BACKGROUND OF THE INVENTION Diabetes mellitus has serious effects on people's health and accompanies various complications. Type II diabetes mellitus accounts for 90% or more of total patients with diabetes mellitus. Representative examples of complications accompanying diabetes include hyperlipidemia, obesity, hypertension, retinopathy and renal insufficiency (Paul Zimmer, et al., Nature, 2001,414, 782). Sulfonylureas (stimulating insulin secretion in pancreatic cells), biguanides (inhibiting glucose production in the liver), a-glucosidase inhibitors (inhibiting glucose absorption in the intestines), etc. have been used as agents to treat diabetes. Recently, peroxisome proliferator-activated receptor gamma (PPAR) accelerators (Thiazolidinediones, increasing insulin sensitivity) have drawn attention as therapeutic agents for diabetes.

However, these drugs have side effects such as hypoglycemia, weight gain and the like (David E. Moller, Nature, 2001,414, 821). Furthermore, these agents raise concerns of

inducing hypoglycemia. Accordingly, there is a strong need to develop diabetes therapeutic agents which can treat hyperglycemia and reduce complications of diabetes mellitus with decreased side effects, without inducing hypoglycemia and weight gain.

Recently, it has been found through in vivo testing that PPARy accelerators (agonists) increase insulin sensitivity and also decrease serum levels of glucose and insulin, which suggest the possibility of such compounds being used as therapeutic agents for treatment of diabetes (Ricote M. , Nature 1998,391, 79-82). Accordingly, fibrates which activate PPARa were used as agents functioning to decrease blood triglyceride (TG) levels by 20-50%, decrease LDLc by 10-15% and increase HDLc by 10-15%, as observed through various experiments (Isseman, I. , et al, Nature 1990, 347,645-650 ; Linton, M. F., Curr. Atheroscler. Rep. 2000,2, 29-35). This fact is supported by reports that the activation of PPARa activates the transcription of enzymes which break down fatty acids to decrease the de novo synthesis of fatty acids in liver, thereby resulting in the decreased production and secretion of TG and VLDL.

Recently, accelerators for human PPARy and PPARa showed positive effects in various arteriosclerosis animal models, which also suggested the possibility of these compounds being used to treat arteriosclerosis (Li, A. C. , et al, J. Clin. Invest. 2000,106 523, Collins, A., Arterioscler., Thromb. , Vasc. Biol. 2002,21, 365-367, Bernadette P.

Neve, et al. Biochemical Pharmacology 2000,60, 1245). Further, since it was reported that PPARy accelerators inhibit factors inducing inflammation, the possibility of PPARy accelerators being used as therapeutic agents for treatment of inflammation was also suggested.

Therefore, the possibility was suggested that compounds activating both PPARa and PPARy can be used in treating diabetes mellitus and hyperlipidemia caused

by diabetes mellitus (Auwerx, J. , Insulin Resistance, Metabolic Disease Diabetic Complications 1999,167-172). Recently, many researchers have also confirmed in animal models that the compounds activating both PPARy and PPARa modulate the blood glucose and lipid levels (Koji Murakami, et al, Diabetes, 1998, 47, 1841, Dawn A.

Brooks, et al. , J. Med. Chem. 2001,44, 2061).

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a novel compound of Formula 1 activating both human PPARy and PPARa with excellent efficacy.

It is a further object of the present invention to provide processes for preparation of such novel compounds.

It is another object of the present invention to provide pharmaceutical compositions for acceleratrating PPARy and PPARa activity comprising a therapeutically effective amount of the novel compound as an active agent.

It is another object of the present invention to provide methods for treating or preventing PPARy and PPARa-related diseases, such as diabetes mellitus, its complications, inflammation and the like, by the use of the novel compound of the present invention as an active agent.

Other objects and advantages of the present invention will become apparent to those skilled in the art from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, there is provided a compound as represented by Formula 1 below.

Formula 1

wherein A is optionally substituted alkyl or cycloalkyl, optionally substituted aromatic or heteroaromatic, optionally substituted amine or amido, optionally substituted alkoxy, optionally substituted sulfonyl, or optionally substituted sulfanyl group; B, D and X are each independently hydrogen, or optionally substituted lower alkyl group; E is hydrogen, or optionally substituted lower alkyl or aromatic group.

The compound (s) of Formula 1 as an active agent for treatment of diseases, even when a separate explanation is not added thereto, is intended to include a pharmaceutically acceptable non-toxic salt, physiologically hydrolyzable ester, hydrate, solvate, isomer, or prodrug thereof.

As used herein, the term"pharmaceutically acceptable non-toxic salt"means alkali metal salts, alkaline earth metal salts, salts of inorganic acids, salts of organic acids, salts with amino acids, etc. The concrete examples of the pharmaceutical salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; and salts of organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid; or

methanesulfonic acid or p-toluenesulfonic acid, and the like. These acid addition salts can be prepared by known methods on the basis of the said Formula 1. The compound of Formula 1 can also be treated with a base to form non-toxic salts, in which the base includes, for example, inorganic bases such as alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide), alkali metal hydrogencarbonates (for example, sodium bicarbonate, potassium bicarbonate), alkali metal carbonates (for example, sodium carbonate, potassium carbonate, calcium carbonate), etc. and amino acids.

As used herein, the term"ester"means a compound species of formula- (R) n- COOR'where R and R'are each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded via carbon of ring) and heteroalicyclic (bonded via a ring carbon), and n is 0 or 1.

As used herein, the term"hydrate"means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound thereto by non-covalent intermolecular forces.

As used herein, the term"solvate"means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound thereto by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans.

As used herein, the term"isomer"means a compound of the present invention or a salt thereof, that has the same chemical formula or molecular formula but is optically or stereochemically different therefrom.

As used herein, the term"prodrug"means an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral

administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example of a prodrug, without limitation, would be a compound of the present invention which is administered as an ester (the"prodrug") to facilitate transport across a cell membrane, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell. A further example of a prodrug might be a short peptide (polyamino acid) bonded to an active group, where the peptide is metabolized to release the active moiety.

Some terms used in the present disclosure are briefly explained below.

When the term"optionally substituted"is used without any separate or additional descriptions in the present disclosure, it means that a substituent group (s) may be covalently bonded to the primary molecule or not. Herein, the substituent group (s) is (are) one or more group (s) individually and independently selected from alkyl, cycloalkyl (including dicycloalky and tricycloakyl), perhaloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, alkoxyalkoxy, arylalkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, 0-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, pyrrolidinone, pyrrolidine, piperidine, piperazine, morpholine, amine, and amino, including mono-and di-substituted amino groups, and the protected derivatives thereof. However, the substituent group (s) is (are) not limited thereto but is (are) intended to include a variety of substituents. In any case, the substituent group (s) could also be optionally substituted.

As used herein, the term"aromatic"means an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e. g., phenyl) and heterocyclic aryl groups (e. g. , pyridine). The term includes monocyclic or fused-ring polycyclic (i. e. , rings which share adjacent pairs of carbon atoms) groups.

The term"heteroaromatic"means an aromatic group which contains at least one heterocyclic ring.

The term"alkyl"means an aliphatic hydrocarbon group. The alkyl moiety may be a"saturated alkyl"group, which means that it does not contain any alkene or alkyne moieties. The alkyl moiety may also be an"unsaturated alkyl"moiety, which means that it contains at least one alkene or alkyne moiety. An"alkene"moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an"alkyne"moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic. The term"lower alkyl"in the present disclosure means an alkyl having 1 to 20 carbon atoms, preferably 1 to 10 atoms, more preferably 1 to 6 atoms, which may also be optionally substituted.

The substituent"R", as a designation used in the present disclosure, appearing by itself and without a number designation refers to a substituent selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl (bonded through a ring carbon), and optionally substituted heteroalicyclic (bonded through a ring carbon).

An"O-carboxy"group refers to a RC (=O) O- group wherein R is as defined herein.

A"C-carboxy"group refers to a-C (=O) OR group wherein R is as defined herein.

An"acetyl"group refers to a-C (=O) CH3 group.

A"trihalomethanesulfonyl"group refers to a Z3CS (=O) 2 group wherein Z is a halogen.

A"cyano"group refers to a-CN group.

An"isocyanato"group refers to a-NCO group.

A"thiocyanato"group refers to a-CNS group.

An"isothiocyanato"group refers to a-NCS group.

A"sulfinyl"group refers to a-S (=O)-R group wherein R is as defined herein.

A"S-sulfonamido"group refers to a-S (=O) 2NR group wherein R is as defined herein.

A"N-sulfonamido"group refers to a RS (=0) 2NH- group wherein R is as defined herein.

A"trihalomethanesulfonamido"group refers to a Z3CS (=0) 2NR-group wherein Z and R are as defined herein, respectively.

An"O-carbamyl"group refers to a-OC (=O)-NR group wherein R is as defined herein.

An"N-carbamyl"group refers to a ROC (=O) NH- group wherein R is as defined herein.

An"O-thiocarbamyl"group refers to a-OC (=S) -NR group wherein R is as defined herein.

An"N-thiocarbamyl"group refers to an ROC (=S) NH- group wherein R is as defined herein.

A"C-amido"group refers to a-C (=O)-NR2 group wherein R is as defined herein.

An"N-amido"group refers to a RC (=O) NH- group wherein R is as defined herein.

The term"perhaloalkyl"refers to an alkyl group in which all of the hydrogen atoms are replaced by halogen atoms.

Other terms used herein can be interpreted as having their usual meanings in the art to which the present invention pertains.

A in Formula 1 above is preferably selected from the below substitutents:

wherein, n is an integer of 1 to 3; Ro is a substituent having the below structure; wherein, Ro', Ro"and Ro"are each independently hydrogen, halogen, or optionally substituted lower alkyl group; Rl and Ra are each independently hydrogen, hydroxy group, optionally substituted lower alkyl group, or optionally substituted alkoxy group;

wherein, n is an integer of 1 to 3; R3 is a substituent having the below structure; wherein, n is an integer of 0 to 2; R3', R3"and R3"'are each independently hydrogen, halogen, or optionally substituted lower alkyl group;

wherein, n is an integer of 1 to 3; R4 is a hydrogen, optionally substituted aromatic or heteroaromatic group, and preferably, is selected from the below substitutents :

wherein, R4', R4"and R4''' are each independently hydrogen, halogen, or optionally substituted linear or branched lower alkyl group; Rs is hydrogen or optionally substituted lower alkyl group; Z is 0 or S ;

wherein, n is an integer of 1 to 3; R6, R7, R9 and Rlo are each independently hydrogen or lower alkyl group; R8 is hydrogen, or-OS02R, wherein R is hydrogen or optionally substituted lower alkyl or aromatic group;

wherein, n is an integer of 1 to 3 Rll, Rl2 and Ri4 are each independently hydrogen, or optionally substituted lower alkyl ; R13 is hydrogen, optionally substituted lower alkyl, optionally substituted carboxylic group, or optionally substituted aromatic group;

wherein, n is an integer of 0 to 2, preferably 0; Ris is hydrogen, or optionally substituted lower alkyl or aromatic group;

wherein, n is an integer of 1 to 3 R16 is hydrogen or lower alkyl group; Rl7 and Ris are each independently hydrogen, halogen, or optionally substituted lower alkyl group; wherein, n is an integer of 1 to 3; Rlg is optionally substituted lower alkyl or aromatic group, preferably aromatic group;

wherein, n is an integer of 1 to 3; R20 and R2l is each independently hydrogen, halogen, or optionally substituted lower alkyl group; and R22 is hydrogen or lower alkyl ; wherein, n is an integer 1 to 3; R23 and R24 are each independently hydrogen, optionally substituted lower alkyl group, optionally substituted carboxylic group, or optionally substituted aromatic group.

B, D and X are preferably each independently hydrogen or methyl.

Since the compounds of Formula 1 according to the present invention have an asymmetric center (asymmetric carbon atom), they can be present in the form of optical isomers such as enantiomer and partial stereoisomer. Furthermore, since the oxime structure in Formula 1 can be present in (E) or (Z)-form, the compounds of Formula 1 can have geometric isomers, of which the (E) -form isomer is more preferable. These

optical isomers and geometric isomers are of course included in the range of the present invention.

In a particularly preferred embodiment, the compounds of Formula 1 are compounds as defined below: () 3-benzyloxyimino-2- {4- [I- (phenyl)-5-methyl-IH-pyrrazole-4-ylmethoxy]-benzyl}- butyric acid methyl ester <BR> () 3-benzyloxyimino-2- {4- [1- (phenyl)-5-methyl-1 H-pyrrazole-4-ylmethoxy]-benzyl}- butyric acid <BR> ) 3-benzyloxyimino-2- {4- [1- (4-isobutyl-phenyl)-lH-pyrrazole-4-ylmethoxy]- benzyl}-butyric acid methyl ester <BR> () 3-benzyloxyimino-2- {4- [1- (4-isobutyl-phenyl)-lH-pyrrazole-4-ylmethoxy]- benzyl} -butyric acid <BR> () 3-methyloxyimino-2- {4- [l- (4-isobutyl-phenyl)-lH-pyrrazole-4-ylmethoxy]- benzyl}-butyric acid methyl ester <BR> () 3-methyloxyimino-2- {4- [1- (4-isobutyl-phenyl)-lH-pyrrazole-4-ylmethoxy]- benzyl} -butyric acid methyl ester <BR> () 3-isopropyloxyimino-2- {4- [1- (4-isobutyl-phenyl)-1 H-pyrrazole-4-ylmethoxy]- benzyl} -butyric acid methyl ester (~) 3-isopropyloxyimino-2-{4-[1-(4-isobutyl-phenyl)-1H-pyrazole- 4-ylmethoxy]- benzyl}-butyric acid <BR> () 3- (4-fluorobenzyloxyimino)-2- {4- [1- (4-isobutyl-phenyl)-lH-pyrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester (~) 3-(4-fluorobenzyloxyimino)-2-{4-[1-(4-isobutyl-phenyl)-1H_py razzole-4-

ylmethoxy]-benzyl}-butyric acid <BR> <BR> <BR> <BR> () 3- (3-fluorobenzyloxyimino)-2- {4- [1- (4-isobutyl-phenyl)-1H-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester <BR> <BR> <BR> <BR> <BR> () 3- (3-fluorobenzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid <BR> <BR> <BR> <BR> <BR> () 3- (4-chlorobenzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester <BR> <BR> <BR> <BR> <BR> 3- (4-chlorobenzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy] -benzyl} -butyric acid <BR> <BR> <BR> <BR> <BR> () 3- (4-methylbenzyloxyimino)-2- {4- [l- (4-methyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester <BR> <BR> <BR> <BR> <BR> () 3- (4-methylbenzyloxyimino)-2- {4- [l- (4-methyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid <BR> <BR> <BR> <BR> <BR> () 3- (2, 4-difluorobenzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester <BR> <BR> <BR> <BR> <BR> () 3- (2, 4-difluorobenzyloxyimino)-2- {4- [1- (4-isobutyl-phenyl)-1H-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid <BR> <BR> <BR> <BR> <BR> () 3-benzyloxyimino-2- {4- [1- (4-chloro-phenyl)-lH-pyrrazole-4-ylmethoxy]-benzyl}- butyric acid methyl ester <BR> <BR> <BR> <BR> <BR> () 3-benzyloxyimino-2- {4- [l- (4-chloro-phenyl)-lH-pyrrazole-4-ylmethoxy]-benzyl}- butyric acid () 3- (4-fluorobenzyloxyimino) -2- {4- [l- (4-chloro-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester <BR> <BR> <BR> () 3- (4-fluorobenzyloxyimino)-2- {4- [l- (4-chloro-phenyl)-lH-pyrrazole-4-

ylmethoxy] -benzyl} -butyric acid () 3-benzyloxyimino-2-{4-[1-(4-methyl-phenyl)-1H-pyrrazole-4-yl methoxy]-benzyl}- butyric acid methyl ester (~) 3-benzyloxyimino-2-{4-[1-(4-methyl-phenyl)-1H-pyrrazole-4-yl methoxy]-benzyl}- butyric acid <BR> <BR> <BR> <BR> <BR> <BR> () 3- (4-fluorobenzyloxyimino)-2- {4- [1- (4-methyl-phenyl)-1H-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid <BR> <BR> <BR> <BR> <BR> <BR> () 3- (4-fluorobenzyloxyimino)-2- {4- [l- (4-methyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid <BR> <BR> <BR> <BR> <BR> <BR> () 3-benzyloxyimino-2- {4- [1- (3, 5-ditrifluoromethyl-phenyl)-1 H-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester <BR> <BR> <BR> <BR> <BR> <BR> () 3-fluorobenzyloxyimino-2- {4- [1- (3, 5-ditrifluoromethy-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid <BR> <BR> <BR> <BR> <BR> <BR> () 3- (4-fluoro-benzyloxyimino-2- {4- [1- (phenyl)-5-methyl-lH-pyrrazole-3- ylmethoxy] -benzyl} -butyric acid methyl ester <BR> <BR> <BR> <BR> <BR> <BR> () 3- (4-fluoro-benzyloxyimino)-2- f 4- [1- (phenyl)-5-methyl-1H-pyrrazole-3- ylmethoxy] -benzyl} -butyric acid <BR> <BR> <BR> <BR> <BR> <BR> () 3- (4-fluorobenzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-5-ethyl-lH-pyrrazole-3- ylmethoxy]-benzyl}-butyric acid methyl ester <BR> <BR> <BR> <BR> <BR> <BR> () 3- (4-fluorobenzyloxyimino)-2- {4- [1- (4-isobutyl-phenyl)-5-ethyl-lH-pyrrazole-3- ylmethoxy]-benzyl}-butyric acid () 3-(4-fluoro-benzyloxyimino)-2-{4-[1-(4-isobutyl-phenyl)-5-pr opyl-1H-pyrrazole-3- ylmethoxy]-benzyl}-butyric acid methyl ester <BR> <BR> <BR> () 3- (4-fluoro-benzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-5-propyl-lH-pyrrazole-3-

ylmethoxy] -benzyl} -butyric acid () 3-benzyloxyimino-2- {4- [1- (phenyl)-5-methyl-lH-pyrrazole-4-ylmethoxy]-benzyl}- butyric acid methyl ester () 3-benzyloxyimino-2- {4-[1-(phenyl)-5-methyl-1H-pyrrazole-4-ylethoxy]-benzyl}- butyric acid () 3-benzyloxyimino-2- {4- [1- (4-isobutyl-phenyl)-1H-pyrrazole-4-ylmethoxy]- benzyl} -2-methyl-butyric acid methyl ester <BR> <BR> <BR> <BR> <BR> () 3-benzyloxyimino-2- {4- [1- (4-isobutyl-phenyl)-lH-pyrrazole-4-ylmethoxy]- benzyl}-2-methyl-butyric acid <BR> <BR> <BR> <BR> <BR> () 2- (benzyloxyimino-methyl)-3- (4- {2- [1- (4-isopropyl-phenyl)-lH-pyrrazole-4-yl]- ethoxy} -phenyl) -propionic acid ethyl ester () 2- (benzyloxyimino-methyl)-3- (4-f2- [l- (4-isopropyl-phenyl)-lH-pyrrazole-4-yl]- ethoxy}-phenyl)-propionic acid 3-ethoxyimino-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5-ylmethoxy)-benzyl]-butyric acid 3- (4-fluorobenzyloxyimino)-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5-ylmethoxy) -benzyl]- butyric acid () 3-benzyloxyimino-2- [4-3- (4-ethylphenyl)- [1, 2,4] oxadiazole-5-ylmethoxy-benzyl] - butyric acid () 3- (4-fluorobenzyloxyimino-2- [4-3- (4-ethylphenyl)- [1, 2,4] oxadiazole-5-ylmethoxy- benzyl] -butyric acid 3- (4-fluorobenzyloxyimino)-2- [4- (3- (4-isopropylplienyl)- [1, 2,4] oxadiazole-5- ylmethoxy) -benzyl] -butyric acid () 3- (4-fluorobenzyloxyimino)-2- [4- (3-4-trifluoromethylphenyl)- [1, 2,4] oxadiazole-5- ylmethoxy] -benzyl] -butyric acid

3-ethoxyimino-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5-ylmethoxy) -benzyl]-pentanoic acid ) 3-ethoxyimino-2-methyl-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5-ylmethoxy)-benzyl]- butyric acid 3-methoxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzyl}-butyric acid methyl ester 3-methoxyimino-2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-etho xy]-benzyl}-butylic acid <BR> <BR> <BR> <BR> <BR> <BR> 3-ethoxyimino-2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethox y]-benzyl}-butyric acid<BR> <BR> <BR> <BR> <BR> <BR> <BR> 3-propyloxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzyl}-butyric acid 3-butyloxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzyl}-butyric acid 3- (2-methyl-propyloxyimino)-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]- benzyl}-butyric acid 3-cyclopropylmethoxyimino-2- {4- [2- (5-methyl-2-plienyl-oxazole-4-yl)-ethoxy]- benzyl}-butyric acid 3-isopropyloxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzyl}- butyric acid 3-benzyloxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzyl}-butyric acid 3-(4-fluorobenzyloxyimino-2-{4-[2-(5-methyl-2-phenyl-oxazole -4-yl)-ethoxy}-benzyl}- butyric acid 3-methoxyimino-2- {4-[2-(2-phenyl)-5-methyl-oxazole-4-yl]-methoxy}-benzyl-

pentanoic acid <BR> <BR> <BR> <BR> <BR> 3-ethoxyimino-2-{4-[2-(2-phenyl)-5-methyl-oxazole4-yl]-metho xy}-benzyl-pentanoic acid 2-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}- benzyl)-3-methoxymino- butylic acid <BR> <BR> <BR> <BR> <BR> 3-ethoxyimino-2- (4- {2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}-benzyl)- butyric acid 2-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}- benzyl)-3- propyloxyimino-butyric acid 3-fluoroethoxyimino-2- (4- {2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}- benzyl) -butyric acid <BR> <BR> <BR> <BR> <BR> 2- (4- {2- [2- (3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}-benzyl)-3-m ethoxyimino- butylic acid 3-ethoxyimino-2- {2-[2-(3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}- benzyl) butyric acid 2- (4- {2- [2- (3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}-benzyl)-3- propyloxyimino-butylic acid 3-cyclomethoxyimino-2- (4-{2-[2-(3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}- benzyl) -butyric acid 3-methoxyimino-2- {4- [2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethoxy]-benzyl}- butyric acid <BR> <BR> <BR> <BR> <BR> 3-ethoxyimino-2- {4- [2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethoxy]-benzyl}-bu tyric acid 2-{4-[2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethoxy]-benzy l}-3-propyloxymino-

butylic acid 3-fluoroethyloxyimino-2- {4- [2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethoxy]- benzyl}-butyric acid 3-methoxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzyl}-2-methyl- butylic acid 3-ethoxyimino-2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethox y}-benzyl}-2-methyl- butylic acid 2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzyl}-2-m ethyl-3- propyloxyimino-butylic acid <BR> <BR> <BR> <BR> <BR> 3-methoxyimino-2- {4- [2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethoxy]-benzyl}-2- methyl-butylic acid <BR> <BR> <BR> <BR> <BR> 3- (4-fluoro-benzyloxyimino)-2- {4- [5-methyl-2- (4-trifluoromethyl-phenyl)-thiazole-4- ylmethoxy]-benzyl}-butyric acid <BR> <BR> <BR> <BR> <BR> 2-f4- [2- (5-methyl-2-p-oxazole-4-ylmethoxy)-benzyl]-3-propyloxyimino- butylic acid 1- [2- (4- {3-benzyloxyimino}-2-carboxy-butyl)-phenoxy]-ethyl-4-phenyl- 1 H-pyrrole-3- carboxylic acid ethyl ester <BR> <BR> <BR> <BR> <BR> 3- [4-fluoro-benzyloxyimino]-2- {4- [2- (4-methansulfonyloxy-phenyl)-ethoxy]-benzyl}- butyric acid <BR> <BR> <BR> <BR> <BR> 3- [4-fluoro-benzyloxyimino]-2- f 4- [l- (4-isopropyl-phenyl)-5-methoxy-1H-pyrrazole-4- ylmethoxy] -benzyl} -butyric acid 2-{4-[1-(4-ethyl-phenyl)-1H-pyrrazole-4-ylmethoxy]-benzyl}-3 -[4-fluoro- benzyloxyimino] -butyric acid 3- [benzyloxyimino]-2-4- [1-4-ethoxy-phenyl]-1 H-pyrrazole-4-ylmethoxy]-benzyl}- butyric acid

3- [4-fluoro-benzyloxyimino]-2-4- [1-4-methyl-phenyl]-5-methoxy-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid 3- [4-fluoro-benzyloxyimino]-2-4- [2- (1-phenyl-1H-pyrrazole-4-yl)-ethoxy]-benzyl]- butyric acid 3- [4-fluoro-benzyloxyimino]-2- {3- [1- (4-isopropyl-phenyl)-1 H-pyrrazole-4-ylmethoxy]- benzyl}-butyric acid 3- [4-fluoro-benzyloxyimino]-2- {3- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]- benzyl}-butyric acid 3- [4-fluoro-benzyloxyimino]-2- {3- [2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethoxy]- benzyl}-butyric acid 3- [4-fluoro-benzyloxyimino]-2- {4-methanesulfonyloxy-benzyl}-butyric acid 2- {4-benzenesulfonyloxy-benzyl}-3- [4-fluoro-benzyloxyimino]-butyric acid 3- [4-fluoro-benzyloxyimino]-2- {4-phenylmethanesulfonyloxy-benzyl}-butyric acid 3- [4-fluoro-benzyloxyimino]-2- {4- [1-phenyl-1 H-pyrrazole-4-ylmethoxy]-benzyl}- butyric acid 3- [ethoxyimino]-2- {4- [2- (5-methyl-1-phenyl-1 H-pyrrazole-3-yl)-ethoxy]-benzyl}- butyric acid 2- {4- [2- (4-methanesulfonyloxy-phenyl)-ethoxy]-benzyl}-3- [methoxyimino]-butyric acid 3- [ethoxyimino]-2- {4- [2- (4-methanesulfonyloxy-phenyl)-ethoxy]-benzyl}-butyric acid 3- [2-fluoro-ethoxyimino]-2- {4- [2- (4-methanesulfonyloxy-phenyl)-ethoxy]-benzyl}- butyric acid 2- {4- [2- (4-methanesulfonyloxy-phenyl)-ethoxy]-benzyl}-3- [propoxyimino] -butyric acid

3- [benzyloxyimino]-2- {4- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}- benzyl}-2-methyl-butylic acid 3-[propoxyimino]-2-{4-[1-(p-tolyl-1H-pyrrazole-4-yl)-methoxy ]-benzyl}-butyric acid <BR> <BR> <BR> <BR> <BR> 3- [4-fluoro-benzyloxyimino]-2- {4- [2- (4-methyl-thiazole-5-yl)-ethoxy]-benzyl}-butyric acid <BR> <BR> <BR> <BR> <BR> 2-{4-[2-(4-methyl-thiazole-5-yl)-ethoxy]-benzyl}-3-[propoxyi mino]-butyric acid<BR> <BR> <BR> <BR> <BR> <BR> <BR> 2- {4- [2- (5-ethyl-pyridine-2-yl)-ethoxy]-benzyl}-3- [propoxyimino]-butyricacid<BR> <BR> <BR> <BR> <BR> <BR> <BR> 2-f 4- [2- (5-ethyl-pyridine-2-yl)-ethoxy]-benzyl}-3- [methoxyimino]-2-methyl-butyric acid 2-{4-[2-(benzoxazole-2-yl-methyl-amino)-ethoxy}-benzyl}-3-[m ethoxyimino]-butyric acid <BR> <BR> <BR> <BR> <BR> <BR> (i) 2- {3- [2- (benzoxazole-2-yl-methylamino)-ethoxy]-benzyl}-3- [methoxyimino]- butylic acid methyl ester (~) 2-{3-[2-(benzoxazole-2-yl-methylamino)-ethoxy]-benzyl}-3-[me thoxyimino]- butyric acid <BR> <BR> <BR> <BR> <BR> ( 3- [ethoxyimino]-2- [4- (5-methyl-2-phenyloxazole-4-ylmethoxy)-benzyl]-butyric acid methyl ester <BR> <BR> <BR> <BR> <BR> ( 3- [ethoxyimino]-2- [4- (5-methyl-2-phenyloxazole-4-ylmethoxy)-benzyl]-butyric acid (~) 3- [propoxyimino]-2- [4- (5-methyl-2-phenyloxazole-4-ylmethoxy)-benzyl]-butyric acid <BR> <BR> <BR> <BR> <BR> <BR> (t) 2-{4-[2-(4-fluorophenyl-5-methyloxazole-4-ylmethoxy)-benzyl] -3-[methoxyimino]- 2-methyl butyric acid () 2- {4- [2- (4-fluorophenyl-5-methyloxazole-4-ylmethoxy)-benzyl]-3- [methoxyimino]-

2-methyl propionic acid () 3- [ethoxyimino] -2- [4- (2-isopropyl-5-methyloxazole-4-ylmethoxy)-benzyl]-butyric acid (~) 2-[4-(2-isopropyl-5-methyloxazole-4-ylmethoxy)-benzyl]-3-[pr opoxyimino]-butyric acid <BR> <BR> <BR> <BR> <BR> () 3- [2-fluoro-ethoxyimino]-2- [4- (5-methyl-2-paratolyloxazole-4-ylmethoxy)-benzyl]- butyric acid <BR> <BR> <BR> <BR> <BR> ) 3- [2-fluoro-ethoxyimino]-2- {4-5-methyl-2- (4-fluorophenyl)-5-methyloxazole-4- ylmethoxy] -benzyl} -butyric acid (t) 2- [4- (3-benzyl- [1, 2,4] oxadiazole-5-ylmethoxy)-benzyl]-3- [methoxyimino]-butyric acid ) 2- [4- (3-benzyl- [1, 2,4] oxadiazole-5-ylmethoxy)-benzyl]-3- [ethoxyimino]-butyric acid <BR> <BR> <BR> <BR> <BR> () 3- [ethoxyimino]-2- {4- [2- (4-ethylphenyl)-5-methyloxazole-4-ylmethoxy]-benzyl}- butyric acid (~) 2-{4-[2-(4-ethylphenyl)-5-methyloxazole-4-ylmethoxy]-benzyl} -3- [propoxyimino] - butyric acid (~) 2-[4-(4-methanesulfonyloxy-benzyloxy)-benzyl]-3-[ethoxyimino ]-butyric acid (~) 3-[methoxyimino]-2-{4-[5-methyl-2-(4-methanesulfanyl-phenyl) -oxazole-4- ylmethoxy]-benzyl}-butyric acid ) 3- [ethoxyimino]-2- {4- [5-methyl-2- (4-methanesulfanyl-phenyl)-oxazole-4- ylmethoxy]-benzyl}-butyric acid <BR> <BR> <BR> <BR> <BR> ) 3- [ethoxyimino]-2- {4- [2- (4-methanesulfonyl-phenyl)-5-methyl-oxazole-4- ylmethoxy]-benzyl}-butyric acid

3- [ethoxyimino]-2- [4- (2-phenylsulfanyl-ethoxy)-benzyl]-butyric acid 3- [ethoxyimino]-2- [4- (2-phenylsulfonyl-ethoxy)-benzyl]-butyric acid methyl ester () 3- [ethoxyimino]-2- [4- (2-phenylsulfbnyl-ethoxy)-benzyl]-butyric acid 3- [ethoxyimino]-2- f 4- [2- (3-oxo-2, 3-dihydro-benzo [1,4] oxazine-4-yl-ethoxy) - benzyl] -butyric acid methyl ester 3- [ethoxyimino]-2- {4- [2- (3-oxo-2, 3-dihydro-benzo [1,4] oxazine-4-yl-ethoxy) - benzyl] -butyric acid In the above compounds," ()" is intended to represent whole optical isomers.

The compounds of Formula I above according to the present invention have different structure from known PPARy and PPARa accelarators and exhibit excellent accelerating effect to human PPARy and PPARa relating to the prevention and treatment of diabetes mellitus, diabetes mellitus-related diseases such as hyperlipidemia, arteriorsclerosis and the like, and inflammation, as will be seen in experimental examples later.

The present invention also relates to processes for preparation of the compounds of Formula 1. A person skilled in the art could easily manufacture the compound of Formula 1 on the basis of the chemical structure thereof by various processes. In other words, it will be possible to prepare the compound of Formula 1, within the scope of the present invention, by the process described in the present disclosure or by combining some of processes known in the prior art. As an illustrative process for such preparation, the compound of Formula 1 can be prepared by reacting the compound of Formula 2 with the compound of Formula 3 in the presence of base, as shwon in Reaction Scheme 1 below.

Reaction Scheme 1

wherein A, B, D, E, X and n are the same as defined in Formula 1, and LG is a leaving group. The example of the leaving group means Cl,-OS02CH3, etc.

The reaction can be conducted in the presence of organic solvent, such as dimethylformamide, dimethylacetamide and acetonitrile and the like, and in some cases, two or more kinds of them can be used. The typical examples of the base includes sodium hydroxide, potassium t-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium bis (trimethylsilyl) amide and the like, and in some cases, two or more kinds of them can be used.

Based upon Reaction Scheme 1 above, the preparation processes for some of the compounds of Formula 1 will be illustrated in the below.

Firstly, a compound in which A in Formula 1 is the substituent (i) can be prepared through reaction scheme 2 below.

Reaction Scheme 2

wherein Ro, Ri R2, B, D, E, X and n are the same as defined in Formula 1.

The reaction condition is the same as previously defined.

The compounds of Formula 2 and 3 can also be prepared by a person skilled in the art on the basis of their chemical structures by various methods. As a representative example, the compounds can be prepared by Reaction Scheme 3 or 4 below. More specifically, the preparation process of the compound in which Ro in Formula 3 is not hydrogen is defined as in the Reaction scheme 3 below, and the preparation process of the compound in which Ro is hydrogen is defined as in Reaction Scheme 4 below.

Reaction Scheme 3 Ru pro yt Ethanoi R4$N LAH/THF R1f N MsCI/TEA/£H2CI2 1 (0N Me2N Q OH Cl Mye N Reaction Scheme 4 I Ro Ro M NC. 1 '"' MSCEAC N H 0 H2N lsoanyl nitriteI MsCI/TEA/CH2cl2 I 2 3 RoNNHz / methanol OH ci The compound of Formula 2 in which Ro is not hydrogen is prepared by reacting hydrazine with enamine to obtain pyrrazole ester, and then reacting it with LAH to give alcohol, followed by halogenation thereof, as shown in Reaction Scheme 3 or 4.

In the Reaction Schemes above, Ro and Rl are the same as in Formula 1, Me means methyl, LAH means Lithium Aluminum Hydride, THF means Tetrahydrofuran, MsCI means Methanesulfonyl Chloride, and TEA means Triethylamine.

Secondly, the compound in which A in Formula 2 is the substituent (ii) can be prepared by Reaction Scheme 5 below.

Reaction Scheme 5 1. 1, 1'-Carbonyl 2, NaHCOaIEtOH N-OH. diimidazole R3-CN--Ra + OTr- 2 CH2C12. cH2cy. . 1 MsCIRriethylamine/N_ R3/1> CH2CI2 NA ''nif N OH Cl, OMs

wherein, R3 is the same as defined in Formula 1, Tr means Triphenylmethyl, and MsCI means Methanesulfonyl Chloride.

The brief explanation of the above reaction is as follows. An aromatic nitrile compound is reacted in the presence of hydroxylamine hydrochloride, sodium hydrogen carbonate, and ethanol or methanol to prepare an aromatic aldoxim. The synthesized aldoxim is subjected to cyclization reaction with glycolic acid protected with trityl in the presence of carbodiimide to produce oxadiazole, then subjected to deprotection to synthesize oxadiazolyl methanol. The synthesized alcohol compound is reacted with MsCI in the presence of base to produce a desired compound.

Thirdly, the compound in which A in Formula 1 is the substituent (iii) and Z is O can be prepared by Reaction Scheme 6 below as the known method (Koji Ando and Masanobu Suzuki W099/50267).

Reaction Scheme 6

Fourthly, the compound in which A in Formula 1 is the substituent (iii) and Z is S can be prepared by Reaction Scheme 7 below as the known method (Chao, Esther, Yu-Hsuan et al. WO01/00603).

Reaction Scheme 7

wherein, Rs is the same as defined in Formula 1, Me means methyl, and Et means ethyl group.

Further, the compound in which B is hydrogen, D is methyl and X is ethyl in Formula 3, can be prepared by Reaction Scheme 8 below as the known method (Roberto Antonioletti, Paolo Bovicelli and Savina Malacona, Tetrahedron, 2002, 58, 589).

Reaction Scheme 8 i O 1 Piperidine/Acetic acid/+ E'NH2 HO (O Benzene Ho NaOAc/Ethanol I O ou te

wherein E is the same as defined in Formula 1.

According to Reaction Scheme 8 above, the condensation reaction with benzaldehyde and ethylaceto acetate is conducted, and then hydrogenation and the following reaction with versatile oximes are conducted to produce a desired compound.

Also, the present invention provides a pharmaceutical composition for accelerating PPARy and PPARa comprising (a) a therapeutically effective amount of the compound of Formula 1, and (b) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.

The term"pharmaceutical composition"as used herein means a mixture of a compound of the invention with other chemical components, such as diluents or carriers.

The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to oral, injection, aerosol, parenteral, and topical administrations.

Pharmaceutical compositions can also be obtained by reacting compounds with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

The term"therapeutically effective amount"means that amount of the compound being administered which will alleviate to some extent one or more of the symptoms of the disease being treated. Thus, a therapeutically effective amount refers to that amount which has the effect of (1) reversing the rate of progress of a disease; (2) inhibiting to some extent or preferably, completely ceasing further progress of the disease; and/or, (3) alleviating to some extent (or, preferably, eliminating) one or more symptoms associated with the disease.

The term"carrier"means a chemical compound that facilitates the

incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

The term"diluent"defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the ionic strength conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

The term"physiologically acceptable"defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

The compounds of Formula 1 can be administered in various pharmaceutical dosage forms in accordance with intended use. In the preparation of pharmaceutical compositions in accordance with the present invention, an active agent, more specifically the compound of Formula 1 may be mixed with one or more physiologically acceptable carriers which can be selected depending on the dosage form to be prepared. For example, the pharmaceutical composition according to the present invention can be formulated into dosage forms suitable for injection or oral administration.

The compound of Formula 1 may be formulated in a conventional manner using known physiologically acceptable carriers and excipients and presented in unit dosage form or in multi-dose containers. The formulations may take such forms as solutions, suspensions or emulsions in oily or aqueous vehicles, and may contain conventional

dispersing, suspending or stabilizing agents. Alternatively, the active ingredient may be in powder form for reconstitution with sterile pyrogen-free water, before use. The compound of Formula 1 may also be formulated into suppositories containing conventional suppository bases such as cocoa butter or other glycerides. Solid dosage forms for oral administration include capsule, tablet, pill, powder and granule.

Preferable dosage forms are capsule and tablet. It is preferable that tablets and pills be coated. The solid dosage forms for oral administration may be obtained by mixing the compound of Formula 1 as an active agent with inactive diluents such as sucrose, lactose, starch and the like and carriers such as lubricant, for example magnesium stearate, including disintegrator, binder and the like.

If necessary, the compound of Formula 1 and composition comprising the same according to the present invention may be administrated in combination with other pharmaceutical agents, for example, other diabetes treating agents.

The term"therapeutically effective amount"means an amount of active ingredients effective to alleviate, ameliorate or prevent symptoms of disease or decrease or delay the onset of clinical markers or symptoms of disease. The therapeutically effective amount may be determined by experiments on the efficacy of compound as an active agent via in vivo and in vitro known model systems for diseases to be treated.

When the formulation is presented in unit dosage form, the compound of Formula 1 as an active agent can be preferably contained in an amount of about 0. 1- 1,000 mg unit dosage. The dosage amount of the compound of Formula 1 will be dependent on the subject's weight and age, the nature and severity of the affliction and the judgment of the prescribing physician. For adult administration, the dosage amount required will be in the range of about 1 to 1000 mg a day depending on the frequency

and strength of the dosage. For intramuscular or intravenous administration to adults, a total dosage amount of about 1-500 mg a day will be sufficient. In some patients, the dosage amount in a day will be higher than that.

The present invention also provides a method for treating or preventing diseases involving human PPARa and PPARy by the use of effective amounts of the compound of Formula 1. "Diseases involving PPARa and PPARy"mean the diseases which can be treated and prevented by activating human PPARa and PPARy, and include, for example, but are in no way limited to diabetes mellitus, complications associated with diabetes mellitus, inflammation, etc. Representative examples of the complications associated with diabetes mellitus are hyperlipidemia, arteriorasclerosis, obesity, hypertension, retinopathy, kidney inefficiency, etc. The term"treating"means ceasing or delaying progress of diseases when the compound of Formula 1 or composition comprising the same is administered to subjects exhibiting symptoms of diseases. The term"preventing"means ceasing or delaying symptoms of diseases when the compound of Formula 1 or composition comprising the same is administered to subjects exhibiting no symptoms of diseases, but having high risk of developing symptoms of diseases.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will now be illustrated in more detail by the following PREPARATIONS and EXAMPLES; however, the scope of the present invention is not limited thereto. In below, processes for synthesis of intermediates for preparing final compounds are illustrated in PREPARATIONS, whereas processes for synthesis of the final compounds using the compound of PREPARATIONS are illustrated in

EXAMPLES.

Preparation Example 1: [1-(1-phenyl)-5-methyl-lH-pyrrazole-4-yl]-methanol (1) Preparation of 2-acethyl-2-dimethylamino-acrylic acid ethyl ester 12.8 ml (100 mmol) of ethylacetate was added to N, N-dimethyl formamide dimethylacetal, and the resulting solution was reacted at 120°C for 2 hours, then start materials was removed under vacuum to obtain 16 g of the title compound.

Mass (EI) 186 (M++1) (2) Preparation of 5-methyl-1-phenyl-lH-pyrrazole-4-carboxylic acid ethyl ester 5 g (27 mmol) of the compound obtained in Procedure (1) above was dissolved in 40 ml of ethanol, and 40 ml of ethanol in which 2.9 g (27 mmol) of phenylhydrazine was dissolved was added thereto and then reacted for 2 hours under reflux. 100 ml of dichloromethane was added thereto, then the resulting solution was washed with saturated sodium carbonate and dried over magnesium sulfate. After distillation under reduced pressure, the residue was purified by column chromatography (eluent: ethylacetate/hexane = 1/5) to obtain 5.43 g (23.6 mmol) of the title compound in a yield of 87%.

NMR : lH-NMR (CDCl3) 8 8.03 (1H, s), 7. 52-7. 26 (5H, m), 4.32 (2H, q, J=7.2Hz), 2.56 (3H, s), 1.37 (3H, t, 7.2Hz) (3) Preparation of [1-(1-phenyl)-5-methyl-lH-pyrazole-4-yl]-methanol 2. 28 g (9.8 mmol) of the compound obtained in Procedure (2) above was

dissolved in 30 ml of anhydrous tetrahydrofuran, and 1.13 g (29 mmol) of lithium aluminum hydride was slowly added thereto at room temperature. The resulting solution was reacted for 2 hours under reflux. The temperature of the reaction was cooled to 0°C, then 1.1 ml of water, 15% sodium hydroxide solution and 3.3 ml of water were slowly added thereto. The reaction was filtered off in the presence of cellite to remove solvent and then purified by column chromatography (eluent: ethylacetate/dichloromethane = 1/2,1/1, methanol/ethylacetate = 1/19) to obtain 1.25 g (6.6 mmol) of the title compound in a yield of 68% yield.

NMR : lH-NMR (CDCl3) 6 7.63 (1H, s), 7. 50-7. 37 (5H, m), 4.60 (2H, d, J=4Hz), 2.35 (3H, s) Preparation Example 2: [l- (4-isopropyl-phenyl)-5-methyl-lH-pyrrazole-4-yl] methanol (1) Preparation of 5-methyl-1-(4-isopropyl-phenyl)-lH-pyrrazole-4-carboxylic acid ethyl ester 992 mg (5 mmol) of the compound obtained in Preparation Example 1 (1) was dissolved in 10 ml of ethanol, then 10 ml of ethanol in which 1.0 g (5.4 mmol) of phenyl hydrazine was dissolved was added thereto and reacted for 2 hours under reflux.

To the resulting solution, 50 ml of dichloromethane was added, followed by washing with saturated sodium carbonate and drying over magnesium sulfate. After distillation under reduced pressure, the residue was purified by column chromatography (eluent: ethylacetate/hexane = 1/7) to obtain 1.15g (4.2 mmol) of the title compound in a yield of 78%.

Mass (EI) 273 (M++1)

(2) Preparation of [1-(4-isopropyl-phenyl)-5-methyl-lH-pyrrazole-4-yl]- methanol 1.15 g (4.2 mmol) of the compound obtained in Procedure (1) was dissolved in 20 ml of anhydrous tetrahydrofuran and 405 mg (9.3 mmol) of lithium aluminum hydride was slowly added thereto at room temperature. The resulting solution was reacted for 2 hours under reflux. The temperature of the reaction was cooled to 0°C, and 0.4 ml of water, 0.4 ml of 15% sodium hydroxide solution and 1.2 ml of water were slowly added thereto. The reaction was filtered off in the presence of cellite to remove solvent and then purified by column chromatography (eluent: ethylacetate/dichloromethane = 1/1 and 3/1) to obtain 842 mg (3.6 mmol) of the title compound in a yield of 86%.

NMR : 1H-NMR (CDC13) 8 7.61 (1H, s), 7. 35-7. 30 (4H, m), 4.59 (2H, s), 3. 00-2. 93 (1H, m), 2.33 (3H, s), 1.59 (1H, brs), 1.28 (6H, d, J=4Hz) Preparation Example 3: [1- (4-isopropyl-phenyl)-5-ethyl-lH-pyrrazole-4-yl]- methanol (1) Preparation of 2-propionyl-3-dimethylamino-acrylic acid ethyl ester 500 mg (3.5 mmol) of ethylpropionyl acetate was added to 0.46 ml (3.6 mmol) of N, N-dimethyl formamide dimethyl acetal, and the resulting solution was reacted for 2 hours at 120°C, then a start material was removed under vacuum to give 600 mg (3.0 mmol) of the title compound in a yield of 86%.

Mass (EI) 200 (M++1) (2) Preparation of 5-ethyl-1-phenyl-lH-pyrrazole-4-carboxylic acid ethyl ester

600 mg (3.0 mmol) of the compound obtained in Procedure (1) was dissolved in 10 ml of ethanol, then 10 ml of ethanol in which 647 mg (4.3 mmol) of phenyl hydrazine was dissolved was added and reacted for 2 hours under reflux. After the reaction, solvent was removed and 20 ml of ethylacetate was added thereto. The solution was washed with saturated sodium carbonate and then dried over magnesium sulfate. After distillation under reduced pressure, the residue was purified by column chromatography (eluent: ethylacetate/hexane = 1/3) to obtain 681 mg (2.4 mmol) of the title compound in a yield of 80%.

Mass (EI) 287 (M++1) (3) Preparation of [1- (1-phenyl)-5-ethyl-lH-pyrrazole-4-yl]-methanol 1 g (3.5 mmol) of the compound obtained in Procedure (2) was dissolved in 10 ml of anhydrous tetrahydrofuran, then 265 mg (6.6 mmol) of lithium aluminum hydride was slowly added thereto at room temperature. The resulting solution was reacted for 2 hours under reflux. The temperature of the reaction was cooled to 0°C, and 0.5 ml of water, 0.5 ml of 15% sodium hydroxide solution and 1.5 ml of water were slowly added thereto. The reaction was filtered off in the presence of cellite to remove solvent and then purified by column chromatography (eluent: ethylacetate/dichloromethane = 1/2, 1/1) to obtain 660 mg (2.7 mmol) of the title compound in a yield of 71%.

Mass (EI) 245 (M++1) NMR : 1H-NMR (CDCl3) 8 7.60 (1H, s), 7.31 (4H, s), 4.60 (2H, s), 2. 99-2. 95 (1H, m), 2.74 (2H, q, J=7.6Hz), 1.59 (1H, brs), 1.28 (6H, d, J=7.2Hz), 1.11 (3H, t, J=7.6Hz) Preparation Example 4: [1- (4-isopropyl-phenyl)-5-propyl-lH-pyrrazole-4-yl]-

methanol (1) Preparation of 2-butyryl-3-dimethylamino-acrylic acid ethyl ester 500 mg (3.0 mmol) of ethylbutyrylacetate was dissolved in 0.46 ml (3.6 mmol) of N, N-dimethyl formamide dimethyl acetal, and the resulting solution was reacted for 2 hours at 120°C, then a start material was removed under vacuum to give 620 mg (2.9 mmol) of the title compound.

Mass (EI) 214 (M++1) (2) Preparation of 5-propyl-1-phenyl-lH-pyrrazole-4-carboxylic acid ethyl ester 600 mg (2.8 mmol) of the compound obtained in Procedure (1) was dissolved in 10 ml of ethanol, then 10 ml of ethanol in which 590 mg (3.9 mmol) of phenyl hydrazine was dissolved was added thereto, and the resulting solution was reacted for 2 hours under reflux. After the reaction, solvent was removed and 20 ml of ethylacetate was added thereto. The reaction was washed with saturated sodium carbonate and dried over magnesium sulfate. After distillation under reduced pressure, the residue was purified by column chromatography (eluent: ethylacetate/hexane = 1/3) to obtain 800 mg (2.7 mmol) of the title compound in a yield of 96%.

Mass (EI) 301 (M++1) (3) Preparation of [1- (1-phenyl)-5-propyl-lH-pyrrazole-4-yl]-methanol 860 mg (2.9 mmol) of the compound obtained in Procedure (2) was dissolved in 10 ml of anhydrous tetrahydrofuran, then 217 mg (5.4 mmol) of lithium aluminum hydride was slowly added at room temperature. The resulting solution was reacted for 2 hours under reflux. The temperature of the reaction was cooled to 0°C, and 0.5 ml of water, 0.5 ml of 15% sodium hydroxide solution and 1.5 ml of water were slowly added thereto. The reaction was filtered off in the presence of cellite to remove solvent and

then purified by column chromatography (eluent: ethylacetate/dichloromethane = 1/2, 1/1) to obtain 721 mg (2. 8 mmol) of the title compound in a yield of 96%.

Mass (EI) 259 (M++1) NMR : lH-NMR (CDCl3) 6 7.61 (1H, s), 7. 31-7. 26 (4H, m), 4.60 (2H, s), 2. 99-2. 96 (1H, m), 2.69 (2H, t, J=8Hz), 1.62 (1H, brs), 1. 52-1. 45 (2H, m), 1.28 (6H, d, J=8Hz), 0.85 (3H, t, J=8. 0Hz) Preparation Example 5: [1- (4-isopropyl-phenyl)-lH-pyrrazole-4-yl]-methanol (1) 5-amino-l- (4-isopropyl-phenyl)-lH-pyrrazole-4-carboxylic acid 3.2 g (17 mmol) of isobutyl-phenyl hydrazine, 2.37 g (20 mmol) potassium carbonate and 2.9 g (17 mmol) of 2-cyano-3-methoxy-acrylic acid ethylester were dissolved in 32 ml, then the resulting solution was reacted for 24 hours under reflux.

After the reaction, the reaction was put in 350 ml of ice water to produce a solid. After filtering and drying of the solid, 4. 18 g (15 mmol) of the title compound was obtained in a yield of 80%.

Mass (EI) 274 (M++1) NMR : lH-NMR (CDCl3) 6 7.77 (1H, s), 7.44 (2H, d, J=8Hz), 7.36 (2H, d, J=8Hz), 5.26 (2H, brs), 4.30 (2H, q, J=8Hz), 2. 99-2. 95 (1H, m), 1.36 (3H, t, J=8Hz), 1.28 (3H, J=8Hz) (2) Preparation of 1- (4-isopropyl-phenyl)-lH-pyrrazole-4-carboxylic acid ethyl ester 4.18 g (15 mmol) of the compound obtained in Procedure (1) and 4.2 g (36 mmol) of isoamylnitrite were dissolved in tetrahydrofuran, then the resulting solution was reacted for 24 hours under reflux. After the reaction, solvent was removed and the

residue was purified by column chromatography (eluent: ethylacetate/hexane = 1/4) to obtain 3.1 g (12 mmol) of the title compound in a yield of 80%.

Mass (EI) 259 (M++1) NMR : lH-NMR (CDCl3) 6 8.37 (1H, s), 8. 08 (1H, s), 7.62 (2H, d, J=8Hz), 7.33 (2H, d, J=8Hz), 4.35 (2H, q, J=8Hz), 2. 98-2. 93 (1H, m), 1.38 (3H, t, J=8Hz), 1. 28 (3H, d, J=8Hz) (3) Preparation of [1- (4-isopropyl-phenyl)-lH-pyrrazole-4-yl]-methanol 5.97 g (23 mmol) of the compound obtained in Procedure (2) was dissolved in 60 ml of anhydrous tetrahydrofuran, then 1.75 g (46 mmol) of lithium aluminum hydride was slowly added thereto at room temperature. The resulting solution was reacted for 24 hours under reflux. The temperature of the reaction was cooled to 0°C, and 0.8 ml of water, 0. 8 ml of 15% sodium hydroxide solution and 2.4 ml of water were slowly added thereto. The reaction was filtered off in the presence of cellite to remove solvent and then purified by column chromatography (eluent: ethylacetate/dichloromethane = 1/1) to obtain 3.63 g (17 mmol) of the title compound in a yield of 73%.

Mass (EI) 317 (M++1) NMR : lH-NMR (CDCl3) 6 7.92 (1H, s), 7.72 (1H, s), 7. 62-7. 58 (2H, m), 7. 35-7. 30 (2H, m), 4.70 (2H, s), 3. 01-2. 95 (1H, m), 1.92 (1H, brs), 1.30 (6H, d, J=9.2Hz) Preparation Example 6 : [1- (4-chloro-phenyl)-1H-pyrrazole-4-yl]-methanol (1) Preparation of 5-amino-l- (4-chloro-phenyl)-lH-pyrazole-4-carboxylic acid ethyl ester 5 g (28 mmol) of chloro-phenyl hydrazine, 3.86 g (28 mmol) of potassium carbonate and 4.7 g (28 mmol) of 2-cyano-3-methoxy-acrylic acid ethyl ester were

added to 100 ml, then the resulting solution was reacted for 24 hours under reflux. After the reaction, 150 ml of ethylacetate was added thereto and the resulting solution was washed twice with 100 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate to remove solvent, whereby 6.88 g (26 mmol) of the title compound was obtained in a yield of 92%.

Mass (EI) 266 (M++1) NMR : lH-NMR (CDCl3) 6 7.78 (1H, s), 7. 52-7. 47 (4H, m), 5.28 (2H, brs), 4.31 (2H, q, J=8Hz), 1.37 (3H, t, J=8Hz) (2) Preparation of 1-(4-isopropyl-phenyl)-lH-pyrrazole-4-carboxylic acid ethyl ester 5.13 g (19 mmol) of the compound obtained in Procedure (1) and 4.5 g (38 mmol) of isoamylnitrite were dissolved in tetrahydrofuran, then the resulting solution was reacted for 24 hours. After the reaction, solvent was removed and 50 ml of ethanol was added thereto. The temperature was raised to melt the reaction product, and then the resulting solution was cooled to conduct recrystallization. The extracted crystal was filtered off to obtain 3.64 g (14 mmol) of the title compound in yield of 76%.

Mass (EI) 252 (M++1) NMR : lH-NMR (CDCl3) 6 8.37 (1H, s), 8.09 (1H, s), 7. 68-7. 64 (2H, m), 7. 47-7. 26 (2H, m), 4.34 (2H, q, J=8Hz), 1.38 (3H, t, J=8Hz) (3) Preparation of [1- (4-isopropyl-phenyl)-lH-pyrrazole-4- yl]-methanol 3.14 g (12.6 mmol) of the compound obtained in Procedure (2) was dissolved in 50 ml of anhydrous tetrahydrofuran, then 951 g (25 mmol) of lithium aluminum hydride

was slowly added thereto at room temperature. The resulting solution was reacted for 2 hours under reflux. The temperature of the reaction was cooled to 0°C, then 0. 8 ml of water, 0.8 ml of 15% sodium hydroxide solution and 2.4 ml of water were slowly added thereto. The reaction was filtered off in the presence of cellite to remove solvent and then purified by column chromatography (eluent: ethylacetate/dichloromethane = 1/1) to obtain 2.3 g (11 mmol) of the title compound in a yield of 87%.

Mass (EI) 209 (M'+1) NMR :'H-NMR (CDC13) 8 7.94 (1H, s), 7.71 (1H, s), 7. 68-7. 59 (2H, m), 7. 45-7. 40 (2H, m), 4.68 (2H, d, J=8Hz), 1.64 (1H, brs) Preparation Example 7: [1- (4-methyl-phenyl)-lH-pyrrazole-4-yl]-methanol 1.5 g of the title compound was obtained from 5.0 g of methyl-phenyl hydrazine as a start material in the same manner as in Preparation Example 5.

Mass (EI) 189 (M++1) NMR : lH-NMR (CDCl3) 6 7. 89 (1H, s), 7.69 (1H, s), 7. 55-7. 53 (2H, m), 7. 26-7. 23 (2H, m), 4.67 (2H, s), 2.38 (3H, s) Preparation Example 8: [1- (3, 5-ditrifloromethyl-phenyl)-lH-pyrrazole-4-yl]- methanol 500 mg of the title compound was obtained from 5.0 g of 3, 5-ditrifloromethyl- phenyl hydrazine as a start material in the same manner as in Preparation Example 4.

Mass (EI) 311 (M++1) NMR : lH-NMR (CDCl3) 6 8.16 (2H, s), 8.04 (1H, s), 7.78 (1H, s), 7.77 (1H, s), 4.73 (2H, d, J=4Hz), 1.70 (1H, brs)

Preparation Example 9: 2- (5-methyl-1-phenyl-lH-pyrrazole-3-yl)-ethanol (1) Preparation of 5-methyl-1-phenyl-lH-pyrrazole-3-carbaldehyde Dichloromethane solution in which 500 mg (2.65 mmol) of the compound obtained in Preparation Example 1 (3) and 457 mg (4.5 mmol) of triethylamine was dissolved was added at room temperature to 6 ml of dimethylsulfoxide in which 634 mg (4.0 mmol) of pyridinesulfate was dissolved, then the reaction was conducted for 4 hours. After the reaction, 20 ml of ethylacetate was added thereto and the resulting solution was washed with 20 ml of water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate to remove solvent, then the residue was purified by column chromatography (eluent: ethylacetate/hexane = 1/1) to obtain 350 mg (1.94 mmol) of the title compound in a yield of 73%.

Mass (EI) 187 (M++1) NMR : lH-NMR (CDCl3) 610. 00 (1H, s), 8.07 (1H, s), 7. 57-7. 41 (5H, m), 2.61 (3H, s) (2) Preparation of 3-(2-methoxy-vinyl)-5-methyl-1-phenyl-lH-pyrrazole Methoxymethyl triphenylphosphine chloride was dissolved in tetrahydrofuran, then the resulting solution was cooled to 0°C. 16 ml of n-butyl lithium (2. 5M/hexane) was added thereto, then 1.4 ml of hexamethylphosphoamide was further added. To the resulting solution, 3 ml of tetrahydrofuran solution in which 300 mg (1.61 mml) of the compound obtained in Procedure (1) was dissolved was added, and the resulting solution was reacted for 3 hours. After the reaction, 20 ml of ethylacetate was added thereto, and the reaction solution was washed with sodium chloride solution. An organic layer was separated and dried over magnesium sulfate, then the residue was purified by

column chromatography (eluent: ethylacetate/hexane = 1/15) to obtain 180 mg (0.86 mmol) of the title compound in a yield of 53%.

Mass (EI) 215 (M++1) Trans-compound, NMR : lH-NMR (CDCl3) 6 7.59 (1H, s), 7. 55-7. 42 (5H, m), 6.84 (1H, d, J=13Hz), 5.60 (1H, d, J=13Hz), 3.69 (3H, s), 2.30 (3H, s) Cis-compound, NMR : lH-NMR (CDCl3) 6 8.04 (1H, s), 7. 55-7. 42 (5H, m), 6.11 (1H, d, J=7Hz), 5.13 (1H, d, J=7Hz), 3.79 (3H, s), 2.30 (3H, s) (3) Preparation of 2-(5-methyl-1-phenyl-lH-pyrrazole-2-yl)-ethanol 180 mg (0.86 mmol) of the compound obtained in Procedure (2) and 2 ml of 3N hydrochloric acid were added to 5 ml of tetrahydrofuran, and the resulting solution was reacted for 3 hours under reflux. After the reaction, 10 ml of ethylacetate was added thereto and then the reaction solution was washed with water. An organic layer was separated and dried over anhydrous magnesium sulfate to remove solvent. The residue was dissolved in 3 ml of methanol, then 43 mg of sodium borohydride was added thereto, followed by reaction for 1 hour. 10 ml of ethylacetate was added thereto, and an organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered off to remove solvent, then the residue was purified by column chromatography (eluent: ethylacetate/hexane = 1/3) to obtain 110 mg (0.54 mmol) of the title compound in a yield of 63%.

Mass (EI) 203 (M++1)

Preparation Example 10: 2- (4-hydroxy-benzyl)-butyric acid methyl ester (1) Preparation of 2-acetyl-3- (4-hydroxy-phenyl) acrylic acid methyl ester 10.5 g (86 mmol) of hydroxy benzaldehyde, 10 g (86 mmol) of methyl acetoacetate, 120 mg (2 mmol) of acetic acid, and 240 mg (3 mmol) of piperidine were added to 200 ml of benzene, and the resulting solution was reacted for 6 hours under reflux using Dean-stark. The reaction solution was cooled to be crystallized and then filtered to obtain 16 g of the title compound.

Mass (EI) 221 (M++1) NMR : lH-NMR (CDCl3) 7.51 (1H, s), 7. 50-7. 35 (2H, m), 6. 90-6. 84 (2H, m), 3.87 (3H, s), 2.40 (3H, s) (2) Preparation of () 2- (4-hydroxy-benzyl)-3-oxo-butyric acid methyl ester 11 g (46 mmol) of the compound obtained in Procedure (1) was dissolved in 100 ml of methanol/ethylacetate (10/1) solution, then 100 mg of palladium hydroxide/C was added thereto to carry out the reaction for 3 hours in a hydrogen atmosphere. After the reaction, the palladium was removed by filtering and solvent was removed to obtain 11 g (50 mmol) of the title compound.

Mass (EI) 223 (M++1) NMR : lH-NMR (CDCl3) 7. 10-7. 00 (2H, m), 6. 80-6. 7 (2H, m), 4. 95-4. 75 (1H, brs), 3.74 (1H, t, J=8Hz), 3.69 (3H, s), 3.09 (2H, d, J=8Hz), 2.18 (3H, s) Preparation Example 11: () 3-methyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester 440 mg (2 mmol) of the compound obtained in Preparation Example 10 (2), 330 mg (4 mmol) of methoxyamine hydrochloride, and 0.84 ml (6 mmol) of

triethylamine were added to ethanol, then the sulting solution was reacted for 24 hours at room temperature. After the reaction, solvent was removed and then 10 ml of dichloromethane was added thereto. The resulting solution was washed twice with 10 ml of water, and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent. The residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 360 mg of the title compound in a yield of 72%.

Mass (EI) 252 (M++1) NMR : lH-NMR (CDCl3) 6 7. 10-7. 01 (2H, m), 6. 75-6. 67 (2H, m), 4.86 (1H, brs), 3.83 (3H, s), 3.66 (3H, s), 3.54 (1H, t, J=8Hz), 3.16 (1H, did, J=14Hz, 8Hz), 2.91 (1H, dd, J=14Hz, 8H), 1.85 (3H, s) Preparation Example 12: () 3-isopropyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester.

133 mg (0.6 mmol) of the compound obtained in Preparation Example 10 (2), 110 mg (0.9 mmol) of isopropoxyamine hydrochloride, and 0.17 ml (1.2 mmol) of triethylamine were added to 5 ml of ethanol, then the resulting solution was reacted for 24 hours at 45°C. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto. The resulting solution was washed twice with 10 ml of water, and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent. The residue was subjected to prep-TLC (eluent: ethylacetate/hexane = 3/7) to obtain 140 mg (0.48 mmol) of the title compound in a yield of 80%.

Mass (EI) 294 (M++1)

NMR : lH-NMR (CDCl3) 6 7. 10-7. 00 (2H, m), 6. 75-6. 65 (2H, m), 3.80-3. 75 (2H, m), 3.66 (3H, s), 3.53 (1H, t, J=8Hz), 3.15 (1H, dd, J=14Hz, 8Hz), 2.90 (1H, dd, J=14Hz, 8H), 1. 95-1. 85 (1H, m), 1.85 (3H, s), 0. 85 (6H, t, J=lOHz) Preparation Example 13: () 3-benzyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester 480 mg (2.2 mmol) of the compound obtained in Preparation Example 10 (2), 787 mg (3.3 mmol) of benzyloxyamine hydrochloride, and 467 mg (3.3 mmol) of triethylamine were added to 10 ml of ethanol, then the resulting solution was reacted for 24 hours at room temperature. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto. The resulting solution was washed twice with 10 ml of water, and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent. It was subjected to prep-TLC (eluent: ethylacetate/hexane = 3/7) to obtain 480 mg (1.47 mmol) of the title compound in a yield of 67%.

Mass (EI) 328 (M++1) NMR : lH-NMR (CDCl3) 6 7.40-7. 20 (5H, m), 7. 01-6. 98 (2H, m), 6. 70-6. 67 (2H, m), 5.07 (2H, s), 4.73 (1H, s), 3.65 (3H, s), 3.54 (1H, t, J=8Hz), 3.15 (1H, dd, J=14Hz, 8Hz), 2.91 (1H, dd, J=14Hz, 8Hz), 1.88 (3H, s) Preparation Example 14: () 3- [4-fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]- butyric acid methyl ester 222 mg (1.0 mmol) of the compound obtained in Preparation Example 10 (2) and 152 mg (1.1 mmol) of 4-fluorobenzyloxyamine were added to 10 ml of ethanol, then the resulting solution was reacted for 48 hours at room temperature. After the

reaction, solvent was removed and 10 ml of dichloromethane was added thereto. The resulting solution was washed twice with 10 ml of water, and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent.

It was subjected to prep-TLC (eluent: ethylacetate/hexane = 3/7) to obtain 310 mg (0.9 mmol) of the title compound in a yield of 90%.

Mass (EI) 346 (M++1) NMR : lH-NMR (CDCl3) 6 7. 30-7. 20 (2H, m), 7. 05-6. 95 (4H, m), 6.69 (2H, d, J=8.4Hz), 5.02 (2H, s), 4.63 (1H, s), 3.66 (3H, s), 3.53 (1H, t, J=7.6Hz), 3.15 (1H, dd, J=14Hz, 8Hz), 2.91 (1H, dd, J=14Hz, 8Hz), 1.87 (3H, s) Preparation Example 15: () 3- [3-fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]- butyric acid methyl ester 160 mg (0.7 mmol) of the compound obtained in Preparation Example 10 (2) and 100 mg (0.7 mmol) of 3-fluorobenzyloxyamine were added to 5 ml of ethanol, then the resulting solution was reacted for 12 hours under reflux. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto. The resulting solution was washed twice with 10 ml of water and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent. It was subjected to prep- TLC (eluent: ethylacetate/hexane = 3/7) to obtain 160 mg (0.46 mmol) of the title compound in a yield of 66%.

Mass (EI) 346 (M++1) NMR : lH-NMR (CDCl3) 6 7. 35-7. 25 (1H, m), 7. 10-6. 95 (5H, m), 6. 75-6. 65 (2H, m), 5.05 (2H, s), 4.65 (1H, s), 3.66 (3H, s), 3.53 (1H, t, J=8Hz), 3.15 (1H, dd, J=14Hz, 8Hz), 2.91 (1H, dd, J=14Hz, 8Hz), 1.88 (3H, s)

Preparation Example 16: () 3- [2, 4-difluorobenzyloxyimino-2- (4-hydroxy- benzyl) ] -butyric acid methyl ester 890 mg (4.0 mmol) of the compound obtained in Preparation Example 10 (2), 700 mg (4.4 mmol) of 2,4-fluorobenzyloxyamine, and 720 mg (8.8 mmol) of sodium acetate were added to 10 ml of methanol, then the resulting solution was reacted for 48 hours at room temperature. After the reaction, solvent was removed and 20 ml of ethylacetate was added thereto. The resulting solution was washed twice with 10 ml of water, and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent. The residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 1.1 g (3.0 mmol) of the title compound in a yield of 75%.

Mass (EI) 364 (M++1) NMR : lH-NMR (CDCl3) 6 7.23 (1H, dd, J=16Hz, 8Hz, ), 7. 05-6. 95 (2H, m), 6. 89-6. 75 (2H, m), 6. 75-6. 65 (2H, m), 5.07 (2H, s), 4.61 (1H, s), 3.66 (3H, s), 3.51 (1H, t, J=8Hz), 3.14 (1H, dd, J=14Hz, 8Hz), 2.90 (1H, dd, J=14Hz, 8Hz), 1.86 (3H, s) Preparation Example 17: () 3- [4-chlorobenzyloxyimino-2- (4-hydroxy-benzyl)]- butyric acid methyl ester 200 mg (0.9 mmol) of the compound obtained in Preparation Example 10 (2), 140 mg (0.9 mmol) of 4-chlorobenzyloxyamine, and 147 mg (1.8 mmol) of sodium acetate were added to 10 ml of methanol, then the resulting solution was reacted for 24 hours at room temperature. After the reaction, solvent was removed and 20 ml of ethylacetate was added thereto. The resulting solution was washed twice with 10 ml of

water, and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent. It was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 257 mg (0.7 mmol) of the title compound in a yield of 77%.

Mass (EI) 362 (M++1) NMR : lH-NMR (CDCl3) 6 7. 25-7. 15 (2H, m), 7. 10-7. 05 (2H, m), 6. 90-6. 82 (2H, m), 6. 70-6. 60 (2H, m), 4.92 (2H, s), 3. 55 (3H, s), 3.41 (1H, t, J=7.6Hz), 3.02 (1H, dd, J=14Hz, 8Hz), 2.78 (1H, dd, J=14Hz, 8Hz), 1.76 (3H, s) Preparation Example 18: () 3- [4-methylbenzyloxyimino-2- (4-hydroxy-benzyl)]- butyric acid methyl ester 200 mg (0.9 mmol) of the compound obtained in Preparation Example 10 (2), 123 mg (0.9 mmol) of 4-methylbenzyloxyamine, and 147 mg (1.8 mmol) of sodium acetate were added to 10 ml of methanol, then the resulting solution was reacted for 24 hours at room temperature. After the reaction, solvent was removed and 20 ml of ethylacetate was added thereto. The resulting solution was washed twice with 10 ml of water, and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent. It was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 238 mg (0.7 mmol) of the title compound in a yield of 77%.

Mass (EI) 342 (M++1) NMR : lH-NMR (CDCl3) 6 7. 22-7. 12 (4H, m), 7. 05-6. 95 (2H, m), 6. 73-6. 65 (2H, m), 5.04 (2H, s), 4.63 (1H, s), 3.66 (3H, s), 3.54 (1H, t, J=7.6Hz), 3.15 (1H, dd, J=14Hz, 8Hz), 2.92 (1H, dd, J=14Hz, 8Hz), 1.87 (3H, s)

Preparation Example 19: () 3-benzyloxyimino-2- (4-hydroxy-benzyl)-2-methyl- butyric acid methyl ester (1) Preparation of 2- (4-hydroxy-benzyl)-2-methyl-3-oxo-butyric acid methyl ester 440 mg (2 mmol) of the compound obtained in Preparation Example 10 (2) and 550 mg (8 mmol) of potassium carbonate were added to 5 ml of dimethylformamide, then 0.12 ml (2 mmol) of methyl iodide was added thereto, and the resulting solution was reacted for 3 hours. After the reaction, 20 ml of ethylacetate was added thereto, then an organic layer was washed twice with 20 ml of water and 10 ml of saturated sodium chloride, followed by drying over magnesium sulfate and filtering to remove solvent.

The residue was purified by column chromatography (eluent: ethylacetate/hexane = 4/6) to obtain 260 mg of the title compound in a yield of 55%.

Mass (EI) 237 (M++1) NMR : lH-NMR (CDCl3) 7. 00-6. 90 (2H, m), 6. 78-6. 68 (2H, m), 4.97 (1H, s), 3.72 (3H, s), 3.20 (1H, d, J=16Hz), 2. 98 (1H, d, J=16Hz), 2.15 (3H, s), 1. 28 (3H, s) (2) Preparation of () 3-benzyloxyimino-2- (4-hydroxy-benzyl)-2-methyl- butyric acid methyl ester 66 mg (0.28 mmol) of the compound obtained in Procedure (1), 52 mg (0.42 mmol) of benzyloxyamine, and 34 mg (0.42 mmol) of sodium acetate were added to 5 ml of ethanol, and the resulting solution was reacted for 3 hours under reflux. After the reaction, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 60 mg (0.17 mmol) of the title compound

at a yield of 63%.

Mass (EI) 342 (M++1) NMR : lH-NMR (CDCl3) 7. 40-7. 25 (5H, m), 6. 95-6. 88 (2H, m), 6. 70-6. 63 (2H, m), 5.10 (2H, s), 4.59 (1H, s), 3.66 (3H, s), 3.20 (1H, d, J=12Hz), 2.99 (1H, d, J=12Hz), 1. 82 (3H, s), 1.25 (3H, s) Example 1: () 3-benzyloxyimino-2-4- [1- (phenyl)-5-methyl-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester 500 mg (2.6 mmol) of the compound obtained in Preparation Example 1 and 1.5 ml of (10.6 mmol) of triethylamine were dissolved in 10 ml of methylene dichloride, then the resulting solution was cooled to 0°C and 610 mg (5.3 mmol) of methane sulfonylchloride was added thereto. After 3 hours, an organic layer was separated by adding 10 ml of saturated sodium bicarbonate and then dried over sodium sulfate to remove solvent. Among the product thus obtained, 11 mg (0.05 mmol) was taken, and 5 ml of acetonitrile was added thereto, and 24 mg (75 micromol) of cesium carbonates and 17 mg (0.05 mmol) of the compound obtained in Preparation Example 1 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 10 mg (0.02 mmol) of the title compound in a yield of 40%.

Mass (EI) 498 (M++1) NMR : lH-NMR (CDCl3) 6 7.70 (1H, s), 7. 52-7. 40 (5H, m), 7.40-7. 25 (5H, m), 7. 11-7. 07 (2H, m), 6. 90-6. 85 (2H, m), 5.09 (2H, s), 4.91 (2H, s), 3.66 (3H, s), 3.56 (1H, t, J=8Hz), 3.18 (1H, dd, J=16Hz, 8Hz), 2.95 (1H, d, J=16Hz, 8Hz), 2.35 (3H, s), 1. 89

(3H, s) Example 2: () 3-benzyloxyimino-2- {4- [1- (phenyl)-5-methyl-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid 5 mg (0.01 mmol) of the compound obtained in Example 1 was added to a mixture of 0.5 ml of tetrahydrofuran, 0.5 ml of methanol and 0.5 ml of 2N lithium hydroxide, and the resulting solution was reacted for 2 hours at room temperature. After the reaction, 0.5 ml of saturated ammonium chloride and 5 ml of ethylacetate were added thereto. An organic layer was separated and then dried over sodium sulfate, followed by filtering. Solvent was removed to obtain 4.2 mg (93 micromol) of the title compound in a yield of 93% yield.

Mass (EI) 484 (M++1) NMR : lH-NMR (CDCl3) 6 7.71 (1H, s), 7. 52-7. 40 (5H, m), 7.40-7. 25 (5H, m), 7. 14-7. 05 (2H, m), 6. 92-6. 85 (2H, m), 5.09 (2H, s), 4.93 (2H, s), 3. 58 (1H, t, J=8Hz), 3. 18 (1H, dd, J=14Hz, 8Hz), 3.02 (1H, d, J=14Hz, 8Hz), 2.35 (3H, s), 1.90 (3H, s) Example 3: () 3-benzyloxyimino-2- {4- [l- (4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester (1) Preparation of [1-(4-isopropyl-phenyl)-5-methyl-lH-pyrrazole-4-yl]-methyl chloride 400 mg (1.8 mmol) of the compound obtained in Preparation Example 5 (3) and 0.77 ml (5.5 mmol) of triethylamine were dissolved in 10 ml of methylene dichloride, the resulting solution was cooled to 0°C. To the resulting solution, 0.21 ml (2.8 mmol) of methane sulfonylchloride was added. After 3 hours, an organic layer was separated by adding 10 ml of After the resulting solution was reacted for saturated sodium

bicarbonate solution and then dried over sodium sulfate, followed by removal of solvent3 hours, solvent was removed and the residue, whereby 360 mg (1.53 mmol) of the title compound was obtained in a yield of 85%.

Mass (EI) 235 (M++1) (2) Preparation of () 3-benzyloxyimino-2 {4- [l- (4-isobutyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid methyl ester Among the compound obtained in Procedure (1) above, 340 mg (1.4 mmol) was taken, and 10 ml of cesium carbonate was added thereto, then 1.4 g (4.3 mmol) of cesium carbonate and 400 mg (1.2 mmol) of the compound obtained in Preparation Example 13 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 543 mg of the title compound in a yield of 71 %.

Mass (EI) 526 (M++1) NMR : lH-NMR (CDCl3) 6 7.95 (1H, s), 7.76 (1H, s), 7. 62-7. 57 (2H, m), 7.36-7. 25 (7H, m), 7. 12-7. 05 (2H, m), 6. 92-6. 85 (2H, m), 5.09 (2H, s), 5.06 (2H, s), 3.66 (3H, s), 3.56 (1H, t, J=8Hz), 3. 18 (1H, dd, J=14Hz, 8Hz), 3. 00-2. 91 (1H, m), 2.94 (1H, d, J=14Hz, 8Hz), 1.89 (3H, s), 1.28 (6H, d, J=llHz) Example 4: () 3-benzyloxyimino-2- {4- [1- (4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid 70 mg (0.13 mmol) of the compound obtained in Example 3 was added to a mixture of 2.5 ml of tetrahydrofuran, 2.5 ml of methanol and 2.5 ml of 2N lithium

hydroxide, and the resulting solution was reacted for 2 hours at room temperature. After the reaction, 2.5 ml of saturated ammonium chloride and 20 ml of ethylacetate were added thereto. An organic layer was separated and dried over sodium sulfate, followed by filtering. Solvent was removed and the residue was purified by column chromatography to obtain 60 mg (113 micromol) of the title compound in a yield of 87%.

Mass (EI) 522 (M++1) NMR : lH-NMR (CDCl3) 6 7.95 (1H, s), 7.76 (1H, s), 7. 62-7. 57 (2H, m), 7.36-7. 25 (7H, m), 7. 12-7. 05 (2H, m), 6. 92-6. 85 (2H, m), 5.09 (2H, s), 5.00 (2H, s), 3.58 (1H, t, J=8Hz), 3.18 (1H, dd, J=14Hz, 8Hz), 3.02 (1H, d, J=14Hz, 8Hz), 3. 00-2. 91 (1H, m), 1. 88 (3H, s), 1.28 (6H, d, J=llHz) Example 5: () 3-methyloxyimmo-2- {4- [l- (4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester 5 ml of acetonitrile was added to 20 mg (0.08 mmol) of the compound obtained in Example 3 (1), then 33 mg (1.0 mmol) of cesium carbonate and 20 mg (0.08 mmol) of the compound obtained in Preparation Example 11 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 20 mg (0.4 mmol) of the title compound in a yield of 50%.

Mass (EI) 450 (M++1) NMR : lH-NMR (CDCl3) 6 7.94 (1H, s), 7.74 (1H, s), 7.58 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 7.12 (2H, d, J=8Hz), 6.89 (2H, d, J=8Hz), 5.00 (2H, s), 3.82 (3H, s), 3.65 (3H, s) 3.54 (1H, t, J=8Hz), 3.18 (2H, dd, J=12Hz, 8Hz), 3. 00-2. 87 (2H, m), 1.84 (3H, s),

1.27 (6H, d, J=8Hz) Example 6: () 3-methyloxyimino-2- {4- [l- (4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester The title compound was synthesized using 10 mg of the compound obtained in Example 5 in the same manner as in Example 4.

Mass (EI) 426 (M++1) NMR : 1H-NMR(CDCl3) # 7.95 (1H, s), 7.75 (1H, s), 7.58 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 7.12 (2H, d, J=8Hz), 6.90 (2H, d, J=8Hz), 5.01 (2H, s), 3.84 (3H, s), 3.57 (1H, t, J=8Hz), 3.19 (2H, dd, J=14Hz, 8Hz), 3.01 (2H, dd, J=14Hz, 8Hz), 3. 01-2. 90 (1H, m), 1.86 (3H, s), 1.28 (6H, d, J=7Hz) Example 7: () 3-isopropyloxyimino-2- 4- [1- (4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester 5 ml of acetonitrile was added to 20 mg (0.08 mmol) of the compound obtained in Example 3 (1), then 33 mg (1.0 mmol) of cesium carbonate and 25 mg (0.086 mmol) of the compound obtained in Preparation Example 12 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 22 mg (0.046 mmol) of the title compound in a yield of 57%.

Mass (EI) 492 (M++1) NMR : lH-NMR (CDCl3) 6 7.94 (1H, s), 7.74 (1H, s), 7. 60-7. 55 (2H, m), 7. 32-7. 27 (2H, m), 7. 12-7. 07 (2H, m), 6. 90-6. 85 (2H, m), 5.00 (2H, s), 3. 88-3. 75 (2H, m), 3.65 (3H, s) 3.54 (1H, t, J=8Hz), 3.18 (1H, dd, J=12Hz, 8Hz), 3. 00-2. 87 (2H, m), 1. 87-1. 80 (1H,

m), 1.85 (3H, s), 1.27 (6H, d, J=8Hz), 0.85 (6H, d, J=6Hz) Example 8: () 3-isopropyloxyimmo-2- {4- [l- (4-isobutyl-phenyl)-lH-pyrazole-4- ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 8 mg of the compound obtained in Example 7 in the same manner as in Example 4.

Mass (EI) 478 (M++1) NMR : lH-NMR (CDCl3) 6 7.95 (1H, s), 7.76 (1H, s), 7. 62-7. 57 (2H, m), 7. 34-7. 28 (2H, m), 7.12 (2H, d, J=9Hz), 6.90 (2H, d, J=9Hz), 5.00 (2H, s), 3.79 (2H, dd, J=6Hz, 4Hz), 3.58 (1H, t, J=7Hz), 3.19 (2H, dd, J=14Hz, 7Hz), 3.03 (1H, dd, J=14Hz, 7Hz), 3. 00-2. 90 (1H, m), 1. 87-1. 80 (1H, m), 1.87 (3H, s), 1.28 (6H, d, J=7Hz), 0. 87 (6H, dd, J=6Hz, 5Hz) Example 9: (~) 3-(4-fluorobenzyloxyimino)-2-{4-[1-(4-isobutyl-phenyl)-1H- pyrazole-4-ylmethoxy]-benzyl}-butyric acid methyl ester 5 ml of acetonitrile was added to 20 mg (0.08 mmol) of the compound obtained in Example 3 (1), then 33 mg (1.0 mmol) of cesium carbonate and 30 mg (0.09 mmol) of the compound obtained in Preparation Example 14 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 26 mg (0.049 mmol) of the title compound in a yield of 61 %.

Mass (EI) 544 (M++1) NMR : 1H-NMR(CDCl3) # 7.97 (1H, s), 7.77 (1H, s), 7. 61-7. 58 (2H, m), 7.32-7. 30 (2H, m), 7. 21-7. 19 (2H, m), 7. 08-7. 06 (2H, d, 8Hz), 7. 02-6. 98 (2H, m), 6.86 (2H, d, J=8Hz),

5.03 (2H, s), 5.00 (2H, s), 3.67 (3H, s), 3.56 (1H, t, J=8Hz), 3.18 (1H, dd, J=14Hz, 8Hz), 2. 97-2. 91 (2H, m), 1.88 (3H, s), 1.28 (6H, d, J=7Hz) Example 10: () 3-(4-fluorobenzyloxyimino)-2-{4-[1-(4-isobutyl-phenyl)-1H- pyrazzole-4-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 10 mg of the compound obtained in Example 9 in the same manner as in Example 4 Mass (EI) 530 (M++1) NMR : lH-NMR (CDCl3) 6 7.97 (1H, s), 7.77 (1H, s), 7. 61-7. 58 (2H, m), 7.32-7. 30 (2H, m), 7. 23-7. 19 (2H, m), 7. 07-6. 99 (4H, m), 6.86 (2H, d, J=8Hz), 5.03 (2H, s), 5.00 (2H, s), 3.58 (1H, t, J=8Hz), 3. 18 (1H, dd, J=14Hz, 8Hz), 3.01 (1H, dd, J=14Hz, 8Hz), 3. 00-2. 92 (1H, m), 1.89 (3H, s), 1.28 (6H, d, J=7Hz) Example 11: () 3- (3-fluorobenzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid methyl ester 5 ml of acetonitrile was added to 20 mg (0.08 mmol) of the compound obtained in Example 3 (1), then 33 mg (1.0 mmol) of cesium carbonate and 30 mg (0.09 mmol) of the compound obtained in Preparation Example 15 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 26 mg (0.049 mmol) of the title compound in a yield of 61%.

Mass (EI544 (M++1) NMR : lH-NMR (CDCl3) 6 7.96 (1H, s), 7.76 (1H, s), 7.59 (2H, d, J=8Hz), 7.32-7. 29 (3H, m), 7. 11-6. 95 (5H, m), 6. 89-6. 85 (2H, m), 5.07 (2H, s), 5.00 (2H, s), 3.67 (3H, s), 3.56 (1H, t, J=8Hz), 3.18 (1H, dd, J=14Hz, 8Hz), 2. 97-2. 91 (2H, m), 1.90 (3H, s), 1.28

(6H, d, J=7Hz) Example 12: (~) 3-(3-fluorobenzyloxyimino)-2-{4-[1-(4-isobutyl-phenyl)-1H- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 10 mg of the compound obtained in Example 11 in the same manner as in Example 4.

Mass (EI) 530 (M++1) NMR : lH-NMR (CDCl3) 6 7.96 (1H, s), 7.76 (1H, s), 7.59 (2H, d, J=8Hz), 7.32-7. 28 (3H, m), 7. 10-6. 97 (5H, m), 6. 90-6. 86 (2H, m), 5.07 (2H, s), 5.01 (2H, s), 3.59 (1H, t, J=8Hz), 3.19 (1H, dd, J=14Hz, 8Hz), 3. 04-2. 94 (2H, m), 1.90 (3H, s), 1.28 (6H, d, J=7Hz) Example 13: () 3- (4-chlorobenzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid methyl ester 5 ml of acetonitrile was added to 60 mg (0.26 mmol) of the compound obtained in Example 3 (1), then 140 mg (0.42 mmol) of cesium carbonate and 80 mg (0.21 mmol) of the compound obtained in Preparation Example 17 were further added thereto.

After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 40 mg (0.071 mmol) of the title compound in a yield of 27%.

Mass (EI) 547 (M++1) NMR : lH-NMR (CDCl3) 8 7.96 (1H, s), 7.76 (1H, s), 7. 59-7. 57 (2H, m), 7.31-7. 26 (4H, m), 7.15 (2H, d, J=8Hz), 7. 08-7. 04 (2H, m), 6. 86-6. 84 (2H, m), 5.02 (2H, s), 5.00 (2H, s), 3.66 (3H, s), 3.54 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 2. 96-2. 90 (2H, m),

1. 87 (3H, s), 1.27 (6H, d, J=7Hz) Example 14: () 3- (4-chlorobenzyloxyimino)-2- {4- [1- (4-isobutyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 10 mg of the compound obtained in Example 13 in the same manner as in Example 4.

Mass (EI) 533 (M++1) NMR : lH-NMR (CDCl3) 6 7.96 (1H, s), 7.76 (1H, s), 7. 59-7. 57 (2H, m), 7.31-7. 26 (4H, m), 7.15 (2H, d, J=8Hz), 7. 08-7. 03 (2H, m), 6. 88-6. 85 (2H, m), 5.02 (2H, s), 5.00 (2H, s), 3.57 (1H, t, J=7Hz), 3.17 (1H, dd, J=14Hz, 7Hz), 3.00 (1H, dd, J=14Hz, 7Hz), 2. 98-2. 91 (1H, m), 1.88 (3H, s), 1.27 (6H, d, J=7Hz) Example 15: () 3- (4-methyIbenzyIoxyimino)-2- {4- [l- (4-methyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid methyl ester 5 ml of acetonitrile was added to 60 mg (0.26 mmol) of the compound obtained in Example 3 (1), then 140 mg (0.42 mmol) of cesium carbonate and 80 mg (0.21 mmol) of the compound obtained in Preparation Example 18 were further added thereto.

After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 40 mg (0.074 mmol) of the title compound in a yield of 28%.

Mass (EI) 526 (M+1) NMR : 1H-NMR(CDCl3) # 7.94 (1H, s), 7.75 (1H, s), 7. 59-7. 57 (2H, m), 7.31-7. 28 (2H, m), 7. 19-7. 12 (4H, m), 7. 09-7. 06 (2H, m), 6. 87-6. 84 (2H, m), 5.03 (2H, s), 5.00 (2H, s), 3.65 (3H, s), 3.55 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 2. 96-2. 91 (2H, m),

2.34 (3H, s), 1. 87 (3H, s), 1.27 (6H, d, J=7Hz) Example 16: () 3- (4-methylbenzyloxyimino)-2- f 4- 1- (4-methyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 10 mg of the compound obtained in Example 15 in the same manner as in Example 4 Mass (EI) 512 (M++1) NMR : lH-NMR (CDCl3) 6 7.93 (1H, s), 7.75 (1H, s), 7. 59-7. 57 (2H, m), 7.31-7. 28 (2H, m), 7. 18-7. 12 (4H, m), 7. 10-7. 04 (2H, m), 6. 90-6. 84 (2H, m), 5.03 (2H, s), 5.00 (2H, s), 3.56 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 3.01 (1H, dd, J=14Hz, 8Hz), 2. 98-2. 91 (1H, m), 2.34 (3H, s), 1.87 (3H, s), 1.27 (6H, d, J=7Hz) Example 17: () 3-(2,4-difluorobenzyloxyimino)-2-{4-[1-(4-isobutyl-phenyl)-1 H- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid methyl ester 5 ml of acetonitrile was added to 120 mg (0.52 mmol) of the compound obtained in Example 3 (1), then 280 mg (0.84 mmol) of cesium carbonate and 170 mg (0.47 mmol) of the compound obtained in Preparation Example 16 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 200 mg (0.36 mmol) of the title compound in a yield of 69%.

Mass (EI) 562 (M++1) NMR : lH-NMR (CDCl3) 6 7.96 (1H, s), 7.76 (1H, s), 7. 59-7. 57 (2H, m), 7.31-7. 29 (2H, m), 7. 19-7. 13 (1H, m), 7. 07-7. 05 (2H, m), 6. 86-6. 84 (2H, m), 6. 82-6. 76 (2H, m), 5.07

(2H, s), 4.99 (2H, s), 3.66 (3H, s), 3.54 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 2. 96-2. 89 (2H, m), 1.87 (3H, s), 1.27 (6H, d, J=7Hz) Example 18: () 3- (2, 4-difluorobenzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 110 mg of the compound obtained in Example 17 in the same manner as in Example 4.

Mass (EI) 548 (M++1) NMR : lH-NMR (CDCl3) 6 7.96 (1H, s), 7.76 (1H, s), 7. 59-7. 57 (2H, m), 7.31-7. 29 (2H, m), 7. 20-7. 14 (1H, m), 7. 07-7. 05 (2H, m), 6. 87-6. 84 (2H, m), 6. 84-6. 78 (2H, m), 5.07 (2H, s), 4.99 (2H, s), 3.57 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 3.00 (1H, dd, J=14Hz, 8Hz), 2. 98-2. 91 (1H, m), 1.87 (3H, s), 1.27 (6H, d, J=7Hz) Example 19: () 3-benzyloxyimino-2- {4- [l- (4-chIoro-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester 200 mg (0.96 mmol) of the compound obtained in Preparation Example 6 (3) and 0.27 ml (1.9 mmol) of triethylamine were dissolved in 10 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.11 ml (1.4 mmol) of methane sulfonylchloride was added thereto. After 3 hours, an organic layer was separated by adding 10 ml of saturated sodium bicarbonate solution and dried over sodium sulfate to remove solvent. To 20 mg (0.09 mmol) of the product thus obtained, 5 ml of acetonitrile was added, and then 33 mg (0.1 mmol) of cesium carbonate and 30 mg (0.09 mmol) of the compound obtained in Preparation Example 13 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent

was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 35 mg (0.07 mmol) of the title compound in a yield of 77%.

Mass (EI) 519 (M++1) NMR : 1H-NMR(CDCl3) # 7.96 (1H, s), 7.78 (1H, s), 7. 64-7. 62 (2H, m), 7.44-7. 42 (2H, m), 7. 35-7. 27 (5H, m), 7. 10-7. 08 (2H, m), 6. 87-6. 85 (2H, m), 5.09 (2H, s), 5.01 (2H, s), 3.66 (3H, s), 3.56 (1H, t, J=8Hz), 3.18 (1H, dd, J=14Hz, 8Hz), 2.95 (1H, dd, J=14Hz, 8Hz), 1.89 (3H, s) Example 20: () 3-benzyloxyimino-2-4- 1- (4-chloro-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 110 mg of the compound obtained in Example 19 in the same manner as in Example 4.

Mass (EI) 505 (M++1) NMR : lH-NMR (CDCl3) 6 7.95 (1H, s), 7.77 (1H, s), 7. 63-7. 61 (2H, m), 7.43-7. 40 (2H, m), 7. 35-7. 27 (5H, m), 7. 10-7. 04 (2H, m), 6. 8-6. 84 (2H, m), 5.07 (2H, s), 4.99 (2H, s), 3.57 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 3.01 (1H, dd, J=14Hz, 8Hz), 1.88 (3H, s) Example 21: (~) 3-(4-fluorobenzyloxyimino)-2-{4-[1-(4-chloro-phenyl)-1H- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid methyl ester 200 mg (0.96 mmol) of the compound obtained in Preparation Example 6 (3) and 0.27 ml (1.9 mmol) of triethylamine were dissolved in 10 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.11 ml (1.4 mmol) of

methane sulfonylchloride was added thereto. After 3 hours, an organic layer was separated by adding 10 ml of After the resulting solution was reacted for saturated sodium bicarbonate solution and then dried over sodium sulfate, followed by removal of solvent3 hours, solvent was removed and the residue. To 20 mg (0.09 mmol) of the product thus obtained, 5 ml of acetonitrile was added, then 33 mg (0.1 mmol) of cesium carbonate and 29 mg (0.08 mmol) of the compound obtained in Preparation Example 14 were furhter added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 30 mg (0.06 mmol) of the title compound in a yield of 62%.

Mass (EI) 537 (M++1) NMR : 1H-NMR(CDCl3) # 7.97 (1H, s), 7.77 (1H, s), 7. 64-7. 61 (2H, m), 7.43-7. 41 (2H, m), 7. 21-7. 18 (2H, m), 7. 07-7. 06 (2H, m), 7. 01-6. 97 (2H, m), 6. 85-6. 83 (2H, m), 5.02 (2H, s), 4.99 (2H, s), 3.66 (3H, s), 3.54 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 2.93 (1H, dd, J=14Hz, 8Hz), 1.87 (3H, s) Example 22: () 3- (4-fIuorobemzyloxyimino)-2- {4- [l- (4-chloro-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 110 mg of the compound obtained in Example 21 in the same manner as in Example 4.

Mass (EI) 223 (M++1) NMR : lH-NMR (CDCl3) 6 7.96 (1H, s), 7.77 (1H, s), 7. 64-7. 61 (2H, m), 7.43-7. 41 (2H, m), 7. 21-7. 18 (2H, m), 7. 07-7. 06 (2H, m), 7. 01-6. 97 (2H, m), 6. 85-6. 83 (2H, m), 5.01 (2H, s), 4.98 (2H, s), 3.56 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 3.00 (1H, dd,

J=14Hz, 8Hz), 1.87 (3H, s) Example 23: () 3-benzyloxyimino-2-f 4- [1- (4-methyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester 45 mg (0.24 mmol) of the compound obtained in Preparation Example 7 and 0.03 ml (0.36 mmol) of triethylamine were dissolved in 10 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.07 ml (0.48 mmol) of mesylchloride was added thereto. After 3 hours, an organic layer was separated by adding 5 ml of After the resulting solution was reacted for saturated sodium bicarbonate solution and then dried over sodium sulfate, followed by removal of solvent3 hours, solvent was removed and the residue. To the product thus obtained, 5 ml of acetonitrile was added, then 96 mg (0.30 mmol) of cesium carbonate and 60 mg (0.22 mmol) of the compound obtained in Preparation Example 13 were added further thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 40 mg (0.08 mmol) of the title compound in a yield of 33%.

Mass (EI) : 498 (M++1) Example 24: () 3-benzyloxyimmo-2- {4- [l- (4-methyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 110 mg of the compound obtained in Example 23 in the same manner as in Example 4.

Mass (EI) 484 (M++1) NMR : lH-NMR (CDCl3) 6 7.95 (1H, s), 7.76 (1H, s), 7. 56-7. 54 (2H, m), 7.36-7. 29 (5H,

m), 7. 27-7. 24 (2H, m), 7. 09-7. 05 (2H, m), 6. 88-6. 86 (2H, m), 5.08 (2H, s), 5.00 (2H, s), 3.58 (1H, t, J=8Hz), 3.18 (1H, dd, J=14Hz, 8Hz), 3.02 (1H, dd, J=14Hz, 8Hz), 2.39 (3H, S), 1. 88 (3H, s) Example 25: () 3- (4-fluorobenzyloxyimino)-2- {4- [l- (4-methyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid 150 mg (0.8 mmol) of the compound obtained in Preparation Example 7 and 0.33 ml (2.4 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.09 ml (1.2 mmol) of methane sulfonylchloride was further added thereto. After 3 hours, an organic layer was separated by adding 5 ml of After the resulting solution was reacted for saturated sodium bicarbonate solution and then dried over sodium sulfate, followed by removal of solvent3 hours, solvent was removed and the residue. To the product thus obtained, 5 ml of acetonitrile was added, then 190 mg (0.60 mmol) of cesium carbonate and 122 mg (0.44 mmol) of the compound obtained in Preparation Example 14 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 160 mg (0.32 mmol) of the title compound in a yield of 40%.

Mass (EI) 516 (M++1) NMR : lH-NMR (CDCl3) 6 7.96 (1H, s), 7.76 (1H, s), 7. 57-7. 54 (2H, m), 7.26-7. 23 (2H, m), 7. 22-7. 18 (2H, m), 7. 07-7. 05 (2H, m), 7. 01-6. 97 (2H, m), 6. 86-6. 84 (2H, m), 5.02 (2H, s), 4.99 (2H, s), 3.66 (3H, s), 3.54 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 2.91 (1H, dd, J=14Hz, 8Hz), 2. 38 (3H, s), 1.87 (3H, s)

Example 26: () 3- (4-fluorobenzyloxyimino)-2- {4- [l- (4-methyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 110 mg of the compound obtained in Example 25 in the same manner as in Example 4.

Mass (EI) 512 (M++1) NMR : lH-NMR (CDCl3) â 7.96 (1H, s), 7.76 (1H, s), 7. 56-7. 53 (2H, m), 7.26-7. 23 (2H, m), 7. 22-7. 18 (2H, m), 7. 05-7. 02 (2H, m), 7. 02-6. 98 (2H, m), 6. 86-6. 84 (2H, m), 5.02 (2H, s), 4.99 (2H, s), 3.57 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 3.00 (1H, dd, J=14Hz, 8Hz), 2.38 (3H, s), 1. 88 (3H, s) Example 27: () 3-benzyloxyimino-2-4- [1- (3, 5-ditrifluoromethyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid methyl ester 100 mg (0.32 mmol) of the compound obtained in Preparation Example 8 and 0.09 ml (0.64 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.04 ml (0.48 mmol) of methane sulfonylchloride was added thereto. After 3 hours, an organic layer was separated by adding 5 ml of After the resulting solution was reacted for saturated sodium bicarbonate solution and then dried over sodium sulfate, followed by removal of solvent3 hours, solvent was removed and the residue. To the product thus obtained, 5 ml of acetonitrile was added, then 130 mg (0.40 mmol) of cesium carbonate and 98 mg (0.30 mmol) of the compound obtained in Preparation Example 13 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to

obtain 75 mg (0.12 mmol) of the title compound in a yield of 40%.

Mass (EI) 620 (M++1) NMR : lH-NMR (CDCl3) ã 8.17 (2H, s), 8. 10 (1H, s), 7.83 (1H, s), 7.78 (1H, s), 7. 34-7. 29 (5H, m), 7. 10-7. 08 (2H, m), 6. 87-6. 84 (2H, m), 5.08 (2H, s), 5.02 (2H, s), 3.65 (3H, s), 3.55 (1H, t, J=8Hz), 3.18 (1H, dd, J=14Hz, 8Hz), 2.94 (1H, dd, J=14Hz, 8Hz), 1. 88 (3H, s) Example 28: (~) 3-fluorobenzyloxyimino-2-{4-[1-(3,5-ditrifluoromethy-phenyl) - lH-pyrrazole-4-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 20 mg of the compound obtained in Example 27 in the same manner as in Example 4.

Mass (EI) 606 (M++1) NMR :'H-NMR (CDCl3) 8 8. 18 (2H, s), 8.10 (1H, s), 7.84 (1H, s), 7.79 (1H, s), 7. 36-7. 27 (5H, m), 7. 11-7. 07 (2H, m), 6. 89-6. 86 (2H, m), 5.09 (2H, s), 5.03 (2H, s), 3.58 (1H, t, J=8Hz), 3.19 (1H, dd, J=14Hz, 8Hz), 3.02 (1H, dd, J=14Hz, 8Hz), 1.90 (3H, s) Example 29: () 3- (4-fluoro-benzyloxyimino-2-4- [1- (phenyl)-5-methyl-lH- pyrrazole-3-ylmethoxy]-benzyl}-butyric acid methyl ester 146 mg (0.65 mmol) of the compound obtained in Preparation Example 2 (2) and 0.18 ml (1.3 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.08 ml (0.97 mmol) of methane sulfonylchloride was added thereto. After 3 hours, an organic layer was separated by adding 5 ml of After the resulting solution was reacted for saturated sodium bicarbonate

solution and then dried over sodium sulfate, followed by removal of solvent3 hours, solvent was removed and the residue. To the product thus obtained, 5 ml of acetonitrile was added, then 470 mg (1.43 mmol) of cesium carbonate and 200 mg (0.57 mmol) of the compound obtained in Preparation Example 14 were added further thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 164 mg (0.30 mmol) of the title compound in a yield of 46%.

Mass (EI) 558 (M++1) NMR : 1H-NMR(CDCl3) # 7.68 (1H, s), 7. 36-7. 30 (4H, m), 7.25-7. 20 (2H, m), 7. 08-7. 06 (2H, m), 7. 02-6. 97 (2H, m), 6. 89-6. 87 (2H, m), 5.03 (2H, s), 4.91 (2H, s), 3.66 (3H, s), 3.55 (1H, t, J=8Hz), 3.18 (1H, dd, J=14Hz, 8Hz), 2. 99-2. 91 (2H, m), 2.34 (3H, s), 1. 88 (3H, s), 1.28 (6H, d, J=7Hz) Example 30: () 3- (4-fluoro-benzyloxyimino)-2-4- [l- (phenyl)-5-methyl-lH- pyrrazole-3-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 50 mg of the compound obtained in Example 29 in the same manner as in Example 4.

Mass (EI) 544 (M++1) NMR : lH-NMR (CDCl3) å 7.68 (1H, s), 7. 36-7. 30 (4H, m), 7.24-7. 20 (2H, m), 7. 07-7. 05 (2H, m), 7. 01-6. 98 (2H, m), 6. 89-6. 87 (2H, m), 5.03 (2H, s), 4.91 (2H, s), 3.57 (1H, t, J=8Hz), 3.18 (1H, dd, J=14Hz, 8Hz), 3. 03-2. 94 (2H, m), 2.34 (3H, s), 1.88 (3H, s), 1.29 (6H, d, J=7Hz) Example 31: () 3- (4-fluorobenzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-5-ethyl-

lH-pyrrazole-3-ylmethoxy]-benzyl}-butyric acid methyl ester 30 mg (0.12 mmol) of the compound obtained in Preparation Example 3 (3) and 0.05 ml (0.35 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.014 ml (0. 18 mmol) of methane sulfonylchloride was added thereto. After 3 hours, an organic layer was separated by adding 5 ml of After the resulting solution was reacted for saturated sodium bicarbonate solution and then dried over sodium sulfate, followed by removal of solvent3 hours, solvent was removed and the residue. To the product thus obtained, 5 ml of acetonitrile was added, then 39 mg (0.18 mmol) of cesium carbonate and 41 mg (0.12 mmol) of the compound obtained in Preparation Example 14 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 33 mg (0.06 mmol) of the title compound in a yield of 40%.

Mass (EI) 572 (M++1) NMR : lH-NMR (CDCl3) 6 7.67 (1H, s), 7. 35-7. 30 (4H, m), 7.24-7. 21 (2H, m), 7. 08-7. 06 (2H, m), 7. 02-6. 98 (2H, m), 6. 89-6. 87 (2H, m), 5.03 (2H, s), 4.92 (2H, s), 3.66 (3H, s), 3.56 (1H, t, J=8Hz), 3.18 (1H, dd, J=14Hz, 8Hz), 2. 99-2. 91 (2H, m), 2.74 (2H, q, J=8Hz), 1. 88 (3H, s), 1.27 (6H, d, J=7Hz), 1.11 (3H, t, J=8Hz) Example 32: () 3- (4-fluorobenzyloxyimino)-2- 4- [1- (4-isobutyl-phenyl)-5-ethyl- lH-pyrrazole-3-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 20 mg of the compound obtained in Example 31 in the same manner as in Example 4.

Mass (EI) 558 (M++1)

NMR : lH-NMR (CDCl3) 6 7.66 (1H, s), 7. 35-7. 30 (4H, m), 7.25-7. 21 (2H, m), 7. 07-7. 05 (2H, m), 7. 03-6. 99 (2H, m), 6. 89-6. 87 (2H, m), 5.03 (2H, s), 4.92 (2H, s), 3.57 (1H, t, J=7Hz), 3.18 (1H, dd, J=14Hz, 7Hz), 3. 03-2. 94 (2H, m), 2.74 (2H, q, J=8Hz), 1.88 (3H, s), 1.29 (6H, d, J=7Hz), 1.11 (3H, t, J=8Hz) Example 33: () 3- (4-fluoro-benzyloxyimino)-2- {4- [l- (4-isobutyl-phenyl)-5-propyl- lH-pyrrazole-3-ylmethoxy]-benzyl}-butyric acid methyl ester 33 mg (0.13 mmol) of the compound obtained in Preparation Example 4 (3) and 0.05 ml (0.35 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.014 ml (0.18 mmol) of methane sulfonylchloride was added thereto. After 3 hours, an organic layer was separated by adding 5 ml of After the resulting solution was reacted for saturated sodium bicarbonate solution and then dried over sodium sulfate, followed by removal of solvent3 hours, solvent was removed and the residue. To the product thus obtained, 5 ml of acetonitrile was added, then 39 mg (0. 18 mmol) of cesium carbonate and 41 mg (0.12 mmol) of the compound obtained in Preparation Example 14 were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 30 mg (0.05 mmol) in a yield of 39%.

Mass (EI) 586 (M++1) NMR : lH-NMR (CDCl3) 6 7.67 (1H, s), 7. 34-7. 30 (4H, m), 7.24-7. 20 (2H, m), 7. 08-7. 06 (2H, m), 7. 02-6. 98 (2H, m), 6. 89-6. 86 (2H, m), 5.03 (2H, s), 4.91 (2H, s), 3.66 (3H, s), 3.56 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 2. 99-2. 91 (2H, m), 2.69 (2H, t, J=8Hz), 1.88 (3H, s), 1. 52-1. 47 (2H, m), 1.29 (6H, m), 0.84 (3H, t, J=7Hz)

Example 34: () 3- (4-fluoro-benzyloxyimino)-2-14- [I- (4-isobutyl-phenyl)-5-propyl- lH-pyrrazole-3-ylmethoxy]-benzyl}-butyric acid The title compound was synthesized using 20 mg of the compound obtained in Example 33 in the same manner as in Example 4.

Mass (EI) 572 (M++1) NMR : lH-NMR (CDCl3) 6 7.67 (1H, s), 7. 34-7. 30 (4H, m), 7.24-7. 21 (2H, m), 7. 09-7. 07 (2H, m), 7. 05-6. 98 (2H, m), 6. 88-6. 86 (2H, m), 5.03 (2H, s), 4.91 (2H, s), 3.57 (1H, t, J=8Hz), 3.18 (1H, dd, J=14Hz, 8Hz), 3. 02-2. 94 (2H, m), 2.69 (2H, t, J=8Hz), 1.88 (3H, s), 1. 52-1. 47 (2H, m), 1.29 (6H, m), 0. 82 (3H, t, J=7Hz) Example 35: () 3-benzyloxyimino-2-4- [1- (phenyl)-5-methyl-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid methyl ester 110 mg (0.54 mmol) of the compound obtained in Preparation Example 9 (3) and 0.15 ml (1.1 mmol) of triethylamine were dissolved in 10 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 50 J. l (0.65 mmol) of methane sulfonylchloride was added thereto. After 3 hours, an organic layer was separated by adding 1 ml of After the resulting solution was reacted for saturated sodium bicarbonate solution and then dried over sodium sulfate, followed by removal of solvent3 hours, solvent was removed and the residue. To the product thus obtained, 5 ml of acetonitrile was added, then 196 mg (0.6 mmol) of cesium carbonate and 196 mg (0.6 mmol) of the compound obtained in Preparation Example 8 (3) were further added thereto. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (eluent:

ethylacetate/hexane = 3/7) to obtain 149 mg (0.03 mmol) in a yield of 55%.

Mass (EI) 512 (M++1) NMR : 1H-NMR(CDCl3) # 7.58 (1H, s), 7. 50-7. 43 (4H, m), 7.40-7. 36 (1H, m), 7. 34-7. 27 (5H, m), 7. 07-7. 05 (2H, m), 6. 80-6. 78 (2H, m), 5.09 (2H, s), 4.10 (2H, t, J=7Hz), 3.56 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 2. 96-2. 90 (3H, m), 2.32 (3H, s), 1.89 (3H, s) Example 36: () 3-benzyloxyimino-2-{4-[1-(phenyl)-5-methyl-1H-pyrrazole-4- ylethoxy]-benzyl}-butyric acid 5 mg (0.01 mmol) of the compound obtained in Example 35 was added to a mixture of 0.5 ml of tetrahydrofuran, 0.5 ml of methanol and 0.5 ml of 2N lithium hydroxide, and the resulting solution was reacted for 2 hours at room temperature. After the reaction, 0.5 ml of saturated ammonium chloride and 5 ml of ethylacetate were added thereto. An organic layer was separated and then dried over sodium sulfate, followed by filtering. Solvent was removed to give 4.0 mg (84 micromol) of the title compound in a yield of 84%.

Mass (EI) 498 (M++1) NMR : lH-NMR (CDCl3) 6 7.58 (1H, s), 7. 50-7. 43 (4H, m), 7.40-7. 36 (1H, m), 7. 34-7. 27 (5H, m), 7. 07-7. 05 (2H, m), 6. 80-6. 78 (2H, m), 5.08 (2H, s), 4.10 (2H, t, J=7Hz), 3.55 (1H, t, J=8Hz), 3.17 (1H, dd, J=14Hz, 8Hz), 3. 01-2. 95 (3H, m), 2.32 (3H, s), 1.89 (3H, s) Example 37: () 3-benzyloxyimino-2-{4-[1-(4-isobutyl-phenyl)-1H-pyrrazole-4- ylmethoxyl-benzyl}-2-methyl-butyric acid methyl ester

24 mg (0.10 mmol) of the compound obtained in Preparation Example 5 (3) was dissolved in 5 ml of acetonitrile, and 40 mg (0.12 mmol) of cesium carbonate and 34 mg (0.10 mmol) of the compound obtained in Preparation Example 19 (2) were added the resulting solution. After the resulting solution was reacted for 3 hours under reflux, solvent was removed and the residue was purified by column chromatography (elute: ethylacetate/hexane = 3/7) to obtain 26 mg (0.05 mmol) of the title compound in a yield of 50%.

Mass (EI) 540 (M++1) NMR : 1H-NMR (CDC13) 8 7.94 (1H, s), 7.75 (1H, s), 7. 59-7. 57 (2H, m), 7.35-7. 26 (7H, m), 6.98 (2H, d, J=8Hz), 6. 83 (2H, d, J=8Hz), 5.10 (2H, s), 4.99 (2H, s), 3.67 (3H, s), 3.22 (1H, d, J=14Hz), 3.01 (1H, d, J=14Hz), 2. 98-2. 91 (1H, m), 1.83 (3H, s), 1.27 (6H, d, J=7Hz), 1.26 (3H, s) Example 38: () 3-benzyloxyimino-2- {4- [1- (4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzy1}-2-methyl-butyric acid The title compound was synthesized using 10 mg of the compound obtained in Example 37 in the same manner as in Example 4.

Mass (EI) 536 (M++1) NMR : lH-NMR (CDCl3) å 7.94 (1H, s), 7.74 (1H, s), 7. 60-7. 58 (2H, m), 7.36-7. 27 (7H, m), 6.97 (2H, d, J=8Hz), 6.83 (2H, d, J=8Hz), 5.06 (2H, s), 5.00 (2H, s), 3.18 (1H, d, J=14Hz), 3.04 (1H, d, J=14Hz), 2. 98-2. 92 (1H, m), 1.95 (3H, s), 1.42 (3H, s), 1. 28 (6H, d, J=7Hz) Example 39: () 2- (benzyloxyimmo-methyl)-3- (4- {2- [l- (4-isopropyI-phenyl)-lH-

pyrrazole-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester (1) Preparation of 2- (4-hydroxy-benzyliden)-malonic acid diethyl ester 12.2 g (100 mmol) of hydroxybenzaldehyde, 16.0 g (100 mmol) of diethylmalonate, 600 mg (10 mmol) of acetic acid, and 1.27g (15 mmol) of pyperidine were added to 200 ml of benzene, and the resulting solution was subjected to reflux reaction for about 8 hours using Dean-stark. After the reaction was cooled, solvent was removed and the residue was recrystallized in diethyl ether to obtain 20 g (75 mmol) of the title compound in a yield of 75%.

Mass (EI) 265 (M++1) (2) Preparation of (f) 2-4- [l- (4-isopropyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyliden}-malonic acid diethyl ester 77 mg (0.36 mmol) of the compound obtained in Example 5 (3) and 110 p1 (0.82 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 38 ul (0.49 mmol) of methane sulfonylchloride was added thereto. After 1 hour, an organic layer was separated by adding 5 ml of saturated sodium bicarbonate solution and then dried over sodium sulfate, followed by removal of solvent. 5 ml of acetonitrile was added to the resulting solution, then 147 mg (0.45 mmol) of cesium carbonate and 88 mg (0.3 mmol) of obtained compound obtained in Procedure (1) above were further added thereto. After the resulting solution was reacted for 3 hours, solvent was removed and the residue was purified by column chromatography (eluent: ethylacetate/hexane = 3/7) to obtain 120 mg (0.23 mmol) of the title compound in a yield of 76%.

Mass (EI) 463 (M++1)

(3) Preparation of 2-f 4- [l- (4-isopropyl-phenyl)-lH-pyrrazol-4-ylmethoxy]- benzyl}-malonic acid diethyl ester 60 mg (0.13 mmol) of the compound obtained in Procedure (2) above was dissolved in 5 ml of ethanol, and 10 mg (0.26 mmol) of sodiumborohydride was added to the resulting solution, then reaction was conducted for 3 hours. After 1 ml of ammonium chloride was added to the reaction, an organic layer was separated by adding 10 ml of ethylacetate and then dried over sodium sulfate. Solvent was removed to obtain 60 mg (0.13 mmol) of the title compound in a yield of 100% yield.

Mass (EI) 465 (M++1) (4) Preparation of () 2- {4- [I- (4-isopropyl-phenyl)-IH-pyrrazol-4-ylmethoxyl- benzyl}-malonic acid monoethyl ester 58 mg (0.12 mmol) of the compound obtained in Procedure (3) above was dissolved in 1 ml of ethanol, and 120 pl (0.12 mmol) of ethanol solution containing 1M potassium hydroxide was added to the resulting solution, then the reation was conducted for 5 hours. After acidification by the use of 1N hydrochloride solution, the product was extracted with 10 ml of ethylacetate, then solvent was removed to obtain 25 mg (0.06 mmol) of the title compound in a yield of 50% yield.

Mass (EI) 437 (M++1) (5) Preparation of () 2-ethylsulfanylcarbonyl-3- {4- [l- (4-isopropyl-phenyl)- lH-pyrrazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester 20 mg (0.05 mmol) of the compound obtained in Procedure (4) above, 4. 5 pl

(0.06 mmol) of thioethanol, and 11 mg (0.05 mmol) of 1,3-dicyclohexylcarbodimide were dissolved in 2 ml of dichloromethane, and 2 mg of dimethyl aminopyridine was added to the resulting solution. After the reaction for 3 hours, 0.5 ml of saturated ammonium chloride and 5 ml of dichloromethane were dropwise added in sequence to separate an organic layer which was then dried over sodium sulfate. The residue was subjected to prep-TLC (eluent: ethylacetate/hexane = 3/7) to obtain 10 mg (0.02 mmol) of the title compound in a yield of 40%.

Mass (EI) 481 (M++1) (6) Preparation of () 2- (benzyloxyimino-methyl)-3- (4- f 2- [1- (4-isopropyl- phenyl)-lH-pyrrazole-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester 8 mg (16 micromol) of the compound obtained in Procedure (5) above was dissolved in 2 ml of acetone, and 40 mg of Pd/C and 16 u, l (100 micromol) of triethylsilyl hydride were added to the resulting solution at 0°C. The solution was heated to room temperature and then the reaction was conducted for 3 hours. After the reaction, Pd/C was removed by filtering and solvent was vaporized, then 1 ml of ethanol and 4 mg (33 micromol) of benzyloxyamine were added thereto, and the resulting solution was reacted for 4 hours. After the reaction, solvent was removed and the residue was subjected to prep-TLC (eluent: ethylacetate/hexane = 3/7) to obtain 3 mg of the title compound.

Mass (EI) 526 (M++1) NMR : lH-NMR (CDCl3) 6 7.95 (1H, s), 7.76 (1H, s), 7. 60-7. 58 (2H, m), 7.49 (1H, d, J=8Hz), 7.37-7. 26 (7H, m), 7. 09-7, 07 (2H, m), 6. 89-6. 87 (2H, m), 5.06 (2H, s), 5.01 (2H, s), 4.12 (2H, q, J=7Hz), 3.52 (1H, q, J=8Hz), 3.10 (1H, dd, J=14Hz, 8Hz),

3. 01-2. 92 (2H, m), 1.28 (6H, d, J=7Hz), 1.20 (3H, t, J=8Hz) Example 40: () 2- (benzyloxyimino-methyl)-3- (4- {2- [1- (4-isopropyl-phenyl)-lH- pyrrazole-4-yl]-ethoxy}-phenyl)-propionic acid 2.5 mg of the title compound was obtained from 3 mg of compound of Example 39 (5) by using lithium hydroxide in the same manner as in Example 19.

Mass (EI) 512 (M++1) NMR : lH-NMR (CDCl3) 6 7.94 (1H, s), 7.76 (1H, s), 7. 59-7. 58 (2H, m), 7.48 (1H, d, J=8Hz), 7.36-7. 27 (7H, m), 7. 11-7, 08 (2H, m), 6. 89-6. 87 (2H, m), 5.07 (2H, s), 5.00 (2H, s), 3.59 (1H, q, J=8Hz), 3.15 (1H, dd, J=14Hz, 8Hz), 3.02 (1H, dd, J=14Hz, 8Hz), 3. 01-2. 92 (1H, m), 1.28 (6H, d, J=7Hz) Preparation Example 20: (3-p-tolyl- [1, 2, 4]-oxadiazole-5-yl)-methanol (1) Preparation of N-hydroxy-4-methyl-benzamidine 4-methyl-benzonitrile (2 g, 17 mmol), hydroxylamine hydrochloride (1.38 g, 20 mmol) and sodium bicarbonate (1.66 g, 20 mmol) were reacted in 30 ml of methanol under reflux for 4 hours. After removing the solvent, 50 ml of ethylacetate was added and the resulting solution was washed three times with 20 ml of water. An organic layer was dried over anhydrous magnesium sulfate and filtered off. Solvent was removed to obtain 1.91 g (12.7 mmolm, yield: 75%) of the title compound.

Mass (EI) 151 (M++1) NMR :'H-NMR (CDC13) 8 7.52 (2H, d, J=8Hz), 7.20 (2H, d, J=8Hz), 4.87 (2H, brs), 2.37 (3H, s)

(2) Preparation of 3-p-tolyl-5-trityloxymethyl- [1, 2,4] oxadiazole Trityl oxyacetic acid (222 mg, 0.7 mmol) and 1,1-carbonyldiimidazole (113 mg, 0.7 mmol) were dissolved in 3 ml of dimethylformamide at room temperature, and the resulting solution was reacted for about 1 hour. Hereto, the compound (100 mg, 0.7 mmol) obtained in Procedure (1) above was added and then heated to 80°C, followed by reaction for about 3 hours. 15 ml of ethylacetate and 5 ml of water were added to the resulting solution, then a water layer was removed. The filtered solution was washed twice with 10 ml of water, and an organic layer was dried over anhydrous magnesium sulfate and filtered off. Solvent was removed to obtain 307 mg (71 mmol, yield: 100%) of the title compound.

Mass (EI) 433 (M++1) NMR : 1H-NMR (CDCl3) 6 7.94 (2H, d, J=8Hz), 7. 54-7. 00 (17H, m), 4.46 (2H, s), 2.41 (3H, s) (3) Preparation of (3-p-tolyl- [1, 2,4] oxadiazole-5-yl) -methanol The compound (307 mg, 0.7 mmol) obtained in Procedure (2) was dissolved in dichloromethane, then 5 ml of trifluoroacetic acid and 1 ml of triethylsilan were added to the resulting solution, followed by reaction 3 hours at room temperature. After the reaction, solvent was removed under reduced pressure and the residue was purified by column chromatography using a 1: 3 (v/v) mixture of ethylacetate and hexane to obtain 92 mg (0.48 mmol, yield: 69%) of the title compound.

Mass (EI) 190 (M++1) NMR : lH-NMR (CDCl3) 7. 97-7. 95 (2H, m), 7. 30-7. 25 (2H, m), 4.95 (2H, s), 2.42 (2H, s), 2.42 (3H, s)

Preparation Example 21: [3- (4-ethyl-phenyl)- [1, 2,4] oxadiazole-5-yl]-methanol (1) Preparation of N-hydroxy-4-ethyl-benzamidine 4-ethyl-benzonitrile (2 g, 15 mmol), hydroxylamine hydrochloride (1.16 g, 17 mmol) and sodium bicarbonate (1.40 g, 17 mmol) were reacted in 30 ml of methanol under reflux for 5 hours. After removing the solvent, 50 ml of ethylacetate was added and the resulting solution was washed three times with 20 ml of water. An organic layer was dried over anhydrous magnesium sulfate and filtered off. Solvent was removed to obtain 2.1 g (12. 8 mmol, yield: 85%) of the title compound.

Mass (EI) 165 (M++1) (2) Preparation of [3- (4-ethyl-phenyl)-5- trityloxymethyl- [1, 2,4] oxadiazole Trityloxyacetic acid (4.07 g, 12.8 mmol) and 1, 1'-carbonyldiimidazole (2.07 g, 12.8 mmol) were dissolved in 40 ml of dimethylformamide at room temperature, and the resulting solution was reacted for about 1 hour. To the resulting solution, the compound (2 g, 12.2 mmol) obtained in Procedure (1) above was added and then heated to 80°C, followed by reaction for about 3 hours. Hereto, 150 ml of ethylacetate and 50 ml of water were added, then a water layer was removed. The filtered solution was washed twice with 100 ml of water, and an organic layer was dried over anhydrous magnesium sulfate and filtered off. Solvent was removed to obtain 3.5 g (81 mmol, yield: 63%) of the title compound.

Mass (EI) 433 (M++1) (3) Preparation of [3- (4-ethyl-phenyl)- [1, 2,4] oxadiazole-5-yl]-methanol

The compound (3.5 g, 81 mmol) obtained in Procedure (2) above was dissolved in 50 ml of dichloromethane, then 50 ml of trifluoroacetic acid and 5 ml of triethylsilan were added to the resulting solution, followed by reaction for 3 hours at room temperature. After the reaction, solvent was removed under reduced pressure, and 50 ml of ethylacetate was added thereto, then the pH of the resulting solution was adjusted to 7 using aqueous sodium hydroxide, followed by washing with 10 ml of water. An organic layer was separated and then dried over anhydrous magnesium sulfate, followed by removal of solvent. The filtered solution was purified by column chromatography using a 1: 2 (v/v) mixture of ethylacetate and hexane to obtain 1.63 g (80 mmol, yield: 99%) of the title compound.

Mass (EI) 205 (M++1) NMR : lH-NMR (CDCl3) 6 8.01 (2H, d, J=8Hz), 7.32 (2H, d, J=8Hz), 4.96 (2H, d, J=8Hz), 2. 75-2. 69 (3H, m), 1.28 (3H, t, J=8Hz) Preparation Example 22: [3- (4-isopropyl-phenyl)- [1, 2,4] oxadiazole-5-yl]-methanol (1) Preparation of N-hydroxy-4-isopropyl-benzamidine 2.18 g (12.1 mmol, yield: 89%) of the title compound was synthesized using 4- isopropyl benzonitrile (2 g, 13.7 mmol) in the same manner as in Preparation Example 21 (1).

Mass (EI) 179 (M++1) NMR : lH-NMR (CDCl3) 6 7.55 (2H, d, J=8Hz), 7.26 (2H, dd, J=8Hz, 4Hz), 4.85 (2H, brs), 2. 96-2. 90 (1H, m), 1.26 (6H, d, J=8Hz) (2) Preparation of [3- (4-isopropyl-phenyl)-5-trityloxymethyl- [1, 2,4] oxadiazole

520 mg (1.12 mmol, yield: 72%) of the title compound was synthesized using N-hydroxy-4-isopropyl-benzamidine (275 mg, 1.54 mmol) obtained in Procedure (1) above in the same manner as in Preparation Example 21 (2).

Mass (EI) 461 (M"+1) (3) Preparation of [3- (4-isopropyl-phenyl)- [1, 2, 4] oxadiazole-5-yl]-methanol 128 mg (0.67 mmol, yield: 94%) of the title compound was synthesized using [3-(4-isopropyl-phenyl)-5-trityloxymethyl-[1, 2,4] oxadiazole (330 mg, 0.71 mmol) obtained in Procedure (2) above in the same manner as in Preparation Example 21 (3).

Mass (EI) 219 (M++1) NMR : lH-NMR (CDCl3) 6 7.97 (2H, d, J=8Hz), 7.33 (2H, d, 8Hz), 4.98 (2H, s), 4.80 (1H, brs), 2. 99-2. 94 (1H, m), 1.29 (6H, d, J=8Hz) Preparation Example 23: [3- (4-trifluoromethyl-phenyl)- [1, 2,4] oxadiazole-5-yl]- methanol (1) Preparation of N-hydroxy-4-trifluoromethyl-benzamidine 2.14 g (10.4 mmol, yield: 89%) of the title compound was synthesized using 4- trifluoromethyl benzonitrile (2 g, 11.6 mmol) in the same manner as in Preparation Example 21 (1).

Mass (EI) 205 (M++1) NMR : lH-NMR (CDCl3) 6 7.76 (2H, d, J=8Hz), 7.67 (2H, d, J=8Hz), 4.92 (2H, brs) (2) Preparation of [3- (4-trifluoromethyl-phenyl)-5-trityloxymethyl- [1, 2,4] oxadiazole

730 mg (1.5 mmol, yield: 95%) of the title compound was synthesized using [3- (4-trifluoromethyl-phenyl)- [1, 2,4] oxadiazole-5-yl] -methanol (321 mg, 1.57 mmol) obtained in Procedure (1) above in the same manner as in Preparation Example 21 (2).

Mass (EI) 493 (M++1) (3) Preparation of [3- (4-trifluoromethyl-phenyl)- [1, 2,4] oxadiazole-5-yl]- methanol 314 mg (1. 28 mmol, yield: 85%) of the title compound was synthesized using [3- (4-trifluoromethyl-phenyl)-5-trityloxymethyl- [1, 2,4] oxadiazole (730 mg, 1.5 mmol) obtained in Procedure (2) above in the same manner as in Preparation Example 21 (3).

Mass (EI) 245 (M++1) NMR : lH-NMR (CDCl3) 6 8.21 (2H, d, J=8Hz), 7.76 (2H, d, J=8.4Hz), 4.99 (2H, s), 3.11 (1H, brs) Preparation Example 24: 2- (4-hydroxy-benzyl)-butyric acid methyl ester (1) Preparation of 2- (4-hydroxy-benzyliden)-3-oxo-butanoic acid methyl ester 10.5 g (86 mmol) of hydroxy benzaldehyde, 10 g (86 mmol) of methylacetoacetate, 120 mg (2 mmol) of acetic acid, and 240 mg (3 mmol) of pyperidine were added to 200 ml of benzene, and the resulting solution was reacted for about 6 hours under reflux using Dean-stark. The product was cooled and crystallized, then filtered to obtain 16 g of the title compound.

Mass (EI) 221 (M++1) NMR :'H-NMR (CDC13) 8 7.51 (1H, s), 7. 50-7. 35 (2H, m), 6. 90-6. 84 (2H, m), 3.87 (3H, s), 2.40 (3H, s)

(2) Preparation of () 2- (4-hydroxy-benzyl)-3-oxo-butyric acid methyl ester 11 g (46 mmol) of the compound obtained in Procedure (1) above was dissolved in 100 ml of ethanol/ethylacetate solution (10/1), then 100 mg of palladium hydroxide/C was added thereto, and the resulting solution was reacted for 3 hours in a hydrogen atmosphere. After the reaction, palladium was removed by filtraion, then solvent was removed to obtain 11 g (50 mmol) of the title compound.

Mass (EI) 223 (M++1) NMR : lH-NMR (CDCl3) 8 7. 10-7. 00 (2H, m), 6. 80-6. 7 (2H, m), 4. 95-4. 75 (1H, brs), 3.74 (1H, t, J=8Hz), 3.69 (3H, s), 3.09 (2H, d, J=8Hz), 2.18 (3H, s) Preparation Example 25: () 3-propyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 24 (2) and 176 mg (2.5 mmol) of propyloxyamine hydrochloride were added to 5 ml of methanol, and the resulting solution was reacted at room temperature for 24 hours. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and then dried over magnesium sulfate to obtain 591 mg (2.1 mmol) of the title compound at 96% yield.

Mass (EI) 280 (M++1) NMR : lH-NMR (CDCl3) 6 7. 08-7. 03 (2H, m), 6. 74-6. 71 (2H, m), 4.70 (1H, s), 3. 99-3. 92 (2H, m), 3.64 (3H, s), 3.52 (1H, dd, J=7.6Hz, 8Hz), 3.15 (1H, dd, J=8Hz, 16Hz), 2.90 (1H, m), 1.85 (3H, s), 1. 63-1. 54 (2H, m), 0.87 (3H, t, J=7.6Hz)

Preparation Example 26: () 3-benzyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester 480 mg (2.2 mmol) of the compound obtained in Preparation Example 24 (2), 787 mg (3.3 mmol) of benzyloxyaminehydrochloride and 467 mg (3.3 mmol) of triethylamine were added to 10 ml of ethanol, and the resulting solution was reacted at room temperature for 24 hours. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto, followed by washing twice with 10 ml of water. An organic layer, obtained was separated and dried over magnesium sulfate, then subjected to prep-TLC to obtain 480 mg (1.47 mmol) of the title compound at 67% yield.

Mass (EI) 328 (M++1) NMR : lH-NMR (CDCl3) 8 7.40-7. 20 (5H, m), 7. 10-7. 00 (2H, m), 6. 75-6. 65 (2H, m), 5.07 (2H, s), 4.61 (1H, s), 3.65 (3H, s), 3.53 (1H, t, J=8Hz) Preparation Example 27: () 3- [4-fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]- butyric acid methyl ester 222 mg (1.0 mmol) of the compound obtained in Preparation Example 25 (2) and 152 mg (1.1 mmol) of 4-fluorobenzyloxyamine were added to 10 ml of ethanol, and the resulting solution was reacted at room temperature for 24 hours. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over magnesium sulfate, then subjected to prep-TLC (ethylacetate/hexane = 3/7) to obtain 310 mg (0.9 mmol) of the title compound at 90% yield.

Mass (EI) 346 (M++1) NMR : lH-NMR (CDCl3) 6 7. 30-7. 20 (2H, m), 6. 95-7. 05 (4H, m), 6.69 (2H, d,

J=8.4Hz), 5.02 (2H, s), 4.63 (1H, s), 3.66 (3H, s), 3.53 (1H, t, J=7.6Hz), 3.15 (1H, abx, Jab=14Hz, Jax=7. 6Hz), 2.91 (1H, abx, Jab=14Hz, Jax=7. 6Hz), 1. 87 (3H, s) Preparation Example 28: () 2- (4-hydroxy-benzyl)-3-oxo-pentanoic acid methyl ester (1) Preparation of 2- (4-hydroxy-benzyliden)-3-oxo-pentanoic acid methyl ester 8.4 g (35.8 mmol, yield: 87%) of the title compound was obtained using 5 g (41 mmol) of hydroxy benzaldehyde and 5.1 ml (41 mmol) of methylpropyonylacetate in the same manner as in Preparation Example 24 (1).

Mass (EI) 235 (M++1) 'H-NMR (CDCl3) 7.51 (1H, s), 7. 50-7. 35 (2H, m), 6. 90-6. 84 (2H, m), 3. 87 (3H, s), 2.40 (3H, s) (2) Preparation of 2- (4-hydroxy-benzyl)-3-oxo-pentanoic acid methyl ester 2.9 g (12.2 mmol, yield: 92%) of the title compound was obtained using 2- (4- hydroxy-benzyliden)-3-oxo-pentanoic acid methyl ester (3.1 g, 13.2 mmol) in the same manner as in Preparation Example 24 (2).

Mass (EI) 237 (M++1) NMR : lH-NMR (CDCl3) 7. 04-7. 01 (2H, m), 6. 75-6. 71 (2H, m), 4.95 (1H, brs), 3.75 (1H, t, J=7.6Hz), 3. 68 (3H, s), 3.09 (2H, d, J=7.6Hz), 2.52 (1H, dd, J=7.2Hz, 14.4Hz), 2.34 (1H, dd, J=7.2Hz, 14.4Hz), 2.18 (3H, s) Preparation Example 29: () 2- (4-hydroxy-benzyl)-3-methoxyimino-pentanoic acid methyl ester 550 mg (1. 83 mmol, 87% yield, E: Z=1 : 1) of the title compound was obtained

using 0.5 g (2.1 mmol) of 2- (4-hydroxy-benzyl)-3-oxo-pentanoic acid methyl ester obtained in Preparation Example 28 (2) in the same manner as in Preparation Example 25.

Mass (EI) 266 (M++1) 'H-NMR (CDCl3) (E: Z=1: 1) 8 7. 07-7. 04 (4H, m), 6. 74-6. 71 (4H, m), 4.82 (2H, brs), 3.84 (3H, s), 3.81 (3H, s), 3.66 (3H, s), 3.63 (3H, s), 3.49 (1H, dd, J=12. 8Hz, 6. 8Hz), 3.18 (1H, dd, J=7.2Hz, 16.8Hz), 3.14 (1H, dd, J=8.8Hz, 14Hz), 2. 96-2. 91 (2H, m), 2. 37-2. 22 (2H, m), 2. 07-1. 94 (2H, m), 0.99 (6H, t, J=7.2Hz) Preparation Example 30: () 2- (4-hydroxy-benzyl)-3-methoxyimino-2-methyl- butyric acid methyl ester (1) Preparation of () 2- (4-hydroxy-benzyl)-2-methyl-3-oxo-butyric acid methyl ester 500 mg (2.25 mmol) of () 2- (4-hydroxy-benzyl)-3-oxo-butylic acid methyl ester, 0.14 ml (2.25 mmol) of iodomethane, and 620 mg (4.5 mmol) of anhydrous potassium carbonate were stirred in DMF at room temperature for 5 hours. 50 ml of ethylacetate was added and the resulting solution was washed with water. An organic layer was dried over anhydrous magnesium sulfate and then purifed by columchromatography to obtain 270 mg (1.14 mmol) of the title compound in a yield of 50%.

Mass (EI) 237 (M++1) NMR : lH-NMR (CDCl3) 6. 95-6. 93 (2H, m), 6. 73-6. 70 (2H, m), 4.97 (1H, brs), 3.72 (3H, s), 3.20 (1H, d, J=16Hz), 2.98 (1H, d, J=16Hz), 2.15 (3H, s), 1.28 (3H, s) (2) Preparation of () 2- (4-hydroxy-benzyl)-2-methoxyimino-2-methyl-butylic

acid methyl ester 100 mg (0.42 mmol) of the compound obtained in Procedure (1) above and 39 mg (0.46 mmol) of methoxyamine hydrochloride were added to 2 ml of methanol, and the resulting solution was reacted at 70°C for 10 hours. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over magnesium sulfate, then the residue was purified by column chromatography to obtain 120 mg (0.45 mmol) of the title compound in a yield of 97%.

Mass (EI) 266 (M++1) NMR : lH-NMR (CDCl3) 6. 97-6. 94 (2H, m), 6. 73-6. 70 (2H, m), 3. 85 (3H, s), 3.68 (3H, s), 3.23 (1H, d, J=12Hz), 2.97 (1H, d, J=12Hz), 1.78 (3H, s), 1.28 (3H, s) Example 41: () 3-ethoxyimino-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5-ylmethoxy)- benzyl]-butyric acid (1) Preparation of 3-ethoxyimino-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5-ylmethoxy)- benzyl] -butyric acid methyl ester 20 mg (0.10 mmol) of the compound obtained in Preparation Example 20 (3) was dissolved in 1 ml of dichloromethane, and 44 jj. l (0.31 mmol) of triethyl was added thereto. To the reaction solution, 16 u. l (0.20 mmol) of mesylchloride was added and the resulting solution was reacted for about 1 hour. After the reaction, 5 ml of ethylacetate was added and then an organic layer was washed twice with 5 ml of water. The organic layer was dried over anhydrous magnesium sulfate and filtered off to remove solvent.

To the resulting solution, 1 ml of acetenitrile, 51 mg (0.16 mmol) of cesium carbonate and 29 mg (0.10 mmol) of the compound obtained in Preparation Example 25 were added, and the resulting solution was reacted for 3 hours under reflux. After the reaction,

10 ml of ethylacetate was added thereto, and an organic layer was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and filtered off, then the residue was purified by the column chromatography (ethylacetate/hexane = 1/3) to obtain 20 mg (0.044 mmol) of the title compound in a yield of 44%.

Mass (EI) 452 (m++l) NMR : lH-NMR (CDCl3) 6 7.97 (2H, d, J=8.4Hz), 7.28 (2H, d, J=8Hz), 7.12 ( (2H, d, J=8. 8Hz), 6.92 (2H, d, J=8.4Hz), 5.30 (2H, s), 3. 98-3. 93 (2H, m), 3.65 (3H, s), 3.54 (1H, dd, J=8Hz, 7.6Hz), 3.17 (1H, dd, J=8Hz, 14.4Hz), 2.93 (1H, dd, J=7.6Hz, 14Hz), 2.41 (3H, s), 1. 84 (3H, s), 1. 67-1. 51 (2H, m), 0.87 (3H, t, J=7.2Hz) (2) Preparation of () 3-ethoxyimino-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5- ylmethoxy)-benzyl]-butylic acid 20 mg (0.044 mmol) of the compound obtained in Procedure (1) above was dissolved in 2 ml of tetrahydrofuran/water/methanol solution (1/1/1, v/v/v), and 15 mg (0.63 mmol) of lithium hydroxide was added thereto, and the resulting solution was reacted for 3 hours. After the reaction, 1 ml of saturated ammonium chloride and 5 ml of ethylacetate were added to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate and filtered off, and then the solvent was removed. The residue was purified by column chromatography to give 14 mg (0.032 mmol) of the title compound in a yield of 73%.

Mass (EI) 438 (M++1) NMR : lH-NMR (CDCl3) 6 7.98 (2H, d, J=8Hz), 7.28 (2H, d, J=8Hz), 7. 13-7. 07 (2H, m), 6. 89-6. 84 (2H, m), 5.24 (2H, s), 3. 97-3. 90 (2H, m), 3. 55-3. 45 (1H, m), 3. 20-3. 11 (1H, m),

2. 97-2. 85 (1H, m), 2.40 (3H, s), 1.82 (3H, s), 1. 60-1. 45 (2H, m), 0.86 (3H, t, J=7. 3Hz) Example 42: () 3- (4-fluorobenzyloxyimino)-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5- ylmethoxy)-benzyl]-butyric acid (1) Preparation of () 3- (4-fluorobenzyloxyimino)-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5-ylmethoxy)-benzyl]-butyric acid methyl ester 716 mg (3.76 mmol) of the compound obtained in Preparation Example 20 (3) was dissloved in 10 ml of dichloromethane, and 1.04 ml (7.5 mmol) of triethylamine was added thereto. The reaction solution was cooled to 0°C, and 440 ll (5.67 mmol) of mesylchloride was added thereto, followed by reaction for about 1 hour at room temperature. After the reaction, 100 ml of ethylacetate was added thereto, and an organic layer was washed twice with 50 ml of saturated sodium chloride. The organic layer dried over anhydrous magnesium sulfate and filtered off to remove solvent. To the resulting solution, 20 ml of acetenitrile, 1. 68 g (5.1 mmol) of cesium carbonate and 1.07 g (3.1 mmol) of the compound obtained in Preparation Example 27 were added, followed by reaction for 3 hours under reflux. After the reaction, 100 ml of ethylacetate was added thereto, and an organic layer was washed with 50 ml of ammonium chloride.

The organic layer was dried over anhydrous magnesium sulfate and filtered off, and then the residue was purified by column chromatography to give 1.7 g (3.2 mmol) of the title compound in a yield of 87%.

Mass (EI) 518 (M++1) NMR : lH-NMR (CDCl3) 6 7. 98 (2H, d, J=8Hz), 7. 29-7. 20 (4H, m), 7.07 (2H, d, J=8.4Hz), 7.00 (2H, d, J=8.8Hz), 6.89 (2H, d, J=7. 6Hz), 5.29 (2H, s), 5.00 (2H, s), 3.64 (3H, s), 3.52 (1H, dd, J=7.6Hz, 7.6Hz), 3.15 (1H, dd, J=7.6Hz, 14.4Hz), 2.90 (1H, dd, J=8Hz,

14Hz), 2.41 (3H, s), 1.85 (3H, s) (2) Preparation of 3- (4-fluorobenzyloxyimino)-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5-ylmethoxy) -benzyl] -butyric acid 594 mg (1.14 mmol) of the compound obtained in Procedure (1) above was dissolved in 5 ml of tetrahydrofuran/water/methanol solution (1/1/1, v/v/v), and 100 mg (3.4 mmol) of lithium hydroxide was added thereto, and the resulting solution was reacted for 3 hours. After the reaction, 10 ml of saturated ammonium chloride and 50 ml of ethylacetate were added to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate and filtered off, followed by removing the solvent.

The residue was purified by column chromatography to give 500 mg (0.99 mmol) of the title compound in a yield of 87%.

Mass (EI) 504 (M++1) NMR : 1H-NMR (CDC13) 8 7.97 (2H, d, J=8Hz), 7. 29-7. 20 (4H, m), 7.07 (2H, d, J=8. 8Hz), 7.00 (2H, d, J=8.8Hz), 6.89 (2H, d, J=8.4Hz), 5.29 (2H, s), 5.00 (2H, s), 3.55 (1H, dd, J=8. 0Hz, 7.2Hz), 3.15 (1H, dd, J=7.2Hz, 14Hz), 2.97 (1H, dd, J=8Hz, 14Hz), 2.41 (3H, s), 1.86 (3H, s) Example 43: () 3-benzyloxyimino-2- [4-3- (4-ethylphenyl)- [1, 2,4] oxadiazole-5- ylmethoxy-benzyl] -butyric acid (1) Preparation of 3-benzyloxyimino-2- [4-3- (4-ethylphenyl)- [1, 2,4] oxadiazole-5-ylmethoxy-benzyl]-butyric acid methyl ester 100 mg (0.49 mmol) of the compound obtained in Preparation Example 21 (3) was dissloved in 5 ml of dichloromethane, and 210 jjl (1.5 mmol) of triethyl was added

thereto. To the reaction solution, 57 RI (0.73 mmol) of mesylchloride was added thereto, then the resulting solution was reacted for about 1 hour. After the reaction, 10 ml of ethylacetate was added thereto, and an organic layer was washed twice with 5 ml of water. The organic layer was dried over anhydrous magnesium sulfate and filtered off to remove solvent. To resulting solution, 5 ml of acetenitrile, 325 mg (1.0 mmol) of cesium carbonate and 152 mg (0.46 mmol) of the compound obtained in Preparation Example 7 were added, followed by reaction for 3 hours under reflux. After the reaction, 10 ml of ethylacetate was added thereto, and an organic layer was washed with saturated ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate and filtered off, and then the residue was purified by column chromatography to give 182 mg (0.34 mmol) of the title compound in a yield of 70%.

Mass (EI) 532 (M++1) NMR: 1H-NMR (CDCl3) 8 8.00 (2H, d, J=8. 4Hz), 7. 33-7. 26 (6H, m), 7.07 (2H, d, J=8.8Hz), 6.89 (2H, d, J=8.4Hz), 5.29 (2H, s), 5.04 (2H, s), 3.64 (3H, s), 3.52 (1H, dd, J=7.6Hz, 8. 0Hz), 3.16 (1H, dd, J=7.6Hz, 14.4Hz), 2.90 (1H, dd, J=8Hz, 14.4Hz), 2.71 (2H, q, J=7. 6Hz), 1.87 (3H, s), 1.25 (3H, t, J=7.6Hz) (2) Preparation of 3-benzyloxyimino-2- [4- (3- (4-ethylphenyl)- [1, 2,4] oxadiazole-5-ylmethoxy)-benzyl]-butyric acid 10 mg (0.018 mmol) of the compound obtained in Procedure (1) above was dissolved in 2 ml of tetrahydrofuran/water/methanol (1/l/l, v/v/v) solution, and 10 mg (0.34 mmol) of lithium hydroxide was added thereto, and the resulting solution was reacted for 3 hours. After the reaction, 1 ml of saturated ammonium chloride and 5 ml of ethylacetate were added to separate an organic laayer. The organic layer was dried over

anhydrous magnesium sulfate and filtered off, followed by removing the solvent. The residue was purified by column chromatography to give 2.5 mg (0. 005 mmol) of the title compound in a yield of 27%.

Mass (EI) 518 (@+1) NMR : 1H-NMR (CDC13) 8 8.01 (2H, d, J=8. 0Hz), 7. 35-7. 26 (6H, m), 7.06 (2H, d, J=8.8Hz), 6.88 (2H, d, J=8.4Hz), 5.30 (2H, s), 5.06 (2H, s), 3.55 (1H, dd, J=8. 0Hz, 8. 0Hz), 3.16 (1H, dd, J=8. 0Hz, 12Hz), 2.99 (1H, dd, J=8Hz, 12Hz), 2.72 (2H, q, J=8. 0Hz), 1. 87 (3H, s), 1.25 (3H, t, J=7.6Hz) Example 44: 3- (4-fluorobenzyloxyimino-2- [4-3- (4-ethylphenyl)- [1,2, 4] oxadiazole-5-ylmethoxy-benzyl]-butyric acid (1) Preparation of () 3- (4-fluorobenzyloxyimino-2- [4-3- (4-ethylphenyl)- [1, 2,4] oxadiazole-5-ylmethoxy-benzyl]-butyric acid methyl ester 100 mg (0.49 mmol) of the compound obtained in Preparation Example 21 (3) was dissloved in 5 ml of dichloromethane, and 210 ll (1.5 mmol) of triethyl was added thereto. To the reaction solution, 57 1 (0.73 mmol) of mesylchloride was added dropwise thereto, followed by reaction for about 1 hour. After the reaction, 10 ml of ethylacetate was added thereto, and an organic layer was washed twice with 5 ml of water. The organic layer dried over anhydrous magnesium sulfate and filtered off to remove solvent. To resulting solution, 5 ml of acetenitrile, 325 mg (1.0 mmol) of cesium carbonate and 130 mg (0.40 mmol) of the compound obtained in Preparation Example 27 were added, followed by reaction for 3 hours under reflux. After the reaction, 10 ml of ethylacetate was added thereto, and then an organic layer was washed the organic layer with saturated ammonium chloride. The organic layer was dried over anhydrous

magnesium sulfate and filtered off, and then the residue was subjected to prep-TLC chromatography (ethylacetate/hexane = 1/3) to obtain 190 mg (0.36 mmol) of the title compound in a yield of 73%.

Mass (EI) 532 (M++1) NMR : lH-NMR (CDCl3) 6 8. 01 (2H, d, J=8.4Hz), 7.32 (2H, d, J=8Hz), 7. 25-7. 22 (2H, m), 7.08 (2H, d, J=8.8Hz), 7. 02-6. 97 (2H, m), 6.90 (2H, d, J=8.4Hz), 5.30 (2H, s), 4.99 (2H, s), 3.65 (3H, s), 3.53 (1H, dd, J=7.6Hz, 8. 0Hz), 3.16 (1H, dd, J=7.6Hz, 14.4Hz), 2.93 (1H, dd, J=7.6Hz, 14.4Hz), 2.72 (2H, q, J=7.6Hz), 1.86 (3H, s), 1.25 (3H, t, J=7.6Hz) (2) Preparation of () 3- (4-fluorobenzyloxyimino-2- [4-3- (4-ethylphenyl)- [1, 2,4] oxadiazole-5-ylmethoxy-benzyl]-butyric acid 20 mg (0.038 mmol) of the compound obtained in Procedure (1) above was dissolved in 2 ml of tetrahydrofuran/water/methanol (1/1/1, v/v/v) solution, and then 10 mg (0.34 mmol) of lithium hydroxide was added thereto, followed by reaction for 3 hours. After the reaction, 1 ml of saturated ammonium chloride and 5 ml of ethylacetate were added to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate and filtered off, followed by removing the solvent. The residue was purified by column chromatography to give 13 mg (0.025 mmol) of the title compound in a yield of 68%.

Mass (EI) 518 (M++1) NMR : lH-NMR (CDCl3) 6 8.00 (2H, d, J=8.4Hz), 7.30 (2H, d, J=8.4Hz), 7. 26-7. 20 (2H, m), 7.08 (2H, d, J=7.6Hz), 7. 03-6. 93 (2H, m), 6. 89 (2H, d, J=8.8Hz), 5.30 (2H, s), 4.99 (2H, s), 3. 55-3. 52 (1H, m), 3.15 (1H, dd, J=6.8Hz, 14Hz), 2.97 (1H, dd, J=7.6Hz, 14Hz), 2.71 (2H, q, J=7.6Hz), 1.86 (3H, s), 1.25 (3H, t, J=7.6Hz)

Example 45: () 3- (4-fluorobenzyloxyimino)-2- [4- (3- (4-isopropylphenyl)- [1,2, 4] oxadiazole-5-ylmethoxy)-benzyl]-butyric acid 20 mg (0.036 mmol, yield: 26%) of () 3- (4-fluorobenzyloxyimino)-2- [4- (3- tolyl- [1, 2,4] oxadiazole-5-ylmethoxy) -benzyl] -butylic acid methyl ester was synthesized using [3- (4-isopropyl-phenyl)- [1, 2,4] oxadiazole-5-yl] -methanol (30 mg, 0.137 mmol) obtained in Preparation Example 22 (3) and () 3- [4-fluorobenzyloxyimino-2- (4- hydroxy-benzyl) ] -butylic acid methyl ester (52 mg, 0.15 mmol) obtained in Preparation Example 27 in the same manner as in Example 44 (1). From the above compound, 15 mg (0. 0282, yield: 78%) of the title compound was obtained in the same manner as in Example 44 (2).

Mass (EI) 532 (M++1) NMR : lH-NMR (CDCl3) 6 8.00 (2H, d, J=8.4Hz), 7.33 (2H, d, J=8.4Hz), 7. 25-7. 20 (2H, m), 7.07 (2H, d, J=8.4Hz), 7. 02-6. 97 (2H, m), 6. 88 (2H, d, J=8.8Hz), 5.30 (2H, s), 4.99 (2H, s), 3.55 (1H, dd, J=7.6Hz, 7.2Hz)), 3.16 (1H, dd, J=8. 8Hz, 17.6Hz), 3. 00-2. 93 (2H, m), 1.86 (3H, s), 1.27 (6H, d, J=7.2Hz) Example 46: () 3- (4-fluorobenzyloxyimino)-2- [4- (3-4-trifluoromethylphenyl)- [1, 2,4] oxadiazole-5-ylmethoxy]-benzyl]-butyric acid 23 mg (0.04 mmol, yield: 36%) of () 3- (4-fluorobenzyloxyimino)-2- [4- (3- (4- trifluoromethylphenyl)- [1, 2,4] oxadiazole-5-ylmethoxy) -benzyl] -butyric acid methyl ester was synthesized using [3- (4-trifluoromethyl-phenyl)- [1, 2, 4] oxadiazole-5-yl]- methanol (30 mg, 0.122 mmol) obtained in Preparation Example 23 (3) and () 3- [4- fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]-butylic acid methyl ester (38 mg, 0.11

mmol) obtained in Preparation Example 27 in the same manner as in Example 44 (1).

From the above compound, 18 mg (0.032 mmol, yield: 80%) of the title compound was obtained in the same manner as in Example 44 (2).

Mass (EI) 558 (M++1) NMR : lH-NMR (CDCl3) 6 8.22 (2H, d, J=8. 0Hz), 7.75 (2H, d, J=8. 0Hz), 7. 25-7. 20 (2H, m), 7.07 (2H, d, J=8. 4Hz), 7.06 (2H, dd, J=8. 8Hz, 8.8Hz), 6. 89 (2H, d, J=8.4Hz), 5.32 (2H, s), 4.99 (2H, s), 3.55 (1H, dd, J=7.6Hz, 7.6Hz), 3.16 (1H, dd, J=7.2Hz, 14.4Hz), 2.98 (1H, dd, J=8. 0Hz, 14.4Hz), 1.86 (3H, s), 1.25 (3H, t, J=7.6Hz) Example 47: (f) 3-ethoxyimino-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5-ylmethoxy) - benzyl]-pentanoic acid 15 mg (yield: 45%) of 3-ethoxyimino-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5- ylmethoxy) -benzyl] -pentanoic acid methyl ester was synthesized using () 2- (4- hydroxy-benzyl)-3-methoxyimino-pentanoic acid methyl ester (20 mg, 0.096 mmol) obtained in Preparation Example 29 and (3-p-tolyl- [1, 2,4] oxadiazole-5-yl) -methanol (20 mg, 0.077 mmol) obtained in Preparation Example 20 (3) in the same manner as in Example 44 (1). From the above compound (15 mg, 0.034 mmol), 10 mg (yield: 68%) of the title compound was obtained in the same manner as in Example 44 (2).

Mass (EI) 424 (M++1) NMR : lH-NMR (CDCl3) 6 7. 99-7. 95 (2H, m), 7. 31-7. 27 (2H, m), 7. 17-7. 14 (2H, m), 6. 96-6. 92 (2H, m), 5.30 (2H, s), 3. 83 (3H, s), 3.53 (1H, t, J=8Hz), 3. 18-3. 12 (1H, m), 3. 03-2. 95 (1H, m), 2.42 (3H, s), 2. 30-2. 22 (1H, m), 2. 20-2. 15 (1H, m), 0.99 (3H, t, J=8Hz)

Example 48: () 3-ethoxyimino-2-methyl-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5- ylmethoxy) -benzyl] -butyric acid 9 mg (yield: 60%) of () 3-ethoxyimino-2-methyl-2- [4- (3-tolyl- [1, 2,4] oxadiazole-5-ylmethoxy) -benzyl] -butyric acid methyl ester was synthesized using () 2- (4-hydroxy-benzyl)-3-methoxyimino-2-methyl-butylic acid methyl ester (15 mg, 0.057 mmol) obtained in Preparation Example 30 (2) and (3-p-tolyl- [1, 2,4] oxadiazole-5-yl) -methanol (15 mg, 0.072 mmol) obtained in Preparation Example 20 (3) in the same manner as in Example 44 (1). From the above compound (15 mg, 0.034 mmol), 9 mg (yield: 61%) of the title compound was obtained in the same manner as in Example 44 (2).

Mass (EI) 424 (M++1) NMR : lH-NMR (CDCl3) 6 7.97 (2H, d, J=8Hz), 7.29 (2H, d, J=8Hz), 7.07 (2H, d, J=12Hz), 6.92 (2H, d, J=12Hz), 5.30 (2H, s), 3.83 (3H, s), 3.12 (2H, dd, J=16Hz, 24Hz), 2.42 (3H, s), 1.88 (3H, s), 1.37 (3H, s) Preparation Example 31: 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol (1) Preparation of 2-benzoylamino-succinic acid 4-methyl ester 10 g (54 mmol) of 2-amino-succinic acid 4-methyl ester hydrochloride was added to 100 ml of water at 5°C, and 14.4 g (137 mmol) of sodium carbonate was slowly added thereto while stirring. 7.9 g (56 mmol) of benzoyl chloride was added thereto for 15 minutes, while the resulting solution was kept below 5°C. After stirring for 2 hours, 100 ml of water was added thereto and the resulting solution was washed with 40 ml of dichloromethane. An aqueous layer was adjusted to pH 2 using 6N hydrochloride solution and then extracted with 200 ml and 100 ml of ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and filtered off, and then the

residue was purified by column chromatography to give 12.58 g (39 mmol) of the title compound in a yield of 73%.

NMR : lH-NMR (CDCl3) 6 7. 83-7. 81 (2H, m), 7. 46-7. 44 (3H, m), 5. 13-5. 09 (1H, m).

3.72 (3H, s), 3.20 (1H, dd, J=4Hz, 16Hz), 3.02 (1H, dd, J=4Hz, 16Hz) Mass (EI) 252 (M++1) (2) Preparation of 3-benzoylamino-4-oxo-pentanoic acid methyl ester 10.3 g (40.9 mmol) of 2-benzoylamino-succinic acid 4-methyl ester obtained in Procedure (1) above was mixted with 15.5 ml (164 mmol) of acetic anhydride, 501 mg (4.1 mmol) of dimethyl aminopyridine and 0.23 ml (2.09 mmol) of methylmorphorine in toluene while stirring at 60°C for 2 hours. Ethylacetate was added thereto and the resulting solution was washed with water, then an organic layer was dried over anhydrous magnesium sulfate. The residue was purified by column chromatography to give 7.75 g (yield: 75%) of the title compound.

NMR : lH-NMR (CDCl3) 8 7. 84-7. 82 (2H, m), 7. 57-7. 45 (3H, m), 4. 99-4. 96 (1H, m), 3.73 (3H, s), 3.13 (1H, dd, J=4Hz, 16Hz), 2.91 (1H, dd, J=4Hz, 16Hz), 2.31 (3H, s) Mass (EI) 250 (M++1) (3) Preparation of (5-methyl-2-phenyl-oxazole-4-yl) -acetic acid methyl ester 7.75 g (31 mmol) of 3-benzoylamino-4-oxo-pentanoic acid methyl ester obtained in Procedure (2) above was added to 156 ml of toluene, and 39 ml (41 mmol) of phosphorous oxy chloride was added to the resulting solution, followed by stirring at 140°C for 4 hours. The reaction solution was slowly added to ice water and then extracted with ethylacetate. An organic solution was dried over magnesium sulfate, and

then the residue was purified by column chromatography to give 7.15 g (yield: 99%) of the title compound.

NMR : lH-NMR (CDCl3) 6 7. 99-7. 97 (2H, m), 7. 44-7. 40 (3H, m), 3.72 (3H, s), 3.57 (2H, s), 2.36 (3H, s) Mass (EI) 232 (M++1) (4) Preparation of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol 7.15 g (30.9 mmol) of (5-methyl-2-phenyl-oxazole-4-yl) -acetic acid methyl ester obtained in Procedure (3) above was dissolved in tetrahydrofuran, and 2.35 g (61.9 mmol) of lithium aluminum hydride was slowly added to the resulting solution at 0°C, followed by stirring for 10 minutes. The solution was heated to room temperature and then reacted for 2 hours, thereafter it was again cooled to 0°C. Then, 2.35 ml of water, 2.35 ml of 15% sodium hydroxide and 7.05 ml of water were added dropwise in seqeunce. A solid thus obtained was filtered off, and the filtered solution was distilled and then the residue was purified by column chromatography to give 3.28 g of the title compound in a yield of 52%.

NMR : lH-NMR (CDCl3) 8 7. 99-7. 95 (2H, m), 7. 45-7. 40 (3H, m), 3.93 (2H, t, J=4Hz), 3.35 (1H, brs), 2.72 (2H, t, J=4Hz), 2.33 (3H, s), Mass (EI) 204 (M++1) Preparation Example 32: 2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol (1) Preparation of 2- (4-fluoro-benzoylamino)-succinic acid 4-methyl ester 7.8 g (yield: 100%) of the title compound was synthesized using 5 g (27.2 mmol) of 2-amino-succinic acid 4-methyl ester hydrochloride and 4.53 g (28.5 mmol)

of 4-fluorobenzoic chloride in the same manner as in Preparation Example 31 (1).

NMR : lH-NMR (CDCl3) 6 7. 85-7. 81 (2H, m), 7. 15-7. 10 (2H, m), 5. 13-5. 07 (1H, m), 3.72 (3H, s), 3.18 (1H, dd, J=4.4Hz, 17.6Hz), 3.00 (1H, dd, J=4.4Hz, 17.6Hz) Mass (EI) 270 (M++1) (2) Preparation of 3- (4-fluoro-benzoylamino)-4-oxo-pentanoic acid methyl ester 6.3 g (yield: 81%) of the title compound was obtained using 7. 8 g (28. 9 mmol) of 2- (4-fluoro-benzoylamino)-succinic acid 4-methyl ester obtained in Procedure (1) above in the same manner as in Preparation Example 31 (2).

Mass (EI) 268 (M++1) (3) Preparation of [5-methyl-2- (4-fluoro-phenyl)-oxazole-4-yl]-acetic acid methyl ester 4.5 g (yield: 76%) of the title compound was obtained using 6.3 g (23.5 mmol) of 3- (4-fluoro-benzoylamino)-4-oxo-pentanoic acid methyl ester obtained in Procedure (3) above in the same manner as in Preparation Example 31 (3).

Mass (EI) 250 (M++1) (4) Preparation of 2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol 1.87 g (yield: 46%) of the title compound was obtained using 4.5 g (18.0 mmol) of [5-methyl-2- (4-fluoro-phenyl)-oxazole-4-yl]-acetic acid methyl ester obtained in Procedure (3) above in the same manner as in Preparation Example 31 (4).

NMR : lH-NMR (CDCl3) 6 7. 98-7. 94 (2H, m), 7. 14-7. 09 (2H, m), 3. 93-3. 92 (2H, m),

3.23 (1H, brs), 2.72 (2H, t, J=4Hz), 2.33 (3H, d, J=4Hz) Mass (EI) 222 (M++1) Preparation Example 33: 2- [2- (3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol 1.22 g (yield of three steps: 33%) of the title compound was obtained using 3 g (16.3 mmol) of 2-amino-succinic acid 4-methyl ester hydrochloride according to the method of Preparation Examples 31 (1), 32 (2), 33 (3) and 34 (4).

NMR : 1H-NMR (CDCl3) 6 7. 78-7. 75 (1H, m), 7. 68-7. 64 (1H, m), 7. 43-7. 37 (1H, m), 7. 13-7. 08 (1H, m), 3. 94-3. 93 (2H, m), 3.07 (1H, brs), 2.73 (2H, t, J=4Hz), 2.35 (3H, d, J=4Hz) Mass (EI) 222 (M++1) Preparation Example 34: 2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethanol 207 mg (yield of three steps: 18%) of the title compound was obtained using 1 g (5.44 mmol) of 2-amino-succinic acid 4-methyl ester hydrochloride according to the method of Preparation Examples 31 (1), 32 (2), 33 (3) and 34 (4).

NMR : lH-NMR (CDCl3) 6 7. 60-7. 58 (1H, m), 7. 38-7. 37 (1H, m), 7. 10-7. 07 (1H, m), 4. 13-4. 11 (2H, m), 2.94 (1H, brs), 2.71 (2H, t, J=4Hz), 2.32 (3H, s) Mass (EI) 210 (M++1) Preparation Example 35: [5-methyl-2- (4-trifluoromethyl-phenyl)-thiazole-4-yl]- methanol (1) Preparation of 4-trifluoromethyl-thiobenzamide 500 mg (2.92 mmol) of 4-trifluorobenzonitrile was reacted with 702 mg (8.7

mmol) of sodium hydrosulfide at 60°C for 3 hours, and ethanol as a solvent was distilled off. Ethylacetate was added and the resulting solution was washed with water.

An organic layer was dried over anhydrous magnesium sulfate and solvent was distilled off, then the residue was purified by column chromatography to give 517 mg (yield: 95%) of the title compound. Without further purification, the next procedure was conducted.

Mass (EI) 152 (M++1) (2) Preparation of 4-methyl-2- (4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester 571 mg (2.78 mmol) of 4-trifluoromethyl-thiobenzamide obtained in Procedure (1) above and 481 mg (2.92 mmol) of ethyl 2-chloroacetoacetate were added to ethanol as a solvent and heated to 80°C for 19 hours. After the reaction, the solvent was distilled to be removed to obtain 113 mg of the title compound using column chromatography in a yield of 12%.

NMR : lH-NMR (CDCl3) 6 8.08 (2H, d, J=8Hz), 7.71 (2H, d, J=8Hz), 4.35 (2H, q, J=8Hz), 2. 80 (2H, s), 1.40 (3H, t, J=8Hz), Mass (EI) 316 (M++1) (3) Preparation of [5-methyl-2- (4-trifluoromethyl-phenyl)-thiazole-4-yl]- methanol 71 mg (yield: 71%) of the title compound was synthesized using 110 mg (0.348 mmol) of 4-methyl-2- (4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester obtained in Procedure (2) above in the same manner as in Preparation

Example 31 (4).

NMR : lH-NMR (CDC13) 6 7.96 (2H, d, J=8Hz), 7.64 (2H, d, J=8Hz), 4.80 (2H, s), 2.80 (1H, brs), 2.41 (3H, s) Mass (EI) 274 (M++1) Preparation Example 36: 2- (4-hydroxy-benzyl)-butyric acid methyl ester (1) Preparation of 2-acetyl-3- (4-hydroxy-phenyl) acrylic acid methyl ester 10.5 g (86 mmol) of hydroxy benzaldehyde, 10 g (86 mmol) of methyl acetoacetate, 120 mg (2 mmol) of acetic acid and 240 mg (3 mmol) of pyperidine were added to 200 ml of benzene and reacted using Dean-stark for 6 hours under reflux. The resulting solution was cooled to be subjected to crystallization, then filtered to obtain 16 g of the title compound.

NMR : lH-NMR (CDCl3) 6 7.51 (1H, s), 7. 50-7. 35 (2H, m), 6. 90-6. 84 (2H, m), 3.87 (3H, s), 2.40 (3H, s) Mass (EI) 221 (M++1) (2) Preparation of 2- (4-hydroxy-benzyl)-3-oxo-butyric acid methyl ester 11 g (46 mmol) of the compound obtained in Procedure (1) above was dissolved in 100 ml of methanol/ethylacetate (10/1) solution, and 100 mg of palladium hydroxide/C was added, then the resulting solution was reacted for 3 hours in a hydrogen atmospohere. After the reaction, palladium was removed by filtering, and solvent was removed to obtain 11 g (50 mmol) of the title compound.

NMR : lH-NMR (CDCl3) 6 7. 10-7. 00 (2H, m), 6. 80-6. 7 (2H, m), 4. 95-4. 75 (1H, brs), 3.74 (1H, t, J=8Hz), 3.69 (3H, s), 3.09 (2H, d, J=8Hz), 2.18 (3H, s)

Mass (EI) 223 (M++1) Preparation Example 37: (~) 3-methyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester 440 mg (2 mmol) of the compound obtained in Preparation Example 36 (2), 330 mg (4 mmol) of methoxyamine hydrochloride, and 0.84 ml (6 mmol) of triethylamine were added to ethanol, and the resulting solution was reacted for 24 hours at room temperature. After the reaction, solvent was removed, and 10 ml of dichloromethane was added thereto, then the resulting solution was washed twice with 10 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 360 mg of the title compound in a yield of 72%.

NMR : lH-NMR (CDCl3) 6 7. 10-7. 01 (2H, m), 6. 75-6. 67 (2H, m), 4.86 (1H, brs), 3.83 (3H, s), 3.66 (3H, s), 3.54 (1H, t, J=8Hz), 3.16 (1H, dd, J=14Hz, 8Hz), 2.91 (1H, dd, J=14Hz, 8H), 1.85 (3H, s) Mass (EI) 252 (M++1) Preparation Example 38: () 3-ethyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester 1.0 g (4.5 mmol) of the compound obtained in Preparation Example 36 (2), 530 mg (5.4 mmol) of ethoxyamine hydrochloride, and 920 mg (11.2 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed, and 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water. An

organic layer was separated and dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 834 mg of the title compound in a yield of 70%.

NMR : lH-NMR (CDCl3) 6 7. 08-7. 03 (2H, m), 6. 74#6.71 (2H, m), 4.73 (1H, brs), 4.07 (2H, q, J=8Hz), 3.66 (3H, s), 3.53 (1H, t, J=8Hz), 3.16 (1H, dd, J=14Hz, 8Hz), 2.91 (1H, dd, J=14Hz, 8H), 1. 85 (3H, s), 1.18 (3H, t, J=8Hz) Mass (EI) 266 (M++1) Preparation Example 39 : () 3-propyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 276 mg (2.5 mmol) of n-propoxyamine hydrochloride, and 406 mg (4.9 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed, and 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 591 mg (2.1 mmol) of the title compound using in a yield of 96%.

NMR :'H-NMR (CDCl3) 8 7. 08-7. 03 (2H, m), 6. 74-6. 71 (2H, m), 4.70 (1H, s), 4. 00-3. 93 (2H, m), 3.66 (3H, s), 3.53 (1H, t, J=8Hz), 3.14 (1H, dd, J=8Hz, 12Hz), 2. 94-2. 88 (1H, m), 1.85 (3H, s), 1. 64-1. 28 (2H, m), 0.87 (3H, t, J=7.6Hz) Mass (EI) 280 (M++1) Preparation Example 40: () 3-butyloxyimino-2- (4-hydroxy-benzyl)-butyric acid

methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 311 mg (2.5 mmol) of n-butoxyamine hydrochloride and 406 mg (4.9 mmol) of sodium acetate were added to 10 ml of methanol and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed and 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate to give 615 mg (2.1 mmol) of the title compound using column chromatography (ethylacetate/hexane = 3/7) in a yield of 96%.

NMR : lH-NMR (CDCl3) 6 7. 08-7. 03 (2H, m), 6. 74-6. 71 (2H, m), 4.72 (1H, s), 4.01 (2H, t, J=6. 8Hz), 3.66 (3H, s), 3.52 (1H, t, J=8Hz), 3. 18-3. 12 (1H, m), 2.90 (1H, dd, J=7.6Hz, 14Hz), 1.75 (3H, s), 1. 60-1. 51 (2H, m), 1. 39-1. 24 (2H, m), 0.89 (3H, t, J=7.2Hz) Mass (EI) 294 (M++1) Preparation Example 41: () 3- (2-fluoro-ethyloxyimino)-2- (4-hydroxy-benzyl)- butyric acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 286 mg (2.5 mmol) of 2-fluoroethoxyamine hydrochloride, and 406 mg (4.9 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed and 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 628 mg (2.2 mmol) of the title compound in a yield of 99%.

NMR : lH-NMR (CDCl3) 6 7. 08-7. 00 (2H, m), 6. 75-6. 72 (2H, m), 4.61 (1H, brs), 4. 60-4. 47 (2H, m), 4. 29-4. 18 (2H, m), 3.67 (3H, s), 3.51 (1H, t, J=8Hz), 3. 19-3. 13 (1H, m), 2. 93-2. 88 (1H, m), 1.89 (3H, s) Mass (EI) 284 (M++1) Preparation Example 42: () 3- (2-methyl-propyl) oxyimino-2- (4-hydroxy-benzyl)- butyric acid methyl ester 133 mg (0.6 mmol) of the compound obtained in Preparation Example 36 (2), 110 mg (0.9 mmol) of isobutoxyamine hydrochloride, and 0.17 ml (1.2 mmol) of triethylamine were added to 5 ml of ethanol, and the resulting solution was reacted for 24 hours at 45°C. After the reaction, solvent was removed, and 10 ml of dichloromethane was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate. Then, the residue was subjected to prep-TLC (ethylacetate/hexane = 3/7) to obtain 140 mg (0.48 mmol) of the title compound in a yield of 80%.

NMR : lH-NMR (CDCl3) 6 7. 10-7. 00 (2H, m), 6. 75-6. 65 (2H, m), 3.80-3. 75 (2H, m), 3.66 (3H, s), 3.53 (1H, t, J=8Hz), 3.15 (1H, dd, J=14Hz, 8Hz), 2.90 (1H, dd, J=14Hz, 8H), 1. 95-1. 85 (1H, m), 1. 85 (3H, s), 0.85 (6H, t, J=lOHz) Mass (EI) 294 (M++1) Preparation Example 43: () 3-isopropoxyimino-2- (4-hydroxy-benzyl)-butylic acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 276 mg (2.5 mmol) of isopropoxyamine hydrochloride, and 406 mg (4.9 mmol) of

sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed, and 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 447 mg (1.68 mmol) of the title compound in a yield of 76%.

NMR : lH-NMR (CDCl3) 6 7. 08-7. 02 (2H, m), 6. 74-6. 70 (2H, m), 4.70 (1H, s), 4. 30-4. 24 (1H, m), 3.65 (3H, s), 3.53 (1H, t, J=8Hz), 3.15 (1H, dd, J=8Hz, 16Hz), 2.91 (1H, dd, J=8Hz, 12Hz), 1.83 (3H, s), 1.18 (3H, d, J=6. 0Hz), 1.10 (3H, d, J=6. 4Hz) Mass(EI) 266(M++1) Preparation Example 44: (~) 3-cyclopropylmethoxyimino-2-(4-hydroxy-benzyl)- butyric acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 417 mg (3.4 mmol) of cyclopropylmethoxyamine hydrochloride, and 406 mg (4.9 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed and, 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 620 mg (2.1 mmol) of the title compound in a yield of 96%.

NMR : lH-NMR (CDCl3) 6 7. 10-7. 00 (2H, m), 6. 74-6. 71 (2H, m), 4.65 (1H, s), 3. 85-3. 80 (2H, m), 3.65 (3H, s), 3.52 (1H, t, J=8Hz), 3. 18-3. 12 (1H, m), 2. 96-2. 88 (1H, m), 1.87 (3H, s), 1. 15-1. 00 (1H, m), 0. 53-0. 47 (2H, m), 0. 25-0. 22 (2H, m)

Mass (EI) 292 (M++1) Preparation Example 45: () 3-benzyloxyimino-2- (4-hydroxy-benzyl)-butylic acid methyl ester 480 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 787 mg (3.3 mmol) of benzyloxyamine hydrochloride, and 467 mg (3.3 mmol) of triethylamine were added to 10 ml of ethanol, and the resulting solution was reacted for 24 hours at room temperature. After the reaction, solvent was removed, and 10 ml of dichloromethane was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate, then the residue was subjected to prep-TLC (ethylacetate/hexane = 3/7) to obtain 480 mg (1.47 mmol) of the title compound in a yield of 67%.

NMR : lH-NMR (CDCl3) 6 7.40-7. 20 (5H, m), 7. 01-6. 98 (2H, m), 6. 70-6. 67 (2H, m), 5.07 (2H, s), 4.73 (1H, s), 3.65 (3H, s), 3.54 (1H, t, J=8Hz), 3.15 (1H, dd, J=14Hz, 8Hz), 2.91 (1H, dd, J=14Hz, 8Hz), 1.88 (3H, s) Mass (EI) 328 (M++1) Preparation Example 46: () 3- [4-fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]- butyric acid methyl ester 222 mg (1.0 mmol) of the compound obtained in Preparation Example 36 (2) and 152 mg (1.1 mmol) of 4-fluorobenzyloxyamine were added to 10 ml of ethanol, and the resulting solution was reacted for 48 hours at room temperature. After the reaction, the solvent was removed, and 10 ml of dichloromethane was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over

anhydrous magnesium sulfate, then the residue was subjected to prep-TLC (ethylacetate/hexane = 3/7) to obtain 310 mg (0.9 mmol) of the title compound in a yield of 90%.

NMR : lH-NMR (CDCl3) 7. 30-7. 20 (2H, m), 6. 95-7. 05 (4H, m), 6.69 (2H, d, J=8.4Hz), 5.02 (2H, s), 4.63 (1H, s), 3.66 (3H, s), 3.53 (1H, t, J=7.6Hz), 3.15 (1H, abx, Jab=14Hz, Jax=7.6Hz), 2.91 (1H, abx, Jab=14Hz, Jax=7.6Hz), 1. 87 (3H, s) Mass (EI) 346 (M++1) Preparation Example 47: () 3-benzyloxyimino-2- (4-hydroxy-benzyl)-2-methyl- butyric acid methyl ester (1) Preparation of 2- (4-hydroxy-benzyl)-2-methyl-3-oxo-butylic acid methyl ester 440 mg (2.0 mmol) of the compound obtained in Preparation Example 36 (2) and 550 mg (8 mmol) of potassium carbonate were added to 5 ml of dimethylformamide, then 0.12 ml (2 mmol) of methyliodide was added to the resulting solution, followed by reaction for 3 hours. After the reaction, 20 ml of ethylacetate was added thereto, and an organic layer was washed twice with 20 ml of water and then saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Then, the residue was purified by column chromatography (ethylacetate/hexane = 4/6) to obtain 260 mg of the title compound in a yield of 55%.

NMR : lH-NMR (CDCl3) 6 7. 00-6. 90 (2H, m), 6. 78-6. 68 (2H, m), 4.97 (1H, s), 3.72 (3H, s), 3.20 (1H, d, J=16Hz), 2. 98 (1H, d, J=16Hz), 2.15 (3H, s), 1.28 (3H, s) Mass (EI) 237 (M++1)

(2) Preparation of 3-benzyloxyimino-2- (4-hydroxy-benzyl)-2-methyl-butylic acid methyl ester 66 mg (0.28 mmol) of the compound obtained in Procedure (1) above, 52 mg (0.42 mmol) of benzyloxyamine, and 34 mg (0.42 mmol) of sodium acetate were added to 5 ml of ethanol, and the resulting solution was reacted for 5 hours under reflux. After the reaction, solvent was removed and then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 60 mg (0.17 mmol) of the title compound in a yield of 63%.

NMR : lH-NMR (CDCl3) 6 7. 40-7. 25 (5H, m), 6. 95-6. 88 (2H, m), 6. 70-6. 63 (2H, m), 5.10 (2H, s), 4.59 (1H, s), 3.66 (3H, s), 3.20 (1H, d, J=12Hz), 2.99 (1H, d, J=12Hz), 1. 82 (3H, s), 1.25 (3H, s) Mass (EI) 342 (M++1) Preparation Example 48: 3-methoxyimino-2- (4-hydroxy-benzyl)-2-methyl-butyric acid methyl ester 100 mg (0.42 mmol) of the compound obtained in Preparation Example 47 (1), 39 mg (0.47 mmol) of methoxyamine hydrochloride, and 34 mg (0.42 mmol) of sodium acetate were added to 5 ml of methanol, and the resulting solution was reacted for 5 hours under reflux. After the reaction, solvent was removed and then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 100 mg (0.35 mmol) of the title compound in a yield of 83%.

NMR :'H-NMR (CDCl3) 8 6. 97-6. 94 (2H, m), 6. 73-6. 70 (2H, m), 3.85 (3H, s), 3.68 (3H, s), 3.23 (1H, d, J=12Hz), 2.98 (1H, d, J=12Hz), 1.78 (3H, s), 1.24 (3H, s) Mass (EI) 286 (M++1)

Preparation Example 49: 3-ethoxyimino-2- (4-hydroxy-benzyl)-2-methyl-butyric acid methyl ester 80 mg (0.34 mmol) of the compound obtained in Preparation Example 47 (1), 36 mg (0.37 mmol) of methoxyamine hydrochloride, and 34 mg (0.42 mmol) of sodium acetate were added to 5 ml of methanol, and the resulting solution was reacted for 5 hours under reflux. After the reaction, solvent was removed and then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 92 mg (0.33 mmol) of the title compound in a yield of 98%.

NMR : lH-NMR (CDCl3) 6 6. 96-6. 94 (2H, m), 6. 73-6. 70 (2H, m), 4.72 (1H, brs), 4.09 (3H, q, J=8Hz), 3.68 (3H, s), 3.22 (1H, d, J=14Hz), 2.98 (1H, d, J=14Hz), 1.80 (3H, s), 1. 67-1. 62 (2H, m), 1.25 (3H, s), 1.22 (3H, t, J=8Hz) Mass (EI) 280 (M++1) Preparation Example 50: 3-propyloxyimino-2- (4-hydroxy-benzyl)-2-methyl-butylic acid methyl ester 80 mg (0.34 mmol) of the compound obtained in Preparation Example 47 (1), 41 mg (0.37 mmol) of n-propoxyamine hydrochloride, and 34 mg (0.42 mmol) of sodium acetate were added to 5 ml of methanol, and the resulting solution was reacted for 5 hours under reflux. After the reaction, solvent was removed and then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 90 mg (0.33 mmol) of the title compound in a yield of 98%.

NMR : lH-NMR (CDCl3) 6 6. 96-6. 94 (2H, m), 6. 73-6. 69 (2H, m), 4.72 (1H, brs), 4.00 (3H, t, J=8Hz), 3.68 (3H, s), 3.21 (1H, d, J=14Hz), 2. 98 (1H, d, J=14Hz), 1.80 (3H, s),

1. 67-1. 62 (2H, m), 1.25 (3H, s), 0.92 (3H, t, J=8Hz) Mass (EI) 294 (M'+1) Preparation Example 51: () 3-methyloxyimino-2- (4-hydroxy-benzyl)-pentanoic acid methyl ester (1) Preparation of 2- (4-hydroxy-benzyliden)-3-oxo-pentanoic acid methylester 5 g (40 mmol) of hydroxy benzaldehyde, 5.1 g (39 mol) of 3-oxo-pentanoic acid methyl ester, 60 mg (1 mmol) of acetic acid, and 120 mg (1.5 mmol) of piperidine were added to 100 ml of benzene, and the resulting solution was reacted for 6 hours under reflux using Dean-stark. After solvent was removed, the residue was purified by column chromatography (ethylacetate/hexane = 3/1) to obtain 8.4 g (3.6 mmol) of the title compound in a yield of 90%.

NMR : lH-NMR (CDCl3) 6 7.54 (1H, s), 7. 36-7. 33 (2H, m), 6. 85-6. 82 (2H, m), 3.86 (3H, s), 2.74 (2H, q, J=7Hz), 1.16 (3H, t, J=7Hz) Mass (EI) 235 (M++1) (2) Preparation of () 2- (4-hydroxy-benzyl)-3-oxo-pentanoic acid methyl ester 3.1 g (12.5 mmol) of the compound obtained in Procedure (1) was dissolved in 50 ml of methanol, and then 100 mg of palladium hydroxide/C was added thereto, and the resulting solution was reacted for 3 hours in a hydrogen atmosphere. After the reaction, the reaction solution was filtered to remove palladium, thereby 3.0 g (12 mmol) of the title compound was obtained in a yield of 96% yield.

NMR : lH-NMR (CDCl3) 6 7. 04-7. 01 (2H, m), 6. 75-6. 71 (2H, m), 4.89 (1H, brs), 3.75 (1H, t, J=8Hz), 3.68 (3H, s), 3.09 (2H, d, J=8Hz), 2.53 (1H, q, J=7Hz), 2.34 (1H, q,

J=7Hz), 0.99 (3H, t, J=7Hz) Mass (EI) 237 (M++1) (3) Preparation of () 3-methyloxyimino-2- (4-hydroxy-benzyl)-pentanoic acid methyl ester 500 mg (2.1 mmol) of the compound obtained in Procedure (2) above, 190 mg (2.2 mmol) of methoxyamine hydrochloride, and 380 mg (4.6 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed, then 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 550 mg (2.1 mmol) of the title compound in a yield of 100%.

NMR : lH-NMR (CDCl3) 6 7. 07-7. 05 (2H, m), 6. 74-6. 71 (2H, m), 4.84 (1H, brs), 3.83 (3H, s), 3.65 (3H, s), 3.50 (1H, dd, J=9Hz, 7Hz), 3.14 (1H, dd, J=14Hz, 9Hz), 2.94 (1H, dd, J=14Hz, 9Hz), 2. 37-2. 29 (1H, m), 2. 05-1. 95 (1H, m), 0.99 (3H, t, J=7Hz) Mass (EI) 266 (M++1) Preparation Example 52: () 3-ethyloxyimino-2- (4-hydroxy-benzyl)-pentanoic acid methyl ester 300 mg (1.3 mmol) of the compound obtained in Preparation Example 51 (2), 140 mg (1.4 mmol) of ethoxyamine hydrochloride, and 230 mg (2.8 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed, and 10 ml of

ethylacetate was added, followed by washing twice with 10 ml of water. An organic layer was separated and dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 330 mg (1.2 mmol) of the title compound in a yield of 92%.

NMR : lH-NMR (CDCl3) 6 7. 07-7. 05 (2H, m), 6. 75-6. 71 (2H, m), 4. 09-4. 04 (2H, m), 3. 81 (3H, s), 3.66 (3H, s), 3.50 (1H, t, J=7Hz), 3.19 (1H, dd, J=14Hz, 7Hz), 2.95 (1H, dd, J=14Hz, 7Hz), 2. 39-2. 29 (1H, m), 2. 05-1. 95 (1H, m), 1.20 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz) Mass (EI) 280 (M++1) Preparation Example 53: (5-methyl-2-p-toluyl-oxazole-4-yl) -methanol (1) Preparation of 2-hydroxyimino-3-oxo-butylic acid methyl ester A solution in which 5.94 g (86 mmol) of sodium nitrite was dissolved in 14.8 ml of water was slowly added dropwise to a mixed solution of 10 g (86 mmol) of 3-oxo- butylic acid methyl ester and 12.5 ml of acetic acid at 0°C, followed by stirring. After 1 hour, 944.4 ml of water was added thereto and then further stirred for 3 hours. To the resulting solution, 100 ml of ethylether was added and then extraction was conducted twice. An organic layer was separated and washed with sodium bicarbonate, then dried over anhydrous magnesium sulfate. The residue was filtered and distillated to obtain 9.9 g of the title compound in a yield of 79%.

NMR : lH-NMR (CDCl3) 8 3.90 (3H, s), 2.41 (3H, s) Mass (EI) 146 (M++1) (2) Preparation of 5-methyl-3-oxy-2-p-tolyl-oxazole-4-carboxylic acid methyl

ester 3.14 g (21.6 mmol) of 2-hydroxyimino-3-oxo-butyric acid methyl ester obtained in Procedure (1) above and 2.6 g (32.6 mmol) of 4-methylbenzaldehyde were stirred in acetic acid as a solvent at 0°C. Hydrochloride gas was slowly added to the resulting solution for 2 hours, thereby allowing the solution to be saturated with the hydrochloride gas. Hereto, 50 ml of diethylether was added to obtain a solid which was then washed with diethylether to give 4.5 g of the title compound in a yield of 84%.

This compound was used in the following procedure without hesitation and further treatments.

NMR : lH-NMR (CDCl3) 6 8.31 (2H, d, J=8Hz), 7.43 (2H, d, J=8Hz), 4.06 (3H, s), 2. 81 (3H, s), 2.49 (3H, s) Mass (EI) 248 (M++1) (3) Preparation of 5-methyl-2-p-tolyl-oxazole-4-carboxylic acid methyl ester 2.5 g (10.1 mmol) of 5-methyl-3-oxy-2-p-tolyl-oxazole-4-carboxylic acid methyl ester obtained in Procedure (2) above was dissolved in acetic acid, and then 3.34 g (30 mmol) of zinc powder was slowly added to the resulting solution at 0°C. After 2 hours, the zinc powder was removed by filtering, and the residue was washed with water. To the filtered solution, 200 ml of water was added to obtain a solid crystal. This solid obtained by filtering was dried using nitrogen gas to obtain 1.02 g of the title compound in a yield of 40%.

NMR : lH-NMR (CDCl3) 6 7.96 (2H, d, J=8Hz), 7.26 (2H, d, J=8Hz), 3.94 (3H, s), 2.70 (3H, s), 2.09 (3H, s) Mass (EI) 232 (M++1)

(4) Preparation of (5-methyl-2-p-tolyl-oxazole-4-yl)-methanol 800 mg (yield: 63%) of the title compound was synthesized using 1.43 g (6.18 mmol) of 5-methyl-2-p-tolyl-oxazole-4-carboxylic acid methyl ester obtained in Procedure (3) above in the same manner as in Preparation Example 31 (4).

NMR : lH-NMR (CDCl3) 6 7.88 (2H, d, J=8Hz), 7.24 (2H, d, J=8Hz), 4.59 (2H, s), 2.39 (6H, s) Mass (EI) 204 (M++1) Example 49: 3-methoxyimmo-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]- benzyl}-butyric acid methyl ester 150 mg (0.73 mmol) of the compound of 2- (5-methyl-2-phenyl-oxazole-4-yl)- ethanol obtained in Preparation Example 31 and 0.20 ml (1.46 mmol) of triethylamine were dissolved in 5 ml of methylene chloride, and the resulting solution was cooled to 0°C, then 0.084 ml (1.09 mmol) of mesylchloride was further added thereto. After 3 hours, 5 ml of saturated sodium bicarbonate was added to separate an organic layer which was then dried over sodium sulfate. Then, solvent was removed, and 5 ml of acetonitrile was added to the compound thus produced. To the resulting solution, 475 mg (1.46 mmol) of cesium carbonate and 146 mg (0. 58 mmol) of () 3- methyloxyimino-2- (4-hydroxy-benzyl)-butylic acid methyl ester obtained in Preparation Example 37 were added. After the reaction for 3 hours under reflux, solvent was removed, then the residue was purified by column chromatography (ethylacetate/hexane = 3/7) to obtain 120 mg (0.27 mmol) of the title compound in a yield of 40%.

NMR : lH-NMR (CDCl3) 6 7. 98-7. 96 (2H, m), 7. 44-7. 26 (3H, m), 7.07 (2H, d, J=8.4Hz), 6.80 (2H, d, J=8. 0Hz), 4.21 (2H, t, J=5. 1Hz), 3. 81 (3H, s), 3.63 (3H, s), 3.52 (1H, t,

J=7.2Hz), 3.14 (1H, dd, J=8.4Hz, 14Hz), 2.96 (2H, t, J=6.8Hz), 2.89 (1H, dd, J=7.2Hz, 14Hz), 2.36 (3H, s), 1. 84 (3H, s) Mass (EI) 437 (M++1) Example 50: 3-methoxyimino-2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-etho xy]- benzyl}-butylic acid 120 mg (0.27 mmol) of 3-methoxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole- 4-yl)-ethoxy]-benzyl}-butyric acid methyl ester obtained in Example 49 was added to a mixture of 2.5 ml of tetrahydrofuran, 2.5 ml of methanol and 2.5 ml of 2N lithium hydroxide, and the resulting solution was reacted for 2 hours at room temperature. After the reaction, 2.5 ml of saturated ammonium chloride and 20 ml of ethylacetate were added thereto. An organic layer was separated and dried over sodium sulfate, followed by filtering. Then, solvent was removed to give 40 mg of the title compound in a yield of 35%.

NMR : lH-NMR (CDCl3) 6 7. 97-7. 94 (2H, m), 7. 43-7. 40 (3H, m), 7. 10-7. 06 (2H, m), 6.78 (2H, d, J=8. 0Hz), 4. 17-4. 11 (2H, m), 3.79 (3H, s), 3. 52-3. 50 (1H, m), 3.15 (1H, dd, J=8Hz, 12Hz), 2. 96-2. 90 (3H, m), 2.34 (3H, s), 1.82 (3H, s) Mass (EI) 423 (M++1) Example 51: 3-ethoxyimino-2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethox y]- benzyl}-butyric acid 140 mg (yield: 57%) of the title compound was obtained using 114 mg (0.56 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 118 mg (0.44 mmol) of () 3-ethyloxyimino-2- (4-hydroxy-benzyl)-butyric acid

methyl ester obtained in Preparation Example 38 in the same manner as in Examples 49 and 50.

NMR : 1H-NMR(CDCl3) # 7. 98-7. 95 (2H, m), 7. 47-7. 37 (3H, m), 7.14 (2H, d, J=8Hz), 6.81 (2H, d, J=8Hz), 4.19 (2H, t, J=6.4Hz), 4. 1#3. 90 (2H, m), 3. 61-3. 54 (1H, m), 3. 45-3. 40 (1H, m), 3. 08-2. 89 (3H, m), 2.35 (3H, s), 1.83 (3H, s), 1.14 (3H, t, J=6.8Hz) Mass (EI) 437 (M++1) Example 52: 3-propyloxyimino-2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-et hoxy]- benzyl}-butyric acid 6 mg (yield of two steps: 13%) of the title compound was obtained using 20 mg (0.098 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 26 mg (0.097 mmol) of () 3-propyloxyimino-2- (4-hydroxy-benzyl)- butyric acid methyl ester obtained in Preparation Example 39 in the same manner as in Examples 49 and 50.

NMR : lH-NMR (CDCl3) 6 7. 97-7. 95 (2H, m), 7. 44-7. 39 (3H, m), 7. 11-7. 06 (2H, m), 6. 81-6. 78 (2H, m), 4.19 (2H, t, J=8Hz), 3.96 (2H, t, J=8Hz), 3. 56-3. 52 (1H, m), 3. 18-3. 13 (1H, m), 2. 99-2. 94 (3H, m), 2.34 (3H, s), 1.84 (3H, s), 1. 61-1. 52 (2H, m), 0.86 (3H, t, J=8Hz) Mass (EI) 451 (M++1) Example 53: 3-butyloxyimino-2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-eth oxy]- benzyl}-butyric acid 4 mg (yield of two steps: 9%) of the title compound was obtained using 20 mg (0. 098 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation

Example 31 and 27 mg (0. 096 mmol) of () 3-butyloxyimino-2- (4-hydroxy-benzyl)- butyric acid methyl ester obtained in Preparation Example 40 in the same manner as in Examples 49 and 50.

NMR : lH-NMR (CDCl3) 6 7. 97-7. 95 (2H, m), 7. 45-7. 39 (3H, m), 7. 11-7. 05 (2H, m), 6. 81-6. 78 (2H, m), 4.19 (2H, t, J=8Hz), 4.02 (2H, t, J=8Hz), 3.55 (1H, t, J=8Hz), 3. 19-3. 12 (1H, m), 3. 01-2. 92 (3H, m), 2.36 (3H, s), 1.84 (3H, s), 1.34 (2H, t, J=8Hz), 1. 32-1. 24 (2H, m), 0.89 (3H, t, J=8Hz) Mass (EI) 465 (M++1) Example 54: 3-(2-methyl-propyloxyimino)-2-{4-[2-(5-methyl-2-phenyl-oxazo le-4- yl)-ethoxy]-benzyl}-butyric acid 35 mg (yield of two steps: 18%) of the title compound was obtained using 2- (5- methyl-2-phenyl-oxazole-4-yl) -ethanol obtained in Preparation Example 31 (100 mg, 0.49 mmol) and () 3- (2-methyl-propyl) oxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 42 (120 mg, 0.40 mmol) in the same manner as in Examples 49 and 50.

Sodium salt form, NMR : 1H-NMR(CD3OD) # 7. 97-7. 94 (2H, m), 7. 49-7. 44 (3H, m), 7. 08-7. 06 (2H, m), 6. 78-6. 76 (2H, m), 4.19 (2H, t, J=7Hz), 3.66 (1H, dd, J=lOHz, 6Hz), 3.57 (1H, dd, J=lOHz, 6Hz), 3. 33-3. 31 (1H, m), 3.13 (1H, dd, J=lOHz, 6Hz), 2.95 (2H, t, J=7Hz), 2.84 (1H, dd, J=lOHz, 6Hz), 2.37 (3H, s), 1.84 (3H, s), 1. 71-1. 64 (1H, m), 0.74 (6H, t, J=6Hz) Mass (EI) 465 (M++1) Example 55: 3-cyclopropylmethoxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-

ethoxy]-benzyl}-butyric acid 82 mg (yield of two steps: 13%) of the title compound was obtained using 350 mg (1.72 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 380 mg (1.30 mmol) of () 3-cyclopropylmethoxyimino-2- (4- hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 44 in the same manner as in Examples 49 and 50.

Sodium salt form, NMR : 1H-NMR(CD3OD) # 7. 97-7. 94 (2H, m), 7. 49-7. 46 (3H, m), 7. 10-7. 08 (2H, m), 6. 79-6. 77 (2H, m), 4.18 (2H, t, J=7Hz), 3.74 (1H, dd, J=llHz, 7Hz), 3.66 (1H, dd, J=llHz, 7Hz), 3. 33-3. 31 (1H, m), 3.12 (1H, dd, J=lOHz, 6Hz), 2.94 (2H, t, J=7Hz), 2. 86 (1H, dd, J=lOHz, 6Hz), 2.36 (3H, s), 1.85 (3H, s), 0. 96-0. 90 (1H, m), 0. 40-0. 35 (2H, m), 0. 14-0. 10 (2H, m) Mass (EI) 463 (M++1) Example 56: 3-isopropyloxyimino-2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl) - ethoxy]-benzyl}-butyric acid 10 mg (yield of two steps: 22%) of the title compound was obtained using 20 mg (0.098 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 26 mg (0.097 mmol) of () 3-isopropoxyimino-2- (4- hydroxy-benzyl) -butyric acid methyl ester obtained in Preparation Example 43 in the same manner as in Examples 49 and 50.

NMR : lH-NMR (CDCl3) 6 7. 97-7. 95 (2H, m), 7. 43-7. 39 (3H, m), 7. 09-7. 05 (2H, m), 6. 81-6. 78 (2H, m), 4. 29-4. 18 (1H, m), 4.17 (2H, t, J=8Hz), 3.54 (1H, t, J=7. 6Hz), 3.15 (1H, dd, J=7.2Hz, 14Hz), 3. 01-2. 92 (3H, m), 2.35 (3H, s), 1.83 (3H, s), 1.16 (3H, d, J=6Hz), 1. 11 (3H, d, J=6Hz)

Mass (EI) 451 (M++1) Example 57: 3-benzyloxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]- benzyl}-butyric acid 9 mg (yield of two steps: 13%) of the title compound was obtained using 40 mg (0.196 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 45 mg (0.137 mmol) of () 3-benzyloxyimino-2- (4-hydroxy-benzyl)- butyric acid methyl ester obtained in Preparation Example 45 in the same manner as in Examples 49 and 50.

NMR : 1H-NMR(CDCl3) # 7. 98-7. 96 (2H, m), 7. 43-7. 40 (3H, m), 7. 31-7. 26 (5H, m), 7. 02-7. 00 (2H, m), 6. 76-6. 74 (2H, m), 5.07 (2H, s), 4.18 (2H, t, J=7Hz), 3.54 (1H, t, J=7Hz), 3.15 (1H, dd, J=7Hz, 14Hz), 2. 98-2. 93 (3H, m), 2.37 (3H, s), 1.87 (3H, s) Mass (EI) 499 (M++1) Example 58: 3- (4-fluorobenzyloxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)- ethoxy]-benzyl}-butyric acid 6 mg (yield of two steps: 9%) of the title compound was obtained using 30 mg (0.13 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 39 mg (0.11 mmol) of () 3- [4-fluorobenzyloxyimino-2- (4-hydroxy- benzyl) -butyric acid methyl ester obtained in Preparation Example 46 in the same manner as in Examples 49 and 50 NMR : 1H-NMR(CDCl3) # 7. 98-7. 96 (2H, m), 7. 43-7. 39 (3H, m), 7. 22-7. 19 (2H, m), 7. 03-6. 96 (4H, m), 6. 77-6. 75 (2H, m), 5.01 (2H, s), 4.19 (2H, t, J=7Hz), 3.54 (1H, t, J=7Hz), 3.15 (1H, dd, J=7Hz, 14Hz), 2. 99-2. 93 (3H, m), 2.37 (3H, s), 1.84 (3H, s)

Mass (EI) 517 (M++1) Example 59: 3-methoxyimino-2-{4-[2-(2-phenyl)-5-methyl-oxazole-4-yl]-met hoxy}- benzyl-pentanoic acid 4 mg (yield of two steps: 10%) of the title compound was obtained using 25 mg (0.12 mmol) of a 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 23 mg (0.086 mmol) of () 3- [4-methyloxyimino-2- (4-hydroxy- benzyl) -pentanoic acid methyl ester obtained in Preparation Example 51 in the same manner as in Examples 49 and 50.

Mass (EI) : 437 (M++1) NMR : 1H-NMR(CDCl3) # 7. 98-7. 95 (2H, m), 7. 44-7. 39 (3H, m), 7. 09-7. 07 (2H, m), 6. 81-6. 78 (2H, m), 4.19 (2H, t, J=6Hz), 3.83 (3H, s), 3.51 (1H, t, J=7.6Hz), 3.13 (1H, dd, J=7. Hz, 14Hz), 3.01 (1H, dd, J=7Hz, 14Hz), 2.95 (2H, t, J=6Hz), 2.36 (3H, s), 2. 21-2. 11 (1H, m), 2. 09-2. 00 (1H, m), 0.98 (3H, t, J=7Hz) Example 60: 3-ethoxyiminol-2-{4-[2-(2-phenyl)-5-methyl-oxazole4-yl]-meth oxy}- benzyl-pentanoic acid 4 mg (yield of two steps: 20%) of the title compound was obtained using 25 mg (0.12 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 24 mg (0.086 mmol) of () 3-ethyloxyimino-2- (4-hydroxy-benzyl)- pentanoic acid methyl ester obtained in Preparation Example 52 in the same manner as in Examples 49 and 50.

Mass (EI): 451 (M++1) NMR : lH-NMR (CDCl3) 6 7. 98-7. 95 (2H, m), 7. 44~7. 39 (3H, m), 7. 09-7. 06 (2H, m),

6. 81-6. 78 (2H, m), 4.19 (2H, t, J=7Hz), 4.08 (2H, q, J=7Hz), 3.52 (1H, t, J=7.6Hz), 3.13 (1H, dd, J=7Hz, 14Hz), 3.02 (1H, dd, J=7Hz, 14Hz), 2.95 (2H, t, J=7Hz), 2.36 (3H, s), 2. 21-2. 11 (1H, m), 2. 05-1. 95 (1H, m), 1.20 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz) Example 61: 2- (4-2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}-benzyl)-3- methoxymino-butylic acid 7 mg (yield of two steps: 29%) of the title compound was obtained using 15 mg (0.066 mmol) of 2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 32 and 13 mg (0.053 mmol) of () 3-methyloxyimino-2- (4- hydroxy-benzyl) -butyric acid methyl ester obtained in Preparation Example 7 in the same manner as in Examples 49 and 50.

Mass (EI) : 441 (M++1) NMR :'H-NMR (CDC13) 6 7. 97-7. 93 (2H, m), 7. 12-7. 06 (4H, m), 6.79 (2H, d, J=8. 0Hz), 4.18 (2H, t, J=7Hz), 3.81 (3H, s), 3. 52-3. 50 (1H, m), 3.15 (1H, dd, J=7Hz, 13Hz), 2. 96-2. 92 (3H, m), 2.35 (3H, s) Example 62: 3-ethoxyimino-2- (4- {2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]- ethoxy}-benzyl)-butyric acid 8 mg (yield of two steps: 33%) of the title compound was obtained using 15 mg (0.066 mmol) of 2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 32 and 14 mg (0.053 mmol) of () 3-ethoxyimino-2- (4-hydroxy- benzyl) -butyric acid methyl ester obtained in Preparation Example 38 in the same manner as in Examples 49 and 50.

Mass (EI) 332 (m++')

NMR : lH-NMR (CDCl3) 6 7. 97-7. 94 (2H, m), 7. 13-7. 06 (4H, m), 6.79 (2H, d, J=8. 0Hz), 4.18 (2H, t, J=7Hz), 4.06 (2H, q, J=7Hz), 3. 52-3. 50 (1H, m), 3.16 (1H, dd, J=7Hz, 13Hz), 3. 00-2. 93 (3H, m), 2.35 (3H, s), 1.83 (3H, s), 1.17 (3H, t, J=7Hz) Example 63: 2-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}- benzyl)-3- propyloxyimino-butyric acid 7 mg (yield of two steps: 28%) of the title compound was obtained using 15 mg (0.066 mmol) of 2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 32 and 15 mg (0.053 mmol) of () 3-propyloxyimino-2- (4- hydroxy-benzyl) -butyric acid methyl ester obtained in Preparation Example 39 in the same manner as in Examples 49 and 50.

NMR : lH-NMR (CDCl3) 6 7. 97-7. 94 (2H, m), 7. 13-7. 05 (4H, m), 6. 81-6. 78 (2H, m), 4.18 (2H, d, J=7Hz), 3.96 (2H, q, J=7Hz), 3.53 (1H, t, J=7Hz), 3.16 (1H, dd, J=7Hz, 14Hz), 2.98 (1H, dd, J=7Hz, 14Hz), 2.94 (2H, t, J=7Hz), 2.35 (3H, s), 1. 84 (3H, s), 1. 62-1. 52 (2H, m), 0.86 (3H, t, J=7Hz) Mass (EI) 469 (M++1) Example 64: 3-fluoroethoxyimino-2-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-ox azole-4- yl]-ethoxy}-benzyl)-butyric acid 7 mg (yield of two steps: 31%) of the title compound was obtained using 15 mg (0.066 mmol) of 2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 32 and 15 mg (0.053 mmol) of () 3- (2-fluoro-ethyloxyimino)-2- (4-hydroxy-benzyl) -butyric acid methyl ester obtained in Preparation Example 41 in the same manner as in Examples 49 and 50.

NMR : lH-NMR (CDCl3) 6 7. 97-7. 93 (2H, m), 7. 13-7. 06 (4H, m), 6. 81-6. 79 (2H, m), 4. 58-4. 55 (1H, m), 4. 47-4. 43 (1H, m), 4. 29-4. 47 (1H, m), 422-4. 18 (1H, m), 4.18 (2H, d, J=7Hz), 3. 56-3. 50 (1H, m), 3. 18-3. 14 (1H, m), 2. 98-2. 92 (1H, m), 2.95 (2H, t, J=7Hz), 2.35 (3H, s), 1.89 (3H, s) Mass (EI) 473 (M++1) Example 65: 2-(4-{2-[2-(3-fluoro-phenyl)-5-methoxy-oxazole-4-yl]-ethoxy} -benzyl)-3- methoxyimino-butylic acid 8 mg (yield of two steps: 34%) of the title compound was obtained using 15 mg (0.066 mmol) of 2- [2- (3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 33 and 13 mg (0.053 mmol) of () 3-methyloxyimino-2- (4- hydroxy-benzyl) -butyric acid methyl ester obtained in Preparation Example 37 in the same manner as in Examples 49 and 50.

Mass (EI) 441 (M++1) Example 66: 3-ethoxyimino-2- (4- {2- [2- (3-ftuoro-phenyl)-5-methyl-oxazole-4-yl]- ethoxy}-benzyl) butyric acid 9 mg (yield of two steps: 37%) of the title compound was obtained using 15 mg (0.066 mmol) of 2- [2- (3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 33 and 14 mg (0.053 mmol) of () 3-ethyloxyimino-2- (4- hydroxy-benzyl) -butyric acid methyl ester obtained in Preparation Example 38 in the same manner as in Examples 49 and 50.

Mass (EI) 455 (M++1)

Example 67: 2-(4-{2-[2-(3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy}- benzyl)-3- propyloxyimino-butylic acid 4 mg (yield of two steps: 9%) of the title compound was obtained using 20 mg (0.090 mmol) of 2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 32 and 15 mg (0.089 mmol) of () 3-propyloxyimino-2- (4- hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 39 in the same manner as in Examples 49 and 50.

NMR : lH-NMR (CDCl3) 6 7. 76-7. 74 (1H, m), 7. 67-7. 64 (1H, m), 7. 41-7. 35 (1H, m), 7. 11-7. 05 (3H, m), 6.79 (2H, d, J=8. 4Hz), 4.18 (2H, t, J=6.8Hz), 3.95 (2H, t, J=6.4Hz), 3.53 (1H, t, J=7.2Hz), 3.15 (1H, dd, J=7.2Hz, 14.4Hz), 3. 00-2. 88 (3H, m), 2.36 (3H, s), 1.83 (3H, s), 1. 63-1. 52 (2H, m), 0.85 (3H, d, J=7.6Hz) Mass (EI) 469 (M++1) Example 68: 3-cyclomethoxyimino-2- (4- {2- [2- (3-fluoro-phenyl)-5-methyl-oxazole- 4-yl]-ethoxy}-benzyl)-butyric acid 9 mg (yield of two steps: 28%) of the title compound was obtained using 15 mg (0.066 mmol) of 2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 32 and 19 mg (0.066 mmol) of () 3-cyclopropylmethoxyimino- 2- (4-hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 44 in the same manner as in Examples 49 and 50.

Mass (EI) 481 (M+1) Example 69: 3-methoxyimino-2-{4-[2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl )- ethoxy]-benzyl}-butyric acid

12 mg (yield of two steps: 29%) of the title compound was obtained using 20 mg (0.095 mmol) of 2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethanol obtained in Preparation Example 34 and 47 mg (0.10 mmol) of () 3-methyloxyimino-2- (4- hydroxy-benzyl) -butyric acid methyl ester obtained in Preparation Example 37 in the same manner as in Examples 49 and 50.

NMR : lH-NMR (CDCl3) 6 7. 59-7. 58 (1H, m), 7. 38-7. 35 (1H, m), 7. 11-7. 06 (3H, m), 6. 80-6. 78 (2H, m), 4.15 (2H, t, J=6.4Hz), 3.82 (3H, s), 3.54 (1H, t, J=8Hz), 3.16 (1H, dd, J=8Hz, 16Hz), 2. 98-2. 91 (3H, m), 2.33 (3H, s), 1.83 (3H, s) Mass (EI) 429 (M++1) Example 70: 3-ethoxyimino-2- {4- [2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethoxy]- benzyl}-butyric acid 7.1 mg (yield of two steps: 17%) of the title compound was obtained using 20 mg (0.095 mmol) of 2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethanol obtained in Preparation Example 34 and 28 mg (0.10 mmol) of () 3-ethyloxyimino-2- (4-hydroxy- benzyl) -butyric acid methyl ester obtained in Preparation Example 38 in the same manner as in Examples 49 and 50.

NMR : lH-NMR (CDCl3) 6 7. 59-7. 58 (1H, m), 7. 37-7. 35 (1H, m), 7. 10-7. 05 (3H, m), 6. 77-6. 74 (2H, m), 4.16 (2H, t, J=6.8Hz), 4.05 (2H, q, J=6.8Hz), 3.53 (1H, t, J=7.2Hz), 3.15 (1H, dd, J=7.2Hz, 14.4Hz), 3. 00-2. 91 (3H, m), 2.33 (3H, s), 1.83 (3H, s), 1.17 (3H, t, J=7. 2Hz) Mass (EI) 443 (M++1) Example 71: 2-{4-[2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethoxy]-benzy l}-3-

propyloxymino-butylic acid 27 mg (yield of two steps: 21%) of the title compound was obtained using 120 mg (0.57 mmol) of 2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethanol obtained in Preparation Example 34 and 80 mg (0.28 mmol) of () 3-propyloxyimino-2- (4- hydroxy-benzyl) -butyric acid methyl ester obtained in Preparation Example 39 in the same manner as in Examples 49 and 50.

Mass (EI) 457 (M++1) Sodium salt form, NMR : 1H-NMR (CD30D) 8 7.63 (1H, dd, J=4Hz, 1Hz), 7.56 (1H, dd, J=5Hz, 1Hz), 7.16 (1H, dd, J=5Hz, 4Hz), 7. 10-7. 05 (3H, m), 6. 79-6. 76 (2H, m), 4.17 (2H, t, J=6Hz), 3. 87-3. 81 (2H, qm), 3. 35-3. 31 (1H, m), 3.13 (1H, dd, J=6Hz, 14Hz), 2.91 (2H, t, J=6Hz), 2.85 (1H, dd, J=14Hz, 9Hz), 2.33 (3H, s), 1.84 (3H, s), 1.46 (3H, s, J=7Hz), 0.80 (3H, t, J=7Hz) Example 72: 3-fluoroethyloxyimino-2- {4- [2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)- ethoxy]-benzyl}-butyric acid 12 mg (yield of two steps: 27%) of the title compound was obtained using 20 mg (0.095 mmol) of 2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethanol obtained in Preparation Example 34 and 30 mg (0.10 mmol) of () 3- (2-fluoro-ethyloxyimino)-2- (4-hydroxy-benzyl) -butyric acid methyl ester obtained in Preparation Example 41 in the same manner as in Examples 49 and 50.

Mass (EI) 461 (M++1) NMR : lH-NMR (CDCl3) 6 7. 59-7. 58 (1H, m), 7. 37-7. 36 (1H, m), 7. 11-7. 05 (3H, m), 6. 79-6. 74 (2H, m), 4. 57-4. 54 (1H, m), 4. 54-4. 52 (1H, m), 4. 27-4. 10 (4H, m), 3.54 (1H, t, J=8Hz), 3.16 (1H, dd, J=8Hz, 16Hz), 2. 96-2. 91 (3H, m), 2.33 (3H, s), 1.90 (3H, s)

Example 73: 3-methoxyimino-2- {4- [2- (5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]- benzyl} -2-methyl-butylic acid 8 mg (yield: 70%) of the title compound was obtained using 7 mg (0.034 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 7 mg (0.026 mmol) of () 3-methoxyimino-2- (4-hydroxy-benzyl)-2-methyl-butyric acid methyl ester obtained in Preparation Example 48 in the same manner as in Examples 49 and 50.

Mass (EI) : 437 (M++1) NMR : lH-NMR (CDCl3) å 7. 98-7. 96 (2H, m), 7. 45-7. 39 (3H, m), 7. 02-6. 99 (2H, m), 6. 79-6. 77 (2H, m), 4.20 (2H, t, J=8Hz), 3.83 (3H, s), 3.13 (1H, d, J=12Hz), 3.08 (1H, d, J=12Hz), 2.97 (2H, t, J=8Hz), 2.36 (3H, s), 1. 88 (3H, s), 1.36 (3H, s) Example 74: 3-ethoxyimino-2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethox y]- benzyl}-2-methyl-butylic acid 8 mg (yield: 55%) of the title compound was obtained using 8 mg (0.034 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 9 mg (0.032 mmol) of () 3-ethoxyimino-2- (4-hydroxy-benzyl)-2-methyl-butylic acid methyl ester obtained in Preparation Example 49 in the same manner as in Examples 49 and 50.

Mass (EI) 451 (M++1) NMR : 1H-NMR(CDCl3) # 7. 98-7. 96 (2H, m), 7. 45-7. 40 (3H, m), 7. 00-6. 97 (2H, m), 6. 79-6. 77 (2H, m), 4.20 (2H, t, J=8Hz), 4.06 (2H, q, J=7Hz), 3.16 (1H, d, J=14Hz), 3.02 (1H, d, J=14Hz), 2.97 (2H, t, J=8Hz), 2.36 (3H, s), 1.90 (3H, s), 1.36 (3H, s), 1. 18 (3H,

t, J=7Hz) Example 75: 2-{4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzyl}-2-m ethyl-3- propyloxyimino-butylic acid 8 mg (yield: 52%) of the title compound was obtained using 9 mg (0.044 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 9 mg (0.033 mmol) of () 3-propoxyimino-2- (4-hydroxy-benzyl)-2-methyl-butylic acid methyl ester obtained in Preparation Example 50 in the same manner as in Examples 49 and 50.

Mass (EI) 465 (M++1) NMR : lH-NMR (CDCl3) å 7. 98-7. 96 (2H, m), 7. 45-7. 39 (3H, m), 6. 99-6. 97 (2H, m), 6. 79-6. 76 (2H, m), 4.20 (2H, t, J=7Hz), 3.96 (2H, t, J=7Hz), 3.18 (1H, d, J=14Hz), 3.00 (1H, d, J=14Hz), 2.96 (2H, t, J=7Hz), 2.36 (3H, s), 1.91 (3H, s), 1. 58-1. 52 (2H, m), 1.41 (3H, s), 0.87 (3H, t, J=7Hz) Example 76: 3-methoxyimino-2- {4- [2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)- ethoxy]-benzyl}-2-methyl-butylic acid 13 mg (yield: 29%) of the title compound was obtained using 30 mg (0.12 mmol) of 2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-etlianol obtained in Preparation Example 34 and 26 mg (0.098 mmol) of () 3-methoxyimino-2- (4-hydroxy-benzyl)-2- methyl-butylic acid methyl ester obtained in Preparation Example 48 in the same manner as in Examples 49 and 50.

Mass (EI) 443 (M++1) NMR : lH-NMR (CD3OD) 6 7.64 (1H, dd, J=4Hz, 1Hz), 7.57 (1H, dd, J=5Hz, 1Hz), 7.14

(1H, dd, J=5Hz, 4Hz), 7. 04-7. 01 (2H, m), 6. 80-6. 77 (2H, m), 4.20 (2H, t, J=7Hz), 3.87 (3H, s), 3.12 (1H, d, H=14Hz), 2.99 (1H, d, J=14Hz), 2.92 (2H, t, J=7Hz), 2.33 (3H, s), 1. 80 (3H, s), 1.17 (3H, s) Example 77: 3-(4-fluoro-benzyloxyimino)-2-{4-[5-methyl-2-(4-trifluoromet hyl- phenyl)-thiazole-4-ylmethoxy]-benzyl}-butyric acid 20 mg (yield of two steps: 30%) of the title compound was obtained using 30 mg (0.13 mmol) of [5-methyl-2- (4-trifluoromethyl-phenyl)-thiazole-4-yl]-methanol obtained in Preparation Example 35 and 39 mg (0.11 mmol) of () 3- [4- fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]-butyric acid methyl ester obtained in Preparation Example 46 in the same manner as in Examples 49 and 50.

NMR : lH-NMR (CDCl3) 6 8.00 (2H, d, J=8Hz), 7.66 (2H, d, J=8Hz), 7. 20-7. 17 (2H, m), 7.05 (2H, d, J=8. 0Hz), 7. 00-6. 82 (4H, m), 5.13 (2H, s), 5.00 (2H, s), 3.54 (1H, t, J=8Hz), 3. 19-3. 12 (1H, m), 2. 98-2. 90 (1H, m), 2.50 (3H, s), 1.87 (3H, s) Mass (EI) 587 (M++1) Example 78: 2-{4-[2-(5-methyl-2-p-oxazole-4-ylmethoxy)-benzyl]-3- propyloxyimino-butylic acid 14 mg (yield of two steps: 32%) of the title compound was obtained using 20 mg (0.098 mmol) of (5-methyl-2-p-tolyl-oxazole-4-yl) -methanol obtained in Preparation Example 53 and 26 mg (0.097 mmol) of () 3-propyloxyimino-2- (4- hydroxy-benzyl) -butyric acid methyl ester obtained in Preparation Example 39 in the same manner as in Examples 49 and 50.

Mass (EI) 451 (M++1)

NMR : lH-NMR (CDCl3) 6 7.89 (2H, d, J=8Hz), 7.24 (2H, d, J=8Hz), 7. 12-7. 09 (2H, m), 6. 93-6. 89 (2H, m), 4.94 (2H, s), 3.97 (2H, t, J=6.4Hz), 3.55 (1H, t, J=7.6Hz), 3.17 (1H, dd, J=7.2Hz, 14Hz), 2.97 (1H, dd, J=7.6Hz, 14Hz), 2.40 (3H, s), 2.38 (3H, s), 1.85 (3H, s), 1. 62-1. 52 (2H, m), 0.87 (3H, t, J=7.2Hz) Preparation Example 54: 4-phenyl-lH-pyrrole-3-carboxylic acid ethyl ester 5 ml (47 mmol) of benzaldehyde and 13 g (57 mmol) of triethyl phosphonoacetate were dissolved in tetrahydrofuran, then 7.9 g (70 mmol) of potassium t-butoxide was added dropwise to the resulting solution at 0°C, followed by stirring for 2 hours. 7.9 g (70 mmol) of tosylmethyl isocyanide was added thereto and then stirred for 5 hours at room temperature. To the resulting solution, ethylacetate was added and the resulting solution was washed with ammonium chloride. This organic solution was dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography to obtain 7.38 g of the titile compound in a yield of 70%.

NMR : lH-NMR (CDCl3) 6 7. 51-7. 48 (3H, m), 7. 37-7. 33 (2H, m), 7. 29-7. 25 (1H, m), 6. 80-6. 79 (1H, m), 4.21 (2H, q, J=8Hz), 1.24 (2H, t, J=8Hz) Mass (EI) 216 (M++1) Preparation Example 55: 3- (benzyloxyimino)-2- [4- (2-bromo-ethoxy)-benzyl]- butyric acid methyl ester () 3-benzyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester (100 mg, 0.3 mmol), cesium carbonate (200 mg, 0.6 mmol) and dibromoethane (230 mg, 1.2 mmol) were added to acetonitrile, followed by stirring at 80°C for 6 hours. To the resulting solution, ethylacetate was added, followed by washing with ammonium chloride. This organic solution was dried over anhydrous magnesium sulfate, then the

residue was purified by column chromatography to obtain 40 mg of the tilte compound in a yield of 30%.

NMR : lH-NMR (CDCl3) 6 7. 34-7. 25 (5H, m), 7.05 (2H, d, J=4.2Hz), 6. 78-6. 75 (2H, m), 5.07 (2H, s), 4.25 (2H, t, J=6.4Hz), 3.65 (3H, s), 3.61 (2H, t, J=6.4Hz), 3.53 (1H, m), 3.15 (1H, dd, J=8Hz, 14.4Hz), 2.92 (1H, dd, J=8Hz, 14Hz), 1.87 (3H, s) Mass (EI) 435 (M++1) Example 79: 1-[2-(4-{3-benzyloxyimino}-2-carboxy-butyl)-phenoxy]-ethyl-4 - phenyl-lH-pyrrole-3-carboxylic acid ethyl ester 15 mg (0.07 mmol) of 4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester was dissolved in 0.5 ml of dimethylformamide, and 3.4 mg (0.084 mmol) of sodium hydride was added thereto, then the resulting solution was stirred for about 30 minutes, and 30 mg (0.07 mmol) of 3- (benzyloximino)-2- [4- (2-bromo-ethoxy)-benzyl]-butyric acid methyl ester was added thereto. After 12 hours, ethylacetate was further added, and the resulting solution was washed with ammonium chloride. This organic solution was dried over anhydrous magnesium sulfate, and 1-[2-(4-{3-benzyloximino}-2-carboxy- buthyl)-phenoxy]-ethyl-4-phenyl-lH-pyrrol-3-carboxylic acid ethyl ester was synthesized using column chromatography. This compound and lithium hydroxide were stirred in a 1: 1: 1 mixture (1 ml) of tetrahydrofuran, water and methanol for 3 hours, then ethylacetate was added thereto, and the resulting solution was washed with ammonium chloride. The resulting organic solution was dried over anhydrous magnesium sulfate, and the residue was purified by column chromatography to obtain 5 mg of the title compound in a yield of 64%.

NMR : lH-NMR (CDCl3) 6 7. 47-7. 22 (11H, m), 7.00 (2H, d, J=8.4Hz), 6. 74-6. 70 (3H, m),

5.05 (2H, s), 4. 23-4. 16 (6H, m), 3. 52-3. 48 (1H, m), 3. 15-3. 10 (1H, m), 2. 98-2. 94 (1H, m), 1.84 (3H, s), 1.21 (3H, t, J=7.2Hz) Mass (EI) 555 (M++1) Preparation Example 56: methanesulfonic acid 2- (4-methanesulfonyloxy-phenyl)- ethyl ester 60 mg (0.434 mmol) of 4- (2-hydroxy-ethyl)-phenol and 0.19 ml (1.36 mmol) of triethylamine were stirred with in 1 ml of dichloromethane, then 0.084 ml (1.08 mmol) of methane sulfonic chloride was added to the resulting solution at 0°C. After 30 minutes, ethylacetate was further added thereto, followed by washing with ammonium chloride. The resulting organic solution was dried over anhydrous magnesium sulfate, and 121 mg of the title compound was obtained in a yield of 95% without any isolation procedure.

NMR : tH-NMR (CDCl3) 6 7. 31-7. 23 (4H, m), 4.42 (2H, d, J=4Hz), 3.15 (3H, s), 3.08 (2H, t, J=8Hz), 2.91 (3H, s) Mass (EI) 295 (M++1) Example 80: 3- [4-fluoro-benzyloxyiminol-2-14- [2- (4-methansulfonyloxy-phenyl)- ethoxy]-benzyl}-butyric acid 50 mg (0.144 mmol) of (~) 3-[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)]- butyric acid methyl ester, 63 mg (0.216 mmol) of methansulfonic acid 2- (4- methansulfonyloxy-phenyl)-ethyl ester and 93 mg (0.288 mmol) of cesium carbonate were stirred in acetonitrile at 80°C. After 3 hours, the resulting solution was cooled to room temperature, and ethylacetate was further added thereto, followed by washing with ammonium chloride. The resulting organic solution was dried over anhydrous

magnesium sulfate, and 35 mg (yield: 44%) of3- [4-fluoro-benzyloxyimino]-2- {4- [2- (4- methansulfonyloxy-phenyl)-ethoxy]-benzyl}-butyric ester was obtained using column chromatography. This compound and lithium hydroxide were stirred in a 1 : 1 : 1 mixture (1 ml) of tetrahydrofuran, water and methanol for 3 hours, then ethylacetate was further added thereto, and the resulting solution was washed with ammonium chloride. The resulting organic solution was dried over anhydrous magnesium sulfate and the residue was purified by column chromatography to obtain 30 mg of the title compound in a yield of 87%.

NMR : lH-NMR (CDCl3) 6 7. 35-7. 18 (6H, m), 7. 04-6. 96 (4H, m), 6.74 (2H, d, J=8Hz), 5.02 (2H, s), 4.13 (2H, t, J=8Hz), 3. 56-3. 52 (1H, m), 3.12 (3H, s), 3. 11-3. 08 (3H, m), 3. 00-2. 88 (1H, m), 1.86 (3H, s) Mass (EI) 530 (M++1) Preparation Example 57: [1- (4-isopropyl-phenyl)-5-methoxy-lH-pyrrazole-4-yl]- methanol (1) Preparation of 5-hydroxy-1-(4-isopropyl-phenyl)-lH-pyrrazole-3- carboxylic acid ethyl ester 650 mg (3.1 mmol) of diethyl ethoxymethylene malonate, 580 mg (3.1 mmol) of (4-isopropyl-phenyl) hydrazine hydrochloride salt, and 380 mg (3.1 mmol) of sodium acetate were added to ethanol, then the resulting solution was heated for 15 hours. After removal of solvent under a reduced pressure, ethylacetate was added thereto, followed by washing with water. The resulting organic solution was dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography to obtain 520 mg of the title compound in a yield of 61%.

NMR : lH-NMR (CDCl3) 6 7.74 (1H, s), 7.68 (2H, d, J=8Hz), 7.31 (2H, d, J=8Hz), 4.32 (2H, q, J=8Hz), 2. 96-2. 93 (1H, m), 1.38 (2H, t, J=8. 0Hz), 1.27 (6H, d, J=8Hz) Mass (EI) 275 (M++1) (2) Preparation of 1-(4-isopropyl-phenyl)-5-methoxy-lH-pyrrazole-3- carboxylic acid ethyl ester 138 mg (0.5 mmol) of 5-hydroxy-1-(4-isopropyl-phenyl)-lH-pyrrazole-3- carboxylic acid ethyl ester, 0.037 ml (0.6 mmol) of methyl iodide, and 330 mg (1.0 mml) of cesium carbonate were added to dimethylformamide, and the resulting solution was stirred at room temperature for 10 hours. Ethylacetate was added thereto, followed by washing with water. The resulting organic solution was dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography to obtain 90 mg of the title compound in a yield of 62%.

NMR : lH-NMR (CDCl3) 6 7.91 (1H, s), 7.51 (2H, d, J=8. 4Hz), 7.29 (2H, d, J=8.4Hz), 4.32 (2H, q, J=7.2Hz), 4.12 (3H, s), 2. 97-2. 94 (1H, m), 1.37 (2H, t, J=6.8Hz), 1.27 (6H, d, J=7. 2Hz) Mass (EI) 289 (M++1) (3) Preparation of [1- (4-isopropyl-phenyl)-5-methoxy-lH-pyrrazole-3-yl]- methanol 90 mg (0.31 mmol) of 1-4-isopropyl-phenyl-5-methoxy-lH-pyrazole-3- carboxylic acid ethyl ester was dissolved in tetrahydrofuran, then 18 mg (0.47 mmol) of lithium aluminum hydride was added dropwise to the resulting solution at 0°C. After 10 minutes, the solution was heated to room temperature, followed by stirring for 1 hour.

0.018 ml of water, 0.018 ml of 15% sodium hydroxide, and 0.054 ml of water were added thereto in sequence, then filtering was conducted to remove solid. The filtered solution was dried under a reduced pressure, then the residue was purified by column chromatography to obtain 75 mg of the title compound in a yield of 97%.

NMR : lH-NMR (CDCl3) 8 7. 56-7. 50 (2H, m), 7.50 (1H, s), 7. 30-7. 26 (2H, m), 4.61 (2H, d, J=4Hz), 4.02 (3H, s), 2. 96-2. 93 (1H, m), 1.27 (6H, d, J=4Hz) Mass (EI) 247 (m++I) Example 81: 3-14-fluoro-benzyloxyimino]-2-14- [I- (4-isopropyl-phenyl)-5-methoxy- lH-pyrrazole-4-ylmethoxy]-benzyl}-butyric acid 11 mg (0.045 mmol) of [1- (4-isopropyl-phenyl)-5-metlioxy-lH-pyrazole-3-yl]- methanol and 0.019 ml (0.14 mmol) of triethylamine were dissolved in 1 ml of dichloromethane, then 0.006 ml (0.067 mmol) of methanesulfonyl chloride was added to the resulting solution at 0°C. After 30 minutes, ethylacetate was added thereto, followed by washing with ammonium chloride. The resulting organic solution was dried over anhydrous magnesium sulfate, and distillation under reduced pressure was conducted to obtain 14 mg (yield: 95%) of the compound which was then used in the next procedure without further purification.

This compound and 12 mg (0.036 mmol) of (~) 3-[4-fluoro-benzyloxyimino-2- (4-hydroxyimino-2- (4-hydroxy-benzyl))-butyric acid methyl ester and 23 mg (0.072 mmol) of cesium carbonate were dissolved in 1 ml of acetonitrile at 80°C. After 3 hours, the resulting solution was cooled to room temperature, and ethylacetate was added thereto, then the resulting solution was washed with ammonium chloride. The organic solution thus obtained was dried over anhydrous magnesium sulfate to obtain 8 mg

(yield: 40%) of 3- [4-fluoro-benzyloxyimino]-2-14- [l- (4-isopropyl-phenyl)-5-methoxy- 1H-pyrazole-4-ylmethoxy]-benzyl}-butyric acid methyl ester using column chromatography. This compound and lithium hydroxide were stirred in a 1: 1: 1 mixture (1 ml) of tetrahydrofuran, water and methanol for 3 hours, and ethylacetate was added to the resulting solution which was then washed with ammonium chloride. The organic solution thus obtained was dried over anhydrous magnesium sulfate, and the residue was purified by column chromatography to obtain 6 mg of the title compound in a yield of 75%.

NMR : lH-NMR (CDCl3) 6 7. 57-7. 55 (3H, m), 7. 31-7. 21 (4H, m), 7. 07-6. 97 (4H, m), 6.86 (2H, d, J=8.4Hz), 5.30 (2H, s), 4.91 (2H, s), 3.96 (3H, s), 3. 56-3. 52 (1H, m), 3. 16-3. 14 (1H, m), 3. 03-2. 93 (2H, m), 1.88 (3H, s), 1.27 (6H, d, J=6Hz) Mass (EI) 560 (M++1) Preparation Example 58: [1-(4-ethyl-phenyl)-1H-pyrrazole-4-yl]-methanol 4.28 g (yield: 73%) of [1- (4-ethyl-phenyl)-lH-pyrazole-4-il]-methanol was obtained from 5 g (28.9 mmol) of (4-ethyl-phenyl) -hydrazine hydrochloride salt in the same manner as in Preparation Example 4.

NMR : lH-NMR (CDCl3) 6 7.89 (1H, s), 7.69 (1H, s), 7. 58-7. 54 (2H, m), 7. 28-7. 26 (2H, m), 4.67 (2H, d, J=4Hz), 2. 68 (2H, q, J=7.6Hz), 1.26 (3H, t, J=7.6Hz) Mass (EI) 203 (M++1) Example 82: 2- 4- [1- (4-ethyl-phenyl)-lH-pyrrazole-4-ylmethoxy]-benzyl}-3- [4- fluoro-benzyloxyimino]-butyric acid 176 mg (yield: 67%) of 2- {4- [l- (4-ethyl-phenyl)-lH-pyrazole-4-ylmethoxy]-

benzyl}-3- [4-fluoro-benzyloxyimino]-butyric acid methyl ester was obtained from 100 mg (0.49 mmol) of [1-(4-ethyl-phenyl)-1H-pyrazole-4-yl]-methanol and 153 mg (0.442 mmol) of (~) 3-[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 49.6 mg (0.011 mmol) of 2- {4- [l- (4-ethyl- phenyl)-lH-pyrazole-4-ylmethoxy]-benzyl}-3- [4-fluoro-benzyloxyimono]-butyric acid methyl ester and lithium hydroxide were stirred in a 1: 1: 1 mixture (1 ml) of tetrahydrofuran, water and methanol for 3 hours, then ethylacetate was added to the resulting solution which was then washed with ammonium chloride. The organic solution thus obtained was dried over anhydrous magnesium sulfate, and the residue was purified by column chromatography to obtain 5 mg of the title compound in a yield of 85%.

NMR : lH-NMR (CDCl3) 6 7.96 (1H, s), 7.76 (1H, s), 7. 58-7. 55 (2H, m), 7. 27-7. 18 (4H, m), 7. 07-6. 96 (4H, m), 6.85 (2H, d, J=8. 8Hz), 5.02 (2H, s), 4.99 (2H, s), 3. 59-3. 54 (1H, m), 3. 19-3. 14 (1H, m), 3. 00-2. 95 (1H, m), 2.68 (2H, q, J=7.6Hz), 1. 88 (3H, s), 1.26 (3H, t, J=7. 6Hz) Mass (EI) 516 (M++1) Example 83: 3- [benzyloxyimino]-2-4- [1-4-ethoxy-phenyl]-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid 161 mg (yield: 63%) of 2- {4- [l- (4-ethyl-phenyl)-lH-pyrrazole-4-ylmethoxy]- benzyl}-3- [benzyloxyimono]-butyric acid methyl ester was obtained from 100 mg (0.49 mmol) of [1- (4-ethyl-phenyl)-lH-pyrazole-4-yl]-methanol and 146 mg (0.445 mmol) of () 3- [benzyloxyimino]-2- (4-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 49.8 mg (0.015 mmol) of 3- [benzyloxyimino]-2-4- [1-4-ethoxy-

phenyl]-lH-pyrazole-4-ylmethoxy]-benzyl}-butyric acid methyl ester and lithium hydroxide were stirred in a 1: 1: 1 mixture (1 ml) of tetrahydrofuran, water and methanol for 3 hours, and ethylacetate was added to the resulting solution, followed by washing with ammonium chloride. The organic solution thus obtained was dried over anhydrous magnesium sulfate, and the residue was purified by column chromatography to obtain 5 mg of the title compound in a yield of 64%.

NMR : lH-NMR (CDCl3) 6 7.94 (1H, s), 7.75 (1H, s), 7.56 (2H, d, J=8.4Hz), 7. 34-7. 24 (7H, m), 7. 08-7. 04 (2H, m), 6. 87-6. 84 (2H, m), 5. 08 (2H, s), 5.01 (2H, s), 3. 58-3. 55 (1H, m), 3. 19-3. 14 (1H, m), 3. 02-2. 96 (1H, m), 2.68 (2H, q, J=7.6Hz), 1.88 (3H, s), 1.25 (3H, t, J=7.6Hz) Mass (EI) 498 (M++1) Preparation Example 59: [1- (4-ethyl-phenyl)-5-methoxy-lH-pyrrazole-4-yl]- methanol 4.1 g (yield: 60%) of the title compound was obtained from 5 g (32 mmol) of diethyl ethoxymethylenemalonate and 5 g (32 mmol) of (4-methyl-phenyl)-hydrazine hydrochloride salt in the same manner as in Preparation Example 57.

NMR : 1H-NMR(CDCl3) # 7. 53-7. 50 (3H, m), 7. 26-7. 23 (2H, m), 4.61 (2H, d, J=8Hz), 4.00 (3H, s), 2. 39 (3H, s) Mass (EI) 219 (M++1) Example 84: 3- [4-fluoro-benzyloxyimino]-2-4- [1-4-methyl-phenyl]-5-methoxy-1H- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid 25 mg (yield: 36%) of 3- [4-fluoro-benzyloxyimino]-2-4- [1-4-methyl-phenyl]-5-

methoxy-lH-pyrazole-4-ylmethoxy]-benzyl}-butyric acid was obtained from 30 mg (0.13 mmol) of [1- (4-methyl-phenyl)-5-methoxy-lH-pyrazole-4-yl]-methanol and 45 mg (0.13 mmol) of () 3- [4-fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.

NMR : lH-NMR (CDCl3) 6 7.57 (1H, s), 7. 56-7. 50 (2H, m), 7. 25-7. 20 (4H, m), 7. 06-6. 98 (4H, m), 6. 88-6. 85 (2H, m), 5.03 (2H, s), 4.90 (2H, s), 3.94 (3H, m), 3. 59-3. 55 (1H, m), 3. 19-3. 14 (1H, m), 3. 03-2. 98 (1H, m), 2.39 (3H, s) Mass (EI) 532 (M++1) Preparation Example 60: 2-(1-phenyl-1H-pyrazole-3-yl)-ethanol (1) Preparation of 1-phenyl-1H-pyrrazole-3-carbaldehyde 500 mg (2.9 mmol) of 2- (l-phenyl-lH-pyrrazole-3-yl)-methanol and 0.8 ml (5.7 mmol) of triethylamine were stirred in 10 ml of dichloromethane at 0°C. 690 mg (4.3 mmol) of sulfur trioxide pyridine was dissolved in 5 ml of dimethylsulfoxide and the resulting solution was added to reaction solution. After 3 hours later, ethylacetate was added thereto, followed by washing with water. The organic solution thus obtained was dried over anhydrous magnesium sulfate, and the residue was purified by column chromatography to obtain 220 mg of the title compound in a yield of 45%.

NMR : lH-NMR (CDCl3) 6 9.98 (1H, s), 8.44 (1H, s), 8.17 (1H, s), 7. 74-7. 71 (2H, m), 7. 53-7. 49 (2H, m), 7. 42-7. 38 (1H, m) Mass (EI) 173 (M++1) (2) Preparation of (1-phenyl-1H-pyrrazole-3-yl)-acetaldehyde 660 mg (1.9 mmol) of methoxymethyl-triphenylphosphonium chloride was dissolved in 10 ml of tetrahydrofuran, then n-butyl lithium was added to the resulting at

- 78°C. After 30 minutes, the reaction was heated to 0°C and 2 ml of hexamethylphosphoamide was added thereto, then 220 mg (1.3 mmol) of 1-phenyl-lH- pyrrazole-3-carbaldehyde dissolved in 3 ml of tetrahydrofuran was further added thereto.

After stirring for 1 hour, ethylacetate was added, followed by washing with ammonium chloride solution. The organic solution thus obtained was dried over anhydrous ammonium sulfate, the residue was purified by column chromatography to obtain 3- (2- methoxy-vinyl)-1-phenyl-lH-pyrazole. This compound was dissolved in a mixture of 3 ml of 3 N hydrogen chloride solution and 20 ml of tetrahydrofuran, then the resulting solution was stirred with heating for 2 hours. Ethylacetate was added thereto and the resulting solution was washed with water, then the organic solution thus obtained was dried over anhydrous magnesium sulfate, and the residue was purified by column chromatography to obtain 130 mg of the title compound in a yield of 36%.

Mass (EI) 187 (M++1) (3) Preparation of 2-(1-phenyl-lH-pyrrazole-3-yl)-ethanol 130 mg (0.69 mmol) of 2- (l-phenyl-lH-pyrazole-3-yl)-ethanol was dissolved in methanol, then 26 mg (0.69 mmol) sodium borohydride was added slowly to the resulting solution at room temperature. After one hour, ethylacetate was added thereto, followed by washing with water. The organic solution thus obtained was dried over anhydrous magnesium sulfate, and the residue was purified by column chromatography to obtain 110 mg of the title compound in a yield of 84%.

NMR : lH-NMR (CDCl3) 6 7.82 (1H, s), 7. 67-7. 65 (2H, m), 7.61 (1H, m), 7. 47-7. 42 (2H, m), 7. 29-7. 25 (1H, m), 3.85 (2H, q, J=8Hz), 2.81 (2H, t, J=8Hz) Mass (EI) 189 (M++1)

Preparation Example 61: 3- [4-fluoro-benzyloxyimino]-2- (3-hydroxy-benzyl)- butyric acid (1) Preparation of 3-benzyloxy benzaldehyde 300 mg (yield: 60%) of 3-benzyloxy benzaldehyde was obtained from 500 mg (2.3 mmol) of 3-benzyloxy benzyl alcohol in the same manner as in Preparation Example 60- (1).

Mass (EI) 189 (M++1) (2) Preparation of 2-[1-(3-benzyloxy-phenyl)-methyliden]-3-oxo-butyric acid methyl ester 400 mg (yield: 92%) of 2-[1-(3-benzyloxy-phenyl)-methyliden]-3-oxo-butyric acid methyl ester was obtained from 300 mg (60%) of 3-benzyloxy benzaldehyde and 160 mg (1.37 mmol) of methylacetoacetate in the same manner as described above.

Mass (EI) 311 (M++1) (3) Preparation of (i) 2-(3-hydroxy-benzy1)-3-oxo-butyric acid methyl ester 100 mg (yield: 34%) of the title compound was obtained from 400 mg (1.29 mmol) of 2- [1- (3-benzyloxi-phenyl)-methyliden]-3-oxo-butyric acid methyl ester in the same manner as described above.

NMR : lH-NMR (CDCl3) â 7. 16-7. 12 (1H, s), 6. 74-6. 65 (3H, m), 4.88 (1H, s), 3. 80-3. 72 (1H, m), 3.70 (3H, s), 3.11 (2H, d, J=4Hz), 2.19 (3H, s) Mass (EI) 223 (M++1) (4) Preparation of () 3- [4-fluorobenzyloxyimino-2- (3-hydroxy-benzyl)]-

butyric acid methyl ester 100 mg (yield: 67%) of the title compound was obtained from 100 mg (0.45 mmol) of () 2- (3-hydroxy-benzyl)-3-oxo-butyric acid methyl ester in the same manner as in Preparation Example 51- (3).

NMR : 1H-NMR(CDCl3) # 7. 24-7. 21 (2H, m), 7. 12-6. 97 (3H, m), 6. 70-6. 60 (3H, m), 5.03 (2H, s), 4.79 (1H, s), 3.66 (3H, s), 3. 58-3. 54 (1H, m), 3. 19-2. 95 (1H, m), 2. 93-2. 90 (1H, m), 1.87 (3H, s) Mass (EI) 332 (M++1) Example 85 : 3- [4-fluoro-benzyloxyimino]-2-4- [2- (1-phenyl-lH-pyrrazole-4-yl)- ethoxy] -benzyl] -butyric acid 87 mg (yield: 72%) of the title compound was obtained from 100 mg (0.53 mmol) of 2-(1-phenyl-1H-pyrrazole-3-yl)-ethanol and 83 mg (0.24 mmol) of (~) 3-[4- fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.

NMR : 1H-NMR(CDCl3) # 7. 83 (1H, s), 7. 66-7. 64 (3H, m), 7. 45-7. 41 (2H, m), 7. 30-7. 18 (3H, m), 7. 05-6. 95 (4H, m), 6. 83-6. 77 (2H, m), 5.01 (2H, s), 4.12 (2H, t, J=8Hz), 3. 57-3. 53 (1H, m), 3. 18-3. 13 (1H, m), 3. 04-2. 94 (3H, m), 1.86 (3H, s) Mass (EI) 502 (M+1) Example 86: 3- [4-fluoro-benzyloxyimino]-2- {3- [l- (4-isopropyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid 10 mg (yield: 27%) of the title compound was obtained from 15 mg (0.07 mmol) of [1-(4-isopropyl-phenyl)-5-methyl-1H-pyrrazole-4-yl]-methanol and 22 mg

(0.07 mg) of (A) 3- [4-fluorobenzyloxyimino-2- (3-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.

NMR : 1H-NMR(CDCl3) # 7.93 (1H, s), 7.74 (1H, s), 7. 57-7. 55 (2H, m), 7. 30-7. 14 (5H, m), 6. 99-6. 95 (2H, m), 6. 84-6. 72 (3H, m), 5.01 (2H, s), 4.95 (2H, s), 3. 60-3. 58 (1H, m), 3. 23-3. 18 (1H, m), 3. 03-2. 92 (1H, m), 1.85 (3H, s), 1.24 (6H, d, J=8Hz) Mass (EI) 530 (M++1) Example 87 : 3- [4-fluoro-benzyloxyimino]-2- {3- [2- (5-methyl-2-phenyl-oxazole-4-yl)- ethoxy]-benzyl}-butyric acid 15 mg (yield: 19%) of the title compound was obtained from 30 mg (0.15 mmol) of 2- (5-methyl-2-phenyl-oxazole-4-yl)-ethanol and 34 mg (0.1 mg) of () 3- [4- fluorobenzyloxyimino-2- (3-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.

Mass (EI) 517 (M''+1) Example 88: 3-[4-f luoro-benzyloxyimino]-2-{3-[2-(5-methyl-2-thiopen-2-yl-oxazo le -4-yl)-ethoxy]-benzyl}-butyric acid 5 mg (yield: 10%) of the title compound was obtained from 20 mg (0.095 mmol) of 2- (5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethanol and 35 mg (0.1 mmol) of (~) 3-[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.

NMR : 1H-NMR(CDCl3) # 7. 59-7. 58 (1H, m), 7. 37-7. 35 (1H, m), 7. 25-7. 19 (2H, m), 7. 09-7. 06 (1H, m), 7. 03-6. 96 (4H, m), 6.75 (2H, d, J=8. 8Hz), 5.01 (2H, s), 4.16 (2H, t, J=8Hz), 3. 56-3. 52 (1H, m), 3. 18-3. 12 (1H, m), 2. 98-2. 92 (3H, m), 2.35 (3H, s), 1.86 (3H,

s) Mass (EI) 523 (M++1) Example 89: 3- [4-fluoro-benzyloxyimino]-2- {4-methanesulfonyloxy-benzyl}- butyric acid 5 mg (yield: 55%) of 3- [4-fluoro-benzyloxyimino]-2- {4-methanesulfonyloxy- benzyl} -butyric acid was obtained from 20 mg (0.06 mmol) of () 3- [4- fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Preparation Example 55 and Example 50.

NMR : 1H-NMR(CDCl3) # 7. 26-7. 18 (2H, m), 7. 18-7. 12 (4H, m), 7. 03-6. 98 (2H, m), 5.01 (2H, s), 3.66 (3H, s), 3. 56-3. 52 (1H, m), 3. 24-3. 18 (1H, m), 3.12 (3H, s), 3. 01-2. 95 (1H, m), 1.86 (3H, s) Mass (EI) 410 (M++1) Example 90: 2- {4-benzenesulfonyloxy-benzyl}-3- [4-fluoro-benzyloxyimino]- butyric acid 10 mg (yield: 34%) of 2- {4-benzenesulfonyloxy-benzyl}-3- [4-fluoro- benzyloxyimino]-butyric acid was obtained from 20 mg (0.06 mmol) of () 3- [4- fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]-butyric acid methyl ester and 0.012 ml (0.09 mmol) of benzenesulfonyl chloride in the same manner as in Preparation Example 55 and Example 50.

NMR : 1H-NMR(CDCl3) # 7. 83-7. 80 (2H, m), 7. 67-7. 63 (1H, m), 7. 53-7. 49 (2H, m), 7. 26-7. 22 (2H, m), 7. 04-6. 97 (4H, m), 6. 85-6. 83 (2H, m), 5.00 (2H, s), 3.64 (3H, s), 3. 51-3. 47 (1H, m), 3. 19-3. 13 (1H, m), 2. 95-2. 90 (1H, m), 1. 82 (3H, s)

Mass (EI) 472 (M++1) Example 91: 3- [4-fluoro-benzyloxyimino]-2- {4-phenylmethanesulfonyloxy-benzyl}- butyric acid 9.7 mg (yield: 32%) of the title compound was obtained from 20 mg (0.06 mmol) of () 3- [4-fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]-butyric acid methyl ester and 18 mg (0.09 mmol) of benzenesulfonyl chloride in the same manner as in Preparation Example 55 and Example 50.

NMR : 1H-NMR(CDCl3) # 7. 46-7. 40 (4H, m), 7. 25-7. 19 (2H, m), 7.11 (1H, d, J=8Hz), 7. 02-6. 96 (5H, m), 6.67 (1H, d, J=8Hz), 5.00 (2H, s), 4.50 (2H, s), 3.65 (3H, s), 3. 54-3. 50 (1H, m), 3. 21-3. 11 (1H, m), 2. 98-2. 86 (1H, m), 1.85 (3H, s) Mass (EI) 486 (M++1) Preparation Example 62: 1-phenyl-1H-pyrrazole-4-yl-methanol 2.0 g (yield: 38%) of 1-phenyl-1H-pyrrazole-4-yl-methanol was obtained from 3.16 g (29 mmol) of phenyl hydrazine in the same manner as in Preparation Example 4.

NMR :'H-NMR (CDC13) 8 7.93 (1H, s), 7.71 (1H, s), 7. 67-7. 65 (2H, m), 7. 47-7. 43 (2H, m), 7. 31-7. 26 (1H, m), 4.68 (2H, s), 3.68 (1H, s) Mass (EI) 175 (M++1) Example 92: 3- [4-fluoro-benzyloxyimino]-2- {4- [l-phenyl-lH-pyrrazole-4- ylmethoxy]-benzyl}-butyric acid 20 mg (yield: 17%) of 3-[4-fluoro-benzyloxyimino]-2-{4-[1-phenyl-1H- pyrrazole-4-ylmethoxy]-benzyl}-butyric acid was obtained from 63 mg (0.18 mmol) of

() 3- [4-fluorobenzyloxyimino-2- (4-hydroxy-benzyl)]-butyric acid methyl ester and 40 mg (0.23 mmol) of 1-phenyl-lH-pyrrazole-4-yl-methanol in the same manner as in Example 81.

NMR : 1H-NMR(CDCl3) # 8.00 (1H, s), 7.78 (1H, s), 7. 68-7. 66 (2H, m), 7. 46-7. 43 (2H, m), 7.31 (1H, d, J=lHz), 7. 22-7. 17 (2H, m), 7. 07-6. 97 (4H, m), 6.85 (1H, d, J=8Hz), 5.02 (2H, s), 4.99 (2H, s), 3. 59-3. 55 (1H, m), 3. 19-3. 14 (1H, m), 3. 03-2. 98 (1H, m), 1. 88 (3H, s) Mass (EI) 488 (M++1) Example 93: 3- [ethoxyimino]-2- f 4- [2- (5-methyl-1-phenyl-lH-pyrrazole-3-yl)- ethoxy]-benzyl}-butyric acid 14 mg (yield: 26%) of the title compound was obtained from 25 mg (0.12 mmol) of2- (5-methyl-l-phenyl-lH-pyrrazole-3-yl)-ethanol and 23 mg (0.086 mmol) of (~) 3-ethyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Example 81.

NMR : 1H-NMR(CDCl3) # 7. 48-7. 42 (5H, m), 7. 10-7. 08 (2H, m), 6. 88-6. 83 (2H, m), 6.13 (1H, s), 4.23 (2H, t, J=8Hz), 4.06 (2H, q, J=8Hz), 3.66 (3H, s), 3. 65-3. 52 (1H, m), 3. 19-3. 11 (3H, m), 2. 94-2. 89 (1H, m), 2.33 (3H, s), 1. 88 (3H, s), 1.20 (3H, t, J=8Hz) Mass (EI) 436 (M++1) Preparation Example 63: 2-(5-methyl-1-phenyl-lH-pyrrazole-3-yl)-ethanol 150 mg (yield: 27%) of 2-(5-methyl-1-phenyl-1H-pyrrazole-3-yl)-ethanol was obtained from 500 mg (2.65 mmol) of 2- (5-methyl-l-phenyl-lH-pyrrazole-3-yl)- methanol in the same manner as in Preparation Example 60.

NMR : IH-NMR (CDCl3) 6 7. 48-7. 35 (5H, m), 6.05 (1H, s), 3.95 (2H, t, J=8Hz), 2.89 (2H, t, J=8Hz), 2.82 (1H, s), 2.33 (3H, s) Mass (EI) 203 (M++1) Example 94: 2-{4-[2-(4-methanesulfonyloxy-phenyl)-ethoxy]-benzyl}-3- [methoxyimino]-butyric acid 16 mg (yield: 27%) of the title compound was obtained from 27 mg (0.10 mmol) of methanesulfonic acid 2- (4-methanesulfonyloxy-phenyl)-ethyl ester and 40 mg (0.135 mmol) of () 3-methyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Example 81.

Mass (EI) 436 (M++1) Example 95: 3-[ethoxyimino]-2-{4-[2-(4-methanesulfonyloxy-phenyl)-ethoxy ]- benzyl}-butyric acid 5.7 mg (yield: 8.6%) of the title compound was obtained from 71 mg (0.21 mmol) of methanesulfonic acid 2- (4-methanesulfonyloxy-phenyl)-ethyl ester and 39 mg (0.147 mmol) of (~) 3-ethyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Example 81.

NMR : lH-NMR (CDCl3) 6 7.32 (2H, d, J=8Hz), 7.22 (2H, d, J=8Hz), 7. 09-7. 04 (2H, m), 6. 81-6. 75 (2H, m), 4.14 (2H, t, J=6.4Hz), 4.07 (2H, q, J=7.2Hz), 3. 56-3. 52 (1H, m), 3.12 (3H, s), 3. 18-3. 06 (3H, m), 3. 01-2. 95 (1H, m), 1.84 (3H, s), 1.17 (3H, t, J=7.2Hz) Mass (EI) 450 (M++1) Example 96: 3-[2-fluoro-ethoxyimino]-2-{4-[2-(4-methanesulfonyloxy-pheny l)-

ethoxy]-benzyl}-butyric acid 6.7 mg (yield: 9.9%) of the title compound was obtained from 71 mg (0.21 mmol) of methanesulfonic acid 2- (4-methanesulfonyloxy-phenyl)-ethyl ester and 41 mg (0.144 mmol) of (i) 3-(2-fluoro-ethyloxyimino)-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Example 81.

NMR : 1H-NMR(CDCl3) # 7.32 (2H, d, J=7. 2Hz), 7.21 (2H, d, J=6.4Hz), 7.06 (2H, d, J=8. 4Hz), 6.79 (2H, d, J=8.4Hz), 4. 57-4. 53 (1H, m), 4. 45-4. 41 (1H, m), 4.27 (1H, t, J=4.4Hz), 4.20 (1H, t, J=4.4Hz), 4. 15-4. 09 (2H, m), 3. 56-3. 52 (1H, m), 3.12 (3H, s), 3. 18-3. 06 (3H, m), 2. 98-2. 93 (1H, m), 1.89 (3H, s) Mass (EI) 468 (M++1) Example 97 : 2- {4- [2- (4-methanesulfonyloxy-phenyl)-ethoxy]-benzyl}-3- [propoxyimino]-butyric acid 5.8 mg (yield: 8. 7%) of the title compound was obtained from 71 mg (0.21 mmol) of methanesulfonic acid 2- (4-methanesulfonyloxy-phenyl)-ethyl ester and 40 mg (0.143 mmol) of (i) 3-propyloxyimino-2- (4-hydroxy-benzyl)-butyric acid, methyl ester in the same manner as in Example 81.

NMR :'H-NMR (CDCl3) 8 7.32 (2H, d, J=8.4Hz), 7.22 (2H, d, J=8. 4Hz), 7.06 (2H, d, J=8.4Hz), 6.78 (2H, d, J=8. 8Hz), 4.13 (1H, t, J=6.8Hz), 4.00 (1H, t, J=6. 0Hz), 3. 56-3. 52 (1H, m), 3.12 (3H, s), 3. 18-3. 06 (3H, m), 3. 02-2. 96 (1H, m), 1.84 (3H, s), 1.58 (2H, q, J=8.4Hz), 0.85 (3H, t, J=4.4Hz) Mass (EI) 464 (M++1) Example 98: 3- [benzyloxyimino]-2- {4- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-

ethoxy}-benzyl}-2-methyl-butylic acid 7 mg (yield: 54%) of the title compound was obtained from 10 mg (0.03 mmol) of (A) 3-benzyloxyimino-2-(4-hydroxy-benzyl)-2-methyl-butyric acid methyl ester and 5.4 mg (0.024 mmol) of 2- [2- (4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol in the same manner as in Example 81.

NMR : 1H-NMR(CDCl3) # 7. 98-7. 94 (2H, m), 7. 33-7. 24 (3H, m), 7. 12-7. 07 (2H, m), 6.93 (2H, d, J=8.8Hz), 6.72 (2H, d, J=8.8Hz), 5.03 (2H, s), 4.19 (2H, t, J=6.8Hz), 3.13 (1H, d, J=17.6Hz), 3.00 (1H, d, J=17.6Hz), 2.95 (2H, t, J=6.8Hz), 2.37 (3H, s) Mass (EI) 531 (M++1) Example 99: 3-[propoxyimino]-2-{4-[1-(p-tolyl-1H-pyrrazole-4-yl)-methoxy ]- benzyl}-butyric acid 12 mg (yield: 27%) of the title compound was obtained from 25 mg (0.13 mmol) of [1- (4-methyl-phenyl)-5-methyl-lH-pyrrazole-4-yl]-methanol and 29 mg (0.10 mg) of (~) 3-propyloxyimino-2-(3-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.

NMR : 1H-NMR(CDCl3) # 7.93 (1H, s), 7.74 (1H, s), 7. 55-7. 52 (2H, m), 7. 26-7. 23 (2H, m), 7. 15-7. 09 (2H, m), 6. 90-6. 88 (2H, m), 5.01 (2H, s), 3.99 (2H, t, J=6.8Hz), 3. 60-3. 54 (1H, m), 3. 20-3. 15 (1H, m), 3. 03-2. 95 (1H, m), 2.37 (3H, s), 1.85 (3H, s), 1.57 (2H, q, J=7. 6Hz), 0.89 (3H, t, J=7.6Hz) Mass (EI) 436 (M++1) Example 100: 3- [4-fluoro-benzyloxyiminol-2-14- [2- (4-methyl-thiazole-5-yl)- ethoxy]-benzyl}-butyric acid

17 mg (yield: 34%) of the title compound was obtained from 20 mg (0.139 mmol) of 2- (4-methyl-thiazole-5-yl)-ethanol and 37 mg (0.107 mmol) of 3- [4-fluoro- benzyloxyimino]-2-{4-[1-phenyl-1H-pyrrazole-4-ylmethoxy]-ben zyl}-butyric acid in the same manner as in Example 81.

NMR : 1H-NMR(CD3OD) # 8.63 (1H, s), 7. 20-7. 16 (2H, m), 7. 06-7. 02 (2H, m), 6. 99-6. 94 (2H, m), 6. 77-6. 74 (2H, m), 5.00 (2H, s), 4.11 (2H, t, J=6. 0Hz), 3. 51-3. 48 (1H, m), 3. 27-3. 23 (2H, m), 3. 19-3. 14 (1H, m), 2. 94-2. 88 (1H, m), 2.44 (3H, s), 1.89 (3H, s), Mass (EI) 457 (M++1) Example 101: 2-{4-[2-(4-methyl-thiazole-5-yl)-ethoxy]-benzyl}-3-[propoxyi mino]- butyric acid 9 mg (yield: 32%) of the title compound was obtained from 20 mg (0.139 mmol) of 2- (4-methyl-thiazole-5-yl)-ethanol and 37 mg (0.071 mg) of () 3- propyloxyimino-2- (3-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.

NMR : 1H-NMR(CD3OD) # 8.62 (1H, s), 7. 13-7. 08 (2H, m), 6. 80-6. 77 (2H, m), 4.09 (2H, t, J=6.4Hz), 3.96 (2H, t, J=6.8Hz), 3. 56-3. 52 (1H, m), 3.20 (2H, t, J=6.4Hz), 3. 19-3. 14 (1H, m), 2. 99-2. 90 (1H, m), 2.42 (3H, s), 1.85 (3H, s), 1.53 (2H, q, J=7. 2Hz), 0.87 (3H, t, J=7.6Hz), Mass (EI) 391 (M++1) Example 102: 2- 4- [2- (5-ethyl-pyridine-2-yl)-ethoxy]-benzyl}-3- [propoxyimino]- butyric acid 9 mg (yield: 64%) of the title compound was obtained from 10 mg (0.66 mmol)

of 2- (5-ethyl-pyridine-2-yl)-ethanol and 10 mg (0.035 mmol) of (~) 3-propyloxyimino- 2- (3-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.

Mass (EI) 399 (M++1) Example 103: 2-{4-[2-(5-ethyl-pyridine-2-yl)-ethoxy]-benzyl}-3-[methoxyim ino]-2- methyl-butyric acid 8 mg (yield: 53%) of the title compound was obtained from 10 mg (0.66 mmol) of 2- (5-ethyl-pyridine-2-yl)-ethanol and 10 mg (0.039 mmol) of () 3-methoxyimino-2- (4-hydroxy-benzyl) -2-methyl-butyric acid methyl ester in the same manner as in Example 81.

NMR : 1H-NMR(CDCl3) # 8.40 (1H, s), 7. 52-7. 50 (1H, m), 7. 27-7. 23 (1H, m), 7. 07-7. 03 (2H, m), 6. 77-6. 73 (2H, m), 4. 26-4. 22 (2H, m), 3.86 (3H, s), 3. 26-3. 04 (4H, m), 2.63 (2H, q, J=0. 8 Hz), 1. 88 (3H, s), 1.34 (3H, s), 1. 26-1. 20 (2H, m) Mass (EI) 531(M++1) Example 104: 2-{4-[2-(benzoxazole-2-yl-methyl-amino)-ethoxy}-benzyl}-3- [methoxyimino]-butyric acid 6 mg (yield: 37%) of the title compound was obtained from 13 mg (0.048 mmol) of 2- (benzoxazole-2-yl-methyl-amino)-ethanol and 10 mg (0.039 mmol) of (~) 3-methyloxyimino-2- (3-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.

NMR : 1H-NMR(CDCl3) # 7. 36-7. 34 (1H, m), 7. 24-7. 21 (1H, m), 7. 17-7. 13 (1H, m), 7. 17-7. 13 (1H, m), 7.10 (2H, d, J=4.8Hz), 7. 02-6. 98 (1H, m), 6. 78-6. 74 (2H, m), 4. 23-4. 07 (2H, m), 3. 93-3. 86 (2H, m), 3.83 (3H, s), 3. 57-3. 53 (1H, m), 3.30 (3H, s),

3. 19-3. 12 (1H, m), 2. 99-2. 89 (1H, m), 1.87 (3H, s) Mass (EI) 391 (M++1) Preparation Example 64: [2- (4-fluorophenyl)-5-methyloxazole-4-yl]-methanol (1) Preparation of 2- (4-fluorophenyl)-5-methyl-3-oxyoxazole-4-carboxylic acid methyl ester 2.6 g (yield: 59%) of the title compound was synthesized from 2.18 g (17.6 mmol) of 4-fluoro benzaldehyde and 2 g (13.8 mmol) of 2-hydroxyimino-3-oxo-butyric acid methyl ester in the same manner as in Preparation Example 53 (2).

Mass (EI) 252 (MF+1) (2) Preparation of 2- (4-fluorophenyl)-5-methyloxazole-4-carboxylic acid methyl ester 2.1 g (yield: 90%) of the title compound was synthesized from 2.6 g (10 mmol) of the compound obtain in Preparation Example 64 (1) in the same manner as in Preparation Example 53 (3).

NMR : lH-NMR (CDCl3) 6 8. 09-8. 05 (2H, m), 7. 17-7. 12 (2H, m), 3.95 (3H, s), 2.71 (3H, s) Mass (EI) 236 (M++1) (3) Preparation of [2- (4-fluorophenyl)-5-methyloxazole-4-yl]-methanol 1.6 g (yield: 87%) of the title compound was synthesized from 2.1 g (8.9 mmol) of the compound obtained in Preparation Example 64 (2) in the same manner as in Preparation Example 53 (4).

NMR : lH-NMR (CDCl3) 6 8. 01-7. 97 (2H, m), 7. 15-7. 11 (2H, m), 4.59 (2H, d, J=8Hz), 2.40 (3H, s) Mass (EI) 208 (M++1) Preparation Example 65: (5-methyl-2-phenyl-oxazole-4-yl) -methanol (1) Preparation of 5-methyl-3-oxy-2-phenyl-oxazole-4-carboxylic acid methyl ester 1.6 g (yield: 72%) of the title compound was synthesized from 9.93 g (82.7 mmol) of benzaldehyde and 12 g (82.7 mmol) of 2-hydroxyimino-3-oxo-butyric acid methyl ester in the same manner as in Preparation Example 53 (2).

Mass (EI) 234 (M++1) (2) Preparation of 5-methyl-2-phenyl-oxazole-4-carboxylic acid methyl ester 11.5 g (yield: 90%) of the title compound was synthesized from 16 g (59 mmol) of the compound obtained in Preparation Example 65 (1) in the same manner as in Preparation Example 53 (3).

NMR : lH-NMR (CDCl3) 6 8. 09-8. 06 (2H, m), 7. 48-7. 44 (3H, m), 3.95 (3H, s), 2.72 (3H, s) Mass (EI) 218 (M++1) (3) Preparation of (5-methyl-2-phenyl-oxazole-4-yl)-methanol 9.2 g (yield: 92%) of the title compound was synthesized from 11.5 g (53 mmol) of the compound obtained in Preparation Example 65 (2) in the same manner as in Preparation Example 53 (4).

NMR : lH-NMR (CDCl3) 6 8. 01-7. 98 (2H, m), 7. 46-7. 42 (3H, m), 4.60 (2H, s), 2.41 (3H, s) Mass (EI) 190 (M++1) Preparation Example 66: (2-isopropyl-5-methyl-oxazole-4-yl) -methanol (1) Preparation of 2-isopropyl-5-methyl-3-oxy-oxazole-4-carboxylic acid methyl ester 2 g (yield: 73%) of the title compound was synthesized from 2 g (13.7 mmol) of isobutylaldehyde and 1.26 g (17.5 mmol) of 2-hydroxyimino-3-oxo-butyric acid methyl ester in the same manner as in Preparation Example 53 (2).

Mass (EI) 200 (M++1) (2) Preparation of 2-isopropyl-5-methyl-oxazole-4-carboxylic acid methyl ester 450 mg (yield: 25%) of the title compound was synthesized from 2 g (10 mmol) of the compound obtained in Preparation Example 66 (1) in the same manner as in Preparation Example 53 (3).

NMR : lH-NMR (CDCl3) 6 3.92 (3H, s), 3. 12-3. 07 (1H, m), 2.62 (3H, s), 1.37 (6H, d, J=7.2Hz) Mass (EI) 184 (M++1) (3) Preparation of (2-isopropyl-5-methyl-oxazole-4-yl)-methanol 350 mg (yield: 92%) of the title compound was synthesized from 450 mg (2.5 mmol) of the compound obtained in Preparation Example 66 (2) in the same manner as in Preparation Example 53 (4).

NMR : lH-NMR (CDCl3) 6 4.48 (2H, s), 3. 04-2. 98 (1H, m), 2.28 (3H, s), 1. 33 (6H, d, J=7. 2Hz) Mass (EI) 156 (M++1) Preparation Example 67: 2- (2-isopropyl-5-methyl-oxazole-4-yl)-ethanol (1) Preparation of 2-isobutyrylamino-succinic acid 1-benzylester-4-methyl ester 3.7 g (13.5 mmol) of 2-aminosuccinic acid 1-benzyl ester hydrochloride, 1.2 g (13.5 mmol) of isobutyric acid, 3.0 ml (28.4) of triethylamine and 2. 0g (14.9 mmol) of 1-hydroxybenzotriazole were added to 50 ml of dimethylformamide, then 2.9 g (14.9 mmol) of 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide was added to the resulting solution while being stirred. After stirring for 24 hours, ethylacetate was added thereto, followed by washing with water. An organic layer thus obtained was dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography to obtain 4.3 g of the title compound in a yield, of 99%.

NMR : lH-NMR (CDCl3) 6 7. 39-7. 32 (5H, m), 6.48 (1H, d, J=8Hz), 5.20 (1H, d, J=12Hz), 5.16 (1H, d, J=12Hz), 4. 92-4. 88 (1H, m), 3.62 (3H, s), 3.05 (1H, dd, J=12Hz, 4Hz), 2.85 (1H, dd, J=12Hz, 4Hz), 2. 44-2. 37 (1H, m), 1.14 (6H, d, 4Hz) Mass (EI) 308 (M++1) (2) Preparation of 2-isobutyrylamino-succinic acid-4-methyl ester 4.3 g (13.3 mmol) of 2-isobutyrylamino-succinic acid 1-benzylester-4-methyl ester and 400 mg of palladium/C were added to ethanol and the resulting solution was stirred for about 3 hours in a hydrogen atmosphere. After removing palladium by

filtering, solvent was removed to obtain 2.9 g of the title compound in a yield of 100%.

NMR : lH-NMR (CDCl3) 6 6.72 (1H, d, J=4Hz), 3.72 (3H, s), 3.06 (1H, dd, J=4Hz, 16Hz), 2.84 (1H, dd, J=4Hz, 16Hz), 2. 49-2. 42 (1H, m), 1. 20-1. 17 (3H, m) Mass (EI) 218 (M++1) (3) Preparation of 2- (2-isopropyl-5-methyl-oxazole-4-yl)-ethanol 0.40 g (yield: 17%) of the title compound was obtained from 2.9 g (13.3 mmol) of 2-isobutyrylamino-succinic acid-4-methyl ester in the same manner as in Preparation Example 31.

NMR : lH-NMR (CDCl3) 6 3.71 (2H, s), 3.47 (2H, s), 3. 04-2. 99 (1H, m), 2.24 (3H, s), 1.31 (6H, d, J=8Hz) Mass (EI) 170 (M++1) Preparation Example 68: 2- (2, 5-dimethyl-oxazole-4-yl) -ethanol 0.6 g (yield: 26%) of the title compound was obtained from 4.5 g (16 mmol) of 2-aminosuccinic acid-1-benzyl ester-4-methyl ester hydrochloride and 0.99 g (16 mmol) of acetic acid in the same manner as in Preparation Example 31.

NMR : 1H-NMR(CDCl3) # 3. 87-3. 80 (2H, m), 2.61 (2H, t, J=6Hz), 2.36 (3H, s), 2.21 (3H, s) Mass (EI) 142 (M++1) Preparation Example 69: N-hydroxy-2-phenyl-acetamidine 4.0 g (26.6 mmol, yield: 89%) of the title compound was synthesized from 3.5 g (30 mmol) of phenyl-acetonitrile in the same manner as in Preparation Example 22 (1).

Mass (EI) 151 (M++1) Preparation Example 70: (3-benzyl- [1, 2,4] oxadiazole-5-yl) -methanol 0.6 g (yield: 12%) of the title compound was obtained from 4.0 g (26.6 mmol) of N-hydroxy-2-phenyl-acetamidine in the same manner as in Preparation Example 22.

NMR : lH-NMR (CDCl3) 6 7. 37-7. 28 (5H, m), 4. 82 (2H, d, J=4Hz), 4.08 (2H, s) Mass (EI) 191 (M++1) Preparation Example 71: [2- (4-ethyl-phenyl)-5-methyl-oxazole-4-yl]-methanol 0.82 g (yield: 22%) of the title compound was obtained from 2.34 g (17.4 mmol) of 4-ethyl benzaldehyde in the same manner as in Preparation Example 53.

NMR : 1H-NMR(CDCl3) # 7. 91-7. 89 (2H, m), 7. 28-7. 26 (3H, m), 4.59 (2H, d, J=6Hz), 2.69 (2H, q, J=8Hz), 2.40 (3H, s), 2.25 (1H, t, J=6Hz), 1.26 (3H, t, J=8Hz) Mass (EI) 218 (M++1) Preparation Example 72: [5-methyl-2- (4-methylsulfanyl-phenyl)-oxazole-4-yl]- methanol 1.0 g (yield: 24%) of the title compound was obtained from 2.33 ml (17.5 mmol) of 4-methylsulfanyl-benzaldehyde in the same manner as in Preparation Example 53.

Mass (EI) 236 (M++1) Preparation Example 73: [5-methyl-2- (4-methylsulfonyl-phenyl)-oxazole-4-yl]- methanol

200 mg (0. 85 mmol) of [5-methyl-2- (4-methylsulfanyl-phenyl)-oxazole-4-yl]- methanol was dissolved in 5 ml of methanol, and 1.2 g (1.9 mmol) of oxone dissolved in 5 ml of water was added dropwise the resulting solution with being stirred. After stirring for 5 hours, 10 ml of ethylacetate was further thereto, then an organic layer thus obtained was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and filtered off to remove solvent, then the residue was purified by column chromatography to obtain 160 mg (0.60. mmol) of the title compound in a yield of 70%.

NMR : lH-NMR (CDCl3) 6 8.19 (2H, dd, J=6Hz, 2Hz), 8.01 (2H, dd, J=6Hz, 2Hz), 4.61 (2H, d, J=6Hz), 3.09 (3H, s), 2.45 (3H, s), 2.00 (1H, t, J=6Hz) Mass (EI) 268 (M++1) Preparation Example 74: 2- (benzoxazole-2-yl-methylamino)-ethanol 0.5 g (3.3 mmol) of 2-chlorobenzoxazole and 0.5 ml of triethylamine were added to methylene chloride, and 1 ml of 2-methylamino-ethanol was added dropwise to the resulting solution while being stirred. After stirring for 30 minutes, ethylacetate was added thereto and the resulting solution was washed with water. An organic layer thus obtained was dried over anhydrous magnesium sulfate, then the residue was purified by column chromatography to give 0.55 g of the title compound in a yield of 87%.

NMR : lH-NMR (CDCl3) 6 7. 34-7. 32 (1H, m), 7. 27-7. 25 (1H, m), 7. 18-7. 14 (1H, m), 7. 04-6. 99 (1H, m), 3.95 (2H, t, J=6Hz), 3.72 (2H, t, J=6Hz), 3.27 (3H, s) Mass (EI) 193 (MF+1)

Preparation Example 75: () 2- (3-hydroxybenzyl)-3- [methoxyimino]-butyric acid methyl ester 0.15 g (yield: 79%) of the title compound was obtained from 0.15 g (0.68 mmol) of () 2- (3-hydroxybenzyl)-3-oxo-butyric acid methyl ester in the same manner as in Preparation Example 37.

NMR : lH-NMR (CDCl3) 6 7. 16-7. 12 (1H, m), 6. 78-6. 74 (1H, m), 6. 69-6. 66 (2H, m), 3.83 (3H, s), 3.66 (3H, s), 3.56 (1H, t, J=8Hz), 3.18 (1H, dd, J=7.2Hz, 14Hz), 2.89 (1H, dd, J=7.2Hz, 14Hz), 1.85 (3H, s) Mass (EI) 252 (M++1) Preparation Example 76: 2- (4-benzyloxy-benzyl)-2-methyl-malonic acid diethyl ester 500 mg (2.87 mmol) of 2-methylmalonic acid diethyl ester was dissolved in 25 ml of tetrahydrofuran, and 126 mg (3.15 mmol) of sodium hydride was slowly added to the resulting solution at room temperature. After stirring for 30 minutes, 835mg (3.15 mmol) of 1-benzyloxy-4-bromomethyl-benzene was slowly added thereto. After stirring for 3 hours, ethylacetate was added thereto and the resulting solution was washed with water. An organic layer thus obtained was dried over anhydrous magnesium sulfate and then the residue was purified by column chromatography to obtain 0. 89 g of the title compound in a yield of 75%.

NMR : lH-NMR (CDCl3) 6 7. 43-7. 32 (5H, m), 7.04 (2H, d, J=8Hz), 6.87 (2H, d, J=8Hz), 5.03 (2H, s), 4.19 (4H, q, J=8Hz), 3.16 (2H, s), 1.33 (3H, s), 1.25 (6H, t, J=8Hz) Mass (EI) 371 (M++1)

Preparation Example 77: () 2- (4-benzyloxy-benzyl)-2-methyl-3-oxo-propionic acid ethyl ester 300 mg (0.81 mmol) of 2- (4-benzyloxy-benzyl)-2-methyl-malonic acid diethyl ester was dissolved in 20 ml of methylenechloride and 1.62 ml (1.0 M aqueous hexane) of diisopropyl aluminum hydride was slowly added to the resulting solution at-78°C.

After 15 minutes, 5 ml of saturated ammonium chloride solution and 1 ml of 1 N hydrochloride were added dropwise in sequence. The temperature was raised to room temperature and the resulting solution was extracted with ethyl acetate, then an organic layer thus obtained was dried over anhydrous magnesium sulfate, the residue was purified by column chromatography to obtain 0. 105 g of the title compound in a yield of 40%.

NMR : lH-NMR (CDCl3) 6 9.76 (1H, s), 7. 43-7. 36 (5H, m), 7.03 (2H, d, J=8Hz), 6. 87 (2H, d, J=8Hz), 5.03 (2H, s), 4. 18 (2H, q, J=8Hz), 3.16 (1H, d, J=16Hz), 3.02 (1H, d, J=16Hz), 1.26 (3H, s), 1.23 (3H, t, J=8Hz) Mass (EI) 327 (MA Preparation Example 78: 2- (4-benzyloxy-benzyl)-2-methyl-3-oxo-propionic acid ethyl ester 70 mg (yield: 92%) of the title compound was obtained from 0.105 g (0.321 mmol) of 2- (4-benzyloxy-benzyl)-2-methyl-3-oxo-propionic acid ethyl ester in the same manner as in Preparation Example 36 (2).

NMR : lH-NMR (CDCl3) 6 9.76 (1H, s), 6. 99-6. 94 (2H, m), 6. 74-6. 70 (2H, m), 4.19 (2H, q, J=8Hz), 3.50 (1H, s), 3.14 (1H, d, J=16Hz), 3.01 (1H, d, J=16Hz), 1.26 (3H, s), 1.23 (3H, t, J=8Hz)

Mass (EI) 237 (M++1) Preparation Example 79: () 2- (4-hydroxy-benzyl)-3- [methoxyimino]-2-methyl- propionic acid ethyl ester 75 mg (yield: 96%) of the title compound was obtained from 70 mg (0.296 mmol) of (i) 2-(4-benzyloxy-benzyl)-2-methyl-3-oxo-propionic acid ethyl ester in the same manner as in Preparation Example 37.

NMR :'H-NMR (CDC13) 8 7.56 (1H, s), 6. 97-6. 94 (2H, m), 6. 69-6. 67 (2H, m), 5.71 (1H, brs), 4.14 (2H, q, J=8Hz), 3.84 (3H, s), 3.02 (1H, d, J=12Hz), 2.97 (1H, d, J=12Hz), 1.34 (3H, s), 1.23 (3H, t, J=8Hz) Mass (EI) 266 (M++1) Example 105: () 2-{3-[2-(benzoxazole-2-yl-methylamino)-ethoxy]-benzyl}-3- [methoxyimino] -butylic acid methyl ester 100 mg (0.52 mmol) of 2- (benzoxazole-2-yl-methylamino)-ethanol was dissolved in 1 ml of dichloromethane and then 150 gl (1.0 mmol) of triethylamine was added to the resulting solution. To the reaction solution, 60 Ill (0. 78 mmol) of mesylchloride was added and the resulting solution was reacted for 1 hour. After the reaction, 10 ml of ethylacetate was added thereto and an organic layer thus obtained was washed twice with 5 ml of water. The organic layer was dried over anhydrous magnesium sulfate and filtered off to remove solvent. To 13 mg (0.048 mmol) of the resulting compound, 2 ml of acetenitrile, 20 mg (0.06 mmol) of cesium carbonate and 10 mg (0.040 mmol) of the compound obtained in Preparation Example 75 were added, and the resulting solution was reacted for 3 hours under reflux. After the reaction, 10 ml

of ethylacetate was added thereto, and an organic layer thus obtained was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and filtered off to remove solvent, then the residue was purified by column chromatography (ethylacetate/hexane: 1/3) to obtain 8 mg (0.019 mmol) of the title compound in a yield of 47%.

NMR : lH-NMR (CDCl3) 6 7. 37-7. 35 (1H, m), 7. 27-7. 25 (1H, m), 7. 18-7. 14 (2H, m), 7. 03-7. 00 (1H, m), 6. 78-6. 77 (1H, m), 6. 74-6. 72 (2H, m), 4.24 (2H, t, J=4Hz), 3.94 (2H, t, J=4Hz), 3.81 (3H, s), 3.64 (3H, s), 3.56 (1H, t, J=8Hz), 3.35 (3H, s), 3.18 (1H, dd, J=7.2Hz, 14Hz), 2.92 (1H, dd, J=7.2Hz, 14Hz), 1.83 (3H, s) Mass (EI) 426 (M++1) Example 106: () 2-{3-[2-(benzoxazole-2-yl-methylamino)-ethoxy]-benzyl}-3- [methoxyimino]-butyric acid 6 mg (0.014 mmol) of the compound obtained in Example 105 was dissolved in 2 ml of a mixed solution of tetrahydrofuran/water/methanol (1/l/l, v/v/v), and 15 mg (0.63 mmol) of lithium hydroxide was added to the resulting solution which was then reacted for 3 hours. After the reaction, 1 ml of saturated ammonium chloride and 5 ml of ethyl acetate were added to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate and filtered off. Then, solvent was removed to obtain 5 mg (0. 012 mmol) of the title compound in a yield of 86%.

NMR : lH-NMR (CDCl3) 6 7. 37-7. 35 (1H, m), 7. 27-7. 25 (1H, m), 7. 19-7. 13 (2H, m), 7. 03-6. 99 (1H, m), 6. 82-6. 80 (2H, m), 6. 73-6. 71 (1H, m), 4. 23-4. 18 (2H, m), 3. 92-9. 83 (2H, m), 3. 84 (3H, s), 3.56 (1H, t, J=8Hz), 3.30 (3H, s), 3.20 (1H, dd, J=7.2Hz, 14Hz), 2. 98 (1H, dd, J=7.2Hz, 14Hz), 1.89 (3H, s)

Mass (EI) 412 (M++1) Example 107: () 3- [ethoxyimino]-2- [4- (5-methyl-2-phenyloxazole-4-ylmethoxy)- benzyl]-butyric acid methyl ester 16 mg (0.37 mmol, yield: 96%) of the title compound was obtained from 15 mg (0.072 mmol) of 4-chloromethyl-5-methyl-2-phenyloxazole and 10 mg (0.038 mmol) of (~) 3-ethoxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Example 105.

NMR : 1H-NMR(CDCl3) # 8. 02-8. 00 (2H, m), 7. 45-7. 42 (3H, m), 7. 12-7. 09 (2H, m), 6. 93-6. 91 (2H, m), 4.96 (2H, s), 4.06 (2H, q, J=8Hz) 3.65 (3H, s), 3.54 (1H, t, J=8Hz), 3.18 (1H, dd, J=12Hz, 6Hz), 2.93 (1H, dd, J=12Hz, 8Hz), 2.42 (3H, s), 1.85 (3H, s), 1.18 (3H, t, J=8Hz) Mass (EI) 437 (M++1) Example 108: () 3- [ethoxyimino]-2- [4- (5-methyl-2-phenytoxazole-4-ylmethoxy)- benzyl]-butyric acid 5 mg (0. 012 mmol, yield: 51%) of the title compound was obtained from 10 mg (0.023 mmol) of () 3- [ethoxyimino]-2- [4- (5-methyl-2-phenyloxazole-4-ylmethoxy)- benzyl] -butyric acid methyl ester in the same manner as in Example 106.

NMR : 1H-NMR(CDCl3) # 8. 02-8. 00 (2H, m), 7. 45-7. 42 (3H, m), 7. 13-7. 09 (2H, m), 6. 93-6. 91 (2H, m), 4.96 (2H, s), 4.08 (2H, q, J=8Hz) 3.56 (1H, t, J=8Hz), 3.18 (1H, dd, J=12Hz, 6Hz), 3.02 (1H, dd, J=12Hz, 8Hz), 2.42 (3H, s), 1.85 (3H, s), 1.19 (3H, t, J=8Hz) Mass (EI) 423 (M++1)

Example 109: (~) 3-[propoxyimino]-2-[4-(5-methyl-2-phenyloxazole-4-ylmethoxy) - benzyl]-butyric acid 3.1 g (7.2 mmol, yield: 72%) of the title compound was obtained from 2.3 g (11 mmol) of 4-chloromethyl-5-methyl-2-phenyloxazole and 2.9 g (10 mmol) of (i) 3- propyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Example 106.

Sodium salt from, NMR : lH-NMR (CD3OD) 6 8. 00-7. 98 (2H, m), 7. 49-7. 48 (3H, m), 7.13 (2H, d, J=8Hz), 6. 89 (2H, d, J=8Hz), 4.96 (2H, s), 3. 84 (2H, q, J=8Hz) 3.34 (1H, m), 3.15 (1H, dd, J=14Hz, 6Hz), 2.88 (1H, dd, J=14Hz, 8Hz), 2.42 (3H, s), 1.85 (3H, s), 1. 52-1. 45 (2H, m), 0. 83 (3H, t, J=8Hz) Mass (EI) 437 (M++1) Example 110: () 2-{4-[2-(4-fluorophenyl-5-methyloxazole-4-ylmethoxy)-benzyl] -3- [methoxyimino]-2-methyl butyric acid 10 mg (yield: 34%) of the title compound was obtained from 20 mg (0.097 mmol) of [2- (4-fluorophenyl)-5-methyloxazole-4-yl]-methanol and 19 mg (0.067 mmol) of () 3-methoxyimino-2- (4-hydroxy-benzyl)-2-methyl-butyric acid methyl ester in the same manner as in Examples 105 and 106.

NMR : 1H-NMR(CDCl3) # 8. 02-7. 97 (2H, m), 7. 14-7. 09 (2H, m), 7. 05-7. 03 (2H, m), 6. 90-6. 88 (2H, m), 4.94 (2H, s), 3.84 (3H, s), 3.12 (2H, s), 2.42 (3H, s), 1. 88 (3H, s), 1.36 (3H, s) Mass (EI) 441 (M++1) Example 111 : () 2- {4- [2- (4-fluorophenyl-5-methyloxazole-4-ylmethoxy)-benzyl]-3-

[methoxyimino]-2-methyl propionic acid 3 mg (yield: 26%) of the title compound was obtained from 6 mg (0.029 mmol) of [2- (4-fluorophenyl)-5-methyloxazole-4-yl]-methanol and 7 mg (0.026 mmol) of (=L) 3-methoxyimino-2- (4-hydroxy-benzyl)-2-methyl-propionic acid methyl ester in the same manner as in Examples 105 and 106.

NMR : 1H-NMR(CDCl3) # 8. 02-7. 97 (2H, m), 7.51 (1H, s), 7. 14-7. 07 (4H, m), 6. 92-6. 90 (2H, m), 4.94 (2H, s), 3.84 (3H, s), 3.09 (1H, d, J=12Hz), 3.01 (1H, d, J=12Hz), 2.41 (3H, s), 1.39 (3H, s) Mass (EI) 427 (M++1) Example 112: () 3- [ethoxyimino]-2- [4- (2-isopropyl-5-methyloxazole-4-ylmethoxy)- benzyl]-butyric acid 6 mg (0. 015 mmol, yield: 26%) of the title compound was obtained from 15 mg (0.1 mmol) of (2-isopropyl-5-methyl-oxazole-4-yl) -methanol and 10 mg (0. 038 mmol) of (i) 3-ethoxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl in the same manner as in Examples 105 and 106.

NMR : lH-NMR (CDCl3) 6 7. 13-7. 08 (2H, m), 6. 89-6. 85 (2H, m), 4.83 (2H, s), 4.08 (2H, q, J=8Hz) 3.54 (1H, t, J=8Hz), 3.16 (1H, dd, J=12Hz, 6Hz), 3. 07-2. 96 (2H, m), 2.30 (3H, s), 1.84 (3H, s), 1.33 (6H, d, J=7.2Hz), 1.19 (3H, t, J=8Hz) Mass (EI) 389 (M++1) Example 113: ((~) 2- [4- (2-isopropyl-5-methyloxazole-4-ylmethoxy)-benzyl]-3- [propoxyimino]-butyric acid 5 mg (0.012 mmol, yield: 42%) of the title compound was obtained from 15 mg

(0.1 mmol) of (2-isopropyl-5-methyl-oxazole-4-yl)-methanol and 10 mg (0.030 mmol) of (i) 3-ethyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

NMR : 1H-NMR(CDCl3) # 7. 13-7. 07 (2H, m), 6. 92-6. 86 (2H, m), 4.84 (2H, s), 3.98 (2H, q, J=8Hz) 3.54 (1H, t, J=8Hz), 3.16 (1H, dd, J=12Hz, 6Hz), 3. 06-2. 98 (2H, m), 2.30 (3H, s), 1.84 (3H, s), 1. 61-1. 56 (2H, m), 1.33 (6H, d, J=7.2Hz), 0.88 (3H, t, J=8Hz) Mass (EI) 403 (M++1) Example 114: (-) 3- [2-fluoro-ethoxyimino]-2- [4- (5-methyl-2-paratolyloxazole-4- ylmethoxy)-benzyl]-butyric acid 42 mg (0.092 mmol, yield: 32%) of the title compound was obtained from 50 mg (0.24 mmol) of the compound obtained in Preparation Example 53 and 70 mg (0.24 mmol) of (i) 3- (2-fluoro-ethyloxyimino)-2- (4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

Mass (EI) 455 (M++1) Example 115: () 3- [2-fluoro-ethoxyimino]-2- {4-5-methyl-2- (4-fluorophenyl)-5- methyloxazole-4-ylmethoxy]-benzyl}-butyric acid 50 mg (0.11 mmol, yield: 40%) of the title compound was obtained from 60 mg (0.29 mmol) of [2- (4-fluorophenyl)-5-methyloxazole-4-yl]-methanol and 78 mg (0.27 mmol) of (i) 3-(2-fluoro-ethyloxyimino)-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

Mass (EI) 459 (M++1)

Example 116: () 2- [4- (3-benzyl- [l, 2,4] oxadiazole-5-ylmethoxy)-benzyl]-3- [methoxyimino]-butyric acid 10 mg (0.024 mmol, yield: 31%) of the title compound was obtained from 25 mg (0.26 mmol) of (3-benzyl- [1, 2,4] oxadiazole-5-yl) -methanol and 20 mg (0.080 mmol) of () 3-methoxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

NMR : 1H-NMR(CDCl3) # 7. 33-7. 28 (5H, m), 7. 14-7. 10 (2H, m), 6. 89-6. 87 (2H, m), 5.20 (2H, s), 4.20 (2H, s), 3. 83 (3H, s), 3.55 (1H, t, J=7.2Hz), 3.17 (1H, dd, J=7. 2Hz, 14Hz), 2.99 (1H, dd, J=7.2Hz, 14Hz), 1.84 (3H, s) Mass (EI) 410 (M++1) Example 117: 2- [4- (3-benzyl- [1, 2,4] oxadiazole-5-ylmethoxy)-benzyl]-3- [ethoxyimino]-butyric acid 10 mg (0.024 mmol, yield: 34%) of the title compound was obtained from 25 mg (0.26 mmol) of (3-benzyl- [1, 2,4] oxadiazole-5-yl) -methanol and 20 mg (0.075 mmol) (i) 3-ethyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

NMR : 1H-NMR(CDCl3) # 7. 35-7. 28 (5H, m), 7. 15-7. 11 (2H, m), 6. 89-6. 86 (2H, m), 5.19 (2H, s), 4.17 (2H, s), 4.07 (2H, q, J=6Hz), 3.55 (1H, t, J=7.2Hz), 3.17 (1H, dd, J=7.2Hz, 14Hz), 3.01 (1H, dd, J=7.2Hz, 14Hz), 1.85 (3H, s), 1.17 (3H, t, J=6Hz) Mass (EI) 424 (M++1) Example 118: () 3- [ethoxyimino]-2- {4- [2- (4-ethylphenyl)-5-methyloxazole-4- ylmethoxy]-benzyl}-butyric acid

0.24 g (5.3 mmol, yield: 72%) of the title compound was obtained from 0.20 g (0.92 mmol) of [2- (4-ethyl-phenyl)-5-methyl-oxazole-4-yl]-methanol and 0.20 g (0.74 mmol) of 3-ethyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

Sodium salt form, NMR :'H-NMR (CD, OD) 8 7. 91-7. 89 (2H, d, J=8Hz), 7.34 (2H, d, J=8Hz), 7.14 (2H, d, J=8Hz), 6.89 (2H, d, J=8Hz), 4.96 (2H, s), 3. 98-3. 92 (2H, m) 3.32 (1H, m), 3.16 (1H, dd, J=14Hz, 7.2Hz), 2.89 (1H, dd, J=14Hz, 8.8Hz), 2.71 (2H, t, J=7.7Hz), 2.42 (3H, s), 1.85 (3H, s), 1.27 (3H, t, J=7.7Hz), 1.11 (3H, t, J=7.2Hz) Mass (EI) 451 (M++1) Example 119: () 2-{4-[2-(4-ethylphenyl)-5-methyloxazole-4-ylmethoxy]-benzyl} -3- [propoxyimino]-butyric acid 8 mg (0. 017 mmol, yield: 37%) of the title compound was obtained from 20 mg (0.092 mmol) of [2- (4-ethyl-phenyl)-5-methyl-oxazole-4-yl]-methanol and 13 mg (0.047 mmol) of () 3-ethyloxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

NMR : 1H-NMR(CDCl3) # 7. 92-7. 86 (2H, m), 7. 27-7. 25 (2H, m), 7. 14-7. 09 (2H, m), 6. 91-6. 89 (2H, m), 4.94 (2H, s), 3.97 (2H, t, J=8Hz) 3.56 (1H, t, J=8Hz), 3.17 (1H, dd, J=12Hz, 6Hz), 2.99 (1H, dd, J=12Hz, 8Hz), 2.69 (2H, q, J=7.6Hz), 2.40 (3H, s), 1.85 (3H, s), 1. 64-1. 58 (2H, m), 1.26 (3H, t, J=7.6Hz), 0.87 (3H, t, J=8Hz) Mass (EI) 465 (M+1) Preparation Example 80: Methanesulfonic acid 4-chloromethyl-phenyl ester 0.20 g (1.6 mmol) of 4-hydroxymethylphenol and 0.46 ml (3.2 mmol) of

triethylamine were added to methylenechloride, and 0.19 ml (2.4 mmol) of methanesulfonylchloride was slowly added to the resulting solution while being stirred.

After stirring for 30 minutes, ethylacetate was further added thereto and washed with water, then an organic layer thus obtained was dried over anhydrous magnesium sulfate to obtain 0.25 g (yield: 71%) of the title compound.

Mass (EI) 221 (M++1) Example 120: () 2- [4- (4-methanesulfonyloxy-benzyloxy)-benzyl]-3- [ethoxyimino]- butyric acid 0.13 mg (0.030 mmol, yield: 40%) of the title compound was obtained from 20 mg (0.091 mmol) of methanesulfonic acid 4-chloromethyl-phenyl ester and 20 mg (0.074 mmol) of (-) 3-ethoxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

NMR : lH-NMR (CDCl3) 6 7. 49-7. 47 (2H, m), 7. 31-7. 29 (2H, m), 7. 09-7. 07 (2H, m), 6. 88-6. 86 (2H, m), 5.03 (2H, s), 4.08 (2H, q, J=8Hz) 3.56 (1H, t, J=8Hz), 3.16 (3H, s), 3.16 (1H, dd, J=12Hz, 6Hz), 3.02 (1H, dd, J=12Hz, 8Hz), 1.86 (3H, s), 1.19 (3H, t, J=8Hz) Mass (EI) 436 (M++1) Example 121: (-) 3- [methoxyimino]-2- {4- [5-methyl-2- (4-methanesulfanyl-phenyl)- oxazole-4-ylmethoxy]-benzyl}-butyric acid 15 mg (0.033 mmol, yield: 55%) of the title compound was obtained from 30 mg (0.12 mmol) of [5-methyl-2- (4-methylsulfanyl-phenyl)-oxazole-4-yl]-methanol and 15 mg (0.060 mmol) of (~) 3-methoxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

NMR : 1H-NMR(CDCl3) # 7. 91-7. 89 (2H, m), 7. 28-7. 26 (2H, m), 7. 14-7. 06 (2H, m), 6. 92-6. 89 (2H, m), 4.94 (2H, s), 3.85 (3H, s), 3.55 (1H, t, J=8Hz), 3.17 (1H, dd, J=8Hz, 16Hz), 2.97 (1H, dd, J=8Hz, 16Hz), 2.52 (3H, s), 2.41 (3H, s), 1.85 (3H, s) Mass (EI) 455 (M++1) Example 122: () 3- [ethoxyimino]-2- 4- [5-methyl-2- (4-methanesulfanyl-phenyl)- oxazole-4-ylmethoxy]-benzyl}-butyric acid 0.10 mg (0.021 mmol, yield: 38%) of the title compound was obtained from 30 mg (0.12 mmol) of [5-methyl-2- (4-methylsulfanyl-phenyl)-oxazole-4-yl]-methanol and 15 mg (0.056 mmol) of (~) 3-ethoxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

NMR : 1H-NMR(CDCl3) # 7. 92-7. 89 (2H, m), 7. 29-7. 26 (2H, m), 7. 12-7. 09 (2H, m), 6. 92-6. 90 (2H, m), 4.94 (2H, s), 4.08 (2H, q, J=8Hz), 3.56 (1H, t, J=8Hz), 3.17 (1H, dd, J=8Hz, 16Hz), 3.01 (1H, dd, J=8Hz, 16Hz), 2.52 (3H, s), 2.41 (3H, s), 1.86 (3H, s), 1.19 (3H, t, J=8Hz) Mass (EI) 469 (M+1) Example 123: () 3-[ethoxyimino]-2-{4-[2-(4-methanesulfonyl-phenyl)-5-methyl- oxazole-4-ylmethoxy]-benzyl}-butyric acid 0.13 mg (0.026 mmol, yield: 30%) of the title compound was obtained from 30 mg (0.11 mmol) of [5-methyl-2- (4-methylsulfonyl-phenyl)-oxazole-4-yl]-methanol and 23 mg (0.087 mmol) of (~) 3-ethoxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as Examples 105 and 106.

NMR : 1H-NMR(CDCl3) # 8. 21-8. 19 (2H, m), 8. 03-8. 01 (2H, m), 7. 16-7. 10 (2H, m),

6. 95-6. 90 (2H, m), 4.99 (2H, s), 4.08 (2H, q, J=8Hz), 3.57 (1H, t, J=8Hz), 3. 18 (1H, dd, J=8Hz, 16Hz), 3.09 (3H, s), 3.01 (1H, dd, J=8Hz, 16Hz), 2.46 (3H, s), 1.86 (3H, s), 1.19 (3H, t, J=8Hz) Mass (EI) 501 (M++1) Example 124: () 3- [ethoxyimino]-2- [4- (2-phenylsulfanyl-ethoxy)-benzyl]-butyric acid 0.8 mg (0.021 mmol, yield: 28%) of the title compound was obtained from 16 mg (0.075 mmol) of (2-bromo-ethylsulfanyl) -benzene and 20 mg (0.074 mmol) of (~) 3-ethoxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.

NMR : 1H-NMR(CDCl3) # 7. 42-7. 40 (2H, m), 7. 31-7. 20 (3H, m), 7. 11-7. 00 (2H, m), 6. 77-6. 75 (2H, m), 4.11 (2H, t, J=6.4Hz), 4.07 (2H, q, J=7.2Hz), 3.54 (1H, t, J=7. 8Hz), 3.27 (2H, t, J=6.4Hz), 3.15 (1H, dd, J=8Hz, 14Hz), 2.90 (1H, dd, J=7. 8Hz, 14Hz), 1.84 (3H, s), 1.19 (3H, t, J=7.8Hz) Mass (EI) 388 (M++1) Example 125: () 3- [ethoxyimino]-2- [4- (2-phenylsulfonyl-ethoxy)-benzyl]-butyric acid methyl ester 8 mg (0. 018 mmol, yield: 74%) of the title compound was obtained from 10 mg (0.025 mmol) of (-) 3-ethoxyimino-2- [4- (2-phenylsulfanyl-ethoxy)-benzyl]-butyric acid methyl ester in the same manner as in Preparation Example 73.

NMR : lH-NMR (CDCl3) 6 7. 93-7. 91 (2H, m), 7. 69-7. 65 (1H, m), 7. 58-7. 54 (2H, m), 7. 07-7. 02 (2H, m), 6. 56-6. 52 (2H, m), 4.32 (2H, t, J=8Hz), 4.07 (2H, q, J=7.2Hz),

3.65 (3H, s), 3. 58 (2H, t, J=7.8Hz), 3.14 (1H, dd, J=8Hz, 14Hz), 2.89 (1H, dd, J=7.8Hz, 14Hz), 1.83 (3H, s), 1. 18 (3H, t, J=7.8Hz) Mass (EI) 434 (M++1) Example 126: () 3- [ethoxyimino]-2- [4- (2-phenylsulfonyl-ethoxy)-benzyl]-butyric acid 6 mg (yield 80%) of the title compound was obtained from 8 mg (0. 018 mmol) of ( : L) 3- [ethoxyimino]-2- [4- (2-phenylsulfonyl-ethoxy)-benzyl]-butyric acid methyl ester in the same manner as in Example 106.

Mass (EI) 420 (M++1) Preparation Example 81: () 2- [4- (2- (bromo-ethoxy)-benzyl)-3- [ethoxyimino]- butyric acid methyl ester 200 mg (0.74 mmol) of () 3-ethoxyimino-2- (4-hydroxy-benzyl)-butyric acid methyl ester, 5 ml of 1,2-dibromoethane and 1.2 g (3.7 mmol) of cesium carbonate were added to 10 ml of acetonitrile and the resulting solution was reacted for 3 hours under reflux. After the reaction, 10 ml of ethylacetate was added thereto, and an organic layer thus obtained was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered off to remove solvent, then the residue was purified by column chromatography to obtain 150 mg (0.40 mmol) of the title compound in a yield of 54%.

NMR : lH-NMR (CDCl3) 6 7. 17-7. 12 (2H, m), 6. 86-6. 74 (2H, m), 4.29 (2H, t, J=6. 4Hz), 4.08 (2H, q, J=7.2Hz), 3. 68 (3H, s), 3.65 (2H, t, J=6.4Hz), 3.20 (1H, dd, J=8Hz, 14Hz), 2.95 (1H, dd, J=7.8Hz, 14Hz), 1.88 (3H, s), 1.21 (3H, t, J=7. 2Hz)

Mass (EI) 373,375 (M++1) Example 127: () 3- [ethoxyimino]-2- {4- [2- (3-oxo-2, 3-dihydro-benzo [1, 4] oxazine-4- yl-ethoxy)-benzyl]-butyric acid methyl ester 30 mg (0.08 mmol) of () 2- [4- (2- (bromo-ethoxy)-benzyl)-3- [ethoxyimino]- butyric acid methyl ester, 12 mg (0.08 mmol) of 4H-benzo [1, 4] oxazine-3-one and 40 mg (0.12 mmol) of cesium carbonate were added to 10 ml of acetonitrile and the resulting solution was reacted for 3 hours under reflux. After the reaction, 10 ml of ethylacetate was added thereto, and an organic layer thus obtained was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and filtered off to remove solvent, then the residue was purified by column chromatography to obtain 25 mg (0.057 mmol) of the title compound in a yield of 71%.

NMR : lH-NMR (CDCl3) 6 7.30 (1H, dd, J=8Hz, 1. 6Hz), 7. 11-7. 07 (2H, m), 7. 07-6. 98 (3H, m), 6. 78-6. 75 (2H, m), 4.60 (2H, s), 4.30 (2H, t, J=6.4Hz), 4.23 (2H, t, J=6.4Hz), 4.07 (2H, q, J=7.2Hz), 3.64 (3H, s), 3.52 (1H, t, J=7.8Hz), 3.15 (1H, dd, J=8Hz, 14Hz), 2.90 (1H, dd, J=7.8Hz, 14Hz), 1. 83 (3H, s), 1.18 (3H, t, J=7.8Hz) Mass (EI) 441 (M++1) Example 128: () 3- [ethoxyimino]-2- {4- [2- (3-oxo-2, 3-dihydro-benzo [1, 4] oxazine-4- yl-ethoxy)-benzyl]-butyric acid 17 mg (0.040 mmol, yield: 89%) of the title compound was obtained from 20 mg (0.045 mmol) of () 3- [ethoxyimino]-2- {4- [2- (3-oxo-2, 3-dihydro- benzo [1, 4] oxazine-4-yl-ethoxy) -benzyl]-butyric acid methyl ester in the same manner

as in EXAMPLE 106.

NMR: 1H-NMR (CDCl3) 8 7.29 (1H, dd, J=8Hz, 1. 6Hz), 7. 11-7. 07 (2H, m), 7. 07-6. 98 (3H, m), 6. 78-6. 75 (2H, m), 4.60 (2H, s), 4.30 (2H, t, J=6.4Hz), 4.22 (2H, t, J=6.4Hz), 4.07 (2H, q, J=7.2Hz), 3.52 (1H, t, J=7.4Hz), 3.15 (1H, dd, J=7.4Hz, 14Hz), 2. 98 (1H, dd, J=7.4Hz, 14Hz), 1.84 (3H, s), 1.18 (3H, t, J=7.2Hz) Mass (EI) 427 (M++1) Experimental Example 1: Construction of reporter vector containing luciferase structural gene in GAL4 transcription gene sequence A GAL4 response sequence containing 8 repeats of the basic subunit (UAS), containing an Mlul site at the 5'end and HindIII site at 3'end, as follows: 5- GTGCAGGTGCCAGAACATTT CTCTATCGAT AGG TA (CTCGGAGGACAGTACTCCG) TA (CTCGGAGGACAGTACTCCG) TA (CTCGGAGGACAGTACTCCG) TA (CTCGGAGGACAGTACTCCG) TA (CCTCGGAGGACAGTACTCCG) (CTCGGAGGACAGTACTCCG) (CTCGGAGGACAGTACTCCG) (CTCGGAGGACAGTACTCCG) TA CCGTCGACTT TAGAGGGTAT AT-3 (parentheses indicatethe basic subunit UAS), was synthesized by a DNA synthesizer and then subcloned into the multiple cloning site of pGL3-Basic vector (Promega, Cat.

No. E1751). As a result, pGL3-GAL4 vector containing 8xUAS, followed by luciferase structural gene, was constructed.

Experimental Example 2: Construction of vector expressing fusion protein of GAL4 and ligand-binding domain of PPAR protein

A vector, expressing a protein in which the DNA-binding domain of GAL4 is fused with the ligand-binding domain of PPAR under control of SV40 promoter, was constructed using pZeoSV (Invitrogen, Cat. No. V85001) being a mammalian cell expression vector as a basic vector.

(1) Amplification of cDNA encoding DNA-binding domain of GAL4 transcription factor, and insertion thereof into expression vector.

To amplify the DNA-binding domain of GAL4 protein, a basal transcription activator in yeast, the following primer was synthesized using a DNA synthesizer: primer GAL4-HIII (5'-GC AAGCTT GAAGCAAGCCTCCTGAAAG ATG AAG CTA CTG TCT TCT ATC GAA C-3') contains the sequence encoding amino acids 1 to 8 of the N-terminal of the GAL4 DNA-binding domain, and also the restriction enzyme HindIII recognition domain. Another primer GAL4-KI (5'-AA GGTACC GGT AAA TTC CGG CGA TAC AGT CAA CTG TCT TTG A-3') contains the sequence encoding amino acids 141 to 147 of the C-terminal of the DNA-binding domain of GAL4, and also the restriction enzyme Kpnl recognition domain. 2 u, g of the primer GAL4-HIII and 2 ig of the primer GAL4-KI were added into a reaction tube, then 10 ng of plasmid pGBT9 (Clonetech, Cat. No. K1605-A) as a template, and 10 jj. l of 10 x polymerization buffer (50 mM KC1, 100 mM Tris-HCI, pH 9.0, 1% Triton X-100,2. 5 mM MgC12), 10 , ul of 2 mM dNTP (2 mM dGTP, 2 mM dATP, 2 mM dCTP and 2 mM dTTP), 2.5 units of Taq polymerase, and distilled water were further added to a total volume of 100 pl, and PCR was carried out for 25 cycles with denaturation at 95°C for 40 seconds, annealing at 55°C for 30 seconds, and polymerization at 72°C for 1 minute. When the PCR product was separated in 2% agarose gel, it was confirmed that a sequence of

about 488 base pairs was amplified, then the product was seperated and purified from the agarose gel. The DNA fragment thus seperated and purified (hereinafter, referred to as'fragment GAL4-H/K') was fully restricted with HindIII and KpnI in NEB buffer 2 (50 mM NaCI, 10 mM Tris-HCI, 10 mM MgC12, 1 mM dithiothreitol (pH 7.9)), and extracted with phenol/chloroform, then eluted with 20 Ill of TE (10 mM Tris-HCI, 1 mM EDTA, pH 8.0) solution.

Meanwhile, 2 u. g of plasmid pZeoSV was fully restricted with restriction enzymes HindIII and KpnI in NEB buffer 2, and a nucleic acid fragment of about 3.5 kb was seperated and purified in 1% agarose gel. Hereinafter this fragment is referred to as "fragment pZeoSV-H/K".

100 ng of the fragment GAL4-H/K obtained above and 100 ng of the fragment pZeoSV-H/K obtained above were added into a ligation reaction tube, then 2 u. l of 10 x ligation reaction solution (50 mM Tris-HCl (pH 7.8), 10 mM MgCl2, 10 mM dithiothreitol, 1 mM ATP, 25 pg/ml BSA) and 10 units of T4 DNA ligase were added thereto, then distilled water was added to a total volume of 20 ml, followed by incubation for 12 hours. After completion of the reaction, the product was transformed into E. coli HB101 (ATCC 33694) to obtain plasmid pZeo-GAL containing the DNA- binding domain of GAL4 (refer to Fig. 1).

(2) Preparation of DNA fragment encoding human PPARy ligand-binding domain and construction of expression vector of GAL4-Human PPARy chimeric receptor protein The below primers were synthesized from the gene sequence data of human PPARy gene (Genebank NM015869). Primer GLBD-f (5'-GG GGTACC TCT CAT

AAT GCC ATC AGG TTT GGG CGG ATG C-3') contains the sequence encoding from Serl76 to Metl85 of human PPARy gene and also the restriction enzyme KpnI- recognition domain. Primer GLBD-r (5'-CC ACGCGT CTA GTA CAA GTC CTT GTA GAT CTC C-3') contains the sequence encoding from Glu472 to Tyr478 of human PPARy gene and the termination codon, allowing the termination of translation at the 478t" amino acid, and also the restriction enzyme Mlul-recognition domain. A DNA fragment encoding from Serl76 to Tyr478 containing the human PPARy ligand-binding domain was amplified by PCR using the above described primer and also using the full- length cDNA of human PPARy, isolated from human liver cDNA library, as a template.

When the PCR product was separated in 1% agarose gel, it was confirmed that a DNA fragment of about 900 base pairs was amplified, then the product was seperated and purified from the agarose gel. The fragment thus seperated and purified (hereinafter, referred to as'fragment GLBD-K/M') was fully restricted with restriction enzymes KpnI and Maul in NEB buffer 2, and extracted with phenol/chloroform, then eluted with 20 p1 of TE solution.

Meanwhile, 2 u. g of plasmid pZeo-GAL obtained above was fully restricted with restriction enzymes KpnI and MuI in NEB buffer 2, and a nucleic acid fragment of 4.0 kb was seperated and purified in 1% agarose gel. Hereinafter this fragment is referred to as"fragment pZeoGAL-K/M".

100 ng of the fragment GLBD-K/M obtained above and 100 ng of the fragment pZeoGAL-K/M obtained above were added into a ligation reaction tube, then 2 Ill of 10X ligation reaction solution and 10 units of T4 DNA ligase were added thereto, then distilled water was added to a total volume of 20 j, l, followed by incubation for 12 hours. After completion of the reaction, the product was transformed into E. coli HB101

(ATCC 33694) to obtain the expression vector as desired in which the DNA fragment encoding human PPARy ligand-binding domain is inserted into DNA encoding the GAL4 DNA-binding domain of pZeoGAL (hereinafter, referred to as"pZeo-GAL- PPARyLBD").

(3) Preparation of DNA fragment encoding human PPARa ligand-binding domain and construction of expression vector of GAL4-human PPARa chimeric receptor protein The below primers were synthesized from the gene sequence information of human PPARa gene. Primer ALBD-f (5'-GG GGTACC TCA CAC AAC GCG ATT CGT T-3') contains the sequence encoding from Serl67 to Argl75 of human PPARa and also the restriction enzyme KpnI-recognition domain. Primer ALBD-r (5'-CC ACGCGT TCA GTA CAT GTC CCT GTA GAT CTC CTG C-3') contains the sequence encoding from Gln 461 to Tyr4ll including the human PPARa ligand-binding domain and the termination codon, allowing the termination of translation at the 468 th amino acid, and also the restriction enzyme MZuI-recognition domain. A DNA fragment, encoding from Serl67 to Tyr468 containing the human PPARa ligand-binding domain, was amplified by PCR using the above described primer and also using the full length cDNA of human PPARa, isolated from human liver cDNA library, as a template. When the PCR product was separated in 1% agarose gel, it was confirmed that a DNA fragment of about 900 base pairs was amplified, then the product was seperated and purified from the agarose gel. The nucleic acids thus seperated and purified (hereinafter, referred to as 'fragment ALBD-K/M') were fully restricted with restriction enzymes KpnI and Mlul in NEB buffer 2, and extracted with phenol/chloroform, then eluted with 20 u. l of TE

solution.

100 ng of the fragment ALBD-K/M obtained above and 100 ng of the fragment pZeoGAL-K/M obtained above were added into a ligation reaction tube, then 2 1ll of 10X ligation reaction solution and 10 units of T4 DNA ligase were added thereto, then distilled water was added to a total volume of 20 RI, followed by incubation for 12 hours. After completion of the reaction, the product was transformed into E. coli HB 101 (ATCC 33694) to obtain the expression vector as desired in which the DNA fragment encoding human PPARa ligand-binding domain is inserted into DNA encoding the GAL4 DNA-binding domain of pZeoGAL (hereinafter, referred to as"pZeo-GAL- PPARaLBD").

Experimental Example 3: Transformation CV-1 cells derived from monkey kidney were aliquoted into each well of 24- well plate at a density of 6. 0x104 per/well, suspended in DMEM medium (Life Technologies Inc) supplemented with 10% FBS, and cultured for 24 hours at 37°C in 5% C02 atmosphere. After culturing, the growth medium was replaced with 200 ll of OptiMEM medium (Life Technologies Inc) and the cells were used for transformation.

The amount of DNA was 480 ng of pGL3-GAL4, 48 ng of pZeo-GAL-PPARyLBD or pZeo-GAL-PPARaLBD and 128 ng of pCH110 (Amersham, Cat. No. 27-4508-01) per well. 29 Ill of DNA was suspended in OptiMEMTM medium, and 1 p1 of PLUS reagent (Invitrogen) was added thereto and stirred, followed by incubation for 15 minutes at room temperature. To a mixture of DNA and PLUS reagent, 1 1ll of LIPOFECTAMINE (Invitrogen) diluted with OptiMEM medium was added and stirred, followed by incubation for 15 minutes at room temperature. A solution containing the complex of

DNA and LIPOFECTAM1NE thus prepared was added dropwise to CV-1 cells being cultured in 24-well plate and then gently stirred, followed by culturing for 3 hours at 37°C in 5% C02 atmosphere. After the culturing, 260 J. l of DMEMTM medium supplemented with 20% FBS was added to each well and cultured at 37°C in 5% COx atmosphere for 24 hours, and the resulting culture was used for analysis.

Experimental Example 4: Determination of accelerating activity for human PPARa or PPARy (1) Measurement of degree of expression of Luciferase The growth medium was removed from the transformed cells of Experimental Example 3, and the compounds of Examples 1 to 128 were suspended in DMSO and added in DMEM medium supplemented with 5% FBS, then the resulting mixture was added to each well, followed by culturing at 37°C in 5% COx atmosphere for 24 hours.

After the culturing, the culture media was removed and cells were washed twice with PBS (Life Technologies Inc). To each well, 100 u. l of Passive Lysis Buffer (PLB) solution (Promega Corporation) was added and then gently stirred for 20 minutes at room temperature. 20 p1 of cell lysate taken from each well was removed to a Costar 96-well Luminometer and luciferase activity was determined using Luciferase Assay System kit (Promega Corporation) following the instructions of the manufacturer.

(2) Measurement of p-galactosidase activity 20 zip of cell lysate as obtained above was moved to 96-well plate (Falcon, Cat. No. 353911) and added with 100 ul of ONPG (O-nitrophenyl ß-galacti-pyranoside) solution to each well, followed by incubation at 37°C for 2 hours. Then, 50 Ll of 1 M

sodium carbonate (Na2C03) was added to each well and the absorbance was measured at 415 nm by a spectrophotometer.

(3) Degree of activity of ligand The efficacy of transformation in cell lysis buffer was represented by the activity of beta-galactosidase measured in the above, and the comparative activity of luciferase was measured, thereby comparing the degree of the activity of each compound. The experimental results were expressed as an increasing multiple on the basis of the value of the control, in which only 5% DMSO without compound was added. On the basis of this, ECso being the efficacy of the compounds obtained in Examples 1 to 128, was presented in Table 1 below. ECso (Effective concentration fifty) expresses the concentration of a compound which shows 50% of the maximum possible response of the compound.

TABLE 1 Compounds PPARa ECso PPARy ECso Example 1 <1M <100nM Example 2<1M <100nM Examples <1M <100nM Example 4 <1M <100nM Example 5 <1 µM <100 nM Example6 <1M <100nM Example 7 <1 µM <100 nM Example 8 <1 mM <100 nM Example 9 <1M <100nM Example 10 <1M <100nM Example 11 <1 µM <100 nM Example 12 <1 µM <100 nM Example 13 <lpM <100nM Example 14 <1 µM <100 nM Example 15 <1M <100nM Example 16 <1 µM <100 nM Example 17 <1M <100nM Example 18 <1 µM <100 nM Example 19 <1 µM <100 nM Example 20 <1 µM <100 nM Example21 <1M <100nM Example22 <lpM <100nM Example 23 <1 µM <100 nM Example 24 <1 µM <100 nM Example 25 <1 µM <100 nM Example 26 <1 µM <100 nM Example27 <lpM <100nM Example28 <1M <100nM Example 29 <1 µM <100 nM Examplc30 <lpM <100nM Example 31 <1 µM <100 nM Example 32 <1 µM <100 nM Example 33 <1 µM <100 nM Example 34 <1 µM <100 nM Example 35 <1 µM <100 nM Example 36 <1 µM <100 nM Example 37 <1 µM <100 nM Example 38 <1 µM <100 nM Example 39 <1 µM <100 nM Example 40 <1 µM <100 nM Example 41 <1 µM <100 nM Example 42 <1 µM <100 nM Example 43 <1 µM <100 nM Example 44 <1 µM <100 nM Example 45 <1 µM <100 nM Example 46 <1 µM <100 nM Example 47 <1 µM <100 nM Example 48 <1 µM <100 nM Example 49 <1 µM <100 nM Example 50 <1 µM <100 nM Example 51 <1 µM <100 nM Example 52 <1 µM <100 nM Example 53 <1 µM <100 nM Example 54 <1 µM <100 nM Example 55 <1 µM <100 nM Example 56 <1 µM <100 nM Example 57 <1 µM <100 nM Example 58 <1 µM <100 nM Example 59 <1 µM <100 nM Example 60 <1 µM <100 nM Example 61<1M <100nM Example 62 <1 µM <100 nM Example63 <1M <100nM Example 64 <1 µM <100 nM Example 65 <1 µM <100 nM Example 66 <1 µM <100 nM Example 67 <1 µM <100 nM Example68 <1M <100nM Example 69 <1 µM <100 nM Example 70 <1M <100nM Example 71 <1M <100nM Example 72 <1 µM <100 nM Example 73 <1 µM <100 nM Example 74 <1 µM <100 nM Example 75 <1 µM <100 nM Example 76 <1 µM <100 nM Example 77 <1 µM <100 nM Example 78 <1 µM <100 nM Example 79 <1 µM <1000 nM Example 80 <1 µM <1000 nM Example 81 <1 µM <1000 nM Example 82 <1 µM <1000 nM Example 83 <1 µM <1000 nM Example 84 <1 µM <1000 nM Example 85 <1M <1000nM Example 86 <1 µM <1000 nM Example 87 <1 µM <1000 nM Example 88 <1 µM <1000 nM Example 89 <1 µM <1000 nM Example 90 <1 µM <1000 nM Example 91 <1 µM <1000 nM Example 92 <1 µM <1000 nM Example 93 <1 µM <1000 nM Example 94 <1 µM <1000 nM Example 95 <1 µM <1000 nM Example 96 <1 µM <1000 nM Example 97 <1 µM <1000 nM Example 98 <1 µM <1000 nM Example 99 <1 µM <1000 nM Example 100 <1 µM <1000 nM Example 101 <1 µM <1000 nM Example 102 <1 µM <1000 nM Example 103 <1M <1000nM Example 104 <1 µM <1000 nM Example 105 <1 µM <1000 nM Example 106 <1M <1000nM Example 107 <1 µM <1000 nM Example 108 <1 µM <1000 nM Example 109 <1 M <1000 nM Example 110 <1 p, M <1000 nM Example 111 <1 µM <1000 nM Example 112 <1 µM <1000 nM Example 113 <1 µM <1000 nM Example 114 <1 µM <1000 nM Example 115 <1 µM <1000 nM Example 116 <1 µM <1000 nM Example 117 <1 ; nM <1000nM Example 118 <1 µM <1000 nM Example 119 <1 µM <1000 nM Example 120 <1 pM <1000 nM Example 121 <1, uM <1000 nM Example 122 <1 µM <100 nM Example 123 <1 µM <1000 nM Example 124 <1M <1000nM Example 125 <1M <1000nM Example 126 <1 µM <1000 nM Example 127 <1, uM <1000 nM Example 128 <1 pM <1000 nM

CONCLUSIONS As seen in the above table, it is clear that the compound of Formula 1 according to the present invention is very effective for accelerating the activity of PPARy and PPARa. Accordingly, the compound according to the present invention can be used as a drug for treatment or prevention of diseases involving human PPARa and PPARy, for example, diabetes mellitus, complications associated with diabetes mellitus, inflammation, etc.

Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the scope of particular embodiments of the invention indicated by the following claims.