51 {lH,m), 3.87 (3H,s), 6.82 (IH.d), 7.07 (lH,d}, 7.35 (IH.s). (3) 2-Bromo-4-sec-butyl-l-methojcy-benzene (l-15g) is dissolved in tetrahydrofuran (17ml) and the mixture is cooled to -78°C, and thereto is added dropwise 1.6M n-butyllithium in hexanes, and the mixture is stirred 268 at -78°C for 15 minutes. To the reaction solution was added trimethyl borate (1.47g), and the reaction mixture is stirred at -78°C for 30 minutes, and thereto are added a saturated aqueous ammonium chloride solution and ethyl acetate. The mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude 5-sec-butyl-1 -methoxy-benzene boronic acid (950mg). NMR (CDC13): 0.81 (3H,t), 1.22 (3H,d), 1.58 (2H,m), 2.58 (lH,m), 3.90 (3H,s), 6.25 {2H,s), 6.85 (2H,d), 7.25 (lH,d), 7.65 (lH,s). Reference Examples 20 to 23 The corresponding starting compounds are treated in a similar manner to Reference_Example 19 to give the compounds. Reference Example 24 2-Bromo-6-iodo-3-methQxy-pyridine (500mg) is dissolved in dry toluene (5ml) and thereto is added dropwise 1.6M n-butyllithium in hexanes (ml) at -7S°C under nitrogen atmosphere, and the mixture is stirred for 1 hour and thereto is added acetone (0.23ml), and the mixture is stirred overnight. To the reaction solution are added water 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 resulting residue is 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-ol (197mg). MS (m/z): 246/248 [M+H]+ The present compound of formula (1) or a pharmaceutically acceptable derivative thereof has an inhibitory activity against CETP and also shows an activity of increasing HDL cholesterol level and an activity of decreasing LDL cholesterol level. Thus, the compounds of the present invention are useful for prophylaxis and/or treatment of arteriosclerotic diseases, hyperlipemia or dyslipidemia, and the like. CLAIMS 1. A compound of the general formula (1): wherein, Y is a methylene group optionally substituted by a substituentfs) selected from an alkyl group and an oxo group, or a single bond; A is (i) a group selected from 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, an optionally substituted 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, 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, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, ein oxy group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxy group substituted by optionally substituted heterocyclic group, and a carbonyl group substituted by optionally substituted heterocyclic group; (ii) a homocyclic group optionally substituted by 1 to 5 substituents selected independently from the groups as defined above in (i); or (iii) a heterocyclic group optionally substituted by 1 to 5 substituents selected independently from the groups as defmed above in (i); 273 B is a phenyl group optionally substituted by 1 to 4 substituents selected independently from the following groups: an optionally substituted alkynyl group, a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a sulfo 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, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsuliinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxy group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxy group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, and an alkylene group; wherein said aikylene group may have 1 to 3 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms and further optionally may have a substituent(s); R1 is a hydrogen atom or an optionally substituted alkyl group; wherein the alkyl group further may optionally be substituted by a substituent(s) selected from an optionally substituted homocyclic group and an optionally substituted heterocyclic group; R2 is a group selected from 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, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally 274 substituted cycloalkoxy group, 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, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxo group substituted by optionally substituted heterocyclic group, and a carbonyl group substituted by optionally substituted heterocyclic group, or a pharmaceutically acceptable derivative thereof. 2. The compound of claim 1 wherein the homocyclic group is a cycloalkyl group, a phenyl group or a naphthyl group; the heterocyclic group is a thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imida2olinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl, tetra2olyl, pyridyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl, naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromeinyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidazolidinyl, cxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropyrazolyl, 275 imidazopyridyl, dihydropyraanyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl or tetrahydroquinolyl group; a substituent(s) for 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, 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, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxo group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted alkylsulfonyloxy group, an optionally substituted alkynyl group or an optionally substituted alkylene group is/are 1 to 5 groups selected independently from the following groups: a halogen atom; a cyano group; a hydroxy group; a nitro group; a carboxyl group; an oxo group; a thioxo group; a sulfo group; a cycloalkyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoxycarbonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, 276 alkoxycaxbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyloxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkylsulfanyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkylsulfonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkylsuliinyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamolyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an amino group; a mono- or di-alkylamino group optionally substituted by hydroxy group, halogen atom, carboxyl group, Eilkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamoylamino group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylureido group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyt group, 277 mono- or di-alkylamino group, phenyl group or morpholinyl group; a homocyclic group selected from a cycloalkyl group, a phenyl group and a naphthyl group; an oxy group substituted by the homocyclic group as defined above; a carbonyl group substituted by the homocyclic group as defined above; a heterocyclic group selected from a thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl, tetrazolyl, pyridyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl, naphthyridinyl, purinyl, pteridlnyl, dibenzofuranyl, benzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups; an oxy group substituted by the heterocyclic group as defined above; a carbonyl group substituted by the heterocyclic group as defined above; and a group of the formulae: wherein X1 and X3 are each independently CH2, NH, O, S, SO or SO2; X2 and X5 are each independently CH2, O, S, SO or SO2; X4 is NH, O, S, SO or SO2; X6 and X7 are each independently O or S; Xs is S or SO; and n, o, p, q and r are each independently an integer of 1 to 4, and further each of the above groups may optionally be substituted by 1 to 3 substituents selected from the following groups: halogen atom, carboxyl group, hydroxy group, cyano group, 0x0 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, alkylsulfonyl group and tetrazolyl group; or a pharmaceutically acceptable derivative thereof. 3. The compound of claim 2 wherein A is a group of a formula: -A1-A2; wherein A1 is a phenyl, naphthyl, pyrimidinyl, pyridazinyl, pyridyl, triazolyl, tetrazolyl, oxadiazolyl, dihydropyrmidinyl, pyrazinyl, thiazolyl, oxazolyl, dihydrooxazinyl, imidazolyl, pyrazolyl or dihydropyrazinyl group; 279 A2 is a carboxyl group; a cyano group; a nitro group; an alkyl group optionally substituted by a group selected from a hydroxy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkoxy group, a phenylalkoxy group, a hydroxyalkoxy group, a carboxyalkoxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, an oxiranyl group, a dialkyldioxolanyl group, a pyrrolidinyl group optionally substituted by carboxyl group, a piperidyl group optionally substituted by carboxyl group, a piperazinyl group optionally substituted by alkyl group, and a morpholinyl group; an alkenyl group optionally substituted by carboxyl group; an alkoxy group optionally substituted by a group selected from a hydroxy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkoxy group, a phenylalkoxy group, a hydroxyalkoxy group, a carboxyalkoxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfmyl group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alltylureido group optionally substituted by morpholinyl group, an oxiranyl group, a dialkyldioxolanyl group, a pyrrolidinyl group optionally substituted by carboxyl group, a piperidyl group optionally substituted by carboxyl group, a piperazinyl group optionally substituted by alkyl group, and a morpholinyl group; an alkoxycarbonyl group; a hydroxycarbamimidoyl group; an alkylsulfanyl group; an alkylsulfonyl group optionally substituted by carboxyl group; a mono- or di-alkylamino group optionally substituted by hydroxy group, carboxyl group, alkoxy group or mono- or di-alkylamino group; a morpholinyl group optionally substituted by carboxyl group, alkyl group, carboxyalkyl group or alkoxycarbonyl group; an optionally oxidized thiomorpholinyl group; a piperazinyl group optionally substituted by a group selected from an alkyl group, alkanoyl group and hydroxyalkanoyl 280 group; a pyrrolidinyl group optionally substituted by carboxyl group, alkyl group, carboxyalkyl group or alkoxycarbonyl group; a piperidyl group optionally substituted by carboxyl group, alkyl group, carboxyalkyl group or alkoxycarbonyl group; a tetrazolyl group optionally substituted by alkyl group, hydroxyalil group, carbosalkyl group or morpholinylalkyl group; an oxodihydrooxadiazolyl group; a p3T-imidinyl group; or a tetrahydropyranyl group; Ri is a group of a formula: -R11-R12, wherein Rii is an alkylene group; R2 is a substituent(s) selected from a phenyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, thienyl, triazolyl, tetrazolyl, oxadiazolyl, dihydrop5Timidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, dihydrooxazinyl, dihydropjTazinyl and pjn-azolyl group; wherein said substituent(s) may optionally be substituted by 1 to 4 substituents selected independently from 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 di-alkylamino group, alkanoyl group, alkylsulfanyl group, tetrazolyl group and dihydrooxazolyl group; and further each of said alkyl group, alkoxy group, mono- or di-alllamino group, mono- or di-alkylcarbamoyl group, alkanoyl group and alkylsulfanyl group independently may optionally be substituted by 1 to 5 substituents selected independently from halogen atom, hydrojr group, alkoxy group, amino group, morpholinyl group, piperidyl group, pyrrolidinyl group, piperazinyl group, alkylpiperazinyl group and alkanoylpiperazinyl group; R2 is a halogen atom; a hydroxy group; a cyano group; a nitro group; 281 a carbojtyl group; a sulfo group; a cydoalkyl group optionally substituted by carbojl group or alkoxycarbonyl group; an alkyl group optionally substituted by a group selected from a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkocarbonyl group, a tetrazolyl group, a mono- or di-alkylcarbamoyl group, an alkoxy group (said aikoxy group may optionally be substituted by phenyl group, carbol group or hydroxy group), an alkanoyl group, an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an amino, a mono- or di-alkylEimino group optionally substituted by carbojl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alllureido group optionally substituted by morphoUnyl group, an oxiranyl group, a dioxolanyl group optionally substituted by alll group, pyrrolidinyl group optionally substituted by alkojcarbonyl group or carboxyl group, a p5TTolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalll group, a piperidyl group optionally substituted by alko3cycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a morpholinyl group, and a piperidylo: group optionally substituted by edkyl group; an alkenyl group optionally substituted by a group selected from a cyano group, a hydros group, a carboxyl group, a benzyloxycarbonyl group and a tetrazolyl group; an alkenylo: group optionally substituted by carbojQ'l group; an alkoxy group optionally substituted by a group selected from a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may 282 optionally be substituted by carbojcyl group, alkoxycarbonyl group or hydroxy group), an alkoxy group {said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carbojTiiethyl group, an oxiranyl group, a phenyl group optionally substituted by alkojQ' group or carbojcyl group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkojQfcarbonyl group or carboxyl group, a pyrrolidinyl group optioneilly substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a pyrrolidinyl group optionally substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl. group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alll group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a morpholinylcarbonyl group; an alkoxycarbonyl group optionally substituted by phenyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by a group selected from a carboj'l group, a morpholinyl group and an alkoxy group; a hydroxycarbamimidoyl; an allq'lsulfanyl group optionally substituted by a group selected from hydroxy group, carboxyl group and mono- or di-alkylcarbamoyl group; 283 an alkylsulfinyl group; an alkylsulfonyl group optionaliy substituted by a group selected from hydroxy group, carboxyl group, alkoxycarbonyl group and mono- or di-alkylcarbamoyl group; an amino group; a mono- or di-alkylamino group optionally substituted by a group selected from a hydrogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-all(ylcarbamoyl group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carbo;! group, alkoxycarbonyl group or hydroxy group), an aikoxy group (said alkoxy group may optionally be sub stituted by carboil group, formyl group or hydros group), an alkanoyloxy group, an alkylsulfanyl group, an alllsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino optionally substituted by carboxyl group or aikoxy group, a mono- or di-aikylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by aikoxy group or carboxyl group, a morpholinyl group, a pyxrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylallQl or carboxyalkyl group, a pjnrolidinyl group substituted by 0X0 group, a piperidyl group optionally substituted by alkoJOfcarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyaUsyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl optionally substituted by oxo group, a pyrrolidinylcEirbonyl group optionally substituted by carboxyl group, a 284 piperidyloxy group optionally substituted by alkyl group and a morpholinylcarbonyl group; an alkanoylamino group optionally substituted by a group selected from hydroxy group, alkoxy group, carboxyl group and amino group; a mono- or di-alkylcarbamoylamino group optionally substituted by alkoxy group; a morpholinylcarbonylamino group; a sulfamolyl group; a mono- or di-alkylsulfamolyl group; an alkanoyl group optionally substituted by a group selected from hydroxy group, carboxyl group, alkoxycarbonyl group, alkoxy group, mono- or di- alkylamino group and morpholinyl group; or a cyclic group selected from a cycloalkyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl, tetrazolyl, pyridyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl, naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl, carbazolyl, acridinyl, phenainthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyi, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups; 285 wherein said cyclic group may optionally be substituted by the following groups: a halogen atom, an alkoxyalkyl group, an alkyl group optionally substituted by 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylauninoalkoxy group, a carboxyl group, a hydroxy group, a cyano group, an oxo group, an alkyl group, a hydroxyalkyl group, an alkoxycarbonylalkyl group, a carboxyallq'l group, a morpholinylalkyl group, a phenylalkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkojQalkanoyl group, an alkoxy group, a phenylalkoxy group, an alkoxycarbonyl group, a benzloxycarbonyl group, a mono- or di-alllamino group, a mono- or di-alllcarbamoyl group, a mono- or di-alkylsulfamolyl group, an alkylsulfonyl group and a tetrazolyl group; wherein the substituents defined as above may further be substituted by a substituent(s) selected from the following groups: a halogen atom, an alkoqralkyl group, an alkyl group optionally substituted by 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, a cyano group, an oxo group, an alkyl group, a hydroxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalll group, a morpholinylaUl group, a phenylalkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkoxyalkanoyl group, an alkoxy group, a phenylalkoxy group, an alkoxy'carbonyl group, a benzyloxycarbonyl group, a mono- or di-alkylamino group, a mono- or di-alkylcarbamoyl group, a mono- or di-alkylsulfamolyl group, an alkylsulfonyl group and a tetrazolyl group, or a pharmaceutically acceptable derivative thereof. 4. The compound of claim 1 wherein Y is a methylene group optionally substituted by a substituent(s) selected from an alkj'l group and an oxo group, or a single bond; A is a group of a formula: -A1-A2; wherein Ai is a heterocyclic group or a homocyclic group; 286 i-i.- i» till upuunaiiy suDsurutea nomocyclic group, an optionally substituted alkylsulfanyl group, an optionally substituted alllsulfinyl group, an optionally substituted alllsulfonyl group, an optionally substituted alkyl group, a nitro group, a hydroxy group, a cyano group, an optionally substituted alkenyl group, an optionally substituted heterocyclic group, a substituted alkoxy group, a halogen atom, an amino group substituted by 1 to 2 substituents, or a hydrogen atom; B is a phenyl group optionally substituted by 1 to 4 substituents selected independently from a cyano group, a halogen atom, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfmyl group, an optionally substituted alkylsulfonyl group, an amino group substituted by 1 to 2 substituents, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted cycloalko group, a carboxyl group, an optionally substituted cycloalkyl group, an optionally substituted carbamoyl group, an optionally substituted alkyl group, and an optionally substituted alkoxy group; Ri is a hydrogen atom, an alkyl group substituted by a heterocyclic group or an alkyl group substituted by a homocyclic group; wherein said heterocyclic group, homocyclic group or alkyl group may further have a substituent(s); R2 is an optionally substituted alllsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, a cyano group, an optionally substituted alkenyl group, an amino group optionally substituted by 1 to 2 substituents, a halogen atom, an optionally substituted alkoxy group, an optionally substituted carbamoyl group, an oxy group optionally substituted by optionally substituted heterocyclic group, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted homocyclic group, an oxo group optionally substituted by optionally substituted homocyclic group, an optionally substituted alkyl group or a nitro group; 287 provided that when Y is a methylene group and A is a halogen atom, a hydrogen atom, a nitro group, a hydroxy group or a cyano group, then R2 is not an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alko3 group, or an amino group optionally substituted by 1 to 2 substituents, or a pharmaceutically acceptable derivative thereof. 5. The compound of claim 4 wherein Y is a methylene group optionally substituted by a substituent(s) selected from an alkyl group and an oxo group; A is a heterocyclic group; A2 is an optionally substituted heterocyclic group, an optionally substituted alkyl group, a substituted alkoxy group, a halogen atom, an amino group optionally substituted by 1 to 2 substituents, or a hydrogen atom; B is a phenyl group optionally substituted by 1 to 4 groups selected independentiy from a cyano group, a halogen atom, a hydroxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkoxy group, an optionally substituted piperidyl group, a cycloalkyl group, a cycloalkoxy group, an optionally substituted alkyl group and an optionally substituted alkoJQ' group; Ri is a hydrogen atom, or an alkyl group substituted by a phenyl group that is substituted by 1 to 2 groups selected independently from an alkoxy group optionally substituted by 1 to 3 halogen atoms, an alkyl group optionally substituted by 1 to 3 halogen atoms and a cyano group; R2 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 ojq group substituted by optionally substituted heterocyclic group, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted homoQ'clic group, an oxy group substituted by optionally substituted homocyclic group, a 288 hydroxyalkyl group or a nitro group, or a pharmaceutically acceptable derivative thereof. 6. The compound of claim 5 wherein the homocyclic group is a cycloalkyl group, a phenyl group or a naphthyl group; the heterocyclic group is a thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, p5a-azolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl, tetrazolyl, p3Tidyl, imidazopjTidyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolopyridazinyl, triEizolopjaidazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl, naphthyridinyl, purinyl, pteridinyl, diberazofuranyl, benzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidaaolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazoUnyl, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl or tetrahydroquinolyl group; a substituent(s) for an optionally substituted ailkyl group, an optionally substituted 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, an optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alliylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally 289 substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxo group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted alkylsulfonyloxy group, an optionally substituted allnyl group or an optionally substituted allIene group is/are 1 to 5 groups selected independently from the following groups: a halogen atom; a cyano group; a hydroi group; a nitro group; a carboxyl group; an oxo group; a thioxo group; a sulfo group; a cycloalkyl group optionally substituted by hydroxy group, halogen atom, carboJtyl group, alkoxycarbonyl group, mono- or di-alllamino group, phenyl group or morpholinyl group; an alkoicarbonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a carbamoyl group; a mono- or di-alllcarbamoyl group optionally substituted by hydrojQ' group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkyl group optionally substituted by hydroxy group, halogen atom, carboJ'l group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alko3cycarbonyl group, mono- or di-alllamino group, phenyl group or morpholinyl group; an alkanoyloxy group optionally substituted by hydroxy group, hailogen atom, carbojcyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group 290 or morphoHnyl group; an alkylsulfanyl group optionally substituted by hydroxy group, halogen atom, carbo31 group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an ajkylsulfonyl group optionally substituted by hydroxy group, halogen atom, carbojl group, alkoxycarbonyl group, mono- or di-allq'lamino group, phenyl group or morpholinyl group; an alllsailfmyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamolyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an amino group; a mono- or di-alkylamino group optionally substituted by hydros group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylsuifamoylamino group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylureido group optionally substituted by hydroxy group, halogen atom, carbojl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a homocyclic group selected from a cycloalkyl group, a phenyl group and a naphthyl group; an o: group substituted by the homocyclic group as defined above; a carbonyl group substituted by the homocyclic group as defined above; a heterocyclic group selected from a thienyl, fuiyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl, tetrazolyl, pyridyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, p3Tidazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyi, 291 tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl, quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl, naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropjTazolyl, iinidazop5'ridyl, dihydrop5Ta2inyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups; an oxy group substituted by the heterocyclic group as defined above; a carbonyl group substituted by the heterocyclic group as defined wherein X and X3 are each independently CH2, NH, O, S, SO or SO2; X2 and X5 are each independently CH2, O, S, SO or SO2; X" is NH, O, S, SO or SO2; X& and Xare each independently O or S; X is S or SO; and n, o, p, q and r are each independently an integer of 1 to 4, and further wherein each of the above groups may optionally be substituted by 1 to 3 substituents selected from the following groups: halogen atom, carboxyl group, hydroxy 292 group, cyano group, oxo group, thioxo group, alkyl group, hydroxyalkyi group, alkosgcarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydrojcyalkanoyl 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 and tetxazolyl group; or a pharmaceutically acceptable derivative thereof. 7. The compound of claim 6 wherein A is a pyrimidinyl group or a pyridyl group; A2 is (a) a heterocyclic group selected from a piperidyl group and a morpholinyl group, respectively optionally substituted by a substituent(s) selected from a carboxyl group, a carbojalkyl group and an alkyl group; (b) an alkoxy group substituted by a group selected from a carboxyl group, a hydroxy group, an alkoxy group and a cyano group; (c) a halogen atom; (d) an amino group optionally substituted by 1 to 2 substituents independently selected from a carboxyalkyl group, a hydrojcyalkyl group, an alkyl group, an alkoxyalkyl group and an aminoalkyl group optionally substituted by 1 to 2 alkyl groups; (e) a hydrogen atom; B is a phenyl group optionally substituted by 1 to 4 groups selected independently from halogen atom, hydroxy group, alkyl group optionally substituted by 1 to 3 halogen atoms and alkoxy group optionally substituted by 1 to 3 halogen atoms; Ri is a hydrogen atom, or a benzyl group substituted by 1 to 3 groups selected independently from an alkojcy group optionally substituted by 1 to 3 halogen atoms, an alkyl group optionally substituted by 1 to 3 halogen atoms and a cyano group; R2 is (a) an amino group optionally substituted by 1 to 2 groups 293 independently selected from an alkyl group, an alkoxyalkyl group, a cycloalllalll group, an alkojQ'carbonyl group, an alkylcarbonyl group, an alkylcarbamoyl group, a carbojalkyl group, a cycloalkylalkyl group substituted by carboxyalkyl group, a hydroxyalkyl group, a carboxyalkoxycarbonyl group, a carboxydihydrooxaEolyl group, a carboxyalkylcarbonyl group, a phenylalkyl group, an alkoxyalkoxycarbonyl group, an alkoxyalkyicarbonyl group, an alkyl group substituted by piperidyl group, a piperidylalkyl group substituted by carbojalkyl group, and an allQ'l group substituted by phenyl that is optionally substituted by 1 to 2 alkyl groups (said alkyl group may optionally substituted by 1 to 3 halogen atoms); wherein said ailkyl group or alkoj group may further optionally be substituted by 1 to 5 groups selected independently from the following groups: a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group {said mono- or di-allq'lcarbamoyl group may optionally be substituted by carbol group, alkoxycarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alklsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionaiUy substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrroUdinyl group optionally substituted by alkoxycarbonyl group or carboJtyl group, a pjrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a 294 pyrrolidinyl group optionally substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alll group and a morpholinylcarbonyl group; (b) a halogen atom; (c) an alkoxy optionally substituted by a group selected from carboxyl group, cycloalkyl group and alkoxy group; wherein said cycloalkyl group or alkoxy group may optionally be substituted by 1 to 5 groups selected independently from the following groups: a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkcylcarbaunoyl group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carboxyl group, adkoxycarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxo group, an alilsulfanyl group, an alkylsulfonyl group, an alllsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group 295 or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperidyl group optionally substituted by oxo group, a piperidyl group optionally substituted by alkoxycobonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a morpholinylcarbonyl group; (d) a carbamoyl group optionally substituted by 1 to 2 substituents selected independently from alkyl group and carboxyalkyl group, wherein said alkyl group may optionally be substituted by 1 to 5 groups selected independently from the following groups: a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may be substituted by carboxyl, alkoycarbonyl or hydroxy group), an alkoxy group (said alkoxy group may be substituted by carboxyl, formyl or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino optionally substituted by carboxyl or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxyl or carboxyl group, a morpholinyl group, a pyrrolidinyl optionally substituted by alkoxycarbonyl or carboxyl group, a pyrrolidinyl optionally substituted by 296 alkoxycarbonylalkyl or carboxyalkyl group, a pyrrolidinyl substituted by 0X0 group, a piperidyl optionedly substituted by alkoxycarbonyl or carboxyl group, a piperidyl optionally substituted by alkoxycarbonylalkyl or carboxyalkyl group, a piperazinyl optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolany group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a morpholinylcarbonyl group; (e) a hydroxy group; (f) an oxy group substituted by a heterocyclic group selected from pyrimidinyl group and tetrahydropyranyl group; (g) a heterocyclic group selected from a morpholinyl, pyrimidinyl, piperidyl, piperazinyl, pyrazinyl, tetrazolyl, thienyl, fury, dihydroisoquinolyl, pyridyl and pyrrolyl group, which are each optionally substituted by 1 to 3 substituents selected independently from pyrimidinyl group, alkyl group, halogen atom, cyano group, mono- or di-alkylamino group, alkoxy group, phenyl group, carboxyl group, carbamoyl group and carboxyalkyl group; wherein said alkoxy group or alkyl group may optionally be substituted by 1 to 5 groups selected independently from the following groups: a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carboxyl group, alkoxycarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionally substituted by ceirboxyl group or alkoxy 297 group, a mono- or di-alkylsulfamoylanino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxyethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a pyrrolidinyl group substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a phenyl group optionally substituted by morpholinyl group; (h) a phenyl group optionally substituted by 1 to 3 substituents selected independently from halogen atom, alkyl group and alkoxy group; wherein said alkoxy group or alkyl group may further optionally be substituted by 1 to 5 groups selected independently from the following groups: a halogen atom, a cyano group, a hydroxy group, a carboxy group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carboxyl group, alkorcarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an 298 alkylsulfmyl group, an aminosulfonyl group, an amino group, a raono- or di-alkylamino group optionally substitxited by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group, a pyrrolidinyl group substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxy group, a piperidylcxy group optionally substituted by alkyl group and a morpholinylcaxbonyl group; (i) an oxo group substituted by cycloalkyl group; (j) a hydroxyalkyl group; or (k) a nitro group; or a pharmaceutically acceptable derivative thereof. 8. The compound of claim 7 wherein A1 is a pyryimidinyl group or a pyridyl group; A2 is (a) a heterocyclic group selected from piperidyl group and morpholinyl group, which are each optionally substituted by a substituent(s) selected from a carboxyl group, carboxyalkyl group or alkyl group; (b) an alkoj group substituted by a group selected from carboxyl group, hydroxy group, alkojty group and cyano group; 299 (c) a halogen atom; (d) an amino group optionally substituted by 1 to 2 substituents selected independently from carboxyalll group, hydroxyalkyl group, alkyl group, alkoxyalkyl group and aminoalkyl group, respectively optionally substituted by 1 to 2 alkyl groups; (e) a hydrogen atom; B is a phenyl group optionally substituted by 1 to 4 groups selected independently from alkyl group optionally substituted by 1 to 3 halogen atoms and alkoxy group optionally substituted by 1 to 3 halogen atoms; R2 is (a) an amino group optionally substituted by 1 to 2 groups selected independently from an alkyl group, an alkoxyalkyl group, a cycloalkylalkyl group, an alkoxycarbonyl group, an alkylcarbonyl group, an alkylcarbamoyl group, a carboxyalkyl group, a cycloalkylalkyl group substituted by carboxyalkyl group, a hydroxyalkyi group, a carboxyalkoxycarbonyl group, a carboxydihydrooxazolyl group, a carboxyalkylcarbonyl group, a phenylalll group, an alkoxyalkoxycarbonyl group, an alkoxyalkylcarbonyl group, an alkyl group substituted by piperidyl group, a piperidylalkyl group substituted by carboxyalkyl group and an alkyl group substituted by phenyl group that is optionally substituted by 1 to 2 alkyl groups (said alkyl group may optionally be substituted by 1 to 3 halogen atoms); (b) a halogen atom; (c) an alkoxy group optionally substituted by a group selected from a carboxyl group, a cycloalkyl group and an alkoxy group; (d) a carbamoyl group optionally substituted by 1 to 2 substituents selected independently from alkyl group and carboxyalkyl group; 300 (e) a hydroxy group; (f) an 0X0 group substituted by a heterocyclic group selected from a pyrimidinyl group and a tetrahydropyranyl group; (g) a heterocyclic group selected from a pyrimidinyl, pyridyl, morpholinyl, piperidyl, piperazinyl, tetrazolyl, dihydroisoquinolyl and pyrrolyl group, which are each optionally substituted by 1 to 2 substituents selected independently from alkyl group, alkoxy group, phenyl group, carboxyl group, carboxyalkoxy group and carboxyalkyl group; (h) a phenyl group optionally substituted by 1 to 3 substituents selected independently from halogen atom, alkyl group and alkoxy group; (i) an oxo group substituted by cycloalkyl group; (j) a hydroxyalkyl group; (k) a nitro group; or a pharmaceutically acceptable derivative thereof. 9. The compound of claim 8 wherein A is an amino group substituted by 1 to 2 groups selected independently from a piperidyl group optionally substituted by carboxyl group; a morpholinyl group optionally substituted by carboxyl group; an alkoxy group substituted by a group selected from carboxyl group, hydroxyy group, alkoxy group and cyano group; an amino group substituted by 1 to 2 groups selected independently from carboalkyl group and alkyl grup; B is a phenyl group optionally substituted by an alkyl group optionally substituted by 1 to 3 halogen atoms; R2 is (a) an amino group optionally substituted by 1 to 2 groups selected independently from an alkyl group, a cycloalkylalkyl group, an alkoxycarbonyl group, a carboxyalkyl group and a cycloalkylalll group 301 substituted by carboxyalkyl group; (b) an alkoxy group; (c) a phenyl group optionally substituted by a group selected from a halogen atom, an alkyl group and an alkoxy group; fd) a pyridyl group optionally substituted by a group selected from a halogen atom, an alkyl group and an alko group; or a pharmaceutically acceptable derivative thereof. 10. A compound described in anyone of examples No. 7, 24, 75, 57, 13, 54, 12, 65, 63 and 64, or a pharmaceutically acceptable derivative thereof. 11. A compound of the formula (l-A): wherein A1 is an optionally substituted pyrimidin-2-yl group or an optionally substituted pyridin-2-yl group; R1A and R are independently a cyano group or an alkyl group optionally substituted by 1 to 3 halogen atoms; Ring E is an optionally substituted phenyl group; F is an optionally substituted cyclic group; or a pharmaceutically acceptable derivative thereof. 302 wherein ZA is N or CH; A21A is an optionally substituted homocyclic group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl group, a nitro group, a hydroxy group, a cyano group, an optionally substituted alkenyl group, an optionally substituted heterocyclic group, an optionally substituted alkoxy group, a halogen atom, an amino group optionally substituted by 1 to 2 substituents, a carbamoyl group optionally substituted by 1 to 2 substituents, a carboxyl group or a hydrogen atom; R1A is a cyano group or an alkyl group optionally substituted by 1 to 3 hailogen atoms; B' is a group selected independently from an oxo group, a cyano group, a halogen atom, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alklsulfonyl group, an amino group optionally substituted by 1 to 2 substituents, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted cycloalkoxy group, an optionally substituted cycloalll group, a carboxyl group, a carbamoyl group optionally substituted by 1 to 2 substituents, an optionally substituted alkyl group or an optionally substituted alkoxy group; pA is an integer of 0 to 3; D is a pyrimidinyl group, a pyridyl group, a phenyl group, a pyrimidinyloxy group, a tetrazolyl group or an oxazolidinyl group; D' is a group selected independently from a halogen atom, an alkoxyalkyl group, an alkyl group substituted by 1 to 5 halogen atoms, an alkoxy group substituted by 1 to 5 halogen atoms, an alkenyl group, a carbamoyl group, a cycloalkyl group, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, 303 a cyano group, an oxo group, an alkyl group, a hydroxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkyl group, a morpholinylalkyl group, a phenylalkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkoxyalkanoyl group, an alkoxy group, a phenylalkoxy group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a mono- or di-alkylamino group, a mono- or di-alkylcarbamoyl group, a mono- or di-alkylsulfamolyl group, an alkylsulfonyl group, a tetrazolyl group, benzyloxyalkyl group, a cycloalkylalkyl group, an benzyloxy group, an alkoxyalkoxy group, a carboxyalkoxy group, a carboxyalkenyl group, an alkylcarbonylamino group, a carboxyalkoxyalkyl group, a morpholmyl group or a pyridylalkoxy group; q' is an integer of 0 to 3; or a pharmaceutically acceptable derivative thereof. 13. The com.pound of claim 12 wherein A21A is selected from the following group (a) a heterocyclic group selected from a piperidyl group and a morpholinyl group, respectively optionally substituted by a substitutent(s} selected from a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group or an alkyl group; (b) an alkoxy group optionally substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulfmyl group, a mono- or di-alkylamino group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group or an alkoxy group; (c) a halogen atom; (d) an amino group optionally substituted by 1 to 2 substituents independently selected from a carboxyalkyl group, an alkoxycarbonylalkyl group, an alkylsulfonylalkyl group, an aikylsulfinylalkyl group, a hydroxyalkyl group, an alkyl group, an alkoxyalkyl group or an aminoalkyl group optionally substituted by 1 to 2 alkyl groups; (e) a hydrogen atom; (f) an alky] group optionally substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulfmyl group, a mono- or di-alkylamino group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group or an alkoxy group; fg) a carboxyl group; (h) a carbamoyl group optionally substituted by a carboxyalkyl group; or (i) an alkenyl group 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 or an alkoxy group; (j) a morpholinyl group; (k( a piperidinyl group optionally substituted by a carboxyl group or a carboxyalkyl group; B' is a group selected independently from an oxo group, a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms, an alkoxy group optionally substituted by 1 to 3 halogen atoms, a cyano group, a hydroxy group, a cycloalkyl group, an alkoxyalkyl group, a cycloalkoxy group, an alkylsulfanyl group optionally substituted by 1 to 3 halogen atoms, an alkylsulfinyl group optionally substituted by 1 to 3 halogen atoms or an alkylsulfonyl group optionally substituted by 1 to 3 halogen atoms; or a pharmaceutically acceptable derivative thereof. 14. The compound of claim 13 wherein A21A is an alkoxy group optionally substituted by 1 to 2 groups selected from a carboxyl group, a halogen atom, an alkoxycarbonyl group, an alkoxyl group, a hydroxy group, a mono or di-alkylamino group, an alkylsulfinyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl 305 group and an alkylsulfanyl group; an alkyl group optionally substituted by 1 to 2 groups selected from a carboxyl group, a halogen atom, an alkoxycarbonyl group, an alkoxyl group, a hydroxy group, a mono or di-alkylamino group, an alkylsulfinyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl group and an alkylsulfanyl group; a morpholinyl group; a carboxyl group or a carboxyiperidinyl group; B' is a group selected independently from a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms or an alkoxy group optionally substituted by 1 to 3 halogen atoms; D' is a group selected independently from an alkoxy group optionally substituted by 1 to 3 halogen atoms, a halogen atom, a cyano group, an alkylsulfanyl group, a mono or di-alkylamino group, an alkenyl group, an alkyl group optionally substituted by 1 to 3 halogen atoms, a carboxyl group, a hydroxy group, a carboxyalkoxy group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an oxo group, a cycloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylcarbonylamino group, a morpholinyl group or a carboxyalkoxyalkyl group; or a pharmaceutically acceptable derivative thereof. 15. The compound of claim 14, wherein ZA is a N, or a pharmaceutically acceptable derivative thereof. 16. The compound of claim 14, wherein R1A is an alkyl group optionally substituted by 1 to 3 halogen atoms, or a pharmaceutically acceptable derivative thereof. 17. The compound of claim 14, wherein D is a phenyl group, or a pharmaceutically acceptable derivative thereof. 18. The compound of claim 14, wherein D' is a group selected independently from a halogen atom, an alkoxy group or an alkyl group, or a pharmaceutically acceptable derivative thereof. 19. The compound of claim 14, wherein A21A is a morpholinyl group or 305 an alkoxyl group substituted by a carboxyl group, or a pharmaceutically acceptable derivative thereof. 20. A compound described in anyone of examples No. 91, 94, 96, 112, 114, 118 to 123, 131, 133, 136, 138 to 140, 142 to 153, 158 to 163, 165 to 169, 173 to 177, 179 to 182, 185, 186, 190 to 194, 198, 203, 208 to 216, 218 to 223, 231, 239, 240, 241 or a pharmaceutically acceptable derivative thereof. 21. A compound described in anyone of examples No. 154 to 157, 164, 170 to 172, 178, 183, 184, 187 to 189, 195 to 197, 199 to 202, 204 to 207, 217, 224 to 230, 232 to 238, 242 to 252 or a pharmaceutically acceptable derivative thereof. 22. A pharmaceutical composition, which comprises as an active ingredient a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable derivative thereof. 23. A method for prophylaxis or treatment of arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular diseases, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion Injury, restenosis after angioplasty, hypertension, cerebral infarction, cerebral stroke, diabetes, vascular complication of diabetes, thrombotic diseases, obesity, endotoxemia, metabolic syndrome, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, reno-vascular disease, renal disease, splanchnic vascular disease, vascular hemostatic disease, fatty liver disease, steatohepatitis, inflammatory disease, autoimmune disorders and other systemic disease indications, immune function modulation, pulmonary disease, anti-oxidant disease, sexual dysfunction, cognitive dysfunction, schistosomiasis, cancer, regression of xanthoma or Alzheimer's disease, which comprises administering an effective amount of 307 a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable derivative thereof, to a patient in need thereof. 24. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament in treatment of patients suffering from, arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular diseases, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, cerebral stroke, diabetes, vascular complication of diabetes, thrombotic diseases, obesity, endotoxemia, metabolic syndrome, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, reno-vascular disease, renal disease, splanchnic vascular disease, vascular hemostatic disease, fatty liver disease, steatohepatitis, inflammatory disease, autoimmune disorders and other systemic disease indications, immune function modulation, pulmonary disease, anti-oxidant disease, sexual dysfunction, cognitive dysfunction, schistosomiasis, cancer, regression of xanthoma or Alzheimer's disease.

Full Text

DESCRIPTION
TRISUBSTITUTED AMINE COMPOUND
TECHNICAL FIELD
The present invention relates to a compound having an inhibitory activity against cholesteryl ester transfer protein (CETP) and showing an activity of increasing HDL cholesterol level and an activity of decreasing LDL cholesterol level, thereby being useful for prophylaxis and/or treatment of arteriosclerotic diseases, hyperlipemia or dysllpidemia.
BACKGROUND ART
Hypercholesterolemia, especially high serum level of low-density lipoprotein (LDL) cholesterol, has been revealed to be a risk factor of arteriosclerotic diseases by a number of epidemiological surveys. Actually, drugs capable of decreasing LDL cholesterol level such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been used with the aim of preventing coronary artery diseases, and demonstrated to have some benefits in many large scale clinical tests. However, their preventive effect on coronary diseases is limited to some extent, and is not satisfactory enough yet.
Recently, low serum level of high density lipoprotein (HDL) cholesterol has been revealed to be a potent risk factor of arteriosclerotic diseases by a number of epidemiological surveys and large scale clinical tests. HDL is known to have various antiarteriosclerotic effects and attention is focused on the potentiality of drugs increasing HDL cholesterol level as a means for prevention or treatment of arteriosclerotic diseases. However, there are no drugs that can be used in a satisfactory manner for this purpose. Fibrates and HMG-CoA reductase inhibitors have only low activity of increasing HDL cholesterol level; nicotinic acid derivatives can

significantly increase HDL cholesterol level, but have serious toleration issues. Accordingly, there has been a demand for a well-tolerated agent which can significantly elevate HDL cholesterol level, thereby preventing or reversing the progression of atherosclerosis.
It is known that many proteins are involved in the regulation mechanism for catabolism of various lipoproteins. Among them, the role of cholesteryl ester transfer protein (CETP) became to draw attention. CETP is a protein responsible for transfer of cholesteryl ester (CE) and triglyceride between lipoproteins, and mediate the transfer of CE from HDL to LDL or to very low density lipoprotein (VLDL). Accordingly, CETP activity affects greatly the lipid composition in lipoprotein particles. For example, it is known that administration of an active neutralizing monoclonal antibody against CETP to rabbit or hamster elevates HDL cholesterol level and lower LDL cholesterol level. Furthermore, human being having decreased or eliminated CETP activity due to gene mutation shows raised blood HDL cholesterol level and lowered blood LDL cholesterol level. On the other hand, it is known that transgenic mice and rats made to express CETP show lowered HDL cholesterol level and raised LDL cholesterol level. Thus, it is considered that CETP greatly contribute to the regulation of serum lipids, and thereby affecting the change of serum lipid profile such as decrease of HDL cholesterol level and increase of LDL cholesterol level. Accordingly, it is assumed that a high value of CETP activity would induce arteriosclerosis.
In fact, CETP activity varies depending on animal species. It is known that, arteriosclerotic lesions are readily formed by cholesterol loading in animals with high CETP activity such as rabbits, whereas such lesions hardly occur in animals with low CETP activity such as rats. Furthermore, it is confirmed that continuous suppressioii of CETP activity by administration of antisense oligodeoxynuclotide resulted in effects such as increase of blood HDL cholesterol level and reduction in arteriosclerotic

lesions in cholesterol-fed rabbits.
The above findings indicate that CETP activity is in negative correlation with HDL cholesterol, and that inhibition of CETP activity would decrease the degree of risk for arteriosclerotic diseases. It is therefore expected that compounds capable of inhibiting CETP activity can block the transfer of cholesterol from HDL to LDL or VLDL, and thereby increasing HDL cholesterol that tends to prevent arteriosclerosis while lowering LDL cholesterol that tends to promote arteriosclerosis. In this way, such compounds can serve as a useful preventive or therapeutic agent for arteriosclerotic diseases, hyperlipemia or dyslipidemia and provide effective medical treatment for the first time.
Examples of compounds having CETP inhibitory activity include tetrahydroquinoline derivatives. See, PCT International Publication WOOO/17164 pamphlet, PCT International Publication WOOO/17165 pamphlet and PCT International Publication WOOO/17166 pamphlet.
However, these compounds have defects. That is, they are poorly soluble in water and cannot be absorbed enough in vivo, a sufficient blood level for taking medicinal effect can hardly be achieved even when administered as an ordinary formulation for oral administration. See, WO03/63868.
Accordingly, it has been demanded to find a novel compound which eliminates the above-mentioned defects and intensive studies have been done on dibenzylamine type compounds, and the like. See, PCT International Publication WO05/100298 pamphlet, PCT International Publication WO04/020393 pamphlet, PCT International Publication WO 06/056854 pamphlet and JP 2003-221376 A.
DISCLOSURE OF INVENTION
The present invention provides compounds having an excellent inhibitory activity against CETP, thereby useful for prophylaxis and/or

treatment of arteriosclerotic diseases, hyperlipemia or dyslipidemia.
The present inventors have intensively studied in order to achieve the above-mentioned objects, and have found a compound having an inhibitory activity against CETP and showing an activity of increasing HDL cholesterol level and an activity of decreasing LDL cholesterol level, and have accomplished the present invention.
BEST MODES FOR CARRYING OUT THE INVENTION
That is, the present invention provides the following embodiments: 1. A compound of the general formula (1):
)
wherein, Y is a methylene group optionally substituted by a substituent(s) selected from an alkyl group and an oxo group, or a single bond;
A is (i) a group selected from 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, an optionally substituted 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, 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, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxy group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally

substituted heterocyclic group, an oxy group substituted by optionally
substituted heterocyclic group, and a carbonyl group substituted by
optionally substituted heterocyclic group;
(ii) a homocyclic group optionally substituted by 1 to 5 substituents
selected independently from the groups as defined above in (i); or
(iii) a heterocyclic group optionally substituted by 1 to 5 substituents
selected independently from the groups as defined above in (i);
B is a phenyl group optionally substituted by 1 to 4 substituents selected independently from the following groups: an optionally substituted allqnyl group, a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a sulfo group, an optionally substituted alkyl group, an optionally substituted cycloalbyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkojQ' group, am optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionally substituted all^^lsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an o^ group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxy group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, and an all^lene group; wherein said alkylene group may have 1 to 3 heteroatoms selected independentiy from oxygen, sulfur and nitrogen atoms and further optionally may have a substituent(st;
Ri is a hydrogen atom or an optionally substituted alkyl group; wherein the alkyl group further may optionally be substituted by a

substituent(s) selected from an optionally substituted homocyclic group and an optionally substituted heterocyclic group;
R2 is a group selected from an optionally substituted allqaiyl 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, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalko?^ group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionsdly substituted allcylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxo group substituted by optionally substituted heterocyclic group, and a carbonyl group substituted by optionally substituted heterocyclic group, or a pharmaceutically acceptable derivative thereof.
2. The compound of the above embodiment 1 wherein the homocyclic group is a cycloall^l group, a phenyl group or a naphthyl group;
the heterocyclic group is a thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl, tetrazolyl, pjoidyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl, TOorpholinyl, triazinyl, pyrroUdinyi, piperidyl, pyranyl, tetrahydropyrsinyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, p5Tazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl,

isoquinolyl, dihydroisoquinolyl, cinnoiinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl,
naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidazolidinyl, oxazoiidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dJhydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropjo-azolyl, iijiidazopyridyl, dihydropjn-azinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl or tetrahydroquinolyl group;
a substituent(s) for 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, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted all^lsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic groxip, an oxo group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted alkylsulfonyloxy group, an optionally substituted alkynyl group or an optionally substituted alkylene group is/are 1 to 5 groups selected independentiy from the following groups:
a halogen atom; a cyano group; a hydroxy group; a nitro group; a carboxyl group; an oxo group; a thioxo group; a sulfo group; a cycloalkyl

group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoxycarbonyl group optionally substituted by hydrojQ' group, halogen atom, carboxyl group, alko:^carbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an aUcanoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyloxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-all^lamino group, phenyl group or morpholinyl group; an alkylsuKanyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkylsulfonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-all^'laniino group, phenyl group or morpholinyl group; an alkylsulfinyl group optionally substituted by hydro?^ group, halogen atom, carbojQ'l group, alkoxycarbonyl group, mono- or di-allQ'laniino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamolyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an amino group; a mono- or di-alkylamino group

optionally substituted by hydroxy group, halogen atom, carboxyl group,
alkoJQ^carbonyl group, mono- or di-allcylamino group, phenyl group or
morpholinyl group; a mono- or di-allQ'lsulfamoylamino group optionally
substituted by hydroxy group, halogen atom, carbojcyl group,
alkoJ^carbonyl group, mono- or di-all^lamino group, phenyl group or
morpholinyl group; a mono- or di-alkylureido group optionally substituted
by hydroxy group, halogen atom, carbo3cyl group, aUcoxycarbonyl group,
mono- or di-alkylamino group, phenyl group or morpholinyl group; a
homocyclic group selected from a cycloalkyl group, a phenyl group and a
naphthyi group; an o3ty group substituted by the homocyclic group as
defined above; a carbonyl group substituted by the homocyclic group as
defined above; a heterocyclic group selected from a thienyl, furyl, pyrrolyl,
P5TTolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl,
isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, trieizolyl, triazinyl,
triazolidinyl, tetrazolyl, pyridyl, imidazopjTidyl, p5Timidinyl,
thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl,
tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl,
oxotriazinyl, pyridazinyl, pyrazinyl, benzofiiiyl, benzothiazolyl, benzoxazolyl,
tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl,
isoquinolyl, dihydroisoquinolyi, cinnolinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl,
naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups; an oxy group substituted by the heterocyclic group as defined above; a carbonyl group substituted by the heterocyclic group as defined

wherein X^ and X3 are each independently CH2, NH, O, S, SO or SO2; X2
and X5 are each independently CH2, O, S, SO or SO2; X"* is NH, O, S, SO or
SO2; X6 and X^ are each independently O or S; X^ is S or SO; and n, 0, p, q
and r are each independently an integer of 1 to 4, and further each of the
above groups may optionally be substituted by 1 to 3 substituents selected
from the following groups: halogen atom, carboxyl group, hydroxy group,
cyano group, 0x0 group, thioxo group, alkyl group, hydroxyalkyl group,
alkoxycarbonylalkyl group, carboxyalkyl group, morpholinylalkyl group,
phenylalkyl group, alkanoyl group, hydroxyalkanoyl group, alkoxyalkanoyl
group, alkojcy group, phenylalko)^ group, alkoxycarbonyl group,
benzyloxycarbonyl group, mono- or di-alkylamino group, mono- or di-
alkylcarbamoyl group, mono- or di-all^^lsulfamoyl group, alkylsulfonyl
group and tetrazolyl group;
or a pharmaceutically acceptable derivative thereof.
3. The compound of the above embodiment 2 wherein A is a group of a
formula:
-A1-A2;
wherein Ai is a phenyl, naphthyl, pyrimidinyl, pyridazinyl, pyridyl, triazolyl.

tetrazolyl, oxadiazolyl, dihydropyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, dihydrooxazinyl, imidazolyl, pyrazolyl or dihydropyrazinyl group;
A2 is a carboxyl group; a cyano group; a nitro group; an alkyl group optionally substituted by a group selected from a hydroxy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkoxy group, a phenylalkoxy group, a hydrojQ^alkoxy group, a carboxyalkoxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, an oxiranyl group, a dialkyldioxolanyl group, a p3TTolidinyl group optionally substituted by carboxyl group, a piperidyl group optionally substituted by carbojQ'l group, a piperazinyl group optionally substituted by alkyl group, and a morpholinyl group; an alkenyl group optionally substituted by carbo^l group; an alkoxy group optionally substituted by a group selected from a hydrojcy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkoxy group, a phenylalkoxy group, a hydroxyalkoxy group, a carboxyalkoxy group, an all^lsulfanyl group, an eilkylsulfonyl group, an aUQ^lsulfinyl group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, an oxiranyl group, a dialkyldioxolanyl group, a pjTrolidinyl group optionally substituted by carboxyl group, a piperidyl group optionally substituted by carboxyl group, a piperazinyl group optionally substituted by alkyl group, and a morpholinyl group; an alkoxycarbonyl group; a hydroxycarbamimidoyl group; an alkylsulfanyl group; an alkylsulfonyl group optionally substituted by carboxyl group; a mono- or di-alkylamino group optionally substituted by hydroxy group, carboxyl group, alko:^ group or mono- or di-alkylamino group; a morpholinyl group optionally substituted by carboxyl group, alkyl group, carboxyalkyl group or alkoxycarbonyl group; an optionally oxidized

thiomorpholinyl group; a piperazinyl group optionally substituted by a group selected from an alkyl group, alkanoyl group and hydroxyalkanoyl group; a pyrrolidinyl group optionally substituted by carboxyl group, alkyl group, carbojtyalkyl group or alkoxycarbonyl group; a piperidyl group optionally substituted by carboxyl group, alkyl group, carboxyall^l group or alkoxycarbonyl group; a tetrazolyl group optionally substituted by alkyl group, hydroxyall^l group, carboxyalkyl group or morpholinylall^l group; an oxodihydrooxadiazolyl group; a p3Tiinidinyl group; or a tetrahydropyranyl group;
Ri is a group of a formula: -R11-R12,
wherein Rn is an alkylene group;
R12 is a substituent(s) selected from a phenyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, thienyl, triazolyl, tetrazolyl, oxadiazolyl, dihydropyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, dlhydrooxazinyl, dihydropyra^inyl and pjTazolyl group;
wherein said substituent(s) may optionally be substituted by 1 to 4 substituents selected independently from halogen atom, carboxyl group, alkoj^carbonyl group, carbamoyl group, mono- or di-alkyl carbamoyl group, alkyl group, alkoxy group, hydroxy group, nitro group, cyano group, amino group, mono- or di-alkylamino group, alkanoyl group, alkylsulfanyl group, tetrazolyl group and dihydrooxazolyl group; and further each of said alkyl group, alkoxy group, mono- or di-alkylamino group, mono- or di-alkylcarbamoyl group, alkanoyl group and alkylsulfanyl group independentiy may optionally be substituted by 1 to 5 substituents selected independently from halogen atom, hydroxy group, alkoxy group, amino group, morpholinyl group, piperidyl group, p3aTolidinyl group, piperazinyl group, alkylpiperazinyl group and alkanoylpiperazinyl group;
R2 is a halogen atom; a hydroxy group;

a cyano group;
a nitro group;
a carboxyl group;
a sulfo group;
a cycloalkyl group optionally substituted by carboxyl group or
alkoxycarbonyl group;
an alkyl group optionally substituted by a group selected from a halogen
atom, a cyano group, a hydro?^ group, a carboxyl group, an
alkoxycarbonyl group, a tetrazolyl group, a mono- or di-allcylcarbainoyl
group, an alkoxy group (said alkoxy group may optionally be substituted
by phenyl group, carboxyl group or hydroxy group), an aJkanoyl group, an
alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an
alkylsuifinyl group, an amino, a mono- or di-alkylamino group optionally
substituted by carboxyl group or alkoxy group, a mono- or di-
alkylsulfamoylamino group, a mono- or di-alkylureido group optionally
substituted by morpholinyl group, an oxiranyl group, a dioxolanyl group
optionally substituted by alkyl group, pyrrolldinyl group optionally
substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl
group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl
group, a piperidyl group optionally substituted by alkoxycarbonyl group or
carboxyl group, a piperidyl group optionally substituted by
alkoxycarbonylalkyl or carboxyalkyl group, a piperazinyl group optionally
substituted by alkyl group, a hexahydroazepinyl group, a morpholinyl
group, and a piperidyloxy group optionally substituted by alkyl group;
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 by carboxyl group;
an alko^ group optionally substituted by a group selected from a halogen
atom, a cyano group, a hydros^ group, a carboxyl group, an

alkoxycarhanyl group, a tetrazolyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carboj^l graup, alkoxycarbonyl group or hydroxy group), an aOcoxy group (said alkoxy group may optionally be substituted by carboj^l group, formyl group or hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an aikylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carbojqTnethyl group, an oxiranyl group, a phenyl group optionaily substituted by alkoxy group or carboxyl group, a morpholinyl group, a pjTTolidinyl group optionally substituted by alkoxycarbonyl group or carboj^l group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a pyrrolidinyl group optionally substituted by oxo group, a piperidyl group optionally substituted by edkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a pipera2inyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a p3rrimidinyl group, a pjn-idyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidylo;^^ group optionally substituted by alkyl group and a morpholinylcarbonyl group; an alkoxycarbonyl group optionally substituted by phenyl group; a carbamoyl group;
a mono- or di-alkylcarbamoyl group optionally substituted by a group selected from a carboj^l group, a morpholinyl group and an alkoxy group; a hydroxycarbamim.idoyl;

an alkylsulfanyl group optionally substituted by a group selected from hydroxy group, carhoxyl group and mono- or di-aJkylcarbamoy] group; an alkylsuliinyl group;
an all^lsulfonyl group optionally substituted by a group selected from hydroxy group, carboxyl group, alkoscycarbonyl group and mono- or di-alkylcarbamoyl group; an amino group;
a mono- or di-alkylamino group optionally substituted by a group selected from a hydrogen atom, a cyano group, a hydroxy group, a carboxyl group, an alko^carbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyi group (said mono- or di-aikyicarbamoyl group may optionally be substituted by carhoxyl group, alkoxycarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino optionally substituted by carboj^I group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by eilkoxy group or carboj^l group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylall^] or carboxyalkyl group, a pyrrolidinyl group substituted by oxo group, a piperidyl group optionadly substituted by sdkoxycarbonyl group or ceirboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optioneilly substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by

oxo group, an oxathiadiazolyl optionally substituted by oxo group, a
pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a
piperidyloxy group optionally substituted by alkyl group and a
morpholinylcarbonyl group;
an alkanoylamino group optionally substituted by a group selected from
hydroxy group, alkoxy group, carboxyl group and amino group;
a mono- or di-alkylcarbamoylamino group optionally substituted by alkoxy
group;
a morpholinylcarbonylamino group;
a sulfamolyl group;
a mono- or di-allQrlsuIfamolyl group;
an alkanoyl group optionally substituted by a group selected from hydroxy
group, carbojQrl group, alkoxycarbonyl group, alkoxy group, mono- or di-
alkylamino group and morpholinyl group; or
a cyclic group selected from a cycloall^l, phenyl, naphthyl, thienyl, furyl,
pyrrolyl, pyrroUnyl, oxazolyl, thiazolyl, pjTazolyl, imidazolyl, imidazolinyl,
isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl,
triazinyl, triazoHdinyl, tetrazolyl, p3Tidyl, imidazopyridyl, pyrimidinyl,
thiomorphoUnyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl,
tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl,
oxotriazinyl, pjoidazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl,
tetrazolopyridazinyl, triazolop3n-idazinyl, benzimidazolyl, quinolyl,
isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinoHzinyl,
naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidazolidinyl, oxazolidinyl, tetrahydrofurainyl, dioxolanyl, oxiranyl,
dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropjTazolyl,
imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl,

dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups;
wherein said cyclic group may optionally be substituted by the following groups: a halogen atom, an alkojQ'allq'l group, an allQ'l group optionally substituted by 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyi group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, a cyano group, an oxo group, an alkyl group, a hydroxyallcyl group, an alkoxycarbonylalkyl group, a carboxyallQ'l group, a morpholinylalkyl group, a phenylalkyl group, an alkanoyl group, a hydroj^alkanoyl group, an alkoxyalkanoyl group, an alkoxy group, a phenylalkoxy group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a mono- or di-all^lamino group, a mono- or di-alkylcarbamoyl group, a mono- or di-alkylsulfamolyl group, an allcylsulfonyl group and a tetrazolyl group; wherein the substituents defined as above may further be substituted by a substituent(s) selected from the following groups:
a halogen atom, an alkoj^aZkyl group, an alkyl group optionally substituted by 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, a cyano group, an oxo group, an aUcyl group, a hydroxyalkyl group, an alkoxycarbonylall^l group, a carboxyalkyl group, a morpholinylalkyl group, a phenylalkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkoxyalkanoyl group, an alkoxy group, a phenylalkoxy group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a mono- or di-alkylamino group, a mono- or di-alkylcarbamoyl group, a mono- or di-alkylsulfamolyl group, an alkylsulfonyl group and a tetrazolyl group, or a pharmaceutically acceptable derivative thereof.
4. The compound of the above embodiment 1 wherein Y is a methylene group optionally substituted by a substituent{s) selected from an all^l group and an oxo group, or a single bond;
A is a group of a formula:

-A1-A2;
wherein A^ is a heterocyclic group or a homocyclic group;
A2 is an optionally substituted homocyclic group, an optionally substituted allq^lsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted allcylsulfonyl group, an optionally substituted alkyl group, a nitro group, a hydroxy group, a cyano group, an optionally substituted alkenyl group, an optionally substituted heterocyclic group, a substituted alkoxy group, a halogen atom, an amino group substituted by 1 to 2 substituents, or a hydrogen atom;
B is a phenyl group optionally substituted by 1 to 4 substituents selected independently from a cyano group, a halogen atom, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfmyl group, an optionally substituted alkylsulfonyl group, an amino group substituted by 1 to 2 substituents, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted cycloalkoxy group, a carboxyl group, an optionally substituted cycloalkyl group, an optionally substituted carbeunoyl group, an optionally substituted alkyl group, and an optionally substituted alkoxy group;
Ri is a hydrogen atom, an ailkyl group substituted by a heterocyclic group or an alkyl group substituted by a homocyclic group; wherein said heterocyclic group, homocyclic group or alkyl group may further have a substituent(s);
R2 is an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted all^lsulfonyl group, a cyano group, an optionally substituted alkenyl group, an amino group optionally substituted by 1 to 2 substituents, a halogen atom^, an optionally substituted alko?^ group, an optionally substituted carbamoyl group, an oxy group optionally substituted by optionally substituted heterocyclic group, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted homocyclic group, an oxo group optionally

substituted by optionally substituted homocycUc group, an optionally
substituted alkyl group or a nitro group;
provided that when Y is a methylene group and A^ is a halogen atom, a
hydrogen atom, a nitro group, a hydroxy group or a cyano group, then R^ is
not an optionally substituted alkyl group, an optionally substituted alkenyl
group, an optionally substituted alkoj^ group, or an amino group
optionally substituted by 1 to 2 substituents,
or a pharmaceutically acceptable derivative thereof.
5. The compound of the above embodiment 4 wherein Y is a methylene
group optionally substituted by a substituent(s) selected from an alkyl
group and an oxo group;
Ai is a heterocyclic group;
A2 is an optionally substituted heterocyclic group, an optionally substituted alkyl group, a substituted alkoxy group, a halogen atom, an amino group optionally substituted by 1 to 2 substituents, or a hydrogen atom;
B is a phenyl group optionally substituted by 1 to 4 groups selected independently from a cyano group, a halogen atom, a hydroxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkoxy group, an optionally substituted piperidyl group, a cycloalkyl group, a cycloalkoxy group, an optionally substituted alkyl group and an optionally substituted alkoxy group;
Ri is a hydrogen atom, or an alkyl group substituted by a phenyl group that is substituted by 1 to 2 groups selected independently from an alkoxy group optionally substituted by 1 to 3 halogen atoms, an alkyl group optionally substituted by 1 to 3 halogen atoms and a cyano group;
R2 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 oxy group substituted by optionally substituted heterocyclic group, a hydroxy group, an optionally substituted

heterocyclic group, an optionally substituted horaocyclic group, an oxy
group substituted by optionally substituted homocyclic group, a
hydroj^alkyl group or a nitro group,
or a pharmaceutically acceptable derivative thereof.
6. The compound of the above embodiment 5 wherein the homocyclic
group is a cycloalkyl group, a phenyl group or a naphthyl group;
the heterocyclic group is a thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl,
thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl,
oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl,
tetrazolyl, pj^idyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl,
morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl,
thiop3^anyl, oxadinyl, thJadinyl, piperazinyl, triazinyl, oxotriazinyl,
pjT-idazinyl, pjTazinyl, benzofuryl, benzothiazolyl, benzoxazolyl,
tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl,
isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl,
naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropyrazolyl, imidazopjTidyl, dihydrop5T-azinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl or tetrahydroquinolyl group;
a substituent(s) for an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloeilkoxy group, 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, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxo group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted alkylsulfonyloxy group, an optionally substituted alkynyl group or an optionally substituted aUcylene group is/are 1 to 5 groups selected independently from the following groups:
a halogen atom; a cyano group; a hydroxy group; a nitro group; a carboxyl group; an oxo group; a thioxo group; a sulfo group; a cycloalkyi group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, m.ono- or di-ajkylamino group, phenyl group or morpholinyl group; an alkoxycarbonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoj^ group optionally substituted by hydroicy group, halogen atom, carboxyl group, alkoT^carbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyloxy

group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-aU^lamino group, phenyl group or morpholinyl group; an aikylsulfanyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an aHQflsulfonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoj^carbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkylsulfinyl group optionally substituted by hydroxy group, halogen atom^, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamolyl group optionally substituted by hydroscy group, halogen atom, carboJ^l group, alkojcycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an amino group; a mono- or di-alkylamino group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamoylamino group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylureido group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a homocycUc group selected from a cycloalkyl group, a phenyl group and a naphthyl group; an oxy group substituted by the homocycUc group as defined above; a carbonyl group substituted by the homocyclic group as defined above; a heterocyclic group selected from a thienyl, furyl, pyrrolyl, pyrroliny], oxazolyl, thia^olyl, pyrazolyl, imidazolyl, imidazolinyl, Jsoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl, tetrazolyl, pyridyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, pjnrolidinyl, piperidyl, pyranyl.

tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl,
oxotriazinyl, pyridazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl,
tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl,
isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl,
naphthjTidinyl, purinyl, pteridinyl, dtbenzofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxasMlinyl, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropjrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups; an oxy group substituted by the heterocyclic group as defined above; a carbonyl group substituted by the heterocyclic group as defined

wherein X^ and X^ are each independently CH2, NH, O, S, SO or SO2; X^ and X5 are each independently CH2, O, S, SO or SO2; X-^ is NH, O, S, SO or SOa; X& and X^ are each independently O or S; X^ is S or SO; and n, o, p, q and r are each independently an integer of 1 to 4, and further wherein each

of the above groups may optionally be substituted by 1 to 3 substituents selected from the following groups: halogen atom, carboxyl group, hydroxy group, cyano group, oxo group, thioxo group, alkyl group, hydroxyalkyl group, alkoxycarbonylalkyl group, carboxyall^l group, morpholinylalkyl group, phenylalkyl group, alkanoyl group, hydroxyalkanoyl group, alkoxyalkanoyl group, alkoxy group, phenylalkoxy group, alkoxycarbonyl group, benzyloxyceirbonyl group, mono- or di-alkylaxnino group, mono- or di-alkylcarbamoyl group, mono- or di-allq^lsulfamoyl group, alkylsulfonyl group and tetrazolyl group;
or a pharmaceutically acceptable derivative thereof.
7. The compound of the above embodiment 6 wherein A^ is a pyrimidinyl group or a pyridyl group;
A^ is (a) a heterocyclic group selected from a piperidy] group and a morpholinyl group, respectively optionally substituted by a substituent(s) selected from a carboxyl group, a carbojcyalkyl group and an alkyl group;
(b) aji alkoxy group substituted by a group selected from a carboxyl group, a hydroxy group, an alkojcy group and a cyano group;
(c) a halogen atom;
(d) an amino group optionally substituted by 1 to 2 substituents
independently selected from a carboxyalkyl group, a hydroxyalkyl group,
an aUcyl group, an alkoxyall^l group and an aminoalkyl group optionally
substituted by 1 to 2 all^l groups;
(e) a hydrogen atom;
B is a phenyl group optionally substituted by 1 to 4 groups selected independently from halogen atom, hydroxy group, alkyl group optionally substituted by 1 to 3 halogen atoms and alkoxy group optionally substituted by 1 to 3 halogen atoms;
Ri is a hydrogen atom, or a benzyl group substituted by 1 to 3 groups selected independently from an alkoxy group optionally substituted by 1 to 3 halogen atoms, an alkyl group optionally substituted by 1 to 3

halogen atoms and a cyano group;
R2 is (a) an amino group optionally substituted by 1 to 2 groups independently selected from an alkyl group, an alkoxyalkyl group, a cycloalkylalkyl group, an alko^tycarbonyl group, an alkylcarbonyl group, an alkylcarbamoyl group, a carbojQ^alkyl group, a cycloalkylalkyl group substituted by carboxyalkyl group, a hydrojq'all^I group, a carboxyalkoxycarbonyl group, a carbo^dihydrooxazolyl group, a carboxyalkylcarbonyl group, a phenylalkyl group, an alkoxyalkoxycarbonyl group, an alkoxyalkylcarbonyl group, an alkyl group substituted by piperidyl group, a piperidylalkyl group substituted by carboxyalkyl group, and an alkyl group substituted by phenyl that is optionally substituted by 1 to 2 alkyl groups (said alkyl group may optionally substituted by 1 to 3 halogen atoms);
wherein said all^l group or alkoxy group may further optionally be substituted by 1 to 5 groups selected independently from the following groups:
a halogen atom, a cyano group, a hydroj^ group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group {said mono- or di-alkylcarbamoyl group may optionally be substituted by carboxyl group, alkoxycarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxy group, an all^lsulfeinyl group, an allq^lsulfonyl group, an alkylsulfmyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di-allqrlsulfainoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoj^ group or carboJ^l group, a morpholinyl group, a pyrrolidinyl group optionally substituted by

alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkojQrcarbonylalkyl group or carboxyalkyl group, a pyrrolidinyl group optionally substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pjTimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by all^l group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by aUcyl group and a morpholinylcarbonyl group;
(b) a halogen atom;
(c) an alkoxy optionally substituted by a group selected from
carboxyl group, cycloalkyl group and alkoxy group;
wherein said cycloalkyl group or alkoxy group may optionally be substituted by 1 to 5 groups selected independently from the following groups:
a halogen atom, a cyano group, a hydros^ group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-aJkylcarbamoyI group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carboxyl group, alko^Q'carbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carbojQ'l group, formyl group or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alk/lureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyi group, an oxiranyl group, a phenyl group

optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrroUdinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperidyl group optionally substituted by oxo group, a piperidyl group optionally substituted by aUcoxycarobonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alky] group and a morpholinylcarbonyl group;
(d) a carbamoyl group optionally substituted by 1 to 2 substituents selected independently from alkyl group and carboityalkyl group, wherein said all^l group may optionally be substituted by 1 to 5 groups selected independently from the following groups:
a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may be substituted by carbojcyl, alkoxycarbonyl or hydroxy group), an alkoxy group (said alkoxy group may be substituted by carboxyl, formyl or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyJ group, an alkylsulfmy] group, an amincsulfonyl group, an amino group, a mono- or di-allQ'lamino optionally substituted by carboxyl or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxjmiethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy or carboxyl group, a

morpholiny] group, a pyrroMiny] optionally substituted by alkoxycarhonyl
or carboxyl group, a pyrrolidinyl optionally substituted by
alkoxycarbonylalkyl or carboxyalkyl group, a pyrrolidinyl substituted by
oxo group, a piperidyl optionally substituted by alkoscycarbonyl or carboxyl
cup, a piperidyl optionally substituted by alkoxycarbonylalkyl or
irboxyalkyl group, a piperazinyl optionally substituted by alkyl group, a
ixahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolany
oup optionally substituted by alkyl group, an oxadiazolyl group
Jtionedly substituted by oxo group, an oxathiadiazolyl group optionally
ibstituted by oxo group, a pyrroUdinylcarbonyl group optionally
ibstituted by carboxyl group, a piperidyloxy group optionally substituted
f alkyl group and a morpholinylcairbonyl group;
(e) a hydrojo^ group;
(f) an oxy group substituted by a heterocyclic group selected from ^midiny] group and tetrahydropyranyl group;
(g) a heterocyclic group selected from a morpholinyl, pyrimidinyl,
iperidyl, piperazinyl, pyrazinyl, tetrazolyl, thienyl, fury, dihydroisoquinolyl,
yiidyl and pyrrolyl group, which are each optionally substituted by 1 to 3
abstituents selected independently from pjoimidinyl group, alkyl group,
alogen atom, cyano group, mono- or di-alkylamino group, alkoxy group,
henyl group, carbojQrl group, carbamoyl group and carboxyalkyl group;
herein said alkoxy group or alkyl group may optionally be substituted by
to 5 groups selected independently from the following groups:
a halogen atom, a cyano group, a hydroxy group, a carboj^l group, n alkoxycarhonyl group, a tetrazolyl group, a carbamoyl group, a mono-r di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may ptionaliy be substituted by carboj^l group, alkoxycarhonyl group or ydroxy group), an alkoxy group (said alkoxy group may optionally be ubstituted by carboxyl group, formyl group or hydroxy group), an Ikanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an

alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoicy group or carboxyl group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a p57rrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a pyrrolidinyl group substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carbojq'l group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolany] group optionally substituted by alky] group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a phenyl group optionally substituted by morpholinyl group;
(h) a phenyl group optionally substituted by 1 to 3 substituents selected independently from halogen atom, alkyl group and alkoxy group; wherein said alkoxy group or alkyl group may further optionally be substituted by 1 to 5 groups selected independently from the following groups:
a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group (said mono- or di-all^lcarbamoyl group may optionally be substituted by carboxyl group, alkoxycarbonyl group or hydroxy group), an alkoj^ group (said alko^Q^ group may optionally be

substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an gimino group, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrroUdinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrroUdinyl group optionally substituted by alkojQ^carbonylallq'l group, a pyrroUdinyl group substituted by oxo group, a piperidyl group optionaUy substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylall^l group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionaUy substituted by alkyl group, an oxadiazolyl group optionaUy substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrroUdinylcarbonyl group optionaUy substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a morphoUnylcarbonyl group;
(i) an oxo group substituted by cycloailkyl group;
(]') a hydroxyallq^l group; or
(k) a nitro group; or a pharmaceuticaUy acceptable derivative thereof.
8. The compound of the above embodiment 7 wherein A^ is a pyrimidinyl group or a pyridyl group;
A2 is (a) a heterocyclic group selected from piperidyl group and morpholinyl group, which are each optionally substituted by a substituent(s) selected from a carboxyl group, carboxyalkyl group or alkyl group;

(b) an alkoxy group substituted by a group selected from carboxi
group, hydroxy group, alkoxy group and cyano group;
(c) a halogen atom;
(d) an amino group optionally substituted by 1 to 2 substitueni
selected independently from carboxyalkyl group, hydrojcyalkyl group, aOv
group, alkoxyalkyl group and aminoalkyl group, respectively optional]
substituted by 1 to 2 alkyl groups;
(e) a hydrogen atom;
B is a phenyl group optionally substituted by 1 to 4 groups selecte independently from alkyl group optionally substituted by 1 to 3 haloge atoms and alkoxy group optionally substituted by 1 to 3 halogen atoms;

R2 is (a) an amino group optionally substituted by 1 to 2 grouj selected independently from an allcyl group, an alkoxyalkyl group, cycloalkylallcy] group, an alkoxycarbonyi group, an alkylcarbonyl group, an alkylcarbamoyl group, a carboxyalkyl group, a cycloalkylalkyl group substituted by carbojtyall^l group, a hydroxyalkyl group, a carboxyalkoxycarbonyl group, a carboxydihydrooxazolyl group, a carboxyalkylcarbonyl group, a phenylalkyl group, an alkoxyalkoxycarbonyl group, an alkoxyalkylcarbonyl group, an alkyl group substituted by piperidyl group, a piperidylalkyl group substituted by carboj^all^l group and an alkyl group substituted by phenyl group that is optionally substituted by 1 to 2 alkyl groups (said all^^l group may optionally be substituted by 1 to 3 halogen atoms);
(b) a halogen atom;
(c) an alkoxy group optionally substituted by a group selected from a carboxyl group, a cycloalkyl group and an alkoxy group;

(d) a carbamoyl group optionally substituted by 1 to 2 substituents selected independently from alkyl group and carboxyalkyl group; fe) a hydrojQ' group;
(f) an oxQ group substituted by a heterocyclic group selected from a
pyrimidinyl group and a tetrahydropyranyl group;
(g) a heterocyclic group selected from a p3T-imidinyI, pyridyl,
morpholinyl, piperidyl, piperazinyl, tetrazolyl, dihydroisoquinolyl and
P3'rrolyl group, which are each optionally substituted by 1 to 2
substituents selected independently from alkyl group, alkoxy group, phenyl
group, carboxyl group, carboxyalkoxy group and carboxyalkyl group;
(h) a phenyl group optionally substituted by 1 to 3 substituents selected independently from halogen atom, alkyl group and alkoxy group;
(i) an oxo group substituted by cycloalkyl group;
(i) a hydroxyalkyl group;
(k) a nitro group; or a pharmaceutically acceptable derivative thereof.
9. The compound of the above embodiment 8 wherein A2 is an amino group substituted by 1 to 2 groups selected independently from a piperidyl group optionally substituted by carboxyl group; a morpholinyl group optionally substituted by carboxyl group; ain alkoxy group substituted by a group selected from carboxyl group, hydroxy group, alkoxy group and cyano group; an amino group substituted by 1 to 2 groups selected independently from carboxyalkyl group and alkyl group;
B is a phenyl group optionally substituted by an alkyl group optionally substituted by 1 to 3 halogen atoms;

R2 is (a) an amino group optionally substituted by 1 to 2 groups

selected independently from an alkyl group, a cycloalkylalkyl group, an alkoxycarbonyl group, a carboxyalkyl group and a cycloalkylalkyl group substituted by carboxyalkyl group;
(b) an alkoxy group;
{c} a phenyl group optionally substituted by a group selected from a halogen atom, an alkyl group and an alkoxy group;
(d) a pyridyl group optionally substituted by a group selected from a halogen atom, an aUc^l group and an alkoxy group; or a pharmaceutically acceptable derivative thereof.
10. A compound described in anyone of examples No. 7, 24, 75, 57, 13,
54, 12, 65, 63 and 64, or a pharmaceutically acceptable derivative thereof.
11. A compound of the formula (1-A):

wherein
AiiA is an optionally substituted pyrimidin-2-yl group or an optionally substituted pyridin-2-yl group;
R^A and R^^ are independently a cyano group or an alkyl group optionailly substituted by 1 to 3 halogen atoms;
Ring E is an optionally substituted phenyl group;
F is an optionally substituted cyclic group; or a pharmaceutically acceptable derivative thereof.
12. A compound of the formula (I-B):

ZA is N or CH;
A21A is an optionally substituted homocyclic group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl group, a nitro group, a hydroxy group, a cyano group, an optionally substituted alkenyl group, an optionally substituted heterocyclic group, an optionally substituted alkoxy group, a halogen atom, an amino group optionally substituted by 1 to 2 substituents, a carbamoyl group optionally substituted by 1 to 2 substituents, a carboxyl group or a hydrogen atom;
RiA is a cyano group or an alkyl group optionally substituted by 1 to 3 halogen atoms;
B' is a group selected independently from an oxo group, a cyano group, a halogen atom, an optionally substituted all^lsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted all^lsulfonyl group, an amino group optionally substituted by 1 to 2 substituents, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted cycloalkoxy group, an optionally substituted cycloalkyl group, a carboj^l group, a carbamoyl group optionally substituted by 1 to 2 substituents, an optionally substituted alkyl group or an optionally substituted alkoxy group;
pA is an integer of 0 to 3;
D is a pyrimidinyl group, a pyridyl group, a phenyl group, a pyrimidinyloxy group, a tetrazolyl group or ain oxazolidinyl group;

D' is a group selected independently from a halogen atom, an alkoxyalkyl group, an alkyl group substituted by 1 to 5 halogen atoms, an aUcoxy group substituted by 1 to 5 halogen atoms, an alkenyl group, a carbamoyl group, a cycloalkyl group, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, a cyano group, an oxo group, an alkyl group, a hydroxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkyl group, a morpholinylalkyl group, a phenylalkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkojcyalkanoyl group, an alkoxy group, a phenylalko3cy group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a mono- or di-alkylamino group, a mono- or di-alkylcarbamoyl group, a mono- or di-alkylsulfamolyl group, an alkylsulfonyl group, a tetrazolyl group, benzyloxyalkyl group, a cycloall^lalkyl group, an benzyloxy group, an alkoxyalkoxy group, a carboxyalkoxy group, a carboxyalkenyl group, an alkylcarbonylamino group, a carboxyalkoxyalkyl group, a morpholinyl group or a pyridylalkojfy group;
qA is an integer of 0 to 3; or a pharmaceutically acceptable derivative thereof. 13. The compound of the above embodiment 12 wherein
A21A is selected from the following group
(a) a heterocyclic group selected from a piperidyl group and a morpholinyl group, respectively optionally substituted by a substitutent(s) selected from a carbojQ^l group, an alkoxycarbonyl group, a carboxyalkyl group or an alkyl group;
(b) an alkoxy group optionally substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulflnyl group, a mono- or di-allQrlamino group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an all^lsulfanyl group, a hydroxy group or an alkoxy group;
(c) a halogen atom;

(d) an amino group optionally substituted by 1 to 2 substituents
independently selected from a carboj^alkyl group, an alko^^carbonyleilkyl
group, an alkylsulfonylalkyl group, an alkylsuliinylalkyl group, a
hydroxyalkyl group, an alkyl group, an alkoxyalkyl group or an aminoall^l
group optionally substituted by 1 to 2 alkyl groups;
(e) a hydrogen atom;
(f) an alkyl group optionally substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulfmyl group, a mono- or di-alkylamino group, a cyano group, a t:etra2olyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group or an alkoxy group;
(g) a carboxyl group;
(h) a carbamoyl group optionally substituted by a carboxyalkyl group; or
(i) an alkenyl group substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, an all^lsulfmyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group or an alkoxy group;
[j) a morpholinyl group;
(k) a piperidinyl group optionally substituted by a carboxyl group or a carbojo^alkyl group;
B' is a group selected independently from an oxo group, a halogen atom, an allQ'I group optionally substituted by 1 to 3 halogen atoms, an alkoxy group optionally substituted by 1 to 3 halogen atoms, a cyano group, a hydroxy group, a cycloalkyl group, an alkoxyalkyl group, a cycloalkoxy group, an alkylsulfanyl group optionally substituted by 1 to 3 halogen atoms, an alkylsulfmyl group optionally substituted by 1 to 3 halogen atoms or an alkylsulfonyl group optionally substituted by 1 to 3 halogen atoms; or a pharmaceutically acceptable derivative thereof.

14. The compound of the above embodiment 13 wherein
A21A is an alkoxy group optionally substituted by 1 to 2 groups selected from a carboxyl group, a halogen atom, an alkoxycarbonyl group, an alkoxyl group, a hydroxy group, a mono or di-aikylamino group, an alkylsuliinyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl group and an aikylsuifanyl group; an alkyl group optionally substituted by 1 to 2 groups selected from a carboxyl group, a halogen atom, an alkojcycarbonyl group, an alkoxyl group, a hydroxy group, a mono or di-alkylamino group, an alkylsulfinyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl group and an aikylsuifanyl group; a morpholinyl group; a carboxyl group or a carboxj'piperidinyl group;
B' is a group selected independently from a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms or an alkoxy group optionally substituted by 1 to 3 halogen atoms;
D' is a group selected independently from an alkoxy group optionally substituted by 1 to 3 halogen atoms, a halogen atom, a cyano group, an aikylsuifanyl group, a mono or di-alkylamino group, an alkenyl group, an alkyl group optionally substituted by 1 to 3 halogen atoms, a carboxyl group, a hydroxy group, a carbo:cyalkoxy group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an oxo group, a cycloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylcarbonylamino group, a morpholinyl group or a carboxyaJkoxyalkyl group; or a pharmaceutically acceptable derivative thereof.
15. The compound of the above embodiment 14, wherein Z^ is a N, or a pharmaceutically acceptable derivative thereof.
16. The compound of the above embodiment 14, wherein R^^ is an alkyl group optionally substituted by 1 to 3 halogen atoms, or a pharmaceutically acceptable derivative thereof.
17. The compound of the above embodiment 14, wherein D is a phenyl

group, or a pharmaceutically acceptable derivative thereof. IS. The compound of the above embodiment 14, wherein D' is a group selected independently from a halogen atom, an alkoxy group or an alkyl group, or a pharmaceutically acceptable derivative thereof.
19. The compound of the above embodiment 14, wherein A^IA is a morpholinyl group or an alkoxyl group substituted by a carbojo'l group, or a pharmaceutically acceptable derivative thereof.
20. A compound described in anyone of examples No. 91, 94, 96, 112, 114, 118 to 123, 131, 133, 136, 138 to 140, 142 to 153, 158 to 163, 165 to 169, 173 to 177, 179 to 182, 185, 186, 190 to 194, 198, 203, 208 to 216, 218 to 223, 231, 239, 240, 241 or a pharmaceutically acceptable derivative thereof.
21. A compound described in anyone of examples No. 154 to 157, 164, 170 to 172, 178, 183, 184, 187 to 189, 195 to 197, 199 to 202, 204 to 207, 217, 224 to 230, 232 to 238, 242 to 252 or a pharmaceutically acceptable derivative thereof.
22. A pharmaceutical composition, which comprises as an active ingredient a compound according to any one of the above embodiments 1 to 21, or a pharmaceutically acceptable derivative thereof.
23. A method for prophylaxis or treatment of arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hjTierbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hj'percholesterolemia, cardiovascular diseases, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, cerebral stroke, diabetes, vascular complication of diabetes, thrombotic diseases, obesity, endotoxemia, metabolic s3Tidrome, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, reno-vascular disease, renal disease, splanchnic vascular disease, vascular hemostatic disease.

fatty liver disease, steatohepatitis, inflammatory disease, autoimmune disorders and other systemic disease indications, immune function modulation, pulmonary disease, anti-oxidant disease, sexual dysfunction, cognitive dysfunction, schistosomiasis, cancer, regression of xanthoma or Alzheimer's disease, which comprises administering an effective amount of a compound according to any one of the above embodiments 1 to 21, or a pharmaceutically acceptable derivative thereof, to a patient in need thereof.
24. Use of a compound according to any one of the above embodiments
1 to 21, or a pharmaceutically acceptable derivative thereof, for the
manufacture of a medicament in treatment of patients suffering from
arteriosclerosis such as atherosclerosis, peripheral vascular disease,
dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia,
hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia,
cardiovascular diseases, angina, ischemia, cardiac ischemia, stroke,
myocardial infarction, reperfusion injury, restenosis after angioplasty,
hypertension, cerebral infarction, cerebral stroke, diabetes, vascular
complication of diabetes, thrombotic diseases, obesity, endotoxemia,
metabolic syndrome, cerebrovascular disease, coronary artery disease,
ventricular dysfunction, cardiac arrhj^thmia, pulmonary vascular disease,
reno-vascular disease, renal disease, splanchnic vascular disease, vascular
hemostatic disease, fatly liver disease, steatohepatitis, inflam.matory
disease, autoimmune disorders and other systemic disease indications,
immune function modulation, pulmonary disease, anti-oxidant disease,
sexual dysfunction, cognitive dysfunction, schistosomiasis, cancer,
regression of xanthoma or Alzheimer's disease.
25. A compound of a general formula (1-1):

wherein the sjnnbols have the same meanings as defined above, or a pharmaceutically acceptable derivative thereof.
When the compound (1) has one or more asymmetric carbon atoms, the compound (1) of the present invention encompasses racemate, racemic mixture, individual enantiomers or diastereomers. The present compounds also include all such isomers and a mixture thereof.
Also, when the present compound has an alkenyl or all^Tiyl group, CIS (Z)- and trans (Ej- forms may occur. In addition, the present compounds include individual stereoisomer of the compound and optionally, individual tautomeric forms thereof and a mixture thereof.
Separation of diastereomer or cis- and trans- isomers can be achieved by the conventional method such as fractional crystallization, chromatography and HPLC method, and the like. Also the drug containing the individual stereoisomer as needed can be prepared from a corresponding optically active intermediate or alternatively by resolving the corresponding racemate by using the suitable chiral support (e.g. HPLC) or by performing a fractional crystallization of diastereomeric salt formed by reacting a corresponding racemate and a suitable optically active acid or base. Alternatively, the resolution of the mixture of enantiomers can be done by forming on a novel covalently bounded species formed by means of reacting it with a suitable chiral compound. For example, at first, the coupling reaction between a racemic carbojQ^lic acid and a chiral amine or a chiral alcolol gives a mixture of diastereoisomers (amide or ester, respectively) and then it is isolated by the conventional technique such as chromatography, HPLC or fractional crystallization, and the like. Thereafter, the resulting one diastereoisomer can be converted into one enantiomer of the desired compound by cleaving the new covaJent binding with a suitable chemical reaction such as hydrolysis, and the like.
As used herein, the term "pharmaceutically acceptable derivative" represents a pharmaceutical acceptable salt, solvate or prodrug (e.g. ester)

of the present compound, and which can provide (directly or indirectly} the compound of the present invention or an active metabohte or a residue thereof. Such derivatives can be obtained by a person skilled in the art without undue experimentation. See, for example, Burger's Medicinal Chemistry and Drug Discovery 5th ed., vol. 1st, "Principles and Practice". Preferred pharmaceutically acceptable derivative is a salt, a solvate, an ester, a carbamlnic ester and a phosphoric ester. Especially preferred pharmaceutically acceptable derivative is a salt, a solvate and an ester. Most preferred pharmaceutically acceptable derivative is a salt and an ester.
A person skilled in the art of organic chemisty knows that m^any organic compounds can be formed a complex with a solvent of reaction system and which can be precipitated out or crystallized out from the solvent. These complexes are widely known as a "solvate". For example, the complex with water is known as a "hydrate". The solvate of the compound of the present invention falls within the scope of the invention.
As used herein, the "prodrug" represent a compound which convert to the active form having a pharmacological activity by a hydrolysis in vivo (such as in a blood). The example of the pharamaceutically acceptable prodrug is described in the literature: T. Higuchi and V. Stera, Prodrugs as Novel Delivery Systems, "Bioreversible Carriers in Drug Design", Edward B. Roche ed., American Pharmaceutical Association and Pergamon Press, A.C.S. Symposium Series, vol. 14th, (1987); and D. Freisher, S. Roman and H. Barbara, Improved oral drug delivery: solubility limitations overcome by the use of prodrugs, Adveinced Drug Delivery Reviews (1996) 19(2): 115-130).
A prodrug is a carrier that releases the compound of the formula (1) which is bound covalently in vivo when administered to a patient. In general, the prodrug is prepared by the conventional m^ethod or by modifying a functional group such that the moidified moiety is cleaved in

vivo to give a parent compound. Examples of the prodrug include the CQjnpound wherein a hydroJQ^, amine or sulfhydiyl group binds to an optional group such that provide a hydroxy, amine or sulfhydiyl group by cleaving it when administered to a patient. Thus the representative exam.ples of prodrug are the following ones, but not limited thereto; i. e. the derivatives with acetic ester, formic ester and benzoic ester at the functional groups such as alcohol, sulfhydiyl or amine of the compound of the formula (1). In addition, when the functional group is a carboxylic acid, esters such as methyl ester, ethyl ester and double ester, and the like can be used. The esters exhibit inherently the activity in a human body and/or are hydrolyzed under in vivo condition to the active sompound. The suitable pharmaceutically acceptable esters capable of hydrolyzing in vivo include those which are decomposed easily in the human body to release the parent acid compound or a salt thereof.
The compound of the present invention may be a pharmacetically acceptable salt form thereof. The suitable salt is outlined in literature (Berge et. al., J. Pharm. Sci., 66: 1-19 (1977)).
In general, the pharmaceutically acceptable salts can be easily prepared with a desirable acid or base as needed. The resulting salts can be recovered by filtering aifter precipitating it out from the solution or distilling the solvent off.
The suitable additive salts may be formed with an acid forming a nontoxic salt. Examples of the salt include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccarate, benzoate, methanesulfonate, ethane sulfonate, benzenesulfonate and p-toluenesulfonate.
Examples of the pharmaceutically acceptable salt with a base include alkaline metal salts including ammonium salt, sodium salt and

potassium salt; alkaline earth metal salts including calcium salt and magnesium salt as well as salts with organic bases including a primary, secondary and tertiary amine (e.g. isopropylamine, diethylamine, ethanolamine, trimethlamine, dicyclohej^lamine and N-methyl-D-glucamine).
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "alkyl group" or "alkyl" means a straight or branched saturated hydrocarbon chain having 1 to 10 carbon atoms and a cyclic saturated hydrocarbon chain having 3 to 10 carbon atoms. As a straight or branched hydrocarbon chain, those having 2 to 10 carbon atoms are preferred and those having 2 to 6 carbons are more preferred. More preferred exeimples are stradght chain alkyl groups having 1 to 6 carbon atoms, especially those having 1 to 4 carbon atoms. Examples of alkyl group include methyl, ethyl, propyl, isopropyl, butyl, sec-bulyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-penlyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl and isohexyl groups, and the like.
The term "aUcoxy group" or "alkoxy" means a straight or branched alkyloxy group having 1 to 10 carbon atoms and a cyclic alkyloxy group having 3 to 10 carbon atoms. As a straight or branched hydrocarbon chain, those having 2 to 10 carbon atoms are preferred and those having 2 to 6 carbons are more preferred. More preferred examples are straight chain alkoxy groups having 1 to 6 carbon atoms, especially those having 1 to 4 carbon atoms. Examples of alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutojQ', tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy, hexoxy and isohexoxy groups, and the like.
The term "alkylene group" or "alkylene" means a saturated hydrocarbon chain wherein a hydrogen atom is removed from each of the terminal carbons of a straight hydrocarbon chain. Preferred examples include an alkylene group having 1 to 6 carbon atoms, specifically, methylene, ethylene, trimethylene and tetramethylene groups, and the like.

When an alkylene group herein used contains 1 to 3 heteroatoms selected independently from nitrogen, sulfur and oxygen atoms, the term "aikylene" includes a group of the formula:-0-fCH2)m-0-, -S-(CH2)m-S-, -NH-(CH2}m-NH-, or -0-(CH2)m-NH- (wherein m is an integer of 1 to 4}, or the like.
The term "alkanoyl group" or "alkanoyl" means a straight or branched alkylcarbonyl group having 1 to 10 carbon atoms, preferably an alkylcarbonyl group having 1 to 6 carbon atoms, more preferably an alkylcarbonyl group having 1 to 4 carbon atoms. Examples of alkanoyl group include acetyl, propionyl, bulyryl, valeryl and pivaloyl groups, and the like.
The term "alkenyl group" or "alkenyl" means a straight or branched hydrocarbon chain having 2 to 10 carbon atoms and containing at least one double bond, preferably an alkenyl group having 2 to 6 carbon atoms, more preferably an alkenyl group having 2 to 4 carbon atoms Examples of alkenyl group include vinyl, l-propenyl, allyl, isopropenyl, butenyi, butadienyl and pentenyl groups, and the like.
The term "alkynyl group" or "alkjniyr' means a straight or branched hydrocarbon chain having 2 to 10 carbon atoms and containing at least one triple bond, preferably an alkynyl group having 2 to 6 carbon atoms, more preferably an all^Tiyl group having 2 to 4 carbon atoms Examples of alkynyl group include ethinyl, 1-propynyl, isopropynyl, and pentynyl groups, and the like.
As herein used throughout the claims and specification, when the term "mono- or di-alkyl" refers to di-alkyl, the all^^l moieties may be the same or independent from each other.
The cycloalkyl or cycloEilkyl group as used herein is C3-10 cyclic hydroncarbon group and includes for example, cyclopropyl, cyclobutyl, cyclopentyl, cycohecyl, cycloheptyl, cyclooctyl, cyclononyl groups, and the like and preferably C3-6 cyclic hydrocarbon group.
The cycloalkoxy and cycloalkoxy group as used herein is oxy group

substituted by C3-10 cyclic hydrocarbon and includes, for example cyclopropyloxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and the like and preferably oxy group substituted by C3-6 cyclic hydrocarbon group.
The heterocycle or heterocycic group as used herein includes 5 to 8
membered heterocyclic group including 1 to 4 heteroatoms selected from
oxygen, sulfur and nitrogen atoms and dicyclic or tricyclic fused
heterocyclic group fused thereto. Specific examples of the heterocycic
group include, for example, a thienyl, furyl, p5Trolyl, pyrroUnyl, oxazolyl,
thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl,
oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazoUdinyl,
tetrazolyl, pyridyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl,
morphoUnyl, triazinyl, pyrroUdinyl, piperidyl, pyranyl, tetrahydropyranyl,
thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl,
pyridazinyl, pyrazinyl, benzofuiyl, benzothiazolyl, benzoxazolyl,
tetrazolopjTidazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl,
isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indoiyl, quinolizinyl,
naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl or tetrahydroquinolyl group, and the like.
The homocycle or homocyclic group as used herein includes, for example, 3 to 7 membered carbocyclic group optionally fused, such as C6-10 aryl group (e.g. phenyl and napthyl group, and the like), C3-10 cycloalkyl group (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepthyl, and the like), C3-10 cycloalkenyl group (e.g., cyclopropenyl,

cyclobutenyl, cyclopentenyl, cycohexenyl, cycloheptenyl, and the like).
The cyclic group as used herein includes the heterocyclic group and the homocycUc group mentioned above.
EFFECT OF THE INVENTION
The compound (1) of the present invention has an inhibitory activity against CETP and shows the effects on increasing HDL cholesterol level and decreasing LDL choresterol. Thus the compound is useful in a prophylaxis and a treatment of diseases such as arteriosclerosis and hyperlipidemia, and the like.
The present compound (1) can be administered either orally or parenterally, and can be formulated into a suitable pharmaceutical preparations with a conventional pharmaceuticailly acceptable carriers used therefor.
The pharmaceutically acceptable salts of the compound (1) include, for example, alkali metal salts such as lithium, sodium or potassium salt; alkali earth metal salts such as calcium or magnesium salt; salts with zinc or aluminum; salts with organic bases such as ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucosamie, triethanolamine or dehydroabiethylamine; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methane sulfonic acid, ethanesulfonic acid, benzene sulfonic acid or toluenesulfonic acid; or salts derived from acidic amino acids such as aspartic acid or glutamic acid.
Additionally, the pharmaceutically acceptable salts of the compound of the formula (1) include, for example, quaternary salts formed between a

compound of the formula (1) and an alkyl halide or a phenylalkyl halide.
Preferred pharmaceutical preparations for oral administration of the present compound include solid formulations such as tablets, granules, capsules or powders; and liquid formulations such as solutions, suspensions or emulsions. Preferred pharmaceutical preparations for parenteral administration include injections or infusions formulated with injectable distilled-water, physiological saline or aqueous glucose solution; suppository; or inhalation preparation, and the like.
These pharmaceutical preparations comprise a compound (1) of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier which is usually used for oral or parenteral administration. The pharmaceutically acceptable carriers for oral administration include, for example, a binder (syrup, gum acacia, gelatin, sorbit, tragacanth, polj^nylpyrrolidone, and the like), an excipient (lactose, sugar, cornstarch, potassium phosphate, sorbit, glycine, and the like), a lubricant (magnesium stearate, talc, polyethylene glycol, silica, and the like), a disintegrant (potato starch, and the like), and a wetting agent (anhydrous sodium lauryl sulfate, and the like).
Also the pharmaceutically acceptable carriers for parenteral administration include, for example, injectable distilled-water, physiological saline and aqueous glucose solution.
The dose of a compound (1) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration route, age, body weight, disease, and condition/severity, of the patient It however can usually be in the range of about 0.001 - 1,000 mg/kg/day, preferably in the range of about 0.01 - 100 mg/kg/day, more preferably in the range of about 0.1 - 10 mg/kg/day.
The compounds (1) of the present invention have an inhibitory activity against CETP and show an activi^ of increasing HDL cholesterol level and an activity of lowering LDL cholesterol level. Accordingly, they

are useful in the prophylaxis or treatment of a subject (particularly,
mammal including hum.an) suffering from arteriosclerosis such as
atherosclerosis, peripheral vascular disease, dyslipidemia,
hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia,
hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular
diseases, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, cerebral stroke, diabetes, vascular complication of diabetes, thrombotic diseases, obesity, endotoxemia, metabolic syndrome, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhj^mia, pulmonary vascular disease, reno-vasculEir disease, renal disease, splanchnic vascular disease, vascular hemostatic disease, fatty liver disease, steatohepatitis, inflammatory disease, autoimmune disorders and other systemic disease indications, immune function modulation, pulmonary disease, anti-oxidant disease, sexual dysfunction, cognitive dysfunction, schistosomiasis, cancer, regression of xanthoma, Alzheimer's disease, or the like.
In addition, the compounds of the present invention may be used in combination with other drugs useful for treatment of these diseases. For example, a compound of the present invention may be used in combination with an inhibitor of cholesterol ssmthesis such as HMG-CoA reductase inhibitor; an inhibitor of cholesterol absorption such as anion exchange resin; a triglyceride lowering agent such as fibrates, niacin and fish oil; an antihypertensive such as ACE inhibitor, angiotensin receptor blocker, calcium antagonist and beta blocker; an antiobesity agent such as central anorectic, lipase inhibitor and CBl antagonist; an antidiabetic agent such as insulin sensitizer, D2 agonist, sulfonylurea, biguanide, a-glucosidase inhibitor, SGLT inhibitor and DPPIV inhibitor; or other cholesterol reducer such as ACAT inhibitor.
The compound (1) of the present invention may be prepared by the
49

following methods, which should not be construed to be limited thereto.
In each process for preparing a compound of the formula fl) described above, when protection of a functional group contained in any compound is needed, the protection can be carried out in a conventional manner ad libitum. General statement related to protecting groups and their use is provided by Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.
Further in each process, the reaction can be carried out by the conventional method and a procedure for isolation and the purification may be selected from the conventional method such as crystallization, recrystallization and chromatography and preparative HPLC, and the like as appropriate, or may be combined with one another.

wherein the X^i and X^ are a leaving group and the other symbols have the same meanings as defined above (Process I-l)
The compound (4) can be prepared by reacting the compound (2) with the compound (3) in a solvent in the presence of a base.
Any solvent which dose not disturb the reaction can be preferably used as a solvent used, and include, for example, ethers including diethylether, tetrahydrofuran (THF), dioxane, l,2-methoxyeth£ine, diglyme; hydrocarbons including benzene, toluene, hexane, xylene; alcohols including methanol, ethanol, isopropyl alcohol, tert-butanol; esters including ethyl acetate, methyl acetate, butyl acetate; polar solvents including acetone, N,N-dimethylformamide, dimethyl sulfoxide, which can
50

be used alone or in a combination thereof. Prefered solvents in this reaction include ethanol, dioxane, toluene and N,N-dimethylforniamide.
A conventional base may be used as a base, aind includes for example, alkaline metal hydride including sodium hydride and potassium hydride; alkaline metal alkoxide including sodium ethoxide, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide; alkyl lithium including n-butyl lithium and sec-bulyl lithium; alkaline metal amide including lithium diisopropylamide, sodium amide and lithium bis(trimethylsilyl)amide; alkaline metal carbonate including sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkaline metal hydroxide including lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline metal phosphate including sodium and phosphate potassium phosphate; organic base including triethylamine, diisopropylethylamine, pyridine and N- methylmorpholine; preferably triethylamine, sodium bicarbonate, sodium, tert-butoxide, diisopropylethylamine, sodium hydride and potassium tert-butoxide.
The leaving group includes a halogen atom including chlorine atom, bromine atom, iodine atom, and a substituted sulfonyloxy group including methanesulfonyloxy group, p-toluenesulfonyloxy group and trifluoro-methanesulfonyloxy group. (Process 1-2)
The compound (1) can be prepared by reacting the compound (4) with the compound (5) in a same manner as in process I-l or I'-l described below. (Process I'-l)
The process (I-l) may be replaced by the following process I'-l.
In the above process 1-1, the compound (4) can also be prepared by reacting the compound (2) with the compound (3) in the presence or absence of a base or in the presence of a metal catalyst such as palladium catalyst in a suitable solvent.
51

A conventional palladmm catalyst can be used as a palladium catalyst, and include palladium acetate, tetrakis(triphenylphosphine)-palladium, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenyI-phosphine) palladium, dichlorobis{tri-o-tolylphosphine)palladiuni, bis-(triphenylphosphine)palladium acetate, or the like.
As the base, alkaline metal hydroxide including sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxide including barium hydroxide; alkaline metal alkoxide including sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline metal carbonate including sodium carbonate, potassium carhonate, cesium carbonate; alkaline metal bicarbonate including sodium bicarbonate, potassium bicarbonate; alkaline metal phosphate including potassium phosphate; amines including triethyiamine, diisopropyl-ethyiamine, methylpiperidine, dicyclohexyhnethylaimine; and pyridines including pyridine, 4-dimethylaininopyridine can be preferably used.
Additionally, phosphines may be added in the present reaction. As the phosphines, triphenylphosphine, tributylphosphine, tri-tert-butylphosphonium tetrafluoroborate, l,3-bis{diphenylphosphino)propane, 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, l,r-bis(diphenylphosphino}-ferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohejcylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-(dicyc]ohexylphosphino)biphenyl, and the like can be preferably used.
Any solvent which dose not disturb the reaction can be preferably used as a solvent used in the reaction, and include, for example, ethers including diethylether, tetrahydrofuran (THF), dioxane, 1,2-methoxyethane, diglyme; hydrocarbons including benzene, toluene, hexane, xylene; alcohols including methanol, ethanol, isopropyl alcohol, tert-butanol; esters including ethyl acetate, methyl acetate, butyl acetate; polar solvents including acetone, N,N-dimethylformamide, dimethyl sulfoxide, and which can be used alone or in a combination thereof.
52

(Process V-2)
The compound (1) can be prepared by reacting the compound (4) with the compound (5) in a same manner as in process I'-l or I-l. (Method II]

wherein the X*^ is a leaving group and the other symbols have the same meanings as defined above (Process II-l)
The compound (8) can be prepared by reacting the compound (6) with the compound (7) in a same manner as process I-l. (Process II-2)
The compound (1) can be prepared by reacting the compound (8) with the compound (3) in a same manner as in process I-l or T-l. [Method III]
The compound (1) can be prepared by a method III.

wherein the symbols have the same meanings as defined above (Process III-1)
The compound (9) can be prepared by reacting the compound (3) with the compound (7) in a same meinner as in process I-l or process I'-l. (Process III-2)
The compound (1) can be prepared by reacting the compound (9)
53

with the compound (6) in a same manner as in process I-l. [Method IV]
The compound of the general formula (1-a):

wherein the symbols have the same meanings as defined above
, that is, those wherein Y is a methylene group in the compound of the
formula (1), can be prepared by a following method IV.
The compound (1-a) can be prepared by reducing the compound of a general formula (6'):

wherein the symbols have the same meanings as defined above, or its corresponding carboj^lic acid or its corresponding carboxylic acid ester to provide the compound of a general formula (6"):

wherein the symbols have the same meanings as defined above, followed by halogenating the resulting compound and then reacting the resulting compound with the above compound (9) in a solvent in the presence of a base.
The reduction can be carried out by treating a starting compound with a reducing agent in a suitable solvent. Boron hydrides (sodium borohydride, and the like) and aluminum hydrides (lithium aluminum hydride, diisobutylaluminum hydride, £ind the like) can be preferably used as a reducing agent.
The hologenation can be carried out by treating a starting compound with a halogenating agent in a suitable solvent. As the halogenating agent,
54

a conventional halogenating agent including thionyl chloride, phosphorus oxychloride, as well as carbon tetrahalide (e.g., carbon tetrachloride, carbon tetrabromide, and the like) and phosphines (e.g., triphenylphosphine, tritolylphosphine, triethylphosphine, and the like) can be preferably used.
A conventional base may be used as a base and include for example,
alkaline metal hydride including sodium hydride and potassium hydride;
alkaline metal alkoxide including sodium ethoxide, sodium methoxide,
sodium tert-butoxide and potassium tert-butoxide; alkyl lithium including
n-butyl lithium and sec-bulyl lithium; alkaline metal amide including
lithium diisopropylamide, sodium amide and lithium
bis(trimethylsilyl) amide; alkaline metal carbonate including sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkaline metal hydroxide including lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline metal phosphate including sodium and phosphate potassium phosphate; organic base including triethylamine, diisopropylethylamine, pyridine and N- methylmorpholine; preferably triethylamine, sodium bicarbonate, sodium tert-butoxide, diisopropylethylamine, sodium hydride and potassium tert-butoxide.
Any solvent which dose not disturb the reaction can be preferably used as a solvent used, and include, for example, ethers including diethylether, tetrahydrofuran (THF), dioxane, 1,2-methoxyethaiie, diglyme; hydrocarbons including benzene, toluene, hexane, xylene; alcohols including methanol, ethanol, isopropyl alcohol, tert-butanol; esters including ethyl acetate, methyl acetate, buty] acetate; polar solvents including acetone, N,N-dimethylformamide, dimethyl sulfoxide, which can be used alone or in a combination thereof. Prefered solvents in this reaction include ethanol, dioxane, toluene and N,N-dimethylformamide. [Method IV]
The compound (1-a) can also be prepared by the following method
55

IV'.
The compound (l-a) can also be prepared by halogenating the above compound (6") according to the above method IV, foUowd by reacting the resulting compound with the above compound (7) in a solvent in the presence of a base to provide the compound of a general formula (8')

wherein the sjnnbols have the same meanings as defined above, then reacting the resulting compound with the compound (3) acccording to the above process II-2. [Method IV"]
In the above method IV', the compound (8*) can be prepared by reacting the compound (6") with the compound {7) in a solvent in the presence of a reducing agent.
Any solvent which dose not disturb the reaction can be preferably used as a solvent used in the reaction, and include for example, halogens including 1,2-dichloroethane, dichloromethane, chloroform, ethers including diethylether, tetrahydrofuran (THF), dioxane, 1,2-methoxyethane, diglyme; hydroceirbons including benzene, toluene, hexane, xylene; alcohols including methanol, ethanol, isopropyl alcohol, tert-butanol; esters including ethyl acetate, methyl acetate, butyl acetate; polar solvents including acetone, N,N-dimethylformamide, dimethyl sulfoxide, and which can be used alone or in a combination thereof. Especially prefered solvent in this reaction includes l,2-dich2oroethane, dichloromethane and toluene. The reducing reagent includes sodium borohydrides including sodium triacetoxyborohydride, sodium cyanoborohydride; and aluminum hydrides including lithium aluminium hydride and diisobutylaluminium hydride. [Method V]
56

The compound of a general formula (1-b):

wherein R^ is an alkyl group aind the other symbols have the same meanings as defined above, those wherein Y is an alkyl group in the compound (1), can be prepared by undergoing a conventional Grignard reaction of the compound (6') with a reagent of a general formula: R^MgBr wherein the symbol has the same meaning as defined above, to provide the compound of a general formula (6'")'

wherein the symbols have the same meanings as defined above, followed by halogenating the resulting compound in a same manner as in the above method IV, then reacting the resulting compound with the above compound (9) in a solvent in the presence of a base. [Method V)
The compound (1 -b) can also be prepared by the following method V.
The compound (1-b) can also be prepared by haogenating the above compound (6'"} according to the above method V, followed by reacting the resulting compound with the above compound (7) in a solvent in the presence of a base, to provide a compound of a general formula (8"):

wherein the S3Tnbo]s have the same meanings as defined above, then reacting the resulting compound with the compound (3) according to the
57

above process II-2. [Method VI]
The compound of a general formula f 1-c):

wherein the symbols have the same meanings as defined above, those wherein Y is an methylene group substituted by an oxo group in the compound (1), can be prepared by oxidating the compound {6') to provide the compound of a general formula (6""):

wherein the symbols have the same meanings as defined above, followed by halogenating the resulting compound according to the above method IV, then reacting the resulting compound with the above compound (9) in a solvent in the presence of a base. [Method Vr]
The compound (1-c) can also be prepared by the following method VI'.
The compound (1-c) can be prepared by halogenating the above compound (6"") according to the above method VI, followed by reacting the resulting compound with the above compound (7) in a solvent in the presence of a base, to provide a compound of a general formula (8"'):

wherein the ss^mbols have the same meanings as defined above, then reacting the resulting compound with the compound (3) according to the above process II-2.
58

[Method VII]
The compound (1-a) can be prepared by the following method VII. The compound (l-a) can also be prepared by reducing the compound

wherein the symbols have the same meeinings as defined above, to provide the compound of a general formula (6""")-

wherein the symbols have the same meanings as defined above, then reacting the resulting compound with the above compound (9| in a same manner as in the method IV", to provide the compound of a general

wherein the symbols have the same meanings as defined above, and interconverting on R2 moiety. [Method VII']
The compound (1-a) can also be prepared by reacing the above compound (6""") with the above compound (7) in a same manner as in the above method IV" to provide the compound of a general formula (8");
59

wherein the symbols have the same meanings as defined above, followed by-reacting the resulting compound with the compound (3) according to the above process 11-2 to provide the compound (1-d), then interconverting on R2 moiety.
In addition, substituents on the A, B, R^ and R2 may be further interconverted according to the known method after or before a s3Tithesis of the compound (1).
A2 can be interconverted by the following methods (EA) to (EL|.
In the following each process, unless otherwise specified, a
conventional base can be used as the base, and for example, alkaline metal
hydride including sodium hydride, potassium hydride; alkaline metal
hydroxide including sodium hydroxide, potassium hydroxide; alkaline
earth metal hydroxide including barium hydroxide; alkaline metal alkoxide
including sodium m^ethoxide, sodium ethoxide, potassium ethoxide,
potassium tert-butoxide; alkaline metal carbonate including sodium
carbonate, potassium carbonate, cesium carbonate; alkaline metal
bicarbonate including sodium bicarbonate, potassium bicarbonate; amines
including triethylamine, diisopropylethylamine, methylpiperidine,
dimethylaniline, l,8-diazabicyclo[5.4.0]undecene, 1,4-
diazabicyclol2.2.2]octane, l,5-diazabicyclo[4.3.0]nonene; p5THdines
including pyridine, dimethylaminopyridine can be preferably used.
Also in the following each process, a conventional acid can be used as the acid, and for example, unless otherwise specified, an inoroganic acid (e.g. hydrochloric acid, nitric acid and sulfuric acid; origanic acid represented by sulfonic acids (e.g. methane sulfonic acid, p-toluene sulfonic acid and trifluoromethane sulfonic acid, and the like) can be
60

preferably used.
Also in the following each process, any solvent which dose not disturb the reaction can be used as the solvent and specifically include hydrocarbons including pentane, hexane; aromatic hydrocarbons including benzene, toluene, nitrobenzene; halogenated hydrocarbons including dichloro me thane, chloroform; ethers including diethylether, tetraihydrofuran amides including dimethylformamide, N-methylpyrrolidone, l,3-dimethylimidazolidin-2-one; sulfoxides including dimethyl sulfoxide; alcohols including methanol, ethanol; esters including ethyl acetate, butyl acetate; ketones including acetone, methyl ethyl ketone; nitriles including acetonitrile; water, or a mixed solvent thereof.
Also in the following each process, the leaving group includes a halogen atom including chlorine atom, bromine atom, iodine atom, and a substituted sulfonyloiQ' group including methanesulfonyloxy group, trifluoromethanesulfonyloxy group and toluenesulfonyloxy group.
(EA) The compound wherein A^ is a tetrazolyl group and A^ is an alkyl group or a substituted all^l group can be prepared by alkylating a compound wherein A^ is a tetrazolyl group and A^ is a hydrogen atom.
The alkylation can be carried out by reacting with a compound of the formula:
A2A-Z2
wherein A^A is an alkyl group or a substituted alkyl group and Z^ is a
leaving group, in a suitable solvent in the presence or absence of a base, or
by reacting with a compound of the formula:
A2^0H
wherein the symbol has the same meaning as defined above, in a suitable
solvent in the presence of phosphines eind azodicarboxylic esters.
N-alkylation of a compound wherein A^ is a nitrogen-containing heterocyclic group can be carried out in a similar manner as above.
The reaction proceeds more preferably when a catalj^c amount of an
51

alkaline metal iodide (e.g., potassium iodide, and the like) is added.
Both phosphines and azodicarboxylic esters which usually employed in Mitsunobu reaction can be preferably used. Phosphines include, for example, triphenylphosphine, tribulylphosphine, and the like, and azodicarboxylic esters include diethyl azodicarboxylate, diisopropyl azodiformate, and the like.
(EB) The compound wherein Ai is 2-oxodihydropyrimidinyl group
and A2 is an alkyl group or a substituted alkyl group can be prepared by
alkylating a compound of the formula (1) wherein A^ is 2-
hydroxypyrimidinyl group and A^ is a hydrogen atom, with a compound of
the formula:
A2^Z2
wherein the symbols have the same meeining as defined above.
The reaction can be carried out in the same manner as in the above (EA).
(EC) The compound wherein A2 is an optionally substituted amino
group or a group of the formula:

wherein the symbols have the same meaning as defined above, can be prepared by reacting a compound of the formula (1) wherein A^ is a halogen atom, with a corresponding amine or a compound of the formula:

wherein the symbols have the same meanings as defined above.
The reaction can be carried out in the presence or absence of a base, and in the presence or absence of a palladium catalyst in a suitable solvent.
As the palladium catalyst, a conventional palladium catalyst
62

including palladium acetate, tetrakis(triphenylphosphine) palladium,
tris{diben^lideneacetone)dipalladium, dichlorobis(triphenylphosphine)-
palladium, dichlorobis(tri-o-tolylphosphine)palladiuin, bis-
(triphenylphosphine)palladium acetate, or the like can be used.
As the base, alkaline metal hydroxide including sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxide including barium hydroxide; alkaline metal alkoxide including sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide; alkaline metal carbonate including sodium carbonate, potassium carbonate, cesium carbonate; alkaline metal bicarbonate including sodium bicarbonate, potassium bicarbonate; alkaline metal phosphate including potassium phosphate; amines including triethylamine, diisopropylethylamine, methylpiperidine, dicyclohexylmethylamine; and pjoidines including pyridine, 4-dimethylaminop3Tidine can be preferably used.
Additionally, phosphines may be added in the present reaction. As the phosphines, triphenylphosphine, tributylphosphine, tri-tert-butylphosphonium tetrafluoroborate, 1,3-bis(diphenylphosphino)propane, 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, l,r-bis(diphenylphosphino)-ferrocene, 2-{di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylam,ino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, and the like can be preferably used as the phosphines.
(EDJ The compound wherein A2 is an optionally substituted amino group can be prepared by coupling a compound of the formula (1} wherein
A2 is a halogen atom with a compound of the formula:
(R20)3Sn-NR2iR22
wherein R2o is an all^l group and NR21R22 is an optionally substituted amino group.
The coupling reaction can be carried out in the presence of a palladium catalyst in the presence or absence of a base in a suitable
solvent.
63

The palladium catalysts, bases, and phosphines described in the above (EC) can be used in the same manner as in the above (EC).
(EE) The compound wherein A^ is a cyano group can be prepared by
cyanating a compound of the formula (1) wherein A^ is a halogen atom.
The cyanation can be carried out by reacting a starting compound with a metal cyanide including sodium cyanide, potassium cyanide, or zinc cyanide in the presence of a palladium catalyst in a suitable solvent.
The same palladium catalyst as that described in the above (EC) can be preferably used.
(EF) The compound wherein A^ is an optionally substituted
alkoxycarbonyl group can be prepared by reacting a compound of the
formula (1) wherein A2 is a halogen atom, with a corresponding
alkylalcohol under carbon monoxide atmosphere using a palladium
catalyst in the presence of a base in a suitable solvent.
The same palladium catalyst and base as those described in the above (EC) can be preferably used.
Additionally, the reaction can be more preferably carried out by adding a ligand, and phosphines described in the above (EC) can be preferably used as the ligand.
(EG) The compound wherein A2 is an optionally substituted alkenyl
group can be prepared by coupling a compound of the formula (1) wherein
A^ is a halogen atom with a corresponding alkene.
The coupling reaction can be carried out in the presence of a palladium catalyst in the presence or absence of a base in a suitable solvent.
The same palladium catalyst as that described in the above (EC) can be preferably used.
The same base as that described in the above (EC) can be preferably used and silver carbonate can also be used.
Additionally, the reaction can be more preferably carried out by
64

adding a ligand, and phosphines described in the above (EC) can be preferably used as the ligand.
{EG') The compound wherein A^ is an optionally substituted ajkenyl group can be prepared by dehydration reaction of a compound having a hydroxyalkyl group in a substituent A^. The dehydration reaction can be carried out by treating a starting compound with acid.
As the acid, a conventional acid can be used. For example, an inoroganic acid (e.g. hydrochloric acid, nitric acid and sulfuric acid) or an origanic acid (e.g. methane sulfonic acid, p-toluene sulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethane sulfonic acid, and the like) can be preferably used.
(EH) The compound wherein A^ is a boronic acid ester can be prepared by reacting with the compound wherein Pfi is a leaving group with a trialkoxyborane (trimethoxyborane, triisoprGpojQrborane, and the like), a dialkoxyborane (pinacolborane, and the like) or a tetraalkoxydiboron {bis(pinacolato)diboron, and the like) in the presence of palladium catalyst. The leaving group includes a halogen atom including chlorine atom, bromine atom, iodine atom, and a substituted sulfonyloxy group including methane sulfonyloxy group, trifluoromethanesulfonyloxy group, and toluenesulfonyloj^ group. The reaction can be carried out in the same manner as in the above (EC).
(EH*) The compound wherein A^ is a hydroxy group can be prepared by reacting the compound wherein A^ is a boronic acid ester with the peroxide. Aqueous hydrogen peroxide, m-chloroperbenzoic acid and OXONETM (DuPont Co. Ltd), and the like can be perferably used as the peroxide.
(El) The compound wherein A2 is an alkoxy group or a substituted alkoxy group can be prepared by alko^lating the compound (1) wherein A^ is a halogen atom.
The alkoxylation can be carried out by optionally adding a copper
65

catalyst to react with a corresponding alcohol in a suitable solvent or solvent-free in the presence of a base.
The same base as described in the above (EC), in particular, cesium carbonate can be preferably used.
The copper catalyst including copper iodide, copper bromide, copper chloride, copper acetate, copper trifluoromethanesulfonate, and the like can be preferably used.
Additionally, this reaction proceeds more preferably when 1,10-phenanthroline, 2-aminopyridine, or the like is added.
(EJ) The compound wherein A^ is an optionally substituted alkyl group, an optionally substituted heterocyclic group or an optionally substituted aryl group can be prepared by coupling a compound of the formula (1) wherein A^ is a leaving group with a corresponding alkyl, aryl or heterocyclic boronic acid or a corresponding alkyl, aiyl or heterocyclic boronic acid ester.
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.
This reaction can be carried out in the same manner as in the above (EC).
The leaving group is the same as defined above (EH).
(EJ') The compound wherein A^ is an optionally substituted alkyl group, an optionally substituted heterocyclic group or an optionally substituted aiyl group can be prepared by coupling a compound of the formula (1) wherein A^ is a boronic acid or a boronic acid ester with an alkyl, an aryl or a heterocyclic group which have a leaving 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 meinner as in the above (EC). The leaving group is the same as defined above (EH).
(EK) The compound wherein A^ is an alkoxycarbonylalkylsulfonyl
66

group can be prepared by reacting a compound of the formula (1) wherein A2 is a halogen atom with an alkoxycarbonylalkylsulfinic acid alkaline metal salt.
The alkoxycarbonylalkylsulfinic acid alkaline metal salt can be prepared according to the method described, for example, in Baskin et. al., Tetrahedron Lett., 43, 8479 (2002).
Additionally, this reaction can be carried out in the presence of a copper catalyst in a suitable solvent according to the method described in the said literature.
The same copper catalyst as described in (EI) above can be used, and in particular, copper iodide can be preferably used.
(EL) The compound wherein A^ is a group of the formula:

wherein the symbols have the same meaning as defined above, can be prepared by condensing a compound wherein A^ is a hydroxy group with a compound of the formula:

wherein X^i is O, SO, SO2 or NRP (RP is a protecteing group) and q is an integer from 1 to 4, and as needed, removing the protecting group for amino group.
As a protecting group, a conventional protecting group including benzyloxycarbonyl group, tert-butoxycarbonyl group, and the like can be used.
The reaction can be carried out in a suitable solvent in the presence of phosphines and azodicarbojiylic esters. The reaction can be carried out in the same manner as in the above (EA).
The removal of a protecting group can be carried out in a conventional manner including catalj^tic reduction, acid-treatment, and the
67

like, depending on the type of a protecting group.
The same manner as in the above reactions (EA) to (EL) for conversions of A^ can also be applied for conversion of the other substituent as needed.
Additionally, a substituent(s) of a compound (1) of the present invention can be converted into different one(s) within the scope of the compound (1) according to the following methods as appropriate.
In the following each process, a conventional base can be used as the base, and unless otherwise specified, the base described in the above (EA) can be preferably used.
Additionally, in the following each process, a conventional acid can be used as the acid, and unless otherwise specified, a mineral acid including hydrochloric acid, nitric acid, sulfuric acid, or an organic acid represented by sulfonic acids (e.g., methane sulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid) or carbojQrUc acids (e.g., acetic acid, trifluoroacetic acid) can be preferably used.
Further additionally, in the following each process, any solvent which dose not disturb the reaction can be used, and as such, the solvent described in the above (EA) can be preferably used.
The leaving group includes a halogen atom including chlorine atom, bromine atom, iodine atom, and a substituted sulfonyloxy group including m ethane sulfonyloj^ group, trifluoromethane sulfonyloxy group, and toluenesulfonyloj^ group.
(El) The compound wherein A is a heterocyclic group substituted by an optionally substituted amino group or a group of the formula:

wherein the symbols have the same meanings as defined above, can be prepared by reacting a compound (1) wherein A is a heterocyclic group
68

substituted by an optionally substituted alkylsulfonyloxy group, with a corresponding amine or a compound of the formula:

wherein the symbols have the same meaning as defined above in the presence of a palladium catalyst, and in the presence or absence of a base in a suitable solvent or solvent-free.
The reaction can be carried out in the same manner as in the above (EC).
(E2) The compound wherein A is a heterocyclic group substituted by an optionally substituted amino group or a group of the formula:

wherein the ssnnbols have the same meanings as defmed above, can also be prepared by reacting a compound wherein A is a heterocyclic group substituted by a halogen atom or an optionally substituted alkylsulfonyloxy group, with a corresponding amine or a compound of the formula:

wherein the symbols have the same meanings as defined above.
The reaction can be carried out by optionally adding a copper catalyst in the presence or absence of a base in a suitable solvent.
Copper iodide, copper bromide, copper chloride, copper acetate, copper trifluoromethanesulfonate, and the like can be preferably used as the copper catalyst.
The same base as that described in the above (EC) cein be preferably
69

used.
Additionally, the reaction proceeds more preferably when N,N'-
dimethylethylenediamine, 1,10-phenanthroline, ethylene glycol,
phenylphenol, and the like is added.
(E3) The compound wherein A is a heterocyclic group substituted by an optionally substituted alkylsulfanyl group can be prepared by reacting a compound wherein A is a heterocyclic group substituted by a halogen atom or an optionally substituted alkylsulfonyloxy group with a corresponding alkylthiol.
The reaction can be carried out in the same manner as in that described in the above (EI) and more preferably facilitated by adding 1,10-phenanthroline or ethylene glycol.
(E4) The compound wherein A is a heterocyclic group substituted by an optionally substituted heterocyclic group can be prepared by coupling a compound wherein A is a heterocyclic group substituted by a halogen atom or an optionally substituted allq^lsulfonylojQr group with a corresponding heterocyclic tin compound or a corresponding heterocyclic boron compound.
The reaction can be carried out in the same manner as in the above (ED) or (EI).
(E5) The compound wherein A is a heterocyclic group substituted by an alko3^ group can be prepared by reacting a compound wherein A is a heterocyclic group substituted by a halogen atom or an alkylsulfonyl group with a corresponding alkaline metal alkoxide in a suitable solvent. The corresponding alkaline metal alkoxide can be obtained by treating a corresponding alltylalcohol with alkaline metal hydride or alkaline metal in the said solvent.
(E6) The compound having an aminoall^l group as a substituent on A can be prepared by catalytically reducing a compound having a cyano group or a cyanoall^l group as a substituent on A.
70

The catalytic reduction can be carried out by using a catalyst under hydrogen atmosphere in a suitable solvent in a conventional majiner. The catalyst includes a palladium catalyst including palladium-carbon, a nickel catalyst including Raney nickel, a platinum catalyst including platinum-carbon, and the like.
(E?) The compound having an optionally substituted mono- or di-alkylsulfamoylaminoalkyl group as a substituent on A can be prepared by reacting a compound having an aminoalkyl group as a substituent on A with a corresponding halogenated mono- or di-alkylsulfamoyl.
The reaction can be carried out in a suitable solvent in the presence of a base.
(E8) The compound having an optionally substituted mono-alkylcarbamoylaminoalkyl group as a substituent on A can be prepared by reacting a compound having an aminoalkyl group as a substituent on A with a corresponding alkyl isocyanate in a suitable solvent.
(E9) The compound having a group of the formula:

wherein R9 is an all^l group and the other symbols have the same meanings as defined above as a substituent on A can be prepared by reacting a compound having a group of the formula;

wherein the symbols have the same meanings as defined above as a substituent on A with a corresponding alkyl isocyanate (R^IMCO). The reaction can be carried out in the same manner as in the above (E8).
(ElO) The compound having an optionally substituted mono- or di-
71

alkylcarbamoylaminoalkyl group as a substituent on A can be prepared by condensing a compound having an aminoalkyl group as a substituent on A with an optionally substituted mono- or di-alkylamine using a carbonylating agent in a suitable solvent in the presence or absence of a base.
A conventional carbonylating agent such as carbonyldiimidazole, phosgene, triphosgene, and the like can be used.
(Ell) The compound having a morpholinylcarbonylamino group as a substituent on A can be prepared by condensing a compound having an amino group as a substituent on A with morpholine using a carbonylating agent in a suitable solvent. The reaction can be carried out in the same manner as in the above (E ] 0).
(E12) The compound having a group of the formula:

wherein X12 is O or NH, as a substituent on A can be prepared by treating
a compound having a group of the formula;
H-X12-CH2-CONH-
wherein the symbols have the same meanings as defined above as a
substituent on A with a carbonylating agent in a suitable solvent.
The reaction can be carried out in the same manner as in the above (ElO).
(E12') The compound having a group of the formula:

wherein X^^ is O or NH, as a substituent on A can be prepared by treating a compound having a group of the formula;
72

H-X12-CH2- CH2-NH-
wherein the symbols have the same meanings as defined above as a
substituent on A with a carbonylating agent in a suitable solvent.
The reaction can be carried out in the same manner as in the above (ElO).
(El3) The compound having an optionally substituted carbamoyl group as a substituent on A can be prepared by condensing a compound having a carboxyl group as a substituent on A with a desirable amine.
The condensation can be carried out using a condensing agent in a
suitable solvent. A conventional condensing agent such as
dicyclohexylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl}carbodiimide, carbonyldiimidazole, and the like can be preferably used.
Additionally, the condensation can be more preferably carried out by adding an activating agent including 1-hydroxybenzotriazole, 1-hydroxysuccinimide, and the like.
(El4) The compound having a group of the formula:

wherein the symbols have the same meanings as defined above as a substituent on A can be prepared by condensing a compound having a carboxyl group as a substituent on A with a compound of the formula:

wherein the symbols have the same meanings as defined above.
The reaction can be carried out in the same manner as in the above (E13).
(El5) The compound having a tetrazolyl group as a substituent on A can be prepared by reacting a compound having a cyano group as a substituent on A with an alkaline metal azide in the presence of an acid in
73

a suitable solvent.
The alkaline metal azide includes sodium azide, lithium azide, and the like.
An ammonium salt of a halogenated hydrogen including ammonium chloride can be preferably used as the acid.
(E16) The compound having an optionally substituted alkyl tetrazolyl group as a substituent on A can be prepared by alkylating a com^pound having a tetrazolyl group as a substituent on A.
The alkylation can be carried out in the same manner as in the above (EA).
(E17) The compound having an optionally substituted amino group or a group of the formula:

wherein the symbols have the same meanings as defined above as a substituent on A can be prepared by reacting a compound having a halogen atom or an optionally substituted alkylsulfonyloxy group as a substituent on A with a corresponding amine or a compound of the

wherein the s3Tnbols have the same meanings as defined above.
The reaction can be preferably carried out in the presence or absence of a base in a suitable solvent.
(E18) The compound having an optionally substituted alkylamino group or a group of the formula:

74

wherein R^^ is an alkyl group optionally substituted by a hydroxy group, an alkoxycarbonyl group, a morpholinyl group or a phenyl group, and n has the same meaning as defined above, as a substituent on A can be obtained by reacting a compound having an amino group or a group of the formula:

wherein the symbols have the same meanings as defined above as a substituent on A with a corresponding allq'l halide or a corresponding sulfonic alkyl esters.
The sulfonic alkyl esters including methane sulfonic ester, toluenesulfonic ester, trifluoromethanesulfonic ester, and the like can be preferably used.
The reaction can be preferably carried out in the presence or absence of a base in a suitable solvent.
(E19) The compound having a group of the formula:

wherein Xi3 is O or NH, and the other symbol has the same meaning as defined above as a substituent on A, can be prepared by ring-closing a compound having a group of the formula:
Z3-(CH2)n-X13-CH2-CONH-
wherein Z^ is a leaving group and the other S5Tnbols have the same meanings as defined above, as a substituent on A.
The reaction can be preferably carried out in the presence or absence of a base in a suitable solvent.
(E20) The compound having a carboxyl group as a substituent on A can be prepared by hydrolyzing a compound having an alkoxycarbonyl group as a substituent on A.
The hydrolysis can be carried out by treating a starting compound
75

with a base or an acid in a suitable solvent according to a conventional manner. An alkaline metal hydroxide can be preferably used as the base.
(E21) The compound conteiining a carboxyl group as a substituent on A can be prepared by hydrolyzing a compound containing a cyano group as a substituent on A.
The hydrolysis can be carried out by treating a starting compound with an acid or a base in a suitable solvent.
(E22) The compound containing a carbamoyl group as a substituent on A can be prepared by hydrolyzing a compound containing a cyano group as a substituent on A.
The hydrolysis can be carried out by treating a starting compound with an acid or a base in a suitable solvent.
(E23) The compound having a carboxyalkyl group as a substituent on A can also be prepared by catal5^cally reducing a compound having a carboxyalkenyl group, a benzyloxycarbonylalkenyl group or a benzyloxycarbonylalkyl group as a substituent on A.
The catalytic reduction can be carried out in the same manner as in the above {E6}.
{E24) The compound having a hydroxy group as a substituent on A can be prepared by hydrolyzing a compound wherein A has an alkanoylo3cy group.
The hydrolysis can be carried out in the same manner as in the above (E20).
(E25) The compound containing sulfoxide (SO) or sulfone {S02) in a substituent on A can be prepared by oxidizing a compound having S in a substituent on A (e.g., a compound having a thiomorpholinyl group or an alkylsulfanylallq'l group as a substituent on A).
The oxidation can be carried out by treating a starting compound with an oxidizing agent in a suitable solvent.
Peroxides such as hydrogen peroxide, m-chloroperbenzoic acid,
76

acetyl hydroperoxide, and the like can be preferably used as the oxidizing agent.
(E26) The compound containing N-oxide in a substituent on A can be prepared by oxidizing a compound having N in a substituent on A (e.g., a compound having a pyridyl group as a substituent on A).
The oxidation can be carried out in the same manner as in the above (E25).
fE27) The compound having a 1,2-dihydroxyalkyl group as a substituent on A can be prepared by treating a compound having an alkyl group substituted by mono- or di-alkyldioxolanyl group as a substituent on A with an acid in a suitable solvent.
A strongly acidic resin can also be preferably used as the acid, in addition to those previously described.
(E28) The compound having an alkyl group substituted by a hydroxy group and an optionally substituted alkoxy group as substituents on A can be prepared by reacting a compound having an oxylanylalkyl group as a substituent on A with an alkaline metal salt of the corresponding alcohol in a suitable solvent.
The alkaline metal salt of alcohol includes a lithium salt, a sodium salt, a potassium salt, and the like.
(E29) The compound having an alkyl group substituted by a hydroxy group and an amino group, or an alkyl group substituted by a hydroxy group and an optionally substituted mono- or di-alkylamino group as substituents on A can be prepared by reacting a compound having an OJ^lanylalkyl group as a substituent on A with ammonia or a corresponding mono- or di-alkylamines in a suitable solvent.
(E30) The compound having a hydro^carbamimidoyl group as a substituent on A can be prepared by reacting a compound having a cyano group as a substituent on A with hydroxylamine or a salt thereof in a suitable solvent. Any solvent which does not disturb the reaction can be
77

used, and as such, the solvent described in the above (EA) can be preferably used.
(E31) The compound having an oxodihydrooxadiazolyl group as a substituent on A can be prepared by reacting a compound having a hydroxycarbamimidoyl group as a substituent on A with a carbonylating agent in a suitable solvent in the presence or absence of a base.
The same carbonylating agent as that described in the above (ElO) can be used.
(E32) The compound having a sulfo group as a substituent on A can be prepared by hydrolyzing a compound having an alkoxycarbonylalkylsulfonyl group as a substituent on A.
The hydrolysis can be carried out in the same manner as in the above (E20).
(E33) The compound having a sulfamoyl group as a substituent on A can be prepared by condensing a compound having a sulfo group as a substituent on A with a desirable 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, followed by reacting the resulting compound with a desirable amine in the presence or absence of a base.
A conventional halogenating agent including thionyl halide, phosphorus oxyhalide, or the like can be used.
(E34) The compound having a hydroJ^allQ^l group as a substituent on A can be prepared by reducing a compound having a carboj^alkyl group as a substituent on A, or by converting the carboxyl group into an acid anhydride or an ester and then reducing the resulting compound.
A process for conversion into an acid anhydride can be carried out by reacting a starting compound with a halogenated alkyl formate in a suitable solvent in the presence of a base.
A process for conversion into an ester can be carried out by reacting
78

a starting compound with an alcohol in the presence of a condensing agent in a suitable solvent. This process can be carried out in the same manner as in (E33) except that a desirable alcohol is used in place of amine.
The reduction can be carried out by treating the resulting compound with a reducing agent in a suitable solvent.
Boron hydrides (e.g. sodium borohydride), aluminum hydrides (lithium aluminum hydride, diisobutylaluminum hydride, and the like) can be preferably used as the reducing agent.
(E35) The compound having an aromatic group substituted by a cyano group as a substituent on Ri, optionally having one to three heteroatoms independently selected from oxygen atom, sulfur atom and nitrogen atom (hereinafter, referred to as "an aromatic group"), can also be prepared by cyanating a com.pound having an aromatic group substituted by a halogen atom as a substituent on Ri.
The cyanation can be carried out in the same manner as in the above (EE).
(E36) The compound wherein A is a hydrogen atom can be prepared by acid-treatment or reduction of a compound wherein A is a tert-butoxycarbonyl group or a benzyloxycarbonyl group.
The acid-treatment can be carried cut 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).
(E37) The compound wherein A is an optionally substituted alkoxycarbonyl group, or an optionally substituted carbamoyl group can be prepared by reacting a compound wherein A is a hydrogen atom with a carbonylating agent, or a desirable alcohol or a desirable simine in a suitable solvent.
The reaction can be carried out in the same manner as in the above (ElO).
(ESS) The compound having an amino group as a substituent on A
79

can be prepared by undergoing a Curtius rearrangement reaction of a compound having a carboxyl group as a substituent on A.
Curtius rearrangement reaction can be carried out using a conventional azidating agent (e.g., diphenylphosphorylazide, and the like) in a suitable solvent in the presence of a base.
The reaction may also be carried out by adding alcohols to provide a compound having an optionally substituted alkoxycarbonylamino group as a substituent on A, followed by removing the alkoxycarbonyl group.
The removal of the alkoxycarbonyl group can be carried out in a conventional manner such as an acid-treatment or a reduction depending on the type of 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 meinner as in the above (E23).
(E39) The compound having a hydroxy group as a substituent on A can be prepared by cataljTically reducing a compound having a benzyloj^ group as a substituent on A. The reduction can be carried out in the same manner as in the above (E23).
(E40) The compound having an oxo group as a substituent on A can be prepared by oxidizing a compound having a hydroxy group as a substituent on A.
The oxidation can be carried out by using an oxidizing agent in a suitable solvent.
A conventional oxidizing agent can be used as the oxidizing agent, such as chromate-pyridine complex, pjridinium chlorochromate, pyridinium dichromate, Dess-Martin reagent (1,1.1 -tris(acetoxy) -1,1-dihydro-l,2-ben2iodoxol-3-(lH)-one), dimethylsulfoxide, and the like.
(E41) The compound containing an optionally substituted alkoxy group as a substituent on A can be prepared by alkylating a compound containing an oxo group or a hydroxy group as a substituent on A.
The alkylation can be carried out by using a corresponding
80

compound in the same manner as in the above (EA).
(E41 ■) The compound containing an optionally substituted heterocyclyloxy group or an optionally substituted aryloj^ group as a substituent on A can be prepared by coupling a compound containing a hydro;^ group as a substituent on A with a corresponding aiyl compound or a heterocyclic compounds which have a leaving group.
The coupling can be carried out in the same manner as in the above (EC).
The leaving group have the same meaning as defined above (EH).
(E42) The compound having an optionally substituted alkanoylamino group as a substituent on A can be prepared by condensing a compound having an amino group as a substituent on A with a corresponding carbojcylic acid or a reactive derivative thereof.
The condensation with the corresponding carboxylic acid can be preferably carried out in a suitable solvent in the presence of a condensing agent. The reaction can be carried out in the same manner as in the above (E13).
Additionally, the condensation with the reactive derivative of the corresponding carboxylic acid can be carried out in a suitable solvent or solvent-free in the presence or absence of a base.
The reactive derivative includes an acid halide, an acid anhydride, an activated ester, an activated amide, and the like.
(E43) The compound having a group of the formula:

wherein R^t is an alkanoyl group optionally substituted by a hydrojq' group or an alkoxy group, and n has the same meaning as defined above, as a substituent on A can be prepared by condensing a compound of a group of the formula:
81

wherein the symbol has the same meaning as defined above, as a substituent on A with a corresponding carboxylic acid or a reactive derivative thereof.
The reaction can be carried out in the seime manner as in the above (E42).
(E44| The compound having a maleimide group as a substituent on A can be prepared by reacting a compound having an amino group as a substituent on A with a maleic anhydride. The reaction can be carried out in a suitable solvent.
(E45) The compound having an sJkyl group substituted by a pyridyl group and a hydroxy group as substituents on A can be prepared by reacting a compound having an all^l group substituted by a p3Tidyl group of which nitrogen atom is oxidized as a substituent on A with a trifluoroacetic anhydride. The reaction can be carried out in a suitable solvent.
(E46) The compound having a halogen atom as a substituent on A can be prepared by treating a compound having a hydroxy group as a substituent on A with a halogenating agent.
As the halogenating agent, a conventional halogenating agent including thionyl chloride, phosphorus oxychloride, as well as carbon tetrahalide (e.g., carbon tetrachloride, carbon tetrabromide, and the like) and phosphines (e.g., triphenylphosphine, tritolylphosphine, triethylphosphine, and the like) can be preferably used.
(E46') The compound having a halogen atom as a substituent on A can be prepared by treating a compound with a halogenating agent. As the halogenating agent, a conventional halogenating agent such as bromine, N-bromosuccinimide, and the like can be preferably used.
(E47) The compound having a cyanoalkyl group as a substituent on
82

A can be prepared by reducing a compound having a cyanoalkenyl group as a substituent on A.
The reduction can be carried out by treating a starting compound with a reducing agent or by catalytically reducing in a suitable solvent.
Any reducing agent can be used subject that it reduces only a double bond without affecting a cyano group. For example, sodium bis{2-metho3^ethoxy}aluminum hydride in the presence of a copper bromide can be preferably used.
The catal3^c reduction can be carried out in the same manner as in the above (E23).
(E4S) The compound (1) having a hydroj^all^l group as a substituent on A can be prepared by reducing a compound having a formyl group as a substituent on A.
The reduction can be carried out by treating a starting compound with a reducing agent in a suitable solvent.
The reaction can be carried out in the same manner as in the process for reducing in the above {E34}.
(E49) The compound wherein a substituent on B is a hydroxy group can be prepared by demethylating a compound wherein the substituent on B is a methoxy group.
The demethylation can be carried out by treating a starting compound with a demethylating agent in a suitable solvent.
A conventional reagent including trimethylsilyl iodide, hydrogen bromide/acetic acid, boron tribromide, concentrated sulfuric acid, and the like can be used as the demethylating agent.
(E50) The compound wherein a substituent on B is an optionally substituted alkoxy group can be prepared by allQ'lating a compound wherein the substituent on B is a hydrojQr group.
The all^lation can be carried out in the same manner as in the above (EA).
83

(E51) The compound wherein a substituent on B is an optionally substituted alkylaulfonyloxy group can be prepared by alkylsulfonylating a coinpound wherein the substituent on B is a hydroxy group.
The alkylsulfonylation can be carried out by reacting a corresponding all^Isulfonyl halide or a corresponding alkylsulfonic anhydride in a suitable solvent in the presence or absence of a base.
(E52) The compound wherein a substituent on B is a cyano group can be prepared by cyanating a compound wherein 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) The compound wherein a substituent on B is an aminoalkyl group can be prepared by reducing a compound wherein the substituent on B is a cyano group.
The reduction can be carried out in the same manner as in the above (E6).
(E54} The compound wherein a substituent on B is an alkyl group can be prepared by alkylating a compound wherein the substituent on B is an optionally substituted alkylsulfonyloxy group.
The alkylation can be carried out by reacting alkyl aluminums in the presence of a palladium catalyst, a silver catalyst and a copper catalyst in a suitable solvent.
Tetrakis(triphenylphosphine}palladium as the palladium catalyst, silver carbonate as the silver catalyst, copper (I) chloride as the copper catalyst can be preferably used.
(£54) The compound wherein a substituent on B is an optionally substituted alkyl group can be prepared by catalytically reducing a compound wherein a substituent on B is an optionally substituted alkenyl group. The reaction can be carried out in the same manner as in the above (E6).
84

(E55) The compound having an imidazolinyl group or an oxazolinyl group as a substituent on A can be prepared by (i) reacting a compound containing a cyano group as a substituent on A with a desirable alcohol in the presence of an acid in a suitable solvent or solvent-free to provide a compound containing an alkoxycarbonimidoyl group as a substituent on A, and (ii) reacting the compound containing an alkoxycarbonimidoyl group as a substituent on A with 2-aminoethanol or ethylene diamine in a suitable solvent or solvent-free.
{E56i The compound having a carboxyl group as a substituent on A can be prepared by (i) oxidizing a compound containing a hydroxyalkyl group as a substituent on A in the same manner as in the above (E40) to provide a compound containing an oxo group as a substituent on A, and (ii) oxidizing the compound containing an oxo group as a substituent on A.
The oxidization for the second process can be carried out by using an oxidizing agent in a suitable solvent. Sodium^ chlorite, Silver(I) oxide, Sodium periodate and the like can be preferably used as the oxidizing agent.
(E57) The compound having a carbojQ^l group as a substituent on A can be directly prepared by oxidizing a compound containing a hydroxyalkyl group as a substituent on A.
The oxidization can be carried out by using Jones reagent, potassium permanganate, and the like as the oxidizing agent.
(ESS) The compound wherein A is hydrogen atom can be prepared by treating a compound wherein A is ethoxycarbonyl group with a silyl halide or a base. Trimethylsilyl iodide can be preferably used as the silyl halide. Sodium hydroxide can be preferably used as the base.
In each process for preparing a compound (1) described above, when protection of a functional group contained in any compound is needed, the protection can be carried out in a conventional manner as appropriate. General statement related to protecting groups aind their use is provided by
85

Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.
When an amino group is protected by a benzyloxycarbonyl group, the protecting group can be removed by a catalj^c reduction under hydrogen atmosphere in a suitable solvent.
When a hydroxy group is protected by a benzyl group, the protecting group can also be removed by a catal5^c reduction in a similar manner as above.
When an amino group is protected by a tert-butoxycarbonyl group, the protecting group can be removed by treating a starting compound with an acid (e.g., hydrochloric acid, trifluoroacetic acid, toluenesulfonic acid, and the like) in a suitable solvent.
When a hydroxy group is protected by a tetrahydropyranyl group, the protecting group can also be removed by treating a starting com.pound with an acid in a similar manner as above.
Other substituents of the present compouind (1) can also be converted in the same manner as in the reactions (El) to (E58) for conversion of the above groups. [Preparation of a compound (6')]
The compound (6") can be prepared according to the following method (a) or (b).
(a) The compound (6") can be prepared by reacting the compound of

wherein X^t is a leaving group and the other symbols have the same meanings as defined above, with the compound of a general formula (11): H-R2 (11)
wherein the symbol has the same meaning defined above, in the same manner as in the above process I-l or process I'-l.
86

(b) The compound {6) can be prepared by reacting the compound of

wherein P is a protecting group for a carboxyl group and the other symbols have the same meanings as defined above, with the compound fll) in the same manner as in the above process I-l or process I'-l, followed by reducing the resulting compound to provide the compound {6") and further oxidizing the resulting compound.
The reduction and oxidation in the above methods can be carried out by the conventional method. [Preparation of a compound (2)]
The compound (2) can be prepared by oximating the compound (6") to provide the compound of a general formula (13):

wherein the symbols have the same meanings as defined above, followed by reducing the resulting compound.
The oximation can be carried out by the conventional oximation methods, for example, by treating the compound (6') with a salt of hydroj^lamine in the presence of an acid or a base such as alkaline metal hydroxide, sodium acetate or pyridine in an alcohol, acetic acid or pyridine. Also einy acidic material can be used as the agent for preparing a salt of hjdroxyl amine, for example, a mineral acid (e.g. sulfuric acid, phosphoric acid, hydrogen bromide and hydrogen iodide), and organic acid (e.g. acetic cid, oxalic acid, trichloroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, 1,5-naphthalenedisulfonic acid).
The subsequent reduction reaction can be carried out in a conventional manner.
87

The compound (2) can aJso be prepared from the compound {6") using the method of Gabriel synthesis, described in detail in Mitsunobu, O. Comp. Org. Syn. 1991, 6, 79-85. [Preparation of a compound (6'"")]
The compound (6'"") can be prepared from the compound of a general formula (14):

wherein X^s is a leaving group and the other symbols have the same meanings as defined above, by a conventional insertion reaction of carbon monoxide aith a transition metal catalyst.
The reaction can be carried out in an aprotic solvent such as tetrahydrofuran or DMF, and the like. Preferred transition metal includes, for example, a salt form of palladium such as palladium {II)-acetate, and the like or a palladium (0) compound such as tetrakis(triphenylphosphine)palladium, and the like. This kind of an insertion reaction of carbon monoxide can be carried out by the method described in detail in J. Org. Chem. 1992, 57, 5979 or "Organometallic compound-Synthesis and Application-(Tokyo Kagaku Dozin Co., Ltd.), Metal-catalyEed Cross-coupling Reaction (WILLY-VCH), Handbook of Palladium-Catalyzed Organic Reactions (Academic Press)", and the like.
The compound (1-a) wherein A^ is tetrazolyl group and A^ is a hydrogen atom can be prepared by cyanidating the above compound (8') to provide the compound of a general formula (8"");

wherein the symbols have the same meanings as defined above, folowed by reacting with an alkaline metal azide.
88

The cyanidation can be carried out by reacting a starting compound with cyanogen halide in the presence of a base in a suitable solvent.
The cyanogen halide is preferably cyanogen bromide.
The conventional base can be preferably used as a base, such as alkaline metal carbonate (e.g. potassium carbonate) or an alkaline metal bicarbonate (e.g. sodium bicarbonate).
Any solvent which dose not disturb the reaction can be used as a solvent and the solvent illustrated in the above method I can be preferably used.
The conversion of a cyano group into a tetrazolyl group can be achieved by reacting the compound having a cyano group with an alkaline metal azide in the presence of an acid in a suitable solvent.
The alkaline metal azide includes sodium azide and lithium azide, and the like.
The ammonium salt of halogenated hydrogen such as ammonium chloride can be preferably used as an acid.
In addition, for performing the above methods, there can be referred to PCX International Publication WO04/020393 pamphlet, WO05/100298 pamphlet and JP. 2003-221376 A.
The methods for preparation of the compound (1) are applicable to preparation of the corresponding compounds of formula (I-A), (I-B) and (1-
!)■
Many of starting materials and reagents for preparation of the
aforementioned compound of the formula 1 are either commercially
available or disclosed in literatures, or can be readily prepared by a method
that is disclosed in literatures or used generally in the organic synthesis.
Experiment
The inhibitory activily of the compounds of the present invention against CETP was tested in this experiment.
Preparation of Acceptor Microemulsion
89

A solution of l-Palimtoyl-2-oleoyl-sn-gIycero-3-phosphocholine (3.5 mg), cholesteryl oleate (Smg) and triolein (0.7 mg) in chloroform was mixed and lipid was air-dried under nitrogen gas to remove solvent. 1,4-Dioxane (0.25 ml) was then added and the mixture was stirred for dissolution. The resultant lipid solution (0.2 ml) was slowly injected under the surface of Tris-saline-EDTA(TSE) buffer solution [lOmM Tris/HCl (pH 7.4), 0.15M NaCl, 2mM EDTA] (10 ml) with Hamilton syringe, while sonicating in ice-bath. After 1-hour-sonication in ice-bath, the solution was stored at 4 "C.
Preparation of Donor Microemulsion
A solution of egg PC (phosphatidylcholine) (0.33 mg) and BODIFY-CE (0.62 mg) in chloroform was mixed. After removing solvent by air-drying lipid under nitrogen gas, TSE buffer solution (3 ml) was added and the solution was sonicated in ice-bath. This solution was filtered to sterilize through 0.22 pm filter and stored at 4 °C.
Inhibitory Activity against CETP in vitio
A test solution was prepared using dimethyl sulfoxide as a solvent. Plasma from a healthy volunteer was diluted to 0.64 % with TSE buffer, and to the resultant plasma solution (187 |il) was added a test solution (3 \x\] or the solvent alone followed by incubation at 37 °C for 24 hours. After addition of TSE buffer solution (10 \d) containing 5 % donor micro-emulsion and 5 % acceptor microemulsion, the mixture was incubated at 37 °C for 3 hours. Before and after the incubation, the fluorescence intensity was measured at Ex.550nm/Em.600nm. CETP activity was defined as the difference between the measurements obtained before incubation and after incubation. The decreasing rate of the difference in the sample was defined as the inhibition rate of CETP activity. ICso for each sample was calculated from the inhibition rate of CETP activity. Using this protocol, compounds given in Examples were shown to exhibit a CETP inhibitory activity with an ICso of less than or equal to 50 ]iM. EXAMPLES
90

The present invention is illustrated in more detail by Examples and Reference Examples, but the present invention should not be construed to be limited thereto. Example 1
(1) 2-Fluoro-5-trifluoromethyl-benzaldehyde {2.7g) and ethyl-(2-methoxy-ethyl)-amine (2.18g) are dissolved in toluene (20ml), and thereto is added potassium carbonate (5.83g) and the mxture is stirred at 120°C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated brine and the mixture is separated, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—*4:1) to give 2-[ethyl-(2-methoxy-ethyl}-amino]-5-trifluoromethyl-benzaldehyde (3.75g). MS (m/z): 276 [M+H]+
(2) 2-[Ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzaldehyde (3.7g), 3,5-bis-trifluoromethyl-benzylamine (4.23g), acetic acid (1.15ml) are dissolved in 1,2-dichloroethane (SOml), and thereto is added triacetoxy sodium borohydride (5.68g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution are added methylene chloride and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—»4:1) to give (2-[(3,5-bis-trifIuoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-ethyl-(2-methoxy-ethyl)-amine (3.3Sg). MS (m/z)i 503 [M+H]+.
(3) {2-[(3,5-Bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-ethyl-(2-methoxy-ethyl)-amine (3.37g), 5-bromo-2-chlorop3a4midine (2.6g) and N-ethyldiisopropylamine (3.51ml) are dissolved in toluene (50ml) and the mixture is stirred at 120°C overnight. The reaction solution is
91

cooled to room temperature, and thereto are added ethyl acetate and water and the mixture is separated, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—>19:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromop5Timidin-2-yl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-aniine (4.06g). MS (m/z): 659/661 [M+H]*
(4) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-{2-[ethyI-(2-methoxy-ethyl)-ainino]-5-trifluoromethyl-benzyl}-amine (350mg) is dissolved in toluene {5ml) and tris(dibenzylideneacetone)dipalladium (49ing), sodium tert-butoxide (77mg), 2-(di-tert-butylphosphino)biphenyl f63nig) and ethyl piperidine-4-carboxylate (119ial) and the mixture is stirred under nitrogen flow at room temperature overnight. To the reaction solution is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^3:1} to give ethyl l-[2-{(3,5-bis-trifluoromethyl-ben^yl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (212mg). MS (m/z): 7:36 [M+HJ+
(5) Ethyl l-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-{2-methoxy-ethyl)-aminoi-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carbo;^late (205mg) is dissolved in ethanol (2ml) and thereto is added 2N-aqueous sodium hydroxide solution (418^1) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated aqueous citric acid solution, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate =
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1:1^0:1) to give l-[2-((3,5-bis-trifluoromethy]-benzy])-{2-jethy]-(2-methoxy-ethyI)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid (155mg). The resulting carbojq'lic acid is dissolved in ethanol (1ml) and thereto is added 2N-aqueous sodium hydroxide solution (llOpl) and the reaction solution is concentrated under reduced pressure to give l-[2-{(3,5-bis-trifluoromethyI-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino] - 5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid sodium salt (159mg). MS (m/z): 706 [M-Na]-Example 2
(1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (5.0g) and butyl-ethyl-amine (3.95g) are dissolved in toluene (50ml) and thereto is added potassium carhonate (10.78g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—*4:1) to give 2-(butyl-ethyl-amino)-5-trifluoromethyl-benzaldehyde (6.54g). MS (m/z): 274 [M+H]-
(2) 2-(Bu1yl-ethyl-£imino)-5-trifluoromethyl-benzaldehyde (5.5g), 3,5-bis-trifluoromethyl-ben^lamine (7.52g), acetic acid (2.04ml) are dissolved in 1,2-dichloroethane (50ml), and thereto is added triacetoxy sodium borohydride (10. Ig) at room temperature and the mixture is stirred for 2 hours. To the reaction solution are added IN-aqueous sodium hydroxide solution and methylene chloride, and the mixture is separated, and the organic layer is washed with a saturated brine and dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^4:1) to give {2-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-butyl-ethyl-amine (10.48g). MS (m/z); 501 [M+H]+
93

(3) {2-[(3,5-Bis-trifluoromethyl-benzylaiiiino)-methyl]-4-trifluoromethyl-phenylj-butyl-ethyl-amine (4.6g), 5-bromo-2-chloropyriniidine (3.56g) and N-ethyldiisopropylethylamine (4.8ml) are dissolved in toluene (lOOml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-*9:1) to give (3,5-bis-trifluoromethyl-ben^l) - (5-bromo-pyrimidin-2-yl) - [2 - (butyl-ethyl-amino) - 5-trilluoromethyl-benzyl]-amine (5.24g). MS (m/z): 657/659 [M+H]*
(4) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl)-[2-(butyl-ethyl-ainino)-5-trifluoromethyl-benzyl]-amine (3.0g), [1,1'-bis(diphenylphosphino)ferrocenejdichloropalladium methylene chloride complex {112mg), potassium acetate (1.34g) and bis(pinacolate)diboron (1.74g) are dissolved in dimethylsulfoxide (20ml) and the mixture is heated to 80°C under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is dissolved in tetrahydrofuran (70ml) and thereto is added dropwdse a 30 % aqueous hydrogen peroxide solution (15ml) under ice-cooling. On hour thereafter, thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consum.e the excess hydrogen peroxide, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1->3:1) to give 2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-
94

5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (263mg). MS (m/z): 595 [M+H]^
(5) 2-{(3,5-Bis-trifluoromethyl-benzyl}-[2-(buQ^l-ethy]-amino)-5-trifluoroinethyl-benzyll-ainino}-pyriinidin-5-ol (150mg) and ethyl 4-bromobutyrate (44vil) are dissolved in N,N-dimethylformamide (3ml) and thereto is added potassium carbonate (42mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—*3:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-ben2yl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyll-amino}-pyrimidin-5-yloj^)-butyrate (117mg). MS (m/z): 709 [M+H]^
(6) Ethyl 4-(2-{{3,5-bis-trifluoromethyl-benzyl}-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-am.ino}-pjTiniidin-5-yloxy)-butyrate (1 lOmg) is dissolved in ethanol (2ml) and thereto is added a 2N-aqueous sodium hydroxide solution (233pl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated aqueous citric acid solution, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1 to 7:3) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl) - [2-(butyl-ethyl-amino) - 5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (69mg). The resulting carboxylic acid is dissolved in ethanol (0.2mL) and thereto is added 2N-aqueous sodium hydroxide solution (SOpl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-l2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (70mg). MS (m/z): 679 [M-Na]-
95

Example 3
(1) 2-((3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethy-ethyl-ainino)-5~trifluoroinethyl-benzyl]-aniino}-pyriniidin-5-ol (250mg) and 3-bromo-l-propanol (43ial) are dissolved in N^N-dimethylformamide (1ml) and thereto is added potassium carbonate (65mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mbcture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—*3:1) to give 3-(2-{(3,5-bis-trifluorom ethyl-benzyl) - [2-(cyclohej^lmethy-ethyl-amino)-5 - trifluoromethyl-benzyl]-amino}-p3aimidin-5-yloxy}-propan-l-ol (150g). MS (m/z): 693 [M+H]+
(2) 3-(2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethy-ethyI-ainino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ylojcy)-propan-l-ol (140mg) is dissolved in methylene chloride (2ml), and thereto is added l,l,l-tris(acetyloj^)-l,l-dihydro-l,2-benziodoxoI-3-(lH)-one (188mg) at room temperature and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, 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 resulting residue is dissolved in the mixed solvent of tert-butanol (4ml) ad water (1ml) and thereto are added 2-methyl-2-butene (128iil), sodium dihydrogenphosphate dihydrate (44mg) and sodium chlorite (73mg) and the mixture is stirred at room temperature for 30 minutes. Thereto are added ethyl acetate and a IN-hydrochloric acid, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—*2:3) to give 3-(2-{(3,5-bis-
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lTifluoromethyl-benzyl)-[2-(cyclohexylmethy-ethyl-amino)-5-trifluoromethyl-benzyl]-ainino}-pyrimidin-5-yloxy)-propiomc acid (60ing). The resulting carboxylic acid is dissolved in ethanol {0.5ml), and thereto is added IN-aqueous sodium hydroxide solution (85|il) and the reaction solution is concentrated under reduced pressure to give 3-(2-{(3,5-bis-trifluoromethyl-ben^l)-[2-(cyclohexylmethy-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-S-yloxy)-propionic acid sodium salt (60mg). MS (m/z): 705 [M-Na]-. Example 4
(1) Ethyl 4-{2-[[2-{benzyl-ethyl-ainino)-5-trifluoromethyl-benzyl]-(3,5-bis-trifluoromethyl-benzyl)-ainino]-pyrimidin-5-yloxy}-butyrate (4.07g) is dissolved in ethanol (60ml), and thereto is added 10% palladium-carbon {500mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 30 minutes. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1-*17;3) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl}-(2-ethylaniino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyTate (S.lg). MS (m/z): 653 [M+Hj*
(2) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trif]uoromethyl-benzyl)-amino]-pyrimid2n-5-yloxy}-butyrate (200rog) and pjnidine (371 pi) are dissolved in methylene chloride {5ml) , and thereto is added ethyl chlorocarbonate (293vil) under ice-cooling. The reaction solution is stirred at room temperature overnight and the organic solvent is concentrated under reduced pressure. To the residue are added ethyl acetate and an aqueous citric acid solution, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-
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(ethoxycarbonyl-ethyl -amino) -5-trifluoromethyl- benzyl]-aininoj- pyrimidin-5-yloxy)-butyrate (176mg). MS (m/z): 725 [M+H]*
(3) Ethyl 4-(2-{(3,5-bis-txifluoromethyl-benzyl}-[2-(ethoxycarbonyl-ethyl-amino)-5-triflu oromethyl-benzyl j-ainino}-p3Timidin-5-yloxy)-butyrate fl70mg) is dissolved in ethanol (2ml), and thereto is added 2N-aqueous sodium hydroxide solution (352ial) and the mixture is stirred at room temperature for 1.5 hours and concentrated under reduced pressure. To the residue are added ethyl acetate and a IN-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-aniino)-5 - trifluoromethyl-benzyl]-arnino}-p>Timidin-5-yloxy)-butyric acid (147mg). The resulting carboxylic acid is dissolved in ethainol (1ml) and thereto is added 2N-aqueous sodium hydroxide solution {106pl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-ben^I]-amino}-pjT-imidin-5-yloxy)-butyric acid sodium salt (ISlmg). MS (m/z): 695 [M-Na]-Example 5
(1) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-
trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloj^}-bu^ate (lOOmg) and p5Tidine (19pl) are dissolved in methylene chloride (1ml) and thereto is added butyryl chloride (19^1} at room temperature. The reaction solution is stirred at room temperature for 30 minutes, and thereto are added methylene chloride and IN-hydrochloric acid, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-*4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-am.ino}-p3Timidin-5-yloxy)-butyrate
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(84mg). MS (m/z): 723 [M+H]^
(2) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-aniino)-5-trifluoroinethyl-benzyl]-aiiiino}-pyrimidin-5-yloxy)-bufyrate (78ing) is dissolved in ethanol (Iml) and tiiereto is added a 2N-aqueous sodium hydroxide solution (162^1) and the mixture is stirred at room temperature for 3 hours. Thereto are added ethyl acetate and a IN-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{{3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl] - amino}-pyrimidin-5-yloxy}-butyric acid (66mg). The resulting carboxylic acid is dissolved in ethanol (0.5ml), and thereto is added 2N-aqueous sodium hydroxide solution (47fi]) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-triflu oromethyl-benzyl) - [2 - (bulyryl-ethyl-amino)-S-trifluoromethyl-ben^l]-amino|-pyrimidin-5-yloxy)-butyric acid sodium salt (68mg). MS (m/z): 693 [M-Na]' Exam.ple 6
(1) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-
trifluoromethyl-benzyl)-amino]-p5nrimidin-5-yloxy}-butyrate (200mg) and triethylamine (51ial) are dissolved in methylene chloride (1ml), and thereto is added triphosgene (36mg) in a small amount at room temperature. The reaction solution is stirred at room temperature for 10 minutes and concentrated under reduced pressure. The residue is dissolved in tetrahydrofuran (1 ml) and therero is added a 2M ethylamine in tetrahydrofuran (1ml) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution are added ethyl acetate and a IN-hydrochloric acid, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—»■ 1:1) to give
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ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(l,3-diet±iyllureido)-5-
trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (ISlmg). MS (m/z): 724 [M+H]*
(2) Ethyl 4-(2-{{3,5-bis-trifluoroinethyl-benzyl)-[2-(l,3-diethyllureido)-5-
trifluoromethyl-benzyl]-ainino}-pyrimidin-5-yloxy)-butyrate (165mg) is
dissolved in ethanol (3inl) and thereto is added 2N-aqueous sodium
hydroxide solution (342^1) and the mixture is stirred at room temperature
overnight. To the reaction solution are added ethyl acetate and a IN-
hydrochloric acid, 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 resulting residue is purified by
silica gel column chromatography (chloroform : methanol = 1:0—*17:3) to
give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(l,3-diethyllureido}-5-
trifluoromethyl-benzyll-amino}-p5Timidin-5-yloxy)-butyric acid (68mg). MS (m/z): 696 [M+H]* Example 7
(1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (l-3g) and cyclopropylmethyl-propyl-amine (1.15g) are dissolved in toluene (13ml), and thereto is added potassium carbonate (2.81g) and the mixture is stirred at 120'C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = l:0->97:3) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-ben2aldehyde {l-7g). MS (m/z): 286 [M+H]+
(2) 2-(Cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (1.69g} is dissolved in ethanol (10ml) and thereto is added sodium borohydride (224mg) and the mixture is stirred for 15 minutes. To the
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reaction solution are added a saturated aqueous ammonium chloride 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 resulting residue is dissolved in methylene chloride (10ml) and thereto is added thionyl chloride (492|il) under ice-cooling, and the mixture is stirred for 10 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate 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. (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yI)-amine {2.7g) is dissolved in N,N-dimethylformamide (10ml) and thereto is added sodium hydride (62%) (343mg) at room temperature and the mixture is stirred for 30 minutes. Thereto are added dropwise a solution of a residue obtained above in N,N-dimethylformamide (10ml) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—*9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-p5Timidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyll-amine (3.38g). MS (m/z): 669/671 [M+H]* (3) (3,5-Bis-trifluoromethyl-ben^l}-(5-bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-ben2ylj-amine (3.35g) [l,l'-bis(diphenylphosphino)ferroceneldichloropalladium dichloromethane complex (817mg), potassium acetate (1.47g), bis(pinacolate)diboron (2.54g) are dissolved in dimethylsulfoxide (20ml) and the mixture is heated to 80°C under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the insoluble materials is removed by filtration through Celite^'M and
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the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (20ml|, and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (lOml) under ice-cooling. One hour thereafter, thereto is added a saturated aqueous sodium thiosuifate solution under ice-cooling to consume the excess hydrogen peroxide, and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—*4:1) to give 2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-triftuoromethyl-benzyl]-amino}-pyrimidin-5-ol {1.8g). MS (m/z): 607 [M+H]+
(4) 2-{{3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropylm ethyl-pro pyl-an3ino)-5-trifluoromethyl-ben2yl]-aminD}-pyrimidin-5-o] (SOOmg) and ethyl 4-bromobutyrate (SS^il) are dissolved in N,N-dimethylformamide (1ml) and thereto is added potassium carbonate (82mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, 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 resulting residue is purified by silica ge] column chromatography (hexane ; ethyl acGtate = 97:3—*17:3) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cycloprQpylmethyl-propyl-amino) - 5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (296mg). MS (m/z): 721 [M+Hj*
(5) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (290mg) is dissolved in ethanol (5ml) and thereto is added a 2N-aqueous sodium hydroxide solution (604|ilj and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a IN-
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hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropyImethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid {277mg). The resulting carboxylic acid is dissolved in ethanol (Imi) and thereto is added 2N-aqueous sodium hydroxide solution (200vil), and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoro methyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino) - 5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy}-butyric acid sodium salt (278mg). MS (m/z); 691 [M-Na]-Example 8
(1) To toluene (Sml) are added 2-fluoro-5-trifluoromethyl-benzaldehyde
(650mg) and dimethylamine hydrochloride (2.76g), followd by addition of
potassium carbonate {l-4g), and the mixture is stirred at 120'C overnight.
The reaction solution is cooled to room temperature, and thereto are added
ethyl acetate and water, 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 resulting residue is purified by
silica gel column chromatography (hexane : ethyl acetate = 49:1^4:1} to
give 2-dimethylamino-5-triiluoromethyl-ben2aldehyde (529mg). MS (m/z):
218 [M+H]*
(2) 2-Dimethylamino-5-trifluoromethyl-benzaldehyde (144mg) is
dissolved in ethanol (10ml) and thereto is added sodium borohydride
(224mg) at room temperature and the mixture is stirred for 15 minutes. To
the reaction solution are added a saturated aqueous ammonium chloride
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 resulting residue is dissolved in
methylene chloride (2ml) and thereto is added thionyl chloride (58pl) under
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ice-cooling and the mixture is stirred at room temperature for 10 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate 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. Ethyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-ylo:qr]-butyrate (200mg) is dissolved in N,N-dimethylformaniide (1.5ml) and thereto is added sodium hydride (62%) {26mg) under ice-cooling, and the mixture is stirred for 15 minutes. Thereto is added a solution of a residue obtained above in N,N-dimethylformamide (1.5ml), and the mixture is stirred at the same temperature for 15 minutes. To the reaction solution are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—t-9:l) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-dimethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-bu1yrate (97mg). MS (m/z): 653 [M+H]*
(3) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-dimethylamino-5-
trifiuoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (QOmg) is dissolved in ethanol (2ml), and thereto is added a 2N-aqueous sodium hydroxide solution (207^1), and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a IN-hydrochloric acid, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—*1:4) to give 4-{2-[(3,5-bis-triiluoromethyl-benzyl)-(2-dimethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (29mg). The resulting carboxylic acid is dissolved in ethanol (0.5ml) and thereto is added a 2N-aqueous sodium
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hydroxide solution (23vil} and the reaction solution is concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyI-benzyl)-(2-dimethylamino-5-trifluoromethyl-ben^l)-amino]-pyrimidin-5-yloxy}-butyric acid ethyl ester sodium salt (30mg). MS (m/z): 623 [M-Na]-Example 9
(1) 2-Fluoro-5-trifluoromethyl-benzylamine (2.0g) is dissolved in 1,4-dioxane (lOml) and thereto are added N.N-diisopropylethylamine (2.7ml) and 5-bromo-2-chloropyrimidine (3.02g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1 to 7:3) to give (5-bromo-p3Timidin-2-yl)-(2-fluoro-5-triiluoromethyl-benzyl)-amine (1.69g). MS [m/z): 350/352 [M+H]*
(2) (5-Bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (2.10g) is dissolved in N,N-dimethylformamide (10ml) and thereto is added sodium hydride (62.7%) (345mg) under ice-cooling and the mixture is stirred for 30 minutes, and thereto is added l-bromomethyl-3,5-bis-trifluoromethyl-benzene (2.76g) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixtrure is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0^9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-iluoro-5-trifluoromethyl-benzylj-amine (3.30g). MS (m/z): 576/578 [M+H]^
(3) (3,5-Bis-trifluorQmethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-eimine (300mg) is dissolved in toluene (5ml) and tris(dibenzylideneacetone)dipalladium (48mg), 2-(di-tert-butylphosphino)biphenyl (62mg), sodium tert-butoxide (75mg) and
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morpholine (68^1) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by NH-silica gel column chromatography {hexane : ethyl acetate = 19:l-*9:l) to give {3,5-bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl-benzyl)-(5-morphDlin-4-yl-pyrimidin-2-yl)-amine {176mg). MS (m/z): 583 [M+H]* Example 10
(1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyTimidin-2-yl)-(2-fluoro-
5-trifluoromethyl-benzyl)-amine (300mg) is dissolved in toluene {5ml) and thereto are added tris(dibenzylideneacetone)dipalladium (48mg), 2-(di-tert-butylphosphinojbiphenyl (62mg), sodium tert-butoxide (75mg) and ethyl piperidine-4-carboxylate (120pl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by NH-silica gel column chromatography (hexane ; ethyl acetate = 19:1—*9:1) to give l-{2-[(3,5-bis-trifluoromethyl-ben^l)-{2-fluoro-5-trifluoromethyl-ben^l)-amino]-pyrimidin-5-yl}-ethyl piperidine-4-CEirboxylate (Hlmg). MS (m/z): 653 [M+H]*
(2) l-{2-[(3,5-Bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl-
benzyl)-amino]-pyrimidin-5-yl}-ethyl piperidine-4-carboxylate (105mg) is
dissolved in ethanol (4ml) and thereto is added a IN-aqueous sodium
hydroxide solution {2ml), and the mixture is stirred at room temperature
for 2 hour. To the reaction solution are added IN-hydrochloric acid and
ethyl acetate, and the mixture is separated, and the organic layer is
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washed with a saturated brine, dried over magnesium sulfate, and
concentrated under reduced pressure. The resulting residue is purified by
silica gel column chromatography (chloroform : methanol = liO-^Qil) to
give l-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl-
ben^I)-aminoI-pyrimidin-5-yI}-piperidine-4-carboj^Iic acid (Slmg). MS (m/z): 625 [M+H]-^ Example 11
(1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trif!uoromethy]-benzy])-amine f300mg) is dissolved in tetrahydrofuran {3ml) and thereto are added ethyl-carbamic ethyl ester (67mg) and sodium hydride (60%) (23mg) and the mixture is stirred at 120°C under a condition of 192W by a microwave instrument for 1 hour and thereto are added ethyl-carbamic ethyl ester (134mg) and sodium hydride (60%) (46mg) and the mixture is stirred at 120°C under a condition of 192W by a microwave instrument for an additional 1 hour. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—'9:1) to give (3,5-bis-trifluoromethyl-ben^l)-(5-bromo-pyrimidin-2-yl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amine (220mg). MS (m/z): 602/604 [M+H]^
(2) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amine (210mg) is dissolved in toluene (5ml} and thereto are added tris(dibenzylideneacetone)dipalladium (32mg), 2-(di-tert-bulylphosphino)biphenyl (42mg), sodium tert-butoxide (50mg) and ethyl piperidine-4-carboxylate (SOiol) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate 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
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reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = l:0- (3) Ethyl l-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethoxy-5-
trifluoromethyl-benzyl}-amino]-pyrimidin-5-yl}-piperidine-4-carboxylate (llOmg) is dissolved in ethanol (4nil) and thereto is added a iN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = l:0-*-9:l) to give l-{2-[(3,5-bis-trinuoromethyl-benzyl}-(2-ethoxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carboxylic acid (63mg). MS (m/z): 651 [M+H]+ Example 12
(1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (Ig) is dissolved in toluene (5ml) and thereto are added ethyl 7-ethylamino-heptanoate (3.98g) and potassium carbonate (2.88g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 97:3-»83:17) to give ethyl 7-[ethyl-(2-formyl-4-trifiuoromethyl-phenyl)-amino]-heptanoate (1.29g). MS (m/z): 374 [M+H]^
(2) Ethyl 7-[ethyl-(2-formyl-4-trifluoromethyl-phenyl)-amino]-heptanoate (1.29g) is dissolved in a mixed solvent of toluene {5ml) and etheinol (1ml),
108

and thereto is added sodium borohydride {156mg) and the mixture is stirred for 2 hours and 30 minutes. To the reaction solution are added a saturated aqueous ammonium chloride 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—*3:1) to give ethyl 7-[ethyl-(2-hydroxymethyl-4-trifluoromethyl-phenyl)-amino]-heptanoate (589mg). MS (m/z): 376 [M+H] +
(3) Ethyl 7-[ethyl-(2-hydroxymethyl-4-trifluoromethyl-phenyl)-amino]-heptanoate {580mg) is dissolved in toluene (10ml) and thereto is added thionyl chloride (135pl) under ice-cooling, and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added water 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 resulting residue is dissolved in N,N-dimethylformamide (10ml), and thereto are added (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (740mg) and sodium tert-butoxide (178mg) and the mixture is stirred at room temperature overnight. To the reaction solution are added a saturated aqueous ammonium chloride 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 resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 23 : 2-*41: 9) to give ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoate (760mg). MS (m/z): 757/759 [M+H]+
(4) Ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl) - amino]-me thy l}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoate (300mg) is dissolved in toluene (5ml) and thereto are added
109

tris(dibenzyiideneacetone)dipalladmm (37ing), 2-(di-tert-
but7lphosphino}biphenyl (48mg), sodium tert-butoxide (58mg), and morpholine (53>il) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is sepeirated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-sHica gel column chromatography (hexane : ethyl acetate = 9:1-»4:1) to give ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yI-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyI-phenyl)-ethyl-amino]-heptanoate (254mg). MS (m/z): 764 [M+H]*
(5) Ethyl 7-|(2-{[{3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-
p3T-imidin-2-yl)-aminol-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-
heptanoate (250mg) is dissolved in ethanol (4ml), and thereto is added a
IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at
room temperature for 3 hours and 30 minutes. To the reaction solution
are added a IN-hydrochloric acid and ethyl acetate, and the mixture is
separated, eind the organic layer is washed with a saturated brine, dried
over magnesium sulfate, and concentrated under reduced pressure. The
resulting residue is purified by silica gel column chromatography
(chloroform : methanol = 1:0-*19:1) to give 7-l(2-{[(3,5-bis-trifluoromethyl-
benzyl}-(5-morpholin-4-yl-pyTimidin-2-yl)-amino]-methyl}-4-
trifluoromethyl-phenyl)-ethylaminoj-heptanoic add (ISlmg). The resulting
7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-
aminol-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoic acid
{131mg) is dissolved in ethanol (1ml), and thereto is added a IN-aqueous sodium hydroxide solution (178^1), and concentrated under reduced pressure to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-

heptanoic acid sodium salt (133mg). MS (m/z): 734 [M-Na]-Example 13
(1) Ethyl trans-(4-{[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino J-me thyl}-4-trifluoromethyl-phenyll-ethyl-amino]-methyl}-cyclohexyl)-acetate (which is prepared by treating the corresponding starting compound in a same manner as in Example 12 (1)-(3)) (2.6g) is dissolved dimethylsulfoxide (15ml), and thereto are added [l,r-bis(diphenylphosphtno}ferrocene]dichloropalladium dichloromethane complex (73mg), potassium acetate (977mg) and bis(pinacolate)diboron (1.26g), and the mixture is heated to 80°C under nitrogen atmosphere and stirred for 2 hours. The reaction solution is cooled to room temperature and thereto are added a saturated brine and ethyl acetate, and the mixture is separated and the organic layer is washed with a saturated brine again, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (30ml) and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (30ml) under ice-cooling. The mixture is stirred for 1 hour, and thereto is added a saturated aqueous sodium thiosulfate solution to consume the excess hydrogen peroxide and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1 to 7:3) to give ethyl trans-(4-{l(2-{[{3,5-bis-trifluoromethyl-benzyl) -(5 -hydroxy-pjTimidin- 2 -yl)-amino) -methyl}-4-trifluoromethyl-phenyl)-ethylaminol-methyl}-cyclohexyl)-acetate (1.29g). MS (m/z): 721 [M+H]+
(2) Ethyl trans-(4-{[(2-{({3,5-bis-trifluoromethyl-benzyI)-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-4-trinuoromethyl-phenyl)-ethyl-amino]-methyl}-cyclohexyl)-acetate (300mg) is dissolved in N,N-dimethylformamide (4ml), and thereto are added 2-bromoethanol (87|il) and potassium

carbonate (172nig), and tiie mixture is stirred at 60°C for 1 day. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 7:3—»1:1} to give ethyl trans-[4-({[2-({(3,5-bis-trifluoromethyl-ben2yl)-[5-(2-hydroxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-ajTiino}-methyl)-cyclohexyl]-acetate (138mg). MS (m/z): 765 [M+H]* (3) Ethyl trans-[4-({[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-hydroxy-ethoxy)-p5Timidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-methyl)-cyclohexyl]-acetate (122nig) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (Iml) and the mixture is stirred at 60°C for 2 hours. The reaction solution is cooled to room temperature, and thereto are added IN-hydrochloric acid and ethyl acetate, and the mixture is separated, and the orgeinic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 7:3- Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-propionate (which is prepared by treating the corresponding starting compound in a same manner as in Example 12(l}-(4)) (205mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (5ml} and the mixture is stirred at room temperature for 2 hour. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:1^0:1) to give 3-[(2-{[(3,5-bis-trifluoroniethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl}-aniino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-propiomc acid (133mg}. MS (m/z): 680 [M+H]* Example 15
(1} Ethyl 7-[(2-{l(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-
pyrimidin-2-yl}-amino]-methyl}-4-trifluoromethyl-phenyl)-(2-tert-buto3^-ethyl)-aniino]-heptanaate (which is prepared by treating the corresponding starting compound in a same manner as in Example 12(l)-(4)) (260mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (4ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over ma^esium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:l-»3:2) to give ethyl 7-[(2-acetoxy-ethyl)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl} - amino]-methyl}-4-trifluoromethyl-phenyl) - amino]-heptanoate (162mg). MS (m/z): 822 [M+H]+
(2) Ethyl 7-[(2-acetoxy-ethyl)-(2-{[{3,5-bis-trifluorQmethyl.benzyl)-(5-
morpholin-4-yl-pyrimidin-2-yl)-£imino]-methyl}-4-trifluoromethyl-phenyl)-amino]-heptanoate (156mg) is dissolved in ethanol (4ml), and thereto is added iN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 4 hours. To the reaction solution are added IN-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

resulting residue is purified by silica gel column chromatography
(chloroform : methanol = 1:0-^19:1) to give 7-[(2-acetoxy-ethyl)-(2-{|(3,5-
bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-p3T:imidin-2-yl)-amino]-
methyl}-4-trifluoromethyl-phenyl)-amino]-heptanoic acid (144mg). The
resulting 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-
pyTimidin-2-yl)-amino]-methyl}-4-triftuoromethyl-phenyl}-(2-hydroxy-ethyl}-aminoj-heptanoic acid (144mg) is dissolved in ethanol flml), and thereto is added a IN-aqueous sodium hydroxide solution (172vil ), and concentrated under reduced pressure to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl}-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-triauoromethyl-phenyl)-(2-hydroxy-ethyl)-amino]-heptanoic acid sodium salt (ISSmg). MS (m/z): 750 [M-Na]-Example 16
(1) Ethyl 6-[(2-{[{3,S-bis-trifluoromethyl-ben^l)-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-hexaiioate (120mg) is dissolved in tetrahydrofuran (1ml), emd thereto are added 2-methoxyethanol (21^1) and triphenylphosphine (69mg), and thereto is added dropwise 40% diethyl azodicarbojQ'late in toluene (llSpl) under water-cooling, and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 6:1) to give ethyl 6-{[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methojcy-ethoxy}-pyrimidin-2-yl]-amino}-methyl}-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanQate (120mg). MS (m/z): 739 [M+H]*
(2) Ethyl 6-{[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoate (113mg) is dissolved in a mixed solvent of ethanol {2nil) and

tetrahydrofuran (1ml), and thereto is added IM-aqueous sodium hydroxide
solution (1ml), and the mixture is stirred at room temperature for 2 hours.
The reaction solution is made weakly acidic with a 10 % aqueous citric acid
solution, and the mixture is extracted with ethyl acetate, and the organic
layer is washed with a saturated brine, dried over magnesium sulfate, and
concentrated under reduced pressure. The resulting residue is purified by
silica gel column chromatography (chloroform : methanol = 1:0—*49:1} to
give 6-{[2-({{3,5-bis-trifluoromethyl-ben3yl)-[5-(2-methoxy-ethoxy)-
pyrimidin-2-yl]-ainino}-methyl)-4-trifluQromethyl-phenyl]-ethyl-aniino}-hexanoic acid (lllmg). MS (m/z): 711 [M+H]*
(3) 6-{[2-({{3,5-Bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl)-ainino}-methyl)-4-trifluoromethyl~phenyl]-ethyl-aniino}-hexanoic acid (105mg) is dissolved in ethanol (1ml), and thereto is added a 2M-aqueous sodium hydroxide solution (74|il), and the mixture is stirred at room temperature for 5 minutes. The reaction solution is concentrated under reduced pressure to give 6-{I2-({(3,5-bis-trifluorom ethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoic acid sodium salt (102mg). MS (m/z): 709 [M-NaJ-Example 17
(1) (2-Bromo-trifluoromethyl-phenyl}-methanol (5g) is dissolved in N,N-dimethylformamide (45ml) and thereto are added palladium acetate (440mg), l,r-bis(diphenylphosphino)ferrocene {2.17g) and triethylamine (2 (5ml), and the mixture is stirred under carbon monooxide flow at room temperature for 5 minutes and at 90°C for 1 day. The reaction solution is cooled to room temperature, and thereto are added a IN-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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1^^3:2) to give

6-trifluoromethyI-3H-isobenzofuran-l-one (2.77g). MS (m/zj: 203 [M+H]*
(2) 6-Trifluoromethyl-3H-isoben2ofuran-l-one (1.77g) is dissolved in methylene chloride (20ml) and the mixture is cooled to -78'^C, and thereto is added a l.OM diisobutylaluminum hydride in toluene (19.5ml) and the mixture is stirred for 1 hour and 20 minutes. The reaction solution is cooled to room temperature, and thereto are added a saturated aqueous ammonium chloride solution and ethyl acetate, and the m^ixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—*3:2) to give 6-trifluoromethyl-l,3-dihydro-isobenzofuran-l-ol(1.36g|. MS (m/z): 187 [M+H-H20i*
(3) 6-Trifluoromethyl-l,3-dihydro-isobenzofuran-l-ol (4.12g) is dissolved in 1,2-dichloroethane (75ml), and thereto are added 3,5-bis-trifluoromethyl-benzylamine (5.89g), triacetoxy-sodium borohydride (9.0g) and acetic acid (2.3ml), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 7:3^1:1) to give {2-[(3,5-bis-trifluoromethyl-ben2ylainino)-methyl]-4-trifluoromethyl-phenyl}--methanol (7.06g). MS (m/z): 432 [M+H]*
(4) {2-[(3,5-Bis-ti-ifluoromethyl-ben2ylamino)-methyl]-4-trifluoromethyI-phenyl}-n]ethanol (7.0g) is dissolved in toluene (70ml) and thereto are added 5-bromo-2-chloro-pyrimidine {4.7g) and N,N-diisopropylethylamine (4.23ml) and the mixture is heated under reflux for 3 days. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—*3;2) to give (2-{[(3,5-bis-trifluoromethyI-benzy2)-(5-bromo-pyrimidin-2-yl)-amino)-methyl}-4-trifluorcmethyl-phenyl)-methanol (7.37g). MS (m/z): 588/590 [M+H]+
(5) (2-{[(3,5-Bis-trifluoromethyl-benzyl}-(5-bromo-pyrimidin-2-yl)-aniino]-niethyl}-4-trifluoromethyl-phenyl)-methanol (225mg) is dissolved in acetone (5ml), and thereto is added 1.94M Jones reagent {290pl} under ice-coolitig, and the mixture is stirred for 30 minutes. To the reaction solution are added sodium hydrogenesulfite, water 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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-»9:1) to give 2-{[(3,5-bis-trifluorotnethyl-benzyl)-(5-bromo-p5T-imidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoic acid (ISlmg). MS (m/z): 602/604 [M+H]+ (6} 2-{[(3,5-Bis-trifluoromethyl-benzyl}-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyI-benzoic acid (Ig) is dissolved in tetrahydrofuran (10ml), and thereto are added diphenoj^^jhosphinylazide (540pl), triethylamine (695pl) and ethanol (6ml) and the mixture is heated at 60°C for 3 days with stirring. The reaction solution is cooled to room temperature, and thereto are added IN-hydrochloric acid and ethyl acetate, £ind the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0^4: l-»chloroform : methanol = 4:1) to give ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl}-carbamate (660mg). MS (m/z): 645/647 {M+H]* (7) Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyriniidin-2-yl)-

amino]-niethyl}'4-trifluoromethyl-phenyl}-carbamate (980mg) is dissolved in N,N-dimethylformamide (lOml), and thereto is added sodium hydride (60%) (91mg) under ice-cooiing, and the mixture is stirred for 30 minutes and thereto is added ethyl iodide (182^1) and the mixture is stirred at room temperature overnight. Thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^^4:1) to give ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methylS-4-trifluoromethyl-phenyl)-ethyl-carbamate (425mg). MS (m/z): 673/675 [M+H]*
(8) Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbainate (412mg) is dissolved in toluene (5ml) , and thereto are added tris(dibenzylideneacetone)dipalladium (112mg), 2-(di-tert-butylphosphino)biphenyl (146mg), sodium tert-butoxide (176mg) and ethyl piperidine-4-carboxylate (140|il), and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—*-4:l) to give l-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-ainino}-pyrimidin-5-yl}-ethyl piperidine-4-carboxylate (72mg). MS (m/z): 750 [M+H]+
(9) l-(2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trinuoromethyl-benzyl]-amino}-pyrimidin-5-jl)-ethyl piperidine-4-carbo3cylate (70mg) is dissolved in ethanol (4ml), and thereto is added IN-

aqueous sodium hydroxide solution flml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution aire added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—*9:1) to give l-{2-{(3,5-bis-trifluoroinethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-triflu oromethyl-benzyl]-amino}-pyrimidin-5-yll-piperidine-4-carboj^lic acid (44mg). The resulting l-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-aniino)-5-trifluoromethyl-benzyl]-amino)-pyrimidin-5-yl}-piperidine-4-carboxylic acid (44mg) is dissolved in ethanol (1ml), and thereto is added IN-aqueous sodium hydroxide solution (44|il), and then the mixture is concentrated under reduced pressure to give l-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trinuoromethyl-benryl]-amino}-p5T-imidin-5-yl)-piperidine-4-carboxylic acid sodium salt (45mg). MS (m/z): 720 [M-Na]-Example 18
(1) Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-
amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (614mg) is dissolved
in toluene (6.5ml), and thereto are added
tris(diben2ylideneacetone)dipalladium(0) (87mg), 2-(di-tert-
butylphosphino)biphenyl (114mg), morpholine (166]il) and sodium tert-butoxide (183mg) and the mixture is stirred under nitrogen flow at 60°C for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 9:1-^4:1) to give ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl)-4-trifluoromethyl-phenyl)-carbamate (476mg). MS (m/z): 652

[M+H] +
(2) Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-{5-morpholin-4-yl-pyrimidin-2-yl) - amino]-inethyl}-4-trifluoromethyl-phenyl) - carbamate (140mg) is dissolved in N,N-dimethylformainide (Iml), and thereto is added sodium hydride (63%) (12mg) under ice-cooling, and the mixture is stirred at the same temperature for 30 minutes. To the reaction mixture is added ethyl 5-bromo-pentanoate {68iil), and the mixture is stirred at 0°C to room temperature overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give ethyl 5-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-me thy l}-4-trifluoromethyl-phenyl}-ethoxycarbonyl-aminol-pentanoate (137mg). MS (m/z): 780 [M+H]*
(3) Ethyl 5-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethoxycarbonyl-amino]-pentanate (134mg) is dissolved in methanol (1ml), and thereto is added IM-aqueous sodium hydroxide solution (Iml), and the mixture is stirred at room temperature for 1 hour and a half. The reaction solution is made weakly acidic with a 10 % aqueous citric acid solution, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 19:1) to give 5-[(2-{[(3,5-bis-trifluoromethyl-ben^l)-(5-morpholin-4-yl-p5n-imidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethoxycarbonyl-amino]-pentanoic acid (123mg). MS (m/z): 752 [M+H]*
Example 19
(1) 2-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyriniidin-2-yl)-amino]-

methy]}-4-trifluoromethyl'benzoic acid (2,5g) is dissolved in tetrahydrofuran (25ml), and thereto are added diphenoxyphosphinylazide (1.34ml), triethylamine (174ml) and benzyl alcohol (1.3ml) and the mixture is heated at 60°C overnight with stirring. The reaction solution is cooled to room temperature, and thereto is added a IN-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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—*9:1—♦4:1) to give benzyl (2-([(3,5-bis-trifluoromethyl-ben2yl)-(5-bromo-pyrimidin-2-yl)-aminol-methyl}-4-trifluoromethyl-phenyl)-carbamate (2.66g}. MS (m/z): 707/709 [M+H]+ (2} Benzyl (2-([(3,5-bis-trifIuoromethyI-benzyI(-(5-bronio-pyrimidin-2-yI)-aminol-methyl}-4-trifluoromethyl-phenyl)-carbamate (1.5g) is dissolved in NjN-dimethylformamide (15ml}, and thereto is sodium hydride (60%) (127mg} under ice-cooling, and the mixture is stirred for 30 minutes and thereto is added ethyl iodide (255pl), and the mixture is stirred at room temperature overnight. Thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—>17:3) to give benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl) - (5 - bromo-pyrimidin-2-yl}-amino]-methyI}-4-trifluoromethyl-phenyl)-ethyl-carbamate (1.30g). MS (m/z): 735/737 [M+H]*
(3) Benzyl (2-{[(3,5-bis-trifluoromethyI-benzylj-(5-bromo-pyrimidin-2-ylj-
amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamate (1.28g) is
dissolved in toluene (15ml), and thereto are added
tris(diben2yIideneacetone)dipalladium [159mg), 2-(di-tert-
butylphosphino)biphenyl (208mg), sodium tert-butoxide (250mg) and morpholine (230)il) and the mixture is stirred under nitrogen atmosphere

at room temperature overnight. To the reaction solution are added
tris(diben^lideneacetone)dipalladium (159mg), 2- (di-tert-
butylphosphinojbiphenyl (208mg) and sodium tert-butoxide (250mg) and the mixture is stirred for 3 hours and a half. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the orgeinic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—*4:1) to give benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl}-ethyl-carbamate (724nig). MS (m/z): 742 [M+H]*
(4) Benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamate (720mg) is dissolved in ethanol (10ml), and thereto is added 10% palladium-carbon (200mg), and the mixture is stirred under hydrogen atmosphere at room temperature for 2 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 9:1 to 7:3) to give (3,5-bis-trifluoromethyI-benzyl)-(2-ethylamino-5-trifluoromethy}-benzyl)-(5-morpholin-4-yl-pyrimidin-2-y])-amine (569mg). MS (m/z): 608 [M+H]*
(5) (3,5-Bis-trifluoromethyl-ben2yl)-(2-ethylamino-5-trifluoromethyl-benzyl}-[5-morpholin-4-yl-pyrimidin-2-yl)-aniine (200mg) and triethylamine {55]il) is dissolved in methylene chloride (5ml) , and thereto is added triphosgene (39mg) under ice-cooling, and the mixture is stirred under nitrogen atmosphere at room temperature for 30 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is dissolved in tetrahydrofuran (5ml), and thereto are added tert-butyl 3-hydrojQ'-propionate (73vil) and sodium hydride (60%) (20mg), and the mixture is stirred at room temperature overnight. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1 to 7:3) to give tert-bulyl 3-[(2-{[{3,5-bis-trifluoromethyl-benzyl)-{5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyloxy]-propionate (120mg). MS (m/z): 780 [M+H]* (5) Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyloxy]-propionate (114mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (5ml), and the mixture is stirred at room temperature for 1 hour and 30 minutes. Thereto are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-*19:1) to give 3-((2-{[(3,5-bis-trifluoromethyl-bensyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoylojcy]-propionic acid (81mg). The resulting 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyriniidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbainoyloxyl-propionic acid (Slmg) is dissolved in ethanol (1ml), and thereto is added IN-aqueous sodium hydroxide solution (115pl) and concentrated under reduced pressure to give 3-[(2-{[(3,5-bis-trifluQromethyl-ben^l)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethylcarbainoylo3ty]-propionic acid sodium salt (78mg). MS (m/z): 722 [M-Na]-

Example 20
(1) (3,5-Bis-trifluoromethyl-benzyl)-{2-ethylamino-5-trifluoromethyl-ben2yl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (400mg) is dissolved in methylene chloride {5nil}, and thereto is added triethylamine (llOpl) and triphosgene (78mg) under ice-cooling, and the mixture is stirred under nitrogen atmosphere at room temperature for 2 hours. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is dissolved in tetrahydrofuran (5ml), and thereto are added (S)-2-amino-3-tert-butojq'-propionic acid methyl ester hydrochloride (279mg) and triethylainine {183pl), and the mixture is stirred at room temperature for 1 day. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:1—3:7) to give methyl (S)-2-[3-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl'phenyl|-3-ethyl-ureido]-3-tert-butoxy-propionate (462mg). MS (m/z): 809 [M+H]*
(2) Methyl (S)-2-[3-(2-{[(3,5-bis-trinuoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-aniino]-methyl}-4-trifluoromethyl-phenyl)-3-ethyl-ureido]-3-tert-buto^-propionate (455mg) is dissolved in a 4N-hydrochloric acid in dioxane (5ml), and the mixture is stirred at room temperature for 8 hours. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate =

1:1-»0:1) to give methyl {S)-2-[3-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyiimidin-2-yl)-amino]-methyl}-4-triflu oromethyl-phenyl)-3-ethyl-ureidol-3-hydroxy-propionate (285mg). MS (m/z): 753 [M+H]*
(3) Methyl (S}-2-[3-(2-{l(3,5-bis-tri{luoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-3-ethyl-ureido]-3-hydroxy-propionate (280mg) and pyridine (72ial} is dissolved in methylene chloride (5ml), and the mixture is cooled to -20'C, and thereto is added trifluoromethane sulfonic acid anhydride (150pl) and the mixture is stirred at -20'C for 1 hour and 30 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 4:1—*-l:l) to give methyl {S)-2-l(2-{[(3,5-bis-trifluoromethy]-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-aminD]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxBzole'4-carhoxy\ate (197mg). MS (m/z): 735 [M+H]'
(4) Methyl fS)-2-[(2-{f(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yJ-pyrimidin-2-yl}-amino]-methyI)-4-trifluoromethyl-phenyl)-ethyI-aminoj-4,5-dihydro-oxazole-4-carboxyiate (190mg) is dissolved in methanol (4ml) and thereto is added a IN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-»4:1) to give (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morphoUn-4-yl-pyriinidin-2-yl)-amino]-methyl}-4-triflu oromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carbojqrUc acid (130mg). The resulting (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl}-(5-

morpholm-4-yl-p5Timidin-2-yl)-ainino]-niethyl}-4-trifluoroinethyl-phenyl)-ethyl-aininol-4,5-dihydro-oxazole-4-carboxylic acid (130mg) is dissolved in ethanol (1ml), and thereto is added IN-aqueous sodium hydroxide solution (180]al} and concentrated under reduced pressure to give (S)-2-l(2-{j(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyTimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid sodium salt (120mg). MS {m/z}: 729 [M-Na]-Example 21
(1) (3,5-Bis-trifIuoromethyl-benzyl)-(2-ethylamino-5-trifluoromethy]-ben2yl)-(5-morpholin-4-yl-p5Timidin-2-y!)-amine (164mg) is dissolved in methylene chloride (5ml), and thereto are added ethyl 6-(chloroformyl)hexanoate (67mg) and triethylamine (26]al}, and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 17:3-»7:3) to give ethyl 6-[{2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morphoUn-4-yl-pyTimidin-2-yl)-aniino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyl]-hexanoate (147mg). MS (m/z): 778 [M+H]*
(2) Ethyl 6-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyl]-hexanoate (140mg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 2 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol =

l-.0-*9:l) to give 6-[(2-{[(3,5-bis-trifluoromethyl-ben2yl)-(5-niorpholin-4-yl-pyrimidin-2-yl)-amino]-me thyl}-4-trifluoromethy]-phenyl)-ethyl-car barnoyl) -hexanoic acid (137mg). MS (m/z): 750 [M+HJ+ Example 22
(1) 2-{[{3,5-Bis-trifluoromethyl-benzyl)-(S-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoic acid (250mg) is dissolved in tetrahydrofuran (5ml), and thereto are added tert-butyl 3 -ethylamino-propionate {103mg)> l-hydroxybenzotriazole dihydrate (81mg), l-ethy-3-(3-dimethylaininopropyl)carbodiimide hydrochloride (114mg) and triethylamine (83iil), and the mixture is stirred at room temperature overnight. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^4:1) to give tert-butyl 3-[(2-{[ (3,5-bis-trifluoromethyl-benzyl) - {5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoyl)-ethyl-amino]-propionate (310mg). MS (m/z): 757/759 [M+H|*
(2) Tert-butyl 3-[(2-{[{3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-me thy l}-4-trifluoromethyl-benzoyl)-ethyl-amino]-propionate (300mg) is dissolved in toluene {5ml), and thereto are added tris(dibenzylideneacetone)dipalladium (36mg), 2-(di-tert-butylphosphinojbiphenyl (47mg), sodium tert-butoxide (57mg) and morpholine {52jil|, and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 17:3-^7:3) and further by silica

gel column chromatography (hexane : ethyl acetate = 4:1—*3:2) to give tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morphDlin-4-yl-pyriniidm-2-yl}-aminol-methyl}-4-trifluoromethyl-benzoyl}-ethyl-ammo]-propionate (13.3mg). MS (m/z); 764 1M+HJ+
(3) Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoyl)-ethyl-aniino]-propionate (13.3mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (2ml), and the mixture is stirred at room temperature for 4 hours. Thereto are added a saturated aqueous sodium bicairbonate 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 to give 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-p5Timidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoyl)-ethyl-amino]-propionic acid (12mg). MS (m/z): 780 [M+H]+ Example 23
(1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyTimidin-2-yl)-amine (8.55g) is dissolved in N,N-dimethylformainide (20ml), and thereto is added sodium hydride (60%) (855mg) under ice-cooling, and the mixture is stirred for 15 minutes. To the reaction solution are added 2-bromomethyl-l-fluoro-4-trifluoromethyl-benzene (5g), and the mixture is stirred at room temperature overnight. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—»9:1) to give (3,5-bis-trifluoromethyl-benzyI|-(5-bromo-pyrimidin-2-yI)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (11.Ig). MS (m/z); 576/578 [M+H]*
(2) (3,5-Bis-trifluoromethyl-benzyI)-(5-bromo-pyrimidin-2-yI)-(2-fluaro-5-trifluoromethyl-ben^l)-amine (11. Ig) is dissolved in tetrahydrofuran (20ml), and thereto are added benzyl alcohol (6ml) and sodium hydride

(60%) (2.32g), and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 97:3^^9:1) to give (2-benzy]oxy-5-trifluoromethyl-ben^y])-(3,5-bis-trifluoromethyl-ben2yl)-(5-bromo-pyrimidin-2-yl)-amine (12.9g}. MS (m/z): 664/666 [M+H]*
(3) (2-Ben^yloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-ben^I|-(5-bromo-pyrimidin-2-yi}-amine (12.9g) is dissolved in dimethylsulfoxide (150ml), and thereto are added 11,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (3.17g), potassium acetate (5.71g) and bis(pinacolate)diboron (9.S5g), and the miirture is heated to SO°C under nitrogen atmosphere for 1 hour and 30 minutes. The reaction solution is cooled to room temperature, and thereto are added a saturated brine and ethyl acetate, and the mixture is separated, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (150ml), and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (40ml) under ice-cooling. Two hours thereafter, thereto is added a saturated aqueous sodium thiosulfate solution to consume the excess hydrogen peroxide, and thereto is added ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1 to 7:3) to give 2-[(2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-ol (7.68g). MS (m/z): 602 [M+H]*
(4) 2-[(2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethy]-benzyl)-aniino]-pyrimidin-5-ol (7.68g) is dissolved in N,N-

dimethylformamide (lOOml) and thereto are added ethyl 4-bromo-butyrate (2.3ml} and potassium carbonate (2.22g), and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl 4-bromo-butyrate (2.3ml) and potassium carbonate (2.22g), and the mixture is stirred at room temperature 3 days. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1^^4:1) to give ethyl 4-{2-l(2-benzylo3q'-5-triiluoromethyl-benzyl}-(3,5-bis-trifluoromethyl-beniyl)-amino]-pyriniidin-5-ylo)cy}-bulyrate as crude product (11.3g). MS (m/z): 716 [M+H]^
(5) Crude ethyl 4-{2-[(2-benzylo3qr-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-aininol-pyrimidin-5-yloxyS-butyrate (11.3g) is dissolved in ethanol (lOOml) £ind thereto is added 10% palladium-carbon (3g), and the mixture is stirred under hydrogen atmosphere at room temperature for 2 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-^4:1) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimi din-5-yloxy}-butyrate (6.03g). MS (m/z): 626 [M+Hl*
(6) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-ylDxy}-butyrate {200mg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a IN-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 resulting residue is purified by

silica gel column chromatography (chloroforni : methanol = 1:0—*19:1| to
give 4-{2-[(3,5-bis-trifluoroniethyI-beii2yI)-(2-hydro^-5-trifIuoromethyI-
benzy])-amino)-pyrimidin-5-yloxy^}-butyric acid (182mg). The resulting 4-{2-|(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-aiiiino]-pyrimidin-5-yloxy}-butyric acid (184mg) is dissolved in ethanol {5ml), and thereto is added IN-aqueous sodium hydroxide solution (305pl},and concentrated under reduced pressure to give 4-{2-((3,5-bis-trifluoromethyl-ben2ylj - (2 - hydroxy-5-trifluoromethyl-benzyl)-amino)-pyrimidin-5-yIoxy}-buQTric acid sodium salt (lS4mg|. MS (m/z): 598 IM+H]+ Example 24
(1) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-ainino]-p5T:imidin-5-yloxy}-butyrate (300mg) and 3-pentanol (63mg) are dissolved in tetrahydrofuran (4ml}, and thereto are added dropwise triphenylphosphine (lS9mg) and a 40% diethyl azodicarboxylate in toluene (ISOpl) under ice-cooling, and the mixture is stirred at room temperature overnight. Thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0^9:1} to give ethyl 4-(2-{(3,5-bis-trif3uoromethyI-benzyl)-[2-(l-ethyl-propoxy)-5-trifluoromethy]-benzyl)-amino}-pyrimidin-5-ylojQr)-butyrate (195mg). MS (m/z): 696 [M+H)+
(2) Ethyl 4-(2-{(3,5-bis-trinuoromethyl-beiizyl)-I2-(l-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyriiiiidin-5-yloxy)-but5Tate (190mg) is dissolved in ethanol {5ml), and thereto is added a IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = l:0-»93 : 7) to give 4-(2-{{3,5-bis-trifluoromethyl-benzyl)-[2-(l-ethylpropoxy)-5-trifluoromethyl-benzyl]-ainino}-pyriniidin-5-yloxy)-butyric acid (158mg). The resulting 4-(2-{(3,5-bis-trifluoromethyI-benzyl)-[2-(l-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy}-butyric acid (158mg) is dissolved in ethanol (Iml), and thereto is added IN-aqueous sodium hydroxide solution (237|al) and concentrated under reduced pressure to give 4-(2-{{3,5-bis-trifluoromethyl-benzyl)-{2-(l-ethyl-propoxy}-5-trifluoromethyl-benzyll-amino}-p3T-imidin-5-yloxy)-butyric acid sodium salt (149mg). MS (m/z): 656 [M-Na]-Example 25
(1) Ethyl 4-{2-[{3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifIuoromethyI-benzyl}-ainino]-p3rrimidin-5-yIo3cy}-butyrate (200mg) is dissolved in N,N-dimethylformamide (3ml), and thereto are added 2-chloropyrimidine (45mg) and potassium carbonate (55mg), and the mixture is stirred at 85°C overnight. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 41:9—*13:7) to give ethyl 4-(2-{(3,5-bis-trifl.uoromethyl-benzyl) - [2-(pyrimidin-2-ylojq'} - 5-trifluoromethyl-ben2yl]-amino}-pyrimidin-5-yloj^)-butyrate (120mg). MS (m/z): 704 [M+H]*
(2) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-ben2yl)-[2-(pyrimidin-2-yloxy}-5-trifluoromethy]-ben2y]]-amino}-pyrimidin-5-yloxy)-butyrate (115mg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a IN-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 resulting residue is purified by
silica gel column chromatography (chloroform : methanol = 1:0^^9:1) to
give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(p5T-imidin-2-yloxy)-5-
trifluoromethyl-benzyl]-am.ino}-pyrimidin-5-yloxy}-butyTic acid (96nig). MS (m/z): 676 [M+H]+ Example 26
(1) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (3g) and pyridine (580vil) are dissolved in methylene chloride (45ml), and thereto is added trifluoromethane sulfonic acid anhydride (1.2ml) under ice-cooling, and the mixture is stirred under nitrogen atmosphere for 2 hours. The reaction solution is cooled to room temperature, and thereto are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—»^4:1) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl) - (2-trifluoromethane sulfonyloxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (3.44g). MS (m/z): 758 [M+H]*
(2) Ethyl 4-{2-[{3,5-bis-trinuoromethyI-benzyl|-(2-trifluoromethanesulfonyloxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200mg) is dissolved in 1,4-dioxajie (3ml), and thereto are added phenyl borate (64mg), [1>1'-bis(diphenylphosphino)ferrocenejdichloropalladium dichloromethane complex (22mg) and cesium carbonate {172mg), and the mixture is stirred under nitrogen atmosphere at 80°C overnight. To the reaction solution are added water 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1^17:3) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl|-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pjrrimidin-5-yloxy}-butyrate (192mg). MS (m/z): 686 [M+H]*
(3) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl-
biphenyl-2-ylmethyl)-amino]-p5Timidin-2-ylmethyl}-ainino)-p3Timidin-5-yloxy}-butyrate (185mg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml), and the m.ixture is stirred at room temperature for 2 hours. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0^19:1} to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-p5Timidin-5-yloxy}-butyric acid (160mg). The resulting 4-{2-[(3,5-bis-trifluoromethyl-ben2yl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-p3T^midin-5-ylox3^-butyric acid (160mg) is dissolved in ethanol (1ml) and thereto is added IN-aqueous sodium hydroxide solution (245pl) and concentrated under reduced pressure to give 4-{2-[(3,5-bis-trinuoromethyl-benzyl) - (4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (158mg). MS (m/z): 656 [M-Naj-
Example 27
(1) (2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoroniethyl-benzyl}-(5-bromo-pyrim.idin-2-yl)-amine (3.75g) is dissolved in toluene (50ml) and thereto are added tris(dibenzylideneacetone)dipalladium (516mg), 2-(di-tert-butylphosphino)biphenyl (673mg), sodium tert-butoxide (813mg) and morpholine (740ial), and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are

added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the orgeinic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 9:1-^4:1) to give (2-benzyIoxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl}-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (2.46g). MS (m/z): 671 [M+H]'^
(2) (2-Ben2yIoxy-5-trifluoromethyl-benzyI)-(3,5-bis-trifluoromethy]-ben^l)-{5-morpholin-4-yl-pyrimidin-2-yl)-am.ine (2.46g) is dissolved in ethanol (35ml), and thereto is added 10% palladium-carbon (750mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 hour and 30 minutes. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—*3:2) to give 2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl}-aminol-methyl}-4-trifluoromethyl-phenol (1.53g). MS (m/z): 581 [M+H]*
(3) 2-{[(3,5-Bis-trifluoromethyl-ben2yl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenol (150mg) is dissolved in N,N-dimethylformamide (4ml), and thereto are added ethyl 4-bromo-butyrate (74p.l) and potassium carbonate (71mg) and the mixture is stirred at SO^C overnight. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 22:3^^7:3) to give ethyl 4-(2-{[(3,5-bis-triftuoromethyl-ben2yl)-(5-morpholin-4-yl-pyriniidin-2-yl|-aminoJ-methyl}-4-trifluoromethyl-phenoxy)-butyrate (123mg). MS (m/z): 695 fM+Hj*
(4) Ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl}-(5-morpholin-4-yl-

pyrimidin-2-yl)-ainino]-methyl}-4-triiluoroniethyl-phenoxy)-butyrate
(llSmg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous
sodium hydroxide solution (1ml), and the mixture is stirred at room
temperature for 4 hours. To the reaction solution are added a IN-
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 resulting residue
is purified by silica gel column chromatography (chloroform : methanol =
1:0—•■19:1) to give 4-(2-{[(3,5-bis-trifluoromethyl-ben2yl)-(5-morpholin-4-yl-
pyTimidin-2-yl)-amino]-methyl}-4-trifluorom ethyl-phenoj^)-butyric acid
(lOSmg). MS (m/z): 667 [M+H]* Example 28
(1) 2-{[(3,5-Bis-trifluoromethyl-ben2yl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-triiluoromethyl-phenol (300mg) and pjTidine (50^1) are dissolved in methylene chloride (Smlj and thereto is added trifluoromethanesulfonic acid anhydride (104pl) under ice-cooling, and the mixture is stirred under nitrogen atmosphere for 1 hour. The reaction solution is cooled to room temperature, and thereto are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 9:1 to 7:3) to give trifluoromethanesulfonic acid 2-{[(3,5-bis-trifiuoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl ester (330mg). MS (m/z): 713 [M+H]*
(2) Trifluoromethanesulfonic acid 2-{[(3,5-bis-trifluoromethyI-benzyl)-(5-morpholin-4-yl-pyriniidin-2-yl)-ainino]-methyl}-4-trifluoromethyl-phenyl ester (200mg) is dissolved in 1,4-dioxane (3ml), and thereto are added phenyl borate (69mg), [!> 1'-bis(diphenylphosphino)ferroceneldichloropalladium dichloromethane

complex (23mg) and cesium carbonate (183mg), gind the mixture is stirred under nitrogen atmosphere at 80°C for 1 day. The reaction solution is cooled to room temperature, and thereto are added water 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—♦4:1) to give (3,5-bis-trifluoromethyl-benzyl}-(5-morpholin-4-yl-pyTimidin-2-yl)-(4-triiluoromethyl-biphenyl-2-ylmethyl)-amine (52mg). MS (m/z): 641 [M+HJ* Examples 29 to 35
The corresponding starting compounds are treated in a similar manner to Example 1 to give the compounds as listed in Table 1. Example 36
The corresponding starting compound is treated in a similar manner to Example l(l)-(3) to give the compound as listed in Table 1-Examples 37 to 46
The corresponding starting compounds are treated in a similar manner to Example 2 to give the compounds as listed in Table 1. Examples 47 to 48
The corresponding starting compounds are treated in a similar manner to Example 4 to give the compounds as listed in Table 1. Example 49
The corresponding starting compound is treated in a similar manner to Example 5 to give the compound as listed in Table 1. Examples 50 to 53
The corresponding starting compounds are treated in a similar manner to Example 8 to give the compounds as listed in Table 1. Examples 54 to 60
The corresponding starting compounds are treated in a similar manner to Example 12 to give the compounds as listed in Table 1.

Examples 61 to 62
The corresponding starting compounds are treated in a similar manner to Example 12{l)-(3) to give the compounds as listed in Table 1. Examples 63 to 64
The corresponding starting compounds are treated in a similar manner to Example 13 to give the compounds as listed in Table 1. Example 65
The corresponding starting compound is treated in a similar manner to Example 16 to give the compound as listed in Table 1. Example 66
The corresponding starting compound is treated in a similar manner to Example 18 to give the compounds as listed in Table I. Example 67
The corresponding starting compound is treated in a similar manner to Example 20 to give the compound as listed in Table 1. Examples 68 to 71
The corresponding starting compounds are treated in a similar manner to Example 24 to give the compounds as listed in Table I. Examples 72 to 75
The comssponding starting compounds are treated in a similar manner to Example 26 to give the compounds as listed in Table 1.

Example 76
(1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (5g) and cyclopropylmethyl-propyl-amine (5.57ml) is dissolved in toluene (50ml), and thereto is added potassium carbonate (10.7g) and the mixture is stirred at 120*'C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate emd water, 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 resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 20:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (6.8g). MS (m/z): 286 [M+H]*
(2) To ethanol are added (30ml)2-(cyclopropylm ethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (5.8g), hydroxylamine hydrochloride {1.66g) and sodium acetate (1.95g) and the mixture is stirred at room temperature overnight. Ethanol is removed by evaporating under reduced pressure and

thereto is added chloroform and water, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 10:1—»2:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde oxime {5.78g). MS (m/z): 301 [M+H1+
(3) Lithium aluminum hydride (1.4g) is suspended in tetrahydrofuran (50ml} and thereto is added dropwise a 2-(cyclopropylmethyl-propyl-aniino)-5-trifluoromethyl-benzaldehyde oxime {5.7g) in tetrahydrofuran (20ml) under ice-cooUng, and the mixture is stirred at room temperature overnight. To the reaction solution are added water (1.4ml), a 2N-aqueous sodium hydroxide solution (2.8ml) and water (2.8inl) successively under ice-cooling, and the insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (; chloroform : ethyl acetate= 10:1) to give (2-aminomethyl-4-trifluoromethyl-phenyl)-cyclopropylmethyl-propyl-amine as a crude product (5.1g).
(4) The crude (2-aminomethyl-4-trifluoromethyl-phenyl)-cyclopropylmethyl-propyl-amine obtained in (3) (5.06g) is dissolved in dioxane (25ml), and thereto are added N-ethyldiisopropylethylamine (9.19ml) and 5-bromo-2-chlorop3Timidine (8.48g), and the mixture is heated under reflux for 4 hours and 20 minutes. The insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 15:1) to give (S-bromo-pjrrimidin-2-yl) - [2 - (cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amine (6.33g). MS (m/z): 443/445 [M+H]+
(5) (5-Bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amine (2.33g) is dissolved in N,N-dimethylformamide (16.8ml) and thereto is added sodium hydride (60%)

(273mg) under ice-cooling. Twenty minutes thereafter, thereto is added 3-bromomethyl-5-trifluoromethyl-benzonitrile (2.08g) and the mixture is stirred at room temperature for 1 hour and 15 minutes. To the reaction solution are added acetic acid to consume the excess sodium hydride, and thereto are added ethyl acetate and water, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1) to give 3-({(5-bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino) - 5-trifluoromethyl-benzyl]-aminQ}-methyl) - 5-trifluoromethyl-benzonitrile (2.81g). MS (m/z): 626/628 [M+H]*
(6) 3-({(5-Bromo-p5Timidin-2-yl}-[2-(cyclopropylmethyl-propyl-amino)-5-
triflu oromethyl-benzyl] - aminoj-methyl) - 5-trifluoromethyl-benzonitrile
(2.81g) is dissolved in dimethylsulfoxide (12.6ml) and the mixture is
degassed under reduced pressure and flushed with nitrogen gas. Thereto
are added potassium acetate {1.32g), bis(pinacolate)diboron (2.88g} and
[ 1, l'-bis(diphenylphosphino)ferrocene]dichloropalladium methylene
chloride complex (732mg) and the mixture is heated at 80°C under nitrogen atmosphere and stirred for 1 hour and 40 minutes. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (26ml) and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (15.7ml) under ice-cooling. Two hours thereafter, thereto is added a saturated aqueous sodium thiosulfate under ice-cooling to consume the excess hydrogen peroxide, and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by

silica gel column chromatography (hexane : ethyl acetate = 4:1) to give 3-{[[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (1.94g). MS (m/z): 564 (M+HJ*.
(7) Ethyl 3-{[ [2-(cyclopropylmethyl-propyl-amino) - 5-trifluoromethyl-ben^ll-(5-hydroxy-pyrimidin-2-yl)-aininol-methyl}-5-trifluoromethyl-benzonitrile (250mg) and 4-bromobutyrate (76.9^11) is dissolved in N,N-dimethylformamide (3.7mi) and thereto is added potassium carbonate (74mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated, and the organic layer is washed with a saturated brine, dried and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 8:1) to give ethyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino) - 5-trifluoromethyl-benzyl] - amino}-p3Timidin-5-yloxy)-butyrate (220mg). MS (m/z): 678 [M+H]*
(8) Ethyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ylo:ty)-butyrate (240mg) is dissolved in tetrahydrofuran (2.6ml}, and thereto is added IN-aqueous sodium hydroxide solution (2.6ml) and the mixture is stirred at 40°C for additional 30 minutes and warmed to 50°C and stirred for 3 hours. Thereto is added a 2N-aqueous sodium hydroxide solution (650|il) and the mixture is stirred at 50°C for 20 minutes. The reaction solution is cooled to room temperature and thereto are added ethyl acetate and a IN-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 19:1) to give 4-(2-{(3-cyano- 5-triflu oromethyl -ben2yl) -[2 -(cyclopropylmethyl -propyl -amino)- 5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-but5T-ic acid (189mg).

MS (m/2): 650 |M+H]^ Example 77
The corresponding starting compound is treated in a similar manner to Example 76 to give the compounds as listed in Table 2.

Example 78
(1) {2-[(3,5-Bis-trifluoromethyl-ben2ylamino)-methyl]-4-trifluoromethyl-phenyl}-butyl-ethyl-amine (2.0g), 4,6-dichloropyrinudine (1.19g) and N-ethyldiisopropylamine (2.09ml) are dissolved in toluene (lOml) and the mixture is heated under reilux for 3 hours. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-*17:3) to give (3,5-bis-trifluoromethyl-benzyl)-{2-(butyl-ethyl-amino)-5-trifluoromethyl-benzylJ-(6-chloropyrimidin-4-yl)-amine (1.8g). MS (m/z): 613 [M+H]^

(2) (3,5-Bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino}-5-trifluorom ethyl-benzyl]-(6-chloropyrimidin-4-yl)-amine (SOOmg) is dissolved in toluene (5ml), and thereto are added 3-aininopropionic acid tert-butyl ester hydrochloride {888mg) and N-ethyldiisopropylamine (1.7ml), and the mixture is stirred at 120°C overnight. To the reaction solution are added ethyl acetate and a IN-hydrochloric acid, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (hexane : ethyl acetate = 9:1—*3:1) to give tert-butyl 3-(6-{(3,5-bis-trifluoromethyl-benzyl}-[2-(bulyl-ethyl-ainino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-4-ylamino)-propionate (TOmg). MS (m/z): 722 [M+H]-
(3) Tert-butyl 3-(6-{(3,5-bis-trifluoromethyl-benzyl}-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-p3Timidin-4-ylamino)-propionate (60mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (0.5ml) and the mixture is stirred at room temperature for 1.5 hours. To the reaction solution are added ethyl acetate and water, and foUwed by a further addition of a saturated aqueous sodium bicarbonate solution to make the pH of aqueous layer to be about 4, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and the mixture is concentrated under reduced pressure to give 3-{6-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluororoethyl-ben2yl]-amino}-pyrimidin-4-ylamino)-propionic acid (57mg), MS (m/z): 666 [M+H]+
Examples 79 to 83
The corresponding starting compounds are treated in a similar manner to Example 78(2) to give the compounds as listed in Table 3.

solution (0.80ml) and acetic acid (2.1ml), followed by an addition of ti^acetoxy-sodium borohydride (13. Ig) at room temperature over 1 hour with stirring. After the mixture is stirred at room, temperature for additional 30 minutes, to the reaction mixture is added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1) to give (3,5-bis-trifluoromethyl-benzyl)-ethyl-amine (1.52gj. MS (m/z): 272 [M+H]*
(2} (3,5-Bis-trifluoromethyl-benzyl)-ethyl-amine (1.03g) is dissolved in N, N-dimethylformamide (1 Oml), and thereto are added 2 -fluoro-5-triiluoromethyl-benzaldehyde (1.45g) and potassium carbonate (1.48g), and the mixture is stirred under nitrogen atmosphere at 90°C for 3 hours and at room temperature overnight. To reaction mixture is added a saturated brine and water, and the mixture is extracted five times with ethyl acetate and the organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1} to give 2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyI-benzaldehyde (282mg). MS (m/z): 444 [M+H]+ (3) 2-[{3,5-Bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehyde (275mg) is dissolved in ethanol (2.5ml) and thereto are added hydro^lammonium chloride (86mg) and sodium acetate (102mg), and the mixture is stirred at eCC under nitrogen atmosphere for 1 hour and a half. To the reaction solution are added a saturated brine and water, and the mixture is extracted with ethyl acetate, aind the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel

column chromatography (hexane : ethyl acetate = 24:1—»83:17) to give 2-[(3,5-bis-trifluoromethyl-ben^l}-ethyl-aininol-5-trifluoromethyl-benzaldehydeoxime (244mg). MS (m/z): 459 [M+H]-^
(4) 2-[(3,5-Bis-trinuQromethyl-benzyl)-ethyl-aiiiino]-5-trifluoromethyl-benzaldehydeoxime (241mg) is dissolved in methanol (lOml) and thereto is added Raney nickel {0.5g) and the mixture is stirred under hydrogen atmosphere at room temperature overnight. Raney nickel is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—•■O:!) to give (2-aminomethyl-4-trifluoromethyl-phenyl)-(3,5-bis-trifluoromethyl-benzyl)-ethyl-amine {210mg). MS (m/z): 445 [M+H]^
(5) (2-Aminomethyl-4-trifluoromethyl-phenyI)-(3,5-bis-trifluoromethyl-benzyl)-ethyl-amine (165mg) is dissolved in toluene (3ml) and thereto are added tert-butyl 4-(2-chloro-p5aimidin-5-ylo3cy)-butyrate (202mg), tris(dibenzylideneacetone)dipalladium(0) (68mg), (±)-2,2'-bis(diphenylphosphino)-l,l'-binaphthalene (92mg) and sodium tert-butoxide (71mg), and the mixture is stirred under nitrogen flow at SCC for 5 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 7:1) to give tert-butyl 4-(2-{2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-triflu oromethyl-benzylamino}-pyrimidin-5-yloxy)-butyrate (73mg). MS (m/z): 681 [M+H]'
(6) To tert-butyl 4-(2-{2-[[3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzylamino}-pyTimidin-5-yloxy)-but5Tate (84mg) is added a 4N-hydrochloric acid in dioxane (1.5ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution and made weakly acidic

with 10% aquous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 19:1} to give 4-(2-{2-[(3,5-bis-trifluoromethyl-benzy])-ethy]-amino]-5-trifluoromethyl-benzylainino}-p3Timidin-5-y]oxy)-butyric acid (47mg). MS (m/z): 625 [M+H]*

Example 85
(1) 2-Fluoro-5-trifluoromethyl-benzaldehyde (5.38g) and cyclopropylmethyl-propyl-amine (4.75g) is dissolved in toluene (50ml), and thereto are added potassium carbonate (11.6g) and the mixture is stirred at 120°C for 4 hours. The reaction solution is cooled to room temperature, and thereto is added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-+4:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (S.Og). MS (m/z): 286 [M+H]*
(2) 2-(Cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (5.0g) is dissolved in diethylether ISOml} and thereto is added a 2M methyl magnesium bromide in diethylether (7.35ml) under nitrogen flow at -70'C. The mixture is stirred at the sam.e temperature for 30 minutes, and the reaction solution is quenched with a saturated aqueous ammonium

chloride solution and the mixture is extracted with diethylether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—►3:2) to give l-[2-(cyclopropylmethyl-propyl-amino}-5-trif]uoromethyl-phenylj-ethanol (5.43g). MS (m/z): 302 [M+H]*
(3) l-[2-(Cyclopropylinethy]-propyl-amino)-5-trifluoromethy]-phenyl|-ethanol (500mg) is dissolved in methylene chloride (5ml) and thereto is added thionyl chloride (133pl) under ice-cooling and the mixture is stirred at room temperature for 15 minutes. To the reaction solution are added methylene chloride and a saturated aqueous sodium bicarbonate solution, 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 resulting residue and ethyl 4-|2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxyl-butyrate (749mg) are dissolved in N,N-dimethylformamide (5ml) and thereto is added sodium hydride (62%) (64mg) under ice-cooling and the mixture is stirred for 1 hour. Thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1-+4:1) to give ethyl 4-[2-((3,5-bis-trifluoromethyl-benzyl}-{l-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-ainino)-p3TTmidin-5-yloxy]-butyrate (144mg) as a crude product. The resulting ester is dissolved in ethanol (2ml) and thereto is added a 2N-aqueous sodium hydroxide solution (SOOiil) and the mixture is stirred at room temperature for 2 hour and concentrated under reduced pressure. To the residue is added ethyl acetate and a dilute hydrochloric acid 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 resulting residue is purified by silica gel column
chromatography (chloroform : methanol = 1:0-.24:1} to give 4-[2-((3,5-bis-
trifluoroniethyl-benzyl)-{l-[2-(cyclopropylmethyl-propyl-amino)-5-
trifluoromethyl-phenyll-ethyl}-amino)-pyrimidin-5-yloxy]-but5Tic acid
(llmg). MS (m/z): 707 [M+H]* Example 86
l-[2-(Cyclapropylmethyl-propyl-amino)-5-trifluoromethyl-phenyll-ethanol (l.Og) is dissolved in methylene chloride (10ml) and thereto is added thionyl chloride (266pl) under ice-cooling, and the mixture is stirred for 30 minutes and concentrated under reduced pressure. (3,5-bis-trifluoromethyJ-benzyI)-{5-bromo-pyrimidin-2-yl)-amine (1.33g) is dissolved in N,N-dimethylformamide (5ml) and thereto is added sodium hydride (62%) (142mg) under ice-cooUng, and the mixture is stirred for 15 minutes. Thereto are added a solution of a residue obtained above in N,N-dimethylformamide (5ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—*49:1) to give (3,5-bis-trifluoromethyl-benzyl}-(5-bromo-pyrimidin-2-yl)-{l-[2-(cyclopropylmethyl-propyI-aniino)-5-trifluoroniethyI-phenyl]-ethy]}-amine {S15mg). MS (m/z): 683/685 [M+H]* Example 87
(1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-p5Timidin-2-yl}-{l-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-amine (200mg) is dissolved in toluene (3ml), and thereto are added tris(dibenzylideneacetone)dip£illadium (27mg), sodium tert-butoxide (42mg), 2-(di-tert-butylphosphino)biphenyl (35mg) and ethyl piperidine-4-carboxylate (66)il) and the mixture is stirred at room temperature under

nitrogen flow overnight. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (hexane : ethyl acetate = 19:1^^21:4) to give ethyl l-(2-((3,5-bis-trifluoromethyl-ben2yl)-{l-[2-(cyclopropylmethyl-propyl-amino) - 5-triflu oromethyl-phenyl]-ethyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (78mg). MS (m/z): 760 IM+H]^
(2) Ethyl l-|2-((3,5-bis-trifluoromethyl-benzyl)-{l-[2-fcyclopropylmethyl-
propyl-amino) - 5-trifluorom ethyl-phenyl)-ethyl}-ainino)-pyriniidin-5-yl]-
piperJdine-4-carboxylate (75mg) is dissolved in ethanol (1ml), and thereto is
added a 2N-aqueous sodium hydroxide solution (148pl), and the mixture is
stirred at room temperature overnight. Thereto are added ethyl acetate
and a dilute hydrochloric acid 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 resulting residue
is purified by silica gel column chromatography (chloroform : methanol =
1:0->49:1} to give l-12-((3,5-bis-trifluoromethyl-benzyl}-{l-[2-
(cycl op ropylmethyl-propyl-amino) - 5 -trifluoromethyl-phenyl] -ethyl} -amino) -P3a-imidin-5-yl]-piperidine-4-carboxylic acid (54mg). MS (m/z): 732 [M+H]*

Example 88
(1) 2-(Butyl-ethyl-amino)-5-fxifluoromethyl-benzaldehyde (l-72g) is dissolved in a mixed solvent of tert-butanol (8ml) and water (2ml), and thereto are added 2-methyI-2-butene (4ml), sodium dihydrogenphosphate dihydrate (1.37g) and sodium chlorite (l.S2g) under ice-cooling, and the mixture is stirred for 2 hours. Thereto are added ethyl acetate and a IN-hydrochloric acid 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 resulting residue is purified by silica gel column chromatography (chlorofonn : methanol = 1:0—♦9:1) to give 2-(butyl-ethyl-amino)-5-trifluoromethyl-benzoxc acid (1.29mg). MS (m/z): 290 [M+H]*

(2) 2-(Butyl-ethyl-amino)-5-trifluoromethyl-benzoic acid (l-28g) is dissolved in methylene chloride (lOml) and thereto are added oxalyl chloride (578ial) and a catalj^c amount of N,N-dimethylformamide under ice-cooling, and the mixture is stirred for 30 minutes and evaporated under reduced pressure to dryness. The resulting residue is dissolved in methylene chloride (10ml) again and thereto are added dropwise a solution of (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl)-amine (1.77g) and triethylamine (924pl) under ice-cooling. The reaction solution is stirred at room temperature overnight and the mixture is washed with a IN-hydrochloric acid and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—*9:1) to give N-{3,5-bis-trifluoromethyl-benzyl)-N-(5-bromo-p3Timidin-2-yl)-2-(butyl-ethyl-amino)-5-trifluoromethylben0amide (842mg). MS (m/z): 671/673 [M+H]+

The corresponding starting compounds are treated in a similar manner to any of the above Examples to give the compounds as listed in Table 7.

Example 103
(1) Ethyl 4-{2-[(3,5-bis-txifluoromethyl-benzyl)-(2-txifluoro-
methariesulforiyloxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (I.Og) is dissolved in 1,4-dioxane (lOml) and thereto are added [ 1, r -bis(diphenylphosphino)ferTocene]dichloropalladium dichloromethane complex (216mg), bis(pinacolate|diboron (670mg) and potassium acetate (389mg), and the mixture is stirred under nitrogen atmosphere at 80°C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:l->-4:l) to give ethyl 4-(2-{(3,5-bis-triiluoromethyl-

benzyl)-[2-(4,4,5,5-tetrainethyl-(l,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (805mg). MS (m/z): 73&{M+H]-^o
(2) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-(4,4,5,5-tetramethyl-[I,3,2]dioxaboroIan2-yI)-5-trifluoroinethyI-benzyI]-ammo}-p5T:iniidin-5-yloxy)-bu1yrate (200mg) is dissolved in 1,4-dioxane (4inl) and thereto are added 2-bromo-4-methyl-pyridine (70mg), [1.1-bis(diphenylphosphino)ferroceneldichloropalladium dichloromethane complex (22mg) and cesium carbonate (133mg), and the mixture is stirred under nitrogen atmosphere at 80°C for 5 days. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—*4:1) to give ethyl 4-(2-((3,5-bis-trifLuoromethyI-benzyI)-[2-(4-methyI-pyridin-2-yI)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (85mg). MS (m/z): 701 [M+H]*
(3) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-5-trifIuoromethyl-beniyl]-amino}-p3Timidin-5-ylo^}-bu1yrate (SSmg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (Iml) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—*23:2) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-|2-(4-methylpyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (68mg). The resulting carboxylic acid is dissolved in ethanol (1ml), and thereto is added ]^jii ,,n ^rt^i,-i„ h-^rAfnv^Af dnintinn noinll. and the reaction solution

is concentrated under reduced pressure to give 4-(2-{(3,5-bis-
trifluoromethyl-benzyl) - [2 - (4-methyl-pyridin-2-yl) - 5-trifluoromethyl-benzyl]-
amino}-pyrimidin-5-yloxy)-bu1yric acid sodium salt (69mg). MS (m/z): 671
[M-Na]-
Examples 104 to 112
The corresponding starting compounds are treated in a similar manner to Example 103 to give the compounds as listed in Table 9.

Example 113
(1) Trifluoro-methanesulfonic acid 2-{|{3,5-bis-trifluoromethyl-ben^l)-
{5-morphoUn-4-yl-pyrimidin-2-yl)-ainino]-methyl}-4-triflu oromethyl-phenyl
ester (1.19g) is dissolved in 1,4-dioxane (10ml) and thereto are added [1,1'-
bis(diphenylphasphino)ferrocene]dichloropaUadium dichloromethane
complex (273mg), bis(pinacolate)diboron (848mg) and potassium acetate [492mg), and the mixture is stirred under nitrogen atmosphere at SCC overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate and the insoluble materials are removed by filtration through CelitefM. The filtrate is separated, and the organic layer is washed with a saturated brine, dried over magnesium

sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1^7:3) to give (3,5-bis-trifluoromethyI-benzyl)-(5-morphoUn-4-yl-pyrimidin-2-yl)-[2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amine (648mg). MS (m/z); 691 [M+H]+
(2) f3,5-Bis-trinuoromethyl-ben2yl)-(5-morpholin-4-yl-pyrimidin-2-yl}-[2-
(4,4,5,5-tetramethyl-[l,3,2]dioxaborolaii-2-yl)-5-trifluoromethyl-benzyl]-
amine {250mg) is dissolved in 1,4-dioxane (5ml) and thereto are added
ethyl 4-chloro-2-trifluoromethyl-pyriniidine-5-carboxylate (140nig), [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane
complex (30mg) and cesium carbonate (177mg), and the mixture is stirred
under nitrogen atmosphere at SCC overnight. The reaction solution is
cooled to room temperature, and thereto are added water and ethyl acetate
£ind the insoluble materials are removed by filtration through CeliteTM. The
filtrate is separated, and the organic layer is washed with a saturated brine,
dried over magnesium sulfate, and concentrated under reduced pressure.
The resulting residue is purified by sUica gel column chromatography
(hexane : ethyl acetate = 9:1-^4:1) to give ethyl 4-(2-{[(3,5-bis-
trifiuoromethyl-ben2yl}-{5-morpholin-4-yl-p3'rimidin-2-yl)-amino]-methyl}-
4-trifluoromethyl-phenyl) - 2-trinuoromethyl-pyrimidine - 5-carboxylate (199mg). MS (m/z): 783 IM+H]*
(3) Ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-{5-morpholin-4-yl-
pjTiimidin- 2 -yl) -amino] -methyl}-4 -trifluoromethyl-phenyl) -2 -trifiuoromethyl-
pyrimidine-5-carboxylate (194mg) is dissolved in ethanol (4m.l), and thereto
is added IN-aqueous sodium hydroxide solution (1ml) and the mixture is
stirred at room temperature for 2 hours. To the reaction solution are
added a 1 N-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
resulting residue is purified by silica gel column chromatography
172

(chloroform : methanol = 1:0^7:3) to give 4-(2-{[(3,5-bis-trifluoromethyl-
benzyl)-(5-morpholin-4-yl-p5Timidin-2-yl)-amino]-methyl}-4-
trifluoromethyl-phenyl)-2-trifluoromethyl-pyrimidine-5-carboxylic acid
(165mg). MS (m/z): 755 [M+H]* Example 114
1) Ethyl 4-(2-{(3,5-bis-trinuoromethyI-benzyl)-[2-(4,4,5,5-tetramethyl-l,3,21dioxaborolan-2-yl)-5-trifluoromethyl-ben2yll-amino}-p5T-imidin-5-'loxy)-butyrate (SOOmg) is dissolved in 1,4-dioxane (5m^l) and thereto are idded 4-chloro-5-methoj!y-2-methylsulfanil-pyrimidine (117mg), [1,1'-)is{diphenylphosphino) ferrocene] dichloropalladium dichloromethane ;oinplex (33mg) and cesium carbonate (199mg), and the mixture is stirred inder nitrogen atmosphere at 80°C overnight. The reaction solution is ;ooled to room temperature, and thereto are added chloroform and water, uid the insoluble materials are removed by filtration through Celite^^. The iltrate is separated, and the organic layer is dried and concentrated under ■educed pressure. The resulting residue is purified by silica gel column :hromatography {hexane : ethyl acetate = 9:l-*7:3) to give ethyl 4-(2-{(3,5-3is-trifluoromethyl-benzyl)-[2-(5-methoxy-2-methylsulfanil-p3Tiniidin-4-yl}-S-trifluoromethyl-benzyl]-aniino}-pyrimidin-5-ylo7^)-butyrate (165mg). MS m/z): 764 [M+H]+
2) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-(5-methoxy-2-nethylsulfanil-pyrimidin-4-yl)-5-trifluoromethyl-benzyl] - amino}-pyrimidin-5-ylo3^)-bu1yrate (162mg) is dissolved in chloroform (5ml) and thereto is idded m-chloro perbenzoic acid (70%) (63mg) and the mixture is stirred at -oom temperature for 30 minutes. To the reaction solution are added saturated aqueous sodium thiosulfate solution and chloroform, and the nixture is separated, and the organic layer is washed with a saturated Drine, dried over magnesium sulfate, and concentrated under reduced Dressure. The resulting residue is purified by silica gel column :hromatography (hexane : ethyl acetate = 1:0^19:1) to give ethyl 4-(2-{(3,5-
173

bis-trifluoromethyl-benzyi) - [2 - (2-methanesulfinyl-5-methoxy-pyrimidin-4 -yl)-5-trifluQromethyl-benzyl]-ainino}-p3Timidin-5-yloxy)-butyrate (143mg). MS (m/z): 780 [M+H]*
(3) Ethyl 4-(2-{(3,5-bis-trifluoroinethyl-benzyl)-[2-(2-methanesulfmyl-5-methoxy-pyrimidin-4-yl)-5-trifluoromethyl-ben2yl]-ainino}-pyrimidin-5-yloxy}-butyrate (139ing) is dissolved in methanol (5ml) and thereto is added sodium methoxide (48mg} and the mixture is stirred at room temperature overnight and further thereto is added sodium methoxide (48mg), and the mixture is stirred overnight. The reaction solution is concentrated under reduced pressure, and to the residue is added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over ma^esium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 7:3—tl;l) to give methyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2,5-dimethoxy-pyrimidin-4-yl)-5-trifluoromethyI-ben^l]-amino}-pyrimidin-5-yla3^)-butyrate (54mg). MS (m/z): 734 [M+Hi+
(4} Methyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2,5-dimethoxy-
pyrimidin-4-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-y]oxy}-bu^ate (52mg) is dissolved in methanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-*9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2,5-dimethoxy-pyrimidin-4-yl) - 5-trifluorom ethyl-benzyl] - amino}-pyrimidin-5-yloxy)-butyric acid {49mg). MS (m/z): 720 [M+H]^ Example 115
174

(1) Trifluoro-methanesulfonic acid 2-{[(3,5-bis-trifiuoromethyl-benzyl}-(5-morphoUn-4-yl-pyrimidin-2-yl)-amino]-metiiyl}-4-trifluoromethyl-phenyl ester (620ing) is dissolved in 1,4-dioxane (10ml) and thereto are added 2-benzyloxyphenyl boronic acid (398mg), [1,1'-bis{diphenylphosphino)ferrocene)dichloropalladium dichloromethane complex (142mg) and cesium carbonate (567mg), and the mixture is stirred under nitrogen atmosphere at 80°C overnight, The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the insoluble materials are removed by filtration through CeliteTM. The filtrate is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—»4:1) to give {2'-benzyloxy4-trifluoromethyl-biphenyl-2-ylmethyl}-(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-ainine (617mg). MS (m/z): 747 [M+H]+
(2) (2'-Benzyloxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(3,5-bis-trifiuoromethyl-benzyl)-(5-morpholin-4-yl-p5T-imidin-2-yl)-amine (606mg) is dissolved in ethanol (lOml), and thereto is added 10% palladium-carbon (lOOmg) and the mixture is stirred under hydrogen atmosphere at room temperature for 3.5 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:l-*7:3) to give 2'-{[(3,5-bis-trifluoromethyl-benzyl)-{5-morpholin-4-yl-pyrimidin-2-yl)-ainino]-methyI}-4'-trifluoromethyl-biphenyl-2-ol (374mg). MS (m/z): 657 |M+H1+
Example 116
(1) 2'-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4'-trifluoromethyl-biphenyl-2-ol (ISOing) is dissolved in N,N-dimethylformamide (3ml) and thereto are added ethyl 4-bromobu1yrate (SOpl) and potassium carbonate (47mg), and the mixture is stirred at room
175

temperature for 2 hours and at 80°C for 2 hours. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, £ind concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—»'4:1) to give ethyl 4-(2'-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yI-pyrimidin-2-yl)-amino]-niethyl}-4'-trifluoromethyl-biphenyl-2-yloxy)-butyrate (163mg). MS (m/z): 771 [M+H]*
(2) Ethyl 4-(2'-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-
pyrimiditi-2-yl)-amino]-methyl}-4'-trifluoromethyl-biphenyl-2-yloxy)-bulyrate (157mg) is dissolved in ethanol (4ml), and thereto is added IN-aqueous sodium hydroxide solution (1ml), and the mixture is stirred at room temperature for 2 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0^9:1) to give 4-(2'-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-P5Tim,idin-2-yl}-amino]-methyl}-4'-trifluoromethyl-biphenyl-2-ylo3ty)-butyric acid (146mg). The resulting carboxylic acid is dissolved in ethanol (Iml), and thereto is added IN-aqueous sodium hydroxide solution H97ial) and the reaction solution is concentrated under reduced pressure to give 4-(2'-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-p5mmidin-2-yl)-amino]-methyl}-4'-trifluoromethyl-biphenyl-2-yloxy)-butyric acid sodium salt (146mg). MS (m/z): 741 [M-Na]-Example 117
(1) 2-Chloro-5-(trifluoromethyl)benzaldehyde (12.00g) is dissolved in toluene (200ml) and the mixture is degassed under reduced pressure. To this soluton are added tetrakis(triphenylphosphine)palladium (13.29g), 5-
176

isopropyl-2-methoxybenzene boronic acid (14.51g), ethanol {26ml), distilled
water (ISml) and a 2M-aqueous sodium carbonate solution (57.5ml), aind
the m,Lxture is degassed under reduced pressure and heated at SS^C under
nitrogen atmosphere and stirred overnight. The reaction solution is
allowed cool to room temperature, and thereto is added a saturated brine
and the mixture is extracted with ethyl acetate. The organic layer is
washed with a saturated brine, dried over magnesium sulfate, and
concentrated under reduced pressure. The resulting residue is purified by
silica gel column chromatography (hexane : ethyl acetate = 99:1— give 5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde
{14.25g). MS (m/z): 323 [M+H]*
(2) 5'-lsopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (5.0g) is dissolved in 1,2-dichloroethane {20ml) and thereto are added 3,5-bis-{trifluoromethyI)ben^lamine (3.8g), acetic acid (1.1ml) and triacetoxy-sodium borohydride {4.0g), and the mixture is stirred at room temperature overnight. To reaction mixture is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with chloroform. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 10:1) to give {3,5-bis-trifluoromethyl-benzyl}-{5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine {7.2g). MS {m/z): 550 [M+H]+ {3) (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (3.0g} is dissolved in toluene {20ml) and thereto are added 5-bromo-2-chlorop5Timidine {1.6g) and N,N-diisopropylethylamine (1.4ml) and the mixture is heated under reflux overnight. The reaction solution is allowed cool to room temperature, and thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue
177

is purified by silica gel column chromatography (hexane : ethyl acetate = 40:1) to give f3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethy]-biphenyJ-2-yImethyl)-amme (2.6g). MS (m/z); 708/706 [M+HJ+
(4) {3,5-Bis-trifluoromethyl-benzyl)-{5-bromo-pyrimidin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine {1.2g} is dissolved in N,N-dimethylformam.ide (6ml) £ind thereto are added palladium acetate (II) (76mg), l,r-bis(diphenylphosphino}ferrocene (376mg), ethanol (4.0ml) and triethylamine (4.8nil), and the mixture is stirred under carbon monoxide at 90**C overnight. The reaction solution is allowed cool to room temperature, and thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 20:1^^10:1) to give ethyl 2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carboxyIate (l.lg). MS (m/z): 700 [M+H]+
(5) Ethyl 2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methojQ'-4-trifluoromethyl-biphenyl-2-ylniethyl)-amino]-pyrimidine-5-carboxylate (l.lg) is dissolved in a mixed solvent of ethanol (18ml) and tetrahydrofuran (20ml) and thereto is added a 2M-aqueous sodium hydroxide solution (3ml), and the mixture is stirred at 50°C for 1 hour and a half. The reaction solution is concentrated under reduced pressure and thereto is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 25:1) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carbo3^1ic acid
178

(TOOmg). MS (m/z): 672 [M+H]* Example 118
(1) 2-[(3,5-Bis-trifluoromethyl-ben2yI)-(5'-isopropyl-2'-raethoxy-4-trifluoroinethyl-bipheny]-2-ylinethyl)-ainino]-pyrmiidine-5-carboxylic acid (200ing) is dissolved in N,N-dimethylformamide (5ml) and thereto are dded l-(3-dimethylaininopropyl)-3-ethylcarbodiimide hydrochloride 56mg), 1-hydroxy-benzotriazole (60mg), triethylamine (125^11) and 4-minobutyric acid ethyl ester hydrochloride {75mg), and the mixture is tirred at room temperature overnight. To reaction mixture is added a aturated aqueous sodium bicarbonate solution and the mixture is xtracted with ethyl acetate. The organic layer is washed with a saturated irine, dried over magnesium sulfate, and concentrated under reduced iressure. The resulting residue is purified by silica gel column hromatography (hexane : ethyl acetate = 5:2) to give ethyl 4-({2-[(3,5-bis-rifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trTfluoromethyl-iiphenyl-2-ylmethyl)-amino]-p5Tnmidine-5-carbonyl}-amino)-but5^ate 230mg). MS (m/z): 785 [M+H)*
2) Ethyl 4-{{2-[(3,5-bis-trinuoromethyl-benzyl)-(5'-isopropyl-2'-methoxy--trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carbonyl}-imino)-butyrate (230mg) is dissolved in ethanol (5ml) and thereto is added L 2M-aqueous sodium hydroxide solution (1ml) and the mixture is stirred it room temperature for 1 hour and a half. To reaction mixture is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The irganic layer is washed with a saturated brine, dried over magnesium ulfate, and concentrated under reduced pressure. The resulting residue s purified by silica gel column chromatography (chloroform : methanol = 25:1) to give 4-({2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carbonyl}-amino)-butyric acid (220mg). MS (m/z): 757 [M+H]^ Example 119
179

(1) (3,5-Bis-txifIuoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-aiiiine (1.06g) is dissolved in dimethylsulfoxide (5ml), and the mixture is degassed and thereto are added [ 1, l'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (61mg), potassium acetate (442mg) and bis(pinacoIate)diboron (571mg). The mixture is degassed and heated to 80°C under nitrogen flowe and stirred for 45 minutes. The reaction solution is allowed cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (5ml), and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (1.5ml) under ice-cooling and stirred at the same temperature for 1 hour and a half. To reaction mixture is added dropwise saturated aqueous sodium thiosulfate solution under ice-cooling, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4: l-»3:1) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyTimidin-5-ol (866mg). MS (m/z): 644 [M+H]^
(2) 2-{(3,5-Bis-trifluoromethyl-benzyl)-[4-(cyclopropylmethyl-propyl-amino)-2-methoxy-pyrimidin-5-ylmethyl]-amino}-pyrimidin-5-ol (300mg) is dissolved in N,N-dimethylformamide (2ml) and thereto are added potassium carbonate (193mg) and 4-bromo-butyronitrile (139pl), and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The
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resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 17:3^3:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl- 2' -metho5^-4-trifiuoromethyl-biphenyl-2 -ylmethyi) -amino j -pyrimidin-5-yloxy}-bu1yronitrlle (308mg). MS (m/z): 711 [M+H]+ Example 120
4-{2-l(3,5-Bis-trifluoromethyl-beiizyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyronitrile (240mg) is dissolved in N,N-dimethylformamide (7.5ml), and the mixture is degassed and thereto are added sodium azide (220mg) and ammonium chloride (ISlmg) and the mixture is heated to 110°C and stirred overnight. The reaction solution is allowed cool to room temperature, and thereto are added a saturated brine and 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by siEca gel column chromatography (chloroform : methanol = 99:1-*19:1) to give (3,5-bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-methojQ'-4-trifluoromethyl-biphenyl-2-ylmethyl)-{5-[3-(lH-tetrazol-5-yl)-propo:^]-pyrimidin-2-yl}-amine (127mg). MS (m/z): 754 [M+H]-* Example 121
(1) 2-{(2-Benzyloxy-5-trifiuoromethyl-benzyl}-(3,5-bis-trifluoromethyl-benzyl}-amino]-p3Timidin-5-ol (1.33g) is dissolved in tetrahydrofuran (20ml), and thereto are added 2-methylsulfanil-ethanol (290vil), triphenyJphosphine (S70mg) and 40% diethyl azodicarboxylate/toluene solution (1.5ml) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added water 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 resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 99:1—*9:1) to give (2-benzyloxy-5-
181

trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methylsialfanil-ethojq')-pyrimidin.-2-yl]-amine (1.2 Ig). MS (m/z); 676 [M+H]+
(2) (2-Benzyloxy-5-trifluoromethyl-benzyl}-(3,5-bis-trifluoromethyl-beiizyl)-[5-(2-inethylsulfanii-ethoxy)-pyriinidin-2-yl]-ainine {1.2 Ig) is dissolved in chloroform (ISml) and diereto is added m-chloro perbenzoic acid (75%) (906nig) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added saturated aqueous sodium thiosulfate 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—*7:3) to give (2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methanesulfonyl-etho3cy}-pyriniidin-2-ylj-amine(1.09g). MS (m/z): 708 [M+H]*
(3) (2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-ainine (1.07g) is dissolved in ethanol (15ml) and thereto is added 10% palladium-carbon (320mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 7 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give 2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-£imino}-methyl)-4-trifluoromethyl-phenol (400mg). MS (m/z): 618 [M+H1+
(4) 2-({t3,5-Bis-trifluoromethyl-ben2yl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trinuoromethyl-phenol (400mg) and pyridine (79pl) are dissolved in methylene chloride (10ml) and thereto is added trifluoromethanesulfonic acid anhydride (ISSjil) under ice-cooling and the mixture is stirred under nitrogen atmosphere at 0°C for 30
182

minutes. The reaction solution is cooled to room temperature and stirred for 50 minutes, and thereto is added trifiuoromethane sulfonic acid anhydride (Sljal) and the mixture is stirred for 10 minutes. Thereto are added a saturated aqueous sodium bicarbonate 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 is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1^2:1) to give trifiuoromethane sulfonic acid 2-({(3,5-bis-trifluoromethyl-benzyl)-[5-{2-methanesulfonyl-ethoxy)-pyrimidin-2-yl] - amino}-methyl)-4-trifluoromethyl-phenyl ester (386mg). MS (m/z): 750 [M+H]*
(5) Trifiuoromethanesulfonic acid 2-({(3,5-bis-trifluoromethyl-benzyl}-[5-(2-methanesulfonyl-ethoxy}-p3Timidin-2-yl]-amino}-methyl}-4-trifluoromethyl-phenyl ester (llOmg) is dissolved in 1,4-dioxane (2ml) and thereto are added 2,4-dimethoxy-pyrimidine-5-boronic acid (70mg), palladium acetate (13.2mg), 1,1 '-bis(di-tert-butylphosphino)ferrocene (28mg) and tripotassium phosphate (62mg) and the mixture is stirred under nitrogen atmosphere at SCC for 4 hours. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give (3,5-bis-trifluoromethyl-benzyl)-[2-(2,4-dimetha3^-pyrimidin-5-yl)-5-trifluoromethyl-benzyl]-[5-(2-methanesulfonyl-ethoxy)-p5TTmidin-2-yl]-amine (34mg}. MS (m/z): 740 [M+H]* Example 122
The corresponding starting compound is treated in a similar manner to Example 121 to give the compound as listed in Table 10.
183

Sxample 123
1) Ethyl 4-(2-{(3,5-bis-triiluoromethyl-benzyl)-12-(6-isopropenyl-3-
nelJioxy-p5aidm-2-yl)-5-trifluoromethyl-benzyl]-airiino}-pyrimidin-5-yloxy)-
3utyrate (76mg) is dissolved in ethanol (5ml), and thereto is added 10%
Dalladium-carbon (15mg) and the mixture is stirred under hydrogen
itmosphere for 1.5 hours. The catalyst is removed by filtration, and the
iltrate is concentrated under reduced pressure to give ethyl 4-(2-{(3,5-bis-
Tifluoromethyl-benzyl)-[2-(6-isopropyl-3-metho3Q'-p5Tidin-2-yl)-5-
Tifluoromethyl-benzyl]-amino}-p5Timidin-5-yloxy)-butyrate {70mg). MS
m/z): 759 [M+H]*
2) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-
nethoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy}-
185

butyrate (70mg) is dissolved in ethanol (2ml), and thereto is added IN-aqueous sodium hydroxide solution (0.5ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a IN-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 resulting residue is puriiied by silica gel column chromatography (chloroform : methanol = 1:0->9:1) to give 4'(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-(6-isopropyl-3-methoxy-pyridin'2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (62mg). The resulting carboxylic acid is dissolved in ethanol (1ml), and thereto is ^dded IN-aqueous sodium hydroxide solution (85vil) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trinuoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-ben^l)-amino}-pyrimidin-5-yloxy}-butyric acid sodium salt (729mg). MS (m/2): 729 [M-Na)-Example 124
(1) Ethyl 4-{2-((3,5-bis-trifluoromethyl-benzyl)-(2-hydrojcy-5-
trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-but3Tate (300mg) is dissolved in N,N-dimethylformamide (5ml) and thereto are added sodium hydride (60%) (29mg) and 4,6-dichloro-p5T-imidine (107mg) under ice-cooling, and the mijtture is stirred for 30 minutes, and the reaction solution is cooled to room temperature, and thereto is added 4,5-dichloro-pyrimidine (107mg), and the mixture is stirred for 30 minutes. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1-*17:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-(6-chloro-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy}-butyrate (244mg). MS (m/z): 738/740 [M+Hj^
186

(2) Ethyl 4-(2-|(3,5-bis-trifluoromethyl-benzyl)-[2-(6-chIoro-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl j-amino}-pyrimidin-5-yloxy)-bulyrate (170mg) is dissolved in toluene {5ml), and thereto are added diisopropylethylamine (136|al), 2.0M-dunethylamine/tetrahydrofuran solution (0.4ml) and the mixture is stirred at 50°C for 1 day. The reaction solution is cooled to room temperature, and thereto are added aqueous citric acid solution and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1->2:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-(6-dimethylamino-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-bu^ate (llSmg). MS (m/z): 747 [M+H]+
(3) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-dimethylamino-pyTimidin-4~yloxy)-5-trifluoromethyl-ben2yl]-amino}-pyrimidin-5-yloxy)-butyrate (llOmg) is dissolved in ethanol (Sml) and thereto is added IN-aqueous sodium hydroxide solution (1ml) and the mixture is stirred at room temperature for 2 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0^9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-ben^l)-[2-(6-dimethylamino-p5?rimidin-4-yloxy)-5-trifluoromethyl-ben2ryll-amino}-pyrimidin-5-yloxy)-butyric acid (107mg). MS (m/z): 719 [M+H]+
Example 125
The corresponding starting compound is treated in a similar manner to Example 124 to give the compound as listed in Table 11.
187

Example 126
(1) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-trifluoro-
methanesulfonyloxy-5-trifluoromet±iyl-benzyl)-ainino]-p5T-imidin-5-yloxy}-
butyrate (260mg) is dissolved in 1,2-dimethoxyethane (1ml) and thereto are
added (S)-l-(tert-butyl-dimethyl-silanyloxymethyl)-propylamine (140mg),
tris(dibenzyIideneacetone)dipalladium (31mg}, 2-(di-tert-
butylphosphino}biphenyl (41mg) and tripotassium phosphate (l46ing), and the mixture is degassed under reduced pressure and stirred under nitrogen atmosphere at SCC overnight. The reaction solution is allowed cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column
188

chromatography (hexane ; ethyl acetate = 1:0^-10:1) to give ethyl 4-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-I(S)-l-(tert-butyl-diniethyI-sil£inylox5TTiethyl)-propylamino]-5-trifluoromethyl-benzyl}-amino)-p3n-imidin-5-ylo:^]-butjTate (186ing). MS (m/z): 811 [M+H]*
(2) Ethyl 4-[2-((3,5-bis-trinuoroinethyl-benzyl)-{2-[(S)-l-(tert-butyl-dimethyl-silanyloxymethyl)-propylamino] - 5-trifluoromethyl-benzyl}-ainino)-pyrimidin-5-yloxy]-but3Tate (183mg) is dissolved in tetrahydrofuran (SmL) and thereto is added IM-tetrabutylammonium fluoride/tetrahydrofuran solution (1ml) and the mixture is stirred at room temperature for 20 minutes. The reaction solution is concentrated under reduced pressure and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4: l-*2:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl}-[2-((S)-l-hydroxymethyl-propylam.ino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-but3Taet (93mg). MS (m/z): 697 [M+H]+
(3) Ethyl 4-(2-{(3,5-bis-trinuoromethyl-benzyl)-[2-((S)-l-hydroxymethyl-propylamino)-5-trifluoromethyl-benzyl]-aniino}-pyrimidin-5-yloxy')-butyrate (40mg) is dissolved in a mixed solvent of methanol (0.3ml) and tetrahydrofuran (1ml) and thereto is added a IM-aqueous sodium hydroxide solution (0.5ml), and the mixture is stirred at room temperature for 30 minutes. To reaction mixture is added a 10% aqueous citric acid solution and a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-({S)-l-hydro30T^ethyl-propylamino)-5-trinuoromethyl-benzyI]-amino}-pyrimidin-5-yloj^)-butyric acid (41mg). MS (m/z): 669 [M+H]^
189

Example 127
(1) Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-l-hydroxymethyl-propyl-amino) - 5-trinuoromethyl-ben2yl]-amino}-pyrimidin-5-yloxy)-butyrate (102mg) is dissolved in methylene chloride (1.5ml) and thereto is added triethylamine (31}il), followed by an addition of triphosgene (17mg) under water-cooling, and the mixture is stirred at room temperature overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (hexane:ethyl acetate = 9:l--»7:3) to give ethyl 4-{2-{(3,5-bis-trinuoromethyl-benzyl)-[2-((S)-4-ethyl-2-oxo-oxazolidin-3-yl)-5-trifluoromethyl-benzyl]-amino}-p5T-imidin-5-yloxy}-butyrate (94mg). MS (m/z): 723 [M+H]+
(2) Ethyl 4-(2-{(3,5-bis-triiluoromethyl-benzyl)-[2-{(S)-4-ethyl-2-oxo-oxazolidin-3-yl}-5-trifluoromethyl-benzyl]-amino}-pyTimidin-5-yloxy)-butyrate (90mg} is dissolved in a mixed solvent of a methanol (0.5mL) and tetrahydrofuran (1ml) and thereto is added IM-aqueous sodium hydroxide solution (0.5mL) and the mixture is stirred at room temperature for 1 hour. The reaction mixture is made acidic with 10% aqueous citric acid solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = l:0- 190

Example 128
(1) 2-[(3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methojcy-4-trifluoromethyl-biphenyl-2-ylmethyl)-ainino]-p3T-imidin-5-ol (300mg) is dissolved in tetrahydrofuran (2mL), and thereto are added 2-(methylthio)ethanol (162]il} and triphenylphosphine (488mg}, and thereto is added dropwise a 40% diethyl azodicarboj^late/toluene solution (424|il) under water-cooling, and the mixture is stirred at 50°C overnight. Further thereto are added 2-{methylthio)ethanol (243nl) and triphenylphosphine (244mg), and thereto is added dropwise diisopropyl azodicarboxylate (361vil} under water-cooling, and the mixture is stirred at 60°C for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 99:1—♦Q:!) to give (3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[5-(2-methylsulfanil-ethoxy)-pyrimidin-2-yl]-amine (300mg). MS (m/z): 718 [M+H]+
191

(2) (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-metho3cy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-(2-methylsulfanil-ethoxy)-pyrimidin-2-yl]-amine (296mg) is dissolved in chloroform (3ml) and thereto is added m-chloro perbenzoic acid (152ing), and the mixture is stirred at room temperature for 1 hour. To the reaction solution is added a saturated aqueous sodium bicarbonate solution and the mixture is stirred at room temperature for 10 minutes and extracted with chloroform, and the organic layer is washed successively a saturated aqueous sodium bicarbonate solution and a brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 19:1—»2:1, and chloroform : methanol = 97:3^19:1) to give (3,5-bis-trifluoromethyl-benzyI}-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-amine (203mg) (MS (m/z): 750 [M+H]^), and (3,5-bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-methoxy-4-triflu oromethyl-biphenyU2-ylmethyl) - [5-(2-metheinesulfinyl-ethoxy)-pyrimidin-2-yl]-aniine (65mg) (MS (m/z): 734 [M+H]+}.

192

fl) (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethy]-biphenyl-2-ylmet±iyl)-ainine (2.0g) is dissolved in ethanol (20ml), and thereto are added cyanogen bromide (578ing) and sodium bicarbonate (928mg) and the mixture is stirred at room temperature for 2 hours. To reaction mixture is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by sUica gel column chromatography (hexane : ethyl acetate = 10:1—*5:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5'-isoprDpyl-2'-methoj^-4-trifluoromethyl-biphenyl-2-ylmethyl}-cyanamide (1.8g). MS (m/z): 575 [M+H]*
(2) (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-cyanamide (l.Sg) is dissolved in N,N-dimethylformamide (10ml), eind thereto are added sodium azide (407mg) and ammonium chloride (335mg), and the mixture is heated to 100°C and starred for 6 hours. The reaction solution is allowed cool to room temperature, and thereto is added a 10% aqueous citric acid solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 30:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoroinethyl-biphenyl-2-ylmethyl)-(2H-tetrazol-5-yl)-amine (1.9g). MS (m/z): 618 [M+H]*
(3) (3,5-Bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-methoxy-4-trifiuoromethyl-biphenyl-2-ylmethyl)-(2H-tetra2ol-5-yl}-amine (400mg) is dissolved in N.N-dimethylformamide (3ml) and thereto are added triethylamine (2ml) and ethyl 4-bromobutyrae (278^^1) and the mixture is stirred at 50°C for 3 hours. To reaction mixture is added water, and
193

extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1) to give ethyl 4-{5-[(3,5-bis-trifluoro methyl-benzyl} - (5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-aminol-tetrazol-2-yl}-butyrate (360mg) MS (m/z): 732 [M+H]*
(4) Ethyl 4-{5-[(3,5-bis-trifluorGmethyl-benzyl}-(5'-isopropyl-2'-metho^-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyrate (180mg) is dissolved in ethanol (3ml), and thereto is added a 2M-aqueous sodium hydroxide solution {0.5mL) and the mixture is stirred at room temperature for 1 hour and a half. The reaction mixture is made acidic with a IN-hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 20:1) to give 4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyric acid (160mg). MS (m/z): 704 [M+H]*
(5) 4-{5-[(3,5-Bis-trifluaromethyl-benzyl}-{5'-isopropyl-2'-metho:^-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyric acid (154mg) is dissolved in ethanol (3ml), and thereto is added IM-aqueous sodium hydroxide solution (225}il), and concentrated under reduced pressure to give 4-{5-[(3,5-bis-triiluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl- 2 -ylmethyl) -amino] -tetrazol-2 -yl}-butyric acid sodium salt (153mg). MS (m/z): 702 [M-Na] *
Example 130
(1) (3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-triiluoromethyl-biphenyl-2-ylmethyl)-(2 H-tetrazol-5-yl)-amine (300mg) is dissolved in tetrahydrofuran (5ml) and thereto are added
194

triphenylphosphine (l91mg), 2-(methylthio)ethanol (631^1), a 40% diethyl azodicarboxylate/toluene solution (332)^1) and the mixture is stirred at room temperature for 2 hours and a half. To reaction mixture is added water and the mixture is extracted with ether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 12:1) to give (3,5-bis-trifluoromethyl-benzyl]-(5'-isopropyl-2'-methoxy-4-trinuoromethyl-biphenyl-2-ylmethyl)-[2-(2-methylsulfanil-ethyl)-2H-tetrazol-5-yl]-amine (270mg). MS (m/z): 692 [M+H]*
(2) (3,5-Bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-metho3^-4-trifluoromethyl-biphenyl- 2-ylmethyl) - [ 2 -(2 -methylsulfanil-ethyl) -2 H -tetrazol-5-yl]-amine (270mg) is dissolved in chloroform (3ml), and thereto is added m-chloro perbenzoic acid (168mg), and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate, and the organic layer is washed with a brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 40:1) to give (3,5-bis-trifluoromethyl-ben^l)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methanesulfmyl-ethyl)-2H-tetrazol-5-yl]-amine (157mg). MS (m/z): 708 [M+H]+
195

Example 131
(1) 5'-Isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (S.OOg) is dissolved in ethanol (40inl) and thereto are added hydroxyl ammonium chloride (1.29g) and sodium acetate (1.53g), and the mixture is stirred under nitrogen atmosphere at 60°C for 1 hour and a half. The reaction solution is concentrated under reduced pressure, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue (3.3g) is dissolved in methanol (40ml), and thereto is added Raney nickel {5g) £ind the mixture is stirred under hydrogen atmosphere at room temperature overnight. Raney nickel is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—♦19:1) to give C-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-
196

yl)-methylaniine (1.57g). MS (m/z): 324 [M+H]^
(2) C-(5'-isopropyl-2'-methojq'-4-txifluoromethyl-biphenyl-2-yl)-methylajnine (1.54g) is dissolved in toluene (25ml), and thereto are added tert-butyl 4-(2-chloro-pyTimidin-5-yloxy)-biityrate (1.96g), palladium acetate {II} (I95mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (543nig), tetra-n-bulyl ammomum iodide {359mg) and sodium tert-butoxide (560mg), and the mixture is stirred under nitrogen flow at 85°C overnight. The reaction solution is allowed cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 47:3—*3:1) to give tert-butyl 4-{2-[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-bu1yrate (895mg). MS (m/z): 560 [M+H]*
(3) Tert-butyl 4-{2-[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloJ^}-but5T:ate (ISOmg) is dissolved in N,N-dimethyIfGrmamide (1.0ml), and thereto is added l,3-dichloro-5-chloromethyl-benzene (252mg), followed by an addition of sodium hydride (60%) (34mg) under ice-cooling and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-*9:1) to give tert-butyl 4-{2-[(3,5-dichloro-benzyl)-{5'-isopropyl-2'-methojq'-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (184mg). MS (m/z): 720/718 [M+H]*
(4) TQ tert-butyl 4-{2-[(3,5-dichloro-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethy 1-bipheny 1-2 -ylmethyl) -amino] -pyrimidin-5 -yloxy}-butyrate
197

(ISOmg) is added 4N-hydrochloric acid/dioxane solution (2ml} and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : m.ethanol = 1:0-*19:1) to give 4-{2-[(3,5-dichlorobenzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl}-amino]-pyrimidin-5-yloxy}-butyric acid (136mg}. MS (m/z): 664/662 [M+H]+ Examples 132 to 133
The corresponding starting compounds are treated in a similar manner to Example 131 to give the compounds as listed in Table 15.

198

dimethylxanthene (62mg) and palladium acetate (II) (16mg) and the mixture is stirred under nitrogen atmosphere at room temperature for 5 minutes. To the mixed solvent is added the mixed solution of tert-butyl 4-{2-[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (200mg), l-bromo-3,5-bis-trifluoromethyl-benzene (126mg) and toluene (1.5ml), and the mixture is degassed under reduced pressure and thereto is added sodium tert-butoxide (51mg) and the mixture is stirred under nitrogen flow at 80°C overnight. The reaction solution is allowed cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 10:1) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-pheny])-(5'-isopropyI-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino j-pyrimidin-5-yloxyj-butyrate (204mg), MS (m/z): 772 [M+H]*
(2) To tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-phenyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (197mg) is added a 4N-hydrochloric acid in dioxane (2.5ml) and the mixture is stirred at room temperature for 3 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chrom,atography (chloroform : methanol = 1:0-+19:1) to give 4-{2-[(3,5-bis-trifluoromethyI-phenyl)-(5'-isopropyl-2'-methojqr-4-trifluoromethyl-biphenyl-2-ylmethyl)-aminol-p5n:imidin-5-yloxy}-butyric acid (104mg). MS (m/z): 716 [M+H]* Example 135
(1) C-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine {3.47g) is dissolved in dioxane (50ml), and thereto are added
199

5-bromo-2-chloropyriinidine (5.30g) and N,N-diisopropylethylainine {5.74ml) and the mixture is stirred at lOCC for 2 hours and a half. The reaction solution is allowed cool to room temperature, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 50:1—*22:3) to give (5-bromo-pyrimidin-2-yl)-(5'-isopropyl-2'-niethoxy-4-trifluoroinethyl-biphenyl-2-ylmethyl)-amine {4.82g). MS (m/z): 482/480 [M+H]+
(2} (5-Bromo-p3Timidin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-
biphenyl-2-ylmethyl)-amine {3.30g) is dissolved in toluene fSOml), and
thereto are added tris(dibenzylideneacetone)dipalladium (1.26g), 2-(di-tert-
butylphosphino}biphenyl (1.23g), morpholine (2.4ml) and sodium tert-
butoxide (1.32g) and the mixture is degassed under reduced pressure and
stirred under nitrogen flow at 50°C overnight. To the reaction mixture is
added a saturated brine, and extracted with ethyl acetate. The organic
layer is washed with a saturated brine, dried over magnesium sulfate, and
concentrated under reduced pressure. The resulting residue is purified by
silica gel column chromatography (hexane : ethyl acetate = 19:1-+3:1) to
give (5'-isopropyl-2'-methoxy-4-trinuoromethyl-biphenyl-2-ylmethyl)-(5-
morpholin-4-yl-pyrimidin-2-yl)-amine (l.llg). MS (m/z): 487 [M+H]*
(3) (5'-Isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-
morpholin-4-yl-pyrimidin-2-yl}-amine (500mg) is dissolved in N,N-
dimethylformamide {3ml), and thereto is added 3-fluoro-5-(trifluoromethyl-
)benzylbromide (528mg) and thereto is added sodium hydride (60%) {82mg)
under ice-cooling, and the mixture is stirred at room temperature for 2
hours and a half. To the reaction solution are added a saturated brine,
and the mixture is extracted with ethyl acetate. The organic layer is
washed with a saturated brine, dried over magnesium sulfate, and
concentrated under reduced pressure. The resulting residue is purified by
silica gel column chromatography (hexane : ethyl acetate = 49:1—*22:3) to
give (3-fluoro-5-trifluoromethyl-benzyl)-{5'-isopropyl-2'-methoj^-4-
200

tTifluoroinet±iyl-biphenyl-2-ylniethyl)-(5-morpholin-4-yl-pyrimidin-2-yl}-amine (440mg). MS (m/z): 663 [M+H]^
(4) To tetrahydrofuran (6ml) is added sodium hydride (60%) (390mg) under nitrogen atmosphere, followed by an addition dropwise of benzyl alcohol (l.Olml) under water-cooling, and the mixture is stirred at the same temperature for 30 minutes. To this reaction mixture is added a mixture of (3-fIuoro-5-triftuoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - (5-morpholin-4-yl-pyrimidin-2-yl)-amine (430mg) and tetrahydrofuran (4ml) and the mixture is stirred under nitrogen atmosphere at 70'C overnight. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 97:3^^17:3) to give (3-benzyloxy-5-trifluoromethyl-benzyl}-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylinethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (221mg). MS (m/z): 751 [M+H]*
(5) (3-Benzyloxy-5-trifIuoromethyl-benzyI)-(5'-isopropyI-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - (5-morpholin-4-yl-pyrimidin-2-yl)-amine {215mg) is dissolved in methanol (10.5ml), and thereto is added 10% palladium-carbon and the mixture is stirred under hydrogen atmosphere at room temperature for 1 hour. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 4:1—*1:2, and chloroform : methanol 19:1—♦9:1) to give 3-{[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morphoIin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenol {98mg). MS (m/z): 661 [M-1-H1+
(6) 3-{[(5'-Isopropyl-2'-methoxy-4-trifluoromethyI-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yI)-amino]-methyl}-5-trifluoromethyl-phenol
201

(95mg) is dissolved in N,N-dimethylformamide (1ml), and thereto are added potassium carbonate (90mg) and ethyl 4-bromobutyrate (93vil) and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1^4:1) to give ethyl 4-(3-([(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2 -ylmethyl) - (5 -morpholin- 4-yl-pyrimidin- 2 -yl) -aniino]-methyl}-5-trifluoromethyl-pheno3^)but5T-ate (92mg). MS (m/z): 775 [M+H]^
(7) Ethyl 4-{3-{[(5'-isopropyl-2'-methoxy-4-triiluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-pheno3^)butyrate (88mg) is dissolved in a mixed solvent of ethanol (Iml) and tetrahydrofuran (Iml) and thereto is added a IM-aqueous sodium hydroxide solution (Iml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is made acidic with 10% aqueous citric, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—*1:1) to give 4-(3-{[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - (5-morpholin-4-yl-p3^rimidin-2-yl)-amino]-methyl)-5-trifluoromethyl-phenoxy)butyric acid (71mg). MS (m/z): 747 (M+HJ^ (S) 4-(3-{[(5'-Isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - (5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenoxy)butyric acid (69mg) is dissolved in ethanol (1ml) and thereto is added a IM-aqueous sodium hydroxide solution (92^1) and the mixture is stirred at room temperature for 3 minutes, and concentrated under reduced pressure to give 4-(3-{[(5'-isopropyl-2'-methoxy-4-
202

tTifluoromethyI-biphenyl-2-ylmethyl)-(5-rnorpholin-4-y]-pyrirni din--2-71)-aniino]-methyl}-5-trifluoromethyl-phenojq^)butyric acid sodium salt (66mg). MS (m/z): 745 [M-Na] *

Example 136
(1) (2-Benzyloxy-3-chloro-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-p3n-imidiii-2-yl)-ainine (which is prepared by treating the corresponding starting compound in a same manner as in Example 23 (l)-(2)} (700mg) is treated in a similar manner to Example 87
(1) to give l-{2-[(2-benzylojQ'-3-chloro-5-trifluoromethyl-ben^l)-(3,5-bis-
trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-ethyl piperidine-4-
carboxylate (422mg). MS (m/z): 775/777 [M+H]^
(2) Ethyl l-{2-[(2-benzyloxy-3-chloro-5-trifluoromethyl-benzyl)-(3,5-bis-
triflu oromethyl-benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carboxy late
(412mg) is treated in a similar meinner to Example 23 (5) to give ethyl l-{2-
[(3,5-bis-trifluoromethyl-ben^l)-(3-chloro2-hydro3^-5-trifluoromethyl-
benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carbojiylate (277mg). MS
(m/z): 685/687 [M+H]*
203

trifluoroinethyl-benzyl}-amino]-pyriniidin-5-yl}-piperidine-4-carboxylate (274mg) is treated with the corresponding starting compound in a similar manner to Example 26 to give l-{2-[(3,5-bis-trifluoromethyl-benzyl)-(6-chloro-3'-isopropyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-ainino]-P5TT.midin-5-yI}-piperidine-4-carboxylic acid (180mg). MS (m/z): 759/761 [M+Hj^ Example 137
The corresponding starting compound is treated in a similar manner to Example 136 to give the compound as listed in Table 17.

Example 138
(1) (2-Benzyloxy-3-chloro-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-p5T-imidin-2-yl)-amine (2.11g) is treated in a similar manner to Example 23(3)-(5) to give ethyl 4-{2-{(3,5-bis-trifluoromethyl-benzyl) - {3-chloro-2-hydros^'-5-trifIuoromethyl-benzyl}-
204

amino]-pyrimidin-5-yloxy}-butyrate (163mg). MS (m/z): 660/662 [M+H]' (2) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-ben0yl)-{3-chloro-2-hydroxy-5-trifluoromethyl-benzyl)-amino]-p3Timidin-5-yloxy}-butyrate (160mg) is treated with the corresponding starting compound in a similar manner to Example 26 to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(6-chloro-3'-isopropyl-4-trifluoromethyl-biphenyl-2-yhnethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (87mg). MS (m/z): 762/764 fM-Na]-Example 139
(1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-p5T-imidin-2-yl)-(5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amine (which is prepared in a similar manner to Example 117(l)-(3)) (532mg) is treated with the corresponding starting compound in a similar manner to Exainple 2(4} to give 2-((3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-p3Timidin-5-ol (371mg). MS (m/z): 636 [M+H]^
(2) 2-[(3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-4,5,2'-trimetho3cy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ol (160mg) is treated in a similar manner to Example 2(5)-(6) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yl05cy}-butyric acid sodium salt (128mg). MS (m/z): 720 [M-Na]-Examole 140
(1) Ethyl 4-{2-[(3,5-bis-trinuoromethyl-benzyl)-(2-hydroxy-5-
trifluoromethyl-benzyl)-amino]-p3Timidin-5-yloxy}-butyrate (1.39g) is dissolved in chloroform (20ml) and thereto is added N-bromosuccinicimide (475mg} and the mbrture is stirred at room temperature for 2 hours and the reaction solution is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-*4:1} to give ethyl 4-{2-[(3,5-bis-trifluoromethyI-benzyl) - (3-bromo-2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxyj-butyrate (1.29g). MS (m/z): 704/706 [M+Hj*
205

(2) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-ben;yl)-(3-bromo-2-hydroxy-5-trifluoroinethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (1.29g) and pyridine (220vil) are dissolved in methylene chloride (15ml) and thereto is added trifluoromethanesulfonic acid anhydride (460ial( under ice-cooling, and the mixture is stirred under nitrogen atmosphere at 0°C for 45 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:l-t4:l) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(3-bromo-2-trif!uoromethanesulfonyloxy-5-trifluoroniethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (907mg). MS (m/z): 836/838 [M+H]*
(3) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(3-bromo-2-trifluoro-methanesuIfonyloxy-5-trifluoromethyl-benzyl)-amino]-p5Timidin-5-ylo^}-butyrate {300mg) is dissolved in 1,4-dioxane (4ml) and thereto are added [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex {58mg), methyl boric acid (32mg) and cesium carbonate (175mg) and the mixture is stirred under nitrogen atmosphere at SO°C for 3 days. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, £ind the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = IQrl^'lTiS) to give the crude product containing ethyl 4-(2-[(3,5-bis-trifluoromethyI-benzyI)-(3-methyl-2-trifluoro-methanesulfonyloxy-5-trifluoromethyl-ben^l)-amino]-pyrimidin-5-yloxyj-butyrate (207mg]. The resulting crude product (200mg) is dissolved in 1,4-dioxane (4ml) and thereto are added [1,1'-bis(diphenylphosphino)ferrocene|dicWoropal]adium dichloromethane
206

complex (42mg|, 5-isopropyI-2-methoxyphenyl borate (ISOmg) and cesium
carbonate (127mg) and the mixture is stirred under nitrogen atmosphere at
SO^C overnight. The reaction solution is cooled to room temperature, and
thereto are added ethy] acetate and a saturated aqueous sodium
bicarbonate solution, 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 resulting residue is purified by
NH-silica gel column chromatography (hexane : ethyl acetate = 49:1—*17:3),
followed by Gel Permeation Chromatography (JiUGEL; chloroform) to give
ethyl 4-{2-|(3,5-bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-methoxy-6-
methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate {20mg). MS (m/z): 772 [M+HI*
(4) Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl}-(5'-isopropyl-2'-metho3ty-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pjT-imidin-5-y]oxy}-but5T-ate (20mg) is dissolved in ethanol (2ml), and thereto is added a IN-aqueous sodium hydroxide solution (0.5ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a IN-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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-*9:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-6-methyI-4-trifluoromethyI-biphenyJ-2-ylmethyl|-amino]-pyrimidin-5-yloxy}-butyric acid (21mg). The resulting carboxylic acid is dissolved in ethanol (Iml) and thereto is added IN-aqueous sodium hydroxide solution {28p}) and the reaction solution is concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-m.ethoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylinethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (19mg). MS (m/z): 742 |M-Na]-
207

Example 141
(3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - [ 2-(2-methane sulfinyl-ethyl)-2 H-tetra2ol-5-yl]-amine (129mg) is dissolved in chloroform (2ml), and thereto is added m-chloroperbenzoic acid (50mg) and the mixture is stirred at room temperature overnight. To the reaction solution is added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give (3,5-bis-trinuoromethyl-benzyI)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2 -ylmethyl) -(2 - (2 -methane sulfonyl-ethyl}-2H-tetrazol-5-yl]-amine (81mg). MS (m/z): 724 [M+H]*
208

Example 142
(1) Tert-buty] 4-(2-chloropyrimidin-5-yloxy)-butjTate {5.0g) is dissolved in toluene (100ml) and thereto are added palladium acetate (412mg) and 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (1.26g}, and the mixture is stirred under nitrogen atmosphere at 50 °C for 1 hour. The reaction solution is cooled to room temperature, and thereto are added 3,5-bis-trifluoromethyl-henzylamine (5.35g) and sodium tert-butoxide (3.8Sg) andthe mixture is stirred at 35°C for 2 hours. Thereto are added ethyl acetate and water, 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 is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1->2:I) and NH-silica gel column chromatography (hexane : ethyl acetate = 4:1--*2:1) to give tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate (5.59g}. MS (m/z): 480 [M+H]*
(2) (2-Bromo-4,5-dimethoxy-phenyl}-methanol (2.47g) is dissolved in methylene chloride (30ml) and thereto is added thionyl chloride (875pl} and, the mixture is stirred at room temperature for 30 minutes. The reaction
209

solution is concentrated under reduced pressure, and thereto is added to hexane and the resulting crystal is filtered to give l-broino-2-chloromethyl-4,5-dimethoxy-benzene (2.25g). MS (m/z): 229/231
(3) Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-ben2yl-amino)-pyrimidin-5-yloxyl-butyrate (lOOmg) is dissolved in DMF (1ml) and thereto is added sodium hydride (60%) (lO.Smg) under ice-cooling, and the mixture is stirred under ice-cooling for 15 minutes. Thereto is added l-bromo-2-chloromethyl-4,5-dimethoxybenzene (83.1mg) and the mixture is stirred under ice-cooling for 1 hour. To the reaction solution are added aqueous ammonium chloride 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 residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1—*4:1) to give tert-bulyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl}-(2-bromo-4,5-dimethoxy-benzyl)-amino]-pyrimidin-5-yloxy}-but5Tate (116mg). MS (m/z): 708/710 [M+H]*
(4) Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-4,5-dimethoxy-ben2yl)-amino]-p5T-imidin-5-yloxy}-butyrate (150mg) is dissolved in 1,4-dioxane (3ml) and thereto are added {4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (128mg), [1.1'-bis(diphenyIphosphino)ferrocene]dichloropalIadium dichloromethane complex (32mg) and cesium carbonate (196mg), and the mixture is stirred under nitrogen atmosphere at BO^C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the orgainic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 19:1—*17:3) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (140mg). MS
210

(m/z): 796 [M+H]+
(5) To tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4'-nuoro-5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl}-aminol-pyriinidin-5-yloxy}-butyrate (129mg) is added a 4N-hydrogen chloride/dioxane solution (Sml) and the mixture is stirred at room temperature for 7 hours. To the reaction solution are added a. saturated aqueous sodium hydroxide 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 resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0-*.9:1} to give 4-{2-[(3,5-bis-trinuoromethyl-beiizyl)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ylojcy}-butyric acid (lOOmg). MS (m/z): 740 [M+H]^
(6) The resulting carbojc^lic acid obtained in the above (5) is dissolved in ethanol (1ml) and thereto is added IN-aqueous sodium hydroxide solution (128vil), and the reaction solution is concentrated under reduced pressure to give 4-{2-|(3,5-bis-trifluoromethyl-ben^l)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-but^c acid
sodium salt (lOOmg). MS (m/z): 738 [M-Na]-Examples 143 to 152
The corresponding starting compounds are treated in a similar
manner to Example 142 to give the compounds as listed in Table 20. Example 153
The corresponding starting compound is treated in a similar manner
to Example 159 to give the compounds as listed in Table 20.
Examples 154 to 157
The corresponding starting compounds are treated in a similar
manner to Example 160 to give the compounds as listed in Table 20.
Table 20
211

to Example 117(1) and Example 131 to give the compound as listed in
Table 21. Example 159
(1) Tert-bulyryl 4-{2-[(2-bromo-4,5-dimethoxy-benzyl)-(3-cyano-5-
trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (which is prepared by treating the corresponding starting compound in a similar manner to Example 142(l)-(3)} (l.Og) is dissolved in 1,4-dioxane (10ml) and thereto are added [l,l'-bis(diphenylphosphino)ferrocene]dichloropaUadium dichloromethane complex (252mg), bis(pinacolate)diboron (782mg) and potassium acetate (453mg) and the mixture is stirred under nitrogen atmosphere at 80°C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 80:20-^70:30) to give tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (769mg). MS (m/z): 713 1M+H]+
(2) Tert-butyryl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[4,5-dimethGxy-
2-(4,4,5,5-tetramethyl-[l,3,2jdioxaborolan-2-yl)-benzyl]-amino}-pyrimidin-
5-yloxy}-but3Tate (60mg) is dissolved in 1,4-dioxane (1.5ml) and thereto are
added 2-bromo-6-isDprDpenyl-3-methoxy-pyridme (38mg), [1,1'-
bis(diphenylphosphino) ferrocene] dichloropalladium dichloromethane
complex (7mg) and cesium carbonate (55mg), and the mixture is stirred
214

under nitrogen atmosphere at 80°C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated and the organic layer is filtered by NH- silica gel and the mixture is extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 85:15—*70;30) to give tert-butyl 4-(2-{{3-cyano-5-trifluoromethyl-benzyl)-[2-{6-isopropenyl-3-methoxy-pyridin-2-yl)-4,5-dimethoxy-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (17mg). MS (m/z): 734 [M+H]+
(3) Tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropenyl-3-methoxy-p3T-idin-2-yI)-4,5-dimethojQ'-benzylj-amino}-pyriinidin-5-yloxy)-butyrate (36mg) is treated in a similar manner to Example 142(5) to give 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropenyl-3-methoxy-pyridin-2-yl)-4,5-dimethoxy-ben2yl]-amino}-pyrimidin-5-yloxy)-butyric acid (24.5mg). MS (m/z): 678 [M+H]*
(4) 4-(2-{(3-Cyano-5-trifiuoromethyl-benzyl)-[2-(6-isopropenyl-3-methoxy-pyridin-2-yl}-4,5-dimethoj^-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (24.5mg) is dissolved in methanol (2ml), and thereto is added 10% palladium-carbon (lOmg) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 hour. The insoluble material is removed by Alteration and the fiJtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform : methanol = 100:0^85:15) to give 4-(2-{(3-cyano-5-trifIuoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-4,5-dimetho:^-benzyl]-amino}-p3Timidin-5-yloxy)-butyric acid (21mg). MS (m/z): 680 [M+H]+
(5) 4-(2-{(3-Cyano-5-trifluoromethyl-benzyl)-[2-(5-isopropyl-3-methoxy-pyridin-2-yl)-4,5-dimethojQ'-benzyl]-amino}-p5TTniidin-5-yloxy)-butyric acid (21mg) is treated in a similar manner to Example 142(6) to give 4-(2-{(3-cyano-5-trifluoromethyl-benzyl) - (2 - (6-isopropyl3-methoxy-pyridine2-yl)-
215

4,5-dimethoxy-benzyl]-amino}-p3Timidin-5-yloxy)-butyric acid sodium salt (22mg). MS fm/z): 678 [M-Na]-Example 160
Tert-butyryl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl}-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl}-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (195mg) and l-bromo-5-isopropyl-2-methoxy-4-methyl-benzene (130mg) is treated in a similar manner to Examples 159(2),(3) and (5) to give 4-{2-[(3-cyano-5-trifluoromethyl-ben2yl)-(5'-isopropyl-4,5,2'-trimetho3cy-4'-methyl-biphenyl-2-ylmethyl)-amino]-p5T-imidin-5-yloxy}-butyric acid sodium salt (66mg). MS (m/z): 691 [M-Na]-Examples 161 to 162
The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 21.

216

The corresponding starting compounds are treated in a similar manner to Example 142 to give the compounds as listed in Table 22. Enample 169
(1) Tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl}-[2-(6-isopropenyl-3-methoxy-pyTidine-2-yl)-5-trifluorometyl-benzyl]-amino}-pyrimidine -5-yloxy)-butyrate (which is prepared in a similar manner to Example 142(2}-(3) and Example 159(l)-(2))(73mg) is treated in a similar manner to Exeimple 159(4) to give tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methojQ'-p5T4dine-2-yl)-5-trifluorometyl-benzyl]-amino}-pyrimidine-5-yloxy)-butyrate (70mg). MS (m/z): 744 [M+H]+
(2) Tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-ben2yl)-[2-(6-isopropyl-3-methoxy-p3Tidine-2-yl)-5-trifluorometyl-benzyl]-amino}-pyrimidine -5-yloxy)-butyrate (70mg) is treated in a similar manner to Example 142(5)-(6) to give 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridine-2-yl) - 5-trifluorometyl-benzyl] - amino}-pyrimidine-5-yloxy)-butylic acid sodium salt (40mg). MS (m/z): 686 [M-Na]-.
Examples 170 to 172
The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 22.
217

The corresponding starting compounds are treated in a similar manner to Example 142 to give the compounds as listed in Table 23. Example 178
The corresponding starting compound is treated in a similar manner to Example 169 to give the compound as listed in Table 23.

219

(1) 1 -Methoxy-5-methyl-4-nitro-2-trifiuoromethyl-benzene (lOg) is dissolved in methanol (lOOml), and thereto is added 10% palladium-carbon (Ig) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 day. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give 4-methoxy-2-methyl-5-trifluoromethyl-phenylamine (9.07g). MS (m/z): 206 [M+H]+ (2) To copper (II) bromide (ll.Sg) is added acetonitrile (50ml) and followed by addition dropwise of tert-butyl nitrite (8.5ml) under ice-cooling and the mixture is stirred under nitrogen atmosphere for 5 minutes. To
220

reaction mixture is added dropwise a solution of 4-methoxy-5-trifluoromethyl-phenylamine (9.07g) in acetonitrile {20ml) under ice-cooling over 20 minutes and the mixture is stirred at room tem^perature under nitrogen atmosphere overnight. Reaction mixture is concentrated under reduced pressure. To the resulting residure is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1—'0:1) eind NH-silica gel column chromatography (hexane ; ethyl acetate = 1:0—*9:1) to give l-bromo-4-methoxy-2-methyl-5-trifluoromethyl-benzene (3.61g).
(3) l-Bromo-4-methoxy-2-methyl-5-trifluoromethyl-benzene (l.Og), 2,2'-azobisisobutyronitrile (61mg) and N-bromosuccinimide {795mg) are dissolved in carbon tetrachloride (15ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0^^9:1) to give l-bromo-2-bromomethyl-4-metho^-5-trifluoromethyl-benzene (732mg).
(4) Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzyIamino)-pyrimidin-5-ylox/J-butyrate (300mg} is dissolved in N,N-dimethylformamide (4ml) and thereto is added sodium hydride (60%) (33mg) under ice-cooling, and the mixture is stirred for 15 minutes and thereto is added l-bromo-2-bromomethyl-4-methoj{y-5-trifluoromethyl-ben2ene (327mg) and the mixture is stirred at room temperature overnight. Thereto are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—*17:3) to give tert-butyl 4-{2-[(3,5-bis-triiluoromethyl-benzyl)-(2-bromo-5-methoxy-4-
221

trifluoromethyl-benzyl)-amino)-pyrimid.in-5-yloxy}-bu1yrate (256mg). MS
(m/z): 746/748 [M+H]*
(5) Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-
methoxy-4-trinuoroinethyl-benzyl}-ainino]-p5Timidin-5-yloxy}-butyrate
(120mg) is treated in a similar manner to Example 142(4)-(5) to give 4-{2-
[(3,5-bis-trifluoromethyl-benzyl)-{4'-fluoro-5'-isopropyl-4,2'-dimethojQ'-5-
trillUGromethyl-biphenyl-2-ylmethyl) - amiono]-pjTimidin-5-yloxy}-butyric
acid sodium salt (53mg). MS (m/z): 776 [M-Na]-
Example 180
The corresponding starting compound is treated in a similar manner to Example 179 to give the compound as listed in Table 24. Example 181
The corresponding starting compound is treated in a similar manner to Exam.ple 169 to give the compound as listed in Table 24. Examples 182 to 184
The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 24.

222

The corresponding starting compounds are treated in a similar manner to Example 179 to give the compounds as listed in Table 25. Example 187
The corresponding starting compound is treated in a similar manner to Example 169 to give the compound as listed in Table 25. Examples 188 to 189
The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 25.
Table 25
223

(1) 5-Methoxy-2-nitro-4-trifluoromethyl-phenol (5g) and pyridine (2.6ml) are dissolved in methylene chloride {150ml), and the mixture is cooled to 0°C, and thereto is added trifluoromethane sulfonic acid anhydride (5.3ml} and the mixture is stirred at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and
224

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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^^4:1) to give trifluoro-methanesulfonic acid 5-methojty-2-nitro-4-trifluoromethyl-phenyl ester (5.3g).
(2) Trifluoro-methanesulfonic acid 5-methoxy-2-nitro-4-trifluoromethyl-phenyl ester (2.6gJ is dissolved in 1,4-dioxane (20ml) and thereto is added 5-isopropyl-2-methoxy benzene boronic acid (l-5g), [1>1'-bis(diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (575mg) and cesium carbonate {3.44g), and the mixture is stirred under nitrogen atmosphere at 80°C overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1—^17:3) to give 5'-isopropyl-5,2'-dimethoxy-2-nitro-4-trifluoromethyl-biphenyl (2.35g). MS (m/z): 370 [M+H]*
(3) 5'-Isopropyl-5,2'-dimethoxy-2-nitro-4-trifluoromethyl-biphenyl (2.35g) is dissolved in a mixed solvent of tetrahydrofuran (20ml} and methanol (30ml), and thereto is added 10% palladium-carbon (SOOmg) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 day. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—*4:1) to give 5'-isopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-ylamine (1.88g). MS (m/z): 340 [M+H]*
(4) To copper (II) bromide (l.lTg) is added acetonitrile (5ml) and followed
by addition dropwise of tert-butyl nitrite (0.835ml) under ice-cooling and
225

the mixture is stirred under nitrogen atmosphere for 5 minutes. To reaction mixture is added dropwise a solution of 5'-isopropyl-5,2'-dimetho3^-4'trifluoromethyl-biphenyl-2-ylamine (1.48g) in acetonitrile (2ml) under ice-cooling and the mixture is stirred at room temperature under nitrogen atm.osphere overnight. Reaction mixture is concentrated under reduced pressure. To the resulting residure is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = l:0-^-9:1) to give 2-bromo-5'-isopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl (1.29g).
(5) 2-Bromo-5'-isopropyI-5,2'-dimethoxy-4-trifluoromethyl-biphenyl (1.29g} is dissolved in dry tetrahydrofuran (30ml) and thereto is added dropwise 1.6M n-butyllithium in hexanes at -78°C, and the mixture is stirred for 1 hour and thereto is added N,N-dimethylformamide (1.2ml), and the mixture is stirred for 1.5 hours. To the reaction solution are added a saturated aqueous ammonium chloride solution eind 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1-*17:3) to give 5'-isopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (733mg). MS (m/z): 353 [M+H]+
(6) 5'-lsopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde {692mg) is dissolved in a mixed solvent of tetrahydrofuran (12ml), ethanol (3.5ml} and methylene chloride (1ml), and thereto is added sodium borohydride (82mg) and the mixture is stirred at room temperature for 40 minutes. The reaction solution is concentrated under reduced pressure and thereto are added ethyl acetate and water, and the mixture is
226

separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—*4:1) to give (5'-isopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-yl)-methanol (566mg). MS (m/z): 337 [M+H-H201^
(7) (5'-lsopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-yl)-methanol (200mg) is dissolved in toluene (5ml) and thereto is added thionyl chloride (60pl) under ice-cooling, and the mixture is stirred for 3 hours. To the reaction solution are added water 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. 4-[2-(3,5-Bis-trifluoromethyl-ben2ylamino)-pyrimidin-5-y]o3cy]-bmyric acid tert-butyl ester {246mg) is dissolved in N,N-dimethylformainide (5ml) and thereto is added sodium hydride (60%) (23mg) under.ice-cooling, and the mixture is stirred for 20 minutes. Thereto are added a solution of a residue obtained above in N,N-dimethylformamide (Sml) and the mixture is stirred at room temperature 3 hours and 20 minutes. To the reaction solution are added water 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-»17:3) to give tert-butyl 4-{2-[(3,5-bis-trinuoromethyl-benzyl)-{5'-isopropyl-5,2'-dimethojqr-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (74mg). MS (m/z): 816 [M+H]+
(8) Tert-butyl 4-{2-l(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-5,2'-dimethoxy-4-trifluoromethyl-biphenyl-2-ylmethyl) - amino]-pjniimidin-5-yloxyj-butyrate (68mg) is treated in a similar manner to Example 142(5)-(5) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-5,2'-dimethoxy-4-
227

tiiiluorome thy 1-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt {23mg). MS (m/z): 758 [M-Na]-Examples 191
The corresponding starting compound is treated in a similar manner to Example 190 to give the compounds as listed in Table 26.

The corresponding starting compounds are treated in a similar manner to Example 142 to give the compounds as listed in Table 27. Examples 201 to 205
The corresponding starting compounds are treated in a similar manner to Example 160 to give the compounds as listed in Table 27. Examples 206 to 207
The corresponding starting compounds are treated in a similar manner to any of the above Examples to give the compounds as listed in
228

(1) 2-[(3,5-Bis-trifluoroniethyl-beniyl)-(5'-isopropyl-4,5,2'-trimethoxy-
biphenyl-2-ylmethyl)-amino]-pyriinidin-5-ol (60mg) is dissolved in
tetrahydrofuran (1ml) and thereto are added tert-butyl 3-hydroxy-
propionate (336nig), triphenylphosphine (592mg), and thereto is added
dropwise diisopropyl azodicarboj^late {447vil) and the mixture is stirred at
60°C overnight. To the reaction mixture is added a saturated brine, and
the mixture is extracted with ethyl acetate. The organic layer is washed
with a saturated brine, dried over magnesium sulfate, and concentrated
under reduced pressure. To the resulting residue is added isopropylether
and the insoluble material is filtered and the filtrate is concentrated under
reduced pressure. The resulting residue is purified by silica gel column
chromatography (hexane : ethyl acetate = 9:1—>2:1) and NH-silica gel
column chromatography (hexane : ethyl acetate = 9:1—•4:1) to give tert-
butyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-4,5,2'-trimethoxy-
biphenyl-2-ylmethyl)-£unino]-p3Timidin-5-yloxy}-propionate (43mg). MS
(m/z): 764 [M+H]*
(2) To tert-butyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-
4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ylo3^}-
propionate (41mg) is added a 4N-hydrochloric acid/dioxane (4ml) and the
mixture is stirred at room temperature for 9 hours. The reaction mixture
is neutralized with a saturated aqueous sodium bicarbonate solution and
the mixture is made weakly acidic with a 10 % aqueous citric acid solution,
and extracted with ethyl acetate. The organic layer is washed with a
saturated brine, dried over magnesium sulfate, and concentrated under
reduced pressure. The resulting residue is purified by silica gel column
231

chromatography (hexane : ethyl acetate = 4:1—*1:3) and the resulting purified product is dissolved in ethanol (0.5ml) and thereto is added IM-aqueous sodium hydroxide solution (24JJ1) and the mixture is concentrated under reduced pressure to give 3-{2-[(3,5-bis-trifluoroinethyl-benzyl)-(5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyriinidin-5-yloxy}-propionic acid sodium salt (18mg). MS (m/z): 706 [M-Na]-Example 209
Methyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-4,5,2'-
trimethoxy-biphenyl-2-ylmethyl)-aininol-pyrimidin-5-yloxy}-2,2-dimethyl-propionate (which is prepared by treating the corresponding starting compound in a similar manner to Example 208(1)) (85mg) is treated in a similar manner to Example 103(3) to give 3-{2-[(3,5-bis-trifluoromethyl-ben2yl)-(5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-ainino]-pyrimidin-5-yloxy}-2,2-dimethyl-propionic acid sodium salt (52ing). MS (m/z): 734 [M-Na]-Example 210
The corresponding starting compounds is treated in a similar manner to Example 139(2) to give the compound as listed in Table 28.

232

The corresponding starting compound is treated in a similar manner to Example 208 to give the compound as listed in Table 29. Example 212
The corresponding starting compound is treated in a similar manner to Example 209 to give the compound as listed in Table 29. Example 213
The corresponding starting compound is treated in a similar manner to Example 139(2) to give the compound as listed in Table 29.

233

(1) 5'-Isopropenyl-2'-methoxy-4-trifluoroniethyl-biphenyl-2-
carbaldehyde (5.0g) is dissolved in a mixed solvent of tetrahydrofuran
(100ml), ethanol (30ml) and methylene chloride (10ml), and thereto is
added sodium borohydride {646m^g) and the mixture is stirred at room
temperature for 10 minutes. The reaction solution is concentrated under
reduced pressure and thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column
chromatography (hexane : ethyl acetate = 49:1—^:1) to give (5'-isopropenyl-
2'-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methanol (4.73g). MS (m/z):
307 [M+H]+
(2) (5'-Isopropenyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-yl)-
methanol (500mg) is dissolved in methylene chloride (3ml), and thereto is
added dropwise thionyl chloride (248^1) under nitrogen atmosphere under
ice-cooling and the mixture is stirred at room temperature for 15 minutes
234

and the reaction, solution is ice-cooled and thereto is added dropwise triethylamine (647{J1). TO the reaction solution are added diethylether and a saturated brine, and the mixture is separated, and the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The residue and (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-p3Tidin-2-yI)-amine (799mg| is dissolved in N,N-dimethylformamide and thereto is added sodium hydride (123mg) and the mixture is stirred at SCC for 2 hours and a half. The reaction solution is cooled to room temperature, and thereto is added diethylether and water, and the mixture is separated and the organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by sUica gel colum.n chromatography (hexane : ethyl acetate = 49:1—*9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (4Slmg}. IVIS (m/z): 705/707 [M+H\*
(3) (3,5-Bis-trifluoromethyl-ben2yl)-(5-bromo-pyridin-2-yl)-{5'-isopropyl-2'-methoxy-4-trifiuoromethyl-biphenyl-2-ylinethyl)-amine (475mg), [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium methylene chloride complex (55mg), potassium acetate (198mg) and bis(pinacolate)diboron (256mg) are dissolved in dimethyl sulfoxide (2ml), and the mixture is heated to sec under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed twdce with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (10ml), and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (0.75ml) under ice-cooling. The reaction solution is stirred at room temperature overnight, and thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, followed by an addition of water
235

and diethylether, and the mixture is separated. The organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1-»4:1) to give 6-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylinethyl)-aniinoj-P3rridin-3-ol (141mg). MS (m/z): 643 [M+H]+
(4) 6-[(3,5-Bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trtfluoromethyl-biphenyl-2-ylmethyl)-amino]-p5T-idin-3-ol (14lmg) is dissolved in N,N-dimethylformamide (1ml), and thereto is added 60% sodium hydride (lOmg) under ice-cooling and the mixture is stirred for 5 minutes and thereto is added ethyl 4-bromobutyrate (48>il), and the mixture is stirred at room temperature for 1 hour. To the reaction solution is added water under ice-cooling, and the mixture is extracted with methylene chloride, and the organic layer is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^4:1) to give ethyl 4-{6-[(3,5-bis-trifluoromethyl-benzyl) - (5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-buty^ate (154. Img). MS (m/z): 757 [M+H]+
(5) Ethyl 4-{6-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl- 2 -ylmethyl)-amino] -p5Tidin- 3-yloxy}-butyrate (150mg) is dissolved in a mixed solvent of ethanol (1ml) and tetrahydrofuran (2ml) and thereto is added a 2N-aqueous sodium hydroxide solution (0.3ml) and the mixture is stirred at 50°C for 3 hours and 20 minutes. The reaction solution is cooled to room temperature and neutralized with a 2N-hydrochloric acid (0.3ml), and thereto are added methylene chloride and a saturated brine and the mixture Is separated, and the organic layer is concentrated under reduced pressure. The resulting residue is purified by LCMS (column: CAPCELPACK MG2 C18,
236

eluate: a lOpM aqueous carbonic acid solution/acetonitrile 55/45—*40/60) to give 4-{6-[(3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4-trifluoroinethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloJ^}-butyric acid (31.4mg). The resulting carboxylic acid is dissolved in ethanol (1ml) and thereto is added a 2N-aqueous sodium hydroxide solution (42pl) and the reaction solution is concentrated under reduced pressure to give 4-{6-[(3,5-bis-trifluoromethyl-benzyI)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylm ethyl)-amino]-pyridin-3-yloxy}-butyric acid sodium salt (30.6mg). MS (m/z): 727 [M-Na]-Example 215
The corresponding starting compound is treated in a similar manner to Example 214 to give the compound as listed in Table 30.

237

(1) 5'-Isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (S.Og), hydroxylamine hydrochloride (3.45g) and pyridine (28ml) are dissolved in ethanol (140nil), and the mxture is stirred at 80°C for 1 hour. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a IN-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a IN-hydrochloric acid, a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (100ml), and thereto is added Raney nickel, and the mixture is stirred under hydrogen atmosphere at room temperature for 30 minutes and SO^C overnight. The reaction solution is cooled to room temperature, and Raney nickel is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—*23:2) to give C-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (5.50g). MS (m/z): 324 [M+H]+
(2) C-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (107mg) is dissolved in toluene (3ml), and thereto Eire added tris(dibenzylideneacetone)dipalladium (30mg), 1,3-
238

bis(diphenylphosphino)propane (27mg) and sodium tert-butoxide (44mg),
and the mixture is stirred under nitrogen atmosphere at 80°C overnight.
The reaction solution is cooled to room temperature, and to the reaction
solution are added methylene chloride and a saturated aqueous sodium
bicarbonate solution, and the mixture is separated, and the organic layer is
concentrated under reduced pressure. The resulting residue is purified by
silica gel column chromatography (hexane : ethyl acetate = 49:1—*4:1) to
give (5-bromo-pyridin-2-yl}-(5'-isopropyl-2'-methoxy-4-trifiuoromethyl-
biphenyI-2-ylmethyl)-amine (41.3mg). MS (m/zj: 479/481 [M+H1^ (3) (5-Bromo-pyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine {700mg), is dissolved in N,N-dimethylformamide (5ml), and thereto is added sodium hydride (60%) (88mg) under nitrogen atmosphere at -10°C, and the mixture is stirred at the same temperature for 5 minutes, and 3-bromomethyl-5-triiluoromethyl-benzonitrile (77lmg), and the mixture is stirred under ice-cooling for 1 hour and 40 minutes. To the reaction solution are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated, and the organic layer is washed twice with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—*17:3) and (hexane : ethyl acetate = 49:1—t9:l). The residue is dissolved in diethyl ether, and filtered. The filtrate is concentrated under reduced pressure, and the residue obtained above (630mg) is dissolved in tetrahydrofuran (3ml), and thereto are added morphoUne (119ial) and triethyamine (190>il), and the mixture is stirred at 50°C for 4 hours, and the reaction solution is cooled to room temperature, and stirred at same temperature overnight. To the reaction solution are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with water and a saturated brine, and the mixture is dried over magnesium sulfate and is
239

concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1—vlTiS) to give 3-{[(5-bromo-pyridin-2-yl}-(5'-isopropyl-2'-methoj^-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-S-trifluoromethyl-benzonitrile (440mg). MS (m/z): 662/664 [M+H]*
(4) 3-{[(5-Bromo-pyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyI-2-yhnethyl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (435mg) is treated in a similar manner to Example 214(3) to give 3-{[(5-hydroxy-pyridin-2-yl)-(5'-isopropyl-2'-methGxy-4-trif]uoromethyl-biphenyl-2-ylmethyl|-amino]-methyl}-5-trifluoromethyl-benzonitrile (251mg). MS (m/z): 600 [M+H]*
(5) 3-{i(5-Hydroxy-p3T-idin-2-yl)-(5'-isopropyl-2'-metho5Q'-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-5-trifiu oromethyl-benzonitrile (150mg) is dissolved in N,N-dimethyifonnamide (2.5ml), and thereto is added 60% sodium hydride (12mg) under ice-cooling and the mixture is stirred for 30 minutes and thereto is added tert-butyl 4-bromobutyrate (85mg), and the mixture is stirred at room temperature for 6 hours. To the reaction solution is added water under ice-cooling, and the mixture is extracted with methylene chloride, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 9: l-*-3:1) to give tert-butyl 4-{6-[(3-cyano-5-trifluoromethyl-benzyl)-(5'-isopropyl-2'-metho;Q'-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyrate (169mg). MS (m/z): 742 [M+H]*
(6) Tert-butyl 4-{6-[(3-cyano-5-trifluoromethyl-benzyl)-{5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-p5Tidin-3-yloxy}-butyrate (165mg) is treated in a similar manner to Example l42(5)-{6) to give 4-{6-[(3-cyano-5-trifluoromethyl-ben^l)-(5'-isoprGpyl-2'-methoJ^-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-p5Tidin-3-yloxy}-but5Tic acid
240

sodium salt (113.5mg). MS (m/z): 684 (M-Na]-Example 217
The corresponding starting compound is treated in a similar manner to any of the above Examples to give the compound as listed in Table 31.

The corresponding starting compounds are treated in a similar manner to Example 142 to give the compounds as listed in Table 32. Example 220
(1) 5-Benzyloxy-2-bromo-benzaldehyde (l.Og) is dissolved in 1,4-dioxane (30ml) and thereto are added [l,r-bis(diphenylphosphino|ferrocene]-dichloropalladium dichloromethane complex {280mg), (5-isopropyl-2-methoxyphenyl)boronic acid (800mg) and cesium carbonate (1.68g) and the m^ixture is stirred under nitrogen atmosphere at 80°C for 6 hours. The reaction mixture is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over m^nesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—>4:1) to give 4-benzyloxy-5'-
241

isopropyI-2'-raethoxy-biphenyI-2-carbaldehyde (1.19g}. MS (m/z): 361 [M+H](2) 4-Beiizylo3gr-5'-isopropyl-2'-metho?cy-biphenyl-2-carbaldehyde
(1.16g) is dissolved in ethanol (15ml) and thereto is added sodium borohydride (122mg) and the mixture is stirred at room temperature for 10 minutes. Thereto are added a saturated aqueous ammonium chloride 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 to give (4-benzyloxy-5'-isopropyl-2'-methoxy-biphenyl-2-yl)-methanol (1.26g). MS (m/z): 345
(3) (4-Benzyloxy-5'-isopropyl-2'-niethoxy-biphenyl-2-yl)-methanol (l.lOg) is dissolved in methylene chloride (10ml), and thereto is added thionyl chloride (332pl) and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0^9:1) to give 4-ben^loxy-2-chloromethyl-5'-isopr opyl-2'-methoxy-biphenyl (1.15g). MS (m/z): 345
(4) Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxyj-butyrate (l.llg) and 4-benzylo;^-2-chloromethyl-5'-isopropyl-2'-methoxy-biphenyl (805mg) are dissolved in N,N-dimethylformamide (10ml) and thereto is added sodium hydride (60%) (120mg) under ice-cooling, and the mixture is stirred under ice-cooling for 2 hours, and then is stirred at room temperature for 30 minutes. Thereto are added a saturated aqueous ammonium chloride 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 1:0—*4;1| to give tert-butyl 4-{2-[(4-benzyIoxy-5'-isopropyl-2'-methoxy-biphenyI-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (1.14g). MS (m/z): 824 [M+H|242

(5) Tert-butyl 4-{2-[(4-benzyloxy-5'-isopropyl-:(i'-metnoxy-Dipnenyl-2-ylmethyl) - f 3, S-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxyj-butyrate (80mg) is treated in a similar manner to Example 142(5)-(6) to give 4-{2-[(4-benzyloxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylniethyl)-(3,5-b is-trifluQromethyl-benzyl)-aminol-pyrimidin-5-ylo5^}-butyric acid sodium salt(59.5mg). MS (m/z): 766 [M-Na]-Example 221
(1) Tert-butyl 4-{2-[(4-benzyloxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl}-amino]-pyrimidin-5-yloxy}-butyrate (l.Og) is dissolved in ethanol (20ml), and thereto is added 10% palladium-carbon (200mg), and the mixture is stirred under hydrogen atmosphere at room temperature for 4 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure, and thereto is added hexane and the resulting crystal is filtered to give tert-butyl 4-{2-[(3,5-bis-trifluorom ethyl-benzyl)-(4-hydroxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl}-amino]-p5rrimidin-5-yloxy}-butyrate (835mg). MS (m/z): 734 [M+Hj*
(2) Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-hydroxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-amino]-p3Timidin-5-yloxy}-butyrate (70mg) is treated in a similar manner to Example 142{5)-(6) to give 4-{2-[(3,5-Bis-trifluoromethyl-benzyl)-(4-hydroxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (55.4mg). MS (m/z): 676 [M-Na]-
Example 222
(1) Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-ben^l)-(4-hydroxy-5'-
isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-ainino]-pyTimidin-5-yloxy}-
butyrate (70mg) is dissolved in N,N-dimethylformamide (3ml) and thereto is
added potassium carbonate (26.4mg) and iodoethane (29.8mg) and the
mixture is stirred at 50°C for 8 hours. Thereto are added ethyl acetate
and a water, and the mixture is separated, and the organic layer is washed
243

with a saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure. The resulting residue is purified by NH-silica gel
column chromatography (hexane : ethyl acetate = 1:0^^9: l)to give tert-
butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-ethoxy-5'-isopropyl-2'-
methoxy-hiphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (60.5mg). MS (m/z): 762 [M+H]+
(2) Tert-butyl 4-{2-[(3,5-bis-triiluoromethyl-benzyl)-f4-ethoxy-5'-
isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-aniino]-pyrimidin-5-yloxy}-butyrate (59mg) is treated in a similar manner to Example 142(5)-(6) to give 4-{2-[(3,5-bis-trifLuoromethyl-benzyl)-(4-etho3^-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-but5Tic acid sodium salt (48.2mg). MS (m/z): 704 [M-Naj-Example 223
The corresponding starting compound is treated in a similar manner to Example 222 to give the compound as listed in Table 32. Examples 224 to 230
The corresponding starting compounds are treated in a similar manner to any of the above Examples to give the compounds as listed in

244

(1) (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-p5Tiniidin-2-yl)-ainine (315mg) and 4-ben^loxy-2-chloromethyl-5'-isopropyl-2'-methoxy-biphenyl (300mg) are dissolved in N.N-dimethylformamide (5ml) and thereto is added sodium hydride (60%) (40.9mg) under ice-cooUng, and the mixture is stirred at room temperature overnight. Thereto are added a saturated aqueous ammonium chloride 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 resulting residue is purified by silica gel column chromatography (hexane : Sethyl acetate = 1:0—»-97;3) to give (4-benzyloj^-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-ben2yl)-(5-bromo-pyrimidin-2-yl)-amine (458mg). MS (m/z): 744/746 [M+H]*.
246

(2) {4-Benzyloxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl}-(3,5-bis-trifluoromethyl-benzyl}-(5-bronio-p3TTmidin-2-yl)-ainine (433mg) is dissolved in toluene (Sml) and trisfdibenzylideneacetonejdipaUadium (107mg), sodium tert-butoxide (168mg), 2-(di-tert-butylphosphino)biphenyl (69.4mg) and morpholine (152mg) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography {hexane : ethyl acetate = 9:1—♦2:1} to give {4-benzylQxy-5'-isopropyl-2'-methoxy-biphenyl-2-ylmethyl)-{3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (3S4mg). MS (m/z): 751 [M+H]*
(3) (4-Benzyloxy-5'-isopropyl-2'-methojcy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine is treated in a similar manner to Example 221 and 222 to give 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-{5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5'-isopropyl-2'-methoxy-biphenyl-4-yloxy)-butyric acid sodium salt. MS (m/z): 745 [M-Na]-
Example 232
The corresponding starting compound is treated in a similar manner to Example 231 to give the compound as listed in Table 33. Examples 233 to 234
The corresponding starting compounds are treated in a similar manner to any of the above Examples to give the compounds as listed in Table 33.
Table 33

The corresponding starting compounds are treated in a similar manner to any of the above Examples to give the compounds as listed in Table 34. Example 239
The corresponding starting compound is treated in a similar manner to Example 142 to give the compound as listed In Table 35.
248

Cyclohexanecarboxaldehyde (38g), diethylamine hydrochloride (55g) and acetic acid (29ml) are dissolved in methylene chloride (500ml) and thereto is added triacetoxy sodium borohydride (71.8g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution are added a 2N-aqueous sodium hydroxide solution
254

and methylene chloride, and the mixture is separated, and the organic
layer is washed with a saturated brine, dried over magnesium sulfate, and
the mixture is concentrated under reduced pressure to give
cycIohejQrimethy-ethyl-amine (40. Ig) as a crude product. MS (m/z): 142
[M+Hj^
Reference Example 2
3,5-Bis-trifluoromethyl-benzylamine (lOg) and 5-bromo-2-chloro-
pyrimidine (12g) is dissolved in 1,4-dioxane (50ml} and thereto is added
N,N-diisopropylethylamine (10.7ml) and the mixture is heated under reflux
overnight. The reaction solution is cooled to room temperature and
concentrated under reduced pressure. The resulting residue is purified by
silica gel column chromatography {hexane : ethyl acetate = 9:1 to 7:3) to
give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyriinidin-2-yl)-amine
(10. Ig). MS (m/z): 713 [M+H]* Reference Example 3
(1) Ethylamine hydrochloride (2g) is dissolved in methylene chloride (20ml) and thereto are added pyridine (6ml) and ethyl 6-(chloroformyl)hexanoate (7.6g) and the mixture is stirred at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and the mixture is separated, and the organic layer is washed successively with a IN-hydrochloric acid, water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give ethyl 6-ethylcarbamoyl hexanoate (9.29g) as a crude product. MS (m/z): 216 [M+H]+
(2) Crude ethyl 6-ethylcarbamoyl hexanoate (9.29g) is dissolved in tetrahydrofuran (50ml) and thereto is added sodium borohydride (7.35g). The reaction solution is heated under reflux and thereto is added dropwise acetic acid (11ml) and the mixture is heated under reflux for 1 hour and a half. To the reaction solution is added water under ice-cooling eind the mixture is extracted with ethyl acetate. The organic layer is washed with a
255

saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in ethanol (SOml), and thereto is added a 4N-hydrochloric acid in ethyl acetate (7.6nil), and the mixture is 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 a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give ethyl 7-ethylamino-heptanoate (3.98g) as a crude product. MS(m/z): 216 [M+H]-Reference Example 4
(1) 6-Aminohexanoic acid methyl ester hydrochloride (5g) is dissolved in methylene chloride (20ml) and thereto are added pjn-idine (4.5ml) and acetyl chloride (2ml), and the mixture is stirred at room temperature for 1 hour and 45 minutes. To the reaction solution are added a IN-hydrochloric acid 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 to give methyl 6-acetylamino-hexanoate (5.19g) as a crude product. MS (m/z): 188 [M+H]+
(2) Crude methyl 6-acetylainino-hexanoate (5.19g) is dissolved in tetrahydrofuran (50ml) and thereto is added sodium borohydride (5.03g). The reaction solution is heated under reflux and thereto is added dropwise acetic acid {7.6ml) and the mixture is heated under reflux for 1 hour and 30 minutes. To the reaction solution are added water under ice-cooling and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in ethanol (30ml) and thereto is added a 4N-hydrochloric acid in ethyl acetate (7.6ml) and the mixture is 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
256

washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give ethyl 6-ethylaniino-hexanoate (1.74g) as a crude product. MS (m/z): 188 [M+H]* Reference Example 5
(1) (3,5-Bis-trifluoroniethyl-benzyl)-(5-broino-pyriniidin-2-yl)-anune (lOg) and triethylamine (4.18ml) are dissolved in methylene chloride (lOOmL) and thereto is added triphosgene (2.97g) under ice-cooling. The reaction solution is stirred at the same temperature for 30 minutes and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofurein (lOOmL) and thereto are added benzyl alcohol (3.88ml) and triethylamine (10.45ml) at room temperature and the mixture is stirred overnight. The reaction solution is diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution ^nd a IN-hydrochloric acid. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 97:3~>9:1) to give benzyl (3,5-bis-trifli4oromethyl-benzyI)-(5-bromo-pyrimidin-2-yl)-carbamate (11.58g). MS (m/a): 534/536 [M+H]*
(2) Benzyl (3,5-bis-trifluoromethyl-benzyl}-(5-bromo-pyrimidin-2-yI)-carbamate (11. 5g), [ 1,1 '-bis(diphenylphosphinQ)ferrocenel-dichloropalladium dichloromethane complex (3.51g), potassium acetate (6.33g) and bis(pinacolate)diboron (10.9g) are dissolved in dimethylsulfoxide (75ml), and the mixture is heated to 80°C under nitrogen atmosphere and stirred for 30 minutes. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the insoluble materials are removed by filtration through Celite'^M^ 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 resulting residue is dissolved in tetrahydrofuran (100ml)
257

and thereto is added dropwise a 30 % aqueous hydrogen peroxide solution (50ml) under ice-cooling and the mixture is stirred for 1 hour. Thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, followed by an addition of water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0^9:1) to give benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl}-carbamate (9.70g). MS (m/z): 472 [M+H]*
(3) Benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-hydro>^-p5rrimidin-2-yl)-carbamate (9.70g) and ethyl 4-bromobutyrate (3-53g) are dissolved in N,N-dimethylformamide (50mL) and thereto is added potassium carbonate (3.41g) and the mixture is stirred at 50°C for 1 hour. Thereto are added ethyl acetate and a saturated brine, 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 resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1—* 1:1) to give ethyl 4-{2-[benzyloxycarbonyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloJ0^}-butyrate (8.29g). MS (m/z): 586 [M+H]+
(4) Ethyl 4-{2-[benzyloxycarbonyl-(3,5-bis-trifluoromethyl-ben2yl)-aminol-pyrimidin-S-yloxyl-butyrate (3.0g) is dissolved in tetrahydrofuran {20ml) and thereto is added 10% palladium-carbon (SOOmg) and the mixture is stirred under hydrogen atmosphere at room temperature for 2 hours and 30 minutes. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1—*1:1) to give ethyl 4-[2-(3,5-bis-trifluoromethy!-benzylamino)-pyrimidin-5-yloxy]-butyrate (2.22g). MS (m/z): 452 [M+H]^
Reference Example 6
258

(1) 6-Aminohexanoic acid methyl ester hydrochloride (2.50g) is dissolved in tetrahydrofuran (50ml) and thereto are added water (50ml) and sodium bicarbonate (3.44g), followed by an addition dropwise of benzyl chloroformate (2.17ml) under ice-cooling, and the mixture is stirred at the same temperature for 2 hours and a half. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 6-benzyloxycarbonylamino hexanoate (4.16g). MS (m/z): 280 [M+H]^
(2) Methyl 6-benzyloxycarbonylamino-hexanoate (4.15g) is dissolved in N,N-dime thy Iformamide (2.5mL) ans thereto is added sodium hydride (63%) (552mg) under ice-cooling and the mixture is stirred at the same temperature for 1 hour and thereto is added methyl iodide (1.72ml), and the mixture is stirred at the same temperature for an additional 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4:1} to give methyl 6-(benzylo3cycarbonyl-methyl-aniino)-hexanoate (2.25g). MS (m/z): 294 [M+H]^
(3) Methyl 6-(ben^lojQ'carbonyl-methyl-amino)-hexanoate (2.24g) is dissolved in methanol (35ml) and thereto is added 10% palladium-carbon (500mg) and the mixture is stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to give methyl 6-methylamino hexanoate (l.llg). MS (m/z): 160 [M+H]^
Reference Example 7
Propylamine (0.65g) is dissolved in tetrahydrofuran (5ml) and thereto is added pyridine (0.89ml), followed by an addition dropwise of methyl
259

adipoyi chloride (1.96g) under ice-cooling and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (30ml) and thereto is added sodium borohydride (1.93g) at room temperature and the mixture is heated to 65°C and thereto is added dropwise acetic acid (2.92ml) over 1 hour and the mixture is stirred at the same temperature for 9 hours. To reaction mixture is added an ice-cooled dilute hydrochloric acid, and the mixture is stirred for 30 minutes and extracted with ethyl acetate, and the organic layer is washed with a mixed solution of a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in methanol (Sml) and thereto is added a 4N-hydrochloric acid in dioxane (7.5mL) and the mixture is stirred at room temperature overnight. To the reaction mixture is added a saturated aqueous sodium bicarbonate solution and a saturated brine, and the mixture is extracted six times with ethyl acetate and the collected organic layer is dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 6-propylamino-hexanoate (914mg). MS (m/z): 188 [M+H]* Reference Example 8
(1) Tert-butyl piperidine-4-ylmethyI-carbamate [2.00g) is dissolved in tetrahydrofuran (10ml), and thereto is added triethylamine (1.69ml), followed by an addition dropwise of ethyl bromoacetate (1.24mL) in water bath and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure, and to the resulting crystalline residue is added isopropylether
260

and tne mixture is tiitered to give etiiyl |4-(tert-butoxy-carbonylammo-methyl)-piperidin-l-ylj-acetate (1.87g). MS (m/z): 301 [M+H]+
(2) Ethyl [4-(tert-butoxycarbonylainino-niethyl)-piperidin-l-yl]-acetate (1.86g) is dissolved in N,N-dimethylformainide (10ml), and thereto are added sodium hydride (63%) (1.19g) and ethyl iodide (6.0ml), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is made weak basic with a 10% aqueous citric acid solution and a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give ethyl {4-[(tert-butojqfcarbonyl-ethyl-amino)-methyl]-piperidine-l-yl}-acetate (905mg). MS (m/z): 329 [M+H]*
(3) Ethyl {4-[(tert-buto3q^carbonyl-ethyl-amino)-methyl]-piperidine-1 -yl}-acetate (235mg) is dissolved in methylene chloride (1ml) and thereto is added trifluoroacetic acid (1ml) and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to give (4-ethylaminomethyl-piperidin-l-yl)-acetic acid ethyl ester bistrifluoroacetic acid salt (482mg). MS (m/z): 229 [M+H]* Reference Example 9

(1) 2-Tert-butoxy-ethylaraine (2g} is dissolved in methylene chloride (10ml) and thereto are added p3T-idine (940vil) and ethyl 6-(chloroformyl)hexanoate (1.13g) under ice-cooling and the mixture is stirred at room temperature overnight. To the reaction solution are added a IN-hydrochioric acid 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 to give ethyl 6-(2-tert-ethylcarbamoyl)-hexanoate as a crude product (2.96g). MS (m/z): 288 [M+H]+
(2) Crude ethyl 6-{2-tert-ethylcarbamDyl)-hexanoate (2.96g) is dissolved
261

in tetrahydrofuran {15ml) and thereto is added sodium borohydride (1.60g). The reaction solution is heated under reflux and thereto is added dropwise acetic acid {2.4mL) and the mixure is heated under reflux for 1 hour. To the reaction solution is added water under ice-cooling and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, guid concentrated under reduced pressure. The resulting residue is dissolved in ethanol (6ml) and thereto is added a 4N-hydrochloric acid in ethyl acetate (1.5ml) and the mixture is stirred at room temperature for 3 days. To the reaction solution are added a saturated aqueous sodium bicarbonate 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 to give ethyl 7-(2-tert-butoxy-ethylamino)-heptanoate as a crude product (2.6g). MS (m/z): 274 [M+H]+ Reference Example 10
(1) 2-Bromo-pyridine-3-ol (5g) is dissolved in water (150ml) and thereto are added sodium carbonate (6.15g) and iodine (7.65g) and the mixture is stirred at room temperature for 2 hours. Thereto are added a IN-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 is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1^3:1) to give 2-bromo-6-iodD-pyridin-3-ol (4.52g). MS (m/z): 300/302 [M+H]-^
(2) 2-Bromo-6-iodo-pyrid:n-3-ol (2.98g) is dissolved in N,N-dimethylformamide (140ml) and thereto are added cesium carbonate (16.3g) and methyl iodide (1.25mL) and the mixture is stirred at room temperature overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the oi^anic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column
262

chromatography (hexane : ethyl acetate = 19:1^4:1) to give 2-bromo-6-iodo-S-methoxy-pyridine (2.45g). MS (m/z); 314/316 [M+H]+ (3) To 0.5M-isopropenyl magnesium bromide/tetrahydrofuran is added trimethyl borate (3.3ml) and the mixture is stirred under nitrogen atmosphere at room temperature for 30 minutes. To the reaction solution are added 6N-hydrochloric acid and diethylether, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give isopropenylboric acid as a crude product (818mg). The above crude isopropenyl boric acid (287mg) and 2-bromo-6-iodo-3-methoxy-pyridine (SOOmg) are dissolved in a mixed solvent of l,2-diinetho3Q'-ethane (8ml) and ethanol (3.2ml) and thereto are added a IM-aqueous sodium carbonate solution {6.4ml) and tetrakis(triphenylphosphine)palladium (240mg) and the mixture is stirred under nitrogen atmosphere at 80°C for 5 hours. To the reaction solution are added water 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 is purified by silica gel column chromatography (hexane : ethyl acetate = 49:1—*-9:l), followed by NH-silica gel column chromatography (hexane : ethyl acetate = 49:1^^9:1) to give 2-bromo-6-isopropenyl-3-methoxy-pyridine (138mg). MS (m/z): 228/230 [M+H]* Reference Example 11
5-Methoxy-2-methylsulfanil-p5Timidin-4-ol (250mg) is dissolved in acetonitrile (7ml) and thereto are added phoshporus oxychloride (0.7ml) and diethyl aniline {460pl) and the mixture is heated under reflux for 5.5 hours. The reaction solution is evaporated azeotropically with toluene three times, and to the residue are added aqueous citric acid solution and chloroform, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel
263

column chromatography (hexane : ethyl acetate = 19:1^^17:3) to give 4-
chloro-5-methoxy-2-methyl sulfanil-pyrimidine (260mg). MS (m/z):
191/293 [M+HJ + Reference Example 12
(1} 3-Nitro-5-(trifluoromethyl)benzoic acid (50g) is dissolved in tetrahydrofuran (300ml) and thereto is added dropwise a l.OM-borane tetrahydrofuran complex/tetrahydrofuran (300ml) at 0°C under nitrogen atmosphere over 2 hours and the mixture is stirred at 75°C for 1 hour and a half. The reaction solution is allowed cool to room temperature and concentrated under reduced pressure, and thereto is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude (3-nitro-5-trifluoromethyl-phenyl)-methanol. This product is dissolved in methanol (500mL) and thereto is added 10% palladium-carbon (5g) and the mixture is stirred under hydrogen atmosphere at room temperature overnight. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give crude (3-amino-5-trifluoromethyl-phenyl)-methanol. To copper (II) bromide (53.6g) is added acetonitrile (500ml), followed by an addition dropwise of tert-butyl nitrite (35.7ml) under ice-cooling and the mixture is stirred under nitrogen atmosphere for 5 minutes. To reaction mixture is added dropwise a solution of the above crude (3-amino-5-trifluoromethyl-phenyl)-methanol in acetonitrile (200ml) under ice-cooling over 1 hour and 15 minutes and the mixture is stirred at room temperature under nitrogen atmosphere overnight. To reaction mixture is added a IN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively vi^th a IN-hydrochloric acid, water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography
264

(hexane : etiiy! acetate = 7:1— (2) (3-Bromo-5-trifIuoromethyl-phenyl)-methanol (33.9g) is dissolved in N,N-dimethylformamide (400mL) and thereto are added zinc(II) cyanide (16.39g) and tetrakis(triphenylphosphine)palladium (7.68g) and the mixture is heated under nitrogen atmosphere at 120°C for 2 hours. The reaction solution is allowed cool to room temperature, and filtered through CeliteTM, and the filtrate is concentrated under reduced pressure. Thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give 3-hydrox3Tnethyl-5-trifluoromethyl-benzonitrile (23.4g). NMR (CDCI3): 2.09 (lH,t), 4.85 (2H,d), 7.83 (IH.s), 7.87 (2H,s)
(3) S-HydrojqTnethyl-S-triftuoromethyl-benzonitrile (23.4g) is dissolved in methylene chloride (230mL) and thereto is added carbon tetrabromide (42.4g), followed by an addition of triphenylphosphine (32.Og) under ice-cooling and the mixture is stirred at the same temperature for 30 minutes. The reaction solution is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 10:1) to give 3-bromo-methyl5-trifluoromethyl-benzonitrile (25.5g). NMR (CDCI3): 4.51 (2H,s), 7.86 (lH,s), 7.88 (2H,s)
Reference Example 13
2-Chloropyrimidin-5-ol (3.89g) is dissolved in N,N-dimethylformamide (50ml) and thereto are added potassium carbonate (498g) and tert-butyl 4-bromo-bu1yrate (7.36g) and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and
265

concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 24:1-*4:1| to give tert-butyl 4-(2-chloropyTiinidin-5-yloxy)bromobutyrate (6.22g}. MS fm/z): 273 [M+H]-Reference Example 14
2,5-Dibromopyridine (4.74g) is dissolved in toluene (100ml) and thereto are added 3,5-bis-trifluoromethyl-benzylainine (5.84g) and palladium acetate (449.Omg), 2,2'-bis{diphenylphosphino)-l,l'-binaphthyl (1.25g) and sodium tert-butoxide (4.23g) and the mixture is stirred under nitrogen atmosphere at 80°C for 12 hours. The reaction solution is cooled to room temperature, and thereto is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate twice, and the organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 19:1^4:1) to give (3,5-bis-triftuoromethyl-benzyl)-(5-bromopyridin-2-yl)-amine (2.08g). MS (m/z): 399/401 [M+H]+ Reference Example 15
3-Bromomethyl-5-trifiuorometyl-benzonitrile (which is prepared in Referrence Example 12) (15.9g) is dissolved in 7M-ammonia/methanol (550ml), and the mixture is stirred at 50-60°C for 30 minuites. The reaction solution is concentrated under reduced pressure. To the resulting residue are added a saturated aqueous sodium bicarbonate solution and chloroform, and the mixture is separated, and the organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 1:0—*19:1—•■chloroform ; methanol : ammonium hydroxyide solution = 19:1:0.1) to give 3-aminomethyl-5-trifluorometyl-benzonitrile {10.4g). MS (m/z): 201 [M+HJ+
266

Reference Example 16
The corresponding starting compound is treated in a similar manner to Example 142(1) to give the compound. Reference Example 17
(1) 3-Bromo-4-methoxybenzoic acid (2.00g) is dissolved in tetrahydrofuran (50ml), and the mixture is cooled to -78°C, and thereto is added dropwise a I.IM methyllithium in diethyl ether (7.7ml). The mixture is stirred at -78°C for 5 minutes, and thereto is added dropwise a 1.6M tert-butyllithium in n-pentane (13.2ml), and the mixture is stirred at -78'C for 15 minutes, and the mixture is allowed to warm to -45°C, and the mixture is stirred for 45 minutes, and then again cooled to -78°C. Thereto is added dropwise triisopropylborate, and the mixture is stirred at -78°C for 15 minutes, and the mbiture is allowed to warm to room temperature. The mixture is stirred at room temperature for 1.5 hours, and the mixture is concentrated under reduced pressure, and thereto are added water and hexane. The aqueous layer is adjusted pH to 4 by addition of a 6N-hydrochloric acid and a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate and methanol twice. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To the resulting residue is added diethyl ether, and the resulting solids are collected by filteration to give 2-methojQ'-5-carbojtyphenylboronic acid (1.37g) as a crude product.
(2) The crude 2-metho3ty-5-carboxyphenylboronic acid (370mg) is dissolved in N,N-dimethylformamide (10ml), and thereto are added 2.0M-dimethylamine/tetrahydrofuran solution (1.9ml), 1-hydroxybenzotriazole dihydrate (725mg), l-ethy-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (579mg). The mbiture is stirred at room temperature for 3 hours, and thereto is added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate twice. The organic layer is dried over magnesium sulfate and concentrated under reduced
267

pressure. The resulting residue is purified by silica gel column chromatography (chloroform : methanol = 19:1) to give 2-methoxy-5-dimethylcarbamoylphenylboronic acid (210mg). MS (m/z): 224 [M+H]+ Reference Example 18
The corresponding starting compound is treated in a similar manner to Reference_Example,17 to give the compound. Reference Example 19
(1) 4-sec-Butyl-phenol (3.0g) is dissolved in chloroform and thereto is added bromine (1.02ml) and the mixture is stirred at room temperature for 30 minutes. Thereto are added a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and conscentrated under reduced pressure to give 2-bromo-4-sec-butyl-phenol (4.57g). NMR (CDCI3): 0.81 (3H,t). 1.19 (3H,d), 1.56 (2H,m), 2.51 (lH,m), 5.33 (lH,s), 6.93 (lH,d), 7.02 (lH,d), 7.26 (lH,s).
(2) 2-Bromo-4-sec-butyl-phenol (1.50g) is dissolved in N,N-dimethylformamide (10ml) and thereto is added potassium carbonate (l.lSg) and iodomethane (1.12g) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and water, 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 resulting residue is purified by silica gel column chromatography (hexane ; ethyl acetate = 1:0-»20:1) to give 2-bromo-4-sec-butyl-1-methoxy-benzene (l.SSg). NMR (CDCI3): 0.80 (3H,t), 1.20 (3H,d), 1.55 (2H,m), 2.51 {lH,m), 3.87 (3H,s), 6.82 (IH.d), 7.07 (lH,d}, 7.35 (IH.s).
(3) 2-Bromo-4-sec-butyl-l-methojcy-benzene (l-15g) is dissolved in tetrahydrofuran (17ml) and the mixture is cooled to -78°C, and thereto is added dropwise 1.6M n-butyllithium in hexanes, and the mixture is stirred
268

at -78°C for 15 minutes. To the reaction solution was added trimethyl borate (1.47g), and the reaction mixture is stirred at -78°C for 30 minutes, and thereto are added a saturated aqueous ammonium chloride solution and ethyl acetate. The mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude 5-sec-butyl-1 -methoxy-benzene boronic acid (950mg). NMR (CDC13): 0.81 (3H,t), 1.22 (3H,d), 1.58 (2H,m), 2.58 (lH,m), 3.90 (3H,s), 6.25 {2H,s), 6.85 (2H,d), 7.25 (lH,d), 7.65 (lH,s). Reference Examples 20 to 23
The corresponding starting compounds are treated in a similar manner to Reference_Example 19 to give the compounds. Reference Example 24
2-Bromo-6-iodo-3-methQxy-pyridine (500mg) is dissolved in dry toluene (5ml) and thereto is added dropwise 1.6M n-butyllithium in hexanes (ml) at -7S°C under nitrogen atmosphere, and the mixture is stirred for 1 hour and thereto is added acetone (0.23ml), and the mixture is stirred overnight. To the reaction solution are added water 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 resulting residue is 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-ol (197mg). MS (m/z): 246/248 [M+H]+

The present compound of formula (1) or a pharmaceutically acceptable derivative thereof has an inhibitory activity against CETP and also shows an activity of increasing HDL cholesterol level and an activity of decreasing LDL cholesterol level. Thus, the compounds of the present invention are useful for prophylaxis and/or treatment of arteriosclerotic diseases, hyperlipemia or dyslipidemia, and the like.

CLAIMS 1. A compound of the general formula (1):

wherein, Y is a methylene group optionally substituted by a substituentfs) selected from an alkyl group and an oxo group, or a single bond;
A is (i) a group selected from 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, an optionally substituted 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, 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, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, ein oxy group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxy group substituted by optionally substituted heterocyclic group, and a carbonyl group substituted by optionally substituted heterocyclic group;
(ii) a homocyclic group optionally substituted by 1 to 5 substituents selected independently from the groups as defined above in (i); or (iii) a heterocyclic group optionally substituted by 1 to 5 substituents selected independently from the groups as defmed above in (i);
273

B is a phenyl group optionally substituted by 1 to 4 substituents selected independently from the following groups: an optionally substituted alkynyl group, a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a sulfo 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, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsuliinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxy group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxy group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, and an alkylene group; wherein said aikylene group may have 1 to 3 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms and further optionally may have a substituent(s);
R1 is a hydrogen atom or an optionally substituted alkyl group; wherein the alkyl group further may optionally be substituted by a substituent(s) selected from an optionally substituted homocyclic group and an optionally substituted heterocyclic group;
R2 is a group selected from 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, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally
274

substituted cycloalkoxy group, 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, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxo group substituted by optionally substituted heterocyclic group, and a carbonyl group substituted by optionally substituted heterocyclic group, or a pharmaceutically acceptable derivative thereof.
2. The compound of claim 1 wherein the homocyclic group is a cycloalkyl group, a phenyl group or a naphthyl group;
the heterocyclic group is a thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl,
thiazolyl, pyrazolyl, imidazolyl, imida2olinyl, isoxazolyl, isothiazolyl,
oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl,
tetra2olyl, pyridyl, imidazopyridyl, pyrimidinyl, thiomorpholinyl,
morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl,
thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl,
pyridazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl,
tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl,
isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl,
naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenanthridinyl, chromeinyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidazolidinyl, cxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropyrazolyl,
275

imidazopyridyl, dihydropyraanyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl or tetrahydroquinolyl group;
a substituent(s) for 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, 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, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxo group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted alkylsulfonyloxy group, an optionally substituted alkynyl group or an optionally substituted alkylene group is/are 1 to 5 groups selected independently from the following groups:
a halogen atom; a cyano group; a hydroxy group; a nitro group; a carboxyl group; an oxo group; a thioxo group; a sulfo group; a cycloalkyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoxycarbonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group,
276

alkoxycaxbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyloxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkylsulfanyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkylsulfonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkylsuliinyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamolyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an amino group; a mono- or di-alkylamino group optionally substituted by hydroxy group, halogen atom, carboxyl group, Eilkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylsulfamoylamino group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a mono- or di-alkylureido group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyt group,
277

mono- or di-alkylamino group, phenyl group or morpholinyl group; a
homocyclic group selected from a cycloalkyl group, a phenyl group and a
naphthyl group; an oxy group substituted by the homocyclic group as
defined above; a carbonyl group substituted by the homocyclic group as
defined above; a heterocyclic group selected from a thienyl, furyl, pyrrolyl,
pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl,
isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl,
triazolidinyl, tetrazolyl, pyridyl, imidazopyridyl, pyrimidinyl,
thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl,
tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl,
oxotriazinyl, pyridazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl,
tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl,
isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl,
naphthyridinyl, purinyl, pteridlnyl, dibenzofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups; an oxy group substituted by the heterocyclic group as defined above; a carbonyl group substituted by the heterocyclic group as defined above; and a group of the formulae:

wherein X1 and X3 are each independently CH2, NH, O, S, SO or SO2; X2
and X5 are each independently CH2, O, S, SO or SO2; X4 is NH, O, S, SO or
SO2; X6 and X7 are each independently O or S; Xs is S or SO; and n, o, p, q
and r are each independently an integer of 1 to 4, and further each of the
above groups may optionally be substituted by 1 to 3 substituents selected
from the following groups: halogen atom, carboxyl group, hydroxy group,
cyano group, 0x0 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, alkylsulfonyl
group and tetrazolyl group;
or a pharmaceutically acceptable derivative thereof.
3. The compound of claim 2 wherein A is a group of a formula:
-A1-A2;
wherein A1 is a phenyl, naphthyl, pyrimidinyl, pyridazinyl, pyridyl, triazolyl,
tetrazolyl, oxadiazolyl, dihydropyrmidinyl, pyrazinyl, thiazolyl, oxazolyl,
dihydrooxazinyl, imidazolyl, pyrazolyl or dihydropyrazinyl group;
279

A2 is a carboxyl group; a cyano group; a nitro group; an alkyl group optionally substituted by a group selected from a hydroxy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkoxy group, a phenylalkoxy group, a hydroxyalkoxy group, a carboxyalkoxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, an oxiranyl group, a dialkyldioxolanyl group, a pyrrolidinyl group optionally substituted by carboxyl group, a piperidyl group optionally substituted by carboxyl group, a piperazinyl group optionally substituted by alkyl group, and a morpholinyl group; an alkenyl group optionally substituted by carboxyl group; an alkoxy group optionally substituted by a group selected from a hydroxy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkoxy group, a phenylalkoxy group, a hydroxyalkoxy group, a carboxyalkoxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfmyl group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alltylureido group optionally substituted by morpholinyl group, an oxiranyl group, a dialkyldioxolanyl group, a pyrrolidinyl group optionally substituted by carboxyl group, a piperidyl group optionally substituted by carboxyl group, a piperazinyl group optionally substituted by alkyl group, and a morpholinyl group; an alkoxycarbonyl group; a hydroxycarbamimidoyl group; an alkylsulfanyl group; an alkylsulfonyl group optionally substituted by carboxyl group; a mono- or di-alkylamino group optionally substituted by hydroxy group, carboxyl group, alkoxy group or mono- or di-alkylamino group; a morpholinyl group optionally substituted by carboxyl group, alkyl group, carboxyalkyl group or alkoxycarbonyl group; an optionally oxidized thiomorpholinyl group; a piperazinyl group optionally substituted by a group selected from an alkyl group, alkanoyl group and hydroxyalkanoyl
280

group; a pyrrolidinyl group optionally substituted by carboxyl group, alkyl group, carboxyalkyl group or alkoxycarbonyl group; a piperidyl group optionally substituted by carboxyl group, alkyl group, carboxyalkyl group or alkoxycarbonyl group; a tetrazolyl group optionally substituted by alkyl group, hydroxyalil group, carbosalkyl group or morpholinylalkyl group; an oxodihydrooxadiazolyl group; a p3T-imidinyl group; or a tetrahydropyranyl group;
Ri is a group of a formula: -R11-R12,
wherein Rii is an alkylene group;
R2 is a substituent(s) selected from a phenyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, thienyl, triazolyl, tetrazolyl, oxadiazolyl, dihydrop5Timidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, dihydrooxazinyl, dihydropjTazinyl and pjn-azolyl group;
wherein said substituent(s) may optionally be substituted by 1 to 4 substituents selected independently from 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 di-alkylamino group, alkanoyl group, alkylsulfanyl group, tetrazolyl group and dihydrooxazolyl group; and further each of said alkyl group, alkoxy group, mono- or di-alllamino group, mono- or di-alkylcarbamoyl group, alkanoyl group and alkylsulfanyl group independently may optionally be substituted by 1 to 5 substituents selected independently from halogen atom, hydrojr group, alkoxy group, amino group, morpholinyl group, piperidyl group, pyrrolidinyl group, piperazinyl group, alkylpiperazinyl group and alkanoylpiperazinyl group;
R2 is a halogen atom; a hydroxy group; a cyano group; a nitro group;
281

a carbojtyl group; a sulfo group;
a cydoalkyl group optionally substituted by carbojl group or alkoxycarbonyl group;
an alkyl group optionally substituted by a group selected from a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkocarbonyl group, a tetrazolyl group, a mono- or di-alkylcarbamoyl group, an alkoxy group (said aikoxy group may optionally be substituted by phenyl group, carbol group or hydroxy group), an alkanoyl group, an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an amino, a mono- or di-alkylEimino group optionally substituted by carbojl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alllureido group optionally substituted by morphoUnyl group, an oxiranyl group, a dioxolanyl group optionally substituted by alll group, pyrrolidinyl group optionally substituted by alkojcarbonyl group or carboxyl group, a p5TTolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalll group, a piperidyl group optionally substituted by alko3cycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a morpholinyl group, and a piperidylo: group optionally substituted by edkyl group; an alkenyl group optionally substituted by a group selected from a cyano group, a hydros group, a carboxyl group, a benzyloxycarbonyl group and a tetrazolyl group;
an alkenylo: group optionally substituted by carbojQ'l group; an alkoxy group optionally substituted by a group selected from a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may
282

optionally be substituted by carbojcyl group, alkoxycarbonyl group or hydroxy group), an alkoxy group {said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carbojTiiethyl group, an oxiranyl group, a phenyl group optionally substituted by alkojQ' group or carbojcyl group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkojQfcarbonyl group or carboxyl group, a pyrrolidinyl group optioneilly substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a pyrrolidinyl group optionally substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl. group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alll group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a morpholinylcarbonyl group; an alkoxycarbonyl group optionally substituted by phenyl group; a carbamoyl group;
a mono- or di-alkylcarbamoyl group optionally substituted by a group selected from a carboj'l group, a morpholinyl group and an alkoxy group; a hydroxycarbamimidoyl;
an allq'lsulfanyl group optionally substituted by a group selected from hydroxy group, carboxyl group and mono- or di-alkylcarbamoyl group;
283

an alkylsulfinyl group;
an alkylsulfonyl group optionaliy substituted by a group selected from hydroxy group, carboxyl group, alkoxycarbonyl group and mono- or di-alkylcarbamoyl group; an amino group;
a mono- or di-alkylamino group optionally substituted by a group selected from a hydrogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-all(ylcarbamoyl group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carbo;! group, alkoxycarbonyl group or hydroxy group), an aikoxy group (said alkoxy group may optionally be sub stituted by carboil group, formyl group or hydros group), an alkanoyloxy group, an alkylsulfanyl group, an alllsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino optionally substituted by carboxyl group or aikoxy group, a mono- or di-aikylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by aikoxy group or carboxyl group, a morpholinyl group, a pyxrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylallQl or carboxyalkyl group, a pjnrolidinyl group substituted by 0X0 group, a piperidyl group optionally substituted by alkoJOfcarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyaUsyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl optionally substituted by oxo group, a pyrrolidinylcEirbonyl group optionally substituted by carboxyl group, a
284

piperidyloxy group optionally substituted by alkyl group and a
morpholinylcarbonyl group;
an alkanoylamino group optionally substituted by a group selected from
hydroxy group, alkoxy group, carboxyl group and amino group;
a mono- or di-alkylcarbamoylamino group optionally substituted by alkoxy
group;
a morpholinylcarbonylamino group;
a sulfamolyl group;
a mono- or di-alkylsulfamolyl group;
an alkanoyl group optionally substituted by a group selected from hydroxy
group, carboxyl group, alkoxycarbonyl group, alkoxy group, mono- or di-
alkylamino group and morpholinyl group; or
a cyclic group selected from a cycloalkyl, phenyl, naphthyl, thienyl, furyl,
pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl,
isoxazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl,
triazinyl, triazolidinyl, tetrazolyl, pyridyl, imidazopyridyl, pyrimidinyl,
thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl,
tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl,
oxotriazinyl, pyridazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl,
tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl,
isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl,
naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenainthridinyl, chromanyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl,
dihydropyrimidinyl, oxazolinyi, dihydrooxazinyl, dihydropyrazolyl,
imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl,
dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl
groups;
285

wherein said cyclic group may optionally be substituted by the following groups: a halogen atom, an alkoxyalkyl group, an alkyl group optionally substituted by 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylauninoalkoxy group, a carboxyl group, a hydroxy group, a cyano group, an oxo group, an alkyl group, a hydroxyalkyl group, an alkoxycarbonylalkyl group, a carboxyallq'l group, a morpholinylalkyl group, a phenylalkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkojQalkanoyl group, an alkoxy group, a phenylalkoxy group, an alkoxycarbonyl group, a benzloxycarbonyl group, a mono- or di-alllamino group, a mono- or di-alllcarbamoyl group, a mono- or di-alkylsulfamolyl group, an alkylsulfonyl group and a tetrazolyl group; wherein the substituents defined as above may further be substituted by a substituent(s) selected from the following groups:
a halogen atom, an alkoqralkyl group, an alkyl group optionally substituted by 1 to 5 halogen atoms, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group, a cyano group, an oxo group, an alkyl group, a hydroxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalll group, a morpholinylaUl group, a phenylalkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkoxyalkanoyl group, an alkoxy group, a phenylalkoxy group, an alkoxy'carbonyl group, a benzyloxycarbonyl group, a mono- or di-alkylamino group, a mono- or di-alkylcarbamoyl group, a mono- or di-alkylsulfamolyl group, an alkylsulfonyl group and a tetrazolyl group, or a pharmaceutically acceptable derivative thereof.
4. The compound of claim 1 wherein Y is a methylene group optionally substituted by a substituent(s) selected from an alkj'l group and an oxo group, or a single bond;
A is a group of a formula: -A1-A2; wherein Ai is a heterocyclic group or a homocyclic group;
286

i-i.- i» till upuunaiiy suDsurutea nomocyclic group, an optionally substituted alkylsulfanyl group, an optionally substituted alllsulfinyl group, an optionally substituted alllsulfonyl group, an optionally substituted alkyl group, a nitro group, a hydroxy group, a cyano group, an optionally substituted alkenyl group, an optionally substituted heterocyclic group, a substituted alkoxy group, a halogen atom, an amino group substituted by 1 to 2 substituents, or a hydrogen atom;
B is a phenyl group optionally substituted by 1 to 4 substituents selected independently from a cyano group, a halogen atom, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfmyl group, an optionally substituted alkylsulfonyl group, an amino group substituted by 1 to 2 substituents, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted cycloalko group, a carboxyl group, an optionally substituted cycloalkyl group, an optionally substituted carbamoyl group, an optionally substituted alkyl group, and an optionally substituted alkoxy group;
Ri is a hydrogen atom, an alkyl group substituted by a heterocyclic group or an alkyl group substituted by a homocyclic group; wherein said heterocyclic group, homocyclic group or alkyl group may further have a substituent(s);
R2 is an optionally substituted alllsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, a cyano group, an optionally substituted alkenyl group, an amino group optionally substituted by 1 to 2 substituents, a halogen atom, an optionally substituted alkoxy group, an optionally substituted carbamoyl group, an oxy group optionally substituted by optionally substituted heterocyclic group, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted homocyclic group, an oxo group optionally substituted by optionally substituted homocyclic group, an optionally substituted alkyl group or a nitro group;
287

provided that when Y is a methylene group and A is a halogen atom, a
hydrogen atom, a nitro group, a hydroxy group or a cyano group, then R2 is
not an optionally substituted alkyl group, an optionally substituted alkenyl
group, an optionally substituted alko3 group, or an amino group
optionally substituted by 1 to 2 substituents,
or a pharmaceutically acceptable derivative thereof.
5. The compound of claim 4 wherein Y is a methylene group optionally
substituted by a substituent(s) selected from an alkyl group and an oxo
group;
A is a heterocyclic group;
A2 is an optionally substituted heterocyclic group, an optionally substituted alkyl group, a substituted alkoxy group, a halogen atom, an amino group optionally substituted by 1 to 2 substituents, or a hydrogen atom;
B is a phenyl group optionally substituted by 1 to 4 groups selected independentiy from a cyano group, a halogen atom, a hydroxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkoxy group, an optionally substituted piperidyl group, a cycloalkyl group, a cycloalkoxy group, an optionally substituted alkyl group and an optionally substituted alkoJQ' group;
Ri is a hydrogen atom, or an alkyl group substituted by a phenyl group that is substituted by 1 to 2 groups selected independently from an alkoxy group optionally substituted by 1 to 3 halogen atoms, an alkyl group optionally substituted by 1 to 3 halogen atoms and a cyano group;
R2 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 ojq group substituted by optionally substituted heterocyclic group, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted homoQ'clic group, an oxy group substituted by optionally substituted homocyclic group, a
288

hydroxyalkyl group or a nitro group,
or a pharmaceutically acceptable derivative thereof.
6. The compound of claim 5 wherein the homocyclic group is a
cycloalkyl group, a phenyl group or a naphthyl group;
the heterocyclic group is a thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl,
thiazolyl, p5a-azolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl,
oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl, triazolidinyl,
tetrazolyl, p3Tidyl, imidazopjTidyl, pyrimidinyl, thiomorpholinyl,
morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl,
thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl,
pyridazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyl,
tetrazolopyridazinyl, triEizolopjaidazinyl, benzimidazolyl, quinolyl,
isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl,
naphthyridinyl, purinyl, pteridinyl, diberazofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidaaolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazoUnyl, dihydrooxazinyl, dihydropyrazolyl, imidazopyridyl, dihydropyrazinyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl or tetrahydroquinolyl group;
a substituent(s) for an optionally substituted ailkyl group, an optionally substituted 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, an optionally substituted carbamimidoyl group, an optionally substituted alkylsulfanyl group, an optionally substituted alliylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, an optionally
289

substituted sulfamoyl group, an optionally substituted alkanoyl group, an optionally substituted homocyclic group, an oxo group substituted by optionally substituted homocyclic group, a carbonyl group substituted by optionally substituted homocyclic group, an optionally substituted heterocyclic group, an oxo group substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted alkylsulfonyloxy group, an optionally substituted allnyl group or an optionally substituted allIene group is/are 1 to 5 groups selected independently from the following groups:
a halogen atom; a cyano group; a hydroi group; a nitro group; a carboxyl group; an oxo group; a thioxo group; a sulfo group; a cycloalkyl group optionally substituted by hydroxy group, halogen atom, carboJtyl group, alkoxycarbonyl group, mono- or di-alllamino group, phenyl group or morpholinyl group; an alkoicarbonyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; a carbamoyl group; a mono- or di-alllcarbamoyl group optionally substituted by hydrojQ' group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkyl group optionally substituted by hydroxy group, halogen atom, carboJ'l group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkanoyl group optionally substituted by hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or morpholinyl group; an alkoxy group optionally substituted by hydroxy group, halogen atom, carboxyl group, alko3cycarbonyl group, mono- or di-alllamino group, phenyl group or morpholinyl group; an alkanoyloxy group optionally substituted by hydroxy group, hailogen atom, carbojcyl group, alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group
290

or morphoHnyl group; an alkylsulfanyl group optionally substituted by
hydroxy group, halogen atom, carbo31 group, alkoxycarbonyl group,
mono- or di-alkylamino group, phenyl group or morpholinyl group; an
ajkylsulfonyl group optionally substituted by hydroxy group, halogen atom,
carbojl group, alkoxycarbonyl group, mono- or di-allq'lamino group,
phenyl group or morpholinyl group; an alllsailfmyl group optionally
substituted by hydroxy group, halogen atom, carboxyl group,
alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or
morpholinyl group; a mono- or di-alkylsulfamolyl group optionally
substituted by hydroxy group, halogen atom, carboxyl group,
alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or
morpholinyl group; an amino group; a mono- or di-alkylamino group
optionally substituted by hydros group, halogen atom, carboxyl group,
alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or
morpholinyl group; a mono- or di-alkylsuifamoylamino group optionally
substituted by hydroxy group, halogen atom, carboxyl group,
alkoxycarbonyl group, mono- or di-alkylamino group, phenyl group or
morpholinyl group; a mono- or di-alkylureido group optionally substituted
by hydroxy group, halogen atom, carbojl group, alkoxycarbonyl group,
mono- or di-alkylamino group, phenyl group or morpholinyl group; a
homocyclic group selected from a cycloalkyl group, a phenyl group and a
naphthyl group; an o: group substituted by the homocyclic group as
defined above; a carbonyl group substituted by the homocyclic group as
defined above; a heterocyclic group selected from a thienyl, fuiyl, pyrrolyl,
pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl,
isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, triazinyl,
triazolidinyl, tetrazolyl, pyridyl, imidazopyridyl, pyrimidinyl,
thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidyl, pyranyl, tetrahydropyranyl, thiopyranyl, oxadinyl, thiadinyl, piperazinyl, triazinyl, oxotriazinyl, p3Tidazinyl, pyrazinyl, benzofuryl, benzothiazolyl, benzoxazolyi,
291

tetrazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, quinolyl,
isoquinolyl, dihydroisoquinolyl, cinnolinyl, phthalaziny, quinazolinyl,
quinoxalinyl, indolizinyl, dihydroindolyl, indolyl, quinolizinyl,
naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, benzofuranyl,
carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, hexahydroazepinyl,
imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxiranyl, dihydropyrimidinyl, oxazolinyl, dihydrooxazinyl, dihydropjTazolyl, iinidazop5'ridyl, dihydrop5Ta2inyl, tetrahydroquinolyl, benzothienyl, dihydrooxazolyl, oxathiadiazolyl, dihydrooxazolyl and tetrahydroquinolyl groups; an oxy group substituted by the heterocyclic group as defined above; a carbonyl group substituted by the heterocyclic group as defined

wherein X and X3 are each independently CH2, NH, O, S, SO or SO2; X2 and X5 are each independently CH2, O, S, SO or SO2; X" is NH, O, S, SO or SO2; X& and Xare each independently O or S; X is S or SO; and n, o, p, q and r are each independently an integer of 1 to 4, and further wherein each of the above groups may optionally be substituted by 1 to 3 substituents selected from the following groups: halogen atom, carboxyl group, hydroxy
292

group, cyano group, oxo group, thioxo group, alkyl group, hydroxyalkyi
group, alkosgcarbonylalkyl group, carboxyalkyl group, morpholinylalkyl
group, phenylalkyl group, alkanoyl group, hydrojcyalkanoyl 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 and tetxazolyl group;
or a pharmaceutically acceptable derivative thereof.
7. The compound of claim 6 wherein A is a pyrimidinyl group or a
pyridyl group;
A2 is (a) a heterocyclic group selected from a piperidyl group and a morpholinyl group, respectively optionally substituted by a substituent(s) selected from a carboxyl group, a carbojalkyl group and an alkyl group;
(b) an alkoxy group substituted by a group selected from a carboxyl group, a hydroxy group, an alkoxy group and a cyano group;
(c) a halogen atom;
(d) an amino group optionally substituted by 1 to 2 substituents
independently selected from a carboxyalkyl group, a hydrojcyalkyl group,
an alkyl group, an alkoxyalkyl group and an aminoalkyl group optionally
substituted by 1 to 2 alkyl groups;
(e) a hydrogen atom;
B is a phenyl group optionally substituted by 1 to 4 groups selected independently from halogen atom, hydroxy group, alkyl group optionally substituted by 1 to 3 halogen atoms and alkoxy group optionally substituted by 1 to 3 halogen atoms;
Ri is a hydrogen atom, or a benzyl group substituted by 1 to 3 groups selected independently from an alkojcy group optionally substituted by 1 to 3 halogen atoms, an alkyl group optionally substituted by 1 to 3 halogen atoms and a cyano group;
R2 is (a) an amino group optionally substituted by 1 to 2 groups
293

independently selected from an alkyl group, an alkoxyalkyl group, a cycloalllalll group, an alkojQ'carbonyl group, an alkylcarbonyl group, an alkylcarbamoyl group, a carbojalkyl group, a cycloalkylalkyl group substituted by carboxyalkyl group, a hydroxyalkyl group, a carboxyalkoxycarbonyl group, a carboxydihydrooxaEolyl group, a carboxyalkylcarbonyl group, a phenylalkyl group, an alkoxyalkoxycarbonyl group, an alkoxyalkyicarbonyl group, an alkyl group substituted by piperidyl group, a piperidylalkyl group substituted by carbojalkyl group, and an allQ'l group substituted by phenyl that is optionally substituted by 1 to 2 alkyl groups (said alkyl group may optionally substituted by 1 to 3 halogen atoms);
wherein said ailkyl group or alkoj group may further optionally be substituted by 1 to 5 groups selected independently from the following groups:
a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group {said mono- or di-allq'lcarbamoyl group may optionally be substituted by carbol group, alkoxycarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxy group, an alkylsulfanyl group, an alklsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionaiUy substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrroUdinyl group optionally substituted by alkoxycarbonyl group or carboJtyl group, a pjrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a
294

pyrrolidinyl group optionally substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alll group and a morpholinylcarbonyl group;
(b) a halogen atom;
(c) an alkoxy optionally substituted by a group selected from
carboxyl group, cycloalkyl group and alkoxy group;
wherein said cycloalkyl group or alkoxy group may optionally be substituted by 1 to 5 groups selected independently from the following groups:
a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkcylcarbaunoyl group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carboxyl group, adkoxycarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxo group, an alilsulfanyl group, an alkylsulfonyl group, an alllsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino optionally substituted by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group
295

or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperidyl group optionally substituted by oxo group, a piperidyl group optionally substituted by alkoxycobonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a morpholinylcarbonyl group;
(d) a carbamoyl group optionally substituted by 1 to 2 substituents selected independently from alkyl group and carboxyalkyl group, wherein said alkyl group may optionally be substituted by 1 to 5 groups selected independently from the following groups:
a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may be substituted by carboxyl, alkoycarbonyl or hydroxy group), an alkoxy group (said alkoxy group may be substituted by carboxyl, formyl or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino optionally substituted by carboxyl or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxyl or carboxyl group, a morpholinyl group, a pyrrolidinyl optionally substituted by alkoxycarbonyl or carboxyl group, a pyrrolidinyl optionally substituted by
296

alkoxycarbonylalkyl or carboxyalkyl group, a pyrrolidinyl substituted by 0X0 group, a piperidyl optionedly substituted by alkoxycarbonyl or carboxyl group, a piperidyl optionally substituted by alkoxycarbonylalkyl or carboxyalkyl group, a piperazinyl optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolany group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a morpholinylcarbonyl group;
(e) a hydroxy group;
(f) an oxy group substituted by a heterocyclic group selected from pyrimidinyl group and tetrahydropyranyl group;
(g) a heterocyclic group selected from a morpholinyl, pyrimidinyl,
piperidyl, piperazinyl, pyrazinyl, tetrazolyl, thienyl, fury, dihydroisoquinolyl,
pyridyl and pyrrolyl group, which are each optionally substituted by 1 to 3
substituents selected independently from pyrimidinyl group, alkyl group,
halogen atom, cyano group, mono- or di-alkylamino group, alkoxy group,
phenyl group, carboxyl group, carbamoyl group and carboxyalkyl group;
wherein said alkoxy group or alkyl group may optionally be substituted by
1 to 5 groups selected independently from the following groups:
a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carboxyl group, alkoxycarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aminosulfonyl group, an amino group, a mono- or di-alkylamino group optionally substituted by ceirboxyl group or alkoxy
297

group, a mono- or di-alkylsulfamoylanino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxyethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a pyrrolidinyl group substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group or carboxyalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxyl group, a piperidyloxy group optionally substituted by alkyl group and a phenyl group optionally substituted by morpholinyl group;
(h) a phenyl group optionally substituted by 1 to 3 substituents selected independently from halogen atom, alkyl group and alkoxy group; wherein said alkoxy group or alkyl group may further optionally be substituted by 1 to 5 groups selected independently from the following groups:
a halogen atom, a cyano group, a hydroxy group, a carboxy group, an alkoxycarbonyl group, a tetrazolyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group may optionally be substituted by carboxyl group, alkorcarbonyl group or hydroxy group), an alkoxy group (said alkoxy group may optionally be substituted by carboxyl group, formyl group or hydroxy group), an alkanoyloxo group, an alkylsulfanyl group, an alkylsulfonyl group, an
298

alkylsulfmyl group, an aminosulfonyl group, an amino group, a raono- or di-alkylamino group optionally substitxited by carboxyl group or alkoxy group, a mono- or di-alkylsulfamoylamino group, a mono- or di-alkylureido group optionally substituted by morpholinyl group, a cycloalkyl group optionally substituted by carboxymethyl group, an oxiranyl group, a phenyl group optionally substituted by alkoxy group or carboxyl group, a morpholinyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a pyrrolidinyl group optionally substituted by alkoxycarbonylalkyl group, a pyrrolidinyl group substituted by oxo group, a piperidyl group optionally substituted by alkoxycarbonyl group or carboxyl group, a piperidyl group optionally substituted by alkoxycarbonylalkyl group, a piperazinyl group optionally substituted by alkyl group, a hexahydroazepinyl group, a pyrimidinyl group, a pyridyl group, a dioxolanyl group optionally substituted by alkyl group, an oxadiazolyl group optionally substituted by oxo group, an oxathiadiazolyl group optionally substituted by oxo group, a pyrrolidinylcarbonyl group optionally substituted by carboxy group, a piperidylcxy group optionally substituted by alkyl group and a morpholinylcaxbonyl group;
(i) an oxo group substituted by cycloalkyl group;
(j) a hydroxyalkyl group; or
(k) a nitro group; or a pharmaceutically acceptable derivative thereof.
8. The compound of claim 7 wherein A1 is a pyryimidinyl group or a pyridyl group;
A2 is (a) a heterocyclic group selected from piperidyl group and morpholinyl group, which are each optionally substituted by a substituent(s) selected from a carboxyl group, carboxyalkyl group or alkyl group;
(b) an alkoj group substituted by a group selected from carboxyl group, hydroxy group, alkojty group and cyano group;
299

(c) a halogen atom;
(d) an amino group optionally substituted by 1 to 2 substituents
selected independently from carboxyalll group, hydroxyalkyl group, alkyl
group, alkoxyalkyl group and aminoalkyl group, respectively optionally
substituted by 1 to 2 alkyl groups;
(e) a hydrogen atom;
B is a phenyl group optionally substituted by 1 to 4 groups selected independently from alkyl group optionally substituted by 1 to 3 halogen atoms and alkoxy group optionally substituted by 1 to 3 halogen atoms;

R2 is (a) an amino group optionally substituted by 1 to 2 groups selected independently from an alkyl group, an alkoxyalkyl group, a cycloalkylalkyl group, an alkoxycarbonyl group, an alkylcarbonyl group, an alkylcarbamoyl group, a carboxyalkyl group, a cycloalkylalkyl group substituted by carboxyalkyl group, a hydroxyalkyi group, a carboxyalkoxycarbonyl group, a carboxydihydrooxazolyl group, a carboxyalkylcarbonyl group, a phenylalll group, an alkoxyalkoxycarbonyl group, an alkoxyalkylcarbonyl group, an alkyl group substituted by piperidyl group, a piperidylalkyl group substituted by carboxyalkyl group and an alkyl group substituted by phenyl group that is optionally substituted by 1 to 2 alkyl groups (said alkyl group may optionally be substituted by 1 to 3 halogen atoms);
(b) a halogen atom;
(c) an alkoxy group optionally substituted by a group selected from a carboxyl group, a cycloalkyl group and an alkoxy group;
(d) a carbamoyl group optionally substituted by 1 to 2 substituents
selected independently from alkyl group and carboxyalkyl group;
300

(e) a hydroxy group;
(f) an 0X0 group substituted by a heterocyclic group selected from a
pyrimidinyl group and a tetrahydropyranyl group;
(g) a heterocyclic group selected from a pyrimidinyl, pyridyl,
morpholinyl, piperidyl, piperazinyl, tetrazolyl, dihydroisoquinolyl and
pyrrolyl group, which are each optionally substituted by 1 to 2
substituents selected independently from alkyl group, alkoxy group, phenyl
group, carboxyl group, carboxyalkoxy group and carboxyalkyl group;
(h) a phenyl group optionally substituted by 1 to 3 substituents selected independently from halogen atom, alkyl group and alkoxy group;
(i) an oxo group substituted by cycloalkyl group;
(j) a hydroxyalkyl group;
(k) a nitro group; or a pharmaceutically acceptable derivative thereof.
9. The compound of claim 8 wherein A is an amino group substituted by 1 to 2 groups selected independently from a piperidyl group optionally substituted by carboxyl group; a morpholinyl group optionally substituted by carboxyl group; an alkoxy group substituted by a group selected from carboxyl group, hydroxyy group, alkoxy group and cyano group; an amino group substituted by 1 to 2 groups selected independently from carboalkyl group and alkyl grup;
B is a phenyl group optionally substituted by an alkyl group optionally substituted by 1 to 3 halogen atoms;

R2 is (a) an amino group optionally substituted by 1 to 2 groups selected independently from an alkyl group, a cycloalkylalkyl group, an alkoxycarbonyl group, a carboxyalkyl group and a cycloalkylalll group
301

substituted by carboxyalkyl group;
(b) an alkoxy group;
(c) a phenyl group optionally substituted by a group selected from a halogen atom, an alkyl group and an alkoxy group;
fd) a pyridyl group optionally substituted by a group selected from a halogen atom, an alkyl group and an alko group; or a pharmaceutically acceptable derivative thereof.
10. A compound described in anyone of examples No. 7, 24, 75, 57, 13,
54, 12, 65, 63 and 64, or a pharmaceutically acceptable derivative thereof.
11. A compound of the formula (l-A):

wherein
A1 is an optionally substituted pyrimidin-2-yl group or an optionally substituted pyridin-2-yl group;
R1A and R are independently a cyano group or an alkyl group optionally substituted by 1 to 3 halogen atoms;
Ring E is an optionally substituted phenyl group;
F is an optionally substituted cyclic group; or a pharmaceutically acceptable derivative thereof.

302

wherein
ZA is N or CH;
A21A is an optionally substituted homocyclic group, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl group, a nitro group, a hydroxy group, a cyano group, an optionally substituted alkenyl group, an optionally substituted heterocyclic group, an optionally substituted alkoxy group, a halogen atom, an amino group optionally substituted by 1 to 2 substituents, a carbamoyl group optionally substituted by 1 to 2 substituents, a carboxyl group or a hydrogen atom;
R1A is a cyano group or an alkyl group optionally substituted by 1 to 3 hailogen atoms;
B' is a group selected independently from an oxo group, a cyano group, a halogen atom, an optionally substituted alkylsulfanyl group, an optionally substituted alkylsulfinyl group, an optionally substituted alklsulfonyl group, an amino group optionally substituted by 1 to 2 substituents, a hydroxy group, an optionally substituted heterocyclic group, an optionally substituted cycloalkoxy group, an optionally substituted cycloalll group, a carboxyl group, a carbamoyl group optionally substituted by 1 to 2 substituents, an optionally substituted alkyl group or an optionally substituted alkoxy group;
pA is an integer of 0 to 3;
D is a pyrimidinyl group, a pyridyl group, a phenyl group, a pyrimidinyloxy group, a tetrazolyl group or an oxazolidinyl group;
D' is a group selected independently from a halogen atom, an alkoxyalkyl group, an alkyl group substituted by 1 to 5 halogen atoms, an alkoxy group substituted by 1 to 5 halogen atoms, an alkenyl group, a carbamoyl group, a cycloalkyl group, a mono- or di-alkylaminoalkyl group, a mono- or di-alkylaminoalkoxy group, a carboxyl group, a hydroxy group,
303

a cyano group, an oxo group, an alkyl group, a hydroxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkyl group, a morpholinylalkyl group, a phenylalkyl group, an alkanoyl group, a hydroxyalkanoyl group, an alkoxyalkanoyl group, an alkoxy group, a phenylalkoxy group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a mono- or di-alkylamino group, a mono- or di-alkylcarbamoyl group, a mono- or di-alkylsulfamolyl group, an alkylsulfonyl group, a tetrazolyl group, benzyloxyalkyl group, a cycloalkylalkyl group, an benzyloxy group, an alkoxyalkoxy group, a carboxyalkoxy group, a carboxyalkenyl group, an alkylcarbonylamino group, a carboxyalkoxyalkyl group, a morpholmyl group or a pyridylalkoxy group;
q' is an integer of 0 to 3; or a pharmaceutically acceptable derivative thereof. 13. The com.pound of claim 12 wherein
A21A is selected from the following group
(a) a heterocyclic group selected from a piperidyl group and a morpholinyl group, respectively optionally substituted by a substitutent(s} selected from a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group or an alkyl group;
(b) an alkoxy group optionally substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulfmyl group, a mono- or di-alkylamino group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group or an alkoxy group;
(c) a halogen atom;
(d) an amino group optionally substituted by 1 to 2 substituents
independently selected from a carboxyalkyl group, an alkoxycarbonylalkyl
group, an alkylsulfonylalkyl group, an aikylsulfinylalkyl group, a
hydroxyalkyl group, an alkyl group, an alkoxyalkyl group or an aminoalkyl
group optionally substituted by 1 to 2 alkyl groups;

(e) a hydrogen atom;
(f) an alky] group optionally substituted by a group selected from a carboxyl group, an alkoxycarbonyl group, a halogen atom, an alkylsulfmyl group, a mono- or di-alkylamino group, a cyano group, a tetrazolyl group, an alkylsulfonyl group, an alkylsulfanyl group, a hydroxy group or an alkoxy group;
fg) a carboxyl group;
(h) a carbamoyl group optionally substituted by a carboxyalkyl group; or
(i) an alkenyl group 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 or an alkoxy group;
(j) a morpholinyl group;
(k( a piperidinyl group optionally substituted by a carboxyl group or a carboxyalkyl group;
B' is a group selected independently from an oxo group, a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms, an alkoxy group optionally substituted by 1 to 3 halogen atoms, a cyano group, a hydroxy group, a cycloalkyl group, an alkoxyalkyl group, a cycloalkoxy group, an alkylsulfanyl group optionally substituted by 1 to 3 halogen atoms, an alkylsulfinyl group optionally substituted by 1 to 3 halogen atoms or an alkylsulfonyl group optionally substituted by 1 to 3 halogen atoms;
or a pharmaceutically acceptable derivative thereof. 14. The compound of claim 13 wherein
A21A is an alkoxy group optionally substituted by 1 to 2 groups selected from a carboxyl group, a halogen atom, an alkoxycarbonyl group, an alkoxyl group, a hydroxy group, a mono or di-alkylamino group, an alkylsulfinyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl
305

group and an alkylsulfanyl group; an alkyl group optionally substituted by 1 to 2 groups selected from a carboxyl group, a halogen atom, an alkoxycarbonyl group, an alkoxyl group, a hydroxy group, a mono or di-alkylamino group, an alkylsulfinyl group, a cyano group, a tetrazolyl group, an alkylsulfonyl group and an alkylsulfanyl group; a morpholinyl group; a carboxyl group or a carboxyiperidinyl group;
B' is a group selected independently from a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms or an alkoxy group optionally substituted by 1 to 3 halogen atoms;
D' is a group selected independently from an alkoxy group optionally substituted by 1 to 3 halogen atoms, a halogen atom, a cyano group, an alkylsulfanyl group, a mono or di-alkylamino group, an alkenyl group, an alkyl group optionally substituted by 1 to 3 halogen atoms, a carboxyl group, a hydroxy group, a carboxyalkoxy group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an oxo group, a cycloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylcarbonylamino group, a morpholinyl group or a carboxyalkoxyalkyl group; or a pharmaceutically acceptable derivative thereof.
15. The compound of claim 14, wherein ZA is a N, or a pharmaceutically acceptable derivative thereof.
16. The compound of claim 14, wherein R1A is an alkyl group optionally substituted by 1 to 3 halogen atoms, or a pharmaceutically acceptable derivative thereof.
17. The compound of claim 14, wherein D is a phenyl group, or a pharmaceutically acceptable derivative thereof.
18. The compound of claim 14, wherein D' is a group selected independently from a halogen atom, an alkoxy group or an alkyl group, or a pharmaceutically acceptable derivative thereof.
19. The compound of claim 14, wherein A21A is a morpholinyl group or
305

an alkoxyl group substituted by a carboxyl group, or a pharmaceutically acceptable derivative thereof.
20. A compound described in anyone of examples No. 91, 94, 96, 112, 114, 118 to 123, 131, 133, 136, 138 to 140, 142 to 153, 158 to 163, 165 to 169, 173 to 177, 179 to 182, 185, 186, 190 to 194, 198, 203, 208 to 216, 218 to 223, 231, 239, 240, 241 or a pharmaceutically acceptable derivative thereof.
21. A compound described in anyone of examples No. 154 to 157, 164, 170 to 172, 178, 183, 184, 187 to 189, 195 to 197, 199 to 202, 204 to 207, 217, 224 to 230, 232 to 238, 242 to 252 or a pharmaceutically acceptable derivative thereof.
22. A pharmaceutical composition, which comprises as an active ingredient a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable derivative thereof.
23. A method for prophylaxis or treatment of arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular diseases, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion Injury, restenosis after angioplasty, hypertension, cerebral infarction, cerebral stroke, diabetes, vascular complication of diabetes, thrombotic diseases, obesity, endotoxemia, metabolic syndrome, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, reno-vascular disease, renal disease, splanchnic vascular disease, vascular hemostatic disease, fatty liver disease, steatohepatitis, inflammatory disease, autoimmune disorders and other systemic disease indications, immune function modulation, pulmonary disease, anti-oxidant disease, sexual dysfunction, cognitive dysfunction, schistosomiasis, cancer, regression of xanthoma or Alzheimer's disease, which comprises administering an effective amount of
307

a compound according to any one of claims 1 to 21, or a pharmaceutically
acceptable derivative thereof, to a patient in need thereof.
24. Use of a compound according to any one of claims 1 to 21, or a
pharmaceutically acceptable derivative thereof, for the manufacture of a
medicament in treatment of patients suffering from, arteriosclerosis such as
atherosclerosis, peripheral vascular disease, dyslipidemia,
hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia,
hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular
diseases, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, cerebral stroke, diabetes, vascular complication of diabetes, thrombotic diseases, obesity, endotoxemia, metabolic syndrome, cerebrovascular disease, coronary artery disease, ventricular dysfunction, cardiac arrhythmia, pulmonary vascular disease, reno-vascular disease, renal disease, splanchnic vascular disease, vascular hemostatic disease, fatty liver disease, steatohepatitis, inflammatory disease, autoimmune disorders and other systemic disease indications, immune function modulation, pulmonary disease, anti-oxidant disease, sexual dysfunction, cognitive dysfunction, schistosomiasis, cancer, regression of xanthoma or Alzheimer's disease.

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Patent Number

258147

Indian Patent Application Number

4000/CHENP/2008

PG Journal Number

50/2013

Publication Date

13-Dec-2013

Grant Date

09-Dec-2013

Date of Filing

30-Jul-2008

Name of Patentee

MITSUBISHI TANABE PHARMA CORPORATION

Applicant Address

2-10, DOSHO-MACHI 3-CHOME, CHUO-KU, OSAKA-SHI, OSAKA 541-8505

Inventors:

#	Inventor's Name	Inventor's Address
1	NAKAMURA,, YOSHINORI,	C/O MITSUBISHI TANABE PHARMA CORPORATION 2-10, DOSHO-MACHI 3-CHOME, CHUO-KU, OSAKA-SHI, OSAKA 541-8505
2	HAYASHI, NORIMITSU,	C/O MITSUBISHI TANABE PHARMA CORPORATION 2-10, DOSHO-MACHI 3-CHOME, CHUO-KU, OSAKA-SHI, OSAKA 541-8505
3	HIGASHIJIMA, TAKANORI	C/O MITSUBISHI TANABE PHARMA CORPORATION 2-10, DOSHO-MACHI 3-CHOME, CHUO-KU, OSAKA-SHI, OSAKA 541-8505
4	KUBOTA, HITOSHI,	C/O MITSUBISHI TANABE PHARMA CORPORATION 2-10, DOSHO-MACHI 3-CHOME, CHUO-KU, OSAKA-SHI, OSAKA 541-8505
5	OKA, KOZO,	C/O MITSUBISHI TANABE PHARMA CORPORATION 2-10, DOSHO-MACHI 3-CHOME, CHUO-KU, OSAKA-SHI, OSAKA 541-8505

PCT International Classification Number

C07D239/46

PCT International Application Number

PCT/JP07/51861

PCT International Filing date

2007-01-30

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2006-322853	2006-11-30	Japan
2	2006-023572	2006-01-31	Japan